Two dimensional dynamical systems which admit Lie and Noether symmetries

We prove two theorems which relate the Lie point symmetries and the Noether symmetries of a dynamical system moving in a Riemannian space with the special projective group and the homothetic group of the space respectively. The theorems are applied to classify the two dimensional Newtonian dynamical systems, which admit a Lie point/Noether symmetry. Two cases are considered, the non-conservative and the conservative forces. The use of the results is demonstrated for the Kepler - Ermakov system, which in general is non-conservative and for potentials similar to the H\`enon Heiles potential. Finally it is shown that in a FRW background with no matter present, the only scalar cosmological model which is integrable is the one for which 3-space is flat and the potential function of the scalar field is exponential. It is important to note that in all applications the generators of the symmetry vectors are found by reading the appropriate entry in the relevant tables.Comment: 25 pages, 17 table

Adjuvant nivolumab for stage III/IV melanoma: Evaluation of safety outcomes and association with recurrence-free survival

Background Several therapeutic options are now available in the adjuvant melanoma setting, mandating an understanding of their benefit €'risk profiles in order to make informed treatment decisions. Herein we characterize adjuvant nivolumab select (immune-related) treatment-related adverse events (TRAEs) and evaluate possible associations between safety and recurrence-free survival (RFS) in the phase III CheckMate 238 trial. Methods Patients with resected stage IIIB-C or IV melanoma received nivolumab 3 mg/kg every 2 weeks (n=452) or ipilimumab 10 mg/kg every 3 weeks for four doses and then every 12 weeks (n=453) for up to 1 year or until disease recurrence, unacceptable toxicity, or consent withdrawal. First-occurrence and all-occurrence select TRAEs were analyzed within discrete time intervals: from 0 to 3 months of treatment, from >3-12 months of treatment, and from the last dose (regardless of early or per-protocol treatment discontinuation) to 100 days after the last dose. Possible associations between select TRAEs and RFS were investigated post randomization in 3-month landmark analyses and in Cox model analyses (including a time-varying covariate of select TRAE), within and between treatment groups. Results From the first nivolumab dose to 100 days after the last dose, first-occurrence select TRAEs were reported in 67.7% (306/452) of patients. First-occurrence select TRAEs were reported most frequently from 0 to 3 months (48.0%), during which the most common were pruritus (15.5%) and diarrhea (15.3%). Most select TRAEs resolved within 6 months. There was no clear association between the occurrence (or not) of select TRAEs and RFS by landmark analysis or by Cox model analysis within treatment arms or comparing nivolumab to the ipilimumab comparator arm. Conclusion Results of this safety analysis of nivolumab in adjuvant melanoma were consistent with its established safety profile. In the discrete time intervals evaluated, most first-occurrence TRAEs occurred early during treatment and resolved. No association between RFS and select TRAEs was evident. Trial registration number NCT02388906

Gravity modelling along CROP04 seismic profile

The processing and interpretation of seismic lines, together with the analysis of surficial geological data and hydrocarbon wells data, are powerful tools for the investigation of crust structures. Nevertheless, for depths exceeding that portion of crust usually investigated for commercial purposes, only geophysical data are generally available (among the others: NVR seismic from CROP project, DSS data, magnetic data, gravity data). In this context, the possibility of comparing two independent geophysical data sets, such as data from seismic exploration (CROP Project) and gravimetric analysis (Bouguer anomalies), is of particular interest for investigations into the deeper crust portion. In the present work gravity data modelling was used to study deep crust, constraints being provided by WARR data and by reflection seismic data obtained along the CROP04 profile that crosses the Southern Apennines (Italy) from Agropoli (SW) to Barletta (NE). A preliminary interpretation has been made of the regional gravity anomaly trend in deep crust in Southern Italy; the role of this anomaly trend as an independent constraint for the geological interpretation of the CROP04 seismic line is discussed

TELO-SCOPE study: a randomised, double-blind, placebo-controlled, phase 2 trial of danazol for short telomere related pulmonary fibrosis

