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.

[DOES A PRISONER HAVE THE RIGHT TO AUTONOMY? A CASE REPORT].

INTRODUCTION: The case presented discusses a prisoner, Y, in his mid-sixties with longstanding medical conditions, who was sentenced to prolonged incarceration. Y refused conventional medicine because he believed that his medical condition was exacerbated by this treatment and only complementary alternative medicine (CAM) would be helpful. He therefore demanded to be treated only by CAM. He was ready to pay for the treatment out of his own pocket. In the prison where Y was previously incarcerated over the course of 12 years, he had access to CAM remedies which were purchased by his family. After being transferred to the current facility, Y was denied access to these remedies by the prison physicians. He appealed in court against this decision and was supported by a CAM specialist, who ascertained that the remedies under consideration were not hazardous to Y's health. This case report discusses the ethical aspects of a prisoner's autonomy to choose medical treatment even when his/her autonomy has been severely curtailed by virtue of the incarceration.

Will We Miss the Opportunity Again?

Coronavirus disease 2019 (COVID-19), caused by a new coronavirus, first appeared in late 2019. What initially seemed to be a mild influenza quickly revealed itself as a serious and highly contagious disease, and the planet was soon faced with a significant morbidity and mortality associated with this pathogen. For homeopathy, shunned during its 200 years of existence by conventional medicine, this outbreak is a key opportunity to show potentially the contribution it can make in treating COVID-19 patients. This should be done through performance of impeccably controlled, prospective, randomized clinical trials, with publication of their findings in well-ranked conventional medicine journals. If the homeopathy community fails to take advantage of this rare opportunity, it might wait another century for the next major pandemic.

The Hydra-Headed Coronaviruses: Implications of COVID-19 for Homeopathy.

Successful homeopathic prescriptions are based on careful individualization of symptoms, either for an individual patient or collectively in the case of epidemic outbreaks. The ongoing COVID-19 pandemic was initially represented as a severe acute respiratory illness, with eventual dramatic complications. However, over time it revealed to be a complex systemic disease with manifestations derived from viral-induced inflammation and hypercoagulability, thus liable to affect any body organ or system. As a result, clinical presentation is variable, in addition to variations associated with several individual and collective risk factors. Given the extreme variability of pathology and clinical manifestations, a single, or a few, universal homeopathic preventive Do not split medicine(s) do not seem feasible. Yet homeopathy may have a relevant role to play, inasmuch as the vast majority of patients only exhibit the mild form of disease and are indicated to self-care at home, without standard monitoring, follow-up, or treatment. For future pandemics, homeopathy agencies should prepare by establishing rapid-response teams and efficacious lines of communication.

A Placebo-Controlled Double-Blind Randomized Trial with Individualized Homeopathic Treatment Using a Symptom Cluster Approach in Women with Premenstrual Syndrome.

BACKGROUND: In a double-blind placebo-controlled randomized trial with parallel groups, the efficacy of individually prescribed homeopathic medicines was evaluated in women with premenstrual syndrome (PMS). METHODS: In an outpatient department of a university clinic in Jerusalem, Israel (1996-1999), women with PMS, aged 18 to 50 years, entered a 2-month screening phase with prospective daily recording of premenstrual symptoms by the Menstrual Distress Questionnaire (MDQ). They were included after being diagnosed with PMS. A reproducible treatment protocol was used: women received a homeopathic prescription based on symptom clusters identified in a questionnaire. The symptoms were verified during a complementary, structured, interview. Only women whose symptoms matched the symptom profile of one of 14 pre-selected homeopathic medicines were included. Each participant was administered active medicine or placebo via random allocation. Primary outcome measures were differences in changes in mean daily premenstrual symptom (PM) scores by the MDQ. Analysis was by intention-to-treat. RESULTS: A total of 105 women were included: 49 were randomized to active medicine and 56 to placebo. Forty-three women in the active medicine group and 53 in the placebo group received the allocated intervention with at least one follow-up measurement and their data were analyzed. Significantly greater improvement of mean PM scores was measured in the active medicine group (0.443 [standard deviation, SD, 0.32] to 0.287 [SD, 0.20]) compared to placebo (0.426 [SD, 0.34] to 0.340 [SD, 0.39]); p = 0.043. CONCLUSIONS: Individually prescribed homeopathic medicines were associated with significantly greater improvement of PM scores in women with PMS, compared to placebo. Replication, with larger sample size and other refinements, is recommended to confirm the efficacy of this treatment in other settings.

[THE TIME HAS COME! COMPLEMENTARY MEDICINE IN MEDICAL TRAINING IN ISRAEL].

