Improved multifidelity Monte Carlo estimators based on normalizing flows and dimensionality reduction techniques.

We study the problem of multifidelity uncertainty propagation for computationally expensive models. In particular, we consider the general setting where the high-fidelity and low-fidelity models have a dissimilar parameterization both in terms of number of random inputs and their probability distributions, which can be either known in closed form or provided through samples. We derive novel multifidelity Monte Carlo estimators which rely on a shared subspace between the high-fidelity and low-fidelity models where the parameters follow the same probability distribution, i.e., a standard Gaussian. We build the shared space employing normalizing flows to map different probability distributions into a common one, together with linear and nonlinear dimensionality reduction techniques, active subspaces and autoencoders, respectively, which capture the subspaces where the models vary the most. We then compose the existing low-fidelity model with these transformations and construct modified models with an increased correlation with the high-fidelity model, which therefore yield multifidelity estimators with reduced variance. A series of numerical experiments illustrate the properties and advantages of our approaches.

A probabilistic neural twin for treatment planning in peripheral pulmonary artery stenosis.

The substantial computational cost of high-fidelity models in numerical hemodynamics has, so far, relegated their use mainly to offline treatment planning. New breakthroughs in data-driven architectures and optimization techniques for fast surrogate modeling provide an exciting opportunity to overcome these limitations, enabling the use of such technology for time-critical decisions. We discuss an application to the repair of multiple stenosis in peripheral pulmonary artery disease through either transcatheter pulmonary artery rehabilitation or surgery, where it is of interest to achieve desired pressures and flows at specific locations in the pulmonary artery tree, while minimizing the risk for the patient. Since different degrees of success can be achieved in practice during treatment, we formulate the problem in probability, and solve it through a sample-based approach. We propose a new offline-online pipeline for probabilistic real-time treatment planning which combines offline assimilation of boundary conditions, model reduction, and training dataset generation with online estimation of marginal probabilities, possibly conditioned on the degree of augmentation observed in already repaired lesions. Moreover, we propose a new approach for the parametrization of arbitrarily shaped vascular repairs through iterative corrections of a zero-dimensional approximant. We demonstrate this pipeline for a diseased model of the pulmonary artery tree available through the Vascular Model Repository.

Frustrated Total Internal Reflection Measurement System for Pilot Inceptor Grip Pressure.

Sensing the interaction between the pilot and the control inceptors can provide important information about the pilot's activity during flight, potentially enabling the objective measurement of the pilot workload, the application of preventive actions against loss of situational awareness, and the identification of the insurgence of adverse couplings with the vehicle dynamics. This work presents an innovative pressure-sensing device developed to be seamlessly integrated into the grips of conventional aircraft control inceptors. The sensor, based on frustrated total internal reflection of light, is composed of low-cost elements and can be easily manufactured to be applicable to different hand pressure ranges. The characteristics of the sensor are first demonstrated in laboratory calibration tests. Subsequently, applications in flight simulator testing are presented, focusing on the objective representation of the pilot's instantaneous workload.

Impact of a newly established expert clinical pharmacological advice programme based on therapeutic drug monitoring results in tailoring antimicrobial therapy hospital-wide in a tertiary university hospital: Findings after the first year of implementation.

OBJECTIVES: Therapeutic drug monitoring (TDM) may be helpful in tailoring antimicrobial treatment, and expert interpretation of the results may make it more clinically useful. METHODS: This study aimed to assess retrospectively the first-year impact (July 2021 to June 2022) of a newly established expert clinical pharmacological advice (ECPA) programme based on TDM results in tailoring therapy with 18 antimicrobials hospital-wide in a tertiary university hospital. All patients having ≥1 ECPA were grouped in five cohorts [haematology, intensive care unit (ICU), paediatrics, medical wards and surgical wards]. Four indicators of performance were identified: total ECPAs; total ECPAs recommending dosing adjustments/total ECPAs both at first and at subsequent assessments; and turnaround time (TAT) of ECPAs, defined as optimal (<12 h), quasi-optimal (12-24 h), acceptable (24-48 h) or suboptimal (>48 h). RESULTS: A total of 8484 ECPAs were provided for tailoring treatment in 2961 patients, mostly admitted in the ICU (34.1%) and medical wards (32.0%). The proportion of ECPAs recommending dosing adjustments was >40% at first assessment (40.9% haematology; 62.9% ICU; 53.9% paediatrics; 59.1% medical wards; and 59.7% surgical wards), and decreased consistently at subsequent TDM assessments (20.7% haematology; 40.6% ICU; 37.4% paediatrics; 32.9% medical wards; and 29.2% surgical wards). The overall median TAT of the ECPAs was optimal (8.11 h). CONCLUSION: The TDM-guided ECPA programme was successful in tailoring treatment with a wide panel of antimicrobials hospital-wide. Expert interpretation by medical clinical pharmacologists, short TATs, and strict interaction with infectious diseases consultants and clinicians were crucial in achieving this.

