[A multicenter prospective study on early identification of refractory Mycoplasma pneumoniae pneumonia in children].

Objective: To explore potential predictors of refractory Mycoplasma pneumoniae pneumonia (RMPP) in early stage. Methods: The prospective multicenter study was conducted in Zhejiang, China from May 1st, 2019 to January 31st, 2020. A total of 1 428 patients with fever >48 hours to <120 hours were studied. Their clinical data and oral pharyngeal swab samples were collected; Mycoplasma pneumoniae DNA in pharyngeal swab specimens was detected. Patients with positive Mycoplasma pneumoniae DNA results underwent a series of tests, including chest X-ray, complete blood count, C-reactive protein, lactate dehydrogenase (LDH), and procalcitonin. According to the occurrence of RMPP, the patients were divided into two groups, RMPP group and general Mycoplasma pneumoniae pneumonia (GMPP) group. Measurement data between the 2 groups were compared using Mann-Whitney U test. Logistic regression analyses were used to examine the associations between clinical data and RMPP. Receiver operating characteristic (ROC) curves were used to analyse the power of the markers for predicting RMPP. Results: A total of 1 428 patients finished the study, with 801 boys and 627 girls, aged 4.3 (2.7, 6.3) years. Mycoplasma pneumoniae DNA was positive in 534 cases (37.4%), of whom 446 cases (83.5%) were diagnosed with Mycoplasma pneumoniae pneumonia, including 251 boys and 195 girls, aged 5.2 (3.3, 6.9) years. Macrolides-resistant variation was positive in 410 cases (91.9%). Fifty-five cases were with RMPP, 391 cases with GMPP. The peak body temperature before the first visit and LDH levels in RMPP patients were higher than that in GMPP patients (39.6 (39.1, 40.0) vs. 39.2 (38.9, 39.7) ℃, 333 (279, 392) vs. 311 (259, 359) U/L, both P<0.05). Logistic regression showed the prediction probability π=exp (-29.7+0.667×Peak body temperature (℃)+0.004×LDH (U/L))/(1+exp (-29.7+0.667×Peak body temperature (℃)+0.004 × LDH (U/L))), the cut-off value to predict RMPP was 0.12, with a consensus of probability forecast of 0.89, sensitivity of 0.89, and specificity of 0.67; and the area under ROC curve was 0.682 (95%CI 0.593-0.771, P<0.01). Conclusion: In MPP patients with fever over 48 to <120 hours, a prediction probability π of RMPP can be calculated based on the peak body temperature and LDH level before the first visit, which can facilitate early identification of RMPP.

[Spatial autocorrelation and related factors of stroke mortality in Zhejiang Province based on spatial panel model in 2015-2020].

Objective: To explore the spatial autocorrelation and macro influencing factors of stroke mortality in Zhejiang Province in 2015-2020 and provide a scientific basis for stroke prevention and control strategy. Methods: The data on stroke death were obtained from Zhejiang Chronic Disease Surveillance System. The spatial distribution of stroke mortality was explored by mapping and spatial autocorrelation analysis. The spatial panel model analyzed the correlation between stroke mortality and socioeconomic and healthcare factors. Results: From 2015 to 2020, the average stroke mortality was 68.38/100 thousand. The standard mortality of stroke was high in the areas of east and low in the west, high in the south and low in the north. Moreover, positive spatial autocorrelation was observed (Moran's I=0.274-0.390, P<0.001). Standard mortality of stroke was negatively associated with per capita gross domestic product (GDP) (ß=-0.370, P<0.001), per capita health expenditure (ß=-0.116, P=0.021), number of beds per thousand population (ß=-0.161, P=0.030). Standard mortality of ischemic stroke was negatively associated with per capita GDP (ß=-0.310, P=0.002) and standard management rate of hypertension (ß=-0.462, P=0.011). Standard mortality of hemorrhagic stroke was negatively associated with per capita GDP (ß=-0.481, P<0.001), per capita health expenditure (ß=-0.184, P=0.001), number of beds per thousand population (ß=-0.288, P=0.001) and standard management rate of hypertension (ß=-0.336, P=0.029). Conclusions: A positive spatial correlation existed between stroke mortality in Zhejiang Province in 2015-2020. We must focus more on preventing and controlling strokes in relatively backward economic areas. Moreover, to reduce the mortality of stroke, increasing the investment of government medical and health funds, optimizing the allocation of medical resources, and improving the standard management rate of hypertension are important measures.

[The influence of lung metastasis on prognosis of previously untreated gestational trophoblastic neoplasia patients].

