Life cycle assessment and cost evaluation of emerging technologies at early stages: The case of continuous flow synthesis of Rufinamide

In the pharma and fine chemical industries, the development of continuous flow technologies is a process intensification step of primary importance towards the manufacturing of high‐quality products, while reducing the environmental impact and cost of production. The sustainability and profitability of a process can be measured through life cycle Assessment and cost evaluation. However, when applied to emerging technologies, these need to be performed at different stages of the process development in order to limit the uncertainties arising from the scale‐up, and hence providing high‐fidelity projections of environmental impacts and costs at larger scales. The output of the assessment can in fact vary significantly depending on the maturity of the technology and this translates into having different results at commercial scale compared to early estimations. Therefore, in this article, we perform an assessment at two different scales of production, lab and mini‐pilot scale, with the aim of quantifying the uncertainties of the assessment related to the scale‐up, identifying the hotspots of the system, and hence providing guidelines for the further steps of process development. The subject of the assessment is the continuous flow synthesis of Rufinamide. It is the first time that this synthesis is evaluated at pilot‐scale. The results show that low yields in the cycloaddition drastically affect the waste management and the production of precursors, and hence increases environmental impacts and cost of production. This calls for the need of prioritizing the optimization of this synthesis step in order to deploy a green and economically competitive production technology

Feasibility of a cognitive behavioural group intervention to reduce fear of falling and associated avoidance of activity in community-living older people: a process evaluation

BACKGROUND: Fear of falling and associated avoidance of activity are common among older people and may have negative consequences in terms of functional decline, quality of life and institutionalisation. We evaluated the effects of a cognitive behavioural group intervention to reduce fear of falling and associated avoidance of activity among older persons. This intervention showed favourable effects on fear of falling, avoidance of activity, daily activity, and several secondary outcomes. The aim of the present study is to assess the feasibility of this cognitive behavioural group intervention for participants and facilitators. METHODS: The intervention consisted of eight weekly group sessions lasting two hours each and a booster session after six months. Self-administered questionnaires, registration forms and interviews were used to collect data from participants (n = 168) and facilitators (n = 6) on the extent to which the intervention was performed according to protocol, participant attendance, participant adherence, and participants' and facilitators' opinion of the intervention. Quantitative data from the questionnaires and registration forms were analysed by means of descriptive statistics. Qualitative data were categorised based on matching contents of the answers. RESULTS: Facilitators reported no major protocol deviations. Twenty-six percent of the participants withdrew before the start of the programme. Of the persons who started the programme, 84% actually completed it. The participants reported their adherence as good, but facilitators had a less favourable opinion of this. The majority of participants still reported substantial benefits from the programme after six and twelve months of follow-up (71% and 61% respectively). Both participants and facilitators provided suggestions for improvement of the intervention. CONCLUSION: Results of this study show that the current cognitive behavioural group intervention is feasible for both participants and facilitators and fits in well with regular care. Minor refinement of the intervention, however, is warranted to further improve intervention effectiveness and efficiency. Based on these positive findings, we recommend implementing a refined version of this effective and feasible intervention in regular care. TRIAL REGISTRATION: ISRCTN43792817

Design and feasibility testing of a novel group intervention for young women who binge drink in groups

BackgroundYoung women frequently drink alcohol in groups and binge drinking within these natural drinking groups is common. This study describes the design of a theoretically and empirically based group intervention to reduce binge drinking among young women. It also evaluates their engagement with the intervention and the acceptability of the study methods.MethodsFriendship groups of women aged 18–35 years, who had two or more episodes of binge drinking (>6 UK units on one occasion; 48g of alcohol) in the previous 30 days, were recruited from the community. A face-to-face group intervention, based on the Health Action Process Approach, was delivered over three sessions. Components of the intervention were woven around fun activities, such as making alcohol free cocktails. Women were followed up four months after the intervention was delivered. Results The target of 24 groups (comprising 97 women) was recruited. The common pattern of drinking was infrequent, heavy drinking (mean consumption on the heaviest drinking day was UK 18.1 units). Process evaluation revealed that the intervention was delivered with high fidelity and acceptability of the study methods was high. The women engaged positively with intervention components and made group decisions about cutting down. Twenty two groups set goals to reduce their drinking, and these were translated into action plans. Retention of individuals at follow up was 87%.ConclusionsThis study successfully recruited groups of young women whose patterns of drinking place them at high risk of acute harm. This novel approach to delivering an alcohol intervention has potential to reduce binge drinking among young women. The high levels of engagement with key steps in the behavior change process suggests that the group intervention should be tested in a full randomised controlled trial

