Effects of elexacaftor/tezacaftor/ivacaftor on liver fibrosis markers in adults with cystic fibrosis.

BACKGROUND: There are limited studies to date on the effects of elexacaftor/tezacaftor/ivacaftor (E/T/I) on markers of liver fibrosis in adults with cystic fibrosis (CF). This study aims to analyse changes in makers of liver fibrosis before and after initiation of E/T/I in CF adults. METHODS: Outcome measures of liver fibrosis, including liver stiffness measurement (LSM) using FibroScan, AST-to-platelet-ratio index (APRI) and gamma-GT-to-platelet-ratio (GPR) were available in 74 CF adults following initiation of E/T/I. This was compared to historical data collected in 2018 prior to UK availability of E/T/I. RESULTS: The median duration of E/T/I therapy at the time liver fibrosis markers were repeated was 21 (IQR: 17-25) months. There was an increase in APRI from historical measurement to follow-up but no change in LSM or GPR. There were no differences in change in fibrosis markers according to CF liver disease (CFLD) status, although those with a raised LSM at baseline (>6.8 kPa) (n = 14) had a significant reduction in LSM from historical measurement to follow-up versus those with a normal historical value (-3.3 kPa vs 0.25 kPa, p < 0.01). CONCLUSIONS: Apart from APRI, we found no changes in liver fibrosis outcomes after initiation of E/T/I in adults with CF. Those with a historical diagnosis of CFLD had no significant worsening or improvement of liver fibrosis markers. We did observe a reduction in LSM in those with liver nodularity, with an initial highest result suggesting a potential positive treatment effect of E/T/I in this category of those with severe CFLD.

Personality Assessment Inventory suicidality scales: Suicidal Ideation (SUI), Suicide Potential Index (SPI), and S_Chron in an Afghanistan/Iraq-era active and Veteran military sample.

INTRODUCTION: This study validated Personality Assessment Inventory (PAI) Suicidal Ideation (SUI), Suicide Potential Index (SPI), and S_Chron scales against chronic and acute suicide risk factors and symptom validity measures. METHODS: Afghanistan/Iraq-era active-duty and Veteran participants completed a prospective study on neurocognition (N = 403) that included the PAI. The Beck Depression Inventory-II (specifically item 9) administered at two time points assessed acute and chronic suicide risk; the Beck Scale for Suicide Ideation item 20 identified history of suicide attempts. Major depressive disorder (MDD), posttraumatic stress disorder (PTSD), and traumatic brain injury (TBI) were evaluated using structured interviews and questionnaires. RESULTS: All three PAI suicide scales were significantly related to independent indicators of suicidality, with the largest effect for SUI (AUC 0.837-0.849). All three suicide scales were significantly related to MDD (r = 0.36-0.51), PTSD (r = 0.27-0.60), and TBI (r = 0.11-0.30). The three scales were not related to suicide attempt history for those with invalid PAI protocols. CONCLUSIONS: Although all three suicide scales do show significant relationships to other indicators of risk, SUI showed the highest association and greatest resistance to response bias.

Longitudinal effects of elexacaftor/tezacaftor/ivacaftor on liver tests at a large single adult cystic fibrosis centre.

BACKGROUND: Elexacaftor/tezacaftor/ivacaftor (E/T/I) therapy has resulted in substantial improvements in health status for many with cystic fibrosis. Monitoring of liver tests is recommended due to observed rises in transaminases in trials and cases of hepatotoxicity. Comprehensive data in large populations of unselected individuals and those with established CF related liver disease (CFLD) is lacking. METHODS: Patients prescribed E/T/I at a large, adult centre had liver tests monitored at least 3 monthly for 12 months. Changes in individual liver tests were analysed and abnormalities were compared in those with and without CFLD. RESULTS: 255 of 267 eligible patients were included. Mild rises in median ALT, AST and bilirubin from baseline to 3 months (all p < 0.001) within normal limits were noted which were sustained. There were no differences in changes in liver tests between those with or without CFLD. There was a significant difference in alkaline phosphatase for those with raised levels at baseline versus those with normal baseline level (-18.5 vs +2.0 IU/L, p = 0.002). Clinically significant rises in ALT and AST occurred in 8 (3.1%) and 6 (2.4%) cases respectively, with derangements in 2 individuals attributed to therapy. CONCLUSIONS: E/T/I leads to a mild, likely clinically insignificant increase in ALT, AST and bilirubin after 3 months which is sustained but does not appear to increase further in the vast majority. Underlying CFLD should not be a barrier to treatment. Although there was a reduction in ALP when elevated at baseline, this was not unique to those with pre-existing CFLD.

