Dose adjustment of paroxetine based on CYP2D6 activity score inferred metabolizer status in Chinese Han patients with depressive or anxiety disorders: a prospective study and cross-ethnic meta-analysis.

BACKGROUND: Understanding the impact of CYP2D6 metabolism on paroxetine, a widely used antidepressant, is essential for precision dosing. METHODS: We conducted an 8-week, multi-center, single-drug, 2-week wash period prospective cohort study in 921 Chinese Han patients with depressive or anxiety disorders (ChiCTR2000038462). We performed CYP2D6 genotyping (single nucleotide variant and copy number variant) to derive the CYP2D6 activity score and evaluated paroxetine treatment outcomes including steady-state concentration, treatment efficacy, and adverse reaction. CYP2D6 metabolizer status was categorized into poor metabolizers (PMs), intermediate metabolizers (IMs), extensive metabolizers (EMs), and ultrarapid metabolizers (UMs). The influence of CYP2D6 metabolic phenotype on paroxetine treatment outcomes was examined using multiple regression analysis and cross-ethnic meta-analysis. The therapeutic reference range of paroxetine was estimated by receiver operating characteristic (ROC) analyses. FINDINGS: After adjusting for demographic factors, the steady-state concentrations of paroxetine in PMs, IMs, and UMs were 2.50, 1.12, and 0.39 times that of EMs, with PM and UM effects being statistically significant (multiple linear regression, P = 0.03 and P = 0.04). Sex and ethnicity influenced the comparison between IMs and EMs. Moreover, poor efficacy of paroxetine was associated with UM, and a higher risk of developing adverse reactions was associated with lower CYP2D6 activity score. Lastly, cross-ethnic meta-analysis suggested dose adjustments for PMs, IMs, EMs, and UMs in the East Asian population to be 35%, 40%, 143%, and 241% of the manufacturer's recommended dose, and 62%, 68%, 131%, and 159% in the non-East Asian population. INTERPRETATION: Our findings advocate for precision dosing based on the CYP2D6 metabolic phenotype, with sex and ethnicity being crucial considerations in this approach. FUNDING: National Natural Science Foundation of China; Academy of Medical Sciences Research Unit.

Multiple roles of ferric chloride in preparing efficient magnetic hydrochar for sorption of methylene blue from water solutions.

Highly efficient and cheap magnetic materials have application prospects in wastewater treatment. Herein, Fe3O4-loaded hydrochar (HC-Fe3O4) was obtained from hydrothermal carbonization (HTC) of bamboo with FeCl3 and then added with FeCl3 to form a magnetic sorbent via simple precipitation. The HC-Fe3O4 was characterized with various instruments. The characterizations show FeCl3 plays at least two roles as a catalyst and an oxidant in HTC. The specific surface area of hydrochar enlarged from 39.9731 to 60.9887 m2·g-1 after the addition of FeCl3 during HTC, which showed FeCl3 acted as a catalyst in HTC. XRD indicated Fe3O4 was formed by the structure of HC-Fe3O4, which indicated Fe(III) was reduced to Fe(II) during HTC. Sorption of methylene blue (MB) onto HC-Fe3O4 was better fitted by the Langmuir isotherm and pseudo-second-order kinetic models. Sorption is a spontaneous thermodynamic endothermic process and HC-Fe3O4 is easily separated by an applied magnetic field and reused.

Ketone Body Rescued Seizure Behavior of LRP1 Deficiency in Drosophila by Modulating Glutamate Transport.

LRP1, the low-density lipoprotein receptor 1, would be a novel candidate gene of epilepsy according to our bioinformatic results and the animal study. In this study, we explored the role of LRP1 in epilepsy and whether beta-hydroxybutyrate, the principal ketone body of the ketogenic diet, can treat epilepsy caused by LRP1 deficiency in drosophila. UAS/GAL4 system was used to establish different genotype models. Flies were given standard, high-sucrose, and ketone body food randomly. The bang-sensitive test was performed on flies and seizure-like behavior was assessed. In morphologic experiments, we found that LRP1 deficiency caused partial loss of the ellipsoidal body and partial destruction of the fan-shaped body. Whole-body and glia LRP1 defect flies had a higher seizure rate compared to the control group. Ketone body decreased the seizure rate in behavior test in all LRP1 defect flies, compared to standard and high sucrose diet. Overexpression of glutamate transporter gene Eaat1 could mimic the ketone body effect on LRP1 deficiency flies. This study demonstrated that LRP1 defect globally or in glial cells or neurons could induce epilepsy in drosophila. The ketone body efficaciously rescued epilepsy caused by LRP1 knockdown. The results support screening for LRP1 mutations as discriminating conduct for individuals who require clinical attention and further clarify the mechanism of the ketogenic diet in epilepsy, which could help epilepsy patients make a precise treatment case by case.

