Long-lasting redundant gnrh1/3 expression in GnRH neurons enabled apparent switching of paralog usage during evolution.

Expressed subtype of paralogous genes in functionally homologous cells sometimes show differences across species, the reasons for which have not been explained. The present study examined hypophysiotropic gonadotropin-releasing hormone (GnRH) neurons in vertebrates to investigate this mechanism. These neurons express either gnrh1 or gnrh3 paralogs, depending on the species, and apparent switching of the expressed paralogs in them occurred at least four times in vertebrate evolution. First, we found redundant expression of gnrh1 and gnrh3 in a single neuron in piranha and hypothesized that it may represent an ancestral GnRH system. Moreover, the gnrh1/gnrh3 enhancer of piranha induced reporter RFP/GFP co-expression in a single hypophysiotropic GnRH neuron in both zebrafish and medaka, whose GnRH neurons only express either gnrh3 or gnrh1. Thus, we propose that redundant expression of gnrh1/3 of relatively recent common ancestors may be the key to apparent switching of the paralog usage among present-day species.

Genome-wide screens identify SEL1L as an intracellular rheostat controlling collagen turnover.

Accumulating evidence has implicated impaired extracellular matrix (ECM) clearance as a key factor in fibrotic disease. Despite decades of research elucidating the effectors of ECM clearance, relatively little is understood regarding the upstream regulation of this process. Collagen is the most abundant constituent of normal and fibrotic ECM in mammalian tissues. Its catabolism occurs through extracellular proteolysis and cell-mediated uptake of collagen fragments for intracellular degradation. Given the paucity of information regarding the regulation of this latter process, here we execute unbiased genome-wide screens to understand the molecular underpinnings of cell-mediated collagen clearance. Using this approach, we discover a mechanism through which collagen biosynthesis is sensed by cells internally and directly regulates clearance of extracellular collagen. The sensing mechanism appears to be dependent on endoplasmic reticulum-resident protein SEL1L and occurs via a noncanonical function of this protein. This pathway functions as a homeostatic negative feedback loop that limits collagen accumulation in tissues. In human fibrotic lung disease, the induction of this collagen clearance pathway by collagen synthesis is impaired, thereby contributing to the pathological accumulation of collagen in lung tissue. Thus, we describe cell-autonomous, rheostatic collagen clearance as an important pathway of tissue homeostasis.

PTP1B mediates the inhibitory effect of MFGE8 on insulin signaling through the ß5 integrin.

Integrins are cell adhesion receptors that dimerize to mediate cell-cell interactions and regulate processes, including proliferation, inflammation, and tissue repair. The role of integrins in regulating insulin signaling is incompletely understood. We have previously shown that binding of the integrin ligand milk fat globule epidermal growth factor like 8 (MFGE8) to the αvß5 integrin promotes termination of insulin receptor signaling in mice. Upon ligation of MFGE8, integrin ß5 complexes with the insulin receptor beta (IRß) in skeletal muscle, resulting in dephosphorylation of IRß and reduction of insulin-stimulated glucose uptake. Here, we investigate the mechanism by which the interaction between ß5 and IRß impacts IRß phosphorylation status. We show in in vitro and in vivo in skeletal muscle in mice that antibody-mediated blockade of the ß5 integrin inhibits and recombinant MFGE8 promotes PTP1B binding to and dephosphorylation of IRß resulting in increased or reduced insulin-stimulated glucose uptake, respectively. The ß5-PTP1B complex is recruited by MFGE8 to IRß leading to termination of canonical insulin signaling. ß5 blockade enhances insulin-stimulated glucose uptake in wildtype but not Ptp1b KO mice indicating that PTP1B functions downstream of MFGE8 in modulating insulin receptor signaling. Furthermore, in a human cohort, we report serum MFGE8 levels correlate with indices of insulin resistance. These data provide mechanistic insights into the role of MFGE8 and ß5 in regulating insulin signaling.

Three cases of recalcitrant Paecilomyces keratitis in Southern California within a short period.

