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The members of the genus Cunaxa von Heyden, known as free-living predators, feed on small arthropods and invertebrates in soil. The genus comprises more than 70 described species reported from different regions around the world. In this study, a new species, C. acaciae sp. nov., is described and illustrated based on females, and C. womersleyi Baker and Hoffmann is reported as a new record to the cunaxid mite fauna of Saudi Arabia. A new species of the genus Cunaxa von Heyden, C. acaciae sp. nov., is described and illustrated, based on females collected from soil under Acacia sp. (Fabaceae). In addition, C. womersleyi Baker and Hoffmann is reported as new to the cunaxid mite fauna of Saudi Arabia. An updated key to the species of the genus Cunaxa is provided.
BACKGROUND: Connexin-43 (Cx43) is the principal gap junction protein in the heart, mediating electrical coupling and ion exchange between cardiomyocytes to maintain synchronous contraction. Any disruption or malfunction of Cx43 can lead to arrhythmias and other cardiac issues. Understanding the functions and regulation of Cx43 is vital in both basic research and clinical contexts. Propafenone, a class Ic antiarrhythmic drug, has shown promise in rhythm control; however, its precise impact on cardiac cellular physiology, particularly regarding Cx43, remains incompletely understood. The present study investigated propafenone’s effects on Cx43 protein content, physiology, and underlying mechanisms in cell systems. METHODS: Cell lines include human embryonic kidney HEK293 cells transfected with Cx43 (Ex-HEK); differentiated murine embryonic carcinoma EPI7 cells with an epithelioid morphology and visceral endoderm-like END2 cells, both endogenously expressing functional Cx43. Cx43 protein contents were determined by Western blot analysis, whereas immunofluorescence (IF) imaging was used to assess the subcellular localization of Cx43 proteins. Dye injections were used to gain insight into the effects of propafenone on Cx43 function. RESULTS: Full-length Cx43 protein levels were dose-dependently increased after propafenone treatment and IF microscopy showed an intracellular accumulation of Cx43 protein, both on heterologously and endogenously expressed Cx43. Propafenone did not alter the Cx43 half-life, in contrast to the lysosomal inhibitor chloroquine. Finally, gap-junctional coupling was decreased by chronic propafenone treatment. CONCLUSION: We conclude that propafenone increases non-functional Cx43 protein content, resulting in its intracellular accumulation, as a side effect.
Many applications of organophosphonic-acid-grafted titania materials rely directly on their surface properties. Despite a manifold of studies on this type of material, limited information is currently available on the differences in (local) surface interactions induced by the grafting process. Here, multi-frequency spin-probe electron paramagnetic resonance (EPR) was used to probe these differences induced in a number of organophosphonic-acid-grafted titania. Two nitroxide spin probes (TEMPO and 3-carboxy-proxyl (3CP)) were adsorbed on the surfaces of unmodified, propylphosphonic acid (PPA)-modified and 3-aminopropylphosphonic acid (3APPA)-modified TiO2 P25 and TiO2 Hombikat M311. The 3APPA-modified titania adsorbed the most spin-probe molecules, while the PPA-modified titania adsorbed the least, highlighting the impact of the amine functional group. Also, the solvent plays a crucial role with the highest adsorption of spin probes obtained in heptane for TEMPO and in chloroform for 3CP. The EPR data showed clear differences in local polarity sensed by the 3CP and TEMPO when interacting with the different (un)modified titania, revealing the impact of surface Lewis-acid sites, hydroxyl surface interaction sites, type of organophosphonic acid and porosity. The 3CP probe allowed for a better differentiation of the surface polarities. The more polar environment perceived by the nitroxide moiety in the 3CP molecules adsorbed on the (un)modified Hombikat M311 surfaces is probably a result of the relatively higher portion of strong interactive sites compared to the (un)modified P25 surfaces and/or the curvature of the pore walls in Hombikat M311 materials. EPR also revealed clear differences in spin-probe mobility induced by the different surface properties.
