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sSteroid receptor coactivator 3 (SRC-3) is most strongly expressed in regulatory T cells (Tregs) and B cells, suggesting that it plays an important role in the regulation of Treg function. Using an aggressive E0771 mouse breast cell line syngeneic immune-intact murine model, we observed that breast tumors were ‘permanently eradicated’ in a genetically engineered tamoxifen-inducible Treg-cell specific SRC-3 knockout (KO) female mouse that does not possess a systemic autoimmune pathological phenotype. A similar eradication of tumor was noted in a syngeneic model of prostate cancer. A subsequent injection of additional E0771 cancer cells into these mice showed continued resistance to tumor development without the need for tamoxifen induction to produce additional SRC-3 KO Tregs. SRC-3 KO Tregs were highly proliferative and preferentially infiltrated into breast tumors by activating the Chemokine (C-C motif) ligand (Ccl) 19/Ccl21/ Chemokine (C-C motif) Receptor (Ccr)7 signaling axis, generating antitumor immunity by enhancing the interferon-γ/C-X-C Motif Chemokine Ligand (Cxcl) 9 signaling axis to facilitate the entrance and function of effector T cells and Natural Killer cells. SRC-3 KO Tregs also show a dominant effect by blocking the immune suppressive function of WT Tregs. Importantly, a single adoptive transfer of SRC-3 KO Tregs into wild-type E0771 tumor-bearing mice can completely abolish pre-established breast tumors by generating potent antitumor immunity with a durable effect that prevents tumor reoccurrence. Therefore, treatment with SRC-3 deleted Tregs represents a novel approach to completely block tumor growth and recurrence without the autoimmune side-effects that typically accompany immune checkpoint modulators.Significance statementTregs are essential in restraining immune responses for immune homeostasis. SRC-3 is a pleiotropic coactivator, the second-most highly expressed transcriptional coactivator in Tregs, and a suspect in Treg function. The disruption of SRC-3 expression in Tregs leads to a ‘complete lifetime eradication’ of tumors in aggressive syngeneic breast cancer mouse models because deletion of SRC-3 alters the expression of a wide range of key genes involved in efferent and afferent Treg signaling. SRC-3KO Tregs confer this long-lasting protection against cancer recurrence in mice without an apparent systemic autoimmune pathological phenotype. Therefore, treatment with SRC-3 deleted Tregs could represent a novel and efficient future target for eliminating tumor growth and recurrence without the autoimmune side-effects that typically accompany immune checkpoint modulators.

Significance We are at an exciting era of identification of the cell and molecular processes necessary for tissue remodeling and repair. Unlike current systemic therapeutics, our studies reveal pharmacologic stimulation of SRCs modulates macrophage and fibrotic reparative cell responses to promote more effective repair and lasting beneficial remodeling after myocardial infarction., Progressive remodeling of the heart, resulting in cardiomyocyte (CM) loss and increased inflammation, fibrosis, and a progressive decrease in cardiac function, are hallmarks of myocardial infarction (MI)-induced heart failure. We show that MCB-613, a potent small molecule stimulator of steroid receptor coactivators (SRCs) attenuates pathological remodeling post-MI. MCB-613 decreases infarct size, apoptosis, hypertrophy, and fibrosis while maintaining significant cardiac function. MCB-613, when given within hours post MI, induces lasting protection from adverse remodeling concomitant with: 1) inhibition of macrophage inflammatory signaling and interleukin 1 (IL-1) signaling, which attenuates the acute inflammatory response, 2) attenuation of fibroblast differentiation, and 3) promotion of Tsc22d3-expressing macrophages—all of which may limit inflammatory damage. SRC stimulation with MCB-613 (and derivatives) is a potential therapeutic approach for inhibiting cardiac dysfunction after MI.

A distinct 12-hour clock exists in addition to the 24-hour circadian clock to coordinate metabolic and stress rhythms. Here, we show that liver-specific ablation of X-box binding protein 1 (XBP1) disrupts the hepatic 12-hour clock and promotes spontaneous non-alcoholic fatty liver disease (NAFLD). We show that hepatic XBP1 predominantly regulates the 12-hour rhythmicity of gene transcription in the mouse liver and demonstrate that perturbation of the 12-hour clock, but not the core circadian clock, is associated with the onset and progression of this NAFLD phenotype. Mechanistically, we provide evidence that the spliced form of XBP1 (XBP1s) binds to the hepatic 12-hour cistrome to directly regulate the 12-hour clock, with a periodicity paralleling the harmonic activation of the 12-hour oscillatory transcription of many rate-limiting metabolic genes known to have perturbations in human metabolic disease. Functionally, we show that Xbp1 ablation significantly reduces cellular membrane fluidity and impairs lipid homeostasis via rate-limiting metabolic processes in fatty acid monounsaturated and phospholipid remodeling pathways. These findings reveal that genetic disruption of the hepatic 12-hour clock links to the onset and progression of NAFLD development via transcriptional regulator XBP1, and demonstrate a role for XBP1 and the 12-hour clock in the modulation of phospholipid composition and the maintenance of lipid homeostasis., Hepatocyte 12-hour rhythms have a role in cellular stress and metabolic functions. Here, the authors demonstrate disrupting the 12-hour clock through deletion of XBP1 is associated with the development of NAFLD as well as disruption of phospholipid composition and the maintenance of lipid homeostasis.

