As the most common endocrine malignant tumor,the incidence rate of thyroid cancer is increasing year by year.However,the vast majority of subtypes have a good prognosis after traditional surgery,TSH suppression therapy and 131I treatment.With the progressive development of modern medicine,for a few thyroid cancers with poor effects of traditional treatment,molecular diagnosis and targeted therapy have further enriched the therapeutic means of thyroid cancer,in which BRAF mutation is widely present in thyroid cancer,but it often shows primary resistance or poor response to 131I therapy.The factors leading to primary or secondary resistance to targeted drugs with BRAF mutation may include genomic instability,expansion of resistant clones,occurrence of intrinsic mutations,or novel genetic and epigenetic alterations.In this article,we will review the research progress in targeted therapy resistance in BRAF-mutant thyroid cancer.

Premature ejaculation (PE), a common ejaculatory dysfunction in men with high prevalence, is a frequent cause of low sexual satisfaction for both patients and their partners.The etiology of PE is complex, including psychological, anatomical, neurobiological, and behavioral medicine factors, making it difficult to cure.Currently, treatments of PE include psychological interventions, local anesthetics, medications such as dapoxetine, and surgical treatments.Hyaluronic acid (HA) gel injection is an alternative treatment method.By subcutaneously injecting HA gel into the glans penis, the sensory input from nerve endings can be blocked, thereby reducing glans sensitivity.This approach can significantly extend the intravaginal ejaculatory latency time (IELT) and improve patient satisfaction.Moreover, it has advantages such as safety and high tolerability, making it a promising treatment option.In this paper, the technique, efficacy and safety of HA injection therapy for PE are introduced in detail on the basis of exploring other therapies for PE.

Objective:To evaluate postoperative calcitonin level as a prognostic marker in long-term follow-up of medullary thyroid carcinoma(MTC).Methods:Clinical data of 146 MTC cases treated at Tianjin Medical University Cancer Institute and Hospital from Jan 2011 to Dec 2019 were reviewed retrospectively. The relationship between postoperative calcitonin and disease-free survival was analyzed. According to the level of calcitonin six months after operation, patients were divided into normal level group and elevated group.Results:The median tumor size in those 146 cases was (1.78±1.22)cm, and 81 cases had lymph node metastasis. After 6 months of follow-up, 89 cases had normal calcitonin, with median tumor size of (1.63±1.20)cm, and 35 cases had lymph node metastasis . After a median follow-up of 56 months, 78 patients had normal calcitonin, 11 patients had biochemical relapse, 3 patients had structural relapse, and no patients died. 57 cases had a higher calcitonin ,median tumor size (1.97±1.22)cm, 46 cases had lymph node metastasis, 5 cases had distant metastasis, 18 cases had structural recurrence, and 7 patients died. Univariate analysis showed that lymph node metastasis, TNM stage, preoperative calcitonin, lymph node dissection and postoperative calcitonin were correlated with long-term disease-free survival (all P < 0.05). Multivariate analysis showed that postoperative calcitonin and TNM stage were an independent prognosis factor for disease-free survival in MTC patients (all P < 0.05). Conclusion:Postoperative calcitonin is a independent prognostic marker for long-term disease-free survival in MTC patients.

The setting and adjustment of ventilator parameters need to rely on a large amount of clinical data and rich experience. This paper explored the problem of difficult decision-making of ventilator parameters due to the time-varying and sudden changes of clinical patient's state, and proposed an expert knowledge-based strategies for ventilator parameter setting and stepless adaptive adjustment based on fuzzy control rule and neural network. Based on the method and the real-time physiological state of clinical patients, we generated a mechanical ventilation decision-making solution set with continuity and smoothness, and automatically provided explicit parameter adjustment suggestions to medical personnel. This method can solve the problems of low control precision and poor dynamic quality of the ventilator's stepwise adjustment, handle multi-input control decision problems more rationally, and improve ventilation comfort for patients.
Humans ; Ventilators, Mechanical ; Respiration, Artificial ; Neural Networks, Computer