Objective: To investigate the impact of lung metastases on the prognosis of patients with gestational trophoblastic neoplasia (GTN). Methods: Patients with International Federation of Gynaecology and Obstetrics (FIGO) stage Ⅰ-Ⅲ GTN receiving primary chemotherapy in Peking Union Medical College Hospital between July 2014 and December 2018 were retrospectively analyzed and divided into group 1 with lung metastasis and group 2 without lung metastasis. The baseline characteristics and treatment outcomes of the two groups were compared. The optimal cut-off values of the diameter of largest lung nodule associated with recurrence were identified by receiver operating characteristic (ROC) curves. Logistic regression analyses were performed to identify risk factors for prognosis. Survival analysis was performed by Kaplan-Meier method and Log rank test. Results: Of the 381 GTN patients enrolled (216 with lung metastases and 165 without lung metastases), the pretreatment ß human chorionic gonadotrophin [median: 12 572 IU/L (1 832-51 594 IU/L) vs. 5 614 IU/L (559-26 140 IU/L), P=0.001] and FIGO score [median: 3 (1-6) vs. 2 (1-4), P=0.038] were significantly higher in patients with lung metastases than those without lung metastases. In patients with FIGO score≥5, the emergence of resistance (26.76% vs. 10.26%, P=0.036) and median number of chemotherapy courses to achieve complete remission [6 (6-8) vs. 5 (4-6), P<0.001] were significantly higher than patients with lung metastases. In patients with FIGO score 0-4, no significant difference was found in the treatment outcomes between the two groups(P=0.833). Among all patients with lung metastases, the ROC curve showed a sensitivity and specificity of 62.5% and 78.8%, respectively, for predicting recurrence when the length of the largest lung nodule was 1.6 cm, with an area under the curve (AUC) of 0.711 (95% CI: 0.550, 0.871, P=0.044). Multivariate logistic regression analysis suggested a significantly higher recurrence rate when the largest lung nodule was ≥1.6 cm (OR=7.394, 95% CI: 1.003, 54.520, P=0.049). The 1-year disease-free survival rate was significantly lower in patients with the largest lung nodule ≥1.6 cm than in patients with the nodule <1.6 cm (98.2% vs. 82.4%, P=0.001). Conclusions: Lung metastasis is associated with increased first-line chemotherapy resistance in patients with FIGO scores≥5. The diameter of the largest lung metastatic nodule ≥1.6 cm is an effective factor for predicting recurrence.

Safety and efficacy of pralsetinib in RET fusion-positive non-small-cell lung cancer including as first-line therapy: update from the ARROW trial.

BACKGROUND: RET fusions are present in 1%-2% of non-small-cell lung cancer (NSCLC). Pralsetinib, a highly potent, oral, central nervous system-penetrant, selective RET inhibitor, previously demonstrated clinical activity in patients with RET fusion-positive NSCLC in the phase I/II ARROW study, including among treatment-naive patients. We report an updated analysis from the ARROW study. PATIENTS AND METHODS: ARROW is a multi-cohort, open-label, phase I/II study. Eligible patients were ≥18 years of age with locally advanced or metastatic solid tumours and an Eastern Cooperative Oncology Group performance status of 0-2 (later 0-1). Patients initiated pralsetinib at the recommended phase II dose of 400 mg once daily until disease progression, intolerance, consent withdrawal, or investigator's decision. The co-primary endpoints (phase II) were overall response rate (ORR) by blinded independent central review and safety. RESULTS: Between 17 March 2017 and 6 November 2020 (data cut-off), 281 patients with RET fusion-positive NSCLC were enrolled. The ORR was 72% [54/75; 95% confidence interval (CI) 60% to 82%] for treatment-naive patients and 59% (80/136; 95% CI 50% to 67%) for patients with prior platinum-based chemotherapy (enrolment cut-off for efficacy analysis: 22 May 2020); median duration of response was not reached for treatment-naive patients and 22.3 months for prior platinum-based chemotherapy patients. Tumour shrinkage was observed in all treatment-naive patients and in 97% of patients with prior platinum-based chemotherapy; median progression-free survival was 13.0 and 16.5 months, respectively. In patients with measurable intracranial metastases, the intracranial response rate was 70% (7/10; 95% CI 35% to 93%); all had received prior systemic treatment. In treatment-naive patients with RET fusion-positive NSCLC who initiated pralsetinib by the data cut-off (n = 116), the most common grade 3-4 treatment-related adverse events (TRAEs) were neutropenia (18%), hypertension (10%), increased blood creatine phosphokinase (9%), and lymphopenia (9%). Overall, 7% (20/281) discontinued due to TRAEs. CONCLUSIONS: Pralsetinib treatment produced robust efficacy and was generally well tolerated in treatment-naive patients with advanced RET fusion-positive NSCLC. Results from the confirmatory phase III AcceleRET Lung study (NCT04222972) of pralsetinib versus standard of care in the first-line setting are pending.

