Description and outcomes of a simple surgical technique to treat thrombosed autogenous accesses

ObjectiveOwing to the difficulty of removing acute and chronic thrombus from autogenous accesses (AA) by standard surgical and endovascular techniques, many surgeons consider efforts to salvage a thrombosed AA as being futile. We describe a simple technique to extract acute and chronic thrombus from a failed AA. This technique involves making an incision adjacent to the anastomosis, directly extracting the arterial plug, and manually milking thrombus from the access. This report details the outcomes of a series of thrombosed AAs treated by surgical thrombectomy/intervention using this technique for manual clot extraction.MethodsA total of 146 surgical thrombectomies/interventions were performed in 102 patients to salvage a thrombosed AA. Mean follow-up was 15.6 months. Office, hospital, and dialysis unit records were reviewed to identify patient demographics, define procedure type, and determine functional patency rates. Kaplan-Meier survival analysis was used to estimate primary and secondary functional patency rates.ResultsComplete extraction of thrombus from the AA was achieved in 140 of 146 cases (95%). The studied procedure itself was technically successful in 127 cases (87%). Reasons for failure were the inability to completely extract thrombus from the AA in six, failed angioplasty due to long segment vein stenosis or sclerosis in seven or vein rupture in two, and central vein occlusion in one. Three failures occurred for unknown causes ≤3 days of successful thrombectomy. No single factor analyzed (age, sex, race, diabetes status, access type or location) was associated with technical failure. The estimated primary and secondary functional patency rates were 27% ± 5% and 61% ± 6% at 12 months.ConclusionsThe manual clot extraction technique described in this report effectively removed acute and chronic thrombus from failed AAs. Its use, combined with an intervention to treat the underlying cause for AA failure, significantly extended access durability

Prosthetic thigh arteriovenous access: outcome with SVS/AAVS reporting standards

AbstractPurposeDifferences in the reporting methods of results for arteriovenous (AV) access can dramatically affect apparent outcome. To enable meaningful comparisons in the literature, the Society for Vascular Surgery and the American Association for Vascular Surgery (SVS/AAVS) recently published reporting standards for dialysis access. The purpose of the present study was to determine infection rates, patency rates, and possible predictive factors for prosthetic thigh AV access outcomes with the reporting standards of the SVS/AAVS.MethodsA retrospective analysis was performed of all patients who underwent placement of thigh AV access by the Surgical Teaching Service at Greenville Memorial Hospital between 1989 and 2001. Outcomes were determined based on SVS/AAVS Standards for Reports Dealing with AV Accesses. The rate of revision per year of access patency was also determined; this end point more accurately reflects the true cost and morbidity associated with AV access than do patency or infection rates alone.ResultsOne hundred twenty-five polytetrafluoroethylene thigh AV accesses were placed in 100 patients. Nine accesses were excluded from the study, six because there was no patient follow-up and 3 as a result of deaths unrelated to the access procedure and which occurred less than 30 days after access placement. There were six (4%) late access-related deaths. There were 18 (15%) early access failures, related to infection in 14 cases (12%), thrombosis in three cases (2%), and steal in one case (1%). Early failure was more common in patients with diabetes mellitus (P = .036). The primary and secondary functional patency rates were 19% and 54%, respectively, at 2 years. Infection occurred in 48 (41%) accesses. The patency and infection rates were not influenced by patient age, gender, body mass index, or diabetes mellitus. The median number of interventions per year of access patency was 1.68, and this outcome was positively correlated with body mass index (P < .001).ConclusionsProsthetic AV access in the thigh is associated with higher morbidity compared with that reported for the upper extremity, and should be considered only if no upper extremity AV access option is available. Early access failure and the requirement for an increased number of interventions to reestablish and maintain access patency are more common in patients with diabetes mellitus and obesity. The number of interventions per year of access patency is a valuable end point when assessing the outcome of AV access procedures

Zero-shot interpretable phenotyping of postpartum hemorrhage using large language models

Many areas of medicine would benefit from deeper, more accurate phenotyping, but there are limited approaches for phenotyping using clinical notes without substantial annotated data. Large language models (LLMs) have demonstrated immense potential to adapt to novel tasks with no additional training by specifying task-specific instructions. Here we report the performance of a publicly available LLM, Flan-T5, in phenotyping patients with postpartum hemorrhage (PPH) using discharge notes from electronic health records (n = 271,081). The language model achieves strong performance in extracting 24 granular concepts associated with PPH. Identifying these granular concepts accurately allows the development of interpretable, complex phenotypes and subtypes. The Flan-T5 model achieves high fidelity in phenotyping PPH (positive predictive value of 0.95), identifying 47% more patients with this complication compared to the current standard of using claims codes. This LLM pipeline can be used reliably for subtyping PPH and outperforms a claims-based approach on the three most common PPH subtypes associated with uterine atony, abnormal placentation, and obstetric trauma. The advantage of this approach to subtyping is its interpretability, as each concept contributing to the subtype determination can be evaluated. Moreover, as definitions may change over time due to new guidelines, using granular concepts to create complex phenotypes enables prompt and efficient updating of the algorithm. Using this language modelling approach enables rapid phenotyping without the need for any manually annotated training data across multiple clinical use cases

