Decision-Making Confidence of Clinical Competency Committees for Entrustable Professional Activities.

Importance: A competency-based assessment framework using entrustable professional activities (EPAs) was endorsed by the American Board of Surgery following a 2-year feasibility pilot study. Pilot study programs' clinical competency committees (CCCs) rated residents on EPA entrustment semiannually using this newly developed assessment tool, but factors associated with their decision-making are not yet known. Objective: To identify factors associated with variation in decision-making confidence of CCCs in EPA summative entrustment decisions. Design, Setting, and Participants: This cohort study used deidentified data from the EPA Pilot Study, with participating sites at 28 general surgery residency programs, prospectively collected from July 1, 2018, to June 30, 2020. Data were analyzed from September 27, 2022, to February 15, 2023. Exposure: Microassessments of resident entrustment for pilot EPAs (gallbladder disease, inguinal hernia, right lower quadrant pain, trauma, and consultation) collected within the course of routine clinical care across four 6-month study cycles. Summative entrustment ratings were then determined by program CCCs for each study cycle. Main Outcomes and Measures: The primary outcome was CCC decision-making confidence rating (high, moderate, slight, or no confidence) for summative entrustment decisions, with a secondary outcome of number of EPA microassessments received per summative entrustment decision. Bivariate tests and mixed-effects regression modeling were used to evaluate factors associated with CCC confidence. Results: Among 565 residents receiving at least 1 EPA microassessment, 1765 summative entrustment decisions were reported. Overall, 72.5% (1279 of 1765) of summative entrustment decisions were made with moderate or high confidence. Confidence ratings increased with increasing mean number of EPA microassessments, with 1.7 (95% CI, 1.4-2.0) at no confidence, 1.9 (95% CI, 1.7-2.1) at slight confidence, 2.9 (95% CI, 2.6-3.2) at moderate confidence, and 4.1 (95% CI, 3.8-4.4) at high confidence. Increasing number of EPA microassessments was associated with increased likelihood of higher CCC confidence for all except 1 EPA phase after controlling for program effects (odds ratio range: 1.21 [95% CI, 1.07-1.37] for intraoperative EPA-4 to 2.93 [95% CI, 1.64-5.85] for postoperative EPA-2); for preoperative EPA-3, there was no association. Conclusions and Relevance: In this cohort study, the CCC confidence in EPA summative entrustment decisions increased as the number of EPA microassessments increased, and CCCs endorsed moderate to high confidence in most entrustment decisions. These findings provide early validity evidence for this novel assessment framework and may inform program practices as EPAs are implemented nationally.

The Virtual Child.

SUMMARY: We are building the world's first Virtual Child-a computer model of normal and cancerous human development at the level of each individual cell. The Virtual Child will "develop cancer" that we will subject to unlimited virtual clinical trials that pinpoint, predict, and prioritize potential new treatments, bringing forward the day when no child dies of cancer, giving each one the opportunity to lead a full and healthy life.

Ecological patterns and processes of temporal turnover within lung infection microbiota.

