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Background The impact of lumacaftor/ivacaftor on exercise tolerance in people with cystic fibrosis (CF) has not been thoroughly studied. Methods We conducted a multisite Phase 4 trial comparing the impact of lumacaftor/ivacaftor on exercise tolerance with that of placebo in participants ≥ 12 years of age with CF homozygous for F508del-CFTR. The primary endpoint was relative change from baseline in maximum oxygen consumption (VO2max) during cardiopulmonary exercise testing (CPET) at Week 24. The key secondary endpoint was relative change from baseline in exercise duration during CPET at Week 24. Other secondary endpoints included changes in other indices of exercise tolerance and changes in CF assessments; safety and tolerability were assessed as an endpoint. Results Seventy participants were randomized to receive lumacaftor/ivacaftor (n = 34) or placebo (n = 36). The least-squares mean difference for lumacaftor/ivacaftor versus placebo in relative change in VO2max from baseline at Week 24 was −3.2% (95% CI: −9.2, 2.9; P=0.3021); the least-squares mean difference in relative change from baseline in exercise duration at Week 24 was −3.2% (95% CI: −8.0, 1.6). Safety results were consistent with the known lumacaftor/ivacaftor safety profile. Conclusions Definitive conclusions regarding the impact of lumacaftor/ivacaftor on exercise tolerance cannot be drawn from these results; however, multicenter studies using CPETs can be reliably performed with multiple time points and conventional methods, provided that calibration can be achieved. Future studies of exercise tolerance may benefit from lessons learned from this study. NCT02875366.

Nontuberculous mycobacteria (NTM) comprise a heterogeneous group of organisms, with only a small subset known to cause disease in humans. Although NTM infection is not a reportable disease, both the increasing clinical recognition and recent advancements in laboratory diagnostic capabilities of NTM infections in immunocompromised and immunocompetent patients are rapidly evolving. We reviewed antimicrobial agents used to treat the most frequently encountered NTM infections and examined optimized drug dosing strategies, toxicity profiles, drug-drug interactions, and the role of therapeutic drug monitoring. Antimicrobial susceptibility testing and patient monitoring on therapy were also examined. We used PubMed to review the published literature on the management of select NTM pathogens, the common syndromes encountered since 2000, and select pharmacokinetic principles of select antimicrobial agents used since 1990. We included select clinical trials, systematic reviews, published guidelines, and observational studies when applicable. The prolonged duration and the necessity for combination therapy for most forms of NTM disease can be problematic for many patients. A multidisciplinary care team that includes pharmacy engagement may help increase rates of optimal patient tolerability and successful treatment completion.

Objectives To determine in women with clinically stable chronic lung disease (CLD) and healthy women; (1) prevalence of urinary incontinence; (2) risk factors for urinary incontinence; (3) effects of a standard course of specialised physiotherapy treatment (PT) in women with CLD. Design Prospective prevalence study; PT study in CLD subgroup. Setting Tertiary metropolitan public hospital. Participants Women with cystic fibrosis (CF, n = 38), chronic obstructive pulmonary disease (COPD, n = 27) and 69 healthy women without CLD. PT study — 10 women with CLD. Interventions Five continence PT sessions over 3 months. Main outcome measures Prevalence and impact of incontinence (questionnaire), number of leakage episodes (7-day accident diary), pelvic floor muscle function (ultrasound imaging) and quality of life (King’s Health Questionnaire). Results The majority of women in all three groups reported episodes of incontinence (CF 71%; COPD 70%; healthy women 55%). Compared to age-matched healthy controls, women with CF reported more episodes of incontinence (P = 0.006) and more commonly reported stress incontinence (P = 0.001). A logistic regression model revealed that women with CLD were twice as likely to develop incontinence than healthy women (P = 0.05). Women with COPD reported significantly more ‘bother’ with incontinence than age-matched women with incontinence. There was a significant reduction in incontinence episodes following treatment, which was maintained after three months. Conclusions The presence of CLD is an independent predictor of incontinence in women. In older women this is associated with more distress than in age-matched peers without CLD. Larger treatment studies are indicated for women with CLD and incontinence.

Cardiovascular device infection due to rapidly growing mycobacteria (RGM) is rarely encountered in clinical practice. Due to the increasing number of indications and use of cardiovascular devices in an aging population, optimized management of these infections is of great importance. We report seven cases of RGM cardiovascular device infection. Three patients had left-ventricular assist device (LVAD) infections; two patients had cardiovascular implantable device (CIED) infections; and one had an aortic vascular stent infection. Specific cardiac valvular infection was not detected among any of the patients. All patients had a high number of comorbidities which limited some patients from receiving optimal combination antimicrobial therapy. The prognosis of cardiovascular device infections with RGM is guarded with only four patients still alive; however, the treatment approach for each patient varied considerably and often based on concurrent medical conditions, overall adjustments to goals of care, and specific patient preferences. Further analysis of cardiovascular device infections with RGM is warranted to establish a more systematic approach in successful management.

