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Wan-Yi Rao,1,&ast; Fang Xu,1,&ast; Shao-Bing Dai,1 Zhong Mei,2 Xiao-Ping Chen,1 Chang-Cheng Lv,1 Chun-Lei Liu,1 Warwick Ngan Kee,1 Xin-Zhong Chen1 1Department of Anesthesia, Women’s Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China; 2Department of Anesthesiology, Affiliated Xiaoshan Hospital, Hangzhou Normal University, Hangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xin-Zhong Chen, Department of Anesthesia, Women’s Hospital, Zhejiang University School of Medicine, No. 1 Bachelor’s Road, Hangzhou, 310000, People’s Republic of China, Email chenxinz@zju.edu.cnPurpose: Catheter-based techniques such as combined spinal-epidural (CSE) anesthesia which are sometimes indicated for obstetric anesthesia have a complex mechanism of action. The application of the dural puncture epidural (DPE) anesthesia for cesarean section (CS) has not been well investigated. The present study compared the relatively novel DPE technique with epidural (EA) and CSE anesthesia.Patients and Methods: We randomly assigned 150 parturients who underwent elective CS to receive DPE, EA or CSE anesthesia. The primary outcome was the onset of sensory anesthesia to the T5 dermatome assessed using the Cox proportional hazards model. Secondary outcomes included median time to sensory block, quality of block, patient and surgeon satisfaction, APGAR scores and other side effects.Results: For DPE anesthesia versus EA anesthesia, the onset of anesthesia was faster (hazard ratio 2.47 [95% CI 1.56 to 3.90], adjusted P < 0.001) and the median time to surgical level was shorter (16 [IQR 14– 18] min versus 19 [15.5– 21] min, adjusted P < 0.001); the incidence of intraoperative pain was lower (7/48 versus 17/47, adjusted P = 0.046) and the median patient satisfaction score was higher (9 [IQR 9– 10] versus 8 [8– 9.5], adjusted P = 0.004). In the CSE group, the onset of anesthesia was faster than in the other two but the incidence of hypotension was higher (P < 0.001) and the phenylephrine requirement was greater (P < 0.001).Conclusion: DPE anesthesia had a faster onset and better quality of block than EA anesthesia and provided less influence to maternal hemodynamic parameters than CSE anesthesia for CS. These results suggest that the dural puncture plays a significant role in enhancing the effectiveness of epidural top-ups during CSE anesthesia and indicates enlightenment that contributes to the satisfaction of anesthetic effect in DPE technique labor analgesia transferred to CS.Keywords: anesthesia, dural puncture epidural, anesthesia, epidural, cesarean section

Wei Zhang,1,* Yijun Luo,2,* Xiaoli Wang,2 Gaohua Han,1 Peng Wang,1 Wei Yuan,3 Sheng-Bin Dai1 1Department of Oncology, Taizhou People’s Hospital, Taizhou, Jiangsu, People’s Republic of China; 2Department of Oncology, The People’s Hospital of Jiangxi Province, Nanchang, Jiangxi, People’s Republic of China; 3Department of Cardiology, Taizhou People’s Hospital, Taizhou, Jiangsu, People’s Republic of China *These authors contributed equally to this work Purpose: For esophageal cancer patients with a clinical complete response (cCR) after standard-dose radiotherapy with concurrent chemotherapy, data on the survival outcomes and recurrence patterns remain scarce. To evaluate the impact of dose escalation on overall survival for this subset of patients, we carried out the current investigation. Materials and methods: Medical records of 80 esophageal cancer patients with a cCR after standard-dose radiotherapy with concurrent chemotherapy at our center from 2010 to 2014 were allocated into the standard-dose group (50.4 Gy, observation group) or the radiation dose-escalation group (59.4 Gy, control group). In this cohort study, we compared the outcomes between the 2 groups. Results: There were no differences in patient characteristics between the 2 groups. The median recurrence-free survival and overall survival times for all patients were 38 and 54 months, respectively. Patients in the control group had significantly better 5-year recurrence-free survival rate (12% vs 0%, p=0.019) and 5-year overall survival rate (42.8% vs 21.0%, p=0.028) than the observation group. Additionally, local control rate was significantly higher in the control group (p=0.04), and ~60% of treatment failures were local failures even for patients achieving cCR after chemoradiotherapy. There were no significant differences in treatment-related toxicities between the groups. Conclusion: The results of the current study suggest that for esophageal cancer patients with a cCR after standard-dose radiotherapy with concurrent chemotherapy, those with dose-escalated radiotherapy showed significantly better local control, recurrence-free survival, and overall survival than patients receiving 50.4 Gy radiotherapy. Keywords: esophageal squamous cell carcinoma, radiotherapy, survival outcome, recurrence patterns