BACKGROUND: Chronic infection and consequent airway inflammation are the leading causes of morbidity and early mortality for people living with cystic fibrosis (CF). However, lower airway infections across a range of chronic respiratory diseases, including in CF, do not follow classical 'one microbe, one disease' concepts of infection pathogenesis. Instead, they are comprised of diverse and temporally dynamic lung infection microbiota. Consequently, temporal dynamics need to be considered when attempting to associate lung microbiota with changes in disease status. Set within an island biogeography framework, we aimed to determine the ecological patterns and processes of temporal turnover within the lung microbiota of 30 paediatric and adult CF patients prospectively sampled over a 3-year period. Moreover, we aimed to ascertain the contributions of constituent chronic and intermittent colonizers on turnover within the wider microbiota. RESULTS: The lung microbiota within individual patients was partitioned into constituent chronic and intermittent colonizing groups using the Leeds criteria and visualised with persistence-abundance relationships. This revealed bacteria chronically infecting a patient were both persistent and common through time, whereas intermittently infecting taxa were infrequent and rare; respectively representing the resident and transient portions of the wider microbiota. It also indicated that the extent of chronic colonization was far greater than could be appreciated with microbiological culture alone. Using species-time relationships to measure temporal turnover and Vellend's rationalized ecological processes demonstrated turnover in the resident chronic infecting groups was conserved and underpinned principally by the deterministic process of homogenizing dispersal. Conversely, intermittent colonizing groups, representing newly arrived immigrants and transient species, drove turnover in the wider microbiota and were predominately underpinned by the stochastic process of drift. For adult patients, homogenizing dispersal and drift were found to be significantly associated with lung function. Where a greater frequency of homogenizing dispersal was observed with worsening lung function and conversely drift increased with better lung function. CONCLUSIONS: Our work provides a novel ecological framework for understanding the temporal dynamics of polymicrobial infection in CF that has translational potential to guide and improve therapeutic targeting of lung microbiota in CF and across a range of chronic airway diseases. Video Abstract.

Application of generative language models to orthopaedic practice.

OBJECTIVE: To explore whether large language models (LLMs) Generated Pre-trained Transformer (GPT)-3 and ChatGPT can write clinical letters and predict management plans for common orthopaedic scenarios. DESIGN: Fifteen scenarios were generated and ChatGPT and GPT-3 prompted to write clinical letters and separately generate management plans for identical scenarios with plans removed. MAIN OUTCOME MEASURES: Letters were assessed for readability using the Readable Tool. Accuracy of letters and management plans were assessed by three independent orthopaedic surgery clinicians. RESULTS: Both models generated complete letters for all scenarios after single prompting. Readability was compared using Flesch-Kincade Grade Level (ChatGPT: 8.77 (SD 0.918); GPT-3: 8.47 (SD 0.982)), Flesch Readability Ease (ChatGPT: 58.2 (SD 4.00); GPT-3: 59.3 (SD 6.98)), Simple Measure of Gobbledygook (SMOG) Index (ChatGPT: 11.6 (SD 0.755); GPT-3: 11.4 (SD 1.01)), and reach (ChatGPT: 81.2%; GPT-3: 80.3%). ChatGPT produced more accurate letters (8.7/10 (SD 0.60) vs 7.3/10 (SD 1.41), p=0.024) and management plans (7.9/10 (SD 0.63) vs 6.8/10 (SD 1.06), p<0.001) than GPT-3. However, both LLMs sometimes omitted key information or added additional guidance which was at worst inaccurate. CONCLUSIONS: This study shows that LLMs are effective for generation of clinical letters. With little prompting, they are readable and mostly accurate. However, they are not consistent, and include inappropriate omissions or insertions. Furthermore, management plans produced by LLMs are generic but often accurate. In the future, a healthcare specific language model trained on accurate and secure data could provide an excellent tool for increasing the efficiency of clinicians through summarisation of large volumes of data into a single clinical letter.

A Look at Demographics and Transition to Virtual Assessments: An Analysis of Bias in the American Board of Surgery General Surgery Certifying Exams.

