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In the modern world, stress has become a pervasive concern that affects individuals' physical and mental well-being. To address this issue, many wearable devices have emerged as potential tools for stress detection and management by measuring heart rate, heart rate variability (HRV), and various metrics related to it. This literature review aims to provide a comprehensive analysis of existing research on HRV tracking and biofeedback using smartwatches pairing with reliable 3rd party mobile apps like Elite HRV, Welltory, and HRV4Training specifically designed for stress detection and management. We apply various algorithms and methodologies employed for HRV analysis and stress detection including time-domain, frequency-domain, and non-linear analysis techniques. Prominent smartwatches, such as Apple Watch, Garmin, Fitbit, Polar, and Samsung Galaxy Watch, are evaluated based on their HRV measurement accuracy, data quality, sensor technology, and integration with stress management features. We describe the efficacy of smartwatches in providing real-time stress feedback, personalized stress management interventions, and promoting overall well-being. To assist researchers, doctors, and developers with using smartwatch technology to address stress and promote holistic well-being, we discuss the data's advantages and limitations, future developments, and the significance of user-centered design and personalized interventions.

Background: Tofacitinib is an oral Janus kinase inhibitor. This trial assessed the efficacy and safety of tofacitinib versus placebo in patients with polyarticular course juvenile idiopathic arthritis (JIA)., Methods: This double-blind, withdrawal phase 3 trial enrolled patients with polyarticular course JIA (extended oligoarthritis, rheumatoid factor-positive or rheumatoid factor-negative polyarthritis, or systemic JIA without active systemic features) aged 2 years to younger than 18 years, and was done at 64 centres of the Paediatric Rheumatology International Trials Organisation and Pediatric Rheumatology Collaborative Study Group networks in 14 countries. Patients with psoriatic arthritis or enthesitis-related arthritis were enrolled for exploratory endpoints. During part 1 of the study, patients received oral open-label tofacitinib (weight-based doses; 5 mg twice daily or lower) for 18 weeks. Patients achieving at least JIA/American College of Rheumatology 30 response were randomly assigned (1:1) using an Interactive Response Technology system to continue tofacitinib or switch to placebo in part 2 of the study for 26 weeks. The primary endpoint was JIA flare rate by week 44 in part 2 in patients with polyarticular course JIA; the intention-to-treat principle was applied. Safety was evaluated throughout part 1 and part 2 of the study in all patients who received one dose or more of study medication. This trial is registered with ClinicalTrials.gov, NCT02592434., Findings: Between June 10, 2016, and May 16, 2019, of 225 patients enrolled, 184 (82%) patients had polyarticular course JIA, 20 (9%) had psoriatic arthritis, and 21 (9%) had enthesitis-related arthritis. 147 (65%) of 225 patients received concomitant methotrexate. In part 2, 142 patients with polyarticular course JIA were assigned to tofacitinib (n=72) or placebo (n=70). Flare rate by week 44 was significantly lower with tofacitinib (21 [29%] of 72 patients) than with placebo (37 [53%] of 70 patients; hazard ratio 0·46, 95% CI 0·27-0·79; p=0·0031). In part 2 of the study, adverse events occurred in 68 (77%) of 88 patients receiving tofacitinib and 63 (74%) of 85 in the placebo group. Serious adverse events occurred in one (1%) and two (2%), respectively. In the entire tofacitinib exposure period, 107 (48%) of 225 patients had infections or infestations. There were no deaths during this study., Interpretation: The results of this pivotal trial show that tofacitinib is an effective treatment in patients with polyarticular course JIA. New oral therapies are particularly relevant for children and adolescents, who might prefer to avoid injections., Funding: Pfizer., Competing Interests: Declaration of interests NR has received honoraria for consultancy fees or speaker bureaus from Ablynx, AstraZeneca/MedImmune, Biogen, Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly, EMD Serono, F Hoffmann-La Roche, GlaxoSmithKline, Janssen, Merck Sharp and Dohme, Novartis, Pfizer, R-Pharm, Sanofi, Servier, Sinergie, and Sobi. The IRCCS Istituto Giannina Gaslini, where NR works as a full-time public employee, has received contributions from the following pharmaceutical companies in the past 3 years: Bristol-Myers Squibb, Eli Lilly, F Hoffmann-La Roche, GlaxoSmithKline, Janssen, Novartis, Pfizer, and Sobi; this funding has been reinvested for the research activities of the hospital in a fully independent manner, without any involvement of third parties. HIB has received research grants from Bristol-Myers Squibb, MedImmune, Novartis, and Pfizer; is an employee of Cincinnati Children's Hospital Medical Center; has received consulting fees or other remuneration from AbbVie, AstraZeneca/MedImmune, Bayer, Biocon, Boehringer Ingelheim, Janssen, Lilly, Bristol-Myers Squibb, Novartis, Pfizer, Roche, and R-Pharm; and is a member of speaker bureaus for GlaxoSmithKline, Novartis, and Roche. OS is a member of a speaker bureau for Sanofi. AS is a member of a speaker bureau for Eli Lilly. KM has received research grants from Novartis and Pfizer. SP has received consulting fees or other remuneration from Novartis. EZ is a member of speaker bureaus for AbbVie, Novartis, Pfizer, and Roche. ML has received research grants from Amgen. KN has received research grants from Abbott, AbbVie, Amgen, Bristol-Myers Squibb, Patient-Centered Outcomes Research Institute, and Roche. HS has received research grants from Bristol-Myers Squibb, Janssen, Pfizer, Roche, Sanofi, and USB Bioscience. YU is a member of a speaker bureau for Pfizer. DOV has received research grants from Bristol-Myers Squibb, GlaxoSmithKline, Janssen, and Pfizer; and is a member of speaker bureaus for AbbVie and Bristol-Myers Squibb. HBP, KSK, AW, CC, RZ, M-AH, and RMS are employees and stockholders of Pfizer. IL is an employee of IQVIA, who were paid contractors to Pfizer in the development of this manuscript and in providing statistical support. AM has received consulting fees or other remuneration from Aurinia, Bristol-Myers Squibb, Eli Lilly, EMD Serono, Janssen, and Pfizer. DJL's institution, the Cincinnati Children's Hospital Medical Center, has received research grants from Bristol-Myers Squibb, Janssen, Novartis, Pfizer, Roche, and UCB; and has received consulting fees or other remuneration from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, Pfizer, Roche, Takeda, and UCB for the work of DJL. DJL is a Data Safety and Monitoring Board chairperson for Forest Research and the National Institutes of Health. All otjer authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Mental Illnesses, particularly anxiety, insomnia, and depression often involve vicious cycles which are self-perpetuating and can trap one into a more chronic state. For example in the case of insomnia, sympathetic overactivity, intrusive thoughts, and emotional instability due to sleep loss can perpetuate further sleep loss the next night and so on. In this article, we put forward a perspective on breaking these vicious cycles based on preeminent theories in global and spatial cognition, that the foundation of the conscious mind is a spatial coordinate system. Based on this we discuss the potential and future of virtual reality therapeutic applications which utilize massive virtual spaces along with biofeedback designed to help break perpetual cycles in depression, anxiety, and insomnia. "Massive spaces" are those which are truly expansive such as when looking to the clear night sky. These virtual realities may take the form of a night sky, fantastical cosmic scenes, or other scenes such as mountain tops. We also hope to inspire research into such a spatial foundation of mind, use of perceived massive spaces for therapy, and the integration of biofeedback into virtual therapies., Competing Interests: The 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 © 2021 Jerath and Beveridge.)

