Frailty and associated outcomes in patients undergoing percutaneous left atrial appendage occlusion: findings from the NCDR LAAO registry.

BACKGROUND: Frailty is associated with significant morbidity and mortality and may have clinical implications in an advanced age population with atrial fibrillation undergoing left atrial appendage occlusion (LAAO). We sought to develop a novel frailty scale to predict worse outcomes in patients undergoing LAAO. METHODS: Patients in the NCDR LAAO Registry between 2016 and 2021 receiving percutaneous LAAO devices were categorized as non-frail (0 points), pre-frail (1-3 points), or frail (4-5 points) based on a 5-point scale representing multiple domains of frailty: hemoglobin <13.0 g/dL in male, <12.0 g/dL in female; creatinine ≥1.2 mg/dL; albumin <3.5 g/dL; body mass index <20 kg/m2; and increased risk of falls. RESULTS: Of 57,728 patients, 44,360 (76.8%) were pre-frail and 7693 (13.3%) were frail. Compared to non-frail, pre-frail and frail patients were older, had a higher burden of co-morbidities, and more disability based on the Modified Rankin Scale. Compared to non-frail patients after adjustment, frail patients were at higher risk of in-hospital major complication (OR 1.29, 95% 1.02-1.62, p = 0.01), any complication (OR 1.29, 95% CI 1.09-1.52, p = 0.0005), and death (OR 5.79, 95% CI 1.75-19.17, p = 0.001), while no difference was observed in pre-frail patients. At 45-day follow-up, there was no difference in the risk of complications in frail patients as compared to non-frail, although mortality was significantly higher (OR 3.01, 95% CI 1.97-4.85, p < 0.0001). CONCLUSION: A simple and practical frailty scale accurately predicts adverse events in patients undergoing LAAO. The 13% of patients considered frail were at significantly higher risk of in-hospital adverse events and 45-day mortality.

Characterizing Profiles of TBI Severity: Predictors of Functional Outcomes and Well-Being.

OBJECTIVE: To identify profiles of acute traumatic brain injury (TBI) severity and relate profiles to functional and well-being outcomes. SETTING: Acute inpatient rehabilitation and general community settings. PARTICIPANTS: Three hundred and seventy-nine individuals with moderate-severe TBI participating in the Traumatic Brain Injury Model Systems. DESIGN: Longitudinal observational study. MAIN MEASURES: At discharge-length of stay, Functional Independence Measure (FIM), and Disability Rating Scale (DRS). One-year post-injury-Glasgow Outcome Scale-Extended (GOS-E), FIM, and Satisfaction with Life Scale (SWLS). RESULTS: Latent profile analysis (LPA) was used to identify subgroups with similar patterns across 12 indicators of acute injury severity, including duration of posttraumatic amnesia, Glasgow Coma Scale, time to follow commands, and head CT variables. LPA identified 4 latent classes, least to most severe TBI (Class 1: n = 75, 20.3%; Class 2: n = 124, 33.5%; Class 3: n = 144, 38.9%; Class 4: n = 27, 7.3%); younger age, lower education, rural residence, injury in motor vehicle accidents, and earlier injury years were associated with worse acute severity. Latent classes were related to outcomes. Compared with Class 1, hospital stays were longer, FIM scores lower, and DRS scores larger at discharge among individuals in Class 3 and Class 4 (all P s < .01). One-year post-injury, GOS-E and FIM scores were significantly lower among individuals in Class 3 and Class 4 than those in Class 1 ( P s < .01). SWLS scores were lower only among individuals in Class 3 ( P = .036) compared with Class 1; other comparisons relative to Class 1 were not significant. CONCLUSIONS: Meaningful profiles of TBI severity can be identified from acute injury characteristics and may suggest etiologies, like injury in motor vehicle accidents, and premorbid characteristics, including younger age, rural residence, and lower education, that heighten risk for worse injuries. Improving classification may help focus on those at elevated risk for severe injury and inform clinical management and prognosis.

Sex Differences in Procedural Outcomes Among Patients Undergoing Left Atrial Appendage Occlusion: Insights From the NCDR LAAO Registry.

