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.

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.

[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.

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.

Mechanisms of resistance to selective RET tyrosine kinase inhibitors in RET fusion-positive non-small-cell lung cancer.

BACKGROUND: Rearranged during transfection (RET) gene fusions are a validated target in non-small-cell lung cancer (NSCLC). RET-selective inhibitors selpercatinib (LOXO-292) and pralsetinib (BLU-667) recently demonstrated favorable antitumor activity and safety profiles in advanced RET fusion-positive NSCLC, and both have received approval by the US Food and Drug Administration for this indication. Insights into mechanisms of resistance to selective RET inhibitors remain limited. PATIENTS AND METHODS: This study was performed at five institutions. Tissue and/or cell-free DNA was obtained from patients with RET fusion-positive NSCLC after treatment with selpercatinib or pralsetinib and assessed by next-generation sequencing (NGS) or MET FISH. RESULTS: We analyzed a total of 23 post-treatment tissue and/or plasma biopsies from 18 RET fusion-positive patients who received an RET-selective inhibitor (selpercatinib, n = 10; pralsetinib, n = 7; pralsetinib followed by selpercatinib, n = 1, with biopsy after each inhibitor). Three cases had paired tissue and plasma samples, of which one also had two serial resistant tissue specimens. The median progression-free survival on RET inhibitors was 6.3 months [95% confidence interval 3.6-10.8 months]. Acquired RET mutations were identified in two cases (10%), both affecting the RET G810 residue in the kinase solvent front. Three resistant cases (15%) harbored acquired MET amplification without concurrent RET resistance mutations, and one specimen had acquired KRAS amplification. No other canonical driver alterations were identified by NGS. Among 16 resistant tumor specimens, none had evidence of squamous or small-cell histologic transformation. CONCLUSIONS: RET solvent front mutations are a recurrent mechanism of RET inhibitor resistance, although they occurred at a relatively low frequency. The majority of resistance to selective RET inhibition may be driven by RET-independent resistance such as acquired MET or KRAS amplification. Next-generation RET inhibitors with potency against RET resistance mutations and combination strategies are needed to effectively overcome resistance in these patients.

A study on protective effect of morphine against myocardial ischemia-reperfusion injury in rats via CAMP/PKA signaling pathway.

The purpose of this study was to explore the mitigating effect of morphine on the myocardial ischemia-reperfusion injury (MIRI) in rats through the cyclic adenosine monophosphate/protein kinase A (cAMP/PKA) pathway. A total of 30 male Wistar rats were assigned into sham group, MIRI group and morphine group using a random number table. The model of MIRI was routinely established. Then, the pathological changes in the morphology of myocardial tissues were observed via hematoxylin-eosin (HE) staining. The levels of the oxidative stress indicators superoxide dismutase (SOD) and malondialdehyde (MDA), the content of the inflammatory cytokine tumor necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1ß) and IL-6 and the quantity of glutathione peroxidase (GSH-Px), lactate dehydrogenase (LDH), creatine kinase (CK), CK-MB and cardiac troponin I (cTnI) in the myocardial enzyme spectrum were determined and analyzed through enzyme-linked immunosorbent assay (ELISA). Moreover, the messenger ribonucleic acid (mRNA) and protein expressions of cAMP, PKA, cAMP-response element binding protein (CREB) and phosphorylated CREB (p-CREB) in the cAMP/PKA signaling pathway in the myocardial tissues were measured using real-time polymerase chain reaction (PCR) and Western blotting, respectively. The results manifested that compared with those in MIRI group, the levels of myocardial infarct size, LDH, CK, CK-MB, cTnI, MDA, TNF-α, IL-1ß, IL-6 and p-CREB were decreased, while the levels of GSH-Px, SOD, PKA and CREB were increased in the morphine group. In conclusion, morphine may mitigate MIRI in rats through the cAMP/PKA signaling pathway.

A DNA priming and protein boosting immunization scheme to augment immune responses against parvovirus in ducks.