We report on a high-repetition-rate and high-beam-quality all-solid-state nanosecond pulsed deep-red laser source by intracavity second harmonic generation of the actively Q-switched Nd:YVO 4 /KGW Raman laser. The polarization of the 1342 nm fundamental laser was aligned with the Ng and Nm axes of KGW crystal for accessing the eye-safe Raman lasers at 1496 and 1526 nm, respectively. With the aid of the elaborately designed V-shaped resonator and the composite Nd:YVO 4 crystal, excellent mode matching and good thermal diffusion have been confirmed. Under an optimal pulse repetition frequency of 25 kHz, the average output powers of the Raman lasers at 1496 and 1526 nm were measured to be 3.7 and 4.9 W with the superior beam quality factor of M 2  = 1.2, respectively. Subsequently, by incorporating a bismuth borate (BIBO) crystal, the deep-red laser source was able to lase separately two different spectral lines at 748 and 763 nm, yielding the maximum average output powers of 2.5 and 3.2 W with the pulse durations of 15.6 and 11.3 ns, respectively. The resulting beam quality was determined to be near-diffraction-limited with M 2 = 1.28.

Importance: Epidural anesthesia is a primary choice for cesarean delivery, but supplemental analgesics are often required to relieve pain during uterine traction., Objective: To investigate the sedative and analgesic effects of intravenous esketamine administered before childbirth via cesarean delivery with the patient under epidural anesthesia., Design, Setting, and Participants: This multicenter, double-blind randomized clinical trial assessed 903 women 18 years or older who had full-term single pregnancy and were scheduled for elective cesarean delivery with epidural anesthesia in 5 medical centers in China from September 18, 2021, to September 20, 2022., Intervention: Patients were randomized to receive intravenous injection of 0.25 mg/kg of esketamine or placebo before incision., Main Outcomes and Measures: The coprimary outcomes included scores on the numeric rating scale of pain (an 11-point scale, with 0 indicating no pain and 10 indicating the worst pain; a difference of ≥1.65 points was clinically meaningful) and Ramsay Sedation Scale (a 6-point scale, with 1 indicating restlessness and 6 indicating deep sleep without response; a difference of ≥2 points was clinically meaningful) immediately after fetal delivery. Secondary outcomes included neonatal Apgar score assessed at 1 and 5 minutes after birth., Results: A total of 600 women (mean [SD] age, 30.7 [4.3] years) were enrolled and randomized; all were included in the intention-to-treat analysis. Immediately after fetal delivery, the score on the numeric rating scale of pain was lower with esketamine (median [IQR], 0 [0-1]) than with placebo (median [IQR], 0 [0-2]; median difference, 0; 95% CI, 0-0; P = .001), but the difference was not clinically important. The Ramsay Sedation Scale scores were higher (sedation deeper) with esketamine (median [IQR], 4 [3-4]) than with placebo (median [IQR], 2 [2-2]; median difference, 2; 95% CI, 2-2; P < .001). The neonatal Apgar scores did not differ between the 2 groups at 1 minute (median difference, 0; 95% CI, 0-0; P = .98) and at 5 minutes (median difference, 0; 95% CI, 0-0; P = .27). Transient neurologic or mental symptoms were more common in patients given esketamine (97.7% [293 of 300]) than in those given placebo (4.7% [14 of 300]; P < .001)., Conclusions and Relevance: For women undergoing cesarean delivery under epidural anesthesia, a subanesthetic dose of esketamine administered before incision produced transient analgesia and sedation but did not induce significant neonatal depression. Mental symptoms and nystagmus were common but transient. Indications and the optimal dose of esketamine in this patient population need further clarification, but study should be limited to those who require supplemental analgesia., Trial Registration: ClinicalTrials.gov Identifier: NCT04548973.

