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RNA abundance quantification has become routine and affordable thanks to high-throughput "short-read" technologies that provide accurate molecule counts at the gene level. Similarly accurate and affordable quantification of definitive full-length, transcript isoforms has remained a stubborn challenge, despite its obvious biological significance across a wide range of problems. "Long-read" sequencing platforms now produce data-types that can, in principle, drive routine definitive isoform quantification. However some particulars of contemporary long-read datatypes, together with isoform complexity and genetic variation, present bioinformatic challenges. We show here, using ONT data, that fast and accurate quantification of long-read data is possible and that it is improved by exome capture. To perform quantifications we developed lr-kallisto, which adapts the kallisto bulk and single-cell RNA-seq quantification methods for long-read technologies.

Background: Bacteriophage (phage) therapy is a promising alternative antimicrobial approach that has the potential to transform the way we treat bacterial infections. The antibiotic resistance crisis is driving renewed interest in phage therapy. There are currently no licensed phage therapy medicinal products and phage therapy is used in small but growing patient numbers on an unlicensed basis., Objectives: This article provides guidelines on the assessment of patient suitability for unlicensed phage therapy for clinicians in the United Kingdom., Sources: This article builds on Health Improvement Scotland's recommendation for the consideration of phage therapy in difficult-to-treat infections and the experience of the author group, who have collectively assessed the suitability of 30 patients for phage therapy., Content: In the United Kingdom, unlicenced medicines, including phages, may be considered to meet special clinical needs. The use of unlicenced medicines is governed by national legislation and local National Health Service trust policies. Phages can be used in any National Health Service trust and decisions about suitability should be made through existing local clinical management pathways. This article sets out guidelines to support local clinical teams in the assessment of patient suitability for phage therapy. Clinical and microbiological considerations are presented, including allergy and pregnancy., Implications: The assessment of patient suitability for phage therapy is within the scope of local clinical teams. Local assessment through existing clinical management pathways will develop confidence and competence in phage therapy among clinical teams nationally and ensure timely patient care., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

As the number of surgical procedures performed the world over continues to increase, so does the number of anesthetic procedures needed for those surgeries to occur. While much thought and research has been focused on the perspective of the anesthesiologist, little has been explored from the perspective of the patient receiving anesthesia. The purpose of this study was to explore the general public's opinions and experiences of general anesthesia, as well as any change in their perception after having undergone a procedure requiring it. We decided that further inquiry into the subject was warranted, and we decided to run an online Qualtrics survey in order to make that inquiry. The key takeaway from our online anonymous survey shows that there is a significant amount of anxiety related to anesthesia, but that most people specify a large decrease in said anxiety after having undergone the procedure. Noticeably, people were made more comfortable by discussing anesthesia with people who had lived through the experience, and people believed they would be significantly comforted by the presence of therapy animals prior to beginning their procedures. We hope that our exploratory research will promote future research into this topic in order to improve the healthcare outcomes of a significant number of patients. We believe that this data has opened up many potential avenues for further exploration and research, as well as potentially being able to guide surgical practice., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Usman et al.)

The COVID-19 pandemic brought immense attention to the healthcare system and its workers. While much research has been completed about the effects of COVID-19 on the healthcare system, little exists about how the opinions of patients have been altered by this pandemic. We decided to further investigate how the public opinion of healthcare workers (HCWs) has changed to better understand how best we can serve society. The key takeaway from the data was that both the levels of perceived trustworthiness and respectability of healthcare workers decreased following the pandemic. Data showed that the level of perceived respectability decreased from an average of 7.84 to 7.30 and the level of perceived trustworthiness from 7.38 to 6.54, all of these values out of 10. While these changes were not enormous, they demonstrate a striking trend and were found to be significant through a paired t-test. Finally, respondents were also queried about their level of desire in pursuing healthcare as a career field and overwhelmingly there was little interest, with an average level of 1.24 out of 10. We believe our data and results show important trends that all HCWs should be aware of; notably decreasing interest in the field, reduced trust, and decrease in respect, all of which will require further study and analysis. We must consider the current environment in which small mistakes or mistrust can have grave consequences on public health and patient compliance. In addition, the lack of interest in joining the medical community is concerning considering the large efflux of workers leaving the profession. Future studies could focus on how to increase trust in HCWs or attract more people to the healthcare field., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Stolzenberg et al.)

Background: A series of phase 3 clinical trials have demonstrated that elexacaftor plus tezacaftor plus ivacaftor (ELX/TEZ/IVA) is safe and efficacious in people with cystic fibrosis (pwCF) aged ≥12 years with ≥1 F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The impact of this treatment on lifetime clinical outcomes and survival, however, has yet to be assessed., Methods: We used a person-level microsimulation model to estimate the survival and lifetime clinical benefits of ELX/TEZ/IVA treatment versus other CFTR modulator combinations (tezacaftor plus ivacaftor [TEZ/IVA] or lumacaftor plus ivacaftor [LUM/IVA]) or best supportive care (BSC) alone in pwCF aged ≥12 years who are homozygous for F508del-CFTR. Disease progression inputs were derived from published literature; clinical efficacy inputs were derived from an indirect treatment comparison conducted using relevant phase 3 clinical trial data and extrapolations of clinical data., Results: The median projected survival for pwCF homozygous for F508del-CFTR treated with ELX/TEZ/IVA was 71.6 years. This was an increase of 23.2 years versus TEZ/IVA, 26.2 years versus LUM/IVA, and 33.5 years versus BSC alone. Treatment with ELX/TEZ/IVA also reduced disease severity as well as the number of pulmonary exacerbations and lung transplants. In a scenario analysis, the median projected survival for pwCF initiating ELX/TEZ/IVA between the ages of 12 and 17 years was 82.5 years, an increase of 45.4 years compared with BSC alone., Conclusions: The results from our model suggest ELX/TEZ/IVA treatment may substantially increase survival for pwCF, with early initiation potentially allowing pwCF to achieve near-normal life expectancy., Competing Interests: Declaration of Competing Interest Andrea Lopez, Conor Daly, Gabriela Vega-Hernandez, and Jaime L. Ru- bin are employees of Vertex Pharmaceuticals and might own stock or stock options in the company. Gordon MacGre- gor has no conflicts of interest to declare., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Competing Interests: NRCC reports personal fees from Resolve to Save Lives (RTSL), the Pan American Health Organization, and the World Bank, outside the submitted work; and is an unpaid member of World Action on Salt, Sugar and Health and an unpaid consultant on dietary sodium and hypertension control to numerous governmental and non-governmental organizations. Dr Campbell chaired the International Consortium for Quality Research on Dietary Sodium/Salt (TRUE) which is an unpaid voluntary position. Dr Campbell was on the Medical Advisory Board of Switch Health (2022–2023) and was a one-time reviewer of a joint Novartis Canada Alberta Health Services collaborative project to treat dyslipidemia. All the honoraria from Switch Health and Novartis Canada have been donated to the University of Calgary to support a community cardiovascular disease prevention recognition award. FJH is an unpaid member of Action on Salt, and World Action on Salt, Sugar and Health (WASSH). GAM is the unpaid Chair of Action on Salt, Action on Sugar, WASSH, and Blood Pressure UK.

