QL1701 (a proposed trastuzumab biosimilar) versus reference trastuzumab plus docetaxel as first-line therapy for HER2-positive metastatic breast cancer: a multicenter, randomized, double-blinded, parallel-controlled, phase III equivalence trial.

BACKGROUND: QL1701 is a proposed biosimilar to the reference trastuzumab (Herceptin®). This trial compared the efficacy and safety of QL1701 with the reference trastuzumab in first-line treatment of human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. MATERIALS AND METHODS: This randomized, double-blinded, parallel-controlled, phase III equivalence trial was conducted in 73 centers in China. Eligible patients with histologically or cytologically diagnosed HER2-positive metastatic breast cancer were randomly assigned (1 : 1) to receive either QL1701 or reference trastuzumab in combination with docetaxel (every 3 weeks) for eight cycles as the first-line treatment. Then, in patients with objective responses or stable disease, the QL1701 or reference trastuzumab with or without docetaxel was maintained for totally up to 12 months if tolerated. The primary endpoint was 24-week objective response rate (ORR) assessed by an independent review committee (IRC). The equivalence margin was 0.80-1.25 with a 90% confidence interval (CI) for the ORR ratio (QL1701 to reference trastuzumab). RESULTS: Between 29 April 2020 and 15 March 2022, 474 patients were randomized, and 473 received either QL1701 (n = 236) or reference trastuzumab (n = 237). The risk ratio for 24-week ORR was 1.07 (90% CI 0.94-1.21). The 90% CI fell within the pre-specified equivalence margin of 0.80-1.25. The 24-week ORR assessed by IRC was 59.7% (95% CI 53.2% to 66.1%) versus 56.1% (95% CI 49.5% to 62.5%) in QL1701 and the reference trastuzumab, respectively. As of 12 April 2023, there were no notable differences in progression-free survival (median: 8.3 versus 8.4 months) and overall survival (1-year rate: 95.1% versus 93.3%) between the two groups. Safety, pharmacokinetic (PK), and immunogenicity profiles were similar between the two groups. CONCLUSION: QL1701 demonstrated equivalent efficacy and similar safety to the reference trastuzumab when combined with docetaxel in the first-line treatment of patients with HER2-positive metastatic breast cancer, with similar PK and immunogenicity profiles.

[The reconstruction techniques and mid-term clinical outcomes of hip revision for acetabular bone defect after total hip arthroplasty].

Objective: To analyze three reconstruction techniques and mid-term clinical outcomes of hip revision for acetabular bone defect after total hip arthroplasty (THA). Methods: This is a retrospective case series study. Included in the study were 109 patients (109 hips) with acetabular bone defect after THA reconstructions in hip revisions from January 2015 to December 2021 in the Senior Department of Orthopaedics, the Forth Medical Center of Chinese People's Liberation Army General Hospital and the Department of Orthopaedics, the First Medical Center of Chinese People's Liberation Army General Hospital. According to the preoperative simulated surgeries and different bone defect reconstruction techniques, patients were divided into a normal cup group, an augment group or a triflange group,respectively. There were 54 patients (54 hips) in the normal cup group, reconstructed with the uncemented porous metal cup (including Jumbo cup), with 23 males and 31 females, aged (59.6±9.9) years (range:32 to 76 years); 44 patients (44 hips) in the augment group, reconstructed with the individualized three-dimensional (3D) printed porous metal augment and uncemented porous metal cup, with 18 males and 26 females, aged (52.8±13.6) years(range:17 to 76 years); 11 patients (11 hips) in the triflange group, reconstructed by the individualized 3D printed porous metal triflange cup, with 5 males and 6 females, aged (59.4±11.2) years (range: 43 to 78 years). Radiographic results, including rotation center height, rotation center offset, and leg length discrepancy (LLD) and clinical results, including Harris hip score (HHS) and visual analogue scale(VAS) were evaluated outpatient at 3, 6, 12 months after the operation and annually thereafter. The last follow-up was completed in March 2024, and all parameters at the last follow-up and before the operation were compared. Paired sample t test and repeated measurement ANOVA were used for the radiographic and clinical parameters before and after the operation. Results: All hip revisions for patients with acetabular bone defect after THA were completed and followed for more than two years. The follow-up time of the normal cup group was (6.5±1.7) years (range: 2.8 to 9.3 years), and that of the augment group was (6.0±1.3) years (range: 3.5 to 9.0 years). The follow-up time of the triflange group was (2.8±0.6) years (range: 2.0 to 3.8 years). At the last follow-up, the rotation center height, rotation center offset and LLD of 54 hips in the normal cup group were (24.2±5.6) mm, (29.1±5.5) mm and (4.6±3.3) mm, respectively, and the rotation center height and LLD were significantly lower than those of the preoperative hips (t=9.671, P<0.01; t=6.073, P<0.01). In the augment group, the rotational center height, the rotation center offset and the LLD of 44 hips were (22.4±9.0) mm, (25.4±5.5) mm and (6.0±4.0) mm, respectively, which were significantly lower than those of the preoperative hips (t=9.071, P<0.01; t=11.345, P<0.01; t=4.927, P<0.01). In the triflange group, the rotational center height, the rotation center offset and LLD of 11 hips were (22.7±6.0) mm,(30.9±8.0) mm and (5.3±2.2) mm, respectively, and the rotation center height and LLD were significantly lower than those of the preoperative hips (t=2.716, P=0.022; t=6.226, P<0.01). At the last follow-up, fractures occurred in 3 patients and dislocation occurred in 1 patient in the normal cup group, and fracture reduction and closed reduction were administered under anesthesia, respectively. In the augment group, dislocation occurred in 1 patient and open reduction under anesthesia was performed. The HHS and VAS of the three groups improved significantly after surgery and the differences were statistically significant (all P<0.01). There was no complication in the triflange group. The X-ray at the last follow-up showed that all prostheses and augments were in stable positions and no loosening or migration was observed. Conclusions: For patients with acetabular bone defect after THA undergoing hip revisions, preoperative surgical simulation and rehearsal could help surgeons choose convenient and efficient reconstruction techniques. The targeted selection of Jumbo cup, individualized 3D printed metal augment, and customized triflange cup could achieve satisfactory clinical outcomes.

