What Are the Real Issues in Providing Extracorporeal Membrane Oxygenation (ECMO) Support: A Survey.

INTRODUCTION: By using a novel survey our study aimed to assess the challenges ECMO and Critical Care (CC) teams face when initiating and managing patient's ECMO support. METHODS: A qualitative survey-based observational study was performed of members of 2 Critical Care Medicine organizations involved in decision-making around the practice of Extracorporeal Membrane Oxygenation (ECMO). The range of exploratory questions covered ethical principles of informed consent, autonomy and goals of care discussions, beneficence, non-maleficence (offering life-sustaining treatments in end-of-life care), and justice (insurance-related limitations of treatment). Questions also covered pragmatic practice and quality improvement areas, such as exploring whether palliative care or ethics teams were involved in such decision-making. RESULTS: 305 members received the survey links, and a total of 61 completed surveys were received, for an overall response rate of 20% among all eligible members. Only 70% of the participants who manage ECMO patients are involved in the ECMO initiation decision process. The majority do not involve Ethics or Palliative care at the initial ECMO initiation decision step. Of the ethical and moral dilemmas reported, the majority revolved around 1. Prognostication of patients receiving VV and VA ECMO support, 2. Lack of knowledge of patient's wishes and goals, 3. Disconnect between expectations of families and outcomes and 4. Staff moral distress around when to stop ECMO in case of futility. CONCLUSION: Our survey highlights areas of distress and dilemma which have been stressed before in the initiation, management, and outcomes of ECMO patients, however with the increasing use of this modality of cardiopulmonary mechanical support being offered, the survey results can offer a guidance using sound ethical principles.

Hybrid programming-model strategies for GPU offloading of electronic structure calculation kernels.

To address the challenge of performance portability and facilitate the implementation of electronic structure solvers, we developed the basic matrix library (BML) and Parallel, Rapid O(N), and Graph-based Recursive Electronic Structure Solver (PROGRESS) library. The BML implements linear algebra operations necessary for electronic structure kernels using a unified user interface for various matrix formats (dense and sparse) and architectures (CPUs and GPUs). Focusing on density functional theory and tight-binding models, PROGRESS implements several solvers for computing the single-particle density matrix and relies on BML. In this paper, we describe the general strategies used for these implementations on various computer architectures, using OpenMP target functionalities on GPUs, in conjunction with third-party libraries to handle performance critical numerical kernels. We demonstrate the portability of this approach and its performance in benchmark problems.

Survival and Decision-Making in Patients Turned Down for Abdominal Aortic Aneurysm Repair: A Retrospective Study with Focus on COVID-19 Impact.

OBJECTIVES: To investigate and analyse various aspects related to patients who have been placed on a "turn-down list" for elective or emergency repair of abdominal aortic aneurysms (AAA). METHODS: This retrospective study analysed data from the Black Country Vascular Network (BCVN). Multidisciplinary team (MDT) meetings assessed AAA patients referred through National Abdominal Aortic Aneurysm Screening Programme (NAAASP)or directly to vascular surgery. Patients considered unfit for intervention were added to a prospectively kept turndown list. Survival and cause of death data were collected, along with cardiopulmonary exercise testing (CPET) results and British Aneurysm Repair (BAR) scores for some patients. The study covered a period from January 2015 to May 2023. RESULTS: After exclusions 247 (16%) patients were placed on the turndown list with a median age of 85 years (IQR 8 years). The mortality of turndown cases on medical grounds was 74.1%. Survival was significantly higher for patients who completed CPET before being turned down (p = 0.004). Gender analysis revealed a higher proportion of females being turned down compared to males (p = 0.044). COVID-19 led to a notable reduction in the number of discussed cases and interventions, while the turndown rates remained consistent. Survival at one year in turndown patients was 66%, at three it was 29%, at four years it was18% and at 7 years it was 5%. Most patients whose cause of death was known died of respiratory complications (30%) or malignancy (19%). BAR scores and aneurysm size were not significant predictors of mortality. CONCLUSION: Patients on the turndown list have a substantial mortality rate. A significant proportion of female patients were being turned down compared to men and the reasons for this are not clear. Patients who completed CPET before being turned down had a longer survival time. While COVID-19 impacted healthcare services reducing the number of interventions, it did not influence turndown decisions. The study showed that the cause of death for a significant number of patients was respiratory complications or malignancy.

