The Safety and Cost Analysis of Outpatient Laparoendoscopy in the Treatment of Cholecystocholedocholithiasis: A Retrospective Study.

INTRODUCTION: The advantages of single-stage treatment of cholecystocholedocholithiasis are well established, but the conditions for carrying out treatment on an outpatient basis require a review of concepts and practices of medical corporations. OBJECTIVE: To evaluate the practice of treating cholecystocholedocholithiasis by laparoendoscopy on an outpatient basis with cost analysis. METHOD: A retrospective study was conducted on patients with cholecystocholedocholithiasis treated by combined laparoscopic cholecystectomy and endoscopic choledocholithotomy from January 2015 to January 2019. After collecting data from physical and digital medical records, the patients were divided into two groups-AR (n = 42)-ambulatory regimen and HR (n = 28)-hospitalization regimen-which were compared in terms of demographic, clinical and treatment variables and their results, as well as in terms of costs. RESULTS: The mean age of the AR group was lower than that of the HR group and the physical status of the AR patients was better when assessed according to the American Society of Anesthesiologists (ASA) (p = 0.01). There was no difference between groups regarding the risk of choledocholithiasis (p = 0.99). For the AR group, the length of stay was shorter: 11.29 h × 65.21 h (p = 0.02), as was the incidence of postoperative complications assessed by applying the Clavien-Dindo classification: 3 (7.1%) × 11 (39.2%) (p < 0.01). The total mean costs were higher for the HR group (USD 2489.93) than the AR group (USD 1650.98) (p = 0.02). CONCLUSION: Outpatient treatment of cholecystocholedocholithiasis by laparoendoscopy is safe and viable for most cases, has a lower cost and can support the reorientation of training and practice of hepatobiliary surgeons.

Short and Efficient Synthesis of the Antituberculosis Agent Pretomanid from (R)-Glycidol.

An efficient gram-scale synthesis of the antituberculosis agent pretomanid using straightforward chemistry, mild reaction conditions, and readily available starting materials is reported. Four different protecting groups on the glycidol moiety were investigated for their technical feasibility and ability to suppress side reactions. Starting from readily available protected (R)-glycidols and 2-bromo-4-nitro-1H-imidazole, pretomanid could be prepared in a linear three-step synthesis in up to 40% isolated yield. In contrast to most syntheses reported so far, deprotection and cyclization were performed in a one-pot fashion without any hazardous steps or starting materials.

Pure Cut or Endocut for Biliary Sphincterotomy? A Multicenter Randomized Clinical Trial.

INTRODUCTION: Adverse events (AE) after endoscopic retrograde cholangiopancreatography (ERCP) are not uncommon and post-ERCP acute pancreatitis (PEP) is the most important one. Thermal injury from biliary sphincterotomy may play an important role and trigger PEP or bleeding. Therefore, this study evaluated the outcomes of 2 electric current modes used during biliary sphincterotomy. METHODS: From October 2019 to August 2021, consecutive patients with native papilla undergoing ERCP with biliary sphincterotomy were randomized to either the pure cut or endocut after cannulation. The primary outcome was PEP incidence. Secondary outcomes included intraprocedural and delayed bleeding, infection, and perforation. RESULTS: A total of 550 patients were randomized (272 pure cut and 278 endocut). The overall PEP rate was 4.0% and significantly higher in the endocut group (5.8% vs 2.2%, P = 0.034). Univariate analysis revealed >5 attempts ( P = 0.004) and endocut mode ( P = 0.034) as risk factors for PEP. Multivariate analysis revealed >5 attempts ( P = 0.005) and a trend for endocut mode as risk factors for PEP ( P = 0.052). Intraprocedural bleeding occurred more often with pure cut ( P = 0.018), but all cases were controlled endoscopically during the ERCP. Delayed bleeding was more frequent with endocut ( P = 0.047). There was no difference in perforation ( P = 1.0) or infection ( P = 0.4999) between the groups. DISCUSSION: Endocut mode may increase thermal injury leading to higher rates of PEP and delayed bleeding, whereas pure cut is associated with increased intraprocedural bleeding without clinical repercussion. The electric current mode is not related to perforation or infection. Further RCT assessing the impact of electric current on AE with overlapping preventive measures such as rectal nonsteroidal anti-inflammatory drugs and hyperhydration are needed. The study was submitted to the Brazilian Clinical Trials Platform ( http://www.ensaiosclinicos.gov.br ) under the registry number RBR-5d27tn.

