Neonatal hemochromatosis (NH) is an uncommon, severe disorder that results in fetal loss or neonatal death due to liver failure. NH is currently regarded as the phenotypic expression of gestational alloimmune liver disease (GALD). The diagnosis of NH-GALD is rarely prenatally established. In addition to providing a systematic review of the prenatal features that are identifiable using ultrasound (US) and MRI, we suggest a prenatal diagnosis algorithm for use in suspected NH during the first affected pregnancy. From a total of 586 database entries identified in PubMed, Google Scholar, and ResearchGate, we selected 18 studies published from 1993 to 2021 that reported maternal medical and obstetric history, prenatal ultrasound findings, and postpartum outcomes. We investigated the ultrasound and MRI features of these studies, along with the outcome due to this condition. A total of 74 cases were identified. The main reported prenatal US finding was fetal growth restriction (FGR) (33%), followed by oligohydramnios (13%) and hydrops fetalis (13%), with 13% cases described as uneventful. Other rare prenatal findings were fetal anemia, ascites, and abnormal fetal liver and spleen. Most pregnancies ended with fetal/perinatal death or therapeutic interruption of pregnancy. Favorable evolution with treatment (ensanguine transfusion and intravenous immunoglobulin (IVIG)) was reported for only 7% of fetuses. Using T2-weighted MRI, fetal extrahepatic siderosis confirmed prenatally in two cases and postnatally in 11 cases. IVIG treatment throughout subsequent pregnancies was found to significantly improve fetal prognosis. MRI should be indicated in selected cases of oligohydramnios, fetal hydrops, fetal hepatomegaly, ascites, or unexplained FGR or anemia after ruling out all other more frequently encountered conditions. MRI can be used to detect iron overload in the liver and extrahepatic siderosis. Neonatal hemochromatosis (NH) OMIM 231100) is defined as a severe liver illness accompanied by extrahepatic siderosis in newborns 100 is de,5.While the actual incidence of NH is uncertain , relevant findings have resulted in reclassification of NH as both congenital and familial . Even ifInformation regarding fetal hemochromatosis remains scarce. Since its initial description, evidence has largely been gathered from case reports or case series .NH is often only diagnosed at autopsy, and failure to acquire a correct diagnosis in stillbirths or neonatal deaths with liver failure leads to dire consequences for the mother’s future pregnancies . Left unFrom 18 weeks of gestation, intrauterine signs that could suggest NH are fetal growth restriction (FGR), oligohydramnios, fetal hydrops, fetal hepatomegaly, ascites, prematurity, unexplained anemia, or fetal demise in the late-second and third trimesters ,9. TheseThe current review aims to gather the available evidence regarding the antenatal features related to NH-GALD and create an algorithm for potential assessment when there is prenatal suspicion of this rare pathology characterized by a severe prognosis, wherein selected fetuses will be referred for MRI and the initiation of specific treatment where appropriate.We conducted a literature review on the subject, focusing on reports of patients diagnosed with NH and with confirmed extrahepatic siderosis that reported maternal medical and obstetric history, prenatal ultrasound findings, and postpartum outcome.Despite the strong impact of this condition on present and future pregnancies, the prenatal findings that might suggest fetal NH-GALD are often non-specific, leading to an infrequent prenatal diagnosis; therefore, we used strict inclusion criteria.The protocol for systematic review was written in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines . The revThe studies were screened for relevance (abstracts and then full-text articles) based on the PICOS criteria and comprised case reports, case series, and observational studies (study design) of patients diagnosed with NH. These studies reported maternal medical and obstetric history and prenatal ultrasound findings (population), confirmed extrahepatic siderosis (intervention), and the postpartum outcome (outcome).Papers with no description of prenatal evolution of the pregnancy or cases where extrahepatic siderosis was not confirmed (the absence of NH diagnosis is debatable) were excluded. We considered papers in English, French, and Spanish.Using the search method, 586 articles were identified from the databases. A total of 128 duplicate articles were removed from the screening, and five were written in languages other than those being considered. Of the 453 articles remaining after screening by title and abstract, 398 were excluded as they referred to another subject. Of the 50 articles assessed for eligibility, 18 met the inclusion criteria .The 74 cases of postnatally diagnosed NH with confirmed extrahepatic siderosis found in the current literature review are listed in NH was reported to affect mainly multiparous, healthy gravidas at a mean of 33 weeks of gestational age (WGA) (range 21 to 40). A small percentage of the gravidas presented autoimmune pathologies, such as systemic erythematosus lupus (4%), autoimmune thyroiditis (4%), or were part of a consanguineous couple (4%). A significant percentage of the patients (28%) had experienced recurrent fetal/neonatal death or neonatal liver failure. The main prenatal ultrasound finding reported in the 74 cases was FGR (33% cases), followed by oligohydramnios (13% cases) and hydrops fetalis (13% cases). In 13% of the cases, the course of the pregnancy was described as uneventful. Other rare prenatal findings were fetal anemia, ascites, or abnormal fetal liver and spleen . MRI hadMost fetuses had an inauspicious prognosis, with the pregnancies ending in fetal death, perinatal death, or therapeutic interruption of pregnancy. Favorable evolution with treatment was reported for only 7% of the fetuses. Autopsy was the primary method used to confirm diagnosis. The postnatal treatment varied from chelation/antioxidant therapy, with reserve results, to ensanguine transfusion and intravenous immunoglobulin, with a favorable prognosis. When reported, the subsequent pregnancy had favorable evolution in cases of prenatal intravenous immunoglobulin (IVIG) treatment.Following these results, in The objective of this paper was to systematically review the current literature regarding the main prenatal features of patients diagnosed with NH-GALD in order to create an algorithm for potential prenatal suspicion of this rare pathology characterized by a severe prognosis, in which selected fetuses will be referred for fetal MRI and the initiation of specific treatment where appropriate. While neonatal diagnosis has become more reliable, prenatal suspicion of NH in first affected pregnancies is exceptional. We reviewed 18 studies involving 74 fetuses diagnosed with NH and with confirmed extrahepatic siderosis, following which we could draw some conclusions regarding the prenatal features of fetuses with NH.Although the nature of the triggering antigen is still unknown, the central hypothesis regarding the pathogenesis of NH-GALD is focused on liver disease.Fetal hepatocytes suffer injuries through the attack of membrane complexes resulting from transplacental transfer of maternal IgG antibodies , followeIron deposition in diverse places is the ultimate phase in a multi-step process in which liver damage mediated by the complement may be the initial step .Usually, extrahepatic siderosis is encountered in the pancreas, myocardium, thyroid, and salivary glands. Whittington et al. suggested that the possibility of alloimmune gestational should be considered since genetic causes for transmission do not align with known patterns of inheritance . Even ifDuring gestation, fetal iron levels are controlled by placental function, with trophoblastic tissue functioning as duodenal mucosa in tuning iron absorption and balancing the substantial maternal iron pool, thereby carefully regulating the fetal iron pool .Fetal iron stores are regulated via the fetal hepcidin pathway . The damTwo main patterns of iron accumulation have been described: parenchymal iron overload and Kupffer cell hemosiderosis . ParenchKupffer cell hemosiderosis refers to a pattern accumulation of hemosiderin in Kupffer cells and, in some cases, in the portal macrophages and endothelial cells, and secondary iron overload can be encountered. Moreover, mixed patterns of iron accumulation create even more issues, resulting in further difficulties in assessing these cases .More recent data suggest that hepatic C5b-9 deposition could represent an important marker for GALD in an appropriate clinical situation, but the literature data are still contradictory .An excellent study was conducted by Bonilla et al. in which liver tissues and extrahepatic tissues from GALD infants were investigated and compared with normal age-matched tissues. GALD-related liver injury may reduce hepcidin synthesis such that a cascade of reactions may follow, such as impaired placental iron flux feedback control. The authors pointed out that hepatic HAMP  expression was reduced, and the pattern of extrahepatic siderosis is apparently determined by the capacity of various tissues to import non-transferrin-bound iron and not export cellular iron. Their findings suggest that NH is not primarily an iron overload disease .An essential step is distinguishing the NH-GALD–related phenotype from other non-GALD disorders with different clinical presentations and prognoses. In order to accurately diagnose GALD, a comprehensive evaluation must be performed. Shanmugam et al. summarized the investigations that must be conducted to rule out other potential causes of a comparable phenotype . For theThe most frequent causes that should be taken into consideration for the differential diagnosis of NH in neonatal liver failure, other than gestational alloimmune, are presented in Some writers emphasize the importance of the