Causal oscillations in the visual thalamo-cortical network in sustained attention in ferrets.

Sustained visual attention allows us to process and react to unpredictable, behaviorally relevant sensory input. Sustained attention engages communication between the higher-order visual thalamus and its connected cortical regions. However, it remains unclear whether there is a causal relationship between oscillatory circuit dynamics and attentional behavior in these thalamo-cortical circuits. By using rhythmic optogenetic stimulation in the ferret, we provide causal evidence that higher-order visual thalamus coordinates thalamo-cortical and cortico-cortical functional connectivity during sustained attention via spike-field phase locking. Increasing theta but not alpha power in the thalamus improved accuracy and reduced omission rates in a sustained attention task. Further, the enhancement of effective connectivity by stimulation was correlated with improved behavioral performance. Our work demonstrates a potential circuit-level causal mechanism for how the higher-order visual thalamus modulates cortical communication through rhythmic synchronization during sustained attention.

[Analysis of clinical presentation and genetic characteristics of malignant infantile osteopetrosis].

Objective: To investigate the clinical presentation and genetic characteristics of malignant infantile osteopetrosis. Methods: This was a retrospective case study. Thirty-seven children with malignant infantile osteopetrosis admitted into Beijing Children's Hospital from January 2013 to September 2022 were enrolled in this study. According to the gene mutations, the patients were divided into the CLCN7 group and the TCIRG1 group. Clinical characteristics, laboratory tests, and prognosis were compared between two groups. Wilcoxon test or Fisher exact test were used in inter-group comparison. The survival rate was estimated with the Kaplan-Meier method and the Log-Rank test was used to compare the difference in survival between groups. Results: Among the 37 cases, there were 22 males and 15 females. The age of diagnosis was 0.5 (0.2, 1.0) year. There were 13 patients (35%) and 24 patients (65%) with mutations in CLCN7 and TCIRGI gene respectively. Patients in the CLCN7 group had an older age of diagnosis than those in the TCIRGI group (1.2 (0.4, 3.6) vs. 0.4 (0.2, 0.6) years, Z=-2.60, P=0.008). The levels of serum phosphorus (1.7 (1.3, 1.8) vs. 1.1 (0.8, 1.6) mmol/L, Z=-2.59, P=0.010), creatine kinase isoenzyme (CK-MB) (457 (143, 610) vs. 56 (37, 82) U/L, Z=-3.38, P=0.001) and the level of neutrophils (14.0 (9.9, 18.1) vs. 9.2 (6.7, 11.1) ×109/L, Z=-2.07, P=0.039) at diagnosis were higher in the CLCN7 group than that in the TCIRG1 group. However, the level of D-dimer in the CLCN7 group was lower than that in the TCIRGI group (2.7 (1.0, 3.1) vs. 6.3 (2.5, 9.7) µg/L, Z=2.83, P=0.005). After hematopoietic stem cell transplantation, there was no significant difference in 5-year overall survival rate between the two groups (92.3%±7.4% vs. 83.3%±7.6%, χ²=0.56, P=0.456). Conclusions: TCIRGI gene mutations are more common in children with osteopetrosis. Children with TCIRGI gene mutations have younger age, lower levels of phosphorus, CK-MB, and neutrophils and higher level of D-dimer at the onset. After hematopoietic stem cell transplantation, patients with CLCN7 or TCIRGI gene mutations have similar prognosis.

Health-Related Quality of Life Following Simultaneous Resection for Synchronous Colorectal Cancer Liver Metastases.

