Five-Year Outcomes among U.S. Bronchiectasis and NTM Research Registry Patients.

Rationale: Nontuberculous mycobacteria (NTM) are prevalent among patients with bronchiectasis. However, the long-term natural history of patients with NTM and bronchiectasis is not well described. Objectives: To assess the impact of NTM on 5-year clinical outcomes and mortality in patients with bronchiectasis. Methods: Patients in the Bronchiectasis and NTM Research Registry with ⩾5 years of follow-up were eligible. Data were collected for all-cause mortality, lung function, exacerbations, hospitalizations, and disease severity. Outcomes were compared between patients with and without NTM at baseline. Mortality was assessed using Cox proportional hazards models and the log-rank test. Measurements and Main Results: In total, 2,634 patients were included: 1,549 (58.8%) with and 1,085 (41.2%) without NTM at baseline. All-cause mortality (95% confidence interval) at Year 5 was 12.1% (10.5%, 13.7%) overall, 12.6% (10.5%, 14.8%) in patients with NTM, and 11.5% (9.0%, 13.9%) in patients without NTM. Independent predictors of 5-year mortality were baseline FEV1 percent predicted, age, hospitalization within 2 years before baseline, body mass index, and sex (all P < 0.01). The probabilities of acquiring NTM or Pseudomonas aeruginosa were approximately 4% and 3% per year, respectively. Spirometry, exacerbations, and hospitalizations were similar, regardless of NTM status, except that annual exacerbations were lower in patients with NTM (P < 0.05). Conclusions: Outcomes, including exacerbations, hospitalizations, rate of loss of lung function, and mortality rate, were similar across 5 years in patients with bronchiectasis with or without NTM.

Numerical model of pressure generated by elastic compression garments on a compressible human limb analogue.

OBJECTIVE: This study aimed to formulate a numerical approach (finite element modelling (FEM)) to calculate pressure values generated by compression garments on a compressible limb analogue, and to validate the numerical approach using experimental measurements. Existing models were also compared. METHOD: Experimentally measured pressure values and deformation caused by compression bands on a compressible human limb analogue were compared with values predicted using the Young-Laplace equation, a previously formulated analytical model and the FEM. RESULTS: The FEM provided greater accuracy in predicting the pressure generated by compression bands compared to existing models. The FEM also predicted deformation of the limb analogue with good agreement relative to experimental values. CONCLUSION: It was concluded that modelling the non-uniform manner in which the way a limb analogue is compressed should be incorporated into future modelling of the pressures generated by compression garments on a compressible limb analogue. DECLARATION OF INTEREST: The authors have no conflicts of interest to declare.

Nontuberculous mycobacterial (NTM) infections in bronchiectasis patients: A retrospective US registry cohort study.

RATIONALE: Longitudinal epidemiological and clinical data are needed to improve the management of patients with bronchiectasis developing nontuberculous mycobacterial (NTM) pulmonary disease. OBJECTIVES: To describe the epidemiology, patient management, and treatment outcomes of NTM infections in patients with bronchiectasis enrolled in the United States Bronchiectasis and NTM Research Registry (US BRR). METHODS: This was a retrospective cohort study of patients with bronchiectasis and NTM infections enrolled with follow-up in the US BRR in 2008-2019. The study included patients with ≥1 positive NTM respiratory culture in the 24-month baseline period (baseline NTM cohort) and/or during the annual follow-up visits (incident NTM cohort). Incidence, prevalence, baseline patient characteristics, treatment exposure, treatment outcomes, and respiratory clinical outcomes were described in the baseline NTM cohort, incident NTM cohort, and both cohorts combined (prevalent NTM cohort). RESULTS: Between 2008 and 2019, 37.9% (1457/3840) of patients with bronchiectasis in the US BRR met the inclusion criteria for this study and were reported to have Mycobacterium avium complex (MAC) and/or Mycobacterium abscessus complex (MABSC) infections. MAC prevalence increased steadily in the US BRR during 2009-2019; incidence was relatively stable, except for a peak in 2011 followed by a slow decrease. MABSC and mixed MAC/MABSC infections were rare. Most patients with bronchiectasis and NTM infections in the registry were female, White, and aged >65 years. The antibiotics administered most commonly reflected current guidelines. In the prevalent cohort, 44.9% of MAC infections and 37.1% of MABSC infections remained untreated during follow-up, and MAC treatment was initiated with delay (>90 days after positive NTM respiratory culture) twice as frequently as promptly (≤90 days after positive NTM respiratory culture) (68.6% vs 31.4%, respectively). The median time from diagnosis to treatment was shorter for MABSC versus MAC infections (194.0 days [interquartile range (IQR) 8.0, 380.0] vs 296.0 days [IQR 35.0, 705.0], respectively). Among patients with MAC infections who completed treatment, 27.6% were classified as cured and 29.6% as treatment failure during the annual follow-up visit window. For MABSC, these proportions were 25.0% and 28.0%, respectively. CONCLUSIONS: A considerable proportion of MAC and MABSC infections were untreated or treated after initial delay/observation. MABSC infections were more likely to be treated and start treatment sooner than MAC infections. Further longitudinal studies are warranted to evaluate the monitor-with-delay approach and inform clinical guidelines.

