An individualized digital twin of a patient for transdermal fentanyl therapy for chronic pain management.

Fentanyl transdermal therapy is a suitable treatment for moderate-to-severe cancer-related pain. The inter-individual variability of the patients leads to different therapy responses. This study aims to determine the effect of physiological features on the achieved pain relief. Therefore, a set of virtual patients was developed by using Markov chain Monte Carlo (MCMC) based on actual patient data. The members of this virtual population differ by age, weight, gender, and height. Tailored digital twins were developed using these correlated, individualized parameters to propose a personalized therapy for each patient. It was shown that patients of different ages, weights, and gender have significantly different fentanyl blood uptake, plasma fentanyl concentration, pain relief, and ventilation rate. In the digital twins, we included the virtual patients' response to the treatment, namely, pain relief. Therefore, the digital twin was able to adjust the therapy in silico to have more efficient pain relief. By implementing digital-twin-assisted therapy, the average pain intensity decreased by 16% compared to conventional therapy. The median time without pain increased by 23 h over 72 h. Therefore, the digital twin can be successfully used in individual control of transdermal therapy to reach higher pain relief and maintain steady pain relief. (Created with BioRender.com)

Underweight and overweight among children and adolescents in Tuscany (Italy). Prevalence and short-term trends

Introduction. The recent increase in both childhood obesity and adolescent anorexia nervosa in developed countries has under-lined the important consequences that these trends may have on public health, as there is an increased risk that these conditions may become chronic diseases in adulthood. Therefore, it is necessary to monitor prevalence rates and trends in thinness and overweight (including obesity) among children and adolescents at different levels: international, national and sub-national. Since 2001/2002, a nutritional surveillance system has been implemented in the Tuscany Region to estimate the nutritional status and lifestyles of children and adolescents. The main objectives were to assess the prevalence of thinness, overweight and obesity among Tuscan children and adolescents and to provide baseline information on the prevalence of thinness, for the first time calculated according to the new international definitions, for geographical comparisons and descriptions of time trends. Methods. Independent cross-sectional sample surveys were conducted in 2002, 2004 and 2006 in Tuscany, North-Central Italy. Data were collected from stratified two-stage cluster samples of children aged 9 years (n = 3,048 in 2002 and n = 1,430 in 2006) and of adolescents aged 11-13-15 years (n = 1,066, n = 1185 and n = 1,160 in 2004 and n = 1,189, n = 1,211 and n = 1,178 in 2006, respectively). Weights and heights of primary school children were measured by means of standardized methods, while those of adolescents were self-reported. Decimal age was calculated from the date of birth to the date of measurement. Body Mass Index classes were calculated according to the International Obesity Task Force standards. Instead of the term underweight in children, we used the term thinness, which the World Health Organization uses to mean low Body Mass Index for age in adults and adolescents. According to Cole?s recently published cut-offs for thinness, we divided our Body Mass Index values below 18.5 into three grades. Results. This study presents data on the prevalence of different grades of nutritional status (thinness, normal weight, overweight and obesity) among Tuscan school-aged children from primary to high school (9-11-13-15-y-old), assessed by means of Body Mass Index, according to international definitions. From 2002 to 2006 the prevalence of thinness among children aged 9 years decreased from 4.6% to 4.2%, and the prevalence of normal weight from 63.7% to 62.4%; the prevalence of overweight (including obesity) rose from 31.7% to 33.4%. From 2004 to 2006, among pre-adolescents aged 11 years, the prevalence of thinness declined from 11.0% to 10.1%; the prevalence of normal weight rose from 68.4% to 70.2%, and the prevalence of overweight declined from 20.7% to 19.6%. Among adolescents aged 13 years, the prevalence of thinness declined from 9.8% to 8.0%; the prevalence of normal weight rose from 73.5% to 74.0%, and the prevalence of overweight from 16.8% to 17.9%. Among adolescents aged 15 years, the prevalence of thinness declined from 9.8% to 8.7%, and the prevalence of normal weight from 77.0% to 71.6%, while the prevalence of overweight rose from 13.3% to 19.7%. The 2006 data showed that the trend in the prevalence of overweight (including obesity) tended to decrease with age for both sexes, though more markedly in girls (from 34.0% at 9-y of age to 12.2% at 15-y of age) than in boys (from 32.8% at 9-y of age to 22.8% at 13-y of age to 27.5% at 15-y of age). By contrast, the prevalence of thinness increased with age in girls (from 4.9% at 9-y of age to 14,1% at 15-y of age), while boys presented a similar low prevalence at 9 and 15-y of age (3.3% and 3.1%), doubling the values at 11 and 13-y of age (7.5% and 6.5%). The trend in the prevalence of normal weight increased with age from 62.4% at 9-y of age to 74.0% at 13-y of age and to 71.6% at 15-y of age. Boys displayed a higher prevalence than girls only at 9-y of age (63.9% vs. 61.0%). Discussion. The results of this study allow us to analyze data from the nutritional surveillance system in Tuscany using recent definitions of Body Mass Index cut-off points among children, pre-adolescents and adolescents. As a rule, the trend in the prevalence of overweight (including obesity) among girls from 9-y to 15-y-old strongly decreased, while the prevalence of thinness increased. In boys, this decrease was less marked and the prevalence of thinness displayed an irregular trend, with an increment from 9-y to 11-y-old and a decrease from 13-y to 15-y old. The trend in the prevalence of normal weight increased with age, with a higher prevalence among boys than girls

