Hypercapnia is not excluded by normoxia in neuromuscular disease patients: implications for oximetry.

Background: Pulse oximetry is widely used in the assessment of chronic respiratory failure in neuromuscular disease (NMD) patients. Chronic respiratory failure is the major cause of morbidity and mortality, necessitating early diagnosis and intervention. Guidelines suggest that an arterial blood gas (ABG) measurement is indicated if oxygen saturation (S pO2 ) is ≤94% in the absence of lung disease. However, hypercapnia with normoxia (S pO2 ≥95%) has been observed on ABGs of patients with NMD, in particular those with motor neurone disease. Methods: A single-centre retrospective audit of room-air ABGs in stable hypercapnic chronic respiratory failure patients from 1990 to 2020 was performed. Patients with parenchymal lung disease were excluded. Patients were grouped into three main categories: non-NMD, other NMD and motor neurone disease. Findings: 297 ABGs with hypercapnia from 180 patients with extrinsic restrictive lung disease were analysed. No patients with non-NMD, 54% of patients with other NMD and 36% of motor neurone disease patients demonstrated hypercapnia with normoxia (Chi-squared 61.33; p<0.001). The potential mechanism is proposed to be a difference in calculated respiratory quotient. If the alveolar-arterial gradient is assumed to be normal, the calculated respiratory quotient was significantly higher in motor neurone disease patients and other NMD patients compared with non-NMD patients (estimated marginal mean 0.99, 95% CI 0.94-1.03; 0.86 0.76-0.96; 0.73, 0.63-0.83, respectively; p<0.001) by mixed-model analysis. Interpretation: Hypercapnia is not excluded with normal oximetry in NMD patients and may be due to an elevated respiratory quotient. This has implications in the diagnosis and monitoring of respiratory insufficiency in NMD patients with oximetry alone.

A comparison of two obesity-related hypoventilation disorders: Impact on sleep, quality of life and neurocognitive outcomes and the effects of positive airway pressure therapy.

Study Objectives: Symptom impact and neurocognitive function have not been previously compared between patients with obesity-associated hypoventilation disorders (obesity hypoventilation syndrome [OHS]) and hypoventilation in the setting of obesity and obstructive airways disease (OHAD). The aim of this study is to compare baseline sleep-related symptoms, health-related quality of life, and neurocognitive function between OHS and OHAD and the impact of PAP therapy on these outcomes. Methods: Epworth Sleepiness Scale (ESS), Pittsburgh Sleepiness Quality Index (PSQI), SF36, and various neurocognitive tests, in addition to anthropometric, polysomnography, lung function, and blood gas data from participants with OHS and participants with OHAD, were included in the analysis. These data were originally collected in their respective randomized clinical trials, comparing the efficacy of different PAP modes (bilevel PAP vs. CPAP) in resolving hypercapnia. Between groups (OHS vs OHAD), pre- and post-treatment (with 3 months of positive airway pressure) comparisons were made using linear mixed modeling. Results: 45 OHS participants (mean age 51 years old, 33% female, BMI 52 kg/m2, FER 0.81, PaCO2 54 mmHg, AHI 87/h) and 32 OHAD participants (mean age 61years old, 31% female, BMI 43kg/m2, FER 0.60, PaCO2 54 mmHg, AHI 59/h) were included in the analysis. Both OHS and OHAD had similar baseline ESS (14(5.6) vs. 12(5.4)), Global PSQI (10(3.2) vs. 11(4.8)), SF36 and neurocognitive test performances (other than OHAD had lower digit symbol substitution test performance). Treatment with PAP therapy resulted in similar ESS, Global PSQI, and SF36 improvements in both groups. Neurocognitive performance did not significantly improve after PAP therapy in either group. Conclusions: The symptom impact between two separate hypoventilation disorders (OHS and OHAD), in terms of sleepiness, sleep quality, quality of life, and cognitive function, were similar. OHS and OHAD had similar treatment responses in these parameters after 3 months of PAP therapy.Nocturnal ventilatory support in OHS.

Ligand Regulation Strategy to Modulate ROS Nature in a Rhodamine-Iridium(III) Hybrid System for Phototherapy.

