Prevention of systemic toxicity in hyperthermic isolated lung perfusion using radioisotopic leakage monitoring.

RATIONALE: Hyperthermic isolated lung Perfusion (ILuP) is used to deliver high-dose chemotherapy to pulmonary metastases while sparing systemic toxicity. Accurate leakage monitoring is however necessary. This study aimed to verify the accuracy of radionuclide leakage monitoring in patients undergoing ILuP, by comparing this method with serial blood sampling. METHODS: A total of 15 consecutive ILuP procedures were performed on eleven patients affected by lung metastases from soft tissue sarcoma. After establishing isolated perfusion, erythrocytes of systemic blood (SB) were labelled with 0.2 MBq/kg of 99mTc. The baseline SB counting rate (CR) was assessed using a γ-probe. Subsequently, erythrocytes of the circuit blood (CB) were labelled with 2 Mbq/kg of 99mTc. Radioactivity leakage factor (RLF) was continuously measured using a formula, accounting for CR, systemic/circuit activity ratio and total/systemic volume ratio. The TNF-α concentration in SB and CB was measured by enzymelinked immunosorbent assay (ELISA) throughout the procedure. RESULTS: RLF averaged 2.3 ± 1.5%, while the systemic/circuit TNF-α ratio was 0.05 ± 0.12%. These two indices were strictly correlated in all of the procedures (average Rvalue 0.88 ± 0.07). RLF exceeded 5% during three of 15 procedures, prompting the application of compensatory manoeuvres. ELISA confirmed a marked increase in systemic TNF-α levels in these patients (2.6 ± 3.5 ng/ml). Conversely, patients whose RLF did not exceed the 5% threshold presented a mean TNF-α of 0.02 ± 0.005 ng/ml (p < 0.01). CONCLUSIONS: In patients submitted to ILuP, RLF monitoring is feasible and accurate. Moreover, it grants immediate results, permitting for the adoption of corrective manoeuvres for leakage, thus minimising toxicity.

Editorial Perspective: How to optimise frequency band neurofeedback for ADHD.

Attention deficit/hyperactivity disorder (ADHD) is one of the most prevalent paediatric neuropsychiatric disorders and is characterised by hyperactivity, inattention and increased impulsivity. Children with ADHD are often also characterised by deficits in a variety of cognitive domains, including problems in working memory, a generally slower and more variable style of information processing and deficits in temporal processing, inhibitory functions and delay processing. Overarching executive functions like information updating, response inhibition and mental set shifting are also impaired in many, but not all, children with ADHD, demonstrating the neuropsychological heterogeneity characterising this disorder. Deficits in executive functions can persist into adulthood and have a substantial negative impact on everyday life. A variety of approaches are commonly considered for the treatment of ADHD (including pharmacological interventions, patient-centred cognitive-behavioural therapy approaches and specific teacher/parent training programmes). More recently, adding to this multimodal treatment approach, neurofeedback has grown in popularity as an intervention option for patients with ADHD. This article considers this intervention approach and the opportunities for optimising treatment for executive control dysfunctions in ADHD using theta/beta neurofeedback.

Evolution of shockwave lithotripsy (SWL) technique: a 25-year single centre experience of >5000 patients.

OBJECTIVE: To assess the impact of various treatment optimisation strategies in shockwave lithotripsy (SWL) used at a single centre over the last 25 years. PATIENTS AND METHODS: In all, 5017 patients treated between 1989 and 2013 were reviewed and divided into groups A, B, C and D for the treatment periods of 1989-1994 (1561 patients), 1995-2000 (1741), 2001-2006 (1039) and 2007-2013 (676), respectively. The Sonolith 3000 (A and B) and Dornier compact delta lithotripters (C and D) were used. Refinements included frequent re-localisation, limiting maximum shocks and booster therapy in group B and Hounsfield unit estimation, power ramping and improved coupling in group D. Parameters reviewed were annual SWL utilisation, stone and treatment data, retreatment, auxiliary procedures, complications and stone-free rate (SFR). RESULTS: The SFR with Dornier compact delta was significantly higher than that of the Sonolith 3000 (P < 0.001). The SFR improved significantly from 77.58%, 81.28%, 82.58% to 88.02% in groups A, B, C, and D, respectively (P < 0.001). There was a concomitant decrease in repeat SWL (re-treatment rate: A, 48.7%; B, 33.4%; C, 15.8%; and D, 10.1%; P < 0.001) and complication rates (A, 8%; B, 6.4%; C, 4.9%; and D, 1.6%; P < 0.001). This led to a rise in the efficiency quotient (EQ) in groups A-D from 50.41, 58.94, 68.78 to 77.06 (P < 0.001).The auxiliary procedure rates were similar in all groups (P = 0.62). CONCLUSION: In conclusion, improvement in the EQ together with a concomitant decrease in complication rate can be achieved with optimum patient selection and use of various treatment optimising strategies.