Background G551D is a class III mutation of the cystic fibrosis transmembrane regulator (CFTR) that results in impaired chloride channel function in cystic fibrosis (CF). Ivacaftor, a CFTR-potentiating agent improves sweat chloride, weight, lung function, and pulmonary exacerbation rate in CF patients with G551D mutations, but its effect on the airway microbiome remains poorly characterised. Methods Twenty CF patients with at least one G551D mutation from a single centre were recruited to a 4month double-blind, placebo-controlled, crossover study of ivacaftor with 28days of active treatment. Sputum microbiota composition was assessed by 16S rRNA gene amplicon sequencing and quantitative PCR at five key time points, along with regular clinical review, respiratory function assessment, and peripheral blood testing. Results No significant difference in microbiota composition was observed in subjects following ivacaftor treatment or placebo (PERMANOVA P = 0.95, square root ECV=−4.94, 9479 permutations). Microbiota composition variance was significantly greater between subjects, than within subjects over time ( P U test), and an additional within-patient paired assessment of microbiota similarity was therefore performed. Again, change in microbiota composition was not significantly greater during treatment with ivacaftor compared to placebo (Wilcoxon test, P =0.51). A significant change in microbiota composition was however associated with any change in antibiotic exposure, regardless of whether ivacaftor or placebo was administered ( P =0.006). In a small, subgroup analysis of subjects whose antibiotic exposure did not change within the study period, a significant reduction in total bacterial load was observed during treatment with ivacaftor ( P =0.004, two-tailed paired Student's t- test). Conclusions The short-term impact of ivacaftor therapy on sputum microbiota composition in patients with G551D mutations are modest compared to those resulting from antibiotic exposure, and may be masked by changes in antibiotic treatment regimen.

ORKAMBI (ivacaftor-lumacaftor [LUMA]) and KALYDECO (ivacaftor; IVA) are two new breakthrough cystic fibrosis (CF) drugs that directly modulate the activity and trafficking of the defective CFTR underlying the CF disease state. Currently, no therapeutic drug monitoring assays exist for these very expensive, albeit, important drugs. In this study, for the first time HPLC and LC-MS methods were developed and validated for rapid detection and quantification of IVA and its major metabolites hydroxymethyl-IVA M1 (active) and IVA-carboxylate M6 (inactive); and LUMA in the plasma and sputum of CF patients. With a mobile phase consisting of acetonitrile/water:0.1% formic acid (60:40 v/v) at a flow rate of 1 mL/min, a linear correlation was observed over a concentration range from 0.01 to 10 μg/mL in human plasma (IVA R2>0.999, IVA M1 R2> 0.9961, IVA M6 R2>0.9898, LUMA R2>0.9954). The assay was successfully utilized to quantify the concentration of LUMA, IVA, M1 and M6 in the plasma and sputum of CF patients undergoing therapy with KALYDECO (IVA 150 mg/q12 h) or ORKAMBI (200 mg/q12 h LUMA-125 mg/q12 h IVA). The KALYDECO patient exhibited an IVA plasma concentration of 0.97 μg/mL at 2.5 h post dosage. M1 and M6 plasma concentrations were 0.50 μg/mL and 0.16 μg/mL, respectively. Surprisingly, the ORKAMBI patient displayed very low plasma concentrations of IVA (0.06 μg/mL) and M1 (0.07 μg/mL). The M6 concentrations (0.15 μg/mL) were comparable to those of the KALYDECO patient. However, we observed a relatively high plasma concentration of LUMA (4.42 μg/mL). This reliable and novel method offers a simple and sensitive approach for therapeutic drug monitoring of KALYDECO and ORKAMBI in plasma and sputum. The introduction of the assay into the clinical setting will facilitate pharmacokinetics/pharmacodynamic analysis and assist clinicians to develop more cost effective and efficacious dosage regimens for these breakthrough CF drugs.

Ecologists and conservation biologists conducting long-term research programs in the tropics must confront serious ethical challenges that revolve around economic inequalities, cultural differences, supporting the local communities as much as possible, and sharing the knowledge produced by the research. In this collective article, researchers share their experiences and perspectives in dealing with the ethical issues that arise during research activities and cannot be ignored.

Background: Tublosis (TB) and the approaches to successful management are commonly misunderstood health topics among patients and family members within resource-limited settings. Such public misconceptions often result in delayed diagnoses of afflicted patients, suboptimal compliance with prescribed therapies and a negative community social stigma that hinders effective contact investigations. Objective: To determine through an observational field pilot study if videography-based TB education program can be implemented in busy resource-limited outpatient TB clinic settings and improve both patient and family understanding of TB and its treatment, as well as, improve the efficiency of TB medical evaluations and corresponding contact investigations. Methods: We produced and implemented a videography-based health educational pilot strategy in 14 TB clinics within El Salvador to supplement the discussions between health providers, patients and families. Field observations and impressions after the first year of implementation were recorded. Results: After viewing the video, patient impressions revealed greater understanding of TB including how it's transmitted and successfully treated, as well as, a more optimistic outlook of the diagnosis. Family members viewing the video displayed less fear and greater interest in TB and also exhibited more support for relatives undergoing evaluation or treatment. Salvadorian TB health providers reported improvements in patient compliance with treatment, contact investigations of suspected patients, delivery of sputum samples for testing, clinic time-efficiency spent with patients, and an observed reduction of negative family stigma of TB. Conclusions: Our findings suggest that videography-based TB education can be successfully implemented in busy and resource-limited outpatient settings, and can provide a potentially efficient and low-cost effective strategy towards optimizing patient understanding, acceptance and compliance with TB treatment recommendations. This feasibility pilot study provides an opportunity within underresourced clinics for further evaluation regarding the favorable educational and sustainable impact of videography-based health education. Keywords: Tuberculosis, Videography, Education, El Salvador, Communication