The efficacy of photodynamic therapy (PDT) is highly dependent on the photosensitizer features. The reactive oxygen species (ROS) generated by photosensitizers is proven to be associated with immunotherapy by triggering immunogenic cell death (ICD) as well. In this work, we establish a rhodamine-iridium(III) hybrid model functioning as a photosensitizer to comprehensively understand its performance and potential applications in photodynamic immunotherapy. Especially, the correlation between the ROS generation efficiency and the energy level of the Ir(III)-based excited state (T1'), modulated by the cyclometalating (C∧N) ligand, is systematically investigated and correlated. We prove that in addition to the direct population of the rhodamine triplet state (T1) formed through the intersystem crossing process with the assistance of a heavy Ir(III) metal center, the fine-tuned T1' state could act as a relay to provide an additional pathway for promoting the cascade energy transfer process that leads to enhanced ROS generation ability. Moreover, type I ROS can be effectively produced by introducing sulfur-containing thiophene units in C∧N ligands, providing a stronger M1 macrophage-activation efficiency under hypoxia to evoke in vivo antitumor immunity. Overall, our work provides a fundamental guideline for the molecular design and exploration of advanced transition-metal-based photosensitizers for biomedical applications.

Iridium(III) complexes decorated with silicane-modified rhodamine: near-infrared light-initiated photosensitizers for efficient deep-tissue penetration photodynamic therapy.

Meeting the demand for efficient photosensitizers in photodynamic therapy (PDT), a series of iridium(III) complexes decorated with silicane-modified rhodamine (Si-rhodamine) was meticulously designed and synthesized. These complexes demonstrate exceptional PDT potential owing to their strong absorption in the near-infrared (NIR) spectrum, particularly responsive to 808 nm laser stimulation. This feature is pivotal, enabling deep-penetration laser excitation and overcoming depth-related challenges in clinical PDT applications. The molecular structures of these complexes allow for reliable tuning of singlet oxygen generation with NIR excitation, through modification of the cyclometalating ligand. Notably, one of the complexes (4) exhibits a remarkable ROS quantum yield of 0.69. In vivo results underscore the efficacy of 4, showcasing significant tumor regression at depths of up to 8.4 mm. This study introduces a promising paradigm for designing photosensitizers capable of harnessing NIR light effectively for deep PDT applications.

Reproducibility and Accuracy of the PRIMARY Score on PSMA PET and of PI-RADS on Multiparametric MRI for Prostate Cancer Diagnosis Within a Real-World Database.

The PRIMARY score is a 5-category scale developed to identify clinically significant intraprostate malignancy (csPCa) on 68Ga-prostate-specific membrane antigen (PSMA)-11 PET/CT (68Ga-PSMA PET) using a combination of anatomic site, pattern, and intensity. Developed within the PRIMARY trial, the score requires evaluation in external datasets. This study aimed to assess the reproducibility and diagnostic accuracy of the PRIMARY score in a cohort of patients who underwent multiparametric MRI (mpMRI) and 68Ga-PSMA PET before prostate biopsy for the diagnosis of prostate cancer. Methods: In total, data from 242 men who had undergone 68Ga-PSMA PET and mpMRI before transperineal prostate biopsy were available for this ethics-approved retrospective study. 68Ga-PSMA PET and mpMRI data were centrally collated in a cloud-based deidentified image database. Six experienced prostate-focused nuclear medicine specialists were trained (1 h) in applying the PRIMARY score with 30 sample images. Six radiologists experienced in prostate mpMRI read images as per the Prostate Imaging-Reporting and Data System (PI-RADS), version 2.1. All images were read (with masking of clinical information) at least twice, with discordant findings sent to a masked third (or fourth) reader as necessary. Cohen κ was determined for both imaging scales as 5 categories and then collapsed to binary (negative and positive) categories (score 1 or 2 vs. 3, 4, or 5). Diagnostic performance parameters were calculated, with an International Society of Urological Pathology grade group of at least 2 (csPCa) on biopsy defined as the gold standard. Combined-imaging-positive results were defined as any PI-RADS score of 4 or 5 or as a PI-RADS score of 1-3 with a PRIMARY score of 3-5. Results: In total, 227 patients with histopathology, 68Ga-PSMA PET, and mpMRI imaging before prostate biopsy were included; 33% had no csPCa, and 67% had csPCa. Overall interrater reliability was higher for the PRIMARY scale (κ = 0.70) than for PI-RADS (κ = 0.58) when assessed as a binary category (benign vs. malignant). This was similar for all 5 categories (κ = 0.65 vs. 0.48). Diagnostic performance to detect csPCa was comparable between PSMA PET and mpMRI (sensitivity, 86% vs. 89%; specificity, 76% vs. 74%; positive predictive value, 88% vs. 88%; negative predictive value, 72% vs. 76%). Using combined imaging, sensitivity was 94%, specificity was 68%, positive predictive value was 86%, and negative predictive value was 85%. Conclusion: The PRIMARY score applied by first-user nuclear medicine specialists showed substantial interrater reproducibility, exceeding that of PI-RADS applied by mpMRI-experienced radiologists. Diagnostic performance was similar between the 2 modalities. The PRIMARY score should be considered when interpreting intraprostatic PSMA PET images.

