Search

Objective/background Adults with multiple sclerosis (MS) often present with conditions that mimic restless legs syndrome (RLS), thereby adding complexity into the assessment of RLS severity. The current gold-standard measures of RLS severity rely on a fixed seven-day time frame, which limits the ability of these measures for studying acute changes in RLS severity. The present study examined if subjective and objective scores from the suggested immobilization test (SIT) provide a valid and reliable acute measure of RLS severity in persons with MS. Patients/methods Participants with MS and RLS (n = 20) and MS without RLS (n = 20) were matched by age, gender, and disability. All participants completed validated questionnaires for RLS severity followed by the SIT, conducted at 18:00 (±15 min) on the same day of the week for two consecutive weeks. Participants wore accelerometer devices for seven nights to capture periodic limb movements (PLMs) during the night. Results Self-reported RLS severity during the SIT had excellent construct validity and convergent validity, but moderate test-retest reliability. Device-measured PLMs, while not themselves a direct measure of RLS severity, were significantly associated with PLMs during the night and had excellent test-retest reliability during the SIT in adults with MS. Conclusions Our results suggest that the SIT represents a valid acute measure for capturing self-reported sensory aspects of RLS severity and should be considered in future research and clinical practice as a standardized acute measure of subjective RLS severity in adults with MS who present with RLS.

Only survey studies have linked specific individual psychiatric disorders such as anxiety, depression and schizophrenia to Restless Legs Syndrome (RLS), Periodic Limb Movements in Sleep (PLMS) or both. We therefore aim to polysomnographically characterize sleep in a sample of physician-based, newly diagnosed cases of RLS with various ICD-10 psychiatric diagnoses. Retrospective analysis of data from a convenience sample of psychiatric patients (n = 43) per standard clinical sleep disorder cut-offs was conducted. Next, a cluster analysis was performed on the sleep data, taking into account the psychiatric diagnosis, comorbid non-psychiatric somatic problems and medication. We found that 37.2% of our sample showed clinically significant PLMS ≥ 15 and 76.5% exhibited an apnea hypopnea index (AHI) ≥ 5. Sleep structure was unaltered apart from the PLMS-related parameters. Two clusters were statistically identified: Cluster 1 primarily representing recurrent major depressive issues and Cluster 2 representing present but not predominant mood symptomatology as well as mixed disorders with personality problems. The known confounders were controlled. A PLMS index ≥ 15 was differentially distributed among the two clusters with Cluster 1: 10 out of 17 with PLMS index ≥ 15, Cluster 2: 1 out of 16 with PLMS index ≥15, whilst AHI was not different. Patients in Cluster 1 have a higher rate of periodic leg movements than patients in Cluster 2. This suggests that the high association with PLMS is primarily driven by affective disorders. Our findings warrant questioning of RLS symptomatology in patients with psychiatric conditions.

SARS-CoV-2, the virus that causes COVID-19, is constantly mutating, leading to new variants (1). Variants have the potential to affect transmission, disease severity, diagnostics, therapeutics, and natural and vaccine-induced immunity. In November 2020, CDC established national surveillance for SARS-CoV-2 variants using genomic sequencing. As of May 6, 2021, sequences from 177,044 SARS-CoV-2-positive specimens collected during December 20, 2020-May 6, 2021, from 55 U.S. jurisdictions had been generated by or reported to CDC. These included 3,275 sequences for the 2-week period ending January 2, 2021, compared with 25,000 sequences for the 2-week period ending April 24, 2021 (0.1% and 3.1% of reported positive SARS-CoV-2 tests, respectively). Because sequences might be generated by multiple laboratories and sequence availability varies both geographically and over time, CDC developed statistical weighting and variance estimation methods to generate population-based estimates of the proportions of identified variants among SARS-CoV-2 infections circulating nationwide and in each of the 10 U.S. Department of Health and Human Services (HHS) geographic regions.* During the 2-week period ending April 24, 2021, the B.1.1.7 and P.1 variants represented an estimated 66.0% and 5.0% of U.S. SARS-CoV-2 infections, respectively, demonstrating the rise to predominance of the B.1.1.7 variant of concern† (VOC) and emergence of the P.1 VOC in the United States. Using SARS-CoV-2 genomic surveillance methods to analyze surveillance data produces timely population-based estimates of the proportions of variants circulating nationally and regionally. Surveillance findings demonstrate the potential for new variants to emerge and become predominant, and the importance of robust genomic surveillance. Along with efforts to characterize the clinical and public health impact of SARS-CoV-2 variants, surveillance can help guide interventions to control the COVID-19 pandemic in the United States.

The 21st Century Cures Act (Cures Act), signed into law in 2016, was designed to advance new therapies by modernizing clinical trials, funding research initiatives, and accelerating the development and use of health information technology. To analyze the current issues in cancer care related to the implementation and impact of the Cures Act, NCCN convened a multistakeholder working group. Participants discussed the legislation’s impact on the oncology community since enactment and identified the remaining gaps and challenges as experienced by stakeholders. In June 2020, the policy recommendations of the working group were presented at the virtual NCCN Policy Summit: Accelerating Advances in Cancer Care Research: A Lookback at the 21st Century Cures Act in 2020. The summit consisted of informative discussions and a multistakeholder panel to explore the recommendations and the future of the Cures Act. This article explores identified policy recommendations from the NCCN Working Group and the NCCN Policy Summit, and analyzes opportunities to advance innovative cancer care and patient access to data.