OBJECTIVE: The goals of this study were (1) to assess if examiner ratings in the American Board of Surgery (ABS) General Surgery Cetifying Exam (CE) are biased based on the gender, race, and ethnicity of the candidate or the examiners, and (2) if the format of delivering of the exams, in-person or virtual, affects how examiners rate candidates. DESIGN: We included every candidate-examiner combination for first time takers of the general surgery oral exam. Total scores and pass/fail outcomes based on the 4 scores given by examiners to candidates were analyzed using multilevel models, with candidates as random effects. Explanatory variables included the gender, race, and ethnicity of candidates and examiners, and the format of the exam (in-person or virtual). Candidates' first attempt scores on the ABS General Surgery Qualifying Exam (QE) were also included in the models to control for the baseline knowledge of the candidate. Three sets of models were evaluated for each demographic variable (gender, race, ethnicity) due to missingness in data. p-values and coefficients of determination R2 were used to quantify the statistical and practical significance of the model coefficients (an existent relationship between the explored variables on CE scores was considered statistically and practically significant if the p-value was lower than 0.01 and R2 higher than 1%). PARTICIPANTS: All first-time takers of the American Board of Surgery General Surgery Certifying Exam from 2016 to 2022 that had demographic data, and the examiners that participated in those exams. RESULTS: The number of candidates/examiners for the 3 sets of models was 8665/514 (gender), 5906/465 (race), and 4678/295 (ethnicity). The demographic variables, format of the exam, or their interactions were not found to significantly relate to examiner-candidate ratings or pass/fail outcomes. The only variable that was significantly related to CE scores was candidates' QE scores, which was added to the models as a measure of candidates' initial knowledge; this held for all models for total scores (F[1,8659] = 1069.89, p-value < 0.01, R2 = 5% [gender models], F(1,5696.3) = 589.13, p-value < 0.01, R2 = 5% [race models], F(1,4459.5) = 278.33, p-value < 0.01, R2 = 5% [ethnicity models]), and pass/fail outcomes (CI = 1.61-1.73, p-value < 0.01, R2 = 3% [gender models], CI = 1.67-1.85, p-value < 0.01, R2 = 3% [race models], CI = 2.17-2.90, p-value < 0.01, R2 = 3% [ethnicity models]). CONCLUSIONS: This study shows that there is not a relationship between candidate and examiner gender, race, or ethnicity, and exam outcomes based on statistical models looking at examiner-candidate ratings and pass/fail outcomes. In addition, the delivery of the certifying exam in a virtual format appears to have no statistical impact on outcomes compared to in-person delivery. This suggests that the ABS is performing well in both demographic bias and virtual space.

Validity of Entrustable Professional Activities in a National Sample of General Surgery Residency Programs.

BACKGROUND: The American Board of Surgery has endorsed competency-based education as vital to the assessment of surgical training. From 2018 to 2020, a national pilot study was conducted at 28 general surgery programs to evaluate feasibility of implementing entrustable professional activities (EPAs) for 5 common general surgical conditions. ACGME core competency Milestones were also rated for each resident by program clinical competency committees. This study aimed to evaluate the validity of general surgery EPAs compared with Milestones. STUDY DESIGN: Prospectively collected, de-identified EPA Pilot Study data were analyzed. EPAs studied were EPA-1 (gallbladder), EPA-2 (inguinal hernia), EPA-3 (right lower quadrant pain), EPA-4 (trauma), and EPA-5 (consult). Variables abstracted included levels of EPA entrustment (1 to 5) and corresponding ACGME Milestone subcompetency ratings (1 to 5) for the same study cycle. Spearman's correlations were used to evaluate the relationship between summative EPA scores and corresponding Milestone ratings. RESULTS: A total of 493 unique residents received a summative entrustment decision. EPA summative entrustment scores had moderate-to-strong positive correlation with mapped Milestone subcompetencies, with median rho value of 0.703. Among operation-focused EPAs, median rho values were similar between EPA-1 (0.688) and EPA-2 (0.661), but higher for EPA-3 (0.833). EPA-4 showed a strong positive correlation with diagnosis and communication competencies (0.724), whereas EPA-5, mapped to the most Milestone subcompetencies, had the lowest median rho value (0.455). CONCLUSIONS: Moderate-to-strong positive correlation was noted between EPAs and patient care, medical knowledge, and communication Milestones. These findings support the validity of EPAs in general surgery and suggest that EPA assessments can be used to inform Milestone ratings by clinical competency committees.

Neurovascular complications post bronchial artery embolisation in patients with cystic fibrosis. A 7-year single centre retrospective review.

