Extracorporeal Membrane Oxygenation Support in COVID-19 Patients: A Propensity Score Analysis.

Revised guidelines clarify indications for extracorporeal membrane oxygenation (ECMO) support in Coronavirus disease 2019 (COVID-19) patients with acute respiratory distress syndrome (ARDS). Limited data exist to compare clinical outcomes of COVID-19 ARDS patients to non-COVID-19-related ARDS patients when supported with ECMO. An observational propensity-matched study was performed to compare clinical and ECMO-related complications between COVID-19-related ARDS patients (COVID) and non-COVID-19-related ARDS (Control). COVID- patients cannulated from March 1st, 2020, through June 1st, 2021, were included and matched to patients from the historical cohort at our center from 2012 to 2020 based on age, body mass index (BMI), acute physiology and chronic health evaluation (APACHE) II score, and duration ECMO run. The primary outcome was complications during ECMO therapy. A total of 56 patients were propensity matched 1:1 with a mean age of 40.9 years, BMI 32.1 kg/m2, APACHE II score of 26.6, and duration of ECMO support of 22.6 days. In total 18 COVID-19 patients were observed to have more major bleeding complications (18 vs. 9, p = 0.03). Although not statistically significant, they also had more strokes (6 vs. 3) and required more chest tubes (13 vs. 8). Inpatient mortality was not different. ECMO support in COVID-19 patients is associated with more major bleeding complications, strokes, and chest tube placements. The use of ECMO in patients with COVID-19-related ARDS appears to be associated with an increased risk of complications.

Early Mobilization during Extracorporeal Membrane Oxygenation for Cardiopulmonary Failure in Adults: Factors Associated with Intensity of Treatment.

Rationale: Early mobilization of extracorporeal membrane oxygenation (ECMO)-supported patients is increasingly common, but it remains unknown whether there are factors predictive of achieving higher intensity mobilization among those able to participate in physical therapy. Additionally, data regarding the safety and feasibility of early mobilization with femoral cannulation, particularly ambulation, are sparse. Objectives: To determine whether there are factors associated with achieving out-of-bed versus in-bed physical therapy in ECMO-supported patients participating in physical therapy, and whether mobilization with femoral cannulation is safe and feasible. Methods: This large, single-center, retrospective study evaluated adult patients who performed active physical therapy while receiving ECMO. Mixed effects modeling was used to identify predictors of out-of-bed versus in-bed activity. Rates of mobilization with femoral cannulation and adverse events were also reported. Results: Between April 2009 and January 2020, 511 patients were supported with ECMO in a single medical intensive care unit, of whom 177 (35%) underwent active physical therapy and were included in the analysis, including 124 of 141 (88%) bridge to lung transplantation and 53 of 370 (14%) bridge to recovery. These 177 patients accounted for 2,706 active physical therapy sessions, with 138 patients (78%) achieving out-of-bed activity. In total, 108 (61%) patients ambulated (1,284 sessions), 34 of whom had femoral cannulae (250 sessions). Bridge-to-transplant (odds ratio [OR], 17.2; 95% confidence interval [CI], 4.12-72.1), venovenous ECMO (OR, 2.83; 95% CI, 1.29-6.22), later cannulation year (OR, 1.65; 95% CI, 1.37-1.98) and higher Charlson comorbidity index (OR, 1.53; 95% CI, 1.07-2.19) were associated with increased odds of achieving out-of-bed versus in-bed physical therapy, whereas invasive mechanical ventilation (OR, 0.11; 95% CI, 0.05-0.25) and femoral cannulation (OR, 0.19; 95% CI, 0.04-0.92) were associated with decreased odds of performing out-of-bed activities. Adverse events occurred in 2% of sessions. Conclusions: Several patient- and ECMO-related factors were associated with achieving higher intensity of early mobilization in patients participating in rehabilitation. Physical therapy with femoral cannulation was safe and feasible, and complications related to mobilization were uncommon.

Extracorporeal Membrane Oxygenation for Coronavirus Disease 2019: Crisis Standards of Care.

