Background The cystic fibrosis (CF) transmembrane conductance regulator modulator (CFTRm) elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) has demonstrated efficacy and safety in clinical trials and emerging observational studies in people with CF. This study evaluated the real-world impact of ELX/TEZ/IVA in a large cohort of people with CF in the UK. Methods LONGITUDE is an observational, registry-based cohort study using data from the UK CF Registry to evaluate outcomes of ELX/TEZ/IVA in people aged ≥6 years who initiated ELX/TEZ/IVA from August 2019. Key outcomes included percent predicted forced expiratory volume in 1 s (ppFEV1), body mass index (BMI), pulmonary exacerbations (PEx), lung infections, transplants, deaths, and treatment discontinuation. We report results of people ≥12 years with data up to December 31, 2022. Results A total of 5187 people were included (mean follow-up 19.1 months). ppFEV1 improvements were observed at 2 years (10.2; 95 % CI: 9.6, 10.8; n = 1448). A clinically meaningful difference in the annual change of ppFEV1 between ELX/TEZ/IVA-treated people and historical CFTRm-naïve controls was observed, with those treated with ELX/TEZ/IVA having less of a decline in lung function over time by 1.1 percentage points (95 % CI: 0.9, 1.4). A 64.7 % reduction in the rate of PEx, increase in BMI by 1.7 kg/m2 (SD: 2.3), reduced lung infections, and low number of lung transplants and deaths were also observed. Conclusions People with CF aged ≥12 years in the UK who initiated ELX/TEZ/IVA had sustained improvements in multiple CF-related health outcomes, consistent with results from clinical trials. These results support the positive impact of ELX/TEZ/IVA on the lives of people with CF.

Introduction Cystic fibrosis-related diabetes (CFRD) is one of the most clinically impactful comorbidities associated with cystic fibrosis (CF). Current recommended management with insulin therapy is challenging due to variable daily insulin requirements and adds to the significant burden of self-management. This study aims to determine if hybrid closed-loop insulin delivery can improve glucose outcomes compared with standard insulin therapy with continuous glucose monitoring (CGM) in young people (>= 16 years) and adults with CFRD. Methods and analysis This open-label, multicentre, randomised, two-arm, single-period parallel design study aims to randomise 114 young people (>= 16 years) and adults with CFRD. Following a 2-3 weeks' run-in period, during which time participants use a masked CGM, participants with time in target glucose range (3.9-10.0 mmol/L) <80% will be randomised to 26 weeks with hybrid closed-loop insulin delivery or standard insulin therapy with CGM. The primary outcome is the between-group difference in time in target glucose range (3.9-10.0 mmol/L) based on CGM levels during the 26-week study phase. Analyses will be conducted on an intention-to-treat basis. Key secondary outcomes are time above target glucose range (>10.0 mmol/L), mean glucose and HbA1c. Other secondary efficacy outcomes include glucose and insulin metrics, change in forced expiratory volume in 1 s and body mass index. Safety, utility, participant experiences and participant-reported outcome measures will also be evaluated. The trial is funded by the National Institute for Health and Care Research. Ethics and dissemination Ethics approval has been obtained from East of England-Cambridge South Research Ethics Committee. Results will be disseminated by peer-reviewed publications and conference presentations, and findings will be shared with people living with CF, healthcare providers and relevant stakeholders. Trial registration number NCT05562492.

Background Bacteriophage (phage) therapy is a promising alternative antimicrobial approach which 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 licenced 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 infection and the experience of the author group who have collectively assessed the suitability of 30 patients for phage therapy. Content In the UK, unlicensed medicines, including phages, may be considered to meet special clinical needs. The use of unlicensed medicines is governed by national legislation and local NHS Trust policies. Phages can be used in any NHS Trust and decisions about suitability should be made via 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.