“Musica universalis” is an ancient philosophical concept claiming the movements of celestial bodies follow mathematical equations and resonate to produce an inaudible harmony of music, and the harmonious sounds that humans make were an approximation of this larger harmony of the universe. Besides music, electromagnetic waves such as light and electric signals also are presented as harmonic resonances. Despite the seemingly universal theme of harmonic resonance in various disciplines, it was not until recently that the same harmonic resonance was discovered also to exist in biological systems. Contrary to traditional belief that a biological system is either at stead-state or cycles with a single frequency, it is now appreciated that most biological systems have no homeostatic “set point,” but rather oscillate as composite rhythms consisting of superimposed oscillations. These oscillations often cycle at different harmonics of the circadian rhythm, and among these, the ~12-hour oscillation is most prevalent. In this review, we focus on these 12-hour oscillations, with special attention to their evolutionary origin, regulation, and functions in mammals, as well as their relationship to the circadian rhythm. We further discuss the potential roles of the 12-hour clock in regulating hepatic steatosis, aging, and the possibility of 12-hour clock–based chronotherapy. Finally, we posit that biological rhythms are also musica universalis: whereas the circadian rhythm is synchronized to the 24-hour light/dark cycle coinciding with the Earth’s rotation, the mammalian 12-hour clock may have evolved from the circatidal clock, which is entrained by the 12-hour tidal cues orchestrated by the moon., We focus on 12-hour oscillations, with special attention to their evolutionary origin, regulation, and functions in mammals, as well as their relationship to the circadian rhythm.

Our group recently discovered a cell-autonomous mammalian 12h-clock regulating physiological unfolded protein response. Xbp1s ablation impairs 12h-transcript oscillations in vitro, and we now show liver-specific deletion of XBP1s globally impaired murine 12h-transcriptome, but not the circadian rhythms in vivo. XBP1s-dependent 12h-transcriptome is enriched for transcription, mRNA processing, ribosome biogenesis, translation, and protein ER-Golgi processing/sorting in a temporal order consistent with the progressive molecular processing sequence described by the central dogma information flow (CEDIF). The 12h-rhythms of CEDIF are cell-autonomous and evolutionarily conserved in circatidal marine animals. Mechanistically, we found the motif stringency of promoter XBP1s binding sites, but not necessarily XBP1s expression, dictates its ability to drive 12h-rhythms of transcription and further identified GABP as putative novel transcriptional regulator of 12h-clock. We hypothesize the 12h-rhythms of CEDIF allows rush hours’ gene expression and processing, with the particular genes processed at each rush hour regulated by circadian and/or tissue specific pathways.

Previous work from ours and other laboratories have shown that steroid receptor coactivators (SRCs) are involved in heart development and in mitigating cardiac dysfunction in cardiac injury models. Members of the p160 SRC family, SRC-1 (NCOA1), SRC-2 (NCOA2/TIF2/GRIP1) and SRC-3 (NCOA3/AIB1/ACTR/pCIP), interact with nuclear receptors and other transcription factors to drive target gene expression by assembling transcriptional coactivator complexes to increase transcription. This indicates a potential for SRC targeting drugs pertinent to cell migration, proliferation and survival-promoting paracrine interactions in cardiac tissue injury responses. We have identified a small molecule activator of SRCs (MCB-613) that selectively and reversibly binds to SRCs as shown by surface plasmon resonance and is a potent SRC stimulator that acts to greatly enhance SRC transcriptional activity with no apparent toxicity in mice. We postulated that MCB-613 could enable wound repair and preservation of cardiac function after an acute MI by reducing the extent of injury-related fibrosis and the subsequent chronic loss of cardiac function associated with non-contracting scar tissue. We thus tested the effect of MCB-613 on the cardiac injury response by administering MCB-613 two hours after ischemic injury in a mouse model of MI. Along with measurements of functional cardiac output and damage, we sought to identify the cell-type specific responses responsible for MCB-613’s cardio-protective effects by utilizing single cell transcriptomics of cardiac interstitial cells to characterize the effects of SRC stimulation on cardiac function post-MI. We show that MCB-613, a potent small molecule stimulator of steroid receptor coactivators (SRCs) attenuates pathological remodeling post-MI. MCB-613 decreases infarct size, apoptosis, hypertrophy, and fibrosis while maintaining significant cardiac function. MCB-613, when given within hours post-MI, induces lasting protection from adverse remodeling concomitant with: (i) inhibition of macrophage inflammatory signaling and IL-1 signaling which attenuates the acute inflammatory response, (ii) attenuation of fibroblast differentiation, and (iii) promotion of Tsc22d3 expressing macrophages - all of which may limit inflammatory damage. Our results indicate MCB-613 controls the cellular interstitial cardiac repair response to ischemia. Distinct molecular and cellular mechanisms related to stimulation of SRC-3 have been identified that pave the way for the further exploration of SRCs as drug targets that can be engaged to improve the management of myocardial injury response outcomes. SRC stimulation with MCB-613 (and derivatives) is a potential novel therapeutic approach for inhibiting cardiac dysfunction after MI.

