The development and acceptability of an educational and training intervention for recruiters to neonatal trials: the TRAIN project.

BACKGROUND: Suboptimal or slow recruitment affects 30-50% of trials. Education and training of trial recruiters has been identified as one strategy for potentially boosting recruitment to randomised controlled trials (hereafter referred to as trials). The Training tRial recruiters, An educational INtervention (TRAIN) project was established to develop and assess the acceptability of an education and training intervention for recruiters to neonatal trials. In this paper, we report the development and acceptability of TRAIN. METHODS: TRAIN involved three sequential phases, with each phase contributing information to the subsequent phase(s). These phases were 1) evidence synthesis (systematic review of the effectiveness of training interventions and a content analysis of the format, content, and delivery of identified interventions), 2) intervention development using a Partnership (co-design/co-creation) approach, and 3) intervention acceptability assessments with recruiters to neonatal trials. RESULTS: TRAIN, accompanied by a comprehensive intervention manual, has been designed for online or in-person delivery. TRAIN can be offered to recruiters before trial recruitment begins or as refresher sessions during a trial. The intervention consists of five core learning outcomes which are addressed across three core training units. These units are the trial protocol (Unit 1, 50 min, trial-specific), understanding randomisation (Unit 2, 5 min, trial-generic) and approaching and engaging with parents (Unit 3, 70 min, trial-generic). Eleven recruiters to neonatal trials registered to attend the acceptability assessment training workshops, although only four took part. All four positively valued the training Units and resources for increasing recruiter preparedness, knowledge, and confidence. More flexibility in how the training is facilitated, however, was noted (e.g., training divided across two workshops of shorter duration). Units 2 and 3 were considered beneficial to incorporate into Good Clinical Practice Training or as part of induction training for new staff joining neonatal units. CONCLUSION: TRAIN offers a comprehensive co-produced training and education intervention for recruiters to neonatal trials. TRAIN was deemed acceptable, with minor modification, to neonatal trial recruiters. The small number of recruiters taking part in the acceptability assessment is a limitation. Scale-up of TRAIN with formal piloting and testing for effectiveness in a large cluster randomised trial is required.

Low-density lipoprotein cholesterol in adolescents and young adults with type 1 diabetes: Data from the Australasian Diabetes Data Network registry.

AIM: To determine low-density lipoprotein cholesterol (LDL-C) screening frequency and levels, and factors associated with elevated LDL-C, in Australasian youth with type 1 diabetes (T1D). METHODS: Data were extracted from the Australasian Diabetes Data Network (ADDN), a prospective clinical quality registry, on all T1D healthcare visits attended by young people aged 16-25 years (with T1D duration of >1 year) between January 2011 and December 2020. The primary outcomes were elevated LDL-C > 2.6 mmol/L (100 mg/dL) and threshold for treatment: >3.4 mmol/L (130 mg/dL), according to consensus guidelines. Multivariable Generalised Estimated Equations (GEE) were used to examine factors associated with elevated LDL-C across all visits. RESULTS: A cohort of 6338 young people (52.6% men) were identified, of whom 1603 (25.3%) had ≥1 LDL-C measurement documented. At last measurement, mean age, age at T1D diagnosis and T1D duration were 18.3 ± 2.4, 8.8 ± 4.5 and 8.9 ± 4.8 years, respectively. LDL-C was elevated in 737 (46.0%) and at the treatment threshold in 250 (15.6%). In multivariable GEE elevated LDL-C continuously was associated with older age (OR = 0.07; 0.01-0.13, p = 0.02), female sex (OR = 0.31; 0.18-0.43; p < 0.001), higher HbA1c (OR = 0.04; 0.01-0.08; p = 0.01) and having an elevated BMI (OR = 0.17, 0.06-0.39, p < 0.001). CONCLUSIONS: LDL-C screening and levels are suboptimal in this cohort, increasing future cardiovascular complication risk. There is an urgent need to understand how healthcare services can support improved screening and management of dyslipidaemia in this population.

EPIC: an evaluation of the psychological impact of early-phase clinical trials in cancer patients.

