High Threshold Research Articles

Photochromic ionogel with a wide temperature range and fatigue resistance for high-resolution rewritable information record

Recently, photochromic hydrogels have received significant attention and hold substantial promise for rewritable information record. However, the intrinsic instability of hydrogels has restricted their applications. Herein, a photochromic ionogel aiming at extending service life for long-term use is presented by embedding photochromic ammonium molybdate tetrahydrate [(NH4)6Mo7O24·4H2O] (Mo7) in engineered double networks. Covalently cross-linked 2-hydroxyethyl acrylate (HEA) and self-assembled cationic cellulose (JR-400) constitute the networks, and a protic ionic liquid of ethylammonium nitrate (EAN) is immobilized therein. Such a design affords the ionogel comprehensive properties, including high optical transparency (>97%), good adhesion, anti-dehydration, wide operating temperature range (–60 to 150 °C) as well as the sensitive and stable UV-light responsiveness (within 30 s). Besides, the ionogel exhibits admirable mechanical properties of high toughness (over 180 kJ/m3), excellent resilience and a high fatigue threshold (over 1000 cycles with negligible hysteresis). The photochromic process is typically accomplished by photoreduction of Mo7, which is combined with network through electrostatic interaction with quaternized JR-400. The distinctive feature is that EAN serving as both proton donor and electron donor, plays a dominant role in coloration process and formation of charge-transfer complex. The photochromic mechanism which is less well understood in ionic liquid medium, has been revealed. Remarkably, the ionogel used as an information carrier exhibits outstanding stability in a wide operating temperature range. The superiorities of the photochromic ionogel including accurate information recording capacity and application in harsh environments have greatly boosted the high-quality information dissemination and expanded applications of photochromic soft materials.

Three-dimensional cardiac magnetic resonance allows the identification of slow-conducting anatomical isthmuses in tetralogy of Fallot.

Patients with repaired tetralogy of Fallot remain at risk of life-threatening ventricular tachycardia related to slow-conducting anatomical isthmuses (SCAIs). Preventive ablation of SCAI identified by invasive electroanatomical mapping is increasingly performed. This study aimed to non-invasively identify SCAI using 3D late gadolinium enhancement cardiac magnetic resonance (3D-LGE-CMR). Consecutive tetralogy of Fallot patients who underwent right ventricular electroanatomical mapping (RV-EAM) and 3D-LGE-CMR were included. High signal intensity threshold for abnormal myocardium was determined based on direct comparison of bipolar voltages and signal intensity by co-registration of RV-EAM with 3D-LGE-CMR. The diagnostic performance of 3D-LGE-CMR to non-invasively identify SCAI was determined, validated in a second cohort, and compared with the discriminative ability of proposed risk scores. The derivation cohort consisted of 48 (34 ± 16 years) and the validation cohort of 53 patients (36 ± 18 years). In the derivation cohort, 78 of 107 anatomical isthmuses (AIs) identified by EAM were normal-conducting AI, 22 were SCAI, and 7 blocked AI. High signal intensity threshold was 42% of the maximal signal intensity. The sensitivity and specificity of 3D-LGE-CMR for identifying SCAI or blocked AI were 100% and 90%, respectively. In the validation cohort, 85 of 124 AIs were normal-conducting AI, 36 were SCAI, and 3 blocked AI. The sensitivity and specificity of 3D-LGE-CMR were 95% and 91%, respectively. All risk scores showed an at best modest performance to identify SCAI (area under the curve ≤ .68). 3D late gadolinium enhancement cardiac magnetic resonance can identify SCAI with excellent accuracy and may refine non-invasive risk stratification and patient selection for invasive EAM in tetralogy of Fallot.

Remote Field Application of Digital Technology for Hearing Assessments in a Cohort of Pediatric Germ Cell Tumor Survivors.