A neural network approach to optimising treatments for depression using data from specialist and community psychiatric services in Australia, New Zealand and Japan.

This study investigated the application of a recurrent neural network for optimising pharmacological treatment for depression. A clinical dataset of 458 participants from specialist and community psychiatric services in Australia, New Zealand and Japan were extracted from an existing custom-built, web-based tool called Psynary . This data, which included baseline and self-completed reviews, was used to train and refine a novel algorithm which was a fully connected network feature extractor and long short-term memory algorithm was firstly trained in isolation and then integrated and annealed using slow learning rates due to the low dimensionality of the data. The accuracy of predicting depression remission before processing patient review data was 49.8%. After processing only 2 reviews, the accuracy was 76.5%. When considering a change in medication, the precision of changing medications was 97.4% and the recall was 71.4% . The medications with predicted best results were antipsychotics (88%) and selective serotonin reuptake inhibitors (87.9%). This is the first study that has created an all-in-one algorithm for optimising treatments for all subtypes of depression. Reducing treatment optimisation time for patients suffering with depression may lead to earlier remission and hence reduce the high levels of disability associated with the condition. Furthermore, in a setting where mental health conditions are increasing strain on mental health services, the utilisation of web-based tools for remote monitoring and machine/deep learning algorithms may assist clinicians in both specialist and primary care in extending specialist mental healthcare to a larger patient community.

Optimising Two-Stage Vacuum Heat Treatment for a High-Strength Micro-Alloyed Steel in Railway Spring Clip Application: Impact on Microstructure and Mechanical Performance.

The heat treatment process is a vital step for manufacturing high-speed railway spring fasteners. In this study, orthogonal experiments were carried out to obtain reliable optimised heat treatment parameters through a streamlined number of experiments. Results revealed that a better comprehensive mechanical performance could be obtained under the following combination of heat treatment parameters: quenching temperature of 850 °C, holding time of 35 min, medium of 12% polyalkylene glycol (PAG) aqueous solution, tempering temperature of 460 °C, and holding time of 60 min. As one of the most important testing criteria, fatigue performance would be improved with increasing strength. Additionally, a high ratio of martensite to ferrite is proven to improve the fatigue limit more significantly. After this heat treatment process, the metallographic microstructure and mechanical properties satisfy the technical requirements for the high-speed railway practical operation. These findings provide a valuable reference for the practical forming process of spring fasteners.

Expert consensus on the use of systemic glucocorticoids for managing eosinophil-related diseases.

Eosinophil-related diseases represent a group of pathologic conditions with highly heterogeneous clinical presentation and symptoms ranging from mild to critical. Both systemic and localized forms of disease are typically treated with glucocorticoids. The approval of novel biologic therapies targeting the interleukin-5 pathway can help reduce the use of systemic glucocorticoids (SGC) in eosinophilic diseases and reduce the risk of SGC-related adverse effects (AEs). In this article, a panel of experts from different medical specialties reviewed current evidence on the use of SGC in two systemic eosinophilic diseases: Eosinophilic Granulomatosis with PolyAngiitis (EGPA) and HyperEosinophilic Syndrome (HES); and in two single-organ (respiratory) eosinophilic diseases: Chronic RhinoSinusitis with Nasal Polyps (CRSwNP) and Severe Asthma with Eosinophil Phenotype (SA-EP), and contrasted it with their experience in clinical practice. Using nominal group technique, they reached consensus on key aspects related to the dose and tapering of SGC as well as on the initiation of biologics as SGC-sparing agents. Early treatment with biologics could help prevent AEs associated with medium and long-term use of SGC.