[Prevalence and intervention effect of arteriovenous graft stenosis].

Objective: To evaluate the prevalence, intervention methods and effect of arteriovenous graft (AVG) stenosis. Methods: The clinical data of patients who received AVG in the Blood Purification Center, the First Affiliated Hospital of Zhengzhou University from January 2018 to December 2022 were retrospectively analyzed. The patency rate, prevalence and intervention effect of AVG stenosis were analyzed. Results: A total of 475 patients aged (55.5±11.8) years were included, and there were 193 male cases (40.6%) and 282 female cases (59.4%). The patients were followed up for [M (Q1, Q3)] 19 (12, 30) months, and the primary, assisted primary and secondary patency were 14 (5, 27), 27 (13, 55), and 59 (33, 65) months, respectively. There were 799 access events which needed intervention, with a total standardized intervention rate of 0.90 per patient-year. Totally, 431(53.9%, 431/799) stenosis events occurred in 207 AVG. Among 422 AVG stenosis events with complete clinical data, 57.8% (244/422) were multi-site stenosis and 42.2% (178/422) were single-site stenosis. The most common sites of stenosis were graft-vein anastomosis (47.6%, 340/715), venous outflows (22.7%, 162/715), and puncture zone (20.0%, 143/715). In the 414 stenosis with intact follow-up data, 90.8% (376/414) were treated by balloon angioplasty, 8.5% (35/414) received covered stent insertion, and 0.7% (3/414) were intervened by open surgery. Clinical success rate was 98.1% (406/414). The primary patency time after endovascular treatment was 6 (4, 12) months. Covered stent significantly increased post-intervention primary patency time compared withballoon angioplasty [6 (3, 7) months vs 3 (1, 4) months, P=0.020]. Conclusions: Stenosis is the most common complication of AVG, and the most common sites are graft-vein anastomosis, venous outflows, and puncture zone. Intervention of AVG stenosis has a high clinical success rate, and a relatively low post-intervention patency. Covered stent insertion improves the post-intervention patency of AVG, which has a poor effect using balloon expansion.

[Study on the mechanism of early pancreatic exocrine function changes in severely scalded rats].

Objective: To explore the mechanism of early pancreatic exocrine function changes in severely scalded rats. Methods: The experimental research methods was used. Eighty male Sprague-Dawley rats aged 7-8 weeks were divided into simple sham injury group (n=8), sham injury+cholecystokinin octapeptide (CCK8) group (n=8), severe scald+CCK8 group (n=32), and extremely severe scald+CCK8 group (n=32) by the random number table, which were treated accordingly. Immediately after injury of rats in the 2 sham injury groups and 1, 2, 3, and 7 days after injury of rats in the 2 scald groups, the improved methods including pancreatic duct puncture and catheterization were used to dynamically collect the pancreatic-bile juice (PBJ) of rats. The PBJ secretory volume within 1 h was recorded, and the content of pancreatic lipase, α-amylase, and trypsin in PBJ was detected by enzyme-linked immunosorbent assay (ELISA), and the number of samples was 8. The femoral venous blood was collected, and the concentrations of pancreatic lipase and α-amylase in serum were detected by standard colorimetry to reflect their activity (n=8). The pancreatic tissue was extracted, and the levels of interleukin-1ß (IL-1ß) and IL-6 in pancreatic tissue were detected by ELISA (n=8), the expression of hypoxia-inducible factor 1α (HIF-1α) in pancreatic tissue was detected by immunofluorescence method, and the histopathological changes in pancreatic tissue were observed by hematoxylin-eosin staining, the severity of pancreatic tissue injury in the 2 scald groups was evaluated by modified Schmidt method (n=6), and the ultrastructure of acinar cells in pancreatic tissue was observed by transmission electron microscopy. Data were statistically analyzed with analysis of variance for factorial design, Tukey test, independent sample t test, and least significant difference test. Results: Compared with the PBJ secretory volume (0.740±0.030) mL in the pancreatic tissue of rats in simple sham injury group within 1 h immediately after injury, the (0.823±0.033) mL in sham injury+CCK8 group was significantly increased (t=4.92, P<0.05). Compared with that of rats in sham injury+CCK8 group immediately after injury, the PBJ secretory volume of rats within 1 h in severe scald+CCK8 group ((0.681±0.024), (0.608±0.056), (0.525±0.025), and (0.720±0.044) mL) and extremely severe scald+CCK8 group ((0.540±0.025), (0.406±0.021), (0.475±0.036), and (0.690±0.018) mL) was significantly decreased on 1, 2, 3, and 7 days after injury (P<0.05). Compared with that in severe scald+CCK8 group, the PBJ secretory volume of rats within 1 h in extremely severe scald+CCK8 group was significantly decreased on 1 and 2 days after injury (P<0.05). Compared with that of rats in simple sham injury group immediately after injury, the content of pancreatic lipase, α-amylase, and trypsin in PBJ of rats in sham injury+CCK8 group immediately after injury was significantly increased (with t values of 4.56, 3.30, and 4.99, respectively, P<0.05). Compared with that of rats in sham injury+CCK8 group immediately after injury, the content of pancreatic lipase and α-amylase in PBJ of rats in severe scald+CCK8 group and extremely severe scald+CCK8 group was significantly decreased on 1, 2, 3, and 7 days after injury (P<0.05), the trypsin content in PBJ of rats in extremely severe scald+CCK8 group was significantly decreased on 2 days after injury (P<0.05). Compared with that in severe scald+CCK8 group, the content of pancreatic lipase in PBJ of rats in extremely severe scald+CCK8 group was significantly decreased on 1, 2, and 3 days after injury (P<0.05), and the content of α-amylase and trypsin in PBJ was significantly decreased on 1 and 2 days after injury (P<0.05). There were no statistically significant differences in the activities of pancreatic lipase and α-amylase in serum of rats among the 4 groups at various time points after injury (P>0.05). Compared with that of rats in sham injury+CCK8 group immediately after injury, the levels of IL-1ß in pancreatic tissue of rats in severe scald+CCK8 group on 1, 2, and 3 days after injury and in extremely severe scald+CCK8 group on 1, 2, 3, and 7 days after injury were significantly increased (P<0.05), and the levels of IL-6 in pancreatic tissue of rats in severe scald+CCK8 group and extremely severe scald+CCK8 group were significantly increased on 1, 2, 3, and 7 days after injury (P<0.05). Compared with that in severe scald+CCK8 group, the IL-1ß level in pancreatic tissue of rats in extremely severe scald+CCK8 group was significantly increased on 2 and 3 days after injury (P<0.05), and IL-6 level in pancreatic tissue was significantly increased on 2 days after injury (P<0.05). The expression levels of HIF-1α in pancreatic tissue of rats in simple sham injury group and sham injury+CCK8 group immediately after injury were lower; and compared with that in sham injury+CCK8 group immediately after injury, the expression levels of HIF-1α in pancreatic tissue of rats in the 2 scald groups increased to a certain extent at different time points after injury, and the expression position was transited from the edge of the pancreatic tissue to the whole pancreas, the expression levels of HIF-1α in pancreatic tissue of rats in the 2 scald groups tended to be normal on 7 days after injury. Compared with that in simple sham injury group immediately after injury, the proportion of acinar cell cytoplasm in pancreatic tissue of rats in sham injury+CCK8 group was increased; and with the increase of time after injury, edema, hemorrhage, necrosis, and inflammatory infiltration appeared in pancreatic tissue of rats in the 2 scald groups. Compared with that in severe scald+CCK8 group, the scores of edema, inflammatory cell infiltration, bleeding, and necrosis in pancreatic tissue of rats in extremely severe scald+CCK8 group were increased to varying degrees at various time points after injury, and the scores of pancreatic tissue of rats in the 2 scald groups basically recovered to normal on 7 days after injury. Compared with that in simple sham injury group immediately after injury, the number of enzyme granules in acinar cells of pancreatic tissue of rats in sham injury+CCK8 group was increased, and with the increase of time after injury, the enzyme granules in acinar cells of rats in the 2 scald groups were gradually reduced basically. Conclusions: The exocrine functions of pancreas, such as synthesis and secretion of pancreatic enzymes, are decreased in the early stage in severely scalded rats. And the greater the scalded area, the more significant the decline of pancreatic exocrine function. This change may be related to hypoxic injury and inflammation in pancreatic tissue after severe scald.