Meteorological Factors Influence the Presence of Fungi in the Air; A 14-Month Surveillance Study at an Adult Cystic Fibrosis Center.

Background: Cystic fibrosis is an inherited disease that predisposes to progressive lung damage. Cystic fibrosis patients are particularly prone to developing pulmonary infections. Fungal species are commonly isolated in lower airway samples from patients with cystic fibrosis. Fungal spores are prevalent in the air. Methods: We performed environmental air sampling surveillance at the Manchester Adult Cystic Fibrosis Centre, UK (MACFC) over a 14-month period to assess fungal growth inside and outside the CF center. Results: Airborne counts of fungal spores peaked from May to October, both in outdoor and indoor samples. Collection of meteorological data allowed us to correlate fungal presence in the air with elevated temperatures and low wind speeds. Additionally, we demonstrated patient rooms containing windows had elevated fungal counts compared to rooms not directly connected to the outdoors. Conclusions: This study suggests that airborne Aspergillus fumigatus spores were more abundant during the summer months of the survey period, which appeared to be driven by increased temperatures and lower wind speeds. Indoor counts directly correlated to outdoor A. fumigatus levels and were elevated in patient rooms that were directly connected to the outdoor environment via an openable window designed for ventilation purposes. Further studies are required to determine the clinical implications of these findings for cystic fibrosis patients who are predisposed to Aspergillus related diseases, and in particular whether there is seasonal influence on incidence of Aspergillus related conditions and if screening for such complications such be increased during summer months and precautions intensified for those with a known history of Aspergillus related disease.

Influenza B outbreak at an adult cystic fibrosis centre - Clinical impact and factors influencing spread.

INTRODUCTION: An outbreak of Influenza B occurred at a large United Kingdom (UK) regional adult cystic fibrosis (CF) centre in May 2016. This was late in the UK 2015-2016 influenza season and occurred on a specialist ward with strict infection control procedures. This study investigates the spread of influenza, clinical consequences and potential contributing factors. METHODS: Patient records, clinical status and pulmonary function data were reviewed for all inpatients during this period. Respiratory viral PCR results, influenza vaccination status of patients and staff, and environmental factors were also recorded. Affected patients were prospectively monitored for the following three months. RESULTS: 10 of 21 inpatients developed influenza B between 5th and 12th May 2016, an attack rate of 48%. All those characterised were confirmed as the same strain of influenza B/Victoria-lineage. Influenza infection resulted in a mean FEV1 reduction of 10.5% (SD 11.3, p = 0.012), which persisted at 3 months post infection (p = 0.003). Nine of the affected cases rooms were in close proximity on the ward while patients in the two isolation rooms with enhanced ventilation did not become infected. Ventilation measurements in affected rooms ranged from 1.75 to 2.10 air changes/hour, below national recommendations. Seventy percent of affected inpatients had received the 2015/16 trivalent seasonal influenza vaccine, which did not contain a B/Victoria-lineage influenza B virus. CONCLUSION: This influenza B outbreak in CF adults had a high attack rate and a significant clinical impact. Room ventilation and a limited protection from the seasonal influenza vaccine were possible contributory factors.

Global-scale human impact on delta morphology has led to net land area gain.

River deltas rank among the most economically and ecologically valuable environments on Earth. Even in the absence of sea-level rise, deltas are increasingly vulnerable to coastal hazards as declining sediment supply and climate change alter their sediment budget, affecting delta morphology and possibly leading to erosion1-3. However, the relationship between deltaic sediment budgets, oceanographic forces of waves and tides, and delta morphology has remained poorly quantified. Here we show how the morphology of about 11,000 coastal deltas worldwide, ranging from small bayhead deltas to mega-deltas, has been affected by river damming and deforestation. We introduce a model that shows that present-day delta morphology varies across a continuum between wave (about 80 per cent), tide (around 10 per cent) and river (about 10 per cent) dominance, but that most large deltas are tide- and river-dominated. Over the past 30 years, despite sea-level rise, deltas globally have experienced a net land gain of 54 ± 12 square kilometres per year (2 standard deviations), with the largest 1 per cent of deltas being responsible for 30 per cent of all net land area gains. Humans are a considerable driver of these net land gains-25 per cent of delta growth can be attributed to deforestation-induced increases in fluvial sediment supply. Yet for nearly 1,000 deltas, river damming4 has resulted in a severe (more than 50 per cent) reduction in anthropogenic sediment flux, forcing a collective loss of 12 ± 3.5 square kilometres per year (2 standard deviations) of deltaic land. Not all deltas lose land in response to river damming: deltas transitioning towards tide dominance are currently gaining land, probably through channel infilling. With expected accelerated sea-level rise5, however, recent land gains are unlikely to be sustained throughout the twenty-first century. Understanding the redistribution of sediments by waves and tides will be critical for successfully predicting human-driven change to deltas, both locally and globally.

