High risk and low prevalence diseases: Cavernous sinus thrombosis.

INTRODUCTION: Cavernous sinus thrombosis (CST) is a serious condition that carries with it a high rate of morbidity and mortality. OBJECTIVE: This review highlights the pearls and pitfalls of CST, including presentation, diagnosis, and management in the emergency department (ED) based on current evidence. DISCUSSION: CST is a potentially deadly thrombophlebitic disease involving the cavernous sinuses. The most common underlying etiology is sinusitis or other facial infection several days prior to development of CST, though other causes include maxillofacial trauma or surgery, thrombophilia, dehydration, or medications. Staphylococcus aureus, streptococcal species, oral anaerobic species, and gram-negative bacilli are the most frequent bacterial etiologies. The most prevalent presenting signs and symptoms are fever, headache, and ocular manifestations (chemosis, periorbital edema, ptosis, ophthalmoplegia, vision changes). Cranial nerve (CN) VI is the most commonly affected CN, resulting in lateral rectus palsy. Other CNs that may be affected include III, IV, and V. The disease may also affect the pulmonary and central nervous systems. Laboratory testing typically reveals elevated inflammatory markers, and blood cultures are positive in up to 70% of cases. Computed tomography of the head and orbits with intravenous contrast delayed phase imaging is recommended in the ED setting, though magnetic resonance venography demonstrates the highest sensitivity. Management includes resuscitation, antibiotics, and anticoagulation with specialist consultation. CONCLUSION: An understanding of CST can assist emergency clinicians in diagnosing and managing this potentially deadly disease.

Effects of Mindfulness and Life-Skills Training on Emotion Regulation and Anxiety Symptoms in Chinese Migrant Children: A Randomized Controlled Trial.

PURPOSE: China's rapid urbanization has been associated with increased mental health challenges, especially in rural-to-urban migrant children. This study evaluates the effects of mindfulness and life-skills (LS) training on emotional regulation and anxiety symptoms from a randomized controlled trial aimed at improving the mental health of Chinese migrant children. METHODS: Two intervention arms-mindfulness training (MT) and MT plus LS mentorship (MT + LS)-were compared to a waitlist control group of 368 migrant children aged 9-17 years. Volunteers were trained to deliver interventions to 285 migrant children in small groups of 15 for eight weeks weekly. Social integration varied: migrant children mixed with local children at public schools were considered highly integrated, those in migrant-only classrooms at public schools had intermediate levels of integration, and children in private migrant schools had low integration. Emotion regulation and anxiety symptoms were assessed preintervention, postintervention, and three months postintervention. RESULTS: Postintervention and compared to the control group, children with high social integration in the MT arm showed increased cognitive reappraisal ability (p < .05) but higher physical anxiety (p < .01). Children with high social integration in the MT + LS arm had lower anxiety symptoms of harm avoidance (p < .01) and physical anxiety (p < .05). Children with low social integration in the MT + LS arm showed lower cognitive reappraisal (p < .01) and poorer overall emotion regulation abilities (p < .01). Three months later, children with intermediate integration in the MT + LS arm had lower separation anxiety (p < .05) and harm avoidance anxiety (p < .05). No other groups showed significant improvements in emotion regulation or reducing in anxiety symptoms three months postintervention. DISCUSSION: Mindfulness and LS training may benefit Chinese migrant children who have higher levels of social integration but increase anxiety in those with lower social integration. Future research should consider the sociocultural context in which a treatment is implemented.

Comparative evaluation of self-pressurized Air-Q® and Proseal™ LMA® in patients undergoing elective surgery under general anaesthesia: A randomized clinical trial.

