Activation and Signaling Mechanism Revealed by Cannabinoid Receptor-Gi Complex Structures.

Human endocannabinoid systems modulate multiple physiological processes mainly through the activation of cannabinoid receptors CB1 and CB2. Their high sequence similarity, low agonist selectivity, and lack of activation and G protein-coupling knowledge have hindered the development of therapeutic applications. Importantly, missing structural information has significantly held back the development of promising CB2-selective agonist drugs for treating inflammatory and neuropathic pain without the psychoactivity of CB1. Here, we report the cryoelectron microscopy structures of synthetic cannabinoid-bound CB2 and CB1 in complex with Gi, as well as agonist-bound CB2 crystal structure. Of important scientific and therapeutic benefit, our results reveal a diverse activation and signaling mechanism, the structural basis of CB2-selective agonists design, and the unexpected interaction of cholesterol with CB1, suggestive of its endogenous allosteric modulating role.

A bio-orthogonal linear ubiquitin probe identifies STAT3 as a direct substrate of OTULIN in glioblastoma.

While linear ubiquitin plays critical roles in multiple cell signaling pathways, few substrates have been identified. Global profiling of linear ubiquitin substrates represents a significant challenge because of the low endogenous level of linear ubiquitination and the background interference arising from highly abundant ubiquitin linkages (e.g. K48- and K63-) and from the non-specific attachment of interfering proteins to the linear polyubiquitin chain. We developed a bio-orthogonal linear ubiquitin probe by site-specific encoding of a norbornene amino acid on ubiquitin (NAEK-Ub). This probe facilitates covalent labeling of linear ubiquitin substrates in live cells and enables selective enrichment and identification of linear ubiquitin-modified proteins. Given the fact that the frequent overexpression of the linear linkage-specific deubiquitinase OTULIN correlates with poor prognosis in glioblastoma, we demonstrated the feasibility of the NAEK-Ub strategy by identifying and validating substrates of linear ubiquitination in patient-derived glioblastoma stem-like cells (GSCs). We identified STAT3 as a bona fide substrate of linear ubiquitin, and showed that linear ubiquitination negatively regulates STAT3 activity by recruitment of the phosphatase TC-PTP to STAT3. Furthermore, we demonstrated that preferential expression of OTULIN in GSCs restricts linear ubiquitination on STAT3 and drives persistent STAT3 signaling, and thereby maintains the stemness and self-renewal of GSCs.

Ral GTPase promotes metastasis of pancreatic ductal adenocarcinoma via elevation of TGF-ß1 production.

Pancreatic ductal adenocarcinoma (PDAC), caused by activating mutations in K-Ras, is an aggressive malignancy due to its early invasion and metastasis. Ral GTPases are activated downstream of Ras and play a crucial role in the development and progression of PDAC. However, the underlying mechanisms remain unclear. In this study, we investigated the mechanism of Ral-induced invasion and metastasis of PDAC cells using RalGAPß-deficient PDAC cells with highly activated Ral GTPases. Array analysis and ELISA revealed increased expression and secretion of TGF-ß1 in RalGAPß-deficient PDAC cells compared to control cells. Blockade of TGF-ß1 signaling suppressed RalGAPß deficiency-enhanced migration and invasion in vitro and metastasis in vivo to levels similar to controls. Phosphorylation of c-Jun N-terminal kinase, a repressor of TGF-ß1 expression, was decreased by RalGAPß deficiency. These results indicate that Ral contributes to invasion and metastasis of PDAC cells by elevating autocrine TGF-ß1 signaling at least in part by decreasing c-Jun N-terminal kinase activity.

Soluble form of immune checkpoints in autoimmune diseases.

Immune checkpoints are essential regulators of immune responses, either by activating or suppressing them. Consequently, they are regarded as pivotal elements in the management of infections, cancer, and autoimmune disorders. In recent years, researchers have identified numerous soluble immune checkpoints that are produced through various mechanisms and demonstrated biological activity. These soluble immune checkpoints can be produced and distributed in the bloodstream and various tissues, with their roles in immune response dysregulation and autoimmunity extensively documented. This review aims to provide a thorough overview of the generation of various soluble immune checkpoints, such as sPD-1, sCTLA-4, sTim-3, s4-1BB, sBTLA, sLAG-3, sCD200, and the B7 family, and their importance as indicators for the diagnosis and prediction of autoimmune conditions. Furthermore, the review will investigate the potential pathological mechanisms of soluble immune checkpoints in autoimmune diseases, emphasizing their association with autoimmune diseases development, prognosis, and treatment.