Background: Elexacaftor-tezacaftor-ivacaftor has been shown to be safe and efficacious in people with cystic fibrosis and at least one F508del allele. Our aim was to identify a novel cystic fibrosis transmembrane conductance regulator (CFTR) modulator combination capable of further increasing CFTR-mediated chloride transport, with the potential for once-daily dosing., Methods: We conducted two phase 2 clinical trials to assess the safety and efficacy of a once-daily combination of vanzacaftor-tezacaftor-deutivacaftor in participants with cystic fibrosis who were aged 18 years or older. A phase 2 randomised, double-blind, active-controlled study (VX18-561-101; April 17, 2019, to Aug 20, 2020) was carried out to compare deutivacaftor monotherapy with ivacaftor monotherapy in participants with CFTR gating mutations, following a 4-week ivacaftor monotherapy run-in period. Participants were randomly assigned to receive either ivacaftor 150 mg every 12 h, deutivacaftor 25 mg once daily, deutivacaftor 50 mg once daily, deutivacaftor 150 mg once daily, or deutivacaftor 250 mg once daily in a 1:1:2:2:2 ratio. The primary endpoint was absolute change in ppFEV 1 from baseline at week 12. A phase 2 randomised, double-blind, controlled, proof-of-concept study of vanzacaftor-tezacaftor-deutivacaftor (VX18-121-101; April 30, 2019, to Dec 10, 2019) was conducted in participants with cystic fibrosis and heterozygous for F508del and a minimal function mutation (F/MF genotypes) or homozygous for F508del (F/F genotype). Participants with F/MF genotypes were randomly assigned 1:2:2:1 to receive either 5 mg, 10 mg, or 20 mg of vanzacaftor in combination with tezacaftor-deutivacaftor or a triple placebo for 4 weeks, and participants with the F/F genotype were randomly assigned 2:1 to receive either vanzacaftor (20 mg)-tezacaftor-deutivacaftor or tezacaftor-ivacaftor active control for 4 weeks, following a 4-week tezacaftor-ivacaftor run-in period. Primary endpoints for part 1 and part 2 were safety and tolerability and absolute change in ppFEV 1 from baseline to day 29. Secondary efficacy endpoints were absolute change from baseline at day 29 in sweat chloride concentrations and Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain score. These clinical trials are registered with ClinicalTrials.gov, NCT03911713 and NCT03912233, and are complete., Findings: In study VX18-561-101, participants treated with deutivacaftor 150 mg once daily (n=23) or deutivacaftor 250 mg once daily (n=24) had mean absolute changes in ppFEV 1 of 3·1 percentage points (95% CI -0·8 to 7·0) and 2·7 percentage points (-1·0 to 6·5) from baseline at week 12, respectively, versus -0·8 percentage points (-6·2 to 4·7) with ivacaftor 150 mg every 12 h (n=11); the deutivacaftor safety profile was consistent with the established safety profile of ivacaftor 150 mg every 12 h. In study VX18-121-101, participants with F/MF genotypes treated with vanzacaftor (5 mg)-tezacaftor-deutivacaftor (n=9), vanzacaftor (10 mg)-tezacaftor-deutivacaftor (n=19), vanzacaftor (20 mg)-tezacaftor-deutivacaftor (n=20), and placebo (n=10) had mean changes relative to baseline at day 29 in ppFEV 1 of 4·6 percentage points (-1·3 to 10·6), 14·2 percentage points (10·0 to 18·4), 9·8 percentage points (5·7 to 13·8), and 1·9 percentage points (-4·1 to 8·0), respectively, in sweat chloride concentration of -42·8 mmol/L (-51·7 to -34·0), -45·8 mmol/L (95% CI -51·9 to -39·7), -49·5 mmol/L (-55·9 to -43·1), and 2·3 mmol/L (-7·0 to 11·6), respectively, and in CFQ-R respiratory domain score of 17·6 points (3·5 to 31·6), 21·2 points (11·9 to 30·6), 29·8 points (21·0 to 38·7), and 3·3 points (-10·1 to 16·6), respectively. Participants with the F/F genotype treated with vanzacaftor (20 mg)-tezacaftor-deutivacaftor (n=18) and tezacaftor-ivacaftor (n=10) had mean changes relative to baseline (taking tezacaftor-ivacaftor) at day 29 in ppFEV 1 of 15·9 percentage points (11·3 to 20·6) and -0·1 percentage points (-6·4 to 6·1), respectively, in sweat chloride concentration of -45·5 mmol/L (-49·7 to -41·3) and -2·6 mmol/L (-8·2 to 3·1), respectively, and in CFQ-R respiratory domain score of 19·4 points (95% CI 10·5 to 28·3) and -5·0 points (-16·9 to 7·0), respectively. The most common adverse events overall were cough, increased sputum, and headache. One participant in the vanzacaftor-tezacaftor-deutivacaftor group had a serious adverse event of infective pulmonary exacerbation and another participant had a serious rash event that led to treatment discontinuation. For most participants, adverse events were mild or moderate in severity., Interpretation: Once-daily dosing with vanzacaftor-tezacaftor-deutivacaftor was safe and well tolerated and improved lung function, respiratory symptoms, and CFTR function. These results support the continued investigation of vanzacaftor-tezacaftor-deutivacaftor in phase 3 clinical trials compared with elexacaftor-tezacaftor-ivacaftor., Funding: Vertex Pharmaceuticals., Competing Interests: Declaration of interests AZU received grants from the Cystic Fibrosis Foundation and the CFF-Therapeutic Development Network for the present work; received payment or honoraria from Vertex Pharmaceuticals for presentations at CF Centers in UK; and participated in advisory boards for Vertex and Eloxx. VI received grant support from CF TDN for the present work; consulting fees from Mylan for CF—TOBI podhaler advisory board; and grant support from CFF for meeting attendance. PA received support from Vertex Pharmaceuticals for lectures, presentations, and materials; meeting attendance; and participation on data safety monitoring boards or advisory boards. MAM received payment from Vertex for the current work and personal fees for serving on an advisory board; grants from Vertex and from the German Ministry for Education and Research; consulting fees from Boehringer Ingelheim, Arrowhead Pharmaceuticals, Vertex Pharmaceuticals, Santhera, Sterna Biologicals, Enterprise Therapeutics, Antabio, and Abbvie; lecture fees from Boehringer Ingelheim, Arrowhead Pharmaceuticals, and Vertex Pharmaceuticals; travel reimbursement from Boehringer Ingelheim and Vertex Pharmaceuticals; personal fees for participation in an advisory board from Boehringer Ingelheim, Arrowhead Pharmaceuticals, Vertex Pharmaceuticals, Santhera, Enterprise Therapeutics, Antabio, Kither Biotech, Abbvie, and Pari; and serves as an ECFS Board member. EFM received grants and other payments or honoraria from Vertex; and support for meetings or travel from Menarini. BWR received payments from Vertex for the present work, and payments for a presentation in Vancouver, BC, Canada in 2019; and participated on data safety monitoring boards or advisory boards for CF Storm Clinical Trial, Vertex Pharmaceuticals, Janssen, Abbvie, and Insmed. SMR received support for a clinical trial; consulting fees on the design and conduct of clinical trials; support for meeting attendance and for his role as Co-Chair of the Next Generation Steering Committee; received grants or contracts from Novartis, TranslateBio, Galapagos–Abbvie, Synedgen–Synspira, Eloxx, Vertex Pharmaceuticals, and Ionis Astra Zenica; consulting fees from Novartis, Galapagos–Abbvie, Synedgen–Synspira, Vertex Pharmaceuticals, Renovion, Ionis, Cystetic Medicines, and Arcturus; support for meeting attendance from Vertex; has patents planned, issued or pending; serves as a Co-Chair of the Next Generation Steering Committee; and owns stock or stock options with Synedgen–Synspira and Renovion. RCR received clinical trial support and consulting fees from Vertex for the present work; grants from CFF, NIDDK, NHLBI, NICHD, and NIDCD; received consulting fees from Guidepoint Global, Gerson Lehrman Group, and Cystic Fibrosis Foundation; participated on a data safety monitoring or advisory board for NHLBI DSMB. JLT-C received personal consulting fees from Vertex for the present work; received grants from Vertex, Eloxx, and 4DMT for the conduct of a research trial; personal fees from Vertex, Insmed, and 4DMT for trial design consulting; personal fees from Vertex for non-branded speaking; and personal fees from AbbVie for her role as DMC Chair; served as the adult patient care representative to the CFF Board of Trustees, on the CF Foundation's Clinical Research Executive Committee, Clinical Research Advisory Board, and Racial Justice Working Group; as immediate past chair of the CF TDN's Sexual Health, Reproduction and Gender Research Working Group; on the scientific advisory board for Emily's Entourage; on the ATS Respiratory Health Awards Working Group; on the ATS Scientific Grant Review and Clinical Problems Assembly Programming Committees; and served as an associate editor for the Journal of Cystic Fibrosis. ET received payment for the present work and grants for doing clinical trials from Vertex Pharmaceuticals; received payment and reimbursement from Vertex for her role on a steering committee and for presentations at educational events. JB received funding from Vertex Pharmaceuticals for the present work. AH received funding from Vertex Pharmaceuticals for the present work; grant support from NIHR, CF Trust, CF Foundation, and Medical Research Council; payments for educational lectures from Vertex Pharmaceuticals and for an advisory board from Mylan; medical writing support from Vertex; served as Chair of the UK CF Clinical Trials Accelerator Platform and as a board member of the UK CF Medical Association. LMY received salary support from mgH TDN for clinical research activity for the present work. DW has patents planned, issued or pending. DW, LTW, CC, APM, NN, PRS, ST, FVG, and YX are Vertex employees and might own stocks or stock options. GM and CK have nothing to disclose. LV was a clinical pharmacology lead at Vertex during the conduct of this study and conducted PK data analysis for the present study., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Objectives: Cystic fibrosis is a devastating life-limiting genetic condition characterised by a progressive decline in lung function, respiratory infections and premature death. Tezacaftor-ivacaftor is a combined cystic fibrosis transmembrane conductance regulator (CFTR) modulator that targets the underlying cause of the disease. This study aimed to assess the impact of tezacaftor-ivacaftor use in routine clinical practice for adults with cystic fibrosis., Methods: A retrospective observational longitudinal cohort study design was applied to examine the clinical effect of tezacaftor-ivacaftor in routine practice in the West of Scotland Adult Cystic Fibrosis Unit. Adults receiving tezacaftor-ivacaftor for at least 4 weeks were included in this medicine use evaluation.A standardised data form was used to collect patient-level data: demographics, genotype, complications of cystic fibrosis, medicine access process. Fifty-two weeks pre and post tezacaftor-ivacaftor initiation data: lung function, body mass index (BMI), days spent in hospital, days receiving antibiotic treatment for respiratory exacerbations. Anonymised data were collated and analysed using SPSS V.26., Results: Of 121 potential patients, 45 received treatment with tezacaftor-ivacaftor; median age 30 years (range 17-64) at initiation, 56% were male, 76% were deemed to be homozygote and 41 patients continued treatment for at least 52 weeks. There was no significant change in % predicted FEV 1 ; median difference 0 (IQR -3 to 6). There was a significant improvement in BMI, mean 0.6 kg/m 2 (95% CI 0.2 to 1.0), as well as a median 4 (IQR -17 to 0) day reduction in days in hospital and 21 (IQR -42 to 0) day reduction in days receiving antibiotics., Conclusions: The use of tezacaftor-ivacaftor in routine practice for people with cystic fibrosis was associated with improvements in weight, as well as reducing the number of days people needed to spend in hospital and receive antibiotics., Competing Interests: Competing interests: IP has received payment as an external speaker at a Vertex sponsored scientific event. CJ has no competing interests. GM has been the principal and chief investigator on a variety of Vertex studies, and has received funding from Vertex for investigator-led trials, attended advisory boards and received unrestricted educational grants on behalf of the Scottish Cystic Fibrosis Group., (© European Association of Hospital Pharmacists 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Ivacaftor has shown to be effective in patients with cystic fibrosis (CF) with a G551D mutation., Objectives: This work aims to evaluate ivacaftor's effectiveness and safety in the real world, over 5 years, in the West of Scotland CF population., Methods: We evaluated ivacaftor's effect on pulmonary function, body mass index (BMI), hospital bed occupancy, and adverse effects in patients ≥6 years with at least one G551D mutation., Results: Statistically significant increases from baseline were observed in mean per cent predicted forced expiratory volume in 1 s (FEV 1 ) at year 1 (which was maintained at years 2 and 5) and BMI over 5 years in our adolescent/adult cohort. Improvements were observed in per cent predicted FEV 1 within the paediatric cohort with a suggestion of a plateau effect. The increase in paediatric BMI z-score was nonstatistically significant. There was a reduction in the number of pulmonary exacerbations requiring intravenous antibiotics and hospital bed occupancy. Ivacaftor was well tolerated., Conclusion: Ivacaftor was effective in our population., (© 2023 The Authors. The Clinical Respiratory Journal published by John Wiley & Sons Ltd.)