High beam quality 588 nm radiation was realized based on a frequency-doubled crystalline Raman laser. The bonding crystal of YVO 4 /Nd:YVO 4 /YVO 4 was used as the laser gain medium, which can accelerate the thermal diffusion. The intracavity Raman conversion and the second harmonic generation were realized by a YVO 4 crystal and an LBO crystal, respectively. Under an incident pump power of 49.2 W and a pulse repetition frequency of 50 kHz, the 588 nm power of 2.85 W was obtained with a pulse duration of 3 ns, corresponding to a diode-to-yellow laser conversion efficiency of 5.75% and a slope efficiency of 7.6%. Meanwhile, a single pulse's pulse energy and peak power were 57 µJ and 19 kW, respectively. The severe thermal effects of the self-Raman structure were overcome in the V-shaped cavity, which has excellent mode matching, and combined with the self-cleaning effect of `Raman scattering, the beam quality factor M 2 was effectively improved, which was measured optimally to be M x 2  = 1.207, and M y 2  = 1.200, with the incident pump power being 49.2 W.

We demonstrate an efficient wavelength-selectable output in the attractive deep-red spectral region from an intracavity frequency converted Nd:YLF/KGW Raman laser. Driven by an acousto-optic Q-switched 1314 nm Nd:YLF laser, two first-Stokes waves at 1461 and 1490 nm were generated owing to the bi-axial properties of KGW crystal. By incorporating intracavity sum-frequency generation and second-harmonic generation with an angle-tuned bismuth borate (BIBO) crystal, four discrete deep-red laser emission lines were yielded at the wavelengths of 692, 698, 731, and 745 nm. Under the incident pump power of 50 W and the repetition rate of 4 kHz, the maximum average output powers of 2.4, 2.7, 3.3, and 3.6 W were attained with the pulse durations of 3.4, 3.2, 4.3, and 3.7 ns, respectively, corresponding to the peak powers up to 177, 209, 190, and 245 kW. The results indicate that the Nd:YLF/KGW Raman laser combined with an angle-adjusted BIBO crystal provides a reliable and convenient approach to achieve the selectable multi-wavelength deep-red laser with short pulse duration and high peak power.

Recent evidence suggests that innate and adaptive immunity play a crucial role in Parkinson's disease (PD). However, studies regarding specific immune cell classification in the peripheral blood in PD remain lacking. Therefore, we aimed to explore the different immune status in patients with PD at different ages of onset. We included 22 patients; among them were 10 who had early-onset PD (EOPD) and 12 had late-onset PD (LOPD) and 10 young healthy controls (YHCs) and 8 elder HCs (EHCs). Mass cytometry staining technology was used to perform accurate immunotyping of cell populations in the peripheral blood. Motor symptoms and cognitive function were assessed using the Unified Parkinson's Disease Rating Scale (UPDRS) III score and Mini-mental State Examination (MMSE) score, respectively. T test and ANOVA statistical analysis were performed on the frequency of annotated cell population. Linear regression model was used to analyze the correlation between clusters and clinical symptoms. We characterized 60 cell clusters and discovered that the immune signature of PD consists of cluster changes, including decreased effector CD8 + T cells, lower cytotoxicity natural killer (NK) cells and increased activated monocytes in PD patients. In summary, we found that CD8 + T cells, NK cells, and monocytes were associated with PD. Furthermore, there may be some differences in the immune status of patients with EOPD and LOPD, suggesting differences in the pathogenesis between these groups., (© 2022. The Author(s).)

We demonstrated an eye-safe diamond Raman laser intra-cavity pumped by the 1.3 μm fundamental field for the first time, to the best of our knowledge. The first-Stokes laser at 1634 nm was converted from the 1342 nm fundamental laser, which was produced by an in-band pumped double-end diffusion-bonded a-cut Nd:YVO 4 crystal. Under an incident pump power of 21.2 W and an optimal pulse repetition frequency of 25 kHz, the maximum average output power of 2.0 W was obtained with the pulse duration of 5.7 ns and the peak power of 14 kW. The first-Stokes emission was found to be near diffraction limited (M 2 ≈ 1.3) and to have a narrow linewidth (∼0.05 nm FWHM; instrument limited).

