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During Hedgehog (Hh) signal transduction in development and disease, the atypical G protein-coupled receptor (GPCR) SMOOTHENED (SMO) communicates with GLI transcription factors by binding the protein kinase A catalytic subunit (PKA-C) and physically blocking its enzymatic activity. Here, we show that GPCR kinase 2 (GRK2) orchestrates this process during endogenous mouse and zebrafish Hh pathway activation in the primary cilium. Upon SMO activation, GRK2 rapidly relocalizes from the ciliary base to the shaft, triggering SMO phosphorylation and PKA-C interaction. Reconstitution studies reveal that GRK2 phosphorylation enables active SMO to bind PKA-C directly. Lastly, the SMO-GRK2-PKA pathway underlies Hh signal transduction in a range of cellular and in vivo models. Thus, GRK2 phosphorylation of ciliary SMO and the ensuing PKA-C binding and inactivation are critical initiating events for the intracellular steps in Hh signaling. More broadly, our study suggests an expanded role for GRKs in enabling direct GPCR interactions with diverse intracellular effectors.

Abstract Background In emergency settings, difficult intubations often occur unexpectedly despite pre-intubation assessments. Traditional glottic view scoring systems for direct laryngoscope may not apply to video laryngoscopy. With video laryngoscopy, the vertical location of the glottis on the monitor can be clearly defined. If the glottis location is associated with intubation difficulty, it could serve as a simple indicator for anticipating intubation challenges. This study aimed to investigate the relationship between the glottis screen location during video laryngoscopy-guided intubation and the success and timing of the first-attempt intubation. Methods We retrospectively analyzed laryngoscopy recordings from adult intubations in the emergency department of a tertiary teaching hospital in Chiayi, Taiwan, using the C-MAC video laryngoscope between March 2020 and April 2023. The vertical screen location of the vocal cords, determined by the arytenoid cartilage position after laryngeal blade engagement, was categorized into upper and lower locations for analysis. The primary outcome was first-attempt intubation success within 90 s, analyzed using Kaplan-Meier survival curves and multivariable Cox proportional hazard analysis. Results Among 209 laryngoscopy records, 113 had the arytenoid in the lower field of view and 96 in the upper field. Kaplan-Meier analysis showed a significantly lower cumulative success rate for intubations with a higher arytenoid location (log-rank test, P

Abstract In urban areas, emergency vehicles (EVs) need efficient traffic signal preemption to ensure timely responses during peak hours. While emergency vehicle traffic signal preemption (EVTSP) has garnered significant attention in the literature, the issues of queue spillbacks and negative impacts on non‐priority traffic have been relatively underreported. These issues are particularly critical during peak hours, notably in densely populated urban areas. This study presents an EVTSP system that considers queue spillbacks on approaches along the routes of EVs and the negative impacts of signal preemption on non‐priority traffic. The proposed control system has four key components: (1) a queue length management algorithm to ensure that an EV will not be impeded by excessive queues, particularly on its initial approaches along its route; (2) a signal preemption algorithm to guarantee uninterrupted passage of an EV even for approaches experiencing queue spillbacks; (3) a traffic status recovery algorithm to alleviate the extra waiting time for non‐priority vehicles after an EV crosses each intersection; and (4) a signal plan recovery algorithm to smoothly transit traffic signals to normal operation. The experimental results confirm that the proposed system considerably improves the travel time of an EV and mitigates the negative impacts on non‐priority traffic.

Background: Few studies have studied the efficacy of using immersive virtual reality (iVR) to teach surgical skills, especially by using real-world iVR recordings rather than simulations. This study aimed to investigate whether viewing 360° iVR instructional recordings produces greater improvements in basic suturing skills of students without prior medical training, beyond traditional methods like reading written manuals or watching 2D instructional videos. Materials and methods: This was a partially blinded randomized cohort study. 44 pre-university students (aged 17) were randomized equally to either the written instruction manual, 2D instructional video, or iVR recordings. All students first watched a silent 2D demonstration video of the suturing task, before attempting to place three simple interrupted sutures on a piece of meat as a baseline. The time taken for the first attempt was recorded. Students were then given an hour to train using their allocated modality. They attempted the suturing task again, and timings were re-recorded. Four blinded surgically-trained judges independently assessed the quality of the stitches placed both pre and post-intervention. One-way analysis of variance tests (ANOVAs) and independent two-sample t-tests were used to determine the effect of training modality on improvements in suturing scores and time taken to complete suturing from pre to post-training. Results: For suturing scores, the iVR group showed significantly larger score improvements than the Written Manual group (p = 0.031, Cohen's D = 0.92), while this iVR advantage was less pronounced when compared with the 2D Video group (p = 0.16, Cohen's D = 0.65). Similarly for time taken to complete suturing, the iVR group had significantly larger time improvements than the Written Manual group (p = 0.045), although this difference was less robust compared to the 2D Instructional Video group (p = 0.34). Conclusion: This study demonstrates that iVR training using real-world 360° instructional recordings produced significantly greater training gains in suturing scores and efficiency compared to reading written text. iVR training also led to larger training gains in both outcome measures than viewing 2D instructional videos, although the differences between them did not reach statistical significance.

