Changes In Chloride Concentration Research Articles

Effectiveness and safety of elexacaftor/tezacaftor/ivacaftor treatment in children aged 6-11 years with cystic fibrosis in a real-world setting.

Elexacaftor-tezacaftor-ivacaftor (ETI) is a highly effective cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulating therapy for people with CF and at least one F508del variant. However, there is limited data about the safety and efficacy of this therapy in pediatric populations and in real-world settings. This study aimed at evaluating the effectiveness, tolerability, and safety of ETI in children with CF. This was a prospective observational study including all children aged 6-11 years who initiated ETI therapy between October 2022 and March 2023 at the Pediatric CF Center of Milan (Italy). Study outcomes included changes in sweat chloride concentration, FEV1, LCI2.5, body mass index(BMI), tolerance, and safety. Mean changes in study outcomes from baseline through 24 weeks were estimated using mixed-effects regression models. The study included 34 children with CF (median age: 8.3 years). At Week 12, we observed an average decrease in LCI2.5 of 2.3 units (95% confidence interval [CI]: -3.1; -1.5). At Week 24, sweat chloride concentration decreased by 63 mEq/L (95% CI: -69; -58), FEV1 increased by 8.8 percentage point (95% CI: 3.7; 13.9) and BMI increased by 0.15 standard deviation scores (95% CI: 0.04; 0.25). Skin rashes appeared in 6 patients which spontaneously resolved within a few days. One month after treatment initiation, one patient experienced an elevation in liver function test results, which subsequently decreased during follow-up visits without necessitating discontinuation of therapy. Our data indicate that ETI therapy is well tolerated by children with CF and is effective in improving signs of lung function abnormalities from early childhood.

Mild dehydration does not alter acute changes in sweat electrolyte concentrations during exercise.

The purpose of this study was to determine the effect of hydration status on the change in sweat sodium (Na+), chloride (Cl-), and potassium (K+) concentrations during exercise-heat stress. Fifteen subjects (Six female, nine male; 29 ± 9 y; 71 ± 14 kg) completed 90 min of cycling (81% HRmax) in the heat (~33°C, 42% rh) with fluid replacement to maintain euhydration (EUH) or without fluid to dehydrate to 2.4 ± 0.4% body mass loss (DEH). Sweat was collected from the forehead (FH), right scapula (SCAP), and left (LVFA) and right (RVFA) ventral forearms using the absorbent pad technique at the beginning (0-30 min) and end of exercise (60-90 min). Sweat was analyzed for Na+, Cl-, and K+ concentrations using ion chromatography. Data are reported as mean ± SD or median ± IQR. There were no differences (Paired t-tests or Wilcoxon signed-rank tests) between EUH and DEH in the change in sweat Na+ (FH: 24.3 ± 21.5 vs. 30.8 ± 22.4 mmol/L; SCAP: 9.7 ± 6.2 vs. 9.6 ± 8.2 mmol/L; LVFA: 7.5 ± 6.0 vs. 5.6 ± 5.9 mmol/L; RVFA: 8.2 ± 8.6 vs. 7.8 ± 5.2 mmol/L), sweat Cl-, or sweat K+ at any site (p = 0.07-0.99). The change in sweat electrolyte concentrations during 90 min of exercise in the heat was not significantly influenced by mild dehydration in recreational to moderately-trained male and female athletes.

Acute renal response to changes in carbon dioxide in mechanically ventilated female pigs.

Kidney response to acute and mechanically induced variation in ventilation associated with different levels of PEEP has not been investigated. We aimed to quantify the effect of ventilatory settings on renal acid-base compensation. Forty-one pigs undergoing hypo- (<0.2 Lkg-1 min-1, PEEP 25 cmH2O), intermediate (0.2-0.4 Lkg-1 min-1 with either PEEP 5 or 25 cmH2O), or hyper-ventilation (>0.4 Lkg-1 min-1, PEEP 5 cmH2O) for 48 h were retrospectively included. The decrease in pH paralleled the decrease in plasma strong ion difference (SID) in hyper- and intermediately ventilated groups with lower PEEP. In contrast, the plasma SID remained nearly constant in hypo- and intermediately ventilated groups with higher PEEP. Changes in plasma chloride concentration accounted for the changes in plasma SID (conditional R2 = 0.86). The plasma SID changes were paralleled by mirror changes in urinary SID. Higher PEEP (25 cmH2O), compared to lower PEEP (5 cmH2O) dampened or abolished the renal compensation through its effect on hemodynamics (higher central venous and mean pulmonary pressures), irrespective of minute ventilation. During mechanical ventilation, the compensatory renal response to respiratory derangement is immediate and progressive but can be dampened by high PEEP levels.