Childhood cancer survivors treated with platinum-based chemotherapy are at risk of treatment-induced hearing loss. Accurate evaluation of hearing thresholds has historically been limited to clinical audiometry, which is logistically challenging and expensive to include in epidemiologic studies. We evaluated the feasibility of using a remote, tablet-based hearing assessment in a cohort of pediatric germ cell tumor survivors treated with platinum-based chemotherapy. Survivors from the GCT Outcomes and Late effects Data (GOLD) study were recruited to the pilot study (n = 100). Study personnel conducted remote hearing assessments of standard and extended high frequency thresholds using validated tablet-based audiometry (SHOEBOX, Inc.). T tests and Wilcoxon rank-sum tests evaluated differences in assessment characteristics between children and adults. Agreement between self-reported and measured hearing loss was calculated using Cohen κ. We were able to reach 136/168 (81%) eligible participants, of which 100 (74%) agreed to participate. Successful completion of the remote hearing assessment was high [97%; 20 children (ages 7-17), 77 adults (ages 18-31)]. The mean assessment length was 37.6 minutes, and the mean turnaround time was 8.3 days. We observed hearing loss at standard frequencies in 21% of participants. Agreement between self-reported and measured hearing loss was significant (P value = 1.41 × 10-7), with 83.5% concordance. Hearing loss measured using the remote assessment aligns with self-reporting and rates of hearing loss reported in the literature for this population. Remote application of tablet-based audiometry is a feasible and efficacious method for measuring hearing in epidemiologic studies with participants spread across large geographic areas.

Enhanced Thermoelectric Performance of PbTe Nanocomposites with Ag Nanoinclusions

Nanocomposites have already been widely used to enhance thermoelectric performance since they exhibit exceptionally low lattice thermal conductivities. Further improvement is expected to arise from boosting the power factor and charge carrier relevant figure of merit ZT with nanoinclusions. Here we present that Ag nanoscale inclusions embedding in the n-PbTe can meet this requirement. The quantitative relationships between such nanostructures in PbTe and thermoelectric properties, using a versatile model including the details of geometry, electron–phonon interactions, quantization, and tunneling, showed that the Seebeck coefficient can be significantly enhanced due to interface potential barrier induced by Ag nanoinclusions. Additionally, it was found that high-concentration Ag nanoinclusions with 1–2 nm radius can effectively enhance the thermoelectric performance of PbTe through energy-selective carrier scattering, especially around room temperature. The power factor and charge carrier relevant figure of merit ZT can be elevated by at least 80% and 260%, respectively. These findings highlight effective strategies to nanostructuring for overcoming the high threshold to commercial application for cooling and power generation.

Identification of a high threshold value of serum ferritin in the diagnosis of hemophagocytic lymphohistiocytosis in hospitalized children in China

Abstract Objectives To explore and identify an optimal serum ferritin (SF) threshold level in diagnosing hemophagocytic lymphohistiocytosis (HLH) in Chinese children. Methods We conducted a retrospective study of 74 children with HLH admitted to Guangdong Women and Children Hospital between January 2015 and May 2021. Children in-hospital not diagnosed with HLH between January 2021 and May 2021 with a measurement of SF were enrolled as the non-HLH group. Patient charts were reviewed for SF levels upon admission and during hospitalization. A receiver operating characteristic (ROC) curve was utilized to determine the optimal cutoff value of SF for diagnosing childhood HLH. Results This study included a total of 74 children with HLH and 302 children with non-HLH diseases. The difference in SF values between the HLH and non-HLH groups was statistically significant (8,975 μg/L vs. 165.5 μg/L, p<0.001). An optimal SF cutoff value of 1,830 μg/L provided a sensitivity of 88 % and specificity of 79 % in confirming childhood HLH. The area under the curve (AUC) is 0.91 (95 % confidence interval 0.88–0.94, p<0.0001). Conclusions A serum ferritin level elevated above 1,830 μg/L might improve the specificity for HLH diagnosis in Chinese children.

Engineering Chimeric Chemoreceptors and Two-Component Systems for Orthogonal and Leakless Biosensing of Extracellular γ-Aminobutyric Acid.