Importance: Left atrial appendage occlusion (LAAO) has emerged as an alternative to anticoagulation for select patients with atrial fibrillation; however, women have been underrepresented in clinical trials of LAAO, and sex-specific subanalyses are limited. Objective: To evaluate the sex differences in the baseline characteristics of patients undergoing LAAO implant and in the in-hospital outcomes after LAAO implant. Design, Setting, and Participants: A total of 49 357 patients in the National Cardiovascular Data Registry LAAO Registry undergoing LAAO with the Watchman device between January 1, 2016, and June 30, 2019, were included in this study. Exposure: Female or male sex. Main Outcomes and Measures: The primary outcomes were aborted or canceled procedure, major adverse event, any adverse event, prolonged hospital stay longer than 1 day, and death. Unadjusted and multivariable adjusted logistic regression analyses were performed to assess sex differences in in-hospital adverse events. Results: In this cohort study of 49 357 patients (mean [SD] age, 76.1 [8.0] years), 20 388 women (41.3%) and 28 969 (58.7%) men underwent LAAO. Compared with men, women were older and had a higher prevalence of paroxysmal atrial fibrillation, prior stroke, and uncontrolled hypertension but a lower prevalence of congestive heart failure, diabetes, and coronary artery disease. After multivariable adjustment, there were no differences in aborted or canceled procedures between women and men (613 [3.0%] vs 851 [2.9%]; odds ratio [OR] 1.01, 95% CI, 0.90-1.13). Women were more likely than men to experience any adverse event (1284 [6.3%] vs 1144 [3.9%]; P < .001; OR, 1.63; 95% CI, 1.49-1.77; P < .001) or major adverse event (827 [4.1%] vs 567 [2.0%]; P < .001; OR, 2.06; 95% CI, 1.82-2.34; P < .001) owing to pericardial effusion requiring drainage (241 [1.2%] vs 144 [0.5%]) or major bleeding (349 [1.7%] vs 244 [0.8%]). Women were also more likely than men to experience a hospital stay longer than 1 day (3272 [16.0%] vs 3355 [11.6%]; P < .001; adjusted OR, 1.46; 95% CI, 1.38-1.54; P < .001) or death (adjusted OR, 2.01; 95% CI, 1.31-3.09; P = .001), although death was rare and absolute differences were minimal (58 [0.3%] vs 37 [0.1%]; P < .001). Conclusions and Relevance: This study suggests that, compared with men, women have a significantly higher risk of in-hospital adverse events after LAAO. Further research aimed at risk reduction, particularly strategies to reduce the risk of pericardial effusion and major bleeding, in women undergoing LAAO is warranted.

A Comparison of Biomarker Rise in Type 1 and Type 2 Myocardial Infarction.

BACKGROUND: Despite differing underlying pathophysiology, type 1 and type 2 myocardial infarction share many of the same diagnostic criteria and can be challenging to differentiate in clinical practice. Correctly differentiating type 1 from type 2 myocardial infarction is important because they are managed differently. The aim of this study was to compare the patterns of rise of cardiac troponin (cTn) and creatine kinase MB (CK-MB) in type 1 and type 2 myocardial infarction. METHODS: We analyzed retrospective data on 200 patients with myocardial infarction (97 with type 1, 103 with type 2), excluding patients with ST-segment elevation myocardial infarction. The percentage rise from trough to peak values and the ratio of the peak to the upper limit of normal (RULN) were calculated for both cardiac troponin T (cTnT) and CK-MB. The ratio of peak cTnT to peak CK-MB was also calculated before and after adjusting for sex, glomerular filtration rate (GFR), and infarct size. RESULTS: Type 1 myocardial infarction tended to be larger than type 2 myocardial infarction, with a significantly higher mean percentage rise for both cTnT and CK-MB as well as higher mean RULN (207 vs 86 for cTnT, P = 0.02; 9 vs 4 for CK-MB, P = 0.002). There was a trend toward a higher rise of cTnT than CK-MB in type 2 compared with type 1 myocardial infarction, as demonstrated by the ratio of peak cTnT to peak CK-MB (0.09 in type 2 myocardial infarction vs 0.06 in type 1 myocardial infarction, P = 0.06). This difference persisted after adjusting for sex, GFR, and infarct size (P = 0.05). CONCLUSION: Both cTnT and CK-MB rise higher in type 1 than in type 2 myocardial infarction. Meanwhile, cTnT tends to rise out of proportion to CK-MB in type 2 myocardial infarction. These patterns may have considerable implications for the differentiation and subsequent treatment of patients with type 1 versus type 2 myocardial infarction.

