Proceedings of the Second International Meeting on Endemic Mycoses of the Americas (IMEMA), and First International Symposium on Implantation Mycoses (ISIM).

The Second International Meeting on Endemic Mycoses of the Americas (IMEMA) and the First International Symposium on Implantation Mycoses (ISIM) took place in Santiago del Estero, Argentina during September 25-27th, 2023. The conference provided a platform for researchers, clinicians, and experts to discuss the latest developments in the field of endemic and implantation mycoses. Topics included epidemiology, diagnostic advances, treatment strategies, and the impact of environmental factors in the spread of these fungal diseases. IMEMA and ISIM contributed to the regional discourse on the mycoses, emphasizing the importance of international cooperation in addressing these public health challenges.

IMEMA/ISIM, held in Santiago del Estero, Argentina, convened experts to discuss endemic and implantation mycoses, covering topics such as epidemiology, diagnostics, treatment, and advocacy. The event highlighted ongoing efforts in combating these diseases.

B cells and the coordination of immune checkpoint inhibitor response in patients with solid tumors.

Immunotherapy profoundly changed the landscape of cancer therapy by providing long-lasting responses in subsets of patients and is now the standard of care in several solid tumor types. However, immunotherapy activity beyond conventional immune checkpoint inhibition is plateauing, and biomarkers are overall lacking to guide treatment selection. Most studies have focused on T cell engagement and response, but there is a growing evidence that B cells may be key players in the establishment of an organized immune response, notably through tertiary lymphoid structures. Mechanisms of B cell response include antibody-dependent cellular cytotoxicity and phagocytosis, promotion of CD4+ and CD8+ T cell activation, maintenance of antitumor immune memory. In several solid tumor types, higher levels of B cells, specific B cell subpopulations, or the presence of tertiary lymphoid structures have been associated with improved outcomes on immune checkpoint inhibitors. The fate of B cell subpopulations may be widely influenced by the cytokine milieu, with versatile roles for B-specific cytokines B cell activating factor and B cell attracting chemokine-1/CXCL13, and a master regulatory role for IL-10. Roles of B cell-specific immune checkpoints such as TIM-1 are emerging and could represent potential therapeutic targets. Overall, the expanding field of B cells in solid tumors of holds promise for the improvement of current immunotherapy strategies and patient selection.

Epidemiological, clinical, and genomic landscape of coccidioidomycosis in northeastern Brazil.

Coccidioidomycosis, listed as a priority mycosis by the WHO, is endemic in the United States but often overlooked in Central and South America. Employing a multi-institutional approach, we investigate how disease characteristics, pathogen genetic variation, and environmental factors impact coccidioidomycosis epidemiology and outcomes in South America. We identified 292 cases (1978-2021) and 42 outbreaks in Piauí and Maranhão states, Brazil, the largest series outside the US/Mexico epidemic zone. The male-to-female ratio was 57.4:1 and the most common activity was armadillo hunting (91.1%) 4 to 30 days before symptom onset. Most patients (92.8%) exhibited typical acute pulmonary disease, with cough (93%), fever (90%), and chest pain (77%) as predominant symptoms. The case fatality rate was 8%. Our negative binomial regression model indicates that reduced precipitation levels in the current (p = 0.015) and preceding year (p = 0.001) predict heightened incidence. Unlike other hotspots, acidic soil characterizes this region. Brazilian strains differ genomically from other C. posadasii lineages. Northeastern Brazil presents a distinctive coccidioidomycosis profile, with armadillo hunters facing elevated risks. Low annual rainfall emerges as a key factor in increasing cases. A unique C. posadasii lineage in Brazil suggests potential differences in environmental, virulence, and/or pathogenesis traits compared to other Coccidioides genotypes.

Brain Wave Oscillations as an Objective Neurophysiological Biomarker of Homeopathic Subjective Well-Being.

BACKGROUND: Homeopathy uses the "similitude principle" to arouse a therapeutic reaction in the body against its own disorders. For this to occur optimally, the medicinal pathogenetic effects must present similarity with the totality of the individual's symptoms. To assess if this similarity has been successfully achieved, Hahnemann states that "improvement in the disposition and mind"-i.e., subjective well-being-is the most important parameter to consider. AIM: Our aim was to perform a narrative review of the literature, exploring what is known about subjective well-being as a marker of therapeutic action, and to formulate ways in which subjective well-being might be quantifiable and applied in future homeopathy research. RESULTS: The concept of subjective well-being has been extensively studied in the complementary and conventional medical literature. Improved well-being has been observed in clinical trials, including those in the fields of positive psychology and meditation. Positive subjective outcomes of this nature are supported by objective evidence through associated changes in brain oscillatory activity using electroencephalography and/or "brain mapping" by functional magnetic resonance imaging. Neurophysiological responses in the brain have been identified in subjects after they ingested a homeopathic medicine. CONCLUSIONS: The concept of subjective well-being is supported by a body of literature and is a measurable entity. When viewed from the perspective of electrophysiological changes, brain activity is an objective neurophysiological biomarker with a potential to quantify individual well-being in the context of homeopathy research.

