Summary Background Great heterogeneity exists in survival and the interval between onset of motor symptoms and dementia symptoms across synucleinopathies. We aimed to identify genetic and ...pathological markers that have the strongest association with these features of clinical heterogeneity in synucleinopathies. Methods In this retrospective study, we examined symptom onset, and genetic and neuropathological data from a cohort of patients with Lewy body disorders with autopsy-confirmed α synucleinopathy (as of Oct 1, 2015) who were previously included in other studies from five academic institutions in five cities in the USA. We used histopathology techniques and markers to assess the burden of tau neurofibrillary tangles, neuritic plaques, α-synuclein inclusions, and other pathological changes in cortical regions. These samples were graded on an ordinal scale and genotyped for variants associated with synucleinopathies. We assessed the interval from onset of motor symptoms to onset of dementia, and overall survival in groups with varying levels of comorbid Alzheimer's disease pathology according to US National Institute on Aging–Alzheimer's Association neuropathological criteria, and used multivariate regression to control for age at death and sex. Findings On the basis of data from 213 patients who had been followed up to autopsy and met inclusion criteria of Lewy body disorder with autopsy-confirmed α synucleinopathy, we identified 49 (23%) patients with no Alzheimer's disease neuropathology, 56 (26%) with low-level Alzheimer's disease neuropathology, 45 (21%) with intermediate-level Alzheimer's disease neuropathology, and 63 (30%) with high-level Alzheimer's disease neuropathology. As levels of Alzheimer's disease neuropathology increased, cerebral α-synuclein scores were higher, and the interval between onset of motor and dementia symptoms and disease duration was shorter (p<0·0001 for all comparisons). Multivariate regression showed independent negative associations of cerebral tau neurofibrillary tangles score with the interval between onset of motor and dementia symptoms (β −4·0, 95% CI −5·5 to −2·6; p<0·0001; R2 0·22, p<0·0001) and with survival (–2·0, −3·2 to −0·8; 0·003; 0·15, <0·0001) in models that included age at death, sex, cerebral neuritic plaque scores, cerebral α-synuclein scores, presence of cerebrovascular disease, MAPT haplotype, and APOE genotype as covariates. Interpretation Alzheimer's disease neuropathology is common in synucleinopathies and confers a worse prognosis for each increasing level of neuropathological change. Cerebral neurofibrillary tangles burden, in addition to α-synuclein pathology and amyloid plaque pathology, are the strongest pathological predictors of a shorter interval between onset of motor and dementia symptoms and survival. Diagnostic criteria based on reliable biomarkers for Alzheimer's disease neuropathology in synucleinopathies should help to identify the most appropriate patients for clinical trials of emerging therapies targeting tau, amyloid-β or α synuclein, and to stratify them by level of Alzheimer's disease neuropathology. Funding US National Institutes of Health (National Institute on Aging and National Institute of Neurological Disorders and Stroke).