In the Republic of Ireland (ROI), BRCA1/BRCA2 genetic testing has been traditionally undertaken in eligible individuals, after pre-test counselling by a Clinical Geneticist/Genetic Counsellor. Clinical Genetics services in ROI are poorly resourced, with routine waiting times for appointments at the time of this pilot often extending beyond a year. The consequent prolonged waiting times are unacceptable where therapeutic decision-making depends on the patient's BRCA status. "Mainstreaming" BRCA1/BRCA2 testing through routine oncology/surgical clinics has been implemented successfully in other centres in the UK and internationally. We aimed to pilot this pathway in three Irish tertiary centres. A service evaluation project was undertaken over a 6-month period between January and July 2017. Eligible patients, fulfilling pathology and age-based inclusion criteria defined by TGL clinical, were identified, and offered constitutional BRCA1/BRCA2 testing after pre-test counselling by treating clinicians. Tests were undertaken by TGL Clinical. Results were returned to clinicians by secure email. Onward referrals of patients with uncertain/pathogenic results, or suspicious family histories, to Clinical Genetics were made by the treating team. Surveys assessing patient and clinician satisfaction were sent to participating clinicians and a sample of participating patients. Data was collected with respect to diagnostic yield, turnaround time, onward referral rates, and patient and clinician feedback. A total of 101  patients underwent diagnostic germline BRCA1/BRCA2 tests through this pathway. Pathogenic variants were identified in 12 patients (12%). All patients in whom variants were identified were appropriately referred to Clinical Genetics. At least 12 additional patients with uninformative BRCA1/BRCA2 tests were also referred for formal assessment by Clinical Geneticist or Genetic Counsellor. Issues were noted in terms of time pressures and communication of results to patients. Results from a representative sample of participants completing the satisfaction survey indicated that the pathway was acceptable to patients and clinicians. Mainstreaming of constitutional BRCA1/BRCA2 testing guided by age- and pathology-based criteria is potentially feasible for patients with breast cancer as well as patients with ovarian cancer in Ireland., (© 2022. The Author(s), under exclusive licence to Springer Nature B.V.)

Calcitonin gene-related peptide (CGRP) antagonist medications have become the mainstay of acute and chronic migraine management in the outpatient setting and look to become more widely utilized by clinicians once the medications become available in generic form. However, their role in practice has remained limited to the treatment of migraines despite the ubiquitous presence of the molecule throughout the body. The literature surrounding expansion of the utility of these medications is limited; however, there have been several promising publications, and further studies are in the process to quantify their utility in the treatment of other pain-related disorders. This is a qualitative review of the current literature surrounding CGRP, particularly in relation to the treatment of non-migraine pain conditions, and looks to suggest potential utility in the field of chronic pain., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Cooper et al.)