Lessons of the month 1: Salbutamol induced lactic acidosis: clinically recognised but often forgotten.

We present the case of an 83-year-old woman, with known asthma, admitted with increasing dyspnoea, wheeze and a productive cough. In addition to maintenance inhaled therapy, the patient was also on long-term mirtazapine and furosemide. Following acute treatment with nebulised salbutamol she became increasingly dyspnoeic and developed a metabolic acidosis with a significantly raised blood lactate level. After cessation of ß2-adrenergic medication, the patient's clinical condition improved with resolution of her lactic acidosis; salbutamol induced lactic acidosis was diagnosed. This clinical scenario is common but not well described. Here we discuss the mechanisms, investigation and management of raised serum lactate and lactic acidosis in the context of acute asthma and the possible interactions of polypharmacy and comorbidities in the acute medical setting.

Investigation of a Pandoraea apista cluster common to adult and paediatric cystic fibrosis patients attending two hospitals in the same city.

PURPOSE: We examined evidence for transmission of Pandorea apista among cystic fibrosis (CF) patients attending paediatric and adult services in one city who had previously been found to harbour related isolates by pulsed-field gel electrophoresis (PFGE). METHODOLOGY: The whole-genome sequences of 18 isolates from this cluster from 15 CF patients were examined, along with 2 cluster isolates from 2 other centres. The annotated sequence of one of these, Pa14367, was examined for virulence factors and antibiotic resistance-associated genes in comparison with data from a 'non-cluster' isolate, Pa16226. RESULTS: Single-nucleotide polymorphism (SNP) analysis suggested that cluster isolates from the same city differed from one another by a minimum of 1 and a maximum of 383 SNPs (an average of 213 SNPs; standard deviation: 18.5), while isolates from the 2 other hospitals differed from these by a minimum of 34 and 61 SNPs, respectively. Pa16226 differed from all cluster isolates by a minimum of 22 706 SNPs. Evidence for patient-to-patient transmission among isolates from the same city was relatively limited, although transmission from a common source could not be excluded. The annotated genomes of Pa14367 and Pa16226 carried putative integrative and conjugative elements (ICEs), coding for type IV secretion systems, and genes associated with heavy metal degradation and carbon dioxide fixation, and a wide selection of genes coding for efflux pumps, beta-lactamases and penicillin-binding proteins. CONCLUSION: Epidemiological analysis suggested that this cluster could not always be attributed to patient-to-patient transmission. The acquisition of ICE-related virulence factors may have had an impact on its prevalence.

A survey of atmospheric monitoring systems in U.S. underground coal mines.

In 1995 and 2003, the U.S. Mine Safety and Health Administration (MSHA) conducted surveys to determine the number of atmospheric monitoring systems (AMS) that were being used in underground coal mines in the United States. The survey reports gave data for the different AMS manufacturers, the different types of equipment monitored, and the different types of gas sensors and their locations. Since the last survey in 2003, MSHA has changed the regulation requirements for early fire detection along belt haulage entries. As of Dec. 31, 2009, point-type heat sensors are prohibited for use for an early fire detection system. Instead, carbon monoxide (CO) sensors are now required. This report presents results from a new survey and examines how the regulation changes have had an impact on the use of CO sensors in underground coal mines in the United States. The locations and parameters monitored by AMS and CO systems are also discussed.

A model for conditional male trimorphisms.