Double asymmetric synthesis: faster reactions are more selective and a model to estimate relative rate.

The catalysed reaction of an enantiopure substrate with formation of a new chirality element may result in higher diastereoselectivity with one enantiomer of a catalyst (matched pair) than with the other (mismatched pair). The hypothesis that the matched reaction is faster was investigated using literature examples of kinetic resolution procedures that result in the formation of a new stereogenic centre. With one exception from fifteen examples, the selectivity factor (s = kfast/kslow) = kmatched/kmismatched. A model to estimate the relative rate of a fast-matched reaction vs. the corresponding slow-mismatched reaction is proposed. This model also provides insight into the basis of the selectivity displayed in the kinetic resolution procedures studied.

An expedient copper-catalysed asymmetric synthesis of γ-lactones and γ-lactams. Application to the synthesis of lucidulactone A.

The parent Josiphos ligand gave excellent ee values (95-99%) and good yields (60-97%) in the copper-catalysed asymmetric conjugate reduction of ß-aryl α,ß-unsaturated lactones and lactams with PMHS. The substrates were obtained from stereospecific copper-catalysed addition of arylboronic acids to alkynoates followed by deprotection and cyclisation. The acyclic lactam precursors also underwent reduction with good ee values (83-85%) and yields (79-95%). Application of this asymmetric reduction methodology included the synthesis of natural product lucidulactone A.

Functionalization of [2.2]Paracyclophanes via a Reductive Sulfanylation Reaction.

An expeditious route to planar chiral sulfur-based scaffolds has been achieved in two operational steps from cheap and commercial [2.2]paracyclophane hydrocarbon. The sulfur atom was introduced in a specific benzylic position of the [2.2]paracyclophane according to a reductive sulfanylation reaction, which proceeds under two complementary reaction conditions with either the BF3·OEt2/Et3SiH or TFA/BH3·THF combinations. The study was completed by the development of a highly efficient resolution approach by HPLC.

Rate of loading, but not lower limb kinematics or muscle activity, is moderated by limb and aerial variation when surfers land aerials.

We aimed to determine whether there were any differences in how surfers used their lead and trail limbs when landing two variations of a simulated aerial manoeuvre, and whether technique affected the forces generated at landing. Fifteen competitive surfers (age 20.3 ± 5.6 years, height 178.2 ± 9.16 cm, mass 71.0 ± 10.5 kg) performed a Frontside Air (FA) and Frontside Air Reverse (FAR), while we collected the impact forces, ankle and knee muscle activity, and kinematic data. A principal component analysis (PCA) was used to reduce 41 dependent variables into 10 components. A two-way MANOVA revealed that although there were no limb x aerial variation interactions, surfers generated significantly higher relative loading rates at landing for the trail limb compared to the lead limb (+28.8 BW/s; F(1,303) = 20.660, p < 0.0001, η2 = 0.064). This was likely due to the surfers "slapping" the trail limb down when landing, rather than controlling placement of the limb. Similarly, higher relative loading rates were generated when landing the FA compared to the FAR (+23.6 BW/s; F(1,303) = 31.655, p < 0.0001, η2 = 0.095), due to less time over which the forces could be dissipated. No relationships between aerial variation or limb were found for any of the kinematic or muscle activity data. Practitioners should consider the higher relative loading rates generated by a surfer's trail limb and when surfers perform a FA when designing dry-land training to improve the aerial performance of surfing athletes.

Stereoselective Synthesis of All Possible Phosferrox Ligand Diastereoisomers Displaying Three Elements of Chirality: Stereochemical Optimization for Asymmetric Catalysis.

