Lessons learned from the hospital to home community care program in Singapore and the supporting AI multiple readmissions prediction model.

In a prior practice and policy article published in Healthcare Science, we introduced the deployed application of an artificial intelligence (AI) model to predict longer-term inpatient readmissions to guide community care interventions for patients with complex conditions in the context of Singapore's Hospital to Home (H2H) program that has been operating since 2017. In this follow on practice and policy article, we further elaborate on Singapore's H2H program and care model, and its supporting AI model for multiple readmission prediction, in the following ways: (1) by providing updates on the AI and supporting information systems, (2) by reporting on customer engagement and related service delivery outcomes including staff-related time savings and patient benefits in terms of bed days saved, (3) by sharing lessons learned with respect to (i) analytics challenges encountered due to the high degree of heterogeneity and resulting variability of the data set associated with the population of program participants, (ii) balancing competing needs for simpler and stable predictive models versus continuing to further enhance models and add yet more predictive variables, and (iii) the complications of continuing to make model changes when the AI part of the system is highly interlinked with supporting clinical information systems, (4) by highlighting how this H2H effort supported broader Covid-19 response efforts across Singapore's public healthcare system, and finally (5) by commenting on how the experiences and related capabilities acquired from running this H2H program and related community care model and supporting AI prediction model are expected to contribute to the next wave of Singapore's public healthcare efforts from 2023 onwards. For the convenience of the reader, some content that introduces the H2H program and the multiple readmissions AI prediction model that previously appeared in the prior Healthcare Science publication is repeated at the beginning of this article.

Two Singapore public healthcare AI applications for national screening programs and other examples.

This article explains how two AI systems have been incorporated into the everyday operations of two Singapore public healthcare nation-wide screening programs. The first example is embedded within the setting of a national level population health screening program for diabetes related eye diseases, targeting the rapidly increasing number of adults in the country with diabetes. In the second example, the AI assisted screening is done shortly after a person is admitted to one of the public hospitals to identify which inpatients-especially which elderly patients with complex conditions-have a high risk of being readmitted as an inpatient multiple times in the months following discharge. Ways in which healthcare needs and the clinical operations context influenced the approach to designing or deploying the AI systems are highlighted, illustrating the multiplicity of factors that shape the requirements for successful large-scale deployments of AI systems that are deeply embedded within clinical workflows. In the first example, the choice was made to use the system in a semi-automated (vs. fully automated) mode as this was assessed to be more cost-effective, though still offering substantial productivity improvement. In the second example, machine learning algorithm design and model execution trade-offs were made that prioritized key aspects of patient engagement and inclusion over higher levels of predictive accuracy. The article concludes with several lessons learned related to deploying AI systems within healthcare settings, and also lists several other AI efforts already in deployment and in the pipeline for Singapore's public healthcare system.

Fluctuations of consciousness, mood, and science: The interhemispheric switch and sticky switch models two decades on.

Science and medicine aim to identify verifiable and replicable truths. However, the paths to such truths are frequently characterized by swinging pendulums of opposing perspectives. This is especially so in human neuroscience and the brain-based clinical sciences, where the target of investigation is the most complex of all biological systems. This article overviews a set of interrelated neuroscientific and clinical hypotheses, models, experiments, and predictions with which I have been involved for the last two decades. Traversing visual neuroscience, consciousness science, genetics, chronobiology, and biological and clinical psychiatry, the work illustrates how developments in science and medicine can occur through a combination of synthesis, serendipity, and experimentation. The article also reflects on doing science with the inimitable John "Jack" Pettigrew, and outlines how Pettigrew and I conceived, proposed, tested, and developed two new scientific models-one on neural mechanisms of binocular rivalry, the other on the pathophysiology of bipolar disorder. I also provide an update on various aspects of our models and data, and describe lessons learned from Pettigrew on how perspectives in science exhibit their own fluctuations, ironically like the very phenomena on which we worked.

The effect of stimulus strength on binocular rivalry rate in healthy individuals: Implications for genetic, clinical and individual differences studies.

