Tackling Neuroinflammation in Cognitive Disorders with Single-Targeted and Multi-Targeted Histamine H3 Receptor Modulators.

Neuroinflammation is a process involved in a variety of central nervous system (CNS) diseases and is being increasingly recognized as a key mediator of cognitive impairments. Neuroinflammatory responses including glial activation, increased production of proinflammatory cytokines, and aberrant neuronal signaling, contribute to cognitive dysfunctions. Histamine is a key peripheral inflammatory mediator, but plays an important role in neuroinflammatory processes as well. The unique localization of histamine H3 receptor (H3R) in the CNS along with the modulation of the release of other neurotransmitters via its action on heteroreceptors on non-histaminergic neurons have led to the development of several H3R ligands for various brain diseases. H3R antagonists/ inverse agonists have revealed potential to treat diverse neuroinflammatory CNS disorders, including neurodegenerative diseases, attention-deficit hyperactivity syndrome and schizophrenia. In this mini review, we provide a brief overview on the crucial involvement of the histaminergic transmission in the neuroinflammatory processes underlying these cognitive disorders, with a special focus on H3R involvement. The anti-neuroinflammatory potential of single-targeted and multi-targeted H3R antagonists/inverse agonists for the treatment of these conditions is discussed here.

Antihistamines H1 as Potential Anthelmintic Agents against the Zoonotic Parasite Angiostrongylus cantonensis.

Infections caused by parasitic helminths pose significant health concerns for both humans and animals. The limited efficacy of existing drugs underscores the urgent need for novel anthelmintic agents. Given the reported potential of antihistamines against various parasites, including worms, this study conducted a screening of clinically available antihistamines against Angiostrongylus cantonensis-a nematode with widespread implications for vertebrate hosts, including humans. Twenty-one anti-H1 antihistamines were screened against first-stage larvae (L1) of A. cantonensis obtained from the feces of infected rats. Standard anthelmintic drugs ivermectin and albendazole were employed for comparative analysis. The findings revealed four active compounds (promethazine, cinnarizine, desloratadine, and rupatadine), with promethazine demonstrating the highest potency (EC50 = 31.6 µM). Additionally, morphological analysis showed that antihistamines induced significant changes in larvae. To understand the mechanism of action, antimuscarinic activities were reported based on average pK i values for human muscarinic receptor (mAChR) subtypes of the evaluated compounds. Furthermore, an analysis of the physicochemical and pharmacodynamic properties of antihistamines revealed that their anthelmintic activity does not correlate with their activity at H1 receptors. This study marks the first documentation of antihistamines' activity against A. cantonensis, offering a valuable contribution to the quest for novel agents effective against zoonotic helminths.

The histamine H4 receptor antagonist 1-[(5-chloro-2,3-dihydro-1-benzofuran-2-yl)methyl]-4-methyl-piperazine(LINS01007) prevents the development of DSS-induced colitis in mice.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease with growing incidence worldwide. Our group reported the compound 5-choro-1-[(2,3-dihydro-1-benzofuran-2-yl)methyl]piperazine (LINS01007) as H4R antagonist (pKi 6.2) and therefore the effects and pharmacological efficacy on a DSS-induced mice model of UC were assessed in this work. Experimental acute colitis was induced in male BALB/c mice (n = 5-10) by administering 3 % DSS in the drinking water for six days. The test compound LINS01007 was administered daily i.p. (5 mg/kg) and compared to control group without treatment. Body weight, water and food consumption, and the presence of fecal blood were monitored during 7-day treatment period. The levels of inflammatory markers (PGE2, COX-2, IL-6, NF-κB and STAT3) were also analyzed. Animals subjected to the acute colitis protocol showed a reduction in water and food intake from the fourth day (p < 0.05) and these events were prevented by LINS01007. Histological signs of edema, hyperplasia and disorganized intestinal crypts, as well as neutrophilic infiltrations, were found in control mice while these findings were significantly reduced in animals treated with LINS01007. Significant reductions in the levels of PGE2, COX-2, IL-6, NF-κB and STAT3 were observed in the serum and tissue of treated animals. The results demonstrated the significant effects of LINS01007 against DSS-induced colitis, highlighting the potential of H4R antagonism as promising treatment for this condition.