The prognostic value of rapid atrial pacing (RAP)-induced Wenckebach atrioventricular block (W-AVB) as a diagnostic test for predicting permanent pacemaker implantation (PPI) after transcatheter aortic valve replacement (TAVR) remains unclear and requires further validation. The objective of this study was to evaluate the predictive value of RAP-induced W-AVB for PPI and sudden cardiac death within 30 days post-TAVR. This prospective, investigator-initiated, multicenter study (PACE-TAVR) included 640 patients undergoing TAVR across 12 centers. RAP was performed before and after TAVR to assess for W-AVB. Using negative predictive values and negative likelihood ratios, the predictive value of W-AVB was evaluated for the primary end point: sudden cardiac death or guideline-based indications for PPI, including complete AVB or alternating bundle branch block (Class I), and preexisting conduction disturbances with new ECG changes, new-onset left bundle branch block, a positive electrophysiology study, or sinus node dysfunction (Class II). RAP was successfully performed post-TAVR in 556 patients, with RAP-induced W-AVB observed in 192 (34.5%). W-AVB was associated with baseline conduction disturbances, amiodarone use, pre-TAVR RAP-induced W-AVB, and anesthesia type. The primary end point was more frequent in patients with W-AVB (15.6% versus 9.3%; odds ratio, 1.80 [95% CI, 1.06-3.04]; P=0.029). However, the absence of W-AVB had a negative predictive value of only 90.7% and a poor negative likelihood ratio (0.79). The test's utility declined in subgroups at high risk for PPI, including self-expanding valve recipients (odds ratio, 1.47 [95% CI, 0.84-2.58]; negative predictive value, 88.4%; negative likelihood ratio, 0.86) and patients with a baseline or new left bundle branch block (odds ratio, 1.14 [95% CI, 0.54-2.42]; negative predictive value, 81.3%; negative likelihood ratio, 0.95). RAP-induced W-AVB demonstrates limited utility in predicting post-TAVR PPI or sudden cardiac death, particularly in patients at high risk for PPI. Clinicians should be cautious when using this test for post-TAVR rhythm management. URL: https://www.clinicaltrials.gov; Unique identifier: NCT05278585.
Although avoidance can serve an adaptive function in daily life, excessive or persistent avoidance can form a debilitating symptom of anxiety-related disorders. The transition from adaptive to maladaptive avoidance remains poorly understood, but stress is a potential contributing factor. We investigated the effects of chronic restraint stress on two active avoidance procedures: two-way active avoidance (2WAA) and platform-mediated avoidance (PMA). Whereas 2WAA entails a low-cost response, avoidance in the PMA task comes with a cost, i.e., no access to food. We hypothesized that chronic restraint stress would hinder avoidance acquisition in the 2WAA task, but increase avoidance acquisition in the PMA task. In two experiments, male and female rats underwent either chronic restraint stress or a control procedure. In Experiment 1, all rats (N = 31) were then trained in a 2WAA acquisition and extinction procedure, in two contexts. Stressed rats showed significantly reduced avoidance acquisition, while extinction was unaffected. In Experiment 2 (N = 32), stressed rats and controls were trained in a PMA acquisition and extinction procedure. Contrary to our hypothesis, we did not find effects on avoidance acquisition, although we found group and sex differences in lever press suppression. All rats gradually extinguished defensive behaviors during extinction. Overall, chronic restraint stress had limited effects on PMA, but significantly impaired avoidance acquisition in the 2WAA task without affecting its extinction. These divergent effects may relate to differences in response cost or differences in safety of the context (i.e., a permanent safe area in PMA, but not in 2WAA).