Introduction: In China, salt intake is among the highest in the world (~11 g/day) and cardiovascular disease (CVD) accounts for 40% of deaths. We estimated the potential impact of reducing salt intake on CVD events in China, via systolic blood pressure (SBP)., Methods: To develop our model, we extracted the effect of salt reduction on SBP from a meta-regression of randomised trials and a population study, and that of SBP on CVD risk from pooled cohort studies., Results: Reducing population salt intake in China by 1 g/day could lower the risk for ischaemic heart disease by about 4% (95% uncertainty interval 1.8%-7.7%) and the risk for stroke by about 6% (2.4%-9.3%). Should this reduced salt level be sustained until 2030,~9 million (M) (7M-10.8M) CVD events could be prevented, of which ~4M (3.1M-4.9M) would have been fatal. Greater and gradual salt intake reductions, to achieve WHO's target of 30% reduction by 2025 or the Chinese government's target of ≤5 g/day by 2030, could prevent ~1.5 or 2 times more CVD events and deaths, respectively. Should the prolonged effect of salt reduction over several years be accounted for, all estimates of CVD events and deaths prevented would be 25% greater on average., Conclusion: Bringing down the high salt intake levels in China could result in large reductions in CVD. An easily achievable reduction of 1 g/day could prevent ~9M CVD events by 2030. Urgent action must be taken to reduce salt intake in China., Competing Interests: Competing interests: FH is a member of the Consensus Action on Salt & Health group, a non-profit charitable organisation, and its international branch, World Action on Salt & Health, and does not receive any financial support from the Consensus Action on Salt & Health or World Action on Salt & Health. GM is the Chairman of Blood Pressure UK, Chairman of the Consensus Action on Salt & Health, and Chairman of World Action on Salt & Health and does not receive any financial support from any of these organisations. Blood Pressure UK, the Consensus Action on Salt & Health, and World Action on Salt & Health are non-profit charitable organisations. MT and JKM declare no competing interests., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Background: Elexacaftor plus tezacaftor plus ivacaftor is a triple-combination cystic fibrosis transmembrane conductance regulator (CFTR) modulator regimen shown to be generally safe and efficacious in people with cystic fibrosis aged 12 years or older with at least one F508del-CFTR allele. We aimed to assess the magnitude and durability of the clinical effects of this triple combination regimen in people with cystic fibrosis homozygous for the F508del-CFTR mutation., Methods: We conducted a multicentre, randomised, double-blind, active-controlled, phase 3b trial of elexacaftor plus tezacaftor plus ivacaftor at 35 medical centres in Australia, Belgium, Germany, and the UK. Eligible participants were those with cystic fibrosis homozygous for the F508del-CFTR mutation, aged 12 years or older with stable disease, and with a percent predicted FEV 1 of 40-90% inclusive. After a 4-week run-in period, in which participants received tezacaftor 100 mg orally once daily and ivacaftor 150 mg orally every 12 h, participants were randomly assigned (1:1) to receive 24 weeks of either elexacaftor 200 mg orally once daily plus tezacaftor 100 mg orally once daily plus ivacaftor 150 mg orally every 12 h (elexacaftor plus tezacaftor plus ivacaftor group) or tezacaftor 100 mg orally once daily plus ivacaftor 150 mg orally every 12 h (tezacaftor plus ivacaftor group). Randomisation was stratified by percent predicted FEV 1 , age at screening visit, and whether the participant was receiving CFTR modulators at the time of the screening visit. Patients, investigators, and sponsor's study execution team were masked to treatment assignment. The primary endpoint was the absolute change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain score from baseline (ie, at the end of the tezacaftor plus ivacaftor run-in period) up to and including week 24. The key secondary endpoint was the absolute change from baseline in percent predicted FEV 1 up to and including week 24; other secondary endpoints were the absolute change from baseline in sweat chloride concentrations up to and including week 24, and safety and tolerability. All endpoints were assessed in all randomised patients who had received at least one dose of their assigned regimen. This study is registered with ClinicalTrials.gov, NCT04105972., Findings: Between Oct 3, 2019, and July 24, 2020, 176 participants were enrolled. Following the 4-week tezacaftor plus ivacaftor run-in period, 175 participants were randomly assigned (87 to the elexacaftor plus tezacaftor plus ivacaftor group and 88 to the tezacaftor plus ivacaftor group) and dosed in the treatment period. From baseline up to and including week 24, the mean CFQ-R respiratory domain score increased by 17·1 points (95% CI 14·1 to 20·1) in the elexacaftor plus tezacaftor plus ivacaftor group and by 1·2 points (-1·7 to 4·2) in the tezacaftor plus ivacaftor group (least squares mean treatment difference 15·9 points [95% CI 11·7 to 20·1], p<0·0001), the mean percent predicted FEV 1 increased by 11·2 percentage points (95% CI 9·8 to 12·6) in the elexacaftor plus tezacaftor plus ivacaftor group and by 1·0 percentage points (-0·4 to 2·4) in the tezacaftor plus ivacaftor group (least squares mean treatment difference 10·2 percentage points [8·2 to 12·1], p<0·0001), and the mean sweat chloride concentration decreased by 46·2 mmol/L (95% CI 43·7 to 48·7) in the elexacaftor plus tezacaftor plus ivacaftor group and by 3·4 mmol/L (1·0 to 5·8) in the tezacaftor plus ivacaftor group (least squares mean treatment difference -42·8 mmol/L [-46·2 to -39·3], nominal p<0·0001). Most participants (70 [80%] in the elexacaftor plus tezacaftor plus ivacaftor group and 74 [84%] in the tezacaftor plus ivacaftor group) had adverse events that were mild or moderate in severity; serious adverse events occurred in five (6%) of 87 participants in the elexacaftor plus tezacaftor plus ivacaftor group and 14 (16%) of 88 participants in the tezacaftor plus ivacaftor group. One (1%) participant in the elexacaftor plus tezacaftor plus ivacaftor group discontinued treatment due to an adverse event of anxiety and depression. Two (2%) participants in the tezacaftor plus ivacaftor group discontinued treatment due to adverse events of psychotic disorder (n=1) and obsessive-compulsive disorder (n=1)., Interpretation: The elexacaftor plus tezacaftor plus ivacaftor regimen was safe and well tolerated, and led to significant and clinically meaningful improvements in respiratory-related quality of life and lung function, as well as improved CFTR function, changes that were durable over 24 weeks and superior to those seen with tezacaftor plus ivacaftor in this patient population., Funding: Vertex Pharmaceuticals., Competing Interests: Declaration of interests SS received personal fees from Proteostasis Therapeutics, Novartis Pharma, Vertex Pharmaceuticals, Chiesi, and Teva outside of the submitted work; and grants from Galapagos, Proteostasis Therapeutics, Celtaxsys, Flatley, Vertex Pharmaceuticals, Teva, Chiesi, Boehringer Ingelheim, Corbus Pharmaceuticals, and Ionis Pharmaceuticals outside of the submitted work. EFM received personal fees and grants from Vertex Pharmaceuticals during the conduct of the study; personal fees from Roche Pharmaceuticals, Insmed, and Janssen Pharmaceuticals; and other financial support from A Menarini outside of the submitted work. DGD received non-financial support from Vertex Pharmaceuticals during the conduct of the study; personal fees from Vertex Pharmaceuticals, Proteostasis, and Chiesi; and grants from Chiesi outside of the submitted work. JD received advisory board and speaker fees from Vertex Pharmaceuticals outside of the submitted work. EVB received institutional grants from Vertex Pharmaceuticals for the submitted work; and institutional grants from Vertex Pharmaceuticals, Galapagos, and Abbvie for other cystic fibrosis-related trials. MAM received personal fees from Vertex Pharmaceuticals during the conduct of the study; grants from Vertex Pharmaceuticals; and personal fees from Boehringer Ingelheim, Arrowhead Pharmaceuticals, Vertex Pharmaceuticals, Santhera, Galapagos, Sterna Biologicals, Enterprise Therapeutics, Kither Biotech, and Antabio outside of the submitted work. ET received grants and non-financial support from Vertex Pharmaceuticals during the conduct of the study; grants from Abbvie, Boehringer Ingelheim, Bayer, Spyryx, Horizon, Corbus, and Celtaxis; personal fees from Proteostasis and Horizon; and non-financial support from Proteostasis and Spyryx outside of the submitted work. CEW received institutional grants from Vertex Pharmaceuticals during the conduct of the study; grants from Novo Nordisk outside of the submitted work; and personal fees from Vertex Pharmaceuticals, Boehringer Ingelheim, Novartis, DKBmed, Gilead, and In Vivo Academy outside of the submitted work. DWal and SMM have pending patents for methods of treatment for cystic fibrosis, pharmaceutical compositions for treatment of cystic fibrosis, compositions and methods for treatment of cystic fibrosis, and crystalline forms and compositions of CFTR modulators. DWal and SMM have issued patents for crystalline forms and compositions of CFTR modulators. NA, BGB, CH, APL, YL, SMM, ST, JY, and DWal are employees of Vertex Pharmaceuticals and might own stock or stock options in the company. GM and DWat declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Purpose of Review: High dietary sodium is estimated to be the leading dietary risk for death attributed to 1.8 million deaths in 2019. There are uniform recommendations to reduce sodium consumption based on evidence that increased dietary sodium is responsible for approximately a third of the prevalence of hypertension, and meta-analyses of randomized controlled trials show that sodium reduction lowers blood pressure, cardiovascular disease, and total mortality. Nevertheless, there is a perception that the beneficial effect of reducing dietary sodium is controversial. We provide experiential evidence relating to some sources of the controversy and propose potential solutions., Recent Findings: Inappropriate research methodology, lack of rigor in research, conflicts of interest and commercial bias, questions of professional conduct, and lack of policies to protect public interests are likely to contribute to the controversy about reducing dietary sodium. There is a failure to protect policies to reduce dietary sodium from nonscientific threats. Significant efforts need to be made to ensure the integrity of nutritional research and maintain public trust., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: High sodium intake was an established risk factor for stroke and cardiovascular diseases. The objective of this study was to investigate factors associated with high sodium intake based on 24-h urinary sodium excretion from the MyCoSS study., Methods: The cross-sectional survey was conducted among adults aged 18 years and above in Malaysia. A multi-stage stratified sampling was used to represent nationally. Twenty-four-hour urine was collected from a total of 900 respondents. Indirect ion-selective electrode (ISE) method was used to measure sodium intake. Descriptive and logistic regression analysis was applied to determine factors associated with high sodium intake based on 24-h urinary sodium excretion., Results: A total of 798 respondents (76% response rate) completed the 24-h urine collection process. Logistic regression revealed that high sodium intake associated with obese [aOR 2.611 (95% CI 1.519, 4.488)], male [aOR 2.436 (95% CI 1.473, 4.030)], having a waist circumference of > 90cm for adult males [aOR 2.260 ( 95% CI 1.020, 5.009) and >80cm for adult females [aOR 1.210 (95% CI 0.556, 2.631)], being a young adult [aOR 1.977 (95% CI 1.094, 3.574)], and living in urban areas [aOR 1.701 (95% CI 1.094, 2.645)]., Conclusion: Adults who are obese, have a large waist circumference, of male gender, living in urban areas, and belonging to the young adult age group were found to have higher sodium intake than other demographic groups. Hence, reduction of salt consumption among these high-risk groups should be emphasised to reduce the risk of cardiovascular diseases.

