Although there is a need for gender-specific health care, especially within the context of vocational rehabilitation for youth with disabilities, clinicians, trainees, and community service providers commonly report lacking training in gender-sensitive approaches. Therefore, an educational tool designed for clinicians working with youth, that addresses how to approach such issues, could help clinicians to augment the care they provide.The objective of our study was to conduct a pilot evaluation of an educational simulation for health care and service providers focusing on gender-sensitive approaches within the context of supporting youth with disabilities in vocational rehabilitation.We conducted a survey from May to September 2021 to assess the relevance of the simulation content, preliminary perceived impact on gender-sensitive knowledge and confidence, and open-ended feedback of a web-based gender-sensitive educational simulation. A total of 12 health care providers from a variety of professions who had experience working with youth in the context of vocational rehabilitation participated in the survey (11 women and 1 man).Most participants reported that the content of the simulation was relevant and comprehensive. The majority of participants reported that the simulation helped to increase their perceived knowledge or understanding of the topic, changed their perceived understanding of their intervention or approach, and informed their perceived confidence. Our qualitative findings from the open-ended questions highlighted three main themes: (1) relevance of the simulation content, (2) perceived impact for clinical practice , and (3) perceived impact on organizational processes .Our educational simulation shows preliminary potential as an educational tool for service providers working with youth who have a disability within the context of vocational rehabilitation. Further research is needed to assess the impact of the tool with larger samples. The World Health Organization advocates for a broad approach to how sex and gender issues are addressed both within and outside of the health care sector . Gender In this paper, our educational tool focuses on providing gender-sensitive care to youth and young adults because their gendered experiences are often ignored or dismissed despite gender playing a vital role in their health and social outcomes -15. In pIn this study, our educational simulation focuses on gender-sensitive approaches within the context of vocational rehabilitation to youth with disabilities. This topic is important because gender often influences how people with disabilities are engaged within vocational training and employment ,19. For Although several studies highlight a critical need for gender-specific vocational support for youth with disabilities -25, relaThe objective of our study was to conduct a pilot evaluation of an educational simulation on gender-sensitive approach within the context of vocational rehabilitation for youth with disabilities.We conducted a survey to assess the relevance and initial feedback of our web-based simulation educational tool with the intention to examine the methods and procedures to test at a larger scale . After cThis study received institutional research ethics board approval from Holland Bloorview Kids Rehabilitation Hospital and University of Toronto (#0162). All participants provided written consent (or e-consent via REDCap during the pandemic) before taking part in the study . ParticiOur intervention involved an educational simulation, which is an interactive pedagogy allowing clinicians and service providers to practice assessment, patient care, and difficult conversations in a risk-free environment . EducatiData were collected from May to September 2021 and led by the first author with support from a research assistant. Using a purposive sampling strategy, aiming to recruit approximately 10 clinicians in vocational rehabilitation working with various types of patients with disabilities, participants were recruited through invitation letters and advertisements at a pediatric rehabilitation hospital and community-based disability-related organizations and relevant social media platforms. This sample size is considered appropriate for a pilot study to assess the usability of a web-based tool . We screA total of 12 participants (11 self-identified as women and 1 man) took part in the study  and asked about whether participants increased or changed their personal understanding about the topic , whether they changed their beliefs and understandings with respect to an intervention or approach or group of people , and whether it increased their confidence in their professional or daily practice or day-to-day activities . These qIn regard to relevance of the simulation content we also used an adapted question from Malik et al’s  toolkit totally disagree to 5=totally agree) [To assess baseline gender sensitivity we used the Nijmegen Gender Awareness in Medicine Scale , which is a reliable and valid measure . This measure contains statements answered on a 5-point Likert scale (1=y agree) ,44. It my agree) . Here weOther secondary measures included demographic characteristics . Open-ended questions involved what they liked most and least about the simulation and any suggestions for further development.Data were anonymized and exported from REDCap into SPSS, version 25 (IBM Corp), for analysis. Descriptive statistics were used to describe sample characteristics and frequencies for categorical variables.The qualitative data from the open-ended questions were analyzed using a directed content analysis approach . Two resThe baseline level of gender sensitivity ranged from 9 to 17 with a mean of 13.75 see , indicatThe majority of participants  reported that the simulation changed their belief and understanding regarding their intervention or approach . Most participants stated that the simulation helped to increase their perceived confidence in their professional daily practice or activities .On examining the extent to which the simulation showed rapport building and development of a safe environment, the majority of participants agreed  that the tool was comprehensive see . AdditioOur findings highlighted three main themes: (1) relevance of the simulation content , (2) perceived impact for clinical practice , and (3) perceived impact on organizational processes  alongside the simulation. For example, a clinician shared, “service providers could benefit from having resources on how to support youth through the disclosure of disability process,” particularly within the context of the role that gender plays in employment .The second theme focused on clinicians’ perceived impact of the educational simulation on their clinical practice, which involved the following subthemes: gender-sensitive language and communication and building rapport with patients. For example, clinicians described,The simulations gave me the opportunity to reflect…It resonated with me and will impact my practice.#2, Youth FacilitatorAdditionally, the educational tool allowed health care providers to consider how they might incorporate these learnings. To illustrate, a social worker said,I look forward to using the information gained from the video in my clinical practice.#12, Social WorkerA subtheme of the perceived impact of the simulation on clinical practice involved gender-sensitive language and communication. Clinicians described how this educational tool helped them to consider the language they use. To illustrate, an occupational therapist said:This tool will allow me to reflect on the language I use with clients. It has prompted me to reflect on my interactions with clients and avoid using any biased language or making assumptions.#9, Occupational TherapistOthers agreed that watching the interactions in the simulation was helpful for considering how they could incorporate it into their practice and responding to difficult topics.Some participants described how they learned about the importance of gender-sensitive language and being respectful of gender identity. An occupational therapist described:I appreciated that the clinician asked the patient to let her know if she makes a mistake with their pronouns, who they would like to have access to the information about their pronouns (whether it's family or future employers), and about finding a place where they can fit in where their interests and whole person are really respected#6, Occupational TherapistIn using gender-sensitive language and communication, clinicians described how the simulation led them to reflect on their own gender identity while making an effort to reduce gender-based assumptions.Another subtheme, aligned with gender-sensitive language and communication, included building rapport with patients. Participants explained how the simulation was valuable for informing their thinking about using appropriate language and awareness of gender identity and any gender-based biases or assumptions to build rapport with their patients. For example, an occupational therapist described,I appreciated how much useful information was shared with regards to how to build rapport after reflecting on one's own gender bias and how to make sure the focus is on what is important to the patient.#5, Occupational TherapistIn trying to build rapport with a patient, clinicians explained the usefulness of the simulation for learning the importance of being upfront in admitting any mistakes when misgendering a patient.The participants in our study explained how the simulation helped them to think about how their organization could incorporate more gender-sensitive practices, policies, and privacy considerations of whom the gendered information is shared with.Clinicians considered how intake forms were often binary  with no other options for people who are nonbinary. For example, a clinician described,The simulation highlighted the importance of reflecting on our organization processes regarding gender …The simulation did make me reflect that we don't typically ask who we can share information on preferred pronouns with so this is something for our program to consider moving forward.#8, Occupational TherapistOther clinicians contemplated privacy issues regarding how the gender identity information would be shared, which is particularly concerning when working with youth who may not have discussed their gender identity with their parents. To illustrate, an occupational therapist said,It's helpful to remember to ask the client who they want to share this information with.#10, Occupational TherapistOur study addressed an important gap in the literature by exploring a preliminary evaluation of an educational simulation for health care and service providers on gender-sensitive approaches within the context of providing vocational rehabilitation for youth with disabilities. Offering training on this topic could assist with addressing health and social inequalities and optimizing patient outcomes . EducatiThe results of our study underscored the relevance and authenticity of the simulation content, which is an important finding for our pilot study because authenticity is an essential component of simulation and standardized patient methodology . Our finOur findings align with principles of patient-centered and culturally sensitive care models that place emphasis on self-awareness and sensitivity to one’s own values, biases, and power differences while also considering patients’ values and priorities . PreviouOur qualitative findings highlighted how participants reflected on the potential role that gender-sensitive care could play in organizational processes. It was encouraging to see that participants were aware of how gender operates at an institutional level and acknowledged how power dynamics at a leadership level could influence practice at the everyday individual level . Other research on gender-sensitive approaches using simulation training in nursing found that it helped nurses to reflect on the importance of inclusionary hospital policies to protect the rights and dignity of people who are trans . PreviouCaution should be used in interpreting the findings because the majority of the participants in our study self-identified as women. Nevertheless, such a gender-unbalanced sample is a reflection of the gender composition of health care providers within pediatric rehabilitation . Future This pilot study provided preliminary evidence of the usefulness of a gender-sensitive educational simulation. Our results highlighted that the content of the simulation was comprehensive and relevant. Our pilot findings showed that participants perceived that the simulation was helpful for understanding gender-sensitive care, their approach, and their perceived confidence in their daily practice. The qualitative findings emphasized the importance of gender-sensitive language and communication, and building rapport with patients. Further studies should explore the longer-term impact of this educational simulation on clinical practice and behaviors.