Brain wave oscillations as an objective neurophysiological biomarker of homeopathic subjective well-being [Pré-print]

Homeopathy uses the "similitude principle" to arouse a therapeutic reaction in the body against its own disorders. For this to occur optimally, the medicinal pathogenetic effects must present similarity with the totality of the individual's symptoms. To assess if this similarity has been successfully achieved, Hahnemann states that "improvement in the disposition and mind"­i.e., subjective well-being­is the most important parameter to consider. Aim Our aim was to perform a narrative review of the literature, exploring what is known about subjective well-being as a marker of therapeutic action, and to formulate ways in which subjective well-being might be quantifiable and applied in future homeopathy research. The concept of subjective well-being has been extensively studied in the complementary and conventional medical literature. Improved well-being has been observed in clinical trials, including those in the fields of positive psychology and meditation. Positive subjective outcomes of this nature are supported by objective evidence through associated changes in brain oscillatory activity using electroencephalography and/or "brain mapping" by functional magnetic resonance imaging. Neurophysiological responses in the brain have been identified in subjects after they ingested a homeopathic medicine. The concept of subjective well-being is supported by a body of literature and is a measurable entity. When viewed from the perspective of electrophysiological changes, brain activity is an objective neurophysiological biomarker with a potential to quantify individual well-being in the context of homeopathy research.

Tracing histoplasmosis genomic epidemiology and species occurrence across the USA.

ABSTRACTHistoplasmosis is an endemic mycosis in North America frequently reported along the Ohio and Mississippi River Valleys, although autochthonous cases occur in non-endemic areas. In the United States, the disease is provoked by two genetically distinct clades of Histoplasma capsulatum sensu lato, Histoplasma mississippiense (Nam1) and H. ohiense (Nam2). To bridge the molecular epidemiological gap, we genotyped 93 Histoplasma isolates (62 novel genomes) including clinical, environmental, and veterinarian samples from a broader geographical range by whole-genome sequencing, followed by evolutionary and species niche modelling analyses. We show that histoplasmosis is caused by two major lineages, H. ohiense and H. mississippiense; with sporadic cases caused by H. suramericanum in California and Texas. While H. ohiense is prevalent in eastern states, H. mississipiense was found to be prevalent in the central and western portions of the United States, but also geographically overlapping in some areas suggesting that these species might co-occur. Species Niche Modelling revealed that H. ohiense thrives in places with warmer and drier conditions, while H. mississippiense is endemic to areas with cooler temperatures and more precipitation. In addition, we predicted multiple areas of secondary contact zones where the two species co-occur, potentially facilitating gene exchange and hybridization. This study provides the most comprehensive understanding of the genomic epidemiology of histoplasmosis in the USA and lays a blueprint for the study of invasive fungal diseases.

Safety and efficacy of nivolumab in elderly patients with metastatic clear cell renal cell carcinoma: Analysis of the NIVOREN GETUG-AFU 26 study.

INTRODUCTION: Immune checkpoint inhibitors are standard of care in metastatic renal cell carcinoma but their activity and safety in elderly patients is insufficiently explored. We evaluated outcomes of elderly patients with mRCC treated with nivolumab in the GETUG-AFU 26 NIVOREN phase 2 trial (NCT03013335) and conducted exploratory circulating biomarker analyses. METHODS: Patients with mRCC were treated with nivolumab after at least one antiangiogenic therapy. The main endpoint of this analysis was safety in patients ≥ 70 years old (y.o), as per the rate of treatment-related grade 3-5 events (TRAE). Secondary endpoints included overall response rate (ORR), progression-free survival (PFS), overall survival. Exploration of candidate biomarkers associated with aging included baseline circulating cytokines involved in inflammation, adhesion, immune checkpoints, angiogenesis (IL6, IL7, IL8, BAFF, CXCL13, VCAM-1, 4-1BB, VEGF). RESULTS: Of 720 patients, 515 were < 70 y.o and 205 ≥ 70 y.o. Patients ≥ 70 y.o exhibited numerically less IMDC poor risk disease (21.0% vs 26.9%), sarcomatoid component (4.9% vs 9.8%) or brain metastases (5.9% vs. 14.7%), but more previous treatment lines (≥ 2 in 54.1% vs 48.5%). TRAE were higher in patients ≥ 70 y.o (24.9% vs. 17.9%, p = 0.033). Respective ORR (19.2% vs. 22.1%) and median PFS (4.5 versus 3.0 months, HR 0.97 [95%CI 0.81-1.15]) were similar. Overall survival was shorter in patients ≥ 70 y.o (19.3 versus 26.9 months, HR 1.26 [95%CI 1.04-1.51]), but not significantly in a competitive risk model. Only V-CAM1 and 4-1BB were found to be increased in patients ≥ 70 y.o. CONCLUSIONS: Nivolumab displayed higher grade 3/4 TRAE but manageable toxicity in elderly patients, with sustained activity. Elderly patients did not display specific inflammatory or angiogenic circulating profiles.