Low-k SiOx/AlOx Nanolaminate Dielectric on Dielectric Achieved by Hybrid Pulsed Chemical Vapor Deposition.

Selective and smooth low-k SiOx/AlOx nanolaminate dielectric on dielectric (DOD) was achieved by a hybrid water-free pulsed CVD process consisting of 50 pulses of ATSB (tris(2-butoxy)aluminum) at 330 °C and a 60 s TBS (tris(tert-butoxy)silanol) exposure at 200 °C. Aniline selective passivation was demonstrated on W surfaces in preference to Si3N4 and SiO2 at 300 °C. At 200 °C, TBS pulsed CVD exhibited no growth on W or SiO2, but its growth was catalyzed by AlOx. Using a two-temperature pulsed CVD process, ∼2.7 nm selective SiOx/AlOx nanolaminate was deposited on Si3N4 in preference to aniline passivated W. Nanoselectivity was confirmed and demonstrated on nanoscale W/SiO2 patterned samples by TEM analysis. For a 1:1 Si:Al ratio, a dielectric constant (k) value of 3.3 was measured. For a 2:1 Si:Al ratio, a dielectric constant (k) value of 2.5 was measured. The k value well below that of Al2O3 and SiO2 is consistent with the formation of a low-density, low-k SiO2/Al2O3 nanolaminate in a purely thermal process. This is the first report of a further thermal CVD process for deposition of a low-k dielectric and the first report for a selective low-k process on the nanoscale.

Impact of cystic fibrosis multidisciplinary virtual clinics on patient experience, time commitments and costs.

BACKGROUND AND AIMS: The experience of outpatient care may differ for select patient groups. This prospective study evaluates the adult patient experience of multidisciplinary outpatient cystic fibrosis (CF) care with videoconferencing through telehealth compared with face-to-face care the year prior. METHODS: People with CF without a lung transplant were recruited. Patient-reported outcomes were obtained at commencement and 12 months into the study, reflecting both their face-to-face and telehealth through videoconferencing experience, respectively. Three patient cohorts were analysed: (i) participants with a regional residence, (ii) participants with a nonregional including metropolitan residence and (iii) participants with colonised multiresistant microbiota. RESULTS: Seventy-four patients were enrolled in the study (mean age, 37 ± 11 years; 50% male; mean forced expiratory volume in the first second of expiration, 60% [standard deviation, 23]) between February 2020 and May 2021. No differences between models were observed in the participants' rating of the health care team, general and mental health rating, and their confidence in handling treatment plans at home. No between-group differences in the Cystic Fibrosis Questionnaire - Revised (CFQ-R) were observed. Travel duration and the cost of attending a clinic was significantly reduced, particularly for the regional group (4 h, AU$108 per clinic; P < 0.05). A total of 93% respondents preferred to continue with a hybrid approach. CONCLUSION: In this pilot study, participants' experience of care and quality of life were no different with face-to-face and virtual care between the groups. Time and cost-savings, particularly for patients living in regional areas, were observed. Most participants preferred to continue with a hybrid model for outpatient care.

Region-specific changes in brain activity and memory after continuous positive airway pressure therapy in obstructive sleep apnea: a pilot high-density electroencephalography study.

