Pulmonary gas exchange evaluated by machine learning: a computer simulation.

Using computer simulation we investigated whether machine learning (ML) analysis of selected ICU monitoring data can quantify pulmonary gas exchange in multi-compartment format. A 21 compartment ventilation/perfusion (V/Q) model of pulmonary blood flow processed 34,551 combinations of cardiac output, hemoglobin concentration, standard P50, base excess, VO2 and VCO2 plus three model-defining parameters: shunt, log SD and mean V/Q. From these inputs the model produced paired arterial blood gases, first with the inspired O2 fraction (FiO2) adjusted to arterial saturation (SaO2) = 0.90, and second with FiO2 increased by 0.1. 'Stacked regressor' ML ensembles were trained/validated on 90% of this dataset. The remainder with shunt, log SD, and mean 'held back' formed the test-set. 'Two-Point' ML estimates of shunt, log SD and mean utilized data from both FiO2 settings. 'Single-Point' estimates used only data from SaO2 = 0.90. From 3454 test gas exchange scenarios, two-point shunt, log SD and mean estimates produced linear regression models versus true values with slopes ~ 1.00, intercepts ~ 0.00 and R2 ~ 1.00. Kernel density and Bland-Altman plots confirmed close agreement. Single-point estimates were less accurate: R2 = 0.77-0.89, slope = 0.991-0.993, intercept = 0.009-0.334. ML applications using blood gas, indirect calorimetry, and cardiac output data can quantify pulmonary gas exchange in terms describing a 20 compartment V/Q model of pulmonary blood flow. High fidelity reports require data from two FiO2 settings.

Single-FiO2 lung modelling with machine learning: a computer simulation incorporating volumetric capnography.

We investigated whether machine learning (ML) analysis of ICU monitoring data incorporating volumetric capnography measurements of mean alveolar PCO2 can partition venous admixture (VenAd) into its shunt and low V/Q components without manipulating the inspired oxygen fraction (FiO2). From a 21-compartment ventilation / perfusion (V/Q) model of pulmonary blood flow we generated blood gas and mean alveolar PCO2 data in simulated scenarios with shunt values from 7.3% to 36.5% and a range of FiO2 settings, indirect calorimetry and cardiac output measurements and acid- base and hemoglobin oxygen affinity conditions. A 'deep learning' ML application, trained and validated solely on single FiO2 bedside monitoring data from 14,736 scenarios, then recovered shunt values in 500 test scenarios with true shunt values 'held back'. ML shunt estimates versus true values (n = 500) produced a linear regression model with slope = 0.987, intercept = -0.001 and R2 = 0.999. Kernel density estimate and error plots confirmed close agreement. With corresponding VenAd values calculated from the same bedside data, low V/Q flow can be reported as VenAd-shunt. ML analysis of blood gas, indirect calorimetry, volumetric capnography and cardiac output measurements can quantify pulmonary oxygenation deficits as percentage shunt flow (V/Q = 0) versus percentage low V/Q flow (V/Q > 0). High fidelity reports are possible from analysis of data collected solely at the operating FiO2.

The experimental evolution of human culture: flexibility, fidelity and environmental instability.

The past 2 Myr have seen both unprecedented environmental instability and the evolution of the human capacity for complex culture. This, along with the observation that cultural evolution occurs faster than genetic evolution, has led to the suggestion that culture is an adaptation to an unstable environment. We test this hypothesis by examining the ability of human social learning to respond to environmental changes. We do this by inserting human participants (n = 4800) into evolutionary simulations with a changing environment while varying the social information available to individuals across five conditions. We find that human social learning shows some signs of adaptation to environmental instability, including critical social learning, the adoption of up-and-coming traits and, unexpectedly, contrariness. However, these are insufficient to avoid significant fitness declines when the environment changes, and many individuals are highly conformist, which exacerbates the fitness effects of environmental change. We conclude that human social learning reflects a compromise between the competing needs for flexibility to accommodate environmental change and fidelity to accurately transmit valuable cultural information.

Nicotine exposure of male mice produces behavioral impairment in multiple generations of descendants.