histologic findings and the function of autopsy, arguing that biological and molecular tests may be required to rule out alternative diagnoses, such as mitochondrial illnesses . One parEven in suspected cases determined in utero, the detection of liver siderosis is insufficient for diagnosis due to the physiological presence of stainable iron in the neonatal liver, necessitating extrahepatic siderosis for confirmation or the detection of other specific markers that point to gestational alloimmune liver disease .There have been reported cases of children with phosphatidylinositol N-acetylglucosaminyltransferase subunit A (PIGA) germ-line mutations presenting NH features, but their clinical course differs significantly. Therefore, PIGA gene testing is another option to be considered when evaluating newborns who present with NH .FGR is one of the first manifestations visible in ultrasound evaluations that can be suggestive of NH, starting as early as the 18th week . Since FFrequently encountered oligohydramnios is explained by renal tubular dysgenesis due to hepatocyte injury and secondary reduced angiotensinogen production as early as 20 to 25 weeks of gestation ,38.However, the FGR–oligohydramnios sequence related to NH often functions in diagnosis of exclusion during the first affected pregnancy but is also the most likely to be omitted since this clinical picture can be explained on the basis of more common causes. The process exclusion may be sufficiently long to result in an accurate verdict. Therefore, birth or fetal demise can occur, leaving the final diagnosis for neonatal or autopsy evaluation. Most of the time, these children are not born in tertiary centers. Until the transfer is successful and the treatment with immunoglobulin is initiated, the child’s prognosis may be compromised.MRI is the only investigation technique that can guide the prenatal diagnosis algorithm to NH in a first affected pregnancy presenting FGR and oligohydramnios, since liver biopsy is not a viable option. Although expensive at first and not yet a part of the diagnosis algorithm of FGR, prenatal MRI can be used to elucidate a diagnosis of NH and detect placental dysfunction where Doppler flows are still normal , justifyNon-immune hydrops fetalis (NIHF) occurs in the end-stage state of 14 various diseases, according to a meta-analysis conducted by Bellini and colleagues in 2015 , with noAs the fetus grows, unexplained hepatomegaly, sometimes accompanied by ascites, could be encountered during prenatal US surveillance.In 1996, Achiron et al. examined a group of fetuses with various grades of hepatic hyperechogenicity. The authors identified several causes responsible for this particular imaging aspect, ranging from abnormal karyotype through to fetal infection to in utero vascular accidents . They coAn aspect worth mentioning in terms of the difficulties of prenatal diagnosis of NH was described regarding a 33-week fetus presenting on US evaluation with hydrops, oligohydramnios, and placentomegaly. The re-evaluation of fetal ultrasound images resulted in identification of anemia and shrunken liver with multiple regenerative nodules, confirmed by MRI and autopsy . SometimThis particular aspect of the liver, similar to that in adult cirrhosis, is challenging to evaluate in fetuses. Therefore, additional investigations such as fetal MRI are needed to confirm any suspicions.Unexplained fetal anemia, refractory to fetal in utero transfusion, is another US finding that can be prenatally detected without difficulty after introducing middle cerebral artery systolic peak measurement in routine practice. This could raise suspicion of NH .Encountering NH during the first pregnancy in consanguine couples is an aspect for which clinical significance is yet to be revealed . AnotherAlthough there is evidence of its effectiveness , MRI is Fetal MRI in GALD could help assess clinical responses to in utero treatment . The metHowever, depicting the liver overcharged with iron is insufficient for diagnosis, even if other immune manifestations, such as hydrops fetalis, are present. Extrahepatic siderosis is considered a fundamental criterion for diagnosis, but a GALD hypothesis should be raised, even in its absence, when considering confirmed affliction in previous pregnancies. Recent studies emphasize this, recommending that prenatal treatment should not be postponed when there is no finding of extrahepatic non-reticuloendothelial siderosis but there are other specific markers pointing to gestational alloimmune liver disease .Even if fetal organ iron deposition can be demonstrated by MRI, it may not always be present at the moment of examination, as hypothesized as far back as 1990 by Hoogstraten . Cases hThere have been reports of several MRI sequences that can show organ iron overload in the fetus. In the first case of intrauterine hemochromatosis diagnosed with MRI in 1993, Marti-Bonmati et al. used a T2* sequence. Extremely low hepatic parenchymal signal intensity (SI) was shown compared with that of fetal and maternal fat tissue .Presently, fast, single-shot T2-weighted sequences are the primary tool in fetal MRI and the first to raise suspicion of liver iron deposition. The affected fetal liver shows an SI drop that is even more conspicuous when compared with the fetal spleen or maternal liver SI.The same pattern of signal intensity alteration seen in neonates with NH has been described in fetuses with liver siderosis in a few case presentations—lower median SI of the liver on in-phase sequences compared with the opposed-phase SI.The in-phase/opposed-phase SI ratio (SIR) in fetal NH has been reported as approximately 0.5 in an untreated fetus and 0.78 in a fetus with prior IVIG treatment. In one case of prior clinically and histologically proven GALD, Sasaki et al. also calculated the SIR of the fetal liver, spleen, and pancreas to the fetal iliopsoas muscle. They obtained values of 0.7, 1.36, and 1.74, respectively, suggesting that iron deposition in this treated case was limited to the liver ,69.Organ iron load quantification could be achieved with MRI T2* relaxometry techniques, as described in 2013 by Schoennagel et al. in a fetal sheep model and a human neonate with hemochromatosis . Sethi eA French retrospective multicentric study of the importance of autopsy and auto-immune maternal manifestations in neonatal hemochromatosis observed that, in fetuses, iron storage was more frequent in the thyroid than in the pancreas . As far Extrahepatic siderosis can be detected non-invasively by a multi-echo gradient recalled echo T2*-weighted MRI sequence within hours of birth and graded as mild, moderate, or severe based on the echo in which organs start showing darkening/a signal drop ,66.Another essential step in confirming NH where MRI may play an important role is postmortem evaluation. In selected cases where parents’ religious or moral views prevent a classical autopsy evaluation, a virtual evaluation by postmortem MRI might be a valuable alternative with a high grade of acceptability from the genitors. Postmortem MRI can easily depict liver siderosis  or extraIn 2004, Whittington proposed the antenatal administration of a high dose of intravenous immunoglobulin (IVIG), starting in the second trimester, for women with a previous pregnancy with NH . Today, The mechanism by which IVIG administration improves fetal evolution remains unclear, but some theories have been proposed. One considers the dilution of maternal antibodies directed against the fetal liver antigens as a possible mechanism . AnotherAn in utero diagnosis of NH would be a remarkable achievement, as early diagnosis would prove useful for fetal treatment therapy. Based on the wide range of risks posed by a fetal liver biopsy and its relatively poor specificity, a more effective method is required .We consider that a prenatal MRI should be considered earlier in cases presenting FGR with normal Doppler parameters or unexplained non-immune hydrops fetalis, refractory anemia to fetal in utero transfusion, or liver abnormalities in the diagnosis algorithm. Furthermore, for parents that refuse to allow a classical autopsy of the fetus/neonate, postmortem MRI is a non-invasive solution that can easily identify liver siderosis and guide biopsy. To illustrate this idea, a figure of a fetus with confirmed NH investigated using both in vivo and postmortem MRI is rendered in NH-GALD is a rare, severe disorder that results in fetal loss or neonatal death due to liver failure; therefore, the present study is limited by the small number of included studies and the retrospective nature of the reported cases.Despite the strong impact of this condition on present and future pregnancies, the prenatal findings that might suggest fetal NH are often nonspecific. MRI should be indicated in selected cases of unexplained FGR, oligohydramnios, fetal hydrops, fetal hepatomegaly, and ascites or anemia, usually after all the other more frequently encountered conditions have been ruled out. MRI can detect iron overload in the liver and extrahepatic siderosis, confirming NH. For the parents that refuse a fetal autopsy, postmortem MRI should be available for all cases of unexplained fetal and newborn deaths with liver failure, as it can easily detect liver siderosis and guide future investigations. Once the diagnosis is made, the administration of specific IVIG should be initiated immediately after diagnosis, allowing for a much better prognosis. C5b-9 staining of the tissues can confirm the diagnosis from the liver biopsy or autopsy specimen.In subsequent pregnancies, women with a previously NH-affected fetus should be carefully evaluated, and high-dose IVIG treatment should be started at the end of the first trimester, as evidence shows significant improvement in the disease evolution compared with untreated pregnancies. In neonates, exchange transfusion and a high dose of IVIG is the preferred treatment to remove the maternal NH-associated antibody and block its action, including complement activation.