Bronchial artery embolisation (BAE) is a treatment used to manage haemoptysis. We performed a 7-year review of BAE procedures for haemoptysis at our CF centre aiming to evaluate the incidence and outcomes of patients with neurovascular complications post-BAE. Our review suggests that whilst BAE is an effective method for controlling life-threatening haemoptysis, patients are at risk of developing neurovascular complications with long term residual symptoms, and therefore careful consideration should be given in offering BAE, especially to otherwise well patients with chronic small volume haemoptysis and managing teams should have a low threshold to image symptomatic patients.

Pleural procedures: an audit of practice and complications in a regional Australian teaching hospital.

BACKGROUND: Pleural procedures are essential for the investigation and management of pleural disease and can be associated with significant morbidity and mortality. There is a lack of pleural procedure complication data in the Australian and New Zealand region. AIMS: To review pleural procedure practices at Wollongong Hospital with an emphasis on the assessment of complications, use of thoracic ultrasound (TUS), pathology results and comparison of findings with international data. METHODS: Retrospective analysis of medical records was performed on pleural procedures identified through respiratory specialist trainee logbooks at Wollongong Hospital from January 2018 to December 2021. Comparison of complication rates was made to the British Thoracic Society 2011 a national pleural audit. RESULTS: One hundred and twenty-one pleural procedures were identified. There were 71 chest drains, 49 thoracocentesis and one indwelling pleural catheter (IPC) insertion. Ninety-seven per cent of procedures were performed for pleural effusions and 3% for pneumothorax. This audit demonstrated a complication rate (excluding pain) of 16.9% for chest drains and 4.1% for thoracocentesis. This gave an overall complication event rate of 10.8% (excluding pain) for pleural procedures. There was no major bleeding, organ puncture, pleural space infection or death. Bedside TUS was used in 99% of procedures. CONCLUSION: Complication rates for pleural procedures performed by respiratory specialist trainees at Wollongong Hospital are comparable with international outcomes. This audit provides data for comparison on pleural procedure complication rates in Australia. Future studies are required to determine complication rates with IPCs.

How Does the Sequence of the American Board of Surgery Examinations Impact Pass/Fail Outcomes?

OBJECTIVE: Historically, the American Board of Surgery required surgeons to pass the qualifying examination (QE) before taking the certifying examination (CE). However, in the 2020-2021 academic year, with mitigating circumstances related to COVID-19, the ABS removed this sequencing requirement to facilitate the certification process for those candidates who were negatively impacted by a QE delivery failure. This decoupling of the traditional order of exam delivery has provided a natural comparator to the traditional route and an analysis of the impact of examination sequencing on candidate performance. METHODS: All candidates who applied for the canceled July 2020 QE were allowed to take the CE before passing the QE. The sample was then reduced to include only first-time candidates to ensure comparable groups for performance outcomes. Logistic regression was used to analyze the relationship between the order of taking the QE and the CE, controlling for other examination performance, international medical graduate status, and gender. RESULTS: Only first-time candidates who took both examinations were compared (n=947). Examination sequence was not a significant predictor of QE pass/fail outcomes, OR=0.54; 95% CI, 0.19-1.61, P =0.26. However, examination sequence was a significant predictor of CE pass/fail outcomes, OR=2.54; 95% CI, 1.46-4.68, P =0.002. CONCLUSIONS: This important study suggests that preparation for the QE increases the probability of passing the CE and provides evidence that knowledge may be foundational for clinical judgment. The ABS will consider these findings for examination sequencing moving forward.

When is Burkholderia cepacia complex truly eradicated in adults with cystic fibrosis? A 20-year follow up study.