Background Simultaneous treatment of multilevel aortic disease is controversial due to the theoretic increase in morbidity. This study was conducted to define the outcomes in patients treated ...electively with simultaneous thoracic endovascular aortic aneurysm repair (TEVAR) and abdominal aortic endovascular endografting for synchronous aortic pathology. Methods Patients treated with simultaneous TEVAR and endovascular aneurysm repair (T&E) at the University of Florida were identified from a prospectively maintained endovascular aortic registry and compared with those treated with TEVAR alone (TA). The study excluded patients with urgent or emergency indications, thoracoabdominal or mycotic aneurysm, and those requiring chimney stents, fenestrations, or visceral debranching procedures. Demographics, anatomic characteristics, operative details, and periprocedural morbidity were recorded. Mortality and reintervention were estimated using life-table analysis. Results From 2001 to 2011, 595 patients underwent TEVAR, of whom 457 had elective repair. Twenty-two (18 men, 82%) were identified who were treated electively with simultaneous T&E. Mean ± standard deviation age was 66 ± 9 years, and median follow-up was 8.8 months (range, 1-34 months). Operative indications for the procedure included dissection-related pathology in 10 (45%) and various combinations of degenerative etiologies in 12 (55%). Compared with TA, T&E patients had significantly higher blood loss ( P < .0001), contrast exposure ( P < .0001), fluoroscopy time ( P < .0001), and operative time ( P < .0001). The temporary spinal cord ischemia rate was 13.6% (n = 3) for the T&E group and 6.0% for TA ( P = .15); however, the permanent spinal cord ischemia rate was 4% for both groups ( P = .96). The 30-day mortality for T&E was 4.5% (n = 1) compared with 2.1% (n = 10) for TA. Temporary renal injury (defined by a 25% increase over baseline creatinine) occurred in two T&E patients (9.1%), with none requiring permanent hemodialysis; no significant difference was noted between the two groups ( P = .14). One-year mortality and freedom from reintervention in the T&E patients were 81% and 91%, respectively. Conclusions Acceptable short-term morbidity and mortality can be achieved with T&E compared with TA, despite longer operative times, greater blood loss, and higher contrast exposure. There was a trend toward higher rates of renal and spinal cord injury, so implementation of strategies to reduce the potential of these complications or consideration of staged repair is recommended. Short-term reintervention rates are low, but longer follow-up and greater patient numbers are needed to determine procedural durability and applicability.
Background With the US Food and Drug Administration approval of the TAG thoracic device, more thoracic pathologies are being treated using endovascular techniques. Although endovascular abdominal and ...thoracic aortic repairs have some apparent similarities, there are substantive anatomic, pathologic, and technical differences that could impact perioperative outcomes. The purpose of this study is to identify these differences. Methods During a 5-year period, 121 endovascular thoracic aortic repairs (TEVAR) and 450 abdominal aortic repairs (EVAR) were performed at a single institution. Preoperative, intraoperative, and early postoperative data were prospectively collected and retrospectively reviewed. Aggregate outcome measures were compared between the two cohorts, with statistical significance achieved at P < .05. Results The mean age of patients undergoing EVAR was 72.8 ± 8.3 compared with 68.3 ± 13.9 for TEVAR ( P = .02). More women underwent TEVAR (30.6% vs 11.1%, P < .001). Aneurysms undergoing TEVAR were larger than those for EVAR (62.0 mm vs 58.3 mm, P = .01). Intraoperatively, EVAR required 26.2 minutes of fluoroscopy compared with 22.1 minutes for TEVAR ( P < .001). The amount of contrast used was higher in TEVAR (133.6 mL vs 93.6 mL, P < .001). The mean procedure times were 164 minutes for EVAR and 115 minutes for TEVAR ( P < .001). Iliac conduits were required in 46 patients (10.2%) undergoing EVAR, and in 24 (19.8%) undergoing TEVAR ( P = .007). The 30-day or in-hospital mortality was 2.0% for EVAR and 5.0% for TEVAR ( P = NS). The median length of stay was longer for TEVAR (3 days vs 2 days, P = .034). There were 54 postoperative complications in 36 TEVAR patients (29.8%), including 13 neurologic (10.7%), 8 renal (6.6%), 7 pulmonary (5.8%), 6 ischemic (5.0), and 5 (4.1%) hemorrhagic events. Among the EVAR group, 136 (30.2%) patients had postoperative complications, which included 45 ischemic (10.0%), 34 wound (7.6%), 22 renal (4.9%), 12 cardiac (2.7%), 8 pulmonary (1.8%), 5 gastrointestinal (1.1%), and 4 neurologic (0.9%) events. Conclusions A relatively higher proportion of women underwent TEVAR than EVAR, and this was reflected in the greater need for iliac conduits to accommodate the larger delivery catheters of the thoracic devices. Intraoperative imaging techniques were also different, and TEVAR required higher contrast volumes despite shorter overall procedure times. The incidence of strokes and spinal cord ischemia was also higher during TEVAR. Despite apparent similarities of devices and techniques, EVAR and TEVAR are fundamentally different procedures with different perioperative outcomes.
