Application of Metathesis Protocols to the Stereocontrolled Synthesis of some Functionalized ß-Amino Esters and Azaheterocycles.

In this account our aim was to give an insight into the application of metathesis protocols (ROM, RCM, RCEYM, CM, RRM) for the synthesis of various azaheterocyclic frameworks. Due to the high biological potential and importance in peptide chemistry and drug design of ß-amino acids our intention is to give a highlight on the synthetic procedures and transformation of these class of compounds with the above-mentioned metathesis strategies with emphasis on selectivity, stereocontrol, substrate-directing effect or functional group tolerance.

Stereocontrolled synthesis of some novel functionalized heterocyclic amino ester and amide derivatives with multiple stereocenters.

The synthesis of some novel functionalized fused-ring ß-amino lactones and lactams with multiple chiral centers has been attempted from readily available strained bicyclic ß-amino acids via a stereocontrolled synthetic route. The key step was ring-rearrangement metathesis of allyl/propargyl esters or N-allylated/N-propargylated amides of (oxa)norbornene ß-amino acids. The RRM transformations [ring-opening metathesis (ROM)/ring-closing metathesis (RCM) or ring-opening metathesis (ROM)/ring-closing enyne metathesis (RCEYM)] have been investigated using some commercially available catalysts. Importantly, the procedure used in this synthetic process does not affect the configurations of the chiral centers. This means that the structure of the starting (oxa)norbornene ß-amino acids predetermines the configuration of the formed products.

The synthesis of pharmacologically important oxindoles via the asymmetric aldol reaction of isatin and the investigation of the organocatalytic activity of new alicyclic ß-amino acid derivatives.

This work involves the synthesis and subsequent development of a number of novel organocatalysts generated from ß-amino acids bearing diendo and diexo norbornene skeletons to improve their catalytic characteristics. The aldol reaction between isatin and acetone selected as the model reaction, was used to test and study enantioselectivities. The potential impact on enantioselectivity control regarding enantiomeric excess (ee%) was probed by varying the reaction parameters, such as additive, solvent, catalyst loading, temperature and substrate range. The corresponding 3-hydroxy-3-alkyl-2-oxindole derivetives were produced by organocatalyst 7 with good enantioselectivity up to 57% ee in the presence of LiOH. Substrate screening was used to investigate a number of substituted isatins with excellent findings up to 99% ee. Another aspect of this effort involved employing high-speed ball mill apparatus to conduct a mechanochemical study to make this model reaction more environmentally benign and sustainable.

Effect of ractopamine on the release of dopamine from the striatum dissected from mice.

In the past two decades, ractopamine has been used as a feed additive to increase protein synthesis in farmed animals (swine, cattle, and turkeys) and to produce high-quality meat. However, the excessive feeding of animals with ractopamine may result in its accumulation in animal and human tissues after consuming the meat. Ractopamine is a trace amine-associated receptor1 and ß-adrenoceptor agonist banned in the EU but approved in the USA, and it may pose a potential risk to human health. In this paper, the authors, for the first time, provide neurochemical evidence that ractopamine leads to the release of dopamine from nerve terminals of the nigrostriatal pathway in the striatum.

Recent Progress in Aryltrifluoromethylation Reactions of Carbon-Carbon Multiple Bonds.

Due to the increasing relevance of fluorine-containing organic molecules in drug design, the synthesis of organofluorine compounds has gained high significance in synthetic organic chemistry. Trifluoromethylative difunctionalizations of carbon-carbon multiple bonds, with the simultaneous incorporation of a CF3 group and another functional element, have considerable potential. Because of the high importance of carbon-carbon bond-forming reactions in organic synthesis, carbotrifluoromethylations and, in particular, aryltrifluoromethylations or heteroaryltrifluoromethylations are considered to be increasing fields of synthetic organic chemistry. The aim of the current review is to summarize recent developments of aryltrifluoromethylation or heteroaryltrifluoromethylation reactions.