Espiritualidade e religiosidade na prática médica em um hospital universitário / Spirituality and religiosity in medical practice at a university hospital / Espiritualidad y religiosidad en la práctica médica en un hospital universitario

Resumo A religiosidade e a espiritualidade desempenham papéis cruciais na medicina, especialmente na abordagem centrada no paciente, melhorando a relação médico-paciente. Apesar disso, muitos médicos ainda subutilizam esses recursos, muitas vezes devido a insegurança ao lidar com a esfera pessoal da vida dos pacientes. Para abordar essa questão, conduziu-se pesquisa com 128 médicos, incluindo residentes, em um hospital universitário de Minas Gerais, entre agosto e dezembro de 2021, mediante aplicação dos questionários Inventário de Religiosidade de Duke e Escala Multidimensional de Reatividade Interpessoal, além de questões levantadas em estudos anteriores sobre saúde e espiritualidade. Com isso, buscou-se avaliar de que forma profissionais percebem a importância da religiosidade e da espiritualidade na prática clínica e sua relação com posturas éticas e humanistas. Os resultados revelaram correlação significativa entre as duas escalas, indicando associação positiva entre religiosidade e espiritualidade e empatia.

Abstract Religiosity and spirituality are pivotal in medical practice, particularly in fostering a patient-centered approach that enhances the physician-patient relationship. Despite this, many physicians still underutilize these invaluable resources, often due to feelings of uncertainty when navigating the personal aspects of patients' lives. To address this challenge, a survey involving 128 physicians, including residents, was conducted at a university hospital in Minas Gerais between August and December 2021. Utilizing the Duke Religiosity Inventory and Multidimensional Interpersonal Reactivity Scale questionnaires, alongside inquiries drawn from prior studies on health and spirituality, the goal was to assess professionals' perceptions of the significance of religiosity and spirituality in clinical practice and their interplay with ethical and humanistic attitudes. The findings unveiled a significant correlation between the two scales, underscoring a positive connection between religiosity, spirituality, and empathy.

Resumen La religiosidad y la espiritualidad desempeñan un papel clave en la medicina, especialmente en el enfoque centrado en el paciente al mejorar la relación médico-paciente. Muchos médicos aún no utilizan este recurso, debido a la inseguridad a menudo de enfrentar la vida personal de los pacientes. En este estudio se aplicó a 128 médicos y residentes de un hospital universitario de Minas Gerais (Brasil) los cuestionarios Índice de Religiosidad de Duke y Índice de Reactividad Interpersonal Multidimensional entre agosto y diciembre de 2021, así como preguntas planteadas en estudios anteriores sobre salud y espiritualidad. Se pretendió evaluar la percepción de los profesionales sobre la importancia de la religiosidad y la espiritualidad en la práctica clínica y su relación con las actitudes éticas y humanistas. Los resultados revelaron una correlación significativa entre las dos escalas, lo que indica una asociación positiva entre la religiosidad y espiritualidad y la empatía.

Investigation of Structure-Activity Relationships for Benzoyl and Cinnamoyl Piperazine/Piperidine Amides as Tyrosinase Inhibitors.

Melanin is a substance that plays important roles in several organisms. Its function as an antioxidant and metal-complexing agent makes tyrosinase, the key enzyme that controls melanogenesis, an interesting target for designing inhibitors. In this article, we report a set of piperazine/piperidine amides of benzoic and cinnamic acid derivatives as tyrosinase inhibitors with improved potency and drug-likeness. The most potent compound 5b showed a pIC50 of 4.99 in the monophenolase assay, and only compound 3a showed reasonable potency in the diphenolase assay (pIC50, 4.18). These activities are not correlated to antiradical activity, suggesting that the activity is dependent on competition with the substrates. Molecular docking studies indicated that the benzyl substituent of 5b and other analogues perform important interactions in the enzyme that may explain the higher potency of these compounds. Moreover, the compounds present adequate lipophilicity and skin permeability and no relevant cytotoxicity (CC50 > 200 µM) to mammalian cells.