WMsorting: Wavelet Packets Decomposition and Mutual Information Based Spike Sorting Method.

In recent years, the signal processing opportunities with the multi-channel recording and the high precision detection provided by the development of new extracellular multielectrodes are increasing. Hence, designing new spike sorting algorithms are both attractive and challenging. These algorithms are used to distinguish the individual neurons' activity from the dense and simultaneously recorded neural action potentials with high accuracy. However, since the overlapping phenomenon often inevitably arises in the recorded data, they are not accurate enough in practical situations especially when the noise level is high. In this paper, a spike feature extraction method based on the Wavelet Packets Decomposition and the Mutual Information is proposed. This is a highly accurate semi-supervised solution with a short training phase for performing the automation of the spike sorting framework. Further, the evaluations are performed on different public datasets. The raw data is not only suffered from multiple noises (from 5% level to 20% level) but also includes various degrees of overlapping spikes at different times. The clustering results demonstrate the effectiveness of our proposed algorithm. Also, it achieves a good anti-noise performance with ensuring a high clustering accuracy (up to 99.76%) compared with the state of art methods.

Development and validation of a deep-learning algorithm for the detection of polyps during colonoscopy.

The detection and removal of precancerous polyps via colonoscopy is the gold standard for the prevention of colon cancer. However, the detection rate of adenomatous polyps can vary significantly among endoscopists. Here, we show that a machine-learning algorithm can detect polyps in clinical colonoscopies, in real time and with high sensitivity and specificity. We developed the deep-learning algorithm by using data from 1,290 patients, and validated it on newly collected 27,113 colonoscopy images from 1,138 patients with at least one detected polyp (per-image-sensitivity, 94.38%; per-image-specificity, 95.92%; area under the receiver operating characteristic curve, 0.984), on a public database of 612 polyp-containing images (per-image-sensitivity, 88.24%), on 138 colonoscopy videos with histologically confirmed polyps (per-image-sensitivity of 91.64%; per-polyp-sensitivity, 100%), and on 54 unaltered full-range colonoscopy videos without polyps (per-image-specificity, 95.40%). By using a multi-threaded processing system, the algorithm can process at least 25 frames per second with a latency of 76.80 ± 5.60 ms in real-time video analysis. The software may aid endoscopists while performing colonoscopies, and help assess differences in polyp and adenoma detection performance among endoscopists.

The coordinated regulation of Na+ and K+ in Hordeum brevisubulatum responding to time of salt stress.

Hordeum brevisubulatum, called as wild barley, is a useful monocotyledonous halophyte for soil improvement in northern China. Although previously studied, its main salt tolerance mechanism remained controversial. The current work showed that shoot Na+ concentration was increased rapidly with stress time and significantly higher than in wheat during 0-168h of 100mM NaCl treatment. Similar results were also found under 25 and 50mM NaCl treatments. Even K+ was increased from 0.01 to 50mM in the cultural solution, no significant effect was found on tissue Na+ concentrations. Interestingly, shoot growth was improved, and stronger root activity was maintained in H. brevisubulatum compared with wheat after 7days treatment of 100mM NaCl. To investigate the long-term stress impact on tissue Na+, 100mM NaCl was prolonged to 60 days. The maximum values of Na+ concentrations were observed at 7th in shoot and 14th day in roots, respectively, and then decreased gradually. Micro-electrode ion flux estimation was used and it was found that increasing Na+ efflux while maintaining K+ influx were the major strategies to reduce the Na+ concentration during long-term salt stress. Moreover, leaf Na+ secretions showed little contribution to the tissue Na+ decrease. Thereby, the physiological mechanism for H. brevisubulatum to survive from long-term salt stress was proposed that rapid Na+ accumulation occurred in the shoot to respond the initial salt shock, then Na+ efflux was triggered and K+ influx was activated to maintain a stable K+/Na+ ratio in tissues.

[Anatomy study on the fixation technique of buttress plate in the posterior column of the acetabulum].