Digital Therapeutic Care Apps With Decision-Support Interventions for People With Low Back Pain in Germany: Cost-Effectiveness Analysis.

BACKGROUND: Digital therapeutic care apps provide a new effective and scalable approach for people with nonspecific low back pain (LBP). Digital therapeutic care apps are also driven by personalized decision-support interventions that support the user in self-managing LBP, and may induce prolonged behavior change to reduce the frequency and intensity of pain episodes. However, these therapeutic apps are associated with high attrition rates, and the initial prescription cost is higher than that of face-to-face physiotherapy. In Germany, digital therapeutic care apps are now being reimbursed by statutory health insurance; however, price targets and cost-driving factors for the formation of the reimbursement rate remain unexplored. OBJECTIVE: The aim of this study was to evaluate the cost-effectiveness of a digital therapeutic care app compared to treatment as usual (TAU) in Germany. We further aimed to explore under which circumstances the reimbursement rate could be modified to consider value-based pricing. METHODS: We developed a state-transition Markov model based on a best-practice analysis of prior LBP-related decision-analytic models, and evaluated the cost utility of a digital therapeutic care app compared to TAU in Germany. Based on a 3-year time horizon, we simulated the incremental cost and quality-adjusted life years (QALYs) for people with nonacute LBP from the societal perspective. In the deterministic sensitivity and scenario analyses, we focused on diverging attrition rates and app cost to assess our model's robustness and conditions for changing the reimbursement rate. All costs are reported in Euro (€1=US $1.12). RESULTS: Our base case results indicated that the digital therapeutic care strategy led to an incremental cost of €121.59, but also generated 0.0221 additional QALYs compared to the TAU strategy, with an estimated incremental cost-effectiveness ratio (ICER) of €5486 per QALY. The sensitivity analysis revealed that the reimbursement rate and the capability of digital therapeutic care to prevent reoccurring LBP episodes have a significant impact on the ICER. At the same time, the other parameters remained unaffected and thus supported the robustness of our model. In the scenario analysis, the different model time horizons and attrition rates strongly influenced the economic outcome. Reducing the cost of the app to €99 per 3 months or decreasing the app's attrition rate resulted in digital therapeutic care being significantly less costly with more generated QALYs, and is thus considered to be the dominant strategy over TAU. CONCLUSIONS: The current reimbursement rate for a digital therapeutic care app in the statutory health insurance can be considered a cost-effective measure compared to TAU. The app's attrition rate and effect on the patient's prolonged behavior change essentially influence the settlement of an appropriate reimbursement rate. Future value-based pricing targets should focus on additional outcome parameters besides pain intensity and functional disability by including attrition rates and the app's long-term effect on quality of life.

Digital Therapeutic Care and Decision Support Interventions for People With Low Back Pain: Systematic Review.