Recent genome-wide association studies (GWAS) have found cerebellum as a top hit for sleep regulation. Restless legs syndrome (RLS) is a sleep-related sensorimotor disorder characterized by uncomfortable sensations in the extremities, generally at night, which are often relieved by movements. Clinical studies have found that RLS patients have structural and functional abnormalities in the cerebellum. However, whether and how cerebellar pathology contributes to sleep regulation and RLS is not known. GWAS identified polymorphisms in BTBD9 conferring a higher risk of sleep disruption and RLS. Knockout of the BTBD9 homolog in mice (Btbd9) and fly results in motor restlessness and sleep disruption. We performed manganese-enhanced magnetic resonance imaging on the Btbd9 knockout mice and found decreased neural activities in the cerebellum, especially in lobules VIII, X, and the deep cerebellar nuclei. Electrophysiological recording of Purkinje cells (PCs) from Btbd9 knockout mice revealed an increased number of non-tonic PCs. Tonic PCs showed increased spontaneous activity and intrinsic excitability. To further investigate the cerebellar contribution to RLS and sleep-like behaviors, we generated PC-specific Btbd9 knockout mice (Btbd9 pKO) and performed behavioral studies. Btbd9 pKO mice showed significant motor restlessness during the rest phase but not in the active phase. Btbd9 pKO mice also had an increased probability of waking at rest. Unlike the Btbd9 knockout mice, there was no increased thermal sensation in the Btbd9 pKO. Our results indicate that the Btbd9 knockout influences the PC activity; dysfunction in the cerebellum may contribute to the motor restlessness found in the Btbd9 knockout mice.

Restless legs syndrome (RLS) is characterized by an irresistible need to move the legs while sitting or lying at night with insomnia as a frequent consequence. Human RLS has been associated with abnormalities in the endogenous opioid system, the dopaminergic system, the iron regulatory system, anemia, and inflammatory and auto-immune disorders. Our previous work indicates that mice lacking all three subtypes of opioid receptors have a phenotype similar to that of human RLS. To study the roles of each opioid receptor subtype in RLS, we first used mu opioid receptor knockout (MOR KO) mice based on our earlier studies using postmortem brain and cell culture. The KO mice showed decreased hemoglobin, hematocrit, and red blood cells (RBCs), with an appearance of microcytic RBCs indicating anemia. Together with decreased serum iron and transferrin, but increased ferritin levels, the anemia is similar to that seen with chronic inflammation in humans. A decreased serum iron level was also observed in the wildtype mice treated with an MOR antagonist. Iron was increased in the liver and spleen of the KO mice. Normal circadian variations in the dopaminergic and serotoninergic systems were absent in the KO mice. The KO mice showed hyperactivity and increased thermal sensitivity in wakefulness primarily during what would normally be the sleep phase similar to that seen in human RLS. Deficits in endogenous opioid system transmission could predispose to anemia of inflammation and loss of circadian variations in dopaminergic or serotonergic systems, thereby contributing to an RLS-like phenotype.

Although oncology care has evolved, outcome assessment remains a key challenge. Outcome measurement requires identification and adoption of a succinct list of metrics indicative of high-quality cancer care for use within and across healthcare systems. NCCN established an advisory committee, the NCCN Quality and Outcomes Committee, consisting of provider experts from NCCN Member Institutions and other stakeholders, including payers and patient advocacy, community oncology, and health information technology representatives, to review the existing quality landscape and identify contemporary, relevant cancer quality and outcomes measures by reevaluating validated measures for endorsement and proposing new measure concepts to fill crucial gaps. This manuscript reports on 22 measures and concepts; 15 that align with existing measures and 7 that are new.

Objectives Hyper-inflammation caused by COVID-19 may be mediated by mast cell activation (MCA) which has also been hypothesized to cause Long-COVID (LC) symptoms. We determined prevalence/severity of MCA symptoms in LC. Methods Adults in LC-focused Facebook support groups were recruited for online assessment of symptoms before and after COVID-19. Questions included presence and severity of known MCA and LC symptoms and validated assessments of fatigue and quality of life. General population controls and mast cell activation syndrome (MCAS) patients were recruited for comparison if they were ≥18 years of age and never had overt COVID-19 symptoms. Results There were 136 LC subjects (89.7% females, age 46.9 ±12.9 years), 136 controls (65.4% females, age 49.2 ±15.5), and 80 MCAS patients (85.0% females, age 47.7 ±16.4). Pre-COVID-19 LC subjects and controls had virtually identical MCA symptom and severity analysis. Post-COVID-19 LC subjects and MCAS patients prior to treatment had virtually identical MCA symptom and severity analysis. Conclusions MCA symptoms were increased in LC and mimicked the symptoms and severity reported by patients who have MCAS. Increased activation of aberrant mast cells induced by SARS-CoV-2 infection by various mechanisms may underlie part of the pathophysiology of LC, possibly suggesting routes to effective therapy.

