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Abstract: Background: Opioid‐induced constipation (OIC) is a major side effect of opioid use. Centrally acting antagonists result in opioid withdrawal or worsening of pain and lead to use of peripherally acting mu‐opioid receptor antagonists (PAMORAs). The required doses of the PAMORAs, methylnaltrexone and naloxegol, in the treatment of OIC are well established in chronic opioid users. OIC may occur after short duration of opioid treatment; the required doses of naloxone, naltrexone, and PAMORAs in opioid‐naïve subjects (with no opioid use for at least 3 months) are unclear. The aim of this review was to evaluate the PAMORA dose required for opioid‐naïve subjects to achieve similar beneficial effects on symptoms or valid surrogates to those observed in chronic opioid users. Methods: A PubMed search of μ‐opioid antagonists to counter μ‐opioid effects included terms: naloxone, naltrexone, methylnaltrexone, alvimopan, and naloxegol, as well as OIC and colonic transit. Key Results: The approved dose of methylnaltrexone in chronic opioid users, 0.3 mg/kg subcutaneous (SQ), did not affect motility in opioid‐naïve subjects. Trials investigating the required dose of alvimopan showed 0.5‐1 mg dose was efficacious in treating OIC; a 10‐fold higher dose (12 mg) of alvimopan is needed to block effects of codeine on small bowel and colonic transit in opioid‐naïve subjects compared to chronic opioid users. Opioid‐naïve users need 125 mg of naloxegol to reverse the effects of opioids on transit; this is in contrast to the 12.5 to 25 mg needed to treat OIC in chronic opioid users. Conclusions & Inferences: Opioid‐naïve subjects require a higher dose of PAMORA than chronic opioid users to achieve μ‐opioid antagonist effect. [ABSTRACT FROM AUTHOR]

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Introduction: Regulatory decisions on paediatric investigation plans (PIPs) aim at making effective and safe medicines timely available for children with high unmet medical need. At the same time, scientific knowledge progresses continuously leading frequently to the identification of new molecular targets in the therapeutic area of oncology. This, together with further efforts to optimise next generation medicines, results in novel innovative products in development pipelines. In the context of global regulatory development requirements for these growing pipelines of innovative products (e.g. US RACE for children Act), it is an increasing challenge to complete development efforts in paediatric oncology, a therapeutic area of rare and life-threatening diseases with high unmet needs., Objective: Regulators recognise feasibility challenges of the regulatory obligations in this context. Here, we explain the EU regulatory decision making strategy applied to paediatric oncology, which aims fostering evidence generation to support developments based on needs and robust science. Because there is a plethora of products under development within given classes of or within cancer types, priorities need to be identified and updated as evidence evolves. This also includes identifying the need for third or fourth generation products to secure focused and accelerated drug development., Conclusion: An agreed PIP, as a plan, is a living document which can be modified in light of new evidence. For this to be successful, input from the various relevant stakeholders, i.e. patients/parents, clinicians and investigators is required. To efficiently obtain this input, the EMA is co-organising with ACCELERATE oncology stakeholder engagement platform meetings., Competing Interests: Conflict of interest statement The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this article., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Irritable bowel syndrome (IBS) is a chronic gastrointestinal disorder for which no diagnostic tools are currently available. Patients are diagnosed using the Rome IV criteria and subtyped into a diarrhea, constipation, or mixed phenotype based on their dominant stool pattern. A recent development in the biomarker area is the analysis of volatile organic compounds (VOCs). The aim of this study was to evaluate the potential of VOCs as diagnostic and phenotypic biomarkers for IBS in breath and fecal samples., Materials and Methods: Breath and fecal samples from IBS patients and healthy asymptomatic controls (HC) were analyzed with multicapillary column/ion mobility spectrometry (MCC/IMS) and classification models were created based upon VOCs and clinical characteristics., Discussion: Irritable bowel syndrome patients were differentiated from HC by means of volatile profiling in both breath and fecal samples with area under the curve (AUCs) of respectively 0.62 and 0.80. Patient subtypes could also be differentiated from each other with AUCs ranging between 0.65 and 0.78. Furthermore, VOC models could differentiate IBS patients based on clinical characteristics like psychological comorbidities and microbiota-influencing therapies., Conclusion: This study is the first to demonstrate the use of VOC profiling with the help of MCC/IMS to differentiate IBS patients. Furthermore, the importance of clinical characteristics beside the dominant stool pattern in the differentiation of IBS patients was emphasized., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Van Malderen, Hanning, Lambrechts, Haverhals, Van Marcke, Ceuleers, De Man, De Winter, Lamote and De Schepper.)