A novel nonsense mutation of ERCC2 in a Vietnamese family with xeroderma pigmentosum syndrome group D.

Xeroderma pigmentosum (XP) group D, a severe disease often typified by extreme sun sensitivity, can be caused by ERCC2 mutations. ERCC2 encodes an adenosine triphosphate (ATP)-dependent DNA helicase, namely XP group D protein (XPD). The XPD, one of ten subunits of the transcription factor TFIIH, plays a critical role in the nucleotide-excision repair (NER) pathway. Mutations in XPD that affect the NER pathway can lead to neurological degeneration and skin cancer, which are the most common causes of death in XP patients. Here, we present detailed phenotypic information on a Vietnamese family in which four members were affected by XP with extreme sun sensitivity. Genomic analysis revealed a compound heterozygous mutation of ERCC2 that affected family members and single heterozygous mutations in unaffected family members. We identified a novel, nonsense mutation in one allele of ERCC2 (c.1354C > T, p.Q452X) and a known missense mutation in the other allele (c.2048G > A, p.R683Q). Fibroblasts isolated from the compound heterozygous subject also failed to recover from UV-driven DNA damage, thus recapitulating aspects of XP syndrome in vitro. We describe a novel ERCC2 variant that leads to the breakdown of the NER pathway across generations of a family presenting with severe XP.

The Prognosis of Axial vs. Extra-Axial Lesions on Functional Status After Traumatic Brain Injury.

Background: Head computed tomography (CT) scans are widely used in acute head injury for medical triage and surgical decisions, yet there are contradictions on the prognostic value of different head CT classifications. The intra-axial (axial) lesion vs. extra-axial lesion is a well-known systemic classification but has not been applied into clinical practice since there is no evidence-based support for its prognostic value. Hypothesis: Axial injury is related to worse functional independence compared to extra-axial injury at admission to and discharge from acute rehabilitation hospitalization. Design: Observational retrospective study. Settings and participants: Data from 71 participants who were enrolled at an acute rehabilitation hospital in the Northern California Traumatic Brain Injury Model System of Care (NCTBIMS) between 2005 and 2018 were included in the analysis. Main outcome measure and statistical analysis: Results of non-contrast head CT within the first 7 days after injury were analyzed to determine those with axial vs. extra-axial lesions. Functional Independence Measure (FIM) total scores were compared between the axial vs. extra-axial groups at admission and discharge using parametric and non-parametric tests. Results: There were no statistically significant group differences in FIM total scores at rehabilitation admission and discharge between the axial group and extra-axial groups. Conclusion: In this cohort of patients there was no evidence to support the hypothesis that axial injury is related to worse functional independence compared to extra-axial injury at rehabilitation admission and discharge. Utilizing MRI findings or other outcome measures, such as the 10 meter ambulation test or cognitive tests, may provide better sensitivity to potential functional differences.

Burden of Care Implications and Association of Intracranial Hypertension With Extremely Severe Post-traumatic Amnesia After Traumatic Brain Injury: A 5-Year Retrospective Longitudinal Study.

Post-traumatic amnesia (PTA) is characterized by a state of disorientation and confusion following traumatic brain injury (TBI). Few studies have looked at the effect of prolonged PTA on the functional outcomes beyond 1 year post-injury. This study aims to evaluate the burden of care in individuals with extremely severe PTA (esPTA; PTA >28 days) from acute inpatient rehabilitation admission to 5 years post-injury as well as the association between intracranial hypertension (ICH; Intracranial pressure (ICP) ≥20 mmHg) and esPTA status. Three hundred and forty-two individuals with moderate to severe TBI enrolled in the Northern California TBI Model System (TBIMS) of Care were included in this study. The FIM® instrument was chosen as the outcome measurement as it is a widely used functional assessment in the rehabilitation community. Repeated measure ANOVA revealed greater burden of care based on FIM® total scores (p < 0.001) from admission to 5-year follow-up for the esPTA group compared to the non-esPTA group (PTA ≤ 28 days). Unlike the non-esPTA group where FIM® total score plateaued 1 year post-injury, FIM® total score continued to improve up to 2 years post-injury for the esPTA group. The odds of developing esPTA was ~3 times higher for individuals with ICH vs. individuals without ICH (p < 0.001). In conclusion, individuals with esPTA have increased short- and long-term burden of care and the presence of ICH during hospitalization increased the odds of experiencing esPTA. These results may help the rehabilitation team and family in planning care post rehabilitation discharge.

