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Publikācijā pētīts cēloniskais sakars kā civiltiesiskās atbildības par nemantisko kaitējumu vese­lībai priekšnoteikums. Pirmkārt, rakstā aplūkota cēloniskā sakara pierādīšanas problemātika civilprocesā, otrkārt, analizēta ekspertīzes loma un nozīme nemantiskā kaitējuma veselībai pierādīšanā, treškārt, akcentētas zinātnes robežas cēloniskā sakara izziņā un pierādīšanā, ceturt­kārt, uzsvērta cēloņa un seku saistības nozīme atbildības noteikšanā. Rakstā izvirzīta tēze, ka nereti viens cēlonis nerada kaitējumu pilnībā, tas rodas vairāku cēloņu iedarbības rezultātā, tādēļ kaitējums nav saistāms tikai ar vienas personas rīcību. Tas jāņem vērā, apmierinot prasību pilnībā vai daļēji vai arī to noraidot, kā arī nosakot atbildības sadalījumu, ja nodarīts multikauzāls kaitējums. Rakstā piedāvāts vērtēt cēloņa un seku saistības līmeņus, kas var palīdzēt noteikt civiltiesiskās atbildības robežas.

Contemporary dogma has classically attributed hand dysfunction following hemodialysis arteriovenous fistula (AVF) placement to regional ischemia. We hypothesize that hemodynamic perturbations alone do not entirely explain the postoperative changes in hand function and, furthermore, that various elements of hand function are differentially affected following surgery. Methods: Bilateral wrist and digital pressures and upper extremity nerve conduction tests were recorded preoperatively and at 6 weeks and 6 months following upper extremity AVF construction in 46 patients. Concurrently, biomechanical tests were administered to evaluate multiple limb functional domains, including grip strength, dexterity, sensation, and perception of hand function. Results: Mean participant age was 59 ± 14 years (75% male), and 48% were on hemodialysis at the time of access placement. Of the participants, 69% had a brachial-based AVF, and the remainder had radial-based accesses. Six weeks following AVF placement, a significant decrease in access-side digital pressures was observed, with only partial recovery at 6 months (P < 0.0001). Grip strength was significantly worse in the access-side limb (P = 0.0003), and the Disability of Arm, Shoulder and Hand (DASH) questionnaire score substantially worsened postoperatively (P = 0.06). Digital sensation and limb dexterity did not differ between limb sides (P > 0.1) or change significantly over time (P > 0.1). Principal component analyses demonstrated that nerve conduction parameters tended to track the biomechanical parameters, yet both were relatively independent of the hemodynamic parameters. Discussion: Our findings suggest that ischemia alone does not completely explain access-related hand dysfunction and that future study is needed to elucidate alternative mechanisms.

Background: Malignant gliomas are heterogeneous brain tumors with the potential for aggressive disease progression, as influenced by suppressive immunoediting. Given the success and enhanced potential of immune-checkpoint inhibitors in immunotherapy, we focused on the connections between genetic alterations affected by IDH1 mutations and immunological landscape changes and PDL-1 expression in gliomas.Methods: Paired surgically resected tumors from lower-grade gliomas (LGGs) and glioblastomas (GBM) were investigated, and a genetic analysis of patients' primary tumor samples culled from TCGA datasets was performed.Results: The results demonstrate that when compared with IDH1-mutant tumors, IDH1 wildtype tumors represent an immunosuppression landscape and elevated levels of PD-L1 expression. DNA hypo-methylation of the PD-L1 gene, as well as high gene and protein expressions, were observed in the wildtype tumors. We also found that quantitative levels of IDH1 mutant proteins were positively associated with recurrence-free survival (RFS). A key product of the IDH1 mutation (2-hydroxyglutarate) was found to transiently increase DNA methylation and suppress PD-L1 expression.Conclusions: IDH1 mutations impact the immune landscape of gliomas by affecting immune infiltrations and manipulating checkpoint ligand PD-L1 expression. Applications of immune checkpoint inhibitors may be beneficial for chemoradiation-insensitive IDH1-wildtype gliomas.