Introduction: Recent discoveries have identified shortened telomeres and related mutations in people with pulmonary fibrosis (PF). There is evidence to suggest that androgens, including danazol, may be effective in lengthening telomeres in peripheral blood cells. This study aims to assess the safety and efficacy of danazol in adults and children with PF associated with telomere shortening.Methods and analysis: A multi-centre, double-blind, placebo-controlled, randomised trial of danazol will be conducted in subjects aged >5 years with PF associated with age-adjusted telomere length ≤10th centile measured by flow fluorescence in situ hybridisation; or in children, a diagnosis of dyskeratosis congenita. Adult participants will receive danazol 800 mg daily in two divided doses or identical placebo capsules orally for 12 months, in addition to standard of care (including pirfenidone or nintedanib). Paediatric participants will receive danazol 2 mg/kg/day orally in two divided doses or identical placebo for 6 months. If no side effects are encountered, the dose will be escalated to 4 mg/kg/day (maximum 800 mg daily) orally in two divided doses for a further 6 months. The primary outcome is change in absolute telomere length in base pairs, measured using the telomere shortest length assay (TeSLA), at 12 months in the intention to treat population

Analysis of c-KIT expression and KIT gene mutation in human mucosal melanomas

Recent data suggested an increased frequency of KIT aberrations in mucosal melanomas, whereas c-KIT in most types of cutaneous melanomas does not appear to be of pathogenetic importance. However, studies investigating the status of the KIT gene in larger, well-characterised groups of patients with mucosal melanomas are lacking. We analysed 44 archival specimens of 39 well-characterised patients with mucosal melanomas of different locations. c-KIT protein expression was determined by immunhistochemistry, KIT gene mutations were analysed by PCR amplification and DNA sequencing of exons 9, 11, 13, 17 and 18. c-KIT protein expression could be shown in 40 out of 44 (91%) tumours in at least 10% of tumour cells. DNA sequence analysis of the KIT was successfully performed in 37 patients. In 6 out of 37 patients (16%) KIT mutations were found, five in exon 11 and one in exon 18. The presence of mutations in exon 11 correlated with a significant stronger immunohistochemical expression of c-KIT protein (P=0.015). Among the six patients with mutations, in two patients the primary tumour was located in the head/neck region, in three patients in the genitourinary tract and in one patient in the anal/rectal area. In conclusion, KIT mutations can be found in a subset of patients with mucosal melanomas irrespective of the location of the primary tumour. Our data encourage therapeutic attempts with tyrosine kinase inhibitors blocking c-KIT in these patients

Cross-sectional analysis of baseline differences of candidates for rotator cuff surgery: a sex and gender perspective

<p>Abstract</p> <p>Background</p> <p>The word "sex" refers to biological differences between men and women. Gender refers to roles, behaviors, activities, and attributes that a given society considers appropriate for men and women. Traditionally, treatment decisions have been based on patient's sex without including the gender. Assessment of disability secondary to musculoskeletal problems would not be complete or accurate unless potentially relevant biological and non-biological aspects of being a man or woman are taken into consideration. The purposes of this study were to: 1) investigate the difference in pre-operative characteristics between men and women who were candidates for rotator cuff surgery; and, 2) assess the relationship between level of disability and factors that represent sex and factors that signify gender.</p> <p>Method</p> <p>This was a cross-sectional study. The primary outcome measure of disability was a disease-specific outcome measure, the Western Ontario Rotator Cuff (WORC) index, and independent variables were sex, age, hand dominance, shoulder side involvement, BMI, co-morbidity, medication use, work status, smoking habits, strength, range of motion, level of pathology, concurrent osteoarthritis, expectations for recovery, and participation restriction. Parametric, non-parametric, univariable, subgroup, and multivariable analyses were conducted.</p> <p>Results</p> <p>One hundred and seventy patients were included in the study. The mean age was 57 ± 11, 85 were females. Women reported higher levels of disability despite similar or lower levels of pathology. Scores of the WORC were strongly influenced by factors that represented "gender" such as participation restriction (F = 28.91, p < 0.0001) and expectations for improved activities of daily living (F = 5.80, p = 0.004). Painfree combined range of motion, which represented an interaction between "sex" and "gender" was also associated with disability after being adjusted for all other relevant baseline factors (F = 25.82, p < 0.0001).</p> <p>Conclusion</p> <p>Gender-related factors such as expectations and participation limitations have an independent impact on disability in men and women undergoing rotator cuff related surgery.</p