High-throughput sequencing technology has revolutionized gut microbiome research offering opportunities to study the impact of gut microbiota on host physiology. Significant interest has recently focused on the role of human gut microbiota in cardiovascular health. A growing body of evidence suggests that alterations in gut microbiota composition and disruptions in gut microbial metabolism are associated with CVD development.Atrial fibrillation (AF) is a heart rhythm disorder characterized by irregular and tremulous heart beats and is associated with significant CVD burden and high healthcare costs. Besides age and sex, a large number of cardiovascular risk factors may determine the manifestation and progression of AF such as hypertension, obesity, type 2 diabetes, dyslipidemia, coronary artery disease and heart failure. However, these CV risk factors partly explain (slightly >50%) the variability in AF occurrence and thus it is important to identify novel risk markers. Although the importance of gut microbiota on the progression of cardiovascular traits like atherosclerosis and classical CV risk factors has been investigatedEBioMedicine, Palmu et al.In this study published in This is the first large observational study with available microbiota data derived by whole genome untargeted shallow metagenomic sequencing, and adequate phenotypic and lifestyle evaluation, published to date, that examined the relationship between gut microbes and AF. Another strength of the study is the inclusion of an external validation study, making the findings more generalizable to the population. Furthermore, the study by Palmu et al.However, this studyWhile these limitations are significant, this large observational study provided a new direction of CV research by proposing a number of genera that differed in abundance in prevalent or incident AF from that in non-AF individuals. However, the causal relationship between gut microbiota and AF remains unclear. Recently, a bidirectional Mendelian randomization analysis using a Chinese cohort showed that AF had potential causal effects on the abundance of specific gut microbes.The author declares no conflicts of interest or disclosures in relation to the present commentary.


Rapid advances in digital technology and artificial intelligence in recent years have already begun to transform many industries, and are beginning to make headway into healthcare. There is tremendous potential for new digital technologies to improve the care of surgical patients. In this piece, we highlight work being done to advance surgical care using machine learning, computer vision, wearable devices, remote patient monitoring, and virtual and augmented reality. We describe ways these technologies can be used to improve the practice of surgery, and discuss opportunities and challenges to their widespread adoption and use in operating rooms and at the bedside. Historically the field of surgery has justifiably been relatively cautious with deployment of new and potentially disruptive technologies that have not been extensively studied, given the possibility of direct and immediate patient harm3; surgery’s experience with digital technologies so far is no different. However, with the tremendous potential for new digital technologies to improve surgical care, we believe its incorporation into daily surgical practice is inevitable. Indeed fields such as gastroenterology and radiology are already incorporating digital technologies in their practice5. In this npj Digital Medicine special collection, we highlight work being done in several areas of digital technology—machine learning, computer vision, wearable devices, remote patient monitoring, and virtual and augmented reality—all of which we believe are poised to transform surgery in the coming years. In this piece, we describe opportunities and challenges to these technologies’ adoption.Innovations in digital technology have begun to transform the practice of medicine. From FDA approved artificial intelligence systems for endoscopyMachine learning models have the potential to learn complex, nuanced relationships between enormous numbers of clinical variables, including multimodal data, in ways that traditional statistical risk calculators cannot. This advantage may soon be leveraged to better predict the clinical trajectory of patients and help surgeons make more personalized patient care decisions.9.Specifically, AI enabled decision support systems have the potential to predict surgical outcomes. Surgical outcome prediction is important for patient care both preoperatively, in deciding which patients would be candidates for benefit with surgical intervention, as well as postoperatively, in predicting risk of complications. Machine learning algorithms can be applied to both aspects to assist outcome prediction. Mobile applications with these kinds of algorithms have been developed and piloted at multiple large academic institutions10. The study further finds that as machine learning tools are increasingly applied to vascular surgery, model performance continues to improve with newer studies. These findings emphasize that machine learning may one day serve as an important augmentation for analysis, diagnosis, and outcome prediction in surgery.Highlighted in this collection, a review of machine learning models that learned from clinical data in vascular surgery found that several models perform better than existing clinical prediction tools, clinicians, and traditional regression models11. Among the most exciting potential applications of real-time intraoperative computer vision analysis to support safer surgery is providing an augmented reality experience for surgeons to aid in intraoperative decision-making12. Many existing published computer vision models have demonstrated the ability to assess operative complexity, assist with decision-making during minimally invasive procedures, assess the technical skill of surgeons in an automated and scalable fashion, provide intraoperative feedback, assess OR team dynamics, and even predict postoperative outcomes based on intraoperative events15. When combined with these technologies, virtual reality can be used as a training ground for operative skills assessment and education16. While the incorporation of these tools in regular surgical practice is not yet a reality, potential use cases will surely continue to grow as research in this field continues.Computer vision—the application of machine learning algorithms for visual data analysis—holds tremendous potential to impact clinical care wherever images or video data are involved. In this special collection we focus mainly on applications of computer vision for analysis of intraoperative data. Rapid advancements in the field of computer vision, including the increasing use of deep neural networks, have led to the development of algorithms that can accurately identify clinically important aspects of intraoperative video data17. In our collection, Mori et al. use a digital health platform to better understand the nuances of post operative recovery in the home for cardiac surgery patients, far beyond just clinical events captured during postoperative ED visits or clinic visits18.Wearable devices and other personal technologies that collect and transmit physiologic signals and patient reported variables in real time are another important technology with the potential to improve surgery. The use of wearable devices for remote patient monitoring, which enables evaluation of patients beyond traditional in-person encounters with the healthcare system, holds great opportunity for the improvement of postoperative care by enabling remote assessment of surgical wounds, functional status, pain control, and detecting clinical deterioration early. There is emerging evidence that this form of data capture can potentially reduce complication rates19, suggesting that the use of wearable devices for remote patient wound monitoring may be safe, efficient, and reduce health service utilization. Another study shows that the use of a non-contact video camera to monitor vital signs can be used to track early signs of physiological deterioration, to function as a less disruptive, more efficient, early warning system20. These new capabilities may enable an eventual shift in the nucleus of post-surgical care from the hospital back to the home; some large academic medical centers have already established successful digital technology-enabled surgical home hospital programs that allow patients to be safely recover from surgery in their own home21.In addition to understanding the postoperative course overall, recent work shows the potential for remote patient monitoring changing the way postoperative care is delivered. A randomized control trial finds that postoperative surveillance of surgical site infection using a smartphone is just as effective as in person follow-up assessmentWhile there are many emerging digital technologies that hold great promise for surgery, there are also important cautions and considerations for their use.22. Without a critical assessment of digital technologies from an equity lens, these disparities may continue to be perpetuated. Halamka et al. highlight the importance of using existing bias detection tools to detect irregularities in datasets and algorithms before deploying them in surgical practice23.One important concern is equity. There are disparities in surgical outcomes for patients of racial minorities as well as lower socioeconomic status that persist until today. Just one example is in spine surgery, where the risk of postoperative complications has been estimated to be as much as 61% higher for Black patients24. The rapid adoption of sophisticated connected technologies in operating rooms makes them uniquely susceptible to targeted attacks that can cause patient harm. An important contribution in this collection by Gordon et al. explains how health systems can mitigate the risks of cybersecurity attacks in operating rooms, including minimizing real-time connectivity during surgical procedures to only what is necessary, collaborating with vendors on developing safety measures, and establishing downtime procedures25.Another important concern is information security. Operating rooms are growing in terms of technological sophistication and the use of connected devices. Surgical robots for example, are now being widely used at growing rates around the world and increasingly rely on constant connectivity to deliver real-time insights and support. At the same time, the number of cyberattacks on hospitals has also been significantly increasing26 and have since been refining it; most recently in April 2023 they put forth a new draft guidance that recommends continuous product monitoring throughout the product lifecycle with real-world data and allows for small adjustments in performance over time27.A third important consideration is determining how these technologies will be regulated to ensure they are safe and effective. One unique element of AI-enabled technologies is their ability to adapt over time as they are introduced to new data. This may cause unanticipated shifts in performance and ultimately a very different tool from the one that was originally approved. The US Food and Drug Administration (FDA) is in the process of determining how to best regulate these tools. They developed a proposed regulatory framework in 201928. For example, few studies have shown any improvement in care when AI-enabled decision support tools are used29. Some important barriers to clinical impact include translating ML model outputs into clinically actionable insights and incorporating them into existing workflows and clinical decision making processes30. Additionally, these new technologies must be built and rigorously evaluated in a way that is reproducible, transparent, and interpretable to users to earn their trust31. Access to larger and more diverse datasets may help address some of these issues12.Among the most important barriers to widespread adoption of these technologies in surgery is limited evidence of their clinical impact33. As another example, the use of ambient sensing monitors in operating rooms may help automate quality control processes, prevent medical errors, and improve a surgical team’s overall perioperative situational awareness34.The number of new digital technologies with the potential to improve surgical care is rapidly growing. There are many use cases and technologies not covered in this special collection. Generative AI models, such as GPT-4 and DALL-E 2, are only just beginning to be explored in the healthcare literature, yet their tremendous abilities have sparked widespread interest in exploring potential use cases35. Health systems will need to begin investing in the expertise and IT infrastructure necessary to deploy and maintain these tools36. The augmentation of surgery with these emerging digital technologies is necessary for progress toward more efficient and effective patient care.Research in this field should focus on bridging the gap from in silico performance to real-world clinical benefit of new digital technologies. This will involve building out the implementation science of these tools, evaluating them with real-world evidence, and continuing to explore new applications