Background and Aims: Intra-cuff pressure of Air-Q self-pressurized laryngeal airways (Air-Q SP) balances airway pressure and adapts to patient's pharyngeal and periglottic structures, thus improves oropharyngeal leak pressure (OLP).This study was performed to compare efficacy of Air-Q SP with Proseal laryngeal mask airway (PLMA) in patients undergoing elective surgery. Material and Methods: The study design was prospective, randomized and controlled. Ninety patients were randomly assigned to Air-Q SP or PLMA group. All patients were premedicated and shifted to operation theatre. Monitoring was instituted. After securing IV-line, induction with inj. Morphine + Propofol, relaxation with inj. Vecuronium was done. Supraglottic was inserted according to group allocation. Outcome measures were OLP, fibreoptic view of larynx, success rate, device insertion parameters, haemodynamic and respiratory parameters and post-operative laryngopharyngeal complications. Neostigmine + glycopyrrolate were given, device was extubated. Results: All supraglottic airway devices (SADs) were successfully placed in two attempts. The mean initial OLP, OLP at 10 minutes, and device insertion time were significantly lower in Air-Q SP group. Fiber-optic laryngeal view grading was significantly better with Air-Q SP. No significant difference was observed with respect to rate of successful insertion in first attempt, ease of insertion, and manipulations required. The hemodynamic/respiratory parameters and post-operative sore throat in the two both groups were similar. Conclusions: Proseal LMA has a higher OLP than Air-Q SP but average insertion time was better, and fiber-optic grading of laryngeal view was shorter with Air-Q SP. However, Air-Q SP and Proseal LMA were both effective for lung ventilation.

A mechanochemically synthesized Schiff-base engineered 2D mixed-linker MOF for CO2 capture and cationic dye removal.

Developing synthetic strategies for smart materials for the adsorption and separation of toxic chemicals is of great importance. Metal-organic frameworks (MOFs) have been proven to be outstanding adsorbent materials that possess excellent pollutant removal performances in wastewater treatment, including dye recycling. In this work, a neutral Cd(II) based 2D framework with a dual ligand strategy involving -OH functionalized 5-hydroxyisophthalic acid (5-OH-H2IPA) and the amide decorated Schiff base ligand (E)-N'-(pyridin-4-ylmethylene)isonicotinohydrazide (L) has been synthesized by different synthetic routes and characterized by various analytical methods. Thus, crystals of {[Cd(5-OH-IPA)(L)]·CH3OH}n synthesized via diffusion (ADES-7D) and the phase pure bulk product synthesized by conventional reflux (ADES-7C) and the mechanochemical grinding method (ADES-7M) have been established using PXRD data of the respective product showing identical simulated SXRD data to those of ADES-7D. The mechanochemically synthesized ADES-7M possesses a better surface area and CO2 adsorption capability compared to ADES-7C, which is also supported by electron microscopy and particle size measurements. Furthermore, ADES-7 can be used as an efficient adsorbent material for the reversible, selective adsorption (42-99%) and separation of the cationic dyes malachite green (MG), methyl violet (MV), methylene blue (MB), and rhodamine B (RhB) from the mixture of cationic/anionic dyes (methyl orange (MO) and bromocresol green (BCG)) in the aqueous phase. Specifically, ADES-7M possesses better dye capture capability compared to ADES-7C, even in the case of the bigger dye RhB with adsorption differences of 2.38 to 1.01 mg g-1, respectively. The dye adsorption kinetics follows pseudo-second-order kinetics, and the dye adsorption isotherm fits well with the Langmuir/Freundlich adsorption isotherm models. The probable mechanism of adsorption involving the supramolecular interaction between the host MOF and the guest dye has also been proposed.

Association between anxiety, depression symptoms, and academic burnout among Chinese students: the mediating role of resilience and self-efficacy.

BACKGROUND: To explore the associations between anxiety and depression symptoms and academic burnout among children and adolescents in China, and to examine the role of resilience and self-efficacy in addressing academic burnout. METHODS: A total of 2,070 students in grades 4-8 were recruited from two primary and three middle schools in Shanghai, completed the Elementary School Student Burnout Scale (ESSBS), the Multidimensional Anxiety Scale for Children-Chinese (MASC-C), the Center for Epidemiological Studies Depression Scale (CES-D), the Connor-Davidson Resilience Scale (CD-RISC), and the General Self-Efficacy Scale (GSES), with 95.04% effective response rate. Multivariable regression analyses examining the associations between anxiety / depression symptoms and academic burnout (as well as the associations between resilience / self-efficacy and academic burnout) were performed using STATA 16.0 and SmartPLS 3.0. RESULTS: Anxiety symptoms (ß = 0.124, p < 0.01) and depression symptoms (ß = 0.477, p < 0.01) were positively correlated with academic burnout. Resilience partially mediated the association between depression symptoms and academic burnout (ß = 0.059, p < 0.01), with a mediation rate of 12.37%. Self-efficacy partially mediated the associations between anxiety symptoms and academic burnout (ß = 0.022, p < 0.01) and between depression symptoms and academic burnout (ß = 0.017, p < 0.01), with mediation rates of 17.74% and 3.56%, respectively. Resilience and self-efficacy together (ß = 0.041, p < 0.01) formed a mediating chain between depression symptoms and academic burnout, with a mediation rate of 8.6%. CONCLUSIONS: Anxiety and depression symptoms were positively associated with academic burnout. Resilience and self-efficacy were found to mediate the associations partially.

general psychopathology factor in Chinese adolescents and its correlation with trans-diagnostic protective psycho-social factors.

