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Upregulation of MYC is a hallmark of cancer, wherein MYC drives oncogenic gene expression and elevates total RNA synthesis across cancer cell transcriptomes. Although this transcriptional anabolism fuels cancer growth and survival, the consequences and metabolic stresses induced by excess cellular RNA are poorly understood. Herein, we discover that RNA degradation and downstream ribonucleotide catabolism is a novel mechanism of MYC-induced cancer cell death. Combining genetics and metabolomics, we find that MYC increases RNA decay through the cytoplasmic exosome, resulting in the accumulation of cytotoxic RNA catabolites and reactive oxygen species. Notably, tumor-derived exosome mutations abrogate MYC-induced cell death, suggesting excess RNA decay may be toxic to human cancers. In agreement, purine salvage acts as a compensatory pathway that mitigates MYC-induced ribonucleotide catabolism, and inhibitors of purine salvage impair MYC+ tumor progression. Together, these data suggest that MYC-induced RNA decay is an oncogenic stress that can be exploited therapeutically. Significance: MYC is the most common oncogenic driver of poor-prognosis cancers but has been recalcitrant to therapeutic inhibition. We discovered a new vulnerability in MYC+ cancer where MYC induces cell death through excess RNA decay. Therapeutics that exacerbate downstream ribonucleotide catabolism provide a therapeutically tractable approach to TNBC (Triple-negative Breast Cancer) and other MYC-driven cancers., (©2024 The Authors; Published by the American Association for Cancer Research.)

We recently discovered that steroid receptor coactivators (SRCs) SRCs-1, 2 and 3, are abundantly expressed in cardiac fibroblasts (CFs) and their activation with the SRC small molecule stimulator MCB-613 improves cardiac function and dramatically lowers pro-fibrotic signaling in CFs post-myocardial infarction. These findings suggest that CF-derived SRC activation could be beneficial in the mitigation of chronic heart failure after ischemic insult. However, the cardioprotective mechanisms by which CFs contribute to cardiac pathological remodeling are unclear. Here we present studies designed to identify the molecular and cellular circuitry that governs the anti-fibrotic effects of an MCB-613 derivative, MCB-613-10-1, in CFs. We performed cytokine profiling and whole transcriptome and proteome analyses of CF-derived signals in response to MCB-613-10-1. We identified the NRF2 pathway as a direct MCB-613-10-1 therapeutic target for promoting resistance to oxidative stress in CFs. We show that MCB-613-10-1 promotes cell survival of anti-fibrotic CFs exposed to oxidative stress by suppressing apoptosis. We demonstrate that an increase in HMOX1 expression contributes to CF resistance to oxidative stress-mediated apoptosis via a mechanism involving SRC co-activation of NRF2, hence reducing inflammation and fibrosis. We provide evidence that MCB-613-10-1 acts as a protectant against oxidative stress-induced mitochondrial damage. Our data reveal that SRC stimulation of the NRF2 transcriptional network promotes resistance to oxidative stress and highlights a mechanistic approach toward addressing pathologic cardiac remodeling., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: Medical decision-making is often uncertain. The positive predictive value (PPV) and negative predictive value (NPV) are conditional probabilities characterizing diagnostic tests and assessing diagnostic interventions in clinical medicine and epidemiology. The PPV is the probability that a patient has a specified disease, given a positive test result for that disease. The NPV is the probability that a patient does not have the disease, given a negative test result for that disease. Both values depend on disease incidence or prevalence, which may be highly uncertain for unfamiliar diseases, epidemics, etc. Probability distributions for this uncertainty are usually unavailable. We develop a non-probabilistic method for interpreting PPV and NPV with uncertain prevalence., Methods: Uncertainty in PPV and NPV is managed with the non-probabilistic concept of robustness in info-gap theory. Robustness of PPV or NPV estimates is the greatest uncertainty (in prevalence) at which the estimate's error is acceptable., Results: Four properties are demonstrated. Zeroing: best estimates of PPV or NPV have no robustness to uncertain prevalence; best estimates are unreliable for interpreting diagnostic tests. Trade-off: robustness increases as error increases; this trade-off identifies robustly reliable error in PPV or NPV. Preference reversal: sometimes sub-optimal PPV or NPV estimates are more robust to uncertain incidence or prevalence than optimal estimates, motivating reversal of preference from the putative optimum to the sub-optimal estimate. Trade-off between specificity and robustness to uncertainty: the robustness increases as test-specificity decreases. These four properties underlie the interpretation of PPV and NPV., Conclusions: The PPV and NPV assess diagnostic tests, but are sensitive to lack of knowledge that generates non-probabilistic uncertain prevalence and must be supplemented with robustness analysis. When uncertainties abound, as with unfamiliar diseases, assessing robustness is critical to avoiding erroneous decisions.