Building an HIV Learning Health Care Community for Youth in Florida: Opportunities and Challenges.

In Florida, 33% of new HIV infections among men and 21% of new infections among women are among those younger than 29 years of age. We describe the development of a Learning Health Care Community for youth (Y-LHCC) in Orange County, FL. Its core implementation team (iTeam) was composed of representatives from community agencies and academics, whose work was informed by data from the Florida Department of Health (FDOH) and regional research, in-depth interviews (IDIs) with agency representatives, and a pilot implementation of Tailored Motivational Interviewing (TMI) to improve service provision. IDIs revealed limited programming specifically for youth, significant structural challenges providing them with PrEP, and differences in use of evidence-based behavioral interventions to improve HIV services. FDOH provided data on new HIV infections, linkage to care, viral suppression, and PrEP coverage, however, limitations such as minimal data on PrEP referrals and use, agency level data, and inability to generate data quarterly (which would facilitate program improvement) were encountered. Thirty staff members from five agencies serving youth in Orange County participated in TMI training. About half the agency staff (n = 16) completed at least three of the four online training sessions. MI skills improved from pre- (n = 28; M = 1.96) to post TMI training (n = 11; M = 2.48, SD = 0.57); (t(37) = - 3.14, p = 0.0033). The iTeam held seven remote meetings and two in-person half-day meetings at the end of the study, during which they reassessed areas of focus for improving youth services. They also reiterated their commitment to continuing to meet beyond the study period and to engage other agencies in the newly established coalition. Findings highlight the potential of creating a Y-LHCC in Florida as well as some of the challenges that will need to be overcome to achieve ending the HIV Epidemic goals for young people in the region.

RESUMEN: En Florida, el 33% y 21% de las nuevas infecciones del VIH entre hombres y mujeres, respectivamente, fueron entre personas menores de 29 años de edad. Describimos el desarrollo de una Comunidad de Aprendizaje de Atención Médica para jóvenes (Y-LHCC) en el Condado de Orange, FL. Su equipo central de implementación (iTeam) estuvo compuesto de representantes de agencias comunitarias y académicos, cuyo trabajo se basó en datos del Departamento de Salud de Florida (FDOH) e investigaciones regionales, entrevistas en profundidad con representantes de agencias y un programa piloto de implementación de la Entrevista Motivacional a la Medida (TMI) para mejorar la prestación de servicios. Las entrevistas revelaron poca programación específica para los jóvenes, desafíos estructurales significativos para proporcionarles PrEP, y diferencias en el uso de intervenciones conductuales basadas en evidencia para mejorar los servicios de VIH. El FDOH proporcionó datos sobre nuevas infecciones por el VIH, vinculación con la atención médica, supresión viral y cobertura de PrEP. Sin embargo, se encontraron limitaciones en la data, tales como datos limitados sobre derivaciones u uso de PrEP, falta de datos a nivel de agencia, e incapacidad para generar datos trimestrales (lo que facilitaría la mejora de programas en la agencia). Treinta miembros del personal de cinco agencias que atienden a jóvenes en el Condado de Orange participaron en la capacitación de TMI. Aproximadamente la mitad del personal de la agencia (n = 16) completó al menos tres de las cuatro sesiones de capacitación remota. Las habilidades de MI mejoraron desde antes (n = 28; M = 1.96, SD = .042) hasta después del entrenamiento de TMI (n = 11; M = 2.48, SD = 0.57); (t(37) = − 3.14, p = 0.0033). El iTeam realizó siete reuniones remotas y dos reuniones en persona de medio día al final del estudio, durante las cuales reevaluaron las áreas de enfoque para mejorar los servicios para jóvenes. También reiteraron su compromiso de continuar reuniéndose más allá del período de estudio y de involucrar a otras agencias en la coalición recién establecida. Los hallazgos destacan el potencial de crear un Y-LHCC en Florida, así como algunos de los desafíos que deberán superarse para lograr los objetivos de terminar con la epidemia de VIH para los jóvenes de la región.