Heterogeneity in response to Elexacaftor/Tezacaftor/Ivacaftor in people with cystic fibrosis

BackgroundHighly effective modulators of the CFTR channel have been demonstrated to dramatically impact disease progression and outcome. However, real-world data indicates that the magnitude of the clinical benefit is not equal among all patients receiving the treatment. We aimed to assess the variability in treatment response (as defined by the 6-month change in sweat chloride concentration, forced expiratory volume in one second [ppFEV1], body mass index [BMI], and CF Questionnaire-Revised [CFQ-R] respiratory domain score) and identify potential predictors in a group of patients receiving Elexacaftor-Tezacaftor-Ivacaftor (ETI) triple combination therapy. MethodsThis was a single-center, prospective cohort study enrolling adults with CF at a major center in Italy. We used linear regression models to identify a set of potential predictors (including CFTR genotype, sex, age, and baseline clinical characteristics) and estimate the variability in treatment response. ResultsThe study included 211 patients (median age: 29 years, range: 12–58). Median changes (10–90th percentile) from baseline were: - 56 mEq/L (–76; –27) for sweat chloride concentration, +14.5 points (2.5; 32.0) for ppFEV1, +0.33 standard deviation scores (–0.13; 1.05) for BMI and +17 points (0; 39) for the CFQ-R respiratory domain score. The selected predictors explained 23 % of the variability in sweat chloride concentration changes, 18 % of the variability in ppFEV1 changes, 39 % of the variability in BMI changes, and 65 % of the variability in CFQ-R changes. ConclusionsThis study highlights a high level of heterogeneity in treatment response to ETI, which can only be partially explained by the baseline characteristics of the disease.

6-Methoxyquinoline immobilized nylon sensor for monitoring chloride concentration in reinforced concrete

An excess in the threshold concentration of chloride in concrete leads to the initiation of reinforcement corrosion, which in turn results in a reduction in the load-bearing capacity of reinforced concrete (RC) structures. Accordingly, the chloride concentration of RC is periodically investigated via a destructive method, but this process is time-consuming, labor-intensive, and costly. In order to overcome the limitations, this study sought to develop an optical chloride sensor that can be used in structural health monitoring. To this end, nylon was functionalized using formaldehyde and epichlorohydrine, after which 6-methoxy quinoline was covalently immobilized to manufacture a sensor. The developed sensor was found to be capable of measuring chloride concentrations (0–5,000 mM) and exhibited rapid responsiveness and reversibility. In addition, the developed sensor also showed a stable response even when exposed to the pH 13.4 environment for three months, and it could detect changes in chloride concentration even inside the mortar.

Local factors and sources affecting freshwater chloride concentrations in the Toronto region

Increasing chloride concentrations in freshwater streams throughout many areas of North America have raised concern over freshwater salinization. Road salt has been implicated; however, chloride source identification is lacking in the Toronto region. We assessed trends in chloride concentrations in streams and groundwater between 2000 and 2021 within the Toronto region and identified factors contributing to trends. Chloride concentrations increased in 36 of 47 streams and in 5 of 13 groundwater wells. There were no significant relationships between changes in stream chloride concentrations and changes in winter climatic conditions over the study period; however, changes in stream chloride concentrations were positively related to changes in road density. Chloride:bromide ratios indicated that road salt and/or septic effluent was the dominant source of chloride in streams. Inputs varied throughout the year with road salt and/or septic effluent having a higher proportion of inputs during the salting season compared to the non-salting season where a higher proportion of inputs were from basin brines and/or animal waste, landfill leachate, and pristine aquifer. Commercial, industrial, institutional, and medium density residential land uses were also positively correlated with stream chloride. Parking lot cover increased in several catchments suggesting that these too may contribute to trends. These results highlight the importance of continued and enhanced investment in long-term monitoring of freshwater ecosystems. It also highlights the need for urgent action to better control and monitor road salt usage by public and private applicators since urban growth continues to drive increasing chloride trends.