OBJECTIVE: To solve the problem of screw penetrating the joint surface easily by determining the angle of inclination and the mean longth screw plated on the posterior column. METHODS: Ten specimens of adult male cadavers, aged 20 to 74 years old, averaged 54.5 years old, were collected. After removal of the bilateral femurs from the hip joints, and sawing through the sacral and pubic symphysis in the median sagittal plane, 20 semi pelvic specimens were used for this study when the osseous abnormalities were excluded. The specimens were air dried naturelly after the soft tissue attaching to the pelvis had been eliminated. The margin of superior acetabular and inferior acetabular were determined, and the serial cross-sections of the acetabular posterior column were made. The width of posterior column,the width of acetabulum,the width ratio of acetabulum to posterior column, the angle of inclination and the mean length of screw on all entry points were measured. Defined the level parallel to 1/2 section of superior acetabulum was cross-section B; 1/2 section of acetabulum was C; 1/2 section of inferior acettabulum was D. At the different levels, defined the entry point on the outer edge of posterior column of the acetabulum or the trailing edge of acetabulum was B0, C0 or D0; lateral 1/2 of posterior column of the acetabulum was B1, C1 or D1; 1/2 of posterior column of the acetabulum was B2, C2 or D2; medial 1/2 of posterior column of the acetabulum was B3, C3 or D3; the inner edge of posterior column of the acetabulum was B4,C4 or D4. RESULTS: On cross-section B, the angle of inclination and the mean length of screw at B0 was 41 degrees and 44.0 mm; at B1 was 66 degrees and 42.2 mm; at B2 was 91 degrees and 59.5 mm; at B3 was 107 degrees and 64.0 mm; the maximum angle and the mean length at point B4 was 123 degrees and 65.5 mm; the minimum angle and the mean length at point B4 was 109 degrees and 59.0 mm. On cross-section C,the angle and the mean length at point CO was 39 degrees and 39.0 mm; at C1 was 57 degrees and 36.0 mm; at C2 was 74 degrees and 36.0 mm;at C3 was 90 degrees and 36.0 mm; at C4 was 106 degrees and 76.0 mm. On cross-section D,the angle and the mean length at DO was 42 degrees and 35.5 mm; at D1 was 61 degrees and 33.0 mm; at D2 was 81 degrees and 32.0 mm; at D3 was 100 degrees and 31.0 mm; at D4 was 120 degrees and 74.0 mm. CONCLUSION: When using the fixation technique of acetabular posterior column plate, the angles of screw-posterior column are 40 degrees to 60 degrees, 60 degrees to 75 degrees, 75 degrees to 90 degrees and 90 degrees to the angle of parallel to the square area respectively on the region of outer 1/4,outer-middle 1/4,inner-middle 1/4 and inner 1/4 of the acetabulum region, and the screw length is 30 mm.

Assessment of the effect of etomidate on voltage-gated sodium channels and action potentials in rat primary sensory cortex pyramidal neurons.

Although it is known that general anesthetics can suppress cortical neurons׳ activity, the underlying mechanisms are still poorly understood, especially the kinetic changes of voltage-gated Na(+) channels, which are mostly related to neuronal excitability. Some general anesthetics have been reported to affect the voltage-gated Na(+) channels in cell culture derived from humans and animals. However no one has ever investigated the effects of etomidate on voltage-gated Na(+) channels in pyramidal neurons using a brain slice. The present study uses a whole cell patch-clamp technique to investigate the changes of voltage-gated Na(+) channels on primary somatosensory cortex pyramidal neurons under the influence of etomidate. We found that etomidate dose-dependently inhibited Na(+) currents of primary somatosensory cortex pyramidal neurons, while shifted the steady-state inactivation curve towards the left and prolonged the recovery time from inactivation. Conversely, etomidate has no effects on the steady-state activation curve. We demonstrated the detailed suppression process of neural voltage-gated Na(+) channels by etomidate on slice condition. This may offer new insights into the mechanical explanation for the etomidate anesthesia. Finding the effects of anesthetics on primary somatosensory cortex also provides evidence to help elucidate the potential mechanism by which tactile information integrates during general anesthesia.

Superior left ventricle in combination with inferior right ventricle: presenting with balanced hemodynamics and mild symptoms in a late adolescent.

We describe a case of superoinferior ventricles with an unusual superior location of the left ventricle and inferior location of the right ventricle. The patient was a 17-year-old boy who had been admitted for paroxysmal supraventricular tachycardia with pre-excitation syndrome. The cardiac anomaly was first recognized after admission, and the pre-excitation syndrome, eventually, was treated successfully by radiofrequency catheter ablation. This case featured a segmental set notation {S, D, S} with concordant atrioventricular and ventriculoarterial alignments. Persistent left superior vena cava was the only associated defect. To the best of our knowledge, there has been only 1 other reported case of superoinferior ventricles in which the left ventricle was in the superior position. In our case, the patient's hemodynamics were sufficiently normal that he had reached adolescence with only minor adverse events.