Subcutaneous versus intravenous nivolumab for renal cell carcinoma.

BACKGROUND: The evolving oncology treatment paradigm has created an unmet need for administration options that improve patient experiences and health care efficiencies. PATIENTS AND METHODS: CheckMate 67T (NCT04810078) was a phase III, open-label, multicenter, noninferiority trial in which patients with advanced/metastatic clear cell renal cell carcinoma were randomized to subcutaneous nivolumab (1200 mg every 4 weeks; coformulated with recombinant human hyaluronidase PH20 20 000 units) or intravenous nivolumab (3 mg/kg every 2 weeks). The primary objective was to assess the noninferiority of subcutaneous versus intravenous nivolumab by coprimary endpoints determined from a population pharmacokinetics analysis [time-averaged serum concentration over the first 28 days (Cavgd28), and minimum steady-state serum concentration (Cminss); noninferiority threshold: lower boundary of 90% confidence interval (CI) of the geometric mean ratios (GMR) ≥0.8]. Objective response rate (ORR) was a key secondary endpoint powered for noninferiority [noninferiority threshold: lower boundary of 95% CI of relative risk of ORR (subcutaneous versus intravenous nivolumab) ≥0.60]. RESULTS: Overall, 495 patients were randomized. Relative exposure in the subcutaneous versus intravenous arm reported by the GMR of Cavgd28 and Cminss was 2.098 (90% CI 2.001-2.200) and 1.774 (90% CI 1.633-1.927), respectively. After 8 months of minimum follow-up, ORR was 24.2% with subcutaneous nivolumab (95% CI 19.0%-30.0%) versus 18.2% with intravenous nivolumab [95% CI 13.6%-23.6%; relative risk: 1.33 (95% CI 0.94-1.87)]. Coprimary endpoints and ORR met noninferiority thresholds. Additional efficacy and safety measures were similar. CONCLUSIONS: Subcutaneous nivolumab was noninferior to intravenous nivolumab based on pharmacokinetics and ORR. No new safety signals were observed.

Hearing sensitivity: An underlying mechanism for niche differentiation in gleaning bats.

Tropical ecosystems are known for high species diversity. Adaptations permitting niche differentiation enable species to coexist. Historically, research focused primarily on morphological and behavioral adaptations for foraging, roosting, and other basic ecological factors. Another important factor, however, is differences in sensory capabilities. So far, studies mainly have focused on the output of behavioral strategies of predators and their prey preference. Understanding the coexistence of different foraging strategies, however, requires understanding underlying cognitive and neural mechanisms. In this study, we investigate hearing in bats and how it shapes bat species coexistence. We present the hearing thresholds and echolocation calls of 12 different gleaning bats from the ecologically diverse Phyllostomid family. We measured their auditory brainstem responses to assess their hearing sensitivity. The audiograms of these species had similar overall shapes but differed substantially for frequencies below 9 kHz and in the frequency range of their echolocation calls. Our results suggest that differences among bats in hearing abilities contribute to the diversity in foraging strategies of gleaning bats. We argue that differences in auditory sensitivity could be important mechanisms shaping diversity in sensory niches and coexistence of species.

Nivolumab plus low-dose ipilimumab in previously treated patients with microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer: 4-year follow-up from CheckMate 142.