Simple Summary Despite advances in both the surgical and medical management of oesophageal adenocarcinoma (OAC), overall prognosis remains poor, with less than 1 in 5 patients surviving more than 5 years from diagnosis. Patients suitable for treatment with curative intent receive pre-operative chemotherapy, but few (

Neoadjuvant therapy followed by surgery is the standard of care for locally advanced esophageal adenocarcinoma (EAC). Unfortunately, response to neoadjuvant chemotherapy (NAC) is poor (20–37%), as is the overall survival benefit at five years (9%). The EAC genome is complex and heterogeneous between patients, and it is not yet understood whether specific mutational patterns may result in chemotherapy sensitivity or resistance. To identify associations between genomic events and response to NAC in EAC, a comparative genomic analysis was performed in 65 patients with extensive clinical and pathological annotation using whole-genome sequencing (WGS). We defined response using Mandard Tumor Regression Grade (TRG), with responders classified as TRG1–2 (n = 27) and non-responders classified as TRG4–5 (n =38). We report a higher non-synonymous mutation burden in responders (median 2.08/Mb vs. 1.70/Mb, p = 0.036) and elevated copy number variation in non-responders (282 vs. 136/patient, p &lt, 0.001). We identified copy number variants unique to each group in our cohort, with cell cycle (CDKN2A, CCND1), c-Myc (MYC), RTK/PIK3 (KRAS, EGFR) and gastrointestinal differentiation (GATA6) pathway genes being specifically altered in non-responders. Of note, NAV3 mutations were exclusively present in the non-responder group with a frequency of 22%. Thus, lower mutation burden, higher chromosomal instability and specific copy number alterations are associated with resistance to NAC.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19), a global pandemic characterized by an exaggerated immune response and respiratory illness. Age (&gt, 60 years) is a significant risk factor for developing severe COVID-19. To better understand the host response of the aged airway epithelium to SARS-CoV-2 infection, we performed an in vitro study using primary human bronchial epithelial cells from donors &gt, 67 years of age differentiated on an air–liquid interface culture. We demonstrate that SARS-CoV-2 infection leads to early induction of a proinflammatory response and a delayed interferon response. In addition, we observed changes in the genes and pathways associated with cell death and senescence throughout infection. In summary, our study provides new and important insights into the temporal kinetics of the airway epithelial innate immune response to SARS-CoV-2 in older individuals.

Background Patients with restless legs syndrome (RLS) have increased silent microvascular disease by magnetic resonance imaging. However, there has been no previous autopsy confirmation of these magnetic resonance imaging findings. RLS is also frequently associated with inflammatory and immunologically mediated medical disorders. The postmortem cortex in patients with RLS was therefore evaluated for evidence of microvascular and immunological changes. Methods and Results Ten microvascular injury samples of precentral gyrus in 5 patients with RLS (3 men, 2 women; mean age, 81 years) and 9 controls (2 men, 7 women; mean age, 90 years) were studied by hematoxylin and eosin stains in a blinded fashion. None of the subjects had a history of stroke or neurologic insults. In a similar manner, the following immunohistochemistry stains were performed: (1) glial fibrillary acidic protein (representing gliosis, reactive change of glial cells in response to damage); (2) CD3 (a T‐cell marker); (3) CD19 (a B‐cell marker); (4) CD68 (a macrophage marker); and (5) CD117 (a mast cell marker). Patients with RLS had significantly greater silent microvascular disease ( P =0.015) and gliosis ( P =0.003). T cells were increased in RLS compared with controls ( P =0.009) and tended to colocalize with microvascular disease ( P =0.003). Other markers did not differ. There was no correlation between microvascular lesion load and RLS severity or duration. Conclusions Patients with RLS had statistically significantly more silent cerebral microvascular disease and gliosis than controls compatible with previous magnetic resonance imaging studies and with studies showing a link between RLS and hypertension, clinical stroke, and cardiovascular disease. T‐cell invasion may be a secondary phenomenon.

Partial hospitalization programs are an increasingly utilized, multidisciplinary treatment for children with social, emotional, and behavioral needs. Although previous work suggests these programs improve children’s mental health functioning, outcomes research has been limited. This study examines moderators of emotional and behavioral outcomes in children with serious mental illness, with particular focus on demographic (age, race, insurance type, and gender) and family (stressors and supports) factors. The study includes 287 children ages 7–13. Children completed standardized questionnaires at admission and discharge including the Behavior Assessment System for Children-2 the Child Depression Inventory 2, and the Screen for Child Anxiety Related Disorders while caregivers completed the Strengths and Difficulties Questionnaire. Results indicate improvements in children’s anxiety, depressive symptoms, psychological adjustment, and emotional symptoms. Furthermore, children with private insurance reported significant decreases in depressive (p