[The efficacy and safety of intravenous sucrose iron therapy for recurrent iron deficiency anemia].

Objective: To evaluate the efficacy and safety of intravenous iron supplementation in patients with recurrent iron deficiency anemia (IDA) . Methods: This retrospective analysis of 90 patients with recurrent IDA from May 2012 to December 2021 was conducted, comparing the efficacy and safety of the intravenous iron therapy group and the oral iron therapy group. Results: Among the 90 patients with recurrent IDA, 20 were males and 70 were females, with a median age of 40 (range: 14-85) years. A total of 60 patients received intravenous iron supplementation and 30 received oral iron supplementation. The hematologic response rates in the intravenous iron group were significantly higher than those in the oral iron group at 4 and 8 weeks after treatment [80.0% (48/60) vs 3.3% (1/30) and 96.7% (58/60) vs 46.7% (14/30), all P<0.001, respectively]. The median increase in hemoglobin levels was also significantly higher in the intravenous iron group than in the oral iron group [38 (4, 66) g/L vs 7 (1, 22) g/L at week 4 and 44.5 (18, 80) g/L vs 19 (3, 53) g/L at week 8, all P<0.001]. The intravenous iron group had a significantly higher proportion of patients who achieved normal hemoglobin levels than the oral iron group (55.0% vs 0 and 90% vs 43.3%, all P<0.001, respectively). Iron metabolism indicators were tested before and after 8 weeks of treatment in 26 and 7 patients in the intravenous and oral iron groups, respectively. The median increase in serum ferritin (SF) levels in the intravenous iron group 8 weeks after treatment was 113.7 (49.7, 413.5) µg/L, and 54% (14/26) of these patients had SF levels of ≥100 µg/L, which was significantly higher than the median increase in SF levels in the oral iron group [14.0 (5.8, 84.2) µg/L, t=4.760, P<0.001] and the proportion of patients with SF levels of ≥100 µg/L (P=0.013). The incidence of adverse reactions was 3.3% (2/60) in the intravenous iron group, which was significantly lower than that in the oral iron group [20.0% (6/30), P=0.015]. Conclusion: Intravenous iron supplementation is more effective for hematologic response, faster hemoglobin increase, and higher iron storage replenishment rates compared with oral iron supplementation in patients with recurrent IDA, and it is well tolerated by patients.

A Variant in the IRF6 Promoter Associated with the Risk for Orofacial Clefting.