BACKGROUND: In the phase II multicohort CheckMate 142 study, nivolumab plus low-dose (1 mg/kg) ipilimumab provided robust and durable clinical benefit with a manageable safety profile in previously treated patients with microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC) at 13.4- and 25.4-month median follow-up (Overman MJ, Lonardi S, Wong KYM et al. Durable clinical benefit with nivolumab plus ipilimumab in DNA mismatch repair-deficient/microsatellite instability-high metastatic colorectal cancer. J Clin Oncol. 2018;36:773-779. Overman MJ, Lonardi S, Wong KYM, et al. Nivolumab plus low-dose ipilimumab in previously treated patients with microsatellite instability-high/mismatch repair deficient metastatic colorectal cancer: long-term follow-up. J Clin Oncol. 2019;37:635). Here, we present results from the 4-year follow-up of these patients. PATIENTS AND METHODS: Patients received nivolumab (3 mg/kg) plus low-dose (1 mg/kg) ipilimumab every 3 weeks (four doses) followed by nivolumab (3 mg/kg) every 2 weeks until disease progression. Primary endpoint was investigator-assessed objective response rate (ORR; as per RECIST version 1.1). RESULTS: A total of 119 patients were treated; 76% had ≥2 prior lines of therapy. Median follow-up was 50.9 months (range 46.9-62.7 months). Median duration of therapy was 24.9 months [95% confidence interval (CI) 15.8-33.2 months]. Investigator-assessed ORR increased from 55% (95% CI 45% to 64%) at 13.4 months to 65% (95% CI 55% to 73%) at 50.9 months with a disease control rate of 81% (95% CI 72% to 87%). The complete response rate increased from 3% at 13.4 months to 13% at 50.9 months. Partial responses were observed in 52% of patients; 21% had stable disease, and 12% had progressive disease. Median time to response was 2.8 months (range 1.1-37.1 months), and median duration of response was not reached (range 1.4+ to 58.0+ months). At data cut-off, 37 (48%) patients had ongoing responses. Median progression-free survival was not reached [95% CI 38.4 months-not estimable (NE)], and median overall survival was not reached (95% CI NE). Grade 3-4 treatment-related adverse events (TRAEs) were observed in 32% of patients; 13% of patients had any-grade TRAEs leading to discontinuation. CONCLUSIONS: The results confirm long-term benefit of nivolumab plus low-dose ipilimumab for previously treated patients with MSI-H/dMMR mCRC. The safety profile was manageable with no new safety signals.

Patient characteristics and predictors of mortality in 470 adults admitted to a district general hospital in England with Covid-19.

Understanding risk factors for death from Covid-19 is key to providing good quality clinical care. We assessed the presenting characteristics of the 'first wave' of patients with Covid-19 at Royal Oldham Hospital, UK and undertook logistic regression modelling to investigate factors associated with death. Of 470 patients admitted, 169 (36%) died. The median age was 71 years (interquartile range 57-82), and 255 (54.3%) were men. The most common comorbidities were hypertension (n = 218, 46.4%), diabetes (n = 143, 30.4%) and chronic neurological disease (n = 123, 26.1%). The most frequent complications were acute kidney injury (AKI) (n = 157, 33.4%) and myocardial injury (n = 21, 4.5%). Forty-three (9.1%) patients required intubation and ventilation, and 39 (8.3%) received non-invasive ventilation. Independent risk factors for death were increasing age (odds ratio (OR) per 10 year increase above 40 years 1.87, 95% confidence interval (CI) 1.57-2.27), hypertension (OR 1.72, 95% CI 1.10-2.70), cancer (OR 2.20, 95% CI 1.27-3.81), platelets <150 × 103/µl (OR 1.93, 95% CI 1.13-3.30), C-reactive protein ≥100 µg/ml (OR 1.68, 95% CI 1.05-2.68), >50% chest radiograph infiltrates (OR 2.09, 95% CI 1.16-3.77) and AKI (OR 2.60, 95% CI 1.64-4.13). There was no independent association between death and gender, ethnicity, deprivation level, fever, SpO2/FiO2, lymphopoenia or other comorbidities. These findings will inform clinical and shared decision making, including use of respiratory support and therapeutic agents.

Primary Ciliary Dyskinesia Due to Microtubular Defects is Associated with Worse Lung Clearance Index.