All four possible diastereoisomers of phosphinoferrocenyloxazoline (Phosferrox type) ligands containing three elements of chirality were synthesized as single enantiomers. The Sc configured oxazoline moiety (R = Me, i-Pr) was used to control the generation of planar chirality by lithiation, with the alternative diastereoisomer formed by use of a deuterium blocking group. In each case subsequent addition of PhPCl2 followed by o-TolMgBr resulted in a single P-stereogenic diastereoisomer (Sc,Sp,Sphos and Sc,Rp,Rphos, respectively). The alternative diastereoisomers were formed selectively by addition of o-TolPCl2 followed by PhMgBr ((Sc,Sp,Rphos and Sc,Rp,Sphos, respectively). Preliminary application of these four ligand diastereoisomers, together with (Sc,Sp) and (Sc,Rp) Phosferrox (PPh2), to palladium catalyzed allylic alkylation of trans-1,3-diphenylallyl acetate revealed a stepwise increase/decrease in ee, with the configuration of the matched/matched diastereoisomer as Sc,Sp,Sphos (97% ee).

Planar chiral palladacycle precatalysts for asymmetric synthesis.

Chiral non-racemic palladacycles were employed as precatalysts for Pd(0) mediated asymmetric synthesis. Addition of HPAr2/base to a ferrocenyloxazoline planar chiral palladacycle resulted in ligand synthesis and palladium capture to give a bidentate Phosferrox/Pd(0) complex. A series of these complexes were generated in situ and applied successfully as catalysts for asymmetric allylic alkylation.

Lung transplant referral practice patterns: a survey of cystic fibrosis physicians and general pulmonologists.

BACKGROUND: Many individuals with cystic fibrosis (CF) die from respiratory failure without referral for lung transplant. Physician practices that may expedite, delay, or preclude referral, are poorly understood. METHODS: Two parallel, web-based surveys focusing on lung transplant referral triggers and barriers, as well as pre-referral evaluation, were emailed to pulmonologists practicing in the New England region. One questionnaire was sent to CF providers (n = 61), and the second to general pulmonary providers practicing at the same institutions (n = 61). RESULTS: There were 43 (70%) responses to the CF provider survey, and 25 (41%) responses to the general pulmonary ('non-CF') provider survey. Primary reasons for CF providers to refer their patients included: rapidly declining lung function (91%) and a forced expiratory volume in 1 s (FEV1) below 30% predicted (74%). The greatest barriers to referral for both CF and non-CF providers included active tobacco use (65 and 96%, respectively, would not refer), and active alcohol or other substance use or dependence (63 and 80%). Furthermore, up to 42% of CF providers would potentially delay their referral if triple-combination therapy or other promising new, disease-specific therapy were anticipated. In general, non-CF providers perform a more robust pre-referral medical work-up, while CF providers complete a psychosocial evaluation in higher numbers. Across both groups, communication with lung transplant programs was reported to be inadequate. CONCLUSIONS: Physician-level barriers to timely lung transplant referral exist and need to be addressed. Enhanced communication between lung transplant programs and pulmonary providers may reduce these barriers.

Nontuberculous Mycobacteria in Cystic Fibrosis.

Over the past decade, the incidence of nontuberculous mycobacterial (NTM) infection has been increasing in cystic fibrosis patients. Along with this have come a host of complications and burdens to patients that threaten longevity and quality of life. The two main constituents of NTM pulmonary disease, Mycobacterium avium complex (MAC) and M. abscessus, are notoriously difficult to treat with suboptimal clinical responses and are accompanied by high treatment burdens for patients. This review aims to summarize the current knowledge of NTM epidemiology, pathogenesis, professional society guidelines for diagnosis and treatment, and the efficacy of current management recommendations, with attention to cystic fibrosis patients. We go on to examine drugs of emerging but unknown efficacy in clinical use to provide a comprehensive assessment of the current state of management of NTM for cystic fibrosis patients.

Stereoselective and Stereospecific Reactions of Cobalt Sandwich Complexes: Synthesis of a New Class of Single Enantiomer Bulky Planar Chiral P-N and P-P Ligands.