BACKGROUND: The aim of this report is to describe the risk factors, clinical course, and characteristics of three cases of Paecilomyces keratitis presenting concurrently within three months in the same location. We used in vivo confocal microscopy and histopathology to corroborate our clinical findings. OBSERVATIONS: Three eyes of three elderly patients with culture-proven Paecilomyces keratitis were included in this series. These patients resided within a 15-mile radius and presented to a tertiary care eye institute in Southern California between February and April 2022. All three eyes experienced a prolonged, recalcitrant course with recurrence of keratitis in donor corneal tissue despite antifungal therapy and multiple therapeutic penetrating keratoplasties. In vivo confocal microscopy, histopathology, and microbiologic findings corroborated the diagnosis of fungal keratitis with Paecilomyces. With surgical intervention and extensive medical therapy, all three cases resolved after the addition of oral Posaconazole. CONCLUSIONS: Paecilomyces is a rare cause of infectious keratitis. Herein we report three similar cases in elderly patients. All had prolonged, recalcitrant infections that required multiple treatment modalities. Our cases, which were supported by in vivo confocal microscopy and histopathology, highlight the importance of timely and aggressive therapy to prevent recurrence.

Disparities in Retinal Vein Occlusion Presentation and Initiation of Anti-VEGF Therapy: An Academy IRIS® Registry Analysis.

OBJECTIVE: Investigate disparities in retinal vein occlusion (RVO) presentation and initiation of anti-VEGF treatment. DESIGN: Retrospective cohort study. SUBJECTS: Patients in the American Academy of Ophthalmology IRIS® (Intelligent Research in Sight) Registry database (2015-2021) with branch or central RVO and macular edema (ME). METHODS: The association of demographic characteristics and presenting visual acuity (VA) with anti-VEGF treatment initiation were quantified using multivariable logistic regression. MAIN OUTCOME MEASURES: Treatment with ≥ 1 anti-VEGF injection within 12 months after RVO diagnosis. RESULTS: A total of 304 558 eligible patients with RVO and ME were identified. Age at presentation varied by race, ethnicity, sex, and RVO type (all P values < 0.001). Within the first year after RVO presentation, 192 602 (63.2%) patients received ≥ 1 anti-VEGF injection. In a multivariable regression model adjusting for relevant covariates, female (vs. male) patients had lower odds of receiving injections (odds ratio [OR], 0.95; 95% confidence interval [CI], 0.93-0.96; P < 0.0001) as did Black/African American (vs. White) patients (OR, 0.90; 95% CI, 0.88-0.92; P < 0.0001) and Asian (vs. White) patients (OR, 0.95; 95% CI, 0.91-0.99; P = 0.02), whereas older patients (vs. patients aged < 51 years) had higher odds (61-70 years: OR, 1.20; 95% CI, 1.16-1.24; 71-80 years: OR, 1.20; 95% CI, 1.16-1.24; > 80 years: OR, 1.15; 95% CI, 1.11-1.18; all P values < 0.0001). Hispanic (vs. non-Hispanic) patients had a small increased odds of treatment initiation (OR, 1.08; 95% CI, 1.04-1.11; P < 0.0001). Results were similar in the subset of 226 143 patients with VA data. In this subset, patients with presenting VA < 20/40 to 20/200 were most frequently treated in the first year after diagnosis (∼ 70%) and patients with light perception/no light perception (LP-NLP) vision or VA of 20/20 or better were treated least frequently (36.9% and 41.9%, respectively). CONCLUSIONS: In this large national clinical registry, 37% of RVO patients with ME had no anti-VEGF treatment documented in the first year after diagnosis. Black/African American, Asian, and female patients and patients with VA of LP-NLP were least likely to receive treatment. Awareness of this undertreatment and these disparities highlight the need for initiatives to ensure all RVO patients receive timely anti-VEGF injections for optimized visual outcomes. FINANCIAL DISCLOSURES: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

The role of intrapartum fetal head compression in neonatal retinal hemorrhage.