Pulmonary ventilation and respiration are considered to be primarily involved in oxygenation of blood for oxygen delivery to cells throughout the body for metabolic purposes. Other pulmonary physiological observations, such as respiratory sinus arrhythmia, Hering Brewer reflex, cardiorespiratory synchronization, and the heart rate variability (HRV) relationship with breathing rhythm, lack complete explanations of physiological/functional significance. The spectrum of waveforms of breathing activity correlate to anxiety, depression, anger, stress, and other positive and negative emotions. Respiratory pattern has been thought not only to be influenced by emotion but to itself influence emotion in a bi-directional relationship between the body and the mind. In order to show how filling in gaps in understanding could lead to certain future developments in mind-body medicine, biofeedback, and personal health monitoring, we review and discuss empirical work and tracings to express the vital role of bodily rhythms in influencing emotion, autonomic nervous system activity, and even general neural activity. Future developments in measurement and psychophysiological understanding of the pattern of breathing in combination with other parameters such as HRV, cardiorespiratory synchronization, and skin conductivity may allow for biometric monitoring systems to one day accurately predict affective state and even affective disorders such as anxiety. Better affective prediction based on recent research when incorporated into personal health monitoring devices could greatly improve public mental health by providing at-home biofeedback for greater understanding of one's mental state and for mind-body affective treatments such as breathing exercises., (Copyright © 2020 Jerath and Beveridge.)

BACKGROUNDUndifferentiated systemic autoinflammatory diseases (USAIDs) present diagnostic and therapeutic challenges. Chronic interferon (IFN) signaling and cytokine dysregulation may identify diseases with available targeted treatments.METHODSSixty-six consecutively referred USAID patients underwent underwent screening for the presence of an interferon signature using a standardized type-I IFN-response-gene score (IRG-S), cytokine profiling, and genetic evaluation by next-generation sequencing.RESULTSThirty-six USAID patients (55%) had elevated IRG-S. Neutrophilic panniculitis (40% vs. 0%), basal ganglia calcifications (46% vs. 0%), interstitial lung disease (47% vs. 5%), and myositis (60% vs. 10%) were more prevalent in patients with elevated IRG-S. Moderate IRG-S elevation and highly elevated serum IL-18 distinguished 8 patients with pulmonary alveolar proteinosis (PAP) and recurrent macrophage activation syndrome (MAS). Among patients with panniculitis and progressive cytopenias, 2 patients were compound heterozygous for potentially novel LRBA mutations, 4 patients harbored potentially novel splice variants in IKBKG (which encodes NF-κB essential modulator [NEMO]), and 6 patients had de novo frameshift mutations in SAMD9L. Of additional 12 patients with elevated IRG-S and CANDLE-, SAVI- or Aicardi-Goutières syndrome-like (AGS-like) phenotypes, 5 patients carried mutations in either SAMHD1, TREX1, PSMB8, or PSMG2. Two patients had anti-MDA5 autoantibody-positive juvenile dermatomyositis, and 7 could not be classified. Patients with LRBA, IKBKG, and SAMD9L mutations showed a pattern of IRG elevation that suggests prominent NF-κB activation different from the canonical interferonopathies CANDLE, SAVI, and AGS.CONCLUSIONSIn patients with elevated IRG-S, we identified characteristic clinical features and 3 additional autoinflammatory diseases: IL-18-mediated PAP and recurrent MAS (IL-18PAP-MAS), NEMO deleted exon 5-autoinflammatory syndrome (NEMO-NDAS), and SAMD9L-associated autoinflammatory disease (SAMD9L-SAAD). The IRG-S expands the diagnostic armamentarium in evaluating USAIDs and points to different pathways regulating IRG expression.TRIAL REGISTRATIONClinicalTrials.gov NCT02974595.FUNDINGThe Intramural Research Program of the NIH, NIAID, NIAMS, and the Clinical Center.