Increased research to improve preclinical models to inform the development of therapeutics for neonatal diseases is an area of great need. This article reviews five common neonatal diseases - bronchopulmonary dysplasia, retinopathy of prematurity, necrotizing enterocolitis, perinatal hypoxic-ischemic encephalopathy and neonatal sepsis - and the available in vivo, in vitro and in silico preclinical models for studying these diseases. Better understanding of the strengths and weaknesses of specialized neonatal disease models will help to improve their utility, may add to the understanding of the mode of action and efficacy of a therapeutic, and/or may improve the understanding of the disease pathology to aid in identification of new therapeutic targets. Although the diseases covered in this article are diverse and require specific approaches, several high-level, overarching key lessons can be learned by evaluating the strengths, weaknesses and gaps in the available models. This Review is intended to help guide current and future researchers toward successful development of therapeutics in these areas of high unmet medical need., Competing Interests: Competing interests The authors declare no competing or financial interests. The information presented in this article is that of the authors and does not necessarily represent that of their employers. The information in these materials is not a formal dissemination of information by the U.S. Food and Drug Administration, the Federal Institute for Drugs and Medicines Devices, or the Federal Agency for Medicines and Health Products and does not represent agency position or policy., (© 2022. Published by The Company of Biologists Ltd.)

Volatile organic compounds (VOCs) are produced by the human metabolism, inflammation and gut microbiota and form the basis of innovative volatomics research. VOCs detected through breath and faecal analysis hence serve as attractive, non-invasive biomarkers for diagnosing and monitoring irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD). This review describes the clinical applicability of volatomics in discriminating between IBS, IBD and healthy volunteers with acceptable accuracy in breath (70%-100%) and faecal (58%-85%) samples. Promising compounds are propan-1-ol for diagnosing and monitoring of IBD patients, and 1-methyl-4-propan-2-ylcyclohexa-1,4-diene as biomarker for IBS diagnosis. However, these VOCs often seem to be related to inflammation and probably will need to be used in conjunction with other clinical evidence. Furthermore, three interventional studies underlined the potential of VOCs in predicting treatment outcome and patient follow-up. This shows great promise for future use of VOCs as non-invasive breath and faecal biomarkers in personalised medicine. However, properly designed studies that correlate VOCs to IBD/IBS pathogenesis, while taking microbial influences into account, are still key before clinical implementation can be expected., Competing Interests: Declaration of Competing Interest The authors declare no personal conflict of interests., (Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.)

Central nervous system (CNS)-targeted products are an important category of pediatric pharmaceuticals. In view of the significant postnatal maturation of the CNS, juvenile animal studies (JAS) are performed to support pediatric development of these new medicines. In this project, the design and results of juvenile toxicity studies from 15 drug compounds for the treatment of neurologic or psychiatric conditions were analyzed. Studies were conducted mostly in rats; sometimes in addition in dogs and monkeys. The study design of the pivotal JAS was variable, even for compounds with a similar therapeutic indication. Age of the juvenile animals was not consistently related to the starting age of the intended patient population. Of 15 compounds analyzed, 6 JAS detected more severe toxicities and 6 JAS evidenced novel CNS effects compared to their adult counterparts. The effects of CNS on acoustic startle and learning and memory were observed at high dosages. Reversibility was tested in most cases and revealed some small effects that were retained or only uncovered after termination of treatment. The interpretation of the relevance of these findings was often hampered by the lack of matching end points in the adult studies or inappropriate study designs. Detailed clinical observation and motor activity measures were the most powerful end points to detect juvenile CNS effects. The need for more detailed behavioral examinations in JAS, for example, on learning and memory, should, therefore, be decided upon on a case-by-case basis, based on specific concerns in order to avoid overloading the studies.