Two-component systems (TCSs) sensing and responding to various stimuli outside and inside cells are valuable resources for developing biosensors with synthetic biology applications. However, the use of TCS-based biosensors suffers from a limited effector spectrum, hypersensitivity, low dynamic range, and unwanted signal crosstalk. Here, we developed a tailor-made Escherichia coli whole-cell γ-aminobutyric acid (GABA) biosensor by engineering a chimeric GABA chemoreceptor PctC and TCS. By testing different TCSs, the chimeric PctC/PhoQ showed the response to GABA. Chimera-directed evolution and introduction of the insulated chimeric pair PctC/PhoQ*PhoP* produced biosensors with up to 3.50-fold dynamic range and good orthogonality. To further enhance the dynamic range and lower the basal leakage, three strategies, engineering of PhoP DNA binding sites, fine-tuning reporter expression by optimizing transcription/translation components, and a tobacco etch virus protease-controlled protein degradation, were integrated. This chimeric biosensor displayed a low basal leakage, a large dynamic range (15.8-fold), and a high threshold level (22.7 g L-1). Finally, the optimized biosensor was successfully applied in the high-throughput microdroplet screening of GABA-overproducing Corynebacterium glutamicum, demonstrating its desired properties for extracellular signal biosensing.

Remarkable Second Harmonic Generation Response in (C5H6NO)+(CH3SO3)-: Unraveling the Role of Hydrogen Bond in Thermal Driven Nonlinear Optical Switch.

Heat-activated second harmonic generation (SHG) switching materials are gaining interest for their ability to switch between SHG on and off states, offering potential in optoelectronic applications. The novel nonlinear optical (NLO) switch, (C5H6NO)+(CH3SO3)- (4-hydroxypyridinium methylsulfonate, 4HPMS), is a near-room-temperature thermal driven material with a strong SHG response (3.3 × KDP), making it one of the most potent heat-stimulated NLO switches. It offers excellent contrast of 13 and a high laser-induced damage threshold (2.5 × KDP), with reversibility > 5 cycles. At 73 °C, 4HPMS transitions from the noncentrosymmetric Pna21 room temperature phase (RTP) to the centrosymmetric P21/c phase, caused by the rotation of the (C5H6NO)+ and (CH3SO3)- due to partially thermal breaking of intermolecular hydrogen bonds. The reverse phase change exhibits a large 50 °C thermal hysteresis. Density functional theory (DFT) calculations show that (C5H6NO)+ primarily dictates both the SHG coefficient (dij) and birefringence (▵n(Zeiss) = 0.216 vs ▵n(cal.) = 0.202 at 546 nm; Δn(Immersion) = 0.210 vs ▵n(cal.) = 0.198 at 589.3 nm), while the band gap (Eg) is influenced synergistically by (C5H6NO)+ and (CH3SO3)-. Additionally, 4HPMS-RTP also exhibits mechanochromism upon grinding as well as an aggregation-enhanced emission in a mixture of acetone and water.

Charge trapping layer enabled high-performance E-mode GaN HEMTs and monolithic integration GaN inverters

In this work, high threshold voltage and breakdown voltage E-mode GaN HEMTs using an Al:HfOx-based charge trapping layer (CTL) are presented. The developed GaN HEMTs exhibit a wide threshold modulation range of ΔVTH ∼ 17.8 V, which enables the achievement of enhancement-mode (E-mode) operation after initialization process owing to the high charge storage capacity of the Al:HfOx layer. The E-mode GaN HEMTs exhibit a high positive VTH of 8.4 V, a high IDS,max of 466 mA/mm, a low RON of 10.49 Ω mm, and a high on/off ratio of ∼109. Moreover, the off-state breakdown voltage reaches up to 1100 V, which is primarily attributed to in situ O3 pretreatment effectively suppressing and blocking leakage current. Furthermore, thanks to the VTH of GaN HEMTs being tunable by initialization voltage using the proposed CTL scheme, we prove that the direct-coupled FET logic-integrated GaN inverters can operate under a variety of conditions (β = 10–40 and VDD = 3–15 V) with commendable output swing and noise margins. These results present a promising approach toward realizing the monolithic integration of GaN devices for power IC applications.