STUDY OBJECTIVES: Limited channel electroencephalography (EEG) investigations in obstructive sleep apnea (OSA) have revealed deficits in slow wave activity (SWA) and spindles during sleep and increased EEG slowing during resting wakefulness. High-density EEG (Hd-EEG) has also detected local parietal deficits in SWA (delta power) during NREM. It is unclear whether effective continuous positive airway pressure (CPAP) treatment reverses regional SWA deficits, and other regional sleep and wake EEG abnormalities, and whether any recovery relates to improved overnight memory consolidation. METHODS: A clinical sample of men with moderate-severe OSA underwent sleep and resting wake recordings with 256-channel Hd-EEG before and after 3 months of CPAP. Declarative and procedural memory tasks were administered pre- and post-sleep. Topographical spectral power maps and differences between baseline and treatment were compared using t-tests and statistical nonparametric mapping (SnPM). RESULTS: In 11 compliant CPAP users (5.2 ±â€…1.1 hours/night), total sleep time did not differ after CPAP but N1 and N2 sleep were lower and N3 was higher. Centro-parietal gamma power during N3 increased and fronto-central slow spindle activity during N2 decreased (SnPM < 0.05). No other significant differences in EEG power were observed. When averaged specifically within the parietal region, N3 delta power increased after CPAP (p = 0.0029) and was correlated with the change in overnight procedural memory consolidation (rho = 0.79, p = 0.03). During resting wakefulness, there were trends for reduced delta and theta power. CONCLUSIONS: Effective CPAP treatment of OSA may correct regional EEG abnormalities, and regional recovery of SWA may relate to procedural memory improvements in the short term.

Multifunctional bisalkynylplatinum(II) bipyridine complexes with rhodamine-like ligands featuring near-infrared phosphorescence and delayed fluorescence.

A series of platinum(II) bipyridine complexes with two rhodamine-like alkynyl (Rhodyne) ligands were developed to show chemo-induced "ON-OFF" switching capabilities with exceptional near-infrared phosphorescence and delayed fluorescence. This study contributes to the design of versatile photosensitizers with multiple functionalities, including metal ion and biomolecule sensing, photodynamic therapy, and optoelectronics.

Embedding digital sleep health into primary care practice: A triangulation of perspectives from general practitioners, nurses, and pharmacists.

Introduction: While digital health interventions (DHIs) can potentially address the unmet needs for sleep health services, little is known about their implementation in practice. The current study aimed to explore primary care health providers' attitudes and beliefs towards DHIs for sleep and implementation into practice. Methods: A cross-sectional online survey was administered to Australian primary care health professionals: general practitioners (GPs), community nurses, and community pharmacists. Semi-structured interviews were conducted within a sub-sample of participants exploring their experiences with DHIs and perceived barriers/facilitators for embedding DHIs into primary care. Semi-structured interviews were thematically analysed using the framework approach to contextualise survey findings. Results: Ninety-six surveys were returned (GPs = 36, nurses = 30, and pharmacists = 30) and 45 interviews conducted (GPs = 17, nurses = 14, and pharmacists = 14). From the survey, GPs were more likely to endorse familiarity (p = 0.009) and use (p < 0.001) of sleep DHIs in clinical practice than pharmacists and nurses. GPs were more interested in utilising the diagnostic features within a sleep DHI (p = 0.009) compared to other professionals. Thematic analysis of the interviews revealed three major themes, contextualised by profession: (1) Scope for DHIs in Current Practice, (2) Practice Gaps and Training Needs, and (3) Envisioning a Model of Care Using Sleep DHIs. While DHIs can potentially improve care, greater clarity of care pathways and reimbursement structures are needed for integration into practice. Conclusion: Primary care health professionals highlighted the training, care pathway and financial models required to realise the potential for translating findings from efficacy studies for DHIs into primary care to optimise sleep health.

Dielectric-on-Dielectric Achieved on SiO2 in Preference to W by Water-free Chemical Vapor Depositions with Aniline Passivation.