PURPOSE: Neonatal retinal hemorrhage is a common finding in newborns, but the underlying mechanisms are not fully understood. A computational simulation was designed to study the events taking place in the eye and orbit when the head is compressed as the neonate passes through the birth canal. METHODS: A finite element model of the eye, optic nerve sheath, and orbit was simulated and subjected to forces mimicking rises in intracranial pressure (ICP) associated with maternal contractions during normal vaginal delivery. Resulting changes in intraocular pressure (IOP), pressure in the optic nerve sheath, and stress within the sclera and retina were measured. RESULTS: During contractions, increased ICP was transmitted to the orbit, globe, and optic nerve sheath. IOP rose by 2.71 kPa near the posterior pole. Pressure at the center of the optic nerve sheath rose by 7.31 kPa and up to 9.30 kPa at its interface with the sclera. Stress in the retina was highest near the optic disk and reached 10.93, 10.99, and 13.28 kPa in the preretinal, intraretinal, and subretinal layers, respectively. Stress in the sclera peaked at 12.76 kPa. CONCLUSIONS: Increasing ICP associated with natural vaginal delivery increases intraorbital pressure, which applies stress to the retina. Associated retinal deformation may cause tearing of the retinal vasculature. Increased pressure within the optic nerve sheath may occlude the central retinal vein, resulting in outflow obstruction and subsequent rupture. Forces accumulated near the optic disk, likely accounting for the tendency of neonatal retinal hemorrhage to occur posteriorly.

Examining Public Awareness of Ageist Terms on Twitter: Content Analysis.

Background: The World Health Organization, the Centers for Disease Control and Prevention, and the Gerontological Society of America have made efforts to raise awareness on ageist language and propose appropriate terms to denote the older adult population. The COVID-19 pandemic and older adults' vulnerability to the disease have perpetuated hostile ageist discourse on social media. This is an opportune time to understand the prevalence and use of ageist language and discuss the ways forward. Objective: This study aimed to understand the prevalence and situated use of ageist terms on Twitter. Methods: We collected 60.32 million tweets between March and July 2020 containing terms related to COVID-19. We then conducted a mixed methods study comprising a content analysis and a descriptive quantitative analysis. Results: A total of 58,930 tweets contained the ageist terms "old people" or "elderly." The more appropriate term "older adult" was found in 11,328 tweets. Twitter users used ageist terms (eg, "old people" and "elderly") to criticize ageist messages (17/60, 28%), showing a lack of understanding of appropriate terms to describe older adults. Highly hostile ageist content against older adults came from tweets that contained the derogatory terms "old people" (22/30, 73%) or "elderly" (13/30, 43%). Conclusions: The public discourse observed on Twitter shows a continued lack of understanding of appropriate terms to use when referring to older adults. Effort is needed to eliminate the perpetuation of ageist messages that challenge healthy aging. Our study highlights the need to inform the public about appropriate language use and ageism.

Frequent temporal patterns of physiological and biological biomarkers and their evolution in sepsis.

Sepsis is one of the most challenging health conditions worldwide, with relatively high incidence and mortality rates. It is shown that preventing sepsis is the key to avoid potentially irreversible organ dysfunction. However, data-driven early identification of sepsis is challenging as sepsis shares signs and symptoms with other health conditions. This paper adopts a temporal pattern mining approach to identify frequent temporal and evolving patterns of physiological and biological biomarkers in sepsis patients. We show that using these frequent patterns as features for classifying sepsis and non-sepsis patients can improve the prediction accuracy and performance up to 7%. Most of the temporal modeling approaches adopted in the sepsis literature are based on deep learning methods. Although these approaches produce high accuracy, they generally have limited model explainability and interpretability. Using the adopted methods in this study, we could identify the most important features contributing to the patients' sepsis incidence, such as fluctuations in platelet, lactate, and creatinine, or evolution of patterns including renal and metabolic organ systems, and consequently, enhance the findings' clinical interpretability.

MFGE8 inhibits insulin signaling through PTP1B.

The role of integrins in regulating insulin signaling is incompletely understood. We have previously shown that binding of the integrin ligand milk fat globule epidermal growth factor like 8 (MFGE8) to the αvß5 integrin promotes termination of insulin receptor signaling in mice. Upon ligation of MFGE8, ß5 complexes with the insulin receptor beta (IRß) in skeletal muscle resulting in dephosphorylation of IRß and reduction of insulin-stimulated glucose uptake. Here we investigate the mechanism by which the interaction between ß5 and IRß impacts IRß phosphorylation status. We show that ß5 blockade inhibits and MFGE8 promotes PTP1B binding to and dephosphorylation of IRß resulting in reduced or increased insulin-stimulated myotube glucose uptake respectively. The ß5-PTP1B complex is recruited by MFGE8 to IRß leading to termination of canonical insulin signaling. ß5 blockade enhances insulin-stimulated glucose uptake in wild type but not Ptp1b KO mice indicating that PTP1B functions downstream of MFGE8 in modulating insulin receptor signaling. Furthermore, in a human cohort, we report serum MFGE8 levels correlate with indices of insulin resistance. These data provide mechanistic insights into the role of MFGE8 and ß5 in regulating insulin signaling.