Bioelectric oscillations occur throughout the nervous system of nearly all animals, revealed to play an important role in various aspects of cognitive activity such as information processing and feature binding. Modern research into this dynamic and intrinsic bioelectric activity of neural cells continues to raise questions regarding their role in consciousness and cognition. In this theoretical article, we assert a novel interpretation of the hierarchical nature of "brain waves" by identifying that the superposition of multiple oscillations varying in frequency corresponds to the superimposing of the contents of consciousness and cognition. In order to describe this isomorphism, we present a layered model of the global functional oscillations of various frequencies which act as a part of a unified metastable continuum described by the Operational Architectonics theory and suggested to be responsible for the emergence of the phenomenal mind. We detail the purposes, functions, and origins of each layer while proposing our main theory that the superimposition of these oscillatory layers mirrors the superimposition of the components of the integrated phenomenal experience as well as of cognition. In contrast to the traditional view that localizations of high and low-frequency activity are spatially distinct, many authors have suggested a hierarchical nature to oscillations. Our theoretical interpretation is founded in four layers which correlate not only in frequency but in evolutionary development. As other authors have done, we explore how these layers correlate to the phenomenology of human experience. Special importance is placed on the most basal layer of slow oscillations in coordinating and grouping all of the other layers. By detailing the isomorphism between the phenomenal and physiologic aspects of how lower frequency layers provide a foundation for higher frequency layers to be organized upon, we provide a further means to elucidate physiological and cognitive mechanisms of mind and for the well-researched outcomes of certain voluntary breathing patterns and meditative practices which modulate the mind and have therapeutic effects for psychiatric and other disorders., (Copyright © 2019 Jerath, Beveridge and Jensen.)

Objective: To investigate the characteristics and risk factors of a novel parenchymal lung disease (LD), increasingly detected in systemic juvenile idiopathic arthritis (sJIA)., Methods: In a multicentre retrospective study, 61 cases were investigated using physician-reported clinical information and centralised analyses of radiological, pathological and genetic data., Results: LD was associated with distinctive features, including acute erythematous clubbing and a high frequency of anaphylactic reactions to the interleukin (IL)-6 inhibitor, tocilizumab. Serum ferritin elevation and/or significant lymphopaenia preceded LD detection. The most prevalent chest CT pattern was septal thickening, involving the periphery of multiple lobes ± ground-glass opacities. The predominant pathology (23 of 36) was pulmonary alveolar proteinosis and/or endogenous lipoid pneumonia (PAP/ELP), with atypical features including regional involvement and concomitant vascular changes. Apparent severe delayed drug hypersensitivity occurred in some cases. The 5-year survival was 42%. Whole exome sequencing (20 of 61) did not identify a novel monogenic defect or likely causal PAP-related or macrophage activation syndrome (MAS)-related mutations. Trisomy 21 and young sJIA onset increased LD risk. Exposure to IL-1 and IL-6 inhibitors (46 of 61) was associated with multiple LD features. By several indicators, severity of sJIA was comparable in drug-exposed subjects and published sJIA cohorts. MAS at sJIA onset was increased in the drug-exposed, but was not associated with LD features., Conclusions: A rare, life-threatening lung disease in sJIA is defined by a constellation of unusual clinical characteristics. The pathology, a PAP/ELP variant, suggests macrophage dysfunction. Inhibitor exposure may promote LD, independent of sJIA severity, in a small subset of treated patients. Treatment/prevention strategies are needed., Competing Interests: Competing interests: VES reports personal fees from Novartis. GD reports personal fees from Novartis. SC reports personal fees from Novartis and grants from AB2 Bio. GS reports personal fees from Novartis. KB reports personal fees from Novartis. RQC is co-PI of an investigator-initiated clinical trial funded by SOBI. RD reports personal fees from Boehringer Ingelheim, other from NowVitals, personal fees and other from Triple Endoscopy, other from Earables, and NowVitals with patents and lung-related device development. AAG reports grants and personal fees from Novartis and grants from NovImmune. SL reports personal fees from Novartis. RS reports personal fees from Novartis, NovImmune and SOBI. SS reports personal fees from Novartis. MLS reports personal fees from Novartis. LRY reports other from Up-To-Date and other from Boehringer Ingelheim, outside the submitted work. EDM reports grants from Novartis., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

How does the integrated and unified conscious experience arise from the vastly distributed activities of the nervous system? How is the information from the many cones of the retina bound with information coming from the cochlea to create the association of sounds with objects in visual space? In this perspective article, we assert a novel viewpoint on the "binding problem" in which we explain a metastable operation of the brain and body that may provide insight into this problem. In our view which is a component of the Default Space Theory (DST), consciousness arises from a metastable synchronization of local computations into a global coherence by a framework of widespread slow and ultraslow oscillations coordinated by the thalamus. We reinforce a notion shared by some consciousness researchers such as Revonsuo and the Fingelkurts that a spatiotemporal matrix is the foundation of phenomenological experience and that this phenomenology is directly tied to bioelectric operations of the nervous system. Through the oscillatory binding system we describe, cognitive neuroscientists may be able to more accurately correlate bioelectric activity of the brain and body with the phenomenology of human experience.