BACKGROUND: Comorbidity in mental disorders is prevalent among adolescents, with evidence suggesting a general psychopathology factor ("p" factor) that reflects shared mechanisms across different disorders. However, the association between the "p" factor and protective factors remains understudied. The current study aimed to explore the "p" factor, and its associations with psycho-social functioning, in Chinese adolescents. METHODS: 2052 students, aged 9-17, were recruited from primary and secondary schools in Shanghai, China. Multiple rating scales were used to assess psychological symptoms and psycho-social functioning. Confirmatory factor analysis was conducted to verify the fit of models involving different psychopathology domains such as externalizing, internalizing, and the "p" factor. Subsequently, structural equation models were used to explore associations between the extracted factors and psycho-social functioning, including emotion regulation, mindful attention awareness, self-esteem, self-efficacy, resilience, and perceived support. RESULTS: The bi-factor model demonstrated a good fit, with a "p" factor accounting for 46 % of symptom variation, indicating that the psychological symptoms of Chinese adolescents could be explained by internalizing, externalizing, and the "p" factor. Psychologically, a higher "p" was positively correlated with emotion suppression and negatively correlated with mindful attention awareness, emotion reappraisal, self-esteem, and resilience. Socially, a higher "p" was associated with decreased perceived support. LIMITATIONS: Only common symptoms were included as this study was conducted at school. Furthermore, the cross-sectional design limited our ability to investigate causal relationships. CONCLUSIONS: A "p" factor exists among Chinese adolescents. Individuals with higher "p" factor levels were prone to experience lower levels of psycho-social functions.

Guest-responsive coherence time of radical qubits in a metal-organic framework.

Metal-organic frameworks (MOFs) integrated with molecular qubits are promising for quantum sensing. In this study, a new UiO-type MOF with a 5,12-diazatetracene (DAT)-containing ligand is synthesized, and the radicals generated in the MOF exhibit high stability and a relatively long coherence time (T2) responsive to the introduction of various guest molecules.

Colonization, spread and persistence of Salmonella (Typhimurium, Infantis and Reading) in internal organs of broilers.

Transfer of Salmonella to internal organs of broilers over a 35 d grow-out period was evaluated. A total of 360 one-day old chicks were placed in 18 floor pens of 3 groups with 6 replicate pens each. On d 0, broilers were orally challenged with a cocktail of Salmonella (equal population of marked serovars; nalidixic acid-resistant S. Typhimurium, rifampicin-resistant S. Infantis, and kanamycin-resistant S. Reading) to have 3 groups: L (low; ∼2 log CFU/bird); M (medium; ∼5 log CFU/bird); and H (High; ∼8 log CFU/bird). On d 2, 7 and 35, 4 birds/pen were euthanized and ceca, liver, and spleen samples were collected aseptically. Gizzard samples (4/pen) were collected on d 35. The concentration of Salmonella in liver and spleen were transformed to binary outcomes (positive and negative) and fitted in glm function of R using cecal Salmonella concentrations (log CFU/g) and inoculation doses (L, M, and H) as inputs. On d 2, H group showed greater (P ≤ 0.05) cecal colonization of all 3 serovars compared to L and M groups. However, M group showed greater (P ≤ 0.05) colonization of all 3 serovars in the liver and spleen compared to L group. Salmonella colonization increased linearly in the ceca and quadratically in the liver and spleen with increasing challenge dose (P ≤ 0.05). On d 35, L group had greater (P ≤ 0.05) S. Infantis colonization in the ceca and liver compared to M and H groups (P ≤ 0.05). Moreover, within each group on d 35, the concentration of S. Reading was greater than those of S. Typhimurium and S. Infantis for all 3 doses in the ceca and high dose in the liver and gizzard (P ≤ 0.05). Salmonella colonization diminished in the ceca, liver, and spleen during grow-out from d 0 to d 35 (P ≤ 0.05). On d 35, birds challenged with different doses of Salmonella cocktail showed a similar total Salmonella spp. population in the ceca (ca. 3.14 log CFU/g), liver (ca. 0.54 log CFU/g), spleen (ca. 0.31 log CFU/g), and gizzard (ca. 0.42 log CFU/g). Estimates from the fitted logistic model showed that one log CFU/g increase in cecal Salmonella concentration will result in an increase in relative risk of liver and spleen being Salmonella-positive by 4.02 and 3.40 times (P ≤ 0.01), respectively. Broilers from H or M group had a lower risk (28 and 23%) of being Salmonella-positive in the liver compared to the L group when the cecal Salmonella concentration is the same (P ≤ 0.05). Oral challenge of broilers with Salmonella spp. with various doses resulted in linear or quadratic increases in Salmonella colonization in the internal organs during early age and these populations decreased during grow-out (d 35). This research can provide guidance on practices to effectively mitigate the risk of Salmonella from chicken parts and enhance public health.