A central mechanism for controlling circadian gene amplitude remains elusive. We present evidence for a “facilitated repression (FR)” model that functions as an amplitude rheostat for circadian gene oscillation. We demonstrate that ROR and/or BMAL1 promote global chromatin decondensation during the activation phase of the circadian cycle to actively facilitate REV-ERB loading for repression of circadian gene expression. Mechanistically, we found that SRC-2 dictates global circadian chromatin remodeling through spatial and temporal recruitment of PBAF members of the SWI/SNF complex to facilitate loading of REV-ERB in the hepatic genome. Mathematical modeling highlights how the FR model sustains proper circadian rhythm despite fluctuations of REV-ERB levels. Our study not only reveals a mechanism for active communication between the positive and negative limbs of the circadian transcriptional loop, but also establishes the concept that clock transcription factor binding dynamics is perhaps a central tenet for fine-tuning circadian rhythm.

Our group recently characterized a cell-autonomous mammalian 12-h clock independent from the circadian clock, but its function and mechanism of regulation remain poorly understood. Here, we show that in mouse liver, transcriptional regulation significantly contributes to the establishment of 12-h rhythms of mRNA expression in a manner dependent on Spliced Form of X-box Binding Protein 1 (XBP1s). Mechanistically, the motif stringency of XBP1s promoter binding sites dictates XBP1s’s ability to drive 12-h rhythms of nascent mRNA transcription at dawn and dusk, which are enriched for basal transcription regulation, mRNA processing and export, ribosome biogenesis, translation initiation, and protein processing/sorting in the Endoplasmic Reticulum (ER)-Golgi in a temporal order consistent with the progressive molecular processing sequence described by the central dogma information flow (CEDIF). We further identified GA-binding proteins (GABPs) as putative novel transcriptional regulators driving 12-h rhythms of gene expression with more diverse phases. These 12-h rhythms of gene expression are cell autonomous and evolutionarily conserved in marine animals possessing a circatidal clock. Our results demonstrate an evolutionarily conserved, intricate network of transcriptional control of the mammalian 12-h clock that mediates diverse biological pathways. We speculate that the 12-h clock is coopted to accommodate elevated gene expression and processing in mammals at the two rush hours, with the particular genes processed at each rush hour regulated by the circadian and/or tissue-specific pathways., Distinct from the well-known 24-hour circadian clock, this study shows that the mammalian 12-hour clock upregulates genetic information flow capacity during the two "rush hours" (dawn and dusk) in a manner dependent on the transcription factor XBP1s.

Heart rate (HR) is a valuable and widespread measure for physical training programs, although its description of conditioning is limited to the cardiac response to exercise. More comprehensive measures of exercise adaptation include cardiac output (Q̇), stroke volume (SV) and oxygen uptake (V̇O2), but these physiological parameters can be measured only with cumbersome equipment installed in clinical settings. In this work, we explore the ability of pulse transit time (PTT) to represent a valuable pairing with HR for indirectly estimating Q̇, SV and V̇O2 non-invasively. PTT was measured as the time interval between the peak of the electrocardiographic (ECG) R-wave and the onset of the photoplethysmography (PPG) waveform at the periphery (i.e. fingertip) with a portable sensor. Fifteen healthy young subjects underwent a graded incremental cycling protocol after which HR and PTT were correlated with Q̇, SV and V̇O2 using linear mixed models. The addition of PTT significantly improved the modeling of Q̇, SV and V̇O2 at the individual level ([Formula: see text] for SV, 0.548 for Q̇, and 0.771 for V̇O2) compared to predictive models based solely on HR ([Formula: see text] for SV, 0.503 for Q̇, and 0.745 for V̇O2). While challenges in sensitivity and artifact rejection exist, combining PTT with HR holds potential for development of novel wearable sensors that provide exercise assessment largely superior to HR monitors.