AIMS: To evaluate the effect of a DNA priming and protein boosting immunization scheme in ducks. METHODS AND RESULTS: Pekin ducks were immunized with pTCY/VP2 DNA vaccine; on day 14 (D14) after primary immunization, the ducks were boosted with either the same vaccine (DNA + DNA) or the rVP2 vaccine (DNA + rVP2). CpG oligodeoxynucleotides containing three copies of GACGTT motifs were used as the adjuvant in the vaccines. Compared with unimmunized controls, both immunization schemes significantly increased the titre of antigen-specific antibodies, lymphocyte proliferation index, percentage of CD4+ and CD8+ cells in peripheral blood mononuclear cells (PBMCs) and mRNA expression of interferon (IFN)-α, IFN-γ, interleukin (IL)-6 and IL-12 in antigen-stimulated PBMCs. Furthermore, compared with the DNA + DNA homologous scheme, the DNA + rVP2 heterologous scheme significantly increased lymphocyte proliferation, percentage of CD4+ and CD8+ cells in PBMCs and upregulation of mRNA expression of cytokines 2 weeks after the boost (D28). CONCLUSIONS: The DNA + rVP2 immunization scheme enhanced immune responses, mainly Th1 type, against parvovirus in ducks. SIGNIFICANCE AND IMPACT OF THE STUDY: The DNA priming and protein boosting heterologous immunization strategy can be applied to develop vaccines against viral infections in ducks. It can potentially be used in breeding ducks because of long-term immunity may confer protection for ducklings.

Differential Sources for 2 Neural Signatures of Target Detection: An Electrocorticography Study.

Electrophysiology and neuroimaging provide conflicting evidence for the neural contributions to target detection. Scalp electroencephalography (EEG) studies localize the P3b event-related potential component mainly to parietal cortex, whereas neuroimaging studies report activations in both frontal and parietal cortices. We addressed this discrepancy by examining the sources that generate the target-detection process using electrocorticography (ECoG). We recorded ECoG activity from cortex in 14 patients undergoing epilepsy monitoring, as they performed an auditory or visual target-detection task. We examined target-related responses in 2 domains: high frequency band (HFB) activity and the P3b. Across tasks, we observed a greater proportion of electrodes that showed target-specific HFB power relative to P3b over frontal cortex, but their proportions over parietal cortex were comparable. Notably, there was minimal overlap in the electrodes that showed target-specific HFB and P3b activity. These results revealed that the target-detection process is characterized by at least 2 different neural markers with distinct cortical distributions. Our findings suggest that separate neural mechanisms are driving the differential patterns of activity observed in scalp EEG and neuroimaging studies, with the P3b reflecting EEG findings and HFB activity reflecting neuroimaging findings, highlighting the notion that target detection is not a unitary phenomenon.

Patients with chronic periodontitis present increased risk for osteoporosis: A population-based cohort study in Taiwan.

OBJECTIVES: Chronic periodontitis is a bone destructive inflammatory disease with an adverse impact on general health and suggested underlying factors in common with osteoporosis. A few studies have examined the possible relationship between chronic periodontitis and osteoporosis; however, the results remain inconclusive. This longitudinal follow-up study investigated the possible risk of patients with chronic periodontitis to present osteoporosis by using a population-based national health insurance data set in Taiwan. MATERIAL AND METHODS: A random sample consisting of 1 million individuals was collected from Taiwan's national health insurance data set. From the sample, a total of 29 463 patients with newly diagnosed periodontitis from 2002 to 2008 were recruited and compared with a matched cohort of 58 926 patients without periodontitis. All patients were tracked until an osteoporosis diagnosis, or death, until the end of 2011. Associated factors, such as gender, age and comorbidities were examined. Cox proportional-hazards regression was performed to examine the risk of osteoporosis for patients with or without periodontitis. RESULTS: Within the 6-year follow-up period, the incidence rates of osteoporosis in the periodontitis cohort and comparison group were 2.72 and 1.66 per 1000 person-years, respectively. Mild, moderate and severe periodontitis were found to have 1.56, 2.09 and 2.08 times the risk of osteoporosis respectively compared to patients without periodontitis. Log-rank analysis revealed that patients with periodontitis had significantly higher cumulative incidence rates of osteoporosis than the control group (P<.0001). CONCLUSION: This study found that patients with periodontitis had a higher risk of being diagnosed with osteoporosis.

[The correlation between CT score of lung injury and oxygenation index in patients with acute hydrogen sulphide poisoning].