INTRODUCTION: The use of complementary and alternative medicine (CAM) has become increasingly popular in most Western countries. As a result, safety-related issues associated with these practices have become more apparent, including adverse effects and negative interactions with conventional medical therapies. The potential dangers associated with CAM are further exacerbated by the absence of high-quality clinical research on the subject; a lack of a basic understanding of the principles of CAM among physicians; and a reluctance of patients to disclose their use of CAM, including those modalities being used in parallel with conventional medical treatments. The increase in CAM use by their patients and the increased potential for harmful effects and interactions are central to the increasing interest among physicians and other healthcare professionals in learning more about CAM paradigms and practices of care. In light of this increasing interest in CAM, the majority of medical schools in the U.S. and Canada and a large number in Europe are providing their students with compulsory or elective courses on this subject. A similar process is taking place in Israel, with the Faculty of Medicine at the Hebrew University in Jerusalem having completed its first compulsory course in CAM at the Hadassah University Medical Center, Ein Karem. The increased use of CAM presents a number of challenges to the conventional medical profession. Medical schools can and should provide students with the knowledge and skills which will enable them to discuss CAM use with their patients, providing evidence-based guidance on the safe and effective use of these modalities.

Model validity of randomised placebo-controlled trials of non-individualised homeopathic treatment.

BACKGROUND: The comprehensive systematic review of randomised placebo-controlled trials (RCTs) in homeopathy requires examination of a study's model validity of homeopathic treatment (MVHT) as well as its risk of bias (extent of reliable evidence). OBJECTIVE: To appraise MVHT in those RCTs of non-individualised homeopathy that an associated investigation had judged as 'not at high risk of bias'. DESIGN: Systematic review. METHODS: An assessment of MVHT was ascribed to each of 26 eligible RCTs. Another 49 RCTs were ineligible due to their high risk of bias. MAIN OUTCOME MEASURES: MVHT and the prior risk of bias rating per trial were merged to obtain a single overall quality designation ('high', 'moderate', 'low'), based on the GRADE principle of downgrading. RESULTS: The trials were rated as 'acceptable MVHT' (N = 9), 'uncertain MVHT' (N = 10) and 'inadequate MVHT' (N = 7); and, previously, as 'reliable evidence' (N = 3) and 'non-reliable evidence' (N = 23). The 26 trials were designated overall as: 'high quality' (N = 1); 'moderate quality' (N = 18); 'low quality' (N = 7). CONCLUSION: Of the 26 RCTs of non-individualised homeopathy that were judged 'not at high risk of bias', nine have been rated 'acceptable MVHT'. One of those nine studies was designated 'high quality' overall ('acceptable MVHT' and 'reliable evidence'), and is thus currently the only reported RCT that represents best therapeutic practice as well as unbiased evidence in non-individualised homeopathy. As well as minimising risk of bias, new RCTs in this area must aim to maximise MVHT and clarity of reporting.

Update on hormesis and its relation to homeopathy.

INTRODUCTION: Hormesis is a dose-response relationship characterized by a biphasic dose response to stressors with a low dose stimulation and a high dose inhibition. The first systematic description of hormesis appeared toward the close of the 18th century by the German pharmacology professor Hugo Schulz. The stressor agent can be any agent or factor capable of causing a deleterious effect. The biological systems can be diverse: bacteria, fungi, algae, yeasts, animals, humans, protozoa and plants. The range of endpoints covers longevity, reproduction, cancer, survival, growth, metabolic effects and others. Hormesis is a nonspecific phenomenon, which can occur in any biological system and can be caused by any stressor. It is quantifiable and reproducible. The apparent similarity between the basic principle of hormesis and homeopathy's Similia Principle, together with the homeopathic claim that hormesis validates homeopathy caused its marginalization, and its rejection during the past century by central figures in pharmacology. Recent years have seen a slight renaissance in the conventional scientific attitude towards hormesis. METHOD: We compared hormesis and homeopathy. RESULT: There is no convincing evidence of similarity between these two systems. Moreover, there are several crucial differences between them, which seem to refute any idea that they stem from the same root. This paper discusses these differences. The rejection of hormesis on grounds of its similarity to homeopathy is unjustified. CONCLUSION: The authors suggest exploring the differences between both systems. Such exploration may answer the key question of whether they do indeed share a root or embrace the same principles. Such exploration may also spur research within both systems to answer further open questions.

Unequal brothers : are homeopathy and hormesis linked?

The debate between those who believe homeopathy and hormesis derive from the same root and those who believe the two are different phenomena is as old as hormesis. It is an emotionally loaded discussion, with both sides fielding arguments which are far from scientific. Careful analysis of the basic paradigms of the two systems questions the claim of the homeopaths, who find similarities between them. The authors discuss these paradigms, indicating the differences between the claims of homeopathy and hormesis. It is time for thorough and serious research to lay this question to rest. One possible approach is to compare the activity of a hormetic agent, prepared in the usual way, with that of the same agent in the same concentration prepared homeopathically by serial dilution and succussion.