PURPOSE: Primary ciliary dyskinesia (PCD) is characterised by repeated upper and lower respiratory tract infections, neutrophilic airway inflammation and obstructive airway disease. Different ultrastructural ciliary defects may affect lung function decline to different degrees. Lung clearance index (LCI) is a marker of ventilation inhomogeneity that is raised in some but not all patients with PCD. We hypothesised that PCD patients with microtubular defects would have worse (higher) LCI than other PCD patients. METHODS: Spirometry and LCI were measured in 69 stable patients with PCD. Age at testing, age at diagnosis, ethnicity, ciliary ultrastructure, genetic screening result and any growth of Pseudomonas aeruginosa was recorded. RESULTS: Lung clearance index was more abnormal in PCD patients with microtubular defects (median 10.24) than those with dynein arm defects (median 8.3, p = 0.004) or normal ultrastructure (median 7.63, p = 0.0004). Age is correlated with LCI, with older patients having worse LCI values (p = 0.03, r = 0.3). CONCLUSION: This study shows that cilia microtubular defects are associated with worse LCI in PCD than dynein arm defects or normal ultrastructure. The patient's age at testing is also associated with a higher LCI. Patients at greater risk of obstructive lung disease should be considered for more aggressive management. Differences between patient groups may potentially open avenues for novel treatments.

Microbial Community Dynamics and Response to Plant Growth-Promoting Microorganisms in the Rhizosphere of Four Common Food Crops Cultivated in Hydroponics.

Plant growth promoting microorganisms (PGPMs) of the plant root zone microbiome have received limited attention in hydroponic cultivation systems. In the framework of a project aimed at the development of a biological life support system for manned missions in space, we investigated the effects of PGPMs on four common food crops (durum and bread wheat, potato and soybean) cultivated in recirculating hydroponic systems for a whole life cycle. Each crop was inoculated with a commercial PGPM mixture and the composition of the microbial communities associated with their root rhizosphere, rhizoplane/endosphere and with the recirculating nutrient solution was characterised through 16S- and ITS-targeted Illumina MiSeq sequencing. PGPM addition was shown to induce changes in the composition of these communities, though these changes varied both between crops and over time. Microbial communities of PGPM-treated plants were shown to be more stable over time. Though additional development is required, this study highlights the potential benefits that PGPMs may confer to plants grown in hydroponic systems, particularly when cultivated in extreme environments such as space.

Incidence of West Nile virus infection in the Dallas-Fort Worth metropolitan area during the 2012 epidemic.

The 2012 West Nile virus (WNV) epidemic was the largest since 2003 and the North Texas region was the most heavily impacted. We conducted a serosurvey of blood donors from four counties in the Dallas-Fort Worth area to characterize the epidemic. Blood donor specimens collected in November 2012 were tested for WNV-specific antibodies. Donors positive for WNV-specific IgG, IgM, and neutralizing antibodies were considered to have been infected in 2012. This number was adjusted using a multi-step process that accounted for timing of IgM seroreversion determined from previous longitudinal studies of WNV-infected donors. Of 4971 donations screened, 139 (2·8%) were confirmed WNV IgG positive, and 69 (1·4%) had IgM indicating infection in 2012. After adjusting for timing of sampling and potential seroreversion, we estimated that 1·8% [95% confidence interval (CI) 1·5-2·2] of the adult population in the Dallas-Fort Worth area were infected during 2012. The resulting overall estimate for the ratio of infections to reported WNV neuroinvasive disease (WNND) cases was 238:1 (95% CI 192-290), with significantly increased risk of WNND in older age groups. These findings were very similar to previous estimates of infections per WNND case, indicating no change in virulence as WNV evolved into an endemic infection in the United States.

Embryo Development and Morphology of the Rocky Mountain Wood Tick (Acari: Ixodidae).

Dermacentor andersoni Stiles embryogenesis was observed using fluorescent and scanning electron microscopy for eggs held under laboratory conditions (25°C and at 93% relative humidity). Early embryonic cell divisions appeared to be synchronous and holoblastic, giving rise to a uniform blastoderm surrounding the yolk. The cells of the blastoderm became concentrated on one side of the embryo, forming the segmented germ band. Distinct opisthosomal and prosomal segment morphologies, which are characteristic of chelicerate embryos, were observed during germ band elongation. Mouth and leg appendages grew from the prosomal segments. As development progressed, the segments were fused into the idiosoma and capitulum of the free-living larval form. An embryo staging system was established based on embryo developmental morphology and the timing of morphogenetic events. The staging system will serve as a basis for future studies directed at understanding morphogenetic mechanisms or for observing the impact of abiotic factors, such as temperature or humidity, on tick development.