Dynamics of a Single Candidate for Regional Head Election in the Democratic System in Indonesia

As the 2024 regional head elections approach, strategies are needed to maintain the democratic system in Indonesia to anticipate the occurrence of single candidates. The trend of single candidates in regional head elections is a concern for the nation, as the world's third-largest democracy should be able to conduct competitive elections with at least two pairs of regional head candidates. Therefore, it is necessary to investigate the causes of single candidates in regional head elections in Indonesia and to develop strategies to anticipate single candidates in the 2024 regional head elections. This research uses doctrinal/normative legal research methods. The results of this study indicate the factors causing single candidates in regional head elections are: the high cost of political campaigns, high thresholds for candidacy, and the significant power of incumbents. Strategies to anticipate single candidates in regional head elections include fostering political party cadres and encouraging public participation through independent candidates.

Improved dual-threshold quantum image segmentation algorithm and simulation* *This work was supported by National Natural Science Foundation of China (No.61772295), Key Projects of Chongqing Natural Science Foundation Innovation Development Joint Fund (CSTB2023NSCQ-LZX0139), Open Fund of Advanced Cryptography and System Security Key Laboratory of Sichuan Province (Grant No. SKLACSS-202208) and Technology Research Program of Chongqing Municipal Education Commission (Grant no. KJZD-M202000501).

Quantum image segmentation algorithm is crucial for quantum image processing. In this paper, a dual-threshold quantum image segmentation algorithm is designed and simulated in IBM Quantum Experience (IBM Q) platform, which can segment a complex image into three parts using fewer quantum bits. In our algorithm, given a high threshold and a low threshold, grayscale values larger than the high threshold are set to the high threshold and grayscale values smaller than the low threshold are set to the low threshold, with no change for the part between the two thresholds. Then we use a low-cost quantum comparator and design a complete and scalable quantum image segmentation circuit. Analysis of the circuit cost shows that the quantum gates required for the circuit are only related to the grayscale range q and are independent of the image size. The feasibility of the algorithm and the correctness of the quantum circuit are verified by simulation in IBM Q platform, and finally the MSE, PSNR AND SSIM value of the image is analyzed to prove the effectiveness of the segmentation algorithm.

How heterogeneous industrial agglomeration impacts energy efficiency subject to technological innovation:Evidence from the spatial threshold model

The relationship between industrial agglomeration (IA) and energy efficiency (EE) is significant for China to promote high-quality urban economic development and achieve China's dual carbon goals. Since technological innovation (TI) and green TI (GTI) are vital elements in the evolution of socioeconomic change and green development, this study employs a spatial threshold model to explore the technology innovation dependency of the influence of heterogeneous IA on EE based on prefecture-level city panel data of the manufacturing sector from 2006 to 2014 in China. This study finds that diversified IA (DIA) has a spatial threshold impact on EE subject to TI or GTI, while specialized IA (SIA) does not. DIA has significant positive direct, spillover, and overall effects on EE at the high TI and GTI thresholds. The distance attenuation feature is evident in the spatial spillover effect of DIA on EE. DIA impacts EE through its spatial effects on labor pooling, knowledge spillovers, and input sharing. The findings offer insights into the development of IA patterns and the enhancement of EE.

Nb2O5 film optical properties and laser-induced damage by phase-change-driven tuning

Niobium oxide (Nb2O5) is widely used in optical and electrical fields because of its high refractive index, wide band gap, high laser-induced damage threshold (LIDT) and high transparency in the ultraviolet to middle-infrared-wavelength range (0.35–7 μm). In this study, Nb2O5 films with different crystalline phases were successfully prepared on BK7 and Si substrates through electron beam evaporation (EB) and post-annealing. Based on the results of X-ray diffraction (XRD) and Raman spectroscopy analysis, the impact of the post-annealing technique on the structure, and optical and physical properties of Nb2O5 films was thoroughly discussed at the molecular level. The crystal phase of an Nb2O5 film and its molecular bonds considerably affect its properties. The Nb2O5(-12 1 2) film prepared in this study exhibited a higher LIDT (17.72 J/cm2) and a higher RMS (0.447 nm) than the corresponding films prepared in previous studies. Following the post-annealing process, the band gap and refractive index of the prepared films were significantly higher than those of the as-deposited film. Thus, this study has significant guiding implications for Nb2O5 film applications and the development costs of the films.