Model validity of randomised placebo-controlled trials of individualised homeopathic treatment.

BACKGROUND: Though potentially an important limitation in the literature of randomised controlled trials (RCTs) of homeopathy, the model validity of homeopathic treatment (MVHT) has not previously been systematically investigated. OBJECTIVE: As an integral part of a programme of systematic reviews, to assess MVHT of eligible RCTs of individualised homeopathic treatment. METHODS: From 46 previously identified papers in the category, 31 papers (reporting a total of 32 RCTs) were eligible for systematic review and were thus the subject of the study. For each of six domains of assessment per trial, MVHT was judged independently by three randomly allocated assessors from our group, who reached a final verdict by consensus discussion as necessary. RESULTS: Nineteen trials were judged overall as 'acceptable' MVHT, nine as 'uncertain' MVHT, and four as 'inadequate' MVHT. CONCLUSIONS: These results do not support concern that deficient MVHT has frequently undermined the published findings of RCTs of individualised homeopathy. However, the 13 trials with 'uncertain' or 'inadequate' MVHT will be a focus of attention in supplementary meta-analysis. New RCTs of individualised homeopathy must aim to maximise MVHT and to enable its assessment through clear reporting.

[Martin Heidegger, beneficence, health, and evidence based medicine--contemplations regarding ethics and complementary and alternative medicine].

Beneficence is considered a core principle of medical ethics. Evidence Based Medicine (EBM) is used almost synonymously with beneficence and has become the gold standard of efficiency of conventional medicine. Conventional modern medicine and EBM in particular are based on what Heidegger called calculative thinking, whereas complementary medicine (CM) is often based on contemplative thinking according to Heidegger's distinction of different thinking processes. A central issue of beneficence is the striving for health and wellbeing. EBM is little concerned directly with wellbeing, though it does claim to aim at improving quality of life by correcting pathological processes and conditions like infectious diseases, ischemic heart disease but also hypertension and hyperlipidemia. On the other hand, wellbeing is central to therapeutic efforts of CM. Scientific methods to gauge results of EBM are quantitative and based on calculative thinking, while results of treatments with CM are expressed in a qualitative way and based on meditative thinking. In order to maximize beneficence it seems important and feasible to use both approaches, by combining EBM and CM in the best interest of the individual patient.

["Do two walk together unless they have agreed to do so?"--Combining conventional and complementary medicine in the treatment of gastroparesis].

Gastroparesis is a chronic disorder of abnormal gastric motility causing considerable suffering. We describe two cases of gastroparesis which were treated by methods which were not part of routine conventional therapy, but which, nevertheless, led to significant clinical improvement. In the first case, the patient suffered from gastroparesis following a vagal injury while undergoing a lung transplant. During his illness a mega-bezoar formed, a well-described complication of gastroparesis. After conservative measures failed, and in order to avoid a surgical intervention that carried considerable risk under the circumstances, a successful trial consisting of imbibing large amounts of "Coca Cola" and acupuncture was initiated. The bezoar dissolved completely and considerable improvement of the patient's gastric motility was achieved. In the second case, the patient was a young woman suffering from idiopathic gastroparesis, which responded well to treatment with tricyclic antidepressants. Due to her intention to become pregnant, this treatment was discontinued and she was admitted to receive homeopathic treatment. After two failed attempts in finding the right homeopathic remedy to replace the conventional treatment, the third remedy (Sepia) used brought dramatic improvement in her general condition and her dyspepsia. Today, over two years after her successful homeopathic treatment, she is in the middle of her second pregnancy, without any treatment and free of complaints. These two cases are examples of simple solutions for seemingly complicated and complex conditions alleviated by an integration of conventional and complementary/alternative medicine.

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.

Localized reduction of gingival inflammation using site-specific therapy with a topical gingival patch.

METHODS: Sites of inflammation were identified on subjects with moderate-to-severe chronic periodontitis, and were allocated to either patch placement or untreated controls, both for 24 hours. Conventional treatment with scaling and root planing was postponed during the study period. Inflammation was evaluated measuring neutrophilic activity using gingival crevicular fluid (GCF) beta-glucuronidase (b-glu) levels, and clinical response was evaluated using the gingival index (GI). RESULTS: A total of 26 patients were recruited and 36 sites examined, with 22 sites on which the patch was placed and 14 controls. GCF b-glu levels at 24 hours were reduced following patch placement, significantly more so than with controls (17/22 vs. 3/14 sites, respectively; p = 0.002). The patch placement resulted in a significant reduction in mean b-glu levels (-2.52 +/- 1.62), with a reduction from baseline of 29.7%. This compared to untreated controls, for whom the mean b-glu levels and percent change from baseline increased (2.14 +/- 0.89 and 33%, respectively). At 24 hours, GI response rate for treated sites was better than for control sites (18/21 vs. 7/14; p = 0.053). No adverse events were reported in either group. CONCLUSION: This pilot study indicates that a topical gingival patch promotes reduction of gingival inflammation. Further clinical testing of this novel treatment of gingival inflammation is warranted.