Background: Hypertension is one of the most common risk factors for cardiovascular disease and leading cause of mortality globally. The aims of this study were to assess the prevalence of hypertension and its associated risk factors among Malaysian population using data from the Malaysian Community Salt Study (MyCoSS)., Methods: This study was a cross-sectional study using multi-stage stratified sampling method. Data collection was carried out via face-to-face interview at the respondent's home from October 2017 until March 2018. A total of 1047 respondents aged 18 years and above completed the questionnaires and blood pressure measurement. A person who reported diagnosis of hypertension by a physician and had systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg on three readings was categorised as hypertensive. Risk factors of hypertension were analysed using multiple logistic regression., Results: The prevalence of hypertension in the present study was 49.39% (95% CI 44.27-54.51). There was no statistically significant difference in gender. Age, household income, BMI, and diabetes were significantly associated with hypertension. Hypertension found had inverse association with the level of education. Age was the strongest predictor of hypertension (35-44 years old; OR=2.39, 95% CI=1.39-4.09, 45-54 years old; OR=5.50, 95% CI=3.23-9.38, 55-64 years old OR=13.56, 95% CI=7.77-23.64 and 65 years old and above; OR=25.28, 95% CI=13.33-48.66). Those who had higher BMI more likely to be hypertensive as compared to respondents with normal weight (overweight, OR=1.84; 95% CI=1.18-2.86; obese, OR=4.29% CI=2.56-7.29)., Conclusion: The findings showed that hypertension is prevalent among adults in Malaysia. Those with older age, higher BMI, and diabetes are more likely to have hypertension. Efforts regarding lifestyle modification and education could be important in hypertension management and prevention.

Background: Sodium is an essential mineral needed by the human body that must be obtained from food. An excess intake, however, can lead to many diseases. As food is the main source of sodium, this study aims to provide information on high sodium food consumption patterns in the Malaysian adult population., Methods: The Malaysian Community Salt Study (MyCoSS) was a nationwide cross-sectional study, conducted between October 2017 and March 2018. A multistage complex sample was applied to select a nationally representative sample of respondents aged 18 years and above. Face to face interview by a validated Food Frequency Questionnaire (FFQ) comprising 104 food items was used to gain information on high sodium food consumption patterns., Results: A total of 1047 respondents were involved in this study, with 1032 (98.6%) answering the FFQ. From the number, 54.1% exceed the recommendation of sodium intake <2000mg/day by FFQ assessment. The results also demonstrated that fried vegetables (86.4%) were the most common high sodium food consumed, followed by bread (85.9%) and omelet (80.3%). In urban areas, bread was the most common while fried vegetables took the lead in rural areas. By sex, bread was most commonly eaten by males and fried vegetables by females. The results also found that kolok mee/kampua mee contributed the highest sodium, 256.5mg/day in 9.0% adult population, followed by soy sauce 248.1mg/day in 33.2% adult population, and curry noodles 164.2mg/day in 18.5% adult population., Conclusion: Fried vegetables, bread, and soy sauce were the main source of sodium consumption among adult. Reducing the amount of sodium added to these foods should be the top priority to reduce population sodium intake and thereby prevent sodium-related diseases in Malaysia.

Although almost all mycobacterial species are saprophytic environmental organisms, a few, such as Mycobacterium tuberculosis , have evolved to cause transmissible human infection. By analyzing the recent emergence and spread of the environmental organism M. abscessus through the global cystic fibrosis population, we have defined key, generalizable steps involved in the pathogenic evolution of mycobacteria. We show that epigenetic modifiers, acquired through horizontal gene transfer, cause saltational increases in the pathogenic potential of specific environmental clones. Allopatric parallel evolution during chronic lung infection then promotes rapid increases in virulence through mutations in a discrete gene network; these mutations enhance growth within macrophages but impair fomite survival. As a consequence, we observe constrained pathogenic evolution while person-to-person transmission remains indirect, but postulate accelerated pathogenic adaptation once direct transmission is possible, as observed for M. tuberculosis Our findings indicate how key interventions, such as early treatment and cross-infection control, might restrict the spread of existing mycobacterial pathogens and prevent new, emergent ones., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Background: Emerging data suggests a possible role for cysteamine as an adjunct treatment for pulmonary exacerbations of cystic fibrosis (CF) that continue to be a major clinical challenge. There are no studies investigating the use of cysteamine in pulmonary exacerbations of CF. This exploratory randomized clinical trial was conducted to answer the question: In future pivotal trials of cysteamine as an adjunct treatment in pulmonary exacerbations of CF, which candidate cysteamine dosing regimens should be tested and which are the most appropriate, clinically meaningful outcome measures to employ as endpoints?, Methods and Findings: Multicentre double-blind randomized clinical trial. Adults experiencing a pulmonary exacerbation of CF being treated with standard care that included aminoglycoside therapy were randomized equally to a concomitant 14-day course of placebo, or one of 5 dosing regimens of cysteamine. Outcomes were recorded on days 0, 7, 14 and 21 and included sputum bacterial load and the patient reported outcome measures (PROMs): Chronic Respiratory Infection Symptom Score (CRISS), the Cystic Fibrosis Questionnaire-Revised (CFQ-R); FEV1, blood leukocyte count, and inflammatory markers. Eighty nine participants in fifteen US and EU centres were randomized, 78 completed the 14-day treatment period. Cysteamine had no significant effect on sputum bacterial load, however technical difficulties limited interpretation. The most consistent findings were for cysteamine 450mg twice daily that had effects additional to that observed with placebo, with improved symptoms, CRISS additional 9.85 points (95% CI 0.02, 19.7) p = 0.05, reduced blood leukocyte count by 2.46x109 /l (95% CI 0.11, 4.80), p = 0.041 and reduced CRP by geometric mean 2.57 nmol/l (95% CI 0.15, 0.99), p = 0.049., Conclusion: In this exploratory study cysteamine appeared to be safe and well-tolerated. Future pivotal trials investigating the utility of cysteamine in pulmonary exacerbations of CF need to include the cysteamine 450mg doses and CRISS and blood leukocyte count as outcome measures., Clinical Trial Registration: NCT03000348; www.clinicaltrials.gov., Competing Interests: The authors have read the journal's policy and have the following competing interests: Deborah A O’Neil (DO) is the CEO, CSO, and shareholder of the trial sponsor NovaBiotics Ltd. Douglas J Fraser-Pitt (DFP) is a Principal Scientist and salaried employee of the trial sponsor NovaBiotics Ltd. Emma Lovie (EL) is a research scientist and Jennifer Robertson (JR) is a laboratory manager/research scientist; Both are salaried employees of the trial sponsor NovaBiotics Ltd. Graham Devereux (GD) received support from NovaBiotics Ltd to attend the 2018 NACFC. Danielle Wrolstad (DW) reports personal fees through her employer (Precision Medicine Group) from NovaBiotics Ltd, during the study. Rose Franco (RF), Stephen J Bourke (SB), Benjamin T Kopp (BK) and Ryan Dougherty (RD) report grant from NovaBiotics Ltd during the conduct of the study. SB & BK report grants from Vertex outside the submitted work. DFP and DO are authors of patent; WO2016198842A1, IL256162D0 - An amino thiol for use in the treatment of an infection caused by the bacterium mycobacterium spp. DO is also author of the following patents; US9364491B2 (and other territories) - Antimicrobial compositions with cysteamine/A composition comprising an antibiotic and a dispersant; WO2016046524A1 - Use of cysteamine in treating infections caused by yeasts/moulds; US9782423B2 (and other territories) - Antibiotic compositions comprising an antibiotic agent and cysteamine; US9339525B2 (and other territories) - Inhibition of biofilm organisms; and US20190175501A1 pending (and other territories) - Microparticles comprising a sulphur-containing compound. (JR, EL, DFP, and DO) are involved in the development of cysteamine bitartrate as a therapy for cystic fibrosis. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: OligoG is a low molecular-weight alginate oligosaccharide that improves the viscoelastic properties of cystic fibrosis (CF) mucus and disrupts biofilms, thereby potentiating the activity of antimicrobial agents. The efficacy of inhaled OligoG was evaluated in adult patients with CF., Methods: A randomised, double-blind, placebo-controlled multicentre crossover study was used to demonstrate safety and efficacy of inhaled dry powder OligoG. Subjects were randomly allocated to receive OligoG 1050 mg per day (10 capsules three times daily) or matching placebo for 28 days, with 28-day washout periods following each treatment period. The primary end-point was absolute change in percentage predicted forced expiratory volume in 1 s (FEV 1 ) at the end of 28-day treatment. The intention-to-treat (ITT) population (n=65) was defined as randomised to treatment with at least one administration of study medication and post-dosing evaluation., Results: In this study, 90 adult subjects were screened and 65 were randomised. Statistically significant improvement in FEV 1 was not observed in the ITT population. Adverse events included nasopharyngitis, cough and pulmonary exacerbation. The number and proportions of patients with adverse events and serious adverse events were similar between OligoG and placebo group., Conclusions: Inhalation of OligoG-dry powder over 28 days was safe in adult CF subjects. Statistically significant improvement of FEV 1 was not reached. The planned analyses did not indicate a significant treatment benefit with OligoG compared to placebo. Post hoc exploratory analyses showed subgroup results that indicate that further studies of OligoG in this patient population are justified., Competing Interests: Conflict of interest: S. van Koningsbruggen-Rietschel reports grants from Horizon 2020 and personal fees from DZIF, outside the submitted work. Conflict of interest: J.C. Davies reports work on an advisory board and as a clinical trial lead for Algipharma AS, work as UK Lead Investigator and on an advisory board for Bayer AG, work on an advisory board for Boehringer Ingelheim Pharma GmbH & Co. KG, work on an advisory board and clinical trial leadership for Galapagos NV, advisory and clinical trial design assistance for ImevaX GmbH, work on an advisory board for Nivalis Therapeutics, Inc., work on an advisory board and clinical trial design advice for ProQR Therapeutics III B.V., advisory work and clinical trial leadership for Proteostasis Therapeutics, Inc., advisory work for Raptor Pharmaceuticals, Inc., work on an advisory board and National Co-ord/Global Co-I for Vertex Pharmaceuticals (Europe) Limited, work on advisory boards for Enterprise, Novartis, Pulmocide and Flatley, grants from the CF Trust, and educational activities for Teva, outside the submitted work. Conflict of interest: T. Pressler has nothing to disclose. Conflict of interest: R. Fischer has nothing to disclose. Conflict of interest: G. MacGregor has nothing to disclose. Conflict of interest: S.H. Donaldson reports grants from AlgiPharma during the conduct of the study; and grants from Vertex Pharmaceuticals, AstraZeneca and Proteostasis Therapeutics outside the submitted work. Conflict of interest: K. Smerud reports that his employer, Smerud Medical Research International AS, is a contract research organisation that delivered clinical trial management services (clinical trial management, clinical trial applications, data management, statistical planning and analysis, monitoring, and medical writing) to Algipharma and was remunerated for that work. Conflict of interest: N. Meland reports grants from AlgiPharma AS during the conduct of the study. Conflict of interest: J. Mortensen has nothing to disclose. Conflict of interest: M.Ø. Fosbøl has nothing to disclose. Conflict of interest: D.G. Downey reports grants and personal fees from Vertex, Proteostasis, Chiesi and Gilead, outside the submitted work. Conflict of interest: A.H. Myrset reports grants from Cystic Fibrosis Foundation during the conduct of the study, and holds stock in AlgiPharma AB outside the submitted work. Conflict of interest: H. Flaten reports grants from Cystic Fibrosis Foundation during the conduct of the study; and is a qualified person for Pharmacovigilance for AlgiPharma and holds stock in AlgiPharma AB, outside the submitted work. Conflict of interest: P.D. Rye reports grants from Cystic Fibrosis Foundation during the conduct of the study, and is Chief Scientific Officer at AlgiPharma and holds stock in AlgiPharma AB, outside the submitted work; in addition, he has patents WO 2015/128495 and WO 2016/151051 pending., (Copyright ©ERS 2020.)