Bullous pemphigoid has been rarely described in association with renal abnormalities, including membranous glomerulonephropathy, and it has been approximately 20 years since this association was last ...reported. We describe a case of a male patient with a concurrent onset of bullous pemphigoid and membranous glomerulonephropathy and discuss this rare association. A definite common immunologic mechanism that links the two disorders remains elusive.
IMPORTANCE: Cefepime and piperacillin-tazobactam are commonly administered to hospitalized adults for empirical treatment of infection. Although piperacillin-tazobactam has been hypothesized to cause ...acute kidney injury and cefepime has been hypothesized to cause neurological dysfunction, their comparative safety has not been evaluated in a randomized clinical trial. OBJECTIVE: To determine whether the choice between cefepime and piperacillin-tazobactam affects the risks of acute kidney injury or neurological dysfunction. DESIGN, SETTING, AND PARTICIPANTS: The Antibiotic Choice on Renal Outcomes (ACORN) randomized clinical trial compared cefepime vs piperacillin-tazobactam in adults for whom a clinician initiated an order for antipseudomonal antibiotics within 12 hours of presentation to the hospital in the emergency department or medical intensive care unit at an academic medical center in the US between November 10, 2021, and October 7, 2022. The final date of follow-up was November 4, 2022. INTERVENTIONS: Patients were randomized in a 1:1 ratio to cefepime or piperacillin-tazobactam. MAIN OUTCOMES AND MEASURES: The primary outcome was the highest stage of acute kidney injury or death by day 14, measured on a 5-level ordinal scale ranging from no acute kidney injury to death. The 2 secondary outcomes were the incidence of major adverse kidney events at day 14 and the number of days alive and free of delirium and coma within 14 days. RESULTS: There were 2511 patients included in the primary analysis (median age, 58 years IQR, 43-69 years; 42.7% were female; 16.3% were Non-Hispanic Black; 5.4% were Hispanic; 94.7% were enrolled in the emergency department; and 77.2% were receiving vancomycin at enrollment). The highest stage of acute kidney injury or death was not significantly different between the cefepime group and the piperacillin-tazobactam group; there were 85 patients (n = 1214; 7.0%) in the cefepime group with stage 3 acute kidney injury and 92 (7.6%) who died vs 97 patients (n = 1297; 7.5%) in the piperacillin-tazobactam group with stage 3 acute kidney injury and 78 (6.0%) who died (odds ratio, 0.95 95% CI, 0.80 to 1.13, P = .56). The incidence of major adverse kidney events at day 14 did not differ between groups (124 patients 10.2% in the cefepime group vs 114 patients 8.8% in the piperacillin-tazobactam group; absolute difference, 1.4% 95% CI, −1.0% to 3.8%). Patients in the cefepime group experienced fewer days alive and free of delirium and coma within 14 days (mean SD, 11.9 4.6 days vs 12.2 4.3 days in the piperacillin-tazobactam group; odds ratio, 0.79 95% CI, 0.65 to 0.95). CONCLUSIONS AND RELEVANCE: Among hospitalized adults in this randomized clinical trial, treatment with piperacillin-tazobactam did not increase the incidence of acute kidney injury or death. Treatment with cefepime resulted in more neurological dysfunction. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05094154
The 1000 Genomes Project set out to provide a comprehensive description of common human genetic variation by applying whole-genome sequencing to a diverse set of individuals from multiple ...populations. Here we report completion of the project, having reconstructed the genomes of 2,504 individuals from 26 populations using a combination of low-coverage whole-genome sequencing, deep exome sequencing, and dense microarray genotyping. We characterized a broad spectrum of genetic variation, in total over 88 million variants (84.7 million single nucleotide polymorphisms (SNPs), 3.6 million short insertions/deletions (indels), and 60,000 structural variants), all phased onto high-quality haplotypes. This resource includes >99% of SNP variants with a frequency of >1% for a variety of ancestries. We describe the distribution of genetic variation across the global sample, and discuss the implications for common disease studies.
