Prediction of the performance of pre-packed purification columns through machine learning.

Pre-packed columns have been increasingly used in process development and biomanufacturing thanks to their ease of use and consistency. Traditionally, packing quality is predicted through rate models, which require extensive calibration efforts through independent experiments to determine relevant mass transfer and kinetic rate constants. Here we propose machine learning as a complementary predictive tool for column performance. A machine learning algorithm, extreme gradient boosting, was applied to a large data set of packing quality (plate height and asymmetry) for pre-packed columns as a function of quantitative parameters (column length, column diameter, and particle size) and qualitative attributes (backbone and functional mode). The machine learning model offered excellent predictive capabilities for the plate height and the asymmetry (90 and 93%, respectively), with packing quality strongly influenced by backbone (∼70% relative importance) and functional mode (∼15% relative importance), well above all other quantitative column parameters. The results highlight the ability of machine learning to provide reliable predictions of column performance from simple, generic parameters, including strategic qualitative parameters such as backbone and functionality, usually excluded from quantitative considerations. Our results will guide further efforts in column optimization, for example, by focusing on improvements of backbone and functional mode to obtain optimized packings.

Is the routine use of antipseudomonal antibiotics in acutely exacerbated COPD patients indicated: A retrospective analysis in 437 ICU patients.

PURPOSE: Chronic obstructive pulmonary disease (COPD) is a risk factor for acquiring multiple drug resistant bacteria. The main objective of this analysis was to question a beneficial outcome in the routine use of antipseudomonal antibiotics in the empiric treatment of severe AECOPD in Intensive Care Unit patients. MATERIAL AND METHODS: We report a retrospective, observational cohort study in adult patients with severe AECOPD admitted to ICU at a tertiary care university hospital. Antibiotic treatment on admission as well as microbiology samples were analyzed. The influence of SOFA score at admission, age, sex and antibiotic choice upon survival was investigated by multivariable analysis. RESULTS: 437 patients were included. Mean age was 68 years (±10), 46.5% were female. 271/437 patients (62%) were initially treated with antibiotics covering Pseudomonas aeruginosa. Overall, positive microbiology samples were found in 107 patients (24.5%). P. aeruginosa was only found in 3.7%. There was no significant difference in 30-day ICU mortality after adjusting for age, sex and severity of illness (20.4% ± 11.6 in patients with Pseudomonas inactive antibiotics versus 29.3% ± 10.8 in patients with PAA, p=0.113). CONCLUSIONS: Empiric use of antipseudomonal antibiotics did not result in improved ICU survival in this retrospective analysis.

PFAS soil and groundwater contamination via industrial airborne emission and land deposition in SW Vermont and Eastern New York State, USA.

In order to understand the extent to which airborne PFAS emission can impact soil and groundwater, we conducted a sampling campaign in areas of conserved forest lands near Bennington, VT/Hoosick Falls, NY. This has been home to sources of PFAS air-emissions from Teflon-coating operations for over 50 years. Since 2015, the Vermont and New York Departments of Environmental Conservation have documented ∼1200 residential wells and two municipal water systems across a 200 km2 area contaminated with perfluorooctanoic acid (PFOA). Given the large areal extent of the plume, and the fact that much of the contaminated area lies up-gradient and across rivers from manufactures, we seek to determine if groundwater contamination could have resulted primarily from air-emission, land deposition, and subsequent leaching to infiltrating groundwater. Sampling of soils and groundwater in the Green Mountain National Forest (GMNF) downwind of factories shows that both soil and groundwater PFOA contamination extend uninterrupted from inhabited areas into conserved forest lands. Groundwater springs and seeps in the GMNF located 8 km downwind, but >300 meters vertically above factories, contain up to 100 ppt PFOA. Our results indicate that air-emitted PFAS can contaminate groundwater and soil in areas outside of those normally considered down-gradient of a source with respect to regional groundwater flow.

Establishment of an extracorporeal cardio-pulmonary resuscitation program in Berlin - outcomes of 254 patients with refractory circulatory arrest.