Mental disorders present considerable burdens to both individuals and society. Arriving at clinically meaningful treatments, however, is challenged by both high comorbidity among the various disorders, and the highly heterogeneous symptoms even within a specific disorder category. This reflects a reality that mental disorders are driven by multiple facets, including biological, psychological, and socio-environmental elements. Thus, a multi-dimensional approach involving biological, psychological, and socio-environmental factors affords a more comprehensive perspective to understand the mechanisms underpinning mental disorders  Porter,. ArticleMassarwe and Cohen summarized previous work and argued that EER can enhance cognitive and affective processing that is impaired in depression and thus may be particularly beneficial for depressed patients. Their review of behavioral research shows that EER invokes processing related to emotion regulation, cognitive empathy, and reward, all of which are reduced in depression. Their review of neuroimaging findings suggests that these beneficial effects of the EER may be through the recruitment of brain regions associated with emotion regulation and stress reduction , regions involved in empathy  and reward-related regions . The conceptual review by the two authors elucidates the mechanisms underlying the effectiveness of EER in patients with depression and thus offers new therapeutic avenues.Depression is a mental disorder that can have a serious negative impact on how people feel, think, and behave. Extrinsic Emotion Regulation (EER) or providing support to others to regulate emotions, can reduce depressive symptoms such as stubborn thoughts and negative emotions. Marcu et al. examined the resting-state electroencephalogram (EEG)-derived frontal alpha asymmetry, which is one of the most popular electrophysiological markers used to identify depression. The authors investigated the association between resting-state EEG alpha asymmetries from multiple sites  and multiple clinical indicators of depression in clinical populations. They report that alpha asymmetry is stronger in the parietal lobe than in the frontal and extralateral loci. They also found a moderately positive association between extra-lateral alpha asymmetry (eye closure only) and depression severity. However, they did not find significant differences in alpha asymmetry between different depression types. Therefore, the authors recommend further research on the relationship between depression and parietal and extralateral asymmetry indices in the future.Psychological distress is often seen as having a strong association in the development of mental disorders  and Autonomic Nervous System and symptoms of mental disorder between Chronic Prostatitis/Chronic Pelvic Pain Syndrome (CP/CPPS), CP/CPPS plus erectile dysfunction, erectile dysfunction alone, and healthy individuals. The rationale is that CP/CPPS is often associated with mental disorders. However, the reason of it could be due to an often associated condition, erectile dysfunction, which could be a bigger stressor. In this case, how each physical disorder would associate with what amount of stress could be delineated.In Linkas et al. have partially answered the above questions. In their study, they conducted a longitudinal study examining how inflammation, measured by C-reactive protein (CRP) and transforming growth factor-alpha (TGF-α), would affect development of psychological distress in adolescents. In addition, they examined bio-psycho-social factors such as gender, sleep duration, physical exercise and obesity as moderating factors that could buffer or exacerbate the impact of inflammation on adolescents. They found that all these factors play important roles in inflammation responses which result in different levels of psychological distress 2 years later.Additionally, some other associated questions regarding stress and mental disorder using the bio-psycho-social model include: Do the same stressor predicts mental disorders in different individuals in the same manner? What are some potential social factors  and physical factors (obesity and gender) that could buffer or exacerbate the impact of stressors? Are there bio-psycho-social factors that could affect individuals' experience of mental disorder which further influence their stress levels? Research findings from In both collected papers, authors have used psychological (self-report) method together with biological method  for their investigations. These methods yield divergent or convergent results and could afford important information to better understand the diversities of developing outcomes in mental disorders .In a similar vein, Uchmanowicz et al. and Varela-Moreno et al. cannot be understated. It should be clear that the path forward in tackling mental health care must involve creative integration of modern technologies. The exact suite of tools that produce the best compromise in efficacy, accessibility, and economics awaits deserves empirical attention.While not perfect, the benefits of digital health technology to improving patients' quality of life, both as outlined by In summary, our collection of papers contribute to a better understanding of the potential mechanisms underpinning mental disorders and highlight the promising role of digital health technology in supporting mental health patients in the future.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.


Educators identify case tracking (following-up prior patient encounters) as a valued practice to cultivate physician expertise. Much of the existing research has focused on the practices of general medicine providers, where challenges include insufficient time and difficulty tracking patients in the electronic health record (EHR). Subspecialty fellows constitute a group of advanced learners who see a high volume of patients and need to quickly become subject matter experts, yet little is known about their particular needs and motivations around case tracking. In this study, we performed a needs assessment with fellows to inform the design of an EHR-based case tracking dashboard that can facilitate learning from prior patient encounters.We conducted semi-structured interviews with 22 medicine subspecialty fellows (including 4 Infectious Diseases [ID] fellows) at a single academic medical center that explored participants’ motivations, preferences, and practices around case tracking. Interview transcripts were coded and analyzed with directed qualitative content analysis. Results of this analysis will be used to inform the design of a subspecialist EHR-based case tracking dashboard.Participants were motivated to engage in case tracking, with curiosity regarding patient outcomes as a strong motivator. Although some attempted to track all consults, most focused on subsets of patients, feeling that not all encounters were of equal educational value. Participants highlighted particular results, specialty-specific notes, and major outcomes as the most useful information. ID fellows specifically were interested in post-discharge ID clinic encounters, send-out tests, and outcomes of their management decisions. Despite widespread motivation to engage in case tracking, manually adding patients to lists and remembering to follow up poses logistical and time barriers.An ideal EHR case-tracking dashboard would automatically keep a list of patients cared for by fellows and provide easy access to own-specialty notes, specific results of interest, and information on the global clinical course. The ability to highlight specific cases anticipated to have more educational value would also be of benefit.All Authors: No reported disclosures


Epsilon-sarcoglycan (SGCE) myoclonus-dystonia is autosomal dominant (AD) with reduced penetrance due to maternal imprinting 95% of the time. Patients may lack family history delaying diagnosis and treatment. Additionally, counseling patients on their risk of passing on the variant differs for females versus males.A woman in her thirties with typical phenotype of myoclonus-dystonia but lacking an AD pedigree was found to have a pathogenic variant in the SGCE gene. She was counseled that her daughters each have a 2.5% chance of expressing the phenotype.Understanding the genetics of SGCE-myoclonus-dystonia enables effective genetic counseling and arrival at a timely diagnosis and treatment.In an era of advancing genetic analysis and precision medicine-based treatments, neurologists will be faced with increasing responsibility to properly counsel patients on the results of genetic testing. This case highlights a genetics pearl for counseling patients with epsilon-sarcoglycan myoclonus-dystonia, an autosomal dominant condition with penetrance differing by sex. Advances in genetic testing and analysis have provided clinicians and patients with diagnostic clarity, eligibility for clinical trials and, in some cases, a precision medicine-based treatment approach . HoweverMyoclonus-dystonia is a syndrome characterized by isolated myoclonus or myoclonus with dystonia that predominantly affects the upper body. The dystonic phenomenology generally presents as cervical dystonia or writer’s cramp, but lower limb dystonia can occur early in the disease course and then subsequently abate or even remit later in life . The myo3The diagnostic criteria also include a positive family history since myoclonus-dystonia is classically an autosomal dominant disorder with up to 50% of patients demonstrating pathogenic variants in the autosomal dominantly inherited SGCE gene. However, the SGCE maternal allele undergoes imprinting (methylation and silencing) 95% of the time resulting in reduced penetrance . Non-impThe patient is a woman in her thirties who developed jerky arm movements at 3 years of age which progressed over time, worsened with action, and improved with alcohol. Additionally, she developed a jerky tremor of the neck as well as difficulty writing. At 8 years of age, she experienced generalized tonic-clonic seizures that resolved after initiation of levetiracetam. Subsequent brain MRI and electroencephalograms (EEGs) were unremarkable. However, she later developed paroxysmal non-epileptic spells (PNES) confirmed in an epilepsy monitoring unit admission. Her family history was remarkable for similar jerky upper body movements in her brother and a female cousin, but in no family members in prior generations . Her neuDespite lack of autosomal dominant inheritance pattern in her pedigree, clinical suspicion was high for myoclonus-dystonia, so she underwent single gene testing which was positive for a pathogenic variant ) in the epsilon-sarcoglycan (SGCE) gene. Levetiracetam prescribed for epilepsy was ineffective for her myoclonus, so she was started on zonisamide and underwent botulinum toxin injections for cervical dystonia. Over the last 3 years at subsequent follow-up visits, she has reported mild symptomatic improvement with treatment interventions.Following diagnosis, she inquired about the risk of her asymptomatic preschool-aged and teenage daughters. She was counseled that patients under the age of 18 generally should not undergo predictive genetic testing when it will not change medical management, but that typically myoclonus-dystonia presents in childhood with most patients developing symptoms before the age of 20 . There wThis case illustrates a classic clinical presentation of SGCE myoclonus-dystonia, the genetics of SGCE myoclonus-dystonia; autosomal dominant with reduced penetrance when maternally inherited and a genetics pearl on how to counsel patients on the risk of transmission which differs for females versus males as illustrated in In this case, despite a potentially misleading pedigree, knowledge of the classic myoclonus-dystonia phenotype and the phenomenon of reduced penetrance with maternal transmission enabled a targeted approach to diagnosis with single gene testing, avoiding excessive cost to the patient, incidental positive results, as well as variants of uncertain significance that can complicate diagnosis and genetic counseling and delay effective treatment .Arriving at a timely genetic diagnosis for myoclonus-dystonia syndrome can be important for precision medicine-based treatment, namely deep brain stimulation (DBS) surgery if oral medications and botulinum toxin are ineffective. Both myoclonus and dystonia can respond to DBS in SGCE myoclonus-dystonia with acceptable targets including globus pallidus interna (GPi) and/or ventral intermediate nucleus (VIM) of the thalamus 101112. W1011Awareness of effective treatment options is important for SGCE myoclonus-dystonia, because when treatment is delayed, patients may self-medicate with alcohol leading to dependence or develop worsening psychiatric symptoms and quality of life. Additionally, questions of treatment naturally arise following genetic counseling and diagnosis discussions with the patient.Returning to the patient case, she went through life undiagnosed for 30 years and eventually developed non-motor symptoms of anxiety and paroxysmal non-epileptic spells. These spells have resolved since receiving a genetic diagnosis as well as counseling for what to expect for her children and grandchildren. Her quality of life with current treatments is stable but will continue to be monitored, and DBS could be considered in the future if necessary.