Sleep is a quiescent behavioral state during which complex homeostatic functions essential to health and well-being occur. Insomnia is a very common psychiatric disorder leading to a myriad of detrimental effects including loss of concentration, memory, and performance as well as disease. Current pharmaceutical treatments can be expensive, impairing, unhealthy, and habit-forming. Relaxation techniques, such as meditation target the brain and body in contrast to pharmaceutical interventions which solely target neurotransmitter systems in the brain. In this article we present a viewpoint on the treatment of insomnia that techniques of slow, deep breathing (0.1 Hz) in adjunct to sleep hygiene and relaxation therapies may be highly effective in initiating sleep as well as facilitating falling back asleep. The autonomic nervous system is integral to sleep initiation, maintenance, and disruption. Understanding the relationship between the autonomic nervous system and sleep physiology along with the nature of sleep itself remains a challenge to modern science. We present this perspective in light of a prevailing "dysevolution" theory on the pathology of insomnia that proposes hyper-arousal characterized in part by chronic sympathetic hyperactivation and/or parasympathetic hypoactivation disrupts normal sleep onset latency, sleep quality, and sleep duration. We additionally discuss physiological mechanisms responsible for the effectiveness of the breathing treatment we describe. A better understanding of these mechanisms and autonomic pathologies of insomnia may provide support for the effectiveness of such techniques and provide relief to sufferers of this health epidemic.

Background: Juvenile idiopathic arthritis (JIA) is an inflammatory arthritis of unknown etiology, which lasts for greater than 6 weeks with onset before 16 years of age. JIA is the most common chronic rheumatic disease in children. NSAIDs have been the mainstay of initial management with naproxen (NAP) being commonly used, but they may cause serious side effects such as gastric ulcers which can be reduced by concomitant administration of proton pump inhibitors, such as esomeprazole (ESO)., Methods: Primary objective was to evaluate the safety and tolerability of 3 fixed doses of NAP/ESO in JIA patients aged 12 to 16 years. Forty-six children and adolescents with JIA by International League of Associations for Rheumatology criteria, mean age of 13.6 years, from 18 US sites were prospectively enrolled over 2 years and followed for up to 6 months. Doses of the NAP/ESO fixed combination were based on baseline weight. The exploratory efficacy outcome was assessed with the ACR Pediatric-30, - 50, - 70, - 90 Response and the Childhood Health Assessment Questionnaire (CHAQ) discomfort and functional scores at months 1, 3, and 6 as change from baseline. Occurrence and causality were assessed for treatment emergent AEs (TEAEs) and discontinuations were monitored monthly., Results: Forty-six patients received at least 1 dose of naproxen/esomeprazole and 36 completed the trial. Thirty-seven (80.4%) had at least 1 treatment emergent adverse event (TEAE) and, with the exception of 2 events in one patient, all of the TEAEs were mild or moderate. Frequent TEAEs (≥5% of patients) were upper respiratory tract and gastrointestinal related. Eleven (23.9%) had at least 1 TEAE considered to be related to study drug. Four patients (8.7%) discontinued due to a TEAE with one of these being the only serious AE reported, acute hepatitis. Mean number of active joints at baseline was 3.1. Improvement in JIA signs and symptoms occurred at most assessments and by month 6, the percentage of patients with an ACR Pediatric-30, - 50, - 70, and - 90 Response was 47.1, 38.2, 32.4, and 17.6%, respectively. The percent of patients achieving ACR Pediatric response increased over time. CHAQ discomfort improved at each assessment and functional scores improved at all assessments for 'Arising, Walking, and Activities' with several improved for 'Dressing and Grooming, Eating, Hygiene, and Grip'. There was no indication of a dose-related efficacy effect., Conclusion: NAP/ESO was well tolerated in JIA patients aged 12 to 16 years with high levels of response to ACR criteria. No new safety signals were identified for the well-characterized components of this fixed dosed JIA treatment, which was developed to reduce the risk of gastric ulcers., Trial Registration: Clinicaltrials.gov, NCT01544114 . Registered February 21, 2012.

Aside from the nature of consciousness itself, there are still many unsolved problems in the neurosciences. Despite the vast and quickly growing body of work in this field, we still find ourselves perplexed at seemingly simple qualities of our mental being such as why we need to sleep. The neurosciences are at least beginning to take a hold on these mysteries and are working toward solving them. We hold a perspective that metastable consciousness models, specifically the Default Space Model (DSM), provide insights into these mysteries. In this perspective article, we explore some of these curious questions in order to elucidate the interesting points they bring up. The DSM is a dynamic, global theory of consciousness that involves the maintenance of an internal, 3D simulation of the external, physical world which is the foundation and structure of consciousness. This space is created and filled by multiple frequencies of membrane potential oscillations throughout the brain and body which are organized, synchronized and harmonized by the thalamus. The veracity of the DSM is highlighted here in its ability to further understanding of some of the most puzzling problems in neuroscience.

A fundamental function of the visual system is detecting motion, yet visual perception is poorly understood. Current research has determined that the retina and ganglion cells elicit responses for motion detection; however, the underlying mechanism for this is incompletely understood. Previously we proposed that retinogeniculo-cortical oscillations and photoreceptors work in parallel to process vision. Here we propose that motion could also be processed within the retina, and not in the brain as current theory suggests. In this paper, we discuss: 1) internal neural space formation; 2) primary, secondary, and tertiary roles of vision; 3) gamma as the secondary role; and 4) synchronization and coherence. Movement within the external field is instantly detected by primary processing within the space formed by the retina, providing a unified view of the world from an internal point of view. Our new theory begins to answer questions about: 1) perception of space, erect images, and motion, 2) purpose of lateral inhibition, 3) speed of visual perception, and 4) how peripheral color vision occurs without a large population of cones located peripherally in the retina. We explain that strong oscillatory activity influences on brain activity and is necessary for: 1) visual processing, and 2) formation of the internal visuospatial area necessary for visual consciousness, which could allow rods to receive precise visual and visuospatial information, while retinal waves could link the lateral geniculate body with the cortex to form a neural space formed by membrane potential-based oscillations and photoreceptors. We propose that vision is tripartite, with three components that allow a person to make sense of the world, terming them "primary, secondary, and tertiary roles" of vision. Finally, we propose that Gamma waves that are higher in strength and volume allow communication among the retina, thalamus, and various areas of the cortex, and synchronization brings cortical faculties to the retina, while the thalamus is the link that couples the retina to the rest of the brain through activity by gamma oscillations. This novel theory lays groundwork for further research by providing a theoretical understanding that expands upon the functions of the retina, photoreceptors, and retinal plexus to include parallel processing needed to form the internal visual space that we perceive as the external world., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