Perivascular spaces in the brain have been known to communicate with cerebrospinal fluid and contribute to waste clearance in animal models. In this study, we sought to determine the association between MRI-visible enlarged perivascular spaces (EPVS) and disease markers in Parkinson's disease (PD). We obtained longitudinal data from 245 patients with PD and 98 healthy controls from the Parkinson's Progression Marker Initiative. Two trained neurologists performed visual ratings on T2-weighted images to characterize EPVS in the centrum semiovale (CSO), the basal ganglia (BG) and the midbrain. We found that a greater proportion of patients with PD had low grade BG-EPVS relative to healthy controls. In patients with PD, lower grade of BG-EPVS and CSO-EPVS predicted lower CSF α-synuclein and t-tau. Lower grade of BG-EPVS were also associated with accelerated Hoehn &Yahr stage progression in patients with baseline stage 1. BG-EPVS might be a valuable predictor of disease progression.

We demonstrated a narrowband eye-safe intracavity Raman laser by incorporating a fused silica etalon into the fundamental resonator. The KGd(WO 4 ) 2 (KGW) Raman laser was pumped by an actively Q-switched Nd:YLF laser at 1314 nm. Thanks to the KGW bi-axial properties, two distinct eye-safe Raman lasers operating at 1461 and 1490 nm were obtained separately by rotation of the KGW crystal. At an optimized pulse repetition frequency of 4 kHz, the maximum average output powers of 3.6 and 4.0 W were achieved with the peak powers up to approximately 330 and 480 kW, respectively. The eye-safe Stokes emissions were narrow linewidth (∼0.05 nm FWHM; measurement limited) and near diffraction limited (M 2  < 1.4). The powerful narrowband eye-safe Raman lasers are of interest for applications as diverse as laser range finding, scanning lidar and remote sensing.

An actively Q-switched eye-safe orthogonally-polarized dual-wavelength intracavity Raman laser was demonstrated for the first time, to the best of our knowledge. The gain balanced dual-wavelength operation at 1314 and 1321 nm within an in-band pumped Nd:YLF laser was realized by slightly titling the cavity mirrors. Owing to the KGW bi-axial properties, two sets of simultaneous orthogonally-polarized dual-wavelength Raman lasers at 1470, 1490 nm and 1461, 1499 nm were achieved by simply rotating the KGW crystal for 90°, respectively. With an incident pump power of 30 W and an optimized pulse repetition frequency of 5 kHz, the maximum dual-wavelength Raman output powers of 2.6 and 2.4 W were obtained with the pulse widths of 5.8 and 6.3 ns, respectively, corresponding to the peak powers up to 89.7 and 76.5 kW.

Differentiation of human fibroblasts into functional neurons depends on the introduction of viral-mediated transcription factors, which present risks of viral gene integration and tumorigenicity. In recent years, although some studies have been successful in directly inducing neurons through sustained expression of small molecule compounds, they have only been shown to be effective on mouse-derived cells. Thus, herein we delivered vectors containing Epstein-Barr virus-derived oriP/Epstein-Barr nuclear antigen 1 encoding the neuronal transcription factor, Ascl1, the neuron-specific microRNA, miR124, and a small hairpin directed against p53, into human fibroblasts. Cells were incubated in a neuron-inducing culture medium. Immunofluorescence staining was used to detect Tuj-1, microtubule-associated protein 2, neuron-specific nucleoprotein NeuN and nerve cell adhesion molecules in the induced cells. The proportion of Tuj1-positive cells was up to 36.7% after induction for 11 days. From day 21, these induced neurons showed neuron-specific expression patterns of microtubule-associated protein 2, NeuN and neural cell adhesion molecule. Our approach is a simple, plasmid-based process that enables direct reprogramming of human fibroblasts into neurons, and provides alternative avenues for disease modeling and neurodegenerative medicine., Competing Interests: None