Absence of Fas-L aggravates renal injury in acute Trypanosoma cruzi infection

Trypanosoma cruzi infection induces diverse alterations in immunocompetent cells and organs, myocarditis and congestive heart failure. However, the physiological network of disturbances imposed by the infection has not been addressed thoroughly. Regarding myocarditis induced by the infection, we observed in our previous work that Fas-L-/- mice (gld/gld) have very mild inflammatory infiltration when compared to BALB/c mice. However, all mice from both lineages die in the early acute phase. Therefore, in this work we studied the physiological connection relating arterial pressure, renal function/damage and cardiac insufficiency as causes of death. Our results show that a broader set of dysfunctions that could be classified as a cardio/anaemic/renal syndrome is more likely responsible for cardiac failure and death in both lineages. However, gld/gld mice had very early glomerular deposition of IgM and a more intense renal inflammatory response with reduced renal filtration, which is probably responsible for the premature death in the absence of significant myocarditis in gld/gld.Instituto Oswaldo Cruz-Fiocruz Laboratório de Biologia CelularUniversidade Federal do Rio de Janeiro Instituto de Biofísica Carlos Chagas FilhoUniversidade Federal Fluminense Instituto Biomédico Departamento de Fisiologia e FarmacologiaUniversidade Federal de São Paulo (UNIFESP) Escola Paulista de Medicina Disciplina de NefrologiaCentro de Criação de Animais de Laboratório Departamento de Controle de Qualidade AnimalUNIFESP, EPM, Disciplina de NefrologiaSciEL

Blood pressure and site-specific cancer mortality: evidence from the original Whitehall study

Studies relating blood pressure to cancer risk have some shortcomings and have revealed inconsistent findings. In 17498 middle-aged London-based government employees we related systolic and diastolic blood pressure recorded at baseline examination (1967-1970) to the risk of cancer mortality risk at 13 anatomical sites 25 years later. Following adjustment for potential confounding and mediating factors, inverse associations between blood pressure and mortality due to leukaemia and cancer of the pancreas (diastolic only) were seen. Blood pressure was also positively related to cancer of the liver and rectum (diastolic only). The statistically significant blood pressure-cancer associations seen in this large-scale prospective investigation offering high power were scarce and of sufficiently small magnitude as to be attributable to chance or confounding

Susceptibility to pattern glare following stroke

The aim of this work was to measure susceptibility to pattern glare within a stroke group, employing a direct method of assessment. Twenty stroke subjects, aged 38-85 years, were recruited, along with an age-matched control group (n = 20). Assessment of pattern glare susceptibility was undertaken using the pattern glare test. An abnormal degree of pattern glare is present when individuals score >1 on the mid-high spatial frequency difference variable, a relative score that allows for normalization of the subject, or >3 when viewing the mid spatial frequency grating. Stroke subjects demonstrate elevated levels of pattern glare compared to normative data values and a control population, as determined using the pattern glare test. This was most notable when considering the output measure for the mid-high difference variable. The mean score for the mid-high difference variable was 2.15 SD 1.27 for the stroke subjects versus 0.10 SD 1.12 for the control subjects. When considering the mid-high difference variable, 75% of the stroke group recorded an abnormal level of pattern glare compared to 5% in the control group. This study demonstrates an association between stroke subjects and elevated levels of pattern glare. Cortical hyperexcitability has been shown to present following stroke, and this has been proposed as a plausible explanation for the perceptual distortions experienced by individuals susceptible to pattern glare. Further work to assess the benefits of spectral filters in reducing perceptual distortions in stroke patients is currently underway

Identification of Reproduction-Specific Genes Associated with Maturation and Estrogen Exposure in a Marine Bivalve Mytilus edulis

Background: While it is established that vertebrate-like steroids, particularly estrogens (estradiol, estrone) and androgens (testosterone), are present in various tissues of molluscs, it is still unclear what role these play in reproductive endocrinology in such organisms. This is despite the significant commercial shellfishery interest in several bivalve species and their decline. Methodology/Principal Findings: Using suppression subtraction hybridisation of mussel gonad samples at two stages (early and mature) of gametogenesis and (in parallel) following controlled laboratory estrogen exposure, we isolate several differentially regulated genes including testis-specific kinases, vitelline lysin and envelope sequences. Conclusions: The differentially expressed mRNAs isolated provide evidence that mussels may be impacted by exogenous estrogen exposure

Paternal and maternal influences on differences in birth weight between Europeans and Indians born in the UK.

