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Various lines of published evidence have already demonstrated the impact of TRPV1 agonists on energetic metabolism through the stimulation of the sympathetic nervous system (SNS). This study presents a trial investigating if stimulation of the two related sensory receptors TRPA1 and TRPM8 could also stimulate the SNS and impact the energetic metabolism of healthy subjects. The trial was designed to be double-blinded, randomized, cross-over, placebo-controlled with healthy subjects and the impact on the energetic metabolism and the autonomic nervous system (ANS) of cinnamaldehyde, capsaicin and a cooling flavor was measured during the 90 min after ingestion. Energy expenditure and substrate oxidation were measured by indirect calorimetry. An exploratory method to measure ANS activity was by facial thermography and power spectral analysis of heart rate variability using ECG was also used. Following cinnamaldehyde ingestion, energy expenditure was increased as compared to placebo. Furthermore, postprandial fat oxidation was maintained higher compared to placebo after cinnamaldehyde and capsaicin ingestion. Similar peripheral thermoregulation was observed after capsaicin and cinnamaldehyde ingestion. Unlike capsaicin, the dose of cinnamaldehyde was not judged to be sensorially ‘too intense’ by participants suggesting that Cinnamaldehyde would be a more tolerable solution to improve thermogenesis via spicy ingredients as compared to capsaicin.

Background Because the source of protein may play a role in its satiating effect, we investigated the effect of different proteins on satiation and short-term satiety. Methods Two randomized single-blind cross-over studies were completed. In the first study, we investigated the effect of a preload containing 20 g of casein, whey, pea protein, egg albumin or maltodextrin vs. water control on food intake 30 min later in 32 male volunteers (25 ± 4 yrs, BMI 24 ± 0.4 kg/m 2 ). Subjective appetite was assessed using visual analogue scales at 10 min intervals after the preload. Capillary blood glucose was measured every 30 min during 2 hrs before and after the ad libitum meal. In the second study, we compared the effect of 20 g of casein, pea protein or whey vs. water control on satiation in 32 male volunteers (25 ± 0.6 yrs, BMI 24 ± 0.5 kg/m 2 ). The preload was consumed as a starter during an ad libitum meal and food intake was measured. The preloads in both studies were in the form of a beverage. Results In the first study, food intake was significantly lower only after casein and pea protein compared to water control (P = 0.02; 0.04 respectively). Caloric compensation was 110, 103, 62, 56 and 51% after casein, pea protein, whey, albumin and maltodextrin, respectively. Feelings of satiety were significantly higher after casein and pea protein compared to other preloads (P < 0.05). Blood glucose response to the meal was significantly lower when whey protein was consumed as a preload compared to other groups (P < 0.001). In the second study, results showed no difference between preloads on ad libitum intake. Total intake was significantly higher after caloric preloads compared to water control (P < 0.05). Conclusion Casein and pea protein showed a stronger effect on food intake compared to whey when consumed as a preload. However, consuming the protein preload as a starter of a meal decreased its impact on food intake as opposed to consuming it 30 min before the meal.

ObjectivesThe MOSAIC study aimed to evaluate if the Cow’s Milk-related Symptom Score (CoMiSS) can be used as a stand-alone diagnostic tool for cow’s milk protein allergy (CMPA).DesignSingle-blinded, prospective, multicentre diagnostic accuracy study.Setting10 paediatric centres in China.Participants300 non-breastfed infants (median age 16.1 weeks) with suspected CMPA.InterventionsAfter performing the baseline CoMiSS, infants commenced a cow’s milk protein elimination diet with amino acid-based formula for 14 days. CoMiSS was repeated at the end of the elimination trial. Infants then underwent an open oral food challenge (OFC) with cow’s milk-based formula (CMF) in hospital. Infants who did not react during the OFC also completed a 14-day home challenge with CMF. A diagnosis of CMPA was made if acute or delayed reactions were reported.Primary outcome measuresA logistic regression model for CoMiSS to predict CMPA was fitted and a receiver–operator characteristic (ROC) curve generated. An area under the curve (AUC) of ≥0.75 was deemed adequate to validate CoMiSS as a diagnostic tool (target sensitivity 80%–90% and specificity 60%–70%).ResultsOf 254 infants who commenced the OFC, 250 completed both challenges, and a diagnosis of CMPA made in 217 (85.4%). The median baseline CoMiSS in this group fell from 8 (IQR 5–10) to 5 (IQR 3–7) at visit 2 (p<0.000000001), with a median change of −3 (IQR −6 to −1). A baseline CoMiSS of ≥12 had a low sensitivity (20.3%), but high specificity (87.9%) and high positive predictive value (91.7%) for CMPA. The ROC analysis with an AUC of 0.67 fell short of the predefined primary endpoint.ConclusionsThe present study did not support the use of CoMiSS as a stand-alone diagnostic tool for CMPA. Nevertheless, CoMiSS remains a clinically useful awareness tool to help identify infants with cow’s milk-related symptoms.Trial registration numberNCT03004729; Pre-results.