Exposure-response relationship of cabozantinib in patients with metastatic renal cell carcinoma treated in routine care.

BACKGROUND: Interindividual pharmacokinetic variability may influence the clinical benefit or toxicity of cabozantinib in metastatic renal cell carcinoma (mRCC). We aimed to investigate the exposure-toxicity and exposure-response relationship of cabozantinib in unselected mRCC patients treated in routine care. METHODS: This ambispective multicenter study enrolled consecutive patients receiving cabozantinib in monotherapy. Steady-state trough concentration (Cmin,ss) within the first 3 months after treatment initiation was used for the PK/PD analysis with dose-limiting toxicity (DLT) and survival outcomes. Logistic regression and Cox proportional-hazards models were used to identify the risk factors of DLT and inefficacy in patients, respectively. RESULTS: Seventy-eight mRCC patients were eligible for the statistical analysis. Fifty-two patients (67%) experienced DLT with a median onset of 2.1 months (95%CI 0.7-8.2). In multivariate analysis, Cmin,ss was identified as an independent risk factor of DLT (OR 1.46, 95%CI [1.04-2.04]; p = 0.029). PFS and OS were not statistically associated with the starting dose (p = 0.81 and p = 0.98, respectively). In the multivariate analysis of PFS, Cmin, ss > 336 ng/mL resulted in a hazard ratio of 0.28 (95%CI, 0.10-0.77, p = 0.014). By contrast, Cmin, ss > 336 ng/mL was not statistically associated with longer OS. CONCLUSION: Early plasma drug monitoring may be useful to optimise cabozantinib treatment in mRCC patients treated in monotherapy, especially in frail patients starting at a lower than standard dose.

Molecular detection of Paracoccidioides spp. in environmental samples from the Southwestern Amazon.

Paracoccidioidomycosis is an infection with the potential for environmental dissemination, especially in regions of hot and humid climate, where human cases have been recorded in the Southwestern Amazon of Brazil, specifically in the state of Acre. Despite studies providing information about the presence of these fungi in soil and animal samples, such as armadillos, further investigations are still needed to determine the epidemiological distribution of the genus Paracoccidioides. The aim of this study was to detect the occurrence of Paracoccidioides fungi in the Southwestern Amazon. To achieve this, 60 soil samples were collected from armadillo burrows on rural properties in the in the municipalities of Acrelândia, Bujari, Plácido de Castro, Rio Branco, Sena Madureira, and Senador Guiomard, located in the state of Acre, Brazil. Fungal DNA was extracted from these samples using the DNEASY® PowerSoil kit-Quiagen, followed by Nested PCR technique with ITS4 and ITS5 as external primers, and PBITS-E and PBITS-R as internal primers. DNA amplification products of about 380 bp compatible with Paracoccidioides spp. were detected in six samples (10%), being sequenced and identified as P. brasiliensis. These findings indicate that the soils of the Acre state could be considered a potential source for Paracoccidioides spp., suggesting that local infections are likely.

Multi-locus sequencing typing reveals geographically related intraspecies variability of Sporothrix brasiliensis.

Sporotrichosis is a subcutaneous mycosis caused by pathogenic Sporothrix species. Among them, Sporothrix brasiliensis is the main species associated with endemic regions in South America, especially Brazil. It is highly virulent and can be spread through zoonotic transmission. Molecular epidemiological surveys are needed to determine the extent of genetic variation, to investigate outbreaks, and to identify genotypes associated with antifungal resistance and susceptibility. This study investigated the sequence variation of different constitutive genes and established a novel multilocus sequence typing (MLST) scheme for S. brasiliensis. Specific primers were designed for 16 genes using Primer-BLAST software based on the genome sequences of three S. brasiliensis strains (ATCC MYA-4823, A001 and A005). Ninety-one human, animal, and environmental S. brasiliensis isolates from different Brazilian geographic regions (South, Southeast, Midwest and Northeast) andtwo isolates from Paraguay were sequenced. The loci that presented the highest nucleotide diversity (π) were selected for the MLST scheme. Among the 16 studied genetic loci, four presented increased π value and were able to distinguish all S. brasiliensis isolates into seven distinct haplotypes. The PCR conditions were standardized for four loci. Some of the obtained haplotypes were associated with the geographic origin of the strains. This study presents an important advance in the understanding of this important agent of sporotrichosis in Brazil. It significantly increased the discriminatory power for genotyping of S. brasiliensis isolates, and enabled new contributions to the epidemiological studies of this human and animal pathogen in Brazil and in other countries.