Use of tobacco products is injurious to health in men and women. However, tobacco use by pregnant women receives greater scrutiny because it can also compromise the health of future generations. More men smoke cigarettes than women. Yet the impact of nicotine use by men upon their descendants has not been as widely scrutinized. We exposed male C57BL/6 mice to nicotine (200 µg/mL in drinking water) for 12 wk and bred the mice with drug-naïve females to produce the F1 generation. Male and female F1 mice were bred with drug-naïve partners to produce the F2 generation. We analyzed spontaneous locomotor activity, working memory, attention, and reversal learning in male and female F1 and F2 mice. Both male and female F1 mice derived from the nicotine-exposed males showed significant increases in spontaneous locomotor activity and significant deficits in reversal learning. The male F1 mice also showed significant deficits in attention, brain monoamine content, and dopamine receptor mRNA expression. Examination of the F2 generation showed that male F2 mice derived from paternally nicotine-exposed female F1 mice had significant deficits in reversal learning. Analysis of epigenetic changes in the spermatozoa of the nicotine-exposed male founders (F0) showed significant changes in global DNA methylation and DNA methylation at promoter regions of the dopamine D2 receptor gene. Our findings show that nicotine exposure of male mice produces behavioral changes in multiple generations of descendants. Nicotine-induced changes in spermatozoal DNA methylation are a plausible mechanism for the transgenerational transmission of the phenotypes. These findings underscore the need to enlarge the current focus of research and public policy targeting nicotine exposure of pregnant mothers by a more equitable focus on nicotine exposure of the mother and the father.

Foraging zebra finches (Taeniopygia guttata) are public information users rather than conformists.

Social learning enables adaptive information acquisition provided that it is not random but selective. To understand species typical decision-making and to trace the evolutionary origins of social learning, the heuristics social learners use need to be identified. Here, we experimentally tested the nature of majority influence in the zebra finch. Subjects simultaneously observed two demonstrator groups differing in relative and absolute numbers (ratios 1 : 2/2 : 4/3 : 3/1 : 5) foraging from two novel food sources (black and white feeders). We find that demonstrator groups influenced observers' feeder choices (social learning), but that zebra finches did not copy the majority of individuals. Instead, observers were influenced by the foraging activity (pecks) of the demonstrators and in an anti-conformist fashion. These results indicate that zebra finches are not conformist, but are public information users.

Hyperlactatemia in diabetic ketoacidosis is common and can be prolonged: lactate time-series from 25 intensive care admissions.

Hyperlactatemia is a documented complication of diabetic ketoacidosis (DKA). Lactate responses during DKA treatment have not been studied and were the focus of this investigation. Blood gas and electrolyte data from 25 DKA admissions to ICU were sequenced over 24 h from the first Emergency Department sample. Hyperlactatemia (> 2 mmol/L) was present in 22 of 25 DKA presentations [mean concentration = 3.2 mmol/L]. In 18 time-series (72%), all concentrations normalized in ≤ 2.6 h (aggregate decay t1/2 = 2.29 h). In the remaining 7 (28%), hyperlactatemia persisted > 12 h. These were females (P = 0.04) with relative anemia (hemoglobin concentrations 131 v 155 g/L; P = 0.004) and lower nadir glucose concentrations (5.2 v 8.0 mmol/L, P = 0.003). Their aggregate glucose decay curve commenced higher (42 mmol/L v 29 mmol/L), descending towards a lower asymptote (8 mmol/L v 11 mmol/L). Tonicity decay showed similar disparities. There was equivalent resolution of metabolic acidosis and similar lengths of stay in both groups. Hyperlactatemia is common in DKA. Resolution is often rapid, but high lactates can persist. Females with high glucose concentrations corrected aggressively are more at risk. Limiting initial hyperglycemia correction to ≥ 11 mmol/L may benefit.

Biased transformation erases traditions sustained by conformist transmission.

Conformist transmission is a cognitively simple decision-making process by which observers are disproportionately likely to follow the majority. It has been studied in multiple species because theory suggests it can create stable cultural variation. However, the current theory assumes that while conformist transmission favours the majority, it is otherwise unbiased and does not systematically transform information, even though such biases are widely documented. Here, we relax this assumption, requiring conformist observers to infer the size of the majority from finite observations of their group mates. Because such inference can be subject to bias, it can lead to the biased transformation of transmitted information. We find that when individuals are biased (even weakly) the capacity of conformist transmission to sustain traditions is reduced and, in many cases, removed entirely. This suggests that the emphasis on conformist transmission as a source of stable cultural variation may be misplaced.