The coronavirus disease 2019 (COVID-19) pandemic has placed extraordinary strain on global healthcare systems. Use of extracorporeal membrane oxygenation (ECMO) for patients with severe respiratory or cardiac failure attributed to COVID-19 has been debated due to uncertain survival benefit and the resources required to safely deliver ECMO support. We retrospectively investigated adult patients supported with ECMO for COVID-19 at our institution during the first 80 days following New York City's declaration of a state of emergency. The primary objective was to evaluate survival outcomes in patients supported with ECMO for COVID-19 and describe the programmatic adaptations made in response to pandemic-related crisis conditions. Twenty-two patients with COVID-19 were placed on ECMO during the study period. Median age was 52 years and 18 (81.8%) were male. Twenty-one patients (95.4%) had severe ARDS and seven (31.8%) had cardiac failure. Fifteen patients (68.1%) were managed with venovenous ECMO while 7 (31.8%) required arterial support. Twelve patients (54.5%) were transported on ECMO from external institutions. Twelve patients were discharged alive from the hospital (54.5%). Extracorporeal membrane oxygenation was used successfully in patients with respiratory and cardiac failure due to COVID-19. The continued use of ECMO, including ECMO transport, during crisis conditions was possible even at the height of the COVID-19 pandemic.

Gossypiboma Mimicking Fluorodeoxyglucose-avid Lung Nodule.

We present the case of a 55-year-old woman with a fluorodeoxyglucose-avid lung nodule 8 months after a coronary artery bypass graft procedure. This mass was later discovered to be a gossypiboma caused by retained surgical sponge material. There have been prior reports of intrathoracic gossypiboma presenting with various imaging findings; however, none that have presented as a positron emission tomography-avid lung nodule mimicking a malignancy.

A case of olfactory groove meningioma misdiagnosed as schizophrenia.

Olfactory groove meningiomas are relatively uncommon slow-growing tumors which can produce symptoms that progress insidiously. Often, patients present with personality changes and cognitive disturbances. These changes may not become apparent until the tumors become quite large, although other factors, eg, peritumoral edema and resultant brain tissue compression, influence clinical presentation.

Differential phosphorylation of DNA-PKcs regulates the interplay between end-processing and end-ligation during nonhomologous end-joining.

Nonhomologous end-joining (NHEJ) is a major DNA double-strand break repair pathway that is conserved in eukaryotes. In vertebrates, NHEJ further acquires end-processing capacities (e.g., hairpin opening) in addition to direct end-ligation. The catalytic subunit of DNA-PK (DNA-PKcs) is a vertebrate-specific NHEJ factor that can be autophosphorylated or transphosphorylated by ATM kinase. Using a mouse model expressing a kinase-dead (KD) DNA-PKcs protein, we show that ATM-mediated transphosphorylation of DNA-PKcs regulates end-processing at the level of Artemis recruitment, while strict autophosphorylation of DNA-PKcs is necessary to relieve the physical blockage on end-ligation imposed by the DNA-PKcs protein itself. Accordingly, DNA-PKcs(KD/KD) mice and cells show severe end-ligation defects and p53- and Ku-dependent embryonic lethality, but open hairpin-sealed ends normally in the presence of ATM kinase activity. Together, our findings identify DNA-PKcs as the molecular switch that coordinates end-processing and end-ligation at the DNA ends through differential phosphorylations.

Aberrant TCRδ rearrangement underlies the T-cell lymphocytopenia and t(12;14) translocation associated with ATM deficiency.

Ataxia telangiectasia mutated (ATM) is a protein kinase and a master regulator of DNA-damage responses. Germline ATM inactivation causes ataxia-telangiectasia (A-T) syndrome with severe lymphocytopenia and greatly increased risk for T-cell lymphomas/leukemia. Both A-T and T-cell prolymphoblastic leukemia patients with somatic mutations of ATM frequently carry inv(14;14) between the T-cell receptor α/δ (TCRα/δ) and immunoglobulin H loci, but the molecular origin of this translocation remains elusive. ATM(-/-) mice recapitulate lymphocytopenia of A-T patients and routinely succumb to thymic lymphomas with t(12;14) translocation, syntenic to inv(14;14) in humans. Here we report that deletion of the TCRδ enhancer (Eδ), which initiates TCRδ rearrangement, significantly improves αß T cell output and effectively prevents t(12;14) translocations in ATM(-/-) mice. These findings identify the genomic instability associated with V(D)J recombination at the TCRδ locus as the molecular origin of both lymphocytopenia and the signature t(12;14) translocations associated with ATM deficiency.