The incidence of surgical site infection following major lower limb amputation: A systematic review.

Surgical site infections (SSIs) following major lower limb amputation (MLLA) in vascular patients are a major source of morbidity. The objective of this systematic review was to determine the incidence of SSI following MLLA in vascular patients. This review was prospectively registered with the International Prospective Register of Systematic Reviews (CRD42023460645). Databases were searched without date restriction using a pre-defined search strategy. The search identified 1427 articles. Four RCTs and 21 observational studies, reporting on 50 370 MLLAs, were included. Overall SSI incidence per MLLA incision was 7.2% (3628/50370). The incidence of SSI in patients undergoing through-knee amputation (12.9%) and below-knee amputation (7.5%) was higher than the incidence of SSI in patients undergoing above-knee amputation, (3.9%), p < 0.001. The incidence of SSI in studies focusing on patients with peripheral arterial disease (PAD), diabetes or including patients with both was 8.9%, 6.8% and 7.2%, respectively. SSI is a common complication following MLLA in vascular patients. There is a higher incidence of SSI associated with more distal amputation levels. The reported SSI incidence is similar between patients with underlying PAD and diabetes. Further studies are needed to understand the exact incidence of SSI in vascular patients and the factors which influence this.

Relating Standardized Automated Perimetry Performed with Stimulus Sizes III and V in Eyes With Field Loss due to Glaucoma and NAION.

Objective: Standard automated perimetry (SAP) visual field (VF) results are more repeatable using Goldmann stimulus size V (stimV) in eyes with moderate/severe deficits due to glaucoma. There are few reports relating VFs using stimulus size V and III, typically used in the clinic for glaucoma, and none for non-arteritic anterior ischemic optic neuropathy (NAION). We hypothesized that we could compare and relate the VFs with both stimuli for glaucoma and NAION. Methods: We utilized 1992 same-day pairs of stimIII and stimV SAP VFs using the 24-2 strategy for eyes with glaucoma or NAION. We explored the optimal threshold to censor the raw sensitivities, prior to calculating age-standardized total deviations (TD). We determined the mean and standard deviation of the differences among all TD pairs. We computed a line of best fit to determine closeness to the line of unity. Results: The ideal censoring conversion threshold was 21 dB for stimIII and 24 dB for stimV. The difference between stimV and stimIII censored (0.0 ± 1.9 dB) and uncensored (0.4 ± 2.6 dB) TD pairings strongly correlate with each other (r2 = 0.70, p < 0.001). The line of best fit from these pairings has a slope of 0.92, which is similar to that of the line of unity (m = 1). Conclusion: Censoring plus age correction is a valid method of comparison between stimIII and stimV SAP VFs with moderate to severe VF loss due to optic nerve disorders. Translational Relevance: StimIII and stimV TDs are interchangeable in clinical practice.

Successful treatment of a large profunda femoris artery aneurysm and associated pseudoaneurysm using endovascular stenting.

Profunda femoris artery aneurysms are a rare form of peripheral arterial aneurysm. In this report, we present the case of an 83-year-old lady who was found to have a 65 mm aneurysm arising from the proximal left profunda femoris artery and associated pseudoaneurysm. Successful treatment was achieved using an endovascular approach in which two stents were deployed.

Detecting Visual Field Worsening From Optic Nerve Head and Macular Optical Coherence Tomography Thickness Measurements.