Abstract This work presents a series of novel quinoidal organic semiconductors based on diselenophene‐dithioalkylthiophene (DSpDST) conjugated cores with various side‐chain lengths (‐thiohexyl, ‐thiodecyl, and ‐thiotetradecyl, designated DSpDSTQ‐6, DSpDSTQ‐10, and DSpDSTQ‐14, respectively). The purpose of this research is to develop solution‐processable organic semiconductors using dicyanomethylene end‐capped organic small molecules for organic field effect transistors (OFETs) application. The physical, electrochemical, and electrical properties of these new DSpDSTQs are systematically studied, along with their performance in OFETs and thin film morphologies. Additionally, the molecular structures of DSpDSTQ are determined through density functional theory (DFT) calculations and single‐crystal X‐ray diffraction analysis. The results reveal the presence of intramolecular S (alkyl)···Se (selenophene) interactions, which result in a planar SR‐containing DSpDSTQ core, thereby promoting extended π‐orbital interactions and efficient charge transport in the OFETs. Moreover, the influence of thioalkyl side chain length on surface morphologies and microstructures is investigated. Remarkably, the compound with the shortest thioalkyl chain, DSpDSTQ‐6, demonstrates ambipolar carrier transport with the highest electron and hole mobilities of 0.334 and 0.463 cm2 V−1 s−1, respectively. These findings highlight the excellence of ambipolar characteristics of solution‐processable OFETs based on DSpDSTQs even under ambient conditions.

Abstract Four conjugated polymers are integrated with a bacteriorhodopsin D94N‐HmBRI in organic field‐effect transistors (OFETs) with the device architecture of doped Si bottom gate/SiO2 bottom electric/semiconducting polymer/Au electrodes/D94N‐HmBRI top dielectric. Photosensitivity of D94N‐HmBRI in the devices is validated. It is proposed that light activates the conformational change of all‐trans retinal to 13‐cis retinal in D94N‐HmBRI. The D94N‐HmBRI layer then applies momentary dipoles to the semiconductors, affecting threshold voltage, resulting in photosensitivity. Film‐thickness variation, capacitance determination, and grazing‐incidence X‐ray scattering are performed to support the proposed working principle. Quasi dual‐gate OFETs with a highly doped silicon wafer as the bottom gate and light as the top gate are thus realized by combining conjugated polymers with D94N‐HmBRI.

The Fe–Mn–Al–C lightweight steel has been widely studied due to its higher strength-to-weight ratio and potential applications for automotive vehicles, energy, transportation and mining industries. In general, the strength and ductility of the Fe–Mn–Al–C lightweight steel can be improved by the formation of nano-sized (Fe,Mn)3AlCx κ-carbide precipitates by a proper heat treatment below 800 °C. In this work, a unique micrometer scale κ-carbide phase transformation phenomenon induced by the pack aluminization in the Fe–29Mn–9Al–0.9C lightweight steel was firstly reported.Extremely large columnar-like (Fe,Mn)3AlCx κ-carbide grains with average length of 18.1 μm embedded in the Fe3Al matrix were discovered in the interdiffusion zone of aluminization layer, which were totally different from these nanoscale κ-carbides precipitated in the austenitic steel matrix. The increased Al content in the pack aluminide coating/substrate interface reduced the chemical potential of carbon and became the driving force for carbon diffusion toward the coating/substrate interface. Therefore, due to the extremely low solubility of carbon in the Fe3Al phase and the inward diffusion of carbon atoms, very long columnar-like (Fe,Mn)3AlCx κ-carbide phases were thus produced in the interdiffusion zone. The average chemical concentration of the κ-carbide was 43.9Fe–27.3Mn–20.3Al–8.5 C (in at.%). The average hardness, elastic modulus and the lattice parameter of κ-carbide were 8.8 ± 0.3 GPa, 285 ± 10 GPa and 0.3764 nm, respectively. This study provided detailed chemical compositions, hardness and elastic modulus of (Fe,Mn)3AlCx κ-carbide phase for better understanding the carbide precipitation and strengthening mechanism of Fe–Mn–Al–C lightweight steel.