A catalyst architecture with mesoporous silica coating Ru nanoparticles on reduced graphene oxide (mSiO2/Ru/rGO) localizes the 2 nm Ru solely at the closed bottoms of 2.9 nm diameter mesopores. mSiO2/Ru/rGO catalyzes the rapid, selective hydrogenolysis of polyolefins at wax formation rates (νwax) up to 1700 gwax·gRu-1·h-1 and a turnover frequency (TOF) for C-C bond cleavage of 130 ± 8 min-1. The νwax and TOF for mSiO2/Ru/rGO are 23× and 16× those of nonporous Ru/rGO, respectively, indicating that faster chain cleavage is also more selective inside mesopores. The methane yield from mSiO2/Ru/rGO is ca. 30% of the value obtained from Ru/rGO. Methane decreases, and wax selectivity improves with narrow-pore (2.3 nm) mSiO2/Ru/rGO. The reaction rate decreases at lower and higher H2 pressures from its maximum at 37 bar. Log(TOF)-log(PH2) plots reveal rates ∝ [PH2]2.8 or [PH2]-2.0 in the lower or higher pressure ranges, respectively. Corresponding plots for Ru/C give rates ∝ [PH2]1 or [PH2]-2.4. Ru is hydrocarbon-covered at low pressure; thus, the higher H2 order for mSiO2/Ru/rGO indicates that mesopores increase the density of cleavable unsaturated moieties on the Ru surface. The lower H2 order on Ru/C implies a lower density of cleavable groups because saturated segments occupy a larger fraction of the Ru surface. Higher surface occupancy by the hydrocarbon reactant correlates with more methane formation. Therefore, pore confinement, narrower pore diameter in mSiO2/Ru/rGO, or higher H2 pressure leads to lower methane yields. Ru nanoparticles in mSiO2/Ru/rGO maintain equivalent activity and selectivity over five recycling tests.
It has been demonstrated that chronic unpredictable mild stress (CUMS) induces depression-like behaviors in mice. Notably, there are differences among individuals in the extent to which these behaviors are exhibited, similar to humans. In this study, we focused on individual differences and examined which brain areas have differences in neuronal excitability, and which genes are differentially expressed between stress-susceptible mice with depression-like behaviors and stress-resilient mice without depression-like behaviors (Stress-S and -R). After 8 weeks of CUMS, the number of c-Fos positive cells was fewer in Stress-R mice compared to Stress-S mice only in the cingulate cortex and lateral septum. RNA-seq analysis revealed an upregulation of Kcnj2 mRNA, the gene for the inward-rectifying potassium channel (Kir2.1), in the lateral septum of Stress-R mice, without affecting the expression of other potassium channels. The expression of genes related to adult neurogenesis, neuroinflammation, hypothalamic-pituitary-adrenal axis, BDNF, and monoamine hypotheses were similar between Stress-S and -R mice. Intra-septal injections of Kir2.1 activators, flecainide and GPV0057, showed antidepressant effects in the tail-suspension test. These findings suggest that Stress-R behavior is the result of the upregulation of Kir2.1 and decreased neuronal excitability in the lateral septum. They also suggest the uniqueness of this model and the potential to reveal new mechanisms.
B cells are highly abundant lymphocytes and central players in humoral immunity. Although T cells are well known to support humoral responses, how B cells influence T cell responses is less understood. Here, we show that B cells are critical for CD8+ T cell responses to chronic, but not acute, viral infections. In the absence of B cells, T cells responding to chronic infection exhibited severely impaired effector differentiation. This dependency on B cell help was dictated by high antigen loads and strong T cell receptor (TCR) stimulation. Loss of either B cells or interferon-I (IFN-I) signaling led to severe functional deficits in exhausted T cells, implicating B cells as key producers of IFN-I. The IFN-I-dependent T cell response to strong TCR stimulation is mediated, in part, by the transcription factor IRF1. Therefore, during chronic infection, we uncover an important role for B cell-derived IFN-I in modulating T cell responses to strong TCR stimulation.
Cesium chloride (CsCl) is a non-radioactive salt wrongly promoted and used as part of an alternative cancer treatment based on questionable research output published in the mid-eighties. Self-administered cesium can lead to various symptoms. We analyzed the complete set of published case reports of people who have taken cesium to characterize demographics, reasons for intake, clinical effects, reported symptoms, pathophysiology, treatment options, and outcomes, followed by a historical and critical note. A total of 20 cases were included in this literature review. Most patients were females (n = 14), and almost half of the patients were between 40 and 49 years. Most patients used cesium as an alternative treatment for cancer (n = 15). When the route of administration was mentioned, it was most often oral, followed by intravenous use and combined routes. Symptoms occurred across multiple organ systems, including the cardiovascular, neuromuscular and gastrointestinal system. When ECG results were presented, QT prolongation, followed by sinus bradycardia and Torsade de Pointes arrhythmias were most often described. A wide variety of treatments have been provided to the patients. Five patients were reported to have died because of the cesium intake. After absorption, cesium is distributed throughout the body, where it inhibits ion channels, mainly for potassium. These channels, particularly in cardiac cells, are crucial for maintaining normal electrophysiology. The improper promotion of self-administration of cesium as part of an alternative cancer treatment, based on uncorrected scientific misinformation may result in life-threatening cardiac arrhythmia.
