Five-Year Outcomes Among U.S. Bronchiectasis and Nontuberculous Mycobacterial 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. OBJECTIVE: To assess the impact of NTM on 5-year clinical outcomes and mortality in patients with bronchiectasis. METHODS: Patients in the United States Bronchiectasis and Nontuberculous Mycobacteria 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 forced expiratory volume in 1 second % predicted, age, hospitalization within 2 years before baseline, body mass index, and gender (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 irrespective 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.

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.

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.

Supplemental Oxygen Alters the Airway Microbiome in Cystic Fibrosis.

Features of the airway microbiome in persons with cystic fibrosis (pwCF) are correlated with disease progression. Microbes have traditionally been classified for their ability to tolerate oxygen. It is unknown whether supplemental oxygen, a common medical intervention, affects the airway microbiome of pwCF. We hypothesized that hyperoxia significantly impacts the pulmonary microbiome in cystic fibrosis. In this study, we cultured spontaneously expectorated sputum from pwCF in artificial sputum medium under 21%, 50%, and 100% oxygen conditions using a previously validated model system that recapitulates microbial community composition in uncultured sputum. Culture aliquots taken at 24, 48, and 72 h, along with uncultured sputum, underwent shotgun metagenomic sequencing with absolute abundance values obtained with the use of spike-in bacteria. Raw sequencing files were processed using the bioBakery pipeline to determine changes in taxonomy, predicted function, antimicrobial resistance genes, and mobile genetic elements. Hyperoxia reduced absolute microbial load, species richness, and diversity. Hyperoxia reduced absolute abundance of specific microbes, including facultative anaerobes such as Rothia and some Streptococcus species, with minimal impact on canonical CF pathogens such as Pseudomonas aeruginosa and Staphylococcus aureus. The effect size of hyperoxia on predicted functional pathways was stronger than that on taxonomy. Large changes in microbial cooccurrence networks were noted. Hyperoxia exposure perturbs airway microbial communities in a manner well tolerated by key pathogens. Supplemental oxygen use may enable the growth of lung pathogens and should be further studied in the clinical setting. IMPORTANCE The airway microbiome in persons with cystic fibrosis (pwCF) is correlated with lung function and disease severity. Supplemental oxygen use is common in more advanced CF, yet its role in perturbing airway microbial communities is unknown. By culturing sputum samples from pwCF under normal and elevated oxygen conditions, we found that increased oxygen led to reduced total numbers and diversity of microbes, with relative sparing of common CF pathogens such as Pseudomonas aeruginosa and Staphylococcus aureus. Supplemental oxygen use may enable the growth of lung pathogens and should be further studied in the clinical setting.

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.

Lung Histopathology in Coronavirus Disease 2019 as Compared With Severe Acute Respiratory Sydrome and H1N1 Influenza: A Systematic Review.

BACKGROUND: Patients with severe coronavirus disease 2019 (COVID-19) have respiratory failure with hypoxemia and acute bilateral pulmonary infiltrates, consistent with ARDS. Respiratory failure in COVID-19 might represent a novel pathologic entity. RESEARCH QUESTION: How does the lung histopathology described in COVID-19 compare with the lung histopathology described in SARS and H1N1 influenza? STUDY DESIGN AND METHODS: We conducted a systematic review to characterize the lung histopathologic features of COVID-19 and compare them against findings of other recent viral pandemics, H1N1 influenza and SARS. We systematically searched MEDLINE and PubMed for studies published up to June 24, 2020, using search terms for COVID-19, H1N1 influenza, and SARS with keywords for pathology, biopsy, and autopsy. Using PRISMA-Individual Participant Data guidelines, our systematic review analysis included 26 articles representing 171 COVID-19 patients; 20 articles representing 287 H1N1 patients; and eight articles representing 64 SARS patients. RESULTS: In COVID-19, acute-phase diffuse alveolar damage (DAD) was reported in 88% of patients, which was similar to the proportion of cases with DAD in both H1N1 (90%) and SARS (98%). Pulmonary microthrombi were reported in 57% of COVID-19 and 58% of SARS patients, as compared with 24% of H1N1 influenza patients. INTERPRETATION: DAD, the histologic correlate of ARDS, is the predominant histopathologic pattern identified in lung pathology from patients with COVID-19, H1N1 influenza, and SARS. Microthrombi were reported more frequently in both patients with COVID-19 and SARS as compared with H1N1 influenza. Future work is needed to validate this histopathologic finding and, if confirmed, elucidate the mechanistic underpinnings and characterize any associations with clinically important outcomes.

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.

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.

Experimental evaluation and analytical model of the pressure generated by elastic compression garments on a deformable human limb analogue.

Compression garments are extensively used for various therapeutic treatments and are expected to deliver accurate and reproducible compression pressures. This study focuses on developing an analytical model to predict the pressure generation by compression garments on human limb analogues. The analogues consisted of non-compressible and compressible cylinders that were chosen as the first step towards evaluating pressure generation on real human limbs. An experimental platform was developed to quantify the relationship between material properties, initial garment extension and pressure. A mathematical model was presented that provided greater accuracy in predicting the pressure generated by compression garments than the existing Young-Laplace equation for compressible limb analogues.

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.

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).

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.

A microscopic Kapitza pendulum.

Pyotr Kapitza studied in 1951 the unusual equilibrium features of a rigid pendulum when its point of suspension is under a high-frequency vertical vibration. A sufficiently fast vibration makes the top position stable, putting the pendulum in an inverted orientation that seemingly defies gravity. Kapitza's analytical method, based on an asymptotic separation of fast and slow variables yielding a renormalized potential, has found application in many diverse areas. Here we study Kapitza's pendulum going beyond its typical idealizations, by explicitly considering its finite stiffness and the dissipative interaction with the surrounding medium, and using similar theoretical methods as Kapitza. The pendulum is realized at the micrometre scale using a colloidal particle suspended in water and trapped by optical tweezers. Though the strong dissipation present at this scale prevents the inverted pendulum regime, new ones appear in which the equilibrium positions are displaced to the side, and with transitions between them determined either by the driving frequency or the friction coefficient. These new regimes could be exploited in applications aimed at particle separation at small scales.

The Bionic Bra: Using electromaterials to sense and modify breast support to enhance active living.

BACKGROUND: Although the most supportive sports bras can control breast motion and associated breast pain, they are frequently deemed uncomfortable to wear and, as a result, many women report exercise bra discomfort. Given that exercise bra discomfort is associated with decreased levels of physical activity, there is a pertinent need to develop innovative solutions to address this problem. OBJECTIVES: This research aimed to evaluate the use of electromaterial sensors and artificial muscle technology to create a bra that was capable of detecting increases in breast motion and then responding with increased breast support to enhance active living. METHODS: The research involved two phases: (i) evaluating sensors suitable for monitoring and providing feedback on changes in the amplitude and frequency of breast motion, and (ii) evaluating an actuator capable of changing breast support provided by a bra during activity. RESULTS: When assessed in isolation, the developed technologies were capable of sensing breast motion and actuating to provide some additional breast support. CONCLUSIONS: The challenge now lies in integrating both technologies into a functional sports bra prototype, and assessing this prototype in a controlled biomechanical analysis to provide a breast support solution that will enable women to enjoy active living in comfort.

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.