Human Nasal and Lung Tissues Infected Ex Vivo with SARS-CoV-2 Provide Insights into Differential Tissue-Specific and Virus-Specific Innate Immune Responses in the Upper and Lower Respiratory Tract.

The nasal mucosa constitutes the primary entry site for respiratory viruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). While the imbalanced innate immune response of end-stage coronavirus disease 2019 (COVID-19) has been extensively studied, the earliest stages of SARS-CoV-2 infection at the mucosal entry site have remained unexplored. Here, we employed SARS-CoV-2 and influenza virus infection in native multi-cell-type human nasal turbinate and lung tissues ex vivo, coupled with genome-wide transcriptional analysis, to investigate viral susceptibility and early patterns of local mucosal innate immune response in the authentic milieu of the human respiratory tract. SARS-CoV-2 productively infected the nasal turbinate tissues, predominantly targeting respiratory epithelial cells, with a rapid increase in tissue-associated viral subgenomic mRNA and secretion of infectious viral progeny. Importantly, SARS-CoV-2 infection triggered robust antiviral and inflammatory innate immune responses in the nasal mucosa. The upregulation of interferon-stimulated genes, cytokines, and chemokines, related to interferon signaling and immune-cell activation pathways, was broader than that triggered by influenza virus infection. Conversely, lung tissues exhibited a restricted innate immune response to SARS-CoV-2, with a conspicuous lack of type I and III interferon upregulation, contrasting with their vigorous innate immune response to influenza virus. Our findings reveal differential tissue-specific innate immune responses in the upper and lower respiratory tracts that are specific to SARS-CoV-2. The studies shed light on the role of the nasal mucosa in active viral transmission and immune defense, implying a window of opportunity for early interventions, whereas the restricted innate immune response in early-SARS-CoV-2-infected lung tissues could underlie the unique uncontrolled late-phase lung damage of advanced COVID-19. IMPORTANCE In order to reduce the late-phase morbidity and mortality of COVID-19, there is a need to better understand and target the earliest stages of SARS-CoV-2 infection in the human respiratory tract. Here, we have studied the initial steps of SARS-CoV-2 infection and the consequent innate immune responses within the natural multicellular complexity of human nasal mucosal and lung tissues. Comparing the global innate response patterns of nasal and lung tissues infected in parallel with SARS-CoV-2 and influenza virus, we found distinct virus-host interactions in the upper and lower respiratory tract, which could determine the outcome and unique pathogenesis of SARS-CoV-2 infection. Studies in the nasal mucosal infection model can be employed to assess the impact of viral evolutionary changes and evaluate new therapeutic and preventive measures against SARS-CoV-2 and other human respiratory pathogens.

Human Nasal Turbinate Tissues in Organ Culture as a Model for Human Cytomegalovirus Infection at the Mucosal Entry Site.

The initial events of viral infection at the primary mucosal entry site following horizontal person-to-person transmission have remained ill defined. Our limited understanding is further underscored by the absence of animal models in the case of human-restricted viruses, such as human cytomegalovirus (HCMV), a leading cause of congenital infection and a major pathogen in immunocompromised individuals. Here, we established a novel ex vivo model of HCMV infection in native human nasal turbinate tissues. Nasal turbinate tissue viability and physiological functionality were preserved for at least 7 days in culture. We found that nasal mucosal tissues were susceptible to HCMV infection, with predominant infection of ciliated respiratory epithelial cells. A limited viral spread was demonstrated, involving mainly stromal and vascular endothelial cells within the tissue. Importantly, functional antiviral and proleukocyte chemotactic signaling pathways were significantly upregulated in the nasal mucosa in response to infection. Conversely, HCMV downregulated the expression of nasal epithelial cell-related genes. We further revealed tissue-specific innate immune response patterns to HCMV, comparing infected human nasal mucosal and placental tissues, representing the viral entry and the maternal-to-fetal transmission sites, respectively. Taken together, our studies provide insights into the earliest stages of HCMV infection. Studies in this model could help evaluate new interventions against the horizontal transmission of HCMV.IMPORTANCE HCMV is a ubiquitous human pathogen causing neurodevelopmental disabilities in congenitally infected children and severe disease in immunocompromised patients. The earliest stages of HCMV infection in the human host have remained elusive in the absence of a model for the viral entry site. Here, we describe the establishment and use of a novel nasal turbinate organ culture to study the initial steps of viral infection and the consequent innate immune responses within the natural complexity and the full cellular repertoire of human nasal mucosal tissues. This model can be applied to examine new antiviral interventions against the horizontal transmission of HCMV and potentially that of other viruses.