ObjectivesComputed tomography (CT) has been increasingly used in the diagnosis of acute aortic syndrome, and a number of high-risk CT imaging features have been reported. We aimed to identify CT imaging findings suggesting high-risk for acute aortic syndrome by examining clinical outcomes of patients with acute type A aortic intramural hematoma (TAIMH).MethodsThis retrospective study analyzed the relationship of clinical patient characteristics and imaging features with mortality and aortic events in 63 patients receiving initial medical treatment for TAIMH. Multivariate regression analysis was used to determine the predictors of aortic events, and the Kaplan–Meier method was used to analyze survival and aortic events.ResultsDuring a median follow-up of 4.2 years, 25 patients experienced aortic events and 40% of these occurred within 7 days of admission. In total, 12 patients experienced aortic death and 12 patients underwent open aortic surgery or endovascular stenting for aortic disease. In multivariate regression analysis, penetrating atherosclerotic ulcers (PAUs) or ulcer-like projections (ULPs) (P = 0.04) and pericardial effusion (P = 0.03) were independent predictors of aortic events. In the Cox regression model, PAUs/ULPs (P = 0.04) and pericardial effusion (P = 0.04) were independently associated with lower aortic event-free survival.ConclusionIdentification of high-risk CT features is important for clinical decision-making during TAIMH treatment. Early and frequent CT imaging follow-up is required in patients receiving medical treatment. PAUs/ULP and pericardial effusion were the strongest predictors of adverse aortic events.

Diabetic wounds exhibit chronic inflammation and delayed tissue proliferation or remodeling, mainly owing to prolonged proinflammatory (M1) macrophage activity and defects in transition to prohealing/proremodeling (M2a/M2c; CD206+ and/or CD163+) macrophages. We found that topical treatment with ON101, a plant-based potential therapeutic for diabetic foot ulcers, increased M2c-like (CD163+ and CD206+) cells and suppressed M1-like cells, altering the inflammatory gene profile in a diabetic mouse model compared with that in the controls. An in vitro macrophage-polarizing model revealed that ON101 directly suppressed CD80+ and CD86+ M1-macrophage polarization and M1-associated proinflammatory cytokines at both protein and transcriptional levels. Notably, conditioned medium collected from ON101-treated M1 macrophages reversed the M1-conditioned medium‒mediated suppression of CD206+ macrophages. Furthermore, conditioned medium from ON101-treated adipocyte progenitor cells significantly promoted CD206+ and CD163+ macrophages but strongly inhibited M1-like cells. ON101 treatment also stimulated the expression of GCSF and CXCL3 genes in human adipocyte progenitor cells. Interestingly, treatment with recombinant GCSF protein enhanced both CD206+ and CD163+ M2 markers, whereas CXCL3 treatment only stimulated CD163+ M2 macrophages. Depletion of cutaneous M2 macrophages inhibited ON101-induced diabetic wound healing. Thus, ON101 directly suppressed M1 macrophages and facilitated the GCSF- and CXCL3-mediated transition from M1 to M2 macrophages, lowering inflammation and leading to faster diabetic wound healing.

In this work, the plasma electrolytic oxidation (PEO) process using a pulsed bipolar direct current (DC) power supply and sodium aluminate-based electrolyte was employed to grow the oxide layer on the AZ31 Mg alloy. For achieving a higher adhesion or a better corrosion resistance of oxide layer, the Taguchi L9 orthogonal array was adopted to determine the optimal PEO parameters, including anode on-time, anode current setting, cathode current setting, and cathode on-time. According to the signal-to-noise ratio and analysis of variance, the anode on-time was the most important control factor for improving adhesion and corrosion resistance properties of oxide coatings. The surface morphologies of all oxide coatings were typical crater-like microstructures. The oxide layer thickness can be increased by longer anode on-time and higher anode current. The hardness of the oxide layer was between 12.7 and 17.7 GPa due to the formation of MgAl2O4 phase. Through the confirmation experiments using the optimized PEO processing parameters, the maximum adhesion critical load of 41.8 N can be obtained. On the other hand, the highest polarization resistance of 6.68 × 103 kΩ˙cm2 was achieved, which was 6485 times better than the bare AZ31 substrate due to its compact microstructure, and a dense and continuous inner barrier layer at the coating/substrate interface.

