Search

In Australia and the UK, commercialization and corporatization of assisted reproductive technologies have created a marketplace of clinics, products, and services. While this has arguably increased choice for patients, 'choice', shaped by commercial imperatives may not mean better-quality care. At present, regulation of clinics (including clinic-corporations) and clinicians focuses on the doctor-patient dyad and the clinic-consumer dyad. Scant attention has been paid to the conflicts between the clinic-corporation's duty to its shareholders and investors, the medical profession's duty to the corporations within which they practice, and the obligations of both clinicians and corporations to patients and to health systems. Frameworks of regulation based in corporate governance and business ethics, such as stakeholder models and 'corporate social responsibility', have well-recognized limits and may not translate well into healthcare settings. This means that existing governance frameworks may not meet the needs of patients or health systems. We argue for the development of novel regulatory approaches that more explicitly characterize the obligations that both corporations and clinicians in corporate environments have to patients and to society, and that promote fulfilment of these obligations. We consider mechanisms for application in the multi-jurisdictional setting of Australia, and the single jurisdictional settings of the UK., (© The Author(s) 2024. Published by Oxford University Press.)

Regular exercise has many physical and brain health benefits, yet the molecular mechanisms mediating exercise effects across tissues remain poorly understood. Here we analyzed 400 high-quality DNA methylation, ATAC-seq, and RNA-seq datasets from eight tissues from control and endurance exercise-trained (EET) rats. Integration of baseline datasets mapped the gene location dependence of epigenetic control features and identified differing regulatory landscapes in each tissue. The transcriptional responses to 8 weeks of EET showed little overlap across tissues and predominantly comprised tissue-type enriched genes. We identified sex differences in the transcriptomic and epigenomic changes induced by EET. However, the sex-biased gene responses were linked to shared signaling pathways. We found that many G protein-coupled receptor-encoding genes are regulated by EET, suggesting a role for these receptors in mediating the molecular adaptations to training across tissues. Our findings provide new insights into the mechanisms underlying EET-induced health benefits across organs., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Each human genome has tens of thousands of rare genetic variants; however, identifying impactful rare variants remains a major challenge. We demonstrate how use of personal multi-omics can enable identification of impactful rare variants by using the Multi-Ethnic Study of Atherosclerosis, which included several hundred individuals, with whole-genome sequencing, transcriptomes, methylomes, and proteomes collected across two time points, 10 years apart. We evaluated each multi-omics phenotype's ability to separately and jointly inform functional rare variation. By combining expression and protein data, we observed rare stop variants 62 times and rare frameshift variants 216 times as frequently as controls, compared to 13-27 times as frequently for expression or protein effects alone. We extended a Bayesian hierarchical model, "Watershed," to prioritize specific rare variants underlying multi-omics signals across the regulatory cascade. With this approach, we identified rare variants that exhibited large effect sizes on multiple complex traits including height, schizophrenia, and Alzheimer's disease., Competing Interests: S.B.M. is an advisor to BioMarin, MyOme, and Tenaya Therapeutics. A.B. is a stockholder in Alphabet, Inc. and a consultant for Third Rock Ventures., (© 2023 The Author(s).)