Depression in Men and Women One Year Following Traumatic Brain Injury (TBI): A TBI Model Systems Study.

In the general population, females experience depression at significantly higher rates than males. Individuals with traumatic brain injury (TBI) are at substantially greater risk for depression compared to the overall population. Treatment of, and recovery from, TBI can be hindered by depression; comorbid TBI and depression can lead to adverse outcomes and negatively affect multiple aspects of individuals' lives. Gender differences in depression following TBI are not well understood, and relevant empirical findings have been mixed. Utilizing the Patient Health Questionnaire-9 (PHQ-9) 1 year after TBI, we examined whether women would experience more severe depressive symptoms, and would endorse higher levels of depression within each category of depression severity, than would men. Interestingly, and contrary to our hypothesis, men and women reported mild depression at equal rates; PHQ-9 total scores were slightly lower in women than in men. Men and women did not differ significantly in any PHQ-9 depression severity category. Item analyses, yielded significant gender differences on the following items: greater concentration difficulties (cognitive problems) in men and more sleep disturbances (psychosomatic issues) in women per uncorrected two-sample Z-test for proportions analyses; however, these results were not significant after the family-wise Bonferroni correction. Our results indicate that, in contrast to the general population, mild depression in persons with moderate to severe TBI may not be gender-specific. These findings underscore the need for early identification, active screening, and depression treatment equally for men and women to improve emotional well-being, promote recovery, and enhance quality of life following TBI.

Interpretation of Coronary Angiograms Recorded Using Google Glass: A Comparative Analysis.

INTRODUCTION: Google Glass (Google, Inc) is a voice-activated, hands-free, optical head-mounted display device capable of taking pictures, recording videos, and transmitting data via wi-fi. In the present study, we examined the accuracy of coronary angiogram interpretation, recorded using Google Glass. METHODS: Google Glass was used to record 15 angiograms with 17 major findings and the participants were asked to interpret those recordings on: (1) an iPad (Apple, Inc); or (2) a desktop computer. Interpretation was compared with the original angiograms viewed on a desktop. Ten physicians (2 interventional cardiologists and 8 cardiology fellows) participated. One point was assigned for each correct finding, for a maximum of 17 points. RESULTS: The mean angiogram interpretation score for Google Glass angiogram recordings viewed on an iPad or a desktop vs the original angiograms viewed on a desktop was 14.9 ± 1.1, 15.2 ± 1.8, and 15.9 ± 1.1, respectively (P=.06 between the iPad and the original angiograms, P=.51 between the iPad and recordings viewed on a desktop, and P=.43 between the recordings viewed on a desktop and the original angiograms). In a post-study survey, one of the 10 physicians (10%) was "neutral" with the quality of the recordings using Google Glass, 6 physicians (60%) were "somewhat satisfied," and 3 physicians (30%) were "very satisfied." CONCLUSION: This small pilot study suggests that the quality of coronary angiogram video recordings obtained using Google Glass may be adequate for recognition of major findings, supporting its expanding use in telemedicine.

Frequency, Indications, and Outcomes of Guide Catheter Extension Use in Percutaneous Coronary Intervention.