Impact of Inflammation on Voriconazole Exposure in Critically ill Patients Affected by Probable COVID-19-Associated Pulmonary Aspergillosis.

(1) Background: To explore the impact of the degree of inflammation on voriconazole exposure in critically ill patients affected by COVID-associated pulmonary aspergillosis (CAPA); (2) Methods: Critically ill patients receiving TDM-guided voriconazole for the management of proven or probable CAPA between January 2021 and December 2022 were included. The concentration/dose ratio (C/D) was used as a surrogate marker of voriconazole total clearance. A receiving operating characteristic (ROC) curve analysis was performed by using C-reactive protein (CRP) or procalcitonin (PCT) values as the test variable and voriconazole C/D ratio > 0.375 (equivalent to a trough concentration [Cmin] value of 3 mg/L normalized to the maintenance dose of 8 mg/kg/day) as the state variable. Area under the curve (AUC) and 95% confidence interval (CI) were calculated; (3) Results: Overall, 50 patients were included. The median average voriconazole Cmin was 2.47 (1.75-3.33) mg/L. The median (IQR) voriconazole concentration/dose ratio (C/D) was 0.29 (0.14-0.46). A CRP value > 11.46 mg/dL was associated with the achievement of voriconazole Cmin > 3 mg/L, with an AUC of 0.667 (95% CI 0.593-0.735; p < 0.001). A PCT value > 0.3 ng/mL was associated with the attainment of voriconazole Cmin > 3 mg/L (AUC 0.651; 95% CI 0.572-0.725; p = 0.0015). (4) Conclusions: Our findings suggest that in critically ill patients with CAPA, CRP and PCT values above the identified thresholds may cause the downregulation of voriconazole metabolism and favor voriconazole overexposure, leading to potentially toxic concentrations.

Extracorporeal CO 2 Removal During Renal Replacement Therapy to Allow Lung-Protective Ventilation in Patients With COVID-19-Associated Acute Respiratory Distress Syndrome.

The aim of this retrospective multicenter observational study is to test the feasibility and safety of a combined extracorporeal CO 2 removal (ECCO 2 R) plus renal replacement therapy (RRT) system to use an ultraprotective ventilator setting while maintaining (1) an effective support of renal function and (2) values of pH within the physiologic limits in a cohort of coronavirus infectious disease 2019 (COVID-19) patients. Among COVID-19 patients admitted to the intensive care unit of 9 participating hospitals, 27 patients with acute respiratory distress syndrome (ARDS) and acute kidney injury (AKI) requiring invasive mechanical ventilation undergoing ECCO 2 R-plus-RRT treatment were included in the analysis. The treatment allowed to reduce V T from 6.0 ± 0.6 mL/kg at baseline to 4.8 ± 0.8, 4.6 ± 1.0, and 4.3 ± 0.3 mL/kg, driving pressure (ΔP) from 19.8 ± 2.5 cm H 2 O to 14.8 ± 3.6, 14.38 ± 4.1 and 10.2 ± 1.6 cm H 2 O after 24 hours, 48 hours, and at discontinuation of ECCO 2 R-plus-RRT (T3), respectively ( p < 0.001). PaCO 2 and pH remained stable. Plasma creatinine decreased over the study period from 3.30 ± 1.27 to 1.90 ± 1.30 and 1.27 ± 0.90 mg/dL after 24 and 48 hours of treatment, respectively ( p < 0.01). No patient-related events associated with the extracorporeal system were reported. These data show that in patients with COVID-19-induced ARDS and AKI, ECCO 2 R-plus-RRT is effective in allowing ultraprotective ventilator settings while maintaining an effective support of renal function and values of pH within physiologic limits.