Background: Bronchiolitis is the main acute lower respiratory tract infection in infants. Data regarding SARS-CoV-2-related bronchiolitis are limited., Objective: To describe the main clinical characteristics of infants with SARS-CoV-2-related bronchiolitis in comparison with infants with bronchiolitis associated with other viruses., Setting, Patients, Interventions: A multicentre retrospective study was conducted in 22 paediatric emergency departments (PED) in Europe and Israel. Infants diagnosed with bronchiolitis, who had a test for SARS-CoV-2 and were kept in clinical observation in the PED or admitted to hospital from 1 May 2021 to 28 February 2022 were considered eligible for participation. Demographic and clinical data, diagnostic tests, treatments and outcomes were collected., Main Outcome Measures: The main outcome was the need for respiratory support in infants testing positive for SARS-CoV-2 compared with infants testing negative., Results: 2004 infants with bronchiolitis were enrolled. Of these, 95 (4.7%) tested positive for SARS-CoV-2. Median age, gender, weight, history of prematurity and presence of comorbidities did not differ between the SARS-CoV-2-positive and SARS-CoV-2-negative infants. Human metapneumovirus and respiratory syncytial virus were the viruses most frequently detected in the group of infants negative for SARS-CoV-2.Infants testing positive for SARS-CoV-2 received oxygen supplementation less frequently compared with SARS-CoV-2-negative patients, 37 (39%) vs 1076 (56.4%), p=0.001, OR 0.49 (95% CI 0.32 to 0.75). They received less ventilatory support: 12 (12.6%) high flow nasal cannulae vs 468 (24.5%), p=0.01; 1 (1.0%) continuous positive airway pressure vs 125 (6.6%), p=0.03, OR 0.48 (95% CI 0.27 to 0.85)., Conclusions: SARS-CoV-2 rarely causes bronchiolitis in infants. SARS-CoV-2-related bronchiolitis mostly has a mild clinical course., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Variant interpretation remains a major challenge in medical genetics. We developed Meta-Domain HotSpot (MDHS) to identify mutational hotspots across homologous protein domains. We applied MDHS to a dataset of 45,221 de novo mutations (DNMs) from 31,058 individuals with neurodevelopmental disorders (NDDs) and identified three significantly enriched missense DNM hotspots in the ion transport protein domain family (PF00520). The 37 unique missense DNMs that drive enrichment affect 25 genes, 19 of which were previously associated with NDDs. 3D protein structure modeling supports the hypothesis of function-altering effects of these mutations. Hotspot genes have a unique expression pattern in tissue, and we used this pattern alongside in silico predictors and population constraint information to identify candidate NDD-associated genes. We also propose a lenient version of our method, which identifies 32 hotspot positions across 16 different protein domains. These positions are enriched for likely pathogenic variation in clinical databases and DNMs in other genetic disorders., Competing Interests: Declaration of interests The authors have no competing interests., (Copyright © 2022 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Neuropsychological assessment of culturally diverse populations is hindered by barriers in language, culture, education, and a lack of suitable tests. Furthermore, individuals from diverse backgrounds are often unfamiliar with being cognitively tested. The aim of this study was to develop a new neuropsychological test battery and study its feasibility in multicultural memory clinics., Composition of the TULIPA battery (Towards a Universal Language: Intervention and Psychodiagnostic Assessment) entailed a literature review and consultation with experts and individuals from diverse backgrounds. Feasibility was investigated by examining administration and completion rates and the frequency of factors complicating neuropsychological assessment in 345 patients from 37 countries visiting four multicultural memory clinics in the Netherlands., The test battery included existing tests such as the Cross-Cultural Dementia screening (CCD), Rowland Universal Dementia Assessment Scale (RUDAS), tests from the European Cross-Cultural Neuropsychological Test Battery, and newly developed tests. Completion rates for the test battery were generally high (82%-100%), except for CCD Dots subtest B (58%). Although tests of the "core" TULIPA battery were administered often (median: 6 of 7, IQR: 5-7), supplementary tests were administered less frequently (median: 1 of 9; IQR: 0-3). The number of administered tests correlated with disease severity (RUDAS, ρ=.33, adjusted p < .001), but not with other patient characteristics. Complicating factors were observed frequently, e.g. suboptimal effort (29%-50%), fatigue (29%), depression (37%-57%)., The TULIPA test battery is a promising new battery to assess culturally diverse populations in a feasible way, provided that complicating factors are taken into account., Supplemental data for this article is available online at https://doi.org/10.1080/13854046.2022.2043447 .