Steroid 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 preestablished breast tumors by generating potent antitumor immunity with a durable effect that prevents tumor reoccurrence. Therefore, treatment with SRC-3-deleted Tregs represents an approach to completely block tumor growth and recurrence without the autoimmune side effects that typically accompany immune checkpoint modulators.

Introduction: Pathologic remodeling of the brain following ischemic stroke results in neuronal loss, increased inflammation, oxidative stress, astrogliosis, and a progressive decrease in brain function. We recently demonstrated that stimulation of steroid receptor coactivator 3 with the small-molecule stimulator MCB-613 improves cardiac function in a mouse model of myocardial ischemia. Since steroid receptor coactivators are ubiquitously expressed in the brain, we reasoned that an MCB-613 derivative (MCB-10-1), could protect the brain following ischemic injury. To test this, we administered MCB-10-1 to rats following middle cerebral artery occlusion and reperfusion. Methods: Neurologic impairment and tissue damage responses were evaluated on day 1 and day 4 following injury in rats treated with control or 10-1. Results: We show that 10-1 attenuates injury post-stroke. 10-1 decreases infarct size and mitigates neurologic impairment. When given within 30 min post middle cerebral artery occlusion and reperfusion, 10-1 induces lasting protection from tissue damage in the ischemic penumbra concomitant with: (1) promotion of reparative microglia; (2) an increase in astrocyte NRF2 and GLT-1 expression; (3) early microglia activation; and (4) attenuation of astrogliosis. Discussion: Steroid receptor coactivator stimulation with MCB-10-1 is a potential therapeutic strategy for reducing inflammation and oxidative damage that cause neurologic impairment following an acute ischemic stroke., Competing Interests: SRC stimulator compounds are being developed for stroke and other ischemic injury-related diseases by CoRegen, Inc. affiliated with LM, DL, CD, and BO’M. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 McClendon, Garcia, Lazaro, Robledo, Vasandani, Luna, Rao, Srivatsan, Lonard, Dacso, Kan and O’Malley.)

The 12-h clock coordinates lipid homeostasis, energy metabolism, and stress rhythms via the transcriptional regulator XBP1. However, the biochemical and physiological bases for integrated control of the 12-h clock and diverse metabolic pathways remain unclear. Here, we show that steroid receptor coactivator SRC-3 coactivates XBP1 transcription and regulates hepatic 12-h cistrome and gene rhythmicity. Mice lacking SRC-3 show abnormal 12-h rhythms in hepatic transcription, metabolic functions, systemic energetics, and rate-limiting lipid metabolic processes, including triglyceride, phospholipid, and cardiolipin pathways. Notably, 12-h clock coactivation is not only preserved, with its cistromic activation priming ahead of the zeitgeber cue of light, but concomitant with rhythmic remodeling in the absence of food. These findings reveal that SRC-3 integrates the mammalian 12-h clock, energy metabolism, and membrane and lipid homeostasis and demonstrates a role for the 12-h clock machinery as an active transcriptional mechanism in anticipating physiological and metabolic energy needs and stresses., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

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., Competing Interests: The authors declare no competing interest., (Copyright © 2020 the Author(s). Published by PNAS.)

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.

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., Competing Interests: The authors have declared that no competing interests exist.

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., Competing Interests: The authors have declared that no competing interests exist.

"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.

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., (Copyright © 2017 Elsevier Inc. All rights reserved.)

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., (Copyright © 2015 Elsevier Inc. All rights reserved.)

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.

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.

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 proliferation of journals has had an unexpected side effect: it is now difficult to find qualified reviewers willing to devote the time necessary for assessing journal contributions. Although it is difficult to find data, most scientists involved in the academic world have their inboxes deluged with a cornucopia of invitations to submit to new journals, speak at conferences (as a keynote, for sure!), and review articles. New online journals (such as ours) strive to publish the finest and most relevant work for our readers while at the same time maintaining rapid "turn around times" for authors. This requires that a complex system function flawlessly. But, there are some aspects of the system that are creaky; some are broken entirely.

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.