Enhancement of radiosensitivity by the novel anticancer quinolone derivative vosaroxin in preclinical glioblastoma models

Purpose: Glioblastoma multiforme (GBM) is the most aggressive brain tumor. The activity of vosaroxin, a first-in-class anticancer quinolone derivative that intercalates DNA and inhibits topoisomerase II, was investigated in GBM preclinical models as a single agent and combined with radiotherapy (RT). Results: Vosaroxin showed antitumor activity in clonogenic survival assays, with IC50 of 10-100 nM, and demonstrated radiosensitization. Combined treatments exhibited significantly higher γH2Ax levels compared with controls. In xenograft models, vosaroxin reduced tumor growth and showed enhanced activity with RT; vosaroxin/RT combined was more effective than temozolomide/RT. Vosaroxin/ RT triggered rapid and massive cell death with characteristics of necrosis. A minor proportion of treated cells underwent caspase-dependent apoptosis, in agreement with in vitro results. Vosaroxin/RT inhibited RT-induced autophagy, increasing necrosis. This was associated with increased recruitment of granulocytes, monocytes, and undifferentiated bone marrow-derived lymphoid cells. Pharmacokinetic analyses revealed adequate blood-brain penetration of vosaroxin. Vosaroxin/RT increased disease-free survival (DFS) and overall survival (OS) significantly compared with RT, vosaroxin alone, temozolomide, and temozolomide/RT in the U251-luciferase orthotopic model. Materials and Methods: Cellular, molecular, and antiproliferative effects of vosaroxin alone or combined with RT were evaluated in 13 GBM cell lines. Tumor growth delay was determined in U87MG, U251, and T98G xenograft mouse models. (DFS) and (OS) were assessed in orthotopic intrabrain models using luciferasetransfected U251 cells by bioluminescence and magnetic resonance imaging. Conclusions: Vosaroxin demonstrated significant activity in vitro and in vivo in GBM models, and showed additive/synergistic activity when combined with RT in O6- methylguanine methyltransferase-negative and -positive cell lines

Nutritional Surveillance in Tuscany: eating habits at breakfast, mid-morning and afternoon snacks among 8-9 y-old children