Objective:To analyze the risk factors for keratoconus through a systematic review of secondary literature.Methods:Analytical studies from Cochrane Library, PubMed, Embase database, CNKI, Wanfang Periodicals Database, VIP Chinese Science and Technology Journal Database published from January 2000 to May 2021 were searched, most of which were about the keratoconus occurrence and progression and the valid data were extracted.The case-control and the cohort studies were evaluated according to the Newcastle-Ottawa Scale.The categorical variables for combined effect size were odds ratio( OR) and 95% confidence interval ( CI). The heterogeneity was evaluated via the Q test and I2 test.The fixed-effect model was adopted when P>0.1 or I2≤50%, while the random effect model was adopted when I2>50%.The sources of heterogeneity in included evaluation indexes were analyzed through subgroup and sensitivity analysis.The publication bias was evaluated by Egger tests, Harbord tests, Peters tests and funnel plots. Results:A total of 21 papers with 30 124 keratoconus cases and 59 012 control cases enrolled, including 18 case-control studies and 3 cohort studies, whose data were from 10 countries, were included.The NOS scores of the studies were not less than 7 points.The Meta-analysis results indicated that family history ( OR: 8.68, 95% CI: 6.30-11.97), eye rubbing ( OR: 4.62, 95% CI: 3.75-5.70), allergy ( OR: 2.34, 95% CI: 1.73-3.16), obstructive sleep apnea ( OR: 1.53, 95% CI: 1.12-2.10) and Down syndrome ( OR: 7.09, 95% CI: 4.19-11.99) were the risk factors for keratoconus, and mitral valve prolapse ( P>0.05) was not a risk factor for keratoconus, and diabetes ( OR: 0.63, 95% CI: 0.50-0.79) was a protective factor for keratoconus.The subgroup analysis results indicated that the heterogeneity in allergy was partially due to the specific disease classification, and the heterogeneity in diabetes and obstructive sleep apnea was totally owing to the source of the cases.The sensitivity study showed that the results were robust after changing the analysis model.There was no bias in the included studies. Conclusions:Family history, eye rubbing, allergy, obstructive sleep apnea and Down syndrome are risk factors for keratoconus, and diabetes is a protective factor for keratoconus.

To investigate the effectiveness and safety of diverticular peroral endoscopic myotomy (D-POEM) for mid-esophageal diverticulum. Data of consecutive patients in the prospective database with mid-esophageal diverticulum who received D-POEM in West China Hospital, Sichuan University between April 2014 to September 2019 were collected. The modified Eckardt scoring system for mid-esophageal diverticulum was used to evaluate the severity of diverticular symptoms. The effectiveness and safety of D-POEM were evaluated in terms of clinical success, technical success, complications and recurrence. A total of 7 patients with mid-esophageal diverticulum were included. Clinical and technical success was achieved in all patients with operation time of 16-70 minutes. No serious complications (2 cases with minor complications) or recurrence occurred. The follow-up time was 2-16 months. The median modified Eckardt score decreased from 3 points before operation to 0 points after operation. It is preliminarily believed that D-POEM ensures a complete septotomy between normal esophageal lumen and esophageal diverticulum. It is a safe and effective technique for mid-esophageal diverticulum. The modified Eckardt scoring system is suitable for symptom evaluation before and after treatment of mid-esophageal diverticulum.