OBJECTIVE: Optimal management of out of hospital circulatory arrest (OHCA) remains challenging, in particular in patients who do not develop rapid return of spontaneous circulation (ROSC). Extracorporeal cardiopulmonary resuscitation (eCPR) can be a life-saving bridging procedure. However its requirements and feasibility of implementation in patients with OHCA, appropriate inclusion criteria and achievable outcomes remain poorly defined. DESIGN: Prospective cohort study. SETTING: Tertiary referral university hospital center. PATIENTS: Here we report on characteristics, course and outcomes on the first consecutive 254 patients admitted between August 2014 and December 2017. INTERVENTION: eCPR program for OHCA. MESUREMENTS AND MAIN RESULTS: A structured clinical pathway was designed and implemented as 24/7 eCPR service at the Charité in Berlin. In total, 254 patients were transferred with ongoing CPR, including automated chest compression, of which 30 showed or developed ROSC after admission. Following hospital admission predefined in- and exclusion criteria for eCPR were checked; in the remaining 224, 126 were considered as eligible for eCPR. State of the art postresuscitation therapy was applied and prognostication of neurological outcome was performed according to a standardized protocol. Eighteen patients survived, with a good neurological outcome (cerebral performance category (CPC) 1 or 2) in 15 patients. Compared to non-survivors survivors had significantly shorter time between collaps and start of eCPR (58 min (IQR 12-85) vs. 90 min (IQR 74-114), p = 0.01), lower lactate levels on admission (95 mg/dL (IQR 44-130) vs. 143 mg/dL (IQR 111-178), p <  0.05), and less severe acidosis on admission (pH 7.2 (IQR 7.15-7.4) vs. 7.0 (IQR6.9-7.2), p <  0.05). Binary logistic regression analysis identified latency to eCPR and low pH as independent predictors for mortality. CONCLUSION: An eCPR program can be life-saving for a subset of individuals with refractory circulatory arrest, with time to initiation of eCPR being a main determinant of survival.

Dynamic determination of functional liver capacity with the LiMAx test in post-cardiac arrest patients undergoing targeted temperature management-A prospective trial.

BACKGROUND: Transiently increased transaminases is a common finding after cardiac arrest but little is known about the functional liver capacity (LiMAx) during the post-cardiac arrest syndrome and treatment in the intensive care unit (ICU). The aim of this trial was to evaluate liver function capacity in post-cardiac arrest survivors undergoing targeted temperature management (TTM) in ICU. METHODS: Thirty-two post-cardiac arrest survivors were prospectively included with all patients undergoing TTM at 33°C for 24 hours. Blood samples were collected, and LiMAx testing was performed at days 1, 2, 5, and 10 post-cardiac arrest. LiMAx is a non-invasive, in vivo, dynamic breath test determining cytochrome P450 1A2 (CYP1A2) capacity using intravenous (IV) 13 C-methacetin, thus reflecting maximum liver function capacity. Static liver parameters were determined and compared to LiMAx values. RESULTS: A typical pattern of transiently, mildly increased transaminases was demonstrated without fulfilling the criteria for hypoxic hepatitis (HH). CYP1A2 activity was reduced with slow normalization over 10 days (lowest median 48 hours after cardiac arrest: 228.5 (25-75 percentile 105.2-301.7 µg/kg/h, P < .05). Parameters reflecting the liver synthetic function were not impaired, as assessed by, in standard laboratory testing. CONCLUSION: Liver functional capacity is impaired in patients after cardiac arrest undergoing TTM at 33°C. More data are needed to determine if liver functional capacity may add relevant information, especially in the context of pharmacotherapy, to individualize post-cardiac arrest care.

Elimination of glutamate using CRRT for 72 h in patients with post-cardiac arrest syndrome: A randomized clinical pilot trial.

AIM: Glutamine and glutamate are major mediators of secondary brain cell death during post-cardiac arrest syndrome. As there is an equilibrium between brain tissue and plasma concentrations of glutamine and glutamate, their elimination from systemic circulation by extracorporeal blood purification may ultimately lead to reduced secondary cell death in the brain. We hypothesized that systemic glutamine and glutamate can be significantly reduced by continuous venovenous hemodiafiltration (CVVHDF). METHODS: This was a prospective, randomized clinical trial in post cardiac-arrest survivors evaluating standard of care or additional CVVHDF over 72 h immediately after admission. Glutamine and glutamate plasma concentrations were analyzed at eight time points in both groups. Primary endpoint was reduction of glutamine and glutamate plasma concentrations. The trial has been registered at clinical trial.gov (NCT02963298). RESULTS: In total, 41 patients were randomized over a period of 12 months (control n = 21, CVVHDF n = 20). The primary aim reduction of glutamine and glutamate plasma concentrations by CVVHDF, was not achieved; both groups-maintained concentrations within a normal range over the study period (glutamate: 4.7-11.1 mg/dL; glutamine: 0.2-3.7 mg/dL). However, post-filter concentrations of glutamine and glutamate in CRRT patients were significantly decreased as compared to pre-filter concentrations (glutamate: pre-filter median 8.85 mg/dL IQR 7.1-9.6; post-filter 0.95 mg/dL IQR 0.5-2; p < 0.001; glutamine: pre-filter 0.7 mg/dL IQR 0.6-1; post-filter 0.2 mg/dL IQR 0-0.2; p < 0.001). CONCLUSION: In this trial, CVVHDF was not able to statistically significantly lower systemic plasma glutamine and glutamate levels. Post-cardiac arrest patients had plasma glutamine and glutamate levels within the normal range.