This paper summarizes the panel discussion at the IEEE Engineering in Medicine and Biology Point-of-Care Healthcare Technology Conference (POCHT 2013) held in Bangalore India from Jan 16–18, 2013. Modern medicine has witnessed interdisciplinary technology innovations in healthcare with a continuous growth in life expectancy across the globe. However, there is also a growing global concern on the affordability of rapidly rising healthcare costs. To provide quality healthcare at reasonable costs, there has to be a convergence of preventive, personalized, and precision medicine with the help of technology innovations across the entire spectrum of point-of-care (POC) to critical care at hospitals. The first IEEE EMBS Special Topic POCHT conference held in Bangalore, India provided an international forum with clinicians, healthcare providers, industry experts, innovators, researchers, and students to define clinical needs and technology solutions toward commercialization and translation to clinical applications across different environments and infrastructures. This paper presents a summary of discussions that took place during the keynote presentations, panel discussions, and breakout sessions on needs, challenges, and technology innovations in POC technologies toward improving global healthcare. Also presented is an overview of challenges and trends in developing and developed economies with respect to priority clinical needs, technology innovations in medical devices, translational engineering, information and communication technologies, infrastructure support, and patient and clinician acceptance of POC healthcare technologies., This paper summarizes the panel discussion at the IEEE Engineering in Medicine and Biology Point of Care Healthcare Technology Conference (POCHT 2013) held in Bangalore India from Jan 16-18, 2013.

Background: Technology use for symptom management is beneficial for both patients and physicians. Widespread acceptance of technology use in healthcare fuels continued development of technology with ever-increasing sophistication. Although acceptance of technology use in healthcare by medical professionals is evident, less is known about the perceptions, preferences, and use of technology by heart failure (HF) patients. This study explores patients' perceptions and current use of technology for managing HF symptoms (MHFS). Materials and Methods: A qualitative analysis of in-depth individual interviews using a constant comparative approach for emerging themes was conducted. Fifteen participants (mean age, 64.43 years) with HF were recruited from hospitals, cardiology clinics, and community groups. Results: All study participants reported use of a home monitoring device, such as an ambulatory blood pressure device or bathroom scale. The majority of participants reported not accessing online resources for additional MHFS information. However, several participants stated their belief that technology would be useful for MHFS. Participants reported increased access to care, earlier indication of a worsening condition, increased knowledge, and greater convenience as potential benefits of technology use while managing HF symptoms. For most participants financial cost, access issues, satisfaction with current self-care routine, mistrust of technology, and reliance on routine management by their current healthcare provider precluded their use of technology for MHFS. Conclusions: Knowledge about HF patients' perceptions of technology use for self-care and better understanding of issues associated with technology access can aid in the development of effective health behavior interventions for individuals who are MHFS and may result in increased compliance, better outcomes, and lower healthcare costs.

Besides circadian rhythms, oscillations cycling with a 12 hr period exist. However, the prevalence, origin, regulation, and function of mammalian 12 hr rhythms remain elusive. Utilizing an unbiased mathematical approach identifying all superimposed oscillations, we uncovered prevalent 12 hr gene expression and metabolic rhythms in mouse liver, coupled with a physiological 12 hr unfolded protein response oscillation. The mammalian 12 hr rhythm is cell autonomous, driven by a dedicated 12 hr pacemaker distinct from the circadian clock, and can be entrained in vitro by metabolic and ER stress cues. Mechanistically, we identified XBP1s as a transcriptional regulator of the mammalian 12 hr clock. Downregulation of the 12 hr gene expression strongly correlates with human hepatic steatosis and steatohepatitis, implying its importance in maintaining metabolic homeostasis. The mammalian 12 hr rhythm of gene expression also is conserved in nematodes and crustaceans, indicating an ancient origin of the 12 hr clock. Our work sheds new light on how perturbed biological rhythms contribute to human disease.

Most decisions in life involve ambiguity, where probabilities can not be meaningfully specified, as much as they involve probabilistic uncertainty. In such conditions, the aspiration to utility maximization may be self-deceptive. We propose "robust satisficing" as an alternative to utility maximizing as the normative standard for rational decision making in such circumstances. Instead of seeking to maximize the expected value, or utility, of a decision outcome, robust satisficing aims to maximize the robustness to uncertainty of a satisfactory outcome. That is, robust satisficing asks, "what is a 'good enough' outcome," and then seeks the option that will produce such an outcome under the widest set of circumstances. We explore the conditions under which robust satisficing is a more appropriate norm for decision making than utility maximizing.

Circadian rhythmicity, the 24-hour cycle responsive to light and dark, is determined by periodic oscillations in gene transcription. This phenomenon has broad ramifications in physiologic function. Recent work has disclosed more cycles in gene transcription, and to the uncovering of these we apply a novel signal processing methodology known as the pencil method and compare it to conventional parametric, nonparametric, and statistical methods. Methods: In order to assess periodicity of gene expression over time, we analyzed a database derived from livers of mice entrained to a 12-hour light/12-hour dark cycle. We also analyzed artificially generated signals to identify differences between the pencil decomposition and other alternative methods. Results: The pencil decomposition revealed hitherto-unsuspected oscillations in gene transcription with 12-hour periodicity. The pencil method was robust in detecting the 24-hour circadian cycle that was known to exist, as well as confirming the existence of shorter-period oscillations. A key consequence of this approach is that orthogonality of the different oscillatory components can be demonstrated. thus indicating a biological independence of these oscillations, that has been subsequently confirmed empirically by knocking out the gene responsible for the 24-hour clock. Conclusion: System identification techniques can be applied to biological systems and can uncover important characteristics that may elude visual inspection of the data. Significance: The pencil method provides new insights on the essence of gene expression and discloses a wide variety of oscillations in addition to the well-studied circadian pattern. This insight opens the door to the study of novel mechanisms by which oscillatory gene expression signals exert their regulatory effect on cells to influence human diseases.