In children with idiopathic isolated growth hormone deficiency (IIGHD), GH secretion often normalizes by near adult height (NAH). Whether recombinant human GH (rhGH) treatment can be safely discontinued earlier remains unclear. This work aimed to investigate if withdrawing rhGH treatment from mid-puberty onward had no negative effect on attained NAH in adolescents who, after retesting, were no longer GH deficient. A prospective multicenter patient preference study was conducted at pediatric endocrinology departments in multiple centers (2017-2024) with follow-up until NAH (SEENEZ GH Study). Participants included 127 adolescents (95 male, 75%) with childhood IIGHD (GH peak 1.7-10 µg/L) who tested GH sufficient (GH peak >6.7 µg/L) at mid-puberty. Forty-four continued rhGH (GHcont), 83 discontinued (GHstop). A total of 99% of patients completed the study. Intervention included rhGH treatment continuation vs discontinuation from mid-puberty until NAH. The primary outcome measure was NAH-SDS minus target height (TH)-SDS. The secondary outcome was NAH-SDS, total pubertal growth (TPG), and predicted vs attained height gain. Mean (SD) NAH-SDS minus TH-SDS was -0.17 (0.60) in the GHcont and -0.18 (0.62) in the GHstop group (P = .96). Mean NAH-SDS was -0.91 (0.76) (GHcont) vs -0.78 (0.76) (GHstop) (P = .35). Mean (SD) TPG (from start of puberty) in males was 27.5 cm (7.0; GHcont) vs 25.9 cm (6.2; GHstop) (P = .25) and in females 20.5 cm (5.7; GHcont) vs 20.9 cm (7.6; GHstop) (P = .90). Predicted vs attained height gain based on the prediction model did not differ between groups. In adolescents with transient IIGHD, rhGH treatment can be stopped at mid-puberty. These findings support reducing rhGH treatment duration, lowering patient burden and health-care costs.
Vitamin B-12 is a cofactor in folate-mediated 1-carbon metabolism, which generates nucleotides {thymidylate [deoxythymidine monophosphate (dTMP)] and purines} and methionine. Depressed de novo thymidylate (dTMP) synthesis leads to uracil accumulation in DNA. This study aimed to determine how B-12 availability affects mitochondrial DNA (mtDNA) integrity and mitochondrial function in skeletal muscle. B-12 deficiency was modeled in young-adult mice. Intramuscular B-12 injection in aged mice assessed the role of B-12 supplementation in age-related changes in skeletal muscle. Male methionine synthase knockdown (Mtr+/-) and wild-type littermates (Mtr+/+) were weaned to either an AIN93G-based control diet containing 25 μg/kg vitamin B-12 (Mtr+/+, n = 8; Mtr+/-, n = 9) or a B-12-deficient (-B-12) diet containing 0 μg/kg vitamin B-12 (n = 9 per genotype) for 7 wk. Aged (20-22 mo) male C57BL/6N mice were acclimated to an AIN93G control diet 4 wk, then received either weekly injections of saline [vehicle control (30 μL 0.9% NaCl; n = 5) or B-12 (0.65 μg per 30 μL 0.9% NaCl; n = 6) in each of 2 hindleg muscles (1.25 μg B-12 total)] for 8 wk. Outcomes measured included maximal oxygen consumption rate, uracil in mtDNA (a biomarker of mtDNA integrity), mtDNA copy number, and mitochondrial mass. Data were analyzed using a 2-way analysis of variance in the Mtr+/- mouse model exposed to -B-12 diets and by a Student's t-test for B-12 supplementation in aged mice. The tibialis anterior (TA) muscle from Mtr+/- mice exhibited 50% lower (P = 0.01) maximal respiratory capacity of the electron transport chain than did TA from Mtr+/+ mice. Exposure to the -B-12 diet lowered the maximal capacity of complex I in mitochondrially rich muscle (soleus and mitochondria-rich portions of quadriceps and gastrocnemius) by 25% (P = 0.02). Uracil in mtDNA in red muscle and gastrocnemius was elevated ∼10 fold with exposure to -B-12 diet (P = 0.04 and P < 0.001, respectively). In aged mice, gastrocnemius complex IV activity was increased 2-fold with intramuscular B-12 supplementation (P = 0.04). Exposure to a-B-12 diet led to uracil accumulation in mtDNA and impaired maximal oxidative capacity in skeletal muscle. B-12 supplementation improved complex IV maximal capacity in gastrocnemius from aged mice, a model of age-related skeletal muscle decline.