BACKGROUND: Anxiety and depression in patients with cancer is associated with decreased quality of life and increased morbidity and mortality. However, these are often overlooked and untreated. Early-phase clinical trials (EPCTs) recruit patients with advanced cancers who frequently lack future treatment options, which may lead to increased anxiety and depression. Despite this, EPCTs do not routinely consider psychological screening for patients. PATIENTS AND METHODS: This prospective observational study explored levels of anxiety and depression alongside impact of trial participation in the context of EPCTs. The Hospital Anxiety and Depression Scale and the Brief Illness Perceptions Questionnaire were completed at the point of EPCT consent, the end of screening and at pre-specified time points thereafter. RESULTS: Sixty-four patients (median age 56 years; median Eastern Cooperative Oncology Group performance status 1) were recruited. At consent, 57 patients returned questionnaires; 39% reported clinically relevant levels of anxiety whilst 18% reported clinically relevant levels of depression. Sixty-three percent of patients experiencing psychological distress had never previously reported this. Males were more likely to be depressed (P = 0.037) and females were more likely to be anxious (P = 0.011). Changes in anxiety or depression were observed after trial enrolment on an individual level, but not significant on a population level. CONCLUSIONS: Patients on EPCTs are at an increased risk of anxiety and depression but may not seek relevant support. Sites offering EPCTs should consider including psychological screening to encourage a more holistic approach to cancer care and consider the sex of individuals when tailoring psychological support to meet specific needs.

Evaluating the Effects of Pine and Miscanthus Biochar on Escherichia coli, Total Aerobic Bacteria, and Bacterial Communities in Commercial Broiler Litter.

Escherichia coli (E. coli) is a commensal bacteria found in the gastrointestinal tract of poultry; however, some strains are pathogenic and can cause a wide range of diseases. In addition, some strains of pathogenic E. coli can survive in the litter between flocks, making litter management critical for reducing E. coli-associated infections. Biochar (BC) is a porous, carbonaceous material that may be a beneficial litter amendment to reduce moisture and microbial loads. The objectives of this study were to evaluate the effects of pine BC, miscanthus BC, and Poultry Litter Treatment (PLT) on E. coli, total aerobic bacteria populations, and bacterial communities when added to used broiler litter. Pine and miscanthus BC were mixed into poultry litter at inclusion rates of 5%, 10%, 20%, 25%, and 30% w/w. PLT was surface applied at a rate of 0.73 kg/m2. Baseline E. coli and aerobics were measured after a 48-hr litter incubation period and just prior to adding litter treatments. Escherichia coli and aerobics were enumerated 2 and 7 days after adding treatments. Overall, pine BC at 30% had the lowest E. coli and aerobic counts (5.98 and 6.44 log 10 colony-forming units [CFU]/g, respectively); however, they were not significantly different from the control (P ≤ 0.05). At day 2, 30% pine BC inclusion rate treatment resulted in a significant reduction in E. coli and aerobic bacteria counts compared to the control. Miscanthus BC application did not result in significant reductions in E. coli or aerobic bacteria at days 2 or 7. PLT had the highest E. coli (7.07 log 10 CFU/g) and aerobic counts (7.21 log 10 CFU/g) overall. Bacterial community analysis revealed that the alpha and beta diversity between pine BC- and PLT-treated litter were significantly different. However, neither BC type significantly impacted bacterial diversity when compared to the control. Differences in E. coli and aerobic counts between BC types may be attributed to variations in feedstock physiochemical properties.