Quinolinate as a Marker for Kynurenine Metabolite Formation and the Unresolved Question of NAD+ Synthesis During Inflammation and Infection.

Quinolinate (Quin) is a classic example of a biochemical double-edged sword, acting as both essential metabolite and potent neurotoxin. Quin is an important metabolite in the kynurenine pathway of tryptophan catabolism leading to the de novo synthesis of nicotinamide adenine dinucleotide (NAD+). As a precursor for NAD+, Quin can direct a portion of tryptophan catabolism toward replenishing cellular NAD+ levels in response to inflammation and infection. Intracellular Quin levels increase dramatically in response to immune stimulation [e.g., lipopolysaccharide (LPS) or pokeweed mitogen (PWM)] in macrophages, microglia, dendritic cells, and other cells of the immune system. NAD+ serves numerous functions including energy production, the poly ADP ribose polymerization (PARP) reaction involved in DNA repair, and the activity of various enzymes such as the NAD+-dependent deacetylases known as sirtuins. We used highly specific antibodies to protein-coupled Quin to delineate cells that accumulate Quin as a key aspect of the response to immune stimulation and infection. Here, we describe Quin staining in the brain, spleen, and liver after LPS administration to the brain or systemic PWM administration. Quin expression was strong in immune cells in the periphery after both treatments, whereas very limited Quin expression was observed in the brain even after direct LPS injection. Immunoreactive cells exhibited diverse morphology ranging from foam cells to cells with membrane extensions related to cell motility. We also examined protein expression changes in the spleen after kynurenine administration. Acute (8 h) and prolonged (48 h) kynurenine administration led to significant changes in protein expression in the spleen, including multiple changes involved with cytoskeletal rearrangements associated with cell motility. Kynurenine administration resulted in several expression level changes in proteins associated with heat shock protein 90 (HSP90), a chaperone for the aryl-hydrocarbon receptor (AHR), which is the primary kynurenine metabolite receptor. We propose that cells with high levels of Quin are those that are currently releasing kynurenine pathway metabolites as well as accumulating Quin for sustained NAD+ synthesis from tryptophan. Further, we propose that the kynurenine pathway may be linked to the regulation of cell motility in immune and cancer cells.

Current evidence allows multiple models for the peopling of the Americas.

Some recent academic and popular literature implies that the problem of the colonization of the Americas has been largely resolved in favor of one specific model: a Pacific coastal migration, dependent on high marine productivity, from the Bering Strait to South America, thousands of years before Clovis, the earliest widespread cultural manifestation south of the glacial ice. Speculations on maritime adaptations and typological links (stemmed points) across thousands of kilometers have also been advanced. A review of the current genetic, archeological, and paleoecological evidence indicates that ancestral Native American population expansion occurred after 16,000 years ago, consistent with the archeological record, particularly with the earliest securely dated sites after ~15,000 years ago. These data are largely consistent with either an inland (ice-free corridor) or Pacific coastal routes (or both), but neither can be rejected at present. Systematic archeological and paleoecological investigations, informed by geomorphology, are required to test each hypothesis.

Scalp sensor for simultaneous acoustic emission detection and electroencephalography during transcranial ultrasound.

Focused ultrasound is now capable of noninvasively penetrating the intact human skull and delivering energy to specific areas of the brain with millimeter accuracy. The ultrasound energy is supplied in high-intensities to create brain lesions or at low-intensities to produce reversible physiological interventions. Conducting acoustic emission detection (AED) and electroencephalography (EEG) during transcranial focused ultrasound may lead to several new brain treatment and research applications. This study investigates the feasibility of using a novel scalp senor for acquiring concurrent AED and EEG during clinical transcranial ultrasound. A piezoelectric disk is embedded in a plastic cup EEG electrode to form the sensor. The sensor is coupled to the head via an adhesive/conductive gel-dot. Components of the sensor prototype are tested for AED and EEG signal quality in a bench top investigation with a functional ex vivo skull phantom.