Piperazine amides with desirable solubility, physicochemical and drug-like properties: Synthesis and evaluation of the anti-Trypanosoma cruzi activity.

The absence of effective chronic treatment, expansion to non-endemic countries and the significant burden in public health have stimulated the search for novel therapeutic options to treat Chagas disease, a protozoan disease caused by Trypanosoma cruzi. Despite current efforts, no new drug candidates were approved in clinical trials in the past five decades. Considering this, our group has focused on the expansion of a series (LINS03) with low micromolar activity against amastigotes, considering the optimization of pharmacokinetic properties through increasing drug-likeness and solubility. In this work, we report a new set of 13 compounds with modifications in both the arylpiperazine and the aromatic region linked by an amide group. Five analogues showed activity against intracellular amastigotes (IC50 17.8 to 35.9 µM) and no relevant cytotoxicity to mammalian cells (CC50 > 200 µM). Principal component analysis (PCA) was performed to identify structural features associated to improved activity. The data revealed that polarity, hydrogen bonding ability and flexibility were key properties that influenced the antiparasitic activity. In silico drug-likeness assessments indicated that compounds with the 4-methoxycinammyl (especially compound 2b) had the most prominent balance between properties and activity in the series, as confirmed by SAR analysis.

Toward anthelmintic drug candidates for toxocariasis: Challenges and recent developments.

Infections caused by parasitic helminths rank among the most prevalent infections of humans and animals. Toxocariasis, caused by nematodes of the genus Toxocara, is one of the most widespread and economically important zoonotic parasitic infections that humans share with dogs and cats. Despite the completion of the Toxocara canis draft genome project, which has been an important step towards advancing the understanding of this parasite and the search for drug targets, the treatment of toxocariasis has been dependent on a limited set of drugs, necessitating the search for novel anthelmintic agents, specially against Toxocara larvae in tissues. Given that research, development, and innovation are crucial to finding appropriate solutions in the fight against helminthiasis, this paper reviews the progress made in the discovery of anthelmintic drug candidates for toxocariasis. The main compounds reported in the recent years regards on analogues of albendazole, reactive quinone derivatives and natural produts and its analogues. Nanoparticles and formulations were also reviewed. The in vitro and/or in vivo anthelmintic properties of such alternatives are herein discussed as well as the opportunities and challenges for treatment of human toxocariasis. The performed review clarify that the scarcity of validated molecular targets and limited chemical space explored are the main bottlenecks for advancing in the field of anti-Toxocara agents.

Synthetic Analogues of Gibbilimbol B Induce Bioenergetic Damage and Calcium Imbalance in Trypanosoma cruzi.

Chagas disease is an endemic tropical disease caused by the protozoan Trypanosoma cruzi, which affects around 7 million people worldwide, mostly in development countries. The treatment relies on only two available drugs, with severe adverse effects and a limited efficacy. Therefore, the search for new therapies is a legitimate need. Within this context, our group reported the anti-Trypanosoma cruzi activity of gibbilimbol B, a natural alkylphenol isolated from the plant Piper malacophyllum. Two synthetic derivatives, LINS03018 (1) and LINS03024 (2), demonstrated a higher antiparasitic potency and were selected for mechanism of action investigations. Our studies revealed no alterations in the plasma membrane potential, but a rapid alkalinization of the acidocalcisomes. Nevertheless, compound 1 exhibit a pronounced effect in the bioenergetics metabolism, with a mitochondrial impairment and consequent decrease in ATP and reactive oxygen species (ROS) levels. Compound 2 only depolarized the mitochondrial membrane potential, with no interferences in the respiratory chain. Additionally, no macrophages response of nitric oxide (NO) was observed in both compounds. Noteworthy, simple structure modifications in these derivatives induced significant differences in their lethal effects. Thus, this work reinforces the importance of the mechanism of action investigations at the early phases of drug discovery and support further developments of the series.