Preoperative clinical factors predict postoperative functional outcomes after major lower limb amputation: An analysis of 553 consecutive patients

BackgroundDespite being a major determinant of functional independence, ambulation after major limb amputation has not been well studied. The purpose, therefore, of this study was to investigate the relationship between a variety of preoperative clinical characteristics and postoperative functional outcomes in order to formulate treatment recommendations for patients requiring major lower limb amputation.MethodsFrom January 1998 through December 2003, 627 major limb amputations (37.6% below knee amputations, 4.3% through knee amputations, 34.5% above knee amputations, and 23.6% bilateral amputations) were performed on 553 patients. Their mean age was 63.7 years; 55% were men, 70.2% had diabetes mellitus, and 91.5% had peripheral vascular disease. A retrospective review was performed correlating various preoperative presenting factors such as age at presentation, race, medical comorbidities, preoperative ambulatory status, and preoperative independent living status, with postoperative functional endpoints of prosthetic usage, survival, maintenance of ambulation, and maintenance of independent living status. Kaplan-Meier survival curves were constructed and compared by using the log-rank test. Odds ratios (OR) and hazard ratios (HR) with 95% confidence intervals were constructed by using multiple logistic regressions and Cox proportional hazards models.ResultsStatistically significant preoperative factors independently associated with not wearing a prosthesis in order of greatest to least risk were nonambulatory before amputation (OR, 9.5), above knee amputation (OR, 4.4), age >60 years (OR, 2.7), homebound but ambulatory status (OR, 3.0), presence of dementia (OR, 2.4), end-stage renal disease (OR, 2.3), and coronary artery disease (OR, 2.0). Statistically significant preoperative factors independently associated with death in decreasing order of influence included age ≥70 years (HR, 3.1), age 60 to 69 (HR, 2.5), and the presence of coronary artery disease (HR, 1.5). Statistically significant preoperative factors independently associated with failure of ambulation in decreasing order of influence included age ≥70 years (HR, 2.3), age 60 to 69 (HR, 1.6), bilateral amputation (HR, 1.8), and end-stage renal disease (HR, 1.4). Statistically significant preoperative factors independently associated with failure to maintain independent living status in decreasing order of influence included age ≥70 years (HR, 4.0), age 60 to 69 (HR, 2.7), level of amputation (HR, 1.8), homebound ambulatory status (HR, 1.6), and the presence of dementia (HR, 1.6).ConclusionsPatients with limited preoperative ambulatory ability, age ≥70, dementia, end-stage renal disease, and advanced coronary artery disease perform poorly and should probably be grouped with bedridden patients, who traditionally have been best served with a palliative above knee amputation. Conversely, younger healthy patients with below knee amputations achieved functional outcomes similar to what might be expected after successful lower extremity revascularization. Amputation in these instances should probably not be considered a failure of therapy but another treatment option capable of extending functionality and independent living

Multiple roles of GluN2B-containing NMDA receptors in synaptic plasticity in juvenile hippocampus

AbstractIn the CA1 area of the hippocampus N-methyl-d-aspartate receptors (NMDARs) mediate the induction of long-term depression (LTD), short-term potentiation (STP) and long-term potentiation (LTP). All of these forms of synaptic plasticity can be readily studied in juvenile hippocampal slices but the involvement of particular NMDAR subunits in the induction of these different forms of synaptic plasticity is currently unclear. Here, using NVP-AAM077, Ro 25-6981 and UBP145 to target GluN2A-, 2B- and 2D-containing NMDARs respectively, we show that GluN2B-containing NMDARs (GluN2B) are involved in the induction of LTD, STP and LTP in slices prepared from P14 rat hippocampus. A concentration of Ro (1 μM) that selectively blocks GluN2B-containing diheteromers is able to block LTD. It also inhibits a component of STP without affecting LTP. A higher concentration of Ro (10 μM), that also inhibits GluN2A/B triheteromers, blocks LTP. UBP145 selectively inhibits the Ro-sensitive component of STP whereas NVP inhibits LTP. These data are consistent with a role of GluN2B diheretomers in LTD, a role of both GluN2B- and GluN2D- containing NMDARs in STP and a role of GluN2A/B triheteromers in LTP.This article is part of the Special Issue entitled ‘Ionotropic glutamate receptors’

Gene Expression Changes in GABAA Receptors and Cognition Following Chronic Ketamine Administration in Mice

Ketamine is a well-known anesthetic agent and a drug of abuse. Despite its widespread use and abuse, little is known about its long-term effects on the central nervous system. The present study was designed to evaluate the effect of long-term (1- and 3-month) ketamine administration on learning and memory and associated gene expression levels in the brain. The Morris water maze was used to assess spatial memory and gene expression changes were assayed using Affymetrix Genechips; a focus on the expression of GABAA receptors that mediate a tonic inhibition in the brain, was confirmed by quantitative real-time PCR and western blot. Compared with saline controls, there was a decline in learning and memory performance in the ketamine-treated mice. Genechip results showed that 110 genes were up-regulated and 136 genes were down-regulated. An ontology analysis revealed the most significant effects of ketamine were on GABAA receptors. In particular, there was a significant up-regulation of both mRNA and protein levels of the alpha 5 subunit (Gabra5) of the GABAA receptors in the prefrontal cortex. In conclusion, chronic exposure to ketamine impairs working memory in mice, which may be explained at least partly by up-regulation of Gabra5 subunits in the prefrontal cortex