The role of the physiological processes involved in human vision escapes clarification in current literature. Many unanswered questions about vision include: 1) whether there is more to lateral inhibition than previously proposed, 2) the role of the discs in rods and cones, 3) how inverted images on the retina are converted to erect images for visual perception, 4) what portion of the image formed on the retina is actually processed in the brain, 5) the reason we have an after-image with antagonistic colors, and 6) how we remember space. This theoretical article attempts to clarify some of the physiological processes involved with human vision. The global integration of visual information is conceptual; therefore, we include illustrations to present our theory. Universally, the eyeball is 2.4cm and works together with membrane potential, correspondingly representing the retinal layers, photoreceptors, and cortex. Images formed within the photoreceptors must first be converted into chemical signals on the photoreceptors' individual discs and the signals at each disc are transduced from light photons into electrical signals. We contend that the discs code the electrical signals into accurate distances and are shown in our figures. The pre-existing oscillations among the various cortices including the striate and parietal cortex, and the retina work in unison to create an infrastructure of visual space that functionally "places" the objects within this "neural" space. The horizontal layers integrate all discs accurately to create a retina that is pre-coded for distance. Our theory suggests image inversion never takes place on the retina, but rather images fall onto the retina as compressed and coiled, then amplified through lateral inhibition through intensification and amplification on the OFF-center cones. The intensified and amplified images are decompressed and expanded in the brain, which become the images we perceive as external vision., Summary: This is a theoretical article presenting a novel hypothesis about the physiological processes in vision, and expounds upon the visual aspect of two of our previously published articles, "A unified 3D default space consciousness model combining neurological and physiological processes that underlie conscious experience", and "Functional representation of vision within the mind: A visual consciousness model based in 3D default space." Currently, neuroscience teaches that visual images are initially inverted on the retina, processed in the brain, and then conscious perception of vision happens in the visual cortex. Here, we propose that inversion of visual images never takes place because images enter the retina as coiled and compressed graded potentials that are intensified and amplified in OFF-center photoreceptors. Once they reach the brain, they are decompressed and expanded to the original size of the image, which is perceived by the brain as the external image. We adduce that pre-existing oscillations (alpha, beta, and gamma) among the various cortices in the brain (including the striate and parietal cortex) and the retina, work together in unison to create an infrastructure of visual space thatfunctionally "places" the objects within a "neural" space. These fast oscillations "bring" the faculties of the cortical activity to the retina, creating the infrastructure of the space within the eye where visual information can be immediately recognized by the brain. By this we mean that the visual (striate) cortex synchronizes the information with the photoreceptors in the retina, and the brain instantaneously receives the already processed visual image, thereby relinquishing the eye from being required to send the information to the brain to be interpreted before it can rise to consciousness. The visual system is a heavily studied area of neuroscience yet very little is known about how vision occurs. We believe that our novel hypothesis provides new insights into how vision becomes part of consciousness, helps to reconcile various previously proposed models, and further elucidates current questions in vision based on our unified 3D default space model. Illustrations are provided to aid in explaining our theory., (Copyright © 2016. Published by Elsevier Ltd.)

Located within the ascending reticular activating system are nuclei which release neurotransmitters such as acetylcholine, serotonin, dopamine, and norepinephrine. These nuclei have widespread projections that extend into the limbic system and throughout cortex. Activation of these neurotransmitters during awake states leads to arousal, while inhibition leads to the loss of consciousness experienced during slow-wave sleep. Previously, we proposed a mechanism in which cardiorespiratory synchronization may underlie the widespread hyperpolarization that occurs throughout the brain during slow-wave sleep. We further propose that a similar homeostatic mechanism may be involved in sleep-wake transitions and maintaining various arousal states including rapid eye movement sleep, waking, and anxiety. Widespread depolarization associated with more rapid, shallow breathing and desynchronized cardiorespiratory oscillatory activity may underlie waking, anxiety, and rapid eye movement sleep states. The exact voltage values of these widespread membrane potential changes remain unknown and possibly highly variable between different neural areas and cell types. Here, we place these consciousness states on a spectrum of approximated widespread membrane potential values with anxiety states being the most depolarized, followed by waking states, and rapid eye movement sleep. We propose that although these widespread membrane potential changes are minor, they may underlie transitions between and maintenance of varying levels of arousal. Further research on these mechanisms could provide insights into how the brain functions. This homeodynamic arousal mechanism involves the established feed-forward and feedback signaling between the ascending reticular activating system and the hypothalamus, as well as the modulation by cardiorespiratory oscillatory feedback from the body. Understanding the basic mechanisms responsible for the states of sleep, waking, and anxiety could lead to better treatment options in health and disease.