Objective:To establish the urodynamic classification of middle-aged and elderly men with benign prostatic obstruction(BPO), and to analyze the efficacy of transurethral resection of the prostate(TURP) on various types of patients.Methods:A retrospective analysis of middle-aged and elderly male patients with non-neurogenic lower urinary tract symptoms(LUTS) who underwent urodynamic tests from January 2010 to December 2018, including 793 patients with BPO. Urodynamics examination of detrusor without contraction needs to complete cystoscopy to diagnose BPO. During urodynamic examination, the detrusor uninhibited contraction induced by spontaneous or stimulation during the bladder filling period is diagnosed as overactivity of the bladder detrusor(DO), and the LinPURR chart indicates the detrusor underactivity(DU). Based on the persistence of BPO leading to DO, DU, and decreased bladder compliance, 793 male patients with BPO with LUTS were divided into four types, including type Ⅰ(BPO: n=164, 20.7%), type Ⅱ(BPO combined with DO: n=333, 42.00%), type Ⅲ(BPO combined with DU: n=267, 33.7%), type Ⅳ(BPO combined with decreased bladder compliance: n=29, 3.7%). The preoperative comparison between groups showed that the age of type Ⅰ-Ⅳ gradually increased, and the age of type Ⅰ was significantly smaller than other types [(67.3±8.2)years, (69.7±7.7)years, (71.5±7.9)years, (72.4±7.1)years, P<0.05]. Compared with other types, the type Ⅰ’s IPSS-S[(9.1±3.6)points vs.(10.4±3.1) points, (9.2±3.3) points, (10.4±3.1)points, P<0.05], IPSS-V[(13.5±3.4) points vs. (14.2±3.5)points, (14.0±3.5)points, (14.2±2.9)points, P<0.05], IPSS scores[(22.6±5.4)points, (24.7±4.9)points, (23.1±5.3)points, (24.6±4.7)points, P<0.05] were significantly lower than other groups, the maximum bladder capacity [(332.6±83.2)ml vs.(221.4±80.8)ml, (286.7±108.2)ml, (242.3±103.4)ml, P<0.05], the functional bladder capacity was significantly higher than other types[(215.2±90.0)ml, (148.5±76.0)ml, (154.9±87.2)ml, (121.2±72.9)ml, P<0.05]. Type Ⅱ’s IPSS-S[(10.4±3.1)points vs.(9.1±3.6)points, (9.2±3.3)points, P<0.05], nocturia frequency[(3.7±1.8)times vs.(3.2±1.8)times, (3.2±1.6)times, P<0.05], IPSS score[(24.7±4.9)points vs.(22.6±5.4)points, (23.1±5.3)points, P<0.05], quality of life scores [(4.9±0.9) points, (4.6±0.9)points, (4.6±0.9)points, P<0.05] was significantly higher than type Ⅰ and type Ⅲ ( P<0.05). Type Ⅲ and Ⅳ had higher residual urine than type Ⅱ[(121.3±96.4)ml, (121.3±96.4)ml vs.(71.2±73.5)ml, P<0.05]. Type Ⅳ’s IPSS-S[(10.4±3.1)points vs. (9.1±3.6)points, (9.2±3.3)points, P<0.05], IPSS-V[(14.2±2.9) points vs.(13.5±3.4)points, (14.0±3.5)points, P<0.05], the frequency of nocturia[(3.8±1.9)times vs.(3.2±1.8)times, (3.2±1.6)times, P<0.05] was significantly higher than that of type Ⅰ and type Ⅲ, and the quality of life score was higher than type Ⅰ and type Ⅲ[(4.3±0.8)points vs.(4.7±0.9)points, (4.6±0.9)points, P<0.05]. type Ⅱ and type Ⅳ’s bladder compliance[(21.4±24.2)ml/cmH 2O, (11.0±11.4)ml/cmH 2O vs.(33.9±23.7)ml/cmH 2O, (33.1±32.7)ml/cmH 2O, P<0.05], maximum bladder capacity[(221.4±80.8)ml, (242.3±103.4)ml vs.(332.6±83.2)ml, (286.7±108.2)ml, P<0.05], functional bladder capacity[(148.5±76.0)ml, (121.2±72.9)ml vs.(215.2±90.0)ml, (154.9±87.2)ml, P<0.05] were significantly less than type Ⅰ and type Ⅲ( P<0.05). From November 2016 to November 2018, 60 middle-aged and elderly male patients with confirmed BPO and TURP were selected, including type Ⅰ( n=17, 28.3%), type Ⅱ ( n=23, 38.3%), and Ⅲ type ( n=11, 18.3%), Ⅳ type( n=9, 15.1%). Type IV patients are significantly older than other types ( P<0.05), bladder compliance is significantly worse than other types( P<0.05), the maximum bladder capacity is smaller than other types( P<0.05). The follow-up started 3 months after the operation. The content of the follow-up included IPSS, IPSS-S, IPSS-V, nocturia frequency, undisturbed sleep time, nocturia quality of life score, and life quality score. Results:The IPSS scores of type Ⅰ, type Ⅱ, and type Ⅲ after TURP were significantly improved compared with preoperative(19.8±6.2 vs.3.4±1.8; 21.9±5.2 vs.4.6±2.6; 21.5±6.2 vs.5.7±4.6, P<0.05), type Ⅳ urine storage symptom score (9.1±4.1 vs.4.3±3.7), nocturia frequency(3.6±1.5vs.2.3±1.6), nocturia quality of life score (25.3±6.9 vs.31.4±13.7) Compared with preoperatively, there was no significant improvement( P>0.05). The quality of life score improvement of type Ⅳ patients was significantly lower than that of type Ⅰ, type Ⅱ, and type Ⅲ (10.9±9.1 vs.12.2±9.0, 14.4±5.7, 12.7±5.8, P<0.05). The IPSS score of type Ⅳ patients was significantly higher than that of type Ⅰ(7.0±5.8 vs.3.4±1.8), and the nocturia quality of life score was significantly lower than that of each group (31.4±13.7 vs.37.5±4.2, 38.7±3.5, 37.8±3.8, P<0.05). Conclusions:For middle-aged and elderly men with BPO, we divide them into four types based on the results of urodynamic examinations, type Ⅰ(simple BPO), type Ⅱ(BPO combined with DO), type Ⅲ(BPO combined with DU), type Ⅳ(BPO combined with bladder compliance decline). Type Ⅰ patients have the best bladder function, and TURP has the best effect; type Ⅱ has a high symptom score and poor quality of life, and can benefit after TURP; type Ⅲ bladder function is poor, and surgery should be performed as soon as possible to prevent further deterioration of bladder function; type Ⅳ bladder function is the best poor, IPSS score and quality of life score are high, TURP surgery is not effective.