Objective: Annexin A1 (ANXA1), a calcium-dependent phospholipid binding protein, is known to be regulated by microRNA-196a (miR-196a) in esophageal adenocarcinoma, and its high expression in tumor tissue is correlated with the poor prognosis of esophageal squamous cell carcinoma (ESCC). However, the role of ANXA1 in the serum of patients with ESCC remains unclear., Materials and Methods: In this study, we used enzyme-linked immunosorbent assay to evaluate the levels of ANXA1 and real-time polymerase chain reaction to detect the expression of miR-196a in the serum of ESCC patients (healthy donors as controls) and evaluated the relationship between ANXA1 and clinical outcomes., Results: The results showed that the level of serum ANXA1 in ESCC patients was significantly lower than that in controls (P = 0.001) but increased after chemoradiotherapy (P = 0.001). There was no correlation between the baseline level of serum ANXA1 and the short-term efficacy of treatment (P = 0.26) as well as the 1-year progression-free survival (PFS) (P = 0.094). However, there existed a significant correlation between the increases of serum ANXA1 expression and the 1-year PFS (P = 0.04). A higher increase (>2-fold of baseline) in the serum ANXA1 levels was correlated with a poorer PFS (hazard ratio = 3.096, 95% confidence interval 1.239-7.861). There was an inverse correlation between the expressions of miR-196a and ANXA1 in serum (Pearson's correlation of -0.54, P = 0.021)., Conclusion: Our data revealed that the expression of serum ANXA1 in ESCC patients increases after chemoradiotherapy and the increased fold change in serum ANXA1 confers independent negative prognostic impact in ESCC. The higher the increase in serum ANXA1 levels, the poorer the outcome., Competing Interests: There are no conflicts of interest

A picosecond (ps) mid-infrared (MIR) optical parametric amplifier (OPA) with LiInSe 2 crystal was demonstrated for the first time. The MIR OPA was pumped by a 30 ps 1064 nm Nd:YAG laser and injected by a barium boron oxide (BBO)-based widely tunable near-infrared seed. A maximum idler pulse energy of 433 μJ at 4 μm has been obtained under a pump energy of 17 mJ, and the corresponding pulse duration was estimated to be ~13 ps. To our knowledge, this is the highest single pulse energy generated by LiInSe 2 crystal. Furthermore, an idler spectrum tuning from 3.6 to 4.8 μm was investigated at fixed pump energy of 15 mJ.

The aim of the present study was to investigate the radiosensitization effect of triciribine (TCN) on human esophageal squamous cell carcinoma (ESCC) in normoxia or hypoxia and its mechanism. The cytotoxicity and radiosensitization mechanism of TCN were investigated by Cell Counting Kit 8, clonogenic assay, flow cytometry, western blotting (WB) and immunofluorescence staining of phospho-histone H2A.X, Ser139 (γ-H2AX) in ESCC in vitro , while the protein expression levels of AKT, phosphorylated (p)-AKT, hypoxia-inducible factor (HIF)-1α and vascular endothelial growth factor (VEGF) were evaluated by WB in vivo . The cytotoxicity of TCN was dose dependent. Upon exposure to TCN, ESCC cells in hypoxia treated with 4-Gy radiotherapy exhibited an evidently higher apoptotic rate than cells subjected to other treatments. TCN could significantly inhibit the protein expression of p-AKT, HIF-1α and VEGF in vitro and in vivo . The present results suggested that TCN can effectively inhibit AKT, p-AKT, HIF-1α and VEGF, thus conferring radiosensitivity to ESCC in vitro and vivo . TCN is considered as an adjuvant in radiotherapy of ESCC in clinical application.