Background: Clinical studies demonstrate that ivacaftor (IVA) improves health-related quality of life (HRQoL) in patients aged ≥6 years with cystic fibrosis (CF). The real-world impact of IVA and standard of care (SOC) in groups of patients with G551D and F508del mutations, respectively, was assessed using a survey comprising disease-specific and generic HRQoL measures., Methods: Patients with CF aged ≥12 years, or aged 6-11 years with caregiver support, with either (1) a G551D mutation and receiving IVA (G551D/IVA) for ≥3 months, or (2) homozygous for F508del and receiving SOC before lumacaftor/IVA availability (F508del/SOC), were eligible to participate in a cross-sectional survey. Demographic and clinical characteristics, and HRQoL measures were compared between patient groups, and multiple regression analyses were conducted., Results: After differences in patient demographic and clinical characteristics were controlled for, significantly better scores were observed in the G551D/IVA group than in the F508del/SOC group on multiple domains of the validated Cystic Fibrosis Questionnaire-Revised and the EuroQol 5-dimensions 5-level questionnaire., Conclusions: G551D/IVA patients reported better HRQoL than F508del/SOC patients on generic and disease-specific measures in a real-world setting.

The International Consortium for Quality Research on Dietary Sodium/Salt (TRUE) is a coalition of intentional and national health and scientific organizations formed because of concerns low-quality research methods were creating controversy regarding dietary salt reduction. One of the main sources of controversy is believed related to errors in estimating sodium intake with urine studies. The recommendations and positions in this manuscript were generated following a series of systematic reviews and analyses by experts in hypertension, nutrition, statistics, and dietary sodium. To assess the population's current 24-hour dietary sodium ingestion, single complete 24-hour urine samples, collected over a series of days from a representative population sample, were recommended. To accurately estimate usual dietary sodium at the individual level, at least 3 non-consecutive complete 24-hour urine collections obtained over a series of days that reflect the usual short-term variations in dietary pattern were recommended. Multiple 24-hour urine collections over several years were recommended to estimate an individual's usual long-term sodium intake. The role of single spot or short duration timed urine collections in assessing population average sodium intake requires more research. Single or multiple spot or short duration timed urine collections are not recommended for assessing an individual's sodium intake especially in relationship to health outcomes. The recommendations should be applied by scientific review committees, granting agencies, editors and journal reviewers, investigators, policymakers, and those developing and creating dietary sodium recommendations. Low-quality research on dietary sodium/salt should not be funded, conducted, or published., (©2019 Wiley Periodicals, Inc.)

Staphylococcus aureus infections are a cause of significant morbidity and mortality, in addition to representing a considerable economic burden. The aim of this study was to explore a low cost screen printed electrode as a sensor for the detection of S. aureus using impedance spectroscopy. S. aureus was incubated in chambers containing the electrodes and the results analysed using a novel normalisation approach. These results show that it is possible to detect the presence of S. aureus in LB media after 30 min incubation of a 1% growth culture, in addition to being able to see immediate cell concentration dependant changes in 0.9% NaCl. These observations imply that a number of electrochemical mechanisms cause a change in the impedance as a result of the presence of S. aureus, including adsorption to the electrode surface and the metabolism of the bacteria during growth. The study suggests that this detection approach would be useful in a number of clinical scenarios where S. aureus leads to difficult to treat infections., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

There is a significant unmet need for safe and effective anti-inflammatory treatment for cystic fibrosis. The aim of this study was to evaluate the safety of acebilustat, a leukotriene A4 hydrolase inhibitor, and its effect on inflammation biomarkers in patients with cystic fibrosis. Seventeen patients with mild to moderate cystic fibrosis were enrolled and randomized into groups receiving placebo or doses of 50 mg or 100 mg acebilustat administered orally, once daily for 15 days. Sputum neutrophil counts were reduced by 65% over baseline values in patients treated with 100 mg acebilustat. A modestly significant 58% reduction vs. placebo in sputum elastase was observed with acebilustat treatment. Favorable trends were observed for reduction of serum C-reactive protein and sputum neutrophil DNA in acebilustat-treated patients. No changes in pulmonary function were observed. Acebilustat was safe and well tolerated. The results of this study support further clinical development of acebilustat for treatment of cystic fibrosis., (© 2016 The Authors. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Lung infections with Mycobacterium abscessus, a species of multidrug-resistant nontuberculous mycobacteria, are emerging as an important global threat to individuals with cystic fibrosis (CF), in whom M. abscessus accelerates inflammatory lung damage, leading to increased morbidity and mortality. Previously, M. abscessus was thought to be independently acquired by susceptible individuals from the environment. However, using whole-genome analysis of a global collection of clinical isolates, we show that the majority of M. abscessus infections are acquired through transmission, potentially via fomites and aerosols, of recently emerged dominant circulating clones that have spread globally. We demonstrate that these clones are associated with worse clinical outcomes, show increased virulence in cell-based and mouse infection models, and thus represent an urgent international infection challenge., (Copyright © 2016, American Association for the Advancement of Science.)

Introduction: Mortality in patients with cystic fibrosis-related diabetes (CFRD) is higher than that in patients with cystic fibrosis without diabetes. Hypoglycemia, hyperglycemia, and glucose variability confer excess mortality and morbidity in the general inpatient population with diabetes., Methods: We investigated patterns of hypoglycemia and the association of hypoglycemia, hyperglycemia, and glucose variability with mortality and readmission rate in inpatients with CFRD. All capillary blood glucose (CBG) readings (measured using the Abbott Precision web system) of patients with insulin-treated CFRD measured within our health board between January 2009 and January 2015 were. Frequency and timing of hypoglycemia (<4 mmol/L) and was recorded. The effect of dysglycemia on readmission and mortality was investigated with survival analysis., Results: Sixty-six patients were included. A total of 22,711 CBG results were included in the initial analysis. Hypoglycemia was common with 1433 episodes (6.3%). Hypoglycemia ascertainment was highest between 2400 and 0600 h. Hypoglycemia was associated with a significantly higher rate of readmission or death over the 3.5-year follow-up period (P = 0.03). There was no significant association between hyperglycemia or glucose variability and the rate of readmission and mortality., Conclusion: Among inpatients with CFRD hypoglycemia is common and is associated with an increased composite endpoint of readmission and death. As with previously reported trends in general inpatient population this group shows a peak incidence of hypoglycemic during the night.