BACKGROUND: The frequency and outcomes of guide catheter extension use during percutaneous coronary intervention (PCI) have received limited study. METHODS: We retrospectively examined 1539 consecutive PCIs performed between May 2010 and November 2013 to determine the frequency and outcomes of guide catheter extension utilization. RESULTS: During the study period, a guide catheter extension was used in 83 cases (5.4%; 95% confidence interval, 4.3%-6.6%) in 86 vessels. The PCI target vessel was the left anterior descending artery (11%), circumflex (23%), right coronary artery (50%), left main (1%), or a saphenous vein bypass graft (15%). The indications for use (non-mutually exclusive) were to facilitate equipment delivery or provide vessel support/ engagement (84.7%), thrombus aspiration (10.5%), retrieval of lost devices (2.3%), facilitation of reverse controlled antegrade and retrograde tracking and dissection (1%), and selective vessel visualization with contrast (1%). Guide catheter extension success rate was 73.3% and technical and procedural success rates were 91.6% and 90.4%, respectively. Four patients (4.8%) experienced a guide catheter extension-related complication: vessel dissection/injury in 2 cases (1 case required emergency coronary artery bypass graft surgery and 1 case required stenting) and equipment loss in 2 cases (1 detachment of the distal guide-extension marker and 1 shearing of a guidewire tip that embolized to the renal artery). CONCLUSIONS: In a contemporary patient population undergoing PCI, a guide catheter extension was used in approximately 1 of 20 PCIs. Guide catheter extensions can facilitate procedural success, but also carry low risk for device-related complications.

Structure of neurotropic adeno-associated virus AAVrh.8.

Adeno-associated virus rhesus isolate 8 (AAVrh.8) is a leading vector for the treatment of neurological diseases due to its efficient transduction of neuronal cells and reduced peripheral tissue tropism. Toward identification of the capsid determinants for these properties, the structure of AAVrh.8 was determined by X-ray crystallography to 3.5 Å resolution and compared to those of other AAV isolates. The capsid viral protein (VP) structure consists of an αA helix and an eight-stranded anti-parallel ß-barrel core conserved in parvoviruses, and large insertion loop regions between the ß-strands form the capsid surface topology. The AAVrh.8 capsid exhibits the surface topology conserved in all AAVs: depressions at the icosahedral twofold axis and surrounding the cylindrical channel at the fivefold axis, and three protrusions around the threefold axis. A structural comparison to serotypes AAV2, AAV8, and AAV9, to which AAVrh.8 shares ∼ 84%, ∼ 91%, and ∼ 87% VP sequence identity, respectively, revealed differences in the surface loops known to affect receptor binding, transduction efficiency, and antigenicity. Consistent with this observation, biochemical assays showed that AAVrh.8 is unable to bind heparin and does not cross-react with conformational monoclonal antibodies and human donor serum directed against the other AAVs compared. This structure of AAVrh.8 thus identified capsid surface differences which can serve as template regions for rational design of vectors with enhanced transduction for specific tissues and escape pre-existing antibody recognition. These features are essential for the creation of an AAV vector toolkit that is amenable to personalized disease treatment.

Structural and functional characterization of an Isd-type haem-degradation enzyme from Listeria monocytogenes.

Bacterial pathogens have evolved diverse types of efficient machinery to acquire haem, the most abundant source of iron in the human body, and degrade it for the utilization of iron. Gram-positive bacteria commonly encode IsdG-family proteins as haem-degrading monooxygenases. Listeria monocytogenes is predicted to possess an IsdG-type protein (Lmo2213), but the residues involved in haem monooxygenase activity are not well conserved and there is an extra N-terminal domain in Lmo2213. Therefore, its function and mechanism of action cannot be predicted. In this study, the crystal structure of Lmo2213 was determined at 1.75 Šresolution and its haem-binding and haem-degradation activities were confirmed. Structure-based mutational and functional assays of this protein, designated as an Isd-type L. monocytogenes haem-degrading enzyme (Isd-LmHde), identified that Glu71, Tyr87 and Trp129 play important roles in haem degradation and that the N-terminal domain is also critical for its haem-degrading activity. The haem-degradation product of Isd-LmHde is verified to be biliverdin, which is also known to be the degradation product of other bacterial haem oxygenases. This study, the first structural and functional report of the haem-degradation system in L. monocytogenes, sheds light on the concealed haem-utilization system in this life-threatening human pathogen.

Structural insights into the molecular mechanism of Escherichia coli SdiA, a quorum-sensing receptor.