Evaluación de los efectos del biocarbón de pino y de miscanto sobre Escherichia coli, bacterias aerobias totales y comunidades bacterianas en la cama comercial de pollos de engorde. Escherichia coli (E. coli) es una bacteria comensal que se encuentra en el tracto gastrointestinal de las aves comerciales; sin embargo, algunas cepas son patógenas y pueden causar una amplia variedad de enfermedades. Además, algunas cepas de E. coli patógena pueden sobrevivir en la cama entre parvadas, lo que hace que el manejo de la cama sea fundamental para reducir las infecciones asociadas con E. coli. El biocarbón (BC) es un material carbonoso poroso que puede ser un aditivo beneficioso en la cama para reducir la humedad y las cargas microbianas. Los objetivos de este estudio fueron evaluar los efectos del biocarbón de pino, de miscanthus y de un producto comercial para el tratamiento de la cama en avicultura (PLT) sobre E. coli, sobre poblaciones de bacterias aeróbicas totales y comunidades bacterianas cuando se agregan a la cama de pollos de engorde usada. Se mezclaron biocarbón de pino y miscanthus en la cama de aves de corral con tasas de inclusión por peso del 5 %, 10 %, 20 %, 25 % y 30 %. Se aplicó el producto PLT en la superficie a razón de 0.73 kg/m2. La E. coli y los aeróbicos de referencia se midieron después de un período de incubación de la cama de 48 horas y justo antes de agregar los tratamientos de la cama. Se enumeraron Escherichia coli y bacterias aeróbicas 2 y 7 días después de agregar los tratamientos. En general, el biocarbón de pino al 30 % tuvo los recuentos más bajos de E. coli y aeróbicos (5.98 y 6.44 log10 unidades formadoras de colonias [UFC]/g, respectivamente); sin embargo, no fueron significativamente diferentes del control (P ≤ 0.05). En el día 2, el tratamiento con una tasa de inclusión de biocarbón de pino al 30 % dio como resultado una reducción significativa en los recuentos de bacterias aeróbicas y E. coli en comparación con el control. La aplicación de biocarbón de miscanto no resultó en reducciones significativas de E. coli o bacterias aeróbicas en los días 2 o 7. El producto PLT tuvo los recuentos más altos de E. coli (7.07 log10 CFU/g) y aeróbicos en general (7.21 log10 CFU/g). El análisis de la comunidad bacteriana reveló que la diversidad alfa y beta entre la cama tratada con biocarbón de pino y producto PLT era significativamente diferente. Sin embargo, ninguno de los tipos de biocarbón afectó significativamente la diversidad bacteriana en comparación con el control. Las diferencias en los recuentos de E. coli y de bacterias aeróbicas entre los tipos de biocarbón pueden atribuirse a variaciones en las propiedades fisicoquímicas de la materia prima.

A High-End Estimate of Sea Level Rise for Practitioners.

Sea level rise (SLR) is a long-lasting consequence of climate change because global anthropogenic warming takes centuries to millennia to equilibrate for the deep ocean and ice sheets. SLR projections based on climate models support policy analysis, risk assessment and adaptation planning today, despite their large uncertainties. The central range of the SLR distribution is estimated by process-based models. However, risk-averse practitioners often require information about plausible future conditions that lie in the tails of the SLR distribution, which are poorly defined by existing models. Here, a community effort combining scientists and practitioners builds on a framework of discussing physical evidence to quantify high-end global SLR for practitioners. The approach is complementary to the IPCC AR6 report and provides further physically plausible high-end scenarios. High-end estimates for the different SLR components are developed for two climate scenarios at two timescales. For global warming of +2°C in 2100 (RCP2.6/SSP1-2.6) relative to pre-industrial values our high-end global SLR estimates are up to 0.9 m in 2100 and 2.5 m in 2300. Similarly, for a (RCP8.5/SSP5-8.5), we estimate up to 1.6 m in 2100 and up to 10.4 m in 2300. The large and growing differences between the scenarios beyond 2100 emphasize the long-term benefits of mitigation. However, even a modest 2°C warming may cause multi-meter SLR on centennial time scales with profound consequences for coastal areas. Earlier high-end assessments focused on instability mechanisms in Antarctica, while here we emphasize the importance of the timing of ice shelf collapse around Antarctica. This is highly uncertain due to low understanding of the driving processes. Hence both process understanding and emission scenario control high-end SLR.

Cylindrospermopsin impairs tubular transport function in kidney cells LLC-PK1.

Cylindrospermopsin (CYN) has been involved in cases of poisoning in humans following ingestion. Studies have demonstrated that the kidney is the most affected organ. CYN exposure leads to low-molecular-weight proteinuria and increased excretions of the tubular enzymes in mice, suggesting the damage caused by CYN is mainly tubular. However, the mechanism involved in CYN nephrotoxicity remains unknown. Thus, in order to evaluate the effects of CYN exposure (0.1, 0.5 and 1.0 µg/mL) on tubular renal cells LLC-PK1 distinct mechanisms were analyzed by assessing cell death using flow cytometry, albumin uptake by fluorescence analysis, Na+/K+-ATPase activity by a colorimetric method, RT-qPCR of genes related to tubular transport and function as well as internalization of CYN by ELISA. In this study, CYN was found to induce necrosis in all concentrations. CYN also decreased albumin uptake as well as downregulated megalin and dab2 expression, both proteins involved in albumin endocytosis process. Moreover, CYN appears to be internalized by renal tubular cells through a receptor-mediated endocytosis. Finally, the present study demonstrates that CYN is responsible for disrupting tubular cell transport and function in LLC-PK1 cells.