Homeopathy is not placebo effect: proof of scientific evidence for homeopathy

Homeopathy has been a medical practice recognized worldwide for more than two centuries, performing care, teaching and research activities in several health institutions and medical schools. It employs a clinical approach based on heterodox and complementary scientific principles (principle of therapeutic similitude, homeopathic pathogenetic experimentation, use of individualized medicines and dynamized or potentiated doses), with the aim of awakening a curative response in the body against its own disorders and/or diseases. Based on different premises from those used by conventional medical practice, homeopathy is often the target of unfounded and widespread criticism from individuals who systematically deny homeopathic assumptions and any scientific evidence that proves them due to their pseudoskeptical and pseudoscientific stance, which prevents a correct and bias-free analysis. In order to enlighten doctors, researchers, health professionals and the general public, demystifying culturally rooted dogmatic positions and the pseudoskeptical fallacies that "there is no scientific evidence for homeopathy" and "homeopathy is placebo effect", the Technical Chamber of Homeopathy of the Regional Council of Medicine of the State of São Paulo (TC-Homeopathy, Cremesp) prepared the "Special Dossier: Scientific Evidence for Homeopathy" in 2017, made available in three independent editions (online in Portuguese and English; printed in Portuguese) in the Revista de Homeopatia (São Paulo). Then, the dossier was published in Spanish in the La Homeopatía de México journal in 2023 in an edition commemorating the journal's 90th anniversary. Encompassing nine narrative reviews on the various lines of homeopathy research and containing hundreds of scientific articles describing experimental and clinical studies, the Dossier highlighted the state of the art of homeopathic science. Proving and expanding this scientific evidence in 13 chapters, the current work aims to update and clarify knowledge in the area. In addition to elucidating the epistemological premises of the homeopathic model in detail, the work describes the various aspects of basic and clinical research which endorse homeopathic practice and treatment in a continuum of information, data and bibliographic references. The work discusses various topics related to research in homeopathy, covering everything from "homeopathic clinical epidemiology" to "pseudoskeptic and pseudoscientific strategies used in attacks on homeopathy", including "pharmacological basis of the principle of similitude", "experimental studies in biological models", "randomized controlled clinical trials", "systematic reviews, meta-analyses and global reports" and "observational studies", among others. In view of the fact that it becomes fruitless and tiring to describe and analyze all the studies and experiments from the different research lines, we suggest and systematize in the different chapters for those who want to delve deeper into the areas of interest, bibliographical surveys of existing literature through the different databases. As we reiterate throughout the work, despite the difficulties and limitations that exist in developing research in homeopathy due to both methodological aspects and the lack of institutional and financial support, the set of experimental and clinical studies described is indisputable proof that "there is scientific evidence for homeopathy" and "homeopathy is not placebo effect", contrary to falsely disseminated prejudice. However, new studies must continue to be developed to improve clinical practice and elucidate peculiar aspects of the homeopathic paradigm. Acting as an integrative and complementary therapy to other specialties, homeopathy can add efficacy, effectiveness, efficiency and safety to medical practice, acting in a curative and preventive manner, reducing symptomatic manifestations and the predisposition to falling ill, with low cost and minimal adverse events, helping doctors to fulfill their "highest and only mission, which is to make sick people healthy, which is called healing" (Samuel Hahnemann, Organon of Medicine, § 1).

La homeopatía no es efecto placebo: comprobación de las evidencias científicas en homeopatía / Homeopathy is not Placebo Effect: Proof of Scientific Evidence for Homeopathy

