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Spiro-heterocyclic indolenines are privileged scaffolds widely present in numerous indole alkaloids. Here, we develop a novel approach for the one-pot multistep synthesis of different spiro[indole-isoquinolines]. The protocol proposed involves the visible light mediated oxidation of N -aryl tertiary amines using bromochloroform with the generation of a reactive iminium species, which reacts with an isocyanide and an electron-rich aniline in a three-component Ugi-type reaction to give an α-aminoamidine. This compound might undergo an additional visible light-mediated oxidation to furnish a second iminium intermediate, which acts as electrophile in an intramolecular electrophilic aromatic substitution giving the final spiro-indolenine. The scope of the process has been investigated with respect to all three components. Simple operations, mild conditions, and good yields make this strategy a convenient and sustainable way to obtain novel spiro-indolenine derivatives., (Copyright © 2024, Gambuti et al.)

Randomized clinical trials (RCT) and observational studies have highlighted the importance of flavonoid consumption for human health. Several studies have associated a high intake of dietary flavonoids with (a) enhanced metabolic and cardiovascular health, (b) enhanced cognitive and vascular endothelial functions, (c) an improved glycemic response in type 2 diabetes mellitus, and (d) a reduced risk of breast cancer in postmenopausal women. Since flavonoids belong to a broad and diverse family of polyphenolic plant molecules-with more than 6000 compounds interspersed in the human diet-researchers are still uncertain whether the intake of single, individual polyphenols or a large combination of them (i.e., synergistic action) can produce the greatest health benefits for humans. Furthermore, studies have reported a poor bioavailability of flavonoid compounds in humans, which presents a major challenge for determining their optimal dosage, recommended intake, and, consequently, their therapeutic value. Especially because of their scarce bioavailability from foods-along with the overall declining food quality and nutrient density in foods-the role of flavonoid supplementation may become increasingly important for human health. Although research shows that dietary supplements can be a highly useful tool to complement diets that lack sufficient amounts of important nutrients, some caution is warranted regarding possible interactions with prescription and non-prescription drugs, especially when taken concurrently. Herein, we discuss the current scientific basis for using flavonoid supplementation to improve health as well as the limitations related to high intakes of dietary flavonoids.

Objective: While there are several well-established environmental risk factors for rheumatoid arthritis (RA), a paucity of evidence exists linking environmental toxicants with RA prevalence. We aimed to examine the associations between various environmental toxicants and RA among adults in the U.S. general population while adjusting for non-heritable risk factors., Design: Cross-sectional study., Setting: National Health and Nutrition Examination Survey conducted from 2007 to 2016., Participants: The study included 21 987 adult participants (no RA: 20 569; RA: 1418). Participants were excluded (n=7214) if they did not answer questions related to self-reporting of RA, had another or unknown type of arthritis, or did not have interview or biospecimen data., Primary and Secondary Outcome Measures: Association between individual toxicants and body burden scores for polycyclic aromatic hydrocarbons (PAH), phthalates and plasticisers (PHTHTEs) metabolites or volatile organic compounds (VOCs) and participant self-reported RA based on multivariable logistic regression models while adjusting for age, sex, urine creatinine, body mass index, smoking, race, education, family poverty income ratio, any vigorous or moderate activity and dietary fibre., Results: While increased prevalence of RA was observed in participants with the highest quartile of various individual PAHs, only 1-hydroxynaphthalene (OR: 1.8 (1.1 to 3.1); p=0.020) remained associated in a fully adjusted model. PAH body burden was found to be associated with RA (Q4 vs Q1, OR: 2.2 (1.09 to 4.2); p=0.028) in a fully adjusted model. Interestingly, after accounting for PAH body burden, smoking was not associated with RA (OR: 1.4 (0.89 to 2.3); p=0.13). A mediation analysis demonstrated that PAH body burden accounted for 90% of the total effect of smoking on RA. PHTHTE and VOC metabolites were not associated with RA in fully adjusted models., Conclusions and Relevance: PAHs are associated with RA prevalence, mediate the majority of the effects of smoking on RA, and are associated with RA independent of smoking status., Competing Interests: Competing interests: MB reported receiving personal fees from Cleveland HeartLab outside the submitted work. In addition, MB had a patent (No. 20110269150) issued. All other authors have nothing to disclose., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Many strategies were tried by our public health authorities to contain, mitigate, and treat the COVID-19 pandemic. With now 3 years of experience, research is being published that can help us determine what worked, and what did not. Unfortunately, assessing the research is very challenging. Not only are many of the approaches still not rigorously evaluated, but politics and censorship clearly distorted the research and reporting. In this, the first of 2 editorials, I review the research on Physical Strategies, Natural Health Products, and Healthy Lifestyle. In the next editorial I will take on Drugs and Vaccinations., (Copyright © 2023 InnoVision Professional Media Inc.)