Multibody analysis and soft tissue strength refute supersonic dinosaur tail.

Sauropod dinosaurs are well known for their massive sizes and long necks and tails. Among sauropods, flagellicaudatan dinosaurs are characterized by extreme tail elongation, which has led to hypotheses regarding tail function, often compared to a whip. Here, we analyse the dynamics of motion of a 3D model of an apatosaurine flagellicaudatan tail using multibody simulation and quantify the stress-bearing capabilities of the associated soft tissues. Such an elongated and slender structure would allow achieving tip velocities in the order of 30 m/s, or 100 km/h, far slower than the speed of sound, due to the combined effect of friction of the musculature and articulations, as well as aerodynamic drag. The material properties of the skin, tendons, and ligaments also support such evidence, proving that in life, the tail would not have withstood the stresses imposed by travelling at the speed of sound, irrespective of the conjectural 'popper', a hypothetical soft tissue structure analogue to the terminal portion of a bullwhip able to surpass the speed of sound.

Laser-written vapor cells for chip-scale atomic sensing and spectroscopy.

We report the fabrication of alkali-metal vapor cells using femtosecond laser machining. This laser-written vapor-cell (LWVC) technology allows arbitrarily-shaped 3D interior volumes and has potential for integration with photonic structures and optical components. We use non-evaporable getters both to dispense rubidium and to absorb buffer gas. This enables us to produce cells with sub-atmospheric buffer gas pressures without vacuum apparatus. We demonstrate sub-Doppler saturated absorption spectroscopy and single beam optical magnetometry with a single LWVC. The LWVC technology may find application in miniaturized atomic quantum sensors and frequency references.

Relationship between Pharmacokinetic/Pharmacodynamic Target Attainment and Microbiological Outcome in Critically Ill COVID-19 Patients with Documented Gram-Negative Superinfections Treated with TDM-Guided Continuous-Infusion Meropenem.

Objectives: The objective of this study was to explore the relationship between pharmacokinetic/pharmacodynamic (PK/PD) target attainment of continuous-infusion (CI) meropenem and microbiological outcome in critical COVID-19 patients with documented Gram-negative superinfections. Methods: Patients receiving CI meropenem for documented Gram-negative infections at the COVID ICU of the IRCCS Azienda Ospedaliero-Universitaria di Bologna and undergoing therapeutic drug monitoring from January 2021 to February 2022 were retrospectively assessed. Average steady-state meropenem concentrations (Css) were calculated and the Css/MIC ratio was selected as a pharmacodynamic parameter of meropenem efficacy. The Css/MIC ratio was defined as optimal if ≥4, quasi-optimal if between 1 and 4, and suboptimal if <1. The relationship between Css/MIC and microbiological outcome was assessed. Results: Overall, 43 critical COVID-19 patients with documented Gram-negative infections were retrieved. Combination therapy was implemented in 26 cases. Css/MIC ratios were optimal in 27 (62.8%), quasi-optimal in 7 (16.3%), and suboptimal in 9 cases (20.9%). Microbiological failure occurred in 21 patients (48.8%), with no difference between monotherapy and combination therapy (43.8% vs. 53.8%; p = 0.53). The microbiological failure rate was significantly lower in patients with an optimal Css/MIC ratio compared to those with a quasi-optimal or suboptimal Css/MIC ratio (33.3% vs. 75.0%; p = 0.01). Conclusion: Suboptimal attainment of meropenem PK/PD targets may be a major determinant impacting on microbiological failure in critical COVID-19 patients with Gram-negative superinfections.

Eigenfunction martingale estimating functions and filtered data for drift estimation of discretely observed multiscale diffusions.