Substrain-related dependence of Cu(I)-ATPase activity among prion protein-null mice.

The prion protein (PrPC) binds copper and affects copper metabolism, albeit among a poorly understood functional landscape. Much of the data on physiological roles of PrPC were obtained in mice of mixed genetic background deficient of the PrPC-coding gene Prnp. This strategy is currently under scrutiny due to the flanking gene problem, in particular related with a polymorphism, typical of both the 129Sv and 129Ola mouse substrains, in the Sirpa gene located in the vicinity of Prnp. Here we report an investigation of biochemical properties of Cu(I)-ATPases as a function of genotype in two strains of PrPC-deficient mice. We found that both the brain and liver of Prnp-null mice of mixed B6;129Sv background had diminished activity, accompanied by increased catalytic phosphorylation of Cu(I)-ATPase, as compared with the respective wild-type animals. However, no such differences were found between Prnp-null and wild-type mice of a B10;129Ola background. Activity of Cu(I)-ATPase was strongly reduced in brain tissue from mice of 129Sv strain, when compared with wild-type either of B6;129Sv, and especially of mice of the B6 strain. No differences between wild-type and Prnp-null brain tissue were noted in the expression of either Atp7a or b genes, and RFLP analysis indicated that the Sirpa129 polymorphism was present in both the B6;129Sv and B10;129Ola Prnp-null mouse colonies used in this study. The results suggest a novel substrain-dependent effect of 129Sv, but not 129Ola, genotype upon the regulation of the Cu(I)-ATPase catalytic cycle in Prnp-null mice, rather than either a Prnp-dependent, or a 129 strain-dependent effect.

Introduction of a national program for HbA1c testing in Guyana South America and initial results.

Diabetes is an increasing challenge for low- and middle-income countries (LMIC) and access to HbA1c testing is limited. HbA1c, a measure of glycaemic control averaged over 3 months, provides both clinicians and policymakers with a tool to identify the risk of long-term diabetes comorbidity. We describe the steps used to implement standardised testing in Guyana South America and the initial results according to a locally developed protocol as part of a country-wide project to improve the care of people with all forms of diabetes The steps identified include: a standardised method traceable to a recognized international reference standard, participation in a quality control cycle with an international reference laboratory, a clinical pathway for testing to reduce inappropriate use and minimize resource wastage, training of technicians in operation and maintenance of equipment, identification of a suitable space with constant power supply, a reliable procurement system, education of healthcare professionals on interpretation and follow-up of results and feedback of programme results to improve clinical practice. Some steps for implementation of the national HbA1c testing program were initiated better than others. Initial unreliability of the service undermined confidence in the system. Failure to follow the testing protocol led to some patients being tested too soon and others too late. Cost of reagents was about 5.60 USD/test. We trained 340 people in diabetes care and knowledge was improved but were unable to assess whether it was appropriately applied. Over one third of people tested in the 30-70 age group had an HbA1c over 9% (75 mmol/mol) and this did not improve over the 5 years of testing. Despite the difficulties we think our unique experience of implementation of a nationwide HbA1c testing programme has important lessons for other LMICs.

Control of Direct Written Ink Droplets Using Electrowetting.

Here, we investigate the feasibility and effectiveness of electrowetting in the motion control of droplets of different liquids, which are widely used as inks in direct writing (DW)-based three-dimensional (3D) printing processes for various applications. To control the movement of DW ink droplets on dielectric substrates, the electrodes were embedded in the substrate. It is demonstrated that droplets of pure liquid inks, aqueous polymer solution inks, and carbon fiber suspension inks can be moved on multi-angled surfaces. Also, experimental results reveal that droplets of a commercial hydrogel, agar-agar, alginate, xanthan gum, and gum arabic can be moved by electrowetting. Droplets of sizes 200 µm-3 mm were manipulated and moved by the electric field on different dielectric substrates accurately and repeatedly. Effective electrowetting-based control and movement of droplets were observed on horizontal, vertical, and even inverted substrates. These findings imply the feasibility and potential application of electrowetting as a flexible, rapid, and new method for ink droplet control in 3D printing processes.