Background: Bronchiolitis is the leading acute respiratory tract infection in infants during the winter season. Since the beginning of the SARS-CoV-2 pandemic, a reduction in the number of bronchiolitis diagnoses has been registered., Objective: The present study aimed to describe the incidence and clinical features of bronchiolitis during the 2020-2021 winter season in a large cohort of children in Europe and Israel, and to clarify the role of SARS-CoV-2., Setting, Patients, Interventions: We conducted a multicentre observational cross-sectional study in 23 paediatric emergency departments in Europe and Israel. Clinical and demographic data about all the cases of infants diagnosed with bronchiolitis from 1 October 2020 to 30 April 2021 were collected. For each enrolled patient, diagnostic tests, treatments and outcomes were reported., Main Outcome Measures: The main outcome was the prevalence of SARS-CoV-2-positive bronchiolitis., Results: Three hundred and fourteen infants received a diagnosis of bronchiolitis during the study period. Among 535 infants who tested positive for SARS-CoV-2, 16 (3%) had bronchiolitis. Median age, male sex predominance, weight, history of prematurity and presence of comorbidities did not differ between the SARS-CoV-2-positive and SARS-CoV-2-negative groups. Rhinovirus was the most common involved pathogen, while respiratory syncytial virus (RSV) was detected in one case. SARS-CoV-2 bronchiolitis had a mild clinical course, with one patient receiving oxygen supplementation and none requiring paediatric or neonatal intensive care unit admission., Conclusions: During the SARS-CoV-2 pandemic, a marked decrease in the number of bronchiolitis diagnoses and the disappearance of the RSV winter epidemic were observed. SARS-CoV-2-related bronchiolitis was rare and mostly displayed a mild clinical course., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Bone fractures are a common reason for children and adolescents to seek evaluation in the ED. Little is known about the pain experienced after cast immobilisation and discharge from the ED and its optimal management. We aimed to investigate the administration of pharmacological analgesia in the first days after cast immobilisation and to identify possible influencing variables., Methods: A prospective observational cross-sectional study was conducted at the ED of the children's hospital, Institute for Maternal and Child Health of Trieste, Italy, from October 2019 to June 2020. Patients aged 0-17 years with bone fractures were included. The primary outcome was the administration of analgesia during the 10 days following discharge, while secondary outcomes were the associated variables, including age, gender, fracture type and location, the mean limitation in usual activities and the frequency of re-evaluation at the ED for pain. Data were recorded through a questionnaire, completed by caregivers and collected by the researchers mainly through a telephone interview. The primary endpoint was evaluated as the ratio between the number of children who took at least one analgesic dose and the total enrolled children, while Χ 2 or Fisher's exact tests were used to assess secondary outcomes., Results: During the study period, 213 patients, mean age 10 years (IQR: 8-13), were enrolled. Among them, 137 (64.3%) did not take any analgesic during follow-up. Among children who were administered analgesia, 22 (28.9%) received it only on the first day, and 47 (61.8%) for less than 5 days. One hundred and sixty one patients (75.6%) did not report any limitation in usual activities because of pain. The administration of analgesia was not related to the child's age, gender or fracture site. Displaced fractures were associated with significantly more frequent analgesia being taken (OR 5.5, 95% CI 1.4 to 21.0)., Conclusion: Although some studies recommend scheduled analgesic treatment after discharge for bone fractures, this study would suggest analgesia on demand in children with non-displaced fractures, limiting scheduled analgesia to children with displaced fractures., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

