Heterogeneity of CFTR modulator-induced sweat chloride concentrations in people with cystic fibrosis.

BACKGROUND: Sweat chloride (SC) concentrations in people with cystic fibrosis (PwCF) reflect relative CF transmembrane conductance regulator (CFTR) protein function, the primary CF defect. Populations with greater SC concentrations tend to have lesser CFTR function and more severe disease courses. CFTR modulator treatment can improve CFTR function within specific CF genotypes and is commonly associated with reduced SC concentration. However, SC concentrations do not necessarily fall to concentrations seen in the unaffected population, suggesting potential for better CFTR treatment outcomes. We characterized post-modulator SC concentration variability among CHEC-SC study participants by genotype and modulator. METHODS: PwCF receiving commercially approved modulators for ≥90 days were enrolled for a single SC measurement. Clinical data were obtained from chart review and the CF Foundation Patient Registry (CFFPR). Variability of post-modulator SC concentrations was assessed by cumulative SC concentration frequencies. RESULTS: Post-modulator SC concentrations (n = 3787) were collected from 3131 PwCF; most (n = 1769, 47 %) were collected after elexacaftor/tezacaftor/ivacaftor (ETI) treatment. Modulator use was associated with lower SC distributions, with post-ETI concentrations the lowest on average. Most post-ETI SC concentrations were <60 mmol/L (79 %); 26 % were <30 mmol/L. Post-ETI distributions varied by genotype. All genotypes containing at least one F508del allele had individuals with post-ETI SC ≥60 mmol/L, with the largest proportion being F508del/minimal function (31 %). CONCLUSIONS: Post-modulator SC concentration heterogeneity was observed among all genotypes and modulators, including ETI. The presence of PwCF with post-modulator SC concentrations within the CF diagnostic range suggests room for additional treatment-associated CFTR restoration in this population.

Updated diagnostic criteria for neuromyelitis optica spectrum disorder: Similar outcomes of previously separate cohorts.

BACKGROUND: The specificity of the aquaporin-4 antibody to predict recurrent inflammatory central nervous system disease has led to the design of the 2015 neuromyelitis optica spectrum disorder criteria which capture all aquaporin-4 antibody seropositive patients. OBJECTIVE: The purpose of this study was to compare treatment outcomes in aquaporin-4 antibody seropositive patients who met the previous 2006 clinical criteria for neuromyelitis optica with patients who meet the 2015 neuromyelitis optica spectrum disorder criteria. METHODS: The study involved a three-center retrospective chart review of clinical outcomes among aquaporin-4 patients diagnosed with neuromyelitis optica and neuromyelitis optica spectrum disorder. RESULTS: Hazard ratios of relapse during immunosuppressive therapy, relative to pre-therapy, were not significantly different for patients who met the 2006 criteria of neuromyelitis optica versus the 2015 neuromyelitis optica spectrum disorder criteria among those treated with azathioprine ( p = 0.24), mycophenolate mofetil ( p = 0.63), or rituximab ( p = 0.97). CONCLUSION: Reductions in the hazard of relapse during treatment with immunosuppressive therapies, relative to average pre-treatment, were not different for aquaporin-4 antibody seropositive patients categorized using the 2006 criteria of neuromyelitis optica and the 2015 neuromyelitis optica spectrum disorder criteria. These therapeutic findings support the design of the 2015 neuromyelitis optica spectrum disorder criteria which capture all aquaporin-4 antibody seropositive patients.

Efficacy of percutaneous treatment of biliary tract calculi using the holmium:YAG laser.