Esterification of p-Coumaric Acid Improves the Control over Melanoma Cell Growth.

Previous studies reported that p-coumaric acid modulates melanoma growth. Because the esterification of p-coumaric acid (p-CA) enhanced its activity as an antimelanogenic agent, we aimed to determine the antitumor potential of two derivatives, the ethyl and butyl esters, against the murine B16-F10 and the human SK-MEL-25 melanoma cells. Cell viability was determined in vitro by the lactate dehydrogenase release and violet crystal absorption assays. The cell proliferation rate and cell cycle behavior were determined by the colony formation assay and flow cytometry analysis. Although p-CA, at the concentration of 1 mM, failed to exert a significant antitumor activity, the ethyl and butyl ester derivatives caused substantial tumor cell death at doses < 1 mM. Despite a reduction in their direct cytotoxicity at minor doses, both products controlled the melanoma growth by arresting the cell cycle at the G0/G1 (B16-F10) or S/G2 (SK-MEL-25). Furthermore, the in vivo experiments showed that the butyl ester derivative suppressed the lung B16-F10 burden, compared to the p-CA-treated mice. Thus, the esterification of p-coumaric acid improved the control over the proliferation of murine and human melanoma cells and can be considered an approach for designing novel anticancer agents.

Multitargeting approaches to cognitive impairment: Synthesis of aryl-alkylpiperazines and assessment at cholinesterases, histamine H3 and dopamine D3 receptors.

Multitargeting ligands on enzymes and receptors may generate a profile for a potential treatment of cognitive impairment. Considering this, a set of 21 substituted aryl-alkyl-piperazines were designed, prepared and tested for their binding affinities at histamine H3 and dopamine D3 receptors (H3R and D3R, respectively) as well as acetyl- and butyrylcholinesterases (AChE/BChE) as potentially synergistic profile. Initial screening of the compounds at H3R and D3R was done at 1 or 10 µM and 100 µM at AChE and BChE assays. The most promising compounds were then evaluated in full concentration-response curves to estimate the Ki and IC50 values. Results showed that several compounds were ligands at H3R (n = 10), D3R (n = 6), AChE (n = 3), and BChE (n = 9). Compounds LINS05006 (Ki H3R 2.8 µM; D3R 0.7 µM; IC50 BChE 26.3 µM) and LINS05015 (Ki H3R 1.1 µM; D3R 3.1 µM; IC50 AChE 97.8 µM; BChE 43.7 µM) are highlighted since presented affinity in three different. These results suggest that methylpiperazine moiety led to balanced activity at all three classes of targets, and longer linker provided the best affinities. These compounds presented high ligand efficiency values (LE > 0.3) and may have adequate pharmacokinetic profile as suggested by calculated physicochemical properties.

Orofacial myofunctional assessment and quality of life of individuals with Parkinson's disease.

OBJECTIVES: To characterize orofacial myofunctional structures of elders with Parkinson's disease (PD) and examine the relationship with the stages of PD, pharmacotherapy, and quality of life. METHODS: PD Group with 45 elders and a control group (CG) of 10 healthy elders of both sexes were included (60-86 years). Structured interviews, medical records, and clinical examination gathered information on health aspects such as the use of drugs, Hoehn & Yahr stages 1-4, and oral health status. The Mini-Mental State Examination, Parkinson's Disease Questionnaire, and Orofacial Myofunctional Evaluation with Scores for Elders were applied. RESULTS: Better oral health status was found in participants diagnosed as Hoehn & Yahr stage 1 compared to the later stages. OMES-Elders scores for appearance/posture, mobility, breathing, and speech functions were different between groups, and decreased overall OMES-Elders was observed across the Hoehn & Yahr stages. A higher number of masticatory cycles was required for chewing and ingestion of the test food in the PD group compared to CG (p < .05). Significant differences were found in the mobility and daily living activities domains and an overall score of QoL between the Hoehn & Yahr stages 1 and 4, and worst orofacial functioning was accompanied by the worst self-perception of QoL in the communication domain (rho = -0.32; p = .034). The use of xerogenic drugs did not affect the OMES-Elders swallowing domain. CONCLUSION: Worse dental condition and performance of orofacial functions was observed in the elders with PD as the disease progresses, and poorer orofacial performance negatively affects their perception of communication skills.

