Patient Perception of Cough in Interstitial Lung Disease; Impact of Cough Hypersensitivity.

INTRODUCTION: Cough is common in interstitial lung disease (ILD) and is associated with disease progression, yet its mechanisms are understudied. We investigated cough hypersensitivity features and impact in ILD. METHODS: Participants with ILD and cough (n = 195) completed a multiple choice and free text questionnaire on cough sensations/triggers and impacts. RESULTS: The majority of participants were male (54%), aged > 65 (64%), with idiopathic pulmonary fibrosis (IPF, 75%). Common cough triggers were body position (74%), physical activity (72%), and talking (62%). Common laryngeal sensations were globus (43%), and itch/tickle (42%). Cough impacted everyday life in 55%, and all activities in 31%, causing exhaustion (59%), social embarrassment (70%), urinary incontinence (46% females), and syncope/pre-syncope (12%). The total number of cough-provoking sensations/triggers correlated with impacts; ρ = 0.73, p < 0.001. CONCLUSION: Cough hypersensitivity symptoms are prevalent in ILD and detrimentally affect quality of life. Further studies investigating mechanisms of cough hypersensitivity and targeted pharmacotherapy are warranted.

An Iron Macrocyclic Complex Containing Four "Hybrid" Pyridinium Amidate/Amidate N-Donors as a Catalyst for Oxidations with Hydrogen Peroxide.

The macrocyclic proligand [H4 L][OTf]2 , which contains four carboxamide functions and two conjugated pyridinium groups, is easily deprotonated by the weak base sodium acetate to give the corresponding neutral proligand [H2 L]. Metallation of [H2 L] with iron(II) chloride proceeds rapidly to form the macrocyclic complex, [FeIII Cl(L)]. This is an effective catalyst for the oxidation of the organic dye orange II by hydrogen peroxide in aqueous solution, and the kinetic parameters for this reaction have been determined. In striking contrast to an analogous iron-TAML complex that contains two phenyl groups in place of the two pyridinium groups, [FeIII Cl(L)] is a very active oxidation catalyst at pH 7 and is also highly stable towards acid-promoted demetallation at pH 5 or above. The results show that the two pyridinium groups bring greatly enhanced catalytic properties to [FeIII Cl(L)].

Ferrocene-Derived Palladium(II)-Based Metallosupramolecular Structures: Synthesis, Guest Interaction, and Stimulus-Responsiveness Studies.

Using ferrocene-based ligand systems, a series of heterobimetallic architectures of the general formula [PdmLn]x+ were designed with the aim of installing an opening and closing mechanism that would allow the release and binding of guest molecules. Palladium complex formation was achieved through coordination to pyridyl groups, and using 2-, 3-, and 4-pyridyl derivatives provided access to defined PdL, PdL2, and Pd2L4 structures, respectively. The supramolecular complexes were characterized using nuclear magnetic resonance (NMR) and infrared spectroscopy, mass spectrometry, and elemental analysis, and for some examples density functional theory calculations and single-crystal X-ray diffraction analysis. 1H NMR spectroscopy was used to investigate disassembly and reassembly of the metallosupramolecular structures. The former was induced by cleavage of the relatively labile Pd-Npyridyl bonds with the introduction of the competing ligands N,N'-dimethylaminopyridine (DMAP) and Cl- (using tetrabutylammonium chloride) to yield [Pd(DMAP)4]2+ and [PdCl4]2-, respectively. The process was found to be reversible for several of the heterodimetallic compounds, with the addition of H+ or Ag+ triggering complex reassembly. Guest binding studies with several architectures revealed interactions with the anionic guests p-toluenesulfonate and octyl sulfate, but not with neutral molecules. Furthermore, the release of guests was reversibly induced with Cl- ions as a stimulus.

Heterotrimetallic Double Cavity Cages: Syntheses and Selective Guest Binding.

A strategy for the generation of heterotrimetallic double cavity (DC) cages [Pdn Ptm L4 ]6+ (DC1: n=1, m=2; and DC2: n=2, m=1) is reported. The DC cages were generated by combining an inert platinum(II) tetrapyridylaldehyde complex with a suitably substituted pyridylamine and PdII ions. 1 H and DOSY nuclear magnetic resonance spectroscopy (NMR) and electrospray ionization mass spectrometry (ESIMS) data were consistent with the formation of the DC architectures. DC1 and DC2 were shown to interact with several different guest molecules. The structure of DC1, which features two identical cavities, binding two 2,6-diaminoanthraquinone (DAQ) guest molecules was determined by single-crystal X-ray crystallography. In addition, DC1 was shown to bind two molecules of 5-fluorouracil (5-FU) in a statistical (non-cooperative) manner. In contrast, DC2, which features two different cage cavities, was found to interact with two different guests, 5-FU and cisplatin, selectively.