Introduction The International Restless Legs Study Group (IRLSSG) has developed the IRLS (International Restless Legs Syndrome Severity Scale) and validated it as a clinician/researcher administered scale to be used when both patient and examiner are present. The IRLSSG recognized the need for a self-completing scale that can be used economically in clinical practice and in large population-based studies. In this study the validity and the reliability of the IRLS as a self-administered scale (sIRLS) is assessed. Methods Established RLS patients were recruited by eight centers in four countries and consented to participate in this study. The validity of the sIRLS was assessed by patients completing the sIRLS before a clinician administered the IRLS. The reliability of the sIRLS was assessed by patients completing the sIRLS again, two weeks after the first one, provided no change had occurred. Results Overall, 173 patients were recruited and 164 of them were included in the analyses. The sIRLS showed satisfactory scaling assumptions and no relevant floor or ceiling effect. One factor explained 61.3% of the variance. Cronbach's alpha was 0.93 and the item homogeneity index was 0.59. Intraclass correlation coefficient between the sIRLS and the IRLS was 0.94. The sIRLS standard error of measurement was 3.61 (½ SD at baseline = 4.11). The results mostly overlapped those of the IRLS analyzed in parallel. Discussion The sIRLS is a reliable, valid and precise instrument that showed tight association with the IRLS. These findings support the use of the sIRLS for self-evaluation of RLS severity. The responses obtained on the sIRLS and the IRLS scale varied slightly. Therefore, we recommend that either the sIRLS or the IRLS scale be used as the only scale for serial measures over time.

Introduction Restless legs syndrome (RLS) and periodic limb movement disorder (PLMD) have been studied more than any other sleep-related movement disorder in the pediatric population. A common feature to both, periodic limb movements, occurs in many other disorders and also in reportedly healthy children and adolescents. In this review, we discuss the different types of limb movements as it pertains to pediatric RLS and PLMD and provides an update on these disorders. Methods A literature search was performed with the following inclusion criteria: English publication, limb movements, leg movements, periodic limb movements of sleep, periodic limb movements during wake, PLMD, RLS, with each of the modifiers, children, pediatric, and adolescents. Identified publications were reviewed and their reference lists were searched for additional relevant publications. Results A total of 102 references were included in this review. These included epidemiological studies, prospective and retrospective studies, case series, observational data, reviews, and consensus guidelines. A critical summary of these findings is presented. Conclusion The limited evidence-based data support the importance of evaluating limb movements in the context of the clinical symptomatology presented by the child or the adolescent. Further research is needed to (1) better understand the pathophysiological mechanisms resulting in periodic limb movements as encountered in the pediatric PLMD or RLS patient and their impact on the overall health and well-being, (2) develop objective diagnostic criteria for RLS and differentiate it from its “mimics” in the pediatric population, and (3) establish evidence-based guidelines for treatment.

Neoadjuvant therapy followed by surgery is the standard of care for locally advanced esophageal adenocarcinoma (EAC). Unfortunately, response to neoadjuvant chemotherapy (NAC) is poor (P=0.036) and elevated copy number variation in non-responders (282 vs 136/patient,PCDKN2A, CCND1), c-Myc (MYC), RTK/PIK3 (KRAS, EGFR) and gastrointestinal differentiation (GATA6) pathway genes being specifically altered in non-responders. Of note,NAV3mutations were exclusively present in the non-responder group with a frequency of 22%. Thus, lower mutation burden, higher chromosomal instability and specific copy number alterations are associated with resistance to NAC.

Background Restless legs syndrome (RLS) is associated with higher cardiovascular disease (CVD) risk. However, it remains unknown whether treatment of RLS lowers the cardiovascular risk associated with RLS. Methods and Results All data were collected retrospectively, but subjects were prospectively followed forward in time to determine outcomes of interest. We used the Truven Health MarketScan Commercial Claims and Encounters database from January 1, 2006, through December 31, 2014. Participants were 169 393 individuals, which included 24 199 nonpregnant participants with an RLS diagnosis (16 694 receiving treatments for RLS and 7505 without treatment) during 2006 to 2008 and 145 194 age‐ and sex‐matched participants without RLS. All participants were free of CVD before January 1, 2009 (analysis baseline). Incident CVD cases (myocardial infarction, angina, stroke, atrial fibrillation, and heart failure) were identified. We adjusted for potential confounders, such as presence of chronic conditions and medication use. We identified 16 574 incident CVD cases during 2009 to 2014. Relative to the non‐RLS group, the adjusted hazard ratio (HR) for future CVD was 1.26 (95% CI, 1.20–1.32) ( P P P Conclusions RLS was associated with higher future CVD risk. However, RLS was associated with statistically significantly less future cardiovascular risk in RLS patients with treatment than in those without treatment.

There is a gap in the manuals for scoring sleep-related movements because of the absence of rules for scoring large movements. A taskforce of the International Restless Legs Syndrome Study Group (IRLSSG) elaborated rules that define the detection and quantification of movements involving large muscle groups. Consensus on each of the criteria in this article was reached by testing the presence of consensus on a first proposal; if no consensus was achieved, the concerns were considered and used to modify the proposal. This process was iterated until consensus was reached. A preliminary analysis of the duration of movements involving large muscle groups was also carried out on data from two previous studies, which, however, used a visual analysis of video-polysomnographic (PSG) recordings obtained from children or adults. Technical specifications and scoring rules were designed for the detection and quantification of large muscle group movements during sleep with a duration between 3 and 45 seconds in adults or 3 and 30 seconds in children, characterized by an increase in electromyographic activity and/or the occurrence of movement artifact in any combination of at least two recommended channels and not meeting the criteria for any other type of movement. Large muscle group movements are often accompanied by sleep stage changes, arousals, awakenings, and heart rate rises. The absence of clear and detailed rules defining them has likely impeded the development of studies that might disclose their clinical relevance; these new rules fill this gap.