Clinical Features and Outcomes of VAP Due to Multidrug-Resistant Klebsiella spp.: A Retrospective Study Comparing Monobacterial and Polybacterial Episodes.

VAP due to multidrug-resistant (MDR) bacteria is a frequent infection among patients in ICUs. Patient characteristics and mortality in mono- and polybacterial cases of VAP may differ. A single-centre, retrospective 3-year study was conducted in the four ICUs of a Lithuanian referral university hospital, aiming to compare both the clinical features and the 60-day ICU all-cause mortality of monobacterial and polybacterial MDR Klebsiella spp. VAP episodes. Of the 86 MDR Klebsiella spp. VAP episodes analyzed, 50 (58.1%) were polybacterial. The 60-day mortality was higher (p < 0.05) in polybacterial episodes: overall (50.0 vs. 27.8%), in the sub-group with less-severe disease (SOFA < 8) at VAP onset (45.5 vs. 15.0%), even with appropriate treatment (41.7 vs. 12.5%), and the sub-group of extended drug-resistant (XDR) Klebsiella spp. (46.4 vs. 17.6%). The ICU mortality (44.0 vs. 22.5%) was also higher in the polybacterial episodes. The monobacterial MDR Klebsiella spp. VAP was associated (p < 0.05) with prior hospitalization (61.1 vs. 40.0%), diabetes mellitus (30.6 vs. 5.8%), obesity (30.6 vs. 4.7%), prior antibiotic therapy (77.8 vs. 52.0%), prior treatment with cephalosporins (66.7 vs. 36.0%), and SOFA cardiovascular ≥ 3 (44.4 vs. 10.0%) at VAP onset. Patients with polybacterial VAP were more likely (p < 0.05) to be comatose (22.2 vs. 52.0%) and had a higher SAPS II score (median [IQR] 45.0 [35.25-51.1] vs. 50.0 [40.5-60.75]) at VAP onset. Polybacterial MDR Klebsiella spp. VAP had distinct demographic and clinical characteristics compared to monobacterial, and was associated with poorer outcomes.

Effect of obesity on dolutegravir exposure in Black Southern African adults living with HIV.

Background: Dolutegravir, a component of the preferred first-line antiretroviral therapy regimen, has been associated with increased weight gain. South Africa has a high prevalence of obesity, especially among women. Understanding dolutegravir exposure in patients with obesity is important for dose optimisation. Objectives: We compared the pharmacokinetic parameters of dolutegravir in Southern African adults living with HIV with and without obesity. Method: Blood samples were collected at various time points over a 24 h-period for dolutegravir assays. Non-compartmental analysis was conducted and geometric mean ratios (GMRs), with 90% confidence intervals (CIs), were generated to compare dolutegravir pharmacokinetic parameters between the groups. Regression analyses to assess predictors of dolutegravir exposure were done. Results: Forty participants were enrolled, 26 were women and 10 had obesity. Dolutegravir area under the concentration-time curve to 24-h and the maximum concentrations were not statistically significantly lower in participants with obesity: GMR 0.91 (90% CI: 0.71-1.16) and GMR 0.86 (90% CI: 0.68-1.07), respectively. In a multivariate linear regression analysis adjusting for age, gender, body mass index, creatinine clearance and randomisation arm (tenofovir alafenamide or tenofovir disoproxil fumarate), a unit increase in body mass index was associated with 1.2% lower dolutegravir area under the concentration-time curve to 24-h (P = 0.035). Conclusion: Dolutegravir exposure was marginally lower in participants with obesity, but this is not clinically significant. Our findings suggest that there is no need to dose adjust dolutegravir in people with obesity.

Effects of Pregnancy and Breastfeeding on Clinical Outcomes and MRI Measurements of Women with Multiple Sclerosis: An Exploratory Real-World Cohort Study.