The single-nucleotide polymorphism (SNP) rs2235371 (IRF6 V274I) is associated with nonsyndromic cleft lip with or without cleft palate (NSCL/P) in Han Chinese and other populations but appears to be without a functional effect. To find the common etiologic variant or variants within the haplotype tagged by rs2235371, we carried out targeted sequencing of an interval containing IRF6 in 159 Han Chinese with NSCL/P. This study revealed that the SNP rs12403599, within the IRF6 promoter, is associated with all phenotypes of NSCL/P, especially nonsyndromic cleft lip (NSCLO) and a subphenotype of it, microform cleft lip (MCL). This association was replicated in 2 additional much larger cohorts of cases and controls from the Han Chinese. Conditional logistic analysis indicated that association of rs2235371 with NSCL/P was lost if rs12403599 was excluded. rs12403599 contributes the most risk to MCL: its G allele is responsible for 38.47% of the genetic contribution to MCL, and the odds ratios of G/C and G/G genotypes were 2.91 and 6.58, respectively, for MCL. To test if rs12403599 is functional, we carried out reporter assays in a fetal oral epithelium cells (GMSM-K). Unexpectedly, the risk allele G yielded higher promoter activity in GMSM-K. Consistent with the reporter studies, expression of IRF6 in lip tissues from NSCLO and MCL patients with the G/G phenotype was higher than in those from patients with the C/C phenotype. These results indicate that rs12403599 is tagging the risk haplotype for NSCL/P better than rs2235371 in Han Chinese and supports investigation of the mechanisms by which the allele of rs12403599 affects IRF6 expression and tests of this association in different populations.

[Establishment and application of the ten-fold rehydration formula for emergency resuscitation of pediatric patients after extensive burns].

Objective: To investigate the scientificity and feasibility of the ten-fold rehydration formula for emergency resuscitation of pediatric patients after extensive burns. Methods: A retrospective observational study was conducted. The total burn area of 30%-100% total body surface area (TBSA) and body weight of 6-50 kg in 433 pediatric patients (250 males and 183 females, aged 3 months to 14 years) with extensive burns who met the inclusion criteria and admitted to the burn departments of 72 Class A tertiary hospitals were collected. The 6 319 pairs of simulated data were constructed after pairing each body weight of 6-50 kg (programmed in steps of 0.5 kg) and each total burn area of 30%-100% TBSA (programmed in steps of 1%TBSA). They were put into three accepted pediatric rehydration formulae, namely the commonly used domestic pediatric rehydration formula for burn patients (hereinafter referred to as the domestic rehydration formula), the Galveston formula, and the Cincinnati formula, and the two rehydration formulae for pediatric emergency, namely the simplified resuscitation formula for emergency care of patients with extensive burns proposed by the World Health Organization's Technical Working Group on Burns (TWGB, hereinafter referred to as the TWGB formula) and the pediatric ten-fold rehydration formula proposed by the author of this article--rehydration rate (mL/h)=body weight (kg) × 10 (mL·kg-1·h-1) to calculate the rehydration rate within 8 h post injury (hereinafter referred to as the rehydration rate). The range of the results of the 3 accepted pediatric rehydration formulae ±20% were regarded as the reasonable rehydration rate, and the accuracy rates of rehydration rate calculated using the two pediatric emergency rehydration formulae were compared. Using the maximum burn areas (55% and 85% TBSA) corresponding to the reasonable rehydration rate calculated by the pediatric ten-fold rehydration formula at the body weight of 6 and 50 kg respectively, the total burn area of 30% to 100% TBSA was divided into 3 segments and the accuracy rates of the rehydration rate calculated using the 2 pediatric emergency rehydration formulae in each segment were compared. When neither of the rehydration rates calculated by the 2 pediatric emergency rehydration formulae was reasonable, the differences between the two rehydration rates were compared. The distribution of 433 pediatric patients in the 3 previous total burn area segments was counted and the accuracy rates of the rehydration rate calculated using the 2 pediatric emergency rehydration formulae were calculated and compared. Data were statistically analyzed with McNemar test. Results: Substitution of 6 319 pairs of simulated data showed that the accuracy rates of the rehydration rates calculated by the pediatric ten-fold rehydration formula was 73.92% (4 671/6 319), which was significantly higher than 4.02% (254/6 319) of the TWGB formula (χ2=6 490.88,P<0.05). When the total burn area was 30%-55% and 56%-85% TBSA, the accuracy rates of the rehydration rates calculated by the pediatric ten-fold rehydration formula were 100% (2 314/2 314) and 88.28% (2 357/2 670), respectively, which were significantly higher than 10.98% (254/2 314) and 0 (0/2 670) of the TWGB formula (with χ2 values of 3 712.49 and 4 227.97, respectively, P<0.05); when the total burn area was 86%-100% TBSA, the accuracy rates of the rehydration rates calculated by the pediatric ten-fold rehydration formula and the TWGB formula were 0 (0/1 335). When the rehydration rates calculated by the 2 pediatric emergency rehydration formulae were unreasonable, the rehydration rates calculated by the pediatric ten-fold rehydration formula were all higher than those of the TWGB formula. There were 93.07% (403/433), 5.77% (25/433), and 1.15% (5/433) patients in the 433 pediatric patients had total burn area of 30%-55%, 56%-85%, and 86%-100% TBSA, respectively, and the accuracy rate of the rehydration rate calculated using the pediatric ten-fold rehydration formula was 97.69% (423/433), which was significantly higher than 0 (0/433) of the TWGB formula (χ2=826.90, P<0.05). Conclusions: The application of the pediatric ten-fold rehydration formula to estimate the rehydration rate of pediatric patients after extensive burns is more accurate and convenient, superior to the TWGB formula, suitable for application by front-line healthcare workers that are not specialized in burns in pre-admission rescue of pediatric patients with extensive burns, and is worthy of promotion.

[Research advances on the role and mechanism of epidermal stem cells in skin wound repair].

Epidermal stem cells play an pivotal role in skin self-renewal, wound repair, and re-epithelialization process. The emergence of new technologies and concepts such as single-cell sequencing and gene knockout further revealed a new mechanism of epidermal stem cells in epidermal self-renewal and wound repair, providing new ideas for wound repair. In this review, the mechanisms of proliferation, differentiation, and migration of epidermal stem cells are discussed. Combined with the analysis of researches on stem cell heterogeneity and cell plasticity, the physiological function of epidermal stem cells can be further understood. The application advances of epidermal stem cells in wound repair is also summarized, which would provide some advice for workers engaged in clinical and basic research on wound repair.