Sleep represents a major frontier both in clinical myology and as a new possibility for delivering treatment to neuromuscular patients since various neuromuscular cases present a variable degree of disordered sleep and such conditions should be diagnosed and prevented, i.e., sleep apnea and hypoxemia. These sleep disorders are present in dystrophinopathies and in various types of limb-girdle muscular dystrophies (LGMD). Excessive daytime sleepiness (EDS) is found in patients affected by spastic paraparesis or cerebellar ataxia but is rather common in both myotonic dystrophy type 1 and 2, and the correction of sleep disorders is therefore important to improve their daily quality of life (QoL) and consequent daily functioning. Other types of sleep dysfunction such as insomnia, a reduction in rapid eye movement (REM) sleep, loss of normal REM, or sleep-disordered breathing are found in other disorders including myasthenia, ataxias, spastic paraparesis, Charcot–Marie–Tooth disease, and neurogenic disorders, including polyneuropathies, and need appropriate treatment. Research done on this topic aims to incorporate a variety of nuances in metabolic disorders such as those in late-onset Pompe disease and are such as those in late-onset Pompe disease who are susceptible to enzyme replacement therapy (ERT). The overarching goal is to explore both the diagnosis and methodology of sleep-related problems in both genetic and acquired neuromuscular disorders. We also review the type of available treatment opportunities utilized to improve neuromuscular patients’ QoL. The present review aims to introduce how to diagnose sleep-related problems in a series of both genetic and acquired neuromuscular disorders and examine the available treatment opportunities that might be utilized in clinical practice to improve neuromuscular patients’ quality of life (QoL).There are disorders such as cerebellar ataxia or spastic paraparesis where, after correction of sleep disorders, there is a recognizable improvement of cognition. This cognitive feature applies to severe cases of limb-girdle muscular dystrophies (LGMD) where nocturnal bilevel positive airway pressure (BiPAP) treatment brings individuals back to their usual daily life activity and possibly to the work environment.Patients with myasthenia gravis (MG) and other neuromuscular disorders are sometimes difficult to treat because of their respiratory state can be precarious. This can be exacerbated with medications (e.g. benzodiazepines), infections, etc. and they can be thrown into myasthenic crises and respiratory failure. A decades old axiom for the treatment of patients with MG has long been “When in a myasthenic crisis first secure the airway!” With the advances in sleep medicine and treatment of nocturnal sleep apneas disorders, it is no longer necessary to wait for a myasthenic crisis or respiratory failure to start to protect the airway. If sleep disordered breathing  are identified and treated early, valuable time can be saved and perhaps costly hospitalizations avoided. This is particularly important in the field of myasthenia gravis and neuromuscular junction (NMJ) disorders where available treatments may take time before they become effective. This includes long recognized effective treatments (steroids and immunosuppressives) and several new drugs (compliment inhibitors and anti-FcRn therapy) in patients with steroid-resistant MG. It is well-recognized that with the use of biPAP and other modalities of NIV for sleep disordered breathing in these patients, it may be possible not only to avoid myasthenic crises, but also to improve patients’ quality of life. In patients with neuromuscular disorders, including myasthenia and its various forms , the use of biPAP may result in improvement in QoL and cognition.Clinical and drug treatment of excessive daytime sleepiness (EDS) in patients with cerebellar ataxia, spastic paraparesis, myotonic dystrophy type 1 , and sevTo experienced clinicians in the myology field, the observation of latent depression in many NMD patients is common; what is important to acknowledge is that there is a correlation between such depressive symptoms and sleep quality. Furthermore, it is necessary to consider that disrupted sleep induces negative effect both due to frequent episodes of sleep apnea and consequent hypoxia in muscle and NMJ disorders.Sleep is an approachable frontier in clinical myology to improve the treatment of neuromuscular diseases; many neuromuscular patients present various degrees of disordered sleep. We here propose a schematic table  of varioThe arousal system and brain central nervous system (CNS) are variably deranged in congenital, childhood, juvenile, and adult Myotonic Dysitrophy type 1 (DM1) and, to a lesser extent in Myotonic Dystrophy type 2 (DM2), where a congenital form has not been so far recognized. The various forms of myotonic dystrophy type 1 drugs, such as modafinil, and cognitive behavioral treatment (CBT) is used and appear useful to prevent EDS. Mexiletine at the dosages of 150 to 200 mg Three times a day (TID)  has beenPhysical therapy can be performed to improve muscle function; some studies evidenced that exercise programs and functional electric stimulation can be performed safely and result in a temporary improvement of patients’ muscle function –13. A poA very common muscular dystrophy with large clinical variability is represented by facioscapulohumeral dystrophy, now subdivided into FSHD1 and FSHD2, with a spectrum of clinical presentations from infantile to adult oligosymptomatic patents. In some childhood cases of FSHD1, respiratory muscle weakness is prominent with severe clinical manifestations such as pectus excavatum and scoliosis and might be associated with sleep-disordered breathing (SDB), which produces obstructive sleep apnea (OSA) and is associated with hypoxemia for nocturnal hypoventilation (NH). Their prevalence is still to be evaluated in large series since data are relatively scarce.By investigation with questionnaires , both adIn limb-girdle muscular dystrophy (LGMD) syndromes, there are several patients, especially in the more severe recessive LGMD forms (LGMD R), suffering from respiratory disorders, mostly in cases with a juvenile onset. The most frequent recessive forms are represented by LGMD R1 or calpainopathy and LGMD R2 or dysferlinopathy, and in developing countries they are represented mostly by sarcoglycanopathy patients (LGMD R3-R5) who suffer from OSA and SDB, which might be treated by Continuous positive airway pressure (CPAP). Similar episodes of variable extents have been observed in late-onset Pompe disease (LOPD) patients, who often need a ventilator, and when they are treated with ERT, they usually present decreased hours on the ventilator and thus sleep in these adult Pompe patients is improved.It is widely known that, in adolescent boys with Duchenne muscular dystrophy, there is poor sleep quality and nocturnal ventilation is a necessary treatment of their OSA. However, clinical follow-up and observations of sleep quality in milder forms of dystrophinopathy such as BMD, where muscle weakness, cramps, and fatigue with exercise limitation and myoglobinuria occur, and evaluation of consequent QoL, pain, and fatigue remains limited.Recent studies have shown that sleep treatments for SDB improve also QoL in a series of NMD patients and promotes better daily function, but several problems have still to be evaluated.We still do not know which patients with neuromuscular disease are at higher risk of developing a sleep dysfunction and therefore should be actively monitored.Several neurological associations and neuromuscular networks have produced guidelines on the impact of sleep disorders and their treatment. These guidelines describe in most except the mildest forms of neuromuscular diseases high or moderately high the risk of a severe course.The clinical features associated with a high risk of severe SDB include, for instance, the presence of prominent chest muscular weakness or diaphragmatic weakness, resulting in a forced vital capacity (FVC) of less than 60% predicted; such a low FVC is observed especially in patients with kyphoscoliosis but also in rigid spine cases common in LOPD or laminopathies.via a mask or tracheotomy. In NMJ cases, it is common to find a weak cough and weak airway clearance due to oropharyngeal weakness. In both infantile and adult spinal muscular atrophy, patients often present with the presence of tracheostomy.Another risk factor that might be observed in NMJ or motor neuron disease patients is the use of ventilation LGMD patients and dystrophinopathy cases might present cardiac involvement, and the use of medication for heart involvement might worsen during sleep.In metabolic myopathies, one should monitor the risk of deterioration with fasting or infection, since they might present a sudden deterioration overnight for muscle atonia during REM sleep. Another prominent risk is rhabdomyolysis occurring with fever and fasting. In general, in all NMD diseases, severity and poor quality of sleep is due to the occurrence of concomitant diabetes and obesity.In identifying possible risk factors, the clinician should analyze the individual characteristics of neuromuscular patients, and evaluate pharyngeal weakness and the presence of macroglossia. It is important to remember that bulbar manifestations, dysphagia, and aspiration phenomena are linked especially in motor neuron disorders. Factors such as low FVC, diaphragmatic weakness, and consequent defective lung volumes predispose patients to the development of obstructive events.Another risk factor resulting from bulbar center malfunction is central sleep-disordered breathing that might occur in association with cardiomyopathy in muscular dystrophies, DM1, or LOPD, and has been attributed to instability in the control of breathing. This also represents a major contribution to diaphragmatic