Binocular rivalry (BR) occurs when conflicting images concurrently presented to corresponding retinal locations of each eye stochastically alternate in perception. Anomalies of BR rate have been examined in a range of clinical psychiatric conditions. In particular, slow BR rate has been proposed as an endophenotype for bipolar disorder (BD) to improve power in large-scale genome-wide association studies. Examining the validity of BR rate as a BD endophenotype however requires large-scale datasets (n=1000s to 10,000s), a standardized testing protocol, and optimization of stimulus parameters to maximize separation between BD and healthy groups. Such requirements are indeed relevant to all clinical psychiatric BR studies. Here we address the issue of stimulus optimization by examining the effect of stimulus parameter variation on BR rate and mixed-percept duration (MPD) in healthy individuals. We aimed to identify the stimulus parameters that induced the fastest BR rates with the least MPD. Employing a repeated-measures within-subjects design, 40 healthy adults completed four BR tasks using orthogonally drifting grating stimuli that varied in drift speed and aperture size. Pairwise comparisons were performed to determine modulation of BR rate and MPD by these stimulus parameters, and individual variation of such modulation was also assessed. From amongst the stimulus parameters examined, we found that 8cycles/s drift speed in a 1.5° aperture induced the fastest BR rate without increasing MPD, but that BR rate with this stimulus configuration was not substantially different to BR rate with stimulus parameters we have used in previous studies (i.e., 4cycles/s drift speed in a 1.5° aperture). In addition to contributing to stimulus optimization issues, the findings have implications for Levelt's Proposition IV of binocular rivalry dynamics and individual differences in such dynamics.

Evidence that eye-movement profiles do not explain slow binocular rivalry rate in bipolar disorder: support for a perceptual endophenotype.

OBJECTIVES: Presenting conflicting images simultaneously, one to each eye, produces perceptual alternations known as binocular rivalry (BR). Slow BR rate has been proposed as an endophenotype for bipolar disorder (BD) for use in large-scale genome-wide association studies. However, the trait could conceivably reflect eye movement (EM) dysfunction in BD rather than anomalous perceptual processing per se. To address this question, we examined the relationship between EM profiles and BR rate for various stimulus types in BD and healthy subjects. We also examined differences in EM profiles between these groups. METHODS: Employing a repeated-measures within-subjects design, 20 BD outpatients and 20 age- and sex-matched healthy controls completed EM tasks and separate BR tasks involving a range of stimuli with different drift speeds. The association between each EM measure and BR rate was examined with correlational analyses for all stimulus conditions in both groups. Between-group comparisons were performed to determine any differences in those EM measures. Corresponding Bayesian analyses were also conducted. RESULTS: There were no EM measures that showed a significant relationship with BR rate in either the BD group or the healthy group (P≥7.87×10-3 ), where those EM measures were also significantly different between the BD and healthy groups (P≥1.32 × 10-2 ). These findings were verified with Bayes factors. CONCLUSIONS: The results provide evidence that EM profiles do not explain the slow BR endophenotype for BD, thus indicating that the trait reflects anomalous perceptual processing per se. This perceptual trait can be employed in clinical, genetic, mechanistic and pathophysiological studies.

No Relationship Between Binocular Rivalry Rate and Eye-Movement Profiles in Healthy Individuals: A Bayes Factor Analysis.

Binocular rivalry (BR) is an intriguing phenomenon in which conflicting images are presented, one to each eye, resulting in perceptual alternations between each image. The rate of BR has been proposed as a potential endophenotype for bipolar disorder because (a) it is well established that this highly heritable psychiatric condition is associated with slower BR rate than in controls, and (b) an individual's BR rate is approximately 50% genetically determined. However, eye movements (EMs) could potentially account for the slow BR trait given EM anomalies are observed in psychiatric populations, and there has been report of an association between saccadic rate and BR rate in healthy individuals. Here, we sought to assess the relationship between BR rate and EMs in healthy individuals (N = 40, mean age = 34.4) using separate BR and EM tasks, with the latter measuring saccades during anticipatory, antisaccade, prosaccade, self-paced, free-viewing, and smooth-pursuit tasks. No correlation was found between BR rate and any EM measure for any BR task (p > .01) with substantial evidence favoring this lack of association (BF(01) > 3). This finding is in contrast to previous data and has important implications for using BR rate as an endophenotype. If replicated in clinical psychiatric populations, EM interpretations of the slow BR trait can be excluded.