Selective and smooth dielectric-on-dielectric was achieved by water-free single-precursor chemical vapor deposition (CVD) processes with the help of aniline passivation. Aniline selective passivation was demonstrated on W surfaces in preference to SiO2 at 250, 300, and 330 °C. After aniline passivation, selective HfO2, Al2O3, and TiO2 were deposited only on the HF-cleaned SiO2 surface by water-free single-precursor CVD using hafnium tert-butoxide Hf(OtBu)4, aluminum-tri-sec-butoxide (ATSB), and titanium isopropoxide Ti(OiPr)4 as the precursor reactants, respectively. Hf(OtBu)4 and Ti(OiPr)4 single-precursor CVD was carried out at 300 °C, while the ATSB CVD process was conducted at 330 °C. HfO2 and Al2O3 nanoselectivity tests were performed on W/SiO2 patterned samples. Transmission electron microscopy images of the W/SiO2 patterned samples after deposition demonstrated nanoselectivity and low surface roughness of HfO2 and Al2O3 deposition on the SiO2 regions only.

Megakaryocytes respond during sepsis and display innate immune cell behaviors.

Megakaryocytes (MKs) are precursors to platelets, the second most abundant cells in the peripheral circulation. However, while platelets are known to participate in immune responses and play significant functions during infections, the role of MKs within the immune system remains largely unexplored. Histological studies of sepsis patients identified increased nucleated CD61+ cells (MKs) in the lungs, and CD61+ staining (likely platelets within microthrombi) in the kidneys, which correlated with the development of organ dysfunction. Detailed imaging cytometry of peripheral blood from patients with sepsis found significantly higher MK counts, which we predict would likely be misclassified by automated hematology analyzers as leukocytes. Utilizing in vitro techniques, we show that both stem cell derived MKs (SC MKs) and cells from the human megakaryoblastic leukemia cell line, Meg-01, undergo chemotaxis, interact with bacteria, and are capable of releasing chromatin webs in response to various pathogenic stimuli. Together, our observations suggest that MK cells display some basic innate immune cell behaviors and may actively respond and play functional roles in the pathophysiology of sepsis.

Potent ClpP agonists with anticancer properties bind with improved structural complementarity and alter the mitochondrial N-terminome.

The mitochondrial ClpP protease is responsible for mitochondrial protein quality control through specific degradation of proteins involved in several metabolic processes. ClpP overexpression is also required in many cancer cells to eliminate reactive oxygen species (ROS)-damaged proteins and to sustain oncogenesis. Targeting ClpP to dysregulate its function using small-molecule agonists is a recent strategy in cancer therapy. Here, we synthesized imipridone-derived compounds and related chemicals, which we characterized using biochemical, biophysical, and cellular studies. Using X-ray crystallography, we found that these compounds have enhanced binding affinities due to their greater shape and charge complementarity with the surface hydrophobic pockets of ClpP. N-terminome profiling of cancer cells upon treatment with one of these compounds revealed the global proteomic changes that arise and identified the structural motifs preferred for protein cleavage by compound-activated ClpP. Together, our studies provide the structural and molecular basis by which dysregulated ClpP affects cancer cell viability and proliferation.

Armodafinil to reduce the sleepiness related side-effects of sleep restriction therapy being used to treat insomnia disorder: An open label clinical trial pilot study compared with historical controls.

Sleep restriction therapy (SRT) is an effective stand-alone behavioural intervention for insomnia disorder. However, its daytime side effects, particularly sleepiness, may be troubling for patients and/or may be a necessary part of the patient's treatment journey. This pilot trial aims to explore the potential benefit of armodafinil, a wakefulness promoter. Patients were treated with SRT with open label adjunctive armodafinil (150 mg/day). Thirty-three patients from previous studies that have undergone exactly the same SRT intervention acted as controls. The primary outcome measure was the insomnia severity index (ISI), and secondary outcomes were the Epworth sleepiness scale, sleep restriction adherence scale (SRAS), and safety from baseline through to 12 weeks. We recruited 25 patients into the trial. Data for the primary end point (ISI at 12 weeks) was available for 20 of the participants. The baseline insomnia severity index was 20.2 (SD 3.3) and decreased to 9.1 (SE 1.1), with no change, to 10.2 and 11.2 at weeks 6 and 12 respectively (all p > 0.05 compared with baseline). The insomnia severity index values for armodafinil patients were statistically inferior to historical controls at the primary time point of 12 weeks (11.2 vs. 6.7, p < 0.01). Sleep restriction therapy plus armodafinil treatment was associated with frequent minor side effects but was generally safe and acceptable to patients. Sleep restriction therapy was associated with a robust clinical response in the insomnia severity index values for insomnia patients. Based upon historical control data, armodafinil does not appear to have beneficial adjunctive effects in addition to sleep restriction therapy alone.