Abstract ID 98342Poster Board 420Introduction: In January of 2022, the United States Medical Licensing Exam USMLE Step 1 score reporting transitioned from a numerical score to a pass/fail outcome. Similarly, in May of 2022, the Level 1 of the COMLEX board series (completed by Osteopathic medical students) also transitioned from a three-digit score to a simple Pass/Fail assessment. In this study our goal is to identify early predictors from the outcomes of the first two years following this change to pass/fail of the boards and the impact on teaching and learning strategies for pharmacology.Methods: The aggregate data between the years of 2013 to 2023 published by USMLE Step-1 and COMLEX-Level 1 performance reports was analyzed. National satisfaction instruments including: 1) Academic Year Graduating Seniors Survey Report published by the AACOM and 2) All-Schools Summary Report Medical School Graduation Questionnaire, Matriculation Questionnaire, Year-Two Questionnaire, and the Post-MCAT Questionnaire Reports published by AAMC between 2013 and 2023 were also analyzed to develop constructs of satisfaction scores in pharmacology and relate those results to the methods of study and class attendance.Results: Satisfaction scores indicative of preparation for clinical clerkships continued to rise for pharmacology during the past decade (2014-2023). First time takers (MD degree) pass rate dropped during the past decade to 93% in 2022 (down from 96% in 2021). First time takers (DO degree) dropped to 89% (down from 94% in 2021). First time COMLEX Level 1 takers dropped to 90.6% in 2022 (down from 92.2% in 2021). In 2014, only 11.4% of medical students planned to take the USMLE sometime between January to March. This number grew to 36.7% in 2022. Students who chose to take the USMLE during the second year after March was 87.4% in 2014 compared to 60.5% in 2022. Post-MCAT and matriculation reports suggest a change in strategies used for medical admission test preparation.Conclusions: Integration efforts of basic and clinical sciences have been fruitful during the past decade with continued progress in pharmacology satisfaction scores at time of graduation. A growing number of medical schools now offer a three-year curriculum with an emphasis on taking the boards much sooner. These changes come with implications for teaching the appropriate pharmacology content much sooner. The drop in First-time board passing scores in 2022 underscore the importance of students not rushing into the board exams, but it is unclear of the reasons for this effect during the past decade. The Post-MCAT and matriculation reports suggests a shift in strategies used for preparation of standardized testing with habits which focus more on active recall testing and spaced repetition and less on understanding the material which are likely to continue into pre-clerkship period. Today fewer students are coming to class and educators of pharmacology must adapt to newer challenges in an evidence-based and competency-based medical education environment. Pharmacology educators bring the critical thinking part and must continue to create thoughtful learning experiences to engage the student learner in light of new emergent disruptors to learning.

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 ppFEV1 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 ppFEV1 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 ppFEV1 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 ppFEV1 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 ppFEV1 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.

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 FEV1; 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.

Objectives: Aspergillus fumigatus is the commonest fungi to colonise the airways of people with cystic fibrosis (CF). Colonisation, both with or without the presence of allergic bronchopulmonary aspergillosis (AGPA), has been found to be associated with increased respiratory exacerbations, hospitalisations, reduced pulmonary function and CT scan abnormalities. Management with anti-fungal agents has shown limited clinical benefit, as well as issues with side effects and drug resistance. The effect of CFTR modulator therapies; revolutionary in the management of CF in recent years, on Aspergillus related disease in CF has yet to be established. We aimed to assess whether elexacaftor-tezacaftor-ivacaftor (ETI) therapy impacted on Asp. fumigatus serology in a population of adults with CF. Methods: Asp. fumigatus serology was compared before and (at least 3-months) after commencing ETI therapy, in 198 adults with CF in the West of Scotland. Pulmonary function (FEV1) and body mass index (BMI) were also compared. Results: We noted a reduction in all Asp. fumigatus antibodies after commencement on ETI therapy when compared to results prior. Specific Asp. fumigatus IgG (pre-ETI median; 49.0 (IQR 26.8–81.8), post-ETI median; 38.0 (IQR 24.0–70.3) p < 0.001), Specific Asp. fumigatus IgE-M3 (pre-ETI median; 0.34 (IQR 0.34–3.76), post-ETI median; 0.34 (IQR 0.34–2.31) p < 0.001) and Total IgE (pre-ETI median; 72.5 (IQR 23.8–233.0), post-ETI median; 48.0 (IQR 17.0–136.5) p < 0.001). FEV1 and BMI also saw a significant increase. Conclusion: ETI therapy led to a significant decrease in Asp. fumigatus serology. Reduction in both specific IgE and IgG, responsible for IgE sensitisation and ABPA respectively, would likely represent significant clinical benefit in CF through alleviating the burden of aspergillus related disease. This could contribute to the improvement in FEV1 and BMI seen in our study population and add to the body of evidence supporting ETI therapy in the management of CF.