Closing in on the constitution of consciousness.

The science of consciousness is a nascent and thriving field of research that is founded on identifying the minimally sufficient neural correlates of consciousness. However, I have argued that it is the neural constitution of consciousness that science seeks to understand and that there are no evident strategies for distinguishing the correlates and constitution of (phenomenal) consciousness. Here I review this correlation/constitution distinction problem and challenge the existing foundations of consciousness science. I present the main analyses from a longer paper in press on this issue, focusing on recording, inhibition, stimulation, and combined inhibition/stimulation strategies, including proposal of the Jenga analogy to illustrate why identifying the minimally sufficient neural correlates of consciousness should not be considered the ultimate target of consciousness science. Thereafter I suggest that while combined inhibition and stimulation strategies might identify some constitutive neural activities-indeed minimally sufficient constitutive neural activities-such strategies fail to identify the whole neural constitution of consciousness and thus the correlation/constitution distinction problem is not fully solved. Various clarifications, potential objections and related scientific and philosophical issues are also discussed and I conclude by proposing new foundational claims for consciousness science.

Dichoptic viewing methods for binocular rivalry research: prospects for large-scale clinical and genetic studies.

Binocular rivalry (BR) is an intriguing phenomenon that occurs when two different images are presented, one to each eye, resulting in alternation or rivalry between the percepts. The phenomenon has been studied for nearly 200 years, with renewed and intensive investigation over recent decades. The rate of perceptual switching has long been known to vary widely between individuals but to be relatively stable within individuals. A recent twin study demonstrated that individual variation in BR rate is under substantial genetic control, a finding that also represented the first report, using a large study, of genetic contribution for any post-retinal visual processing phenomenon. The twin study had been prompted by earlier work showing BR rate was slow in the heritable psychiatric condition, bipolar disorder (BD). Together, these studies suggested that slow BR may represent an endophenotype for BD, and heralded the advent of modern clinical and genetic studies of rivalry. This new focus has coincided with rapid advances in 3D display technology, but despite such progress, specific development of technology for rivalry research has been lacking. This review therefore compares different display methods for BR research across several factors, including viewing parameters, image quality, equipment cost, compatibility with other investigative methods, subject group, and sample size, with a focus on requirements specific to large-scale clinical and genetic studies. It is intended to be a resource for investigators new to BR research, such as clinicians and geneticists, and to stimulate the development of 3D display technology for advancing interdisciplinary studies of rivalry.

Atom chips on direct bonded copper substrates.

We present the use of direct bonded copper (DBC) for the straightforward fabrication of high power atom chips. Atom chips using DBC have several benefits: excellent copper/substrate adhesion, high purity, thick (>100 µm) copper layers, high substrate thermal conductivity, high aspect ratio wires, the potential for rapid (<8 h) fabrication, and three-dimensional atom chip structures. Two mask options for DBC atom chip fabrication are presented, as well as two methods for etching wire patterns into the copper layer. A test chip, able to support 100 A of current for 2 s without failing, is used to determine the thermal impedance of the DBC. An assembly using two DBC atom chips is used to magnetically trap laser cooled (87)Rb atoms. The wire aspect ratio that optimizes the magnetic field gradient as a function of power dissipation is determined to be 0.84:1 (height:width).

Genetic contribution to individual variation in binocular rivalry rate.