INTRODUCTION: Up to 25% of colorectal cancer patients present with synchronous liver metastases that can be treated with two operations or a single 'simultaneous' operation. Morbidity and mortality appear similar between approaches, however changes in health-related quality-of-life following simultaneous resection are not well reported. METHODS: A prospective, feasibility trial for simultaneous resection of synchronous colorectal liver metastases was conducted. Patients completed the European Organization for Research and Treatment of Cancer QLQ-C30 and LMC21 at baseline (preoperatively), and 4 and 12 weeks postoperatively. Week 4 and 12 scores were compared with baseline using t-tests. Minimally important clinical differences were considered as a 10-point difference from baseline. RESULTS: C30 and QLQ-LMC21 were completed at baseline, 4 weeks, and 12 weeks by 39 (95%), 35 (85%) and 34 (83%) patients, and 39 (95%), 33 (80%) and 33 (80%) patients, respectively; 79% and 75% had at least one MICD according to QLQ-C30 at 4 and 12 weeks. At 4 weeks, physical functioning (mean difference (MD) - 11.9%, p = 0.002), role functioning (MD - 23.6, p = 0.007), and pain (MD + 19.7, p = 0.017) had significant worsening from baseline. At 12 weeks postoperatively, role functioning (MD - 19.7, p = 0.011) and fatigue (MD + 14.3, p = 0.03) were the only domains that remained significantly worse. By 12 weeks, pain and physical functioning had returned to baseline. There were no major demographic differences among those with and without an MICD at 12 weeks. CONCLUSIONS: Simultaneous resection of colorectal liver metastases led to clinically significant worsening fatigue and role functioning that persisted at 12 weeks post-surgery.

Exogenous detection of 13C-glucose metabolism in tumor and diet-induced obesity models.

Metabolic rewiring is a hallmark feature prevalent in cancer cells as well as insulin resistance (IR) associated with diet-induced obesity (DIO). For instance, tumor metabolism shifts towards an enhanced glycolytic state even under aerobic conditions. In contrast, DIO triggers lipid-induced IR by impairing insulin signaling and reducing insulin-stimulated glucose uptake. Based on physiological differences in systemic metabolism, we used a breath analysis approach to discriminate between different pathological states using glucose oxidation as a readout. We assessed glucose utilization in lung cancer-induced cachexia and DIO mouse models using a U-13C glucose tracer and stable isotope sensors integrated into an indirect calorimetry system. Our data showed increased 13CO2 expired by tumor-bearing (TB) mice and a reduction in exhaled 13CO2 in the DIO model. Taken together, our findings illustrate high glucose uptake and consumption in TB animals and decreased glucose uptake and oxidation in obese mice with an IR phenotype. Our work has important translational implications for the utility of stable isotopes in breath-based detection of glucose homeostasis in models of lung cancer progression and DIO.

Disruption of the circadian clock drives Apc loss of heterozygosity to accelerate colorectal cancer.

An alarming rise in young onset colorectal cancer (CRC) has been reported; however, the underlying molecular mechanism remains undefined. Suspected risk factors of young onset CRC include environmental aspects, such as lifestyle and dietary factors, which are known to affect the circadian clock. We find that both genetic disruption and environmental disruption of the circadian clock accelerate Apc-driven CRC pathogenesis in vivo. Using an intestinal organoid model, we demonstrate that clock disruption promotes transformation by driving Apc loss of heterozygosity, which hyperactivates Wnt signaling. This up-regulates c-Myc, a known Wnt target, which drives heightened glycolytic metabolism. Using patient-derived organoids, we show that circadian rhythms are lost in human tumors. Last, we identify that variance between core clock and Wnt pathway genes significantly predicts the survival of patients with CRC. Overall, our findings demonstrate a previously unidentified mechanistic link between clock disruption and CRC, which has important implications for young onset cancer prevention.

[Efficacy and safety of modified hemophagocytic lymphohistiocytosis 04 regimen in Beijing Children's Hospital].