Urban arbovirosis in the state of São Paulo, Brazil: A retrospective study.

BACKGROUND & OBJECTIVES: Dengue represents one of the most important arboviruses in public health, and its etiological agent is transmitted by the bite of dipterans of the genus Aedes. Every year this disease affects a large part of the population of the state of São Paulo in Brazil, particularly due to the availability of favorable environmental conditions for the growth and development of the vector mosquito. This study aimed to verify the distribution of urban arboviruses in the municipalities of the state of São Paulo and the successful experiences of municipal governments to reduce cases, to highlight strategies that have successfully culminated, and which can serve as a basis for prevention strategies. METHODS: Information taken from government databases of the Ministry of Health and demographic data were used, where the incidence rate of 14 selected municipalities in the region of Vale do Paraíba between 2015 and 2019 was determined, and an attempt was made to evidence the strategies used to reduce cases. RESULTS: High incidence rates were observed in 2015 and 2019 concerning the other years of the historical series, due to environmental factors and the variation in the circulating strain. INTERPRETATION & CONCLUSION: The observed data allowed us to infer that the prevention strategies recommended by the evaluated municipalities had a positive effect in the years 2016 to 2018, but unforeseen a priori factors culminated in epidemics, revealing the importance of implementing epidemiological studies using advanced mapping tools, as a way of to minimize the risk of future epidemics.

Pharmacology, prevalence in Germany, and analytical data of cyclobutylmethyl- and norbornylmethyl-type synthetic cannabinoid receptor agonists.

Synthetic cannabinoid receptor agonists (SCRAs) are distributed on the drug market to produce THC-like effects while evading routine drug testing and legislation. The cyclobutylmethyl (CBM) and norbornylmethyl (NBM) side chain specifically circumvented the German legislation and led to the emergence of exploratory SCRAs in 2019-2021. The NBM SCRAs were detected post-amendment of the new psychoactive substances act in 2020, which scheduled all CBM SCRAs. All six SCRAs are full agonists at the cannabinoid receptor 1 compared with Δ9 -tetrahydrocannabinol and CP-55,940. The CBM SCRAs showed binding affinities of Ki : 29.4-0.65 nm and potencies of EC50 : 483-40.1 nm (CBMICA << CBMINACA < CBMeGaClone). The norbornyl derivatives exhibited high affinities (Ki : 1.87-0.25 nm), with indazole being the most affine. Functional activity data confirmed that the indazole derivative tends to be the most potent of all three NBM SCRAs (EC50 : 169-1.78 nm). The sterically demanding NBM side chain increased the affinity and activity of almost all core structures. Future studies should be conducted on similarly voluminous side chain moieties. The 'life cycle' of all SCRAs on the drug market was less than a year. Notably, Cumyl-CBMICA was the most prevalent while also having the weakest cannabimimetic properties. Quantification of Cumyl-CBMICA during peak consumption in late 2019 and early 2020 revealed an increase in the concentration on the herbal material, which, together with forum entries and blog posts, corroborates the low in vitro cannabimimetic properties. Seizure prevalence data indicate that almost all SCRAs continue to be identified in 2022, potentially due to remaining stocks.

Diastereoselectivity is in the Details: Minor Changes Yield Major Improvements to the Synthesis of Bedaquiline.

Bedaquiline is a crucial medicine in the global fight against tuberculosis, yet its high price places it out of reach for many patients. Herein, we describe improvements to the key industrial lithiation-addition sequence that enable a higher yielding and therefore more economical synthesis of bedaquiline. Prioritization of mechanistic understanding and multi-lab reproducibility led to optimized reaction conditions that feature an unusual base-salt pairing and afford a doubling of the yield of racemic bedaquiline. We anticipate that implementation of these improvements on manufacturing scale will be facile, thereby substantially increasing the accessibility of this essential medication.

Structure elucidation of the novel synthetic cannabinoid Cumyl-Tosyl-Indazole-3-Carboxamide (Cumyl-TsINACA) found in illicit products in Germany.