Optical Control of Slow Topological Electrons in Moiré Systems.

Floquet moiré materials possess optically-induced flat-electron bands with steady-states sensitive to drive parameters. Within this regime, we show that strong interaction screening and phonon bath coupling can overcome enhanced drive-induced heating. In twisted bilayer graphene (TBG) irradiated by a terahertz-frequency continuous circularly polarized laser, the extremely slow electronic states enable the drive to control the steady state occupation of high-Berry curvature electronic states. In particular, above a critical field amplitude, high-Berry-curvature states exhibit a slow regime where they decouple from acoustic phonons, allowing the drive to control the anomalous Hall response. Our work shows that the laser-induced control of topological and transport physics in Floquet TBG are measurable using experimentally available probes.

The IHI Rochester Report 2022 on Healthcare Informatics Research: Resuming After the CoViD-19.

In 2020, the CoViD-19 pandemic spread worldwide in an unexpected way and suddenly modified many life issues, including social habits, social relationships, teaching modalities, and more. Such changes were also observable in many different healthcare and medical contexts. Moreover, the CoViD-19 pandemic acted as a stress test for many research endeavors, and revealed some limitations, especially in contexts where research results had an immediate impact on the social and healthcare habits of millions of people. As a result, the research community is called to perform a deep analysis of the steps already taken, and to re-think steps for the near and far future to capitalize on the lessons learned due to the pandemic. In this direction, on June 09th-11th, 2022, a group of twelve healthcare informatics researchers met in Rochester, MN, USA. This meeting was initiated by the Institute for Healthcare Informatics-IHI, and hosted by the Mayo Clinic. The goal of the meeting was to discuss and propose a research agenda for biomedical and health informatics for the next decade, in light of the changes and the lessons learned from the CoViD-19 pandemic. This article reports the main topics discussed and the conclusions reached. The intended readers of this paper, besides the biomedical and health informatics research community, are all those stakeholders in academia, industry, and government, who could benefit from the new research findings in biomedical and health informatics research. Indeed, research directions and social and policy implications are the main focus of the research agenda we propose, according to three levels: the care of individuals, the healthcare system view, and the population view.

How Many Fenestrations Should I Make When Placing a Baerveldt Glaucoma Implant? A Laboratory Study.

Purpose: This study investigates the effect of one versus two fenestrations on both fluid egress and opening pressure from a non-valved glaucoma implant. Methods: In this laboratory study, we used an in vitro closed system comprised of ligated silicone tubing connected to a fluid reservoir and manometer to simulate the tubing found in a Baerveldt glaucoma drainage implant. Fenestrations were created using an 8-0 Vicryl TG140-8 suture needle. Main outcome measures included volume of fluid egress and fenestration opening pressures, which were measured via micropipette and increasing pressure until fluid egress was observed. Results: No significant difference was observed in fluid egress between tubing with one versus two fenestrations at pressures ≤40 mmHg. At 50 mmHg, a statistically significant difference was observed in fluid egress between tubing with one versus two fenestrations (P < 0.05). The first fenestration opened at 10.5 ± 3.77 mmHg and the second fenestration opened at 28.83 ± 5.09 mmHg (average ± standard deviation). Conclusion: Our in vitro findings suggest there may exist a critical pressure >40 mmHg at which the second fenestration starts to play a significant role in fluid drainage. There may be no difference in the amount of fluid egress and effect on intraocular pressure between one or two tube fenestrations when preoperative intraocular pressure is ≤40 mmHg.

MFGE8 links absorption of dietary fatty acids with catabolism of enterocyte lipid stores through HNF4γ-dependent transcription of CES enzymes.