Binocular rivalry occurs when conflicting images are presented in corresponding locations of the two eyes. Perception alternates between the images at a rate that is relatively stable within individuals but that varies widely between individuals. The determinants of this variation are unknown. In addition, slow binocular rivalry has been demonstrated in bipolar disorder, a psychiatric condition with high heritability. The present study therefore examined whether there is a genetic contribution to individual variation in binocular rivalry rate. We employed the twin method and studied both monozygotic (MZ) twins (n = 128 pairs) who are genetically identical, and dizygotic (DZ) twins (n = 220 pairs) who share roughly half their genes. MZ and DZ twin correlations for binocular rivalry rate were 0.51 and 0.19, respectively. The best-fitting genetic model showed 52% of the variance in binocular rivalry rate was accounted for by additive genetic factors. In contrast, nonshared environmental influences accounted for 18% of the variance, with the remainder attributed to measurement error. This study therefore demonstrates a substantial genetic contribution to individual variation in binocular rivalry rate. The results support the vigorous pursuit of genetic and molecular studies of binocular rivalry and further characterization of slow binocular rivalry as an endophenotype for bipolar disorder.

Non-adrenergic non-cholinergic inhibition of gastrointestinal smooth muscle and its intracellular mechanism(s).

Relaxation of gastrointestinal smooth muscle caused by release of non-adrenergic non-cholinergic (NANC) transmitters from enteric nerves occurs in several physiologic digestive reflexes. Likely candidate NANC inhibitory agents include nitric oxide (NO), adenosine triphosphate (ATP), vasoactive intestinal peptide (VIP), pituitary adenylate cyclase-activating peptide (PACAP), carbon monoxide (CO), protease-activated receptors (PARs), hydrogen sulfide (H2S), neurotensin (NT) and beta-nicotinamide adenine dinucleotide (beta-NAD). Multiple NANC transmitters work in concert, are pharmacologically coupled and are closely coordinated. Individual contribution varies regionally in the gastrointestinal tract and between species. NANC inhibition of gastrointestinal smooth muscle involves several intracellular mechanisms, including increase of cyclic guanosine monophosphate (cGMP), increase of cyclic adenosine monophosphate (cAMP) and hyperpolarization of the cell membrane via direct or indirect activation of potassium ion (K+) channels.

Heme-oxygenase-2 immunolabelling in pig jejunum.

Heme-oxygenase-2 generates carbon monoxide in the enteric nervous system and in interstitial cells of Cajal in the canine, mouse and human jejunum. Carbon monoxide is considered a non-adrenergic and non-cholinergic inhibitory neurotransmitter and it establishes and maintains the resting membrane potential in the stomach and small intestine. The aim of this study was to determine the distribution of heme-oxygenase-2 in the enteric nervous system of the pig jejunum. Heme-oxygenase-2 immunoreactivity was found in neurons of myenteric ganglia and in nerve fibers in the circular and longitudinal muscle layers. These results suggest that carbon monoxide is produced in the enteric nervous system of the pig jejunum and might mediate inhibitory neural activity in myenteric ganglia and inhibitory neural input to smooth muscle cells in the circular and longitudinal muscle layers.

The chronic gastrointestinal manifestations of Chagas disease.

Chagas disease is an infectious disease caused by the protozoan Trypanosoma cruzi. The disease mainly affects the nervous system, digestive system and heart. The objective of this review is to revise the literature and summarize the main chronic gastrointestinal manifestations of Chagas disease. The chronic gastrointestinal manifestations of Chagas disease are mainly a result of enteric nervous system impairment caused by T. cruzi infection. The anatomical locations most commonly described to be affected by Chagas disease are salivary glands, esophagus, lower esophageal sphincter, stomach, small intestine, colon, gallbladder and biliary tree. Chagas disease has also been studied in association with Helicobacter pylori infection, interstitial cells of Cajal and the incidence of gastrointestinal cancer.

Applications of cellular systems biology in breast cancer patient stratification and diagnostics.