Origin of Optical Gain in Narrow ZnO Microrods with Whispering Gallery Modes

Due to sufficiently high lasing thresholds, stimulated emission in relatively small ZnO microcrystal lasers is often considered to be fed by an inverted electron–hole plasma (EHP). In this study, the nature of optical gain in such emitters is investigated using ZnO microrods 1–6 µm in diameter synthesized by a modified thermal evaporation method and exhibiting whispering-gallery mode (WGM) lasing in the near ultraviolet range. It is demonstrated that optical gain in these objects is not a consequence of population inversion of the EHP at either low or room temperatures. Instead, the primary gain mechanism is the process of scattering of electron–hole pairs by free electrons. Unlike the case of large ZnO WGM microcavities, in small-diameter microrods this process turns out to be dominant over a wide temperature range.

Predictors of failed left bundle branch pacing implant in heart failure with reduced ejection fraction: Importance of left ventricular diameter and QRS morphology

BackgroundLeft bundle branch pacing (LBBP) is considered an alternative to cardiac resynchronization therapy (CRT). However, LBBP is not suitable for all patients with heart failure. ObjectiveThe aim of our study was to identify predictors of unsuccessful LBBP implantation in CRT candidates. MethodsA cohort of consecutive patients with indications for CRT were included. Clinical, echocardiographic, and electrocardiographic variables were prospectively recorded. ResultsA total of 187 patients were included in the analysis. LBBP implantation was successful in 152 of 187 patients (81.2%) and failed in 35 of 187 patients (18.7%). The causes of unsuccessful implantation were unsatisfactory paced QRS morphology (28 of 35 [80%]), inability to screw the helix (4 of 35 [11.4%]), lead instability (2 of 35 [5.7%]), and high pacing thresholds (1 of 35 [2.8%]). The left ventricular end-diastolic diameter (LVEDD), non-LBBB (left bundle branch block) QRS morphology, and QRS width were predictors of failed implantation according to the univariate analysis. According to the multivariate regression analysis, LVEDD (odds ratio 1.31 per 5-mm increase; 95% confidence interval 1.05–1.63 per 5-mm increase; P = .02) and non-LBBB (odds ratio 3.07; 95% confidence interval 1.08–8.72; P = .03) were found to be independent predictors of unsuccessful LBBP implantation. An LVEDD of 60 mm has 60% sensitivity and 71% specificity for predicting LBBP implant failure. ConclusionWhen LBBP was used as CRT, LVEDD and non-LBBB QRS morphology predicted unsuccessful implantation. Non-LBBB triples the likelihood of failed implantation independent of LVEDD. Caution should be taken when considering these parameters to plan the best pacing strategy for patients.

Impact of histone deacetylase inhibition and arimoclomol on heat shock protein expression and disease biomarkers in primary culture models of familial ALS.