La Homeopatía ha sido una práctica médica de renombre mundial durante más de dos siglos, desarrollando actividades asistenciales, docentes y de investigación en varias instituciones de salud y escuelas de medicina. Emplea un enfoque clínico basado en principios científicos heterodoxos y complementarios (principio de similitud terapéutica, experimentación patogénica homeopática, uso de medicamentos individualizados y dosis dinamizadas), con el objetivo de despertar una respuesta curativa del organismo frente a sus propios trastornos o enfermedades. Partiendo de premisas diferentes a las empleadas por la práctica médica convencional, la Homeopatía suele ser objeto de críticas infundadas y generalizadas por parte de individuos que niegan sistemáticamente los supuestos homeopáticos y cualquier evidencia científica que los demuestre porque tienen una postura pseudoescéptica y pseudocientífica que impide un análisis correcto y desprejuiciado. Son "pseudoescépticos" disfrazados de "pseudocientíficos". Ilustrar a médicos, investigadores, profesionales de la salud y al público en general, desmitificando las posturas dogmáticas culturalmente arraigadas y las falacias pseudoescépticas de que "no hay evidencia científica en la Homeopatía" y "la Homeopatía es un efecto placebo", en 2017, la Cámara Técnica de Homeopatía del Consejo Regional de Medicina del Estado de São Paulo (CT-Homeopatía, Cremesp) elaboró el "Dossier Especial: Evidencia Científica en Homeopatía", disponible en tres ediciones independientes (en línea en portugués e inglés; impresa en portugués) en la Revista de Homeopatía (São Paulo). En 2023, el dossier fue publicado en español en la revista La Homeopatía de México, en una edición conmemorativa del 90 aniversario de la revista. Abarcando nueve revisiones narrativas sobre las diversas líneas de investigación en Homeopatía, que contienen cientos de artículos científicos que describen estudios experimentales y clínicos, el dossier destacó el estado del arte de la ciencia homeopática. Demostrando y ampliando esta evidencia científica, el presente trabajo ("La Homeopatía no es Efecto Placebo": Comprobación de las Evidencias Científicas en Homeopatía) pretende esclarecer los conocimientos en el área en trece capítulos. Además de dilucidar en detalle las premisas epistemológicas del modelo homeopático, el trabajo describe, en un continuo de información, datos y referencias bibliográficas, los diversos aspectos de la investigación básica y clínica que avalan la práctica y el tratamiento homeopático. Discutiendo diversos temas relacionados con la investigación en Homeopatía, el libro aborda desde la "epidemiología clínica homeopática" hasta las "estrategias pseudoescépticas y pseudocientíficas utilizadas en los ataques a la Homeopatía", pasando por el "fundamento farmacológico del principio de similitud", "estudios experimentales en modelos biológicos", "ensayos clínicos controlados aleatorizados", "revisiones sistemáticas, metaanálisis e informes globales" y "estudios observacionales", entre otros. Como hemos reiterado a lo largo del libro, a pesar de las dificultades y limitaciones en el desarrollo de la investigación en Homeopatía, tanto por aspectos metodológicos como por la ausencia de apoyo institucional y financiero, el conjunto de estudios experimentales y clínicos descritos es una prueba irrefutable de que "existen evidencias científicas en Homeopatía" y "la Homeopatía no es efecto placebo", contrariamente al prejuicio falsamente difundido. Actuando como terapia integradora y complementaria a otras especialidades, la Homeopatía puede agregar eficacia, efectividad, eficiencia y seguridad a la práctica médica, reduciendo las manifestaciones sintomáticas y la predisposición a la enfermedad, con bajo costo y mínimos eventos adversos.

Love in the time of climate change: A review of sexual reproduction in the order Onygenales.

Life-threatening infections caused by fungi in the order Onygenales have been rising over the last few decades. Increasing global temperature due to anthropogenic climate change is one potential abiotic selection pressure that may explain the increase in infections. The generation of genetically novel offspring with novel phenotypes through the process of sexual recombination could allow fungi to adapt to changing climate conditions. The basic structures associated with sexual reproduction have been identified in Histoplasma, Blastomyces, Malbranchea, and Brunneospora. However, for Coccidioides and Paracoccidioides, the actual structural identification of these processes has yet to be identified despite having genetic evidence that suggests sexual recombination is occurring in these organisms. This review highlights the importance of assessing sexual recombination in the order Onygenales as a means of understanding the mechanisms these organisms might employ to enhance fitness in the face of a changing climate and provides details regarding the known reproductive mechanisms in the Onygenales.

Bases científicas del principio de curación homeopática en la farmacología moderna / Scientific bases of the homeopathic healing principle in modern pharmacology

La homeopatía emplea el denominado 'principio de similares' como método terapéutico ­ el cual consiste en administrar medicamentos que provocan ciertos síntomas en individuos sanos para tratar síntomas similares en individuos enfermos (similia similibus curantur) - para inducir una reacción curativa secundaria del cuerpo en contra de sus propios trastornos. Esta reacción secundaria (vital, homeostática o paradójica) del cuerpo se basa en el 'efecto de rebote' de los fármacos modernos, un tipo de evento adverso que se produce después de interrumpir varias clases de fármacos prescritos según el 'principio de los contrarios' (contraria contrariis curantur). Objetivo: La presente revisión ha buscado justificar científicamente el principio de curación homeopática frente a la farmacología clínica y experimental a través de un estudio sistemático del efecto de rebote de los fármacos modernos o reacción paradójica del cuerpo. Métodos: Empleando como referencia estudios y revisiones sobre el tema publicados a partir de 1998, actualizamos los datos añadiendo estudios recientes incluidos en la base de datos PubMed. Resultados: El efecto de rebote se produce después de interrumpir varias clases de fármacos con acción contraria a los síntomas de las enfermedades, exacerbándolos a niveles superiores a aquellos previos al tratamiento. Independientemente de la enfermedad, fármaco, dosis y duración del tratamiento, el fenómeno del rebote se manifiesta en una pequeña proporción de los individuos susceptibles. Siguiendo las premisas homeopáticas, los fármacos modernos también podrían usarse según el principio de la similitud terapéutica, empleando entonces el efecto de rebote (reacción paradójica) con propósito curativo. Conclusiones: Evidenciado por cientos de estudios que constatan la similitud de conceptos y manifestaciones, el efecto de rebote de los fármacos modernos justifica científicamente el principio de la cura homeopática. Aunque el fenómeno de rebote es un evento adverso estudiado por la farmacología moderna, no es conocido por los profesionales de la atención médica, lo cual priva a los médicos de un conocimiento indispensable para el manejo seguro de los fármacos.

