The information required by people with inflammatory arthritis to take methotrexate: a mixed-methods systematic review.

OBJECTIVES: This mixed-methods systematic review aimed to identify and synthesize knowledge of the characteristics, content, and preferred format of information to support people with inflammatory arthritis (IA) to take methotrexate. METHODS: A literature search using MEDLINE, The Cochrane Library, Embase, CINAHL, PsychInfo, GreyEU, Web of Science and Open Dissertation was conducted to identify all studies published from 2000 to December 2022. Included studies detailed factors related to methotrexate (MTX) related information needs of people with inflammatory arthritis ≥ 18 years in English. Joanna Briggs Institute Guidelines (JBI) for convergent integrated mixed-methods systematic reviews were followed using validated tools for data extraction and quality. Data was analysed using reflexive thematic analysis. RESULTS: Thirteen studies (seven quantitative, two mixed-methods and four qualitative) were included involving 3425 adults, mainly female n = 2434 (71%), age 20-84 years. An overarching theme of a requirement for person-centred care was developed with three interlinking themes: 1: Accepting the need for treatment with MTX, 2: Concerns about taking MTX, 3: A need for tailored information and support. Limitations of the evidence were use of heterogeneous outcome measures and instruments to measure information needs. CONCLUSION: People with IA have individual, multi-faceted information, and support needs about MTX that are often unresolved when a one-size-fits-all approach is used. The findings can inform rheumatology training to support a person-centred approach to identifying and addressing specific needs, concerns and the development of consistent easy-to-understand accessible MTX information.

Catalytic Synthesis of Potassium Acyltrifluoroborates (KATs) from Boronic Acids and the Thioimidate KAT Transfer Reagent.

We report the synthesis of potassium acyltrifluoroborates (KATs) by a palladium-catalyzed cross-coupling of boronic acids and the thioimidate KAT transfer reagent. The combination of widely available aryl- and vinylboronic acids with commercially available thioimidate 1 using catalytic PdII and a CuII additive enables the preparation of KATs in high yields and with good functional group tolerance. This formal insertion of CO into organoboronic acids can also be applied to boronic acid pinacol esters and potassium organotrifluoroborates using a slightly modified procedure. The cross-coupling can be telescoped into the one-pot synthesis of amides and α-aminotrifluoroborates by exploiting the unique chemistry of KATs and their trifluoroborate iminium (TIM) derivatives.

Synthesis of secondary and tertiary amides without coupling agents from amines and potassium acyltrifluoroborates (KATs).

Although highly effective for most amide syntheses, the activation of carboxylic acids requires the use of problematic coupling reagents and is often poorly suited for challenging cases such as N-methyl amino acids. As an alternative to both secondary and tertiary amides, we report their convenient synthesis by the rapid oxidation of trifluoroborate iminiums (TIMs). TIMs are easily prepared by acid-promoted condensation of potassium acyltrifluoroborates (KATs) and amines and are cleanly and rapidly oxidized to amides with hydrogen peroxide. The overall transformation can be conducted either as a one-pot procedure or via isolation of the TIM. The unique nature of the neutral, zwitterionic TIMs makes possible the preparation of tertiary amides via an iminium species that would not be accessible from other carbonyl derivatives and can be conducted in the presence of unprotected functional groups including acids, alcohols and thioethers. In preliminary studies, this approach was applied to the late-stage modifications of long peptides and the iterative synthesis of short, N-methylated peptides without the need for coupling agents.

EULAR recommendations for the health professional's approach to pain management in inflammatory arthritis and osteoarthritis.

Pain is the predominant symptom for people with inflammatory arthritis (IA) and osteoarthritis (OA) mandating the development of evidence-based recommendations for the health professional's approach to pain management. A multidisciplinary task force including professionals and patient representatives conducted a systematic literature review of systematic reviews to evaluate evidence regarding effects on pain of multiple treatment modalities. Overarching principles and recommendations regarding assessment and pain treatment were specified on the basis of reviewed evidence and expert opinion. From 2914 review studies initially identified, 186 met inclusion criteria. The task force emphasised the importance for the health professional to adopt a patient-centred framework within a biopsychosocial perspective, to have sufficient knowledge of IA and OA pathogenesis, and to be able to differentiate localised and generalised pain. Treatment is guided by scientific evidence and the assessment of patient needs, preferences and priorities; pain characteristics; previous and ongoing pain treatments; inflammation and joint damage; and psychological and other pain-related factors. Pain treatment options typically include education complemented by physical activity and exercise, orthotics, psychological and social interventions, sleep hygiene education, weight management, pharmacological and joint-specific treatment options, or interdisciplinary pain management. Effects on pain were most uniformly positive for physical activity and exercise interventions, and for psychological interventions. Effects on pain for educational interventions, orthotics, weight management and multidisciplinary treatment were shown for particular disease groups. Underpinned by available systematic reviews and meta-analyses, these recommendations enable health professionals to provide knowledgeable pain-management support for people with IA and OA.