Reference intervals for stool calprotectin in preterm neonates and their utility for the diagnosis of necrotizing enterocolitis.

OBJECTIVE: Calprotectin is an antimicrobial protein found in stool when released by granulocytes. We sought to create stool calprotectin reference ranges in preterm neonates and to evaluate whether levels exceeding the upper reference interval are diagnostic for necrotizing enterocolitis (NEC). STUDY DESIGN: Stool calprotectin was measured in premature neonates without gastrointestinal pathology to create reference intervals. For comparison, levels from infants undergoing "rule out NEC" evaluations were plotted on these reference intervals. RESULTS: Stool calprotectin reference intervals were created according to gestational age at birth and corrected gestational age. Levels during "rule out NEC" evaluations were more often above the upper reference interval with NEC vs. those without NEC. CONCLUSIONS: Stools from preterm neonates have a higher range of calprotectin than stools from healthy term neonates. In evaluating preterm neonates for NEC with stool calprotectin, a calprotectin upper reference interval that incorporates corrected gestational age best predicts the diagnosis of NEC.

Videolaryngoscopy versus direct laryngoscopy for emergency orotracheal intubation outside the operating room: a systematic review and meta-analysis.

Videolaryngoscopy (VL) may improve the success of orotracheal intubation compared with direct laryngoscopy (DL). We performed a systematic search of PubMed, Embase, and CENTRAL databases for studies comparing VL and DL for emergency orotracheal intubations outside the operating room. The primary outcome was rate of first-pass intubation, with subgroup analyses by location, device used, clinician experience, and clinical scenario. The secondary outcome was complication rates. Data are presented as [odds ratio (95% confidence intervals); P-values]. We identified 32 studies with 15 064 emergency intubations. There was no difference in first-pass intubation with VL compared with DL [OR=1.28, (0.99-1.65); P=0.06]. First-pass intubations were increased with VL compared with DL in the intensive care unit (ICU) [2.02 (1.43-2.85); P<0.001], and similar in the emergency department or pre-hospital setting. First-pass intubations were similar with GlideScope®, but improved with the CMAC® [1.32 (1.08-1.62); P=0.007] compared with DL. There was greater first-pass intubation with VL compared with DL amongst novice/trainee clinicians [OR=1.95 (1.45-2.64); P<0.001], but not amongst experienced clinicians or paramedics/nurses. There was no difference in first-pass intubation with VL compared with DL during cardiopulmonary resuscitation or trauma. VL compared with DL was associated with fewer oesophageal intubations [OR=0.32 (0.14-0.70); P=0.003], but more arterial hypotension [OR=1.49 (1.00-2.23); P=0.05]. In summary, VL compared with DL is associated with greater first-pass emergency intubation in the ICU and amongst less experienced clinicians, and reduces oesophageal intubations. However, VL is associated with greater incidence of arterial hypotension. Further trials investigating the utility of VL over DL in specific situations are required.

Effect of atmospheric carbon dioxide concentration on the cultivation of bovine Mycoplasma species.

Recommendations for bovine mycoplasma culture CO2 concentrations are varied and were not empirically derived. The objective of this study was to determine whether the growth measures of bovine mycoplasma isolates differed when incubated in CO2 concentrations of 10 or 5% or in candle jars (2.7 ± 0.2% CO2). Growth of Mycoplasma bovis (n = 22), Mycoplasma californicum (n = 18), and other Mycoplasma spp. (n = 10) laboratory isolates was evaluated. Isolate suspensions were standardized to approximately 108 cfu/mL and serially diluted in pasteurized whole milk to achieve test suspensions of 102 and 106 cfu/mL. One hundred microliters of each test dilution was spread in duplicate onto the surface of a modified Hayflick's agar plate. Colony growth was enumerated on d 3, 5, and 7 of incubation. A mixed linear model included the fixed effects of CO2 treatment (2.7, 5, or 10%), species, day (3, 5, or 7), and their interactions, with total colony counts as the dependent variable. Carbon dioxide concentration did not significantly affect overall mycoplasma growth differences, but differences between species and day were present. Colony counts (log10 cfu/mL) of M. bovis were 2.6- and 1.6-fold greater than M. californicum and other Mycoplasma spp., respectively. Growth at 7 d of incubation was greater than d 3 and 5 for all species. These findings were confirmed using field isolates (n = 98) from a commercial veterinary diagnostic laboratory. Binary growth responses (yes/no) of the field isolates were not different between CO2 treatments but did differ between species and day of incubation. On average, 57% of all field isolates were detected by 3 d of incubation compared with 93% on d 7. These results suggest that the range of suitable CO2 culture conditions and incubation times for the common mastitis-causing Mycoplasma spp. may be broader than currently recommended.