Background: Formulation and evaluation of public health policy commonly employs science-based mathematical models. For instance, epidemiological dynamics of TB is dominated, in general, by flow between actively and latently infected populations. Thus modelling is central in planning public health intervention. However, models are highly uncertain because they are based on observations that are geographically and temporally distinct from the population to which they are applied., Aims: We aim to demonstrate the advantages of info-gap theory, a non-probabilistic approach to severe uncertainty when worst cases cannot be reliably identified and probability distributions are unreliable or unavailable. Info-gap is applied here to mathematical modelling of epidemics and analysis of public health decision-making., Methods: Applying info-gap robustness analysis to tuberculosis/HIV (TB/HIV) epidemics, we illustrate the critical role of incorporating uncertainty in formulating recommendations for interventions. Robustness is assessed as the magnitude of uncertainty that can be tolerated by a given intervention. We illustrate the methodology by exploring interventions that alter the rates of diagnosis, cure, relapse and HIV infection., Results: We demonstrate several policy implications. Equivalence among alternative rates of diagnosis and relapse are identified. The impact of initial TB and HIV prevalence on the robustness to uncertainty is quantified. In some configurations, increased aggressiveness of intervention improves the predicted outcome but also reduces the robustness to uncertainty. Similarly, predicted outcomes may be better at larger target times, but may also be more vulnerable to model error., Conclusions: The info-gap framework is useful for managing model uncertainty and is attractive when uncertainties on model parameters are extreme. When a public health model underlies guidelines, info-gap decision theory provides valuable insight into the confidence of achieving agreed-upon goals.

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.

Current methods for monitoring exercise exertion rely upon heart rate monitors, which represent a crude and lagging indicator of conditioning. The rationale for the present study is that both systemic and local metabolic mechanisms are responsible for physical performance, and therefore they should be simultaneously quantified to achieve an objective assessment of human conditioning. We propose a compact, wearable near-infrared spectroscopy (NIRS) device integrated with electrocardiography (ECG) and photoplethysmography (PPG) to simultaneously assess the cardiovascular and local response to exercise. The system was tested on subjects performing a graded maximal exercise by comparing our readings with metabolic variables measured with respiratory gas analysis. We found strong correlations between local deoxyhemoglobin concentration [HHb], heart rate and oxygen uptake, as well as between oxyhemoglobin concentration [HbO(2)] and stroke volume. This study shows that combined NIRS, ECG and PPG measurements yield useful information to understand the interplay between systemic and local muscular responses to exercise.

Background: Men 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., Objective: This 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., Methods: The 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., Results: A 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., Conclusions: Serious 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.

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.

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.

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.

Two infections by swine influenza virus, antigenically similar to A/New Jersey/76 (H1N1) virus, were detected during community epidemics with other influenza viruses. The swinelike viruses were obtained during virological surveillance of acute respiratory illnesses, and the clinical symptoms of these two patients were similar to those caused by other respiratory viruses. Both patients reported contact with swine a few days before onset of illness, but in one case it was brief. Serological studies suggested that one patient may have transmitted the virus to his roommate, but spread into the community was not indicated.

Systemic sepsis resulting from invasive infection remains the leading cause of death among patients hospitalized with major thermal injury. Prevention of infection and death in burn patients requires a thorough knowledge of the multiple predisposing factors involved and expert application of appropriate diagnostic, supportive, and therapeutic modalities. The improved survival in this population is a result of all these factors, not any one. It is this principle and the adherence to a treatment program that encompasses all the modalities which are so essential in the care of burn patients if continuing progress is to be made in this field. This article describes the current management of infection and infection control in burn patients. The burn wound and pulmonary system remain the major foci for infection in this population. Less common types of infection include suppurative thrombophlebitis, suppurative chondritis, bacterial endocarditis, urinary tract sepsis, sinusitis, intra-abdominal sepsis, and infections of the eyes. Prophylaxis protocols involve proper control of the environment and an anticipation of bacterial colonization. A number of specific monitoring and treatment guidelines have evolved that have proved effective over the years in minimizing morbidity and mortality.

The prophylactic effect of low doses of human leukocyte interferon (HuIFN-alpha) against infection with rhinovirus was measured in double-blind, placebo-controlled studies with volunteer subjects. An antihistamine (chlorpheniramine) was given before administration of single or multiple doses of HuIFN-alpha but saturated cotton pledget or by aerosol; volunteers were then challenged with rhinovirus. When the results for all groups were combined, a lower frequency of respiratory illness was demonstrated in the HuIFN-alpha-treated volunteers (20 of 39 vs. 11 of 38, P less than 0.05). A significant improvement in mean symptom scores was found only in the volunteers who received HuIFN-alpha by cotton pledget. The total numbers of isolates of rhinovirus and seroconversions were similar for HuIFN-alpha-treated and control volunteers. No significant side effects were noted in the HuIFN-alpha-treated volunteers. Higher concentrations or improved methods of delivery of HuIFN-alpha will be necessary for improving the clinical efficacy of HuIFN-alpha against viral infections in the respiratory system.