Remote patient monitoring (RPM) holds great promise for reducing the burden of congestive heart failure (CHF). Improved sensor technology and effective predictive algorithms can anticipate sudden decompensation events. Enhanced telemonitoring systems would promote patient independence and facilitate communication between patients and their physicians. We report the development of a novel hand-held device, called Blue Box, capable of collecting and wirelessly transmitting key cardiac parameters derived from three integrated biosensors: 2 lead electrocardiogram (ECG), photoplethysmography and bioelectrical impedance (bioimpedance). Blue Box measurements include time intervals between consecutive ECG R-waves (RR interval), time duration of the ECG complex formed by the Q, R and S waves (QRS duration), bioimpedance, heart rate and systolic time intervals. In this study, we recruited 24 healthy subjects to collect several parameters measured by Blue Box and assess their value in correlating with cardiac output measured with Echo-Doppler. Linear correlation between the heart rate measured with Blue Box and cardiac output from Echo-Doppler had a group average correlation coefficient of 0.80. We found that systolic time intervals did not improve the model significantly. However, STIs did inversely correlate with increasing workloads.

The diagnosis of diabetes, based on measured fasting plasma glucose level, depends on choosing a threshold level for which the probability of failing to detect disease (missed diagnosis), as well as the probability of falsely diagnosing disease (false alarm), are both small. The Bayesian risk provides a tool for aggregating and evaluating the risks of missed diagnosis and false alarm. However, the underlying probability distributions are uncertain, which makes the choice of the decision threshold difficult. We discuss an hypothesis for choosing the threshold that can robustly achieve acceptable risk. Our analysis is based on info-gap decision theory, which is a non-probabilistic methodology for modelling and managing uncertainty. Our hypothesis is that the non-probabilistic method of info-gap robust decision making is able to select decision thresholds according to their probability of success. This hypothesis is motivated by the relationship between info-gap robustness and the probability of success, which has been observed in other disciplines (biology and economics). If true, it provides a valuable clinical tool, enabling the clinician to make reliable diagnostic decisions in the absence of extensive probabilistic information. Specifically, the hypothesis asserts that the physician is able to choose a diagnostic threshold that maximizes the probability of acceptably small Bayesian risk, without requiring accurate knowledge of the underlying probability distributions. The actual value of the Bayesian risk remains uncertain.

Physicians use clinical guidelines to inform judgment about therapy. Clinical guidelines do not address three important uncertainties: (1) uncertain relevance of tested populations to the individual patient, (2) the patient’s uncertain preferences among possible outcomes, and (3) uncertain subjective and financial costs of intervention. Unreliable probabilistic information is available for some of these uncertainties; no probabilities are available for others. The uncertainties are in the values of parameters and in the shapes of functions. We explore the usefulness of info-gap decision theory in patient-physician decision making in managing cholesterol level using clinical guidelines. Info-gap models of uncertainty provide versatile tools for quantifying diverse uncertainties. Info-gap theory provides two decision functions for evaluating alternative therapies. The robustness function assesses the confidence—in light of uncertainties—in attaining acceptable outcomes. The opportuneness function assesses the potential for better-than-anticipated outcomes. Both functions assist in forming preferences among alternatives. Hypothetical case studies demonstrate that decisions using the guidelines and based on best estimates of the expected utility are sometimes, but not always, consistent with robustness and opportuneness analyses. The info-gap analysis provides guidance when judgment suggests that a deviation from the guidelines would be productive. Finally, analysis of uncertainty can help resolve ambiguous situations.

The challenge of eliminating disparities in chronic illness in the United States is hampered by the diversity of the epidemiology of the chronic conditions themselves, and by the individuality of the communities and patients affected by them. This article outlines some of the ways in which the complexity of chronic illness in underserved communities in the United States limits the data and the strategies available to clinicians and patients. We then present the example of chronic heart failure (CHF) to illustrate a possible solution that we are developing for supporting underserved patients’ selfmanagement of chronic illness: individualized health care (through “personal normals” derived from the patient’s own clinical history combined with population-based data), and distributed health care (point of care through wireless biosensors and community health workers). We present some of the possible barriers to the implementation of the model. Conclusion: we believe that this approach is a pathway to empowering CHF patients in underserved communities. Further research is necessary to test the clinical viability of the model and the acceptability of the model for patients, physicians, and families.