weakness. An opposite action such as the recruitment of accessory respiratory muscles might mitigate diaphragm weakness.A polysomnography might be required to evaluate the reduction in REM sleep, and loss of nomal atnia during REM in indivdual LOPD or DM1 patients, which in single cases might have a paradoxical beneficial effect and protect against SDB.On this basis, several risk factors appear with increasing age in several NMDs and are at difference with the normal individual where sleep is a normal restorative function; in NMD patients, if sleep disorders are untreated, a definite cause of disease course deterioration can occur, with worsening of patients’ quality of life.In all but the mildest forms of NMD, airway manifestations can take weeks to months or even years to evolve, but respiratory follow-up is important for clinical myologists, who should recognize based on direct investigation and laboratory exams two major respiratory phenotypes, characterized by rapid or slow progression to respiratory failure.We support the clinical observation that both type and age of the onset of airway problems have to be accurately monitored by a clinical myologist, as well as their evolution over time. This type of care will support practicing myologists in the diagnostic assessment, since, in general, the precise knowledge of the characteristics of NMD patients’ respiratory phenotypes will be useful and possibly increase the level of collaboration with other allied professionals such as dieticians, physical therapists, occupational therapists, geneticists, pulmonologists, and chest therapists, resulting in the increased level of support in the common task of the multidisciplinary management of such patients .To make a diagnosis, the physician will use the patient’s medical history, sleep history, and physical exams. The symptoms suggestive of desaturation during night hours are headache and loss of vigilance during the day.The treating physician might suggest a sleep polysomnography, which can be done in a hospital center, but nowadays also at home. The most common type of polysomnography monitors and registers data about body functions, such as movements, respiration, and blood pressure during sleep. In addition, a polysomnography records Electroencephaloraphy (EEG) brain waves, the oxygen saturation through pulse oximetry, and registers the heart rate using Electrocardiography (EKG) monitoring and breathing during sleep. It also measures eye movements to detect REM sleep and concomitant leg movements or atonia. An Electromyography (EMG) is concomitantly done and video monitoring might be useful.Depending on the available facilities in various countries, this type of sleep study may be done in a sleep disorders unit within a hospital or at a sleep center. A polysomnography will be usually performed at night, but it may be done during the daytime for some NMD patient who usually sleep during the day. Other important clues are given by pulse oximetry, spirometry, and blood gas analysis.The relevance of such a test is not only diagnostic since polysomnography might help determine a treatment plan when the neuromuscular patient has been diagnosed with a sleep disorder.In addition, a polysomnography might be used to adjust the patient to the home environment and use nocturnal ventilation. In Sleep disorders are a common problem in neuromuscular disorders and usually associated with a poor quality of life, worsening of muscle weakness, and systemic implications. In the literature, there are still few articles exploring the topic of sleep problems in neuromuscular disorders; the most recent relevant papers are on DM1 and DM2 , 18, andWe propose a review of sleep disorders in neuromuscular disorders since this is a hot topic and it is important to further construct new knowledge about this topic in the literature.The pathophysiological mechanisms and pathological implications of sleep problems in neuromuscular disorders need more extensive coverage and both clinical and translational research in the field. This minireview focuses on a special tool available in the treatment of sleep disorders with special emphasis on the role and life-saving mechanism of ventilatory support. We aim to emphasize that although ventilatory support is important and can improve QoL and prolongs also lifespan, other treatments are available and, in other cases, drugs or other types of intervention appear useful.In this review, we want to emphasize the importance of following sleep disorders in clinical myology practice: one should be aware that EDS is frequent in DM1 cases, but the concentration difficulties present in DM1 might be treated with variable benefit with modafinil . A mildeAn important risk factor to be treated for is nocturnal apneas that occur both in Duchenne Muscular Dystrophy (DMD) and spinal muscular atrophies (SMA), where nocturnal ventilation can prolong the life span. One concomitant factor changing the scenario of these child disorders is represented by the beneficial effect of current therapy from steroids for DMD to personalized drugs . Without intervention, many children with SMA type 1 die from respiratory failure before their second year of life. While assisted ventilation has improved survival, it often results in ventilator dependence. The development of new Suvival Motor Neuron (SMN) augmenting therapies has renewed optimism, but their long-term impact on respiratory functioning is uncertain, and non-invasive respiratory support remains an important part of SMA management. Despite the importance of respiratory support in SMA, knowledge of sleep disorders in this population is limited; for the high prevalence of nocturnal alveolar hypoventilation in SMA, overnight monitoring of gas exchange or a formal sleep study is recommended. Non-invasive ventilation (NIV) should be initiated for isolated nocturnal hypoventilation and managed by a multidisciplinary pediatric respiratory team with expertise in NIV.In both such genetic motor neuron disorders and in the realm of muscular dystrophies, personalized medicine is advancing and proposing new treatments such as ataluren and tofersen; therefore, all these advances might extend both QoL and lifespan.In the LGMD subtypes, i frequent to observe that most adult calpainpthy patients (LGMD R1) present prominent respiratory insufficiency and sleep apnea, simlar observations are possible in dysferlinopathy cases in advanced stages (LGMD R2) and present and common in most sarcoglycanopathy cases (LGMD R3-R5).We have observed during ERT that in patients with late-onset Pompe disease (LOPD), sleep hours improve; in addition, concomitant exercise and nutrition appear useful to improve QoL . Sleep dAlbeit rare, congenital myasthenic syndromes might present respiratory insufficiency. In particular, infants affected by Acetylcholinesterase collagenic tail peptide also known as AChE Q subunit (COLQ) or Rapsyn defects are at risk of briefly resolved unexplained events and sleep disorders of breathing that might benefit by using the BiPAP apparatus; similarly, in severe myasthenic syndromes, due to DOK7 and MUSK, there are remarkable improvements in cognition and quality of life in patients with these NMJ disorders .CoA drafted the manuscript. CaA and GS revised the manuscript and contributed to individual sections. All authors contributed to the article and approved the submitted version.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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Exposure to adversities in early life appears to affect the development of white matter, especially oligodendrocytes. Furthermore, altered myelination is present in regions subjected to maturation during the developmental time when early adversities are experienced. In this review, studies applying two well-established animal models of early life adversity, namely maternal separation and maternal immune activation, focusing on oligodendrocyte alterations and resulting implications for psychiatric disorders are discussed. Studies revealed that myelination is reduced as a result of altered oligodendrocyte expression. Furthermore, early adversity is associated with increased cell death, a simpler morphology, and inhibited oligodendrocyte maturation. However, these effects seem to be region- specific as some brain regions show increased expression while others show decreased expression of oligodendroglia-related genes, and they occur especially in regions of ongoing development. Some studies furthermore suggest that early adversity leads to premature differentiation of oligodendrocytes. Importantly, especially early exposure results in stronger oligodendrocyte-related impairments. However, resulting alterations are not restricted to exposure during the early pre- and postnatal days as social isolation after weaning leads to fewer internodes and branches and shorter processes of oligodendrocytes in adulthood. Eventually, the found alterations may lead to dysfunction and long-lasting alterations in structural brain development associated with psychiatric disorders. To date, only few preclinical studies have focused on the effects of early adversity on oligodendrocytes. More studies including several developmental stages are needed to further disentangle the role of oligodendrocytes in the development of psychiatric disorders. Emerging evidence points toward alterations in oligodendrocytes and myelination leading to impairments associated with psychiatric disorders such as schizophrenia and depression  paradigm  reported predominantly left-sided alterations. Others found reduced oligodendrocyte-related gene expression in both hemispheres, e.g., Zhang et al . UnfortuImportant to note are temporal and spatial differences between humans and rodents. Humans have an especially prolonged brain maturation and myelination process compared to rodents. While forebrain myelination only requires several weeks in mice and rats, it takes years in humans (Jakovcevski et al. On the genetic level, several hypotheses have been put forward concerning the impact of oligodendrocyte-related genes in animal models. One recent model that has gained considerable attention is the Tcf4/Olig2 model. Tcf4 and Olig2 are transcription factors that seem to play a crucial role in oligodendrocyte differentiation and myelination. More precisely, a heterodimerization of these proteins appears to be crucial in controlling oligodendrocyte differentiation and myelination (Wedel et al. In addition, environmental factors have been shown to effect numerous genes associated with oligodendrocyte differentiation and myelination. Early life stress has been demonstrated to lead to alterations in the expression of genes related to myelination in rodents (Gutman and Nemeroff Taken together, the overall conclusion of the present review is limited by the small number of included studies as well as several differences in research design and methodology. However, most studies do point towards substantial alterations of oligodendrocytes due to early adversity. In light of a translational perspective, it is important to note that between rodents and humans, relevant differences in temporal and spatial distribution and regulatory signals for oligodendrocyte differentiation are present that may influence the exceptional susceptibility of humans to demyelinating diseases (Jakovcevski et al. Comparisons between human and rodent forebrains have delineated that more studies are urgently needed to eventually unravel the implications on oligodendrocytes and their role in the development of psychiatric disorders after early exposure.