Multiple Approaches to the In Situ Generation of Anhydrous Tetraalkylammonium Fluoride Salts for SNAr Fluorination Reactions.

This article focuses on the development of practical approaches to the in situ generation of anhydrous fluoride salts for applications in nucleophilic aromatic substitution (SNAr) reactions. We report herein that a variety of combinations of inexpensive nucleophiles (e.g., tetraalkylammonium cyanide and phenoxide salts) and fluorine-containing electrophiles (e.g., acid fluoride, fluoroformate, benzenesulfonyl fluoride, and aryl fluorosulfonate derivatives) are effective for this transformation. Ultimately, we demonstrate that the combination of tetramethylammonium 2,6-dimethylphenoxide and sulfuryl fluoride (SO2F2) serves as a particularly practical route to anhydrous tetramethylammonium fluoride. This procedure is applied to the SNAr fluorination of a range of electron-deficient aryl and heteroaryl chlorides as well as nitroarenes.

Reagent-free continuous thermal tert-butyl ester deprotection.

Continuous processing enables the use of non-standard reaction conditions such as high temperatures and pressures while in the liquid phase. This expands the chemist's toolbox and can enable previously unthinkable chemistry to proceed with ease. For a series of amphoteric amino acid derivatives, we have demonstrated the ability to hydrolyze the tert-butyl ester functionality in protic solvent systems. Using a continuous plug flow reactor at 120-240°C and 15-40min reaction times, no pH modification or additional reagents are needed to achieve the desired transformation. The method was then expanded to encompass a variety of more challenging substrates to test selectivity and racemization potential. The acid products were generally isolated as crystalline solids by simple solvent exchange after the deprotection reaction in good to high yield and purity.

"Trying to Get a Grip": Language Competence and Self-Reported Satisfaction With Social Relationships Three Decades Post-Childhood Traumatic Brain Injury.

OBJECTIVE: (1) To investigate outcomes in language competence and self-reported satisfaction with social relationships in long-term survivors of childhood traumatic brain injury (TBI); and (2) to establish whether language competence contributes to self-reported satisfaction with social relationships decades after sustaining childhood TBI. PARTICIPANTS: Twelve females and 8 males aged 30 to 55 (mean = 39.80, standard deviation = 7.54) years who sustained a TBI during childhood and were on average 31 years postinjury (standard deviation = 9.69). An additional 20 participants matched for age, sex, handedness, years of education, and socioeconomic status constituted a control group. MAIN MEASURES: Test of Language Competence-Expanded Edition and the Quality of Life in Brain Injury questionnaire. RESULTS: Individuals with a history of childhood TBI performed significantly poorer than their non-injured peers on 2 (Ambiguous Sentences and Oral Expression: Recreating Sentences) out of the 4 Test of Language Competence-Expanded Edition subtests used and on the Quality of Life in Brain Injury subscale assessing satisfaction with social relationships. In the TBI group, scores obtained on the Ambiguous Sentences subtest were found to be a significant predictor of satisfaction with social relationships, explaining 25% of the variance observed. CONCLUSIONS: The implication of high-level language skills to self-reported satisfaction with social relationships many decades post-childhood TBI suggests that ongoing monitoring of emerging language skills and support throughout the school years and into adulthood may be warranted if adult survivors of childhood TBI are to experience satisfying social relationships.

Anhydrous Tetramethylammonium Fluoride for Room-Temperature S(N)Ar Fluorination.

This paper describes the room-temperature S(N)Ar fluorination of aryl halides and nitroarenes using anhydrous tetramethylammonium fluoride (NMe4F). This reagent effectively converts aryl-X (X = Cl, Br, I, NO2, OTf) to aryl-F under mild conditions (often room temperature). Substrates for this reaction include electron-deficient heteroaromatics (22 examples) and arenes (5 examples). The relative rates of the reactions vary with X as well as with the structure of the substrate. However, in general, substrates bearing X = NO2 or Br react fastest. In all cases examined, the yields of these reactions are comparable to or better than those obtained with CsF at elevated temperatures (i.e., more traditional halex fluorination conditions). The reactions also afford comparable yields on scales ranging from 100 mg to 10 g. A cost analysis is presented, which shows that fluorination with NMe4F is generally more cost-effective than fluorination with CsF.

