Objective To analyze the proportion and clinicopathological characteristics of HER2-positive breast cancer patients with BRCA1/2 pathogenic variants, and their response to neoadjuvant anti-HER2 targeted therapy. Methods The clinicopathological data of 531 breast cancer patients with germline BRCA1/2 pathogenic variants (201 with BRCA1 variants and 330 with BRCA2 variants) were analyzed. Results Among the 201 BRCA1 and 330 BRCA2 variants, 17 (8.5%) and 42 (12.7%) HER2-positive breast cancer cases were identified, respectively, accounting for 11.1% of all BRCA1/2-mutated breast cancers. Compared with BRCA1/2-mutated HR-positive/HER2-negative patients, HER2-positive patients did not present any significant differences in clinicopathological features; however, compared with triple-negative breast cancer patients, HER2-positive patients had a later onset age and lower tumor grade. Among the 17 patients who received neoadjuvant anti-HER2 targeted therapy, 10 cases achieved pCR (58.8%), whereas 7 cases did not (41.2%). Conclusion HER2-positive breast cancer accounts for more than 10% of BRCA1/2-mutated patients. Approximately 40% of these patients fail to achieve pCR after neoadjuvant targeted therapy. This phenomenon highlights the possibility of combining anti-HER2 targeted agents with poly (adenosine diphosphate-ribose) polymerase inhibitors.

Objective:To evaluate the efficacy and safety of first-line anti-tuberculosis (TB) drugs combined with linezolid in treatment of children with tuberculous meningitis (TBM).Methods:A retrospective cohort study design was performed . Eight-nine Children diagnosed as TBM during January 1 st 2016 and December 31 st 2023 in Department of Infectious Disease, Children′s Hospital of Chongqing Medical University were enrolled in the study. According to different treatment regimens, children were divided into a group of first-line anti-tuberculous drugs (isoniazid, rifampicin, pyrazinamide, ethambutol (HRZE)) and a group of HRZE and linezolid combination (HRZEL). The efficacy and safety of the 2 regimens were compared and the relationship between linezolid drug concentration and adverse reactions were analyzed. Comparisons between groups were performed using χ2 test and Mann-Whitney U test. Results:The 89 children with TBM included 53 males and 36 females with an onset age of 4.6 (1.4, 9.6) years. There were 27 cases in the HZREL group and 62 cases in the HRZE group. Before treatment, positive rate of interferon-gamma release assays (IGRA) in HRZEL group was lower than that in HRZE group (64% (16/25) vs.92% (55/60), χ2=9.82, P<0.05), but protein level of cerebrospinal fluid (CSF) was higher than that in HRZE group (1.2 (1.0, 2.0) vs.0.8 (0.4,1.4) g/L, Z=0.32, P<0.05). By the end of the intensive phase, there were no significant differences of rates of CSF improvement and etiology negativity between HRZEL group and HRZE group (both P>0.05).The 44 TBM children with high CSF protein (>1 g/L) included 25 males and 19 females with an onset age of 6.7 (3.0, 11.8) years. There were 21 cases in the HZREL group and 23 cases in the HRZE group accordingly. Before treatment, there were no significant differences of positive rate of IGRA test and CSF protein level between the 2 groups (62% (13/21) vs. 87% (20/23), 1.7 (1.1, 2.2) vs. 1.5 (1.2, 1.9) g/L, χ2=3.67, Z=0.23, both P>0.05). There were no significant differences in CSF indicators, etiology negativity or imaging remission between the two groups by the end of intensive phase (all P>0.05). Higher frequencies of granulocytopenia, gastrointestinal symptoms as well as withdrawal or change of drugs were found in HRZEL group when compared to those in HRZE group (44% (12/27) vs. 19% (12/62), 7% (2/27) vs. 0, 33% (9/27) vs. 3% (2/62), χ2=6.01, 4.70, 15.74, all P<0.05). Conclusions:The efficacy of HRZEL regimen is similar to conventional HRZE regimen in children with TBM, but with higher adverse effect. Prudentially evaluating the pros and cons of linezolid in the usage of drug-susceptible TB and carefully monitoring of linezolid associated adverse effects is suggested.