Conditional dimorphisms are widespread in color, morphology, behavior, and life history. Such traits have been successfully modeled in game theory as conditional strategies, and in quantitative genetics as threshold traits. Conditional trimorphisms have recently been unveiled, and here we combine the rock-paper-scissors (RPS) model of game theory and the environmental threshold (ET) model of quantitative genetics to model trimorphisms that are environmentally induced and result from the expression of two thresholds. We investigated the tactic fitness structure for maintenance of alternative reproductive tactics in scarab dung beetles that constitute the first known examples of conditional male trimorphism. We parameterized a novel ternary fitness landscape that explains how conditional male trimorphism in these beetles can be maintained. We tracked changes in tactic frequencies in a wild population of Phanaeus triangularis and detected fitness intransitivity consistent with RPS dynamics. Quantitative predictions of our model compare favorably with corresponding observed parameters. The ternary landscape further reveals how geographic populations of these beetles can evolve between conditional trimorphism and dimorphism. The ternary model also suggests that polyphenic systems could potentially evolve between conditional and purely genetic mediation.

Increased prevalence of Pneumocystis jirovecii colonisation in acute pulmonary exacerbations of cystic fibrosis.

OBJECTIVES: This study examined the prevalence of Pneumocystis jirovecii in the sputum of adults with cystic fibrosis during clinical stability and acute pulmonary exacerbation. METHODS: This was a prospective, longitudinal observational study of patients attending the Manchester Adult Cystic Fibrosis Centre. Sputum samples were analysed for P. jirovecii DNA using PCR at enrolment and up to 5 follow-up visits. Patients were classified as stable or exacerbating using a modified Fuch's pulmonary exacerbation score. RESULTS: 226 samples were tested from 111 patients. P. jirovecii was more likely to be detected in samples at acute pulmonary exacerbation (7/76 (9.2%)) compared with stable visits (3/150 (2%)), p = 0.03. P. jirovecii was detected less frequently if patients had received co-trimoxazole within 3 months of sample collection (0% versus 29.7%, p = 0.03). CONCLUSIONS: Prevalence of P. jirovecii in stable patients is low, but P. jirovecii is detected in approximately 1 in 10 patients experiencing an acute pulmonary exacerbation.

Neuropsychological and social cognitive function in young people at genetic risk of bipolar disorder.

BACKGROUND: Impairments in key neuropsychological domains (e.g. working memory, attention) and social cognitive deficits have been implicated as intermediate (endo) phenotypes for bipolar disorder (BD), and should therefore be evident in unaffected relatives. METHOD: Neurocognitive and social cognitive ability was examined in 99 young people (age range 16-30 years) with a biological parent or sibling diagnosed with the disorder [thus deemed to be at risk (AR) of developing BD], compared with 78 healthy control (HC) subjects, and 52 people with a confirmed diagnosis of BD. RESULTS: Only verbal intelligence and affective response inhibition were significantly impaired in AR relative to HC participants; the BD participants showed significant deficits in attention tasks compared with HCs. Neither AR nor BD patients showed impairments in general intellectual ability, working memory, visuospatial or language ability, relative to HC participants. Analysis of BD-I and BD-II cases separately revealed deficits in attention and immediate memory in BD-I patients (only), relative to HCs. Only the BD (but not AR) participants showed impaired emotion recognition, relative to HCs. CONCLUSIONS: Selective cognitive deficits in the capacity to inhibit negative affective information, and general verbal ability may be intermediate markers of risk for BD; however, the extent and severity of impairment in this sample was less pronounced than has been reported in previous studies of older family members and BD cases. These findings highlight distinctions in the cognitive profiles of AR and BD participants, and provide limited support for progressive cognitive decline in association with illness development in BD.

Evaluation of detection and response times of fire sensors using an atmospheric monitoring system.

Atmospheric monitoring systems (AMS) are required when using air from conveyor belt entries to ventilate working sections in U.S. underground coal mines. AMS technology has the potential to increase fire safety mine-wide, but research is needed to determine the detection and response times for fires of a variety of combustible materials. To evaluate the potential of an AMS for fire detection in other areas of a coal mine, a series of full-scale fire experiments were conducted to determine detection and response times from fires of different combustible materials that are found in U.S. underground coal mines, including high- and low-volatility coals, conveyor belts, brattice materials, different types of wood, diesel fuel, and a foam sealant. These experiments were conducted in the Safety Research Coal Mine (SRCM) of the U.S. National Institute for Occupational Safety and Health (NIOSH) located in Pittsburgh, PA, using a commercially available AMS that is typical of current technology. The results showed that through proper selection of sensors and their locations, a mine-wide AMS can provide sufficient early fire warning times and improve the health and safety of miners.

Characterisation and cytotoxic screening of metal oxide nanoparticles putative of interest to oral healthcare formulations in non-keratinised human oral mucosa cells in vitro.