The chemotherapy resistance of esophageal adenocarcinomas (EAC) is underpinned by cancer cell extrinsic mechanisms of the tumor microenvironment (TME). We demonstrate that by targeting the tumor-promoting functions of the predominant TME cell type, cancer associated fibroblasts (CAF) with phosphodiesterase type 5 inhibitors (PDE5i) we can enhance the efficacy of standard-of-care chemotherapy. In ex-vivo conditions PDE5i prevented the transdifferation of normal fibroblasts to CAF and abolished the tumor-promoting function of established EAC CAF. Using shotgun proteomics and single cell RNA-Seq we revealed PDE5i specific regulation of pathways related to fibroblast activation and tumor promotion. Finally, we confirmed the efficacy of PDE5i in combination with chemotherapy in close-to-patient and in vivo PDX-based model systems. These findings demonstrate that CAF drive chemotherapy resistance in EAC and can be targeted by repurposing PDE5i, a safe and well tolerated class of drug administered to millions of patients world-wide to treat erectile dysfunction.

STUDY OBJECTIVES: Postural orthostatic tachycardia syndrome (POTS) and restless legs syndrome (RLS) are both characterized by sleep disturbance along with autoimmune/inflammatory features and autonomic dysfunction. However, to our knowledge, there has been no direct study looking at the prevalence of RLS in patients with POTS patients compared with healthy participants (controls). METHODS: Ninety-six physician-diagnosed patients with POTS (89 female and 7 male) and 130 controls (99 female and 31 male) were administered the Cambridge Hopkins questionnaire. Participants who were diagnosed with probable or definite RLS on the Cambridge Hopkins questionnaire were then contacted to determine the severity of RLS with the International Restless Legs Scale. RESULTS: More patients with POTS (15 of 96; 15.6%) than controls (6 of 130; 4.6%) were diagnosed with probable or definite RLS on the Cambridge Hopkins questionnaire (P = .0048). A sensitivity analysis with only female respondents yielded similar results. RLS severity was in the moderate range (12.23 ± 9.22). CONCLUSIONS: There is a higher prevalence of RLS in patients with POTS patients compared with controls. This association may have to do with shared increased inflammatory/autoimmune load and autonomic dysfunction. CITATION: Dodson C, Bagai K, Weinstock LB, et al. Restless legs syndrome is increased in postural orthostatic tachycardia syndrome. J Clin Sleep Med. 2021;17(4):791–795.

This systematic review and meta-analysis evaluated the diagnostic accuracy of screening instruments for restless legs syndrome (RLS) and reports sensitivity, specificity, positive (PPV) and negative predictive values (NPV). Searches for primary studies were conducted in electronic databases. Of the 1541 citations identified, 52 were included in the meta-analysis. The methodological quality of each study was evaluated using QUADAS-2. Only 14 studies assessed the reference standard in all participants or in all screen-positives and a selection of screen-negatives. Bivariate meta-analysis of these 14 studies estimated median sensitivity to be 0.88 (0.72-0.96) and specificity 0.90 (0.84-0.93); based on a population prevalence of 5%, the calculated PPV was 0.31 (0.27-0.34). For all 52 studies, with either full or partial verification of RLS status, we constructed best-case scenario sensitivities and specificities at pre-defined levels of prevalence: across all samples, when prevalence is 5%, the median best-case scenario PPV is 0.48 with significant between-study heterogeneity. No RLS screening instruments can currently be recommended for use without an expert clinical interview in epidemiological studies. For conditions with statistically low prevalence such as RLS, the specificity, not the sensitivity, of a screening instrument determines true prevalence. Therefore, future instruments should maximize specificity. We provide guidelines on RLS ascertainment in epidemiological studies that requires a two-step process with clinical interview following a screening test, and given the poor reporting quality of many RLS epidemiological studies, we include an RLS reporting checklist.

Restless legs syndrome (RLS) is a common disorder. The population prevalence is 1.5% to 2.7% in a subgroup of patients having more severe RLS with symptoms occurring 2 or more times a week and causing at least moderate distress. It is important for primary care physicians to be familiar with the disorder and its management. Much has changed in the management of RLS since our previous revised algorithm was published in 2013. This updated algorithm was written by members of the Scientific and Medical Advisory Board of the RLS Foundation based on scientific evidence and expert opinion. A literature search was performed using PubMed identifying all articles on RLS from 2012 to 2020. The management of RLS is considered under the following headings: General Considerations; Intermittent RLS; Chronic Persistent RLS; Refractory RLS; Special Circumstances; and Alternative, Investigative, and Potential Future Therapies. Nonpharmacologic approaches, including mental alerting activities, avoidance of substances or medications that may exacerbate RLS, and oral and intravenous iron supplementation, are outlined. The choice of an alpha2-delta ligand as first-line therapy for chronic persistent RLS with dopamine agonists as a second-line option is explained. We discuss the available drugs, the factors determining which to use, and their adverse effects. We define refractory RLS and describe management approaches, including combination therapy and the use of high-potency opioids. Treatment of RLS in pregnancy and childhood is discussed.