BackgroundAngiogenesis and immune cell infiltration are key features of gliomas and their manipulation of the microenvironment, but their prognostic significance remains indeterminate. We evaluate the interconnection between tumor-infiltrating lymphocyte (TIL) and tumor blood-vasculatures in the context of glioma progression.MethodsPaired tumor tissues of 44 patients from three tumor-recurrent groups: diffuse astrocytomas (DA) recurred as DA, DA recurred as glioblastomas (GBM), and GBM recurred as GBM were evaluated by genetic analysis, immunohistochemistry for tumor blood vessel density, TIL subsets, and clinical outcomes. These cells were geographically divided into perivascular and intratumoral TILs. Associations were examined between these TILs, CD34+ tumor blood vessels, and clinical outcomes. To determine key changes in TIL subsets, microarray data of 15-paired tumors from patients who failed antiangiogenic therapy- bevacizumab, and 16-paired tumors from chemo-naïve recurrent GBM were also evaluated and compared.ResultsUpon recurrence in primary gliomas, similar kinetic changes were found between tumor blood vessels and each TIL subset in all groups, but only CD4+ including Foxp3+ TILs, positively correlated with the density of tumor blood vessels. CD4 was the predominant T cell population based on the expression of gene-transcripts in primary GBMs, and increased activated CD4+ T cells were revealed in Bevacizumab-resistant recurrent tumors (not in chemo-naïve recurrent tumors). Among these TILs, 2/3 of them were found in the perivascular niche; Foxp3+ T cells in these niches not only correlated with the tumor vessels but were also an independent predictor of shortened recurrence-free survival (RFS) (HR = 4.199, 95% CI 1.522–11.584, p = 0.006).ConclusionThe minimal intratumoral T cell infiltration and low detection of CD8 transcripts expression in primary GBMs can potentially limit antitumor response. CD4+ and perivascular Foxp3+ TILs associate with tumor angiogenesis and tumor progression in glioma patients. Our results suggest that combining antiangiogenic agents with immunotherapeutic approaches may help improve the antitumor efficacy for patients with malignant gliomas.

Controversy persists regarding the use of protamine during carotid endarterectomy (CEA), despite real world evidence to support its use. The purpose of this study was to determine the impact of protamine reversal of heparin anticoagulation on the outcome of CEA in the USA. A prospective national registry (Society for Vascular Surgery Vascular Quality Initiative) of 72 787 patients undergoing elective asymptomatic CEA by 1879 surgeons from 316 centres in the USA and Canada from 2012 to 2018 was reviewed. Protamine use varied by both surgeon (20% rare use [< 10%], 30% variable use [11%–79%], 50% routine use [> 80% cases]) and geographical region (44% vs. 96%). Temporal trends in protamine use were also determined. End points included post-operative re-operation for bleeding, as well as potential protamine related thrombotic complications, including stroke, death, and myocardial infarction (MI). Predictors of end points were determined by multivariable logistic regression. Propensity matching was additionally used to control for differences between groups. Of the 72 787 patients who underwent CEA, 69% received protamine, while 31% did not. Protamine use increased over time from 60% (2012) to 73% (2018). In total, 378 patients (0.7%) in the protamine treated group underwent re-operation for bleeding vs. 342 patients (1.4%) in the untreated cohort (p <.001). Protamine use did not affect the rate of MI (0.7% vs. 0.8%; p =.023), stroke (1.1% vs. 1.0%; p =.20), or in hospital death (0.2% vs. 0.2%; p = 0.70) between treated and untreated patients, respectively. On multivariable analysis, protamine use was independently associated with reduced risk of re-operation for bleeding (odds ratio 0.5, 95% confidence interval 0.39–0.55; p <.001). Independent of protamine exposure, the consequences of a return to the operating room (RTOR) for bleeding were statistically significant, with a sevenfold increase in MI (RTOR 4.9% vs. no RTOR 0.7%; p <.001), an eightfold increase in stroke (RTOR 7.2% vs. no RTOR 0.9%; p <.001), and a 13 fold increase in death (RTOR 2.4% vs. no RTOR 0.2%; p <.001). Protamine reduces serious bleeding complications at the time of CEA without increasing the risk of MI, stroke, or death, in this large North American analysis. Based on this and previous regional work regarding protamine use in CEA, it is believed that there is now sufficient evidence to support its routine use, and it should be considered as a benchmark for quality during CEA. [ABSTRACT FROM AUTHOR]