Comparing Kidney Health Outcomes in Children, Adolescents, and Adults With Focal Segmental Glomerulosclerosis.

Importance: Focal segmental glomerulosclerosis (FSGS) is a common cause of end-stage kidney disease (ESKD) across the lifespan. While 10% to 15% of children and 3% of adults who develop ESKD have FSGS, it remains uncertain whether the natural history differs in pediatric vs adult patients, and this uncertainty contributes to the exclusion of children and adolescents in clinical trials. Objective: To examine whether there are differences in the kidney health outcomes among children, adolescents, and adults with FSGS. Design, Setting, and Participants: This cohort study used pooled and parallel analyses, completed July 5, 2022, from 3 complimentary data sources: (1) Nephrotic Syndrome Rare Disease Clinical Research Network (NEPTUNE); (2) FSGS clinical trial (FSGS-CT); and (3) Kidney Research Network (KRN). NEPTUNE is a multicenter US/Canada cohort study; FSGS-CT is a multicenter US/Canada clinical trial; and KRN is a multicenter US electronic health record-based registry from academic and community nephrology practices. NEPTUNE included 166 patients with incident FSGS enrolled at first kidney biopsy; FSGS-CT included 132 patients with steroid-resistant FSGS randomized to cyclosporine vs dexamethasone with mycophenolate; and KRN included 184 patients with prevalent FSGS. Data were collected from November 2004 to October 2019 and analyzed from October 2020 to July 2022. Exposures: Age: children (age <13 years) vs adolescents (13-17 years) vs adults (≥18 years). Covariates of interest included sex, disease duration, APOL1 genotype, urine protein-to-creatinine ratio, estimated glomerular filtration rate (eGFR), edema, serum albumin, and immunosuppressive therapy. Main Outcomes and Measures: ESKD, composite outcome of ESKD or 40% decline in eGFR, and complete and/or partial remission of proteinuria. Results: The study included 127 (26%) children, 102 (21%) adolescents, and 253 (52%) adults, including 215 (45%) female participants and 138 (29%) who identified as Black, 98 (20%) who identified as Hispanic, and 275 (57%) who identified as White. Overall, the median time to ESKD was 11.9 years (IQR, 5.2-19.1 years). There was no difference in ESKD risk among children vs adults (hazard ratio [HR], 0.67; 95% CI, 0.43-1.03) or adolescents vs adults (HR, 0.85; 95% CI, 0.52-1.36). The median time to the composite end point was 5.7 years (IQR 1.6-15.2 years), with hazard ratio estimates for children vs adults of 1.12 (95% CI, 0.83-1.52) and adolescents vs adults of 1.06 (95% CI, 0.75-1.50). Conclusions and Relevance: In this study, the association of FSGS with kidney survival and functional outcomes was comparable at all ages.

The impact of bone mineral density screening on incident fractures and healthcare resource utilization among postmenopausal breast cancer survivors treated with aromatase inhibitors.

Bone mineral density screening prior to initiating aromatase inhibitor therapy was associated with lower incident bone fractures and healthcare resource utilization among postmenopausal breast cancer survivors. INTRODUCTION: Postmenopausal women with hormone receptor-positive breast cancer (BC) often receive aromatase inhibitor (AI) therapy. However, AIs induce bone loss and BC survivors are at an increased risk of bone fractures. This study determined whether receipt of baseline dual-energy x-ray absorptiometry (DXA) screening is associated with decreased incident fractures and lower healthcare resource utilization. METHODS: We retrospectively analyzed 22,713 stage 0-III primary BC survivors who received AI therapy ≤ 1 year prior to BC diagnosis from the Medicare-Linked Surveillance, Epidemiology, and End-Results database. We categorized DXA screening for those who had a procedural claim within 12 months prior through 6 months after first AI claim. We used propensity score methods to assess the association of DXA screening with bone fractures and health resource utilization. RESULTS: Of the study cohort, 62% received a DXA screening. Women with comorbid dementia, renal disease, and congestive heart failure were less likely to receive a DXA. After adjusting for confounders, BC survivors who received a DXA had a 32% decreased risk of any bone fracture compared to those who did not (hazard ratio (HR): 0.68, 95% confidence interval (CI): 0.60-0.76, p < 0.001). Similarly, those who received a DXA were less likely to be hospitalized (HR 0.73 (0.62-0.86)) or use outpatient services (HR 0.85 (0.74-0.97)). CONCLUSIONS: Bone density screening is associated with decreased incident bone fractures and a lower likelihood of utilizing healthcare resource for fracture-related events. Postmenopausal BC survivors treated with AIs should undergo appropriate bone density screening to reduce morbidity, mortality, and health care expenses.