Effect of early mobilization on the development of pneumonia in patients with traumatic brain injury in the neurosurgical intensive care unit: A historical controls study.

BACKGROUND: Pneumonia has a high incidence in traumatic brain injury (TBI) patients and lacks effective treatments. Early mobilization (EM) may be a potentially effective treatment. AIM: To explore the impact of EM on TBI-related pneumonia in the neurosurgical intensive care unit (NICU). METHOD: This study was a historical control study. 100 TBI patients who received EM intervention were prospectively included as the experimental group (EM cohort), and 250 TBI patients were retrospectively included as the control group. The propensity score matching (PSM) method was employed to balance baseline and minimize potential bias. The relationship between EM and TBI-related pneumonia was investigated by univariate and multivariate logistic regression, then further determined by subgroup analysis. The influence of other variables was excluded by interaction analyses. Finally, the effect of EM on the prognosis of TBI patients was analysed by comparing the Glasgow Coma Scale (GCS) and the hospital stay. RESULTS: After screening, 86 patients were included in the EM cohort and 199 patients were included in the control cohort. There were obvious differences between the two cohorts at baseline, and these differences were eliminated after PSM, when the incidence of pneumonia was significantly lower in the EM cohort than in the control cohort (35.0% vs. 61.9%, p < .001). Multivariate logistic regression showed that EM was an independent risk factor for TBI-related pneumonia and was significantly associated with a decreased incidence of pneumonia. This correlation was present in most subgroups and was not affected by other variables (p for interaction >.05). Patients in the EM cohort had shorter length of ICU stay (6 vs. 7 days, p = .017) and higher GCS at discharge (12 vs. 11, p = .010). CONCLUSION: EM is a safe and effective treatment for TBI patients in NICU, which can reduce the incidence of pneumonia, help to improve prognosis and shorten the length of ICU stay. RELEVANCE TO CLINICAL PRACTICE: Although the utilization rate of EM is low in TBI patients for various reasons, EM is still an effective method to prevent complications. Our study confirms that a scientific and detailed EM strategy can effectively reduce the incidence of pneumonia while ensuring the safety of TBI patients, which is worthy of further research and clinical application.

All-trans retinoic acid enhances the cytotoxic effect of decitabine on myelodysplastic syndromes and acute myeloid leukaemia by activating the RARα-Nrf2 complex.

BACKGROUND: Decitabine (DAC) is used as the first-line therapy in patients with higher-risk myelodysplastic syndromes (HR-MDS) and elderly acute myeloid leukaemia (AML) patients unsuitable for intensive chemotherapy. However, the clinical outcomes of patients treated with DAC as a monotherapy are far from satisfactory. Adding all-trans retinoic acid (ATRA) to DAC reportedly benefitted MDS and elderly AML patients. However, the underlying mechanisms remain unclear and need further explorations from laboratory experiments. METHODS: We used MDS and AML cell lines and primary cells to evaluate the combined effects of DAC and ATRA as well as the underlying mechanisms. We used the MOLM-13-luciferase murine xenograft model to verify the enhanced cytotoxic effect of the drug combination. RESULTS: The combination treatment reduced the viability of MDS/AML cells in vitro, delayed leukaemia progress, and extended survival in murine xenograft models compared to non- and mono-drug treated models. DAC application as a single agent induced Nrf2 activation and downstream antioxidative response, and restrained reactive oxygen species (ROS) generation, thus leading to DAC resistance. The addition of ATRA blocked Nrf2 activation by activating the RARα-Nrf2 complex, leading to ROS accumulation and ROS-dependent cytotoxicity. CONCLUSIONS: These results demonstrate that combining DAC and ATRA has potential for the clinical treatment of HR-MDS/AML and merits further exploration.

Airflow obstruction and small airway dysfunction following pulmonary tuberculosis: a cross-sectional survey.