Introduction.The prevalence of overweight and obesity in children is rapidly increasing in many countries. For that it has been interesting to investigate the eating habits of 8-9 y-old Tuscany children by paying attention to their meals frequency per day and their food choices in total and in relation to children?s Body Mass Index (BMI) classes. In addition we considered some environment factors that could affect the children eating behaviours, such as mother?s BMI and their education level. Methods. A statistical sample of 3,076 (1,583 males, 1,493 females), 8-9 year-old school-children was collected; weight and height were measured using standardized personnel and instruments. BMI classes were calculated using Cole et al.?s cutoff for children and adolescents. In order to evaluate the consumption frequency of individual meals and various foods, a Food Frequency Questionnaire (FFQ) was used, which was completed by the children themselves at school. A self-administered questionnaire revealed the weight and height of parents and their educational levels. Three educational levels were established: high, medium and low. Results. The results showed that 92.3% of children ate breakfast from 4-7 times a week, the vast majority at home, while only 3% declared consuming breakfast never or almost never. The most preferred breakfast consisted of milk and biscuits for all children?s BMI classes. 95.9% of children reported having mid-morning snack at school; fruit juice and tea are the most frequently consumed liquid foods, and pizza, salami sandwiches and pre-packaged snacks are the most frequently consumed solid foods in all BMI classes. 93.6% ate afternoon snack for the most part at home, even if 12% of children reported consuming it elsewhere; fruit juice and tea with pizza, sandwiches and pre-packaged snacks are still the most highly consumed foods by all children?s BMI classes. The consumption frequency of breakfast (P inf. 0.001), mid-morning (P inf. 0.05) and afternoon snack (P inf. 0.05) of 8-9 y-old Tuscany children decrease with increase the children?s BMI classes. The same tendency may be noted for the consumption frequency of breakfast in relation to mother?s BMI (P inf. 0.05) and their education level (P inf. 0.05). This data strengthens the thesis that some home environments can affect the children?s eating behaviours. Conclusion. No substantial differences in food choices at the meals analyzed were determined among normal weight, over weight and obese children. Children of normal weight had a greater tendency to consume meals more regularly. Mother?s BMI and their education level can have influence on children?eating behaviours

Empty rituals? A qualitative study of users’ experience of monitoring & evaluation systems in HIV interventions in western India

In global health initiatives, particularly in the context of private philanthropy and its ‘business minded’ approach, detailed programme data plays an increasing role in informing assessments, improvements, evaluations, and ultimately continuation or discontinuation of funds for individual programmes. The HIV/AIDS literature predominantly treats monitoring as unproblematic. However, the social science of audit and indicators emphasises the constitutive power of indicators, noting that their effects at a grassroots level are often at odds with the goals specified in policy. This paper investigates users' experiences of Monitoring and Evaluation (M&E) systems in the context of HIV interventions in western India. Six focus groups (totalling 51 participants) were held with employees of 6 different NGOs working for government or philanthropy-funded HIV interventions for sex workers in western India. Ten donor employees were interviewed. Thematic analysis was conducted. NGO employees described a major gap between what they considered their “real work” and the indicators used to monitor it. They could explain the official purposes of M&E systems in terms of programme improvement and financial accountability. More cynically, they valued M&E experience on their CVs and the rhetorical role of data in demonstrating their achievements. They believed that inappropriate and unethical means were being used to meet targets, including incentives and coercion, and criticised indicators for being misleading and inflexible. Donor employees valued the role of M&E in programme improvement, financial accountability, and professionalising NGO-donor relationships. However, they were suspicious that NGOs might be falsifying data, criticised the insensitivity of indicators, and complained that data were under-used. For its users, M& E appears an ‘empty ritual’, enacted because donors require it, but not put to local use. In this context, monitoring is constituted as an instrument of performance management rather than as a means of rational programme improvement

Colorectal cancer screening in LHU4 Chiavarese, Italy: ethical, methodological and outcome evaluations at the end of the first round