We propose a novel method for drift estimation of multiscale diffusion processes when a sequence of discrete observations is given. For the Langevin dynamics in a two-scale potential, our approach relies on the eigenvalues and the eigenfunctions of the homogenized dynamics. Our first estimator is derived from a martingale estimating function of the generator of the homogenized diffusion process. However, the unbiasedness of the estimator depends on the rate with which the observations are sampled. We therefore introduce a second estimator which relies also on filtering the data, and we prove that it is asymptotically unbiased independently of the sampling rate. A series of numerical experiments illustrate the reliability and efficiency of our different estimators.

Artificial intelligence-based prediction of transfusion in the intensive care unit in patients with gastrointestinal bleeding.

OBJECTIVE: Gastrointestinal (GI) bleeding commonly requires intensive care unit (ICU) in cases of potentialhaemodynamiccompromise or likely urgent intervention. However, manypatientsadmitted to the ICU stop bleeding and do not require further intervention, including blood transfusion. The present work proposes an artificial intelligence (AI) solution for the prediction of rebleeding in patients with GI bleeding admitted to ICU. METHODS: A machine learning algorithm was trained and tested using two publicly available ICU databases, the Medical Information Mart for Intensive Care V.1.4 database and eICU Collaborative Research Database using freedom from transfusion as a proxy for patients who potentially did not require ICU-level care. Multiple initial observation time frames were explored using readily available data including labs, demographics and clinical parameters for a total of 20 covariates. RESULTS: The optimal model used a 5-hour observation period to achieve an area under the curve of the receiving operating curve (ROC-AUC) of greater than 0.80. The model was robust when tested against both ICU databases with a similar ROC-AUC for all. CONCLUSIONS: The potential disruptive impact of AI in healthcare innovation is acknowledge, but awareness of AI-related risk on healthcare applications and current limitations should be considered before implementation and deployment. The proposed algorithm is not meant to replace but to inform clinical decision making. Prospective clinical trial validation as a triage tool is warranted.

Laparoscopic Incisional and Ventral Hernia Repair with Absorbable Tacks in a Long Term Follow-up: A Retrospective Control Study.

BACKGROUND: Laparoscopic Incisional and Ventral Hernia Repair (LIVHR) is a safe and worldwide accepted procedure performed using absorbable tacks. The aim of the study was to evaluate recurrence rate in a long term follow-up and whether the results of laparoscopic IVH repair in the elderly (≥65 years old) are different with respect to results obtained in younger patients. METHODS: One hundred and twenty-nine consecutive patients (74 women and 55 men, median age 67 years, range = 30-87 years) with ventral (N = 42, 32.5%) or post incisional (N = 87, 67.5%) hernia were enrolled in the study. Patients were divided into two groups according to their age: group A (N = 55, 42.6%) aged <65 years and group B (N = 74, 57.4%) aged ≥65 years. RESULTS: The mean operative time was not significantly different between groups (66.7 ± 37 vs. 74 ± 48.4 min, p = 0.4). To the end of 2016, seven recurrences had occurred (group A = 3, group B = 4, p = 1). Complications occurred in 8 (16%) patients in group A and 21 (28.3%) patients in group B. CONCLUSION: In conclusion, our results confirm that the use of absorbable tacks does not increase recurrence frequency and laparoscopic incisional and ventral repair is a safety procedure also in elderly patients.

Reintervention After Heller Myotomy for Achalasia: Is It Inevitable?

BACKGROUND: Few studies of reintervention after Heller myotomy for achalasia set patients' expectations, assist therapeutic decision making, and direct follow-up. Therefore, we investigated the frequency and type of symptoms and reinterventions after myotomy based on achalasia type. METHODS: From January 2006 to March 2013, 248 patients who had preoperative high-resolution manometry and a timed barium esophagram (TBE) underwent Heller myotomy, 62 (25%) for type I, 162 (65%) for type II, and 24 (10%) for type III achalasia. Postoperative surveillance, including TBE, was performed at 8 weeks, then annually. Median follow-up was 36 months. End points were all symptom types and modes of reintervention, endoscopic or surgical. Reintervention was based on both symptoms and objective TBE measurements. RESULTS: Eventually most patients (169 of 218; 69%) experienced at least one symptom after myotomy. Fifty patients underwent 85 reinterventions, 41 endoscopic only, 4 surgical only, and 5 both. Five-year freedom from reintervention was 62% for type I, 74% for type II, and 87% for type III, most occurring within 6 months, although later in type III. At 5 years, number of reinterventions per 100 patients was 72 for type I, 51 for type II, and 13 for type III. After each reintervention, there was approximately a 50% chance of another within 2 years. CONCLUSIONS: Patients' expectations when undergoing Heller myotomy for achalasia must be that symptoms will only be palliated, and patients who have worse esophageal function-achalasia type I-may require one or more postoperative reinterventions. Thus, we recommend that patients with achalasia have lifelong annual surveillance after Heller myotomy that includes TBE.