Homeopathic Treatment for COVID-19-Related Symptoms: A Case Series.

BACKGROUND: Severe acute respiratory syndrome due to coronavirus 2 (SARS CoV-2) is a novel infectious disease, which has quickly developed into a pandemic. The spectrum of COVID-19 symptoms is broad, ranging from a mild, self-limiting respiratory tract illness to severe progressive pneumonia, multi-organ failure and possible death. Despite much effort and multiple clinical trials, there are, to date, no specific therapeutic agents to treat or cure the coronavirus infection. CASE REPORTS: The present paper presents 5 cases of patients with moderate to severe COVID-19 infections, 2 of them hospitalized in the intensive care unit, who were successfully treated with homeopathy. RESULTS: All 5 patients responded to homeopathic treatment in an unexpectedly short time span, improving both physically and mentally. CONCLUSION: The present case series emphasizes the rapidity of response among moderate to severely ill patients to homeopathic treatment, when conventional medical options have been unable to relieve or shorten the disease. The observations described should encourage use of homeopathy in treating patients with COVID-19 during the acute phase of the disease.

SARS-CoV-2 Omicron Induces Enhanced Mucosal Interferon Response Compared to other Variants of Concern, Associated with Restricted Replication in Human Lung Tissues.

SARS-CoV-2 Omicron variant has been characterized by decreased clinical severity, raising the question of whether early variant-specific interactions within the mucosal surfaces of the respiratory tract could mediate its attenuated pathogenicity. Here, we employed ex vivo infection of native human nasal and lung tissues to investigate the local-mucosal susceptibility and innate immune response to Omicron compared to Delta and earlier SARS-CoV-2 variants of concern (VOC). We show that the replication of Omicron in lung tissues is highly restricted compared to other VOC, whereas it remains relatively unchanged in nasal tissues. Mechanistically, Omicron induced a much stronger antiviral interferon response in infected tissues compared to Delta and earlier VOC-a difference, which was most striking in the lung tissues, where the innate immune response to all other SARS-CoV-2 VOC was blunted. Notably, blocking the innate immune signaling restored Omicron replication in the lung tissues. Our data provide new insights to the reduced lung involvement and clinical severity of Omicron.

Hypnosis and acupuncture (hypnopuncture) for prurigo nodularis: a case report.

Prurigo Nodularis (PN) is a chronic pruritic skin condition for which current conventional therapies are of limited benefit and with potentially toxic effects. Acupuncture--the insertion of thin needles at specific points on the skin--has been shown to alleviate itching through a number of itch-associated mediator effects. Hypnosis has been shown to modify and reduce the intensity of itching as well. A 44 year-old woman presented with a 30-year history of a diffuse itchy rash diagnosed as PN. She had tried various antihistamine and corticosteroid medications, to no avail. A treatment regimen using hypnosis and acupuncture (hypnopuncture) was initiated, with significant reduction in the itching, size and number of skin lesions. Hypnopuncture may offer a synergistic and augmented response to treatment, though further research is needed to understand the true benefits of this combined regimen.

[From Nebuchadnezzar to the randomized controlled trial--milestones in the development of clinical research].

The first clinical experiment is described in the bible: The prophet Daniel is reported being nourished during ten days by seeds and water only, in order to check if his physical state would deteriorate as a result of this minimal nutrition. In the 15th century, French surgeon Ambroise Parí experimented with a mixture of turpentine, egg protein and rose oil to treat combat wounds, which is thought to be the first clinical study to be reported. In the 19th century British scientist James Lind designed the first controlled prospective study with parallel groups, proving that ingesting citrus fruit prevents scurvy. A short time afterwards British scientist John Haygarth was the first to use a placebo drug in a clinical study. Important work on placebo was conducted by the American scientists Austin Flint and later by Henry K. Beecher, who showed that placebo itself has biological properties. The importance of comparative studies was first understood by French psychologist CLaude Bernard. He is considered the founder of the modern scientific method based on observation, analysis of data and examination of hypotheses. Bernard's work was based on the work of fellow Frenchman Pierre Charles Alexandre Louis, who is justly considered a founding father of modern epidemiology, and who was the first to use statistics in clinical experiments. Random distributions in clinical studies were reported even before this time, for instance in the work of the Flemish physician Johannes Baptista van Helmont. Danish Nobel prize winner Johannes Fibiger pioneered the use of selection bias in his work with diphtheria serum.