Objective: To evaluate the efficacy and safety of Beijing Children's Hospital (BCH) modified hemophagocytic lymphohistiocytosis (HLH) 04 regimen in the treatment of childhood HLH. Methods: A retrospective cohort study was conducted. From January 2016 to December 2017, 110 children with HLH who were treated with the modified HLH-04 regimen (replacing dexamethasone with methylprednisolone during the induction period, reducing the dose and frequency of etoposide, and not using cyclosporine except for autoimmune-related HLH) at the Hematology Oncology Center of Beijing Children's Hospital were selected as the modified group, while 102 children treated with the standard HLH-04 regimen from January 2012 to December 2015 were selected as the control group. The early remission rate, survival rate and adverse reactions of two groups were compared. Rank sum test and chi square test were used for comparison between groups. Results: The age of onset in the modified group was 1.9 (1.1, 3.5) years, with 65 males and 45 females. The age of onset in the control group was 2.0 (1.2, 4.6) years, with 47 males and 55 females. No significant difference was found in age and gender between 2 groups (both P>0.05). Except for fibrinogen (1.3 (1.0, 1.7) vs. 1.1 (0.8, 1.4) g/L, Z=-2.67, P=0.008) and natural killer cell activity (13.9 (13.4, 16.3) % vs.14.9 (12.0, 16.1) %, Z=-2.34, P=0.028), there were no statistically significant differences in etiology, disease duration, first clinical presentation, or laboratory tests between 2 groups (all P>0.05). At 2 months and 3 years, there were no statistically significant differences in overall survival between 2 groups (84.5% (93/110) vs.76.5% (78/102), 78.2% (86/110) vs. 67.6% (69/102), χ2=2.28, 3.07, P=0.131, 0.080). The first 3 weeks were the most common time for bone marrow suppression in the modified group, with a lower incidence than in the control group (47.3% (52/110) vs. 62.7% (64/102), χ2=5.11, P=0.024). The modified group had a lower rate of fungal infections than the control group (3.6% (4/110) vs. 13.7% (14/102), χ2=6.93, P=0.008). Compared with the control group, fewer children in the modified group died as a result of side effects from chemotherapy (8.0% (2/25) vs.30.3% (10/33), χ2=4.31, P=0.038). Conclusion: The BCH modified HLH-04 regimen reduced the intensity of chemotherapy, with overall efficacy no worse than the standard HLH-04 regimen, and significantly reduced the rate of chemotherapy-related myelosuppression, fungal infection and mortality.

[Ruxolitinib combined with liposomal doxorubicin, etoposide, methylprednisolone+/-PEG-asparaginase in treatment of relapsed/refractory pediatric hemophagocytic lymphohistiocytosis].

Objective: To investigate the efficacy and safety of ruxolitinib, liposomal doxorubicin, etoposide, methylprednisolone+/-PEG-asparaginase (RU-DEP+/-L) in the treatment of relapsed/refractory (R/R) pediatric hemophagocytic lymphohistiocytosis (HLH). Methods: The clinical data of R/R pediatric HLH, who accepted the RU-DEP+/-L regimen at Beijing Children's Hospital from January 2018 to December 2019 was retrospectively analyzed. Results: A total of 16 patients were included in this study, including 13 males and 3 females, aged[M(Q1,Q3)] 1 (1, 2) years at diagnosis. Thirteen patients were diagnosed with Epstein-Barr virus (EBV)-HLH, 2 with EBV-induced primary HLH, and 1 with unclear etiology, among which 3 patients were co-infected with CMV. After the first-line treatment, 11 patients had no response, and 5 patients relapsed after complete response. Nine patients received the RU-L-DEP regimen, and 7 patients received the RU-DEP regimen. The overall response rate and complete response of RU-DEP+/-L treatment were 10/16 and 3/16, respectively. The negative conversion rate of plasma EBV-DNA was 7/15. The median follow-up time was 35.1 (2.4, 40.7) months, and 9/16 patients were survival. The 3-year overall survival rate after RU-DEP+/-L treatment in response and accepted hematopoietic stem cell transplantation (HSCT) was higher than that without response and did not receive HSCT (P=0.048). Among the 16 patients, 9 had varying degrees of myelosuppression, and 13 had an infection. Conclusions: RU-DEP+/-L can be used as a salvage treatment in R/R pediatric HLH, which can provide a bridge to HSCT and play an important role in the control of HLH. The main adverse reactions are myelosuppression and infection, which can be tolerated.

[Effects of clinical application of free anterolateral thigh perforator lobulated flap in repair of electrical burn wounds on head based on the concept of donor site protection].