OBJECTIVES: Pulmonary function impairment and chronic respiratory symptoms after tuberculosis are relatively common in low-income and middle-income countries. We aimed to estimate the impact of post-tuberculosis (post-TB) on pulmonary function. METHODS: This large cross-sectional, population-based study included subjects aged 15 years or older with technically acceptable postbronchodilator spirometry measurements. Post-TB was diagnosed on the basis of radiological evidence and/or medical history. Airflow obstruction was defined as a postbronchodilator forced expiratory volume in 1 s/forced vital capacity ratio below the lower limit of normal of Global Lung Function Initiative (GLI) lung function equations. Small airway dysfunction was diagnosed if at least two of the following indicators were less than 65% of predicted: maximal mid-expiratory flow, forced expiratory flow (FEF) 50% or FEF 75%. RESULTS: In this population sample (N=8680, mean age: 40.1 years), 610 (7.0% (95% CI 6.5 to 7.6) participants were post-TB. Post-TB subjects had more frequent respiratory symptoms (46.8% vs 28.3%). Among post-TB subjects, 130 (21.3% (95% CI 18.1 to 24.8)) had airflow obstruction; OR of airflow obstruction was significantly associated with post-TB after adjustment for other confounding factors (OR 1.31, 95% CI 1.05 to 1.62). Post-TB was also associated with small airway dysfunction (OR 1.28, 95% CI1.07 to 1.53), which was present in 297 (48.9% (95% CI 33.9 to 53.0)) post-TB subjects. CONCLUSIONS: Our findings support existing knowledge that post-TB is positively associated with pulmonary function impairment and make for frequent respiratory symptoms. Post-TB should be considered as a potentially important cause of airflow obstruction and respiratory symptoms in patients originating from countries with a high burden of tuberculosis.

Combined effect of ozone and household air pollution on COPD in people aged less than 50 years old.

OBJECTIVES: Air pollution has been suggested as an important risk factor for chronic obstructive pulmonary disease (COPD); however, evidence of interactive effects on COPD between different factors was sparse, especially for young adults. We aimed to assess the combined effects of ambient ozone (O3) and household air pollution on COPD in young individuals. METHODS: We conducted a population-based study of residents aged 15-50 years in the low-income and middle-income regions of western China. We used multivariable logistic regression models to examine the associations between long-term ozone exposure and COPD in young individuals. RESULTS: A total of 6537 young cases were identified among the participants, with a COPD prevalence rate of 7.8 (95% CI 7.2% to 8.5%), and most young COPD individuals were asymptomatic. Exposure to household air pollution was associated with COPD in young patients after adjustment for other confounding factors (OR 1.82, 95% CI 1.41 to 2.37). We also found positive associations of COPD with O3 per IQR increase of 20 ppb (OR 1.92, 95% CI 1.59 to 2.32). The individual effects of household air pollution and O3 were 1.68 (95% CI 1.18 to 2.46) and 1.55 (95% CI 0.99 to 2.43), respectively, while their joint effect was 3.28 (95% CI 2.35 to 4.69) with the relative excess risk due to interaction of 1.05 (95% CI 0.33 to 1.78). CONCLUSIONS: This study concludes that exposure to ambient O3 and household air pollution might be important risk factors for COPD among young adults, and simultaneous exposure to high levels of the two pollutants may intensify their individual effects.

Photon-limited Cherenkov imaging of radiation therapy dose.

Cherenkov imaging is a unique verification tool that could provide both dosimetric and tissue functional information during radiation therapy. However, the number of interrogated Cherenkov photons in tissue is always limited and tangled with stray radiation photons, severely frustrating the measurement the signal-to-noise ratio (SNR). As such, here, a noise-robust photon-limited imaging technique is proposed by comprehensively exploiting the physical rationale of low-flux Cherenkov measurements together with the spatial correlations of the objects. Validation experiments confirmed that the Cherenkov signal could be promisingly recovered with high SNR by irradiating at as few as one x ray pulse from a linear accelerator (10 mGy dose), and the Cherenkov excited luminescence imaging depth can be extended by >100% on average, for most concentrations of phosphorescent probe. This approach demonstrates that improved applications in radiation oncology could be seen when signal amplitude, noise robustness, and temporal resolution are comprehensively considered in the image recovery process.