Lethal action of Licarin A derivatives in Leishmania (L.) infantum: Imbalance of calcium and bioenergetic metabolism.

Natural metabolites present an extraordinary chemo-diversity and have been used as the inspiration for new drugs. Considering the need for new treatments against the neglected parasitic disease leishmaniasis, three semi-synthetic derivatives of natural neolignane licarin A were prepared: O-acetyl (1a), O-allyl (1b), and 5-allyl (1c). Using an ex vivo assay, compounds 1a, 1b, and 1c showed activity against the intracellular amastigotes of Leishmania (L.) infantum, with IC50 values of 9, 13, and 10 µM, respectively. Despite no induction of hemolytic activity, only compound 1b resulted in mammalian cytotoxicity (CC50 = 64 µM). The most potent compounds (1a and 1c) resulted in selectivity indexes >18. The mechanism of action of compound 1c was evaluated by fluorescent/luminescent based techniques and MALDI-TOF/MS. After a short incubation period, increased levels of the cytosolic calcium were observed in the parasites, with alkalinization of the acidocalcisomes. Compound 1c also induced mitochondrial hyperpolarization, resulting in decreased levels of ATP without altering the reactive oxygen species (ROS). Neither plasma membrane damages nor DNA fragmentation were observed after the treatment, but a reduction in the cellular proliferation was detected. Using MALDI-TOF/MS, mass spectral alterations of promastigote proteins were observed when compared to untreated and miltefosine-treated groups. This chemically modified neolignan induced lethal alterations of the bioenergetic and protein metabolism of Leishmania. Future PKPD and animal efficacy studies are needed to optimize this promising natural-derived compound.

Investigation of structure−activity relationships for benzoyl and cinnamoyl piperazine/piperidine amides as Tyrosinase inhibitors

Melanin is a substance that plays important roles in several organisms. Its function as an antioxidant and metal-complexing agent makes tyrosinase, the key enzyme that controls melanogenesis, an interesting target for designing inhibitors. In this article, we report a set of piperazine/piperidine amides of benzoic and cinnamic acid derivatives as tyrosinase inhibitors with improved potency and drug-likeness. The most potent compound 5b showed a pIC50 of 4.99 in the monophenolase assay, and only compound 3a showed reasonable potency in the diphenolase assay (pIC50, 4.18). These activities are not correlated to antiradical activity, suggesting that the activity is dependent on competition with the substrates. Molecular docking studies indicated that the benzyl substituent of 5b and other analogues perform important interactions in the enzyme that may explain the higher potency of these compounds. Moreover, the compounds present adequate lipophilicity and skin permeability and no relevant cytotoxicity (CC50 > 200 μM) to mammalian cells.

Neurotoxicity Assessment of 1-[(2,3-Dihydro-1-Benzofuran-2-yl)Methyl]Piperazine (LINS01 Series) Derivatives and their Protective Effect on Cocaine-Induced Neurotoxicity Model in SH-SY5Y Cell Culture.