Spinal cord ischemia (SCI) is a dreaded complication of thoracic endovascular aortic repair (TEVAR). There are limited national data describing the incidence and influence of in-hospital SCI recovery on survival. Moreover, no robust preoperative SCI risk assessment models currently exist. The purpose of this analysis was to analyze the Vascular Quality Initiative to determine the national incidence, survival association, and preoperative predictors of SCI after TEVAR. All Vascular Quality Initiative TEVAR procedures (June 2014-June 2019) were reviewed. The primary end point was development of in-hospital SCI, defined as any new neurologic deficit or paralysis not attributable to intracranial disease. Secondary end points were disease-specific SCI rates and long-term out-of-hospital survival. Functional outcomes (transient vs permanent SCI) were independently determined by treating physicians. Kaplan-Meier analysis and Cox proportional hazards methodology were used to assess the association of SCI with survival. A logistic regression model of candidate preoperative SCI predictors was created, and bootstrapped backward elimination (retaining predictors with ≥50% selection frequency) was used for model reduction. Model fit and performance statistics were validated by adjustment for Efron's optimism. The overall rate of SCI was 3.7% (n = 422/11,473; transient, 1.6% [n = 179]; permanent, 2.1% [n = 243]). Patients who developed any SCI had significantly lower Kaplan-Meier survival estimate compared with those without SCI (1-year survival: SCI, 65%; no SCI, 87%; P <.0001), and patients with permanent SCI had notably worse survival than patients with transient SCI (1-year survival: permanent SCI, 54%; transient SCI, 80%; P <.0001). Disease-specific incidence of any SCI was as follows: aneurysm, 3.4%; dissection, 5.3%; aneurysm from dissection, 4.1%; trauma, 1.1%; penetrating ulceration, 2.4%; intramural hematoma, 5.7%; penetrating ulceration and intramural hematoma, 4.3%; and aortic thrombus, 4.8%. Several factors were selected on multivariable analysis as the most robust preoperative predictors of any SCI, including distal landing zone 5 to zone 10, nonelective case, creatinine concentration >1.38 mg/dL, smoking history, American Society of Anesthesiologists class, adjunctive procedure, nonwhite race, and preoperative hypertension (area under the curve = 0.72; Nagelkerke R 2 = 0.06). SCI is a devastating complication after TEVAR that is associated with worse overall survival, particularly when no functional recovery occurs by hospital discharge. Disease-specific, real-world benchmarks for SCI rates are provided that may inform quality initiatives focused on reducing this complication. Importantly, this analysis is the first description of a preoperative prediction model derived from national data for determining SCI risk after TEVAR. These predictors should be used to identify high-risk patients to balance the risk of SCI and its associated increased short-term mortality with the risk of the underlying disease. Furthermore, all available adjunctive measures should be implemented in these high-risk patients to reduce risk of SCI. [ABSTRACT FROM AUTHOR]