The host- and bacteria-derived extracellular polysaccharide coating of the lung is a considerable challenge in chronic respiratory disease and is a powerful barrier to effective drug delivery. A low molecular weight 12-15-mer alginate oligosaccharide (OligoG CF-5/20), derived from plant biopolymers, was shown to modulate the polyanionic components of this coating. Molecular modeling and Fourier transform infrared spectroscopy demonstrated binding between OligoG CF-5/20 and respiratory mucins. Ex vivo studies showed binding induced alterations in mucin surface charge and porosity of the three-dimensional mucin networks in cystic fibrosis (CF) sputum. Human studies showed that OligoG CF-5/20 is safe for inhalation in CF patients with effective lung deposition and modifies the viscoelasticity of CF-sputum. OligoG CF-5/20 is the first inhaled polymer therapy, represents a novel mechanism of action and therapeutic approach for the treatment of chronic respiratory disease, and is currently in Phase IIb clinical trials for the treatment of CF.

Epithelial cells are polarized and have tight junctions that contribute to barrier function. Assessment of barrier function typically involves measurement of electrophysiological parameters or movement of nonionic particles across an epithelium. Here, we describe measurement of transepithelial electrical conductance or resistance, determination of dilution potential, and assessment of flux of nonionic particles such as dextran or mannitol, with particular emphasis on Ussing chamber techniques.

Introduction: Staffing of rural and remote facilities is a challenge throughout the world. Umthombo Youth Development Foundation (UYDF) has been running a rurally based scholarship scheme since 1999.The aim of this review is to present data on the number of students selected, their progress, graduation and work placement from inception of the scheme until 2013., Methods: Data were extracted from the UYDF data base using a data collection template to ensure all important information was captured., Results: Since 1999, 430 rural students across 15 health disciplines have been supported by UYDF. The annual pass rate has been greater than 89%, and less than 10% of students have been excluded from university. All graduates have spent time working in rural areas (excluding the 32 currently doing internships) and 72% (52/73) of those with no work-back obligation continue to work in rural areas., Discussion and Conclusion: The UYDF model is built around local selection, compulsory academic and peer mentoring and social support, comprehensive financial support and experiential holiday work. The results are encouraging and highlight the fact that rural students can succeed at university and will come back and work in rural areas. With 46% of the South African population situated rurally, greater thought and effort must be put into the recruitment and training of rural scholars as a possible solution to the staffing of rural healthcare facilities. The UYDF provides a model which could be replicated in other parts of South Africa.

Introduction: The scientific evidence base in support of salt reduction is strong but the data required to translate these insights into reduced population salt intake are mostly absent. The aim of this research project is to develop the evidence base required to formulate and implement a national salt reduction programme for India., Methods and Analysis: The research will comprise three components: a stakeholder analysis involving government, industry, consumers and civil society organisations; a population survey using an age-stratified and sex-stratified random samples drawn from urban (slum and non-slum) and rural areas of North and South India; and a systematic quantitative evaluation of the nutritional components of processed and restaurant foods. The stakeholder interviews will be analysed using qualitative methods to summarise the main themes and define the broad range of factors influencing the food environment in India. The population survey will estimate the mean daily salt consumption through the collection of 24 h urine samples with concurrent dietary surveys identifying the main sources of dietary sodium/salt. The survey of foods will record the nutritional composition of the chief elements of food supply. The findings from this research will be synthesised and proposals for a national salt reduction strategy for India will be developed in collaboration with key stakeholders., Ethics and Dissemination: This study has been approved by the Human Research Ethics Committees of the University of Sydney and the Centre for Chronic Disease Control in New Delhi, and also by the Indian Health Ministry's Screening Committee. The project began fieldwork in February 2014 and will report the main results in 2016. The findings will be targeted primarily at public health policymakers and advocates, but will be disseminated widely through other mechanisms including conference presentations and peer-reviewed publications, as well as to the participating communities., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

The United Kingdom has successfully implemented a salt reduction programme. We carried out a comprehensive analysis of the programme with an aim of providing a step-by-step guide of developing and implementing a national salt reduction strategy, which other countries could follow. The key components include (1) setting up an action group with strong leadership and scientific credibility; (2) determining salt intake by measuring 24-h urinary sodium, identifying the sources of salt by dietary record; (3) setting a target for population salt intake and developing a salt reduction strategy; (4) setting progressively lower salt targets for different categories of food, with a clear time frame for the industry to achieve; (5) working with the industry to reformulate food with less salt; (6) engaging and recruiting of ministerial support and potential threat of regulation by the Department of Health (DH); (7) clear nutritional labelling; (8) consumer awareness campaign; and (9) monitoring progress by (a) frequent surveys and media publicity of salt content in food, including naming and shaming, (b) repeated 24-h urinary sodium at 3-5 year intervals. Since the salt reduction programme started in 2003/2004, significant progress has been made as demonstrated by the reductions in salt content in many processed food and a 15% reduction in 24-h urinary sodium over 7 years (from 9.5 to 8.1 g per day, P<0.05). The UK salt reduction programme reduced the population's salt intake by gradual reformulation on a voluntary basis. Several countries are following the United Kingdom's lead. The challenge now is to engage other countries with appropriate local modifications. A reduction in salt intake worldwide will result in major public health improvements and cost savings.

Background: We set out to determine the magnitude of antigen-specific memory T helper cell responses to Pseudomonas aeruginosa in healthy humans and patients with cystic fibrosis., Methods: Peripheral blood human memory CD4(+) T cells were co-cultured with dendritic cells that had been infected with different strains of Pseudomonas aeruginosa. The T helper response was determined by measuring proliferation, immunoassay of cytokine output, and immunostaining of intracellular cytokines., Results: Healthy individuals and patients with cystic fibrosis had robust antigen-specific memory CD4(+) T cell responses to Pseudomonas aeruginosa that not only contained a Th1 and Th17 component but also Th22 cells. In contrast to previous descriptions of human Th22 cells, these Pseudomonal-specific Th22 cells lacked the skin homing markers CCR4 or CCR10, although were CCR6(+). Healthy individuals and patients with cystic fibrosis had similar levels of Th22 cells, but the patient group had significantly fewer Th17 cells in peripheral blood., Conclusions: Th22 cells specific to Pseudomonas aeruginosa are induced in both healthy individuals and patients with cystic fibrosis. Along with Th17 cells, they may play an important role in the pulmonary response to this microbe in patients with cystic fibrosis and other conditions.

Introduction: Breast Q questionnaire measures patient's perceptions following breast reconstruction using quality of life and satisfaction. This study assessed patient reported outcomes following mastectomy and reconstruction utilizing Breast Q., Methods: All consecutive Letterkenny Hospital patients undergoing mastectomy and breast reconstruction between August 2008 and February 2011 were invited to complete Breast Q evaluation of their care. Collected data included: age; presenting complaint, height, weight; type of operation. RUMM 2020 program evaluated satisfaction where 0 is very dissatisfied to 100 very satisfied., Results: 30/33 (91%) patients completed Breast Q; mean age 43 ± 11 (range 29-64); mean BMI 27.3 ± 5 (range 21.7-43.1). 27 patients were symptomatic, and 3 were image detected. 23 had a latissimus dorsi reconstruction, 11 of these with implant augmentation, 5 had a DIEP and 2 implant only reconstruction. The mean satisfaction score of 79.7 indicating good to excellent results. Post reconstructive outcomes were not statistically different from pre-operative perceptions in key areas such as satisfaction with breasts, psychosocial and sexual well-being., Conclusion: This study identified outcomes as good as if not superior to international averages with preservation of satisfaction with breast and psychosocial well-being. Breast Q could help form a template for national benchmarks in patients undergoing mastectomy and reconstruction., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

To study the relationship between pre-dialysis plasma sodium and blood pressure (BP), we performed an audit of patients who were on stable haemodialysis at St Bartholomew's and The Royal London Hospital from 1 June 2009 to 15 June 2010. There were 651 patients with 7445 dialysis sessions where both plasma biochemistry and BP were measured before haemodialysis. We found a significant association between plasma sodium and both systolic and diastolic BP. A 1 mmol l(-1) increase in plasma sodium was related to 0.65/0.36 mm Hg increase in BP (P<0.001 for both systolic and diastolic BP) after adjusting for potential confounding factors, including weight gain between dialyses and plasma albumin, both of which are crude indices of extracellular fluid volume. A separate analysis excluding individuals who were on BP treatment showed a similar relationship, with a 1-mmol l(-1) increase in plasma sodium associated with 0.82/0.56 mm Hg increase in BP (P<0.001 for both, N=177). These results provide further support for the accumulating evidence that plasma sodium has an important role in regulating BP, which may be independent of extracellular volume. Our findings in conjunction with other evidence suggest that small changes in plasma sodium could be an important mechanism for the beneficial effects of lower dialysate sodium and lower salt intake on BP in haemodialysis patients.