Self-assembly of choline-based surface-active ionic liquids and concentration-dependent enhancement in the enzymatic activity of cellulase in aqueous medium.

The micellization of choline-based anionic surface-active ionic liquids (SAILs) having lauroyl sarcosinate [Sar]-, dodecylsulfate [DS]-, and deoxycholate [Doc]- as counter-ions was investigated in an aqueous medium. Density functional theory (DFT) was employed to investigate the net interactional energy (Enet), extent of non-covalent interactions, and band gap of the choline-based SAILs. The critical micelle concentration (cmc) along with various parameters related to the surface adsorption, counter-ion binding (ß), and polarity of the cores of the micelles were deduced employing surface tension measurements, conductometric titrations and fluorescence spectroscopy, respectively. A dynamic light scattering (DLS) system equipped with zeta-potential measurement set-up and small-angle neutron scattering (SANS) were used to predict the size, zeta-potential, and morphology, respectively, of the formed micelles. Thermodynamic parameters such as standard Gibb's free energy and standard enthalpy change of micellization were calculated using isothermal titration calorimetry (ITC). Upon comparing with sodium salt analogues, it was established that the micellization was predominantly governed by the extent of hydration of [Cho]+, the head groups of the respective anions, and the degree of counter-ion binding (ß). Considering the concentration dependence of the enzyme-SAIL interactions, aqueous solutions of the synthesized SAILs at two different concentrations (below and above the cmc) were utilized as the medium for testing the enzymatic activity of cellulase. The activity of cellulase was found to be ∼7- to ∼13-fold higher compared to that observed in buffers in monomeric solutions of the SAILs and followed the order: [Cho][Sar] > [Cho][DS] > [Cho][Doc]. In the micellar solution, a ∼4- to 5-fold increase in enzymatic activity was observed.

Consensus Paper: Cerebellum and Reward.

Cerebellum is a key-structure for the modulation of motor, cognitive, social and affective functions, contributing to automatic behaviours through interactions with the cerebral cortex, basal ganglia and spinal cord. The predictive mechanisms used by the cerebellum cover not only sensorimotor functions but also reward-related tasks. Cerebellar circuits appear to encode temporal difference error and reward prediction error. From a chemical standpoint, cerebellar catecholamines modulate the rate of cerebellar-based cognitive learning, and mediate cerebellar contributions during complex behaviours. Reward processing and its associated emotions are tuned by the cerebellum which operates as a controller of adaptive homeostatic processes based on interoceptive and exteroceptive inputs. Lobules VI-VII/areas of the vermis are candidate regions for the cortico-subcortical signaling pathways associated with loss aversion and reward sensitivity, together with other nodes of the limbic circuitry. There is growing evidence that the cerebellum works as a hub of regional dysconnectivity across all mood states and that mental disorders involve the cerebellar circuitry, including mood and addiction disorders, and impaired eating behaviors where the cerebellum might be involved in longer time scales of prediction as compared to motor operations. Cerebellar patients exhibit aberrant social behaviour, showing aberrant impulsivity/compulsivity. The cerebellum is a master-piece of reward mechanisms, together with the striatum, ventral tegmental area (VTA) and prefrontal cortex (PFC). Critically, studies on reward processing reinforce our view that a fundamental role of the cerebellum is to construct internal models, perform predictions on the impact of future behaviour and compare what is predicted and what actually occurs.