The brain is considered to be the primary generator and regulator of emotions; however, afferent signals originating throughout the body are detected by the autonomic nervous system (ANS) and brainstem, and, in turn, can modulate emotional processes. During stress and negative emotional states, levels of cardiorespiratory coherence (CRC) decrease, and a shift occurs toward sympathetic dominance. In contrast, CRC levels increase during more positive emotional states, and a shift occurs toward parasympathetic dominance. The dynamic changes in CRC that accompany different emotions can provide insights into how the activity of the limbic system and afferent feedback manifest as emotions. The authors propose that the brainstem and CRC are involved in important feedback mechanisms that modulate emotions and higher cortical areas. That mechanism may be one of many mechanisms that underlie the physiological and neurological changes that are experienced during pranayama and meditation and may support the use of those techniques to treat various mood disorders and reduce stress.

The Global Workspace Theory and Information Integration Theory are two of the most currently accepted consciousness models; however, these models do not address many aspects of conscious experience. We compare these models to our previously proposed consciousness model in which the thalamus fills-in processed sensory information from corticothalamic feedback loops within a proposed 3D default space, resulting in the recreation of the internal and external worlds within the mind. This 3D default space is composed of all cells of the body, which communicate via gap junctions and electrical potentials to create this unified space. We use 3D illustrations to explain how both visual and non-visual sensory information may be filled-in within this dynamic space, creating a unified seamless conscious experience. This neural sensory memory space is likely generated by baseline neural oscillatory activity from the default mode network, other salient networks, brainstem, and reticular activating system.

In this article, we examine phantom limb syndrome to gain insights into how the brain functions as the mind and how consciousness arises. We further explore our previously proposed consciousness model in which consciousness and body schema arise when information from throughout the body is processed by corticothalamic feedback loops and integrated by the thalamus. The parietal lobe spatially maps visual and non-visual information and the thalamus integrates and recreates this processed sensory information within a three-dimensional space termed the "3D default space." We propose that phantom limb syndrome and phantom limb pain arise when the afferent signaling from the amputated limb is lost but the neural circuits remain intact. In addition, integration of conflicting sensory information within the default 3D space and the loss of inhibitory afferent feedback to efferent motor activity from the amputated limb may underlie phantom limb pain., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Understanding the autonomic nervous system and homeostatic changes associated with emotions remains a major challenge for neuroscientists and a fundamental prerequisite to treat anxiety, stress, and emotional disorders. Based on recent publications, the inter-relationship between respiration and emotions and the influence of respiration on autonomic changes, and subsequent widespread membrane potential changes resulting from changes in homeostasis are discussed. We hypothesize that reversing homeostatic alterations with meditation and breathing techniques rather than targeting neurotransmitters with medication may be a superior method to address the whole body changes that occur in stress, anxiety, and depression. Detrimental effects of stress, negative emotions, and sympathetic dominance of the autonomic nervous system have been shown to be counteracted by different forms of meditation, relaxation, and breathing techniques. We propose that these breathing techniques could be used as first-line and supplemental treatments for stress, anxiety, depression, and some emotional disorders.

Respiration influences various pacemakers and rhythms of the body during inspiration and expiration but the underlying mechanisms are relatively unknown. Understanding this phenomenon is important, as breathing disorders, breath holding, and hyperventilation can lead to significant medical conditions. We discuss the physiological modulation of heart rhythm, blood pressure, sympathetic nerve activity, EEG, and other changes observed during inspiration and expiration. We also correlate the intracellular mitochondrial respiratory metabolic processes with real-time breathing and correlate membrane potential changes with inspiration and expiration. We propose that widespread minor hyperpolarization occurs during inspiration and widespread minor depolarization occurs during expiration. This depolarization is likely a source of respiratory drive. Further knowledge of intracellular and extracellular ionic changes associated with respiration will enhance ourunderstanding of respiration and its role as a modulator of cellular membrane potential. This could expand treatment options for a wide range of health conditions, such as breathing disorders, stress-related disorders, and further our understanding of the Hering-Breuer reflex and respiratory sinus arrhythmia., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

One of the most compelling questions still unanswered in neuroscience is how consciousness arises. In this article, we examine visual processing, the parietal lobe, and contralateral neglect syndrome as a window into consciousness and how the brain functions as the mind and we introduce a mechanism for the processing of visual information and its role in consciousness. We propose that consciousness arises from integration of information from throughout the body and brain by the thalamus and that the thalamus reimages visual and other sensory information from throughout the cortex in a default three-dimensional space in the mind. We further suggest that the thalamus generates a dynamic default three-dimensional space by integrating processed information from corticothalamic feedback loops, creating an infrastructure that may form the basis of our consciousness. Further experimental evidence is needed to examine and support this hypothesis, the role of the thalamus, and to further elucidate the mechanism of consciousness., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Although sleep physiology has been extensively studied, many of the cellular processes that occur during sleep and the functional significance of sleep remain unclear. The degree of cardiorespiratory synchronization during sleep increases during the progression of slow-wave sleep (SWS). Autonomic nervous system (ANS) activity also assumes a pattern that correlates with the progression of sleep. The ANS is an integral part of physiologic processes that occur during sleep with the respective contribution of parasympathetic and sympathetic activity varying between different sleep stages. In our paper, we attempt to unify the activities of various physiologic systems, namely the cardiac, respiratory, ANS and brain, during sleep into a consolidated picture with particular attention to the membrane potential of neurons. In our unified model, we explore the potential of sleep to promote restorative processes in the brain., (Copyright © 2014 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: Juvenile localized scleroderma (LS) is a chronic inflammatory skin disorder associated with substantial morbidity and disability. Although a wide range of therapeutic strategies has been reported in the literature, a lack of agreement on treatment specifics and accepted methods for clinical assessment has made it difficult to compare approaches and identify optimal therapy. Our objective was to develop standardized treatment plans, clinical assessments, and response criteria for active, moderate to high severity juvenile LS., Methods: A core group of pediatric rheumatologists, dermatologists, and a lay advisor was engaged by the Childhood Arthritis and Rheumatology Research Alliance (CARRA) to develop standardized treatment plans and assessment parameters for juvenile LS using consensus methods/nominal group techniques. Recommendations were validated in 2 face-to-face conferences with a larger group of practitioners with expertise in juvenile LS and with the full membership of CARRA, which encompasses the majority of pediatric rheumatologists in the US and Canada., Results: Consensus was achieved on standardized treatment plans that reflect the prevailing treatment practices of CARRA members. Standardized clinical assessment methods and provisional treatment response criteria were also developed. Greater than 90% of pediatric rheumatologists responding to a survey (66% of CARRA membership) affirmed the final recommendations and agreed to utilize these consensus plans to treat patients with juvenile LS., Conclusion: Using consensus methodology, we have developed standardized treatment plans and assessment methods for juvenile LS. The high level of support among pediatric rheumatologists will support future comparative effectiveness studies and enable the development of evidence-based guidelines for the treatment of juvenile LS., (Copyright © 2012 by the American College of Rheumatology.)