Predictors of adjuvant treatment for pancreatic adenocarcinoma at the population level.

BACKGROUND: In the present study, we aimed to describe, at the population level, patterns of adjuvant treatment use after curative-intent resection for pancreatic adenocarcinoma (pcc) and to identify independent predictors of adjuvant treatment use. METHODS: In this observational cohort study, patients undergoing pcc resection in the province of Ontario (population 13 million) during 2005-2010 were identified using the provincial cancer registry and were linked to administrative databases that include all treatments received and outcomes experienced in the province. Patients were defined as having received chemotherapy (ctx), chemoradiation (crt), or observation (obs). Clinicopathologic factors associated with the use of ctx, crt, or obs were identified by chi-square test. Logistic regression analyses were used to identify independent predictors of adjuvant treatment versus obs, and ctx versus crt. RESULTS: Of the 397 patients included, 75.3% received adjuvant treatment (27.2% crt, 48.1% ctx) and 24.7% received obs. Within a single-payer health care system with universal coverage of costs for ctx and crt, substantial variation by geographic region was observed. Although the likelihood of receiving adjuvant treatment increased from 2005 to 2010 (p = 0.002), multivariate analysis revealed widespread variation between the treating hospitals (p = 0.001), and even between high-volume hepatopancreatobiliary hospitals (p = 0.0006). Younger age, positive lymph nodes, and positive surgical resection margins predicted an increased likelihood of receiving adjuvant treatment. Among patients receiving adjuvant treatment, positive margins and a low comorbidity burden were associated with crt compared with ctx. CONCLUSIONS: Interinstitutional medical practice variation contributes significantly to differential patterns in the rate of adjuvant treatment for pcc. Whether such variation is warranted or unwarranted requires further investigation.

Negative predictive value of preoperative computed tomography in determining pathologic local invasion, nodal disease, and abdominal metastases in gastric cancer.

BACKGROUND: Before undergoing curative-intent resection of gastric adenocarcinoma (ga), most patients undergo abdominal computed tomography (ct) imaging to determine contraindications to resection (local invasion, distant metastases). However, the ability to detect contraindications is variable, and the literature is limited to single-institution studies. We sought to assess, on a population level, the clinical relevance of preoperative ct in evaluating the resectability of ga tumours in patients undergoing surgery. METHODS: In a provincial cancer registry, 2414 patients with ga diagnosed during 2005-2008 at 116 institutions were identified, and a primary chart review of radiology, operative, and pathology reports was performed for all patients. Preoperative abdominal ct reports were compared with intraoperative findings and final pathology reports (reference standard) to determine the negative predictive value (npv) of ct in assessing local invasion, nodal involvement, and intra-abdominal metastases. RESULTS: Among patients undergoing gastrectomy, the npv of ct imaging in detecting local invasion was 86.9% (n = 536). For nodal metastasis, the npv of ct was 43.3% (n = 450). Among patients undergoing surgical exploration, the npv of ct for intra-abdominal metastases was 52.3% (n = 407). CONCLUSIONS: Preoperative abdominal ct imaging reported as negative is most accurate in determining local invasion and least accurate in nodal assessment. The poor npv of ct should be taken into account when selecting patients for staging laparoscopy.

Cardiovascular safety of the glucagon-like peptide-1 receptor agonist taspoglutide in people with type 2 diabetes: an individual participant data meta-analysis of randomized controlled trials.