A computationally efficient 3DHZETRN code with enhanced neutron and light ion (Z ≤ 2) propagation was recently developed for complex, inhomogeneous shield geometry described by combinatorial objects. Comparisons were made between 3DHZETRN results and Monte Carlo (MC) simulations at locations within the combinatorial geometry, and it was shown that 3DHZETRN agrees with the MC codes to the extent they agree with each other. In the present report, the 3DHZETRN code is extended to enable analysis in ray-trace geometry. This latest extension enables the code to be used within current engineering design practices utilizing fully detailed vehicle and habitat geometries. Through convergence testing, it is shown that fidelity in an actual shield geometry can be maintained in the discrete ray-trace description by systematically increasing the number of discrete rays used. It is also shown that this fidelity is carried into transport procedures and resulting exposure quantities without sacrificing computational efficiency.

Extensively drug-resistant (XDR) tuberculosis (TB) is an unfortunate by-product of mankind's medical and pharmaceutical ingenuity during the past 60 years. Although new drug developments have enabled TB to be more readily curable, inappropriate TB management has led to the emergence of drug-resistant disease. Extensively drug-resistant TB describes Mycobacterium tuberculosis that is collectively resistant to isoniazid, rifampin, a fluoroquinolone, and an injectable agent. It proliferates when established case management and infection control procedures are not followed. Optimized treatment outcomes necessitate time-sensitive diagnoses, along with expanded combinations and prolonged durations of antimicrobial drug therapy. The challenges to public health institutions are immense and most noteworthy in underresourced communities and in patients coinfected with human immunodeficiency virus. A comprehensive and multidisciplinary case management approach is required to optimize outcomes. We review the principles of TB drug resistance and the risk factors, diagnosis, and managerial approaches for extensively drug-resistant TB. Treatment outcomes, cost, and unresolved medical issues are also discussed.

Supportive care guidelines recommend antimold prophylaxis in hematopoietic stem cell transplant (HSCT) recipients deemed to have high risk for invasive fungal infection, leading to long-term use of voriconazole after allogeneic HSCT in patients who remain immunocompromised. Voriconazole has been associated with periostitis, exostoses, and fluoride excess in patients after solid organ transplantation, HSCT, and leukemia therapy. The aims of this study were to describe the frequency and clinical presentation of patients presenting with pain and fluoride excess among allogeneic HSCT patients taking voriconazole, to identify when a plasma fluoride concentration was measured with respect to voriconazole initiation and onset of pain, and to describe the outcomes of patients with fluoride excess in the setting of HSCT. A retrospective review was conducted of all adult allogeneic HSCT patients receiving voriconazole at Mayo Clinic in Rochester, Minnesota, between January 1, 2009 and July 31, 2012. Of 242 patients included, 32 had plasma fluoride measured to explore the etiology of musculoskeletal pain. In 31 patients with fluoride measurement while on voriconazole, 29 (93.5%) had elevated levels. The median plasma fluoride was 11.1 μmol/L (range, 2.4 to 24.7). The median duration of voriconazole was 163 days (range, 2 to 1327). The median time to fluoride measurement was 128 days after voriconazole initiation (range, 28 to 692). At 1 year after the start of voriconazole after HSCT, 15.3% of patients had developed pain associated with voriconazole use and 35.7% developed pain while on voriconazole after 2 years. Of the patients with an elevated fluoride level, 22 discontinued voriconazole; pain resolved or improved in 15, stabilized in 3, and worsened in 4 patients. Ten patients continued voriconazole; pain resolved or improved in 7, was attributable to alternative causes in 2, and undefined in 1. Serum creatinine, estimated glomerular filtration rate, alkaline phosphatase, and voriconazole concentration did not predict for fluoride excess and associated pain. Periostitis due to fluoride excess is a common adverse effect of voriconazole that should be considered in patients presenting with pain and is often reversible after drug discontinuation. Alternative antifungal agents with a lower risk for fluoride excess should be considered in patients receiving voriconazole who develop fluoride excess and pain.