Objective: To explore correlation between chest CT score and oxygenation index in patients with acute hydrogen sulphide poisoning, whether CT score can be applied to assess acute lung injury after acute hydrogen sulfide poisoning and provide basis and reference. Methods: The clinic and a series of CT datas of 32 acute hydrogen sulphide poisoning cases were retrospectively analysed and compared, According to GBZ31-2002 (the diagnostic standard of occupational H(2)S acute poisoning) , these patients were divided into 2 grouds including moderate groud and severe groud; The CT score were improved, referenceing the scoring criteria of the chest X-ray; The difference of the CT score and the oxygenation index were analyzed between moderate and severe group in the acute phase and the disperse phase; The correlation between CT score and oxygenation index were analyzed. Results: The CT score in moderate poisoning group were lower than severe group (2.26±1.37 vs 10.44±2.55, 1.34±0.65 vs 4.55±2.45, all P<0.05) in the acute phase and the dissipation phase.The oxygen index of the 19 cases in the acute phase were 307.55±28.29, and the oxygen index of the 8 cases in the dissipation phase was 435.75±37.00; The oxygen index of the 9 cases in the acute phase and the dissipation phase were respectively 193.17±36.41, 347.67±44.49. The oxygen partial pressure and oxygenation index in severe group were significantly lower than those in moderate group (all P<0.01) in the acute phase and the dissipation phase. Pearman correlation analysis showed that the CT score were negatively correlated to the oxygen index in the acute phase and the dissipation phase, respectively (r=-0.97、-0.75, all P<0.01) . Conclusions: The CT score of lung injury and oxygenation index is negatively correlated. The CT score can be used to evaluate the degree of lung injury, and can be used in the evaluation of acute lung injury after acute hydrogen sulfide poisoning.

Molecular identification and seasonal infections of species of Fasciola in ruminants from two provinces in China.

We determined the prevalence and seasonality of infections by Fasciola of goats and bovine species (cattle and water buffalo) in Hubei and Anhui provinces of China. Faecal samples were collected at 2- to 3-month intervals from 200 goats in Hubei province and from 152 bovine species in Anhui province. All faecal samples were examined for the presence of parasites. We determined the nucleotide sequences of the first and second internal transcribed spacers (ITS-1 and ITS-2) of the nuclear ribosomal DNA (rDNA) of 39 Fasciola worms from Anhui province. The prevalence of Fasciola infection in goats ranged between 3.5 and 37.0%, with mean eggs per gram (EPG) ranging between 29.0 and 166.0. Prevalence and EPG exhibited downward trends over time with significant differences. The prevalence of Fasciola infection in cattle ranged between 13.3 and 46.2% (mean EPG, 36.4-100.0), and that of water buffalo ranged between 10.3 and 35.4% (mean EPG, 25.0-89.6), with a higher prevalence of infection and EPG from June to October compared with December to March. Analysis of ITS-1 and ITS-2 sequences revealed that F. hepatica and F. gigantica were present in all bovine species of Anhui province and that F. gigantica mainly infected water buffalo. This is the first demonstration of Fasciola infection in Hubei province and detection of F. hepatica and F. gigantica in Anhui province. The present study of Hubei province shows that mass treatment of livestock with closantel sodium injections in April and August/September controlled Fasciola infection effectively.

Further studies into the photodissociation pathways of 2-bromo-2-nitropropane and the dissociation channels of the 2-nitro-2-propyl radical intermediate.

These experiments investigate the decomposition mechanisms of geminal dinitro energetic materials by photolytically generating two key intermediates: 2-nitropropene and 2-nitro-2-propyl radicals. To characterize the unimolecular dissociation of each intermediate, we form them under collision-free conditions using the photodissociation of 2-bromo-2-nitropropane; the intermediates are formed at high internal energies and undergo a multitude of subsequent unimolecular dissociation events investigated herein. Complementing our prior work on this system, the new data obtained with a crossed-laser molecular beam scattering apparatus with VUV photoionization detection at Taiwan's National Synchrotron Radiation Research Center (NSRRC) and new velocity map imaging data better characterize two of the four primary 193 nm photodissociation channels. The C-Br photofission channel forming the 2-nitro-2-propyl radicals has a trimodal recoil kinetic energy distribution, P(ET), suggesting that the 2-nitro-2-propyl radicals are formed both in the ground electronic state and in two low-lying excited electronic states. The new data also revise the HBr photoelimination P(ET) forming the 2-nitropropene intermediate. We then resolved the multiple competing unimolecular dissociation channels of each photoproduct, confirming many of the channels detected in the prior study, but not all. The new data detected HONO product at m/e = 47 using 11.3 eV photoionization from both intermediates; analysis of the momentum-matched products allows us to establish that both 2-nitro-2-propyl → HONO + CH3CCH2 and 2-nitropropene → HONO + C3H4 occur. Photoionization at 9.5 eV allowed us to detect the mass 71 coproduct formed in OH loss from 2-nitro-2-propyl; a channel missed in our prior study. The dynamics of the highly exothermic 2-nitro-2-propyl → NO + acetone dissociation is also better characterized; it evidences a sideways scattered angular distribution. The detection of some stable 2-nitropropene photoproducts allows us to fit signal previously assigned to H loss from 2-nitro-2-propyl radicals. Overall, the data provide a comprehensive study of the unimolecular dissociation channels of these important nitro-containing intermediates.