The S385Y/D469T/R520Q variant of E. coli transketolase was evolved previously with three successive smart libraries, each guided by different structural, bioinformatical or computational methods. Substrate-walking progressively shifted the target acceptor substrate from phosphorylated aldehydes, towards a non-phosphorylated polar aldehyde, a non-polar aliphatic aldehyde, and finally a non-polar aromatic aldehyde. Kinetic evaluations on three benzaldehyde derivatives, suggested that their active-site binding was differentially sensitive to the S385Y mutation. Docking into mutants generated in silico from the wild-type crystal structure was not wholly satisfactory, as errors accumulated with successive mutations, and hampered further smart-library designs. Here we report the crystal structure of the S385Y/D469T/R520Q variant, and molecular docking of three substrates. This now supports our original hypothesis that directed-evolution had generated an evolutionary intermediate with divergent binding modes for the three aromatic aldehydes tested. The new active site contained two binding pockets supporting π-π stacking interactions, sterically separated by the D469T mutation. While 3-formylbenzoic acid (3-FBA) preferred one pocket, and 4-FBA the other, the less well-accepted substrate 3-hydroxybenzaldehyde (3-HBA) was caught in limbo with equal preference for the two pockets. This work highlights the value of obtaining crystal structures of evolved enzyme variants, for continued and reliable use of smart library strategies.

IGF-I CA repeat polymorphisms, especially the allele containing CA19 repeats, have been reported to be associated with the risk for various types of cancers. However, the results still remain controversial and ambiguous. This meta-analysis was performed to evaluate the association between IGF-I CA19 repeat polymorphisms and the risk of cancer. Total 18 studies with IGF-I CA19 repeat genotyping on 9,873 patients and 15,607 controls were analyzed. We used random-effects model with a pooled OR of 0.69 (95% CI = 0.60-0.79) for the recessive genetic model, 0.97 (95% CI = 0.86-1.10) for the dominant genetic model, 0.99 (95% CI = 0.86-1.14) for the homozygote comparison and 1.06 (95% CI = 0.91-1.23) for the heterozygote comparison. In the subgroup analysis of recessive model, OR (95% CI) was 0.65 (0.52-0.80) in breast cancer, 0.68 (0.53-0.86) in prostate cancer, and 0.71 (0.52-0.96) in Caucasian. In conclusion, IGF-1 CA19 repeat polymorphisms are unlikely to be a major determinant of susceptibility to cancer. However, the subgroup analysis of recessive model indicates that IGF-I CA19 repeat polymorphisms may reduce the risk of certain types of cancer or in a specific population.

An efficient all-solid-state picosecond (ps) ultraviolet (UV) laser at 335 nm was demonstrated based on frequency quadrupling of a mode-locked 1342 nm MOPA system. An output power of 0.95 W was obtained under a fundamental wave power of 16.38 W, corresponding to a conversion efficiency of 5.8% from infrared to UV. The repetition rate and pulse duration were 77 MHz and 20.2 ps, respectively. The beam quality factor M(2) was measured to be 1.56. This is, to the best of our knowledge, the highest output power at 335 nm.

Background: There is no reliable method to monitor renal blood flow intraoperatively. In this study, we evaluated the feasibility and reproducibility of left renal blood flow measurements using transesophageal echocardiography during cardiac surgery., Methods: In this prospective noninterventional study, left renal blood flow was measured with transesophageal echocardiography during three time points (pre-, intra-, and postcardiopulmonary bypass) in 60 patients undergoing cardiac surgery. Sonograms from 6 subjects were interpreted by 2 blinded independent assessors at the time of acquisition and 6 mo later. Interobserver and intraobserver reproducibility were quantified by calculating variability and intraclass correlation coefficients., Results: Patients with Doppler angles of >30 degrees (20 of 60 subjects) were eliminated from renal blood flow measurements. Left renal blood flow was successfully measured and analyzed in 36 of 60 (60%) subjects. Both interobserver and intraobserver variability were <10%. Interobserver and intraobserver reproducibility in left renal blood flow measurements were good to excellent (intraclass correlation coefficients 0.604-0.999). Left renal arterial luminal diameter for the pre, intra, and postcardiopulmonary bypass phases, ranged from 3.8 to 4.1 mm, renal arterial velocity from 25 to 35 cm/s, and left renal blood flow from 192 to 299 mL/min., Conclusion: In patients undergoing cardiac surgery, it was feasible in 60% of the subjects to measure left renal blood flow using intraoperative transesophageal echocardiography. The interobserver and intraobserver reproducibility of renal blood flow measurements was good to excellent.