Reducing complexity in acid-base diagnosis - how far should we go?

PURPOSE: To place in context the potential value of isolated plasma strong ion difference (SID) calculations and strong ion gap (SIG) calculations versus suggested cut-down versions such as SIDa adj and the BICgap respectively. METHODS: Stewart's physical chemical approach is seen as a mathematical model of isolated plasma not displacing traditional Copenhagen and Boston approaches. Scanning tools for unmeasured ions based on the Principle of Electrical Neutrality such as the SIG and suggested cut-down versions such as the albumin adjusted anion gap and the BICgap are evaluated for accuracy and clinical usefulness. RESULTS: Plasma SID and abbreviations such as SIDa adj are not independent variables in vivo since they vary with PCO due to Gibbs Donnan ion traffic. They can also exhibit positive and negative bias, and SID values must be partnered with non-volatile weak acid concentrations when evaluating metabolic acid-base status. The BICgap calculation is a cut down version of the SIG fixed for pH 7.4. It includes phosphate but is otherwise similar in form to the albumin corrected anion gap, with similar sensitivity and specificity characteristics. CONCLUSIONS: Clinicians are unlikely to find SID calculations or cut-down versions such as the SIDa adj clinically useful. The albumin corrected anion gap is in current use and easily determined by mental arithmetic from point of care anion gap printouts plus recent plasma albumin measurements. Any slight advantage of the BICgap would be offset by the complexity of its calculation.

A theory limited in scope and evidence.

What promised to be a refreshing addition to cumulative cultural evolution, by moving the focus from cultural transmission to technological innovation, falls flat through a lack of thoroughness, explanatory power, and data. A comprehensive theory of cumulative cultural change must carefully integrate all existing evidence in a cohesive multi-level account. We argue that the manuscript fails to do so convincingly.

Selective Uptake Into Drug Resistant Mammalian Cancer by Cell Penetrating Peptide-Mediated Delivery.

Research over the past decade has identified several of the key limiting features of multidrug resistance (MDR) in cancer therapy applications, such as evolving glycoprotein receptors at the surface of the cell that limit therapeutic uptake, metabolic changes that lead to protection from multidrug resistant mediators which enhance degradation or efflux of therapeutics, and difficulty ensuring retention of intact and functional drugs once endocytosed. Nanoparticles have been demonstrated to be effective delivery vehicles for a plethora of therapeutic agents, and in the case of nucleic acid based agents, they provide protective advantages. Functionalizing cell penetrating peptides, also known as protein transduction domains, onto the surface of fluorescent quantum dots creates a labeled delivery package to investigate the nuances and difficulties of drug transport in MDR cancer cells for potential future clinical applications of diverse nanoparticle-based therapeutic delivery strategies. In this study, eight distinct cell penetrating peptides were used (CAAKA, HSV1-VP22, HIV-TAT, HIV-gp41, Ku-70, hCT(9-32), integrin-ß3, and K-FGF) to examine the different cellular uptake profiles in cancer versus drug resistant melanoma (A375 & A375-R), mesothelioma (MSTO & MSTO-R), and glioma (rat 9L and 9L-R, and human U87 & LN18) cell lines. The results of this study demonstrate that cell penetrating peptide uptake varies with drug resistance status and cell type, likely due to changes in cell surface markers. This study provides insight into developing functional nanoplatform delivery systems in drug resistant cancer models.

A head to head evaluation of 8 biochemical scanning tools for unmeasured ions.