Despite extensive efforts to understand the monogenic contributions to perturbed glucose homeostasis, the complexity of genetic events that fractionally contribute to the spectrum of this pathology remain poorly understood. Proper maintenance of glucose homeostasis is the central feature of a constellation of comorbidities that define the metabolic syndrome. The ability of the liver to balance carbohydrate uptake and release during the feeding-to-fasting transition is essential to the regulation of peripheral glucose availability. The liver coordinates the expression of gene programs that control glucose absorption, storage, and secretion. Herein, we demonstrate that Steroid Receptor Coactivator 2 (SRC-2) orchestrates a hierarchy of nutritionally responsive transcriptional complexes to precisely modulate plasma glucose availability. Using DNA pull-down technology coupled with mass spectrometry, we have identified SRC-2 as an indispensable integrator of transcriptional complexes that control the rate-limiting steps of hepatic glucose release and accretion. Collectively, these findings position SRC-2 as a major regulator of polygenic inputs to metabolic gene regulation and perhaps identify a previously unappreciated model that helps to explain the clinical spectrum of glucose dysregulation.

Free flap surgery is a procedure where healthy tissue is transferred from a donor site to a recipient site of the body to fill a defect without maintaining the original blood supply to the flap. The anastomosis of the vascular network of the flap to the blood vessels adjacent to the recipient site has associated risks of arterial and/or venous occlusions that must be promptly detected to avoid temporary or permanent tissue damage. In this work, we present a skin-contact diffusion optical imaging (DOI) system able to continuously provide a three-dimensional representation of the flap oxygenation to promptly detect vascular occlusions potentially occurring in the flap. Multiple near-infrared LEDs and photodetectors were embedded into a self-contained optical sensor for prolonged monitoring of concentration changes of oxygenated (HbO) and deoxygenated hemoglobin (HbR) at multiple locations and depths. A time-efficient algorithm mapped measured oxygenation changes in a three-dimensional volume to allow surgeons and clinical personnel to detect and localize abnormal blood perfusion changes during or after surgery, in time for corrective intervention. The image reconstruction algorithm was validated using computerized flap models in which oxygenation was synthetically altered, whereas the optical system was preliminarily tested on a healthy forearm simulating a flap undergoing arterial and venous occlusions, proving the feasibility of implementing DOI in the form of a wearable patch for prolonged perfusion monitoring.

Source Citation Welk B, McArthur E, Ordon M, et al. Association of suicidality and depression with 5α-reductase inhibitors. JAMA Intern Med. 2017;177:683-91. 28319231

Congestive heart failure (CHF) is a chronic medical condition, and early detection of acute cardiac events caused by CHF can lead to life saving results. In this paper, we present Blue Scale, a measuring device that allows both patients and their physicians to monitor cardiac health at home on a daily basis by providing the necessary feedback for early cardiac event detection. Blue Scale measures electrocardiography (EKG), systolic time intervals through photoplethysmography (PPG), weight, and whole body bioimpedance. Collected datasets are transmitted to a central database using a secure Wi-Fi 802.11b/g protocol for remote data analysis and disease management. Following a test deployment in different populations, we conclude that off-device signal processing is required to ensure the accuracy of derived measurements. Furthermore, our anomaly emulation experiments yield average Z-scores of below 2 for most EKG and PPG related metrics, and the resulting Z-scores also vary significantly across different patients. These observations indicate that a standard 95% confidence interval is not sufficient for attribute-by-attribute anomaly detection, and any cardiac monitoring systems need to be tailored to each individual.

Growing emphasis on ambulatory service delivery in academic medical centers has heightened interest in improving operational efficiencies, while providing an optimal educational experience for medical students and residents. One significant challenge in the academic environment is maximizing resource utilization (both physical plant and personnel), through scheduling and operational effectiveness. This article examines how academic ambulatory practices can apply operational and scheduling process redesign methodologies to improve throughput and productivity, while enhancing the educational experience for students/residents.

SUBJECT and PURPOSE: This translational epidemiologic study conducted online aims to confirm preclinical data on the chemopreventive potential of chloroquine (aminoquinoline), a well-characterized anti-malarial drug. BACKGROUND: Exposure to chloroquine, an off-patent anti-malarial drug with a 60-year history of use by millions, reduces the incidence of breast cancer in genetically programmed rats by 37%. METHODS and SCOPE: About 65% of Peace Corps volunteers received chloroquine prophylactically between 1965 and 1990. Therefore, we will collect chloroquine exposure, breast cancer risk, and breast cancer diagnosis data from returned volunteers who served during this period through an online application. We will characterize participants into chloroquine exposed and unexposed groups, based on country of service and self-reported exposure status. The cost and time efficiencies afforded by this study design will allow the translation of preclinical data on breast cancer chemoprevention into public health and potentially promote the repositioning of a well-characterized and inexpensive drug.

Chronic disease is the new great health challenge. Management requires the patient to have real-time information about the state of his or her illness in order to make informed judgments. We designed and built a family of small, inexpensive biosensors to monitor cardiac output, blood pressure, airway flow and other parameters. They connect via mobile phone or WiFi allowing people with chronic disease to monitor and modify their illnesses thus avoiding unexpected exacerbations or decompensation events. The combination of ubiquitous computing and personalized interpretation algorithms can be expected to provide a substantially higher quality interaction between the health care establishment and the chronic disease patient. Although not the solution to the health care dilemma, empowerment is an important feature of improved outcomes.