Starting from (η5 -acetylcyclopentadienyl)(η4 -tetraphenylcyclobutadiene)cobalt(I), highly enantioselective (99 % ee) (S)-CBS catalysed ketone reduction followed by stereospecific alcohol-azide exchange, azide reduction and dimethyllation gave (R)-(η5 -α-N,N-dimethylaminoethylcyclopentadienyl)(η4 -tetraphenylcyclobutadiene) cobalt(I) (Arthurs' amine). This underwent highly diastereoselective cyclopalladation to give di-µ-acetate-bis-(R)-[(η5 -(Sp )-2-(α-N,N-dimethylaminoethyl)cyclopentadienyl, 1-C, N)(η4 -tetraphenylcyclobutadiene)cobalt(I)]dipalladium, and highly diastereoselective lithiation to give (R)-(η5 -(Sp )-1-(α-N,N-dimethylaminoethyl)-2-(diphenylphosphino)cyclopentadienyl)(η4 -tetraphenylcyclobutadiene)cobalt(I) (PPCA) following the addition as electrophile of chlorodiphenylphosphine. This PN-ligand was converted into (R)-(η5 -(Sp )-1-(α-dicyclohexylphosphinoethyl)-2-(diphenylphosphino)cyclopentadienyl)(η4 -tetraphenylcyclobutadiene)cobalt(I), a PP-ligand (Rossiphos), by stereospecific amine-phosphine exchange using HPCy2 . These air-stable P-N and P-P complexes are the first examples of a new class of bulky planar chiral ligands for application in asymmetric catalysis.

Catalyst Optimisation for Asymmetric Synthesis by Ligand Chirality Element Addition: A Perspective on Stereochemical Cooperativity.

The concept of matched and mismatched stereochemical pairings has been utilised extensively in organic synthesis, with the cooperativity resulting from the former enabling many reactions to proceed with high stereoselectivity. This approach was first developed to improve the diastereoselectivity of a reaction by matching the configuration of an enantiopure reagent or catalyst with the configuration of an enantiopure substrate. It has been extended to the asymmetric transformation of prochiral substrates controlled by reagents and catalysts containing two or more stereogenic centres. Matched and mismatched pairings may again be identified, with the former resulting in higher product enantioselectivity. This Minireview examines stereochemical pairings within catalysts generated from the combination of a metal with an enantiopure ligand; specifically examples in which the ligand diastereoisomers examined for cooperativity are formally the result of the addition of a chiral element to an existing enantiopure ligand. Comparison of all three ligands in each of the fifty-six examples examined reveals that, in the majority of cases, the added element of chirality increases and decreases the enantioselectivity with respect to the parent ligand. The iterative application of this effect offers a potentially powerful method for catalyst optimisation for use in asymmetric synthesis.

Combined Elbow Release and Humeral Rotational Osteotomy in Arthrogryposis.

PURPOSE: The purpose of this study was to determine if a simultaneous posterior elbow release and humeral osteotomy to correct both the elbow extension contracture and the humeral internal rotation contracture in children with arthrogryposis can produce similar results as a posterior elbow release alone. METHODS: This study was a retrospective chart review of consecutive patients with arthrogryposis treated surgically for elbow extension contracture between 2007 and 2014. A total of 43 procedures in 36 patients had adequate available follow-up data and were included in the study. The postoperative range of motion reported was measured at the early follow-up (3-6 months), midterm follow-up (between 1 and 2 years), and the most recent long-term follow-up (after 2 years) from the date of surgery. Patients were grouped into 2 groups (simultaneous and release) based on the necessity of performing an ipsilateral humeral rotation osteotomy at the time of the release. RESULTS: At early follow-up, patients in both groups increased their total arc of motion. There was a significant difference in extension and arc of motion at midterm follow-up (between 1 and 2 years) between the simultaneous and the release groups with the simultaneous group significantly losing both terminal extension and total arc of motion. At more than 2 years follow-up, there remained a statistically significant difference in arc of motion, with the release group having a significantly larger arc of motion. Patients who underwent dual plating had a much larger arc of motion at early follow-up than the K-wire or single-plate fixation group, despite having similar preoperative extension, flexion, and arc of motion. This difference was also significant at late follow-up. CONCLUSIONS: Patients with posterior release alone had significantly greater improvement in total arc of motion and significantly better elbow extension than patients who underwent a simultaneous humeral osteotomy. However, rigid fixation with early mobilization may yield results comparable with the release alone group. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV.

Enantiopure Ferrocene-Based Planar-Chiral Iridacycles: Stereospecific Control of Iridium-Centred Chirality.

Reaction of [IrCp*Cl2 ]2 with ferrocenylimines (Fc=NAr, Ar=Ph, p-MeOC6 H4 ) results in ferrocene C-H activation and the diastereoselective synthesis of half-sandwich iridacycles of relative configuration Sp *,RIr *. Extension to (S)-2-ferrocenyl-4-(1-methylethyl)oxazoline gave highly diastereoselective control over the new elements of planar chirality and metal-based pseudo-tetrahedral chirality, to give both neutral and cationic half-sandwich iridacycles of absolute configuration Sc ,Sp ,RIr . Substitution reactions proceed with retention of configuration, with the planar chirality controlling the metal-centred chirality through an iron-iridium interaction in the coordinatively unsaturated cationic intermediate.