To investigate relationships between distinct schizotypy risk profiles in childhood and the full spectrum of parental mental disorders.true schizotypy, introverted schizotypy, and affective schizotypy) relative to the children showing no risk, according to maternal and paternal diagnoses of seven types of mental disorders.Participants were 22,137 children drawn from the New South Wales Child Development Study, for whom profiles of risk for schizophrenia-spectrum disorders in middle childhood (age ~ 11 years) were derived in a previous study. A series of multinomial logistic regression analyses examined the likelihood of child membership in one of three schizotypy profiles ; those in the affective  and introverted schizotypy profiles  were also more likely to have been exposed to any parental mental disorder, relative to children showing no risk.All types of parental mental disorders were associated with membership in all childhood schizotypy profiles. Children in the Childhood schizotypy risk profiles appear not to be related specifically to familial liability for schizophrenia-spectrum disorders; this is consistent with a model where liability for psychopathology is largely general rather than specific to particular diagnostic categories.The online version contains supplementary material available at 10.1007/s00127-023-02455-7. Schizotypy refers to a set of observable behavioural, cognitive, and personality characteristics that reflect liability for schizophrenia , 2. The The strongest known predictor for schizophrenia-spectrum disorders is having an affected first degree biological relative . IndividWhile the relationship of schizotypy to familial schizophrenia-spectrum disorders has been well established, there has been limited research examining schizotypy among offspring of parents with mental disorder diagnoses other than schizophrenia. Use of population registers and/or familial high-risk studies have indicated that children of parents with mental disorder are at increased risk of a broad range of psychopathology, not limited to the specific type of disorder that their parent is diagnosed with –21. FurtOnly a few recent studies have explored the relationship of subthreshold psychosis symptoms with familial liability outside the schizophrenia-spectrum. One familial high-risk study found that offspring of parents with any severe mental illness  were more likely than controls (i.e. children of parents with no disorder) to experience disturbances in thought, perception, and other mental processes associated with psychosis, and that likelihood did not differ across disorder classifications . Offspriwithin an individual offspring  codes converted to ICD-10-AM codes) for any emergency department visit, admission to hospital or episode of ambulatory (i.e. community or outpatient) service contact up until 31 December 2016 were categorised into seven broad diagnostic categories :As well as these seven types of mental disorder diagnoses, we derived a global index of ‘any parental mental disorder’ (not specific to any category) evident among either parent (i.e. at least one parent) as well as indicators of ‘any mental disorder’ for mothers and fathers separately.Three socio-demographic factors  were considered potential confounders of the relationship between parental mental disorder and childhood schizotypy and were included as covariates in adjusted models. Each child’s sex was determined from responses on the MCS. A binary indicator of Indigenous background was determined if either the child or their parent(s) were designated as of Aboriginal and Torres Strait Islander background in any available record in the NSW-CDS collection . Socio-eno risk for schizophrenia-spectrum disorders). Analyses were conducted first for “any parental mental disorder diagnosis” , then for (any) maternal diagnoses and paternal diagnoses, separately. An indicator of both parents (i.e. mother and father) having received any type of psychiatric diagnosis was also investigated. Then, analyses were conducted using the seven broad disorder categories described above, first for any parent, then for maternal mental disorder diagnoses, and last for paternal mental disorder diagnoses. Analyses resulted in odds ratios (ORs) with 95% confidence intervals (CIs) as measures of effect size, with ORs of 1.00–1.49 interpreted as small, 1.50–2.49 as medium, and 2.50 or more as large [A series of unadjusted and adjusted multinomial regression analyses were used to estimate associations between parental mental disorder diagnosis and offspring membership in one of the three schizotypy profiles, relative to the children showing no schizotypy , with the exception of the affective schizotypy group which was more strongly associated with paternal  affective psychoses and common mental disorders in both unadjusted and adjusted analyses, and with paternal personality disorders in adjusted analyses only. Children who had a history of both parents being diagnosed with a mental disorder had the highest odds of being in any of the schizotypy groups (compared to just one parent diagnosed), with medium sized associations with the introverted schizotypy and affective schizotypy groups, and large associations with the true schizotypy group.Children exposed to any parental mental disorder (in at least one parent) were at greater odds of membership in each of the three schizotypy risk groups, compared to the ed Table  and adjued Table . Childretrue schizotypy group (with medium to large effect sizes), relative to the odds ratios for membership in the introverted and affective schizotypy groups . In unadjusted analyses, associations were generally in the small to medium sized range for most types of parental mental disorder diagnosis with the exception of personality disorders, substance use disorders and other child-onset disorders, which had large effect sizes in relation to child membership in the true schizotypy group. As for the analyses of the ‘any parental mental disorder’ index, there were not substantial differences in size of associations between maternal and paternal mental disorders when analyses were conducted separately. When analyses were adjusted for child sex, Indigenous background, and socio-economic disadvantage, the size of associations attenuated slightly, but most remained significant. Exceptions were the associations between any parental diagnosis of schizophrenia-spectrum disorder and offspring affective schizotypy, and any parental diagnosis of affective psychotic disorder or child-onset disorder with offspring introverted schizotypy, which were no longer significant after adjustment for demographic indicators.All seven categories of parental mental disorder diagnoses were associated with increased odds of offspring membership in each of the three schizotypy risk groups, in both unadjusted and adjusted analyses. For every category of mental disorder, the largest odds were for membership in the true schizotypy group, relative to the likelihood of being classed in the introverted schizotypy or affective schizotypy groups. However, no particular diagnostic category of parental mental disorder was specifically associated with any subtype of schizotypy in offspring.In a large Australian population-based cohort, children with at least one parent diagnosed with a mental disorder were more likely to self-report particular combinations of cognitive, behavioural and unusual perceptual experiences that placed them in one of three schizotypal risk profiles at age 11 years, relative to children of parents without a history of mental disorder diagnosis. There was some evidence of differential relationships between familial liability to mental disorder and the three distinct subgroups of schizotypy, with parental mental illness being more strongly associated with membership of the true schizotypy group compared to children of unaffected parents, while children with affected parents had only a small increase in odds of being classified into either the introverted or affective schizotypy groups. These findings are consistent with previous research indicating that the negative  features of schizotypy are more strongly related to familial liability for schizophrenia-spectrum disorders than positive  features [true schizotypy group was distinguished by a pattern of high cognitive disorganisation, impulsive non-conformity, introversion, and self-other disturbance, while the affective schizotypy group was characterised by high unusual experiences and affective symptoms.Children of parents with mental disorder diagnoses were two- to threefold more likely to be classed in the features , given tn = 15), so it is unlikely that these specific personality disorders were driving the relationship with offspring schizotypy.The association between parental mental disorder diagnosis and offspring schizotypy was consistent across a broad range of parental mental disorder diagnoses, including psychotic, affective, personality, and substance use disorders, indicating that offspring schizotypy was not specifically related to any one parental mental disorder diagnostic category. This is consistent with previous findings suggesting that intergenerational transmission of mental illness is generally non-specific –21, 41 aaffective schizotypy group was more strongly associated with several paternal mental disorders  than the equivalent maternal disorders. As girls are overrepresented in the affective schizotypy group, this may be consistent with previous research indicating opposite-sex-specific parent-of-origin effects in the intergenerational