Background: Chronic diseases are the leading cause of premature death and disability in the world with overnutrition a primary cause of diet-related ill health. Excess energy intake, saturated fat, sugar, and salt derived from processed foods are a major cause of disease burden. Our objective is to compare the nutritional composition of processed foods between countries, between food companies, and over time., Design: Surveys of processed foods will be done in each participating country using a standardized methodology. Information on the nutrient composition for each product will be sought either through direct chemical analysis, from the product label, or from the manufacturer. Foods will be categorized into 14 groups and 45 categories for the primary analyses which will compare mean levels of nutrients at baseline and over time. Initial commitments to collaboration have been obtained from 21 countries., Conclusions: This collaborative approach to the collation and sharing of data will enable objective and transparent tracking of processed food composition around the world. The information collected will support government and food industry efforts to improve the nutrient composition of processed foods around the world.

Maternal inheritance of mtDNA is the rule in most animals, but the reasons for this pattern remain unclear. To investigate the consequence of overriding uniparental inheritance, we generated mice containing an admixture (heteroplasmy) of NZB and 129S6 mtDNAs in the presence of a congenic C57BL/6J nuclear background. Analysis of the segregation of the two mtDNAs across subsequent maternal generations revealed that proportion of NZB mtDNA was preferentially reduced. Ultimately, this segregation process produced NZB-129 heteroplasmic mice and their NZB or 129 mtDNA homoplasmic counterparts. Phenotypic comparison of these three mtDNA lines demonstrated that the NZB-129 heteroplasmic mice, but neither homoplasmic counterpart, had reduced activity, food intake, respiratory exchange ratio; accentuated stress response; and cognitive impairment. Therefore, admixture of two normal but different mouse mtDNAs can be genetically unstable and can produce adverse physiological effects, factors that may explain the advantage of uniparental inheritance of mtDNA., (Copyright © 2012 Elsevier Inc. All rights reserved.)

High dietary salt is a major contributor to increased blood pressure, the leading risk for death worldwide. In several countries, national programmes to reduce dietary salt have been implemented with leadership and involvement of hypertension experts. Other hypertension experts may be interested in assisting or leading a national programme to reduce dietary salt, however, may not have the experience or training to do so. The article is based on the experiences of three hypertension experts who have led the development of national dietary salt reduction programmes in the United Kingdom, Australia and Canada. The article advises developing leadership and a coalition, conducting a nation-specific environmental scan of facilitators and barriers, estimating the national health and financial costs of high dietary salt and the benefits of reducing salt intake, obtaining core documents to provide the scientific rational for the programme, developing a policy statement to outline the required actions to be undertaken, engaging government and industry, using media to gain public support, overcoming industry supported opposition and sustaining the effort long term. Resources and potential sources for international collaboration are provided as well as caveats for developing the programme within the specific nations' context and overall effort to improve health. Developing and leading a national salt reduction programme is a major commitment, however, reducing dietary salt is estimated to be one of the most effective strategies to improve a nation's health.

Cardiovascular disease (CVD) is the leading cause of death and disability worldwide. Raised blood pressure (BP), cholesterol and smoking, are the major risk factors. Among these, raised BP is the most important cause, accounting for 62% of strokes and 49% of coronary heart disease. Importantly, the risk is throughout the range of BP, starting at systolic 115 mm Hg. There is strong evidence that our current consumption of salt is the major factor increasing BP and thereby CVD. Furthermore, a high salt diet may have direct harmful effects independent of its effect on BP, for example, increasing the risk of stroke, left ventricular hypertrophy and renal disease. Increasing evidence also suggests that salt intake is related to obesity through soft drink consumption, associated with renal stones and osteoporosis and is probably a major cause of stomach cancer. In most developed countries, a reduction in salt intake can be achieved by a gradual and sustained reduction in the amount of salt added to food by the food industry. In other countries where most of the salt consumed comes from salt added during cooking or from sauces, a public health campaign is needed to encourage consumers to use less salt. Several countries have already reduced salt intake, for example, Japan (1960-1970), Finland (1975 onwards) and now the United Kingdom. The challenge is to spread this out to all other countries. A modest reduction in population salt intake worldwide will result in a major improvement in public health.

Objectives: Hypertension has been associated with impaired cognition. Diffusion tensor imaging (DTI) and magnetic resonance spectroscopy were applied to assess white matter abnormalities in treated vs untreated hypertension and if these correlated with neuropsychological performance., Methods: Subjects were 40 patients with medically treated hypertension (mean age 69.3 years), 10 patients with untreated hypertension (mean age 57.6 years) and 30 normotensive controls (mean age 68.2 years). Hypertension was defined as a previous diagnosis and taking hypertensive medication, or a resting blood pressure of >140/90 mmHg on the day of assessment., Results: Patients with treated hypertension performed worse on immediate (P = 0.037) as well as delayed memory tasks (P = 0.024) compared with normotensive controls. Cognitive performance was worse in untreated compared with treated hypertension on executive functions (P = 0.041) and psychomotor speed (P = 0.003). There was no significant correlation between cognition and any of the imaging parameters in treated hypertension. However, in untreated hypertension the results revealed a positive correlation between an executive functioning and attention composite score and DTI mean diffusivity values (P = 0.016) and between psychomotor speed and spectroscopy NAA/tCr levels (P = 0.015)., Conclusions: These results suggest there is cognitive impairment in hypertension. Treated hypertension was associated with deficits in memory while untreated hypertension revealed a more 'subcortical' pattern of cognitive impairment.

In the presence of aldosterone, plasma sodium in the high physiological range stiffens endothelial cells and reduces the release of nitric oxide. We now demonstrate effects of extracellular potassium on stiffness of individual cultured bovine aortic endothelial cells by using the tip of an atomic force microscope as a mechanical nanosensor. An acute increase of potassium in the physiological range swells and softens the endothelial cell and increases the release of nitric oxide. A high physiological sodium concentration, in the presence of aldosterone, prevents these changes. We propose that the potassium effects are caused by submembranous cortical fluidization because cortical actin depolymerization induced by cytochalasin D mimics the effect of high potassium. In contrast, a low dose of trypsin, known to activate sodium influx through epithelial sodium channels, stiffens the submembranous cell cortex. Obviously, the cortical actin cytoskeleton switches from gelation to solation depending on the ambient sodium and potassium concentrations, whereas the center of the cell is not involved. Such a mechanism would control endothelial deformability and nitric oxide release, and thus influence systemic blood pressure.

Rationale: Markers of inflammatory activity are important for assessment and management of many respiratory diseases. Markers that are currently unrecognized may be more valuable than those presently believed to be useful., Objectives: To identify potential biomarkers of suppurative and inflammatory lung disease in induced sputum samples., Methods: Induced sputum was collected from 20 healthy control subjects, 24 patients with asthma, 24 with chronic obstructive pulmonary disease, 28 with cystic fibrosis (CF), and 19 with bronchiectasis. Twelve patients with CF had sputum sampled before and after antibiotic therapy for an infective exacerbation. The fluid phase of induced sputum was analyzed by surface-enhanced laser desorption/ionization time-of-flight (SELDI-TOF) mass spectroscopy on three protein array surfaces. Some protein markers were selected for identification, and relevant ELISA assays sought. For 12 patients with CF, both SELDI-TOF and ELISA monitored changes in inflammatory responses during infective exacerbations., Measurements and Main Results: SELDI-TOF identified potential biomarkers that differentiated each of the disease groups from healthy control subjects: at a significance of P < 0.01, there were 105 for asthma, 113 for chronic obstructive pulmonary disease, 381 for CF, and 377 for bronchiectasis. Peaks selected for protein identification yielded calgranulin A, calgranulin B, calgranulin C, Clara cell secretory protein, lysosyme c, proline rich salivary peptide, cystatin s, and hemoglobin alpha. On treatment of an infective CF exacerbation, SELDI-TOF determined falls in levels of calgranulin A and calgranulin B that were mirrored by ELISA-measured falls in calprotectin (heterodimer of calgranulins A and B)., Conclusions: Proteomic screening of sputum yields potential biomarkers of inflammation. The early development of a clinically relevant assay from such data is demonstrated.