Kinase-dead ATM protein causes genomic instability and early embryonic lethality in mice.

Ataxia telangiectasia (A-T) mutated (ATM) kinase orchestrates deoxyribonucleic acid (DNA) damage responses by phosphorylating numerous substrates implicated in DNA repair and cell cycle checkpoint activation. A-T patients and mouse models that express no ATM protein undergo normal embryonic development but exhibit pleiotropic DNA repair defects. In this paper, we report that mice carrying homozygous kinase-dead mutations in Atm (Atm(KD/KD)) died during early embryonic development. Atm(KD/-) cells exhibited proliferation defects and genomic instability, especially chromatid breaks, at levels higher than Atm(-/-) cells. Despite this increased genomic instability, Atm(KD/-) lymphocytes progressed through variable, diversity, and joining recombination and immunoglobulin class switch recombination, two events requiring nonhomologous end joining, at levels comparable to Atm(-/-) lymphocytes. Together, these results reveal an essential function of ATM during embryogenesis and an important function of catalytically inactive ATM protein in DNA repair.

Overlapping functions between XLF repair protein and 53BP1 DNA damage response factor in end joining and lymphocyte development.

Nonhomologous end joining (NHEJ), a major pathway of DNA double-strand break (DSB) repair, is required during lymphocyte development to resolve the programmed DSBs generated during Variable, Diverse, and Joining [V(D)J] recombination. XRCC4-like factor (XLF) (also called Cernunnos or NHEJ1) is a unique component of the NHEJ pathway. Although germ-line mutations of other NHEJ factors abrogate lymphocyte development and lead to severe combined immunodeficiency (SCID), XLF mutations cause a progressive lymphocytopenia that is generally less severe than SCID. Accordingly, XLF-deficient murine lymphocytes show no measurable defects in V(D)J recombination. We reported earlier that ATM kinase and its substrate histone H2AX are both essential for V(D)J recombination in XLF-deficient lymphocytes, despite moderate role in V(D)J recombination in WT cells. p53-binding protein 1 (53BP1) is another substrate of ATM. 53BP1 deficiency led to small reduction of peripheral lymphocyte number by compromising both synapse and end-joining at modest level during V(D)J recombination. Here, we report that 53BP1/XLF double deficiency blocks lymphocyte development at early progenitor stages, owing to severe defects in end joining during chromosomal V(D)J recombination. The unrepaired DNA ends are rapidly degraded in 53BP1(-/-)XLF(-/-) cells, as reported for H2AX(-/-)XLF(-/-) cells, revealing an end protection role for 53BP1 reminiscent of H2AX. In contrast to the early embryonic lethality of H2AX(-/-)XLF(-/-) mice, 53BP1(-/-)XLF(-/-) mice are born alive and develop thymic lymphomas with translocations involving the T-cell receptor loci. Together, our findings identify a unique function for 53BP1 in end-joining and tumor suppression.

Ataxia telangiectasia-mutated protein and DNA-dependent protein kinase have complementary V(D)J recombination functions.

Antigen receptor variable region exons are assembled during lymphocyte development from variable (V), diversity (D), and joining (J) gene segments. Each germ-line gene segment is flanked by recombination signal sequences (RSs). Recombination-activating gene endonuclease initiates V(D)J recombination by cleaving a pair of gene segments at their junction with flanking RSs to generate covalently sealed (hairpinned) coding ends (CEs) and blunt 5'-phosphorylated RS ends (SEs). Subsequently, nonhomologous end joining (NHEJ) opens, processes, and fuses CEs to form coding joins (CJs) and precisely joins SEs to form signal joins (SJs). DNA-dependent protein kinase catalytic subunit (DNA-PKcs) activates Artemis endonuclease to open and process hairpinned CEs before their fusion into CJs by other NHEJ factors. Although DNA-PKcs is absolutely required for CJs, SJs are formed to variable degrees and with variable fidelity in different DNA-PKcs-deficient cell types. Thus, other factors may compensate for DNA-PKcs function in SJ formation. DNA-PKcs and the ataxia telangiectasia-mutated (ATM) kinase are members of the same family, and they share common substrates in the DNA damage response. Although ATM deficiency compromises chromosomal V(D)J CJ formation, it has no reported role in SJ formation in normal cells. Here, we report that DNA-PKcs and ATM have redundant functions in SJ formation. Thus, combined DNA-PKcs and ATM deficiency during V(D)J recombination leads to accumulation of unjoined SEs and lack of SJ fidelity. Moreover, treatment of DNA-PKcs- or ATM-deficient cells, respectively, with specific kinase inhibitors for ATM or DNA-PKcs recapitulates SJ defects, indicating that the overlapping V(D)J recombination functions of ATM and DNA-PKcs are mediated through their kinase activities.