PAU Smart Seeder: a novel way forward for rice residue management in North-west India.

In winter, the paddy residues become wet during morning and late evening due to dew, which restricts the operation of sowing machines (Happy Seeder and Super Seeder) into paddy residues, as wet residues do not slide on furrow openers/tines. A PAU Smart Seeder (PSS) was developed and evaluated for a four-wheel tractor that can sow wheat with optimum crop establishment in combined harvested rice fields. The PSS were evaluated for its performance under varying straw load, forward speed, and rotor speed in terms of fuel consumption, field capacity, seed emergence, and grain yield. The crop establishment and wheat yield of PSS was also compared with the existing straw management machines Happy Seeder (HS) and Super Seeder (SS) under heavy paddy residue conditions. The effect of the straw load was more pronounced on dependent variables than the effect of the speed index. PSS performance was best at a forward speed of 2.6 km h-1, rotor speed of 127.5 rpm, and a straw load of 6 t ha-1. Average fuel consumption using PSS was lower than SS but higher than HS. Wheat emergence was higher by 15.6 and 25.7% on the PSS plots compared to HS and SS, respectively. Average wheat grain yield in PSS plots was significantly higher by 12.7 and 18.9% than SS and HS, respectively in one experiment, while the grain yield was similar for both PSS and HS in other experiments. PSS has a novel mechanism to manage paddy straw and simultaneously sow wheat into a heavy straw load (> 8 t ha-1) mixture of anchored and loose straw. In conclusion, PSS showed promise for in-situ management of rice straw as it eliminates most of the operational problems encountered by the existing seeders (HS and SS).

Correlation of clinical and radiological scores for evaluation of activity in patients having thyroid-associated orbitopathy: A prospective observational study.

PURPOSE: To find a correlation between the clinical (vision-inflammation-strabismus-appearance [VISA] score) and radiological (apparent diffusion coefficient [ADC] values) scores for evaluating disease activity in patients with thyroid-associated orbitopathy. DESIGN: A prospective comparative study. METHODS: Our study was performed for consecutively diagnosed thyroid-associated orbitopathy (TAO) patients. Clinical evaluation included the VISA classification system with the basic thyroid workup. An inflammatory score of <4/8 was considered inactive and ≥4/8 as an active disease. Every included patient underwent a diffusion-weighted magnetic resonance imaging (DW-MRI) scan of the orbits. The orbital parameters evaluated on imaging included the proptosis, thickness, as well as the ADC values of extraocular muscles. RESULTS: We studied 33 consecutive patients (23 females, 69.7%) with a mean age of 41.8 years. The majority (n = 27, 81.8%) were hyperthyroid, four were hypothyroid, and two were euthyroid. In the VISA classification, nine patients had active TAO (≥4/8 inflammation score), while 24 had inactive disease. There was a positive correlation between the inflammation score and ADC values of medial rectus (MR), inferior rectus (IR) and lateral rectus (LR). We had nine patients with inflammation scores ≥4. With receiver operating characteristic (ROC) curve analysis, we found that the ADC value of IR can predict disease activity with 68% sensitivity and MR-ADC can predict active TAO with 87% sensitivity. CONCLUSION: The ADC parameters of DW-MRI are objective and less operator dependent than the clinical TAO activity scores like VISA classification. A randomized control trial may provide robust data on this correlation.

Balloon dacryoplasty: A boon for dacryologists in managing persistent congenital nasolacrimal duct obstructions.

PURPOSE: To study the outcomes of balloon dacryoplasty (BD) or (BDCP) in children with persistent congenital nasolacrimal duct obstruction (pCNLDO) by using new and reused balloon catheters. METHODS: Our retrospective analysis focused on managing pCNLDO by using the BD or BDCP technique. The study included children aged >1 year to <12 years who underwent single or multiple probings before. Our specific lacrimal workup included a detailed history and examination, as published earlier. We used conventional, straight, 2 mm × 13 mm/3 mm × 15 mm lacrimal balloons (FCI, Ophthacath). We have described a technique to use the same catheter for three BD procedures (1 new + 2 reuse). The outcomes were categorized as complete success, partial success, and failure. The minimum follow-up of each child was 6 months. RESULTS: We analyzed 64 children (89 eyes) with a mean age of 58 months (15-132 months). All children (100%) had epiphora with discharge and positive FDDT. All children underwent BD under general anesthesia - new balloons in 59 eyes and reused balloons in 30 eyes. The balloons were plasma sterilized akin to vitrectomy cutters and tubings of phaco machines. We noted three leaks from reused balloons (2 from the balloon tip and 1 from the plastic hub). At a mean follow-up of 14.5 months, complete success was noted in 77 eyes (86.5%) (52 new and 25 reuse), while 8 eyes had partial success (8.9%) (4 new and 4 reuse). Failure of BD was noted in four eyes (4.5%) (3 new and 1 reuse). None had significant complications with new or reused balloons. CONCLUSION: BD or BDCP is a quick, safe, easy, and effective procedure that resolves pCNLDO symptoms satisfactorily. Carefully reusing a conventional balloon catheter is possible with comparable efficacy and no additional complications in pCNLDO.