Global progress against malaria has stagnated and novel medical interventions to prevent malaria are needed to fill gaps in existing tools and improve protection against infection and disease. Candidate selection for next-generation interventions should be supported by the best available evidence. Target product profiles and preferred product characteristics play a key role in setting selection criteria requirements and early endorsement by health authorities. While clinical evidence and expert opinion often inform product development decisions, integrating modelling evidence early and iteratively into this process provides an opportunity to link product characteristics with expected public health outcomes. Population models of malaria transmission can provide a better understanding of which, and at what magnitude, key intervention characteristics drive public health impact, and provide quantitative evidence to support selection of use-cases, transmission settings, and deployment strategies. We describe how modelling evidence can guide and accelerate development of new malaria vaccines, monoclonal antibodies, and chemoprevention. Nekkab, Malinga, Braunack-Mayer et al. discuss how modelling can be incorporated early on in the research and development of malaria tools alongside clinical evidence and expert opinion. In addition, population models can provide estimates of potential effectiveness of novel interventions to inform product criteria and support decision-making. Estimated malaria deaths in this region rose from 568,000 in 2019 to 625,000 in 2020 and declined marginally to 619,000 deaths in 2021. Moreover, the emergence of partial resistance to treatment with artemisinin in some parts of Africa threatens the efficacy of artemisinin-based combination therapies. Increasing insecticide resistance and invasion of the primary mosquito vector in India, Anopheles stephensi, into Africa may also lead to increasing transmission in urban areas, which could reverse progress made over recent decades3.There is an urgent need to accelerate development of novel malaria interventions to prevent infections and severe disease. Progress to reduce the impact of malaria has stalled worldwide alongside disruptions to services during the COVID-19 pandemic. Malaria cases in the African Region increased from 225 per 1000 population at-risk in 2019 to 234 in 2020 and remained similar at 229 cases per 1000 population in 20214. Furthermore, current malaria prevention measures do not reach all children. For example, seasonal malaria chemoprevention (SMC) is only recommended and deployed in highly seasonal settings with low drug resistance risk. Implementation of intermittent preventive treatment of malaria in pregnancy using sulfadoxine-pyrimethamine (IPTp-SP) is not recommended in low transmission or high SP resistance settings and there is limited guidance on the adverse consequences of drug–drug interactions5. Resource constraints, limited access to care, and low chemoprevention adherence in children and pregnant women, who are vulnerable to severe outcomes, continue to be major challenges. The development of novel interventions for malaria prevention must be accelerated to meet current and future needs. Incorporating all forms of evidence to guide decision-making early on during the product development pipeline will be vital in accelerating the process.While the 2021 World Health Organization’s (WHO) recommendation of the first malaria vaccine, RTS,S, was a major milestone, the vaccine took 30 years to develop, test, and pilot, and its availability, acceptance and use has not yet been demonstrated6. The Bill & Melinda Gates Foundation is developing intervention Target Product Profiles (iTPPs) to optimise investment in three next-generation medical interventions for prevention: novel immunological seasonal therapeutics using mAbs and long-acting injectable drugs, multi-seasonal interventions using second-generation malaria vaccines, and novel candidates or repurposed drugs for second-generation oral chemoprevention. In the case of malaria iTPPs for example, the documents define characteristics for development of novel intervention by how they are likely to be used and their indication, product components, target population and setting, safety, formulation, and pre-qualification date targets among other criteria for a base and upside case.Global funders, regulatory agencies, and researchers are expanding their pipelines for next-generation medical interventions for malaria prevention, guided by reference documents for candidate selection and investment decision-making in research and development (R&D). While guidance documents vary, they essentially outline the necessary characteristics required to support development decisions and optimisation of innovative products. The WHO developed Preferred Product Characteristics (PPCs), informed by technical working groups and public consultation, to guide and promote the development of various malaria prevention interventions such as vaccines, chemoprevention, and, recently, for monoclonal antibodies (mAbs) as well as vector control interventions. Medicines for Malaria Venture (MMV) also uses Target Candidate Profiles (TCPs) to support product development partnerships, pipeline development for long-acting injectable drugs, and repurposing, recombining, and developing antimalarials for SMCPrioritisation should be given to establishing a comprehensive evidence base to iteratively inform guidance documents and support selection of the most promising candidates, thus accelerating the development of novel medical interventions to prevent malaria. We argue that this evidence base should encompass the full range of quantitative and qualitative findings from clinical trials, modelling, and expert opinion. In the case of malaria prevention, selecting candidates that maximise the potential to achieve high public health impact and accelerate implementation requires decisions based on well-informed product criteria accounting for potential R&D bottlenecks, resources, and timeframes. Importantly, modelling evidence should be incorporated early in the drug development process, as modelling can uniquely link product criteria or properties to likely public health impact, which is not possible before or during clinical trials and is only possible after implementation. In addition to modelling existing interventions, modelling can estimate the potential range of impact on disease burden of a novel intervention to support building a value proposition document used to attract commercial development partners and engage with diverse stakeholders and partners that include those in malaria country programs and health agencies. Such modelling analyses also allow translation of clinical trial evidence to population impact across transmission settings, deployment strategies, or use-cases. Here, we focus our discussion on malaria prevention tools; however, this framework can also be expanded to malaria treatment, vector control, and to other diseases.7. While increased global investment has helped accelerate development in recent years, candidate selection guidance documents and priority use-cases are mainly informed by expert opinion and results of early stage clinical trials. Guidance documents have an important role to play in shortening R&D timelines and reducing costs, targeting priority use-cases and unmet needs, while ensuring selected candidates have a higher probability of demonstrating high impact for their given use-case. We posit that well informed decision-making along the product development pipeline, from discovery, proof-of-concept, and program implementation to impact, requires the iterative use of a comprehensive evidence-base that includes modelling evidence and allows for decisions to be adapted as new evidence becomes available  as well as the population-level benefit of deploying such a product to communities by quantifying the additional public health gains. Pharmaceutical approaches have traditionally prioritised efficacy outcomes at the individual level. For example, pharmacokinetics and pharmacodynamics (PK/PD) modelling support optimisation of drug availability and duration to improve drug efficacy for a particular disease target within the treated individual. In contrast, prevention targets for infectious diseases require considering both the individual-level benefit and an understanding of a product’s public health benefit, including changes to immunity acquisition by delaying infections or via any impact on population-level transmission dynamics. This is essential when we consider medical interventions that impact susceptibility to infection or aim to prevent disease progression to clinically relevant presentations or severe disease.8. While clinical evidence is essential to inform efficacy estimates and eventual registration and funding decisions for products, clinical evidence also informs model parameters, and modelling evidence in turn can improve clinical trial planning and design. For modelling evidence to be integrated within this process, it is essential for experts to be consulted early in the process to design research questions that modelling can address; an iterative loop between clinical trials, modelling, and expert opinion will reshape and transform criteria in guidance documents to support candidate selection.While clinical trials evaluate the individual-level benefit of products, they do not estimate the total public health benefit over extended time frames or capture any potential benefits of interrupting onward transmission with population-level interventions. Modelling captures these dynamics to link individual and community benefits, allowing clinical trial evidence to be integrated into updated models or public health estimates, and can also support translating clinical trial results into implementation considerations. In early product development stages, population-level modelling can provide quantitative evidence linking an intervention’s minimum key performance criteria, such as efficacy or duration with its projected public health impact and benefit to communities towards meeting health targets, thus contributing to a robust evidence baseDeveloping an accelerated and iterative process for the development of novel malaria prevention interventions should account for the following components.9. Addressing health inequity, in particular low access to health services and first line treatment for symptomatic children and low bed net distribution coverage is essential to bridging the gaps of malaria programs and elimination strategies. As social, financial, and epidemiological factors drive change over time, including inequity, unmet needs should be revisited in an iterative manner to anticipate future scenarios. Defining these unmet needs will allow for prioritisation and evaluation of supply requirements for various timeframes and public health goals, such as for elimination.The first step requires identifying who and where a malaria prevention intervention can meet the health needs of exposed populations. One approach is to consider the WHO-defined high burden high impact (HBHI) settings, ranking communities with mapped under-five mortality as a proxy for need. However, unmet needs can also be defined in communities without current prevention interventions, such as East Africa where SMC is not recommended or settings with perennial malaria transmission, or infants and pregnant women who are more vulnerable to severe outcomes and require higher consideration of drug safetyOnce unmet needs have been articulated, the use-case definition is an important driver to prioritise development of a new intervention and should be defined rigorously at each TCP, iTPP, or PPC update to ensure candidates are addressing unmet health needs. A use-case defines the target population(s) who will receive a new malaria prevention intervention , and where and when it should be deployed, ultimately influencing other criteria, including: product properties , logistic requirements , intervention characteristics , and deployment strategy . Considering these factors, modelling can evaluate how use-cases influence an intervention’s minimum criteria and vice versa.In the early stages, shaping novel malaria intervention characteristics in guidance documents should also be guided by community engagement through discussions between global funders, health agencies, researchers, evidence generators , product developers, local community leaders, and implementation specialists. These discussions should inform the identification of knowledge gaps, potential bottlenecks, and potential additional use-cases to refine the public health value proposition. Developing