transmission of psychosis [When analyses were conducted separately for maternal and paternal mental disorders, there were largely no differences in the strength of relationships between parental mental disorder diagnosis and offspring schizotypy. The exception was that the sychosis . Childresychosis , 19, andaffective schizotypy group), but also for children with high levels negative and disorganised symptoms but without high levels of PLEs (i.e. the true and introverted schizotypy groups). While schizotypy has generally been assumed to represent liability for schizophrenia-spectrum disorders, there is limited research examining the relationship of schizotypy with other non-psychotic mental health outcomes, and it is possible that schizotypy represents liability for a broader range of expressions of mental illness. In addition to evidence for the transdiagnostic intergenerational transmission of mental disorders [Contrary to our hypotheses, children of parents with schizophrenia-spectrum disorders were not the most likely to be represented in the three schizotypy risk profiles, but in fact had amongst the lowest odds of membership in any of the schizotypal risk profiles. This adds to previous findings that PLEs in offspring are associated with parental mental disorders other than schizophrenia-spectrum disorders –30, by sisorders –21, 41, isorders , 44. It isorders , 45. NotFindings that any type of parental mental disorder diagnosis is related to offspring schizotypy are consistent with a model of transdiagnostic intergenerational transmission of mental disorder that likely operates via both genetic and environmental factors , 46. Witafter offspring schizotypy was measured. These data were included since only the dates of diagnosis (and not the date of symptom onset) were available. It was therefore assumed that these records would largely relate to mental disorders present before offspring schizotypy was measured. Although the reverse association  is unlikely, this cannot be ruled out. Finally, schizotypy was measured by self-report questionnaire, which is typically less effective than clinical interview at distinguishing relatives of people with schizophrenia from controls [Strengths of the study include the large sample size, which allowed us to examine a broad range of parental mental disorders including relatively rare disorders , and avoided the sampling bias associated with a high-risk sampling approach. Further, the person-centred analysis approach  allowed us to delineate groups of people with distinct patterns of schizotypal traits, rather than examining individual dimensions of schizotypy in a way that ignores population or sample heterogeneity. However, the main limitation of this study is that parental mental health diagnoses were derived from health  department records only, such that parents who received care from private mental health or primary care practitioners, or who were unable to access mental health services would be classified as unexposed. Our findings may therefore underestimate the strength of associations. Further, any mental disorder diagnoses recorded before the period for which health data were available (approximately four years prior to the children’s birth) would not have been captured in the available records, potentially leading to the misclassification of children as not exposed to parental mental disorders. Second, data on presentations for parent mental diagnoses could have been recorded up to a year controls . Childrecontrols . HoweverClarifying the familial link between a broad spectrum of parental mental disorders and offspring schizotypy in childhood is important for understanding intergenerational pathways to adult mental disorder. The present results indicate that schizotypy in middle childhood is not specific to offspring of parents with schizophrenia-spectrum disorders, but that schizotypy is more common among offspring of parents with any type of mental disorder diagnosis. Evidence of differential relationships of familial liability to mental disorder among the distinct schizotypy risk profiles in the child population further suggests that there may be graded liability for mental health risk among the offspring of parents with mental disorders. Future research of childhood schizotypy as a potential mediator of familial liability to severe mental illness is warranted in genetically informed, intergenerational population samples.Supplementary file1 (DOCX 26 KB)Below is the link to the electronic supplementary material.


Implicit Motives are non-conscious needs that drive human behavior towards the achievement of incentives that are affectively incited. Repeated affective experiences providing satisfying rewards have been held responsible for the building of Implicit Motives. Responses to rewarding experiences have a biological basis via close connections with neurophysiological systems controlling neurohormone release. We propose an iteration random function system acting in a metric space to model experience–reward interactions. This model is based on key facts of Implicit Motive theory reported in a broad number of studies. The model shows how (random) responses produced by intermittent random experiences create a well-defined probability distribution on an attractor, thus providing an insight into the underlying mechanism leading to the emergence of Implicit Motives as psychological structures. Implicit Motives’ robustness and resilience properties appear theoretically explained by the model. The model also provides uncertainty entropy-like parameters to characterize Implicit Motives which hopefully might be useful, beyond the mere theoretical frame, when used in combination with neurophysiological methods. The Complex System approach  has beenThis work attempts to address the mathematical modeling of the Implicit Motive (IM) construct within the well-established Motive Disposition Theory (MDT) ,3. IMs an Ach), the need for Power (n Pow), and the need for Affiliation (n Aff). The first one is the need to reach a standard of excellence while avoiding goals that are excessively difficult or too easily achieved  and NE [Norepinephrine] in response to various types of stimulation and to determine just what types of situations are most likely to give rise to increased outputs of one or the other hormone. In this way, we could begin to get an understanding of how motives are formed, based on early affective learning in connection with naturally occurring incentive situations”.One possible conjecture, which would be consistent with the IM construct, would be that the individual-specific reward intensities, n learns  and withn learns  pointingHopefully, the proposed model and the parameters involved might help in the research areas of implicit motives and affective neurosciences . Since nsonality ,22,44.Despite the fact that this work aims to be no more than a theoretical contribution, we hope it opens the door to an experimental approach. Following works should address the problem of calibrating the quantitative parameters that the model proposes through IM measurements techniques, both psychological and physiological, to be used in further practical applications  responses produced by intermittent random experiences create a well-defined probability distribution on an attractor which, in this manner, becomes the core of the Implicit Motive entity and a mathematical support of the psychological IM construct. Implicit Motive robustness and resilience properties appear theoretically explained by the model.The simplified model also provides significant uncertainty entropy-like parameters that may be useful to characterize the psychological structure of an individual IM, an interesting byproduct of the model. Since neurophysiological methods allow the measuring of endocrine and hormone responses related to different motivational scenarios, such measures might serve as inputs in the model ,18,22. T


Demodex folliculorum and Demodex brevis are commonly present on facial skin and frequently noted via Reflectance Confocal Microscopy (RCM) examination. These mites inhabit follicles and are often seen in groups of two or more, although D. brevis is usually found as a solitary mite. When observed through RCM, they are typically present as refractile, round groupings seen on a transverse image plane inside the sebaceous opening, as they are vertically oriented, and their exoskeletons refract under near-infrared light. Inflammation may occur, leading to a variety of skin disorders; nonetheless, these mites are considered to be part of normal skin flora. a 59-year-old woman presented to our dermatology clinic for confocal imaging  of a previously excised skin cancer for margin evaluation. She did not exhibit symptoms of rosacea or active inflammation of the skin. Incidentally, a solitary demodex mite was noted in a milia cyst nearby the scar. The mite appeared to be trapped in the keratin-filled cyst and was positioned horizontally to the image plane such that its entire body was captured in a coronal orientation as a stack. Demodex identification using RCM can provide clinical diagnostic value in the context of rosacea or inflammation; in our case, this solitary mite was thought to be part of the patient’s normal skin flora. Demodex are practically ubiquitous on the facial skin of older patients and are frequently noted during RCM examination; however, the orientation of the mite referenced herein is uncommon, allowing for a unique view of its anatomy. The use of RCM to identify demodex may become more routine as access to technology grows.