Increased CXCL10 (IP-10) is associated with advanced myeloproliferative neoplasms and its loss dampens erythrocytosis in mouse models

Key studies in pre-leukemic disorders have linked increases in pro-inflammatory cytokines with accelerated phases of the disease, but the precise role of the cellular microenvironment in disease initiation and evolution remains poorly understood. In myeloproliferative neoplasms (MPNs), higher levels of specific cytokines have been previously correlated with increased disease severity (tumor necrosis factor-alpha [TNF-α], interferon gamma-induced protein-10 [IP-10 or CXCL10]) and decreased survival (interleukin 8 [IL-8]). Whereas TNF-α and IL-8 have been studied by numerous groups, there is a relative paucity of studies on IP-10 (CXCL10). Here we explore the relationship of IP-10 levels with detailed genomic and clinical data and undertake a complementary cytokine screen alongside functional assays in a wide range of MPN mouse models. Similar to patients, levels of IP-10 were increased in mice with more severe disease phenotypes (e.g., JAK2 V617F/V617F TET2 -/- double-mutant mice) compared with those with less severe phenotypes (e.g., CALR del52 or JAK2 +/V617F mice) and wild-type (WT) littermate controls. Although exposure to IP-10 did not directly alter proliferation or survival in single hematopoietic stem cells (HSCs) in vitro, IP-10 -/- mice transplanted with disease-initiating HSCs developed an MPN phenotype more slowly, suggesting that the effect of IP-10 loss was noncell-autonomous. To explore the broader effects of IP-10 loss, we crossed IP-10 -/- mice into a series of MPN mouse models and showed that its loss reduces the erythrocytosis observed in mice with the most severe phenotype. Together, these data point to a potential role for blocking IP-10 activity in the management of MPNs

The Effects of NR2 Subunit-Dependent NMDA Receptor Kinetics on Synaptic Transmission and CaMKII Activation

N-Methyl-d-aspartic acid (NMDA) receptors are widely expressed in the brain and are critical for many forms of synaptic plasticity. Subtypes of the NMDA receptor NR2 subunit are differentially expressed during development; in the forebrain, the NR2B receptor is dominant early in development, and later both NR2A and NR2B are expressed. In heterologous expression systems, NR2A-containing receptors open more reliably and show much faster opening and closing kinetics than do NR2B-containing receptors. However, conflicting data, showing similar open probabilities, exist for receptors expressed in neurons. Similarly, studies of synaptic plasticity have produced divergent results, with some showing that only NR2A-containing receptors can drive long-term potentiation and others showing that either subtype is capable of driving potentiation. In order to address these conflicting results as well as open questions about the number and location of functional receptors in the synapse, we constructed a Monte Carlo model of glutamate release, diffusion, and binding to NMDA receptors and of receptor opening and closing as well as a model of the activation of calcium-calmodulin kinase II, an enzyme critical for induction of synaptic plasticity, by NMDA receptor-mediated calcium influx. Our results suggest that the conflicting data concerning receptor open probabilities can be resolved, with NR2A- and NR2B-containing receptors having very different opening probabilities. They also support the conclusion that receptors containing either subtype can drive long-term potentiation. We also are able to estimate the number of functional receptors at a synapse from experimental data. Finally, in our models, the opening of NR2B-containing receptors is highly dependent on the location of the receptor relative to the site of glutamate release whereas the opening of NR2A-containing receptors is not. These results help to clarify the previous findings and suggest future experiments to address open questions concerning NMDA receptor function

Axiomatic Choice Theory Traveling between Mathematical Formalism, Normative Choice Rules and Psychological Measurement, 1944-1956

The following analysis is meant to contribute to a history of rational choice theory. More specifically, I provide a multi-layered account of rational choice theory in terms of its biography as a scientific object. I argue that its axiomatic version, choice theory traveled between different research sites, specified within the context of different mathematical formalisms and occupying different epistemic functions; it was being applied to prescribe rules of proper behavior, as representation of behavioral hypotheses, and as measurement device to capture individual values. New modifications of what I call 'axiomatic choice theory' did not fully replace old versions of it, which prevents the reconstruction of its 'travels' as a continuous process and acknowledges the different versions of axiomatic choice theory that are currently used in the social sciences, particularly in economics. Furthermore, by revealing the diversity of its manifestations within the context of social networks and within particular research sites, the account of axiomatic choice theory developed here will ultimately contributes to an explanation of the disunity and confusion surrounding current debates about rational choice theory and allows for providing a more nuanced picture of its nature and scope. Jacob Marschak's professional development is used as a guide through this history of axiomatic choice theory to illustrate its journey