RF Heating of Gold Cup and Conductive Plastic Electrodes during Simultaneous EEG and MRI.

PURPOSE: To investigate the heating of EEG electrodes during magnetic resonance imaging (MRI) scans and to better understand the underlying physical mechanisms with a focus on the antenna effect. MATERIALS AND METHODS: Gold cup and conductive plastic electrodes were placed on small watermelons with fiberoptic probes used to measure electrode temperature changes during a variety of 1.5T and 3T MRI scans. A subset of these experiments was repeated on a healthy human volunteer. RESULTS: The differences between gold and plastic electrodes did not appear to be practically significant. For both electrode types, we observed heating below 4°C for straight wires whose lengths were multiples of ½ the radiofrequency (RF) wavelength and stronger heating (over 15°C) for wire lengths that were odd multiples of » RF wavelength, consistent with the antenna effect. CONCLUSIONS: The antenna effect, which has received little attention so far in the context of EEG-MRI safety, can play as significant a role as the loop effect (from electromagnetic induction) in the heating of EEG electrodes, and therefore wire lengths that are odd multiples of » RF wavelength should be avoided. These results have important implications for the design of EEG electrodes and MRI studies as they help to minimize the risk to patients undergoing MRI with EEG electrodes in place.

Bison phylogeography constrains dispersal and viability of the Ice Free Corridor in western Canada.

The Ice Free Corridor has been invoked as a route for Pleistocene human and animal dispersals between eastern Beringia and more southerly areas of North America. Despite the significance of the corridor, there are limited data for when and how this corridor was used. Hypothetical uses of the corridor include: the first expansion of humans from Beringia into the Americas, northward postglacial expansions of fluted point technologies into Beringia, and continued use of the corridor as a contact route between the north and south. Here, we use radiocarbon dates and ancient mitochondrial DNA from late Pleistocene bison fossils to determine the chronology for when the corridor was open and viable for biotic dispersals. The corridor was closed after ∼23,000 until 13,400 calendar years ago (cal y BP), after which we find the first evidence, to our knowledge, that bison used this route to disperse from the south, and by 13,000 y from the north. Our chronology supports a habitable and traversable corridor by at least 13,000 cal y BP, just before the first appearance of Clovis technology in interior North America, and indicates that the corridor would not have been available for significantly earlier southward human dispersal. Following the opening of the corridor, multiple dispersals of human groups between Beringia and interior North America may have continued throughout the latest Pleistocene and early Holocene. Our results highlight the utility of phylogeographic analyses to test hypotheses about paleoecological history and the viability of dispersal routes over time.

Biofield Physiology: A Framework for an Emerging Discipline.

Biofield physiology is proposed as an overarching descriptor for the electromagnetic, biophotonic, and other types of spatially-distributed fields that living systems generate and respond to as integral aspects of cellular, tissue, and whole organism self-regulation and organization. Medical physiology, cell biology, and biophysics provide the framework within which evidence for biofields, their proposed receptors, and functions is presented. As such, biofields can be viewed as affecting physiological regulatory systems in a manner that complements the more familiar molecular-based mechanisms. Examples of clinically relevant biofields are the electrical and magnetic fields generated by arrays of heart cells and neurons that are detected, respectively, as electrocardiograms (ECGs) or magnetocardiograms (MCGs) and electroencephalograms (EEGs) or magnetoencephalograms (MEGs). At a basic physiology level, electromagnetic activity of neural assemblies appears to modulate neuronal synchronization and circadian rhythmicity. Numerous nonneural electrical fields have been detected and analyzed, including those arising from patterns of resting membrane potentials that guide development and regeneration, and from slowly-varying transepithelial direct current fields that initiate cellular responses to tissue damage. Another biofield phenomenon is the coherent, ultraweak photon emissions (UPE), detected from cell cultures and from the body surface. A physiological role for biophotons is consistent with observations that fluctuations in UPE correlate with cerebral blood flow, cerebral energy metabolism, and EEG activity. Biofield receptors are reviewed in 3 categories: molecular-level receptors, charge flux sites, and endogenously generated electric or electromagnetic fields. In summary, sufficient evidence has accrued to consider biofield physiology as a viable scientific discipline. Directions for future research are proposed.