(350/350) BACKGROUND: Standardized implant protocols have shown promise in improving outcomes in transcatheter aortic valve replacement (TAVR). However, the impact of implant depth on clinical outcomes remains unclear. To evaluate clinical and hemodynamic outcomes across varying TAVR implantation depths using data from the Optimize PRO study. This prospective, multicenter Optimize PRO study included patients with symptomatic severe aortic stenosis undergoing TAVR with Evolut PRO/PRO+ systems. Patients were stratified by core laboratory-adjudicated non-coronary cusp implant depth. The echocardiographic outcome composite included none/trace paravalvular regurgitation, aortic mean gradient ≤10mmHg and no prosthesis-patient-mismatch at discharge. Patients (N=603) were stratified by implant depth: <1mm (N=88), 1 to ≤3mm (N=196), >3 to ≤5mm (N=170), and >5mm (N=149). Baseline characteristics were similar across implant depth groups, except for a higher proportion of females in higher implant depths. Higher implant depths were associated with less resheathing and recapture (27.3% [24/88], 33.7% [66/196], 48.8% [83/170], 51.7% [77/149]; P<.001), and shorter median [Q1, Q3] hospital stay (days: 1[1,1], 1[1,2], 2 [1,3], 2 [1,4]; P<.001). Rates of valve migration (0% [95% CI:NA], 0.5% [95% CI:0.1-3.6], 0.6% [95% CI:0.1-4.1], 1.3% [95% CI:0.3-5.3]; P=.63) were low across implant depth groups. The 1-year all-cause mortality or all-stroke rate was comparable across implant depth groups (8.1% [95% CI:3.9-16.2], 7.2% [95% CI:4.3-11.8], 10.7% [95% CI:6.9-16.5], 12.5% [95% CI:8.1-19.2]; P=.40). After 1 year, higher implant depths were associated with lower rates of permanent pacemaker implantation (PPI, 2.3% [95% CI:0.6-8.8], 9.2% [95% CI:5.9-14.3], 15.9% [95% CI:11.2-22.4], 20.3% [95% CI:14.6-27.7]; P<.001). Rates of New York Heart Association functional class I were numerically different across implant depth groups but did not reach statistical significance (NYHA, 77.8% [56/72], 71.8% [130/181], 65.2% [101/155], 67.7% [84/124], P=.09 across all classes). In males, echo outcome composite rates were not statistically different across depth groups (58.6%[17/29], 50.6% [39/77], 43.8% [35/80], 36.1% [26/72]; P=.14), although the exploratory trend test reached statistical significance (P=.02). Higher TAVR device implantation was associated with improved clinical outcomes with similar safety events, including valve migration, across depths. The long-term effect of this approach including the ability to perform redo-TAVR safely, will be further studied in the future.
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Elastic MicroPhase separation (EMPS) provides a simple route to create soft materials with homogeneous microstructures by leveraging the supersaturation of crosslinked polymer networks with liquids. At low supersaturation, network elasticity stabilizes a uniform mixture, but beyond a critical threshold, metastable microphase-separated domains emerge. While previous theories have focused on describing qualitative features about the size and morphology of these domains, they do not make quantitative predictions about EMPS phase diagrams. In this work, we extend Flory-Huggins theory to quantitatively capture EMPS phase diagrams by incorporating strain-stiffening effects. This model requires no fitting parameters and relies solely on independently measured solubility parameters and large-deformation mechanical responses. Our results confirm that strain-stiffening enables metastable microphase separation within the swelling equilibrium state and reveal why the microstructures can range from discrete droplets to bicontinuous networks. This works highlights the critical role of nonlinear elasticity in controlling phase-separated morphologies in polymer gels.