[Prevalence and risk factors of deep venous thrombosis of lower extremity in patients with stage â ¢ and â £ pressure ulcers on admission].

Objective: To investigate the incidence and risk factors of deep venous thrombosis (DVT) of lower extremity in patients with stage Ⅲ and Ⅳ pressure ulcer on admission. Methods: A retrospective case series study was conducted. A total of 241 patients with stage Ⅲ and Ⅳ pressure ulcers who met the inclusion criteria and were discharged from the Department of Wound Repair of the First People's Hospital of Zhengzhou from January 1, 2015 to December 31, 2019 were enrolled in this study, including 134 males and 107 females, aged 22 to 93 years, with a median age of 68 years; 37 patients were with stage Ⅲ pressure ulcers and 204 patients were with stage Ⅳ pressure ulcers. The DVT occurrence of patients was recorded. According to whether DVT of lower extremity veins was diagnosed by color Doppler ultrasound within 48 h after admission or not, the patients were divided into DVT group (n=37) and non-DVT group (n=204). Data of patients in the two groups were collected and compared, including gender, age, duration of pressure ulcer, time in bed, and combination with diabetes, hypertension, coronary heart disease, cerebral infarction, pneumonia, sepsis/septic shock, and paraplegia, and the plasma D-dimer level and Caprini score within 24 h after admission. Data were statistically analyzed with independent sample t test, Mann-Whitney U test, chi-square test, and Fisher's exact probability test. The indicators with statistically significant differences between the two groups were analyzed with multivariate logistic regression analysis to screen the independent risk factors influencing the DVT of lower extremity in 241 patients with stage Ⅲ and Ⅳ pressure ulcers on admission. Results: The incidence of DVT of lower extremity was 15.4% (37/241), of which 86.5% (32/37) were asymptomatic DVT. Among the DVT of 46 lower limbs, only 29 involved the inferior genicular veins, accounting for 63.0%. There were no statistically significant differences in gender, duration of pressure ulcer, combination with diabetes, hypertension, coronary heart disease, cerebral infarction, pneumonia, and sepsis/septic shock of patients between the two groups (P>0.05), while there were statistically significant differences in age, time in bed, combination with paraplegia, the plasma D-dimer level and Caprini score of patients between the two groups(t=-3.19, Z=-2.04, χ2=4.44, Z=-3.89, t=-2.14, respectively, P<0.05 or P<0.01). Multivariate logistic regression analysis showed that age and plasma D-dimer level were independent risk factors influencing the DVT of lower extremity in 241 patients with stage Ⅲ and Ⅳ pressure ulcers on admission (with odds ratios of 1.03 and 1.18, respectively, with 95% confidence intervals of 1.00-1.06 and 1.05-1.33, respectively, P<0.05 or P<0.01). Conclusions: The patients with stage Ⅲ and Ⅳ pressure ulcers have a higher incidence of DVT on admission, with age and plasma D-dimer level being the independent risk factors for DVT of lower extremity. It is necessary to pay attention to the targeted screening of DVT and education of its prevention.

[Establishment and application of the tenfold rehydration formula for emergency resuscitation of adult patients after extensive burns].

Objective: To explore the scientificity and feasibility of the tenfold rehydration formula for emergency resuscitation of adult patients after extensive burns. Methods: A retrospective observational study was conducted. The total burn area (30%-100% total body surface area (TBSA)) and body weight (45-135 kg) of 170 adult patients (135 males and 35 females, aged (42±14) years) with extensive burns admitted to the Fourth Medical Center of PLA General Hospital from December 2016 to December 2019 were collected. The 6 461 pairs of simulated data obtained after pairing each body weight in 45 to 135 kg (programmed in steps of 1 kg) with each area in 30% to 100% TBSA (programmed in steps of 1%TBSA) were plugged into four recognized rehydration formulas--Parkland's formula, Brooke's formula, the 304th PLA Hospital formula, and the Third Military Medical University formula and two emergency rehydration formulas--the simplified first aid resuscitation plan for extensive burn patients proposed by the World Health Organization's Technical Working Group on Burns (TWGB, hereinafter referred to as the TWGB formula) and the tenfold rehydration formula proposed by the author of this article to calculate the rehydration rate within 8 hours after injury (hereinafter referred to as the rehydration rate), with results being displayed by a programming step of 10%TBSA for the total burn area. Taking the calculation results of four recognized rehydration formulas as the reasonable rehydration rate, the accuracy of rehydration rates calculated by two emergency rehydration formulas were calculated and compared. The body weight of 45-135 kg was divided into three segments by the results of maximum body weight at a reasonable rehydration rate calculated by the tenfold rehydration formula when the total burn area was 30% and 100% TBSA, respectively. The accuracy of rehydration rate calculated by two emergency rehydration formulas in each body weight segment was compared. When the rehydration rates calculated by two emergency rehydration formulas were unreasonable, the differences in rehydration rates between the two were compared. Statistical distribution of the aforementioned three body weight segments in the aforementioned 170 patients was counted. Using the total burn area and body weight data of the aforementioned 170 patients, the accuracy of rehydration rate calculated by two emergency rehydration formulas was calculated and compared as before. Data were statistically analyzed with McNemar test. Results: When the total burn area was 30%, 40%, 50%, 60%, 70%, 80%, 90%, and 100% TBSA, respectively, and the body weight was 45-135 kg, the rehydration rates calculated by two emergency rehydration formulas did not exceed the maximum of the calculated results of four recognized rehydration formulas; the rehydration rate calculated by the TWGB formula did not change accordingly with total burn area, while the rehydration rate calculated by the tenfold rehydration formula did not change accordingly with body weight. Substituting 6 461 pairs of simulated data showed that the accuracy of rehydration rate calculated by the tenfold rehydration formula was 43.09% (2 784/6 461), which was significantly higher than 2.07% (134/6 461) of the TWGB formula, χ2=2 404.80, P<0.01. When the body weights were 45-62 kg and 63-93 kg, the accuracy rates of rehydration rate calculated by the tenfold rehydration formula were 100% (1 278/1 278) and 68.42% (1 506/2 201), respectively, which were significantly higher than 0 (0/1 278) and 0.05% (1/2 201) of the TWGB formula, χ2=1 276.00, 1 501.01, P<0.01; when the body weight was 94-135 kg, the accuracy rate of rehydration rate calculated by the tenfold rehydration formula was 0 (0/2 982), which was significantly lower than 4.46% (133/2 982) of the TWGB formula, χ2=131.01, P<0.01. When the rehydration rates calculated by two emergency rehydration formulas were both unreasonable, the rehydration rate calculated by the tenfold rehydration formula was greater than that calculated by the TWGB formula in most cases, accounting for 79.3% (2 808/3 543). Among the 170 patients, the proportions of those weighing 45-62, 63-93, and 94-135 kg were 25.29% (43/170), 65.88% (112/170), and 8.82% (15/170), respectively. Among the 170 patients, the accuracy rate of rehydration rate calculated by the tenfold rehydration formula was 69.41% (118/170), which was significantly higher than 3.53% (6/170) of the TWGB formula, χ2=99.36, P<0.01. Conclusions: Applying the tenfold rehydration formula to calculate the emergency rehydration rate in adults after extensive burns is simpler than four recognized rehydration formulas, and is superior to the TWGB formula. The tenfold rehydration formula is suitable for the front-line medical staffs that are not specialized in burns in pre-admission rescue of adult patients with extensive burns, which is worth popularizing.

