Preparative Scale Applications of C-H Activation in Medicinal Chemistry.

C-H activation is an attractive methodology to increase molecular complexity without requiring substrate prefunctionalization. In contrast to well-established cross-coupling methods, C-H activation is less explored on large scales and its use in the production of pharmaceuticals faces substantial hurdles. However, the inherent advantages, such as shorter synthetic routes and simpler starting materials, motivate medicinal chemists and process chemists to overcome these challenges, and exploit C-H activation steps for the synthesis of pharmaceutically relevant compounds. In this review, we will cover examples of drugs/drug candidates where C-H activation has been implemented on a preparative synthetic scale (range between 355 mg and 130 kg). The optimization processes will be described, and each example will be examined in terms of its advantages and disadvantages, providing the reader with an in-depth understanding of the challenges and potential of C-H activation methodologies in the production of pharmaceuticals.

Sterically controlled isodesmic late-stage C-H iodination of arenes.

Aryl iodides are key motifs in organic chemistry due to their versatility as linchpins in metal-mediated cross-coupling reactions for synthesis and drug discovery. These scaffolds are typically prepared indirectly from prefunctionalized starting materials or via electrophilic aromatic iodination protocols. These methods are limited to specific regioisomers by their inherent selectivities and/or the availability of the required starting materials. Herein, we describe the sterically controlled iodination of arenes through an isodesmic C-H/C-I bond metathesis approach enabled by our dual ligand-based catalysts for arene-limited nondirected C-H activation. The protocol gives direct access to a complementary product spectrum with respect to traditional methods. Its synthetic utility is demonstrated by a broad scope and the suitability for late-stage modification.

T2Candida assay: diagnostic performance and impact on antifungal prescribing.

Objectives: To assess the performance of T2Candida for the diagnosis of invasive candidiasis (IC) against gold standards of candidaemia or consensus IC definitions, and to evaluate the impact of T2Candida on antifungal drug prescribing. Methods: A retrospective review was undertaken of all T2Candida (T2MR technology, T2 Biosystems) performed from October 2020 to February 2022. T2Candida performance was evaluated against confirmed candidaemia or against proven/probable IC within 48 hours of T2Candida, and its impact on antifungal drug prescriptions. Results: T2Candida was performed in 61 patients, with 6 (9.8%) positive results. Diagnostic performance of T2Candida against candidaemia had a specificity of 85.7% and negative predictive value (NPV) of 96.8%. When comparing T2Candida results with consensus definitions of IC, the specificity and NPV of T2Candida was respectively 90% (54/60) and 98.2% (54/55) for proven IC, and 91.4% (53/58) and 96.4% (53/55) for proven/probable IC. Antifungals were initiated in three of six patients (50%) with a positive T2Candida result. Thirty-three patients were receiving empirical antifungals at the time of T2Candida testing, and a negative result prompted cessation of antifungals in 11 (33%) patients, compared with 6 (25%) antifungal prescriptions stopped following negative beta-d-glucan (BDG) testing in a control population (n = 24). Conclusions: T2Candida shows high specificity and NPV compared with evidence of Candida bloodstream infection or consensus definitions for invasive Candida infection, and may play an adjunctive role as a stewardship tool to limit unnecessary antifungal prescriptions.

A Case of Varicella-Zoster Virus Meningomyelitis in an HIV-1-Infected Patient: Facing the Challenges Related to Its Management and Prognosis.

Varicella-zoster virus (VZV) myelitis is a rare complication of herpes zoster. Diagnosing and treating this entity may be challenging. Clinical outcomes vary and neurological sequelae may be seen despite treatment. We report a case of a 43-year-old woman with human immunodeficiency virus type 1 (HIV-1) infection (CD4 cell count 191 cells/µL - 14%; undetectable viral load) who was started on antiretroviral treatment eight months before. She presented with VZV meningitis and transverse myelitis and concomitant thoracic vesicular rash at the dermatomal level T6. Neurological examination revealed neck stiffness, paraplegia, sensory level below T4, and autonomic dysfunction. Magnetic resonance imaging (MRI) revealed signs of myelitis from C4 to T10 and VZV DNA by polymerase chain reaction (PCR) was positive (20,00,000 cp/mL) in the cerebrospinal fluid (CSF). The patient completed four weeks of intravenous acyclovir and systemic corticosteroids. Repeat lumbar puncture returned negative for VZV PCR and MRI showed spinal cord improvement. However, only partial neurological improvement was observed after six months. Some features of the present case may be associated with an unfavorable outcome, including high VZV viral load in the CSF and rapid progression of neurological deficits to paraplegia and sphincter dysfunction. Moreover, the recovery of CD4+ cells from 4% to 14% after starting antiretroviral treatment might also have contributed to the extension of myelopathy. Further studies are needed to improve the understanding of VZV myelitis course and optimize its treatment.