Gene duplication is recognized as a critical process in genome evolution; however, many questions about this process remain unanswered. Although gene duplicability has been observed to differ by duplication mechanism and evolutionary rate, there is so far no broad characterization of its determinants. Many features correlate with this difference in duplicability; however, our ability to exploit these observations to advance our understanding of the role of duplication in evolution is hampered by limitations within existing work. In particular, the existence of methodological differences across studies impedes meaningful comparison. Here, we use consistent definitions of duplicability in the human lineage to explore these associations, allow resolution of the impact of confounding factors, and define the overall relevance of individual features. Using a classifier approach and controlling for the confounding effect of duplicate longevity, we find a subset of gene features important in differentiating genes duplicable by small-scale duplication from those duplicable by whole-genome duplication, revealing critical roles for gene dosage and expression costs in duplicability. We further delve into patterns of functional enrichment and find a lack of constraint on duplicate retention in any context for genes duplicable by small-scale duplication. Duplicate genes created by whole-genome duplication have a different evolutionary trajectory than those created by small-scale processes, with the two sets of genes differing in various important biological properties. However, understanding this phenomenon has been hampered by study differences. This study provides a comprehensive and rigorous comparison of a broad range of genetic features and points to gene dosage effects as the major differentiator.Gene duplication has long been considered an important mechanism in shaping the gene content and structure of genomes including those of vertebrates . It playThe duplicability of a given gene, that is the likelihood of its evolutionary duplication and long-term retention, differs depending on the mechanism of duplication, with retained WGD duplicates rarely successfully duplicated by SSD . This stOne clear candidate to explain these differences is dosage balance constraint . Under tHere, we perform a comprehensive comparison of duplicate groups in the human genome, allowing us to combine a broad spectrum of genomic, proteomic, and expression traits under a consistent set of definitions and with the possibility to identify confounding factors. We find that dosage-related features and the number of unique protein domain types present are the strongest distinguishing features between SSDs and ancestral vertebrate (2R) ohnologs. Patterns of functional enrichment additionally inform our overall picture of duplicability, indicating that while 2R ohnologs are generally refractory to duplication by SSD there is no particular constraint preventing retention of SSD-duplicable genes in duplicate following WGD. Combining these findings gives us a view of duplicability wherein gene dosage is the primary driving factor of duplicate retention post-WGD and gene families that include paralogs originating from both mechanisms may most usefully be considered as SSD-duplicable genes with chance ohnolog retention. This view of gene duplicability is consistent with previous reports spanning many diverse taxa, consolidating and uniting them under a single study design with internally consistent analysis protocols.We classified 19,548 human genes as one of singleton (no duplicate copies detected within vertebrates), SSD paralog, or ohnolog. For stringency, we assessed paralog pairs using three ohnolog data sets and made the final assignment based on the majority classification for a given gene across three published data sets  are considered, the median expression of WGD genes is always higher than SSD genes, indicating WGD genes are the more highly expressed group regardless of tissue context .Sequence conservation and constraint may be the most studied category of features with respect to duplication type differences. Evolutionary rates of paralogs are often presumed to reflect relaxation of constraint owing to redundancy, but there is evidence that SSD duplicability is higher for less constrained, faster evolving genes . In the We examined evolutionary constraint in the duplicate groups by comparing evolutionary rate and population genetics-based metrics , while SSD duplications may have occurred anywhere in the human lineage from the vertebrate ancestor to the human-specific branch. Identified ohnologs are, by definition, long-lived while only a small portion of SSDs are retained in the long term . PreviouFor the most part, features where duplication type has no significant effect when controlling for age either did not significantly differ in our earlier pairwise comparisons or differed only weakly relative to other features  which differed significantly between WGD and SSD genes in both the original pairwise comparisons and after controlling for age, where we used values from the regression analysis for each feature to control for age  across 100 iterations compared to 0.7963 (95% CI: 0.7938–0.7988)) ; we also see, improvement in a bias towards classifying older duplicates as WGD . OhnoloWhile we find gene dosage to be a key determinant of duplication differences, naturally gene families exist which retain duplicates of both duplication class. Small contributions from other gene features could explain this, but a more complete picture of duplicability requires assessment of gene function. Different classes of duplicate are known to show specific functional enrichments. We replicate these known patterns, finding enrichments for developmental, regulatory and signaling functions in WGD genes as well as depletions for base cellular functions such as translation . SimilarGiven observed overlaps in the sets of functions most strongly enriched/depleted across groups, we decided to investigate the overall overlaps within all significant enrichments/depletions . We obseThese shared depleted terms in the two non-WGD groups should represent functions which are preferentially retained post-WGD. That we do not see such agreement between singletons and WGD suggests there is not a similar class of functions promoting SSD retention. This idea is supported by asymmetry between the two duplicate types; 71.2% of SSD depleted terms are enriched in WGD genes, while only 7.5% of terms enriched in SSDs are depleted in WGD genes. Overall, it seems that WGD gene functions are primarily shaped by functions which promote duplicate retention following WGD (purifying selection maintaining the ohnologs) while SSD functions are shaped by avoiding functions of genes which would be detrimental to duplicate in this manner.The results presented here reinforce previous studies that have shown that WGD and SSD have significantly different evolutionary outcomes. Numerous previous studies have analyzed the relationship between gene duplication mechanisms and other genetic, genomic, and proteomic features. In this work, we provide a comprehensive analysis of a broad range of characteristics in the context of the vertebrate 2R WGD and vertebrate SSD that benefits from both an internally consistent set of ohnologs, SSD paralogs, and singletons, and, importantly, includes a rigorous examination of potentially confounding features. In particular, the random forest classifier provides insight into which features are making the greatest contribution to the differences in gene duplicability by either mechanism. Comparison of functional enrichments across groups additionally supports the idea that ohnolog retention occurs primarily, though not exclusively, in gene families which are refractory to SSD, while the reverse is not true (there is no evidence to support a large set of genes that are refractory to post-WGD retention).We examined differences between duplication types across a wide range of features covering gene length, composition, structure, regulation, and constraint. The most extreme differences between SSD and WGD genes generally fall under either features relating to gene length or those relating to constraint on sequence changes. We further showed that these differences cannot be fully explained by differences in duplication antiquity, although gene age does have a dramatic effect on how strongly these features contribute to accuracy in classifying duplicate type. It is significant that these features demonstrate a stronger relationship to duplicate age than duplication mechanism as, within our data set, they are also the features with the most accumulated evidence for differing strongly between the duplicate groups. This clearly shows that duplicate age must be considered when comparing features of duplicate genes.The features that we find to contribute most strongly to the random forest classifier accuracy on controlling for this age effect indicate a strong influence of gene dosage effects in determining successful duplication, most notably gene expression level and probability of haploinsufficiency. The biological relevance of the dominance of the number of unique domains as a top predictor of duplicate class is less clear within current models of duplicate retention. The fact that the number of unique domains seems to provide information not given by the absolute number of domains  implicatThe difference in isoform count was unexpectedly large, with SSD genes having far fewer than either singletons or 2R WGD genes. One potential explanation for this could be the idea of alternatively spliced transcripts acting as “internal paralogs” , with anThe overall goal of this work was to confirm and consolidate previous studies of duplicability by creating an integrated view of differences between duplicate categories, so that these differences could be used to make deductions about what promotes or hinders duplicate retention under each mechanism. It is clear from the single feature comparisons that human WGD genes are longer and more broadly expressed as well as being highly constrained and regulated, with the most relevant features implicating dosage and functional diversity as important determinants of duplicate type. It remains to be discovered what about these features drives different evolutionary outcomes following WGD or SSD.One final outstanding question is whether these findings for vertebrate duplications can be generalized to duplicability in other lineages. While we do not attempt to address this here, and to completely address this question would require further work in defining duplicate status and genetic features in a comparable manner across species, we do note some parallels across lineages. Recent work in amphioxus  indicateA list of 19,548 human protein coding genes, as well as a list of human paralog pairs with an estimate of duplication timing (last common ancestor) was obtained from Ensembl v99 . Regionsand there is no conserved microsyteny between the duplicates. Microsynteny was defined as having at least one other paralagous pair linking the surrounding region (within five genes either side of the genes being tested), following from methods used in Considering each ohnolog set separately, a paralogous pair was designated as originating from WGD if the pair was present in the list of ohnolog pairs, and as SSD if not. Pairs designated as SSD were further examined for evidence of retroduplication, as this mode of duplication is outside the scope of this work and it cannot be assumed that these pairs behave similarly to SSDs. Paralog pairs were defined as potentially retroduplicated if one member of the pair has zero introns while the other has three or more, or if at least one member of the pair has zero introns and the other has less than three A measure of cellular essentiality, the CRISPR score, was taken from We also examine a number of population-based measures of gene essentiality. These metrics differ from the CRISPR score as they use modeling to estimate the expected frequency of mutation or loss of function in a given gene and define essentiality based the difference between this expected frequency and that observed. We examine a number of these metrics including pLI , Phi Ba, LoFtoolShet , RVIS  if they have fewer common variants than expected given the total functional variance for the gene. Although they share this framework, these metrics are distinct in the data used with RVIS considering variants using only information from humans, while EvoTol incorporates whether a variant is “damaging” across evolutionary time. Similarly, Phi, pLI, and Shet all use estimates from probabilistic models  to measure tolerance of mutation, estimating probability of haploinsufficiency, probability of LOF intolerance, and the selection coefficient, respectively. The missense Z score quantifies the deviation in missense mutation frequency relative to the expectation of a neutral mutation model, making it the only metric included here which focuses fully on sequence changes rather than including mainly truncating variants. Finally, LoFTool is the only metric included which is built on multiple of the others, combining information from both EvoTol and the missense Z score to consider a breadth of functional information.τ which is given by N is the number of tissues and x is the expression value for the iτ essentially represents the average difference across tissues from the maximal gene expression, scaled relative to the maximal gene expression; a value of 0 indicates a housekeeping gene while a value of 1 indicates a tissue specific gene. For the purposes of this calculation, different development stages were treated as separate tissues. This measure of tissue specificity was determined to be the most robust when benchmarked by Gene expression levels  were obtained from GTEx (v8) . ExpressA, supplementary fig. 10B, We considered the “age” of a given gene to be the age of the oldest duplication node within the vertebrate gene family, with gene family membership defined as all paralogs of a gene originating within the vertebrate lineage, according to duplication timing provided by Ensembl . For thesupplementary fig. 10dN/dS with macaque orthologs), number of introns, average intron length, intron coverage, regulatory motifs, protein domains, unique protein domains (from domains), % GC content, and % GC3 content (determined from CDS sequence from Ensembl). In cases where a feature may differ between different transcripts/protein products of a gene, the value for the longest transcript was used.PPIs were obtained from the Human Interactome . Codon aIn the case of “evolutionary rate”, we use the ratio of nonsynonymous mutation rate to synonymous mutation rate  . This meSelected hyperparameters  for these classifiers were determined from a randomized grid search with 10-fold cross- validation set to maximize F1 score, with a model trained on the selected gene features. Following this step, the estimated best hyperparameters were the same as defaults except in the case of the number of estimators (39 rather than the default of 100). Classes were weighted (Feature importances were calculated using the rfpimp Python package , using pModel training and feature importance calculation was repeated 100 times using the final hyperparameters and feature set with each pass using different randomly selected training and validation data sets in order to estimate how variable the importance rankings were due to randomness in the model.To control for the effects of duplicate age differences, another model was constructed and importances calculated in the same manner using residuals from regressing each feature on age (equation of the form Correlation can impact feature importance estimates, reducing importance for individual features. This issue becomes more prevalent with increasing correlation strength and number of correlated features , as the evad174_Supplementary_DataClick here for additional data file.