Purpose: Compare the use of optic disc and macular optical coherence tomography measurements to predict glaucomatous visual field (VF) worsening. Methods: Machine learning and statistical models were trained on 924 eyes (924 patients) with circumpapillary retinal nerve fiber layer (cp-RNFL) or ganglion cell inner plexiform layer (GC-IPL) thickness measurements. The probability of 24-2 VF worsening was predicted using both trend-based and event-based progression definitions of VF worsening. Additionally, the cp-RNFL and GC-IPL predictions were combined to produce a combined prediction. A held-out test set of 617 eyes was used to calculate the area under the curve (AUC) to compare cp-RNFL, GC-IPL, and combined predictions. Results: The AUCs for cp-RNFL, GC-IPL, and combined predictions with the statistical and machine learning models were 0.72, 0.69, 0.73, and 0.78, 0.75, 0.81, respectively, when using trend-based analysis as ground truth. The differences in performance between the cp-RNFL, GC-IPL, and combined predictions were not statistically significant. AUCs were highest in glaucoma suspects using cp-RNFL predictions and highest in moderate/advanced glaucoma using GC-IPL predictions. The AUCs for the statistical and machine learning models were 0.63, 0.68, 0.69, and 0.72, 0.69, 0.73, respectively, when using event-based analysis. AUCs decreased with increasing disease severity for all predictions. Conclusions: cp-RNFL and GC-IPL similarly predicted VF worsening overall, but cp-RNFL performed best in early glaucoma stages and GC-IPL in later stages. Combining both did not enhance detection significantly. Translational Relevance: cp-RNFL best predicted trend-based 24-2 VF progression in early-stage disease, while GC-IPL best predicted progression in late-stage disease. Combining both features led to minimal improvement in predicting progression.

Myoferlin: A Potential Marker of Response to Radiation Therapy and Survival in Locally Advanced Rectal Cancer.

PURPOSE: Patients with locally advanced rectal cancer often require neoadjuvant chemoradiation therapy to downstage the disease, but the response is variable with no predictive biomarkers. We have previously revealed through proteomic profiling that myoferlin is associated with response to radiation therapy. The aims of this study were to further validate this finding and explore the potential for myoferlin to act as a prognostic and/or therapeutic target. METHODS AND MATERIALS: Immunohistochemical analysis of a tissue microarray (TMA) for 111 patients was used to validate the initial proteomic findings. Manipulation of myoferlin was achieved using small interfering RNA, a small molecular inhibitor (wj460), and a CRISPR-Cas9 knockout cell line. Radiosensitization after treatment was assessed using 2-dimensional clonogenic assays, 3-dimensional spheroid models, and patient-derived organoids. Underlying mechanisms were investigated using electrophoresis, immunofluorescence, and immunoblotting. RESULTS: Analysis of both the diagnostic biopsy and tumor resection samples confirmed that low myoferlin expression correlated with a good response to neoadjuvant long-course chemoradiation therapy. High myoferlin expression was associated with spread to local lymph nodes and worse 5-year survival (P = .01; hazard ratio, 3.5; 95% CI, 1.27-10.04). This was externally validated using the Stratification in Colorectal Cancer database. Quantification of myoferlin using immunoblotting in immortalized colorectal cancer cell lines and organoids demonstrated that high myoferlin expression was associated with increased radioresistance. Biological and pharmacologic manipulation of myoferlin resulted in significantly increased radiosensitivity across all cell lines in 2-dimensional and 3-dimensional models. After irradiation, myoferlin knockdown cells had a significantly impaired ability to repair DNA double-strand breaks. This appeared to be mediated via nonhomologous end-joining. CONCLUSIONS: We have confirmed that high expression of myoferlin in rectal cancer is associated with poor response to neoadjuvant therapy and worse long-term survival. Furthermore, the manipulation of myoferlin led to increased radiosensitivity in vitro. This suggests that myoferlin could be targeted to enhance the sensitivity of patients with rectal cancer to radiation therapy, and further work is required.

Changes in an enzyme ensemble during catalysis observed by high-resolution XFEL crystallography.

Enzymes populate ensembles of structures necessary for catalysis that are difficult to experimentally characterize. We use time-resolved mix-and-inject serial crystallography at an x-ray free electron laser to observe catalysis in a designed mutant isocyanide hydratase (ICH) enzyme that enhances sampling of important minor conformations. The active site exists in a mixture of conformations, and formation of the thioimidate intermediate selects for catalytically competent substates. The influence of cysteine ionization on the ICH ensemble is validated by determining structures of the enzyme at multiple pH values. Large molecular dynamics simulations in crystallo and time-resolved electron density maps show that Asp17 ionizes during catalysis and causes conformational changes that propagate across the dimer, permitting water to enter the active site for intermediate hydrolysis. ICH exhibits a tight coupling between ionization of active site residues and catalysis-activated protein motions, exemplifying a mechanism of electrostatic control of enzyme dynamics.