ATM damage response and XLF repair factor are functionally redundant in joining DNA breaks.

Classical non-homologous DNA end-joining (NHEJ) is a major mammalian DNA double-strand-break (DSB) repair pathway. Deficiencies for classical NHEJ factors, such as XRCC4, abrogate lymphocyte development, owing to a strict requirement for classical NHEJ to join V(D)J recombination DSB intermediates. The XRCC4-like factor (XLF; also called NHEJ1) is mutated in certain immunodeficient human patients and has been implicated in classical NHEJ; however, XLF-deficient mice have relatively normal lymphocyte development and their lymphocytes support normal V(D)J recombination. The ataxia telangiectasia-mutated protein (ATM) detects DSBs and activates DSB responses by phosphorylating substrates including histone H2AX. However, ATM deficiency causes only modest V(D)J recombination and lymphocyte developmental defects, and H2AX deficiency does not have a measurable impact on these processes. Here we show that XLF, ATM and H2AX all have fundamental roles in processing and joining DNA ends during V(D)J recombination, but that these roles have been masked by unanticipated functional redundancies. Thus, combined deficiency of ATM and XLF nearly blocks mouse lymphocyte development due to an inability to process and join chromosomal V(D)J recombination DSB intermediates. Combined XLF and ATM deficiency also severely impairs classical NHEJ, but not alternative end-joining, during IgH class switch recombination. Redundant ATM and XLF functions in classical NHEJ are mediated by ATM kinase activity and are not required for extra-chromosomal V(D)J recombination, indicating a role for chromatin-associated ATM substrates. Correspondingly, conditional H2AX inactivation in XLF-deficient pro-B lines leads to V(D)J recombination defects associated with marked degradation of unjoined V(D)J ends, revealing that H2AX has a role in this process.

Compensatory cerebral adaptations before and evolving changes after surgical decompression in cervical spondylotic myelopathy.

OBJECT: The goal of this study was to compare cortical sensorimotor adaptations associated with neurological deterioration and then recovery following surgical decompression for cervical spondylotic myelopathy (CSM). METHODS: Eight patients with CSM underwent functional MR (fMR) imaging during wrist extension and the 3-finger pinch task, along with behavioral assessments before and 3 and 6 months after surgery. Six healthy control volunteers were scanned twice. RESULTS: Cervical spine MR imaging demonstrated successful cord decompression. The patients improved after surgery on the modified Japanese Orthopaedic Association score for the upper extremity, which correlated with the changes in task-associated activation in specific sensorimotor regions of interest. Pinch-related activation in sensorimotor cortex contralateral to the movement paradigm was reduced before surgery then increased toward the extent of healthy controls after surgery. Before surgery, patients showed broader activation in ipsilateral sensorimotor cortex during wrist extension than during pinch, but activations became similar to those of healthy controls after surgery. Pinch-related activation volume in the ipsilateral sensorimotor cortex and the magnitude of activation in the contralateral dorsal premotor cortex evolved linearly across time after surgery, along with wrist extension-related activation magnitude in the contralateral supplementary motor area. CONCLUSIONS: Serial fMR imaging studies in CSM can capture the adaptations in specific sensorimotor cortices that accompany clinical deterioration and postsurgical improvement in sensorimotor function associated with damage and partial recovery of conduction in corticospinal pathways. These adaptive regions can be monitored by serial fMR imaging to detect a critical loss of supraspinal reserve in compensatory plasticity, which might augment clinical information about the need for surgical decompression.

Reliable assessment of lower limb motor representations with fMRI: use of a novel MR compatible device for real-time monitoring of ankle, knee and hip torques.