Objective: To explore the effects of clinical application of free anterolateral thigh perforator lobulated flap in repair of electrical burn wounds on head based on the concept of donor site protection. Methods: A retrospective observational study was conducted. Eight patients with electrical burns with huge scalp defects and exposed skulls were admitted to the First Affiliated Hospital of Zhengzhou University, from May 2017 to December 2019, who were all males, aged 21-57 (39±13) years, sustaining multiple deep partial thickness to full-thickness electrical burns to 5%-14% total body surface area. Among the scalp burn sites of the patients, 1 case was posterior occipital, 2 cases were parietal occipital, 4 cases were parietal temporal, and 1 case was frontotemporal. After debridement, the defect area was 10 cm×9 cm-16 cm×14 cm. The incision area of the free anterolateral thigh perforator lobulated flap was 22 cm×6 cm-30 cm×9 cm. The artery and vein of flap were anastomosed with superficial temporal artery and vein or facial artery and vein, and the other vein of skin flap was anastomosed with superficial vein of recipient area. The donor site of skin flap was closed by layer interrupted tension-reducing suture. After the operation, the survival of flop, donor site wound healing and complications were observed. The flap appearance, wound healing of donor sites, long-term complications and functional recovery of donor sites were observed on follow-up. Results: After the operation, the flaps of 8 patients survived completely without vascular crisis. The donor sites of flaps in all the patients healed well with no osteofascial compartment syndrome. Seven patients were followed up for 3 to 12 months, and 1 case was lost to follow up. During follow-up, the flaps of the patients' heads were in good appearance but with alopecia. The donor sites showed linear scars, which were well hidden. There were no significant differences in sensory and motor functions between the two sides, and no complications were found such as muscle hernia. Conclusions: Free anterolateral thigh perforator lobulated flap has a good clinical effect in the early repair of electrical burn wounds with huge scalp defect and skull exposure on head, and the donor wounds can be directly closed and sutured, greatly reducing the damage to the donor area.

Predicting vigilance vulnerability during 1 and 2 weeks of sleep restriction with baseline performance metrics.

Study Objectives: We attempted to predict vigilance performance in adolescents during partial sleep deprivation using task summary metrics and drift diffusion modelling measures (DDM) derived from baseline vigilance performance. Methods: In the Need for Sleep studies, 57 adolescents (age = 15-19 years) underwent two baseline nights of 9-h time-in-bed (TIB), followed by two cycles of weekday sleep-restricted nights (5-h or 6.5-h TIB) and weekend recovery nights (9-h TIB). Vigilance was assessed daily with the Psychomotor Vigilance Task (PVT), with the number of lapses (response times ≥ 500 ms) as the primary outcome measure. The two DDM predictors were drift rate, which quantifies the speed of information accumulation and determines how quickly an individual derives a decision response, and non-decision time range, which indicates within-subject variation in physical, non-cognitive responding, e.g. motor actions. Results: In the first week of sleep curtailment, faster accumulation of lapses was significantly associated with more lapses at baseline (p = .02), but not the two baseline DDM metrics: drift and non-decision time range (p > .07). On the other hand, faster accumulation of lapses and greater increment in reaction time variability from the first to the second week of sleep restriction were associated with lower drift (p < .007) at baseline. Conclusions: Among adolescents, baseline PVT lapses can predict inter-individual differences in vigilance vulnerability during 1 week of sleep restriction on weekdays, while drift more consistently predicts vulnerability during more weeks of sleep curtailment. Clinical Trial Information: Effects of Napping in Sleep-Restricted Adolescents, clinicaltrials.gov, NCT02838095. The Cognitive and Metabolic Effects of Sleep Restriction in Adolescents (NFS4), clinicaltrials.gov, NCT03333512.

When Azoles Cannot Be Used: The Clinical Effectiveness of Intermittent Liposomal Amphotericin Prophylaxis in Hematology Patients.