Quantification and composition of pharmaceutical waste in New Zealand.

This study aimed to quantify the amount of pharmaceutical waste produced in New Zealand, and determine the composition of pharmaceutical waste from community pharmacies in Auckland, New Zealand. Pharmaceutical waste collected in New Zealand is increasing, peaking at 542 tonne in 2019. Pharmaceutical waste collected from hospitals and pharmacies in Auckland increased by more than fourfold from 2016 to 2020. An audit of the types of pharmaceutical waste collected from community pharmacies revealed that the most common classes of drugs identified in this waste stream belonged to the nervous system, cardiovascular system and alimentary tract, and metabolism. Following examination of the contents of 12 pharmaceutical waste bins, 475 different pharmaceutical products were identified, highlighting the breadth of drugs in this waste stream. A range of dosage forms and hence materials were identified, which could present challenges for future waste treatment approaches. Hazardous drugs were identified including cytotoxic compounds, which should go into a separate waste stream for incineration. There is a need for similar data to be collected from multiple sites to fully appreciate the magnitude and composition of pharmaceutical waste. This will allow for the suitability of current practices for managing this hazardous waste stream to be evaluated.

Carbon Monoxide is an Inhibitor of HIF Prolyl Hydroxylase Domain 2.

Hypoxia-inducible factor prolyl hydroxylase domain 2 (PHD2) is an important oxygen sensor in animals. By using the CO-releasing molecule-2 (CORM-2) as an in situ CO donor, we demonstrate that CO is an inhibitor of PHD2. This report provides further evidence about the emerging role of CO in oxygen sensing and homeostasis.

A Reduced-Symmetry Heterobimetallic [PdPtL4 ]4+ Cage: Assembly, Guest Binding, and Stimulus-Induced Switching.

A strategy is presented that enables the quantitative assembly of a heterobimetallic [PdPtL4 ]4+ cage. The presence of two different metal ions (PdII and PtII ) with differing labilities enables the cage to be opened and closed selectively at one end upon treatment with suitable stimuli. Combining an inert PtII tetrapyridylaldehyde complex with a suitably substituted pyridylamine and PdII ions led to the assembly of the cage. 1 H and DOSY NMR spectroscopy and ESI mass spectrometry data were consistent with the quantitative formation of the cage, and the heterobimetallic structure was confirmed using single-crystal X-ray crystallography. The structure of the host-guest adduct with a 2,6-diaminoanthraquinone guest molecule was determined. Addition of N,N'-dimethylaminopyridine (DMAP) resulted in the formation of the open-cage [PtL4 ]2+ compound and [Pd(DMAP)4 ]2+ complex. This process could then be reversed, with the reformation of the cage, upon addition of p-toluenesulfonic acid (TsOH).

Non-insulin treatments for Type 1 diabetes: critical appraisal of the available evidence and insight into future directions.

Intensive insulin therapy is the mainstay of treatment for people with Type 1 diabetes, but hypoglycaemia and weight gain are often limiting factors in achieving glycaemic targets and decreasing the risk of diabetes-related complications. The inclusion of pharmacological agents used traditionally in Type 2 diabetes as adjuncts to insulin therapy in Type 1 diabetes has been explored, with the goal of mitigating such drawbacks. Pramlintide and metformin result in modest HbA1c and weight reductions, but their use is limited by poor tolerability and, in the case of pramlintide, by frequency of injections and cost. The addition of glucagon-like peptide-1 receptor agonists to insulin results in improved glycaemic control, reduced insulin doses and weight loss, but this is at the expense of higher rates of hypoglycaemia and hyperglycaemia with ketosis. Sodium-glucose co-transporter-2 and dual sodium-glucose co-transporter-2 and -1 inhibitors also improve glucose control, but with reductions in weight and insulin requirements potentiating the risk of acidosis-related events and hypoglycaemia. The high proportion of people with Type 1 diabetes not achieving glycaemic targets, the negative clinical impact of intensive insulin therapy and the rise in obesity and cardiovascular disease and mortality, underline the need for individualized clinical care. The evaluation of new therapies, effective in Type 2 diabetes, as adjuncts to insulin therapy represents a promising strategy, particularly given the beneficial effects on cardiovascular and renal outcomes in people with Type 2 diabetes with or at high risk of complications that are also observed in patients with Type 1 diabetes. As the population with Type 1 diabetes ages, our mission is to evolve and provide better tools and improved therapies to excel, not only in glycaemic control but also in risk reduction and reduction of complications.