The purpose of this study was to assess the safety, tolerability, pharmacokinetics, pharmacodynamics, and immunogenicity of BOS161721, a humanized immunoglobulin G1 triple mutation (M252Y/S254T/T256E) monoclonal antibody that inhibits interleukin‐21 (IL‐21) bioactivity. This randomized, single‐center, double‐blind, placebo‐controlled study randomized healthy volunteers 3:1 to single ascending intravenous and subcutaneous doses of BOS161721 (range 1–240 mg) or placebo. BOS161721 and placebo groups had similar rates of adverse events, mostly mild; none led to study discontinuation. There were no clinically significant findings in physical examination, vital signs, or laboratory assessment. In the pooled BOS161721 population, four subjects (8.5%) tested antidrug antibody‐positive predose, and seven (14.9%) postdose. Absolute CD4+ lymphocyte count remained normal throughout follow‐up. BOS161721 administered subcutaneously was absorbed slowly, with a median time to maximum concentration (Tmax) of 144 hours across doses (range 1–15 days) and a mean apparent terminal elimination half‐life of 80–87 days for doses ≥ 30 mg. Area under the concentration‐time curve from time zero to infinity (AUC0‐inf) and maximum observed concentration (Cmax) were linear across doses > 10 mg. Subcutaneous bioavailability was 64%. Phosphorylated signal transducer and activator of transcription 3 (pSTAT3) decreased dose‐dependently with threshold characteristics at doses of ≥ 10 mg. Downregulation in BATF, IL6, LAG3, and SOCS3 genes caused by IL‐21 stimulation was reversed dose‐dependently. BOS161721 was well‐tolerated across doses, suppressed IL‐21‐induced pSTAT3 dose‐dependently, and reversed downregulation of genes critical to tolerance induction and T‐cell exhaustion induced by IL‐21. Further clinical studies are ongoing in patients with systemic lupus erythematosus, in which IL‐21 has a pathogenetic role.

Clinical trials continue to be the gold standard for evaluating new medical technologies. New advancements in modern computation power have led to increasing interest in Bayesian methods. Despite the multiple benefits of Bayesian approaches, application to clinical trials has been limited. Based on insights from the survey of clinical researchers in drug development conducted by the Drug Information Association Bayesian Scientific Working Group (DIA BSWG), insufficient knowledge of Bayesian approaches was ranked as the most important perceived barrier to implementing Bayesian methods. Results of the same survey indicate that clinical researchers may find the interpretation of results from a Bayesian analysis to be more useful than conventional interpretations. In this article, we illustrate key concepts tied to Bayesian methods, starting with familiar concepts widely used in clinical practice before advancing in complexity, and use practical illustrations from clinical development.

Oropharyngeal dysphagia is prevalent in several at-risk populations, including post-stroke patients, patients in intensive care and the elderly. Dysphagia contributes to longer hospital stays and poor outcomes, including pneumonia. Early identification of dysphagia is recommended as part of the evaluation of at-risk patients, but available bedside screening tools perform inconsistently. In this study, we developed algorithms to detect swallowing impairment using a novel accelerometer-based dysphagia detection system (DDS). A sample of 344 individuals was enrolled across seven sites in the United States. Dual-axis accelerometry signals were collected prospectively with simultaneous videofluoroscopy (VFSS) during swallows of liquid barium stimuli in thin, mildly, moderately and extremely thick consistencies. Signal processing classifiers were trained using linear discriminant analysis and 10,000 random training–test data splits. The primary objective was to develop an algorithm to detect impaired swallowing safety with thin liquids with an area under receiver operating characteristic curve (AUC) > 80% compared to the VFSS reference standard. Impaired swallowing safety was identified in 7.2% of the thin liquid boluses collected. At least one unsafe thin liquid bolus was found in 19.7% of participants, but participants did not exhibit impaired safety consistently. The DDS classifier algorithms identified participants with impaired thin liquid swallowing safety with a mean AUC of 81.5%, (sensitivity 90.4%, specificity 60.0%). Thicker consistencies were effective for reducing the frequency of penetration–aspiration. This DDS reached targeted performance goals in detecting impaired swallowing safety with thin liquids. Simultaneous measures by DDS and VFSS, as performed here, will be used for future validation studies.