We aimed to evaluate the sensitivity and specificity of 8 biochemical scanning tools in signalling the presence of unmeasured anions. We used blood gas and biochemical data from 15 patients during and after cardio-pulmonary bypass. Sampling time-points were pre-bypass (T1), 2 min post equilibration with priming fluid containing acetate and gluconate anions (T2), late bypass (T3) and 4 h after surgery (T4). We calculated the anion gap (AG), albumin-corrected anion gap (AGc), whole blood base excess (BE) gap, plasma BE gap, standard BE gap and the strong ion gap (SIG), plus 2 new indices-the unmeasured ion index (UIX) and unmeasured plasma anions according to the interstitial, plasma and erythrocyte acid-base model (IPEua). Total measured plasma concentrations of acetate and gluconate [XA] were proxies for unmeasured plasma anions. [XA] values (mmol/L) were 1.41 (0.87) at T1, 11.73 (3.28) at T2, 4.80 (1.49) at T3 and 1.36 (0.73) at T4. Corresponding [albumin] values (g/L) were 32.3 (2.0), 19.8 (2.6), 21.3 (2.5) and 29.1 (2.3) respectively. Only the AG failed to increase significantly at T2 in response to a mean [XA] surge of >10 mEq/L. At an [XA] threshold of 6 mEq/L, areas under receiver -operator characteristic curves in rank order were IPEua and UIX (0.88 and 0.87 respectively), SIG (0.81), AGc (0.79), standard BE gap (0.77), plasma BE gap (0.71), BE gap (0.70) and AG (0.59). Similar ranking hierarchies applied to positive and negative predictive values. We conclude that during acute hemodilution UIX and IPEua are superior to the anion gap (with and without albumin correction) and 4 other indices as scanning tools for unmeasured anions.

Plasma sodium measurements by direct ion selective methods in laboratory and point of care may not be clinically interchangeable.

An estimated 25 % of indirect ion selective electrode (ISE) ICU plasma sodium measurements differ from corresponding direct ISE values by at least 4 mmol/L, the dominant factor being indirect ISE over-estimation driven by hypoproteinemia. Since direct measurements are considered unaffected by protein concentrations, we investigated whether direct ISE plasma sodium measurements in the laboratory and at point of care in ICU show sufficient agreement to be clinically interchangeable. From a 5 year clinical chemistry database, 9910 ICU plasma samples were assessed for agreement between direct ISE sodium measurements in ICU (ABL 700) and in the central laboratory (Vitros Fusion). The relationship between differences in paired plasma sodium measurements (Vitros-ABL) and total plasma protein concentrations was evaluated by generalized estimating equation linear regression. Patients were hypo-proteinemic [mean (SD) total protein concentration 56.9 (9.04) g/L]. Mean (SD) paired Vitros-ABL sodium measurements was -0.087 (1.74) mmol/L, range -14 to +10 mmol/L. Disagreement at ≥|4|mmol/L, ≥|3|mmol/L and ≥|2|mmol/L was present in 409 (4.1 %), 1333 (13.4 %) and 3591 (36.2 %) pairs respectively. Test-retest disagreement estimates within either source alone were substantially lower. Small negative Vitros-ABL differences associated with low plasma protein concentrations were reversed at high protein concentrations. Disagreement between plasma sodium concentrations monitored by two common direct ISE analyzers was substantially less than reported between direct and indirect ISE devices, although a protein influence of low clinical importance persisted. Disagreement was sufficient to jeopardize safe interchangeable interpretation in situations with a low tolerance for imprecision, such as hyponatremia correction.

The development of adaptive conformity in young children: effects of uncertainty and consensus.

Human culture relies on extensive use of social transmission, which must be integrated with independently acquired (i.e. asocial) information for effective decision-making. Formal evolutionary theory predicts that natural selection should favor adaptive learning strategies, including a bias to copy when uncertain, and a bias to disproportionately copy the majority (known as 'conformist transmission'). Although the function and causation of these evolved strategies has been comparatively well studied, little is known of their development. We experimentally investigated the development of the bias to copy-when-uncertain and conformist transmission in children from the ages of 3 to 7, testing predictions derived from theoretical models. Children first attempted to solve a binary-choice quantity discrimination task themselves using asocial information, but were then given the decisions of informants, and an opportunity to revise their answer. We investigated whether children's revised judgments were adaptively contingent on (i) the difficulty of the trial and (ii) the degree of consensus amongst informants. As predicted, older but not younger children copied others more on more difficult trials than on easier trials, even though older children also showed a tendency to stick with their initial, asocial decision. We also found that older children, like adults, were disproportionately receptive to non-total majorities (i.e. were conformist) whereas younger children were receptive only to total (i.e. unanimous) majorities. We conclude that, whilst the mechanism for incorporating social information into decision-making is initially very blunt, across the course of early childhood it converges on the adaptive learning mechanisms observed in adults and predicted by cultural evolutionary theory. A video abstract of this article can be viewed at http://youtu.be/Qb6JINGYqVk.