[Application of rigid curved laryngoscope in the examination of hypopharynx and the treatment of early hypopharyngeal cancer].

Objective: To evaluate the efficacy of curved suspension laryngoscope assistant transoral surgery (CLATOS) in the examination of hypopharynx, and diagnosis and surgery of early hypopharyngeal carcinoma. Methods: Thirty-four patients who underwent detailed examination for lower part of hypopharynx and surgery for early hypopharyngeal carcinoma with CLATOS technique in the Second Affiliated Hospital of Harbin Medical University from January 2019 to January 2020 were analyzed retrospectively. The age ranged from 42 to 74 years old including 28 males and 6 females. Among them, 25 patients complaining of foreign body sensation in the pharynx for more than half a year with a poor exposure of the lower pharynx in the examination with flexible laryngoscope in the outpatient department were admitted to the hospital for the further examination with rigid curved laryngoscopy and 9 patients with stage T1-2 hypopharyngeal squamous cell carcinoma were operated with CLATOS technique. Preoperative, intraoperative and postoperative data were analized. Results: One case of squamous cell carcinoma in esophageal entrance (T1N0M0) and one case of carcinoma in pyriform sinus (T1N0M0) with cervical esophageal carcinoma (T1N0M0) were found in the 25 patients with foreign body sensation in the pharynx. En bloc resection of cancer was obtained in 9 patients with stage T1-2 hypopharyngeal carcinomas and 2 of them underwent tracheotomy. One patient with T1 retrocricoid carcinoma was found to have a carcinoma in situ at the lower part of posterior hypopharyngeal wall in the examination during follow-up, which was resected simultaneously. Postoperatively this patient developed a stenosis in the esophageal entrance, which was dilated twice until swallowing normally. Two patients of T2N0M0 and one of T2N1M0 underwent bilateral neck lymph node dissection just after the removal of primary tumors. During follow-up, none of the 9 patients showed tumor recurrence and complications such as dysphonia and dyspnea. Conclusion: CLATOS technique can provide a promising way in the examination of hypopharynx and the detection of early lesions of hypopharynx and esophageal entrance, and this technique has also the advantages such as full visual angle and easy operation for the resection of early hypopharyngeal carcinoma. The quality of life of patients can be improved while the tumor is removed en bloc with this technique.

MicroRNA-206 inhibits tumor metastasis of nasopharyngeal carcinoma through targeting G6PD.

Nasopharyngeal carcinoma (NPC) is a main type of otolaryngological malignancy. In many cancers, miR-206 functions as a tumor suppressor, suppressing cell proliferation, migration and invasion. The purpose of this study was to explore how miR-206 worked on cell metastasis in NPC. The mRNA levels of miR-206 and G6PD were determined in NPC tissues and cell lines by RT-qPCR and Western blot. Transwell assay was applied to evaluate the migratory and invasive capacities. Dual luciferase reporter assay was employed to confirm that miR-206 mediated the expression of G6PD in C666-1 cells. In this study, miR- 206 was downregulated, whereas G6PD was upregulated in NPC tissues and cell lines. In addition, G6PD was identified as a direct target gene of miR-206 in C666-1 cells. The expression of G6PD was mediated by miR-206, which could partially reverse the inhibitory effects of miR-206 on the migration, invasion and EMT in C666-1 cells. In conclusion, miR-206 regulated the migratory, invasive and EMT abilities through directly targeting the 3'-UTR of G6PD mRNA in C666-1 cells. The newly identified miR-206/G6PD axis provides novel insight into the pathogenesis of nasopharyngeal carcinoma.

[Changes of insulin secretion and its signal transduction mechanism at early stage of severe scald in rats].