Influence of core body temperature on Tryptophan metabolism, kynurenines, and estimated IDO activity in critically ill patients receiving target temperature management following cardiac arrest.

BACKGROUND/AIMS: Temperature control improves neurological prognosis in comatose cardiac arrest (CA) survivors. Previous reports demonstrate that most affected patients show signs of significant systemic inflammation. In an effort to better characterize potential temperature-related effects on key inflammatory pathways, we investigate the course of Tryptophan (Trp) levels, Tryptophan catabolites (including kynurenines) and indoleamine-2,3-dioxygenase (IDO)-activity in post CA patients. MATERIAL/METHODS: In an observational blinded endpoint analysis, a total of n=270 serial samples from 20 post CA patients (63.1±16.6 yrs., 45% shockable rhythm, mean time to return of spontaneous circulation (ROSC) 26.6±16.0min) treated with target temperature management (TTM) were analyzed. Core body temperatures, course of Trp, Trp catabolites (incl. kynurenines), and estimated IDO-activity were followed up for a maximum of 7 days after ROSC. Patients were followed up until hospital discharge or death and functional outcome was recorded. RESULTS: Over the 7-day observational interval, marked changes in Trp serum levels and IDO-activity were noted. In general, Trp serum levels but not IDO-activity seemed to parallel with the course of core body temperature. In explorative analyses, a correlation of Trp (rho=0.271 (95%-CI: 0.16-0.38, p<0.0001) and IDO-activity (rho=-0.155, 95%-CI: -0.27 to -0.037, p=0.01) with core body temperature was observed. Linear mixed effect models revealed a positive significant association of core body temperature with Trp serum levels (Likelihood ratio test χ(2)=6.35, p=0.012). In patients with good (vs. unfavorable) outcome, a tendency toward higher Trp serum levels, lower IDO-activity, and lower Kynurenic acid levels was noted. CONCLUSIONS: We observed significant changes in Trp catabolism and IDO-activity that appeared temperature associated in post CA patients. Under hypothermia, decreased serum levels of Trp and increased IDO-activity were noted. We speculate from our data that IDO-induction during hypothermia contributes to the previously described increased susceptibility to infection or sepsis under reduced temperatures.

Good neurological outcome despite very low regional cerebral oxygen saturation during resuscitation--a prospective preclinical trial in 29 patients.

BACKGROUND: Noninvasive regional cerebral oxygen saturation (rSO2) measurement using near-infrared spectroscopy (NIRS) might inform on extent and duration of cerebral hypoxia during cardiopulmonary resuscitation (CPR). This information may be used to guide resuscitation efforts and may carry relevant early prognostic information. METHODS: We prospectively investigated non-traumatic out-of-hospital cardiac arrest (OHCA) patients on scene. NIRS was started either during CPR or shortly after (<2 min) return of spontaneous circulation (ROSC) by emergency medical service (EMS). Outcome was determined at intensive care unit (ICU) discharge and 6 months after cardiac arrest. RESULTS: A total of 29 OHCA patients were included. In 23 patients NIRS was started during CPR and in 6 patients immediately after ROSC. 18 (62.1%) patients did not reach ROSC. Initial rSO2 during CPR was very low (<50% in all 23 patients, < 30% in 19 of 23 patients) with no significant difference between patients achieving ROSC and those who did not. Of five patients with ROSC, in whom NIRS was recorded during CPR, two reached a good six-months outcome (initial rSO2 22%) and three died during the ICU stay (initial rSO2 15, 16 and 46%). In six patients with NIRS started immediately after ROSC (<2 min), rSO2 was substantially higher (54-85 %) than in patients during CPR (p = 0.006). DISCUSSION AND CONCLUSION: Initial frontal brain rSO2 determined by NIRS during CPR was generally very low and recovered rapidly after ROSC. Very low initial rSO2 during CPR was compatible with good neurological outcome in our limited cohort of patients. Further studies are needed to assess in larger cohorts and more detail the implications of very low initial rSO2 during CPR on scene.

Clopidogrel pharmacokinetics and pharmacodynamics in out-of-hospital cardiac arrest patients with acute coronary syndrome undergoing target temperature management.