INTRODUCTION: Pregnancy represents an important event for women with multiple sclerosis (MS) and is often accompanied by post-partum disease reactivation. To date, the influence of this reproductive phase on long-term MS outcomes is still largely unexplored. The objective of the study was characterise a large real-world cohort of women with MS to evaluate the effects of pregnancy and breastfeeding on short- and long-term clinical and magnetic resonance imaging (MRI) outcomes while exploring the relationships with MRI measurements of brain atrophy. METHODS: MS patients with and without pregnancy were recruited. Clinical relapses and MRI activity of the year before conception versus the year after delivery were evaluated. Regression models were performed to investigate the relationships between long-term MS outcomes (EDSS score and MRI brain measurements obtained by SIENAX software) and pregnancy and breastfeeding duration. RESULTS: Two hundred ten women with MS were enrolled; of them, 129 (61.4%) had at least one pregnancy. Of all pregnancies (n = 212), those that occurred after MS onset (90 [42.4%]) were examined to evaluate the short-term outcomes. A higher annualised relapse rate in the post-partum year versus the pre-conception year (0.54 ± 0.84 vs. 0.45 ± 0.71; p = 0.04) was observed. A regression analysis showed that clinical activity after delivery was associated with clinical activity of the year before conception (p = 0.001) as well as duration of breastfeeding (p = 0.022). Similarly, post-partum MRI activity was associated with pre-conception MRI activity (p = 0.026) and shorter breastfeeding duration (p = 0.013). Regarding long-term outcomes, having had at least one pregnancy during MS was associated with a lower EDSS score (p = 0.021), while no relationships were reported with MRI measurements. Conversely, a breastfeeding duration > 6 months was associated with lower white matter volume (p = 0.008). CONCLUSIONS: Our study underlines the importance of considering the effects of pregnancy and breastfeeding on short- and long-term MS outcomes. In the current therapeutic landscape, pregnancy planning and treatment optimisation in the post-partum period, in particular for women who choose to breastfeed, are fundamental for the management of these biological phases so central in a woman's life.

Design, organisation and impact of treatment optimisation studies in breast, lung and colorectal cancer: The experience of the European Organisation for Research and Treatment of Cancer.

BACKGROUND: Treatment optimisation studies (TOSs) are clinical trials which aim to tackle research questions that are often left unaddressed within the current drug development paradigm due to a lack of financial and regulatory incentives to undertake them. Examples include comparative effectiveness, therapeutic sequencing and dose de-escalation studies. Trials of this nature have historically been primarily carried out by academic institutions and not-for-profit organisations such as the European Organisation for Research and Treatment of Cancer (EORTC). OBJECTIVES: Our objective was to conduct an in-depth analysis of the breast, lung and colorectal cancer TOSs that have been performed by the EORTC in the past four decades. METHODS: We searched the EORTC clinical trials database for relevant studies and subsequently analysed them based on a number of predefined criteria relating to their design, organisation and scientific impact. RESULTS: The 113 EORTC TOSs examined in this analysis were mainly standard-sized, international, multicentre phase III trials using a relatively simple, randomised, open-label design and comparing pharmacological combination regimens against standard-of-care treatments in terms of their potential to improve overall survival of patients with cancer. Although they were typically financially and/or materially supported by the industry, their legal sponsor was nearly always an independent party that did not benefit monetarily from their outcomes. If meaningful findings were obtained, their results, regardless of whether positive or negative, were published in high-impact journals, and the corresponding articles usually received a considerable number of citations. CONCLUSIONS: Our analysis provides an empirical framework for setting up future TOSs based on the EORTC experience in oncology.

Natural acidic deep eutectic solvent to obtain cellulose nanocrystals using the design of experience approach.

In this study, a new approach to optimize the cellulose nanocrystals (CNCs) extraction using acidic natural deep eutectic solvents (NADES) was introduced using, for the first time, design of experiment method. Choline chloride:oxalic acid dihydrate with a molar ratio of 1:1 was used to extract CNCs. Then, three most important parameters were varied to design the experiment: (i) cotton fibre concentrations, (ii) temperature and (iii) treatment time. Two outcomes were studied: the CNC yield and the crystallinity. The mathematical model for crystallinity perfectly described the experiments, while the model for CNC yield provided only a tendency. For a reaction time of 6 h at 95 °C with a fibre concentration of 2 %, the expected optimum CNC yield was approximately 35.5 ±â€¯2.7 % with a crystallinity index of 80 ±â€¯1 %. The obtained experimental results confirmed the models with 43.6 ±â€¯1.9 % and 81 ±â€¯1 % for the CNC yield and the crystallinity index, respectively. This study shows that it is possible to predict the CNC yield CNC and their crystallinity thanks to predictive mathematical models, which gives a great advantage to consider in the near future a scale up of the extraction of cellulose nanocrystals using this original family of green solvents.