A female neonate was born with asymmetric lower limbs, the right leg appearing enlarged, with thickened, reddish-purple skin and ectasic superficial reticulum (figure 1A,B). Limb pulses were present and symmetrical. The girl's family history and prenatal scans were unremarkable. Laboratory findings were within the normal range, except for a mild thrombocytopenia (90 000/μL), which spontaneously resolved during the next few days. A leg X-ray and the Doppler analysis ruled out the presence of calcifications and venous varices, respectively. Ultrasound showed significant skin thickening, with marked dermal hypertrophy and hyperechogenicity. Magnetic resonance showed circumferential thickening of the derma, with mild hypertrophy of some perforating vessels (figure 2). A biopsy of the right thigh showed capillary malformations on histology., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Nurses play a pivotal role during pediatric procedural sedation and their perspective is an important indicator for the quality of care. The aim of this study is to examine nurses' satisfaction comparing four different pharmacological regimens used for pediatric sedation outside of the operating room. A prospective observational study was conducted in a third-level pediatric teaching hospital, involving all the nurses with experience in the field of pediatric procedural sedation. A 13-item survey was used to assess the level of nurses' satisfaction for the quality of sedation with four different analgesic-sedative drugs. Fifty-one questionnaires were completed by pediatric nurses, with a median length of experience of 10 years. Regarding the overall quality of the sedation, the highest median satisfaction scores were observed for propofol (8, IQR 7-9), dexmedetomidine (8, IQR 6-8) and midazolam (8, IQR 7-9). Ketamine (5, IQR 3-7) displayed the lowest score. When asked to rate their level of perceived safety, nurses gave high scores to all the four drugs studied, with no statistically significant difference between them. Non-pharmacological techniques during procedural sedation were judged as important by 38 (74.5%) nurses. According to this sample of pediatric nurses, the best quality of procedural sedation in children outside of the operating room is obtained with propofol, dexmedetomidine and midazolam. During procedural sedation, nurses feel safe overall, regardless of the pharmacological regimen used. Moreover, they highlighted the relevance on non-pharmacological approaches in the preparation of the child for the procedure.

Research Question: What are the views of the medical directors of fertility clinics on IVF add-ons?, Design: A total of 93 UK clinics were emailed with an invitation for their medical director to participate. Ten IVF clinic medical directors were interviewed to discuss their views on the use of IVF add-ons. Some of the interviewees were medical directors of an IVF clinic with multiple branches across the UK, meaning the total number of clinics accounted for in this study was 35 out of the 93 contacted. Thematic analysis was used to analyse the data., Results: The participants consisted of seven males and three females, with six from solely private clinics and four with NHS and private patients. Four themes were identified: clinical decision-making and the patient-doctor relationship; regulations and the add-on traffic light system; research and evidence; and commercialization and financialization of the IVF sector., Conclusions: UK IVF medical directors had a wide variety of views and experienced different pressures to offer IVF add-ons. The add-on discussion touches on core aspects of professional identity and the meaning of medical practice. The add-on debate points to broader changes in the organization of the IVF sector, which affect key aspects of practising (reproductive) medicine, including the patient-doctor relationship and responsibility for clinical decision-making, and the relationship between regulator and IVF clinic and between scientific evidence and clinical practice., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Abstract: A 14-year-old adolescent girl presented with severe abdominal pain, tenderness, and guarding in the right upper quadrant associated with nonbilious vomiting, scleral icterus, and fever. Laboratory tests were consistent with acute hepatitis A virus-related cholestatic hepatitis. A point-of-care ultrasound showed mild gallbladder wall thickening with increased color Doppler flow and pericholecystic fluid collection, in the absence of gallstones or biliary ducts dilatation, thus suggesting acute acalculous cholecystitis. Both the clinical symptoms and the point-of-care ultrasound findings completely resolved within 1 week after admission with conservative treatment., Competing Interests: Disclosure: The authors declare no conflict of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Unarousable child with short bowelA 4-year-old boy was admitted with progressive lethargy of a few hours' duration and no other symptoms. His medical history was relevant for short bowel syndrome (SBS), following neonatal volvulus, with residual bowel length of 23 cm and intact ileocecal valve. He had similar self-limiting episodes in the past, after weaning parenteral nutrition, especially after eating large meals. The day before, he had consumed a large amount of apples.Arterial blood gas (ABG) analysis showed metabolic acidosis with normal lactacidaemia (pH 7.09, pCO 2 19 mm Hg, pO 2 101 mm Hg, HCO3 5.8 mmol/L, BE -24, anion gap 29.4, chloride 116 mmol/L, L-lactate level 4 mmol/L).On admission, the child could be awakened, but he was confused with slurred speech (Glasgow Coma Scale 14), with a body temperature of 37 C°, a heart rate of 125 beats/min and a respiratory rate of 38 breaths/min. The abdomen was distended, without guarding and with normal bowel sounds. Blood glucose levels were normal, as well as white blood cell count, liver and kidney function test and C reactive protein. An abdominal ultrasound ruled out an intussusception. An abdominal X-ray was performed too (see figure 1)., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Despite being a standard of care for children undergoing stressful procedures, little data exist on parental perception of pediatric sedation., Aims: This study aimed to investigate recovery characteristics and parental satisfaction for pediatric sedations performed with four widely used sedative regimens., Methods: A prospective observational study was conducted at the Institute for Maternal and Child Health of Trieste, Italy, enrolling children undergoing procedural sedation with one of the following pharmacological regimens: propofol, propofol + midazolam, ketamine + propofol, and dexmedetomidine + midazolam. A questionnaire was used to assess the occurrence of symptoms upon recovery from sedation and the following day, and the caregivers' satisfaction for both the recovery pattern and the overall sedation experience, according to a numerical rating scale (0-10). Answers were collected through a telephone survey. The primary outcome was the difference in the quality of the recovery as perceived by caregivers; the secondary and tertiary outcomes were the perceived quality of the overall sedation experience and the frequency of sedation-related adverse events, respectively., Results: Data from 655 patients, 149 receiving propofol, 245 propofol + midazolam, 134 ketamine + propofol, and 127 dexmedetomidine + midazolam, were analyzed. The level of parents' satisfaction for both the recovery and the sedation experience was overall high and increased with the patients' age in all the pharmacological groups (Spearman's rank correlation, ρ .083, p = .033, and ρ .087, p = .026, respectively), with no statistically significant differences between groups when adjusting for age. The occurrence of irritability, prolonged sleepiness, hyperactivity, unsteadiness, hallucinations, emesis, and respiratory distress at any moment negatively affected parental satisfaction., Conclusions: In this study, caregivers' satisfaction with pediatric sedation was high, regardless of the regimen used. Lower parental satisfaction was associated with younger age, irritability after sedation, prolonged sleepiness, hyperactivity, unsteadiness, hallucinations, emesis, and respiratory distress., (© 2021 John Wiley & Sons Ltd.)