Escherichia coli SdiA is a quorum-sensing (QS) receptor that responds to autoinducers produced by other bacterial species to control cell division and virulence. Crystal structures reveal that E. coli SdiA, which is composed of an N-terminal ligand-binding domain and a C-terminal DNA-binding domain (DBD), forms a symmetrical dimer. Although each domain shows structural similarity to other QS receptors, SdiA differs from them in the relative orientation of the two domains, suggesting that its ligand-binding and DNA-binding functions are independent. Consistently, in DNA gel-shift assays the binding affinity of SdiA for the ftsQP2 promoter appeared to be insensitive to the presence of autoinducers. These results suggest that autoinducers increase the functionality of SdiA by enhancing the protein stability rather than by directly affecting the DNA-binding affinity. Structural analyses of the ligand-binding pocket showed that SdiA cannot accommodate ligands with long acyl chains, which was corroborated by isothermal titration calorimetry and thermal stability analyses. The formation of an intersubunit disulfide bond that might be relevant to modulation of the DNA-binding activity was predicted from the proximal position of two Cys residues in the DBDs of dimeric SdiA. It was confirmed that the binding affinity of SdiA for the uvrY promoter was reduced under oxidizing conditions, which suggested the possibility of regulation of SdiA by multiple independent signals such as quorum-sensing inducers and the oxidation state of the cell.

Impact of late post-traumatic seizures on physical health and functioning for individuals with brain injury within the community.

PRIMARY OBJECTIVE: To better characterize, describe and highlight issues that individuals with TBI and active LPTS may face in their daily lives. DESIGN: Prospective multi-centre mixed method qualitative and quantitative interview. PARTICIPANTS: Twenty-five individuals, 5-13 years post-injury, who had reported having LPTS and TBI. MEASURES: Disability Rating Scale (DRS); Supervision Rating Scale (SRS); Glasgow Outcome Scale-Extended (GOS-E); Perceived Stress Scale (PSS); Craig Handicap Assessment Reporting Technique-Short Form (CHART-SF) sub-scales: Physical Independence, Cognitive Independence, Mobility, Occupation, Social Integration; and Craig Hospital Inventory of Environmental Factors (CHIEF); and qualitative interview questions pertaining to management of the seizure disorder and its effect on the individual's health, function, community integration and participation. RESULTS: Data are presented regarding seizure activity and management; return to driving post-seizure; coping and participation; and standardized outcome measures. CONCLUSIONS: Individuals with TBI and LPTS are at a double-barrelled disadvantage regarding ongoing physical, cognitive, psychosocial and reintegration issues following brain injury and epilepsy. Clearer clinical guidelines and treatment strategies need to be developed to help ameliorate these ongoing issues. Additional research is needed to identify what the rehabilitation community can do to continue to facilitate people living safely and independently.

A hierarchical modeling approach to data analysis and study design in a multi-site experimental fMRI study.

We propose a hierarchical Bayesian model for analyzing multi-site experimental fMRI studies. Our method takes the hierarchical structure of the data (subjects are nested within sites, and there are multiple observations per subject) into account and allows for modeling between-site variation. Using posterior predictive model checking and model selection based on the deviance information criterion (DIC), we show that our model provides a good fit to the observed data by sharing information across the sites. We also propose a simple approach for evaluating the efficacy of the multi-site experiment by comparing the results to those that would be expected in hypothetical single-site experiments with the same sample size.

Multiplexed detection of mRNA using porosity-tuned hydrogel microparticles.

Transcriptional profiling, which is directly or indirectly associated with expressed protein levels, has been used in various applications including clinical prognosis and pharmaceutical investigation of drug activities. Although the widely used reverse transcription polymerase chain reaction (RT-PCR) allows for the quantification of absolute amounts of mRNA (mRNA) from inputs as small as a single cell, it is an indirect detection method that requires the amplification of cDNA copies of target mRNAs. Here, we report the quantification of unmodified full-length transcripts, using poly(ethylene) glycol diacrylate (PEGDA) hydrogel microparticles synthesized via stop flow lithography (SFL). We show that PEG600 serves as an effective porogen to allow for the capture of large (∼1000-3700 nt long) mRNAs. Our relatively simple hydrogel-based mRNA detection scheme uses a multibiotinylated universal label probe and provides assay performance (limit of detection of ∼6 amol of an in-vitro-transcribed model target) comparable to an existing commercial bead-based technology that uses branched DNA (bDNA) signal amplification. We also demonstrate a 3-plex mRNA detection, without cross-reactivity, using shape-encoded "intraplex" hydrogel microparticles. Our ability to tune the porosity of encoded hydrogel microparticles expands the utility of this platform to now quantify biomacromolecules ranging in size from large mRNAs to small miRNAs.