Tumors are complex structures of malignant cells and stromal cells that function as an integrated system that promotes tumor progression. Immune cells and other stromal components serve vital cooperative functions that often support tumor growth and metastasis; stromal content and function are strongly associated with disease progression and clinical outcome in cancer patients. Cellular systems biology considers tissues and tumors, and the cells within them, as integrated and interactive networks that function in concert as a system. Assessment of tumors as a "system" within the system of a patient using the cellular systems biology approach has the potential to improve on the current diagnostic tools for breast cancer by creating high content profiles of an individual patient's tumor. The application of cellular systems biology (CSB) profiling to early drug discovery using cellular models of disease [1] and to drug development using the CellCiphr Cytotoxicity Profiling panels [2] can optimize the efficacy and decrease the potential toxicity of compounds taken into pre-clinical trials. However, it has become clear that patient sub-populations can respond differently to drug candidates in clinical trials due to patient variability. Therefore, cellular systems biology can also be a powerful approach to patient stratification for clinical trials and could become an important diagnostic tool. This review describes how the cellular systems biology approach can be applied to patient stratification and diagnostics in breast cancer, focusing on the advantages of quantifying functional biomarkers representing key tumor system processes in intact tissues from patients in order to make highly specific and sensitive predictions towards development of individualized medicine for breast cancer. We discuss the state-of-the-art of multiplexing of functional biomarkers in tissues and the practical utilization of the cellular systems biology approach in creating classifiers for patient stratification and diagnostics.

The chronic gastrointestinal manifestations of Chagas disease: [review]

Chagas disease is an infectious disease caused by the protozoan Trypanosoma cruzi. The disease mainly affects the nervous system, digestive system and heart. The objective of this review is to revise the literature and summarize the main chronic gastrointestinal manifestations of Chagas disease. The chronic gastrointestinal manifestations of Chagas disease are mainly a result of enteric nervous system impairment caused by T. cruzi infection. The anatomical locations most commonly described to be affected by Chagas disease are salivary glands, esophagus, lower esophageal sphincter, stomach, small intestine, colon, gallbladder and biliary tree. Chagas disease has also been studied in association with Helicobacter pylori infection, interstitial cells of Cajal and the incidence of gastrointestinal cancer.

The changing face of perceptual rivalry.

Functional brain-imaging studies of house-face binocular rivalry and Rubin's vase-faces illusion have consistently reported face perception-dependent activity in the right fusiform gyrus. Here we use Rubin's illusion and report that activation of the left hemisphere by caloric vestibular stimulation increases the predominance of the faces percept in a substantial number of test subjects. While partially supporting the brain-imaging lateralization reports, our findings also challenge these studies by suggesting that neural mechanisms of Rubin's illusion cannot be limited to extrastriate perception-dependent processing. In accordance with our previously proposed interhemispheric switch model, the present findings support the notion that perceptual rivalry engages high-level cortical structures that mediate unihemispheric attentional selection.

The use of tDCS and CVS as methods of non-invasive brain stimulation.

Transcranial direct current stimulation (tDCS) and caloric vestibular stimulation (CVS) are safe methods for selectively modulating cortical excitability and activation, respectively, which have recently received increased interest regarding possible clinical applications. tDCS involves the application of low currents to the scalp via cathodal and anodal electrodes and has been shown to affect a range of motor, somatosensory, visual, affective and cognitive functions. Therapeutic effects have been demonstrated in clinical trials of tDCS for a variety of conditions including tinnitus, post-stroke motor deficits, fibromyalgia, depression, epilepsy and Parkinson's disease. Its effects can be modulated by combination with pharmacological treatment and it may influence the efficacy of other neurostimulatory techniques such as transcranial magnetic stimulation. CVS involves irrigating the auditory canal with cold water which induces a temperature gradient across the semicircular canals of the vestibular apparatus. This has been shown in functional brain-imaging studies to result in activation in several contralateral cortical and subcortical brain regions. CVS has also been shown to have effects on a wide range of visual and cognitive phenomena, as well as on post-stroke conditions, mania and chronic pain states. Both these techniques have been shown to modulate a range of brain functions, and display potential as clinical treatments. Importantly, they are both inexpensive relative to other brain stimulation techniques such as electroconvulsive therapy (ECT) and transcranial magnetic stimulation (TMS).