AIMS: To study the short-term cardiovascular effects of the once-weekly glucagon-like peptide-1 receptor agonist taspoglutide. METHODS: We conducted a meta-analysis of individual-participant data from nine randomized controlled trials in the T-Emerge programme, which assessed the efficacy and safety of taspoglutide in type 2 diabetes. Our primary outcome was a composite of death from cardiovascular disease (CVD) and acute myocardial infarction, stroke and hospitalization for unstable angina. RESULTS: Overall, 7056 individuals were included in the analysis, and there were 67 primary endpoint events during 7478 person-years of follow-up (40 vs 27 events in the intervention vs control groups, respectively). The odds ratio for the composite endpoint among people randomized to taspoglutide was 0.94 (95% confidence interval 0.57-1.56), which was robust across multiple subgroups. Longer-term data were not available as the development of taspoglutide was stopped because of gastrointestinal intolerance and serious hypersensitivity reactions. CONCLUSIONS: The available data suggest that short-term, once-weekly administration of taspoglutide was not associated with an excess risk of CVD, and provide insights relevant to the development of other novel once-weekly incretin mimetics.

Modern Multi-line Slot Machine Games: The Effect of Lines Wagered on Winners, Losers, Bonuses, and Losses Disguised as Wins.

We simulated the commercially available multi-line slot machine game "Money Storm," including its bonus wins. Our results show that after a specified amount of time (such as 1 or 50 h), when players played a single line, there were marked differences between one player and the next-a few won a lot, others lost far more than average. When playing 20 lines there were fewer big winners and fewer players quickly losing a large percentage of their money. We simulated a Gambler's Ruin scenario whereby players arrived with $100 and made $1 wagers until broke. Again we saw a reduction in the variability among player as the number of lines wagered increased, fewer players lost their entire bankroll quickly, and fewer players had big wins. The bonus wins in Money Storm contribute approximately 24% to the payback of the game, and our simulations of bonus wins shows that with 20 lines wagered the players spend approximately 11% of their time in bonus wins. With one line wagered, there are no losses disguised as wins while with 20 lines wagered the majority of hits are losses disguised as wins. Players using multi-line machines can thus tune the characteristics of the machine gambling experience to match their preferred pattern, though most seem in practice to bet on the most possible lines. Our results serve to inform researchers, counsellors, gamblers and others about how slot machines are designed, and the effect that wagering on multiple lines has on short-term and long-term play, bonus wins, and losses disguised as wins.

Pyruvate carboxylase deficiency type C; variable presentation and beneficial effect of triheptanoin.

Pyruvate carboxylase is a mitochondrial enzyme essential for the tricarboxylic acid cycle (TCA), gluconeogenesis and fatty-acid synthesis. Pyruvate carboxylase deficiency (PCD) mostly presents with life-limiting encephalopathy (types A/B). A milder type C presentation is rare, with a comparatively favourable prognosis. Therapies remain essentially supportive. Triheptanoin is an odd-chain triglyceride, with the potential to replenish TCA intermediates (anaplerosis), and its metabolites cross the blood-brain-barrier. Outcomes of triheptanoin treatment in PCD types A/B have been disappointing, but have not been reported in type C. Here, we present two new patients with PCD type C, and report the response to treatment with triheptanoin in one. Patient 1 (P1) presented with neonatal-onset lactic acidosis and recurrent symptomatic lactic acidosis following exercise and during illnesses, with frequent hospitalisations. Speech development was delayed. MRI-brain showed delayed cerebral myelination. Patient 2 (P2) presented with episodic ketoacidosis, hyperlactataemia and hypoglycaemia at 2 years of age, with gross motor delay and mild global volume loss on MRI brain. Treatment with triheptanoin was commenced in P1 at 3 years of age with up-titration to 35 mL/day (25% of daily energy intake) over 6 months, due to transient diarrhoea. Dietary long-chain triglycerides were restricted, with fat-soluble vitamin supplementation. Subsequently, hospitalisations during intercurrent illnesses decreased, post-exertional hyperlactataemia resolved and exercise tolerance improved. Continued developmental progress was observed, and repeat MRI 18 months after initiation showed improved myelination. Triheptanoin was well-tolerated and appeared efficacious during 2 years' follow-up, and has potential to restore energy homeostasis and myelin synthesis in PCD type C.