Acyl azolium fluorides for room temperature nucleophilic aromatic fluorination of chloro- and nitroarenes.

The reaction of acid fluorides with N-heterocyclic carbenes (NHCs) produces anhydrous acyl azolium fluorides. With appropriate selection of acid fluoride and NHC, these salts can be used for the room temperature SNAr fluorination of a variety of aryl chlorides and nitroarenes.

Small deletion in C9orf72 hides a proportion of expansion carriers in FTLD.

Frontotemporal lobar degeneration is a highly familial disease and the most common known genetic cause is the repeat expansion mutation in the gene C9orf72. We have identified 2 brothers with an expansion mutation in C9orf72 using Southern blotting that is undetectable using repeat-primed polymerase chain reaction. Sequencing using high concentrations of DNA denaturants of a bacterial artificial chromosome clone obtained from one of the brothers identified a 10-base pair deletion adjacent to the expansion that presumably confers strong secondary structure that interferes with the genotyping. Using an alternative method, we have identified missed expansion carriers in our cohort, and this number has increased by approximately 25%. This observation has important implications for patients undergoing genetic testing for C9orf72.

Acyl anion free N-heterocyclic carbene organocatalysis.

Reaction discovery using N-heterocyclic carbene organocatalysis has been dominated by the chemistry of acyl anion equivalents. Recent studies demonstrate that NHCs are far more diverse catalysts, with a variety of reactions discovered that proceed without acyl anion equivalent formation. In this tutorial review selected examples of acyl anion free NHC catalysis using carbonyl compounds are presented.

1,3-Dipolar cycloaddition of unstabilised azomethine ylides by Lewis base catalysis.

Lewis base catalysed 1,3-dipolar cycloaddition between α,ß-unsaturated acyl fluorides and N-[(trimethylsilyl)methyl]amino ethers has been achieved using 1 mol% DMAP. Competition experiments and (19)F-NMR studies indicate that the cycloaddition occurs preferentially between the α,ß-unsaturated acyl fluoride and the unstabilised azomethine ylide. In addition, an enantioselective variant, using chiral isothiourea catalysts, has been achieved with 14% ee.

Synthetic and quantum mechanical studies into the N-heterocyclic carbene catalyzed (4 + 2) cycloaddition.

The N-heterocyclic carbene catalyzed (4 + 2) cycloaddition between α,ß-unsaturated acid fluorides and TMS dienol ethers provides cyclohexene fused ß-lactone intermediates stable below -20 °C. These can be intercepted reductively or with organolithium reagents to produce diastereomerically pure cyclohexenes (>20:1 dr) with up to four contiguous stereocenters. The mechanism has been investigated using theoretical calculations and by examining secondary kinetic isotope effects. Together these studies implicate the formation of a diastereomerically pure ß-lactone intermediate by a stepwise (4 + 2) cycloaddition involving Michael addition, aldol cyclization, and lactonization.

N-Heterocyclic carbene-catalyzed (4+2) cycloaddition/decarboxylation of silyl dienol ethers with α,ß-unsaturated acid fluorides.

Herein we report the first all-carbon N-heterocyclic carbene-catalyzed (4 + 2) cycloaddition. The reaction proceeds with α,ß-unsaturated acid fluorides and silyl dienol ethers and produces 1,3-cyclohexadienes with complete diastereocontrol (dr >20:1) while demonstrating a new type of reaction cascade exploiting α,ß-unsaturated acyl azoliums.

N-heterocyclic carbene-catalyzed generation of alpha,beta-unsaturated acyl imidazoliums: synthesis of dihydropyranones by their reaction with enolates.

Catalytic generation of alpha,beta-unsaturated acyl imidazolium cations and enolates has been achieved, and their involvement in a Michael addition acylation sequence exploited, to provide a range of dihydropyranones. alpha,beta-Unsaturated enol esters, or alpha,beta-unsaturated acid fluorides in association with TMS enol ethers, serve as appropriate substrates for this reaction. The transformation can also be achieved enantioselectively using catalysts derived from chiral triazolium salts.