Influence of Silicon Supplementation on Growth, Immunity, Antioxidant, Hormonal Profile and Bone Health Biomarkers in Pre-ruminant Crossbred Calves.

Silicon (Si), a newer trace element, is believed to be important for healthy bone formation and to decrease bone resorption, improving the quality of bone by manipulating several hormones and enzymes. Therefore, the current investigation was conducted to determine the impact of Si supplementation on growth, immunity, antioxidant, hormonal profile and biomarkers of bone health in pre-ruminant crossbred calves. Twenty-four crossbred calves (5-7 days) were selected on the basis of their body weight (BW 31.65 ± 0.46 kg) and divided into 4 groups (n = 6) and fed as per ICAR (2013) feeding standards except that these were additionally supplemented with 0 (Si0), 50 (Si50), 100 (Si100) and 150 (Si150) mg of Si/kg dry matter (DM) in four respective groups for 90 days. Every month, peripheral blood samples were drawn (0, 30, 60 and 90 days post supplementing with Si) and analysed for antioxidant status, hormonal profile and bone health biomarkers. It is reported that dietary Si supplementation improved (P < 0.05) net body weight gain (kg), average daily gain (g) and average dry matter intake (kg), whereas feed intake (kg/100 kg BW), was not altered due to Si supplementation. Structural growth measurements were significantly higher (P < 0.05) in Si100 and Si150 groups as compared to Si50 and control groups. However, immune response (humoral as well as cell-mediated immunity), erythrocytic antioxidant enzymes (superoxide dismutase, SOD, glutathione peroxidase, GPx and catalase), plasma ferric reducing total antioxidant power (FRAP) activity and the plasma concentration of total immunoglobulins (TIg) remained unaffected by Si supplementation. Silicon increased (P < 0.05) the concentration of plasma growth hormone (GH), vitamin D3, bone alkaline phosphatase (BALP) and osteocalcin (OCN) in Si100 and Si150 groups, but the levels of calcitonin, parathyroid hormone (PTH) and hydroxyproline (HYP) remained similar among all the groups. As a result of the current investigation, it can be inferred that the inclusion of 100 and 150 mg of Si/kg DM was effective in improving the growth performance, growth hormone, vitamin D3 and bone health status in pre-ruminant calves. However, supplementation of 150 mg of Si/kg DM had no additional benefit; therefore 100 mg of Si/kg DM is the optimum level of Si supplementation in pre-ruminant calves.

Isolated cavernous venous malformation of the eyelid.

Cavernous hemangioma, currently known as "cavernous venous malformation," is a common, benign, non-infiltrative, slowly progressive vascular malformation of the orbit presenting in adults. We report the case of a 9-year-old girl who presented with a painless palpable mass over the right upper eyelid of 7 years' duration. A computed tomography scan of the orbits revealed a heterogeneously enhancing, well-circumscribed mass in the right upper eyelid with no orbital extension. A transcutaneous excisional biopsy with histopathology disclosed cavernous venous malformation. The majority of cavernous venous malformations are intraconal and present in the fourth to fifth decade of life.

Future Directions: The Phenomenology of Irritable Mood and Outbursts: Hang Together or Hang Separately1.