Uso do coagulante/floculante emergente à base de moringa no tratamento de água com verificação da composição e toxicidade do lodo produzido: tratamento de água com Moringa e toxicidade do lodo / Use of emergent moringa-based coagulant/flocculant for water treatment with verification of composition and toxicity of the produced sludge: water treatment with Moringa and toxicity of the sludge

RESUMO O presente estudo consistiu em avaliar a eficiência dos processos de tratamento convencional de água, por meio do coagulante natural Moringa oleifera Lam, com e sem casca, para o tratamento de água bruta captada do Rio Poxim, Aracaju, SE, Brasil. Após essa avaliação, realizou-se a análise da composição química e da toxicidade do lodo. As etapas de coagulação/floculação e decantação (30 e 60 minutos) foram realizadas em jar test com o coagulante, seguidas de filtração rápida descendente. A eficácia dos coagulantes foi analisada por meio da caracterização da água nas dosagens de 100, 200, 300 e 400 mg.L-1, por meio de análises físico-químicas, englobando os parâmetros pH, cor aparente e turbidez. O lodo proveniente do tratamento, em ambas as situações em estudo, foi caracterizado em relação à composição de proteína, amido e lipídio, além de ter sido verificada a toxicidade do resíduo por intermédio do crescimento e da germinação da Lactuca sativa. Como resultado, a moringa demonstrou potencial no tratamento de água pra consumo humano, principalmente o extrato de moringa com casca, tendo como dosagem ótima 300 mg.L-1 tanto para os parâmetros de cor quanto para a turbidez. Em relação ao pH, constatou-se que os tratamentos não promoveram variação significativa em relação aos valores da água bruta. Quanto à caracterização do lodo, foi possível verificar que em sua constituição há presença tanto de lipídio quanto de proteínas e ausência de amido; além disso, seu resíduo apresentou-se como atóxico para o meio ambiente.

ABSTRACT The present study aimed at evaluating the efficiency of conventional water treatment processes using the natural coagulant Moringa oleifera Lam, with and without shell, for the treatment of raw water captured in the Poxim River, Aracaju, state of Sergipe, Brazil. After this evaluation, the chemical composition of the sludge and its toxicity was analyzed. The stages of coagulation/flocculation and decanting (30 and 60 min) were performed in jar test with the coagulant, followed by rapid descending filtration. The effectiveness of the coagulants was analyzed by the characterization of the water in dosages of 100, 200, 300, and 400 mg.L-1, according to physicochemical analyses, including the parameters pH, apparent color, and turbidity. The treatment sludge, in both situations under study, was characterized in relation to the composition of protein, starch and lipid, in addition to verifying the toxicity of the residue by the growth and germination of Lactuca sativa. As a result, moringa showed potential in the treatment of water for human consumption, mainly the extract of moringa in shell, with an optimal dosage of 300 mg.L-1 for both color and turbidity parameters. Regarding pH, the treatments did not promote significant variation in the raw water values. In terms of sludge characterization, the presence of lipids and proteins was verified, but not that of starch. In addition, the sludge residue was considered nontoxic to the environment.

Reactivation of SARS-CoV-2 after Asymptomatic Infection while on High-Dose Corticosteroids. Case Report.

As SARS-CoV-2 and its related clinical syndrome (COVID-19) became a pandemic worldwide, questions regarding its clinical presentation, infectivity, and immune response have been the subject of investigation. We present a case of a patient previously considered recovered from nosocomially transmitted asymptomatic COVID-19 illness, who presented with new respiratory, radiological, and RT-PCR findings consistent with COVID-19, while on high-dose prednisolone due to a suspected secondary demyelinating disease. Importantly, it led to three subsequent cases within patient's household after discharge from the hospital. After reviewing this case in light of current evidence and debates surrounding SARS-CoV-2 RT-PCR results, we hypothesize that patients on corticosteroids may have particular viral shedding dynamics and should prompt a more conservative approach in regard to isolation discontinuation and monitoring.

Artemether/Lumefantrine for the Treatment of P. malariae in a Patient on Hemodialysis.

The combination of artemether/lumefantrine is indicated for the treatment of acute uncomplicated Plasmodium falciparum malaria. There have been no clinical trials to assess the efficacy of this medication in patients with renal impairment. While it is unlikely that artemether/lumefantrine would be removed during dialysis, clinical experience regarding drug use in this setting is limited. In this article, the authors report successful treatment of Plasmodium malariae malaria on a patient with end-stage kidney disease undergoing hemodialysis.

Eficacia da limpeza ou desinfecao do meato urinario antes da cateterizacao urinaria: revisao sistematica / Eficacia de la limpieza o desinfeccion del meato urinario antes del cateterismo urinario: revision sistematica / Effectiveness of cleaning or disinfecting the urinary meatus before urinary catheterization: a systematic review

As infeções do trato urinário associadas à cateterização são muito frequentes no contexto comunitário e hospitalar. Existem atualmente várias recomendações para sua prevenção, contudo, quando abordado o soluto a utilizar no meato urinário previamente à algaliação continuam a persistir dúvidas. Assim, este estudo procurou determinar a eficácia da limpeza do meato urinário com água ou soro fisiológico comparativamente à sua assepsia por meio de uma revisão sistemática com metanálise. Para isso foram seguidos os princípios propostos pelo Cochrane Handbook , a análise crítica realizada por dois investigadores e a análise estatística com recurso ao programa STATA 11.1. Podemos concluir que a limpeza ou desinfeção do meato urinário previamente à cateterização vesical não é estatisticamente significativa (OR=1,07, IC 95%=0,68-1,68, p=0,779), existindo alguma evidência de que a utilização de água/soro fisiológico reduz as taxas de ITU.