Objective: To observe the changes of insulin secretion in the early stage of severe scald in rats, and to explore its signal transduction mechanism. Methods: Twenty-four male Wistar rats aged 7 weeks were divided into sham injury alone (SIA) group, sham injury+ BPV (HOpic) (SIB) group, scald alone (SA) group, and scald+ BPV (HOpic) (SB) group using the random number table, with 6 rats in each group. Full-thickness scald of 50% total body surface area was inflicted in rats of SA and SB groups by a 6-s immersion of the abdomen and a 12-s immersion of the back in 94 ℃ hot water. Rats in SIA and SIB groups received sham injuries through immersion of the back and abdomen in 37 ℃ warm water for 6 and 12 seconds respectively. From 0 (immediately) to 2 day (s) after injury, the rats in groups SB and SIB were intraperitoneally injected with the phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) signaling pathway enhancer BPV (HOpic) solution (0.5 mg/mL) at the dosage of 0.6 mg/kg once a day, and the rats in groups SA and SIA were intraperitoneally injected with the same volume of dimethyl sulfoxide once a day. At post injury hour (PIH) 72, the tail blood of rats was sampled for measuring fasting blood glucose (FBG) with a glucometer, and the pancreatic tissue samples of rats was harvested for observing the pathological manifestations of islets by hematoxylin-eosin staining, counting the docked granules per 10 µm membrane of islet beta cells and calculating the proportion of insulin vesicles through the observation of the ultrastructure of islet beta cells by transmission electron microscope, and detecting the phosphorylation level of Akt in the pancreatic PI3K/Akt signaling pathway by Western blotting. Data were statistically analyzed with one-way analysis of variance and least significant difference test. Results: (1) At PIH 72, the rat FBG levels in SIA and SIB groups were normal and similar (P>0.05). Compared with the levels of those two groups, the rat FBG level in SA group was increased significantly (P<0.01), while the level in SB group showed no obvious change (P>0.05). Compared with that in SA group, the rat FBG level in SB group was decreased significantly (P<0.01). (2) At PIH 72, the morphology of rat islets was complete and the islet cells distributed regularly in SIA and SIB groups. Compared with those in SIA and SIB groups, the morphology of rat islets was incomplete, the insulin vesicles in islets were common, the islet cells distributed irregularly, and the cytoplasm of some islet beta cells was lightly stained or translucent in SA group; the morphology of islets in SB group did not change obviously. Compared with those in SA group, the morphology of islets was comparatively complete, the insulin vesicles in islets were less common, the islet cells distributed comparatively regularly, and the lightly stained or translucent cytoplasm of islet beta cells was less in SB group. (3) At PIH 72, the number of docked granules per 10 µm membrane of rat islet beta cells and the proportion of insulin vesicles in SIA and SIB groups were similar (P>0.05). Compared with those in SIA and SIB groups, the number of docked granules per 10 µm membrane of rat islet beta cells in SA group was decreased significantly (P<0.01), while the proportion of insulin vesicles was increased significantly (P<0.01); the number of docked granules per 10 µm membrane of rat islet beta cells in SB group was obviously decreased (P<0.05), while the proportion of insulin vesicles did not change obviously (P>0.05). Compared with those in SA group, the number of docked granules per 10 µm membrane of rat islet beta cells in SB group was significantly increased (P<0.01), while the proportion of insulin vesicles was significantly decreased (P<0.01). (4) At PIH 72, the phosphorylation levels of Akt in SIA, SIB, SA, and SB groups were 0.91±0.03, 0.98±0.03, 0.78±0.08, and 0.87±0.08, respectively. Compared with that in SIA group, the phosphorylation level of Akt was increased obviously in SIB group (P<0.05) but was decreased significantly in SA group (P<0.01), while the level in SB group did not change obviously (P>0.05). Compared with the level in SIB group, the phosphorylation levels of Akt in SA and SB groups were decreased significantly (P<0.01). Compared with that in SA group, the phosphorylation level of Akt in SB group was increased significantly (P<0.05). Conclusions: At the early stage post severe scald in rats, the activity of the pancreatic PI3K/Akt signaling pathway and the function of insulin secretion are reduced. Improving the activity of the pancreatic PI3K/Akt signaling pathway in rats can ameliorate the function of insulin secretion and recover the physiological level of blood glucose.

[Alternative donor HSCT for 109 children with acquired severe aplastic anemia: a single center retrospective analysis].

Objective: To investigate the efficacy of alternative donor (AD) in the treatment of aplastic anemia (AA) in children. Methods: The clinical data of AA children who received AD HSCT in our center from Apr. 2010 to Dec. 2016 were retrospectively analyzed. The overall survival (OS) rate, implant success rate, incidence of acute and chronic graft-versus-host disease (GVHD) were statistically analyzed. Results: A total of 109 children with acquired AA, including 64 severe AA (SAA) , 32 very severe AA (VSAA) and 13 transfusion dependent non-severe AA (NSAA) , were recruited in this retrospective AD HSCT study, the median age was 6 (0.8-18) years old. Of them, 44 patients with 10/10 matched unrelated donor (MUD) , 44 patients with mismatched unrelated donor (MMUD) and 21 patients with mismatched related donor (MMRD) . All patients did not receive ATG before HSCT and the active infection was excluded. Except 3 patients suffered from a second graft failure (2 of them rescued by second HSCT) , 106/109 (97.2%) were engrafted with neutrophil and platelet recovery occurring at a median of 13 days (range, 9-19) and 16 days (range, 10-81) post-transplant. Until day 100 post transplantation, the incidence was 74.3% (81/109) for acute GVHD (aGVHD) and 39.4% (43/109) for grade Ⅱ-Ⅳ aGVHD, 30.7% (31/101) and 9.9% (10/101) for overall chronic GVHD (cGVHD) and moderate cGVHD, respectively, and nobody developed an extend cGVHD. After median follow up of 39 (0.7-103) months for all patients, 13 of 109 patients died. The estimated 5-year overall survival (OS) of the entire cohort was 88.1% (95%CI 81.1%-91.4%) with no difference among the MUD, MMUD and MMRD cohort (93.2%, 84.1% and 85.7%, respectively, P=0.361) . Conclusion: These excellent outcomes suggest that unmanipulated AD PBSC is a good HSCT source for children with SAA. It's reasonable to consider AD HSCT as first line therapy for SAA children without matched sibling donor. Better strategies are required to prevent GVHD.

MiR-1-3p suppresses cell proliferation and invasion and targets STC2 in gastric cancer.