Purpose: To delineate the genotype-phenotype correlation in individuals with likely pathogenic variants in the CLTC gene., Methods: We describe 13 individuals with de novo CLTC variants. Causality of variants was determined by using the tolerance landscape of CLTC and computer-assisted molecular modeling where applicable. Phenotypic abnormalities observed in the individuals identified with missense and in-frame variants were compared with those with nonsense or frameshift variants in CLTC., Results: All de novo variants were judged to be causal. Combining our data with that of 14 previously reported affected individuals (n = 27), all had intellectual disability (ID), ranging from mild to moderate/severe, with or without additional neurologic, behavioral, craniofacial, ophthalmologic, and gastrointestinal features. Microcephaly, hypoplasia of the corpus callosum, and epilepsy were more frequently observed in individuals with missense and in-frame variants than in those with nonsense and frameshift variants. However, this difference was not significant., Conclusions: The wide phenotypic variability associated with likely pathogenic CLTC variants seems to be associated with allelic heterogeneity. The detailed clinical characterization of a larger cohort of individuals with pathogenic CLTC variants is warranted to support the hypothesis that missense and in-frame variants exert a dominant-negative effect, whereas the nonsense and frameshift variants would result in haploinsufficiency.

In the last decade, the in-vitro fertilization (IVF) sector has witnessed a shift from so-called 'reactive IVF' to a new model of proactive fertility care. Whereas IVF was traditionally developed to treat people who found they were unable to conceive, the indication for IVF has broadened significantly to include a much wider group of potential patients through a new focus on proactive treatment of future (in)fertilities. This shift combines a number of new trends pertaining to preservation, prediction, private equity and platformization, all of which have gained influence in contemporary assisted reproduction. This article focuses on the emergence of company-sponsored fertility benefits, which combines each of these trends. Whereas fertility benefits - especially egg freezing insurance - have primarily been discussed in terms of women's empowerment or disenfranchisement, this article instead calls attention to the discursive, clinical and infrastructural shifts in contemporary assisted reproduction that have emerged with the rising popularity of these benefits. The analysis addresses these underdiscussed aspects of fertility benefits by focusing on the dynamics of demand; the shifts in the rationalization of intensified treatment pathways in the face of new reimbursement practices; and the online, platform-based infrastructures that are built to provide these treatments. In doing so, it analyses how this remaking of fertility towards an ethos of proactive fertility management reflects broader capitalist tailwinds., (© 2021 Published by Elsevier Ltd.)

