Rotavirus hospitalisation in New Zealand children under 3 years of age

Objective: To describe the epidemiology of severe rotavirus gastroenteritis and to estimate the hospitalisation rates of this illness in New Zealand children under 3 years of age. Methods: Children under 3 years of age with acute diarrhoea admitted to 1 of 8 study hospitals between 1 May 1998 and 30 April 2000 were surveyed. Their socio-demographic, treatment and length-of-stay data were recorded and stool samples tested by a rotavirus-specific enzyme-linked immunoassay. National hospital discharge data for infectious diarrhoea (International Classification of Diseases, ninth revision, 003–009) were reviewed, allowing population-based estimates for rotavirus-related hospitalisation in New Zealand. Results: Of 2019 enrolled children, 1138 (56.4%) provided stools for testing, and of these 485 (42.6%) tested rotavirus positive. Rotavirus detection varied significantly by age (26.8% for 0 to 5 months, 42.5% for 6 to 11 months and 52.1% for children aged 12 to 35 months; P < 0.001), and by season (51.2% in winter/spring vs. 24.5% in summer/autumn; P < 0.001). While those infected with rotavirus were more likely to be dehydrated (50.6% vs. 37.4%; P < 0.001), their median hospital stay was similar (1.0 vs. 2.0 days; P = 0.09) to other children with acute gastroenteritis. The estimated national hospitalisation rate for rotavirus diarrhoea in children under 3 years, standardised for age and season, was 634 (95% CI 597, 672) per 100 000. In New Zealand, rotaviruses result in 1 in 52 children being hospitalised by 3 years of age. Conclusions: Rotavirus diarrhoea is an important, potentially vaccine-preventable cause of hospitalisation in New Zealand children, especially during winter and spring seasons

Entrectinib in patients with advanced or metastatic <i>NTRK</i> fusion-positive solid tumours: integrated analysis of three phase 1-2 trials

BACKGROUND: Entrectinib is a potent inhibitor of tropomyosin receptor kinase (TRK) A, B, and C, which has been shown to have anti-tumour activity against NTRK gene fusion-positive solid tumours, including CNS activity due to its ability to penetrate the blood-brain barrier. We present an integrated efficacy and safety analysis of patients with metastatic or locally advanced solid tumours harbouring oncogenic NTRK1, NTRK2, and NTRK3 gene fusions treated in three ongoing, early-phase trials. METHODS: An integrated database comprised the pivotal datasets of three, ongoing phase 1 or 2 clinical trials (ALKA-372-001, STARTRK-1, and STARTRK-2), which enrolled patients aged 18 years or older with metastatic or locally advanced NTRK fusion-positive solid tumours who received entrectinib orally at a dose of at least 600 mg once per day in a capsule. All patients had an Eastern Cooperative Oncology Group performance status of 0-2 and could have received previous anti-cancer therapy (except previous TRK inhibitors). The primary endpoints, the proportion of patients with an objective response and median duration of response, were evaluated by blinded independent central review in the efficacy-evaluable population (ie, patients with NTRK fusion-positive solid tumours who were TRK inhibitor-naive and had received at least one dose of entrectinib). Overall safety evaluable population included patients from STARTRK-1, STARTRK-2, ALKA-372-001, and STARTRK-NG (NCT02650401; treating young adult and paediatric patients [aged ≤21 years]), who received at least one dose of entrectinib, regardless of tumour type or gene rearrangement. NTRK fusion-positive safety evaluable population comprised all patients who have received at least one dose of entrectinib regardless of dose or follow-up. These ongoing studies are registered with ClinicalTrials.gov, NCT02097810 (STARTRK-1) and NCT02568267 (STARTRK-2), and EudraCT, 2012-000148-88 (ALKA-372-001). FINDINGS: Patients were enrolled in ALKA-372-001 from Oct 26, 2012, to March 27, 2018; in STARTRK-1 from Aug 7, 2014, to May 10, 2018; and in STARTRK-2 from Nov 19, 2015 (enrolment is ongoing). At the data cutoff date for this analysis (May 31, 2018) the efficacy-evaluable population comprised 54 adults with advanced or metastatic NTRK fusion-positive solid tumours comprising ten different tumour types and 19 different histologies. Median follow-up was 12.9 months (IQR 8·77-18·76). 31 (57%; 95% CI 43·2-70·8) of 54 patients had an objective response, of which four (7%) were complete responses and 27 (50%) partial reponses. Median duration of response was 10 months (95% CI 7·1 to not estimable). The most common grade 3 or 4 treatment-related adverse events in both safety populations were increased weight (seven [10%] of 68 patients in the NTRK fusion-positive safety population and in 18 [5%] of 355 patients in the overall safety-evaluable population) and anaemia (8 [12%] and 16 [5%]). The most common serious treatment-related adverse events were nervous system disorders (three [4%] of 68 patients and ten [3%] of 355 patients). No treatment-related deaths occurred. INTERPRETATION: Entrectinib induced durable and clinically meaningful responses in patients with NTRK fusion-positive solid tumours, and was well tolerated with a manageable safety profile. These results show that entrectinib is a safe and active treatment option for patients with NTRK fusion-positive solid tumours. These data highlight the need to routinely test for NTRK fusions to broaden the therapeutic options available for patients with NTRK fusion-positive solid tumours. FUNDING: Ignyta/F Hoffmann-La Roche

Effects of crystallographic orientation on corrosion behavior of magnesium single crystals

The corrosion behavior of magnesium single crystals with various crystallographic orientations was examined in this study. To identify the effects of surface orientation on the corrosion behavior in a systematic manner, single-crystal specimens with ten different rotation angles of the plane normal from the [0001] direction to the [1010] direction at intervals of 10&deg; were prepared and subjected to potentiodynamic polarization and potentiostatic tests as well as electrochemical impedance spectroscopy (EIS) measurements in 3.5 wt.% NaCl solution. Potentiodynamic polarization results showed that the pitting potential (E pit) first decreased from &minus;1.57 V SCE to &minus;1.64 V SCE with an increase in the rotation angle from 0&deg; to 40&deg;, and then increased to &minus;1.60 V SCE with a further increase in the rotation angle to 90&deg;. The results obtained from potentiostatic tests are also in agreement with the trend in potentiodynamic polarization tests as a function of rotation angle. A similar trend was also observed for the depressed semicircle and the total resistances in the EIS measurements due to the facile formation of MgO and Mg(OH)2 passive films on the magnesium surface. In addition, the amount of chloride in the passive film was found first to increase with an increase in rotation angle from 0&deg; to 40&deg;, then decrease with a further increase in rotation angle, indicating that the tendency to form a more protective passive film increased for rotation angle near 0&deg; [the (0001) plane] or 90&deg; [the (1010) plane]. <br /