Protein misfolding and mislocalization are common themes in neurodegenerative disorders, including motor neuron disease, and amyotrophic lateral sclerosis (ALS). Maintaining proteostasis is a crosscutting therapeutic target, including the upregulation of heat shock proteins (HSP) to increase chaperoning capacity. Motor neurons have a high threshold for upregulating stress-inducible HSPA1A, but constitutively express high levels of HSPA8. This study compared the expression of these HSPs in cultured motor neurons expressing three variants linked to familial ALS: TAR DNA binding protein 43kDa (TDP-43)G348C, fused in sarcoma (FUS)R521G, or superoxide dismutase I (SOD1)G93A. All variants were poor inducers of Hspa1a, and reduced levels of Hspa8 mRNA and protein, indicating multiple compromises in chaperoning capacity. To promote HSP expression, cultures were treated with the putative HSP coinducer, arimoclomol, andclass I histone deacetylase inhibitors, to promote active chromatin for transcription, and with the combination. Treatments had variable, often different effects on the expression of Hspa1a and Hspa8, depending on the ALS variant expressed, mRNA distribution (somata and dendrites), and biomarker of toxicity measured (histone acetylation, maintaining nuclear TDP-43 and the neuronal Brm/Brg-associated factor chromatin remodeling complex component Brg1, mitochondrial transport, FUS aggregation). Overall, histone deacetylase inhibition alone was effective on more measures than arimoclomol. As in the FUS model, arimoclomol failed to induce HSPA1A or preserve Hspa8 mRNA in the TDP-43 model, despite preserving nuclear TDP-43 and Brg1, indicating neuroprotective properties other than HSP induction. The data speak to the complexity of drug mechanisms against multiple biomarkers of ALS pathogenesis, as well as to the importance of HSPA8 for neuronal proteostasis in both somata and dendrites.

Recess-free enhancement-mode AlGaN/GaN RF HEMTs on Si substrate

Enhancement-mode (E-mode) GaN-on-Si radio-frequency (RF) high-electron-mobility transistors (HEMTs) were fabricated on an ultrathin-barrier (UTB) AlGaN (<6 nm)/GaN heterostructure featuring a naturally depleted 2-D electron gas (2DEG) channel. The fabricated E-mode HEMTs exhibit a relatively high threshold voltage (V TH) of +1.1 V with good uniformity. A maximum current/power gain cut-off frequency (f T/f MAX) of 31.3/99.6 GHz with a power added efficiency (PAE) of 52.47% and an output power density (P out) of 1.0 W/mm at 3.5 GHz were achieved on the fabricated E-mode HEMTs with 1-µm gate and Au-free ohmic contact.

Enhanced field-effect mobility (>250 cm2/V·s) in GaN MOSFETs with deposited gate oxides via mist CVD

We report an enhanced field-effect mobility (>250 cm2·V−1·s−1) in GaN MOSFETs. High mobility was achieved by reducing the oxidation of the GaN surface, which was a major factor affecting channel mobility in GaN MOSFETs. Among various gate oxide deposition methods, mist CVD using O3 suppressed GaN surface oxidation. The best field-effect mobility was observed using mist CVD-deposited gate oxides, achieving a peak mobility of 266 cm2·V−1·s−1 with a high threshold voltage of 4.8 V.

Discussion on the relationship between gut microbiota and glioma through Mendelian randomization test based on the brain gut axis.

In the realm of Gut-Brain axis research, existing evidence points to a complex bidirectional regulatory mechanism between gut microbiota and the brain. However, the question of whether a causal relationship exists between gut microbiota and specific types of brain tumors, such as gliomas, remains unresolved. To address this gap, we employed publicly available Genome-Wide Association Study (GWAS) and MIOBEN databases, conducting an in-depth analysis using Two-Sample Mendelian Randomization (MR). We carried out two sets of MR analyses. The preliminary analysis included fewer instrumental variables due to a high genome-wide statistical significance threshold (5×10-8). To enable a more comprehensive and detailed analysis, we adjusted the significance threshold to 1×10-5. We performed linkage disequilibrium analysis (R2 <0.001, clumping distance = 10,000kb) and detailed screening of palindromic SNPs, followed by MR analysis and validation through sensitivity analysis. Our findings reveal a causal relationship between gut microbiota and gliomas. Further confirmation via Inverse Variance Weighting (IVW) identified eight specific microbial communities related to gliomas. Notably, the Peptostreptococcaceae and Olsenella communities appear to have a protective effect, reducing glioma risk. This study not only confirms the causal link between gut microbiota and gliomas but also suggests a new avenue for future glioma treatment.