BACKGROUND: Patients unable to take azoles are a neglected group lacking a standardized approach to antifungal prophylaxis. We evaluated the effectiveness and safety of intermittent liposomal amphotericin B (L-AMB) prophylaxis in a heterogenous group of hematology patients. METHODS: A retrospective cohort of all hematology patients who received a course of intravenous L-AMB, defined as 1 mg/kg thrice weekly from July 1, 2013 to June 30, 2018, were identified from pharmacy records. Outcomes included breakthrough-invasive fungal disease (BIFD), reasons for premature discontinuation, and acute kidney injury. RESULTS: There were 198 patients who received 273 courses of L-AMB prophylaxis. Using a conservative definition, the BIFD rate was 9.6% (n = 19 of 198) occurring either during L-AMB prophylaxis or up to 7 days from cessation in patients who received a course. Probable/proven BIFD occurred in 13 patients (6.6%, 13 of 198), including molds in 54% (n = 7) and non-albicans Candidemia in 46% (n = 6). Cumulative incidence of BIFD was highest in patients with acute myeloid leukemia (6.8%) followed by acute lymphoblastic leukemia (2.7%) and allogeneic stem cell transplantation (2.5%). The most common indication for L-AMB was chemotherapy, or anticancer drug-azole interactions (75% of courses) dominated by vincristine, or acute myeloid leukemia clinical trials, followed by gut absorption concerns (13%) and liver function abnormalities (8.8%). Acute kidney injury, using a modified international definition, complicated 27% of courses but was not clinically significant, accounting for only 3.3% (9 of 273) of discontinuations. CONCLUSIONS: Our findings demonstrate a high rate of BIFD among patients receiving L-AMB prophylaxis. Pragmatic trials will help researchers find the optimal regimen of L-AMB prophylaxis for the many clinical scenarios in which azoles are unsuitable, especially as targeted anticancer drugs increase in use.

[Association between genotype and clinical phenotype in children with primary hemophagocytic lymphohistiocytosis].

Objective: To investigate the association between genotype and clinical phenotype in children with primary hemophagocytic lymphohistiocytosis (HLH). Methods: Clinical data of 38 children with primary HLH at Beijing Children's Hospital from November 2015 to October 2020 were analyzed retrospectively. According to whether destructive mutation site, familial HLH (FHL) or non-familial HLH, degranulation pathway and non-degranulation pathway were detected in them, these patients were divided into different groups. Clinical characteristics, laboratory tests and functional tests were analyzed in different groups. Wilcoxon test or chi-square test were used for comparison between groups. Results: Among 38 cases, there were 23 males and 15 females. The age of onset was 2.5 (0.1-13.7) years. PRF1 (13/38, 34%) and UNC13D (12/38, 32%) gene mutations had the highest detectable rate. Correlation analysis between genotypes and phenotypes suggested that patients in destructive mutation sites group (n=25) had a younger age of onset than that in non-destructive mutation sites group (n=13) (1.0 (0.1-9.0) vs. 4.0 (0.4-13.4) years, Z=-2.711, P=0.005). The incidence of central nervous system involvement and convulsion was higher in patients in familial HLH group (n=26) than that in non-familial HLH group (n=12)(62% (16/26) vs. 2/12, χ²=6.631, P=0.015; 54% (14/26) vs. 2/12, χ²=4.656, P=0.040). The levels of soluble CD25, bilirubin, interferon γ (IFN-γ) and interleukin 10 (IL-10) were higher in degranulation pathway impairment group than that in the non-degranulation pathway impairment group (38 444 (2 393-44 000) vs.15 304 (1 620-36 937) ng/L,Z=2.634,P=0.008; 23.5 (6.3-126.4) vs. 6.0 (3.6-31.0) µmol/L, Z=2.992, P=0.003; 20.7 (0-248.7) vs. 11.9 (2.6-21.0) ng/L, Z=2.156, P=0.031; 20.7 (4.3-2 500.0) vs. 11.8 (4.0-88.0) ng/L, Z=2.210, P=0.027). However, the levels of neutrophils, ferritin and lactate dehydrogenase (LDH) in degranulation pathway impairment group were lower in the non-degranulation pathway impairment group (0.5 (0.1-8.0)×109 vs. 1.0 (0.9-2.3)×109/L, Z=-3.197, P=0.001; 1 133 (78-10 452) vs. 3 048 (630-37 900) µg/L, Z=-2.407, P=0.016; 410 (188-1 254) vs. 599 (389-3 147) U/L, Z=-2.489, P=0.013). Conclusions: PRF1 and UNC13D gene mutations are most common in primary HLH. Patients with destructive gene mutations have a younger age of onset. Patients with familial HLH are more likely to have central nervous system involvement and convulsions. The levels of sCD25, bilirubin, IFN-γ and IL-10 are higher in the degranulation pathway patients.