BACKGROUND: Low back pain (LBP) is the leading cause of worldwide years lost because of disability, with a tremendous economic burden for health care systems. Digital therapeutic care (DTC) programs provide a scalable, universally accessible, and low-cost approach to the multidisciplinary treatment of LBP. Moreover, novel decision support interventions such as personalized feedback messages, push notifications, and data-driven activity recommendations amplify DTC by guiding the user through the program while aiming to increase overall engagement and sustainable behavior change. OBJECTIVE: This systematic review aims to synthesize recent scientific literature on the impact of DTC apps for people with LBP and outline the implementation of add-on decision support interventions, including their effect on user retention and attrition rates. METHODS: We searched bibliographic databases, including MEDLINE, Cochrane Library, Web of Science, and the Physiotherapy Evidence Database, from March 1, 2016, to October 15, 2020, in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines and conducted this review based on related previously published systematic reviews. Besides randomized controlled trials (RCTs), we also included study designs with the evidence level of at least a retrospective comparative study. This enables the consideration of real-world user-generated data and provides information regarding the adoption and effectiveness of DTC apps in a real-life setting. For the appraisal of the risk of bias, we used the Risk of Bias 2 Tool and the Risk of Bias in Non-Randomized Studies of Interventions Tool for the RCTs and nonrandomized trials, respectively. The included studies were narratively synthesized regarding primary and secondary outcome measures, DTC components, applied decision support interventions, user retention, and attrition rates. RESULTS: We retrieved 1388 citations, of which 12 studies are included in this review. Of the 12 studies, 6 (50%) were RCTs and 6 (50%) were nonrandomized trials. In all included studies, lower pain levels and increased functionality compared with baseline values were observed in the DTC intervention group. A between-group comparison revealed significant improvements in pain and functionality levels in 67% (4/6) of the RCTs. The study population was mostly homogeneous, with predominantly female, young to middle-aged participants of normal to moderate weight. The methodological quality assessment revealed moderate to high risks of biases, especially in the nonrandomized trials. CONCLUSIONS: This systematic review demonstrates the benefits of DTC for people with LBP. There is also evidence that decision support interventions benefit overall engagement with the app and increase participants' ability to self-manage their recovery process. Finally, including retrospective evaluation studies of real-world user-generated data in future systematic reviews of digital health intervention trials can reveal new insights into the benefits, challenges, and real-life adoption of DTC programs.

In Situ Hybridization of PRRSV-1 Combined with Digital Image Analysis in Lung Tissues of Pigs Challenged with PRRSV-1.

Betaarterivirus suid 1 and 2 are the causative agents of porcine reproductive and respiratory syndrome (PRRS), which is one of the most significant diseases of the swine industry, causing significant economic losses in the main pig producing countries. Here, we report the development of a novel, RNA-based in situ hybridization technique (RNAscope) to detect PRRS virus (PRRSV) RNA in lung tissues of experimentally infected animals. The technique was applied to lung tissues of 20 piglets, which had been inoculated with a wild-type, highly pathogenic PRRSV-1 strain. To determine the RNAscope's applicability as a semi-quantitative method, we analysed the association between the proportion of the virus-infected cells measured with an image analysis software (QuPath) and the outcome of the real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) tests performed in parallel. The results of the quantitative approach of these two molecular biological methods show significant association (pseudo R2 = 0.3894, p = 0.004). This is the first time RNAscope assay has been implemented for the detection of PRRSV-1 in experimental animals.

Selective Transformation of Norbornadiene into Functionalized Azaheterocycles and ß-Amino Esters with Stereo- and Regiocontrol.

Novel functionalized azaheterocycles with multiple chiral centers have been accessed from readily available norbornene ß-amino acids or ß-lactams across a stereocontrolled synthetic route, based on ring-opening metathesis (ROM) of the staring unsaturated bicyclic amino esters, followed by selective cyclization through ring-closing metathesis (RCM). The RCM transformations have been studied under various experimental conditions to assess the scope of conversion, catalyst, yield, and substrate influence. The structure of the starting norbornene ß-amino acids predetermined the structure of the new azaheterocycles, and the developed synthetic route took place with the conservation of the configuration of the chiral centers.

A study on selective transformation of norbornadiene into fluorinated cyclopentane-fused isoxazolines.

This work presents an examination of the selective functionalization of norbornadiene through nitrile oxide 1,3-dipolar cycloaddition/ring-opening metathesis (ROM)/cross-metathesis (CM) protocols. Functionalization of commercially available norbornadiene provided novel bicyclic scaffolds with multiple stereogenic centers. The synthesis involved selective cycloadditions, with subsequent ROM of the formed cycloalkene-fused isoxazoline scaffolds and selective CM by chemodifferentiation of the olefin bonds of the resulting alkenylated derivatives. Various experimental conditions were applied for the CM transformations with the goal of exploring substrate and steric effects, catalyst influence and chemodifferentiation of the olefin bonds furnishing the corresponding functionalized, fluorine-containing isoxazoline derivatives.