Narrowing the knowledge gaps for melanoma

Cutaneous melanoma originates from pigment producing melanocytes or their precursors and is considered the deadliest form of skin cancer. For the last 40 years, few treatment options were available for patients with late-stage melanoma. However, remarkable advances in the therapy field were made recently, leading to the approval of two new drugs, the mutant BRAF inhibitor vemurafenib and the immunostimulant ipilimumab. Although these drugs prolong patients' lives, neither drug cures the disease completely, emphasizing the need for improvements of current therapies. Our knowledge about the complex genetic and biological mechanisms leading to melanoma development has increased, but there are still gaps in our understanding of the early events of melanocyte transformation and disease progression. In this review, we present a summary of the main contributing factors leading to melanocyte transformation and discuss recent novel findings and technologies that will help answer some of the key biological melanoma questions and lay the groundwork for novel therapies

Global, regional, and national burden of stroke and its risk factors, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019

Background Regularly updated data on stroke and its pathological types, including data on their incidence, prevalence, mortality, disability, risk factors, and epidemiological trends, are important for evidence-based stroke care planning and resource allocation. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) aims to provide a standardised and comprehensive measurement of these metrics at global, regional, and national levels. Methods We applied GBD 2019 analytical tools to calculate stroke incidence, prevalence, mortality, disability-adjusted life-years (DALYs), and the population attributable fraction (PAF) of DALYs (with corresponding 95% uncertainty intervals [UIs]) associated with 19 risk factors, for 204 countries and territories from 1990 to 2019. These estimates were provided for ischaemic stroke, intracerebral haemorrhage, subarachnoid haemorrhage, and all strokes combined, and stratified by sex, age group, and World Bank country income level. Findings In 2019, there were 12·2 million (95% UI 11·0–13·6) incident cases of stroke, 101 million (93·2–111) prevalent cases of stroke, 143 million (133–153) DALYs due to stroke, and 6·55 million (6·00–7·02) deaths from stroke. Globally, stroke remained the second-leading cause of death (11·6% [10·8–12·2] of total deaths) and the third-leading cause of death and disability combined (5·7% [5·1–6·2] of total DALYs) in 2019. From 1990 to 2019, the absolute number of incident strokes increased by 70·0% (67·0–73·0), prevalent strokes increased by 85·0% (83·0–88·0), deaths from stroke increased by 43·0% (31·0–55·0), and DALYs due to stroke increased by 32·0% (22·0–42·0). During the same period, age-standardised rates of stroke incidence decreased by 17·0% (15·0–18·0), mortality decreased by 36·0% (31·0–42·0), prevalence decreased by 6·0% (5·0–7·0), and DALYs decreased by 36·0% (31·0–42·0). However, among people younger than 70 years, prevalence rates increased by 22·0% (21·0–24·0) and incidence rates increased by 15·0% (12·0–18·0). In 2019, the age-standardised stroke-related mortality rate was 3·6 (3·5–3·8) times higher in the World Bank low-income group than in the World Bank high-income group, and the age-standardised stroke-related DALY rate was 3·7 (3·5–3·9) times higher in the low-income group than the high-income group. Ischaemic stroke constituted 62·4% of all incident strokes in 2019 (7·63 million [6·57–8·96]), while intracerebral haemorrhage constituted 27·9% (3·41 million [2·97–3·91]) and subarachnoid haemorrhage constituted 9·7% (1·18 million [1·01–1·39]). In 2019, the five leading risk factors for stroke were high systolic blood pressure (contributing to 79·6 million [67·7–90·8] DALYs or 55·5% [48·2–62·0] of total stroke DALYs), high body-mass index (34·9 million [22·3–48·6] DALYs or 24·3% [15·7–33·2]), high fasting plasma glucose (28·9 million [19·8–41·5] DALYs or 20·2% [13·8–29·1]), ambient particulate matter pollution (28·7 million [23·4–33·4] DALYs or 20·1% [16·6–23·0]), and smoking (25·3 million [22·6–28·2] DALYs or 17·6% [16·4–19·0]). Interpretation The annual number of strokes and deaths due to stroke increased substantially from 1990 to 2019, despite substantial reductions in age-standardised rates, particularly among people older than 70 years. The highest age-standardised stroke-related mortality and DALY rates were in the World Bank low-income group. The fastest-growing risk factor for stroke between 1990 and 2019 was high body-mass index. Without urgent implementation of effective primary prevention strategies, the stroke burden will probably continue to grow across the world, particularly in low-income countries.publishedVersio