Barriers to the Entry of Biofield Healing Into "Mainstream" Healthcare.

In this article, we describe barriers to the entry of biofield healing into mainstream contemporary science and clinical practice. We focus on obstacles that arise from the social nature of the scientific enterprise, an aspect of science highlighted by the influential work of Thomas Kuhn (1922-1996), one of the most important- and controversial-philosophers of science in the 20th century. Kuhn analyzed science and its revolutionary changes in terms of the dynamics within scientific communities. Kuhn's approach helps us understand unconventional medical theories and practices such as biofield healing. For many years, these were called "complementary and alternative medicine" (CAM). However, because most people use nonmainstream approaches in conjunction with conventional treatments, the National Institutes of Health and many practitioners now prefer "Complementary and Integrative Medicine" (CIM) where integrative implies "bringing conventional and complementary approaches together in a coordinated way."(1) Biofield healing fits the integrative model well, provides a novel approach to therapeutic intervention, and is developing in a manner that can integrate with current medical science in simple ways. Yet, it still remains outside the conventional framework because of its conceptual bases, which contrast sharply with conventional assumptions regarding the nature of reality.

Inferring demographic structure with moccasin size data from the Promontory Caves, Utah.

The moccasin assemblage Julian Steward recovered from the Promontory caves in 1930-31 provides a novel example in which material culture can be used to understand the structure of an AD thirteenth century population. Several studies shed light on the relationship between shoe size, foot size, and stature. We develop an anthropometric model for understanding the composition of the Promontory Cave population by using moccasin size as a proxy for foot size. We then predict the stature of the individual who would have worn a moccasin. Stature is closely related to age for children, subadults and adult males. Although there are predictable sex and age factors biasing moccasin discard practices, moccasin dimensions suggest a relatively large proportion of children and subadults occupied the Promontory caves. This bison and antelope hunting population appears to have thrived during its stay on Promontory Point.

The effect of omega-3 fatty acids on biomarkers of inflammation: a rapid evidence assessment of the literature.

INTRODUCTION: Previous studies of omega-3 fatty acids report improved outcomes where inflammation is a key factor. The objective of this systematic review is to evaluate effects of omega-3s on inflammatory biomarkers. METHODS: Randomized clinical studies that measured the influence of omega-3 fatty acids on inflammatory biomarkers were identified using a comprehensive search. Eligible studies were rated with the American Dietetic Association Evidence Analysis Manual and Grading of Recommendations, Assessment, Development and Evaluation (GRADE) process to examine study quality and risk/benefit. RESULTS: 112 studies were included. Over 65% reported statistically significant effects. The majority were scored as low risk of bias (high quality) and scored strong (cardiac populations and critically ill) to weak (Alzheimer's Disease, hypertriglyceridemia/diabetes, and obesity) on the risk/benefit ratio evidence for modulation of inflammatory biomarkers. There was inadequate data to determine a GRADE for inflammatory biomarker studies for some conditions (healthy individuals, rheumatoid arthritis, metabolic syndrome, renal disease, pregnancy, or children). CONCLUSION: Clinical literature on the effects of omega-3 fatty acids on inflammatory biomarkers contains mostly small sample sizes, is neutral to high quality, and report mixed effects. Larger studies examining dose and delivery are needed.

Nonlinear effects of nanoparticles: biological variability from hormetic doses, small particle sizes, and dynamic adaptive interactions.