High blood pressure is an important component of pre-eclampsia. The underlying mechanism of development of hypertension in pre-eclampsia is complicated and still remains obscure. Several theories have been advanced including endothelial dysfunction, uteroplacental insufficiency leading to generalized vasoconstriction, increased cardiac output, and sympathetic hyperactivity. Increased blood flow and pressure are thought to lead to capillary dilatation, which damages end-organ sites, leading to hypertension, proteinuria and edema. Additional theories have been put forward based on epidemiological research, implicating immunological and genetic factors. None of these theories have been substantiated. Based on a review of literature this paper postulates that the initiating event for the development of pre-eclampsia is intermittent hypoxia associated with irregular breathing during sleep, hypoapnea, apnea, inadequate respiratory excursions during the waking hours and inadequate cardiopulmonary synchronization (abnormal sympatho-vagal balance).

Pranayamic breathing, defined as a manipulation of breath movement, has been shown to contribute to a physiologic response characterized by the presence of decreased oxygen consumption, decreased heart rate, and decreased blood pressure, as well as increased theta wave amplitude in EEG recordings, increased parasympathetic activity accompanied by the experience of alertness and reinvigoration. The mechanism of how pranayamic breathing interacts with the nervous system affecting metabolism and autonomic functions remains to be clearly understood. It is our hypothesis that voluntary slow deep breathing functionally resets the autonomic nervous system through stretch-induced inhibitory signals and hyperpolarization currents propagated through both neural and non-neural tissue which synchronizes neural elements in the heart, lungs, limbic system and cortex. During inspiration, stretching of lung tissue produces inhibitory signals by action of slowly adapting stretch receptors (SARs) and hyperpolarization current by action of fibroblasts. Both inhibitory impulses and hyperpolarization current are known to synchronize neural elements leading to the modulation of the nervous system and decreased metabolic activity indicative of the parasympathetic state. In this paper we propose pranayama's physiologic mechanism through a cellular and systems level perspective, involving both neural and non-neural elements. This theoretical description describes a common physiological mechanism underlying pranayama and elucidate the role of the respiratory and cardiovascular system on modulating the autonomic nervous system. Along with facilitating the design of clinical breathing techniques for the treatment of autonomic nervous system and other disorders, this model will also validate pranayama as a topic requiring more research.

This article discusses the literature on pediatric-onset mixed connective tissue disease (MCTD) and adds 34 new cases. Although not benign, pediatric-onset MCTD carries less mortality than adult-onset disease.

Linear scleroderma is an unusual disorder characterized by linear streaks of fibrotic skin involvement, which can lead to severe limb deformities and contractures. The authors present a case of severe wrist contracture in a child with linear scleroderma treated by release of the contracture with coverage of the exposed carpus with an abductor digiti minimi flap and skin graft. Reports of successful treatment of extremity deformities are rare. At 1 year this correction appears to have been successful.

Objective: To evaluate demographic and clinical characteristics, duration of time between disease onset (date of first rash and/or weakness), and diagnosis/therapy, as well as socioeconomic status, of children with newly diagnosed juvenile dermatomyositis (JDM)., Methods: Structured telephone interview of families of a cohort of 79 children with JDM: interval between onset of symptoms to diagnosis, median of 3 months (range 0.5-20.0)., Results: At diagnosis, all the children had rash (100%) and proximal muscle weakness (100%); 58 (73%) had muscle pain; 51 (65%) fever; 35 (44%) dysphagia; 34 (43%) hoarseness; 29 (37%) abdominal pain; 28 (35%) arthritis; 18 (23%) calcinosis, and 10 (13%) melena. Muscle derived enzymes were normal in 10% of the children. Of the 43 children who had an electromyogram (EMG), 8 (19%) had normal results. Fifty-one children had a muscle biopsy; the results were normal/nondiagnostic in 10 (20%). Median time from disease onset to diagnosis was different between racial groups: Caucasians (n=59) 2.0 months: for minorities (n=20), 6.5 months, (p=0.0008). The median time from disease onset to therapy was: Caucasians. 3.0 months; minorities, 7.2 months (p=0.002). Report of calcinosis was associated with increased time to diagnosis and therapy (p=0.04). In the 33 children whose first symptom occurred in June-September, rash preceded or accompanied onset of muscle weakness in 83% (n=27). Ninety-one percent of the children were given steroid therapy and 9% received methotrexate as well., Conclusion: The results of an undirected site for muscle biopsy or EMG may not be diagnostic. Minority children had a longer interval between first JDM symptom and diagnosis/therapy than Caucasian children. Delay in diagnosis/therapy was associated with calcinosis.