The impact of hypertonic saline on damage control laparotomy after penetrating abdominal trauma.

The inability to achieve primary fascial closure (PFC) after emergency laparotomy increases the rates of adverse outcomes including fistula formation, incisional hernia, and intraabdominal infection. Hypertonic saline (HTS) infusion improves early PFC rates and decreases time to PFC in patients undergoing damage control laparotomy (DCL) after injury. We hypothesized that in patients undergoing DCL after penetrating abdominal injury, HTS infusion would decrease the time to fascial closure as well as the volume of crystalloid required for resuscitation without inducing clinically relevant acute kidney injury (AKI) or electrolyte derangements. We retrospectively analyzed all penetrating abdominal injury patients undergoing DCL within the University of Pennsylvania Health System (January 2015-December 2018). We compared patients who received 3% HTS at 30mL/h (HTS) to those receiving isotonic fluid (ISO) for resuscitation while the abdominal fascia remained open. Primary outcomes were the rate of early PFC (PFC within 72h) and time to PFC; secondary outcomes included acute kidney injury, sodium derangement, ventilator-free days, hospital length of stay (LOS), and ICU LOS. Intergroup comparisons occurred by ANOVA and Tukey's comparison, and student's t, and Fischer's exact tests, as appropriate. A Shapiro-Wilk test was performed to determine normality of distribution. Fifty-seven patients underwent DCL after penetrating abdominal injury (ISO n = 41, HTS n = 16). There were no significant intergroup differences in baseline characteristics or injury severity score. Mean time to fascial closure was significantly shorter in HTS (36.37h ± 14.21 vs 59.05h ± 50.75, p = 0.02), and the PFC rate was significantly higher in HTS (100% vs 73%, p = 0.01). Mean 24-h fluid and 48-h fluid totals were significantly less in HTS versus ISO (24h: 5.2L ± 1.7 vs 8.6L ± 2.2, p = 0.01; 48h: 1.3L ± 1.1 vs 2.6L ± 2.2, p = 0.008). During the first 72h, peak sodium (Na) concentration (146.2mEq/L ± 2.94 vs 142.8mEq/L ± 3.67, p = 0.0017) as well as change in Na from ICU admission (5.1mEq/L vs 2.3, p = 0.016) were significantly higher in HTS compared to ISO. Patients in the HTS group received significantly more blood in the trauma bay compared to ISO. There were no intergroup differences in intraoperative blood transfusion volume, AKI incidence, change in chloride concentration (△Cl) from ICU admit, Na to Cl gradient (Na:Cl), initial serum creatinine (Cr), peak post-operative Cr, change in creatinine concentration (△Cr) from ICU admission, creatinine clearance (CrCl), initial serum potassium (K), peak ICU K, change in K from ICU admission, initial pH, highest or lowest post-operative pH, mean hospital LOS, ICU LOS, and ventilator-free days. HTS infusion in patients undergoing DCL after penetrating abdominal injury decreases the time to fascial closure and led to 100% early PFC. HTS infusion also decreased resuscitative fluid volume without causing significant AKI or electrolyte derangement. HTS appears to offer a safe and effective fluid management approach in patients who sustain penetrating abdominal injury and DCL to support early PFC without inducing measurable harm. Level III.

Qualitative and quantitative evaluation of computed tomography changes in adults with cystic fibrosis treated with elexacaftor-tezacaftor-ivacaftor: a retrospective observational study.