A gold nanoparticle pentapeptide: gene fusion to induce therapeutic gene expression in mesenchymal stem cells.

Mesenchymal stem cells (MSC) have been identified as having great potential as autologous cell therapeutics to treat traumatic brain injury and spinal injury as well as neuronal and cardiac ischemic events. All future clinical applications of MSC cell therapies must allow the MSC to be harvested, transfected, and induced to express a desired protein or selection of proteins to have medical benefit. For the full potential of MSC cell therapy to be realized, it is desirable to systematically alter the protein expression of therapeutically beneficial biomolecules in harvested MSC cells with high fidelity in a single transfection event. We have developed a delivery platform on the basis of the use of a solid gold nanoparticle that has been surface modified to produce a fusion containing a zwitterionic, pentapeptide designed from Bax inhibiting peptide (Ku70) to enhance cellular uptake and a linearized expression vector to induce enhanced expression of brain-derived neurotrophic factor (BDNF) in rat-derived MSCs. Ku70 is observed to effect >80% transfection following a single treatment of femur bone marrow isolated rat MSCs with efficiencies for the delivery of a 6.6 kbp gene on either a Au nanoparticle (NP) or CdSe/ZnS quantum dot (QD). Gene expression is observed within 4 d by optical measurements, and secretion is observed within 10 d by Western Blot analysis. The combination of being able to selectively engineer the NP, to colocalize biological agents, and to enhance the stability of those agents has provided the strong impetus to utilize this novel class of materials to engineer primary MSCs.

Investigating the effects of social information on spite in an online game.

While humans are highly cooperative, they can also behave spitefully. Yet spite remains understudied. Spite can be normatively driven and while previous experiments have found some evidence that cooperation and punishment may spread via social learning, no experiments have considered the social transmission of spiteful behaviour. Here we present an online experiment where, following an opportunity to earn wealth, we asked participants to choose an action towards an anonymous partner across a full spectrum of social behaviour, from spite to altruism. In accordance with cultural evolutionary theory, participants were presented with social information that varied in source and content. Across six conditions, we informed participants that either the majority or the highest earner had chosen to behave spitefully, neutrally or altruistically. We found an overall tendency towards altruism, but at lower levels among those exposed to spite compared with altruism. We found no difference between social information that came from the majority or the highest earner. Exploratory analysis revealed that participants' earnings negatively correlated with altruistic behaviour. Our results contrast with previous literature that report high rates of spite in experimental samples and a greater propensity for individuals to copy successful individuals over the majority.

The ideal crystalloid - what is 'balanced'?

PURPOSE OF REVIEW: This review explores the contemporary definition of the term 'balanced crystalloid' and outlines optimal design features and their underlying rationale. RECENT FINDINGS: Crystalloid interstitial expansion is unavoidable, but also occurs with colloids when there is endothelial glycocalyx dysfunction. Reduced chloride exposure may lessen kidney dysfunction and injury with a possible mortality benefit. Exact balance from an acid-base perspective is achieved with a crystalloid strong ion difference of 24 mEq/l. This can be done simply by replacing 24 mEq/l of chloride in 0.9% sodium chloride with bicarbonate or organic anion bicarbonate substitutes. Potassium, calcium and magnesium additives are probably unnecessary. Large volumes of mildly hypotonic crystalloids such as lactated Ringer's solution reduce extracellular tonicity in volunteers and increase intracranial pressure in nonbrain-injured experimental animals. A total cation concentration of 154 mmol/l with accompanying anions provides isotonicity. Of the commercial crystalloids, Ringer's acetate solution is close to balanced from both acid-base and tonicity perspectives, and there is little current evidence of acetate toxicity in the context of volume loading, in contrast to renal replacement. SUMMARY: The case for balanced crystalloids is growing but unproven. A large randomized controlled trial of balanced crystalloids versus 0.9% sodium chloride is the next step.

Zinc deficiency regulates hippocampal gene expression and impairs neuronal differentiation.