Climate change is driving species to shift their distribution ranges, potentially altering the level of genomic structuring and connectivity between populations. Additionally, fishing practices might further reduce genomic diversity and limit the potential adaptability of species to environmental changes. We use whole-genome sequencing for the first time to explore current and historical patterns of genomic diversity in European hake (Merluccius merluccius) from the Northeast Atlantic, focusing on the recently expanded distribution range in the North Sea. Genomic data revealed a complex scenario in the North Sea and neighbouring regions, with three distinct populations: North Sea, Celtic Sea and Portugal. Individuals from the Kattegat, Skagerrak and west coast of Denmark were highly differentiated from those in the Celtic Sea and waters around Ireland. The Northern North Sea appears as a transition zone, with individuals from higher latitudes assigned to the Celtic Sea group and those from lower latitudes to the North Sea group. The more distant Portuguese individuals appeared as a third distinct population. Although the differentiation among these populations was shallow when the entire dataset was used, a subset of 99,364 outlier markers revealed a much deeper divergence. Demographic analyses indicated that these populations are relatively young and have large effective population sizes and thus without sufficient time to build a signature of differentiation by genetic drift. At the same time, selection for local adaptation is strong enough to overcome the effects of contemporary gene flow. Our findings have important implications for managing the European hake stocks in the Northeastern Atlantic, highlighting the need for management measures that address shifts in species and population distribution due to climate change, as well as needing to account for different populations contributing to fisheries within a single stock. Preserving the genomic diversity within and among fish stocks is crucial for maintaining the long-term resilience of marine ecosystems and the services they provide.
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The relationships among tricuspid regurgitation (TR) reduction after tricuspid transcatheter edge-to-edge repair (T-TEER), changes in right-sided heart function, and outcomes are poorly explored. This study aims to explore the relationship between functional remodeling and subsequent outcomes and the associations among T-TEER, residual TR, and outcomes. Changes in echocardiographic parameters from baseline to 1 year, overall and according to TR reduction were evaluated by a centralized echocardiographic core laboratory in patients included in the Tri.Fr (Evaluation of Tricuspid Valve Percutaneous Repair System in the Treatment of Severe Secondary Tricuspid Disorders) trial. A total of 300 patients (aged 78 ± 5 years; 53.7% women) were enrolled; 152 patients were allocated to the T-TEER + guideline-directed medical therapy (GDMT) group, and 148 were allocated to the GDMT group. Patients in the T-TEER + GDMT group demonstrated a significant decrease in most of parameters of right ventricular (RV) function, whereas patients in the GDMT group exhibited no significant changes in RV metrics at 1 year. The clinical composite score improved progressively with each successive grade of TR reduction. The positive effect of T-TEER on the composite clinical score was observed irrespective of baseline right atrial volume but only in patients with normal RV-pulmonary artery coupling (defined by a tricuspid annular plane systolic excursion-to-systolic pulmonary artery pressure ratio ≥0.40). At 1 year, patients with an improved clinical composite score had a lower right atrial volume index compared with patients whose clinical score remained unchanged or worsened (median 112 mL/m2 [Q1-Q3: 78.0-146 mL/m2] vs median 141 mL/m2 [Q1-Q3: 107-173 mL/m2]; P = 0.004). Although T-TEER can decrease TR severity, its impact on conventional RV function parameters and RV-pulmonary artery coupling remains limited. RV functional recovery has a smaller influence on clinical outcomes at 1 year compared with achieving optimal reduction in TR severity. (Evaluation of Tricuspid Valve Percutaneous Repair System in the Treatment of Severe Secondary Tricuspid Disorders [Tri.Fr]; NCT04646811).