Enterocytes modulate the extent of postprandial lipemia by storing dietary fats in cytoplasmic lipid droplets (cLDs). We have previously shown that the integrin ligand MFGE8 links absorption of dietary fats with activation of triglyceride (TG) hydrolases that catabolize cLDs for chylomicron production. Here, we identify CES1D as the key hydrolase downstream of the MFGE8-αvß5 integrin pathway that regulates catabolism of diet-derived cLDs. Mfge8 knockout (KO) enterocytes have reduced CES1D transcript and protein levels and reduced protein levels of the transcription factor HNF4γ. Both Ces1d and Hnf4γ KO mice have decreased enterocyte TG hydrolase activity coupled with retention of TG in cLDs. Mechanistically, MFGE8-dependent fatty acid uptake through CD36 stabilizes HNF4γ protein level; HNF4γ then increases Ces1d transcription. Our work identifies a regulatory network that regulates the severity of postprandial lipemia by linking dietary fat absorption with protein stabilization of a transcription factor that increases expression of hydrolases responsible for catabolizing diet-derived cLDs.

Anterior Chamber Washout During Ahmed Valve Glaucoma Surgery Reduces the Incidence of Hypertensive Phase.

PRCIS: Intraoperative anterior chamber (AC) washout reduces the odds of hypertensive phase (HP) by 95% compared with those not receiving washout during Ahmed glaucoma implant (AGI), suggesting AC washout is an effective prophylaxis for postoperative HP. PURPOSE: To characterize the incidence of postoperative HP in patients receiving AC washout at the time of AGI. PATIENTS AND METHODS: A total of 24 patients with medically refractory glaucoma who underwent AGI surgery at a tertiary academic medical center in Southern California from December 2018 through March 2021 were included in this retrospective comparative case series. Patients who received a pediatric implant and underwent concurrent intraocular surgery or did not complete a minimum of 6 months of follow-up were excluded. Nine patient's eyes received AC washout and 15 controls that were analyzed through 6 months postprocedure. HP was defined as intraocular pressure (IOP) above 21 mm Hg within 6 months postprocedure with maximum tolerated medical therapy. AC washout was performed by irrigating the AC with a 5 mL balanced salt solution before placing the tube of the AGI into the AC. The rate of postoperative HP, defined as peak IOP >21 mm Hg, at 6 months follow-up, was observed as the primary outcome measure. RESULTS: Patients included in the study had a high mean preoperative IOP ( X̅ = 44.11, SD = 13.85). There were no baseline differences between the washout and control groups. The odds of HP were significantly reduced (odds ratio: 0.050; 95% CI: 0.004, 0.706; P = 0.027) for patients who underwent intraoperative AC washout compared with those who did not. Bivariate analysis of subject baseline characteristics revealed that only washout status was significantly different in subjects with HP compared with subjects without HP ( P = 0.015). A multivariate logistic regression model using washout status and autoimmune conditions as covariates was significant in predicting HP ( X2 (2) = 12.337, P = 0.002), with washout as a significant predictor when controlling for autoimmune comorbidities ( P = 0.027). CONCLUSIONS: AC washout significantly decreases the odds of HP after AGI surgery. AC washout with balanced salt solution adds minimal time and risks to surgery and therefore may be an effective adjunct during AGI placement.

Genome-wide screens identify SEL1L as an intracellular rheostat controlling collagen turnover.

Accumulating evidence has implicated impaired extracellular matrix (ECM) clearance as a key factor in fibrotic disease. Despite decades of research elucidating the effectors of ECM clearance, relatively little is understood regarding the upstream regulation of this process. Collagen is the most abundant constituent of normal and fibrotic ECM in mammalian tissues. Its catabolism occurs through extracellular proteolysis and cell-mediated uptake of collagen fragments for intracellular degradation. Given the paucity of information regarding the regulation of this latter process, we executed unbiased genome-wide screens to understand the molecular underpinnings of cell-mediated collagen clearance. Using this approach, we discovered a previously unappreciated mechanism through which collagen biosynthesis is sensed by cells internally and directly regulates clearance of extracellular collagen. The sensing mechanism is dependent on endoplasmic reticulum-resident protein SEL1L and occurs via a noncanonical function of SEL1L. This pathway functions as a homeostatic negative feedback loop that limits collagen accumulation in tissues. In human fibrotic lung disease, the induction of this collagen clearance pathway by collagen synthesis is impaired, thereby contributing to the pathological accumulation of collagen in lung tissue. Thus cell-autonomous, rheostatic collagen clearance is a previously unidentified pathway of tissue homeostasis.

Control becomes habitual early on when learning a novel motor skill.