Evaluation of vegetable protein in canine diets: Assessment of performance and apparent ileal amino acid digestibility using a broiler model.

Recent technological advances in the human food industry with respect to meat processing have decreased the availability of animal proteins to the pet food industry which typically formulates diets with an excess of animal protein. In the long term, this is not sustainable; thus, alternative protein sources need to be investigated. This study examined three canine diets, comparing a typical animal protein-based diet (control) with two experimental diets where the animal protein was substituted in part with vegetable protein (formulated based either on total protein or amino acid content) using a broiler model. Each diet was fed to six cages each containing two birds from day 15, 18 cages in total (36 birds). Excreta were collected from days 19 to 21. On day 23, birds were euthanized and weighed, and their ileal digesta were collected and pooled for each cage. In addition, one leg per cage was collected for evaluation of muscle mass. Results showed no significant difference in animal performance (feed intake or live weight gain) or muscle to leg proportion across the diets. Birds fed the control diet and the diet balanced for amino acid content exhibited the greatest coefficients of apparent metabolizability for nitrogen (p < .001). Birds fed the diets that contained partial replacement of animal with vegetable protein generally had greater ileal digestibility of amino acids compared to birds fed the control (animal protein) diet. Analysis of excreta showed no dietary difference in terms of dry matter content; however, birds fed the diet balanced for total protein and the diet balanced for amino acid content had significantly greater excreta nitrogen than the control (p = .038). Overall, the study suggests vegetable proteins when formulated based on amino acid content are a viable alternative to animal proteins in canine diets.

ASD restricted and repetitive behaviors associated at 17q21.33: genes prioritized by expression in fetal brains.

Autism spectrum disorder (ASD) is a behaviorally defined condition that manifests in infancy or early childhood as deficits in communication skills and social interactions. Often, restricted and repetitive behaviors (RRBs) accompany this disorder. ASD is polygenic and genetically complex, so we hypothesized that focusing analyses on intermediate core component phenotypes, such as RRBs, can reduce genetic heterogeneity and improve statistical power. Applying this approach, we mined Caucasian genome-wide association studies (GWAS) data from two of the largest ASD family cohorts, the Autism Genetics Resource Exchange and Autism Genome Project (AGP). Of the 12 RRBs measured by the Autism Diagnostic Interview-Revised, seven were found to be significantly familial and substantially variable, and hence, were tested for genome-wide association in 3104 ASD-affected children from 2045 families. Using a stringent significance threshold (P<7.1 × 10-9), GWAS in the AGP revealed an association between 'the degree of the repetitive use of objects or interest in parts of objects' and rs2898883 (P<6.8 × 10-9), which resides within the sixth intron of PHB. To identify the candidate target genes of the associated single-nucleotide polymorphisms at that locus, we applied chromosome conformation studies in developing human brains and implicated three additional genes: SLC35B1, CALCOCO2 and DLX3. Gene expression, brain imaging and fetal brain expression quantitative trait locus studies prioritize SLC35B1 and PHB. These analyses indicate that GWAS of single heritable features of genetically complex disorders followed by chromosome conformation studies in relevant tissues can be successful in revealing novel risk genes for single core features of ASD.

Supplementation of culture medium with L-carnitine improves the development and cryotolerance of in vitro-produced porcine embryos.