Saliva antibody profiles are associated with reaction threshold and severity of peanut allergic reactions

BackgroundReaction threshold and severity in food allergy are difficult to predict, and there is a lack of non-invasive predictors. ObjectivesWe sought to determine the relationships between pre-challenge levels of peanut (PN)-specific antibodies in saliva and reaction threshold, severity, and organ-specific symptoms during peanut allergic reactions. MethodsWe measured PN-specific antibody levels in saliva collected from 127 children with suspected peanut allergy prior to double-blind, placebo-controlled peanut challenges where reaction threshold, severity, and symptoms were rigorously characterized. Low-threshold peanut allergy was defined as reaction to <300mg of peanut protein cumulatively consumed. A consensus severity grading system was used to grade severity. We analyzed associations between antibody levels and reaction threshold, severity, and organ-specific symptoms. ResultsAmong the 127 children, those with high pre-challenge saliva PN IgE had higher odds of low-threshold peanut allergy (OR 3.9, 95%CI 1.6-9.5), while those with high saliva PN IgA: PN IgE or PN IgG4:PN IgE had lower odds of low-threshold peanut allergy (OR 0.3, 95%CI 0.1-0.8, and OR 0.4, 95%CI 0.2-0.9, respectively). Children with high pre-challenge saliva PN IgG4 had lower odds of severe peanut reactions (OR 0.4, 95%CI 0.2-0.9). Those with high saliva PN IgE had higher odds of respiratory symptoms (OR 8.0, 95%CI 2.2-26.8). Saliva PN IgE modestly correlated with serum PN IgE levels (Pearson r=0.31, P=0.0004). High and low saliva PN IgE levels further distinguished reaction threshold and severity in participants stratified by serum PN IgE, suggesting endotypes. ConclusionSaliva PN antibodies could aid in non-invasive risk stratification of peanut allergy threshold, severity, and organ-specific symptoms.

Association of dipeptidyl peptidase-4 inhibitor initiation at glycated haemoglobin

Therapeutic inertia, hypoglycaemia and poor treatment persistence can lead to glycaemic fluctuation and poor outcomes in type 2 diabetes (T2D). We compared glycated haemoglobin (HbA1c) variability, insulin initiation, severe hypoglycaemia and clinical events in patients with T2D initiated dipeptidyl peptidase-4 inhibitors (DPP4is) at low versus high HbA1c thresholds. Using territory-wide electronic medical records in Hong Kong, we curated a propensity score-matched cohort of patients initiated DPP4i at HbA1c <7.5% versus ≥7.5% in 2007-2019. We expressed the HbA1c variability score (HVS) as a proportion of HbA1c varied by ≥0.5% compared with preceding values. We used the Cox model to compare the risks of insulin initiation and clinical outcomes, adjusted for time-varying variables between the two groups. Mediation analysis estimated the effects of HbA1c variability on outcomes. Among 6874 insulin-naïve patients who initiated DPP4i, 88.7% were treated with metformin and 79.6% with sulphonylureas at baseline (54.9% men; mean age 65.2 ± 11.4 years). After a median follow-up of 4.6 years, compared with the high-threshold plus high-HVS group (≥50%), the low-threshold plus low-HVS (<50%) group had reduced hazard ratios (95% confidence interval) of insulin initiation (0.35, 0.31-0.40), severe hypoglycaemia (0.38, 0.34-0.44), major adverse cardiovascular endpoints (0.76, 0.66-0.88), heart failure (0.42, 0.36-0.49), end-stage kidney disease (0.65, 0.36-0.49) and mortality (0.45, 0.35-0.57). Reduced HbA1c variability explained 31.1%-81.2% of the effect size of DPP4i initiation at HbA1c <7.5% versus ≥7.5% on outcomes. In Chinese patients with T2D, avoiding therapeutic inertia with intensified glycaemic control at HbA1c <7.5% using drugs with low risk of hypoglycaemia and good tolerability, such as DPP4i, delayed insulin treatment, reduced HbA1c variability and improved clinical events.