2020 SARS-CoV-2 diversification in the United States: Establishing a pre-vaccination baseline

In 2020, SARS-CoV-2 spread across the United States (U.S.) in three phases distinguished by peaks in the numbers of infections and shifting geographical distribution. We investigated the viral genetic diversity in each phase using sequences publicly available prior to December 15th, 2020, when vaccination was initiated in the U.S. In Phase 1 (winter/spring), sequences were already dominated by the D614G Spike mutation and by Phase 3 (fall), genetic diversity of the viral population had tripled and at least 54 new amino acid changes had emerged at frequencies above 5%, several of which were within known antibody epitopes. These findings highlight the need to track the evolution of SARS-CoV-2 variants in the U.S. to ensure continued efficacy of vaccines and antiviral treatments. One Sentence SummarySARS-CoV-2 genetic diversity in the U.S. increased 3-fold in 2020 and 54 emergent nonsynonymous mutations were detected.

Transcranial alternating current stimulation entrains alpha oscillations by preferential phase synchronization of fast-spiking cortical neurons to stimulation waveform.

Computational modeling and human studies suggest that transcranial alternating current stimulation (tACS) modulates alpha oscillations by entrainment. Yet, a direct examination of how tACS interacts with neuronal spiking activity that gives rise to the alpha oscillation in the thalamo-cortical system has been lacking. Here, we demonstrate how tACS entrains endogenous alpha oscillations in head-fixed awake ferrets. We first show that endogenous alpha oscillations in the posterior parietal cortex drive the primary visual cortex and the higher-order visual thalamus. Spike-field coherence is largest for the alpha frequency band, and presumed fast-spiking inhibitory interneurons exhibit strongest coupling to this oscillation. We then apply alpha-tACS that results in a field strength comparable to what is commonly used in humans (<0.5 mV/mm). Both in these ferret experiments and in a computational model of the thalamo-cortical system, tACS entrains alpha oscillations by following the theoretically predicted Arnold tongue. Intriguingly, the fast-spiking inhibitory interneurons exhibit a stronger entrainment response to tACS in both the ferret experiments and the computational model, likely due to their stronger endogenous coupling to the alpha oscillation. Our findings demonstrate the in vivo mechanism of action for the modulation of the alpha oscillation by tACS.

[Venetoclax with low-dose cytarabine for patients with untreated acute myeloid leukemia ineligible for intensive chemotherapy: results from the Chinese cohort of a phase three randomized placebo-controlled trial].

Objective: To investigate the safety and efficacy of venetoclax with low-dose cytarabine (LDAC) in Chinese patients with acute myeloid leukemia (AML) who are unable to tolerate intensive induction chemotherapy. Methods: Adults ≥ 18 years with newly diagnosed AML who were ineligible for intensive chemotherapy were enrolled in this international, randomized, double-blind, placebo-controlled trial. Globally, patients (n=211) were randomized 2∶1 to either venetoclax with LDAC or placebo with LDAC in 28-d cycles, with LDAC on days 1-10. The primary endpoint was OS; the secondary endpoints included response rates, event-free survival, and adverse events. Results: A total of 15 Chinese patients were enrolled (venetoclax arm, n=9; placebo arm, n=6) . The median age was 72 years (range, 61-86) . For the primary analysis, the venetoclax arm provided a 38% reduction in death risk compared with the placebo[hazard ratio (HR) , 0.62 (95%CI 0.12-3.07) ]. An unplanned analysis with an additional 6 months of follow-up demonstrated a median OS of 9.0 months for venetoclax compared with 4.1 months for placebo. The complete remission (CR) rates with CR with incomplete blood count recovery (CRi) were 3/9 (33%) and 0/6 (0%) , respectively. The most common non-hematologic adverse effects (venetoclax vs placebo) were hypokalemia[5/9 (56%) vs 4/6 (67%) ], vomiting[4/9 (44%) vs 3/6 (50%) ], constipation[2/9 (22%) vs 4/6 (67%) ], and hypoalbuminemia[1/9 (11%) vs 4/6 (67%) ]. Conclusion: Venetoclax with LDAC demonstrated meaningful efficacy and a manageable safety profile in Chinese patients consistent with the observations from the global VIALE-C population, making it an important treatment option for patients with newly diagnosed AML who are otherwise ineligible for intensive chemotherapy.