Introduction. The screening programmes are very challenging from the ethical perspective, and their impact in terms of morbidity and mortality make secondary colorectal cancer prevention a valuable public health intervention. Methods. The target population people aged 50-69 years receive an invitation card with a test-tube for the fecal occult blood test (FOBT) and an immunochemical test is used for fecal occult blood. Subjects positive to FOBT are invited to perform a gastroenterologic examination and a full colonoscopy. Results. In the firt round of screening, 100% of the target population has been invited with an adhesion rate of 41.3%. A total of 1,739 FOBT-positive subjects have been invited to the second level of the screening. 1,429 of them have performed the gastroenterologic examination (83.9%). To date 956 full colonoscopies have been completed and the rate of subjects affected by carcinoma, malignant polyp and advanced adenoma has been equal to 23.5%. Discussion. Thanks to the reminders already sent, an increasing compliance has been registered with an increased rate of subjects with a low schooling that have performed a FOBT test. With the aim to optimize all the operative aspects of the screening programme it is already ongoing a set of meetings between health workers of Local Health Unit 4 and General Practioners

Mitochondria are the main source and one of the targets of Pb (lead)-induced oxidative stress in the yeast Saccharomyces cerevisiae

The yeast Saccharomyces cerevisiae is a useful model organism for studying lead (Pb) toxicity. Yeast cells of a laboratory S. cerevisiae strain (WT strain) were incubated with Pb concentrations up to 1,000 μmol/l for 3 h. Cells exposed to Pb lost proliferation capacity without damage to the cell membrane, and they accumulated intracellular superoxide anion (O2 .−) and hydrogen peroxide (H2O2). The involvement of the mitochondrial electron transport chain (ETC) in the generation of reactive oxygen species (ROS) induced by Pb was evaluated. For this purpose, an isogenic derivative ρ0 strain, lacking mitochondrial DNA, was used. The ρ0 strain, without respiratory competence, displayed a lower intracellular ROS accumulation and a higher resistance to Pb compared to the WT strain. The kinetic study of ROS generation in yeast cells exposed to Pb showed that the production of O2 .− precedes the accumulation of H2O2, which is compatible with the leakage of electrons from the mitochondrial ETC. Yeast cells exposed to Pb displayed mutations at the mitochondrial DNA level. This is most likely a consequence of oxidative stress. In conclusion, mitochondria are an important source of Pb-induced ROS and, simultaneously, one of the targets of its toxicity.The authors thank the FCT Strategic Project PEst-OE/EQB/LA0023/2013

Effects of an H3R Antagonist on the Animal Model of Autism Induced by Prenatal Exposure to Valproic Acid

Autism spectrum disorders (ASD) are a group of neurodevelopmental disorders primarily characterized by impaired social interaction and communication, and by restricted repetitive behaviors and interests. Ligands of histamine receptor 3 (H3R) are considered potential therapeutic agents for the treatment of different brain disorders and cognitive impairments. Considering this, the aim of the present study is to evaluate the actions of ciproxifan (CPX), an H3R antagonist, on the animal model of autism induced by prenatal exposure to valproic acid (VPA). Swiss mice were prenatally exposed to VPA on embryonic day 11 and assessed for social behavior, nociceptive threshold and repetitive behavior at 50 days of life. The treatment with CPX (3 mg/kg) or saline was administered 30 minutes before each behavioral test. The VPA group presented lower sociability index compared to VPA animals that were treated with CPX. Compared to the Control group, VPA animals presented a significantly higher nociceptive threshold, and treatment with CPX was not able to modify this parameter. In the marble burying test, the number of marbles buried by VPA animals was consistent with markedly repetitive behavior. VPA animals that received CPX buried a reduced amount of marbles. In summary, we report that an acute dose of CPX is able to attenuate sociability deficits and stereotypies present in the VPA model of autism. Our findings have the potential to help the investigations of both the molecular underpinnings of ASD and of possible treatments to ameliorate the ASD symptomatology, although more research is still necessary to corroborate and expand this initial data