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 (FEV1 ) 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 FEV1 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.

BackgroundA 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.MethodsWe 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.ResultsThe 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.ConclusionsThe 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.

As we move towards completion of a second year of remote medical pharmacology instruction due to the Covid‐19 global pandemic, osteopathic medical students are also dealing with changes in the USMLE Step‐1 and/or COMLEX Level‐1 with the new Pass/Fail System in 2022. Unlike previous generations, Gen Z are inundated with an abundance of digital information that is readily and freely available, including professional advice from external sources which are not part of the formal curriculum (unspecified social networks, handed down Anki cards, etc.). Misinformation and/or misconstrued or unqualified advice for rapidly mastering pharmacology material over time can lead to development of myths which can be found in comments provided within the student evaluation of faculty. Identifying trends and/or myths in the feedback provided by the students can serve as a meaningful tool for faculty self‐reflection and will also help faculty steer students away from common misinformation as well.

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 FEV1 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 FEV1, 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 FEV1 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 FEV1 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. Copyright (C) 2021 Elsevier Ltd. All rights reserved.

Cystic fibrosis [CF] is a systemic illness resulting from loss of function of the CFTR protein on secretory epithelium. CF liver disease [CFLD] remains under recognised, despite being the third leading cause of mortality in CF.1 This study determined the prevalence of CFLD and CFLD-cirrhosis in a cohort of adult CF patients. Adherence to local surveillance protocols for diagnosing and monitoring these conditions, including engagement of specialist hepatology services, was assessed. The study identified 270 patients with a diagnosis of CF in the West of Scotland Adult Cystic Fibrosis Service. Electronic clinical records were reviewed to determine the prevalence of pre-existing diagnoses of CFLD and assess for evidence of cirrhosis in these patients. The study assessed if standards, as determined by local protocols, of liver monitoring and hepatology service involvement in non-CFLD, CFLD and CFLD-cirrhosis patients were met. The average age of the cohort was 32 years (range 16–71) and 145 were male. There was a pre-existing diagnosis of CFLD in 80/270 patients (30%), with evidence of cirrhosis in 23 patients (29% of CFLD patients; 9% of the total cohort). Of those with CFLD/CFLD-cirrhosis, regular follow up with or previous discharge from hepatology services occurred in 34/80 patients (43%). The local standard of yearly liver function tests [LFT] in non-CFLD and non-cirrhotic CFLD patients and 6-monthly LFT in CFLD-cirrhosis patients was met in 241/270 individuals (89%). The local standard of ultrasound 5-yearly in non-CFLD patients, 2 yearly in non-cirrhotic CFLD patients and 6 monthly in CFLD-cirrhosis patients was met in 190/270 individuals (70%). Of those with CFLD, 41/80 (51%) had been assessed with Fibroscan. Of those with CFLD-cirrhosis 15/23 (65%) had an AFP measured at any point with 2/23 (9%) having had an AFP within 6 months and 17/23 (73%) had received an OGD at any point. [See table 1]. CFLD is a source of significant morbidity and mortality in CF patients and affects 30% of our patient population, with 9% of our CF cohort having evidence of cirrhosis. Despite this, a risk of delayed or missed diagnosis has been identified due to non-CFLD patients not receiving LFT and USS monitoring as per local protocol. There is also significant room for improvement in ensuring those with CFLD and CFLD-cirrhosis are referred to hepatology services which would also assist in ensuring appropriate ongoing disease monitoring - particularly Fibroscan to aid diagnosis of CFLD-cirrhosis and ensure appropriate HCC and variceal surveillance. Reference Debray D, Kelly D, Houwen R, Strandvik B, Colombo C. Best practice guidance for the diagnosis and management of cystic fibrosis-associated liver disease. J Cyst Fibros 2011;10:29–36.