Radical intermediates in the addition of OH to propene: photolytic precursors and angular momentum effects.

We investigate the photolytic production of two radical intermediates in the reaction of OH with propene, one from addition of the hydroxyl radical to the terminal carbon and the other from addition to the center carbon. In a collision-free environment, we photodissociate a mixture of 1-bromo-2-propanol and 2-bromo-1-propanol at 193 nm to produce these radical intermediates. The data show two primary photolytic processes occur: C-Br photofission and HBr photoelimination. Using a velocity map imaging apparatus, we measured the speed distribution of the recoiling bromine atoms, yielding the distribution of kinetic energies of the nascent C3H6OH radicals + Br. Resolving the velocity distributions of Br((2)P(1/2)) and Br((2)P(3/2)) separately with 2 + 1 REMPI allows us to determine the total (vibrational + rotational) internal energy distribution in the nascent radicals. Using an impulsive model to estimate the rotational energy imparted to the nascent C3H6OH radicals, we predict the percentage of radicals having vibrational energy above and below the lowest dissociation barrier, that to OH + propene; it accurately predicts the measured velocity distribution of the stable C3H6OH radicals. In addition, we use photofragment translational spectroscopy to detect several dissociation products of the unstable C3H6OH radicals: OH + propene, methyl + acetaldehyde, and ethyl + formaldehyde. We also use the angular momenta of the unstable radicals and the tensor of inertia of each to predict the recoil kinetic energy and angular distributions when they dissociate to OH + propene; the prediction gives an excellent fit to the data.

α-1,3-N-acetylgalactose aminotransferase gene 539G>C mutation leads to the A2B isoform.

In this study, the phenotypic identification and molecular mechanism of one case of an A2B subtype pedigree was investigated. ABO blood groupings were identified by serological methods and sequence amplification was performed by polymerase chain reaction (PCR) using TA cloning and DNA sequencing analysis to identify the pedigree and the ABO gene haploid of the proband. There were both A and B antigens on the proband's red blood cells, and anti-A1 antibodies were found in the serum. Direct sequencing of the 6th and 7th exons of the ABO gene showed the A208/B101 genotype, and haploid determination revealed the A208 and B101 alleles. Compared with the A102 allele sequence, the A208 allele was mutated at the 539 G>C site. Pedigree analysis showed that the ABO blood phenotypes of the proband's father, mother, husband, and daughter were A2, B, AB, and A2B, respectively, and their genotypes were A208/O02, B101/B101, A102/B101, and A208/B101, respectively. The father of the proband had anti-A1 antibodies and the A208 allele of the proband was inherited from her father, which can be passed on to her daughter. The α-1, 3-N-acetylgalactose aminotransferase gene 539G>C mutation resulted in A2B phenotype generation, and individual serum contained the anti-A1 antibody.

[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.

Reduced door-to-balloon times in acute ST-elevation myocardial infarction patients undergoing primary percutaneous coronary intervention.

BACKGROUND: Primary percutaneous coronary intervention (PCI) in patients with ST-elevation myocardial infarction (STEMI) significantly reduces mortality and morbidity, particularly when door-to-balloon (D2B) time is < 90 min. We sought to minimize preventable delays by instituting an on-site cardiology team-based approach in the emergency department (ED). METHODS: The on-site group comprised 146 consecutive patients with STEMI undergoing primary PCI after implementation of the on-site strategy. This new patient care model was compared with the conventional care administered before instituting the on-site cardiology team-based strategy in ED, which included 90 patients (interim group) receiving primary PCI at a catheterization room in the same building as the ED, and 147 patients (pre-on-site group) undergoing primary PCI at a catheterization room two blocks away from the ED. RESULTS: Median D2B time decreased from 107 min in the pre-on-site group to 72 min in the interim group, and to 47 min in the on-site group, respectively (p < 0.001). The percentage of D2B times < 90 min increased from 34% to 78% and 96%, respectively among the three groups (p < 0.001). Hospitalization costs were significantly reduced in the on-site and interim vs. pre-on-site groups ($5944, $5999, and $6581, respectively; p = 0.008). In-hospital mortality did not differ significantly among the three groups (4.8%, 2.2%, and 6.1%, respectively; p = 0.387). CONCLUSIONS: Institution of an on-site cardiology team-based approach in the ED significantly reduces D2B time in STEMI patients eligible for primary PCI.

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.