Excessive levels of dopamine in the synaptic cleft, induced by cocaine for example, activates dopaminergic receptors, mainly D1R, D2R, and D3R subtypes, contributing to neurotoxic effects. New synthetic 1-[(2,3-dihydro-1-benzofuran-2-yl)methyl]piperazine derivatives (the LINS01 compounds), designed as histaminergic receptor (H3R) ligands, are also dopaminergic receptor ligands, mainly D2R and D3R. This study aims to evaluate the neurotoxicity of these new synthetic LINS01 compounds (LINS01003, LINS01004, LINS01011, and LINS01018), as well as to investigate their protective potential on a cocaine model of dopamine-induced neurotoxicity using SH-SY5Y cell line culture. Neurotoxicity was assessed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), lactate dehydrogenase (LDH), and automated cell counting with fluorescent dyes (acridyl orange and propidium iodide) assays. Concentration-response curves (CRCs) were performed for all LINS compounds and cocaine using MTT assay. The results show that LINS series did not decrease cell viability after 48h of exposure-except for 100 µM LINS01018, which was discontinued from the study. Likewise, MTT, LDH, and fluorescent dyes staining showed no difference is cell viability for LINS compounds at 10 µM. When incubated with 2.5 mM cocaine (lethal concentration 50) for 48h, 10 µM of each LINS compound, metoclopramide (D2R antagonist) and haloperidol (D2R/D3R antagonist), ameliorated cocaine-induced neurotoxicity. However, only metoclopramide, haloperidol, and LINS01011 compound significantly decreased LDH released in the culture medium, suggesting that this new synthetic compound presents a more robust effect. This preliminary in vitro neurotoxicity study suggests that LINS01 compounds are not neurotoxic, and that they play a promising role in preventing cocaine-induced neurotoxicity.

Cellulose nanocrystals as nucleating agents for the strain induced crystallization in natural rubber.

Vulcanized natural rubber (NR)/cellulose nanocrystals (CNC) composites with a CNC content of up to 5 wt% using physical blending and dicumyl peroxide crosslinking were prepared. The tensile properties were investigated at slow and high strain rates. The slow strain rate tests revealed an increase of the elastic modulus concomitant with a decrease of strain at the crystallization onset while increasing the CNC fraction. The high strain rate tests performed near adiabatic conditions demonstrated the ability of the CNC to improve the elastocaloric properties of the NR matrix, with an increase of 30% and 15% of heating and cooling capacities, respectively, in the presence of 3 wt% CNC. Such results were ascribed to (i) a higher thermoelastic effect, due to strain amplification in the NR matrix in the presence of CNC and (ii) a nucleating effect of the CNC on strain induced crystallization. This series of materials can be proposed as a promising eco-friendly alternative to conventional carbon black filled rubber as potential green elastocaloric materials (heating pump, cooling machines).

Evaluation of the histamine H3 receptor antagonists from LINS01 series as cholinesterases inhibitors: Enzymatic and modeling studies.

Histamine is involved in several central nervous system processes including cognition. In the last years, H3 receptor (H3 R) antagonists have been widely explored for their potential on dementias and other cognitive dysfunctions, and the cooperative role between histamine and acetylcholine neurotransmissions on cognitive processes is widely known in literature. This motivated us to assess the potential of 1-[(2,3-dihydrobenzofuran-1-yl)methyl]piperazines (LINS01 compounds) as inhibitors of cholinesterases, and thus this work presents the inhibitory effect of such compounds against acetyl (AChE) and butyrylcholinesterase. A set of 16 selected compounds were evaluated, being compounds 2d and 2e the most potent inhibitors of both cholinesterases (IC50 13.2-33.9 µM) by competitive mechanism, as indicated by the kinetic assays. Molecular docking simulations suggested that the allylpiperazine and dihydrobenzofuran motifs present in these compounds are important to perform π-interactions with key tryptophan residues from the enzymes, increasing their affinity for both H3 R and cholinesterases. Metric analysis support that compound 2d (LINS01022) should be highlighted due to its balanced lipophilicity (ClogP 2.35) and efficiency (LE 0.32) as AChE inhibitor. The results add important information to future design of dual H3 R-cholinesterases ligands.

Association of COVID-19 Incidence and Mortality Rates With School Reopening in Brazil During the COVID-19 Pandemic.