A wide variety of organisms and conditions have been reported to cause pericarditis in patients that present and die with AIDS. Although pericarditis is remarkably common in patients dying of AIDS, no consistent pattern of cause emerges. Patients with AIDS are susceptible to pericarditis as a concomitant of the terminal condition, but it seldom contributes to the patient's death. Alternatively, pericarditis (as opposed to silent pericardial effusion) as a cardinal symptom in a patient's illness is likely to have an origin that can be ascribed to organisms typically associated with infectious pericarditis in those patients who have profound cellular immunodeficiency. Thus, it is important to make the diagnosis of infectious or neoplastic pericarditis in the setting of AIDS, since control of the agent has the potential of influencing the clinical course. In the absence of signs of hemodynamic compromise or inflammation, pericardial effusion may be accepted as an accompaniment of pleural effusions or ascites in the appropriate clinical context. Invasive diagnostic measures may be reserved for those cases in which pericardial disease is a prominent feature of the symptom complex or of accompanying pleural effusion. The study of epidemiology and biology of AIDS is a rapidly changing field. Explanations of the high incidence of pericardial disease in terminal disease may emerge with broad-ranging studies of the incidence of myocarditis in AIDS as well as the relative contribution to pericardial disease of agents used in the treatment of the illness.

Background Congestive Heart Failure (CHF) is a serious cardiac condition that brings high risks of urgent hospitalization and death. Remote monitoring systems are well-suited to managing patients suffering from CHF, and can reduce deaths and re-hospitalizations, as shown by the literature, including multiple systematic reviews. Methods The monitoring system proposed in this paper aims at helping CHF stakeholders make appropriate decisions in managing the disease and preventing cardiac events, such as decompensation, which can lead to hospitalization or death. Monitoring activities are stratified into three layers: scheduled visits to a hospital following up on a cardiac event, home monitoring visits by nurses, and patient's self-monitoring performed at home using specialized equipment. Appropriate hardware, desktop and mobile software applications were developed to enable a patient's monitoring by all stakeholders. For the first two layers, we designed and implemented a Decision Support System (DSS) using machine learning (Random Forest algorithm) to predict the number of decompensations per year and to assess the heart failure severity based on a variety of clinical data. For the third layer, custom-designed sensors (the Blue Scale system) for electrocardiogram (EKG), pulse transit times, bio-impedance and weight allowed frequent collection of CHF-related data in the comfort of the patient's home. We also performed a short-term Heart Rate Variability (HRV) analysis on electrocardiograms self-acquired by 15 healthy volunteers and compared the obtained parameters with those of 15 CHF patients from PhysioNet's PhysioBank archives. Results We report numerical performances of the DSS, calculated as multiclass accuracy, sensitivity and specificity in a 10-fold cross-validation. The obtained average accuracies are: 71.9% in predicting the number of decompensations and 81.3% in severity assessment. The most serious class in severity assessment is detected with good sensitivity and specificity (0.87 / 0.95), while, in predicting decompensation, high specificity combined with good sensitivity prevents false alarms. The HRV parameters extracted from the self-measured EKG using the Blue Scale system of sensors are comparable with those reported in the literature about healthy people. Conclusions The performance of DSSs trained with new patients confirmed the results of previous work, and emphasizes the strong correlation between some CHF markers, such as brain natriuretic peptide (BNP) and ejection fraction (EF), with the outputs of interest. Comparing HRV parameters from healthy volunteers with HRV parameters obtained from PhysioBank archives, we confirm the literature that considers the HRV a promising method for distinguishing healthy from CHF patients.

The leadership at EMBS created the IEEE Journal of Translational Engineering in Health and Medicine (JTEHM) to address the critical need to disseminate innovative translational research in health and medicine. The journal's unique aim is to support the movement of biotechnological innovations from idea to clinical trials and commercialization. We intend for JTEHM to provide a vehicle for the consilience of engineering, medicine and health, and translation. Translation is the critical step to take technological advances from the lab into the clinical environment to improve clinical practice and healthcare. We chose the open-access route not because it is easier (it is not) but because it lays waste to the barrier of cost of reading. We are proud to introduce JTEHM with an open-source, continuous-publication platform that allows multimedia presentation of clinically significant translational technologies, along with editorial blogs and comments from experts, entrepreneurs and clinicians. The papers published in JTEHM are accessible through IEEE Xplore and will be in PubMed soon, as well as in downloadable PDF versions with additional material. We welcome submission of your research findings and clinical translation studies.