Dietary practices in pyridoxine non-responsive homocystinuria: a European survey.

BACKGROUND: Within Europe, the management of pyridoxine (B6) non-responsive homocystinuria (HCU) may vary but there is limited knowledge about treatment practice. AIM: A comparison of dietetic management practices of patients with B6 non-responsive HCU in European centres. METHODS: A cross-sectional audit by questionnaire was completed by 29 inherited metabolic disorder (IMD) centres: (14 UK, 5 Germany, 3 Netherlands, 2 Switzerland, 2 Portugal, 1 France, 1 Norway, 1 Belgium). RESULTS: 181 patients (73% >16 years of age) with HCU were identified. The majority (66%; n=119) were on dietary treatment (1-10 years, 90%; 11-16 years, 82%; and >16 years, 58%) with or without betaine and 34% (n=62) were on betaine alone. The median natural protein intake (g/day) on diet only was, by age: 1-10 years, 12 g; 11-16 years, 11 g; and >16 years, 45 g. With diet and betaine, median natural protein intake (g/day) by age was: 1-10 years, 13 g; 11-16 years, 20 g; and >16 years, 38 g. Fifty-two percent (n=15) of centres allocated natural protein by calculating methionine rather than a protein exchange system. A methionine-free l-amino acid supplement was prescribed for 86% of diet treated patients. Fifty-two percent of centres recommended cystine supplements for low plasma concentrations. Target treatment concentrations for homocystine/homocysteine (free/total) and frequency of biochemical monitoring varied. CONCLUSION: In B6 non-responsive HCU the prescription of dietary restriction by IMD centres declined with age, potentially associated with poor adherence in older patients. Inconsistencies in biochemical monitoring and treatment indicate the need for international consensus guidelines.

Dietary management of urea cycle disorders: European practice.

BACKGROUND: There is no published data comparing dietary management of urea cycle disorders (UCD) in different countries. METHODS: Cross-sectional data from 41 European Inherited Metabolic Disorder (IMD) centres (17 UK, 6 France, 5 Germany, 4 Belgium, 4 Portugal, 2 Netherlands, 1 Denmark, 1 Italy, 1 Sweden) was collected by questionnaire describing management of patients with UCD on prescribed protein restricted diets. RESULTS: Data for 464 patients: N-acetylglutamate synthase (NAGS) deficiency, n=10; carbamoyl phosphate synthetase (CPS1) deficiency, n=29; ornithine transcarbamoylase (OTC) deficiency, n=214; citrullinaemia, n=108; argininosuccinic aciduria (ASA), n=80; arginase deficiency, n=23 was reported. The majority of patients (70%; n=327) were aged 0-16y and 30% (n=137) >16y. Prescribed median protein intake/kg body weight decreased with age with little variation between disorders. The UK tended to give more total protein than other European countries particularly in infancy. Supplements of essential amino acids (EAA) were prescribed for 38% [n=174] of the patients overall, but were given more commonly in arginase deficiency (74%), CPS (48%) and citrullinaemia (46%). Patients in Germany (64%), Portugal (67%) and Sweden (100%) were the most frequent users of EAA. Only 18% [n=84] of patients were prescribed tube feeds, most commonly for CPS (41%); and 21% [n=97] were prescribed oral energy supplements. CONCLUSIONS: Dietary treatment for UCD varies significantly between different conditions, and between and within European IMD centres. Further studies examining the outcome of treatment compared with the type of dietary therapy and nutritional support received are required.

Loss-of-function mutations in the cathepsin C gene result in periodontal disease and palmoplantar keratosis.