Siewert III esophagogastric junction adenocarcinoma: does TNM 8th save us?

Siewert III cancers were classified as esophageal cancers by the TNM 7th edition (TNM7), while being defined as gastric cancers by the new TNM 8th edition (TNM8). Aim of this study was to compare previous and present TNM classifications of Siewert III. From 2000 to 2015, 309 patients with Siewert III adenocarcinoma were treated at ten high-volume centers, belonging to the GIRCG (Italian Research Group for Gastric Cancer). We retrospectively analyzed overall survival according to TNM classifications: gastric TNM8 was compared with either gastric TNM7 or esophageal TNM7. Median number of lymph nodes harvested was 31 (interquartile range 22-44). Agreement between gastric TNM7 and TNM8 was very good (weighted kappa 92.3%, IC 95% 90.3-94.1%). Accordingly, stage migration was observed in 54 of 309 patients (17.5%), with 12 patients upstaged (3.9%) and 42 downstaged (13.6%). Cox models including either gastric TNM7 or TNM8 achieved similar goodness-of-fit and c-index. Differences were much larger, when shifting from esophageal TNM7 to gastric TNM8: the agreement was much lower (weighted kappa 69.1%, 65.2-73.2%), with 196 of 309 patients (63.4%) downstaging. The corresponding Cox model presented the lowest goodness-of-fit and discrimination ability. Gastric TNM7 and TNM8 were largely superimposable, so that stage migration was minor and prognostic significance was similar. At variance, stage migration was substantial when shifting from esophageal TNM7 to TNM8. Moreover, survival models with esophageal TNM7 presented the worst goodness-of-fit and the lowest discrimination ability. This further supports placing Siewert III among gastric cancers, as done in TNM8.

Value of routine timed barium esophagram follow-up in achalasia after myotomy.

OBJECTIVES: The value of routine timed barium esophagram (TBE) in longitudinal follow-up of achalasia after Heller myotomy is unknown. We prospectively prescribed a yearly follow-up TBE. Purposes were to characterize esophageal emptying over time after myotomy, identify preoperative TBE measures associated with follow-up TBE, and characterize follow-up TBE over time in relationship to reintervention. METHODS: From March 1995 to April 2013, 635 patients underwent Heller myotomy for achalasia; 559 had at least 1 follow-up TBE. Temporal trends of 1335 follow-up TBEs in all nonreintervention and reintervention patients were assessed. Multivariable longitudinal analysis identified preoperative TBE measures associated with follow-up TBE. RESULTS: On average, TBE height and width at 1 and 5 minutes decreased approximately 50% and 60%, respectively, at first postoperative follow-up, and remained stable or slightly decreased for up to 5 years. Wider TBE width at 5 minutes was associated with greater follow-up TBE height and width at 1 minute. Of 118 patients undergoing reintervention, 64 (57%) had only 1 reintervention, with follow-up TBE returning to that of nonreintervention patients. Patients whose follow-up TBE remained abnormal underwent a further reintervention, some normalizing on subsequent TBE, and some not. CONCLUSIONS: Follow-up TBE is valuable postmyotomy, particularly if there is substantial esophageal dilatation preoperatively. Follow-up TBE reassures patients with stable or decreasing TBE measures, permitting decreased follow-up intensity. Reintervention should not be considered a myotomy failure, because a successful, single, nonsurgical reintervention often results in long-term successful palliation. More than 1 reintervention requires intensification of TBE follow-up, facilitating treatment planning.

Radical surgery for gastric cancer in octogenarian patients.