OBJECTIVE: MiR-1 has been reported to act as an inhibitory microRNA in gastric cancer (GC). This study aimed to investigate the regulatory mechanism by which miR-1-3p blocks the progression of GC by targeting stanniocalcin 2 (STC2). PATIENTS AND METHODS: The expression level of miR-1-3p in GC was assessed via quantitative Real Time-Polymerase Chain Reaction (qRT-PCR). Expressions of STC2 were measured by qRT-PCR and Western blot analysis. Proliferation and invasion assays were detected by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) and transwell assays, respectively. Moreover, the dual-luciferase reporter assay was used to confirm the binding sites between miR-1-3p and STC2. RESULTS: MiR-1-3p was significantly down-regulated in GC. Moreover, abnormal expression of miR-1-3p was correlated with GC tumor size. Functionally, overexpression of miR-1-3p inhibited proliferation and invasion in GC by inhibiting stanniocalcin 2 (STC2) expressions. In contrast, STC2 was significantly up-regulated in GC. Furthermore, miR-1-3p negatively regulated STC2 expression in GC. The upregulation of STC2 weakened the inhibitory effect of miR-1-3p in GC. CONCLUSIONS: MiR-1-3p suppressed cell proliferation and invasion by targeting STC2 in GC, providing a novel therapeutic target for GC.

[A family of tumor necrosis factor receptor-associated periodic syndrome].

Objective: To analyze the clinical manifestations and gene variations of tumor necrosis factor receptor-associated periodic syndrome (TRAPS). Methods: Clinical data and gene testing of four children and three adult relatives in a family from Puning, Guangdong were retrospectively analyzed. CD4(+)T cells, CD8(+)T cells, B cells, monocytes and NK cells were assessed by flow cytometry. Plasma level of TNFR receptors were assessed by enzyme linked immunosorbent assay (ELISA). TNFRSF1A gene variation was identified by second generation sequencing. Swiss-Model was used to analyze the potential impact of TNFRSF1A gene variation on its protein tertiary structure. Results: For all the patients,periodic fever was the main clinical feature,combined with arthralgia,myalgia,multiple serositis,periorbital edema and migratory cutaneous rash,accompanied with elevated level of acute-phase reactants and increased white blood cell counts during each episode. This disease was found in both gender and every generation in this family. The median age of onset was 2 years, ranging from 6 months to 30 years. The plasma level of TNFR1 of the patients range from 0 to 12.4 ng/L,which was lower than that of the normal controls range from 18.0~22.2 ng/L,while the level of TNFR2 was normal. Also, the numbers of T cells, B cells and monocytes were within normal range; however,number of NK cells in the patients (0.070±0.034) was lower than that in the normal controls (0.152±0.122). The TNFRSF1A variation,located in exon 3: c.295T>A (p.C99S),was found in the proband as well as the other 6 family members,which could induce change of the side chain of amino acid according to the prediction of the three-dimensional structure,subsequently affecting the binding to the receptor. Conclusions: TRAPS is characterized by periodic fever,arthralgia,myalgia,multiple serositis,periorbital edema and migratory cutaneous rash,with a significant decrease in plasma level of TNFR1 and NK cells. The gene sequencing analysis revealed a pathogenic variation in TNFRSF1A gene.

[Analysis of infants with moderate to severe laryngomalacia].

Objective:To investigate the clinical features and the treatment of moderate-severe laryngeallacia, and the application of CO2laser supraglotation in laryngeallacia.Method:Collecting the clinical data of 18 infants with moderate-to-severe laryngeallacia diagnosed in our hospital,10 cases were moderate. Eight cases were severe children; according to the classification of laryngeallacia, most of them were mixed type, including 2 cases of type Ⅱ, 3 cases of type Ⅲ, 5 cases of typeⅠ + type Ⅱ, 7 cases of typeⅡ+ type Ⅲ, and 1 case of typeⅠ+ typeⅡ + type Ⅲ. Among them, 8 patients underwent CO2laser supraglotation,10 patients underwent conservative treatment.The children underwent surgery to evaluate the improvement of laryngeal wheezing, respiration, body weight, and Diet situation. All children were followed up for 12 months.Result:Eight cases with severe laryngeallacia receving CO2laser supraglotation had rapid improvement after surgery, including laryngeal wheezing, dyspnea, and cough symptoms. They were completely cured 3 months after surgery; None of the 10 cases of moderate children were cured in 3 months, 2 cases of laryngeal wheezing and dyspnea basically disappeared in 6 months, 7 cases improved, 1 case was in the plateau stage; Despnea in 8 cases of children basically disappeared 12 months later and 2 cases with mild throat wheezing, continuing conservative treatment; The weight changes, diet and respiration were closely monitored in all 18 children. The weight of the 5 children after surgery in the 3, 6 and 12 months were significantly higher than that in the untreated children. The difference was statistically significant (P<0.05).Conclusion: Electronic laryngoscope should be taked when children are suspected of laryngeal asthma, which could help diagnose moderate-severe laryngeallacia. Follow-up should be done closely. CO2laser supraglottic surgery for severe laryngeallacia, can relieve dyspnea, throat wheezing, eating difficulties and gain weight. The surgical is safety with very slight trauma and less complications, which is worth promoting; for moderate laryngeal softening, close follow-up is recommended, most of which can be treated conservatively. If there is a change in the condition, surgery should be considered.

[Genes and molecular mechanisms affecting the correlation between liver cancer and diabetes mellitus].

Hepatocellular carcinoma (HCC) is a common and high incidence disease in China. It is presently thought that diabetes is one of the independent risk factor for HCC. Diabetes and liver cancer are closely related, but the relationship and mechanism of diabetes and liver cancer are quite complex and controversial. Insulin resistance, glucose metabolism and lipid metabolism disorders, and abnormal release of inflammatory mediators are the common bases of these two diseases. The molecular mechanisms of glycogen synthase kinase-3, toll like receptor 4, CCL5, CXCL14 and NCOA5, TCF7L2 genes affecting the correlation between liver cancer and diabetes mellitus are discussed and explained to provide the basis for the study and treatment of disease.