Chronic obstructive pulmonary disease (COPD) is the 3rd leading cause of death in the United States and is primarily caused by cigarette smoking. Increased numbers of mucus-producing secretory (“goblet”) cells defined as goblet cell metaplasia or hyperplasia (GCMH), contributes significantly to COPD pathophysiology. The objective of this study was to determine whether NOTCH signaling regulates goblet cell differentiation in response to cigarette smoke. Primary human bronchial epithelial cells (HBECs) from nonsmokers and COPD smokers were differentiated in vitro on air-liquid interface and exposed to cigarette smoke extract (CSE) for 7 days. NOTCH signaling activity was modulated using (1) the NOTCH/γ-secretase inhibitor Dibenzazepine (DBZ), (2) lentiviral over-expression of the NOTCH3-intracellular domain (NICD3) or (3) NOTCH3-specific siRNA. Cell differentiation and response to CSE were evaluated by qPCR, Western blotting, immunostaining and RNA-Seq. We found that CSE exposure of nonsmoker airway epithelium induced goblet cell differentiation characteristic of GCMH. Treatment with DBZ suppressed CSE-dependent induction of goblet cell differentiation. Furthermore, CSE induced NOTCH3 activation, as revealed by increased NOTCH3 nuclear localization and elevated NICD3 protein levels. Over-expression of NICD3 increased the expression of goblet cell associated genes SPDEF and MUC5AC, whereas NOTCH3 knockdown suppressed CSE-mediated induction of SPDEF and MUC5AC. Finally, CSE exposure of COPD airway epithelium induced goblet cell differentiation in a NOTCH3-dependent manner. These results identify NOTCH3 activation as one of the important mechanisms by which cigarette smoke induces goblet cell differentiation, thus providing a novel potential strategy to control GCMH-related pathologies in smokers and patients with COPD.

Study Objectives Evaluate serum and brain noniron metals in the pathology and genetics of restless legs syndrome (RLS). Methods In two independent studies (cohorts 1 and 2), in which subjects either remained on medications or tapered off medications, we analyzed serum levels of iron, calcium, magnesium, manganese, copper, and zinc both in RLS patients and controls, and assessed the prevalence of the MEIS1 and BTBD9 risk alleles previously established through genome-wide association studies. Human brain sections and a nematode genetic model were also quantified for metal levels using mass spectrometry. Results We found a significant enrichment for the BTBD9 risk genotype in the RLS affected group compared to control (p = 0.0252), consistent with previous literature. Serum (p = 0.0458 and p = 0.0139 for study cohorts 1 and 2, respectively) and brain (p = 0.0413) zinc levels were significantly elevated in the RLS patients versus control subjects. Conclusion We show for the first time that serum and brain levels of zinc are elevated in RLS. Further, we confirm the BTBD9 genetic risk factor in a new population, although the zinc changes were not significantly associated with risk genotypes. Zinc and iron homeostasis are interrelated, and zinc biology impacts neurotransmitter systems previously linked to RLS. Given the modest albeit statistically significant increase in serum zinc of ~20%, and the lack of association with two known genetic risk factors, zinc may not represent a primary etiology for the syndrome. Further investigation into the pathogenetic role that zinc may play in restless legs syndrome is needed.

Background: There are a few of the questionnaires for the diagnosis, severity and quality of life of adult Restless Legs Syndrome (RLS) that are utilized but not yet validated in children. Even fewer of these types of instruments have been developed specifically for Pediatric RLS. Methods: This article is a review of instruments used in adult RLS, their applicability to children and of instruments specifically developed for childhood RLS. Results: A single question for the diagnosis of RLS has been validated for adults and utilized in one epidemiology study of adolescents with RLS. The Pediatric Emory RLS questionnaire has been developed as a diagnostic instrument for childhood RLS, utilized in two studies of RLS in children, but not yet validated. The IRLS (International Restless Legs Scale), the CGI (Clinical Global Impression), and the RLS-6, which have been utilized for determining adult RLS severity, were administered without difficulty in one therapeutic study of adolescent RLS. In addition, the IRLS has also been utilized in another 5 studies of childhood and adolescent RLS. The pediatric Restless Legs Syndrome Severity Scale (P-RLS-SS) has been developed for use in children but not yet validated. A modification of the P-RLS-SS based upon rating the severity of the 4 diagnostic criteria for RLS has been developed for children but not yet validated. There are no Quality of Life Studies developed for Pediatric RLS. However, 3 separate studies utilized the general Peds Quality of Life Inventory (PedsQL) in RLS children and adolescents and one of these studies also employed the general Sleep Behavior Questionnaire (SBQ) and yet another of these studies also employed the Pediatric Symptom checklist (PSC). Discussion: There is a need for the development and validation of instruments specific to Pediatric RLS. Meanwhile, we recommend the use of the Pediatric RLS instruments that have been developed and we recommend use of the adult scales in adolescent RLS where language barriers are not a problem. If adult scales are used in younger children, we recommend that they be administered in conjunction with an ongoing discussion between the parent and the child during the scale administration.

Health policy in America has shifted rapidly over the last decade, and states are increasingly exercising greater authority over health policy decision-making. This localization and regionalization of healthcare policy poses significant challenges for patients with cancer, providers, advocates, and policymakers. To identify the challenges and opportunities that lay ahead of stakeholders, NCCN hosted the 2019 Policy Summit: The State of Cancer Care in America on June 27, 2019, in Washington, DC. The summit featured multidisciplinary panel discussions to explore the implications for access to quality cancer care within a shifting health policy landscape from a patient, provider, and lawmaker perspective. This article encapsulates the discussion from this NCCN Policy Summit.