Objective To compare the clinicopathological characteristics between primary and contralateral cancers in patients with metachronous bilateral breast cancer (MBBC) who carried a BRCA1/2 germline pathogenic variant. Methods A total of 496 BRCA1/2 carriers with primary unilateral breast cancer were included (196 with BRCA1 and 300 with BRCA2). Clinicopathological information of patients was collected, and the median follow-up for the entire cohort was 10.4 years (0.4-20.8 years). Results Among all patients, 31 (15.8%) of the 196 BRCA1 carriers and 49 (16.3%) of the 300 BRCA2 carriers had MBBC, respectively. Among the 31 BRCA1 carriers who developed MBBC, the proportion of triple-negative breast cancer (TNBC) in primary cancer and contralateral cancer was 61.3% and 67.7%, respectively. If the primary cancer of BRCA1-mutated MBBC was TNBC, the probability of the contralateral breast cancer with TNBC was 89.5% (17/19), which was significantly higher than that if the primary cancer was non-TNBC (33.3%, 4/12) (P=0.004). Among the 49 BRCA2 carriers who developed MBBC, the predominant molecular phenotype of the primary and contralateral cancers was HR+ & HER2- (77.6% and 67.3%, respectively; P=0.53). Conclusion Approximately 60% of BRCA1 carriers exhibit TNBC. If a BRCA1 carrier with a TNBC primary breast cancer had an MBBC, the probability of the contralateral breast cancer being TNBC phenotype is almost 89.5%.

Objective:To evaluate the effect of stratified management of cardiovascular diseases risk in community population based on China-PAR.Methods:It was a single arm study. Beijing Jiaotong University faculty and staff who participated in annual health check-up from 2019 to 2021 and met the inclusion/exclusion criteria were enrolled in the study. The general data, physical examination and laboratory test results, including age, residence region, waist circumference, total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C),blood pressure (BP), taking antihypertensive drugs,diabetes, family history of cardiovascular diseases,were collected. Participants were stratified according to China-PAR assessment model and then stratified management was carried out. For low-risk populations, family doctors provided online guidance or outpatient follow-up if necessary after their first interview. For middle and high-risk groups, outpatient and telephone follow-up were arranged in addition to online guidance. Relevant examinations were completed and drug treatment or adjustment were given by doctors when necessary. Frequency of outpatient follow-up for middle and high-risk groups was different and patients in these two groups were scored again at the end of 2-year follow-up.Results:A total 284 participants were enrolled,197 participants (69.4%) were males with a age of (46.9±8.8) years. Among them, 205 participants (72.2%) were in low-risk group, including 136 males (66.3%), and their 10-year risk of cardiovascular diseases was (2.5±0.1)%; 59 participants (20.8%) were in middle-risk group, including 43 males (72.9%), and their 10-year risk of cardiovascular diseases was (7.1±0.2)%;20 participants (7.0%) were in high-risk group,including 18 males (90.0%) and their 10-year risk of cardiovascular diseases was (14.0±1.1)%. After 2 years follow-up, the proportion of dietary imbalances and alcohol drinking, waist circumference, blood pressure, fasting glucose levels and risk score decreased significantly in high risk group ( P<0.05). The proportion of dietary imbalances, waist circumference, blood pressure, total cholesterol, and LDL-C levels decreased significantly in medium risk group ( P<0.05). In high-risk group, 2 participants (10.0%) converted to low-risk, 8 participants (40.0%) converted to middle-risk. In middle-risk group, 5 participants (8.5%) converted to low-risk and 7 participants (11.9%) converted to high-risk. Conclusion:The risk factors and risk stratification of cardiovascular disease in community population can be improved by stratified management based on China-PAR risk assessment model.

H 1-antihistamines are widely used in the treatment of various allergic diseases, but there are still many challenges in the safe and rational use of H 1-antihistamines in pediatrics, and there is a lack of guidance on the prescription review of H 1-antihistamines for children.In this paper, suggestions are put forward from the indications, dosage, route of administration, pathophysiological characteristics of children with individual difference and drug interactions, so as to provide reference for clinicians and pharmacists.