The 3DHZETRN formalism was recently developed as an extension to HZETRN with an emphasis on 3D corrections for neutrons and light ions. Comparisons to Monte Carlo (MC) simulations were used to verify the 3DHZETRN methodology in slab and spherical geometry, and it was shown that 3DHZETRN agrees with MC codes to the degree that various MC codes agree among themselves. One limitation of such comparisons is that all of the codes (3DHZETRN and three MC codes) utilize different nuclear models/databases; additionally, using a common nuclear model is impractical due to the complexity of the software. It is therefore difficult to ascertain if observed discrepancies are caused by transport code approximations or nuclear model differences. In particular, an important simplification in the 3DHZETRN formalism assumes that neutron production cross sections can be represented as the sum of forward and isotropic components, where the forward component is subsequently solved within the straight-ahead approximation. In the present report, previous transport model results in specific geometries are combined with additional results in related geometries to study neutron leakage using the Webber 1956 solar particle event as a source boundary condition. A ratio is defined to quantify the fractional neutron leakage at a point in a finite object relative to a semi-infinite slab geometry. Using the leakage ratio removes some of the dependence on the magnitude of the neutron production and clarifies the effects of angular scattering and absorption with regard to differences between the models. Discussion is given regarding observed differences between the MC codes and conclusions drawn about the need for further code development. Although the current version of 3DHZETRN is reasonably accurate compared to MC simulations, this study shows that improved leakage estimates can be obtained by replacing the isotropic/straight-ahead approximation with more detailed descriptions.

Background Mycobacterium avium complex (MAC) and Achromobacter xylosoxidans (AX) are uncommon sources of neurosurgical infections, particularly in immunocompetent hosts. We report the first published case of intracranial AX abscess and polymicrobial AX-MAC abscess, as well as the fourth MAC abscess in a non-immunocompromised patient. Methods This case report was conducted via retrospective chart review. A literature review was completed in compliance with Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Results Ten years following mucocele resection, a 60-year-old man presented with sinus congestion and headache. Head imaging revealed a left frontal lesion abutting the cribriform plate and ethmoid roof. The patient had a left frontal craniotomy for abscess drainage. Intraoperative cultures demonstrated polymicrobial growth of AX and MAC, managed with antimicrobial therapy and staged skull base reconstruction. Three cases of MAC abscess and 16 cases of AX ventriculitis or meningitis have been reported in immunocompetent patients. All MAC cerebral abscesses occurred in adults, one of whom succumbed to the infection. Of the 9 AX meningitis cases, 4 occurred in neonates and 2 in pediatric patients. Six of the 7 AX ventriculitis cases occurred after neurosurgical operations at the same hospital from contaminated chlorhexidine basins. Except for the neonates, AX ventriculitis or meningitis patients had undergone neurosurgery or had a history of cranial trauma. There were no reports of polymicrobial AX-MAC intracranial abscess. Conclusions AX and MAC are rare causes of intracranial infection. Patients with these pathogens identified in the central nervous system require a multidisciplinary approach for successful management.

Objectives To determine the prevalence and impact of urinary incontinence (UI) in men with cystic fibrosis (CF). Design Prospective observational study. Setting Adult CF clinics at tertiary referral centres. Participants Men with CF ( n =80) and age-matched men without lung disease ( n =80). Interventions Validated questionnaires to identify the prevalence and impact of UI. Main outcome measures Prevalence of UI and relationship to disease specific factors, relationship of UI with anxiety and depression. Results The prevalence of UI was higher in men with CF (15%) compared to controls (10%) ( p =0.339). Men with CF and UI had higher scores for anxiety than those without UI (mean 9.1 (SD 4.8) vs 4.7 (4.1), p =0.003), with similar findings for depression (6.8 (4.6) vs 2.8 (3.4), p =0.002) using the Hospital Anxiety and Depression Scale. Conclusions Incontinence is more prevalent in adult men with CF than age matched controls, and may have an adverse effect on mental health. The mechanisms involved are still unclear and may differ from those reported in women.

A computationally efficient 3DHZETRN code capable of simulating High (H) Charge (Z) and Energy (HZE) and light ions (including neutrons) under space-like boundary conditions with enhanced neutron and light ion propagation was recently developed for a simple homogeneous shield object. Monte Carlo benchmarks were used to verify the methodology in slab and spherical geometry, and the 3D corrections were shown to provide significant improvement over the straight-ahead approximation in some cases. In the present report, the new algorithms with well-defined convergence criteria are extended to inhomogeneous media within a shielded tissue slab and a shielded tissue sphere and tested against Monte Carlo simulation to verify the solution methods. The 3D corrections are again found to more accurately describe the neutron and light ion fluence spectra as compared to the straight-ahead approximation. These computationally efficient methods provide a basis for software capable of space shield analysis and optimization.

The computationally efficient HZETRN code has been used in recent trade studies for lunar and Martian exploration and is currently being used in the engineering development of the next generation of space vehicles, habitats, and extra vehicular activity equipment. Code development has been based on a progression of approximations first assuming all particles are produced in the initiator direction of incidence (straight-ahead) later improved by treating neutrons produced in the backward hemisphere as moving straight-back (bi-directional). A new version (3DHZETRN) capable of transporting High charge (Z) and Energy (HZE) and light ions (including neutrons) under space-like boundary conditions with enhanced neutron and light ion propagation in transverse directions is developed. Herein, new algorithms for light ion and neutron propagation with well defined convergence criteria in 3D objects is developed and tested against Monte Carlo simulations of 3D effects.