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.

Introduction After more than a year of pharmacology delivery through a virtual curriculum to help prepare medical students to successfully complete the USMLE Step-1 and/or COMLEX Level-1 (for osteopathic medical students), these high stakes board exams will transition to a Pass/Fail system in 2022. To reflect on the effectiveness of the pharmacology educational approaches used before and after the rapid implementation of emergency remote teaching, board results outcomes, faculty student evaluations and student feedback were reviewed and compared to results from national satisfaction instruments during the past decade. Our hypothesis is that satisfaction with the pre-clerkship pharmacology instruction will increase during the clerkship years as measured by the satisfaction instruments after graduation. Methods The aggregate data published between 2010-2020 by national satisfaction instruments including: 1) Academic Year Graduating Seniors Survey Report published by the AACOM and 2) All-Schools Summary Report Medical School Graduation Questionnaire published by the AAMC, was used to develop a construct of satisfaction scores in pharmacology. Pharmacology faculty student evaluations from the Alabama College of Osteopathic Medicine were analyzed using a thematic analysis method for student satisfaction. Class performance outcomes on boards were also analyzed. Results The population of medical students graduating has increased over the past decade, and national satisfaction instruments show that satisfaction of pharmacology instruction amongst the medical graduates also increased with the highest satisfaction score achieved in 2019 (2.13) and 2020 (2.14) compared to the lowest achieved in 2012 (1.97). Similarly, more osteopathic medical graduates agreed that instruction of clinical pharmacology was appropriate in 2019 (85%) compared to the lowest in 2011 (75%) (data from 2020 not yet available). Conclusions Pre-clerkship student satisfaction can be difficult to assess during a very stressful period, especially before the boards. Pharmacology teaching is more intense, and in our institution, it has yielded positive outcomes in board passing rates. In March of 2020, pharmacology faculty were faced with the challenge of rapidly transitioning into emergency remote teaching due to the Covid-19 pandemic. This pandemic will likely continue to disrupt medical education well into the end of 2021, just before the USMLE Step-1/COMLEX Level-1 boards implement the pass/fail grading system. With all these changes and disruptions, pharmacology education is at a crossroads and it hinges on the future direction.

Bikram yoga is practiced in a room heated to 105°F with 40% humidity for 90 min. During the class a large volume of water and electrolytes are lost in the sweat, specifically, sodium is lost, the main cation of the extracellular fluid. There is little known about the volume of sweat and the amount of sodium lost in sweat during Bikram yoga or the optimum quantity of fluid required to replace these losses. The participants who took part in this small feasibility study were five females with a mean age of 47.4 ± 4.7 years and 2.6 ± 1.6 years of experience at Bikram yoga. The total body weight, water consumed, serum sodium concentration, serum osmolality, and serum aldosterone levels were all measured before and after a Bikram yoga practice. Sweat sodium chloride concentration and osmolality were measured at the end of the practice. The mean estimated sweat loss was 1.54 ± 0.65 L, while the amount of water consumed during Bikram yoga was 0.38 ± 0.22 L. Even though only 25% of the sweat loss was replenished with water intake during the Bikram yoga class, we did not observe a change in serum sodium levels or serum osmolality. The sweat contained 82 ± 16 mmol/L of sodium chloride for an estimated total of 6.8 ± 2.1 g of sodium chloride lost in the sweat. The serum aldosterone increased 3.5‐fold from before to after Bikram yoga. There was a decrease in the extracellular body fluid compartment of 9.7%. Sweat loss in Bikram yoga predominately produced a volume depletion rather than the dehydration of body fluids. The sweating‐stimulated rise in serum aldosterone levels will lead to increased sodium reabsorption from the kidney tubules and restore the extracellular fluid volume over the next 24 hr.

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 (FEV1) 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 FEV1 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 FEV1 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.

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.