BACKGROUND: Burkholderia cepacia complex (BCC) infection in cystic fibrosis (CF) is associated with increased morbidity and mortality. Current UK guidance recommends segregation of people with CF according to infection status. To date there is no universally agreed consensus on the number of negative samples or time interval since last isolation of BCC for eradication to be deemed successful. METHODS: All cases of new BCC isolation at Manchester Adult Cystic Fibrosis Centre were followed-up between May 2002-May 2022. The number of subsequent positive and negative sputum samples for BCC were recorded, as well as eradication treatment received. Eradication was deemed successful if there were ≥3 negative sputum samples and no further positive sputum samples for the same species and strain ≥12 months until the end of follow-up. RESULTS: Of 46 new BCC isolation, 25 were successfully eradicated and 21 resulted in chronic infection. 5 (16.7%) cases with exclusively negative sputum samples 6-12 months after initial isolation had subsequent samples that were culture-positive for BCC and 3 (10.7%) cases with exclusively negative sputum samples after 12-24 months had subsequent culture-positive samples. Cases where BCC was eradicated had a greater median number of days of eradication treatment (42, IQR 21-63) compared to those in whom BCC isolation resulted in chronic infection (28, IQR 14-42), p = 0.04. CONCLUSIONS: A cautious approach to segregation should be maintained after new isolation of BCC in CF, as some individuals with ≥3 negative samples 12-24 months after initial isolation had subsequent sputum samples culture-positive for BCC.

Sleep apnea multi-level surgery trial: long-term observational outcomes.

STUDY OBJECTIVES: The sleep apnea multi-level surgery (SAMS) randomized clinical trial showed surgery improved outcomes at 6 months compared to ongoing medical management in patients with moderate or severe obstructive sleep apnea (OSA) who failed continuous positive airway pressure therapy. This study reports the long-term outcomes of the multi-level surgery as a case series. METHODS: Surgical participants were reassessed >2 years postoperatively with the same outcomes reported in the main SAMS trial. Primary outcomes were apnea-hypopnea index (AHI) and Epworth sleepiness scale (ESS), with secondary outcomes including other polysomnography measures, symptoms, quality of life, and adverse events. Long-term effectiveness (baseline to long-term follow-up [LTFU]) and interval changes (6 month to LTFU) were assessed using mixed effects regression models. Control participants were also reassessed for rate of subsequent surgery and outcomes. RESULTS: 36/48 (75%) of surgical participants were reevaluated (mean (standard deviation)) 3.5 (1.0) years following surgery, with 29 undergoing polysomnography. AHI was 41/h (23) at preoperative baseline and 21/h (18) at follow-up, representing persistent improvement of -24/h (95% CI -32, -17; p < 0.001). ESS was 12.3 (3.5) at baseline and 5.5 (3.9) at follow-up, representing persistent improvement of -6.8 (95% CI -8.3, -5.4; p < 0.001). Secondary outcomes were improved long term, and adverse events were minor. Interval change analysis suggests stability of outcomes. 36/43 (84%) of the control participants were reevaluated, with 25 (69%) reporting subsequent surgery, with symptom and quality of life improvements. CONCLUSION: Multi-level upper airway surgery improves OSA burden with long-term maintenance of treatment effect in adults with moderate or severe OSA in whom conventional therapy failed. CLINICAL TRIAL: Multi-level airway surgery in patients with moderate-severe obstructive sleep apnea (OSA) who have failed medical management to assess change in OSA events and daytime sleepiness; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=366019&isReview=true; ACTRN12614000338662.

FcγRIIB Is an Immune Checkpoint Limiting the Activity of Treg-Targeting Antibodies in the Tumor Microenvironment.

Preclinical murine data indicate that fragment crystallizable (Fc)-dependent depletion of intratumoral regulatory T cells (Treg) is a major mechanism of action of anti-CTLA-4. However, the two main antibodies administered to patients (ipilimumab and tremelimumab) do not recapitulate these effects. Here, we investigate the underlying mechanisms responsible for the limited Treg depletion observed with these therapies. Using an immunocompetent murine model humanized for CTLA-4 and Fcγ receptors (FcγR), we show that ipilimumab and tremelimumab exhibit limited Treg depletion in tumors. Immune profiling of the tumor microenvironment (TME) in both humanized mice and humans revealed high expression of the inhibitory Fc receptor, FcγRIIB, which limits antibody-dependent cellular cytotoxicity/phagocytosis. Blocking FcγRIIB in humanized mice rescued the Treg-depleting capacity and antitumor activity of ipilimumab. Furthermore, Fc engineering of antibodies targeting Treg-associated targets (CTLA-4 or CCR8) to minimize FcγRIIB binding significantly enhanced Treg depletion, resulting in increased antitumor activity across various tumor models. Our results define the inhibitory FcγRIIB as an immune checkpoint limiting antibody-mediated Treg depletion in the TME, and demonstrate Fc engineering as an effective strategy to overcome this limitation and improve the efficacy of Treg-targeting antibodies.