New chemical moieties continue to appear in synthetic cannabimimetics (SC), the largest group of new psychoactive substances in the EU. We describe the first comprehensive characterisation of the novel SC Cumyl-Tosyl-Indazole-3-Carboxamide (Cumyl-TsINACA) (N-[2-phenylpropan-2-yl]-1-tosyl-1H-indazole-3-carboxamide) from seized case samples. Structure elucidation was performed within the EU-project ADEBAR plus to facilitate confident identification by other researchers and practitioners worldwide. Characteristic MS fragmentations include the cleavage of the sulfonamide bond (S-N), the aryl sulfone bond (C-S) and the elimination rearrangement of SO2 in the side chain. Cumyl-TsINACA is a full receptor agonist at hCB1 (Emax  = 228%) with very weak binding affinity (Ki  = 292 nm) and low functional activity (EC50  = 31 µm). Thermal degradation of Cumyl-TsINACA was observed under GC conditions. The degree to which the tosyl side chain is cleaved due to pyrolysis primarily depends on solvent, the use of glass wool in the liner and injector temperature. The determination of the constitution by NMR spectroscopy was ambiguous due to the high number of neighbouring, non-proton-bearing atoms. Therefore, other possible structures compatible with the NMR correlations were generated using the WebCocon software. The unambiguous structural evidence was finally obtained by spectra comparison after the synthesis of Cumyl-TsINACA. The low thermal stability, as well as the low affinity and potency, renders this compound unfavourable for the use as a psychoactive substance. Thus, we do not expect widespread adoption of this SC.

Ovicidal and toxicological effect of hydroalcoholic extracts of Euphorbia milli var splendens, Synadenium carinatum Boiss and Tagetes minuta L. against Ancylostoma spp.: In vitro study.

Nematodes of the Ancylostomidae family consist of important parasitic species. The control of such parasitosis represents an important challenge, given the constant high rate of reinfection of some hosts, among which the domestic dog, as well as the high environmental contamination. Another factor that can have a negative influence is the toxicity of the chemicals used for environmental decontamination, highlighting the need to design research to identify new control strategies for this parasitosis, among which the use of plant extracts. Thus, the objective of this research was to evaluate the toxicity and ovicidal activity of hydroalcoholic extracts obtained by percolation of three plants: Tagetes minuta L., Euphorbia milli var splendens (Bojer ex Hook.) Ursch & Leandri and Synadenium carinatum Boiss, against Ancylostoma spp. In addition, these extracts were tested at different concentrations for toxicity against Artemia salina L. and Allium cepa L. It was observed that the hydroalcoholic extract of all plant species evaluated induced moderate ovicide activity at all the tested concentration, with emphasis on E. milii, which was the only plant species that presented significantly low toxicity in the concentration of 12.5 µL/mL when compared to the other species evaluated.

A concise route to MK-4482 (EIDD-2801) from cytidine.

A two-step route to MK-4482 (EIDD-2801, 1) was developed consisting of an esterification and hydroxamination of cytidine. The selective acylation and direct amination eliminate the need for protecting and activating groups and proceed in overall yield of 75%, a significant advancement over the reported yield of 17%. The step count is reduced from five transformations to two, and expensive uridine is replaced with the more available cytidine.

Total synthesis and biological evaluation of seven new anti-inflammatory oxacyclododecindione-type macrolactones.

Through variation of our previously published total synthesis of two highly active anti-inflammatory macrolactones from the oxacyclododecindione family (J. Tauber, M. Rohr, T. Walter, G. Erkel and T. Opatz, Org. Biomol. Chem., 2015, 13, 7813-7821), seven new representatives of this compound class were prepared. Substitution of the 14-hydroxy group in oxacyclododecindione with a methyl substituent provided a readily accessible non-natural analogue which has similar pharmacological properties to the scarcely available natural product. Since the producible amount of substance is therefore no longer restricted by low fermentation yields, extensive in vivo studies become possible for the first time. Based on this finding, further investigations on structure-activity relationships were undertaken by variation of the halogen atom, which showed that exchange or omission of the chloro substituent led to significantly lower binding affinities. Furthermore, it was found that elongation of the crucial and characteristic aliphatic side chain at C-10 also increased the IC50 value in the biological assays of interest.

Synthesis of 4-amino-5-fluoropyrimidines and 5-amino-4-fluoropyrazoles from a ß-fluoroenolate salt.

A synthesis of fluorinated pyrimidines under mild conditions from amidine hydrochlorides and the recently described potassium 2-cyano-2-fluoroethenolate was developed. A broad substrate scope was tested and mostly excellent yields were obtained. The synthesis of fluorinated aminopyrazoles from the same fluorinated precursor could be demonstrated but proceeded with lower efficiency.