BACKGROUND: Target temperature management (TTM) after cardiac arrest (CA) improves outcome in patients with acute coronary syndrome (ACS). Previous data point to an interaction between hypothermia and drug metabolism, potentially impacting on platelet function in patients on antiplatelet therapy. PURPOSE: To compare clopidogrel metabolism and platelet function in clopidogrel naïve ACS patients treated with TTM (33°C, n=15) and in ACS patients (troponin positive) without TTM (n=18). METHODS: Platelet function was measured by multiple electrode platelet aggregometry (MEA), light transmittance aggregometry (LTA) and VASP analysis before and after administration of a 600mg clopidogrel loading dose. Plasma levels of clopidogrel and its metabolites were measured. All patients were screened for CYP2C19*2 polymorphism and scheduled for PCI. TTM was carried out for 24h at a target temperature of 33°C using a computer feedback surface cooling device in cardiac arrest patients. RESULTS: Plasma concentration of clopidogrel and metabolites was lower in the TTM group after 2 and 4h, respectively (all p<0.005 vs. controls), and platelet function tests revealed an attenuated response to clopidogrel with respect to baseline platelet activity in the TTM group. This was significant for MEA, LTA and VASP analysis (all p<0.05). Moreover, there was no significant difference in genotype and platelet function determined ex vivo at 33 or 37°C, respectively. CONCLUSION: Inhibition of platelet function is significantly lessened in TTM at 33°C, likely due to reduced clopidogrel absorption. Patients with TTM might thus have a higher risk for further cardiovascular events despite antiplatelet therapy with clopidogrel.

Therapeutic temperature management after cardiac arrest and the risk of bleeding: systematic review and meta-analysis.

AIM: Prognosis after cardiac arrest in the era of modern critical care is still poor with a high mortality of approximately 90%. Around 30% of the survivors have neurological impairments. Targeted temperature management (TTM) is the only treatment option which can improve mortality and neurological outcome. It is so far unclear if bleeding complications occur more often in patients undergoing TTM treatment. METHODS: We conducted a systematic literature research in September 2013 including three major databases i.e. MEDLINE, EMBASE and CENTRAL. All studies were rated in respect to the ILCOR Guidelines and concerning their level of evidence and quality. We then performed a meta-analysis on bleeding disposition under TTM. RESULTS: We initially found 941 studies out of which 34 matched our requirements and were thus included in our overview. Five studies including 599 patients were summarized in a meta-analysis concerning bleeding complications of all severities. There was a trend toward higher bleeding in patients treated with TTM (RR: 1.30, 95% CI: 0.97-1.74) which did not reach significance (p=0.085). Seven studies with an overall 599 patients were included in our meta-analysis on bleeding requiring transfusion. There was no significant difference in the incidence of severe bleeding with a risk ratio of 0.97 (95% CI: 0.61-1.56, p=0.909). CONCLUSIONS: The data included in our meta-analysis indicate that, concerning the risk of bleeding, TTM is a safe method for patients after cardiac arrest. We did not observe a significantly higher risk for bleeding in patients undergoing TTM.

Natural variability in species-specific vocalizations constrains behavior and neural activity.

A listener's capacity to discriminate between sounds is related to the amount of acoustic variability that exists between these sounds. However, a full understanding of how this natural variability impacts neural activity and behavior is lacking. Here, we tested monkeys' ability to discriminate between different utterances of vocalizations from the same acoustic class (i.e., coos and grunts), while neural activity was simultaneously recorded in the anterolateral belt region (AL) of the auditory cortex, a brain region that is a part of a pathway that mediates auditory perception. Monkeys could discriminate between coos better than they could discriminate between grunts. We also found AL activity was more informative about different coos than different grunts. This difference could be attributed, in part, to our finding that coos had more acoustic variability than grunts. Thus, intrinsic acoustic variability constrained the discriminability of AL spike trains and the ability of rhesus monkeys to discriminate between vocalizations.

Serial plasma choline measurements after cardiac arrest in patients undergoing mild therapeutic hypothermia: a prospective observational pilot trial.