Vitamin D is critical for many physiological functions in humans. Numerous population-wide assessments have shown that vitamin D deficiency is very common. Unfortunately, far too many studies intending to assess the clinical efficacy of supplementation are poorly designed. They look at vitamin D as an isolated agent, independent of the complex matrix required for it to be physiologically effective and at dosages inadequate for much of the population. These errors cause inappropriate and invalid results that are then misused to not only recommend against supplementation but to also recommend against even measuring vitamin D levels. This editorial addresses the weaknesses of typical vitamin D research, such as VITAL, and the key factors that must be addressed for accurate vitamin D research., (Copyright © 2022 InnoVision Professional Media Inc.)

As the COVID-19 pandemic has raged on, considerable research has been performed around the world evaluating the environmental, genetic, lifestyle, and nutritional factors that significantly impact the COVID-19 pandemic. Many studies have now shown that key risk factors for SARS-CoV-2 infection, severity, and even death are modifiable. Patients, whether partially vaccinated, fully vaccinated, or not vaccinated, are expecting their clinicians to provide them with evidence-based guidance and to help them prioritize the factors most important for them. In this editorial we review the current state of the research on modifiable risk factors for SARS-CoV-2 infection, disease severity, and death., (Copyright © 2021 InnoVision Professional Media Inc.)

About a century ago when research into the nutritional components of food began, scientists were limited by the technology and physiological understanding of the time. Nonetheless, this pioneering research revealed the importance of many nutrients for the maintenance of life and prevention of overt deficiency diseases. Unfortunately, the necessary simplifications led to the unrecognized assumption that the constituents in food not required for life were not important. This justified growing food chemically rather than organically because essential nutrients were largely (but not entirely) conserved. However, as technology advanced-especially at the turn of this century-much was revealed. Nutrients considered single molecules when discovered were now realized to represent multiple variants and vitamers with significantly different physiological effects, and many of the molecules considered "unimportant" have huge impacts on health and resistance to disease., (Copyright © 2021 InnoVision Professional Media Inc.)

In this second of a 2-part editorial, we continue our discussion of the importance of being aware that some clinically important prescription drugs can impair bone metabolism. While obviously most critical for women (and men) with osteopenia or osteoporosis, the guidance here is directly relevant to all patients as many are already experiencing decreased bone regeneration even if not severe enough for a formal diagnosis. Part One covered aromatase inhibitors, gonadotropin-releasing hormone agonists, anticonvulsants, benzodiazepines, antidepressants, insulin sensitizers, and NSAIDs and acetaminophen. Part Two covers opioids, glucocorticoids, calcineurin inhibitors, gastric acid blockers, diuretics, anti-coagulants, thyroid hormone medications, and contraceptives., (Copyright © 2021 InnoVision Professional Media Inc.)

Prescription and over-the-counter drugs have been effectively used to manage many diseases and to provide symptom relief. Unfortunately, their use may also result in adverse drug reactions and unintended consequences. Proper use of these powerful agents requires understanding both their desired effects and their potential downsides. Fully understanding the unintended consequences can be challenging. Virtually all safety studies are carried out for far shorter periods of time than the actual use of these agents in the real world. Some may take years of use before their sequelae are recognized. This is especially a problem where bone health is concerned since the damage caused by years of minor disruption in function does not show up until compounded by other factors, such as andropause and menopause. This 2-part editorial covers the primary classes of drugs that require bone health monitoring and that may require alternative prescriptions or mitigation strategies. Part One covers aromatase inhibitors, gonadotropin-releasing hormone agonists, anticonvulsants, benzodiazepines, antidepressants, insulin sensitizers, and NSAIDs and acetaminophen. Part Two covers opioids, glucocorticoids, calcineurin inhibitors, H2 blockers, diuretics, anticoagulants, thyroid medications, and contraceptives., (Copyright © 2021 InnoVision Professional Media Inc.)