Nanoparticles are increasingly being utilised in the innovation of consumer product formulations to improve their characteristics; however, established links between their properties, dose and cytotoxicity are not well defined. The purpose of this study was to screen four different nanomaterials of interest to oral care product development in the absence of stabilisers, alongside their respective bulk equivalents, within a non-keratinised oral epithelial cell model (H376). Particle morphology and size were characterised using scanning electron microscopy (SEM) and dynamic light scattering (DLS). The H376 model showed that zinc oxide (ZnO) was the most cytotoxic material at concentrations exceeding 0.031% w/v, as assessed using the lactate dehydrogenase (LDH) and dimethylthiazolyl-diphenyl-tetrazolium-bromide (MTT) assays. ZnO cytotoxicity does not appear to be dependent upon size of the particle; a result supported by SEM of cell-particle interactions. Differences in cytotoxicity were observed between the bulk and nanomaterial forms of hydroxyapatite and silica (SiO2); titanium dioxide (TiO2) was well tolerated in both forms at the doses tested. Overall, nano-size effects have some impact on the cytotoxicity of a material; however, these may not be as significant as chemical composition or surface properties. Our data highlights the complexities involved at the nano-scale, in both the characterisation of materials and in relation to cytotoxic properties exerted on oral epithelial cells.

Factors associated with vancomycin nephrotoxicity in the critically ill.

Vancomycin is a glycopeptide antibiotic commonly used in the management of methicillin-resistant Staphylococcus aureus infection. The recent increase in prevalence of methicillin-resistant Staphylococcus aureus with reduced susceptibility to vancomycin has prompted experts to advocate for higher target trough serum concentrations. This study aimed to evaluate the potential consequences of more aggressive vancomycin therapy, by examining the association between higher serum concentrations and acute kidney injury (AKI) in a population of critically ill patients. We collected data for all patients who received vancomycin over a five-year period and evaluated the prevalence of new-onset AKI using the Risk, Injury, Failure, Loss and End-stage (RIFLE) kidney disease criteria. One-hundred and fifty-nine patients provided complete data, with 8.8% manifesting new onset AKI while receiving vancomycin. The median age was 57 (44 to 68) years, while the median trough serum concentration was 16 (10 to 19) mg/l. Multivariate logistic regression analysis identified mean trough concentration (OR=1.174, P=0.024), APACHE II score (OR=1.141, P=0.012) and simultaneous aminoglycoside prescription (OR=18.896, P=0.002) as significant predictors of AKI. These data suggest higher trough vancomycin serum concentrations are associated with greater odds of AKI in the critically ill.

Rapid Detection of Emerging Pathogens and Loss of Microbial Diversity Associated with Severe Lung Disease in Cystic Fibrosis.

Respiratory infection in cystic fibrosis (CF) is polymicrobial, but standard sputum microbiology does not account for the lung microbiome or detect changes in microbial diversity associated with disease. As a clinically applicable CF microbiome surveillance scheme, total sputum nucleic acids isolated by a standard high-throughput robotic method for accredited viral diagnosis were profiled for bacterial diversity using ribosomal intergenic spacer analysis (RISA) PCR. Conventional culture and RISA were performed on 200 paired sputum samples from 93 CF adults; pyrosequencing of the 16S rRNA gene was applied to 59 patients to systematically determine bacterial diversity. Compared to the microbiology data, RISA profiles clustered into two groups: the emerging nonfermenting Gram-negative organisms (eNFGN) and Pseudomonas groups. Patients who were culture positive for Burkholderia, Achromobacter, Stenotrophomonas, and Ralstonia clustered within the eNFGN group. Pseudomonas group RISA profiles were associated with Pseudomonas aeruginosa culture-positive patients. Sequence analysis confirmed the abundance of eNFGN genera and Pseudomonas within these respective groups. Low bacterial diversity was associated with severe lung disease (P < 0.001) and the presence of Burkholderia (P < 0.001). An absence of Streptococcus (P < 0.05) occurred in individuals with lung function in the lowest quartile. In summary, nucleic acids isolated from CF sputum can serve as a single template for both molecular virology and bacteriology, with a RISA PCR rapidly detecting the presence of dominant eNFGN pathogens or P. aeruginosa missed by culture (11% of cases). We provide guidance for how this straightforward CF microbiota profiling scheme may be adopted by clinical laboratories.