priority questions that inform modelling scenarios, such as comparing impact in seasonal and perennial settings or optimised number of rounds and timing of deployment, help guide evidence generation by informing clinical trial design and site selection targeting specific epidemiological settings, and the selection of model scenarios for predicting public health impact.Pre-clinical and early clinical evidence of first candidates provides initial profiling of feasibility, safety, and PK/PD relationships. This then informs where, and for which use-cases, a candidate can meet health needs, the expectations of regulatory approval, and implementation factors such as supply, delivery, and deployment strategies. In addition, early clinical evidence for these candidates sets threshold criteria for selection of future candidates that are expected to achieve non-inferiority, and informs model parameterisation to narrow down the exploration space between individual-level effects and population-level impact.Mathematical models of malaria transmission can guide thinking along the entire product development pipeline from clinical trial translation to use-case decisions for implementation. Modelling can initially explore the major drivers of an intervention’s impact across a broad spectrum of scenarios to identify what clinical evidence needs to be generated early. In addition, models can support the clinical evidence generation process by identifying minimum thresholds, linking intervention characteristics to health goals to inform guidance documents to the level of detail required for appropriate candidate selection by product developers. Modelling can provide evidence on where potential candidates would be best implemented to maximise impact and help drive policy and procurement decisions.Modelling can be integrated at each step in the development process to support articulating unmet needs, testing use-cases, translating clinical evidence, and setting achievable health goals to update guidance documents and adapt to new clinical evidence. As a result, evidence-based guidance and decision-making becomes an iterative process where modelling continuously supports the refinement of candidate profiles, rather than a linear process of development.The Swiss Tropical and Public Health Institute Disease Modelling group and the Bill & Melinda Gates Foundation have developed a collaborative framework that integrates the process described above to iteratively inform next-generation iTPPs for seasonal, multi-seasonal, and second-generation SMC interventions for malaria prevention. In June 2021, workshops were organised to identify challenges and priority questions and to launch the platform with a broad range of experts and stakeholders, including those based in malaria endemic regions and ensuring gender equity. These discussions focused on the importance of guidance documents during R&D, patient-centred development, community advocacy for target population acceptability, and, when to stop or to continue funding new interventions. Working groups identified the following priorities for modelling: (1) describing trade-offs between intervention and implementation factors; (2) translating clinical trial and modelling evidence to inform policy and investments; (3) informing clinical trial design and identification of standard of care (SOC) comparators; (4) accounting for financial resources and cost-of-goods; and (5) defining burden reduction criteria and timelines for achieving elimination.8. Modelling the mechanisms of individual-level factors and population-level transmission dynamics links predictions of public health burden reduction to key intervention characteristics. By predicting across an entire parameter space of intervention characteristics , modelling can quantify the importance and level of contribution of each characteristic to health outcomes and identify the minimum value at which intervention characteristics achieve defined health targets to directly inform iTPP criteria for different use-cases. Together with stakeholders from the 2021 convening, priority questions for modelling were ranked by most relevant scenarios to model at a first iteration for each given intervention by accounting for unmet health needs and priority use-cases. Clinical evidence, where and when available, informed parameter ranges to explore trade-offs and minimum criteria comprehensively. We give examples of this process in Table The collaborative framework generates modelling evidence using dynamic, individual-based malaria transmission models, such as the OpenMalaria model that was developed over a period of 15 years. Detailed models are coupled with additional analytical and statistical approaches to enable rapid and computationally efficient searches of multi-dimensional parameter spaces spanning a wide range of intervention characteristics and settingsModels provide supportive information for decision-making or informing candidate selection, funding, and target product profiles alongside other diverse sources, including clinical evidence and expert opinion. Although not the sole source informing selection criteria, models have a unique role to play before and during clinical trials and as clinical evidence is being acquired. While the additional role of modelling is clear, all models have limitations. To be informative for selection criteria, models must capture essential disease dynamics while remaining simple enough to run. Population model prediction uncertainty comes from model structure and parameter values. For example, assumptions about human behaviour patterns or intervention effect will impact predictions. Some use cases, such as pregnant women or travellers, are more challenging to model due to limited data. Discussions around a model’s limitations in generating evidence to inform TPPs is inherently part of the process itself, which requires stakeholders to formulate specific questions that are fit for purpose. The conversations around models, their limitations, and sources of uncertainty, and how to translate predictions to tangible evidence become the most valuable output.10. Unlike vaccines, where immune correlates of protection are challenging to define, mAbs offer the potential to provide early PK/PD evidence. While the first-generation candidate CIS43LS has demonstrated high and prolonged protection, sufficient PD evidence from dose de-escalation data are not yet available11. Modelling can address this knowledge gap by generating a comprehensive spectrum of PD characteristics from forthcoming early clinical trials to provide a broad range of potential impact predictions that can be refined iteratively as more data is generated.Population-level transmission modelling can translate clinical efficacy outcomes to population-level effectiveness by integrating pharmacological evidence informing individual-level protection. Take, for example, monoclonal antibodies for infection prevention in seasonal settings. Currently very little is known about the PK/PD relationship of monoclonal antibodies. Previous modelling has shown that the protection of an anti-infective malaria monoclonal over time, informed by PK/PD data and models, is an important driver of public health impact13.For malaria prevention, imperfect tools, such as perennial malaria chemoprevention (PMC), SMC, and RTS,S vaccination, have been deployed in moderate to high transmission settings. The public health and cost-effectiveness targets for novel interventions can be informed by the standard-of-care (SOC) comparators when the use-case is well defined and alternative interventions already exist. In the absence of a comparator, ranges of desired health targets can be iteratively assessed, but comparison of effectiveness to existing prevention technologies is critical to refine the value proposition for further R&D investment. Without population-based modelling before Phase 3 clinical trials, it is challenging to evaluate the effectiveness of candidates with early clinical data alone. Modelling can quantify effectiveness for different intervention characteristics, use-cases, and evaluation periods, as well as easily translate different endpoints to guide policy decisions. For example, the public health impact and cost-effectiveness of the RTS,S malaria vaccine was evaluated by four independent modelling groups using different mathematical models of malaria transmission. This body of work estimated disability-adjusted life years (DALYs) for both a three-dose and four-dose vaccine schedule more than four years prior to the start of the pilot studies. These cost-effectiveness estimates demonstrated that a partially efficacious vaccine could have significant impact at the population level, critical for the WHO’s recent recommendation of RTS,S14. Currently, the efficacy profiles of first-generation anti-infective vaccines like RTS,S and, potentially, R21 support their use in seasonal settings. Yet, many questions remain regarding implementation factors, combinations of the vaccine with oral chemoprevention programs, and impact across different epidemiological settings. Modelling can support this by predicting the likely impact of such factors prior to expensive clinical trials and pilot studies and explore the feasibility of these tools to achieve future elimination targets.Guidance documents for mAbs, next-generation chemoprevention, and vaccines in development currently prioritise preventing clinical illness and severe disease in vulnerable populations, including infants, children under five, and pregnant women. When use-cases are uncertain, modelling can simulate scenarios for different age groups, seasonal profiles, and transmission intensities to demonstrate where interventions will be most impactful and reassess when new evidence is onboarded. For example, WHO recommends malaria vaccines for children aged five to 17 months old in perennial settings with potential for seasonal application in children under five years old. However, these target ages and seasonal use-case only came to light as clinical evidence was accrued because the vaccine prevented infections for a shorter duration than hoped during the Phase 3 studiesThe malaria vaccine example described here provides a lesson to heed for novel malaria intervention development. Firstly, use-cases of novel interventions should be re-evaluated with an improved understanding of the limits of an intervention’s efficacy and duration. Thus, understanding the efficacy and duration of novel malaria interventions as early as possible will help not only to select or reject candidates and optimise duration properties, but also assess and reassess appropriate use-cases iteratively. Modelling supports this by demonstrating the trade-offs between deployment factors and intervention characteristics to identify minimum criteria well before Phase 3 trials. In some cases it will provide efficacy and duration cut-offs (clear ‘no-go’ criteria) for candidate use in different uses-cases. However, if early clinical evidence suggests candidates will struggle to ever meet these initial efficacy and duration requirements defined by iTPPs use-cases, the community should not always discard classes of candidates or novel interventions, but critically and discriminately revaluate if there is value of this efficacy and duration profile for another use-case for malaria prevention.With increasing threats of malaria drug and insecticide resistance, there is now a need for novel malaria prevention interventions to improve public health impact. As the malaria community moves forward to invest in next-generation interventions, guidance documents are crucial to ensure that the best evidence supports the criteria for candidate section and decision-making for implementation. While clinical evidence and expert opinion will initially play an essential role in informing these criteria, mathematical modelling can accelerate this process and provide robust evidence of candidate characteristics and deployment strategies that are likely to lead to a higher public health impact for different use-cases and enhance the value proposition for a given development candidate. Modelling should be incorporated early in the evidence generation process, to improve the translation of clinical trial efficacy estimates and to support use-case and implementation strategy decisions. Public health impact predictions from modelling studies that include detailed intervention dynamics are currently underutilised for setting selection criteria early in development. Thus, including such analytic tools early on provides a unique opportunity to accelerate the development of malaria interventions for optimised use-cases and deployment strategies.