Researchers are increasingly focused on the nanoscale level of organization where biological processes take place in living systems. Nanoparticles (NPs, e.g., 1-100 nm diameter) are small forms of natural or manufactured source material whose properties differ markedly from those of the respective bulk forms of the "same" material. Certain NPs have diagnostic and therapeutic uses; some NPs exhibit low-dose toxicity; other NPs show ability to stimulate low-dose adaptive responses (hormesis). Beyond dose, size, shape, and surface charge variations of NPs evoke nonlinear responses in complex adaptive systems. NPs acquire unique size-dependent biological, chemical, thermal, optical, electromagnetic, and atom-like quantum properties. Nanoparticles exhibit high surface adsorptive capacity for other substances, enhanced bioavailability, and ability to cross otherwise impermeable cell membranes including the blood-brain barrier. With super-potent effects, nano-forms can evoke cellular stress responses or therapeutic effects not only at lower doses than their bulk forms, but also for longer periods of time. Interactions of initial effects and compensatory systemic responses can alter the impact of NPs over time. Taken together, the data suggest the need to downshift the dose-response curve of NPs from that for bulk forms in order to identify the necessarily decreased no-observed-adverse-effect-level and hormetic dose range for nanoparticles.

Integrative nanomedicine: treating cancer with nanoscale natural products.

Finding safer and more effective treatments for specific cancers remains a significant challenge for integrative clinicians and researchers worldwide. One emerging strategy is the use of nanostructured forms of drugs, vaccines, traditional animal venoms, herbs, and nutraceutical agents in cancer treatment. The recent discovery of nanoparticles in traditional homeopathic medicines adds another point of convergence between modern nanomedicine and alternative interventional strategies. A way in which homeopathic remedies could initiate anticancer effects includes cell-to-cell signaling actions of both exogenous and endogenous (exosome) nanoparticles. The result can be a cascade of modulatory biological events with antiproliferative and pro-apoptotic effects. The Banerji Protocols reflect a multigenerational clinical system developed by homeopathic physicians in India who have treated thousands of patients with cancer. A number of homeopathic remedy sources from the Banerji Protocols (eg, Calcarea phosphorica; Carcinosin-tumor-derived breast cancer tissue prepared homeopathically) overlap those already under study in nonhomeopathic nanoparticle and nanovesicle tumor exosome cancer vaccine research. Past research on antineoplastic effects of nano forms of botanical extracts such as Phytolacca, Gelsemium, Hydrastis, Thuja, and Ruta as well as on homeopathic remedy potencies made from the same types of source materials suggests other important overlaps. The replicated finding of silica, silicon, and nano-silica release from agitation of liquids in glassware adds a proven nonspecific activator and amplifier of immunological effects. Taken together, the nanoparticulate research data and the Banerji Protocols for homeopathic remedies in cancer suggest a way forward for generating advances in cancer treatment with natural product-derived nanomedicines.

Encontrar tratamientos más seguros y más eficaces para cánceres específicos sigue siendo un desafío significativo para los médicos integrales e investigadores en todo el mundo. Una estrategia emergente es el uso de formas nanoestructuradas de fármacos, vacunas, venenos animales tradicionales, hierbas y agentes nutracéuticos en el tratamiento del cáncer. El reciente descubrimiento de las nanopartículas en medicinas homeopáticas tradicionales aporta otro punto de convergencia entre la nanomedicina moderna y las estrategias intervencionistas alternativas. Una manera en la que los remedios homeopáticos podrían iniciar efectos anticancerígenos incluye acciones de señalización entre células de nanopartículas exógenas y endógenas (exosoma). El resultado puede ser una cascada de acontecimientos biológicos moduladores con efectos antiproliferativos y proapoptóticos. Los protocolos de Banerji reflejan un sistema clínico multigeneracional desarrollado por médicos homeopáticos en la India que han tratado a millares de pacientes con cáncer. Un número de fuentes de remedios homeopáticos de los protocolos de Banerji (p. ej., calcárea fosfórica; carcinosina, tejido derivado del tumor de cáncer de mama preparado homeopáticamente) se solapan con aquellos estudiados en la investigación de la vacuna para el cáncer de exosomas tumorales nanovesiculares y nanopartículas no homeopáticas). Anteriores investigaciones sobre los efectos antineoplásicos de nanoformas de extractos botánicos como la Phytolacca, Gelsemium, Hydrastis, Thuja y Ruta así como sobre la potencia de los remedios homeopáticos derivados de las mismas clases de materiales de origen sugieren otras coincidencias importantes. El descubrimiento replicado de la liberación de silicio, silicona y nanosilicio de la agitación de líquidos en cristal añade un activador inespecífico probado y un amplificador de los efectos inmunológicos. En conjunto, los datos de la investigación de nanopartículas y los protocolos de Banerji de remedios homeopáticos en el cáncer sugieren un camino a seguir para avanzar en el tratamiento del cáncer con nanomedicinas derivadas de productos naturales.