Retrospective cohort study of hypersomnias of central origin from two Australian tertiary sleep disorders services.

BACKGROUND: Hypersomnias of central origin (HOCO) are diverse in origin and symptomatology and remain poorly described in an Australian population. We hypothesised that the rate of human leukocyte antigen (HLA) DQB1*0602 positivity in the Australian cohort would be comparable to international registries. AIMS: The current study aims to evaluate epidemiological and clinical characteristics of Australian patients with HOCO, including prevalence of HLA DQB1*0602 positivity, the most specific HLA marker associated with narcolepsy. METHODS: This is a retrospective study. Patients ≥ 16 years of age presenting with symptoms of hypersomnolence who attended one of two Australian sleep centres (New South Wales and Queensland) in the preceding 24 months and had undergone both HLA serology and multiple sleep latency tests (MSLTs) were included. Main outcome measures included demographics, HLA DQB1*0602 positivity, MSLT, and clinical parameters (presence of auxiliary narcolepsy symptoms, laboratory tests, relevant prescribed medications). RESULTS: Eighty-eight patients were included. HLA DQB1*0602 positivity was highest in those with type 1 narcolepsy (NT1) (95.7%) and lowest in those without a classifiable disorder (9.1%). Mean sleep latency was lowest and number of sleep-onset rapid eye movement periods (SOREMPs) highest in the NT1 group. Comorbid disorders, particularly depression and overweight/obesity, were prevalent in all cohorts. Across all diagnostic groups, dexamphetamine was the most commonly prescribed agent for excessive daytime sleepiness. CONCLUSIONS: Patients with HOCO assessed in two specialised Australian clinics demonstrate comparable clinical characteristics to other published cohorts internationally; however, available pharmacological agents in Australia do not reflect international standards of care.

64Cu-SAR-Bombesin PET-CT Imaging in the Staging of Estrogen/Progesterone Receptor Positive, HER2 Negative Metastatic Breast Cancer Patients: Safety, Dosimetry and Feasibility in a Phase I Trial.

Breast cancers are most frequently oestrogen receptor (ER) and progesterone receptor (PR) positive and [18F]Fluorodeoxyglucose PET-CT (FDG) has lower sensitivity for these subtypes. The gastrin-releasing peptide receptor (GRPR) is overexpressed in ER+/PR+ breast cancers. This study assessed the safety and potential of [64Cu]Cu-Sarcophagine (SAR)-Bombesin PET/CT (BBN) in re-staging metastatic ER+/PR+/human epidermal growth-factor-2-negative (HER2-) breast cancer. Seven patients with metastatic ER+/PR+/HER2- breast cancer undergoing staging underwent [64Cu]Cu-SAR-BBN PET-CT. Bloods, vital signs and electrocardiogram, blood tracer-clearance and dosimetry were undertaken. GRPR status was assessed in available metastatic biopsy samples. Staging with conventional imaging ([18F]FDG, bone scan and diagnostic CT) was within 3 weeks of [64Cu]Cu-SAR-BBN PET/CT. PET scans were assessed visually and quantitatively. Seven patients underwent imaging. One of the seven had de-novo metastatic breast cancer and six of the seven recurrent metastatic disease. Two of the seven had lobular subtype. No adverse events were reported. All seven patients were positive on conventional imaging (six of seven on FDG). [64Cu]Cu-SAR-BBN imaging was positive in five of the seven. Both [64Cu]Cu-SAR-BBN-negative patients had disease identified on [18F]FDG. One patient was [64Cu]Cu-SAR-BBN positive/[18F]FDG negative. Four of seven patients were [64Cu]Cu-SAR-BBN positive/[18F]FDG positive. In these four, mean SUVmax was higher for [64Cu]Cu-SAR-BBN than [18F]FDG (SUVmax 15 vs. 12). In the classical lobular subtype (two of seven), [64Cu]Cu-SAR-BBN was more avid compared to [18F]FDG (SUVmax 20 vs. 11, and 20 vs. <3). Dosimetry calculations estimated whole-body effective dose for 200 MBq of [64Cu]Cu-SAR-BBN to be 1.9 mSv. [64Cu]Cu-SAR-BBN PET/CT appears safe and may have diagnostic value in metastatic ER+/PR+/HER2- breast cancer, particularly the lobular subtype. Further evaluation is warranted.