Patterns of brain dynamic functional connectivity are linked with attention-deficit/hyperactivity disorder-related behavioral and cognitive dimensions.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is a clinically heterogeneous neurodevelopmental disorder defined by characteristic behavioral and cognitive features. Abnormal brain dynamic functional connectivity (dFC) has been associated with the disorder. The full spectrum of ADHD-related variation of brain dynamics and its association with behavioral and cognitive features remain to be established. METHODS: We sought to identify patterns of brain dynamics linked to specific behavioral and cognitive dimensions using sparse canonical correlation analysis across a cohort of children with and without ADHD (122 children in total, 63 with ADHD). Then, using mediation analysis, we tested the hypothesis that cognitive deficits mediate the relationship between brain dynamics and ADHD-associated behaviors. RESULTS: We identified four distinct patterns of dFC, each corresponding to a specific dimension of behavioral or cognitive function (r = 0.811-0.879). Specifically, the inattention/hyperactivity dimension was positively associated with dFC within the default mode network (DMN) and negatively associated with dFC between DMN and the sensorimotor network (SMN); the somatization dimension was positively associated with dFC within DMN and SMN; the inhibition and flexibility dimension and fluency and memory dimensions were both positively associated with dFC within DMN and between DMN and SMN, and negatively associated with dFC between DMN and the fronto-parietal network. Furthermore, we observed that cognitive functions of inhibition and flexibility mediated the relationship between brain dynamics and behavioral manifestations of inattention and hyperactivity. CONCLUSIONS: These findings document the importance of distinct patterns of dynamic functional brain activity for different cardinal behavioral and cognitive features related to ADHD.

Human GLP-1 receptor transmembrane domain structure in complex with allosteric modulators.

The glucagon-like peptide-1 receptor (GLP-1R) and the glucagon receptor (GCGR) are members of the secretin-like class B family of G-protein-coupled receptors (GPCRs) and have opposing physiological roles in insulin release and glucose homeostasis. The treatment of type 2 diabetes requires positive modulation of GLP-1R to inhibit glucagon secretion and stimulate insulin secretion in a glucose-dependent manner. Here we report crystal structures of the human GLP-1R transmembrane domain in complex with two different negative allosteric modulators, PF-06372222 and NNC0640, at 2.7 and 3.0 Å resolution, respectively. The structures reveal a common binding pocket for negative allosteric modulators, present in both GLP-1R and GCGR and located outside helices V-VII near the intracellular half of the receptor. The receptor is in an inactive conformation with compounds that restrict movement of the intracellular tip of helix VI, a movement that is generally associated with activation mechanisms in class A GPCRs. Molecular modelling and mutagenesis studies indicate that agonist positive allosteric modulators target the same general region, but in a distinct sub-pocket at the interface between helices V and VI, which may facilitate the formation of an intracellular binding site that enhances G-protein coupling.

The Effectiveness of Tuina in Relieving Pain, Negative Emotions, and Disability in Knee Osteoarthritis: A Randomized Controlled Trial.

OBJECTIVE: To evaluate the effectiveness of Tuina in relieving the pain, negative emotions, and disability of patients with knee osteoarthritis (KOA). DESIGN: Single-center, parallel, randomized controlled trial. SETTING: Shanghai Guanghua Integrated Chinese and Western Medicine Hospital, Shanghai, China. SUBJECTS: Adult patients with KOA who were able to speak Chinese and self-report symptoms were eligible. METHODS: A total of 104 patients were randomly allocated to receive the 6-week treatment of Tuina (Tuina group) or celecoxib (celecoxib group). Data on pain, negative emotions, and disability were collected at baseline, at week 2, 4, and 6, and follow-up (1 month after the last treatment). The primary outcomes were the pressure pain thresholds. The secondary outcomes were: (1) numerical rating scale at rest and with movement; (2) Hamilton Anxiety Scale; (3) Hamilton Depression Scale; (4) Western Ontario and McMaster Universities Osteoarthritis Index; and (5) clinical effective rate. The adverse events of the trial were evaluated. RESULTS: In total, 99 patients completed the follow-up. Generalized linear mixed models were constructed to analyse the between-group differences. Statistically significant differences were found in the interaction effects (P < .05). In evaluating the group effect, statistical differences were found at week 6 and follow-up (P < .05). Further, all variables showed a time effect (P < .05). A statistical difference in the clinical effective rate was found between the Tuina and celecoxib groups (P < .05). CONCLUSIONS: Tuina produced superior effects for pain, negative emotions, and disability over time, as compared to celecoxib in patients with KOA.