Las infecciones del tracto urinario asociadas con cateterismo son muy comunes en el contexto comunitario y hospitalario. Actualmente existen varias recomendaciones para su prevención. Sin embargo, las dudas persisten en la elección del soluto utilizado en el meato urinario antes del cateterismo. Por lo tanto, este estudio trata de determinar la eficacia de la limpieza del meato urinario con agua/solución salina comparativamente con su asepsia, mediante la realización de una revisión sistemática con meta-análisis. Para lo cual, se siguieron los principios propuestos por el Manual Cochrane, el análisis crítico realizado por dos investigadores y el análisis estadístico utilizando el programa STATA 11.1. Podemos concluir que la limpieza o desinfección del meato urinario antes del cateterismo no es estadísticamente significativo (OR=1,07, 95%CI=0,68-1,68, p=0,779) existiendo algunas evidencias de que el uso de agua/solución salina reduce las tasas de ITU.

The urinary tract infections associated with catheterization are very common in hospital and home care contexts. Currently there are several recommendations for its prevention, however, when approaching the kind of solute used in the urinary meatus prior to catheterization doubts continue to persist. Thus this study aimed at determining the effectiveness of cleaning the urinary meatus with water or saline comparing to its sterilization through a systematic review and meta-analysis. In order to do so, the principles proposed by the Cochrane Handbook were followed, a critical analysis was conducted by two researchers and the statistical analysis was performed with the use of STATA 11.1. We concluded that the cleaning or disinfection of the urinary canal prior to bladder catheterization is not statistically significant (OR=1.07, CI 95%=0.68-1.68, p=0.779) and that there is some evidence that the use of water/saline reduces rates of UTI (urinary tract infection).

[Effectiveness of cleaning or disinfecting the urinary meatus before urinary catheterization: a systematic review]. / Eficácia da limpeza ou desinfeção do meato urinário antes da cateterização urinária: revisão sistemática.

The urinary tract infections associated with catheterization are very common in hospital and home care contexts. Currently there are several recommendations for its prevention, however, when approaching the kind of solute used in the urinary meatus prior to catheterization doubts continue to persist. Thus this study aimed at determining the effectiveness of cleaning the urinary meatus with water or saline comparing to its sterilization through a systematic review and meta-analysis. In order to do so, the principles proposed by the Cochrane Handbook were followed, a critical analysis was conducted by two researchers and the statistical analysis was performed with the use of STATA 11.1. We concluded that the cleaning or disinfection of the urinary canal prior to bladder catheterization is not statistically significant (OR=1.07, CI 95%=0.68-1.68, p=0.779) and that there is some evidence that the use of water/saline reduces rates of UTI (urinary tract infection).

Effects of exercise training on papain-induced pulmonary emphysema in Wistar rats.

The purpose of the present study was to evaluate the role of exercise training on the development of papain-induced emphysema in rats. Our hypothesis was that the increase in pulmonary tissue stretching associated with exercise could increase the severity of a protease-induced emphysema. Wistar rats were randomly assigned to four groups (n = 10 for each group) that received, respectively, intratracheal infusion of papain (6 mg in 1 ml of 0.9% NaCl) or vehicle and were submitted or not to a protocol of exercise on a treadmill. Rats exercised at 13.3 m/min, 6 days/wk, for 9 wk (increasing exercise time, from 10 to 35 min). We measured respiratory system elastance and resistance, the size and weight of the heart, and pulmonary mean linear intercept (Lm). After 9 wk of exercise training, there were no differences in respiratory system resistance and elastance values among the four experimental groups. Volume of the heart was significantly greater in rats submitted to exercise training (P = 0.007) compared with sedentary rats due to increases in volumes of both right and left cardiac chambers. Lm was significantly greater in rats that received papain compared with saline-infused rats (P = 0.025). Surprisingly, this was true, even though there was no significant decrease in elastance, possibly due to connective tissue remodeling. However, Lm was significantly greater in papain + exercise rats compared with rats that received papain and were not submitted to exercise. We conclude that exercise training can increase alveolar damage induced by papain infusion.

Cultura de paz: estratégias, mapas e bússolas / Culture of peace: strategies, maps and compasses

Cultura da paz: estratégias, mapas e bússolas apresenta um conjunto de textos atuais, pertinentes e socialmente comprometidos que revelam as preocupações e atuações diretas de pessoas que tratam da educação e da promoção da cultura de paz em um contexto que articula reflexão teórica e prática cotidianas, que vão desde esforços para traçar o histórico da temática, sua conceituação, objetivos e metodologias, passando pelo papel da educação na promoção da cidadania, a relevância dos valores éticos e morais, e do enfoque nas diferentes culturas, o respeito às diferenças no processo educativo, na formação de professores e na seleção dos conteúdos escolares, indo até o planejamento das ações nas escolas, através dos projetos de educação para a paz. (AU).