Anti-seizure medications (ASMs) are the main therapy for epilepsy.There are many kinds of ASMs with complex mechanism of action, so it is difficult for pharmacists to examine prescriptions.This paper put forward some suggestions on the indications, dosage forms/routes of administration, appropriateness of usage and dosage, combined medication and drug interaction, long-term prescription review, individual differences in pathophysiology of children, and drug selection when complicated with common epilepsy, for the reference of doctors and pharmacists.

Genetic gain-of-function mutations of warm temperature-sensitive transient receptor potential vanilloid 3 (TRPV3) channel cause Olmsted syndrome characterized by severe itching and keratoderma, indicating that pharmacological inhibition of TRPV3 may hold promise for therapy of chronic pruritus and skin diseases. However, currently available TRPV3 tool inhibitors are either nonselective or less potent, thus impeding the validation of TRPV3 as therapeutic target. Using whole-cell patch-clamp and single-channel recordings, we report the identification of two natural dicaffeoylquinic acid isomers isochlorogenic acid A (IAA) and isochlorogenic acid B (IAB) that selectively inhibit TRPV3 currents with IC₅₀ values of 2.7 ± 1.3 and 0.9 ± 0.3 μmol/L, respectively, and reduce the channel open probability to 3.7 ± 1.2% and 3.2 ± 1.1% from 26.9 ± 5.5%, respectively. In vivo evaluation confirms that both IAA and IAB significantly reverse the ear swelling of dermatitis and chronic pruritus. Furthermore, the isomer IAB is able to rescue the keratinocyte death induced by TRPV3 agonist carvacrol. Molecular docking combined with site-directed mutations reveals two residues T636 and F666 critical for the binding of the two isomers. Taken together, our identification of isochlorogenic acids A and B that act as specific TRPV3 channel inhibitors and gating modifiers not only provides an essential pharmacological tool for further investigation of the channel pharmacology and pathology, but also holds developmental potential for treatment of dermatitis and chronic pruritus.

Antipyretic-analgesics are currently one of the most prescribed drugs in children.The clinical application of antipyretic-analgesics for children in our country still have irrational phenomenon, which affects the therapeutic effect and even poses hidden dangers to the safety of children.In this paper, suggestions were put forward from the indications, dosage form/route, dosage suitability, pathophysiological characteristics of children with individual differences and drug interactions in the symptomatic treatment of febrile children, so as to provide reference for the general pharmacists when conducting prescription review.