Porcine oocytes and embryos contain substantial amounts of lipid, with little known regarding its metabolic role during development. This study investigated the role of lipid metabolism and the interaction between carbohydrate and lipid substrates in porcine embryos. Following in vitro fertilisation, presumptive zygotes were transferred to culture medium supplemented with L-carnitine, a co-factor required for the metabolism of fatty acids. In porcine zygote medium-3 (PZM-3), which contains pyruvate and lactate, 3mM L-carnitine was the only dose that improved cleavage rates compared with the control. In the absence of carbohydrates, all doses of L-carnitine from 1.5 to 12mM increased cleavage rates compared with the control. Culture in a PZM-3-based sequential media system (Days 0-3: pyruvate and lactate; Days 4-7: glucose) significantly increased blastocyst cell numbers compared with culture in standard PZM-3. Supplementing PZM-3 with 3mM L-carnitine produced blastocysts with cell numbers equivalent to those obtained in the sequential media system. After vitrification, the post-warming survival rates of blastocysts obtained in media supplemented with 3mM L-carnitine were significantly greater than those of blastocysts obtained in standard PZM-3. In conclusion, L-carnitine supplementation improved embryo development when the medium contained pyruvate and lactate or was lacking carbohydrates completely, indicating a role for fatty-acid metabolism when the embryo's requirements for carbohydrates are not adequately met.

Assessment of the construct validity of the Australian Health Star Rating: a nutrient profiling diagnostic accuracy study.

BACKGROUND/OBJECTIVES: Nutrient profiling models classify the healthiness of foods based on their nutritional composition and provide the science that underlies nutrition signposting schemes. The two objectives were to examine the construct validity of the Health Star Rating (HSR) system by determining its diagnostic accuracy and to detect the optimal HSR cutoff points to define healthiness in packaged dairy foods. We hypothesised that ultra-processed dairy, defined by NOVA, would have less stars (less healthy) and non-ultra-processed dairy would have more stars (more healthy). SUBJECTS/METHODS: The diagnostic accuracy of the HSR system used for 621 dairy foods for sale in an Australian regional supermarket was investigated. The healthiness of packaged dairy was measured using the NOVA food classification system. RESULTS: The dairy beverages model was found to discriminate between healthy and less healthy dairy beverages as classified by NOVA (AUC: 0.653; 95% CI: 0.556-0.750; P=0.005). A receiver operating characteristic curve analysis for dairy beverages demonstrated that the optimal cutoff point corresponded to a rating of four stars. There was no discrimination power when using the HSR for predicting the health value of yoghurt and other dairy, or cheeses. CONCLUSIONS: At the optimal cutoff point of four stars the HSR has a high sensitivity but a low specificity to correctly classify healthy packaged dairy beverages, as defined by NOVA. We provide evidence to support the construct validity of the HSR model for dairy beverages, but not for the models used for yoghurts and other dairy products, or cheeses.

A randomized, open-label, multicenter, phase II study evaluating the efficacy and safety of BTH1677 (1,3-1,6 beta glucan; Imprime PGG) in combination with cetuximab and chemotherapy in patients with advanced non-small cell lung cancer.

Introduction BTH1677, a 1,3-1,6 beta-glucan immunomodulator, stimulates a coordinated anti-cancer immune response in combination with anti-tumor antibody therapies. This phase II study explored the efficacy, pharmacokinetics (PK), and safety of BTH1677 combined with cetuximab/carboplatin/paclitaxel in untreated stage IIIB/IV non-small cell lung cancer (NSCLC) patients. Methods Patients were randomized 2:1 to the BTH1677 arm (N=60; BTH1677, 4 mg/kg, weekly; cetuximab, initial dose 400 mg/m2 and subsequent doses 250 mg/m2, weekly; carboplatin, 6 mg/mL/min AUC (area-under-the-curve) by Calvert formula, once each 3-week cycle [Q3W]); and paclitaxel, 200 mg/m2, Q3W) or Control arm (N=30; cetuximab/carboplatin/paclitaxel as above). Carboplatin/paclitaxel was discontinued after 4-6 cycles; patients who responded or remained stable received maintenance therapy with BTH1677/cetuximab (BTH1677 arm) or cetuximab (Control arm). Investigator and blinded central radiology reviews were conducted. Efficacy assessments included objective response rate (ORR; primary endpoint), disease control rate, duration of objective response, time-to-progression and overall survival (OS); safety was assessed by adverse events (AEs). Potential biomarker analysis for BTH1677 response was also conducted. Results Compared to control treatment, the addition of BTH1677 numerically increased ORR by both investigator (47.8% vs 23.1%; p=0.0468) and central (36.6% vs 23.1%; p=0.2895) reviews. No other endpoints differed between arms. PK was consistent with previous studies. BTH1677 was well tolerated, with AEs expected of the backbone therapy predominating. Biomarker-positive patients displayed better ORR and OS than negative patients. Conclusions BTH1677 combined with cetuximab/carboplatin/paclitaxel was well tolerated and improved ORR as first-line treatment in patients with advanced NSCLC. Future patient selection by biomarker status may further improve efficacy ClinicalTrials.gov Identifier: NCT00874848.