STUDY OBJECTIVES: Mast cell activation syndrome (MCAS) is an inflammatory and allergic disorder. We determined the prevalence of restless legs syndrome (RLS) in MCAS because each common syndrome may be inflammatory in nature and associated with dysautonomia. METHODS: Individuals with MCAS were evaluated for RLS by two standard questionnaires. Prevalence comparisons included spouse control patients and two prevalence publications. MCAS diagnosis required mast cell (MC) symptoms in ≥ 2 organs plus ≥ 1 elevated MC mediators, improvement with MC therapy, and/or increased intestinal MC density. Clinical variables were studied. RESULTS: There were 174 patients with MCAS (146 female, 28 male, mean age 44.8 years) and 85 spouse control patients (12 female, 73 male, mean age 50.9 years). Patients with MCAS as a whole had a higher prevalence of RLS (40.8%) than spouse control (12.9%) (P < .0001) Male patients with MCAS had a higher prevalence of RLS (32.1%) than male controls (12.3%, odds ratio [OR] 3.4, confidence interval [CI] 1.2–9.7, P = .025), American men (8.4%, OR 5.2, CI 2.2–12.0, P < .001), and French men (5.8%, OR 7.7, CI 3.4–17.1, P < .001). Female patients with MCAS also had a higher prevalence of RLS (42.5%) than female controls (16.7%) but this did not reach statistical significance perhaps because of the sample size of the female controls. However, female patients with MCAS had a statistically higher prevalence of RLS than American women (10.0%, OR 6.7, CI 4.5–9.7, P < .0001) and French women (10.8%, OR 6.1, CI 4.4–8.6, P < .0001). CONCLUSIONS: RLS appears to be associated with MCAS. Effects of mast cell mediators, inflammation, immune mechanisms, dysautonomia, or hypoxia may theoretically activate RLS in MCAS. CITATION: Weinstock LB, Walters AS, Brook JB, Kaleem Z, Afrin LB, Molderings GJ. Restless legs syndrome is associated with mast cell activation syndrome. J Clin Sleep Med. 2020;16(3):401–408.

Quality measurement is a critical component of advancing a health system that pays for performance over volume. Although there has been significant attention paid to quality measurement within health systems in recent years, significant challenges to meaningful measurement of quality care outcomes remain. Defining cost can be challenging, but is arguably not as elusive as quality, which lacks standard measurement methods and units. To identify industry standards and recommendations for the future, NCCN recently hosted the NCCN Oncology Policy Summit: Defining, Measuring, and Applying Quality in an Evolving Health Policy Landscape and the Implications for Cancer Care. Key stakeholders including physicians, payers, policymakers, patient advocates, and technology partners reviewed current quality measurement programs to identify success and challenges, including the Oncology Care Model. Speakers and panelists identified gaps in quality measurement and provided insights and suggestions for further advancing quality measurement in oncology. This article provides insights and recommendations; however, the goal of this program was to highlight key issues and not to obtain consensus.

Key points Restless legs patients complain about sensory and motor symptoms leading to sleep disturbances. Symptoms include painful sensations, an urge to move and involuntary leg movements. The responsible mechanisms of restless legs syndrome are still not known, although current studies indicate an increased neuronal network excitability. Reflex studies indicate the involvement of spinal structures. Peripheral mechanisms have not been investigated so far. In the present study, we provide evidence of increased hyperpolarization-activated cyclic nucleotide-gated (HCN) channel-mediated inward rectification in motor axons. The excitability of sensory axons was not changed. We conclude that, in restless legs syndrome, an increased HCN current in motoneurons may play a pathophysiological role, such that these channels could represent a valuable target for pharmaceutical intervention. Abstract Restless legs syndrome is a sensorimotor network disorder. So far, the responsible pathophysiological mechanisms are poorly understood. In the present study, we provide evidence that the excitability of peripheral motoneurons contributes to the pathophysiology of restless legs syndrome. In vivo excitability studies on motor and sensory axons of the median nerve were performed on patients with idiopathic restless legs syndrome (iRLS) who were not currently on treatment. The iRLS patients had greater accommodation in motor but not sensory axons to long-lasting hyperpolarization compared to age-matched healthy subjects, indicating greater inward rectification in iRLS. The most reasonable explanation is that hyperpolarization-activated cyclic nucleotide-gated (HCN) channels open at less hyperpolarized membrane potentials, a view supported by mathematical modelling. The half-activation potential for HCN channels (Bq) was the single best parameter that accounted for the difference between normal controls and iRLS data. A 6 mV depolarization of Bq reduced the discrepancy between the normal control model and the iRLS data by 92.1%. Taken together, our results suggest an increase in the excitability of motor units in iRLS that could enhance the likelihood of leg movements. The abnormal axonal properties are consistent with other findings indicating that the peripheral system is part of the network involved in iRLS.