Objective:To introduce the surgical method of Ortho-Bridge system (OBS) in the treatment of distal femoral fractures in elderly patients and investigate its clinical effect.Methods:From January 2018 to July 2021, 24 elderly patients who suffered distal femoral fractures were treated with bilateral OBS. There were 8 males and 16 females aging from 62 to 87 years, with an average age of 72.6 years. It included 15 cases of simple distal femoral fractures. According to AO classification, there were one case of A1, two of A2, five of A3, two of C1, three of C2 and two of C3. Nine cases of femoral periprosthetic fractures after total knee arthroplasty (TKA) were classified as type II according to rorabeck's classification. After operation, all patients were guided to perform knee joint functional exercise and to measure the range of motion of the knee joint. Then imaging examinations were used to evaluate the fracture healing and measure the femoral-tibial and femoral angles. The American Hospital for Special Surgery (HSS) knee joint scoring system was used to evaluate the knee function.Results:All 24 patients successfully completed the operation. The operation time was 84-115 min, with an average of 96.6 min; the intraoperative blood loss was 150-335 ml, with an average of 240 ml. All patients were followed up for 8-17 months, with an average of 13.6 months. Except for 1 case of nonunion due to few primary bone grafts, which required secondary bone grafting, the other 23 cases achieved bone union. The healing time was 3.5-6 months, with an average of 4.6 months. At 1, 3, and 6 months after operation and at the last follow-up, the flexion angles of knee were 92.2°±10.2°, 98.6°±13.3°, 106.4°±13.7°, 115.7°±15.3°, and the extension angles were -4.7°±4.1°, -1.2°±4.2°, 0.7°±4.5°, 1.8°±4.6°, respectively; and all differences were statistically significant ( F=17.03 and 12.68, P<0.001). The knee flexion and extension angles at the last follow-up were greater than 1, 3, and 6 months after operation, and the differences were statistically significant ( P<0.001). The femoral-tibial angle was 171.2°±2.4° and 170.7°±3.2°, and the femoral angle was 80.3°±1.7° and 79.6°±2.1°, respectively, at the immediate postoperative and last follow-up, with no significant difference. The HSS scores at 1, 3, 6 months after operation and at the last follow-up were 71.5±7.5, 74.6± 9.3, 78.9±10.4 and 84.7±9.4 respectively, with significant difference ( F=9.17, P<0.001). At the last follow-up, the HSS score was higher than that at 1, 3, and 6 months after the operation, and the differences were statistically significant ( P<0.001), and the knee function was evaluated according to the HSS scoring system: excellent in 12 cases, good in 9, fair in 3, with an excellent and good rate of 88% (21/24). There was no OBS crack or fixation failure in all patients, and no prosthetic loosening and instability occurred in patients with periprosthetic femoral fractures after TKA. Statistical analysis of the data at the last follow-up between the distal femoral fracture group and the periprosthetic femoral fracture group after TKA showed that the knee flexion function and HSS score of the periprosthetic femoral fracture group after TKA (126.8°±3.7°, 92.2±4.1) were both better than the simple distal femur fracture group (108.9°±15.7°, 80.2±8.8). The difference was statistically significant ( t=4.22, 4.52, P<0.05). One patient had incision fat liquefaction and healed after debridement; bone nonunion occurred in 1 case, which healed after iliac bone grafting. Conclusion:Double OBS has a good clinical effect in the treatment of distal femoral fractures in the elderly, especially in patients with periprosthetic femoral fractures after TKA.