Homeopathy employs the so-called 'principle of similars' as therapeutic method - which consists in administering medicines that cause certain symptoms in healthy individuals to treat similar symptoms in sick individuals (similia similibus curantur) - to induce a secondary and healing reaction by the body against its own disorders. This secondary (vital, homeostatic or paradoxical) reaction of the body is based on the 'rebound effect' of modern drugs, a type of adverse event that occurs following discontinuation of several classes of drugs prescribed according to the 'principle of contraries' (contraria contrariis curantur). Aim: The present review sought to scientifically substantiate the homeopathic healing principle vis-à-vis experimental and clinical pharmacology through a systematic study of the rebound effect of modern drugs or paradoxical reaction of the body. Methods: Employing as reference studies and revisions on the subject published since 1998, we updated the data adding recent studies included in database PubMed. Results: The rebound effect occurs after discontinuation of several classes of drugs with action contrary to the symptoms of diseases, exacerbating them to levels above the ones before treatment. Regardless of disease, drug, dose and duration of treatment, the rebound phenomenon manifests in a small proportion of susceptible individuals. Following the homeopathic premises, modern drugs might also be used according to the principle of therapeutic similitude, thus employing the rebound effect (paradoxical reaction) with curative intent. Conclusions: Evidenced by hundreds of studies that attest to the similarity of concepts and manifestations, the rebound effect of modern drugs scientifically substantiates the principle of homeopathic cure. Although the rebound phenomenon is an adverse event studied by modern pharmacology, it is not known by health care professionals, thus depriving doctors of knowledge indispensable for safe management of drugs.

Efectos de las diluciones homeopáticas altas sobre las plantas: revisión de la literatura / Effects of high homeopathic dilutions on plants: a review of the literature

Entre los supuestos no convencionales de la homeopatía, el uso de medicamentos en diluciones altas (HD, por sus siglas en inglés) es una causa de objeciones y escepticismo entre la comunidad científica, formada dentro del paradigma de la dependencia de la dosis de la farmacología clásica. La investigación que busca evidenciar los efectos de las HD homeopáticas recurre a varios modelos experimentales (in vitro, plantas y animales). Objetivo: Describir los resultados de estudios con alta calidad metodológica que han demostrado los efectos positivos de las HD homeopáticas sobre las plantas. Métodos: Tomando como fuente de referencia las revisiones publicadas hasta 2015, actualizamos la información añadiendo datos de estudios recientes incluidos en la base de datos PubMed. Resultados: De los 167 estudios experimentales analizados, 48 cumplieron los criterios mínimos de calidad metodológica, de los cuales 29 detectaron efectos específicos de las diluciones homeopáticas altas sobre las plantas mediante la comparación con controles adecuados. Conclusiones: A pesar de que la mayor parte de los experimentos presentaba una calidad metodológica por debajo del estándar, los estudios que emplearon sistemáticamente reproducibilidad y controles negativos demostraron indiscutibles efectos significativos de las HD homeopáticas sobre las plantas.

Among the non-conventional assumptions of homeopathy, the use of medicines in high dilutions (HD) is a cause for objections and skepticism among the scientific community, trained within the dose-dependency paradigm of classic pharmacology. Research aiming at evidencing the effects of homeopathic HD has resource to several experimental models (in vitro, plants and animals). Aim: To describe the results of studies with high methodological quality that demonstrated positive effects of homeopathic HD on plants. Methods: Taking reviews published until 2015 as reference source, we updated the information through addition of data from recent studies included in database PubMed. Results: From 167 experimental studies analyzed, 48 met the minimum criteria of methodological quality, from which 29 detected specific effects of homeopathic high dilutions on plants through comparison to adequate controls. Conclusions: Despite the substandard methodological quality of most experiments, studies with systematic use of negative controls and reproducibility demonstrated significant indisputable effects of homeopathic HD on plants.