Habitat assessments for biodiversity conservation are often complicated by the lack of detailed knowl- edge of a study species' distribution. As an alternative to resource-intensive field-based methods to obtain such information, remotely sensed products can be utilized in species distribution models to infer a species' distribution and ecological needs. Here we demonstrate how to arbitrate among a variety of remotely sensed predictor variables to estimate the distribution and ecological needs of an endangered butterfly species occurring mainly in inaccessible areas. We classified 19 continuous environmental pre- dictor variables into three conceptually independent predictor classes, terrain, land cover, and vertical vegetation structure, and compared the accuracy of competing Maxent habitat models consisting of dif- ferent combinations of each class. Each class contributed, though disproportionately, to our most reliable model that considered all 19 variables. We confirm that variables obtained from remote sensors can effectively estimate the distribution and ecological needs of a relatively unknown imperiled species occurring in inaccessible locations. Importantly, increasing the variety of predictor classes through multi-sensor fusion resulted in greater model accuracy than increasing the absolute number of predictor variables.

To compare the effectiveness of self-collected and health care worker (HCW)-collected nasal swabs for detection of influenza viruses and determine the patients' preference for type of collection.We enrolled adult patients presenting with influenzalike illness to the Emergency Department at Mayo Clinic, Rochester, Minnesota, from January 28, 2011, through April 30, 2011. Patients self-collected a midturbinate nasal flocked swab from their right nostril following written instructions. A second swab was then collected by an HCW from the left nostril. Swabs were tested for influenza A and B viruses by real-time reverse transcription-polymerase chain reaction, and percent concordance between collection methods was determined.Of the 72 paired specimens analyzed, 25 were positive for influenza A or B RNA by at least one of the collection methods (34.7% positivity rate). When the 14 patients who had prior health care training were excluded, the qualitative agreement between collection methods was 94.8% (55 of 58). Two of the 58 specimens (3.4%) from patients without health care training were positive only by HCW collection, and 1 of 58 (1.7%) was positive only by patient self-collection. A total of 53.4% of patients (31 of 58) preferred the self-collection method over the HCW collection, and 25.9% (15 of 58) had no preference.Self-collected midturbinate nasal swabs provide a reliable alternative to HCW collection for influenza A and B virus real-time reverse transcription-polymerase chain reaction.

Summary Background and aims Inhalation of hypertonic saline (HTS) has short term positive effects on airways clearance in non-cystic fibrosis (CF) bronchiectasis, however its long term effects are unknown. The aim of this study was to determine the effect of HTS 6% on exacerbations, quality of life (QOL) and respiratory function over 12 months in non-CF bronchiectasis. Methods Forty patients were randomised to inhale isotonic saline (IS) 0.9% or HTS 6% daily for 12 months. Participants recorded their symptoms in a daily diary. Quality of life and respiratory function were measured after three, six and 12 months. Number of exacerbations and changes in sputum colonisation were recorded at 12 months. Participants, assessors and clinicians were blinded to group allocation. Results The exacerbation rate at 12 months was similar in the two groups and similar clinically significant improvements in QOL were seen in both groups. The FEV 1 increased in both groups after six months (mean 90 ml, 95% confidence interval 11–169 ml) with no difference between groups ( p = 0.394). The FEF 25–75% significantly improved at all time points (mean increase at 12 months 187 ml, 69–304 ml) with no difference between groups ( p = 0.705). There was a reduction in sputum colonisation in both groups ( p = 0.046). Conclusions Inhalation of HTS or IS has similar effects on exacerbations, QOL, sputum colonisation and respiratory function over 12 months in non-CF bronchiectasis. The trial was registered with both Clinical Trials.gov – NCT00484263 and Australian New Zealand Clinical Trials Registry – ACTRN12607000367448.