Objective: We present a rare case of well-differentiated papillary mesothelioma (WDPM) found incidentally in a 59-year-old woman with endometrial cancer. Case report: A 59-year-old nulliparous obese woman with a past history of hypertension and diabetes mellitus presented with postmenopausal bleeding for 11 months. Two months prior to this admission, an episode of massive vaginal bleeding lasting for a day was noticed by the patient. Hysteroscopy was performed after her visit to our outpatient department. Papillary tumors with active bleeding were found in the uterine cavity. Endometrial biopsy showed adenocarcinoma, endometrioid type characterized by papillary architecture lined by columnar cells with mild nuclear pleomorphism. The patient proceeded to magnetic resonance imaging (MRI), which demonstrated a 6.4 × 5.5 × 4.9 cm intrauterine mass. Her tumor marker levels were elevated (CA 125 87.8 IU/ml, CA19-9160.54 IU/ml). The patient then underwent a staging surgery and final pathology revealed stage IA endometrial cancer. During surgery, multiple nodules were found in the peritoneum, initially considered as tumor metastasis and eventually proved to be WDPM. Conclusion: In conclusion, the simultaneous occurrence of WDPM with endometrial cancer is a rare entity. Although no standardized treatment has been established, WDPMs have a relatively favorable prognosis compared to malignant mesotheliomas.

Abstract Background Veno-arterial extracorporeal membrane oxygenation (ECMO) is increasingly being utilized in patients with massive pulmonary embolism (PE). However, the efficacy and the safety remain uncertain. This study aimed to investigate clinical courses and outcomes in ECMO-treated patients with acute PE. Methods Twenty-one patients with acute PE rescued by ECMO from January 2012 to December 2019 were retrospectively analysed. Clinical features, laboratory biomarkers, and imaging findings of these patients were reviewed, and the relationship with immediate outcome and clinical course was investigated. Results Sixteen patients (76.2%) experienced refractory circulatory collapse requiring cardiopulmonary resuscitation (CPR) or ECMO support within 2 h after the onset of cardiogenic shock, and none could receive definitive reperfusion therapy before ECMO initiation. Before or during ECMO support, more than 90% of patients had imaging signs of right ventricular (RV) dysfunction. In normotension patients, the computed tomography (CT) value was a valuable predictor of rapid disease progression compared with cardiac troponin I level. Ultimately, in-hospital death occurred in ten patients (47.6%) and 90% of them died of prolonged CPR-related brain death. Cardiac arrest was a significant predictor of poor prognosis (p = 0.001). Conclusions ECMO appears to be a safe and effective circulatory support in patients with massive PE. Close monitoring in intensive care unit is recommended in patients with RV dysfunction and aggressive use of ECMO may reduce the risk of sudden cardiac arrest and improve clinical outcome.

Abstract The glazes in celadon are Ca‐Al‐Si‐O based glasses with a trace of Fe species doped as a coloring agent. The color of celadon is generated by a dual‐coloring mechanism of chemico‐compositional coloring by Fe species, and structural coloring by inhomogeneities. In order to identify the effects on the structural coloring mechanism, Fe doped Ca‐Al‐Si‐O glasses based on the composition of celadon were systematically synthesized by a thermal melting method to compare with that of the shard of ancient Ru‐ware. The results show that the as‐prepared glazes consisted of bubbles, crystalline precipitates, and dual‐phasic glass areas. The crystalline precipitates are mainly facet anorthite grains surrounded by Ca‐Al‐Si‐O glasses. Spinodal decomposition of the Ca‐Al‐Si‐O glasses was observed, whose morphologies are either a spherical or a worm‐like patterns. From the analysis of optical spectra, the intensities of wavelengths in the green (495‐570 nm), yellow (570‐590 nm), and orange (590‐620 nm) are in mixture hybrid. The dominant factor of the structural coloring might due to Rayleigh scattering by the nano‐textures of duel‐phasic glasses (50‐100 nm), which increases the blue opalescence. The spinodal decomposition of celadon porcelain after the anorthite grains precipitated was also identified in this study.