Introduction: The availability of highly effective triple cystic fibrosis transmembrane conductance regulator (CFTR) modulator combination therapy with elexacaftor-tezacaftor-ivacaftor (ETI) has improved pulmonary outcomes and quality of life of people with cystic fibrosis (pwCF). The aim of this study was to assess computed tomography (CT) changes under ETI visually with the Brody score and quantitatively with dedicated software, and to correlate CT measures with parameters of clinical response. Methods: Twenty two adult pwCF with two consecutive CT scans before and after ETI treatment initiation were retrospectively included. CT was assessed visually employing the Brody score and quantitatively by YACTA, a well-evaluated scientific software computing airway dimensions and lung parenchyma with wall percentage (WP), wall thickness (WT), lumen area (LA), bronchiectasis index (BI), lung volume and mean lung density (MLD) as parameters. Changes in CT metrics were evaluated and the visual and quantitative parameters were correlated with each other and with clinical changes in sweat chloride concentration, spirometry [percent predicted of forced expiratory volume in one second (ppFEV1)] and body mass index (BMI). Results: The mean (SD) Brody score improved with ETI [55 (12) vs. 38 (15); p < 0.001], incl. sub-scores for mucus plugging, peribronchial thickening, and parenchymal changes (all p < 0.001), but not for bronchiectasis (p = 0.281). Quantitatve WP (p < 0.001) and WT (p = 0.004) were reduced, conversely LA increased (p = 0.003), and BI improved (p = 0.012). Lung volume increased (p < 0.001), and MLD decreased (p < 0.001) through a reduction of ground glass opacity areas (p < 0.001). Changes of the Brody score correlated with those of quantitative parameters, exemplarily WT with the sub-score for mucus plugging (r = 0.730, p < 0.001) and peribronchial thickening (r = 0.552, p = 0.008). Changes of CT parameters correlated with those of clinical response parameters, in particular ppFEV1 with the Brody score (r = -0.606, p = 0.003) and with WT (r = -0.538, p = 0.010). Discussion: Morphological treatment response to ETI can be assessed using the Brody score as well as quantitative CT parameters. Changes in CT correlated with clinical improvements. The quantitative analysis with YACTA proved to be an objective, reproducible and simple method for monitoring lung disease, particularly with regard to future interventional clinical trials.

P110 Change in sweat chloride concentration after elexacaftor/tezacaftor/ivacaftor initiation: results from 12 months follow-up in the Danish cystic fibrosis cohort

Pulmonary function tests are the gold standard for evaluating disease status and treatment response in persons with cystic fibrosis (CF). Pulmonary function, however, is an outcome influenced by multiple circumstances. Sweat chloride (SwCl) concentration is a reliable outcome, solely reflecting the activity of the CF transmembrane conductance regulator protein. In the present study, we aim to evaluate the effect of ETI treatment on SwCl concentration.

P021 Change in sweat chloride concentration following elexacaftor/tezacaftor/ivacaftor in siblings with cystic fibrosis heterozygous for R334W/N1088D/R75Q mutations

Objectives: The introduction of elexacaftor-tezacaftor-ivacaftor (ETI) has been life-changing for many people with cystic fibrosis (CF). Clinical improvement is associated with significant but variable reduction in sweat chloride concentration. We describe the sweat chloride concentration levels and clinical response following ETI therapy in two siblings with CF and a CFTR R75Q mutation. Although R75Q is categorised as non-CF causing (as per CFTR2 database) with in vitro studies suggesting normal chloride conductance, this variant is associated with disrupted bicarbonate conductance and is ETI-responsive.

Numerical analysis on the applicability of sorption isotherm models in aquifers and its correlation with recharged water movement

ABSTRACT Sorption is a necessary process influencing the subsurface solute or contaminant transport. There are many adsorption isotherms, and selecting one to represent the system is likely to remain an elusive goal. Also, the lack of observed data and its associated certainty may hinder the determination of sorption parameters. This study investigated the influence of different isotherms – linear adsorption assumption, Freundlich isotherm, Langmuir isotherm, and Redlich – Peterson isotherm, on chloride concentrations. The numerical model also gauged the extent of recharged waters migrating from the injection well. Temporal analysis of groundwater resident volumes helped to understand better the change in chloride concentrations with the selected isotherm. The residual solute concentrations from the isotherms followed the order: Redlich – Peterson < Freundlich < Langmuir. The results highlighted the importance of obtaining a range of sorption values rather than a single value from one fitted isotherm for the productive aid in groundwater decision making.

The effects of feeding and transport length on the welfare of white rhinoceroses (Ceratotherium simum simum) during long-distance translocations: a preliminary study.