Objective:To investigate the effects of TNF-α knockout on liver and spleen neutrophil responses to Vibrio vulnificus bloodstream infection in a mouse model. Methods:(1) TNF-α-knockout (TNF-α -/-) and wild-type (WT) C57BL/6J mice aged 6-8 weeks were randomly divided into four groups with six in each group: uninfected WT group, infected WT group, uninfected TNF-α -/- group and infected TNF-α -/- group. The mouse model of bloodstream infection was constructed by intraperitoneal injection of Vibrio vulnificus CGMCC1.1758 (2×10 8 CFU/200 μl), while the mice in the uninfected groups were injected intraperitoneally with equal amount of PBS. (2) Liver immune cells and splenocytes were isolated 4 h after infection and subjected to analyze the percentages and numbers of neutrophils, and the changes in cell viability, cellular reactive oxygen species (ROS) level and phagocytosis by flow cytometry. In addition, effects of Vibrio vulnificus bloodstream infection on mTOR signaling pathway in murine neutrophils were evaluated in vivo. Results:(1)Compared with the uninfected WT group, the percentages and numbers of neutrophils in liver and spleen tissues of the infected WT group increased significantly. The percentage and number of liver neutrophils were significantly higher in the infected TNF-α -/- group than in the infected WT group, but no significant difference in spleen neutrophils was detected between the two groups. (2) Compared with the infected WT group, the phagocytosis of liver neutrophils rather than that of spleen neutrophils was enhanced in the infected TNF-α -/- group. (3) The survival rates of neutrophils in both liver and spleen were decreased, while the cellular ROS level was significantly increased in the infected WT group compared with those of the uninfected WT group. Compared with the infected WT group, the infected TNF-α -/- group had increased survival rates of both liver and spleen neutrophils, but decreased level of ROS. (4) The levels of p-AKT (S473) in liver and spleen neutrophils of the infected WT group were lower than those of the uninfected WT group. Compared with the infected WT group, the infected TNF-α -/- group had lower level of p-AKT (S473) in liver neutrophils, but higher p-AKT (S473) level in spleen neutrophils. There were no significant differences in p-4E-BP1(T37/46) levels between the uninfected WT group and the infected WT group. The p-4E-BP1 (T37/46) level in liver neutrophils was lower in the infected TNF-α -/- group than in the infected WT group, but no significant difference in p-4E-BP1 (T37/46) levels in spleen neutrophils was observed between the two groups. Conclusions:TNF-α had different effects on the neutrophils in spleen and liver tissues of mice with Vibrio vulnificus bloodstream infection. It played a critical role in regulating the recruitment, phagocytic function and mTOR signaling of liver neutrophils after Vibrio vulnificus infection in vivo.

Objective:To observe and investigate the effect of HIF-2α in the process of neovascularization of proliferative diabetic retinopathy (PDR).Methods:Retrospective clinical study. From July 2014 to July 2015, 60 eyes of 57 PDR patients diagnosed in Ophthalmology Department of Affiliated Hospital of Qingdao University were included in the study. Twenty-eight eyes of 27 patients received intravitreal injections of 0.5 mg ranibizumab (0.05 ml) at 2-7 days before surgery (ranibizumab group) and other 32 eyes of 30 patients did not (group without ranibizumab). Eighteen eyes of 18 patients with epiretinal membranes were included as controls. Pathological specimens of PDR fibrovascular membrane and premacular membrane were obtained during vitrectomy. The immunohistochemical staining and real-time PCR (RT-PCR) were used to detecting the expression of HIF-2α, Dll4 and VEGF. Kruskal-wallis test was used to compare the expression differences of correlation factors between groups. Spearman correlation analysis was used to analyze the relationship between the two variables.Results:The immunohistochemical staining revealed that there were positive expression of HIF-2α, Dll4 and VEGF in all PDR membranes, regardless of the injection of the ranibizumab. The levels of HIF-2α, Dll4 and VEGF protein in the group without ranibizumab were higher than those of the ranibizumab group ( t=4.36, 6.01, 4.82; P=0.000, 0.008, 0.016). RT-PCR showed that the differences of the mRNA expression of HIF-2α, Dll4 and VEGF were all statistically significant among the PDR patients and controls ( H=18.81,19.60, 20.50; P=0.000, 0.000, 0.000). The expression of HIF-2α, Dll4 and VEGF in the PDR membranes was higher than that of epiretinal membranes from non-diabetic patients. In the PDR patients,the expression of HIF-2α, Dll4 and VEGF of the group without ranibizumab was higher than that of the ranibizumab group. The spearman correlation analysis showed that the expression of mRNA between HIF-2α and Dll4, HIF-2α and VEGF were both significantly correlated ( r=0.95, 0.87; P<0.05). Conclusions:The expression of HIF-2α in the PDR membranes was higher than that of the controls. It is positively correlated with the expression of the DLL4 and VEGF.