A Risk Score Model for Locoregional Recurrence Following Upfront Surgery for Pancreatic Adenocarcinoma: Implications for Adjuvant Therapy.

AIMS: The aims of the study were to identify predictors of locoregional failure (LRF) following surgery for pancreatic adenocarcinoma, develop a prediction risk score model of LRF and evaluate the impact of postoperative radiation therapy (PORT) on LRF. MATERIALS AND METHODS: A retrospective review was conducted on patients with stages I-III pancreatic adenocarcinoma who underwent surgery at our institution (2005-2016). Univariable and then multivariable analyses were used to evaluate clinicopathological factors associated with LRF for patients who did not receive PORT. The risk score of LRF was calculated based on the sum of coefficients of the predictors of LRF. The model was applied to the entire cohort to evaluate the impact of PORT on the high- and low-risk groups for LRF. RESULTS: In total, 467 patients were identified (median follow-up 22 months). Among patients who did not receive PORT (n = 440), predictors of LRF were pN+, involved or close ≤1 mm margin(s), moderately and poorly differentiated tumour grade and lymphovascular invasion. After adding patients who received PORT, the 2-year LRF in the high-risk group was 57% for patients who did not receive PORT (n = 242) and 32% among patients who received PORT (n = 22), with an absolute benefit to LRF of 25% (95% confidence interval 5-52%, P = 0.07). The 2-year overall survival for the high-versus the low-risk group was 36% versus 67% (P < 0.001). CONCLUSION: This risk group classification could be used to identify pancreatic adenocarcinoma patients with higher risk of LRF who may benefit from PORT. However, validation and prospective evaluation are warranted.

HCN Channel Phosphorylation Sites Mapped by Mass Spectrometry in Human Epilepsy Patients and in an Animal Model of Temporal Lobe Epilepsy.

Because hyperpolarization-activated cyclic nucleotide-gated (HCN) ion channels modulate the excitability of cortical and hippocampal principal neurons, these channels play a key role in the hyperexcitability that occurs during the development of epilepsy after a brain insult, or epileptogenesis. In epileptic rats generated by pilocarpine-induced status epilepticus, HCN channel activity is downregulated by two main mechanisms: a hyperpolarizing shift in gating and a decrease in amplitude of the current mediated by HCN channels, Ih. Because these mechanisms are modulated by various phosphorylation signaling pathways, we hypothesized that phosphorylation changes occur at individual HCN channel amino acid residues (phosphosites) during epileptogenesis. We collected CA1 hippocampal tissue from male Sprague Dawley rats made epileptic by pilocarpine-induced status epilepticus, and age-matched naïve controls. We also included resected human brain tissue containing epileptogenic zones (EZs) where seizures arise for comparison to our chronically epileptic rats. After enrichment for HCN1 and HCN2 isoforms by immunoprecipitation and trypsin in-gel digestion, the samples were analyzed by mass spectrometry. We identified numerous phosphosites from HCN1 and HCN2 channels, representing a novel survey of phosphorylation sites within HCN channels. We found high levels of HCN channel phosphosite homology between humans and rats. We also identified a novel HCN1 channel phosphosite S791, which underwent significantly increased phosphorylation during the chronic epilepsy stage. Heterologous expression of a phosphomimetic mutant, S791D, replicated a hyperpolarizing shift in Ih gating seen in neurons from chronically epileptic rats. These results show that HCN1 channel phosphorylation is altered in epilepsy and may be of pathogenic importance.

The impact of particulate matter air pollution (PM2.5) on atherosclerosis in modernizing China: a report from the CATHAY study.