OBJECTIVES: Proliferating adult stem cells in the subgranular zone of the dentate gyrus have the capacity not only to divide, but also to differentiate into neurons and integrate into the hippocampal circuitry. The present study identifies several hippocampal genes putatively regulated by zinc and tests the hypothesis that zinc deficiency impairs neuronal stem cell differentiation. METHODS: Genes that regulate neurogenic processes were identified using microarray analysis of hippocampal mRNA isolated from adult rats fed zinc-adequate or zinc-deficient (ZD) diets. We directly tested our hypothesis with cultured human neuronal precursor cells (NT2), stimulated to differentiate into post-mitotic neurons by retinoic acid (RA), along with immunocytochemistry and western analysis. RESULTS: Microarray analysis revealed the regulation of genes involved in cellular proliferation. This analysis also identified a number of genes known to be involved in neuronal differentiation, including the nuclear RA receptor, retinoid X receptor (RXR), doublecortin, and a transforming growth factor-beta (TGF-ß) binding protein (P < 0.05). Zinc deficiency significantly reduced RA-induced expression of the neuronal marker proteins doublecortin and ß-tubulin type III (TuJ1) to 40% of control levels (P < 0.01). This impairment of differentiation may be partially mediated by alterations in TGF-ß signaling. The TGF-ß type II receptor, responsible for binding TGF-ß during neuronal differentiation, was increased 14-fold in NT2 cells treated with RA (P < 0.001). However, this increase was decreased by 60% in ZD RA-treated cells (P < 0.001). DISCUSSION: This research identifies target genes that are involved in governing neurogenesis under ZD conditions and suggests an important role for TGF-ß and the trace metal zinc in regulating neuronal differentiation.

Inferring the age and sex of ancient potters from fingerprint ridge densities: A data-driven, Bayesian mixture modelling approach.

The density of epidermal ridges in a fingerprint varies predictably by age and sex. Archaeologists are therefore interested in using recovered fingerprints to learn about the ancient people who produced them. Recent studies focus on estimating the age and sex of individuals by measuring their fingerprints with one of two similar metrics: mean ridge breadth (MRB) or ridge density (RD). Yet these attempts face several critical problems: expected values for adult females and adolescent males are inherently indistinguishable, and inter-assemblage variation caused by biological and technological differences cannot be easily estimated. Each of these factors greatly decreases the accuracy of predictions based on individual prints, and together they condemn this strategy to relative uselessness. However, information in fingerprints from across an assemblage can be pooled to generate a more accurate depiction of potter demographics. We present a new approach to epidermal ridge density analysis using Bayesian mixture models with the following key benefits:•Age and sex are estimated more accurately than existing methods by incorporating a data-driven understanding of how demographics and ridge density covary.•Uncertainty in demographic estimates is automatically quantified and included in output.•The Bayesian framework can be easily adapted to fit the unique needs of different researchers.

Balance between fluorescence enhancement and association affinity in fluorescent heteroditopic indicators for imaging zinc ion in living cells.

A fluorescent heteroditopic indicator for the zinc(II) ion possesses two different zinc(II) binding sites. The sequential coordination of zinc(II) at the two sites can be transmitted into distinct fluorescence changes. In the heteroditopic ligand system that our group developed, the formations of mono- and dizinc(II) complexes along an increasing gradient of zinc(II) concentration lead to fluorescence enhancement and an emission bathochromic shift, respectively. The extents of these two changes determine the sensitivity and, ultimately, the effectiveness of the heteroditopic indicator in quantifying zinc(II) ion over a large concentration range. In this work, a strategy to increase the degree of fluorescence enhancement upon the formation of the monozinc(II) complex of a heteroditopic ligand under simulated physiological conditions is demonstrated. Fluorination of the pyridyl groups in the pentadentate N,N,N'-tris(pyridylmethyl)ethyleneamino group reduces the apparent pK(a) value of the high-affinity site, which increases the degree of fluorescence enhancement as the monozinc(II) complex is forming. However, fluorination impairs the coordination strength of the high-affinity zinc(II) binding site, which in the triply fluorinated ligand reduces the binding strength to the level of the low-affinity 2,2'-bipyridyl. The potential of the reported ligands in imaging zinc(II) ion in living cells was evaluated. The subcellular localization properties of two ligands in five organelles were characterized. Both benefits and deficiencies of these ligands were revealed, which provides directions for the near future in this line of research.