Evaluating efficacy and real-world effectiveness for novel therapies targeting rare mutations or patient subpopulations with unmet needs is a growing challenge in health economics and outcomes research (HEOR). In these settings it may be difficult to recruit enough patients to run adequately powered randomized clinical trials, resulting in greater reliance on single-arm trials or basket trial designs. Additionally, evidence networks for performing network meta-analysis may be sparse or disconnected when comparing available treatments in narrower patient populations. These challenges create an increased need for use of appropriate methods for handling small sample sizes, structural modelling assumptions and more nuanced decision rules to arrive at “best-available evidence” on comparative and non-comparative efficacy/effectiveness. We advocate for greater use of Bayesian methods to address these challenges as they can facilitate efficient and transparent borrowing of information across varied data sources under flexible modelling assumptions, probabilistic sensitivity analysis to assess model assumptions, and more nuanced decision-making where limited power reduces the utility of classical frequentist hypothesis testing. We illustrate how Bayesian methods have been recently used to overcome several challenges of rare indications in HEOR, including approaches to borrowing information from external data sources, evaluation of efficacy in basket trials, and incorporating non-randomized studies into network meta-analysis. Lastly, we provide several recommendations for HEOR practitioners on appropriate use of Bayesian methods to address challenges in the rare disease setting. In these cases, the novel treatments that are urgently needed by patients may be passed over if typical large-sample, dichotomous statistical significance thresholds are treated as an unquestioned default by decision-makers.A core task of health economics and outcomes research (HEOR) is to compare the effectiveness of two or more competing treatments. Over the past several decades, researchers in HEOR have been working to realize the promise of a “big data” revolution in which an excess of evidence can be brought to bear on any given decision problem . HoweverWhile Bayesian methods have seen substantial uptake in the area of meta-analysis–for example, in guidance from the UK National Institute for Health and Care Excellence’s (NICE) Decision Support Unit (DSU) –, we sugBayesian inference defines a probability model for data which is a function of parameters (the likelihood), and a probability model for parameters before any data are observed (the prior). After data are observed, the prior and the likelihood are used to calculate a probability distribution for the parameters given the data (the posterior). If there is information available which is related directly to the model parameters, it can be included in the prior. If there is information available in the form of additional data from another source, it can be included in the likelihood. The posterior distribution contains all available information about the model parameters, and in practice is a very useful mathematical object. For example, functions of the posterior such as the probability that one treatment is superior to another, or the expected benefit of selecting one treatment over another, or the distribution of predicted patient outcomes in a given population, can all be obtained without much additional computational effort. In the frequentist approach, many of these derived quantities are not available, and even if they are available their calculation is considerably more burdensome.Because Bayesian methods lead to probability statements about model parameters, they are vital to formal decision analysis and thus HTA  from external data in a transparent manner. These methods allow for down-weighting of the external data to mitigate potential bias arising from different parameter values in the current population compared to the external populations. One established approach is to borrow information by means of a power prior . The powAnother prior-based approach to Bayesian borrowing is to formulate a meta-analytic predictive (MAP) prior for the parameter of interest . As an ePower prior and robust MAP prior methods have different strengths and weaknesses in practice. Power prior methods can be more challenging to implement , but they have a simple form and can easily be adapted to incorporate disparate sources of external information. MAP prior methods will be more familiar to those experienced with Bayesian meta-analysis, and may be easier to explain and justify in many HEOR settings. Both approaches can incorporate aggregate data and/or individual patient data (IPD) from multiple sources, and both can be used for tipping point analysis if desired . In one In cases where a structural relationship among data sources can be assumed, Bayesian hierarchical models (BHMs) are another option for partial pooling of information in which hierarchical dependencies of key parameters are modeled explicitly . BHMs asTo illustrate the utility of BHMs in the HEOR space, we focus on some recent applications to analyses of basket trials. Basket trial designs include patients with multiple cancer types which share a common targetable mutation or biomarker. In these basket trials, sample sizes tend to be extremely limited, treatment responses are expected to vary among tumour types, and control arms are often omitted. In the BHM approach to analysis of basket trials, exchangeability of tumour types may be a clinically tenuous assumption . While hierarchical models can be implemented under both a Bayesian and classical frequentist approach, a key advantage of Bayesian approaches is the ability to incorporate prior information and perform probabilistic sensitivity analyses when faced with challenging settings with limited available data. For example, use of weakly informative priors can avoid issues of extreme overfitting to the data. Additionally, it can be difficult to reliably estimate the heterogeneity parameters for a hierarchical model when the number of groups  is very small. In these situations, multiple prior distributions can be used to assess how sensitive conclusions are to assumptions about the degree of heterogeneity in outcomes across groups.Beyond applications to basket trials, BHMs have been used to incorporate disparate data sources, structural assumptions, and borrowing approaches when no single source is sufficient for inference and decision-making. For example, Meta-analyses which synthesize the published evidence on relative treatment effects generally rely on RCT evidence only. However, when estimating real world effectiveness or efficacy/effectiveness in key patient populations of interest, or when RCT evidence is lacking due to the rarity of some indications, incorporating information from non-randomized studies (NRS) using real-world data becomes appropriate . RelevanSeveral promising approaches exist for incorporating NRS into a network meta-analysis (NMA) or pairwise meta-analysis which are both conducive to down-weighting the NRS either statically or dynamically, and to probabilistic sensitivity analysis. etc.) can be modelled using a Gaussian distribution where the mean and variance represent systematic and non-systematic components of the bias, respectively. This allows for incorporation of NRS data into the meta-analysis with potential bias adjustment and down-weighting—either by means of a bias-adjusted priors or through direct incorporation into the likelihood. As new drug development is focusing more and more on narrower indications, HEOR practitioners are increasingly faced with challenges of limited data. These limitations arise from difficulties recruiting enough patients to conduct adequately powered RCTs , narrowing of indications or subpopulations of interest leading to smaller numbers of relevant studies being identified in systematic literature reviews (and greater risk of disconnected or tenuous networks in NMAs), and more reliance on evidence from ITCs that are unlikely to yield precise estimates of relative treatment effects. Consequently, we present several recommendations for how Bayesian methods (including many of the approaches outlined above) can be used to help mitigate some of these pitfalls.Firstly, since Bayesian approaches allow for weakly informative priors to be specified before analyzing the data, use of sensible default priors can mitigate some of the risks of model overfitting when data are very limited without imposing overly strong assumptions. With weakly informative defaults, the prior can be easily overwhelmed when informative data are available. An example of this can be found in the Secondly, if strong modelling assumptions are needed to synthesize the limited amount of available data, probabilistic sensitivity analyses should be conducted to assess robustness to deviations from these assumptions. For example, if it is infeasible to conduct a random effects NMA due to too few studies in the network, different heterogeneity assumptions can be assessed by fitting modified random effects NMAs in which different strong priors are used for the heterogeneity parameters, each reflecting a plausible scenario. In this context, fixed effects NMA can be viewed as a special case of random effects NMA, and use of informative priors on heterogeneity parameters allows for sensitivity analysis even when data are too limited to estimate these parameters.p-value threshold. For example, if we are performing an ITC between two treatments that have received regulatory approval based on single-arm trials, and it is infeasible to conduct an adequately powered ITC, it may be sensible to prioritize reimbursement of one drug over the other based on the posterior probability of superiority (a quantity which is directly available in Bayesian inference). This would arguably constitute a “best-available evidence” standard in this example.Lastly, if precision/power are anticipated to be extremely limited , it may be worth considering a context-appropriate decision rule rather than a default In summary, Bayesian methods provide a principled framework for quantifying the amount of evidence in favour of a particular conclusion, are well-suited to combining information from multiple data sources under various structural assumptions, and can facilitate probabilistic sensitivity analyses to probe these structural assumptions. For these reasons we believe that Bayesian methods should play an increasing role in health economics and outcomes research.