Application of 3D Printing Navigation Template Technology in Severe Hallux Valgus Surgery.

OBJECTIVES: To explore the application of 3D printed navigation template technology in severe Hallux valgus surgery. METHODS: Forty-eight patients with severe Hallux valgus were selected. There were 24 cases in the control group underwent hallux valgus osteotomy using traditional methods and fixed with fully threaded hollow screws during the surgery. There were 24 cases in the 3D group who underwent personalized osteotomy using 3D printing navigation template technology. Patients were followed up regularly for six months after surgery. RESULTS: The surgery time of the 3D group was shorter than that of the control group, and the intraoperative bleeding was reduced (P<0.05). Compared with the preoperative data, the HVA and IMA significantly reduced immediately and 1, 3, and 6 months after surgery (P<0.05). The VAS scores decreased significantly, while the AOFAS and SF-36 scores increased (P<0.05). At three months and six months after surgery, the VAS score of the 3D group was lower than that of the control group, while the SF-36 score was higher (P<0.05). During the follow-up period, both groups had no recurrent cases or complications. CONCLUSIONS: The 3D printing navigation template technology improves patients' prognosis, functional recovery, and quality of life.

Frequencies and patterns of symptoms in Chinese adults with accommodative and binocular dysfunctions.

PURPOSE: Recent studies have found that children with convergence insufficiency experience higher frequencies of performance-related symptoms (e.g., losing concentration), but data on performance-related symptoms among adults with accommodative dysfunctions (ADs) and/or binocular dysfunctions (BDs) are lacking, which might cause misdiagnosis, diagnostic confusion, or exacerbation of attention deficits. We aimed to describe frequencies and symptom patterns in adults with ADs and/or BDs who were treated at optometric clinics and explore any correlations between visual symptoms and clinical findings. METHODS: This cross-sectional study divided 235 participants (age: 23.7 ± 2.9 years) into three groups: ADs, BDs, and normal binocular vision (NBV) groups. Convergence Insufficiency Symptom Survey (CISS), refractive examinations, and binocular tests were administered to all participants. After 1-to-1 propensity score matching, outcomes were assessed using Mann‒Whitney U test and Pearson's correlation analysis among three groups. RESULTS: In this sample, the number (frequency) of individuals with ADs and/or BDs was 117 (49.8%). ADs and BDs groups experienced significantly more performance-related symptoms (feeling sleepy, losing concentration, trouble remembering, reading slowly, losing place, and having to re-read; all P < 0.05) than the NBV group. Significant correlations were observed between performance-related symptoms and clinical findings, including accommodative amplitude (r = - 0.294), accommodative facility (r = - 0.452), near phoria (r = - 0.261), near point of convergence (r = 0.482), and positive fusional vergence (r = - 0.331) (all P < 0.001). CONCLUSION: ADs and/or BDs are commonly present in adults treated at optometric clinics, and adults diagnosed with ADs and/or BDs exhibit more performance-related symptoms than participants with NBV.

Oxycodone vs. tramadol in postoperative parent-controlled intravenous analgesia in children: a prospective, randomized, double-blinded, multiple-center clinical trial.