'Desculturización,' urbanization, and nutrition transition among urban Kichwas Indigenous communities residing in the Andes highlands of Ecuador.

BACKGROUND: The nutrition transition continues to affect populations throughout the world. The added impact of market integration and urbanization exacerbates the impact of the nutrition transition upon Indigenous populations worldwide. OBJECTIVES: This study aims to explore the nutritional concerns of the urban Kichwas community residing in the Andes highlands of Ecuador. STUDY DESIGN: This is a qualitative study. METHODS: Eight focus groups were conducted with Kichwas men and women in November 2015 in the Imbabura province of the Andes in Ecuador. DATA ANALYSIS: Applied thematic analysis was used to analyze findings regarding nutrition. RESULTS: The participants shared concerns regarding increased intake of fast food, poor meal timing, and a shift in the child's food preferences that rejects traditional foods. They attributed these concerns to urbanization resulting from an increase in dual-income households and a loss of cultural identity. CONCLUSIONS: Synergistic cultural factors are related to nutritional concerns voiced by the urban Kichwas community. PUBLIC HEALTH IMPLICATIONS: Syndemic theory is a useful interpretive lens regarding nutritional trends within the Kichwas communities as they relate to the increased risk of chronic disease.

Recent Advances in Metallaaromatic Chemistry.

Metallaaromatics can be broadly defined as aromatic compounds in which one of the ring atoms is a transition metal. The metallabenzenes are one important class of these compounds that has undergone extensive study recently. Closely related species such as fused-ring metallabenzenes, heterometallabenzenes, π-coordinated metallabenzenes and metallabenzynes have also attracted considerable attention. Although many metallaaromatics can be considered as metalla-analogues of classic organic aromatic compounds, this is not always the case. Recent seminal studies have shown that metallapentalenes and metallapentalynes, which are metalla-analogues of the anti-aromatic compounds pentalene and pentalyne, are in fact aromatic and highly stable. Very unusual spiro-metallaaromatic compounds have also recently been isolated. In this concepts article, key features of all these intriguing metallaaromatic compounds are discussed with reference to the structural, spectroscopic, reactivity and theoretical studies that have been undertaken. These compounds continue to generate much interest, not only because of the contributions they make to fundamental chemical understanding, but also because of the promise of possible practical applications.

Syntheses of Amino-Substituted Iridabenzofurans and Subsequent Selective N-Functionalisation.

The first examples of amino-substituted fused-ring metallabenzenes, the cationic iridabenzofuran [Ir(C7 H4 O{NH2 -2}{OMe-7})(CO)(PPh3 )2 ][O3 SCF3 ] (5) and neutral analogue Ir(C7 H4 {NH2 -2}{OMe-7})Cl(PPh3 )2 (6), can be prepared by reduction of the corresponding nitro-substituted iridabenzofurans with zinc and concentrated hydrochloric acid. N-functionalised derivatives of 5 and 6 are formed through alkylation, sulfonylation or acylation. Thus, consecutive treatments with methyl triflate and base gives the corresponding trimethylammonium-substituted iridabenzofurans while sulfonamide derivatives are formed with p-toluenesulfonyl chloride. N-Acylation of 5 or 6 with acid chlorides, however, selectively form either amide or imide products depending on the charge on the metal and the steric size of the acid chloride. Cationic 5 gives amide substituted products regardless of the conditions whereas neutral 6 rapidly undergoes di-N-acylation with excess benzoyl chloride under mild conditions to give the imide-substituted product Ir(C7 H4 O{N[C(O)Ph]2 -2}{OMe-7})Cl(PPh3 )2 (13). Selective mono-acylation of 6 can be achieved with one equivalent of benzoyl chloride or with excess of the sterically congested pivaloyl chloride.

Versatile supercontinuum generation in parabolic multimode optical fibers.

We demonstrate that the pump's spatial input profile can provide additional degrees of freedom in tailoring at will the nonlinear dynamics and the ensuing spectral content of supercontinuum generation in highly multimoded optical fibers. Experiments and simulations carried out at 1550 nm indicate that the modal composition of the input beam can substantially alter the soliton fission process as well as the resulting Raman and dispersive wave generation that eventually lead to supercontinuum in such a multimode environment. Given the multitude of conceivable initial conditions, our results suggest that it is possible to pre-engineer the supercontinuum spectral content in a versatile manner.

Waiting time variation in Early Intervention Psychosis services: longitudinal evidence from the SEPEA naturalistic cohort study.