Bayesian methods bring flexibility and speed to clinical trial design and analysis, and with increased access to the necessary computational power, are transforming today's clinical research. Both methods have particular strengths, in varying situations. [...]this paper considers both Bayesian methods used for Bayesian trials, as well as examples of how Bayesian methods can strengthen insights of trials that are Frequentist. [...]as participants in what are typically firstin-human trials, there is very little known about the response of a drug within the human body, especially regarding toxicity. [...]patients and sponsors benefit from a trial design that enables frequent interim looks, opportunities for adjusting doses, and stopping for futility when required. The recently published case study redesigning the Phase III OSCAR (High Frequency OSCillation in Acute Respiratory Distress Syndrome (ARDS)) trial using Bayesian methods showed that the Bayesian sequential design could shorten the trial duration by 15 to 40 weeks and recruited 231 to 336 fewer patients.6 Authors of another trial illustrated that by using Bayesian designs, the trial could have declared adrenaline superior for 30-day survival with 1,500 fewer patients.7 The advantages of Bayesian analysis have also been shown by post-hoc Bayesian analysis of two recent high-profile trials, EOLIA and ANDROMEDA-SHOCK.

IntroductionThe symptoms of cow’s milk protein allergy (CMPA) in infancy can be non-specific which may delay a correct diagnosis and cause adverse clinical outcomes. The diagnosis of non-IgE-mediated CMPA is particularly complex as it involves a 2 to 4 week elimination diet followed by oral food challenge (OFC). The Cow’s Milk-related Symptom Score (CoMiSS) is a clinical resource for primary healthcare providers which aims to increase awareness of CMPA symptoms to facilitate an earlier diagnosis. The aim of the present study is to assess if the CoMiSS can be used as a potential diagnostic tool in infants with suspected CMPA.Methods and analysisExclusively formula-fed infants aged 0–6 months presenting with symptoms suggestive of CMPA will be included in this prospective, multicentre trial which will be conducted in 10 centres in China. All infants will commence a 2-week trial of an amino acid-based formula (AAF) while eliminating all cow milk protein from their diets. After the AAF treatment period, infants will undergo an open OFC in hospital with standard cow’s milk formula, followed by an open home challenge for another 2 weeks. Clinical symptoms will be documented on standardised symptom scorecards. The CoMiSS will be determined at study entry (CoMiSS 1, before the start of the AAF), after 2 weeks (CoMiSS 2, before the OFC) and after a further period of 2 weeks or when symptoms suggestive of CMPA reappear (CoMiSS 3). Weight and length will be measured at each visit. The difference between CoMiSS 1 and 2 as a predictor of the OFC outcome will also be assessed. The diagnostic accuracy of the baseline CoMiSS will be calculated.Ethics and disseminationThe study was approved by the Hunan Children’s Hospital Medical Ethics Committee, Hunan, China. The findings of this trial will be submitted for publication in a peer-reviewed journal in paediatric nutrition or gastroenterology. Abstracts will be submitted to the relevant national and international conferences.Trial registration number NCT03004729; Pre-results.

BackgroundNew safe and effective TB vaccine strategies to replace infant BCG vaccination are needed urgently. We evaluated the safety, reactogenicity and immunogenicity of three doses of the live-attenuated Mycobacterium tuberculosis (Mtb) vaccine candidate, MTBVAC, in comparison to BCG in South African newborns.MethodsHealthy infants, HIV-unexposed, BCG-naïve newborns without history of close TB contact were randomly allocated into three sequential cohorts to receive a single intradermal dose of BCG (SSI, 2.5×105 CFU) or MTBVAC (2.5×104; 2.5×105 CFU; or 2.5×106 CFU).Results228 pregnant women consented, and 99 newborns were enrolled. Seventy-eight infants across all 3 cohorts had local reactions, all rated mild, except one grade 2 erythema. Induration, swelling, and erythema was more common with increased MTBVAC dosage. Induration and swelling were more common in MTBVAC 2.5x106 than in BCG and reactogenicity in MTBVAC 2.5x105 was same as BCG. Twelve infants experienced 14 vaccine-unrelated SAEs including one death due to bronchopneumonia. Eight infants commenced TB treatment for unconfirmed pulmonary TB (BCG n=4 and MTBVAC 2.5x104 CFU n=4) and one for unconfirmed TB meningitis (BCG). MTBVAC was highly immunogenic at all 3 doses, inducing predominantly Th1-cytokine-expressing CD4 T-cells, which peaked at day 56 and waned thereafter. The 2.5×105 and 2.5×106 CFU MTBVAC doses were more immunogenic than BCG, inducing very similar response magnitudes and phenotypes. Vaccination with any MTBVAC dose resulted in QFT conversion in most infants at Day 56, but these responses waned and reverted to QFT-negative in more than half by the end of the 1-year follow-up period. ConclusionMTBVAC appeared safe and well tolerated and immunogenic at doses between 2.5×104 CFU and 2.5×106 CFU in South Africans newborns. The 2.5×105 CFU MTBVAC dose was selected for the ongoing phase 3 trial in a high TB prevalence setting.