Background: Meckel's diverticulum is present in about 2% of the population. The literature reports 3.2% incidence of tumors within Meckel's diverticulum; the tumors are predominantly benign., Objective and Methods: The purpose of this study was to evaluate malignant tumors in Meckel's diverticulum through systematic review of the literature and review of electronic medical records including pathology reports over 14 years at the Mayo Clinic, Rochester, USA., Results: A literature review over the last 10 years identified 37 citations with 402 patients (median age: 58 years; 68.9% males). The predominant malignancy reported was neuroendocrine tumor 84.6%, followed by gastrointestinal stromal tumor 8.2%, and adenocarcinoma 6%. At the time of diagnosis, 29.5% of patients had metastases. In the Mayo Clinic electronic medical records review, there were 19 patients (5.1% of them surgically removed Meckel's diverticulum) who had a malignancy associated with Meckel's diverticulum: 63.2% neuroendocrine tumor, 10.5% gastrointestinal stromal tumor, 5.3% adenocarcinoma, 5.3% pancreatic epithelial neoplasia, and 15.8% metastases from secondary location. Median size of the malignancy was 7 mm, and 17/19 malignancies were coincidental findings. Most neuroendocrine tumors infiltrated the submucosa, while gastrointestinal stromal tumor and adenocarcinoma invaded the serosa. At the time of diagnosis, 33.3% of patients had metastases., Conclusion: About 5% of Meckel's diverticulums resected were associated with malignant tumors, most commonly neuroendocrine tumor, and a significant portion of Meckel's diverticulum malignancy was metastatic at the time of discovery.

Background: The shoulder complex is highly loaded during swimming. No studies were found analyzing the changes in shoulder girdle strength in young swimmers, through the years., Objective: To analyze the changes in strength of internal rotators and external rotators of the arm, lower trapezius and supraspinatus and in the external rotators/internal rotators ratio in young elite swimmers through 3 years., Methods: 31 adolescent elite swimmers (14-18 years, of both sexes) participated in the study. Isometric strength of the shoulder girdle muscles was performed using a handheld dynamometer during 3 years., Results: For boys absolute data, internal rotators increased from the first to the second (p=0.0001; mean difference 45.6N; 95%CI 26.7-65.0) and third years (p=0.01; mean difference: 32.4; 95%CI: 9.3-55.5). Considering the weight-normalized data, internal rotators increased from the first to the second year (p<0.0001; mean difference: 0.52; 95%CI: 0.26-0.78), external rotators decreased from the first to the third year (p=0.003; mean difference: -0.33; 95%CI: -0.53 to -0.13) and from the second to the third year (p=0.0004; mean difference: -0.29; 95%CI: -0.46 to -0.12) and supraspinatus decreased from the second to the third year (p=0.006; mean difference: -0.17; 95%CI: -0.28 to -0.06). For girls, there were no significant differences in the absolute strength. Considering the weight-normalized data, lower trapezius decreased from the first to the third year (p=0.02; mean difference: -0.15; 95%CI: -0.27 to 0.03). Considering both sexes, the external rotators/internal rotators ratio decreased from the first to the second (p<0.0001; mean difference -0.12N; 95%CI -0.13 to -0.11) and third years (p<0.0001; mean difference -0.15N; 95%CI -0.16 to -0.14)., Conclusion: Muscle imbalance can occur in the shoulder girdle in young swimmers in 3 years, with increased internal rotators and decreased external rotators and supraspinatus strength in boys, and decreased strength of the lower trapezius in girls. Attention should be given in young swimmers' shoulder girdle muscle balance., (Copyright © 2018 Associação Brasileira de Pesquisa e Pós-Graduação em Fisioterapia. Publicado por Elsevier Editora Ltda. All rights reserved.)

Paracetamol (acetaminophen) remains the first line for the treatment of pain and fever in pregnancy. Recently published epidemiological studies suggested a possible association between paracetamol exposure in utero and attention-deficit-hyperactivity disorder/hyperkinetic disorder (ADHD/HKD) or adverse development issues in children. However, the effects observed are in the weak to moderate range, and limitations in the studies' design prevent inference on a causal association with ADHD/HKD or child neurological development. In parallel, recent animal data showed that cognition and behaviour may be altered following exposure to therapeutic doses of paracetamol during early development. These effects may be mediated by interference of paracetamol with brain-derived neurotrophic factor, neurotransmitter systems (including serotonergic, dopaminergic, adrenergic, as well as the endogenous endocannabinoid systems), or cyclooxygenase-2. However, no firm conclusion can be made on the relevance of these observations to humans. We conclude that additional well-designed cohort studies are necessary to confirm or disprove the association. In the context of current knowledge, paracetamol is still to be considered safe in pregnancy and should remain the first-line treatment for pain and fever., (© 2015 Mac Keith Press.)