Naturally Occurring Triploidy in Cannabis.

Polyploidy is a significant evolutionary process in plants that involves the duplication of genomic content and has been recognized as a key mechanism driving plant diversification and adaptation. In natural populations, polyploids frequently arise from unreduced gametes, which subsequently fuse with reduced or unreduced gametes, resulting in triploid or tetraploid offspring, respectively. Cannabis sativa L. is a diploid species, but recent work using artificially induced polyploidy has demonstrated its potential advantages in an agricultural setting. Further, recent work has identified that some elite clonal cultivars, vis. Mac1, are triploid, with no indication that they were artificially produced. The current study was conducted to determine if polyploidy is a naturally occurring phenomenon in cannabis and to estimate the frequency of this phenomenon across populations. To do this, the presence of natural triploid individuals was evaluated in 13 seedling populations of cannabis using a flow cytometry analysis. Among the examined populations, natural triploids were identified in 10 groups with an average frequency of approximately 0.5%. The highest frequency of natural triploids was observed in a self-pollinated population at 2.3%. This research demonstrates that polyploidy is a naturally occurring event in cannabis and triploids are present at an average of approximately 0.5%, or 1 in 200 plants. These data shed light on the natural variation in ploidy within cannabis populations and contribute valuable insights to the understanding of cannabis genetics and breeding practices.

Improving detection of cystic fibrosis related liver disease using liver fibrosis assessment tools.

Background & aims: Cystic Fibrosis related liver disease (CFLD) is the 3rd largest cause of death in Cystic Fibrosis (CF). As advances in pulmonary therapies have increased life-expectancy, CFLD has become more prevalent. Current guidelines may underdiagnose liver fibrosis, particularly in its early stages. Newer modalities for the assessment of fibrosis may provide a more accurate assessment. FibroScan is validated in assessing fibrosis for several aetiologies including alcohol and fatty liver, the CFLD cohort have an entirely different phenotype so the cut off values are not transferrable. We appraised fibrosis assessment tools to improve diagnosis of CFLD. Methods: A prospective cohort (n = 114) of patients from the Manchester Adult Cystic Fibrosis Centre, UK were identified at annual assessment. Demographic data including co-morbidity, CFTR genotyping, biochemistry and imaging were used alongside current guidelines to group into CFLD and CF without evidence of liver disease. All patients underwent liver stiffness measurement (LSM) and assessment of serum-based fibrosis biomarker panels. A new diagnostic criterion was created and validated in a second, independent cohort. Results: 12 of 114 patient classified as CFLD according to the European Cystic Fibrosis Society best practice guidelines. No specific risk factors for development of CFLD were identified. Liver enzymes were elevated in patients with CFLD. Serum biomarker panels did not improve diagnostic criteria. LSM accurately predicted CFLD. A new diagnostic criterion was proposed and validated in a separate cohort, accurately predicating CFLD in 10 of 32 patients (31 %). Conclusion: We present a cohort of patients with CF assessed for the presence of liver fibrosis using blood biomarkers and LSM based platforms. We propose a new, simplified diagnostic criteria, capable of accurately predicting liver disease in patients with CF.Clinical trials number: NCT04277819.

Association Between Elevated Blood Eosinophils and Chronic Kidney Disease Progression: Analyses of a Large United States Electronic Health Records Database.