Papillon-Lefèvre syndrome, or keratosis palmoplantaris with periodontopathia (PLS, MIM 245000), is an autosomal recessive disorder that is mainly ascertained by dentists because of the severe periodontitis that afflicts patients. Both the deciduous and permanent dentitions are affected, resulting in premature tooth loss. Palmoplantar keratosis, varying from mild psoriasiform scaly skin to overt hyperkeratosis, typically develops within the first three years of life. Keratosis also affects other sites such as elbows and knees. Most PLS patients display both periodontitis and hyperkeratosis. Some patients have only palmoplantar keratosis or periodontitis, and in rare individuals the periodontitis is mild and of late onset. The PLS locus has been mapped to chromosome 11q14-q21 (refs 7, 8, 9). Using homozygosity mapping in eight small consanguineous families, we have narrowed the candidate region to a 1.2-cM interval between D11S4082 and D11S931. The gene (CTSC) encoding the lysosomal protease cathepsin C (or dipeptidyl aminopeptidase I) lies within this interval. We defined the genomic structure of CTSC and found mutations in all eight families. In two of these families we used a functional assay to demonstrate an almost total loss of cathepsin C activity in PLS patients and reduced activity in obligate carriers.

Accounting for the High Enrollment of African Americans on Winship Cancer Institute's Myeloma Clinical Trials.

Background: Thirty-four percent of Multiple Myeloma (MM) clinical trial participants at Winship Cancer Institute (Winship) are African American (AA); however, AAs make up only 4.5 percent of myeloma clinical trial participants in the United States. Given our high enrollment, we aimed to measure AAs' trust in providers and identify if clinical trial enrollment barriers exist. Methodology: A member of the ethics research team surveyed AA patients who had consented to a MM clinical trial at Winship. Three validated surveys were used: Trust in Medical Research (TMR); Human Connection (THC) which measures how much patients feel they are heard and valued by their physicians; and the Duke Intrinsic Religiosity Scale (DUREL) which measures strength of religious engagement and belief. The survey also included questions about the impact of side effects, distance to the trial center and trial related costs on the decision to participate in clinical trial. Results: Ninety-two percent (61/67) of patients approached consented. The mean TMR score and the mean THC score were significantly higher (P-value < 0.001) than the results obtained in key national surveys (TMR 14.9 compared to 11.65; THC 57.7 compared to 54.6). These two surveys were significantly correlated, meaning trust and human connection increase or decrease in tandem. The 3 religiosity subscale results showed high religiosity (3.84, 4.36, and 4.35 with 5 being the highest score). The mean scores of the importance of the investigational agent's side effects, trial costs, and distance to trial center on the decision to enroll in a clinical trial were also high (8.5, 7.8, and 6.5, respectively, with 10 being the most important). Conclusion: In our study population, high trust and human connection overcame other trial participation barriers: strong religious beliefs and concerns about side effects, costs, and travel distance. We present a roadmap to guide investigators to increase human connection, and hopefully trust.

The development and evaluation of the Screening Tool for the Assessment of Malnutrition in Paediatrics (STAMP©) for use by healthcare staff.

BACKGROUND: The early identification of malnutrition and nutrition risk through nutrition screening is common practice in adult clinical care but, in children, this has been hampered by the lack of an appropriate nutrition screening tool. The present study aimed to develop and evaluate a simple, child-specific nutrition screening tool for administration by non-nutrition healthcare professionals. METHODS: In a two-phase observational study, significant predictors of nutrition risk were identified using a structured questionnaire. These were then combined to produce a nutrition screening tool. For evaluation purposes, the reliability, sensitivity and specificity of the newly-developed Screening Tool for the Assessment of Malnutrition in Paediatrics (STAMP(©)) were estimated by comparing the classification of nutrition risk using the tool with that determined by a full nutritional assessment by a registered dietitian. RESULTS: A total of 122 children were recruited for development phase and a separate cohort of 238 children was recruited for the evaluation phase. Low percentile weight for age, reported weight loss, discrepancy between weight and height percentile and recently changed appetite were all identified as predictors of nutrition risk. These predictors, together with the expected nutrition risk of clinical diagnoses, were combined to produce STAMP(©). Evaluation of STAMP(©) demonstrated fair to moderate reliability in identifying nutrition risk compared to the nutrition risk classification determined by a registered dietitian (κ = 0.541; 95% confidence interval = 0.461-0.621). Sensitivity and specificity were estimated at 70% (51-84%) and 91% (86-94%), respectively. CONCLUSIONS: The present study describes the development and evaluation of a new nutrition screening tool specifically for use in a UK general paediatric inpatient population.