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Dostopno za:
DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
The mouse (Mus musculus) is the premier animal model for understanding human disease and development. Here we show that a comprehensive understanding of mouse biology is only possible with the ...availability of a finished, high-quality genome assembly. The finished clone-based assembly of the mouse strain C57BL/6J reported here has over 175,000 fewer gaps and over 139 Mb more of novel sequence, compared with the earlier MGSCv3 draft genome assembly. In a comprehensive analysis of this revised genome sequence, we are now able to define 20,210 protein-coding genes, over a thousand more than predicted in the human genome (19,042 genes). In addition, we identified 439 long, non-protein-coding RNAs with evidence for transcribed orthologs in human. We analyzed the complex and repetitive landscape of 267 Mb of sequence that was missing or misassembled in the previously published assembly, and we provide insights into the reasons for its resistance to sequencing and assembly by whole-genome shotgun approaches. Duplicated regions within newly assembled sequence tend to be of more recent ancestry than duplicates in the published draft, correcting our initial understanding of recent evolution on the mouse lineage. These duplicates appear to be largely composed of sequence regions containing transposable elements and duplicated protein-coding genes; of these, some may be fixed in the mouse population, but at least 40% of segmentally duplicated sequences are copy number variable even among laboratory mouse strains. Mouse lineage-specific regions contain 3,767 genes drawn mainly from rapidly-changing gene families associated with reproductive functions. The finished mouse genome assembly, therefore, greatly improves our understanding of rodent-specific biology and allows the delineation of ancestral biological functions that are shared with human from derived functions that are not.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Objective The first multicenter randomized controlled trial was designed and conducted to assess the safety and effectiveness of totally percutaneous endovascular aortic aneurysm repair (PEVAR) with ...use of a 21F endovascular stent graft system and either an 8F or 10F suture-mediated closure system (the PEVAR trial, NCT01070069 ). A noninferiority trial design was chosen to compare percutaneous access with standard open femoral exposure. Methods Between 2010 and 2012, 20 U.S. institutions participated in a prospective, Food and Drug Administration–approved randomized trial to evaluate percutaneous femoral artery access and closure by a “preclose” technique in conjunction with endovascular abdominal aortic aneurysm repair. A total of 151 patients were allocated by a 2:1 design to percutaneous access/closure (n = 101) or open femoral exposure (n = 50 FE). PEVAR procedures were performed with either the 8F Perclose ProGlide (n = 50 PG) or the 10F Prostar XL (n = 51 PS) closure devices. All endovascular abdominal aortic aneurysm repair procedures were performed with the Endologix 21F profile (outer diameter) sheath-based system. Patients were screened by computed tomography with three-dimensional reconstruction and independent physician review for anatomic suitability and adequate femoral artery anatomy for percutaneous access. The primary trial end point (treatment success) was defined as procedural technical success and absence of major adverse events and vascular complications at 30 days. An independent access closure substudy evaluated major access-related complications. Clinical utility and procedural outcomes, ankle-brachial index, blood laboratory analyses, and quality of life were also evaluated with continuing follow-up to 6 months. Results Baseline characteristics were similar among groups. Procedural technical success was 94% (PG), 88% (PS), and 98% (FE). One-month primary treatment success was 88% (PG), 78% (PS), and 78% (FE), demonstrating noninferiority vs FE for PG ( P = .004) but not for PS ( P = .102). Failure rates in the access closure substudy analyses demonstrated noninferiority of PG (6%; P = .005), but not of PS (12%; P = .100), vs FE (10%). Compared with FE, PG and PS yielded significantly shorter times to hemostasis and procedure completion and favorable trends in blood loss, groin pain, and overall quality of life. Initial noninferiority test results persist to 6 months, and no aneurysm rupture, conversion to open repair, device migration, or stent graft occlusion occurred. Conclusions Among trained operators, PEVAR with an adjunctive preclose technique using the ProGlide closure device is safe and effective, with minimal access-related complications, and it is noninferior to standard open femoral exposure. Training, experience, and careful application of the preclose technique are of paramount importance in ensuring successful, sustainable outcomes.
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