Background: Blood eosinophils can increase in response to infection, inflammation, and hypersensitivity reactions, yet their involvement in the progression of chronic kidney disease (CKD) is poorly understood. This study explores the relationship between blood eosinophils and CKD progression among patients in a real-world setting. Methods: This retrospective study analyzed data obtained from the Optum® de-identified electronic health records dataset in the United States. Patients diagnosed with CKD stage 3 or 4 (International Classification of Diseases diagnosis code or estimated glomerular filtration rate [eGFR] <60 mL/min) between January 2011 and March 2018 were included and followed until progression to the next CKD stage, death, or dropout. The primary objective of this study was to assess the relationship between blood eosinophil counts (bEOS) and CKD progression, adjusting for clinical and demographic features as well as known risk factors for CKD stages 3-4. The primary outcomes were CKD progression and all-cause mortality. Results: We found that high eosinophilic levels (bEOS ≥300 cells/µL) were associated with CKD progression from stage 3 to stages 4 or 5 (hazard ratio [HR] ranging from 1.30 to 1.50) and from stages 4 to 5 (HR ranging from 1.28 to 1.50). Among patients with CKD progression, those with blood eosinophils ≥300 cells/µL appeared to have a relatively lower eGFR, higher all-cause mortality, and reduced time to CKD progression and death than those with <300 cells/µL. Factors including sex, race, hypertension, anemia, and treatments for cardiovascular and hematopoietic drugs were associated with CKD progression. Conclusion: Elevated eosinophils may increase the risk for CKD progression. Larger studies are needed to assess whether the risk of mortality is increased among patients with elevated eosinophils.

Aortic annulus rupture after transcatheter aortic valve replacement: successful management of a dangerous complication.

OBJECTIVE: Aortic annulus rupture remains one of the most fatal complications of TAVR. While attempts have been made to describe and predict this complication, the data remains insufficient without evidence-based guidelines for management of this rare complication. METHODS: Here we describe a series of 3 aortic annulus ruptures after TAVR which were managed successfully to hospital discharge. RESULTS: Patient 1 suffered annulus rupture during balloon valvuloplasty prior to TAVR. The patient became hypotensive, and echocardiogram showed pericardial effusion. The patient underwent pericardiocentesis which transiently improved the blood pressure, but bleeding continued. The patient was transitioned to an open surgical aortic valve replacement due to ongoing hemorrhage. The chest was left open with delayed closure on post-op day 2. The patient was discharged on post-op day 15. Patient 2 was undergoing TAVR valve expansion. The patient became hypotensive. An echocardiogram revealed pericardial effusion. Pericardiocentesis yielded 200 mL of blood. SURGIFLO (Johnson & Johnson Wound Management, Somerville, NJ) was injected into the pericardial space. Aortic root angiography confirmed no further contrast extravasation. A pericardial drain was left in place for 2 days, and the patient was discharged on post-op day 7. Patient 3 received a TAVR valve and post-placement dilation due to paravalvular leak. The echocardiogram showed a pericardial effusion. Pericardiocentesis was performed, yielding 500 cc of blood. The patient's healthcare proxy declined emergent surgery; thus, a pericardial drain was placed. No hemostatic agents were used, and drainage reduced over several hours. The drain was removed on post-op day 3, and the patient was discharged on post-op day 8. CONCLUSIONS: Based on the timelines in these three cases, and interventions used, the following steps may be employed in the event of annulus rupture: identification of hemodynamic instability, echocardiogram to confirm pericardial effusion, emergent pericardiocentesis, pericardial drain placement for evacuation of the pericardial space and use of hemostatic agents, repeat aortogram to rule out ongoing extravasation. If hemostasis is unable to be achieved and/or the patient becomes hemodynamically unstable at any point, rapid transition to emergent surgical management is necessary. This management strategy proved successful for this case series and warrants further investigation.