Objective:To investigate clinical efficacy of conformal sphincter preservation operation (CSPO) versus intersphincteric resection (ISR) in the treatment of low rectal cancer.Methods:The retrospective cohort study was conducted. The clinicopathological data of 183 patients with low rectal cancer who were admitted to two medical centers (117 in the Changhai Hospital of Naval Medical University and 66 in the Huashan Hospital of Fudan University) from August 2011 to April 2020 were collected. There were 110 males and 73 females, aged (57±11)years. Of 183 patients, 117 cases undergoing CSPO were allocated into CSPO group, and 66 cases undergoing ISR were allocated into ISR group, respectively. Observation indicators: (1) surgical situations of patients with low rectal cancer in the two groups; (2) postoperative complications of patients with low rectal cancer in the two groups; (3) follow-up; (4) influencing factors for prognosis of patients with low rectal cancer; (5) influencing factors for satisfaction with the anal function of patients with low rectal cancer. Follow-up was conducted using outpatient examination, questionnaire and telephone interview to determine local recurrence, distal metastasis, survival, stomal closure, satisfaction with the anal function of patients. Measurement data with normal distribution were represented as Mean±SD, and comparison between groups was analyzed using the t test. Measurement data with skewed distribution were represented as M (range). Count data were described as absolute numbers or percentages, and comparison between groups was analyzed using the chi-square test. Comparison of ordinal data was analyzed using the rank sum test.The Kaplan-Meier method was used to draw survival curves, and life table method was used to calculate survival rates. Log-rank test was used for survival analysis. Univariate analysis was performed using the linear regression. Variables with P<0.10 in the univariate linear regression analysis were included for multivariate analysis. Multivariate analysis was performed using the COX stepwise regression model and linear regression analysis. Results:(1) Surgical situations of patients with low rectal cancer in the two groups: cases with laparoscopic surgery, operation time, volume of intraoperative blood loss, distance from tumor to distal margin, cases with postoperative chemotherapy, duration of postoperative hospital stay were 44, (165±54)minutes, (142±101)mL, (0.6±0.4)cm, 76, (6.6±2.5)days for the CSPO group, respectively, versus 55, (268±101)minutes, (91±85)mL, (1.9±0.6)cm, 9, (7.9±4.7)days for the ISR group, showing significant differences between the two groups ( χ2=35.531, t=8.995, -3.437, -3.088, χ2=44.681, t=2.267, P<0.05). (2) Postoperative complications of patients with low rectal cancer in the two groups: 19 patients in the CSPO group had complications. There were 6 cases with grade Ⅰ complications, 12 cases with grade Ⅱ complications, 1 case with grade Ⅲb complication. Fourteen patients in the ISR group had complications. There were 4 cases with grade Ⅰ complications, 7 cases with grade Ⅱ complications, 1 case with grade Ⅲa complication, 2 cases with grade Ⅲb complications. There was no significant difference in the postoperative complications between the two groups ( χ2=0.706, P>0.05). Patients with complications in the two groups were improved after symptomatic and supportive treatment. There was no perioperative death in the postoperative 30 days of the two groups. (3) Follow-up: 183 patients received follow-up. Patients of the CSPO group and ISR group were followed up for (41±27)months and (37±19)months, respectively, showing no significant difference between the two groups ( t=-1.104, P>0.05). There were 2 cases with local recurrence and 9 cases with distal metastasis of the CSPO group, respectively, versus 3 cases and 4 cases of the ISR group, showing no significant difference between the two groups ( χ2=1.277, 0.170, P>0.05). The 3-year disease-free survival rate and 3-year total survival rate were 84.0% and 99.0% for the CSPO group, versus 88.6% and 92.8% for the ISR group, showing no significant difference between the two groups ( χ2=0.218, 0.002, P>0.05). The stomal closure rate was 92.16%(94/102) and 96.97%(64/66) for 102 patients of CSPO group and 66 patients of ISR group up to postoperative 12 months,respectively, showing no significant difference between the two groups ( χ2=1.658, P>0.05). Of the 8 cases without stomal closure in the CSPO group, 2 cases refused due to advanced age, 4 cases subjectively refused, and 2 cases were irreducible due to scar caused by radiotherapy. Two cases in the ISR group had no stomal closure including 1 case of postoperative liver metastasis and 1 case of subjective refusal. There were 92 and 61 patients followed up to 12 months after stomal closure, of which 75 cases and 38 cases completed questionnaires of satisfaction with the anal function. The satisfaction score with the anal function was 6.8±2.8 and 5.4±3.0 for CSPO group and ISR group, respectively, showing a significant difference between the two groups ( t=-2.542, P<0.05). Fifty-four cases in the CSPO group and 21 cases in the ISR group had satisfaction score with the anal function >5, showing no significant difference between the two groups ( χ2=3.165, P>0.05). (4) Influencing factors for prognosis of patients with low rectal cancer: results of COX stepwise regression analysis showed that gender and pT staging were independent influencing factors for disease-free survival rate of patients with low rectal cancer ( hazard ratio=2.883, 1.963, 95% confidence interval as 1.090 to 7.622, 1.129 to 3.413, P<0.05). Gender and pT staging were independent influencing factors for total survival rate of patients with low rectal cancer ( hazard ratio=10.963,3.187, 95% confidence interval as 1.292 to 93.063, 1.240 to 8.188, P<0.05). (5) Influencing factors for satisfaction with the anal function of patients with low rectal cancer: results of univariate analysis showed that surgical method and tumor differentiation degree were related factors for satisfaction with the anal function of patients with low rectal cancer (partial regression coefficient=1.464, -1.580, 95% confidence interval as 0.323 to 2.605, -2.950 to -0.209, P<0.05). Results of multivariate analysis showed that surgical method, tumor differentiation degree and preoperative radiotherapy were independent influencing factors for satisfaction with the anal function of patients with low rectal cancer (partial regression coefficient=1.637, -1.456, -1.668, 95% confidence interval as 0.485 to 2.788, -2.796 to -0.116, -2.888 to -0.447, P<0.05). Conclusion:Compared with ISR, CSPO can safely preserve the anus in the treatment of low rectal cancer, without increasing the incidence of postoperative complications, which can also guarantee the oncological safety and improve the postoperative anal function.