OBJECTIVE: Choline is related to phospholipid metabolism and is a marker for global ischaemia with a small reference range in healthy volunteers. The aim of our study was to characterize the early kinetics of plasma free choline in patients after cardiac arrest. Additionally, we investigated the potential of plasma free choline to predict neurological outcome. METHODS: Twenty patients admitted to our medical intensive care unit were included in this prospective, observational trial. All patients were enrolled between May 2010 and May 2011. They received post cardiac arrest treatment including mild therapeutic hypothermia which was initiated with a combination of cold fluid and a feedback surface cooling device according to current guidelines. Sixteen blood samples per patient were analysed for plasma free choline levels within the first week after resuscitation. Choline was detected by liquid chromatography-tandem mass spectrometry. RESULTS: Most patients showed elevated choline levels on admission (median 14.8 µmol/L; interquartile range; IQR 9.9-20.1) which subsequently decreased. 48 hours after cardiac arrest choline levels in all patients reached subnormal levels at a median of 4.0 µmol/L (IQR 3-4.9; p = 0.001). Subsequently, choline levels normalized within seven days. There was no significant difference in choline levels when groups were analyzed in relation to neurological outcome. CONCLUSIONS: Our data indicate a choline deficiency in the early postresucitation phase. This could potentially result in impaired cell membrane recovery. The detailed characterization of the early choline time course may aid in planning of choline supplementation trials. In a limited number of patients, choline was not promising as a biomarker for outcome prediction.

Knowing too little or too much: the effects of familiarity with a co-performer's part on interpersonal coordination in musical ensembles.

Expert ensemble musicians produce exquisitely coordinated sounds, but rehearsal is typically required to do so. Ensemble coordination may thus be influenced by the degree to which individuals are familiar with each other's parts. Such familiarity may affect the ability to predict and synchronize with co-performers' actions. Internal models related to action simulation and anticipatory musical imagery may be affected by knowledge of (1) the musical structure of a co-performer's part (e.g., in terms of its rhythm and phrase structure) and/or (2) the co-performer's idiosyncratic playing style (e.g., expressive micro-timing variations). The current study investigated the effects of familiarity on interpersonal coordination in piano duos. Skilled pianists were required to play several duets with different partners. One condition included duets for which co-performers had previously practiced both parts, while another condition included duets for which each performer had practiced only their own part. Each piece was recorded six times without joint rehearsal or visual contact to examine the effects of increasing familiarity. Interpersonal coordination was quantified by measuring asynchronies between pianists' keystroke timing and the correlation of their body (head and torso) movements, which were recorded with a motion capture system. The results suggest that familiarity with a co-performer's part, in the absence of familiarity with their playing style, engenders predictions about micro-timing variations that are based instead upon one's own playing style, leading to a mismatch between predictions and actual events at short timescales. Predictions at longer timescales-that is, those related to musical measures and phrases, and reflected in head movements and body sway-are, however, facilitated by familiarity with the structure of a co-performer's part. These findings point to a dissociation between interpersonal coordination at the level of keystrokes and body movements.

A precluding but not ensuring role of entrained low-frequency oscillations for auditory perception.

Oscillatory activity in sensory cortices reflects changes in local excitation-inhibition balance, and recent work suggests that phase signatures of ongoing oscillations predict the perceptual detection of subsequent stimuli. Low-frequency oscillations are also entrained by dynamic natural scenes, suggesting that the chance of detecting a brief target depends on the relative timing of this to the entrained rhythm. We tested this hypothesis in humans by implementing a cocktail-party-like scenario requiring subjects to detect a target embedded in a cacophony of background sounds. Using EEG to measure auditory cortical oscillations, we find that the chance of target detection systematically depends on both power and phase of theta-band (2-6 Hz) but not alpha-band (8-12 Hz) oscillations before target. Detection rates were higher and responses faster when oscillatory power was low and both detection rate and response speed were modulated by phase. Intriguingly, the phase dependency was stronger for miss than for hit trials, suggesting that phase has a inhibiting but not ensuring role for detection. Entrainment of theta range oscillations prominently occurs during the processing of attended complex stimuli, such as vocalizations and speech. Our results demonstrate that this entrainment to attended sensory environments may have negative effects on the detection of individual tokens within the environment, and they support the notion that specific phase ranges of cortical oscillations act as gatekeepers for perception.

Incoherent photon conversion in selectively infiltrated hollow-core photonic crystal fibers for single photon generation in the near infrared.

At present, there exist a number of on-demand single photon sources with high emission rates and stability even at room temperature. However, their emission wavelength is restricted to specific transitions in single quantum emitters. Single photon generation in the near infrared, possibly within the telecom band, though most urgently needed, is particularly crucial. In this paper, we suggest an experimental method to convert visible single photons from a defect center in diamond to the near infrared. The conversion relies on efficient absorption by colloidal quantum dots and subsequent Stokes-shifted emission. The desired target wavelength can be chosen almost arbitrarily by selecting quantum dots with a suitable emission spectrum. A hollow core photonic crystal fiber selectively filled with a solution of quantum dots was used to achieve at the same time a single photon absorption probability of near unity and a very high re-collection efficiency of Stokes-shifted fluorescence (theoretically estimated to be 26%). A total conversion efficiency of light of 0.1% is achieved. Experimental strategies to significantly enhance this number are presented.