A patient with acute bacterial endocarditis in whom ischaemic contracture of the left ventricle (stone-heart syndrome) developed during aortic and mitral valve replacement had an emergency implantation of an intracorporeal partial artificial heart (an abdominal left-ventricular assist device of ALVAD). This device functioned as a total artificial heart for nearly 6 days, while a donor heart for transplantation was sought. The ALVAD was then removed, and the patient received allografts of a heart and a kidney. The transplanted heart functioned well, but the patient died 15 days later from gram-negative sepsis. There was no evidence of cardiac or renal allograft rejection.

The abdominal left ventricular assist device (ALVAD) is an order of magnitude more effective than conventional intra-aortic balloon pumping (IABP) in unloading and providing circulatory support to the failing left ventricle. This is a report of a unique case which demonstrates that in the absence of pulmonary vascular obstruction or constriction, the ALVAD can substitute for both left and right heart function. A 21-year-old patient with a congenital bicuspid aortic valve developed acute valvular endocarditis which rapidly progressed to congestive heart failure. An operation was undertaken, the mitral and aortic valves were excised and replaced by porcine heterografts, and a fistula from the right sinus of Valsalva to the right ventricle was closed. When coronary circulation was restored, irreversible ischemic contracture of the left ventricle, or "stone heart" syndrome, developed and emergency ALVAD or partial artificial heart implantation was effected. This device functioned as a total artificial heart for nearly six days, while a donor heart was sought. The patient then underwent removal of the ALVAD and cardiac and renal allografting. The transplanted heart functioned well, but the patient expired fifteen days later from gram-negative sepsis.

Systemic antibiotics are a valuable therapeutic modality in the burned patient when properly used. Injudicious use, however, may not only fail to be beneficial to the patient but also may produce harmful effects--either through direct toxicity or by contributing to the emergence of resistant strains of micro-organisms. General guidelines and principles for systemic antibiotic use include the following: The burned patient, despite all efforts, will be exposed to microorganisms. No single agent or combination of agents can destroy all the organisms to which the burned patient is exposed. Treatment involves first identifying the organism responsible for clinical sepsis, then choosing appropriate agents. Combinations of antibiotics are not always synergistic or even additive in effect. Multiagent therapy may have the untoward effect of predisposing to superinfection by yeast, fungi, or resistant organisms. Antibiotics should be used for a long enough period to produce an effect, but not long enough to allow for emergence of opportunistic or resistant organisms. Dosages must be adjusted based on serum concentrations when serum assays are available. In general prophylactic systemic antibiotics are indicated in only a few clinical situations including the immediate preoperative and postoperative periods associated with excision and autografting, and possibly in the early phases of burns in children. The penetration of systemic antibiotics into burn eschar remains an area not fully studied; hence, they cannot be the only therapeutic modality used to treat burn wound infection. Systemic dosages of antibiotics in burns will require alteration depending on the clinical status of the patient. The choice of agent requires a thorough knowledge of side effects, toxicity, and potential benefit. Above all, active surveillance and monitoring of the burned patient and the environment in which he or she is being treated is mandatory for effective treatment. The increasing number of new antimicrobial agents has presented a new dilemma to the practicing clinician because many of these agents have not been evaluated thoroughly in the burned population. With further studies, the armamentarium of the burn treatment team will inevitably increase. It is in this manner only that so many of the unanswered questions will be solved, and that infection will start to decline as the major cause of death in the burned population.

The Argyll Robertson pupil, a miotic pupil that fails to react to direct light, has been described for more than a century. Originally associated with tabes dorsalis, the sign has now been found in a number of conditions with lesions in the area of the nucleus of Edinger-Westphal. Magnetic resonance imaging studies have localized the lesion in patients with sarcoidosis and multiple sclerosis. With the declining incidence of neurosyphilis, the sign is increasingly likely to indicate another cause, although an assiduous search for lues should also be undertaken.

The Department of Veterans Affairs (VA) is undergoing change in the way it delivers health care. Forces underlying this change include demographics of its population, new fiscal constraints, and the requirements of its academic affiliates. The benefit to the medical school affiliates will be the availability of patients in a structure useful for outpatient teaching of medical students and houseofficers. Barriers to effective delivery of ambulatory health care and education in VA facilities are (1) the historic focus on episodic, inpatient care, (2) continuous changes in eligibility requirements, (3) increases in patient care responsibilities for affiliated faculty, and (4) concomitant withdrawal of resources from the VA at a time when costs of health care and education are increasing. The VA medical centers will be increasingly forced to investigate innovative models for patient care delivery and education in the ambulatory setting.