Open repair of extent II and III thoracoabdominal aortic aneurysms (TAAA) is associated with substantial morbidity. Alternative strategies, such as hybrid operations combining proximal thoracic endovascular aortic repair with either staged open distal TAAA repair or visceral debranching (hybrid), as well as fenestrated/branched endografts (FEVAR), have been increasingly reported; however, benefits of these approaches compared with direct open surgery remain unclear. The purpose of this study was to compare outcomes of these three different strategies in the management of extent II/III TAAA. All extent II/III TAAA repairs (2002-2018) for nonmycotic, degenerative aneurysm or chronic dissection at a single institution were reviewed. The primary end point was 30-day mortality. Secondary end points included incidence of spinal cord ischemia (SCI), complications, unplanned re-operation, 90-day readmission, and out-of-hospital survival. To mitigate impact of covariate imbalance and selection bias, intergroup comparisons were made using inverse probability weighted-propensity analysis. Cox regression was used to estimate survival while cumulative incidence was used to determine reoperation risk. One hundred ninety-eight patients (FEVAR, 92; hybrid, 40; open, 66) underwent repair. In unadjusted analysis, compared with hybrid/open patients, FEVAR patients were significantly older with more cardiovascular risk factors, but less likely to have a connective tissue disorder or dissection-related indication. Unadjusted 30-day mortality and complication rates were: 30-day mortality, FEVAR 4%, hybrid 13%, open 12% (P =.01); and complications, FEVAR 36%, hybrid 33%, open 50% (P =.11). Permanent SCI was not different among groups (FEVAR 3%, hybrid 3%, open 6%; P =.64). In adjusted analysis, 30-day mortality risk was greater for open vs FEVAR (hazard ratio, 3.6; 95% confidence interval, 1.4-9.2; P =.01) with no difference for hybrid vs open/FEVAR. There was significantly lower risk of any SCI for open vs FEVAR (hazard ratio, 0.3; 95% confidence interval, 0.09-0.96; P =.04); however, no difference in risk of permanent SCI was detected among the three groups. There was no difference in complications or unplanned reoperation, but open patients had the greatest risk of unplanned 90-day readmission. There was a time-varying effect on survival probability, with open repair having a significant survival disadvantage in the first 1 to 6 months after the procedure compared with hybrid/FEVAR patients (Cox model P =.03), but no difference in survival at 1 and 5 years (1- and 5-year survival: FEVAR, 86 ± 3%, 55 ± 8%; hybrid, 86 ± 5%, 60 ± 11%; open 69 ± 7%, 59 ± 8%; Cox-model P =.10). Extent II/III TAAA repair, regardless of operative strategy, is associated with significant morbidity risk. FEVAR is associated with the lowest 30-day mortality risk compared with hybrid and open repair when estimates are adjusted for preoperative risk factors. These data support greater adoption of FEVAR as first-line therapy to treat complex TAAA disease in anatomically suitable patients who present electively. [ABSTRACT FROM AUTHOR]

Controversy exists surrounding gender outcome disparity and abdominal aortic aneurysm (AAA) repair. Previous reports have demonstrated worse outcomes for women undergoing open aneurysm repair (OAR); however, these differences are less evident with endovascular aneurysm repair (EVAR). Epidemiologic studies have documented that women score higher on most frailty assessment scales but paradoxically have longer life expectancy compared to men. The interaction of gender/frailty and the influence on outcomes and practice patterns surrounding EVAR and OAR is poorly described. This analysis characterizes the association of frailty/sex interactions on mortality as well as patient selection surrounding elective AAA repair in the Society for Vascular Surgery Vascular Quality Initiative. All elective infrarenal AAA (EVAR + OAR; 2003-2017) cases were queried from the Vascular Quality Initiative database. Each patient was assigned a previously published modified frailty index (mFI) score derived from comorbidity and preoperative functional status data. Cox proportional hazard models, adjusted for statistically significant covariates, including procedural complexity, determined associations within full models and sex-stratified models. A total of 20,750 elective AAA cases were analyzed (EVAR 15,893 [77%]; OAR 4857 [23%]). Thirty-day mortality for EVAR and OAR was 0.7% (n = 115) and 3.5% (n = 169), respectively. Patients who died were significantly more likely to be older (EVAR, 78 vs 73 years; OAR, 74 vs 69 years; P <.0001), have larger AAA diameters (EVAR, 59 vs 56 mm; P =.005; OAR, 62 vs 59 mm; P =.001), higher mFI scores (EVAR, 3.2 vs 2.4; OAR, 3.1 vs 2.2; P <.0001), and be of female sex (EVAR hazard ratio = 1.66 [95% confidence interval, 1.10-2.52]; P =.007; OAR-1.43 [1.02-1.99]; P =.003). Significant differences in the gender distribution of frailty scores among EVAR patients were evident (mean mFI: male 2.42 vs female 2.34; P =.02), but no difference was detected for OAR (male 2.17 vs female 2.22; P =.38). The mFI was a strong independent predictor of mortality (30 days: EVAR hazard ratio = 1.36 [1.22-1.53] and OAR 1.46 [1.32-1.60]; 1 year: EVAR 1.32 [1.25-1.39] and OAR-1.38 [1.28-1.48]). There was no interaction between mFI and gender on the association with mortality. Across frailty strata, male patients were nearly twofold more likely to undergo either elective EVAR or OAR for an AAA below recommended minimum diameter thresholds (male, <5.5 cm; female, <5.0 cm). Greater mFI score did not alter OAR selection but was associated with less frequent EVAR of small AAA. Given the strong association between frailty and postoperative mortality, mFI can be used as a predictive tool to aid in surgical planning of patients undergoing elective AAA repair. While mFI can predict postoperative mortality for both men and women, it does not account for the survival disparity between sexes, and further research is warranted to explain this difference. There appear to be significant gender differences in patient selection based on current Society for Vascular Surgery–endorsed treatment thresholds that may have important implications on the appropriateness of AAA care delivery nationally. [ABSTRACT FROM AUTHOR]

Abstract Background Acute mesenteric ischemia (AMI) is a challenging clinical problem associated with significant morbidity and mortality. Few contemporary reports focus specifically on patients undergoing open mesenteric bypass (OMB) or delineate outcome differences based on bypass configuration. This is notable, because there is a subset of patients who are poor candidates for endovascular intervention including those with flush mesenteric vessel occlusion, long segment occlusive disease, and a thrombosed mesenteric stent and/or bypass. This analysis reviewed our experience with OMB in the treatment of AMI and compared outcomes between patients undergoing either antegrade or retrograde bypass. Methods A single-center, retrospective review was performed to identify all patients who underwent OMB for AMI from 2002 to 2016. A preoperative history of mesenteric revascularization, demographics, comorbidities, operative details, and outcomes were abstracted. The primary end point was in-hospital mortality. Secondary end points included complications, reintervention, and overall survival. Kaplan-Meier estimation and Cox proportional hazards regression were used to analyze all end points. Results Eighty-two patients (female 54%; age 63 ± 12 years) underwent aortomesenteric bypass (aortoceliac/superior mesenteric, n = 44; aortomesenteric, n = 38) for AMI. A history of prior stent/bypass was present in 20% (n = 16). A majority (76%; n = 62) underwent antegrade bypass and the remainder received retrograde infrarenal aortoiliac inflow. Patients receiving antegrade OMB were more likely to be male (53% vs 25%; P =.02), have coronary artery disease (48% vs 25%; P =.06), chronic obstructive pulmonary disease (52% vs 25%; P =.03), and peripheral arterial disease (60% vs 35%; P =.05). Concurrent bowel resection was evenly distributed (antegrade, 45%; retrograde, 45%; P =.9) and 37% (n = 30) underwent subsequent resection during second look operations. The median duration of stay was 16 days (interquartile range, 9-35 days) and 78% (n = 64) experienced at least one major complication with no difference in rates between antegrade/retrograde configurations. In-hospital mortality was 37% (n = 30; multiple organ dysfunction, 22; bowel infarction, 4; hemorrhage/anemia, 2; arrhythmia, 1; stroke, 1; 30-day mortality, 26%). The median follow-up was 8 months (interquartile range, 1-26 months). The 1- and 3-year primary patency rates were both 82% ± 6% (95% confidence interval, 71%-95%), with 10 patients requiring reintervention. Estimated survival at 1 and 5 years was 57% ± 6% and 50% ± 6%, respectively. Bypass configuration was not associated with complication rates (P >.10), in-hospital mortality (log-rank, P =.3), or overall survival (log-rank, P =.9). However, a higher risk of reintervention was observed in patients undergoing retrograde bypass (hazard ratio, 3.0; 95% confidence interval, 0.9-11.0; P =.08). Conclusions OMB for AMI results in significant morbidity and mortality, irrespective of bypass configuration. Antegrade OMB is associated with comparable outcomes as retrograde OMB. The bypass configuration choice should be predicated on patient presentation, anatomy, physiology, and surgeon preference; however, an antegrade configuration may provide a lower risk of reintervention. [ABSTRACT FROM AUTHOR]