Aetiology of Significant Liver Test Abnormalities in a Single-Centre Cohort of People with Cystic Fibrosis Exposed to Elexacaftor/Tezacaftor/Ivacaftor, Utilizing the Updated RUCAM.

BACKGROUND: The cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulator elexacaftor/tezacaftor/ivacaftor (E/T/I) has been associated with substantial multisystem benefits for people with CF eligible for therapy. In a minority, tolerance has been limited by hepatic toxicity. It is unknown whether there may be particular risk factors for significant drug-induced elevation in transaminases. OBJECTIVE: We aimed to determine the cause of raised transaminases following the introduction of E/T/I, and whether E/T/I can safely be continued in some individuals with elevated transaminases. METHODS: At a large, single, adult CF centre, individuals with transaminases >3 × the upper limit of normal (ULN) since commencing E/T/I underwent clinical assessment to exclude known causes of raised transaminases. Where an alternative cause could not be identified, individuals were discussed with hepatology to advise on further investigations to establish aetiology in addition to calculation of the updated Roussel Uclaf Causality Assessment Method (RUCAM) score to assess causality grading of drug-induced liver injury (DILI) due to E/T/I, and to guide management of ongoing CFTR modulator therapy. RESULTS: Of 337 adults taking E/T/I for a median of 27 months, 19 (5.6%) had transaminases >3 × ULN. In 12 individuals, there was clear evidence of an aetiology unrelated to E/T/I (RUCAM scores -2 to 1 [excluded-unlikely]). Of the remaining cases, two had RUCAM scores in the 'possible' range and one had a RUCAM score in the 'probable' range. Liver biopsy was performed in four individuals, showing hepatic steatosis in one individual, normal histology in one individual, and hepatocyte necrosis suggestive of DILI in two individuals. E/T/I was suspended in those with hepatocyte necrosis, with one permanent discontinuation due to synthetic dysfunction. One individual with hepatocyte necrosis on histology was successfully re-established on E/T/I therapy. CONCLUSIONS: Alternative causes were identified in the majority of patients with clinically significant increases in transaminases following E/T/I, highlighting the importance of thorough investigation. Multidisciplinary assessment involving an experienced hepatologist is crucial in cases of diagnostic uncertainty or suggestion of significant DILI, as discontinuation of therapy can have significant consequences for individuals.

Influence of highly effective modulator therapy on the sputum proteome in cystic fibrosis.

BACKGROUND: There have been dramatic clinical improvements in people with cystic fibrosis (PwCF) commenced on the cystic fibrosis conductance regulator (CFTR) modulator elexacaftor/tezacaftor/ivacaftor (ETI). Sputum proteomics is a powerful research technique capable of identifying important airway disease mechanisms. Using this technique, we evaluated how ETI changes the sputum proteome in PwCF. METHODS: Sputum samples from 21 CF subjects pre- and post- ETI, 6 CF controls ineligible for ETI, and 15 healthy controls were analysed by liquid chromatography mass spectrometry. RESULTS: Post-ETI, mean FEV1 % increased by 13.7 % (SD 7.9). Principal component and hierarchical clustering analysis revealed that the post-ETI proteome shifted to an intermediate state that was distinct from pre-ETI and healthy controls, even for those achieving normal lung function. Functional analysis showed incomplete resolution of neutrophilic inflammation. The CF control sputum proteome did not alter. At the protein-level many more proteins increased in abundance than decreased following ETI therapy (80 vs 30; adjusted p value <0.05), including many that have anti-inflammatory properties. Of those proteins that reduced in abundance many were pro-inflammatory neutrophil-derived proteins. Several important respiratory proteases were unchanged. CONCLUSIONS: Sputum proteomics can provide insights into CF lung disease mechanisms and how they are modified by therapeutic intervention, in this case ETI. This study identifies imbalances in pro- and anti- inflammatory proteins in sputum that partially resolve with ETI even in those achieving normal spirometry values. This post-ETI intermediate state could contribute to ongoing airway damage and therefore its relevance to clinical outcomes needs to be established.