Willis method modification with a view to improving routine coproparasitological diagnosis

Intestinal parasites still cause high morbidity and mortality, due to poor hygiene and sanitary conditions, and therefore indiscriminate treatment has been routine practice advocated by the Public Health staff. Although there is a consensus regarding the need to diagnose such diseases, this is not performed with the necessary care, due to great demand and the lack of a wide ranged and highly sensitive technique. In this sense, most clinical laboratories use routine methods for fecal examination such as the Lutz sedimentation or modified Ritchie methods, which are complete and easy to execute, but do not have adequate sensitivity to detect low density eggs and protozoan cysts, especially when there is a predominance of low parasite burdens. In contrast, there are methods that are based on the flotation of low density developmental forms, namely, the Willis method (NaCl flotation d=1.120), which is rapid, easy to perform and allows high density egg flotation but with low sensitivity for protozoan cysts; and the Faust method, which is based on centrifugal flotation of developmental forms in a 33% ZnSO4 (d=1.200) solution, but with the disadvantage of being lengthy and requiring a centrifuge. In this study, we verified the applicability of introducing an alteration in the Willis method, which consisted in the substitution of NaCl by ZnSO4 in order to combine the advantages of this method with the Faust method. 208 samples were assessed by the Willis and Ritchie methods and by the proposed method (modified Willis). The latter proved superior to the other two (ρ <0,0001 ­ X2) regarding the detection of protozoan cysts, but similar to the Ritchie method in regard to other diagnosed parasites, therefore demonstrating the high potential for the introduction of this modified method in the routine of fecal diagnosis

Correlação entre a curva de aprendizado e a dor referida pela paciente durante o procedimento histeroscópico ambulatorial sem anestesia / Correlation between the learning curve and the pain reported by the patient during outpatient hysteroscopy procedure without anesthesia

Introdução: a histeroscopia é considerada padrão-ouro na avaliação do útero e das doenças associadas a ele. Seu uso como técnica diagnóstica é uma prática ambulatorial, normalmente bem tolerado pelas pacientes, permitindo a retomada das atividades logo após o seu término. O ensino da técnica histeroscópica tende a ser demorado, apresentando lenta curva de aprendizado. Por isso, definir o impacto da curva de aprendizado da histeroscopia na intensidade da dor pode ajudar a melhorar a organização dos serviços de histeroscopia, maximizando o aprendizado e reduzindo o desconforto das pacientes. Objetivos: analisar, com a construção de uma curva de aprendizado a possível relação entre o número de procedimentos histeroscópicos realizados pelo médico e a intensidade da dor relatada pelo paciente no exame. Métodos: coorte prospectiva feita com 403 pacientes submetidas à histeroscopia no Hospital Universitário São José (HUSJ). Resultados: 72,45% dos pacientes classificaram a dor como leve e 5,95% como forte. Além disso, a curva de aprendizado construída apresentou tendência negativa. Discussão: a tendência negativa da curva mostra que quanto mais exames o aluno realiza, menos dor a paciente sente no progredir do aprendizado. Entretanto, nos quatro meses finais, foi identificada certa estabilização da curva, indicando que o processo de aprendizado foi mais intenso no início do curso. Conclusão: apesar das limitações encontradas na realização da pesquisa, é visível que estudos nessa área devem ser mantidos, visando à melhoria da técnica, à correção de falhas e ao bem-estar do paciente.

Introduction: Hysteroscopy is considered the gold standard in the evaluation of the uterus and its diseases. Its use as a diagnostic technique is an outpatient procedure, usually well tolerated by patients, allowing resumption of activities right after its completion. The teaching of the hysteroscopic technique tends to be time consuming, with a slow learning curve. Therefore, defining the impact of the histeroscopy's learning curve on the intensity of the pain felt by the patients can help improving the organization of hysteroscopy services, maximizing learning and reducing patient discomfort. Objectives: To analyze, with the construction of a learning curve, the possible relationship between the number of hysteroscopic procedures performed by the doctor and the intensity of pain reported by the patient during the exam. Methods: A prospective cohort study with 403 patients who underwent hysteroscopy in the Hospital Universitário São José (HUSJ). Results: 72.45% of the patients rated the pain as mild and 5.95% , as strong. Furthermore,the learning curve constructed presented a negative tendency. Discussion: The downward trend of the curve shows that the more procedures the trainee performs the less pain the patient feels along the learning process. However, in the final four months, a stabilization of the curve was identified, indicating that the process of learning was more intense at the beginning of the course. Conclusion: Despite the limitations encountered in conducting the survey, it is obvious that studies in this area should be maintained in order to improve technique, correct faults and upgrade patient welfare.