PURPOSE: Early Intervention Psychosis [EIP] services have gained traction internationally, but are currently undergoing various forms of reconfiguration. In England, such services are now mandated to ensure 50% of accepted referrals commence care within 14 days, but no empirical evidence exists. We sought to estimate waiting times to EIP services in a large, representative epidemiological cohort in England, and investigate possible reasons for any variation. METHODS: We estimated median waiting time from referral to acceptance by EIP services and investigated whether this varied by clinical, demographic or neighbourhood-level factors, amongst 798 participants, 16-35 years old, presenting to six EIP services over 3.5 years in a defined catchment area serving 2.5 million people. We used parametric survival analysis to inspect variation in waiting times (in days). RESULTS: Median waiting time was 15 days (interquartile range 7-30), although this varied across services (p < 0.01). Waiting times increased over the case ascertainment period by an average of 4.3 days (95% CI 1.3, 6.2; p < 0.01). Longer waiting times were associated with greater diagnostic uncertainty, indexed by an organic presentation (+ 9.1 days; 95% CI 1.9, 16.6; p < 0.01), polysubstance abuse (+ 2.6; 0.6, 3.9; p < 0.01), absence of psychotic disorder (+1.8; -0.1, 3.0; p = 0.05) and insidious onset (+1.8; -0.1, 3.0; p = 0.06). Waiting times did not vary by most demographic or neighbourhood-level characteristics. CONCLUSIONS: EIP services operate close to new waiting time standards in England, with little systematic variation by sociodemographic position. However, waiting times increased over the study period, coinciding with substantial service reorganisation. Longer waiting times associated with greater diagnostic uncertainty highlight opportunities to reduce delays in certain clinical groups at initial referral.

A Metallaanthracene and Derived Metallaanthraquinone.

Metalla-analogues of archetypal aromatic molecules are attracting ever increasing interest. Although metallabenzenes (which fall within this class) have been well studied, fused-ring metallabenzenes are rare and of the linear polycyclic metallaaromatic hydrocarbons, only metallanaphthalene is known. Herein we report the first metallaanthracene, [Ir(C13 H8 {CH2 CO2 Me-5})Cl(PPh3 )2 ]O3 SCF3 (5), which represents the next member of this series of polycyclic compounds. Structurally, 5 has a number of features in common with anthracene including fused-ring planarity and bond-length alternation. In analogues of classic reactions of anthracene, 5 forms a Diels-Alder adduct with maleic anhydride and on oxidation the unprecedented fused-ring metallaanthraquinone, [Ir(C15 H6 O{Br-6}{OMe-7}{=O-8}{=O-15})Br(PPh3 )2 ], is obtained.

Financial Impact of Liver Sharing and Organ Procurement Organizations' Experience With Share 35: Implications for National Broader Sharing.

The Share 35 policy for organ allocation, which was adopted in June 2013, allocates livers regionally for candidates with Model for End-Stage Liver Disease scores of 35 or greater. The authors analyzed the costs resulting from the increased movement of allografts related to this new policy. Using a sample of nine organ procurement organizations, representing 17% of the US population and 19% of the deceased donors in 2013, data were obtained on import and export costs before Share 35 implementation (June 15, 2012, to June 14, 2013) and after Share 35 implementation (June 15, 2013, to June 14, 2014). Results showed that liver import rates increased 42%, with an increased cost of 51%, while export rates increased 112%, with an increased cost of 127%. When the costs of importing and exporting allografts were combined, the total change in costs for all nine organ procurement organizations was $11 011 321 after Share 35 implementation. Extrapolating these costs nationally resulted in an increased yearly cost of $68 820 756 by population or $55 056 605 by number of organ donors. Any alternative allocation proposal needs to account for the financial implications to the transplant infrastructure.

Decoupled polarization dynamics of incoherent waves and bimodal spectral incoherent solitons.

We consider the propagation of strongly incoherent waves in optical fibers in the framework of the vector nonlinear Schrödinger equation (VNLSE) accounting for the Raman effect. On the basis of the wave turbulence theory, we derive a kinetic equation that greatly simplifies the VNLSE and provides deep physical insight into incoherent wave dynamics. When applied to the study of polarization effects, the theory unexpectedly reveals that the linear polarization components of the incoherent wave evolve independently from each other, even in the presence of weak fiber birefringence. When applied to light propagation in bimodal fibers, the theory reveals that the incoherent modal components can be strongly coupled. After a complex transient, the modal components self-organize into a vector spectral incoherent soliton: The two solitons self-trap and propagate with a common velocity in frequency space.

Visible supercontinuum generation in a graded index multimode fiber pumped at 1064 nm.