BACKGROUND: Management of acute postoperative pain is one of the major challenges in pediatric patients. Oral oxycodone has shown good pain relief in postoperative pain relief in children, but no studies have investigated intravenous oxycodone in this context. OBJECTIVE: whether oxycodone PCIA can provide adequate and safe postoperative pain relief, in comparison to tramadol as reference opioid drug. DESIGN: a randomized, double-blind, parallel, multi-center clinical trial. SETTING: five university medical centers and three teaching hospitals in China. PARTICIPANTS: patients aged 3-month-old to 6-year-old undergoing elective surgery under general anesthesia. INTERVENTION: patients were randomly allocated to either tramadol (n = 109) or oxycodone (n = 89) as main postoperative opioid analgesic. Tramadol or oxycodone were administered with a loading dose at the end of surgery (1 or 0.1 mg.kg-1, respectively), then with a parent-controlled intravenous device with fixed bolus doses only (0.5 or 0.05 mg.kg-1, respectively), and a 10-min lockout time. OUTCOMES: the primary outcome was adequate postoperative pain relief, defined as a face, legs, activity, cry, and consolability (FLACC) score < 4/10 in the post-anesthesia care unit (PACU), with no need for an alternative rescue analgesia. FLACC was measured 10 min after extubation then every 10 min until discharge from PACU. Analgesia was currently conducted with the boluses of either tramadol or oxycodone if FLACC was ≥ 3, up to three bolus doses, after what rescue alternative analgesia was administered. RESULTS: tramadol and oxycodone provided a similar level of adequate postoperative pain relief in PACU and in the wards. No significant differences were either noted for the raw FLACC scores, the bolus dose demand in PACU, the time between the first bolus dose and discharge from PACU, analgesic drug consumption, bolus times required in the wards, function activity score, or the parents' satisfaction. The main observed side effects in both groups were nausea and vomiting, with no difference between groups. However, patients in the oxycodone group showed less sedation levels and had a shorter stay in the PACU, compared with the tramadol group. CONCLUSIONS: an adequate postoperative analgesia can be achieved with intravenous oxycodone, this with less side effects than tramadol. It can therefore be a choice for postoperative pain relief in pediatric patients. TRIAL REGISTRATION: The study was registered at www.chictr.org.cn (Registration number: ChiCTR1800016372; date of first registration: 28/05/2018; updated date:06/01/2023).

The preoperative geriatric nutritional risk index predicts long-term prognosis in elderly locally advanced rectal cancer patients: a two-center retrospective cohort study.

BACKGROUND: The objective is to explore the value of preoperative geriatric nutritional risk index (GNRI) in evaluating long-term prognosis in elderly locally advanced rectal cancer (LARC) patients who accepted neoadjuvant chemoradiotherapy (NCRT) and to compare GNRI with established nutritional markers, including prognostic nutritional index (PNI) and controlling nutritional status (CONUT) score. METHODS: Preoperative GNRI was retrospectively assessed in 172 LARC patients aged ≥ 60 years who underwent radical resection after NCRT at two centers. Optimal cutoff value of GNRI was determined by X-tile program. The association of GNRI with clinicopathological parameters and nutritional markers was analyzed. The survival ability of markers was evaluated using time-dependent receiver-operating characteristic (ROC) curve analysis. Finally, survival analysis was performed using Kaplan-Meier and Cox regression analysis. RESULTS: GNRI was highly correlated with nutritional markers. An optimal cutoff value for the GNRI was 96. In the time-dependent ROC curve, GNRI demonstrated a stable predictive ability for both disease-free survival (DFS) and overall survival (OS). Multivariate analysis showed that GNRI was the only nutritional marker that independently predicted DFS (HR 2.457, 95% CI 1.066-5.665, P = 0.035) and OS (HR 9.002, 95% CI 3.100-26.146, P < 0.001). As an additional benefit, GNRI was able to stratify survival in subgroups of ypTNM and tumor response. CONCLUSION: Preoperative GNRI is a promising predictor of long-term survival for elderly LARC patients undergoing NCRT, superior to the established nutritional markers.

Efficacy and Safety of Acupuncture Combined with Yishen Granule in Elderly Adults with Mild Cognitive Impairment: A Multicenter, Randomized Controlled Trial.

Objective: Mild cognitive impairment (MCI) is a clinical disease that is prevalent in the elderly. Traditional Chinese herbs (TCHs) and acupuncture are valuable therapeutic options for MCI. This study aimed to assess the efficacy and safety of acupuncture and Yishen Granule (YSG) in restoring cognitive function in elderly patients with MCI. Methods: A multicenter, randomized, double-blind, parallel-group, controlled trial (8-week intervention) was conducted at two tertiary hospitals in Shanghai, China. A total of 120 participants were randomly divided into four groups (n = 30 per group): A, acupuncture with YSG; B, acupuncture with placebo herbal medicine; C, sham acupuncture with YSG; D, sham acupuncture with placebo herbal medicine. The primary outcome was a change in Montreal Cognitive Assessment (MoCA), while the secondary outcome was to evaluate improvement in the Mini-Mental State Examination (MMSE). Assessments were conducted at baseline and weeks 4 and 8. Results: Of the 120 patients (69.17 ± 6.57 years; 71 women [59.17%] and 49 men [40.83%]) included in the study, 106 (88.33%) completed the study. Two-way repeated measures ANOVA showed that the MoCA and MMSE scores in group A were significantly different from those in group D at week 4 (P < .05). At week 8, the MoCA and MMSE scores in groups A, B, and C were significantly improved compared with those in group D (P < .001 for all), and the delayed recall score in group A was significantly greater than those in groups B and C (P < .05). Acupuncture and YSG were well tolerated and safe, and no serious adverse events were reported. Conclusions: Acupuncture, YSG, and the combination of both improved cognitive function, with the combined therapy being the most effective, which can be beneficial in preventing dementia and improving the quality of life of the elderly.