Predicting the unpredictable: critical analysis and practical implications of predictive anticipatory activity.

A recent meta-analysis of experiments from seven independent laboratories (n = 26) indicates that the human body can apparently detect randomly delivered stimuli occurring 1-10 s in the future (Mossbridge etal., 2012). The key observation in these studies is that human physiology appears to be able to distinguish between unpredictable dichotomous future stimuli, such as emotional vs. neutral images or sound vs. silence. This phenomenon has been called presentiment (as in "feeling the future"). In this paper we call it predictive anticipatory activity (PAA). The phenomenon is "predictive" because it can distinguish between upcoming stimuli; it is "anticipatory" because the physiological changes occur before a future event; and it is an "activity" because it involves changes in the cardiopulmonary, skin, and/or nervous systems. PAA is an unconscious phenomenon that seems to be a time-reversed reflection of the usual physiological response to a stimulus. It appears to resemble precognition (consciously knowing something is going to happen before it does), but PAA specifically refers to unconscious physiological reactions as opposed to conscious premonitions. Though it is possible that PAA underlies the conscious experience of precognition, experiments testing this idea have not produced clear results. The first part of this paper reviews the evidence for PAA and examines the two most difficult challenges for obtaining valid evidence for it: expectation bias and multiple analyses. The second part speculates on possible mechanisms and the theoretical implications of PAA for understanding physiology and consciousness. The third part examines potential practical applications.

Ultraweak photon emission as a non-invasive health assessment: a systematic review.

We conducted a systematic review (SR) of the peer reviewed scientific literature on ultraweak photon emissions (UPE) from humans. The question was: Can ultraweak photon emissions from humans be used as a non-invasive health assessment? A systematic search was conducted across eight relevant databases: PubMed/MEDLINE, BIOSIS, CINAHL, PSYCHINFO, All of Cochrane EBM databases, GIDEON, DoD Biomedical Research, and clinicaltrials.gov from database inception to October 2011. Of the 1315 studies captured by the search strategy, 56 met the inclusion criteria, out of which 1 was a RCT, 27 were CCT, and 28 were observational and descriptive studies. There were no systematic reviews/meta-analyses that fit the inclusion criteria. In this report, the authors provide an assessment of the quality of the RCT included; describe the characteristics of all the included studies, the outcomes assessed, and the effectiveness of photon emission as a potential health assessment tool. This report demonstrates that the peer reviewed literature on UPE and human UPE measurement in particular is surprisingly large. Most of the human UPE literature is of good to high quality based on our systematic evaluation. However, an evaluation tool for systematically evaluating this type of "bio-evaluation" methodology is not currently available and would be worth developing. Publications in the peer reviewed literature over the last 50 years demonstrate that the use of "off-the-shelf" technologies and well described methodologies for the detection of human photon emissions are being used on a regular basis in medical and research settings. The overall quality of this literature is good and the use of this approach for determining inflammatory and oxidative states of patients indicate the growing use and value of this approach as both a medical and research tool.

Spontaneous EEG-Functional MRI in Mesial Temporal Lobe Epilepsy: Implications for the Neural Correlates of Consciousness.

The combination of electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) has been shown to have great potential for providing a greater understanding of normal and diseased states in both human and animal studies. Simultaneous EEG-fMRI is particularly well suited for the study of epilepsy in that it may reveal the neurobiology of ictal and interictal epileptiform discharges and noninvasively localize epileptogenic foci. Spontaneous, coherent fluctuations of neuronal activity and the coupled hemodynamic responses have also been shown to provide diagnostic markers of disease, extending our understanding of intrinsically structured ongoing brain activity. Following a short summary of the hardware and software development of simultaneous EEG-fMRI, this paper reviews a unified framework of integrating neuronal and hemodynamic processes during epileptic seizures and discusses the role and impact of spontaneous activity in the mesial temporal lobe epilepsies with particular emphasis on the neural and physiological correlates of consciousness.