We invite systematic consideration of the metaphors of cycles and circulation as a long-term theme in the history of the life and environmental sciences and medicine. Ubiquitous in ancient religious and philosophical traditions, especially in representing the seasons and the motions of celestial bodies, circles once symbolized perfection. Over the centuries cyclic images in western medicine, natural philosophy, natural history and eventually biology gained independence from cosmology and theology and came to depend less on strictly circular forms. As potent 'canonical icons', cycles also interacted with representations of linear and irreversible change, including arrows, arcs, scales, series and trees, as in theories of the Earth and of evolution. In modern times life cycles and reproductive cycles have often been held to characterize life, in some cases especially female life, while human efforts selectively to foster and disrupt these cycles have harnessed their productivity in medicine and agriculture. But strong cyclic metaphors have continued to link physiology and climatology, medicine and economics, and biology and manufacturing, notably through the relations between land, food and population. From the grand nineteenth-century transformations of matter to systems ecology, the circulation of molecules through organic and inorganic compartments has posed the problem of maintaining identity in the face of flux and highlights the seductive ability of cyclic schemes to imply closure where no original state was in fact restored. More concerted attention to cycles and circulation will enrich analyses of the power of metaphors to naturalize understandings of life and their shaping by practical interests and political imaginations., (© 2021. The Author(s).)

Whereas large-scale statistical analyses can robustly identify disease-gene relationships, they do not accurately capture genotype-phenotype correlations or disease mechanisms. We use multiple lines of independent evidence to show that different variant types in a single gene, SATB1, cause clinically overlapping but distinct neurodevelopmental disorders. Clinical evaluation of 42 individuals carrying SATB1 variants identified overt genotype-phenotype relationships, associated with different pathophysiological mechanisms, established by functional assays. Missense variants in the CUT1 and CUT2 DNA-binding domains result in stronger chromatin binding, increased transcriptional repression, and a severe phenotype. In contrast, variants predicted to result in haploinsufficiency are associated with a milder clinical presentation. A similarly mild phenotype is observed for individuals with premature protein truncating variants that escape nonsense-mediated decay, which are transcriptionally active but mislocalized in the cell. Our results suggest that in-depth mutation-specific genotype-phenotype studies are essential to capture full disease complexity and to explain phenotypic variability., (Copyright © 2021 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Opioid-related mortality in adolescents is spreading in the US, with prescription opioids playing a crucial role in the development of addiction. We traced back to the process leading to the so called "opioid overflow", trying to identify any modifiable attitude.Since the late 1990s, pain was labelled as the "fifth vital sign" and its proper management was prompted, encouraging the use of opioids for any pain scored at a Numerical Rating Scale (NRS) of 7 or higher. This assumption has some remarkable limitations. NRS is a proxy of pain severity in children, and pain measurement should be strengthened by a more comprehensive pain evaluation. Moreover, while remaining a fundamental therapeutic right of patients suffering postoperative or chronic severe pain, opioids show no evidence of superiority respect to non-opioid regimens in the management of pain from several acute conditions.Italy, as other European countries, is often reluctant to the use of opioids, even when highly recommendable, missing the opportunity of properly treating those selected patients with severe pain. Both attitudes can be viewed as the result of an extreme simplification of the complex process of pain evaluation and treatment, by means of a 'one-size-fits-all' approach.This highlights the need for a systematic and patient-tailored attitude to children in pain, avoiding applying guidelines without question. Good clinical practice must rely on guidelines, which, however, as often based on partial and insufficient data, can be questioned by emerging new evidence, and should not substitute our rational thinking, and capability to understand each patient, avoiding excessive conformism.

Competing Interests: Competing interests: None declared.