The European Organisation for Research and Treatment of Cancer, State of Science in radiation oncology and priorities for clinical trials meeting report.

BACKGROUND: New technologies and techniques in radiation oncology and imaging offer opportunities to enhance the benefit of loco-regional treatments, expand treatment to new patient populations such as those with oligometastatic disease and decrease normal tissue toxicity. Furthermore, novel agents have become available which may be combined with radiation therapy, and identification of radiation-related biomarkers can be studied to refine treatment prescriptions. Finally, the use of artificial intelligence (AI) capabilities may also improve treatment quality assurance or the ease with which radiation dosing is prescribed. All of these potential advances present both opportunities and challenges for academic clinical researchers. METHODS: Recently, the European Organisation for Research and Treatment of Cancer addressed these topics in a meeting of multiple stakeholders from Europe and North America. The following five themes radiobiology-based biomarkers, new technologies - particularly proton beam therapy, combination systemic and radiation therapy, management of oligometastatic disease and AI opportunities in radiation oncology were discussed in a State of Science format to define key controversies, unanswered questions and propose clinical trial priorities for development. CONCLUSIONS: Priorities for clinical trials implementing new science and technologies have been defined. Solutions to integrate the multidimensional complexity of data have been explored. New types of platforms and partnerships can support innovative approaches for clinical research in radiation oncology.

Beating non-communicable diseases in primary health care: The contribution of pharmacists and guidance from FIP to support WHO goals.

According to the World Health Organization (WHO), more than 36 million people die annually from non-communicable diseases (NCDs), representing over 60% of deaths worldwide, 15 million of which occur before the age of 70 years. Prevention and control of NCDs and their risk factors require interventions that are therapeutically cost-effective, affordable by the patient and/or health systems and feasible, based upon local resources. This commentary paper sets a basis of global evidence to advocate, nationally and internationally, for an expanded role for pharmacists in NCD management by compiling best practices and examples. It encourages pharmacists around the world to act upon NCDs, from prevention and screening activities, to patient referral when appropriate, and to pharmacist-led, patient-centred NCD management to improve outcomes and quality of life. Priority NCDs fall into four areas: cardiovascular diseases, diabetes, asthma/chronic obstructive pulmonary disease and cancer. Building on the key roles they already play as primary healthcare professionals in the community, pharmacists can provide focused interventions, specialised counselling and care coordination, improving patient engagement to achieve better outcomes in the global fight against NCDs.

Treatment optimisation for hepatitis C in the era of combination direct-acting antiviral therapy: a systematic review and meta-analysis.

Background: Prior to direct-acting antiviral (DAA) therapy, personalised medicine played an important role in the treatment of hepatitis C virus (HCV). Whilst simplified treatment strategies are central to treatment scale-up, some patients will benefit from treatment optimisation. This systematic review and meta-analysis explores treatment optimisation strategies in the DAA era. Methods: We systematically searched Medline, Embase, and Web of Science for studies that adopted a stratified or personalised strategy using a licensed combination DAA regimen, alone or with additional agents. We performed a thematic analysis to classify optimisation strategies and a meta-analysis of sustained virologic response rates (SVR), exploring heterogeneity with subgroup analyses and meta-regression. Results: We included 64 studies (9450 participants). Thematic analysis found evidence of three approaches: duration, combination, and/or dose optimisation. We separated strategies into those aiming to maintain SVR in the absence of predictors of failure, and those aiming to improve SVR in the presence of predictors of failure. Shortened duration regimens achieve pooled SVR rates of 94.2% (92.3-95.9%) for 8 weeks, 81.1% (75.1-86.6%) for 6 weeks, and 63.1% (39.9-83.7%) for ≤4 weeks. Personalised strategies (100% vs 87.6%; p<0.001) and therapy shortened according to ≥3 host/viral factors (92.9% vs 81.4% or 87.2% for 1 or 2 host/viral factors, respectively; p=0.008) offer higher SVR rates when shortening therapy. Hard-to-treat HCV genotype 3 patients suffer lower SVR rates despite treatment optimisation (92.6% vs 98.2%; p=0.001). Conclusions: Treatment optimisation for individuals with multiple predictors of treatment failure can offer high SVR rates. More evidence is needed to identify with confidence those individuals in whom SVR can be achieved with shortened duration treatment.