Objective: To determine, in a case-control study, if patients with new-onset juvenile dermatomyositis (juvenile DM) have increased symptoms prior to onset, exposure to certain environmental conditions, frequency of familial autoimmune diseases, or antibody titers, compared with 2 control groups., Methods: A structured interview with the families of 80 children with juvenile DM, 40 children with juvenile rheumatoid arthritis (JRA), or 23 healthy children, from the same geographic area as the children with juvenile DM, was conducted. All children's sera were tested for antibody to Toxoplasma gondii, herpes simplex virus (HSV), or coxsackievirus B (CVB)., Results: A high proportion of children with juvenile DM had constitutional symptoms 3 months before the disease-onset date (P = 0.013 versus control children). Children with JRA had more relatives with rheumatoid arthritis (P = 0.0001) and pernicious anemia (P = 0.003) than did children with juvenile DM or healthy children. Among children < or =7 years of age, elevated enteroviral titers were more frequent in those with juvenile DM (81%) and in healthy controls (90%) than in those with JRA (64%), suggesting a common environmental exposure. Titers to T gondii, HSV, or CVB 1-6 were normal., Conclusion: Frequencies of familial autoimmune disease, exposure to environmental factors, or elevated antibody titers to T gondii, HSV, or CVB are not increased in juvenile DM. Children with juvenile DM do have symptoms of illness 3 months before the disease-onset date, and young patients have elevated enteroviral titers, as do young geographic controls.

Diffuse dark blue-black chromonychia was observed in 17 of 33 (52%) black patients with systemic lupus erythematosus (SLE), but not in 47 non-SLE black patients. About half of these patients had active disease. A comparison was made between patients with SLE with chromonychia and those without but no distinctive clinical or laboratory variable differentiated the 2 groups. This pattern of nail hyperpigmentation has not previously been associated with SLE.

Positive direct immunofluorescence findings have been occasionally reported for human renal amyloidosis. However, no substantial information describing the frequency of immunomicroscopic pattern has been reported. Twenty-seven renal biopsy specimens with proven amyloidosis were studied by direct immunofluorescence using monospecific antisera against IgG, IgA, IgM, IgD, IgE, kappa and lambda light chains, C3, C4 properdin, alpha-2 macroglobulin, albumin, transferrin, and fibrinogen. Ten biopsy specimens were negative. The remaining specimens showed principally a diffuse immunofluorescent staining of the mesangial areas with various of the above fluorescein-labeled antisera except IgE, albumin, and transferrin antisera, which gave a consistently negative reaction. IgD, properdin, or fibrinogen were weakly identified in only one case. Immunoglobulins and C3 were observed in 14 cases. Kappa and/or lambda light chains were found in nine of ten biopsy specimens so tested. Positive immunofluorescent staining of other elements of the nephron was rarely observed. These results suggest that various immunoreactants, in addition to light chains, can be frequently detected in renal amyloidosis and that passive nonselective absorption of plasma proteins does not explain these immunomicroscopic findings.

This study assessed the influence of internal health locus of control (IHLC) and anxiety on the adolescent's response to the treatment of mild and moderate pain. Fifty-four adolescents (ages 16-22 years) from two adolescent clinics presenting with mild to moderate pain caused by dysmenorrhea, muscle sprain or strain, headache, or backache were studied. Following a physical examination and a pretest assessment of pain, IHLC, and the Spielberger State-Trait Anxiety Inventory, subjects were randomly assigned in a double-blind fashion to groups receiving placebo (n = 16), 100 mg of naproxen sodium (n = 19), or 200 mg naproxen sodium (n = 19) and assessed at 1, 2, 3, and 4 hours. Based on a repeated-measure analysis of covariance test, there were no differences between groups in the pretest measurements. All treatment groups had a decrease in pain over the 4 hours (p less than 0.0001). Patients from one institution had more pain reduction than at the other (p less than 0.0001), and females had more pain reduction than males (p less than 0.034). Subjects receiving 200 mg of naproxen sodium had more pain relief (p less than 0.034) than subjects taking placebo at hour 2. Baseline anxiety was positively associated with pain after receiving placebo, but inversely associated with pain after taking naproxen sodium. The IHLC appeared to have a positive effect on the response to naproxen sodium, but no effect on the response to placebo.

Cardiac performance was studied by radionuclide angiography at rest and during exercise in 22 adolescents with sickle cell (SC) anemia and the results were compared with those in 12 control subjects. At rest, cardiac contractility was normal; cardiac output and end-diastolic volume were increased. At maximal exercise, heart rate, cardiac output response, and work capacity were reduced; the reduction was related to the degree of anemia. Left ventricular end-diastolic volume decreased with exercise most markedly in patients with ischemic exercise electrocardiograms. An abnormal ejection fraction response to exercise occurred in 4 patients; electrocardiographic signs of ischemia developed in all 4, and wall motion abnormalities in 2. Those patients who had electrocardiographic signs of ischemia had a significantly lower heart rate, ejection fraction, and cardiac output response to exercise, and a lower hematocrit level than subjects with normal results on exercise electrocardiography. The increase in cardiac output was not sufficient to maintain a normal level of exercise. The decrease in end-diastolic volume suggests that diastolic function was abnormal during exercise. Cardiac dysfunction was manifested by an abnormal ejection fraction response, wall motion abnormalities, and incomplete left ventricular filling during exercise.