The environmental metals cadmium, lead, and mercury, and chemicals such as pesticides, phthalates, and bisphenols, disrupt bone metabolism in many ways. Body levels of these toxins directly correlate, in a dose-dependent manner, with risk of fracture and osteoporosis. This editorial provides a brief summary of key research showing mechanisms of damage, sources, and key strategies to decrease body load., (Copyright © 2021 InnoVision Professional Media Inc.)

Humans suffer the highest burden of chronic disease in every age group ever in human history. Why? While many theories have been proposed, presented here are thoughts on a unified theory of disease to understand causes and provide guidance for health restoration and disease prevention. My thesis is that the combination of high and increasing body load of heavy metals, meta-metals and persistent and non-persistent environmental chemicals; multiple nutrient deficiencies and insufficiencies and loss of "unimportant" molecules from the food supply; dis-synchronization with the environment; and genetic susceptibility combine to disrupt physiology and cause disease., (Copyright © 2020 InnoVision Professional Media Inc.)

This paper presents an evidence-based strategy for improving clinical outcomes in COVID-19. Recommendations are based on the phases of the disease, because optimal interventions for one phase may not be appropriate for a different phase. The four phases addressed are: Prevention, Infection, Inflammation and Recovery. Underlying this phased approach is recognition of emerging evidence for two different components of pathophysiology, early infection and late stage severe complications. These two aspects of the disease suggest two different patterns of clinical emphasis that seem on the surface to be not entirely concordant. We describe the application of therapeutic strategies and appropriate tactics that address four main stages of disease progression for COVID-19. Emerging evidence in COVID-19 suggests that the SARS-CoV-2 virus may both evade the innate immune response and kill macrophages. Delayed innate immune response and a depleted population of macrophages can theoretically result in a blunted antigen presentation, delaying and diminishing activation of the adaptive immune response. Thus, one clinical strategy involves supporting patient innate and adaptive immune responses early in the time course of illness, with the goal of improving the timeliness, readiness, and robustness of both the innate and adaptive immune responses. At the other end of the disease pathology spectrum, risk of fatality in COVID-19 is driven by excessive and persistent upregulation of inflammatory mechanisms associated with cytokine storm. Thus, the second clinical strategy is to prevent or mitigate excessive inflammatory response to prevent the cytokine storm associated with high mortality risk. Clinical support for immune system pathogen clearance mechanisms involves obligate activation of immune response components that are inherently inflammatory. This puts the goals of the first clinical strategy (immune activation) potentially at odds with the goals of the second strategy(mitigation of proinflammatory effects). This creates a need for discernment about the time course of the illness and with that, understanding of which components of an overall strategy to apply at each phase of the time course of the illness. We review evidence from early observational studies and the existing literature on both outcomes and mechanisms of disease, to inform a phased approach to support the patient at risk for infection, with infection, with escalating inflammation during infection, and at risk of negative sequelae as they move into recovery., (Copyright © 2020 InnoVision Health Media Inc.)

The next step in reestablishing credibility seams to us honesty and recognizing we all share a common goal of the health and wellness of the human community and the planet. Everyone agrees that the current healthcare system, despite its many incredible successes, is also showing its limitations and is no longer sustainable. We believe the solution starts with us the researchers and editors. A good first step might be formally recognizing the errors and showing how we can and intend to get better.

Stroke is the third cause of death and the first cause of disability in Argentina. Ischemic events constitute 80% of cases. It requires the implementation of systematized protocols that allow reducing the time of care, morbidity and mortality. Specialists from nine medical societies related to the care of patients with cerebrovascular disease participated in the consensus. A separate agenda was agreed upon in chapters and for the writing of them, work groups were formed with members of different medical specialties. The level of recommendation was discussed and agreed upon for each topic based on the best clinical evidence available for each of them. An adaptation to the local scope of the recommendations was made when it was considered necessary.The American Heart Association system was used to draft the recommendations and their level of evidence. The correction and editing were done by five external reviewers, who did not participate in the writing and with extensive experience in vascular pathology. Once the preliminary document was finalized, a general meeting was held with all the members of the working groups and the reviewers to reach final recommendations. The consensus covers the management of ischemic stroke in the pre-hospital phase, initial evaluation in the emergency center, recanalization therapies (thrombolysis and/ or mechanical thrombectomy), decompressive craniectomy, neuroimaging and clinical care in the hospital.