Mycobacteria cause a broad repertoire of human disease. In the nervous system, the most important of the mycobacteria are Mycobacterium tuberculosis and Mycobacterium leprae . Nontuberculous mycobacteria, historically known as atypical mycobacteria or mycobacteria other than tuberculosis (MOTT), have also been implicated in nervous system disease, but only rarely. Mycobacteria share the characteristic of producing surface lipids that render them acid-fast, meaning that they cannot be decolorized by acid alcohol after staining. Although some other organisms (such as Nocardia ) sometimes are acid-fast, most organisms with this staining characteristic are mycobacteria. Mycobacteria generally are slow-growing, and in the laboratory they need supplemented media and a 5% to 10% CO 2 atmosphere.

The Epstein-Barr virus (EBV) is one of the herpes viruses that infect humans. Other members of this group include herpes simplex types I and II, varicella-zoster virus, cytomegalovirus, human herpes virus types 6, 7, and 8, and simian herpes B virus ( Herpes simiae ). The latter is primarily an infection of nonhuman primates, with humans as accidental hosts. Herpes viruses share some common characteristics. They all produce viral latency, meaning that the viral genetic material is integrated into that of the host. However, this does not mean that the virus is completely dormant because there is production and display of virus antigens of EBV on host cell surfaces. EBV is different from other human herpes viruses in that it has several distinct antigens that do not cross-react. These antigens provide unique serologic markers for EBV activity.

Background: Asthma is the most common chronic disease in childhood, disproportionately affecting urban, minority, and disadvantaged children. Individualized care plans supported by daily lung-function monitoring can reduce morbidity and mortality. However, despite 20 years of interventions to increase adherence, only 50% of US youth accurately follow their care plans, which leads to millions of preventable hospitalizations, emergency room visits, and sick days every year. We present a feasibility study of a novel, user-centered approach to increasing young people’s lung-function monitoring and asthma self-care. Promoting Lung Assessment in Youth (PLAY) helps young people become active managers of their asthma through the Web 2.0 principles of participation, cocreation, and information sharing. Specifically, PLAY combines an inexpensive, portable spirometer with the motivational power and convenience of mobile phones and virtual-community gaming. Objective: The objective of this study was to develop and pilot test InSpire, a fully functional interface between a handheld spirometer and an interactive game and individualized asthma-care instant-messaging system housed on a mobile phone. Methods: InSpire is an application for mobile smartphones that creates a compelling world in which youth collaborate with their physicians on managing their asthma. Drawing from design-theory on global timer mechanics and role playing, we incentivized completing spirometry maneuvers by making them an engaging part of a game young people would want to play. The data can be sent wirelessly to health specialists and return care recommendations to patients in real-time. By making it portable and similar to applications normally desired by the target demographic, InSpire is able to seamlessly incorporate asthma management into their lifestyle. Results: We describe the development process of building and testing the InSpire prototype. To our knowledge, the prototype is a first-of-its kind mobile one-stop shop for asthma management. Feasibility testing in children aged 7 to 14 with asthma assessed likability of the graphical user interface as well as young people’s interest in our incentivizing system. Nearly 100% of children surveyed said they would play games like those in PLAY if they involved breathing into a spirometer. Two-thirds said they would prefer PLAY over the spirometer alone, whereas 1/3 would prefer having both. No children said they would prefer the spirometer over PLAY. Conclusions: Previous efforts at home-monitoring of asthma in children have experienced rapid decline in adherence. An inexpensive monitoring technology combined with the computation, interactive communication, and display ability of a mobile phone is a promising approach to sustainable adherence to lung-function monitoring and care plans. An exciting game that redefines the way youth conduct health management by inviting them to collaborate in their health better can be an incentive and a catalyst for more far-reaching goals.

BackgroundMen diagnosed with localized prostate cancer face a potentially life-altering treatment decision that can be overwhelming. Enhancing patient knowledge through education can significantly reduce feelings of uncertainty while simultaneously increasing confidence in decision making. Serious games have been shown in other populations to increase health knowledge and assist with the health decision-making process. We developed an interactive serious game, Time After Time, which translates evidence-based treatment outcome data into an accessible and understandable format that men can utilize in their prostate cancer treatment decision-making process. The game specifically aims to raise men’s awareness and understanding of the impact of health-related quality of life issues associated with the major treatment options and to enrich their conversations with their health care providers. ObjectiveThis study determined the acceptability and usability of the alpha version of Time After Time, an interactive decision aid for men diagnosed with localized prostate cancer, in order to inform future iterations of the serious game. MethodsThe study employed a mixed methods approach to assess the acceptability and usability of the Time After Time serious game using qualitative focus groups and a quantitative Likert scale survey. ResultsA total of 13 men who had already completed treatment for localized prostate cancer completed the survey and participated in focus group meetings. The majority of the study participants rated Time After Time as an appropriate decision tool for localized prostate cancer and verified that it meets its goals of increasing focus on side effects and generating questions for the patient’s health care team. However, participants also expressed concerns about game usability and the diversity of information covered regarding treatment options and potential treatment outcomes. ConclusionsSerious games are a promising approach to health education and decision support for older men. Participants were receptive to the idea of a serious game as a decision aid in localized prostate cancer. However, usability issues are a major concern for this demographic, as is clarity and transparency of data sources.