Translocation is a valuable conservation tool, but poses significant risks for the transported rhinoceroses. Interventions reducing these risks are required to ensure positive welfare during transportation. The aim of this study was to evaluate the effect of journey duration and feeding during the transport of white rhinoceroses (Ceratotherium simum simum). A total of 32 animals were transported by road during two events, five days apart. Fifteen rhinoceroses in the first transport event (37.0 ± 2.4 hr duration) were not fed, while 17 rhinoceroses in the second event (32.2 ± 1.5 hr duration) were offered lucerne. Blood samples were collected at capture and after transport for the evaluation of changes in serum clinical chemistry analytes. The Wilcoxon rank-sum test was used to compare differences between the groups. In all rhinoceroses, transport resulted in changes in serum electrolyte, metabolite and enzyme concentrations, indicating a loss in total body water, nutritional shifts, stress and fatigue. Fed rhinoceroses, transported over a shorter time, displayed greater changes in osmolality (p < 0.006), serum sodium and chloride concentrations (p = 0.005 and = 0.001, respectively) indicating a greater degree of total body water loss than non-fed rhinoceroses. Feeding and a shorter transport duration reduced, but did not prevent, nutritional challenges. A greater increase in the muscle enzymes CK and AST (p = 0.027 and = 0.001, respectively), indicated greater fatigue in non-fed rhinoceroses transported over a longer time. Further work to distinguish the effects of feeding and journey duration is required to better understand the role feeding may play in mitigating welfare challenges during rhinoceros translocation.

Laboratory evaluation of operating conditions for chloride removal from diethanolamine using ion exchange resin and introduction of optimal parameters

In this study, a strong anionic resin was used to remove the chloride ion in the diethanolamine of sweetening unit of gas refinery. A laboratory pilot has been investigated as a resin-filled bed to evaluate the reaction temperature, chloride ion concentration, resin saturation, resin recovery rate, optimal reaction temperature, diethanolamine flow rate, hydrogen strength and resin performance in this work. The resin saturation time, capacity of resin, optimal reaction temperature and changes in chloride concentration of the output stream from resin were determined in this research. Finally, the optimal amount of water to regulate the pH of the resin and the optimal amount of 4% sodium hydroxide solution to recycle the resin were calculated. It was found that one liter of resin is able to absorb 20.77 g of chloride. The temperature of 50 °C was considered as the optimal temperature of ion exchange reaction by comparing the amount of caustic and water consumption for resin recovery and regulation of neutral acidity, respectively. In this study, the amount of 4 wt.% caustic and water at a temperature of 50 °C for recovery of 134 g of resin obtained was equal to 8.5 and 5 L, respectively.

Water chemistry and periphyton biomass in the Rideau River: Have conditions changed after 24 years?

Over the past three decades, the Rideau River (Ontario, Canada) watershed has experienced a land-use change from rural and agricultural land towards urban land, and the introduction and expansion of invasive species. This study examined spatial and temporal patterns of periphyton biomass (chlorophyll-a and ash-free dry mass) collected from riffle zones in 1995 and 2019 along a 66-km stretch of the Rideau River. This study also examined long-term changes in water nutrient and chloride concentrations collected through the Provincial Water Quality Monitoring Network between 2000 and 2018. Declines in total nitrogen between 2000 and 2018 occurred in areas that have not experienced urbanization since the 2000s. In contrast, declines in total phosphorus and increases in chloride between 2000 and 2018 occurred at midstream and downstream sites that have undergone urbanization during the same time period. Conductivity also showed an increase with distance downstream similarly in both 1995 and 2019. Average total phosphorus and total Kjeldahl nitrogen concentrations were lower in 2019 compared to 1995 but did not increase with distance downstream as seen in many river systems, including the Rideau River, in earlier years. Periphyton biomass did not change along the length of the river between 1995 and 2019, despite the declines in nutrient concentrations. These findings highlight the persistence of riverine periphyton in a multi-use watershed experiencing ongoing anthropogenic changes.

Effect of initial serum chloride level on the association between intravenous chloride load and mortality in critically ill patients: A retrospective cohort study.

To assess the effect of intravenous chloride load on prognosis in intensive care unit (ICU) patients with different initial serum chloride levels. Participants from the Medical Information Mart for Intensive Care IV database were divided into low, normal (>100 and ≤110 mEq/L), and high chloride groups according to initial chloride levels. Records of intravenous fluids were extracted to calculated the volume adjusted chloride load (VACL) and VACL per body weight (VACL-W). The associations of VACL, VACL-W, and changes in serum chloride concentration (ΔCl) with mortalities were investigated in different initial chloride groups. Respectively, 4593 (20.9%), 13,364 (60.9%), and 3978 (18.1%) patients had a low, normal, and high initial chloride level. Interactions were found between initial chloride levels and VACL, VACL-W, and ΔCl on mortality risks. In normal and high chloride groups, increased VACL, VACL-W, and ΔCl were associated with higher ICU and hospital mortalities. However, in the low chloride group, multivariable models found no associations between VACL, VACL-W, or ΔCl with mortalities. High chloride load and increased serum chloride level were associated with poor outcomes in patients with normal or high initial chloride levels, but not in those with a low initial chloride level.