Dietary management of urea cycle disorders: UK practice.

BACKGROUND: There is no published data describing UK dietary management of urea cycle disorders (UCD). The present study describes dietary practices in UK inherited metabolic disorder (IMD) centres. METHODS: Cross-sectional data from 16 IMD centres were collected by a questionnaire describing the management of UCD patients on prescribed protein-restricted diets. RESULTS: One hundred and seventy-five patients [N-acetylglutamate synthase deficiency, n = 3; carbamoyl phosphate synthase deficiency (CPS), n = 8; ornithine transcarbamoylase deficiency (OTC), n = 75; citrullinaemia, n = 41; argininosuccinic aciduria (ASA), n = 36; arginase deficiency, n = 12] were reported; 70% (n = 123) aged 0-16 years; 30% (n = 52) >16 years. Prescribed median protein intake decreased with age (0-6 months: 2 g kg(-1) day(-1); 7-12 months: 1.6 g kg(-1) day(-1); 1-10 years: 1.3 g kg(-1) day(-1); 11-16 years: 0.9 g kg(-1) day(-1) and >16 years: 0.8 g kg(-1) day(-1)) with little variation between disorders. Adult protein prescription ranged 0.4-1.2 g kg(-1) day(-1) (40-60 g day(-1)). In the previous 2 years, 30% (n = 53) were given essential amino acid supplements (EAAs) (CPS, n = 2; OTC, n = 20; citrullinaemia, n = 15; ASA, n = 7; arginase deficiency, n = 9). EAAs were prescribed for low plasma quantitative essential amino acids (n = 13 centres); inadequate natural protein intake (n = 11) and poor metabolic control (n = 9). From diagnosis, one centre prescribed EAAs for all patients and one centre for severe defects only. Only 3% (n = 6) were given branch chain amino acid supplements. Enteral feeding tubes were used by 25% (n = 44) for feeds and 3% (n = 6) for medications. Oral energy supplements were prescribed in 17% (n = 30) of cases. CONCLUSIONS: In the UK, protein restriction based on World Health Organization 'safe intakes of protein', is the principle dietary treatment for UCD. EAA supplements are prescribed mainly on clinical need. Multicentre collaborative research is required to define optimal dietary treatments.

Long-term memory in frog-eating bats.

Long-term memory has clear advantages for animals but also has neurological and behavioral costs1-3. Encoding memories is metabolically expensive1. Older memories can interfere with retrieval of more recent memories3, prolong decision-making and reduce cognitive flexibility2,3. Given these opposing selection pressures, understanding how long memories last can shed light on how memory enhances or constrains animals' abilities to exploit their niches. Although testing memory retention in wild animals is difficult, it is important because captive conditions do not reflect the complex cognitive demands of wild environments, and long-term captivity changes the brain4 (Data S1A). Here, we trained wild-caught frog-eating bats (Trachops cirrhosus) to find prey by flying to a novel acoustic cue. After they learned the rewarded sound, we released them back into the wild, and then re-captured some of them one to four years later. When re-tested, all eight 'experienced' bats that previously learned the novel prey sounds flew to those sounds within seconds, whereas 17 naïve bats tested with the same sounds showed weak responses. Experienced bats also showed behavior indicating generalization of memories between novel sounds and rewards over time. The frog-eating bat's remarkably long memory indicates that an ability to remember rarely encountered prey may be advantageous for this predator and suggests hitherto unknown cognitive abilities in bats.