The International Space Station (ISS) provides the proving ground for future long duration human activities in space. Ionizing radiation measurements in ISS form the ideal tool for the experimental validation of radiation environmental models, nuclear transport code algorithms and nuclear reaction cross sections. Indeed, prior measurements on the Space Transportation System (STS; Shuttle) have provided vital information impacting both the environmental models and the nuclear transport code development by requiring dynamic models of the Low Earth Orbit (LEO) environment. Previous studies using Computer Aided Design (CAD) models of the evolving ISS configurations with Thermo-Luminescent Detector (TLD) area monitors, demonstrated that computational dosimetry requires environmental models with accurate non-isotropic as well as dynamic behavior, detailed information on rack loading, and an accurate six degree of freedom (DOF) description of ISS trajectory and orientation. It is imperative that we understand ISS exposures dynamically for crew career planning, and insure that the regulatory requirements of keeping exposure as low as reasonably achievable (ALARA) are adequately implemented. This is especially true as ISS nears some form of completion with increasing complexity, resulting in a larger drag coefficient, and requiring operation at higher altitudes with increased exposure rates. In this paper ISS environmental model is configured for 11A (circa mid 2005), and uses non-isotropic and dynamic geomagnetic transmission and trapped proton models. ISS 11A and LEO model validations are important steps in preparation for the design and validation for the next generation manned vehicles. While the described cutoff rigidity, trapped proton and electron formalisms as coded in a package named GEORAD (GEOmagnetic RADiation) and a web interface named OLTARIS (On-line Tool for the Assessment of Radiation in Space) are applicable to the LEO, Medium Earth Orbit (MEO) and Geosynchronous Earth Orbit (GEO) at quiet solar periods, in this report, the validation of the models using available measurements are limited to STS and ISS nominal operational altitudes (300–400 km) range at LEO where the dominant fields within the vehicle are the trapped proton and attenuated Galactic Cosmic Ray (GCR) ions. The described formalism applies to trapped electron at LEO, MEO and GEO as well. Due to the scarcity of available electron measurements, the trapped electron capabilities of the GEORAD are not discussed in this report, but are accessible through OLTARIS web interface. GEORAD and OLTARIS interests are in the study of long term effects (i.e. a meaningful portion of solar cycle). Therefore, GEORAD does not incorporate any short term external field contribution due to solar activity. Finally, we apply these environmental models to selected target points within ISS 6A (circa early 2001), 7A (circa late 2001), and 11A during its passage through the South Atlantic Anomaly (SAA) to assess the validity of the environmental models at ISS altitudes.

Summary Introduction In our institution, patients with suspected pulmonary TB undergo multiple induced-sputum sampling for microscopy, culture and nucleic acid amplification (NAA) with the MTD ® Gen-probe assay. Those with negative induced-sputum results still suspected with TB are then referred for bronchoscopy. We sought to determine the diagnostic yield of bronchoscopy in these patients with negative initial induced-sputum results both via smear and NAA testing. Methods We identified 30 consecutive cases of suspected pulmonary TB between 2001 and 2007, who had undergone a diagnostic bronchoscopy after negative results on induced-sputum smears and the MTD ® Gen-probe on at least 2 samples. Results The cohort (M = 20 & F = 10) had a median age of 37 (range 16–85 yrs); were predominantly foreign born (27/30); HIV-negative (29/30) individuals with strongly positive TST's (mean 18 + 5 mm). Induced-sputum cultures were negative for M-TB in all patients after a full 60-day incubation period. BAL was culture positive for M-TB in 3/30 cases (10%) with 2 strains being pan-sensitive and the third being INH resistant. BAL microscopy with acid-fast smear ( n = 30) and BAL Gen-probe ( n = 23) were negative in all cases. A third of the patients (9/27, 33%) with negative bronchoscopy results were treated for culture negative TB. Treatment for latent TB was initiated in 5/27 (18%) individuals whereas 13/27 (48%) received no further treatment. Conclusion Bronchoscopy provided diagnostic confirmation of pulmonary TB in 10% of subjects at least 2 negative induced-sputum samples by smear microscopy and NAA testing.

Classic tissue effects of β(2)-adrenergic receptor activation include skeletal muscle glycogenolysis and vascular smooth muscle relaxation, factors relevant to obesity and hypertension, respectively. In a population-based study, we examined 2 common amino acid substitutions in the β(2)-adrenergic receptor gene (ADRB2) in relation to body composition and blood pressure. A cross-sectional analysis of 1893 African-descent men living in Tobago and participating in a prostate cancer screening study was performed. Body mass index, waist circumference, blood pressure, dual-energy x-ray absorptiometry body composition, and ADRB2 (Arg16Gly; Gln27Glu) genotype were determined. Twenty-six percent were obese (body mass index ≥30 kg/m(2)), and 50% were hypertensive. ADRB2 Arg16Gly and Gln27Glu alleles were in linkage disequilibrium (D' = 0.96, r(2) = 0.15). ADRB2 16Gly-containing and 27Glu-containing genotypes were equally frequent in low, medium, and high tertiles of percentage of body fat mass (16Gly-containing genotypes: 73.4%, 74.4%, and 74.5%, P(trend) = .66; 27Glu-containing genotypes: 27.6%, 23.8%, and 25.4%, P(trend) = .39) and in normal blood pressure, prehypertensive, and hypertensive men (16Gly-containing genotypes: 73.4%, 72.8%, and 74.4%, P(trend) = .61; 27Glu-containing genotypes: 25.6%, 24.1%, and 26.7%, P(trend) = .50). In a high-obesity and high-hypertension risk population with ancestry in common with African Americans, genetic variation defined by 2 common ADRB2 amino acid substitutions was not associated with body composition or hypertension.

