Biliary disease and cholecystectomy after initiation of elexacaftor/ivacaftor/tezacaftor in adults with cystic fibrosis

Individuals with cystic fibrosis (CF) have an increased risk for gallbladder abnormalities and biliary tract disease, but the reported incidence of these manifestations of CF varies widely in the literature. With the approval of elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA), increasing numbers of CF patients have been initiated on highly effective cystic fibrosis transmembrane regulator (CFTR) modulator therapy. While elevations in hepatic panel are known potential side effects of CFTR modulators, there have been no published cases of biliary disease or acute cholecystitis attributed to these medications. In this case series, we describe seven patients at two adult CF centers with biliary colic shortly after initiation with ELX/TEZ/IVA, six of whom required cholecystectomy.     

Multi-dimensional clinical phenotyping of a national cohort of adult cystic fibrosis patients

BackgroundCystic Fibrosis (CF) is a multi-systemic disorder resulting from genetic variation in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene which can result in bronchiectasis, chronic sinusitis, pancreatic malabsorption, cholestatic liver disease and distal intestinal obstructive syndrome. This study generates multi-dimensional clinical phenotypes that capture the complexity and spectrum of the disease manifestations seen in adult CF patients using statistically robust techniques.MethodsPre-transplant clinical data from adult (age ≥18 years) CF patients (n = 992) seen in six regionally distinct US CF centers between 1/1/2014 and 6/30/2015 were included. Demographic, spirometry, nutritional, microbiological and therapy data were used to generate clusters using the Random Forests statistical-learning and Partitioning around Medoids (PAM) clustering algorithms. Five commonly measured demographic, physiological and nutritional parameters were needed to create the final phenotypes that are highly similar to a regionally matched group of patients from the CF Foundation Patient RegistryResultsThis approach identified high-risk phenotypes with expected characteristics including high rates of pancreatic insufficiency, diabetes and Pseudomonas aeruginosa colonization. It also identified unexpected populations including a) a male-dominated, well-nourished group with good lung function with a high prevalence of severe genotypes (i.e. 60% subjects had two minimal function CFTR variations), b) and an older, “survivor” phenotype that had high rates of chronic P. aeruginosa infection.ConclusionsThis study identified recognizable phenotypes that capture the clinical complexity in a statistically robust manner and which may aide in the identification of specific genetic and environmental factors responsible for these disease manifestation patterns.     

Adverse childhood experiences and the development of Down syndrome regression disorder

Down syndrome regression disorder (DSRD) is a clinical symptom cluster of acute or subacute neurocognitive regression in otherwise health persons with Down syndrome. The objective of this study was to evaluate if adverse childhood experiences (ACEs) were more prevalent in children with DSRD than those with DS alone. A survey-based, cohort-based study was performed. Caregivers of individuals with DSRD with onset of symptoms between age 10 and 30 years and DS alone were administered the ACEs questionnaire via an online REDCap survey. A total of 159 responses were collected after excluding incomplete surveys and those not meeting criteria for DSRD. Individuals with DSRD were not more likely to experience ACEs (p = 0.18, 95% confidence interval [CI]: 0.43–1.17). In those with ACEs prior to the onset of symptoms, the median time prior was 7 months (interquartile range: 5–10). Individuals with DSRD were more likely to report three or more ACEs (52, 33%) compared to those with DS alone (39, 22%) (p = 0.02, 95% CI: 1.08–2.87). Exposure to ACEs were not predictive of response to particular therapeutic interventions although those with multiple ACEs 3 months prior to the onset of symptoms was associated with lower response rates to benzodiazepines and immunotherapy (p = 0.02, 95% CI: −3.64–−1.13). This study provides preliminary data that individuals with DSRD experience ACEs at a similar rate to individuals with only DS alone, although three or more ACEs, often preceding the onset of symptoms, was more prevalent in individuals with DSRD.     

Is hypoxic pulmonary vasoconstriction important during single lung ventilation in the lateral decubitus position?

Hypoxic pulmonary vasoconstriction (HPV) has not been demonstrated in human single lung anaesthesia in the lateral decubitus position (LDP). The purpose of this study was to determine whether (1) HPV occurs in the non-dependent, nonventilated lung, and (2) if the infusion of sodium nitroprusside (SNP) inhibits HPV During intravenous anaesthesia the tracheas of seven patients were intubated with double lumen endotracheal tubes. Standard monitors plus radial and pulmonary arterial catheters were placed. Patients were positioned in the LDP and haemodynamic and gas exchange data were recorded for each of three stages; I: two-lung ventilation, II: single, dependent lung ventilation (1LV) and III: 1LV with infusion of SNP. In stage II the PaO₂ decreased from 531 ± 42 mmHg to 285 ± 42 mmHg (P < 0.05) and Qs/Qt increased from 12.3 ± 2.7 to 29.0 ± 6.3% (P < 0.05). With SNP infusion there was a 30% increase in cardiac index (CI) (P < 0.05). The SNP infusion was not associated with changes in Qs/ Qt or PaO₂. This model demonstrates changes in Qs/ Qt and PaO₂ associated with single-lung ventilation in ASA I and II patients in the LDP but we were unable to demonstrate inhibition of HPV by SNP.     

NM-Win: A Personal Computer-Based Microsoft® Windows™ Front-End to NONMEM IV

A Microsoft Windows-based front-end, NM-Win, has been written to provide a more user-friendly environment to do nonlinear mixed effect modeling with the NONMEM program. NM-Win utilizes an object-oriented interface design which allows users to view and edit control, PRED, and/or data files using Windows Notepad. In addition, calls made to the Microsoft FORTRAN compiler and linker which generate the final NONMEN executable are performed simply by clicking the Run NONMEN button. During the executive step, iterations can be viewed in a window to check the progress of the run. Errors encountered while NONMEN or NM-TRAN is running are brought to a window for ease in debugging. Advanced options allow the user the flexibility of compiling user-written PRED files and creating linker response files. While the PC platform is not optimal for large data set or complex models, it does permit easier debugging and offers multitasking while Windows is running.