Method for appraising model validity of randomised controlled trials of homeopathic treatment: multi-rater concordance study.

BACKGROUND: A method for assessing the model validity of randomised controlled trials of homeopathy is needed. To date, only conventional standards for assessing intrinsic bias (internal validity) of trials have been invoked, with little recognition of the special characteristics of homeopathy. We aimed to identify relevant judgmental domains to use in assessing the model validity of homeopathic treatment (MVHT). We define MVHT as the extent to which a homeopathic intervention and the main measure of its outcome, as implemented in a randomised controlled trial (RCT), reflect 'state-of-the-art' homeopathic practice. METHODS: Using an iterative process, an international group of experts developed a set of six judgmental domains, with associated descriptive criteria. The domains address: (I) the rationale for the choice of the particular homeopathic intervention; (II) the homeopathic principles reflected in the intervention; (III) the extent of homeopathic practitioner input; (IV) the nature of the main outcome measure; (V) the capability of the main outcome measure to detect change; (VI) the length of follow-up to the endpoint of the study. Six papers reporting RCTs of homeopathy of varying design were randomly selected from the literature. A standard form was used to record each assessor's independent response per domain, using the optional verdicts 'Yes', 'Unclear', 'No'. Concordance among the eight verdicts per domain, across all six papers, was evaluated using the kappa (κ) statistic. RESULTS: The six judgmental domains enabled MVHT to be assessed with 'fair' to 'almost perfect' concordance in each case. For the six RCTs examined, the method allowed MVHT to be classified overall as 'acceptable' in three, 'unclear' in two, and 'inadequate' in one. CONCLUSION: Future systematic reviews of RCTs in homeopathy should adopt the MVHT method as part of a complete appraisal of trial validity.

A randomized controlled study to evaluate the efficacy of noninvasive limb cover for chronic phantom limb pain among veteran amputees.

OBJECTIVE: To assess the efficacy of a noninvasive limb cover for treating chronic phantom limb pain (PLP). DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: Outpatient clinic. PARTICIPANTS: We randomly assigned 57 subjects to 2 groups: true noninvasive limb cover (n=30) and sham noninvasive limb cover (n=27). Inclusion criteria included age of 18 years or greater, upper or lower extremity amputation with healed residual limb, and 3 or more episodes of PLP during the previous 6 weeks. INTERVENTIONS: Subjects received 2 true or sham noninvasive limb covers to be worn over the prosthesis and residual limbs 24 hours a day for 12 weeks. MAIN OUTCOME MEASURES: Primary outcome measure was the numerical pain rating scale of PLP level (0-10). Secondary outcomes included overall pain level (0-10), PLP frequency per week, and the Veterans RAND 12-Item Health Survey (VR-12). We collected data at baseline and at 6- and 12-week follow-up visits. RESULTS: Demographic and clinical characteristics were not significantly different between groups. The true noninvasive limb cover group reported nonsignificant reductions in PLP from 5.9±1.9 at baseline to 3.9±1.7 at the 12-week follow-up. The sham noninvasive limb cover group also had nonsignificant reducations in PLP from 6.5±1.8 to 4.2±2.3. PLP did not differ significantly between the 2 groups at 6 weeks (mean difference, 0.8; 95% confidence interval [CI], -1.4 to 3) or at 12 weeks (mean difference, 0.2; 95% CI, -1.9 to 2.3). Similarly, overall pain level, PLP episodes per week, and VR-12 physical and mental health component scores did not differ between the 2 groups at 6 and 12 weeks. CONCLUSIONS: A true noninvasive limb cover did not significantly decrease PLP levels or the frequency of PLP episodes per week, overall bodily pain levels, or VR-12 physical and mental health component scores compared with a sham noninvasive limb cover in our veteran amputee sample.