Global, regional, and national burden of disorders affecting the nervous system, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

Background Disorders affecting the nervous system are diverse and include neurodevelopmental disorders, late-life neurodegeneration, and newly emergent conditions, such as cognitive impairment following COVID-19. Previous publications from the Global Burden of Disease, Injuries, and Risk Factor Study estimated the burden of 15 neurological conditions in 2015 and 2016, but these analyses did not include neurodevelopmental disorders, as defined by the International Classification of Diseases (ICD)-11, or a subset of cases of congenital, neonatal, and infectious conditions that cause neurological damage. Here, we estimate nervous system health loss caused by 37 unique conditions and their associated risk factors globally, regionally, and nationally from 1990 to 2021. Methods We estimated mortality, prevalence, years lived with disability (YLDs), years of life lost (YLLs), and disability-adjusted life-years (DALYs), with corresponding 95% uncertainty intervals (UIs), by age and sex in 204 countries and territories, from 1990 to 2021. We included morbidity and deaths due to neurological conditions, for which health loss is directly due to damage to the CNS or peripheral nervous system. We also isolated neurological health loss from conditions for which nervous system morbidity is a consequence, but not the primary feature, including a subset of congenital conditions (ie, chromosomal anomalies and congenital birth defects), neonatal conditions (ie, jaundice, preterm birth, and sepsis), infectious diseases (ie, COVID-19, cystic echinococcosis, malaria, syphilis, and Zika virus disease), and diabetic neuropathy. By conducting a sequela-level analysis of the health outcomes for these conditions, only cases where nervous system damage occurred were included, and YLDs were recalculated to isolate the non-fatal burden directly attributable to nervous system health loss. A comorbidity correction was used to calculate total prevalence of all conditions that affect the nervous system combined. Findings Globally, the 37 conditions affecting the nervous system were collectively ranked as the leading group cause of DALYs in 2021 (443 million, 95% UI 378–521), affecting 3·40 billion (3·20–3·62) individuals (43·1%, 40·5–45·9 of the global population); global DALY counts attributed to these conditions increased by 18·2% (8·7–26·7) between 1990 and 2021. Age-standardised rates of deaths per 100 000 people attributed to these conditions decreased from 1990 to 2021 by 33·6% (27·6–38·8), and age-standardised rates of DALYs attributed to these conditions decreased by 27·0% (21·5–32·4). Age-standardised prevalence was almost stable, with a change of 1·5% (0·7–2·4). The ten conditions with the highest age-standardised DALYs in 2021 were stroke, neonatal encephalopathy, migraine, Alzheimer's disease and other dementias, diabetic neuropathy, meningitis, epilepsy, neurological complications due to preterm birth, autism spectrum disorder, and nervous system cancer. Interpretation As the leading cause of overall disease burden in the world, with increasing global DALY counts, effective prevention, treatment, and rehabilitation strategies for disorders affecting the nervous system are needed. Funding Bill & Melinda Gates Foundation