BACKGROUND: Air pollution has been associated with an increase in cardiovascular diseases incidence. To evaluate whether air pollution can accelerate atherogenic processes, we assessed the effects of air pollution on important surrogate markers of atherosclerosis [brachial flow-mediated dilation (FMD) and carotid intima-media thickness (IMT)]. METHODS: A total of 1656 Han Chinese (mean age 46.0 + 11.2 years; male 47%) in Hong Kong, Macau, Pun Yu, Yu County and the 3-Gorges Territories (Yangtze River) were studied between 1996 and 2007 [Chinese Atherosclerosis in the Aged and Young Project (the CATHAY Study)]. Cardiovascular risk profiles were evaluated. Particulate matter with an aerodynamic diameter <2.5 µm (PM2.5) parameters were computed from satellite sensors. Brachial FMD and carotid IMT were measured by ultrasound. RESULTS: Health parameters [age, gender, body mass index, waist : hip ratio (WHR) and glucose)] were similar in lowest and highest PM2.5 exposure tertiles, systolic and diastolic blood pressures and triglycerides were higher (P < 0.001) and low-density cholesterol (LDL-C) was lower in the top PM2.5 tertile (P < 0.001). Brachial FMD [7.84 ± 1.77, 95% confidence interval (CI) 7.59-8.10%, vs 8.50 ± 2.52, 95% CI 8.23-8.77%, P < 0.0001) was significantly lower and carotid IMT (0.68 ± 0.13 mm, 95% CI 0.67-0.69 mm vs 0.63 mm ± 0.15 mm 95% CI 0.62-0.64 mm; P < 0.0001) was significantly thicker in the top PM2.5 tertile compared with the lowest tertile. On multiple regression, FMD was inversely related to PM2.5 (beta = 0.134, P = 0.015) independent of gender, age and blood pressure (model R2 = 0.156, F-value = 7.6, P < 0.0001). Carotid IMT was significantly correlated with PM2.5 exposure (beta = 0.381, P < 0.0001) independent of age, location, gender, WHR, blood pressure and LDL-C (model R2 = 0.408, F-value = 51.4, P-value <0.0001). CONCLUSIONS: Air pollution is strongly associated with markers of early atherosclerosis, suggesting a potential target for preventive intervention.

[Meta-analysis of the effects of triamcinolone acetonide alone and in combination with 5-fluorouracil for treating keloids].

Objective: To compare the efficacy and safety of triamcinolone acetonide (TA) alone and in combination with 5-fluorouracil (5-FU) for treating keloids using meta-analysis. Methods: Databases including PubMed, Embase, and Cochrane Library were retrieved with the search terms of " triamcinolone acetonide, 5-fluorouracil, glucocorticoid, fluorouracil, keloid, scar, TAC, 5-FU, hypertrophic scar " and databases including Chinese Journal Full-Text Database, Chinese Biomedical Database, and Wanfang Data were retrieved with the search terms of ",, 5-,," in Chinese to obtain the publicly published randomized controlled trials about the effects of TA alone and in combination with 5-fluorouracil for treating keloids from the establishment of each database to august 2019. The outcome indexes included effective proportion of treatment, incidence proportion of adverse reactions, and recurrence proportion of keloids. RevMan 5.3 and Stata 14.0 statistical software were used to conduct a meta-analysis of eligible studies. Results: A total of 1 326 patients with keloids were included in 14 studies, including 668 patients in TA+ 5-fluorouracil group whose keloids were injected with TA and 5-fluorouracil and 658 patients in TA alone group whose keloids were injected with TA alone. A total of 7 articles achieved 1 to 3 points in modified Jadad score, while 7 articles achieved 4 to 7 points in modified Jadad score. Patients in TA+ 5-fluorouracil group had a higher effective proportion of treatment than that of TA alone group (relative risk=1.28, 95% confidence interval=1.16-1.41, P<0.01). Subgroup analysis showed that the quality of the included literature and ethnic factors might be the source of heterogeneity in effective proportion of treatment. Patients in TA+ 5-fluorouracil group had a lower incidence proportion of adverse reactions than that of TA alone group (relative risk=0.44, 95% confidence interval=0.25-0.75, P<0.01). Patients in TA+ 5-fluorouracil group had a lower recurrence proportion of keloids than that of TA alone group (relative risk=0.25, 95% confidence interval=0.14-0.44, P<0.01). There was no publication bias in incidence proportion of adverse reactions (P>0.05), while the effective proportion of treatment and recurrence proportion of keloids had publication bias (P<0.05). Conclusions: TA combined with 5-fluorouracil is more effective than TA alone for treating keloids, with less incidence of adverse reactions and recurrence.