Safety and activity of alectinib plus bevacizumab in patients with advanced ALK-rearranged non-small-cell lung cancer: a phase I/II study.

BACKGROUND: Alectinib, a second-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI), is highly effective in advanced ALK-rearranged non-small-cell lung cancer and represents a standard first-line therapy. New strategies are needed, however, to delay resistance. We conducted a phase I/II study to assess the safety and efficacy of combining alectinib with bevacizumab, a monoclonal antibody against vascular endothelial growth factor. PATIENTS AND METHODS: Patients with advanced ALK-rearranged non-squamous non-small-cell lung cancer were enrolled. The phase I portion employed a dose de-escalation strategy with alectinib and bevacizumab starting at the individual standard doses. The primary objective was to determine the recommended phase II dose (RP2D). In phase II, the primary objective was to evaluate the safety of the combination at the RP2D; the secondary objective was to determine extracranial and intracranial efficacy. RESULTS: Eleven patients were enrolled between September 2015 and February 2020. Most patients (82%) had baseline brain metastases. Six patients (55%) were treatment-naive; five (46%) had received prior ALK TKIs (crizotinib, n = 3; ceritinib, n = 1; crizotinib then brigatinib, n = 1). No dose-limiting toxicities occurred. RP2D was determined as alectinib 600 mg orally twice daily plus bevacizumab 15 mg/kg intravenously every 3 weeks. Three patients experienced grade 3 treatment-related adverse events: pneumonitis related to alectinib, proteinuria related to bevacizumab, and hypertension related to bevacizumab. Treatment-related intracranial hemorrhage was not observed. Six (100%) of six treatment-naive patients and three (60%) of five ALK TKI-pretreated patients had objective responses; median progression-free survival was not reached (95% confidence interval, 9.0 months-not reached) and 9.5 months (95% confidence interval, 4.3 months-not reached), respectively. Intracranial responses occurred in four (100%) of four treatment-naive and three (60%) of five TKI-pretreated patients with baseline brain metastases. The study was stopped prematurely because of slow accrual. CONCLUSIONS: Alectinib plus bevacizumab was well tolerated without unanticipated toxicities or dose-limiting toxicities.

APOL1 genotype-associated morphologic changes among patients with focal segmental glomerulosclerosis.

BACKGROUND: The G1 and G2 alleles of apolipoprotein L1 (APOL1) are common in the Black population and associated with increased risk of focal segmental glomerulosclerosis (FSGS). The molecular mechanisms linking APOL1 risk variants with FSGS are not clearly understood, and APOL1's natural absence in laboratory animals makes studying its pathobiology challenging. METHODS: In a cohort of 90 Black patients with either FSGS or minimal change disease (MCD) enrolled in the Nephrotic Syndrome Study Network (58% pediatric onset), we used kidney biopsy traits as an intermediate outcome to help illuminate tissue-based consequences of APOL1 risk variants and expression. We tested associations between APOL1 risk alleles or glomerular APOL1 mRNA expression and 83 light- or electron-microscopy traits measuring structural and cellular kidney changes. RESULTS: Under both recessive and dominant models in the FSGS patient subgroup (61%), APOL1 risk variants were significantly correlated (defined as FDR <0.1) with decreased global mesangial hypercellularity, decreased condensation of cytoskeleton, and increased tubular microcysts. No significant correlations were detected in MCD cohort. Independent of risk alleles, glomerular APOL1 expression in FSGS patients was not correlated with morphologic features. CONCLUSIONS: While APOL1-associated FSGS is associated with two risk alleles, both one and two risk alleles are associated with cellular/tissue changes in this study of FSGS patients. Our lack of discovery of a large group of tissue differences in FSGS and no significant difference in MCD may be due to the lack of power but also supports investigating whether machine learning methods may more sensitively detect APOL1-associated changes.

[Study of portal venous pressure gradient to predict high-hepatic encephalopathy-risk population post TIPS].

Transjugular intrahepatic portosystemic shunt (TIPS) can effectively reduce the portal venous pressure and relieve the clinical complications related to portal hypertension. However, hepatic encephalopathy (HE) is still the main complication post TIPS. Studies have shown that patients over 65 years old with liver function reserve in Child-Pugh grade C are the high-HE-risk group post TIPS, and early TIPS treatment can benefit the survival of these high-risk patients. In this study, TIPS was used to treat 60 cases aged > 65 years old and liver function reserve in Child-Pugh grade C (decompensated liver cirrhosis) with esophagogastric variceal bleeding. The clinical results of 1-year was observed and the porto systemic gradient (PSG) was evaluated. The relationship between the incidence of HE and the PSG of patients with and without HE were compared to evaluate the effect of PSG on the incidence of HE.