We observe efficient supercontinuum generation that extends into the visible spectral range by pumping a low differential mode group delay graded index multimode fiber in the normal dispersion regime. For a 28.5 m long fiber, the generated spectrum spans more than two octaves, starting from below 450 nm and extending beyond 2400 nm. The main nonlinear mechanisms contributing to the visible spectrum generation are attributed to multipath four-wave mixing processes and periodic spatio-temporal breathing dynamics. Moreover, by exploiting the highly multimodal nature of this system, we demonstrate versatile generation of visible spectral peaks in shorter fiber spans by altering the launching conditions. A nonlinearly induced mode cleanup was also observed at the pump wavelength. Our results could pave the way for high brightness, high power, and compact, multi-octave continuum sources.

Serotype-specific differences in short- and longer-term mortality following invasive pneumococcal disease.

Invasive pneumococcal disease (IPD), caused by infection with Streptococcus pneumoniae, has a substantial global burden. There are over 90 known serotypes of S. pneumoniae with a considerable body of evidence supporting serotype-specific mortality rates immediately following IPD. This is the first study to consider the association between serotype and longer-term mortality following IPD. Using enhanced surveillance data from the North East of England we assessed both the short-term (30-day) and longer-term (⩽7 years) independent adjusted associations between individual serotypes and mortality following IPD diagnosis using logistic regression and extended Cox proportional hazards models. Of the 1316 cases included in the analysis, 243 [18·5%, 95% confidence interval (CI) 16·4-20·7] died within 30 days of diagnosis. Four serotypes (3, 6A, 9N, 19 F) were significantly associated with overall increased 30-day mortality. Effects were observable only for older adults (⩾60 years). After extension of the window to 12 months and 36 months, one serotype was associated with significantly increased mortality at 12 months (19 F), but no individual serotypes were associated with increased mortality at 36 months. Two serotypes had statistically significant hazard ratios (HR) for longer-term mortality: serotype 1 for reduced mortality (HR 0·51, 95% CI 0·30-0·86) and serotype 9N for increased mortality (HR 2·30, 95% CI 1·29-4·37). The association with serotype 9N was no longer observed after limiting survival analysis to an observation period starting 30 days after diagnosis. This study supports the evidence for associations between serotype and short-term (30-day) mortality following IPD and provides the first evidence for the existence of statistically significant associations between individual serotypes and longer-term variation in mortality following IPD.

The Estimated Six-Year Mercury Dry Deposition Across North America.

Dry deposition of atmospheric mercury (Hg) to various land covers surrounding 24 sites in North America was estimated for the years 2009 to 2014. Depending on location, multiyear mean annual Hg dry deposition was estimated to range from 5.1 to 23.8 µg m-2 yr-1 to forested canopies, 2.6 to 20.8 µg m-2 yr-1 to nonforest vegetated canopies, 2.4 to 11.2 µg m-2 yr-1 to urban and built up land covers, and 1.0 to 3.2 µg m-2 yr-1 to water surfaces. In the rural or remote environment in North America, annual Hg dry deposition to vegetated surfaces is dominated by leaf uptake of gaseous elemental mercury (GEM), contrary to what was commonly assumed in earlier studies which frequently omitted GEM dry deposition as an important process. Dry deposition exceeded wet deposition by a large margin in all of the seasons except in the summer at the majority of the sites. GEM dry deposition over vegetated surfaces will not decrease at the same pace, and sometimes may even increase with decreasing anthropogenic emissions, suggesting that Hg emission reductions should be a long-term policy sustained by global cooperation.

Bactericidal activity and mechanism of action of AZD5847, a novel oxazolidinone for treatment of tuberculosis.

Treatment of tuberculosis (TB) is impaired by the long duration and complexity of therapy and the rising incidence of drug resistance. There is an urgent need for new agents with improved efficacy, safety, and compatibility with combination chemotherapies. Oxazolidinones offer a potential new class of TB drugs, and linezolid-the only currently approved oxazolidinone-has proven highly effective against extensively drug-resistant (XDR) TB in experimental trials. However, widespread use of linezolid is prohibited by its significant toxicities. AZD5847, a novel oxazolidinone, demonstrates improved in vitro bactericidal activity against both extracellular and intracellular M. tuberculosis compared to that of linezolid. Killing kinetics in broth media and in macrophages indicate that the rate and extent of kill obtained with AZD5847 are superior to those obtained with linezolid. Moreover, the efficacy of AZD5847 was additive when tested along with a variety of conventional TB agents, indicating that AZD5847 may function well in combination therapies. AZD5847 appears to function similarly to linezolid through impairment of the mycobacterial 50S ribosomal subunit. Future studies should be undertaken to further characterize the pharmacodynamics and pharmacokinetics of AZD5847 in both in vitro and animal models as well is in human clinical trials.