Formación médica en la terapéutica no convencional en el mundo (homeopatía y acupuntura) / Medical training in non-conventional therapeutics in the world (homeopathy and acupuncture)

Utilizadas de forma complementaria, alternada o integrada con la medicina convencional, la demanda de la población por las terapias no convencionales se ha incrementado considerablemente en las últimas décadas, requiriendo de los médicos un conocimiento de las nociones básicas de tales enfoques terapéuticos para orientar a sus pacientes en relación con tratamientos distintos a aquellos que suelen prescribir. Entre las mismas, la homeopatía y la acupuntura se han considerado especialidades médicas en Brasil durante varias décadas. Objetivo: Describir el estado actual de la formación médica en terapias no convencionales (homeopatía y acupuntura) alrededor del mundo. Métodos: Actualizamos los datos relacionados con los estudios y revisiones publicados hasta 2013 a través de una revisión de los estudios más recientes incluidos en la base de datos PubMed. Resultados: En todos los países, la enseñanza de terapias no convencionales se considera un tema relevante para la formación de médicos como una función del creciente interés de la población en su uso, con un amplia variedad de enfoques dirigidos a los estudiantes de licenciatura y posgrado, médicos residentes y profesionales con otras especialidades médicas. Conclusiones: Las escuelas brasileñas de medicina deben proporcionar a los estudiantes de licenciatura y posgrado, así como a los médicos residentes, un conocimiento preciso de los supuestos teóricos y enfoques clínico-terapéuticos propios de la homeopatía y la acupuntura, entre otras terapias no convencionales.

Used as complementary to, alternating or integrated with mainstream medicine, the population's demand for non-conventional therapies has substantially increased in the past decades, requiring from doctors knowledge on the basic notions of such therapeutics to orient their patients regarding treatments different to the ones they usually prescribe. Among them, homeopathy and acupuncture are considered medical specialties in Brazil for various decades. Aim: To describe the current state of medical education in non-conventional therapies (homeopathy and acupuncture) around the world. Methods: We updated data resulting from studies and reviews published until 2013 through a review of more recent studies included in database PubMed. Results: In all countries the teaching of non-conventional therapies is considered a relevant topic for the training of doctors as a function of the increasing interest of the population in their use, with a broad range of approaches targeting undergraduate and graduate students, medical residents and doctors from other medical specialties. Conclusions: The Brazilian medical schools must provide undergraduate and graduate students and medical residents accurate knowledge on the theoretical assumptions and clinical-therapeutic approaches proper to homeopathy and acupuncture, among other non-conventional therapies.

Estrógeno potenciado en el tratamiento homeopático del dolor pélvico asociado a endometriosis: un estudio aleatorizado, doble ciego, controlado con placebo, de 24 semanas / Potentiated estrogen in the homeopathic treatment of pelvic pain associated with endometriosis: a 24-week randomized, double-blind, placebo-controlled study

Evaluar la eficacia y seguridad del estrógeno potenciado en comparación con el placebo en el tratamiento homeopático del dolor pélvico asociado a endometriosis (EAPP, por sus siglas en inglés). Diseño del estudio: El presente fue un estudio clínico aleatorizado, doble ciego, controlado con placebo, de 24 semanas, el cual incluyó a 50 mujeres de entre 18 y 45 años de edad con diagnóstico de endometriosis infiltrante profunda con base en ultrasonido transvaginal o imágenes de resonancia magnética después de preparación intestinal, así como puntaje ≥ 5 en una escala visual analógica (VAS: rango de 0 a 10 puntos) para el dolor pélvico asociado con la endometriosis. Se administró estrógeno potenciado (12cH, 18cH y 24cH) o placebo dos veces al día por vía oral. La medida principal de resultado fue el cambio en la severidad de los puntajes parcial y global de EAPP (VAS) de la línea basal a la semana 24, determinada como la diferencia en el puntaje medio de cinco modalidades de dolor pélvico crónico (dismenorrea, dispareunia profunda, dolor pélvico no cíclico, dolor intestinal cíclico y/o dolor urinario cíclico). Las medidas secundarias de resultado fueron la diferencia media de puntaje para la calidad de vida evaluada con el Cuestionario de Salud SF-36, los síntomas de depresión en el Inventario de la Depresión de Beck (BDI) y los síntomas de ansiedad en el Inventario de Ansiedad de Beck (BAI). Resultados: El puntaje global de EAPP (VAS: rango de 0 a 50 puntos) se redujo en 12.82 (p < 0.001) en el grupo tratado con estrógeno potenciado de la línea basal a la semana 24. El grupo que utilizó estrógeno potenciado también presentó una reducción en el puntaje parcial (VAS: rango de 0 a 10 puntos) en tres modalidades de EAPP: dismenorrea (3.28; p < 0.001), dolor pélvico no cíclico (2.71; p = 0.009) y dolor intestinal cíclico (3.40; p < 0.001). El grupo de placebo no mostró cambio significativo alguno en los puntajes global o parcial de EAPP. Además, el grupo de estrógeno potenciado mostró un mejoramiento significativo en tres de ocho ámbitos de SF-36 (dolor de cuerpo, vitalidad y salud mental) y síntomas de depresión (BDI). El grupo de placebo no mostró un mejoramiento significativo a este respecto. Estos resultados demuestran la superioridad del estrógeno potenciado sobre el placebo. Se asociaron pocos eventos adversos con el estrógeno potenciado. Conclusiones: El estrógeno potenciado (12cH, 18cH y 24cH) en dosis de 3 gotas dos veces al día durante 24 semanas fue significativamente más efectivo que el placebo para reducir el dolor pélvico asociado con la endometriosis. Registro del estudio clínico: ClinicalTrials.gov Identificador: https://clinicaltrials.gov/show/NCT02427386.