BackgroundNocturnal oxyhaemoglobin desaturation is common in cystic fibrosis (CF) but the effect on quality of life (QoL) remains unknown.MethodsSixty stable CF outpatients with mean age 31±8years (mean±1SD), BMI 20.8±3.2kg/m2 and FEV1 42±13% predicted had arterial blood gas sampling, lung function testing, overnight pulse oximetry and completed the CF QoL questionnaire, Epworth Sleepiness Scale and Medical Research Council dyspnoea scale.Results11 (18%) of the CF patients were ‘desaturators,’ (SpO2

The origin of the aluminum equivalent shield approximation in space radiation analysis can be traced back to its roots in the early years of the NASA space programs (Mercury, Gemini and Apollo) wherein the primary radiobiological concern was the intense sources of ionizing radiation causing short term effects which was thought to jeopardize the safety of the crew and hence the mission. Herein, it is shown that the aluminum equivalent shield approximation, although reasonably well suited for that time period and to the application for which it was developed, is of questionable usefulness to the radiobiological concerns of routine space operations of the 21st century which will include long stays onboard the International Space Station (ISS) and perhaps the moon. This is especially true for a risk based protection system, as appears imminent for deep space exploration where the long-term effects of Galactic Cosmic Ray (GCR) exposure is of primary concern. The present analysis demonstrates that sufficiently large errors in the interior particle environment of a spacecraft result from the use of the aluminum equivalent approximation, and such approximations should be avoided in future astronaut risk estimates. In this study, the aluminum equivalent approximation is evaluated as a means for estimating the particle environment within a spacecraft structure induced by the GCR radiation field. For comparison, the two extremes of the GCR environment, the 1977 solar minimum and the 2001 solar maximum, are considered. These environments are coupled to the Langley Research Center (LaRC) deterministic ionized particle transport code High charge (Z) and Energy TRaNsport (HZETRN), which propagates the GCR spectra for elements with charges (Z) in the range 1 ⩽ Z ⩽ 28 (H–Ni) and secondary neutrons through selected target materials. The coupling of the GCR extremes to HZETRN allows for the examination of the induced environment within the interior of an idealized spacecraft as approximated by a spherical shell shield, and the effects of the aluminum equivalent approximation for a good polymeric shield material such as generic polyethylene (PE). The shield thickness is represented by a 25 g/cm2 spherical shell. Although, one could imagine the progression to greater thickness, the current range will be sufficient to evaluate the qualitative usefulness of the aluminum equivalent approximation. Upon establishing the inaccuracies of the aluminum equivalent approximation through numerical simulations of the GCR radiation field attenuation for PE and aluminum equivalent PE spherical shells, we further present results for a limited set of commercially available, hydrogen rich, multifunctional polymeric constituents to assess the effect of the aluminum equivalent approximation on their radiation attenuation response as compared to the generic PE.

An increase in edge area reduces the effective size of habitat fragments and thus the area available for habitat-interior specialists. However, it is unclear how edge effects compare at different ecotones in the same system. We investigated the response of a small mammal community associated with Afromontane forests to edge effects at three different habitat transitions: natural forest to grassland (natural edge, structurally different vegetation types), natural forest to mature plantation (human-altered edge, structurally similar vegetation types) and natural forest to harvested plantation (human-altered edge, structurally different vegetation types). We predicted that edge effects should be less severe at natural ecotones and at similarly structured contiguous vegetation types than human-altered ecotones and differently structured contiguous vegetation types, respectively. We found that forest species seemed to avoid all habitat edges in our study area. Surprisingly, natural edges supported a less diverse small mammal community than human-altered forest edges. However, edge effects were observed deeper into native forests surrounded by mature alien plantations (and more so at harvested plantations) than into native forests surrounded by native grasslands. The net effect of mature plantations was therefore to reduce the functional size of the natural forest by creating a larger edge. We suggest that when plantations are established a buffer zone of natural vegetation be left between natural forests and newly established plantations to mitigate the negative effects of plantation forestry.

A rapid analytical procedure for the prediction of a micro-dosimeter response function in low Earth orbit (LEO), correlated with the Space Transportation System (STS, shuttle) Tissue Equivalent Proportional Counter (TEPC) measurements is presented. The analytical model takes into consideration the energy loss straggling and chord length distribution of the detector, and is capable of predicting energy deposition fluctuations in a cylindrical micro-volume of arbitrary aspect ratio (height/diameter) by incoming ions through both direct and indirect (ray) events. At any designated (ray traced) target point within the vehicle, the model accepts the differential flux spectrum of Galactic Cosmic Rays (GCR) and/or trapped protons at LEO as input. On a desktop PC, the response function of TEPC for each ion in the GCR/trapped field is computed at the average rate of 30 seconds/ion. The ionizing radiation environment at LEO is represented by O'Neill fs GCR model (2004), covering charged particles in the 1 less than or equal to Z less than or equal to 28. O'Neill's free space GCR model is coupled with the Langley Research Center (LaRC) angular dependent geomagnetic cutoff model to compute the transmission coefficient in LEO. The trapped proton environment is represented by a LaRC developed time dependent procedure which couples the AP8MIN/AP8MAX, Deep River Neutron Monitor (DRNM) and F10.7 solar radio frequency measurements. The albedo neutron environment is represented by the extrapolation of the Atmospheric Ionizing Radiation (AIR) measurements. The charged particle transport calculations correlated with STS 51 and 114 flights are accomplished by using the most recent version (2005) of the LaRC deterministic High charge (Z) and Energy TRaNsport (HZETRN) code. We present the correlations between the TEPC model predictions (response function) and TEPC measured differential/integral spectra in the lineal energy (y) domain for both GCR and trapped protons, with the conclusion that the model correctly accounts for the increase in flux at low y values where energetic ions are the primary contributor. We further discuss that, even with the incorporation of angular dependency in the cutoffs, comparison of the GCR differential/integral flux between STS 51 and 114 TEPC measured data and current calculations indicates that there still exists an underestimation by the simulations at low to mid range y values. This underestimation is partly related the exclusion of the secondary pion particle production from the current version of HZETRN.