To valuate feasibility and results of radical surgery in octogenarian patients with gastric cancer. We collected data on 60 patients that underwent gastrectomy with an R0 resection at our Institution from 2010 to 2015. Patients were divided into two groups: octogenarian (OG) (n = 26), consisting of patients aged 80-89 years, and younger (YG) (n = 34), consisting of patients under 80 years of age. All patients were treated with total or subtotal gastrectomy with lymphadenectomy. A D2-lymphadenectomy was performed in 11 and 24 patients, a D1+ in 5 and 4, a D1 in 8 and 6, and a D0 in 2 and 0 cases in OG and YG respectively. The overall morbidity rate was 42.3% (11/26) in OG and 29.4% (10/34) in YG, while 90-days mortality was observed in four (15.4%) and one (2.9%) patients in OG and YG, respectively. The median hospital stay was 9 days (2-31) and 9.5 days (6-66) in OG and YG, respectively. Gastrectomy with radical resection and limited lymphadenectomy should be recommended for octogenarian patients with good performance status and low co-morbidity.

Siewert III adenocarcinoma: treatment update.

Siewert III cancer, although representing around 40% of EGJ cancers and being the EGJ cancer with worst prognosis, does not have a homogenous treatment, has few dedicated studies, and is often not considered in study protocols. Although staged as an esophageal cancer by the TNM 7th ed., it is considered a gastric cancer by new TNM 8th ed. Our aim was to consolidate the current literature on the indications and treatment options for Siewert III adenocarcinoma. A review of the literature was performed to better delineate treatment indications (according to stage, surgical margins, type of lymphatic spread and lymphadenectomy) and treatment strategy. The treatment approach is strictly dependent on cancer site and nodal diffusion. T1m cancers have insignificant risk of nodal metastases and can be safely treated with endoscopic resections. The risk of nodal metastases increases markedly starting from T1sm cancers and requires surgery with lymphadenectomy. The site of this type of cancer and the nodal diffusion require a total gastrectomy and distal esophagectomy, with 5 cm of clear proximal and distal margins and a D2 abdominal and inferior mediastinal lymphadenectomy. Multimodal treatments are indicated in all locally advanced and node positive cancers. Siewert III cancers are gastric cancers with some peculiarities and require dedicated studies and deserve more consideration in the current literature, especially because their treatment is particularly challenging.

ypN0: Does It Matter How You Get There? Nodal Downstaging in Esophageal Cancer.

BACKGROUND: ypN0 following induction treatment for advanced esophageal cancer improves survival. Importance of how ypN0 is achieved is unknown. This study evaluates survival in "natural" N0 (cN0/ypN0) and "downstaged" N0 (cN+/ypN0) patients. METHODS: Among patients treated with induction treatment and surgery, 83 CT scans were retrieved in digital format and re-evaluated by a radiologist, blinded to pathological nodal status: 28 natural N0, 37 downstaged N0, and 18 ypN+. Impact of N0 classification on survival and associations with survival were identified. RESULTS: Survival varied with ypN: 3-year survival was 84 % for natural N0 patients, 59 % for downstaged N0, and 20 % for ypN+ (p < .001). Compared with natural N0 patients, risk of cancer mortality was 3.8 for downstaged N0 and 7.6 for ypN+ (p = .01). Survival was also stratified by ypT: compared with ypT0 natural N0, who had the best survival, intermediate survival was seen in ypT+ natural N0 [hazard ratio (HR), 1.3] and ypT0 downstaged N0 (HR, 1.8), and poor survival in ypT+ downstaged N0 (HR, 9.5) and ypN+ (HR, 12.0) (p = .026). CONCLUSIONS: Natural N0 and downstaged N0 patients are different clinical entities: downstaging cN+ with induction treatment producing downstaged N0 improves survival only if there is concomitant primary cancer downstaging to ypT0. Intermediate survival is seen in downstaged N0 patients with complete tumor response. Natural N0 patients experience intermediate survival with incomplete response (ypT+). Complete response in natural N0 patients produces the best survival. Means of obtaining ypN0 status matters and requires a complete response for downstaged N0 patients to benefit from induction treatment.