This study describes the use of a novel magnetic resonance imaging (MRI) compatible system capable of measuring isometric ankle, knee and hip joint torques in real-time during functional MRI (fMRI) testing in healthy volunteers. The motor representations of three isometric torques--ankle dorsiflexion, ankle plantarflexion and knee extension--were studied at two time points. The reliability of motor performance and fMRI-derived measures of brain activity across sessions was examined. Reproducible motor performance was observed for each of the tasks; torques of the requested amplitude, assisted by visual feedback, were generated at the relevant joint with good accuracy, both within and across the two sessions. Significant blood oxygen level dependent (BOLD) signal increases were observed in the left primary sensorimotor cortex (SM1) in the paracentral lobule and in secondary motor areas for all tasks. Within these areas there was substantial overlap of the motor representations though differential activation was observed in SM1, with greater activation of inferior paracentral lobule during knee extension than for either ankle task. Also, BOLD signal decreases were observed bilaterally within SM1 in the hand knob region for all tasks. No major session-related effects were identified at the group level. High intraclass correlation coefficients were observed for t-values of voxels in cortical motor areas for each contraction type for individuals, suggesting that fMRI-derived activity across time points was reliable. These findings support the use of this apparatus in serial studies of lower limb function.

Cortical reorganization in patients with cervical spondylotic myelopathy.

OBJECT: Recent investigations have demonstrated that the cerebral cortex can reorganize as a result of spinal cord injury and may play a role in preserving neurological function. Reorganization of cortical representational maps in patients with cervical spondylotic myelopathy (CSM) has not been previously described. The authors sought to determine the feasibility of using functional magnetic resonance (fMR) imaging in patients with CSM to investigate changes in the cortical representation of the wrist and ankle before and after surgical intervention. METHODS: Four patients with clinical and imaging evidence of CSM were prospectively enrolled in this study. The patients underwent preoperative neurological examination, functional assessment, cervical imaging, and brain fMR imaging. The fMR imaging activation task undertaken was either wrist extension or ankle dorsiflexion, depending on whether the patient's primary impairment was hand dysfunction or gait difficulty. The cohort then underwent further evaluations at 6 weeks and 3 and 6 months postoperatively. In addition, five healthy volunteers underwent fMR imaging at two different time points and served as controls. In the healthy volunteers fMR imaging demonstrated areas of focal cortical activation limited to the contralateral primary motor area for the assigned motor tasks; the activation patterns were stable throughout repeated imaging. In comparison, in patients with CSM fMR imaging demonstrated expansion of the cortical representation of the affected extremity. Surgical decompression resulted in improvements in neurological function and reorganization of the representational map. CONCLUSIONS: The findings of this preliminary study demonstrate the potential of fMR imaging to assess changes in cortical representation before and after surgical intervention in patients with CSM. A future study involving a larger cohort of patients as well as the stratification of patients with CSM, based on the aforementioned factors that influence cortical adaptation, will allow a more detailed quantitative analysis.

Evolution of FMRI activation in the perilesional primary motor cortex and cerebellum with rehabilitation training-related motor gains after stroke: a pilot study.

BACKGROUND: Previous studies report that motor recovery after partial destruction of the primary motor cortex (M1) may be associated with adaptive functional reorganization within spared M1. OBJECTIVE: To test feasible methodologies for evaluating relationships between behavioral gains facilitated by rehabilitative training and functional adaptations in perilesional M1 and the cerebellum. METHODS: Four patients with hemiparesis for more than 3 months after a cortical lesion partially within M1 and 12 healthy volunteers participated. Functional magnetic resonance imaging (fMRI) using a finger-tapping task and concurrent behavioral assessments, including the Fugl-Meyer Motor Assessment of the upper extremity and the Wolf Motor Function Test, were conducted before and after 2 weeks of arm-focused training; 2 patients were further examined 6 and 12 months later to evaluate long-term persistence of brain-behavior adaptations. RESULTS: All patients showed higher activation magnitude in perilesional M1 than healthy controls before and after therapy. Further long-term functional gains paralleled the decrease of activation magnitude in perilesional M1 in the 2 more impaired cases. CONCLUSION: The evolution of suggestive correlations between serial scans of fMRI adaptive activity within the primary motor cortex and the cerebellum in relation to relevant behavioral changes over the course of 2 weeks of task-specific therapy and then no formal therapy suggests that repeated assessments may be best for monitoring therapy-induced neuroplasticity. This approach may help develop optimal rehabilitation strategies to maximize poststroke motor recovery as well as improve the search for brain-behavior correlations in functional neuroimaging research.