Objective:To evaluate the effect of transurethral resection of the prostate on nocturia and sleep quality in men with benign prostatic hyperplasia.Methods:This retrospective study included 122 patients who underwent TURP(transurethral resection of the prostate) for BPH(benign prostatic hyperplasia)from December 2016 to December 2018.The age was(69.7±7.9)years old. There was 20 cases with diabetes and 40 cases with hypertension. The preoperative mean prostate volume was (64.4±41.2)ml and mean BMI was (24.3±2.7)kg/m 2. The preoperative IPSS score was (20.5±5.5) points, the number of nocturia events(assessed by the seventh question of IPSS) was (4.4±1.9) times, hours of undisturbed sleep (HUS) was (1.7±1.0) h, 110 cases with HUS <3 h; nocturia quality-of-life questionnaire (N-QOL) was (24.9±6.3) points, quality of life (QOL) was (4.4±0.9) points. 111 patients had the urodynamic examination done. The maximum urine flow rate was (6.4±3.1) ml/s, the maximum bladder volume was (318.5±83.6) ml, the residual urine volume was (153.9±158.9) ml, and the maximum detrusor pressure was (78.4±35.5)cmH 2O.Detrusor muscle strength decreased in 27 cases, 18 cases had OAB, 9 cases of effective bladder capacity declined and 60 cases had bladder outlet obstruction. 42 cases had an effective bladder volume <200 ml, of which 33 had a maximum bladder capacity >200 ml with nocturia (4.5±1.9) times, 9 cases had a maximum bladder capacity ≤200 ml with nocturia (4.7±1.7) times. All 122 patients were treated with TURP. Result:122 patients were followed up for 3-20 months. After operation the number of nocturia significantly decreased to (1.9±1.23) times ( P<0.05), HUS significantly improved to(3.4±1.3) h ( P<0.05), and 91 cases had HUS ≥3 with 82.7% remission rate; N-QOL significantly improved to (37.3±6.7) points ( P<0.05), IPSS significantly decreased to (4.9±4.2) points ( P<0.05), and QOL significantly decreased (0.8±0.9) points ( P<0.05). 121 patients had nocturia ≥2 voids before surgery, and 96 patients had improved (≥50% reduction of nocturnal frequency). There were 68 patients with nocturia ≥2 voids after operation with total score of preoperative IPSS (21.8±5.3), and 54 patients with nocturia <2 voids with total score of preoperative IPSS (19.2±5.5)( P<0.05). Patients with a effective bladder capacity less than 200 ml were divided into a group with a maximum bladder volume ≤200 ml and a group with a maximum bladder capacity>200 ml. The nocturia did not improve significantly after surgery ( P>0.05) in the group with a maximum bladder volume ≤200 ml, and the nocturia in the group with a maximum bladder capacity >200 ml had significantly improvement ( P<0.05). The group with a maximum bladder capacity ≤200 ml had nocturia (3.4±1.5) times after surgery, which was no significant different from that before surgery ( P=0.12); nocturia (1.9±1.1) times after operation in the group with maximum bladder volume>200 ml, and there was significant difference compared with before surgery ( P<0.05). Conclusion:TURP can significantly prolong the HUS of BPH patients with nocturia, and improve the life and sleep quality of patients. TURP partly reduces the number of nocturia, but some patients still suffer from nocturia after operation. The high total score of IPSS before operation and the maximum bladder volume ≤200 ml are the risk factors for nocturia after operation.