These eight articles range from specialty grand challenge (1), hypothesis and theory (1) to reviews (3) and original research (3). 64 authors worldwide contributed to this Research Topic, which has been downloaded 4,900 times and viewed by 20,000 scientists globally. These articles have already been cited 24 times in the literature, and the impact of these articles is expected to increase over time.In this editorial, in collaboration with the Research Topic editors of the molecular and cellular pathology section in Frontiers in Cell and Developmental Biology journal, we have showcased 8 articles , pediatric soft tissue sarcoma (rhabdomyosarcoma), congenital lung disorders, and cartilage formation. The remaining articles discuss molecular targets and mechanisms underlying neural (eye), skeletal, and vascular cells.Ramchandran), a detailed summary of the past, present, and future direction of endothelial cell biology was provided. The field of EC biology has moved from descriptive phenomenology science to one that offers deep mechanistic insight into molecular pathways and cross talk signaling between cell types in an organ. Various types of ECs within an organ are being discovered, and how these cells communicate within their environment are being delineated. Further, cellular organelles with newer function in ECs are being discovered and hypothesized. For example, cilia, a hair-like microtubule organelle found on the apical surface of ECs was hypothesized to play a role in the pathogenesis of HHT, which is characterized by defective capillary network that leads to direct connections between arteries and veins . This defective vascular remodeling causes dilated superficial vessels referred to as artery-vein malformations (AVMs). The authors posit that loss of endothelial cilia will curtail transforming growth factor-β (TGF-β) signaling, a key signaling pathway associated with HHT pathogenesis  and their role in retinitis pigmentosa (RP), an inherited retinal disease characterized by progressive degeneration of photoreceptors and or retinal pigment epithelium leading to blindness. The review describes the mutations in PRPF genes implicated in RPs, the various animal models of disease for PRPF-RPs, and the role for these factors beyond splicing and therapeutic strategies for PRPF-RPs.All organs in the human body are perfused by vessels, and thus our vasculature and the cells associated with it are of prime importance to organogenesis, function, and maintenance. Endothelial cells (ECs) that line the vasculature encounter blood flow. Systemic ECs respond to flow by aligning with the direction of flow . In a spogenesis . This loEenjes et al. They elegantly describe lung specification, bud formation, patterning, and outgrowth mechanisms and molecules involved in each of these process in exquisite detail. They also describe the individual cellular components in the lung and their plasticity function that can assist in regeneration mechanisms during stress or damage conditions. In the final pediatric focused article in this collection, the Research Topic highlighted is cancer-based. Rhabdomyosarcoma, a soft tissue sarcoma is classified by the presence or absence of a fusion protein (PAX3-FOXO1) into two molecular subtypes, namely, fusion positive (FP) or fusion negative (FN) tumors. FN tumors are resistant to chemotherapy and newer strategies are needed to target these cells. Perrone et al., in their original research article propose Spermine Oxidase, an enzyme that regulates polyamine catabolism, and oxidizes spermine to spermidine. These metabolites are important for apoptosis and DNA damage response in cells. Spermine oxidase enzyme is downregulated in FN tumor lines, and thus re-introducing this enzyme into FN tumor cell line is likely to induce DNA damage and sensitize these cells to irradiation. Induction of specific metabolism-related targets in cancer resistant cells warrants further analysis.The capillary bed interfaces closely with epithelial cells to promote organ development, which is extensively studied in development of lungs. A detailed and comprehensive review that describes the cell types, molecular pathways and signals associated with embryonic and adult lung development was provided by Smo) or the regulator suppressor of fused homolog (Sufu) act in a chondrocyte cell autonomous manner to regulate its proliferation and differentiation. Using two different conditional deletion strategies in mice where Smo or Sufu were knocked out in different populations of chondrocytes, Xiu et al. demonstrated that in juvenile stage, hedgehog signaling functions in resting and/or columnar chondrocytes to maintain growth plate. Bone cells are composed of osteoblasts, osteocytes, osteoclasts, and progenitor cells. In the heart valve, during aging, calcification of matrix is detrimental. This process occurs via the osteogenic transition of vascular smooth muscle cells. A non-coding H19 RNA has been identified to promote osteoblastic transition of vascular smooth muscle cells by acting as a competitive endogenous RNA that sponges microRNA miR-140-5p. Xu et al. showed that H19 directly interacted with miR-140-5p, which then activated downstream signaling (Satb2-ERK/MAPK) to promote calcification. These data provide a novel mechanism for targeting arterial calcification, a common underlying condition in patients with type 2 diabetes mellitus, end-stage renal disease, obesity-related disease, and aging.We next highlight three articles that discuss mechanisms and molecules related to bone and cartilage tissue regeneration in distinct contexts. Cartilage is thin avascular flexible tissue compared to bones which are vascularized and rigid structures containing calcified matrix. Chondrocytes are cells that form the cartilage and are involved in regeneration processes during limb development. During limb elongation in juvenile mice, the hedgehog signaling pathway receptor encoded by smoothened , a secreted protein that belongs to a member of mitochondrial-derived peptides acts both intracellularly and in paracrine fashion. Emerging evidence supports an important role of HN in the regulation of osteoclasts and osteoblasts, the two of the key cell types that maintain bone homeostasis. These Research Topic of eight articles in this editorial showcase demonstrate the innovative approaches that these investigators have taken to address mechanistic related questions underlying disease pathology.


Introduction: Tension pneumomediastinum and coronary artery thrombosis (CAT) secondary to blunt polytrauma are, rare yet have the potential for serious complication.Case Report: A 40-year-old man presented to the emergency department following a motorcycle accident. He was found to have multiple orthopedic injuries, pneumothorax, and pneumomediastinum. An electrocardiogram showed myocardial infarction. He developed obstructive shock physiology that resolved with mediastinal percutaneous needle drainage. Subsequent coronary angiography revealed acute thrombosis of the left circumflex artery.This is a rare case of traumatic tension pneumomediastinum associated with coronary artery thrombosis requiring coronary stenting. Emergency physicians should be mindful of CAT in the setting of blunt chest injury. Polytrauma following motorcycle accidents is associated with significant morbidity and mortality. In the United States, motorcycle accidents have a fatality rate 28 times higher than other motor vehicle collisions and represent 14% of all motor vehicle fatalities.Blunt cardiac injury is associated with approximately one fifth of all deaths caused by BCT in motor vehicle collisions.A 40-year-old man presented to the emergency department (ED) via emergency medical services following a high-speed motorcycle versus automobile collision. Due to respiratory distress and decreased breath sounds in the right lung field, needle decompression was performed on scene by paramedics. Upon arrival to the ED, the patient was hemodynamically stable with a heart rate of 89 beats per minute and blood pressure 120/74 millimeters of mercury (mm Hg). His mentation was intact. Physical exam revealed extensive right-sided chest wall ecchymosis and tenderness.Point-of-care ultrasound (POCUS) demonstrated reduced lung sliding on the right and no intraperitoneal free fluid; however, cardiac windows were suboptimal and non-diagnostic. Bedside chest radiograph showed multiple right-sided rib fractures with apical and lateral pneumothorax. Computed tomography (CT) demonstrated fractures of right ribs 3–11 with accompanying pneumothorax, sternomanubrial joint dislocation with retrosternal hematoma, and pneumomediastinum . AdditioA 14-French pigtail catheter was placed into the right hemithorax without immediate complication. Twelve-lead electrocardiogram was remarkable for ST-segment elevation in leads aVR and aVL with diffuse ST depression in leads II, III, aVF, and V1–V6 concerning for BCI and prompting cardiology consultation . An initRepeat POCUS demonstrated bilateral lung sliding and no intra-abdominal free fluid; similarly, the chest tube and pleural drainage apparatus were functioning normally. Again, cardiac windows could not be obtained due to presumed air scattering. Because of significant pneumomediastinum seen on CT, obstructive shock physiology from the mediastinal free air was suspected. An emergent bedside percutaneous needle drainage in the left fifth intercostal space was performed, yielding 9 mL of blood with scant air bubbles. The patient’s blood pressure immediately improved, and cardiac windows were subsequently visualized on POCUS.With high suspicion for acute myocardial infarction, the patient was taken for emergent coronary angiography. Transthoracic and transesophageal ultrasounds obtained in the cardiac catheterization lab did not demonstrate pericardial fluid or cardiac tamponade. Angiography demonstrated 95% thrombotic occlusion of the proximal left circumflex artery at the origin of the first obtuse marginal branch without evidence of coronary artery dissection . PercutaCPC-EM CapsuleWhat do we already know about this clinical entity?Coronary artery thrombosis (CAT) and tension pneumomediastinum are potential causes of morbidity and mortality in blunt chest trauma.What makes this presentation of disease reportable?A CAT in the absence of coronary dissection is rare and may be attributable to the vascular stasis caused by obstructive shock physiology.What is the major learning point?Clinicians should consider CAT in polytrauma patients with chest pain and concerning ECG findings, particularly when tension physiology occurs.How might this improve emergency medicine practice?Early involvement of multidisciplinary specialists and careful consideration of interventional strategies can improve patient outcomes in CAT associated with polytrauma.Aspirin and ticagrelor were initiated immediately after PCI. Norepinephrine and amiodarone were administered for cardiogenic shock and non-sustained ventricular tachycardia, respectively, both of which resolved within 48 hours. Following cardiac stabilization, the inpatient team addressed the patient’s spinal injury, although urgent operative intervention was deferred because of hemodynamic instability and the bleeding risk associated with antiplatelet therapy. Prior to spinal fixation on hospital day three, ticagrelor was changed to tirofiban infusion, which was held prior to the first incision and resumed postoperatively. Ticagrelor was re-started following the removal of a spinal drain on postoperative day two. The patient remained stable for the remainder of hospitalization and was discharged on aspirin and ticagrelor on hospital day 14.On a follow-up phone call with the patient almost six months after the injury, he reported that he was back to working full time and feeling fully recovered. He recalled the accident and arriving to the ED, although he did not recall undergoing tube thoracostomy placement or percutaneous needle drainage. He was advised to continue aspirin and ticagrelor for at least six months.This patient’s ED course and management were complex due to the number and severity of his injuries. He developed obstructive shock physiology. We hypothesize that both blood and air in the mediastinum resulted in obstructive shock. In general, the differential diagnoses of obstructive shock in the setting of BCT include tension pneumothorax, pneumomediastinum, pneumopericardium, hemopericardium, and large retrosternal hematoma.In addition to the retrosternal hematoma, pneumomediastinum identified on CT and the presence of air bubbles during percutaneous needle drainage suggest that the air in the mediastinum also contributed to the development of obstructive shock. Traumatic pneumomediastinum in BCT can be caused by several injuries, such as tracheoesophageal injury, alveolar injury, hollow viscus injury, or facial (sinus) injury.Isolated CAT following BCT in the absence of concurrent coronary artery dissection is a rare complication that has been reported sparingly in the literature; therefore, its epidemiology is difficult to define.4In this instance, the presence of a CAT in the left circumflex artery may suggest an etiology other than direct trauma. It has been postulated that tension physiology from a pneumothorax can lead to reduced coronary artery blood flow thereby causing vascular stasis and thrombus formation.Co-occurrence of an unstable spinal injury and liver injury complicated the decision to administer anti-platelet and anti-coagulant medication in this case. Antiplatelet and anticoagulation therapy to treat CAT must be weighed against the risk of hemorrhage in a critically injured trauma patient. Severity of concomitant injuries, compressibility of current or possible hemorrhage, underlying hematologic conditions, and current medication usage must all be considered. Contrary to aspirin, clopidogrel, and ticagrelor, whose antiplatelet effects may continue for days, heparin and tirofiban are favored in patients with CAT. Both agents are associated with low to medium risk of bleeding because of their relatively short half-life and titratability.Coronary artery thrombosis and pneumomediastinum are uncommon complications of blunt cardiac injury, yet both injuries are associated with significant complications and present diagnostic challenges and treatment dilemmas, particularly in the setting of multisystem trauma. Emergency clinicians must be cognizant of the complications of blunt chest trauma and be prepared to identify and stabilize these patients while definitive care is pending.