ObjectivesVeno-arterial extracorporeal membrane oxygenation (ECMO) is increasingly used to treat high-risk pulmonary embolism (PE). However, its efficacy and safety remain uncertain. This retrospective cohort study aimed to determine whether ECMO could improve the clinical outcomes of patients with high-risk PE.MethodsForty patients with high-risk PE, who were admitted to Kaohsiung Chang Gung Memorial Hospital between January 2012 and December 2019, were included in this study. Demographic data and clinical outcomes were compared between patients treated without ECMO (non-ECMO group) and those treated with ECMO (ECMO group). Appropriate statistical tools were used to compare variables between groups and the survival was analyzed using the Kaplan–Meier method.ResultsThe overall in-hospital mortality rate was 55%, in which 65% (26/40) of patients presented with cardiac arrest with a mortality rate of 77%, which was higher than that of patients without cardiac arrest (14%). There was no significant difference in major complications and in-hospital mortality between the non-ECMO and ECMO groups. However, in subgroup analysis, compared with patients treated without ECMO, earlier ECMO treatment was associated with a reduced risk of cardiac arrest (P = 0.023) and lower in-hospital mortality (P = 0.036). A log-rank test showed a significantly higher cumulative overall survival in the earlier ECMO treatment group (P = 0.033).ConclusionsIn this retrospective cohort study, earlier ECMO treatment was associated with lower in-hospital mortality among unstable patients without cardiac arrest. Our findings suggest that ECMO can be considered as an initial treatment option for patients with high-risk PE in higher-volume hospitals.

Objective: Lower serum low-density lipoprotein cholesterol (LDL-C) levels are associated with increased intracerebral hemorrhage (ICH) risk. However, reverse causality and residual confounding has not attracted public attention. Therefore, we assessed whether people with LDL-C have increased risk of mortality adjusting for potential confounders using two large Taiwan cohorts.Methods: The Mei-Jhao (MJ) cohort has 414,372 adults participating in a medical screening program with 378 ICH deaths within 15 years of follow-up (1994–2008). Cox proportional hazards regressions estimated hazard death ratios according to LDL-C levels. We identified 4,606 ICH patients from the Taiwan Stroke Registry (TSR) and analyzed the impact of LDL-C on 3-month mortality.Results: Low cholesterol (LDL-C

With advancements in cardiopulmonary rehabilitation over the past few decades, the survival rate of patients with congenital heart disease (CHD) has increased. However, the Cardiopulmonary fitness (CPF) of these patients is poor. Here, we aimed to investigate CPF in preschoolers with CHD (aged 4 to 6 years) using cardiopulmonary exercise testing. We retrospectively compared 102 healthy preschoolers with 80 preschoolers with CHD. The latter had lower peak oxygen consumption, oxygen consumption at anaerobic threshold and metabolic equivalent at anaerobic threshold. The same result was observed in boys with CHD, but not in girls, when sex was sub-analyzed. Considering the body composition, children with CHD had a lower fat-free mass index (FFMI) than their healthy peers. Healthy preschoolers with a normal body mass index (BMI) had higher anaerobic threshold and peak metabolic equivalent values than overweight or underweight children. This was categorized under the BMI reference of the Ministry of Health and Welfare in Taiwan. In conclusion, the CPF difference between the CHD and healthy groups was identified as early as in preschool age, and better CPF in healthy preschoolers within the normal BMI range suggests the importance of weight control in young children.

Hybrid natural products produced via mixed biosynthetic pathways are unique and often surprise one with unexpected medicinal properties in addition to their fascinating structural complexity/diversity. In view of chemical structures, hybridization is a way of diversifying natural products usually through dimerization of two similar or dissimilar subcomponents through a C–C or N–C covalent linkage. Here, we report four structurally attractive diterpene–alkaloid conjugates polyalongarins A–D (1–4), clerodane-containing aporphine and proaporphine alkaloids, the first of its kind from the barks of Taiwanese Polyalthia longifolia (Sonn.) Thwaites var. pendula. In addition to conventional spectroscopic analysis, single crystal X-ray crystallography was employed to determine the chemical structures and stereo-configurations of 1. Compounds 1–4 were subsequently subjected to in vitro antiviral examination against DENV2 by evaluating the expression level of the NS2B protein in DENV2-infected Huh-7 cells. These compounds display encouraging anti-DENV2 activity with superb EC50 (2.8–6.4 μM) and CC50 values (50.4–200 μM). The inhibitory mechanism of 1–4 on NS2B was further explored drawing on in-silico molecular docking analysis. Based on calculated binding affinities and predicted interactions between the functional groups of 1–4 and the allosteric-site residues of the DENV2 NS2B-NS3 protease, our analysis concludes that the clerodane–aporphine/proaporphine-type hybrids are novel and effective DENV NS2B-NS3 protease inhibitors.