Objective The ideal stent combination for chimney endovascular aneurysm repair remains undetermined. Therefore, we sought to identify optimal aortic and chimney stent combinations that are associated with the best outcomes by analyzing the worldwide collected experience in the PERformance of chImney technique for the treatment of Complex aortic pathoLogiES (PERICLES) registry. Methods The PERICLES registry was reviewed for patients with pararenal aortic disease electively treated from 2008 to 2014. Eleven different aortic devices were identified with three distinct subgroups: group A (n = 224), nitinol/polyester; group B (n = 105), stainless steel/polyester; and group C (n = 69), nitinol/expanded polytetrafluoroethylene. The various chimney stent subtypes included the balloon-expandable covered stent (BECS), self-expanding covered stent, and bare-metal stent. Deidentified aortic and chimney device combinations were compared for risk of chimney occlusion, type IA endoleak, and survival. Effects of high-volume centers (>100 cases), use of an internal lining chimney stent, number of chimney stents, and number of chimney stent subtypes deployed were also considered. We considered demographics, comorbidities, and aortic anatomic features as potential confounders in all models. Results The 1- and 3-year freedom from BECS chimney occlusion was not different between groups (group A, 96% ± 2% and 87% ± 5%; groups B and C, 93% ± 3% and 76% ± 10%; Cox model, P = .33). Similarly, when non-BECS chimney stents were used, no difference in occlusion risk was noted for the three aortic device groupings; however, group C patients receiving BECS did have a trend toward higher occlusion risk relative to group C patients not receiving a BECS chimney stent (hazard ratio [HR], 4.0; 95% confidence interval [CI], 0.85-18.84; P = .08). Patients receiving multiple chimney stents, irrespective of stent subtype, had a 1.8-fold increased risk of occlusion for each additional stent (HR, 1.8; 95% CI, 1.2-2.9; P = .01). Use of a bare-metal endolining stent doubled the occlusion hazard (HR, 2.1; 95% CI, 1.0-4.5; P = .05). Risk of type IA endoleak (intraoperatively and postoperatively) did not significantly differ for the aortic devices with BECS use; however, group C patients had higher risk relative to groups A/B without BECS (C vs B: odds ratio [OR], 3.2 [95% CI, 1-11; P = .05]; C vs A/B: OR, 2.4 [95% CI, 0.9-6.4; P = .08]). Patients treated at high-volume centers had significantly lower odds for development of type IA endoleak (OR, 0.2; 95% CI, 0.1-0.7; P = .01) irrespective of aortic or chimney device combination. Mortality risk was significantly higher in group C + BECS vs group A + BECS (HR, 5.3; 95% CI, 1.6-17.5; P = .006). The 1- and 3-year survival for groups A, B, and C (+BECS) was as follows: group A, 97% ± 1% and 92% ± 3%; group B, 93% ± 3% and 83% ± 7%; and group C, 84% ± 7% and 63% ± 14%. Use of more than one chimney subtype was associated with increased mortality (HR, 3.2; 95% CI, 1.4-7.5; P = .006). Conclusions Within the PERICLES registry, use of nitinol/polyester stent graft devices with BECS during chimney endovascular aneurysm repair is associated with improved survival compared with other aortic endografts. However, this advantage was not observed for non-BECS repairs. Repairs incorporating multiple chimney subtypes were also associated with increased mortality risk. Importantly, increasing chimney stent number and bare-metal endolining stents increase chimney occlusion risk, whereas patients treated at low-volume centers have higher risk of type IA endoleak. [ABSTRACT FROM AUTHOR]