On the subtle tuneability of cellulose hydrogels: implications for binding of biomolecules demonstrated for CBM 1.

Cellulose-based hydrogel materials prepared by regeneration from cellulose solutions in ionic liquids, or ionic liquid containing solvent mixtures (organic electrolyte solutions), are becoming widely used in a range of applications from tissue scaffolds to membrane ionic diodes. In all such applications knowledge of the nature of the hydrogel with regards to porosity (pore size and tortuosity) and material structure and surface properties (crystallinity and hydrophobicity) is critical. Here we report significant changes in hydrogel properties, based on the choice of cellulose raw material (α- or bacterial cellulose - with differing degree of polymerization) and regeneration solvent (methanol or water). Focus is on bioaffinity applications, but the findings have wide ramifications, including in biomedical applications and cellulose saccharification. Specifically, we report that the choice of cellulose and regeneration solvent influences the surface area accessible to a family 1 carbohydrate-binding module (CBM), CBM affinity for the cellulose material, and rate of migration through the hydrogel. By regenerating bacterial cellulose in water, a maximum accessible surface area of 33 m2 g-1 was achieved. However, the highest CBM migration rate, 1.76 µm2 min-1, was attained by regenerating α-cellulose in methanol, which also resulted in the maximum affinity of the biomolecule for the material. Thus, it is clear that if regenerated cellulose hydrogels are to be used as support materials in bioaffinity (or other) applications, a balance between accessible surface area and affinity, or migration rate, must be achieved.

Additive effects of oxytocin receptor gene polymorphisms on reward circuitry in youth with autism.

Several common alleles in the oxytocin receptor gene (OXTR) are associated with altered brain function in reward circuitry in neurotypical adults and may increase risk for autism spectrum disorders (ASD). Yet, it is currently unknown how variation in the OXTR relates to brain functioning in individuals with ASD, and, critically, whether neural endophenotypes vary as a function of aggregate genetic risk. Here, for we believe the first time, we use a multi-locus approach to examine how genetic variation across several OXTR single-nucleotide polymorphisms (SNPs) affect functional connectivity of the brain's reward network. Using data from 41 children with ASD and 41 neurotypical children, we examined functional connectivity of the nucleus accumbens (NAcc) - a hub of the reward network - focusing on how connectivity varies with OXTR risk-allele dosage. Youth with ASD showed reduced NAcc connectivity with other areas in the reward circuit as a function of increased OXTR risk-allele dosage, as well as a positive association between risk-allele dosage and symptom severity, whereas neurotypical youth showed increased NAcc connectivity with frontal brain regions involved in mentalizing. In addition, we found that increased NAcc-frontal cortex connectivity in typically developing youth was related to better scores on a standardized measure of social functioning. Our results indicate that cumulative genetic variation on the OXTR impacts reward system connectivity in both youth with ASD and neurotypical controls. By showing differential genetic effects on neuroendophenotypes, these pathways elucidate mechanisms of vulnerability versus resilience in carriers of disease-associated risk alleles.

Ethno-Cultural Considerations in Cardiac Patients' Medication Adherence.

We aimed to develop an in-depth understanding about factors that influence cardiac medication adherence among South Asian, Chinese, and European White cardiac patients. Sixty-four patients were purposively sampled from an ongoing study cohort. Interviews were audio-recorded and transcribed for analyses. Physicians' culturally sensitive communication and patients' motivation to live a symptom-free and longer life enhanced adherence. European Whites were motivated to enhance personal well-being and enjoy family life. South Asians' medication adherence was influenced by the desire to fulfill the will of God and family responsibilities. The Chinese were motivated to avoid pain, illness, and death, and to obey a health care provider. The South Asians and Chinese wanted to ultimately reduce medication use. Previous positive experiences, family support, and establishing a routine also influenced medication adherence. Deterrents to adherence were essentially the reverse of the motivators/facilitators. This analysis represents an essential first step forward in developing ethno-culturally tailored interventions to optimize adherence.