Recognition of the importance of irritable mood and outbursts has been increasing over the past several decades. This "Future Directions" aims to develop a set of recommendations for future research emphasizing that irritable mood and outbursts "hang together," but have important distinctions and thus also need to "hang separately." Outbursts that are the outcome of irritable mood may be quite different from outbursts that are the trigger or driving force that make youth and his/her environment miserable. What, then, is the relation between irritable mood and outbursts? As the field currently stands, we not only cannot answer this question, but we may also lack the tools to effectively do so. Here, we will propose recommendations for understanding the phenomenology of irritable mood and outbursts so that more directed and clinically useful assessment tools can be designed. We discuss the transdiagnostic and treatment implications that relate to improvements in measurement. We describe the need to do more than repurpose our current assessment tools, specifically interviews and rating scales, which were designed for different purposes. The future directions of the study and treatment of irritable mood and outbursts will require, among others, using universally accepted nomenclature, supporting the development of tools to measure the characteristics of each irritable mood and outbursts, understanding the effects of question order, informant, development and longitudinal course, and studying the ways in which outbursts and irritable mood respond to treatment.

Ensuring Stakeholder Feedback in the Design and Conduct of Clinical Trials for Rare Diseases: ISCTM Position Paper of the Orphan Disease Working Group.

The 1983 Orphan Drug Act in the United States (US) changed the landscape for development of therapeutics for rare or orphan diseases, which collectively affect approximately 300 million people worldwide, half of whom are children. The act has undoubtedly accelerated drug development for orphan diseases, with over 6,400 orphan drug applications submitted to the US Food and Drug Administration (FDA) from 1983 to 2023, including 350 drugs approved for over 420 indications. Drug development in this population is a global and collaborative endeavor. This position paper of the International Society for Central Nervous System Clinical Trials and Methodology (ISCTM) describes some potential best practices for the involvement of key stakeholder feedback in the drug development process. Stakeholders include advocacy groups, patients and caregivers with lived experience, public and private research institutions (including academia and pharmaceutical companies), treating clinicians, and funders (including the government and independent foundations). The authors articulate the challenges of drug development in orphan diseases and propose methods to address them. Challenges range from the poor understanding of disease history to development of endpoints, targets, and clinical trials designs, to finding solutions to competing research priorities by involved parties.

Pharmacogenetic Factors Influence Escitalopram Pharmacokinetics and Adverse Events in Youth with a Family History of Bipolar Disorder: A Preliminary Study.

Introduction: Escitalopram is an effective and generally well-tolerated antidepressant, but children of parents with bipolar disorder (BD) may be at increased risk for adverse events associated with antidepressants, including increased irritability, restlessness, impulsivity, and manic symptoms. This risk may be influenced by polymorphisms in genes encoding cytochrome P450 enzymes (CYP2C19 or CYP2D6), the serotonin transporter (SLC6A4), and the serotonin receptor 2A subtype (HTR2A). We explored whether gene-drug interactions influence the emergence of adverse events in depressed and/or anxious youth with a family history of BD. Materials and Methods: Children and adolescents aged 12-17 years with a first-degree relative with bipolar I disorder were treated with escitalopram and monitored for adverse effects, underwent pharmacogenetic testing, and provided serum escitalopram levels. Emergence of adverse events was determined by study clinicians, and symptoms were tracked using the Treatment-Emergent Activation and Suicidality Assessment Profile (TEASAP) and Pediatric Adverse Events Rating Scale. Clinical Pharmacogenetics Implementation Consortium guidelines were used to determine CYP2C19 and CYP2D6 phenotypes. Results: Slower CYP2C19 metabolizers had greater dose-normalized 24-hour area under the curve (AUC0-24; p = 0.025), trough concentrations (Ctrough; p = 0.013), and elimination half-lives (t1/2; p < 0.001). CYP2D6 phenotype was not significantly associated with any pharmacokinetic parameter. Slower CYP2D6 metabolizers had increased TEASAP akathisia (p = 0.015) scores. HTR2A A/A and A/G genotypes were associated with increased TEASAP "self-injury, suicidality, and harm to others" subscale scores (p = 0.017). Escitalopram maximum concentration, AUC0-24, CYP2C19 phenotype, and SLC6A4 genotype were not associated with adverse events. Conclusions: CYP2C19 phenotype influences escitalopram pharmacokinetics whereas CYP2D6 phenotype does not. Slower CYP2D6 metabolism was associated with increased akathisia, and HTR2A A/A or A/G genotypes were associated with increased risk of self-harm or harm to others. Larger cohorts are needed to identify associations between genetic test results and antidepressant-associated adverse events. Trial Registration: ClinicalTrials.gov identifier: NCT02553161.