Weight gain and obesity are important health problems associated with psychiatric disorders and/or with psychotropic drug treatments. There is a high inter-individual variability in the susceptibility to drug induced weight gain and/or other cardiometabolic disorders.To study the genetic, clinical and environmental risk factors for weight gain and onset of metabolic syndrome during psychotropic treatment.Analysis in PsyMetab, a large (n>3000) ongoing longitudinal prospective cohort study investigating cardiometabolic disorders in psychiatric patients.Aside from well-known clinical risk factors for metabolic worsening , we recently identified additional risk factors, such as the socio-economic status, a low status being associated with increased worsening of cardiometabolic parameters. Results from ongoing studies on the moderate dose dependencies of the metabolic effects of antipsychotics will be shown, as well as the clinical consequences. An epigenome-wide association study (EWAS) performed in 78 patients before and after one month of treatment  and a genome-wide association study (GWAS) in 1924 patients  will also be presented, as well as the use of polygenic risk scores to predict patients at risks for dyslipidemia Many factors contribute to the differences in weight gain and metabolic disorders induced by psychotropic drugs. The use of specific algorithms and/or polygenic risk scores can help to identify patients at risks. However, when starting a psychotropic drug at risk, a prospective monitoring of clinical (e.g. weight and blood pressure) and biochemical  parameters is essential.None Declared


This study aimed to investigate the contemporary characteristics of sedentary behavior and physical activity levels in breast cancer survivors. The cross-sectional data of 10,073 community-dwelling Korean women aged ≥50 years in the Korea National Health and Nutrition Examination Survey were analyzed. The differences in sedentary behavior, walking activity, and moderate-to-vigorous physical activity (MVPA) levels between breast cancer survivors, other cancer survivors, and women with no history of cancer were compared by complex-sample general linear models. Breast cancer survivors spent significantly less mean time in sedentary behavior than other cancer survivors and women with no history of cancer; however, among them, 48.34% spent a long sedentary time of ≥420 min/day. Breast cancer survivors had a significantly higher level of walking activity and similar total MVPA levels compared to women with no history of cancer. When comparing domain-specific MVPA levels, breast cancer survivors showed significantly lower work-related MVPA levels than women with no history of cancer. In recent years, community-dwelling Korean breast cancer survivors were less sedentary, walked more, and had equivalent MVPA levels compared with women with no history of cancer. Considering the growing emphasis on healthy lifestyles, our results may reflect more contemporary behavior trends of breast cancer survivors. Physical activity is defined as any bodily movement produced by skeletal muscles that requires energy expenditure, either for leisure, transportation, or work . PhysicaThe benefits of physical activity in patients with cancer and in the general population have been well established by many previous studies . RegularMany breast cancer survivors suffer from impairments of the upper extremities, depression, or cognitive decline after treatment, which leads to limitations in activities of daily living and participation in work, sports, and leisure activities ,8. TheseConsidering the increasing incidence and survival rate of patients with breast cancer, the role of physical activity among breast cancer survivors in leading a healthy life has been increasingly emphasized . Neverthhttps://knhanes.kdca.go.kr (accessed on 29 November 2022)). All participants of the KNHANES provided informed consent before participation, and the requirement for ethical approval was exempted by the Institutional Review Board of our hospital because the current study uses the publicly available data of the KNHANES.This cross-sectional study utilized the data from the Korea National Health and Nutrition Examination Survey (KNHANES) VI, VII, and VIII . The Korn = 1102) and with double primary cancer in the breast and other organs (n = 12), 10,073 female participants were finally included in the current study. Women who had ever been diagnosed with cancer by a doctor were defined as cancer survivors [n = 193), survivors of cancers other than breast cancer (n = 644), and those without a history of cancer (9236) [A total of 47,309 participants  were recruited for the KNHANES between 2014 and 2019. Among the total participants, 20,546 participants  were aged 50 years or older (43.43%). After excluding people with a missing history of cancer (urvivors . In the r (9236) . BecauseSedentary behavior and moderate-to-vigorous physical activity were evaluated using a validated Korean version of the World Health Organization (WHO) Global Physical Activity Questionnaire (GPAQ) . The GPABecause the information on walking and resistance exercise is not obtainable via the GPAQ, walking activity and resistance exercise were separately surveyed . Walking2). Information on education level (>9 years or ≤9 years) and residence area  was obtained. Those who worked for more than 1 h in the past week with the purpose of earning income or worked as unpaid family workers for more than 18 h were considered to have an occupation (employed state). Individuals who had never consumed alcohol or had not consumed alcohol at all in the last year were classified as non-drinkers.Height was measured with the minimum requirement that the heels and buttocks touched the vertical board while standing. Weight was measured in a state of exhaling breath, wearing light clothing only. Body mass index was calculated using measured weight (kg) divided by height squared , as appropriate. All statistics were calculated using the Statistical Package for the Social Sciences, version 22 . p-values < 0.05 were considered statistically significant.The characteristics of participants by cancer status  were compared using the complex-sample Student’s Among the 10,073 women aged 50 years or older, the prevalence of breast cancer survivors, other cancer survivors, and individuals with no history of cancer was 1.88%, 6.65%, and 91.47%, respectively. Characteristics of participants are compared by cancer status in Meanwhile, the levels of total moderate-to-vigorous physical activity and resistance exercise were not significantly different among breast cancer survivors, other cancer survivors, and participants with no history of cancer . The meaThe current study presents the contemporary sedentary behavior and physical activity patterns in community-dwelling Korean breast cancer survivors aged 50 years or older. Breast cancer survivors spent less sedentary time than other cancer survivors and participants with no history of cancer. Furthermore, breast cancer survivors walked significantly more than females without a history of cancer. However, total moderate-to-vigorous physical activity levels were similar between survivors of breast cancer, survivors of cancers other than breast cancer, and those without a history of cancer. With regard to domain-specific moderate-to-vigorous physical activity, travel- and recreation-related moderate-to-vigorous physical activity were not significantly different across the three groups, but work-related moderate-to-vigorous physical activity was significantly lower in the survivors of breast and other cancers than in the participants without a history of cancer.Regarding our findings that Korean breast cancer survivors spent less sedentary time than the non-cancer controls and other cancer survivors, the results of our study differed from earlier studies reporting that breast cancer survivors are more sedentary than women who did not have cancer ,24,25. HWhile breast cancer survivors were less sedentary than females without a history of cancer and survivors of other cancers, approximately half of them still spent a relatively long time in sedentary behavior—over 7 h per day. Given that the prevalence of sedentary individuals is still high among breast cancer survivors, community-based tailored physical activity-promoting programs, incorporating moderate-to-vigorous physical activity as well as simple walking, are necessary. Recent studies suggest that sedentary behavior has a negative impact on health outcomes that are independent of the overall amount of physical activity, and that spending more time in physical activity cannot reduce the detrimental effect of prolonged sedentary behavior on health outcomes . The WHOThe results of our study indicated that community-dwelling breast cancer survivors walked significantly more than women without a history of cancer. This notable result is encouraging for public health, given that walking is the most easily accessible and a relatively light form of physical activity . To our Inconsistency persists regarding the moderate-to-vigorous physical activity levels in breast cancer survivors compared with controls ,24,26. TThe results of our study that breast cancer survivors were sedentary, walked more, and performed similar moderate-to-vigorous physical activity compared to controls may reflect the physical modality preference of breast cancer survivors. A pilot randomized controlled trial found that reductions in sedentary time were greater in participants randomized to the lower-intensity physical activity group than in those randomized to the higher-intensity physical activity group and control group . A crossAs with the previous literature reporting reduced work engagement and work ability in breast cancer survivors , our stuThe strength of our study is that it presents contemporary real-world data from breast cancer survivors living in the Korean community, rather than hospitalized patients under treatment for breast cancer. Since research on the physical activity and sedentary behavior of Asian breast cancer survivors is lacking, our study provides valuable insight into the behavioral patterns of