Enantiomerically Pure [2.2]Paracyclophane-4-thiol: A Planar Chiral Sulfur-Based Building Block Readily Available by Resolution with an Amino Acid Chiral Auxiliary.

Acyl chloride of N-phthaloyl-(S)-isoleucine is an efficient chiral auxiliary for the resolution of (±)-[2.2]paracyclophane-4-thiol. A preparative protocol, based on the conversion into diastereoisomeric thiolesters and separation by two fractional crystallizations and column chromatography, was developed. Deprotection with LiAlH4 allowed isolation of the individual thiol enantiomers in good yield (∼40%) and high enantiomeric purity (ee >93%). The absolute configurations were determined by comparison of the optical rotation value of the products with literature data and were confirmed by X-ray crystallography.

Enantioselective synthesis and application to the allylic imidate rearrangement of amine-coordinated palladacycle catalysts of cobalt sandwich complexes.

The reaction of (η(5)-(N,N-dimethylaminomethyl)cyclopentadien-yl)(η(4)-tetraphenylcyclobutadiene)cobalt with sodium tetrachloropalladate and (R)-N-acetylphenylalanine gave planar chiral palladacycle di-µ-chloridebis[(η(5)-(Sp)-2-(N,N-dimethylaminomethyl)cyclopentadienyl,1-C,3'-N)(η(4)-tetraphenylcyclobutadiene)cobalt]dipalladium [(Sp )-Me2 -CAP-Cl] in 92% ee and 64% yield. Enantiopurity (>98% ee) was achieved by purification of the monomeric (R)-proline adducts and conversion back to the chloride dimer. Treatment with AgOAc gave (Sp)-Me2-CAP-OAc which was applied to asymmetric transcyclopalladation (up to 78% ee). The (R)-N-acetylphenylalanine mediated palladation methodology was applicable also to the corresponding N,N-diethyl (82% ee, 39% yield) and pyrrolidinyl (>98% ee, 43% yield) cobalt sandwich complexes. A combination of 5 mol % of the latter [(Sp)-Pyrr-CAP-Cl] and AgNO3 (3.8 equiv) is a catalyst for the allylic imidate rearrangement of an (E)-N-aryltrifluoroacetimidate (up to 83% ee), and this catalyst system is also applicable to the rearrangement of a range of (E)-trichloroacetimidates (up to 99% ee). This asymmetric efficiency combined with the simplicity of catalyst synthesis provides accessible solutions to the generation of non-racemic allylic amine derivatives.

Alcohol and opiate misuse in adults with cystic fibrosis.

BACKGROUND: International consensus statements on depression and anxiety in adolescents and adults with cystic fibrosis (awCF) recommend assessment for comorbid substance misuse. However, at CF centers, the frequency and impact of substance misuse have not been well characterized, and best practices for prevention, identification, and evidence-based treatment have not been routinely implemented. METHODS: Medical records of 148 awCF over 3 years were reviewed to determine the prevalence of substance misuse (alcohol or opiates) and its relationship with clinical variables and healthcare utilization. Independent sample t test for continuous outcomes and χ2 test for binary outcomes were used to compare groups with and without substance misuse. RESULTS: Substance misuse was documented in 28 (19%) awCF, equally distributed between alcohol (n = 13) and opiates (n = 15). Adults with substance misuse were more likely to be male. The prevalence of diagnosed anxiety and depression did not differ significantly between groups, but those with substance misuse had more severe anxiety (Generalized Anxiety Disorder-7 Item [GAD-7]: 10.0 ± 6.1 vs. 3.3 ± 4.4; p < 0.001) and depressive symptoms (Patient Health Questionnaire-9: 10.4 ± 6.5 vs. 4.0 ± 4.8; p < 0.001). Adults with substance misuse had higher annual rates of missed outpatient CF visits, more frequent "sick" visits, more frequent and longer hospitalizations, and a higher mortality rate. CONCLUSIONS: In awCF, substance misuse is common and associated with adverse indicators of emotional and physical health, including via proxy of service utilization, suggesting that systematic approaches to addressing substance misuse in CF clinics should be considered. Prospective, longitudinal study is warranted to elucidate the complex relationships between depression, anxiety, substance misuse, and health outcomes in individuals with CF.