Bile Duct Ligation Changes the Inhibitory Control of Vasopressin Neurons in Male Rats

Dilutional hyponatremia typically is caused by increased Arginine Vasopressin (AVP) secretion. This increases the risk of complications and mortality in patients with liver cirrhosis. Liver cirrhosis in male rats increases AVP release but the underlying mechanisms are still under investigation. In other models of chronic AVP release, changes in chloride homeostasis alters the inhibitory control of AVP neurons in the supraoptic nucleus (SON) causing GABA mediated excitation instead of inhibition. In the bile duct ligation (BDL) model of cirrhosis, changes in either intracellular chloride concentration or cell firing activity have not been directly tested. We hypothesize that liver cirrhosis increases intracellular chloride concentration leading to a decrease in GABA‐mediated inhibition of SON neurons from male rats.To test this hypothesis, we injected an adeno‐associated virus with a vasopressin promoter and a ratiometric chloride indicator, AAV2‐0VP1‐ClopHensorN into the SON of adult male Sprague‐Dawley rats. The rats either received BDL surgery, which was used to model liver cirrhosis, or a sham ligation surgery. All BDL rats had significantly higher liver weight to body weight ratio (n = 10‐20, p &lt; 0.05), lower plasma osmolality (n = 10‐20, p &lt; 0.001) and lower hematocrit (n = 10‐20, p &lt; 0.05) as compared to sham rats. All rats were anesthetized with isoflurane (2‐3%), their brains were collected, and slices containing the SON were prepared. Loose‐cell patch recordings were made at 31±1oC using standard artificial cerebrospinal fluid. Labeled AVP cells and unlabeled SON cells were tested with focal application of muscimol (100µM), a GABAA receptor agonist.Cells from BDL rats showed impaired GABAA‐mediated inhibition in response to muscimol, as compared to those from sham rats. All putative AVP SON neurons from sham rats (4/4) showed decreased activity following muscimol while half of the putative AVP SON neurons (7/14) from BDL rats were excited (p &lt; 0.001). Similar results were observed in experiments were the injections missed the SON. In these experiments, all SON neurons from sham rats were inhibited by muscimol (26/26) while thirty‐five percent of SON neurons from BDL rats (16/45) were excited by muscimol (p = 0.001). ClopHensorN based chloride imaging showed that muscimol application was associated with decreased intracellular chloride concentrations in putative AVP cells from BDL rats as compared to sham rats (n = 31‐32, p = 0.001). The results show that liver cirrhosis impairs the normal inhibitory response of SON neurons to GABAA receptor activation which could contribute to increased cell activity and dilutional hyponatremia in male rats.

Hypochloraemia following admission to hospital with heart failure is common and associated with an increased risk of readmission or death: a report from OPERA-HF.

Hypochloraemia is common in patients hospitalized with heart failure (HF) and associated with a high risk of adverse outcomes during admission and following discharge. We assessed the significance of changes in serum chloride concentrations in relation to serum sodium and bicarbonate concentrations during admission in a cohort of 1002 consecutive patients admitted with HF and enrolled into an observational study based at a single tertiary centre in the UK. Hypochloraemia (<96 mmol/L), hyponatraemia (<135 mmol/L), and metabolic alkalosis (bicarbonate >32 mmol/L) were defined by local laboratory reference ranges. Outcomes assessed were all-cause mortality, all-cause mortality or all-cause readmission, and all-cause mortality or HF readmission. Cox regression and Kaplan-Meier curves were used to investigate associations with outcome. During a median follow-up of 856 days (interquartile range 272-1416), discharge hypochloraemia, regardless of serum sodium, or bicarbonate levels was associated with greater all-cause mortality [hazard ratio (HR) 1.44, 95% confidence interval (CI) 1.15-1.79; P = 0.001], all-cause mortality or all-cause readmission (HR 1.26, 95% CI 1.04-1.53; P = 0.02), and all-cause mortality or HF readmission (HR 1.41, 95% CI 1.14-1.74; P = 0.002) after multivariable adjustment. Patients with concurrent hypochloraemia and natraemia had lower haemoglobin and haematocrit, suggesting congestion; those with hypochloraemia and normal sodium levels had more metabolic alkalosis, suggesting decongestion. Hypochloraemia is common at discharge after a hospitalization for HF and is associated with worse outcome subsequently. It is an easily measured clinical variables that is associated with morbidity or mortality of any cause.