Inwardly rectifying potassium (KIR) channels are essential regulators of membrane potential in excitable and non-excitable tissues. Although KIR channels exhibit a biophysical preference for potassium influx due to voltage-dependent block of outward current by polyamines and Mg2+, under physiological conditions, they predominantly mediate K+ efflux. This outward current not only is essential for stabilizing the resting membrane potential, limiting cellular excitability and coordinating rhythmic activity in excitable tissues such as the heart and muscle, but also functions in endocrine and exocrine organs and neural tissues. A growing list of pathogenic KIR mutations that reduce or abolish channel activity has been linked to channelopathies, including Andersen syndrome and EAST/SeSAME syndrome, among others. These loss-of-function phenotypes underscore the therapeutic need for selective KIR channel activators. However, pharmacological tools remain limited and subtype-selective activation is rare. Small molecules such as ML297 selectively activate Kir3.1/3.2-containing channels, whereas GiGA1 and VU0529331 target Kir3.2-containing subunits. Several clinically used drugs (e.g. propafenone) modulate Kir2.1 and novel compounds such as GPV0057 show improved selectivity. However, no KIR channel activators have advanced to clinical trials and key subtypes such as Kir1.1 and Kir7.1 lack known openers. This review evaluates the current knowledge of KIR-targeted agonists, with a focus on their potential to address PIP2-dependent loss-of-function mutations in KIR channels. We emphasize the urgent need for subtype-specific KIR openers, the development of PIP2-independent mechanisms of action and comprehensive preclinical characterization to overcome translational barriers. Addressing these challenges may provide new therapeutic opportunities for rare channelopathies associated with KIR channel dysfunction.
BACKGROUND: Medication adherence includes initiation, implementation, and persistence. Population-level estimates are commonly based on administrative claims, yet these may not fully capture patient behavior. This study developed a framework to estimate adherence to antihypertensive treatment using linked self-reported data and medication refill records from a representative Belgian sample. METHODS: We linked participants of the 2018 Belgian Health Interview Survey (BHIS) with Belgian Compulsory Health Insurance (BCHI) records via pseudonymized identifiers. Chronic hypertension patients were defined as those with at least one antihypertensive prescription in the year prior to the study and ≥ 30 consecutive days of treatment during the study year. Adherence was assessed using three approaches: (1) regimen-level Proportion of Days Covered in 2018 (PDCY) capturing implementation and persistence; (2) Proportion of Days Covered in a flexible period (PDCF) capturing implementation during persistence; and (3) BHIS-based self-reported medication use at the interview date cross-validated with prescriptions. We also calculated Medication Possession Ratios (MPR) for drug class–specific adherence. Agreement between methods was tested with Cohen’s Kappa and McNemar’s test; predictors of adherence were analyzed using logistic regression. RESULTS: Of 2,475 chronic hypertension patients (22.6% of BHIS sample; mean age 67.1 years, 52.8% female), adherence rates were similar across indicators (PDCY: 58.3%; PDCF: 57.1%; BHIS: 61.4%). Kappa values indicated fair, consistent agreement, while McNemar’s test showed no systematic differences between methods. Logistic models identified age, multimorbidity, and polypharmacy as significant predictors of adherence, with effect sizes varying by measurement approach. CONCLUSIONS: Findings suggest that short-term adherence measured via self-report provides a reasonable proxy for long-term adherence. Linking survey and administrative data offers a robust and practical alternative to claims-only approaches.
To evaluate health-related quality of life (HRQoL) in adolescents with idiopathic isolated growth hormone deficiency (IIGHD) who tested GH-sufficient, comparing those who discontinued recombinant human growth hormone (rhGH) at mid-puberty with those who continued until near-adult height (NAH). This multicentre prospective study used a patient-preference design. Previous findings showed NAH did not differ between groups. Height influences quality of life (QoL), particularly during adolescence when appearance and social comparison affect psychological development. The impact of height and treatment decisions on HRQoL during puberty remains unclear. Adolescents with IIGHD who had received rhGH for ≥3 years and tested GH-sufficient in mid-puberty chose to continue or discontinue treatment. HRQoL was assessed at mid-puberty and NAH using QoLISSY (patient and parent reports), supplemented by KIDSCREEN-52, SDQ, and EQ-5D-Y. Of 127 participants, 44 continued rhGH and 83 discontinued. Questionnaire completion was 58% (n=74) at mid-puberty and 66% (n=84) at NAH. No significant differences in patient-reported QoL were observed between groups at either time point. Parents reported higher QoL in the discontinuation group at mid-puberty. Overall, QoL scores were within normal ranges and positively correlated with height SDS at both time points. Discontinuing rhGH in adolescents with IIGHD who tested GH-sufficient at mid-puberty does not appear to negatively affect perceived QoL. Parental reports suggest greater well-being in the discontinuation group, possibly reflecting pre-existing satisfaction with height and health. These findings emphasize considering both physical and psychosocial factors in treatment decisions and incorporating patient and parent perspectives during puberty.