When people perform the same task repeatedly, their behavior becomes habitual, or inflexible to changes in the goals or structure of a task. Although habits have been hypothesized to be a key aspect of motor skill acquisition, there has been little empirical work investigating the relationship between skills and habits. To better understand this relationship, we examined whether and when people's behavior would become habitual as they learned a challenging new motor skill: maneuvering an on-screen cursor with a nonintuitive bimanual mapping from hand to cursor position. After participants practiced using this mapping for up to 10 days, we altered the mapping between the hands and the cursor to assess whether participants could flexibly adjust their behavior or would habitually persist in performing the task the way they had originally learned. We found that participants' behavior became habitual within 2 days of practice, at which point they were still relatively unskilled. Further practice led to improved skill but did not alter the strength of habitual behavior. These data demonstrate that motor skills become habitual after relatively little training but can nevertheless further improve with practice. We suggest that building habits early in learning may be a crucial step in acquiring new motor skills.NEW & NOTEWORTHY Habits and motor skills have often been thought to be deeply related, but very few studies have empirically examined the relationship between the two. We present evidence that habits emerge early in learning, long before a motor skill has been fully learned. Our results suggest that habits may play an integral role in the learning and performance of motor skills from even the early stages of acquiring a new skill.

De novo motor learning of a bimanual control task over multiple days of practice.

Although much research on motor learning has focused on how we adapt our movements to maintain performance in the face of imposed perturbations, in many cases, we must learn new skills from scratch or de novo. Compared with adaptation, relatively little is known about de novo learning. In part, this is because learning a new skill can involve many challenges, including learning to recognize new patterns of sensory input and generate new patterns of motor output. However, even with familiar sensory cues and well-practiced movements, the problem of quickly selecting the appropriate actions in response to the current state is challenging. Here, we devised a bimanual hand-to-cursor mapping that isolates this control problem. We find that participants initially struggled to control the cursor under this bimanual mapping, despite explicit knowledge of the mapping. Performance improved steadily over multiple days of practice, however. Participants exhibited no aftereffects when reverting to a veridical cursor, confirming that participants learned the new task de novo, rather than through adaptation. Corrective responses to mid-movement perturbations of the target were initially weak, but with practice, participants gradually became able to respond rapidly and robustly to perturbations. After 4 days of practice, participants' behavior under the bimanual mapping almost matched performance using a veridically mapped cursor. However, there remained a small but persistent difference in performance level. Our findings illustrate the dynamics and limitations of learning a novel controller and introduce a promising paradigm for tractably investigating this aspect of motor skill learning.NEW & NOTEWORTHY We examine motor learning in a novel task in which participants must use both hands to control an on-screen cursor via a nonintuitive interface. Participants gradually improved their ability to control the cursor over multiple practice sessions, but their control was worse than baseline even after 4 days. These results reveal the timescale and limitations of de novo learning-an important but understudied form of learning.

Mental health conditions and unsafe driving behaviors: A naturalistic driving study on ADHD and depression.

INTRODUCTION: Road injuries remain a persistent public health concern across the world. The task of driving is complicated by mental health conditions, which may affect drivers' executive functioning and cognitive resource allocation. This study examines whether attention-deficit/hyperactivity disorder (ADHD) and depression are associated with unsafe driving behaviors. METHOD: Generalized linear mixed models were employed to estimate the association of self-reported ADHD and depression with 18 unsafe driving behavior types found prior to at-fault crashes and near-crashes using a large-scale naturalistic driving dataset. Driver demographics, cognitive traits, environmental factors, and driver random effects were included to reduce confounding and biases. RESULTS: Controlling for other covariates, people with self-reported ADHD were more likely to have performed improper braking or stopping (OR = 4.89, 95% CI 1.82-13.17) prior to an at-fault crash or near-crash, while those with self-reported depression did not have a significant association with any unsafe driving behavior. CONCLUSIONS: After accounting for demographic, cognitive, and environmental covariates, individuals with ADHD and depression were not prone to purposefully aggressive or reckless driving. Instead, drivers with self-reported ADHD may unintentionally execute unsafe driving behaviors in particular driving scenarios that require a high level of cognitive judgment. PRACTICAL APPLICATIONS: These findings can inform the curriculum design of driver's education programs that help learners with mental health conditions gain practice in certain road scenarios, for example, more practice on preemptively reducing speed instead of making sudden brakes and smooth turning on curved roads for students with ADHD. Furthermore, specific advanced driver assistance systems may prove particularly helpful for drivers with ADHD, such as detection of leading objects and curve speed warning.