BACKGROUND: Ethnic groups differ significantly in adult physique and birth weight. We aimed to improve understanding of maternal versus paternal contributions to ethnic differences in birth weight, by comparing the offspring of same-ethnic versus mixed-ethnic unions amongst Europeans and South Asian Indians in the UK. METHODOLOGY AND PRINCIPAL FINDINGS: We used data from the UK Office for National Statistics Longitudinal Study (LS) and the Chelsea and Westminster Hospital (CWH), London. In the combined sample at all gestational ages, average birth weight of offspring with two European parents was significantly greater than that of offspring with two Indian parents [Δ = 344 (95% CI 329, 360) g]. Compared to offspring of European mothers, the offspring of Indian mothers had lower birth weight, whether the father was European [Δ = -152 (95% CI -92, -212) g] or Indian [Δ = -254 (95% -315, -192) g]. After adjustment for various confounding factors, average birth weight of offspring with European father and Indian mother was greater than that of offspring with two Indian parents [LS: Δ = 249 (95% CI 143, 354) g; CWH: Δ = 236 (95% CI 62, 411) g]. Average birth weight of offspring with Indian father and European mother was significantly less than that of offspring with two European parents [LS: Δ = -117 (95% CI -207, -26) g; CWH: Δ = -83 (-206, 40) g]. CONCLUSIONS/SIGNIFICANCE: Birth weight of offspring with mixed-ethnic parentage was intermediate between that of offspring with two European or two Indian parents, demonstrating a paternal as well as a maternal contribution to ethnic differences in fetal growth. This can be interpreted as demonstrating paternal modulation of maternal investment in offspring. We suggest long-term nutritional experience over generations may drive such ethnic differences through parental co-adaptation

Ambulatory health service users' experience of waiting time and expenditure and factors associated with the perception of low quality of care in Mexico

<p>Abstract</p> <p>Background</p> <p>A principal reason for low use of public health care services is the perception of inferior quality of care. Studying health service user (HSU) experiences with their care and their perception of health service quality is critical to understanding health service utilization. The aim of this study was to define reference points for some aspects of health care quality and to analyze which HSU experiences resulted in perceptions of overall low quality of care.</p> <p>Methods</p> <p>Data from the National Health Survey 2006 were used to compare the experiences of HSUs with their ambulatory care at Ministry of Health and affiliated institutions (MOH), social security institutions (SSI) and private institutions (PrivI). Reference points of quality of care related to waiting time and expenditure were defined for each of the three types of institutions by analyzing HSU experiences rated as 'acceptable'. A multivariable logistic regression model was used to identify the principal factors associated with the general perception of low quality of care.</p> <p>Results</p> <p>A total of 11,959 HSUs were included in the analysis, of whom 37.6% (n = 4,500) HSUs received care at MOH facilities; 31.2% (n = 3,730) used SSI and 31.2% (n = 3,729) PrivI. An estimated travel and waiting time of 10 minutes respectively was rated as acceptable by HSUs from all institutions. The differences between the waiting time rated as acceptable and the actual waiting time were the largest for SSI (30 min) in comparison to MoH (20 min) and PrivI (5 min) users. The principal factors associated with an overall perception of low quality of care are type of institution (OR 4.36; 95% CI 2.95-6.44), waiting time (OR 3.20; 95% CI 2.35-4.35), improvement of health after consultation (OR 2.93; CI 2.29-3.76) and consultation length of less than 20 minutes (2.03; 95% CI 1.60-2.57).</p> <p>Conclusions</p> <p>The reference points derived by the HSUs' own ratings are useful in identifying where quality improvements are required. Prioritizing the reduction of waiting times and improving health status improvement after consultation would increase overall quality of care ratings.</p

Antiangiogenic Agents in Combination with Chemotherapy in Patients with Advanced Non-Small Cell Lung Cancer

Most patients with non-small cell lung cancer (NSCLC) present with advanced disease requiring systemic chemotherapy. Treatment with the antiangiogenic agent bevacizumab in combination with standard platinum-based doublet chemotherapy has been shown to improve outcomes in patients with advanced NSCLC. Several multitargeted antiangiogenic tyrosine kinase inhibitors (e.g., sorafenib, sunitinib, cediranib, vandetanib, BIBF 1120, pazopanib, and axitinib) are also being evaluated in combination with standard chemotherapy. Here we review current clinical data with combination therapy involving antiangiogenic agents and cytotoxic chemotherapy in patients with advanced NSCLC