For the success of NASA’s new vision for space exploration to Moon, Mars and beyond, exposures from the hazards of severe space radiation in deep space long duration missions is ‘a must solve’ problem. The payload penalty demands a very stringent requirement on the design of the spacecrafts for human deep space missions. The exploration beyond low Earth orbit (LEO) to enable routine access of space will require protection from the hazards of the accumulated exposures of space radiation, Galactic Cosmic Rays (GCR) and Solar Particle Events (SPE), and minimizing the production of secondary radiation is a great advantage. There is a need to look to new horizons for newer technologies. The present investigation revisits electrostatic active radiation shielding and explores the feasibility of using the electrostatic shielding in concert with the state-of-the-art materials shielding and protection technologies. The full space radiation environment has been used, for the first time, to explore the feasibility of electrostatic shielding. The goal is to repel enough positive charge ions so that they miss the spacecraft without attracting thermal electrons. Conclusions are drawn for the future directions of space radiation protection.

With increasing numbers of cystic fibrosis (CF) patients surviving to adulthood, issues related to vocation inevitably arise and warrant specific attention. We examined the percentage of participants with CF currently working and explored risk factors for work disability among adults with CF.We recruited 50 consecutive patients from an adult cystic fibrosis service. Demographic, employment history, illness severity indicators and CF-attributed work disability factors were evaluated. Demographic risk factors for work disability using the illness severity measures of FEV(1), S-K score, CRDQ, and recent hospitalisation as independent variables were determined.Factorial analysis of a disability index (DI) indicated no dependency on FEV(1) or S-K score, but dependency on quality of life indices (p0.05), age (p0.05) and hospital admission rate (p0.05). Hours worked per week were dependent on quality of life (p0.01) (mastery of disease domain), fewer hospital admissions (p0.01) and age (p0.05). Sixty-eight percent of the sample reported that CF resulted in significant impediments to employment. However, few had sought vocational guidance (6%).Determinants of workforce participation shows that hours worked and perceived disability are more dependent on mastery of disease, age, and time in hospital, than on clinical severity scores. Health professionals may assist productivity through career counselling or tailored programs.

Results for the radiation environment to be found on the planet Mars due to Galactic Cosmic Rays (GCR) and Solar Particle Events (SPE) has been obtained. Primary particle environments computed for Martian conditions are transported within the Mars atmosphere, modeled in a time-dependent way in terms of density, pressure, and temperature vs. altitude, down to the surface, with topography and backscattering patterns taken into account. The atmospheric chemical and isotopic composition has been modeled over results from the in-situ Viking Lander measurements for both major and minor components. The surface topography has been determined by using a model based on the data provided by the Mars Orbiter Laser Altimeter (MOLA) instrument on board the Mars Global Surveyor (MGS) spacecraft. The surface itself has been modeled in both the dry (‘regolith’) and volatile components. Mars regolith composition has been modeled based on the measurements obtained with orbiter and lander spacecraft from which an average composition has been derived. The volatile inventory properties, both in the regolith and in the seasonal and perennial polar caps, has been taken into account by modeling the deposition of volatiles and its variations with geography and time all throughout the Martian year, from results from imaging data of orbiter spacecraft. Results are given in terms of fluxes, doses and LET, for most kinds of particles, namely protons, neutrons, alpha particles, heavy ions, pions, and muons for various soil compositions.

In view of manned missions targeted to the Moon, for which radiation exposure is one of the greatest challenges to be tackled, it is of fundamental importance to have available a tool, which allows the determination of the particle flux and spectra at any time and at any point of the lunar surface. With this goal in mind, a new model of the Moon's radiation environment due to Galactic Cosmic Rays (GCR) and Solar Particle Events (SPE) has been developed. Primary particles reach the lunar surface, and are transported all throughout the subsurface layers, with backscattering patterns taken into account. The surface itself has been modeled as regolith and bedrock, with composition taken from the results of the instruments flown on the Apollo missions. Subsurface environments like lava tubes have been considered in the analysis. Particle transport has been performed with both deterministic and Monte Carlo codes with an adaptation for planetary surface geometry. Results are given in terms of fluxes, doses and LET, for most kinds of particles for various kinds of soil and rock chemical compositions.