A state-of-the-art review of curve squeal noise: Phenomena, mechanisms, modelling and mitigation

[EN] Curve squeal is an intense tonal noise occurring when a rail vehicle negotiates a sharp curve. The phenomenon can be considered to be chaotic, with a widely differing likelihood of occurrence on different days or even times of day. The term curve squeal may include several different phenomena with a wide range of dominant frequencies and potentially different excitation mechanisms. This review addresses the different squeal phenomena and the approaches used to model squeal noise; both time-domain and frequency-domain approaches are discussed and compared. Supporting measurements using test rigs and field tests are also summarised. A particular aspect that is addressed is the excitation mechanism. Two mechanisms have mainly been considered in previous publications. In many early papers the squeal was supposed to be generated by the so-called falling friction characteristic in which the friction coefficient reduces with increasing sliding velocity. 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Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Background: Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. // Methods: We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung's disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. // Findings: We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung's disease) from 264 hospitals (89 in high-income countries, 166 in middle-income countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in low-income countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. // Interpretation: Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between low-income, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

A phase Ib study of NUC-1031 in combination with cisplatin for the first-line treatment of patients with advanced biliary tract cancer (ABC-08)

Background: Cisplatin/gemcitabine is standard first‐line treatment for patients with advanced biliary tract cancer (ABC). NUC‐1031 (phosphoramidate transformation of gemcitabine) is designed to enhance efficacy by maximizing intratumoral active metabolites. Methods: Patients with untreated ABC, Eastern Cooperative Oncology Group performance status 0–1 received NUC‐1031 (625 or 725 mg/m2) and cisplatin (25 mg/m2) on days 1 and 8, every 21 days. Primary objectives were safety and maximum tolerated dose; secondary objectives were objective response rate (ORR), pharmacokinetics, progression‐free survival (PFS), and overall survival (OS). Results: Twenty‐one patients (median age 61 years, n = 13 male; 17 cholangiocarcinoma, 2 ampullary, and 2 gallbladder cancer) received NUC‐1031 625 mg/m2 (n = 8 and expansion n = 7; median six cycles) or 725 mg/m2 (n = 6; median 7.5 cycles). Treatment was well tolerated; most common treatment‐emergent grade 3–4 adverse events occurring in more than one patient with 625 mg/m2 NUC‐1031 were increased gamma‐glutamyl transferase (GGT), 40%; alanine aminotransferase, 20%; bilirubin, 13%; neutropenia, 27%; decreased white cell count, 20%; thrombocytopenia, 13%; nausea, 13%; diarrhea, 13%; fatigue, 13%; and thrombus, 20% and with 725 mg/m2, increased GGT, 67%, and fatigue, 33%. NUC‐1031 725 mg/m2 was selected as the recommended dose with cisplatin in ABC. ORR was 33% (one complete response, six partial responses), DCR was 76%, median PFS was 7.2 months (95% confidence interval [CI], 4.3–10.1), and median OS was 9.6 months (95% CI, 6.7–13.1). The median estimates of area under the plasma concentration–time curve from time 0 to last measurable time and maximum concentration were highest for NUC‐1031 (218–324 μg•h/mL and 309–889 μg/mL, respectively) and lowest for di‐fluoro‐deoxycytidine (0.47–1.56 μg•h/mL and 0.284–0.522 μg/mL, respectively). Conclusion: This is the first study reporting on the combination of NUC‐1031 with cisplatin in ABC and demonstrated a favorable safety profile; 725 mg/m2 NUC‐1031 in combination with cisplatin is undergoing phase III trial evaluation in ABC. (ClinicalTrials.gov ID: NCT02351765; EudraCT ID: 2015‐000100‐26). Implications for Practice: The prognosis for patients with advanced biliary tract cancer (ABC) is approximately 1 year, and new treatment options are required. The cisplatin/gemcitabine combination is standard first‐line treatment for patients with ABC. NUC‐1031 is a phosphoramidate transformation of gemcitabine and is designed to enhance efficacy by maximizing intratumoral active metabolites. This phase Ib study (ABC‐08) demonstrated a favorable safety profile of NUC‐1031 in combination with cisplatin for the first‐line treatment of patients with ABC, and 725 mg/m2 NUC‐1031 was recommended in combination with cisplatin for phase III trial evaluation; the NuTide:121 global randomized study is currently enrolling

Reproductive studies in ipecac (Psychotria ipecacuanha (Brot.) stockes; Rubiaceae): pollen development and morphology

The aim of this work was to carry out the reproductive studies on Brazilian accessions of ipecac, Psychotria ipecacuanha. It presented heterostyly, with brevistylous and longistylous flowers. The pollen development was observed from the sections of the anthers embedded in resin. Anther development was normal as usually observed in dicotyledones, displaying four layers: outer epidermis, endothecium, middle layer and inner tapetum. The pollen was bicellular and filled with starch at the microspore stage. Pollen morphology was studied using SEM, which showed pollen polymorphism within and between the two floral morphs. Five types of pollen with reticulate or perforate exine were identified. The characteristics showed that the sexual process was as important as the vegetative propagation for the reproduction of this species.<br>Foram realizados estudos reprodutivos em acessos brasileiros de poaia, Psychotria ipecacuanha. Poaia apresenta heterostilia, com flores brevistilas e longistilas. O desenvolvimento do pólen foi estudado em cortes de anteras embebidas em resina. O desenvolvimento da antera seguiu o padrão normal para as dicotiledôneas, a qual apresentou quatro camadas: epiderme, endotécio, camada média, e tapete, a mais interna. O pólen apresentou-se bicelular e preenchido com amido no estágio de micrósporo. A morfologia do pólen foi estudada utilizando-se MEV. Foi observado polimorfismo polínico dentro e entre as duas formas florais. Foram identificados cinco tipos de grãos de pólen, com exina reticulada ou perfurada. Em seu hábitat natural, sabe-se que essa espécie apresenta propagação por multiplicação vegetativa, mas as características estudadas demonstraram que o mecanismo sexuado é tão importante para a reprodução dessa espécie quanto à propagação vegetativa