Surgery-related isolated proximal median neuropathy is a rare complication. Brachial plexus injury is a possible complication after major cardiac surgery; however, isolated mononeuropathy is less frequently documented. We present an unusual case of isolated proximal median neuropathy after aortic dissection repair surgery in a 39-year-old man. Electrodiagnostic study and ultrasound examinations helped in localizing the lesion to the axillary region. Serial follow-ups showed improvement in electrodiagnostic parameters, which were compatible with clinical symptoms. Partial recovery was achieved at the seventh month follow-up. This case report aimed to increase awareness of nerve stretching during open heart surgery and demonstrate the diagnosis and clinical follow-up by concomitant use of electrodiagnostic and nerve ultrasound studies.

Parkinson's disease (PD) is a progressive motor neurodegenerative disorder, characterized by a selective loss of dopaminergic neurons in the substantia nigra. The complexity of disease etiology includes both genetic and environmental factors. No effective drug that can modify disease progression and protect dopamine neurons from degeneration is presently available. Human α-Synuclein A30P (A30P) is a mutant gene identified in early onset PD and showed to result selective dopamine neuron loss in transgenic A30P flies and mice. Paraquat (PQ) is an herbicide and an oxidative stress generator, linked to sporadic PD. We hypothesized that vital PD modifier genes are conserved across species and would show unique transcriptional changes to oxidative stress in animals expressing a PD-associated gene, such as A30P. We also hypothesized that manipulation of PD modifier genes would provide neuroprotection across species. To identify disease modifier genes, we performed two independently-duplicated experiments of microarray, capturing genome-wide transcriptional changes in A30P flies, chronically fed with PQ-contaminated food. We hypothesized that the best time point of identifying a disease modifier gene is at time when flies showed maximal combined toxicity of A30P transgene and PQ treatment during an early stage of disease and that effective disease modifiers gene are those showing transcriptional changes to oxidative stress in A30P expressing and not in wild type animals. Fly Neprilysin3 (Nep3) is one identified gene that is highly conserved. Its mouse and human homolog is endothelin-converting enzyme-1 (Ece1). To investigate the neuroprotective effect of Ece1, we used NS1 cells and mouse midbrain neurons expressing A30P, treated with or without PQ. We found that ECE1 expression protected against A30P toxicity on cell viability, on neurite outgrowth and ameliorated A30P accumulation in vitro. Expression of ECE1 in vivo suppressed dopamine neuron loss and alleviated the corresponding motor deficits in mice with A30P-expression. Our study leverages a new approach to identify disease modifier genes using a stress-enhanced PD animal model.

Background: Metoclopramide is used to relieve gastrointestinal symptoms, however, it could cause adverse reactions of motor disorders. The aim of this study was to investigate whether metoclopramide treatment has a duration–response or dose–response effect and to estimate the risk of developing Parkinsonism following different and specific durations of treatment. Methods: A cohort study of newly diagnosed type 2 diabetes mellitus in 45- to 79-year-old patients, between 1999 and 2008, was selected using the Longitudinal Health Insurance Database 2005. A nested case–control study was conducted in the diabetes cohort in which all incident cases of Parkinsonism were identified. We randomly matched each case with up to 10 controls from the risk set. Conditional logistic regression was utilized to estimate odds ratio of Parkinsonism associated with metoclopramide use. Results: A total of 34,685 patients with diabetes were assembled as the cohort, and 541 incident Parkinsonism cases were identified. There were duration–response and dose–response effects on the risk of developing Parkinsonism. Compared with never-use patients, the adjusted odds ratios (ORs) of continuing therapy for 0–1 month, 1–2 months, 2–3 months, 3–5 months, and more than 5 months were 1.17 [95% confidence interval (CI) 0.93–1.45], 1.44 (95% CI 1.04–2.00), 1.74 (95% CI 1.14–2.65), 1.90 (95% CI 1.23–2.93), and 2.17 (95% CI 1.50–3.12), respectively. Conclusions: With metoclopramide treatment, regardless of less or more than 3 months of use, the risk of developing Parkinsonism in patients with newly diagnosed diabetes escalated with the duration of therapy. Therefore, we recommend close monitoring for the development of Parkinsonism in patients treated with metoclopramide, particularly (but not limited to) those with prolonged exposure.