BACKGROUND: Few Western studies have focused on percutaneous techniques using percutaneous transhepatic choledochoscopy (PTHC) and holmium:yttrium-aluminum-garnet (YAG) laser to ablate biliary calculi in patients unable or unwilling to undergo endoscopic or surgical removal of the calculi. The authors report the efficacy of the holmium:YAG laser in clearing complex biliary calculi using percutaneous access techniques. METHODS: This study retrospectively reviewed 13 non-Asian patients with complex secondary biliary calculi treated percutaneously using holmium:YAG laser. Percutaneous access was accomplished via left, right, or bilateral hepatic ducts and upsized for passage of a 7-Fr video choledochoscope. Lithotripsy was performed under choledochoscopic vision using a holmium:YAG laser with 200- or 365-microm fibers generating 0.6 to 1.0 joules at 8 to 15 Hz. Patients underwent treatment until stone clearance was confirmed by PTHC. Downsizing and subsequent removal of percutaneous catheters completed the treatment course. RESULTS: Seven men and six women with an average age of 69 years underwent treatment. All the patients had their biliary tract stones cleared successfully. Of the 13 patients, 3 were treated solely as outpatients. The average length of percutaneous access was 108 days. At this writing, one patient still has a catheter in place. The average number of holmium:YAG laser treatments required for stone clearance was 1.6, with no patients requiring more than 3 treatments. Of the 13 patients, 8 underwent a single holmium:YAG laser treatment to clear their calculi. Prior unsuccessful attempts at endoscopic removal of the calculi had been experienced by 7 of the 13 patients. Five patients underwent percutaneous access and subsequent stone removal as their sole therapy for biliary stones. Five patients were cleared of their calculi after percutaneous laser ablation of large stones and percutaneous basket retrieval of the remaining stone fragments. There was one complication of pain requiring admission, and no deaths. CONCLUSIONS: The use of PTHC with holmium:YAG laser ablation is safe and efficacious, but requires prolonged biliary access and often multiple procedures to ensure clearance of all calculi.

Effects of acid aspiration-induced lung injury on left ventricular function.

BACKGROUND: Acid aspiration-induced acute lung injury (AALI) leads to myocardial leukosequestration and edema in rats and hemodynamic depression in dogs, but the effects of AALI on left ventricular (LV) function have not been carefully studied. METHODS: We examined the effects of 0.1 N HCl administration into the lung on LV function, leukosequestration, and edema in pentobarbital-anesthetized, atropinized (n = 8), or autonomically blocked (n = 7) dogs. Saline solution was administered into the lungs of a control group of autonomically blocked dogs (n = 6). LV contractility was assessed by end-systolic elastance (EES) and preload recruitable stroke work (PRSW). Active relaxation was assessed by the time constant of LV pressure decline (tau). RESULTS: AALI resulted in significant (p < 0.05) decreases in mean arterial pressure and cardiac output and increases in pulmonary artery pressure and systemic vascular resistance in atropinized and autonomically blocked dogs but not in saline control group. In atropinized dogs tau did not change after injury, but EES and PRSW were increased significantly at 2 and 3 hours after injury, despite significant myeloperoxidase activity and extravascular fluid wet-dry weight ratios. EES, PRSW, and tau did not change in the autonomically blocked dogs in response to AALI or in the saline control group. CONCLUSIONS: We concluded that AALI results in a baroreflex mediated enhancement of LV contractility in dogs, despite mild myocardial leukosequestration and edema formation.

Relationships in different parts of the nephron between enzymes of glycerol metabolism and the metabolite changes which result from large glycerol loads.

Glycerol metabolism in 9 defined parts of rat nephron was studied by measurement of glycerol kinase and observation of effects of large glycerol loads on related metabolites and on ATP and total adenylate. Glycerol kinase with glycerol as substrate was highest in the proximal convoluted tubule, slightly lower in straight portions, 20 to 25 times lower in distal segments, and almost indetectable elsewhere. With dihydroxyacetone as substrate, enzyme distribution differed little except for 30% lower activity in proximal convoluted segments. Methods of measurement with 10-40 ng of freeze-dried tissue are described. Glycerol loads produced large accumulations of glycerol 3-phosphate in proximal segments and in distal convoluted tubules. In the control nephron, fructose bisphosphate plus triose phosphates was 1 times higher in distal straight and convoluted segments than in proximal segments. Increases with glycerol loads were limited to proximal straight tubules (2-fold) and the thin limb area (60%). Glucose-6-P increased 3-fold in the late portion of the proximal straight tubule but not elsewhere. ATP and total adenylate were markedly depleted no phosphorylated intermediates accumulated. Levels of Pi were decreased in whole cortex and medullar following glycerol loads.