Importance: School closures because of COVID-19 have left 1.6 billion students around the world without in-person classes for a prolonged period. To our knowledge, no study has documented whether reopening schools in low- and middle-income countries during the pandemic was associated with increased aggregate COVID-19 incidence and mortality with appropriate counterfactuals. Objective: To test whether reopening schools under appropriate protocols during the COVID-19 pandemic was associated with increased municipal-level COVID-19 cases and deaths in São Paulo State, Brazil. Design Setting and Participants: This observational study of municipalities in São Paulo State, Brazil, uses a difference-in-differences analysis to examine the association between municipal decisions to reopen schools during the COVID-19 pandemic and municipal-level COVID-19 case and death rates between October and December 2020. The study compared 129 municipalities that reopened schools in 2020 with 514 that did not and excluded data for 2 municipalities that reopened schools and closed then again. Main Outcomes and Measures: New COVID-19 cases and deaths per 10 000 inhabitants up to 12 weeks after school reopenings and municipal-level aggregate mobility for a subset of municipalities. Results: There were 8764 schools in the 129 municipalities that reopened schools compared with 9997 in the control group of 514 municipalities that did not reopen schools. The municipalities that reopened schools had a cumulative COVID-19 incidence of 20 cases per 1000 inhabitants and mortality of 0.5 deaths per 1000 inhabitants in September 2020 (the baseline period) compared with an incidence of 18 cases per 1000 inhabitants and mortality of 0.45 deaths per 1000 inhabitants during the baseline period in the comparison group. The findings indicated that there were no statistically significant differences between municipalities that authorized schools to reopen and those that did not for (1) weekly new cases (difference-in-differences, -0.03; 95% CI, -0.09 to 0.03) and (2) weekly new deaths (difference-in-differences, -0.003; 95% CI, -0.011 to 0.004) before and after October 2020. Reopening schools was not associated with higher disease activity, even in relatively vulnerable municipalities, nor aggregate mobility. Conclusions and Relevance: The findings from this study suggest that keeping schools open during the COVID-19 pandemic did not contribute to the aggregate disease activity.

Histamine research advancements in the second year of the COVID-19 pandemic: report of the European Histamine Research Society (EHRS).

In the light of cancellation of the 50th Annual Meeting of the European Histamine Research Society (EHRS) due to continuing challenges and restrictions imposed by the coronavirus disease 2019 (COVID-19) outbreak, the EHRS Council decided to organize a series of online events spread in 2021 to allow dissemination of histamine research progress and advancement among the Society members and beyond. This report summarizes the outcomes of the EHRS Council initiative that comprised the organization of four webinars, each focusing on a highly relevant histamine research scientific area. These included insights into novel therapeutic targets related to the histaminergic system in the eye, histamine intolerance, and the role of histamine and the histaminergic system in the regulation of the nervous system, as well as an update on studies leading to the development of novel methods for histamine detection. The outcome of this series of virtual events conformed that histamine research continued to develop despite the pandemic, and we witnessed stimulating advancements in 2021. Importantly, the EHRS Council brought histaminologists together in this unprecedented time.

The impacts of remote learning in secondary education during the pandemic in Brazil.

The transition to remote learning in the context of coronavirus disease 2019 (COVID-19) might have led to dramatic setbacks in education. Taking advantage of the fact that São Paulo State featured in-person classes for most of the first school quarter of 2020 but not thereafter, we estimate the effects of remote learning in secondary education using a differences-in-differences strategy that contrasts variation in students' outcomes across different school quarters, before and during the pandemic. We also estimate intention-to-treat effects of reopening schools in the pandemic through a triple-differences strategy, contrasting changes in educational outcomes across municipalities and grades that resumed in-person classes or not over the last school quarter in 2020. We find that, under remote learning, dropout risk increased by 365% while test scores decreased by 0.32 s.d., as if students had only learned 27.5% of the in-person equivalent. Partially resuming in-person classes increased test scores by 20% relative to the control group.