Analysis of the Evolution of the MoxR ATPases.

MoxR proteins comprise a family of ATPases Associated with diverse cellular Activities (AAA+). These proteins are widespread and found across the diversity of prokaryotic species. Despite their ubiquity, members of the group remain poorly characterized. Only a few examples of MoxR proteins have been associated with cellular roles, where they have been shown to perform chaperone-like functions. A characteristic feature of MoxR proteins is their association with proteins containing the von Willebrand factor type A (VWA) domain. In an effort to understand the spread and diversity of the MoxR family, an evolutionary approach was undertaken. Phylogenetic techniques were used to define nine major subfamilies within the MoxR family. A combination of phylogenetic and genomic approaches was utilized to explore the extent of the partnership between the MoxR and VWA domain containing proteins (VWA proteins). These analyses led to the clarification of genetic linkages between MoxR and VWA proteins. A significant partnership is described here, as seven of nine MoxR subfamilies were found to be linked to VWA proteins. Available genomic data were also used to assess the intraprotein diversification of MoxR and VWA protein sequences. Data clearly indicated that, in MoxR proteins, the ATPase domain is maintained with high conservation while the remaining protein sequence evolves at a faster rate; a similar pattern was observed for the VWA domain in VWA proteins. Overall, our data present insights into the modular evolution of MoxR ATPases.

Daily Inhaled Corticosteroids Treatment Abolishes Airway Hyperresponsiveness to Mannitol in Defence and Police Recruits.

Background: Airway hyperresponsiveness (AHR) is a key pathophysiological feature of asthma and causes exercise-induced bronchoconstriction (EIB). Indirect bronchial provocation tests (BPTs) (e.g., exercise, mannitol) aid to diagnose asthma and identify EIB. Daily inhaled corticosteroids (ICS) can abolish AHR caused by indirect stimuli. Where strenuous physical exertion is integral to an occupation, identification of those at risk of EIB is important and documentation of inhibition of AHR with ICS is required before recruitment. Methods/Objectives: A retrospective analysis was performed on 155 potential recruits with AHR to mannitol who underwent follow-up assessment after daily ICS treatment to determine the proportion that can abolish AHR using ICS and to determine any predictors of the persistence of AHR. Results: Airway hyperresponsiveness was abolished in the majority (84%, n = 130) over the treatment period (mean ± SD 143 ± 72days), and it was defined as the provoking dose of mannitol to cause a 15% fall in FEV1 (cumulative inhaled dose of mannitol to cause 15% fall in FEV1, PD15) improved from (GeoMean) 183 to 521 mg. Compared with recruits in whom AHR was abolished with daily ICS (i.e., no 15% fall in FEV1 to the maximum cumulative dose of mannitol of 635 mg), in those where AHR remained (16%, n = 25), baseline AHR was more severe (PD15: 85 mg vs. 213 mg, P < 0.001), baseline FEV1% was lower (89 vs. 96%; 95%CI:2-12, P=0.004), and they had a longer follow-up duration (180 vs. 136 days; 13-74, P = 0.006). Baseline FEV1% (adjusted odds ratio 0.85; 95%CI:0.77-0.93), FEV1/FVC (0.78; 0.67-0.90), FEF25-75% (1.15; 1.06-1.25), and airway reactivity to mannitol (%Fall/cumulative dose of mannitol multiplied by 100) (1.07; 1.03-1.11) predicted AHR remaining after daily ICS. Conclusion: Airway hyperresponsiveness to mannitol can be abolished after 20 weeks of daily treatment with ICS. Inhibition of AHR is likely due to attenuation of airway inflammation in response to ICS treatment. Increased airway reactivity and lower spirometry variables predicted the persistence of AHR. Thus, those with a slower response to daily ICS on AHR can potentially be identified at the commencement of monitoring ICS using inhaled mannitol.