Abstracts from Hydrocephalus 2021: The Thirteenth Meeting of the International Society for Hydrocephalus and Cerebrospinal Fluid Disorders

Abstracts from Hydrocephalus 2021: The Thirteenth Meeting of the International Society for Hydrocephalus and Cerebrospinal Fluid Disorders

Identification and pharmacological characterization of histamine-gated chloride channels in the fall armyworm, Spodoptera frugiperda

Histamine-gated chloride channels (HACls) mediate fast inhibitory neurotransmission in invertebrate nervous systems and have important roles in light reception, color processing, temperature preference and light-dark cycle. The fall armyworm, Spodoptera frugiperda is a main destructive pest of grain and row crops. However, the pharmacological characterization of HACls in S. frugiperda remain unknown. In this study, we identified two cDNAs encoding SfHACl1 and SfHACl2 in S. frugiperda. They had similar expression patterns and were most abundantly expressed in the head of larvae and at the egg stage. Electrophysiological analysis with the two-electrode voltage clamp method showed that histamine (HA) and γ-aminobutyric acid (GABA) activated inward currents when SfHACls were singly or collectively expressed with different ratios in Xenopus laevis oocytes. These channels were ≥2000-fold more sensitive to HA than to GABA. They were anion-selective channels, which were highly dependent on changes in external chloride concentrations, but insensitive to changes in external sodium concentrations. The insecticides abamectin (ABM) and emamectin benzoate (EB) also activated these channels with the EC50 to SfHACl1 lower than that to SfHACl2. And the EC50s of ABM and EB to the co-expressed channels gradually increased with increase in the injection ratio of SfHACl2 cRNA. Homology models and docking simulations revealed that HA bound to the large amino-terminal extracellular domain of SfHACl1 and SfHACl2 by forming 4 and 2 hydrogen bonds, respectively. The docking simulations of ABM and EB had similar binding sites in the transmembrane regions. Overall, these findings indicated that HACls act as targets for macrolide, and this study provides theoretical guidance for further derivatization of abamectin insecticides.

Riociguat for the treatment of Phe508del homozygous adults with cystic fibrosis

BackgroundRiociguat is a first-in-class soluble guanylate cyclase stimulator for which preclinical data suggested improvements in cystic fibrosis transmembrane conductance regulator (CFTR) function. MethodsThis international, multicenter, two-part, Phase II study of riociguat enrolled adults with cystic fibrosis (CF) homozygous for Phe508del CFTR. Part 1 was a 28-day, randomized, double-blind, placebo-controlled study in participants not receiving CFTR modulator therapy. Twenty-one participants were randomized 1:2 to placebo or oral riociguat (0.5 mg three times daily [tid] for 14 days, increased to 1.0 mg tid for the subsequent 14 days). The primary and secondary efficacy endpoints were change in sweat chloride concentration and percent predicted forced expiratory volume in 1 second (ppFEV1), respectively, from baseline to Day 14 and Day 28 with riociguat compared with placebo. ResultsRiociguat did not alter CFTR activity (change in sweat chloride) or lung function (change in ppFEV1) at doses up to 1.0 mg tid after 28 days. The most common drug-related adverse event (AE) was headache occurring in three participants (21%); serious AEs occurred in one participant receiving riociguat (7%) and one participant receiving placebo (14%). This safety profile was consistent with the underlying disease and the known safety of riociguat for its approved indications. ConclusionsThe Rio-CF study was terminated due to lack of efficacy and the changing landscape of CF therapeutic development. The current study⁠, within its limits of a small sample size, did not provide evidence that riociguat could be a valid treatment option for CF.Clinical trial registration number: NCT02170025.