To evaluate the efficacy and safety of potentized estrogen compared to placebo in homeopathic treatment of endometriosis-associated pelvic pain (EAPP). Study design: The present was a 24-week, randomized, doubleblind, placebocontrolled trial that included 50 women aged 18-45 years old with diagnosis of deeply infiltrating endometriosis based on magnetic resonance imaging or transvaginal ultrasound after bowel preparation, and score ≥ 5 on a visual analogue scale (VAS: range 0 to 10 points) for endometriosis-associated pelvic pain. Potentized estrogen (12cH, 18cH and 24cH) or placebo was administered twice daily per oral route. The primary outcome measure was change in the severity of EAPP global and partial scores (VAS) from baseline to week 24, determined as the difference in the mean score of five modalities of chronic pelvic pain (dysmenorrhea, deep dyspareunia, non-cyclic pelvic pain, cyclic bowel pain and/or cyclic urinary pain). The secondary outcome measures were mean score difference for quality of life assessed with SF-36 Health Survey Questionnaire, depression symptoms on Beck Depression Inventory (BDI), and anxiety symptoms on Beck Anxiety Inventory (BAI). Results: The EAPP global score (VAS: range 0 to 50 points) decreased by 12.82 (p < 0.001) in the group treated with potentized estrogen from baseline to week 24. Group that used potentized estrogen also exhibited partial score (VAS: range 0 to 10 points) reduction in three EAPP modalities: dysmenorrhea (3.28; p < 0.001), non-cyclic pelvic pain (2.71; p = 0.009), and cyclic bowel pain (3.40; p < 0.001). Placebo group did not show any significant changes in EAPP global or partial scores. In addition, the potentized estrogen group showed significant improvement in three of eight SF-36 domains (bodily pain, vitality and mental health) and depression symptoms (BDI). Placebo group showed no significant improvement in this regard. These results demonstrate superiority of potentized estrogen over placebo. Few adverse events were associated with potentized estrogen. Conclusions: Potentized estrogen (12cH, 18cH and 24cH) at a dose of 3 drops twice daily for 24 weeks was significantly more effective than placebo for reducing endometriosis-associated pelvic pain.

Para aquellos que demandan evidencias científicas de la homeopatía [Editorial] / For those who demand scientific evidence of homeopathy [Editorial]

El dossier comienza con una revisión titulada "Homeopatía: una breve descripción de esta especialidad médica", que aborda los aspectos históricos, sociales y políticos de la institucionalización de la homeopatía en Brasil y su inclusión en los sistemas de atención médica. Además, describe las razones por las que los pacientes buscan este enfoque terapéutico. La revisión "Formación médica en la terapéutica no convencional en el mundo (homeopatía y acupuntura)" enfatiza la relevancia de la inclusión de la homeopatía y la acupuntura en el plan de estudios de las escuelas de medicina en muchos países alrededor del mundo. Tal inclusión ­ actualizada a través de distintas modalidades específicas para estudiantes de licenciatura y posgrado, médicos residentes y médicos en ejercicio ­ es resultado del creciente interés de los pacientes, el cual conduce a un interés similar entre los médicos por aprender sobre tales formas de medicina. Con el objetivo de proporcionar fundamentos científicos al principio de similitud terapéutica a través del estudio sistemático del efecto de rebote de los fármacos modernos, la revisión titulada "Bases científicas del principio de curación homeopática en la farmacología moderna" aborda cientos de estudios publicados en revistas científicas de alto impacto que demuestran una similitud conceptual y fenomenológica entre el efecto de rebote y la reacción vital (o acción secundaria) que desencadena el tratamiento homeopático. Para ampliar las implicaciones de dicha similitud, el autor describe el uso de los fármacos modernos con base en el principio de similitud terapéutica, conduciendo a la aplicación del efecto de rebote (reacción paradójica del cuerpo) con intención curativa. Para dar cuenta de la plausibilidad del uso homeopático de las diluciones altas (HD), el presente dossier incluye tres revisiones que describen los avances realizados en investigación fundamental a lo largo de las últimas décadas: "La solidez de la investigación homeopática fundamental", "Efectos de las diluciones homeopáticas altas sobre los modelos in vitro: revisión de la literatura" y "Efectos de las diluciones homeopáticas altas sobre las plantas: revisión de la literatura". Tales revisiones abordan cientos de experimentos y docenas de líneas de investigación que demuestran en conjunto los efectos de las diluciones altas (HD) en los modelos físico-químicos y biológicos (in vitro, en plantas y animales).