middle-aged and older Asian female breast cancer survivors. Therefore, the results of this study may suggest the future direction for interventions to reduce sedentary behavior and promote physical activity in breast cancer survivors living in the community. The limitations of our study stem from the cross-sectional design of the KNHANES, which cannot reveal the causal relationships between variables, such as the association between physical activity and breast cancer. Second, the self-reported surveys of physical activity and sedentary behavior could confer recall bias. In addition, the data obtained by self-reported questionnaires and objective physical activity measures may show different results. Third, because there are no detailed cancer-related data in the KNHANES, such as the stage and treatment status, their effects are unknown. Moreover, since the KNHANES does not include information on participants prior to cancer diagnosis, it was not possible to adjust for pre-cancer factors during the analyses. Finally, considering the differences in demographic and cancer-related factors across the various countries, the results of our study may not be generalizable to other populations.Community-dwelling Korean breast cancer survivors aged 50 years or older were less sedentary and walked more than women without a history of cancer. However, moderate-to-vigorous physical activity levels were similar between breast cancer survivors, other cancer survivors, and women with no history of cancer. Community-dwelling breast cancer survivors may prefer walking as a mode of physical activity in order to be less sedentary. Therefore, future prospective studies and randomized controlled trials are needed to examine the factors associated with the types of physical activity chosen by breast cancer survivors to reduce sedentary behavior. By synthesizing the findings of our study and future studies, personalized programs can be developed to convert sedentary time into physical activity in community-dwelling breast cancer survivors. In addition, healthcare professionals should regularly recommend increasing physical activity, assuming that half of the breast cancer survivors spend a long time being sedentary.


Despite improvements in cancer patient outcomes seen in the past decade, tumor resistance to therapy remains a major impediment to achieving durable clinical responses. Intratumoral heterogeneity related to genetic, epigenetic, transcriptomic, proteomic, and metabolic differences between individual cancer cells has emerged as a driver of therapeutic resistance. This cell to cell heterogeneity can be assessed using single cell profiling technologies that enable the identification of tumor cell clones that exhibit similar defining features like specific mutations or patterns of DNA methylation. Single cell profiling of tumors before and after treatment can generate new insights into the cancer cell characteristics that confer therapeutic resistance by identifying intrinsically resistant sub-populations that survive treatment and by describing new cellular features that emerge post-treatment due to tumor cell evolution. Integrative, single cell analytical approaches have already proven advantageous in studies characterizing treatment-resistant clones in cancers where pre- and post-treatment patient samples are readily available, such as leukemia. In contrast, little is known about other cancer subtypes like pediatric high grade glioma, a class of heterogeneous, malignant brain tumors in children that rapidly develop resistance to multiple therapeutic modalities, including chemotherapy, immunotherapy, and radiation. Leveraging single cell multi-omic technologies to analyze naïve and therapy-resistant glioma may lead to the discovery of novel strategies to overcome treatment resistance in brain tumors with dismal clinical outcomes. In this review, we explore the potential for single cell multi-omic analyses to reveal mechanisms of glioma resistance to therapy and discuss opportunities to apply these approaches to improve long-term therapeutic response in pediatric high grade glioma and other brain tumors with limited treatment options. High grade glioma (HGG) are aggressive and highly malignant tumors of the central nervous system  and littThe abysmal survival rate seen in adult HGG is often attributed to these tumors exhibiting stem cell-like phenotypes associated with poor response to radiation, temozolomide (TMZ) and other therapies . DespiteBecause of technological limitations, most initial attempts at using single cell technologies to dissect glioma heterogeneity have profiled only one layer of biological regulation in isolation, such as cell to cell variation in transcription through single cell RNA sequencing (scRNAseq). Since cellular heterogeneity can occur at the level of the genome, epigenome, transcriptome, proteome, and metabolome, these unidimensional datasets may impart an incomplete or skewed understanding of the underlying factors driving heterogeneity . New tecpHGG is a rare and aggressive form of brain cancer that primarily affects children and adolescents . The disCurrent treatment paradigms for pHGG may vary based on patient age and tumor subtype, but they often include combinations of radiation, chemotherapy, surgery, immunotherapy, and targeted small molecules . For somImproved molecular and genetic profiling of pHGG tumors and research in pre-clinical models has led to the discovery of multiple targeted therapies, including both small molecule inhibitors of various enzymes and immunotherapeutic approaches. Targeted small molecule inhibitors for pHGG treatment include: chromatin-targeting drugs like the histone deacetylase inhibitors vorinostat and panobinostat ; the DRDMore recently, immunotherapeutic approaches using oncolytic viruses, cancer vaccines, and autologous T cell therapy have shown promise in animal models and are under investigation in the clinic. Specifically, clinical trials assessing pHGG patient response to CAR-T cells directed against various tumor antigens, including GD2, B7-H3, and HER2, have led to improved symptoms or stable disease in some patients but have yet to improve overall survival . Early pIn addition to the adverse side effects that can accompany each of these treatment modalities, another factor to consider when developing new therapies is that treatment failure in pHGG commonly occurs due to intrinsic or acquired resistance to therapy . OvercomDifferences between the genome, epigenome, transcriptome, proteome, and metabolome of individual tumor cells in a single patient can all contribute to intratumoral heterogeneity associated with therapeutic resistance . VariablMultiple techniques are now available for targeted “omic” profiling of the major subtypes of biological molecules at a single cell resolution . Many ofVarious research groups have also sought to understand the relationship between genetic mutations, DNA methylation and heterogeneous gene expression profiles in glioma patient samples. For example, studies integrating scRNAseq and DNA methylation profiling have uncovered correlations between DNA methylation patterns and gene expression associated with the expression of glial differentiation genes and response to environmental stress . An addiin situ analysis) or high throughput  can therefore complement single cell data from disassociated samples to reveal the regional heterogeneity, and local interactions between, cell types of interest in patient tumors , can offer much faster, cheaper, and readily interpretable assessments of tumor heterogeneity while still assaying large numbers of cells. However, the information provided will be more biased than sequencing-based single cell profiling since non-sequencing techniques rely on a relatively small number of probes or antibodies, which may result in more limited findings from exploratory studies  the expansion of subclonal populations showing intrinsic resistance; 2) the emergence of altered tumor cell phenotypes as these cells adapt or evolve upon exposure to therapy and escape killing; and 3) dynamic changes to the tumor microenvironment, including the interactions between brain tumor cells and normal neurons, glia, and tumor-associated immune cells. Before the advent of single cell technologies, previous research into the molecular underpinnings of therapeutic resistance relied on bulk approaches that assessed molecular changes induced by treatment at low resolution and averaged across large numbers of cells without the ability to separately profile tumor, non-tumor, and immune populations. In this review, we have highlighted how sophisticated, new technologies now enable researchers to layer multi-dimensional datasets to simultaneously profile genetic, epigenetic, transcriptomic, and proteomic aberrations at a single cell level to describe dynamic changes to the glioma cellular landscape in response to treatment.Most of the existing single cell multi-omic analyses of glioma published thus far have focused on either determining how tumor cell phenotypes diverge from normal tissue or on sub-classifying tumors into different molecular subgroups. Applying single cell multi-omic profiling to pre- and post-treatment pHGG tumors has the potential to reveal the consequences of various therapies on tumor composition and to identify markers of treatment susceptibility and resistance. These types of analyses are expected to generate data that can be applied to ultimately improve patient outcomes in several ways: by identifying novel treatment strategies and combination therapies to target the mechanisms by which glioma escapes therapy, by predicting the outcomes of different treatment modalities in a patient-specific manner that accounts for heterogeneity in therapeutic responses between cells in the same tumor, and by assessing how tumor-immune interactions affect response to therapy and resistance. Obtaining a more holistic view of the complex interplay between diverse tumor cell populations and their environment through multi-omic single cell analyses provides an opportunity to revolutionize therapeutic approaches to cancer treatment and make precision oncology practice more precise.