Genetic Diversity, Population Structure, and Environmental Adaptation Signatures of Chinese Coastal Hard-Shell Mussel Mytilus coruscus Revealed by Whole-Genome Sequencing.

The hard-shell mussel (Mytilus coruscus) is widespread in the temperate coastal areas of the northwest Pacific and holds a significant position in the shellfish aquaculture market in China. However, the natural resources of this species have been declining, and population genetic studies of M. coruscus are also lacking. In this study, we conducted whole-genome resequencing (WGR) of M. coruscus from eight different latitudes along the Chinese coast and identified a total of 25,859,986 single nucleotide polymorphism (SNP) markers. Our findings indicated that the genetic diversity of M. coruscus from the Zhoushan region was lower compared with populations from other regions. Furthermore, we observed that the evolutionary tree clustered into two primary branches, and the Zhangzhou (ZZ) population was in a separate branch. The ZZ population was partly isolated from populations in other regions, but the distribution of branches was not geographically homogeneous, and a nested pattern emerged, consistent with the population differentiation index (FST) results. To investigate the selection characteristics, we utilized the northern M. coruscus populations (Dalian and Qingdao) and the central populations (Zhoushan and Xiangshan) as reference populations and the southern ZZ population as the target population. Our selection scan analysis identified several genes associated with thermal responses, including Hsp70 and CYP450. These genes may play important roles in the adaptation of M. coruscus to different living environments. Overall, our study provides a comprehensive understanding of the genomic diversity of coastal M. coruscus in China and is a valuable resource for future studies on genetic breeding and the evolutionary adaptation of this species.

Effects of propofol intravenous general anesthesia and inhalational anesthesia on T-lymphocyte activity after breast cancer surgery: A meta-analysis.

Background: Breast cancer is one of the most common cancers in women. General anesthesia is a commonly used anesthesia method for breast cancer surgery, and studies have confirmed that general anesthesia can induce immunosuppression in breast cancer patients and increase the metastasis rate of tumors. However, the difference between the effects of intravenous general anesthesia and inhalation anesthesia on the function of T-lymphocytes is still controversial, and it is necessary to explore reasonable anesthesia methods to reduce immunosuppression caused by surgery and anesthesia. Materials and Methods: Databases (Embase, PubMed, Cochrane Library, CBM, CNKI, and Wanfang) were searched (up to October 2022) for randomized controlled trials (RCTs) comparing intraoperative inhalation anesthesia and propofol intravenous anesthesia in breast cancer patients, with the outcome of T-lymphocyte subsets. The meta-analysis was performed by STATA 14.0. Results: Six RCTs with 352 patients were included in the study. Compared with inhalation anesthesia, there was no difference in T-lymphocyte subsets between the two groups immediately after surgery, but the activities of CD4+ T cells in patients with propofol anesthesia were higher (standard mean difference [SMD] = 0.234, 95% confidence interval [CI]: 0.003-0.466, P = 0.047, I2 = 44.1%) than those under inhalation anesthesia 1 day after surgery, and CD4+/CD8+ activities in patients with propofol anesthesia were higher (SMD = 304, 95% CI: 0.072-0.537, P = 0.010, I2 = 48.0%) than those under inhalation anesthesia 1 day after surgery. Conclusion: There were no differences in the effects of propofol and inhalation anesthetics on T-lymphocytes immediately after surgery, but the inhibitory effects of inhalation anesthetics on CD4+ and CD4+/CD8+ cells were stronger 1 day after surgery.