Background Imatinib mesylate is a potent inhibitor of the Abl, KIT and platelet derived growth factor (PDGF) receptor tyrosine kinases. Preclinical data suggest that combining imatinib mesylate with anti-estrogen therapy may be synergistic in hormone receptor-positive breast cancer. We report results of the first phase II trial evaluating the efficacy of the novel combination of imatinib mesylate and letrozole in the treatment of postmenopausal women with metastatic breast cancer. Patients and Methods 45 postmenopausal women with hormone receptor-positive metastatic breast cancer whose tumors demonstrated c-kit and/or PDGFR-β positivity were treated with imatinib mesylate 400 mg PO twice daily and letrozole 2.5 mg PO once daily until disease progression or unacceptable toxicity. Results There were no complete responses and five partial responses for an objective response rate of 11%. An additional 16 patients had stable disease lasting at least 24 weeks for a clinical benefit rate of 46.7%. The median progression-free and overall survival was 8.7 months (95% confidence interval: 3.8-11.4 months) and 44.3 months (95% confidence interval: 34.0-55.3 months), respectively. The most common grade 3 or higher treatment related adverse events were fatigue and diarrhea, occurring in 9 (20%) and 7 patients (16%), respectively. Conclusion The combination of imatinib mesylate and letrozole is well tolerated but appears to have limited efficacy in the treatment of hormone receptor-positive metastatic breast cancer.

Quality measurement is at the heart of efforts to achieve high-quality surgical and medical care at a lower cost. Without accurate quality measures, it is not possible to appropriately align incentives with quality. The aim of these National Quality Forum (NQF) guidelines is to provide measure developers and other stakeholders with guidance on the standards used by the NQF to evaluate the scientific acceptability of performance measures. Using a methodologically rigorous and transparent process for evaluating health care quality measures is the best insurance that alternative payment plans will truly reward and promote higher quality care. Performance measures need to be credible in order for physicians and hospitals to willingly partner with payers in efforts to improve population outcomes. Our goal in creating this position paper is to promote the transparency of NQF evaluations, improve the quality of performance measurements, and engage surgeons and all other stakeholders to work together to advance the science of performance measurement.

Due to high levels of expression in aggressive tumors, high mobility group AT-hook 1 (HMGA1) has recently attracted attention as a potential anti-tumor target. However, HMGA1 is also expressed in normal somatic progenitor cells, raising the question: how might systemic anti-HMGA1 therapies affect the structure and function of normal tissue differentiation? In the present study, RNA sequencing data demonstrated HMGA1 is highly expressed in human airway basal stem/progenitor cells (BC), but decreases with BC differentiation in air-liquid interface cultures (ALI). BC collected from nonsmokers, healthy smokers, and smokers with chronic obstructive pulmonary disease (COPD) displayed a range of HMGA1 expression levels. Low initial expression levels of HMGA1 in BC were associated with decreased ability to maintain a differentiated ALI epithelium. HMGA1 down-regulation in BC diminished BC proliferation, suppressed gene expression related to normal proliferation and differentiation, decreased airway epithelial resistance, suppressed junctional and cell polarity gene expression, and delayed wound closure of airway epithelium following injury. Furthermore, silencing of HMGA1 in airway BC in ALI increased the expression of genes associated with airway remodeling in COPD including squamous, epithelial-mesenchymal transition (EMT), and inflammatory genes. Together, the data suggests HMGA1 plays a central role in normal airway differentiation, and thus caution should be used to monitor airway epithelial structure and function in the context of systemic HMGA1-targeted therapies.

Restless legs syndrome (RLS) is a distinct disorder, differing from chronic pain in many ways. Refractory RLS is characterized by unresponsiveness to dopamine agonists or alpha-2-delta ligands due to inadequate efficacy, augmentation, or adverse effects. This may result in severely impaired quality of life, profound insomnia, and suicidal depression. Opioid therapy is a mainstay in the management of these patients. This article summarizes the basic science and clinical evidence in support of their use, including the positive result of a large controlled multicenter study of 306 subjects, and outlines an approach to their use in clinical practice. Treatable explanations for RLS refractoriness, such as low iron stores, and other therapeutic options, such as combination therapy, should be considered before prescribing opioids. The agents most commonly used are oxycodone and methadone, but tramadol, codeine, morphine, and hydrocodone can also be considered. Controlled-release medication should be used for evening dosage and short-acting drugs, if needed, during the day. Effective doses are considerably lower than used for chronic pain (oxycodone 10-30 mg daily; methadone 5-20 mg daily) and the risk of opioid use disorder is relatively low. However, sensible precautions should be undertaken, including assessing opioid risk with standard questionnaires, using an opioid contract, using urine drug screens, consulting state prescription drug monitoring programs, and frequent reevaluation of effectiveness and side effects. Opioid use in selected patients with refractory RLS may be life-transforming with favorable risk-benefit ratio.

Objective To investigate the pharmacokinetics (PK) of rotigotine transdermal system in adolescents with moderate-to-severe idiopathic restless legs syndrome (RLS). Methods This multicenter, open-label, dose-escalation study enrolled patients ≥13 to SS /f; L) of unconjugated rotigotine for each dose step, calculated for the PK per-protocol set (PKPPS). Other PK, safety, and efficacy variables (International RLS Study Group Rating Scale [IRLS]; Clinical Global Impressions Item 1 [CGI-1]) were assessed. Results Of 24 patients who received rotigotine, 23 completed all dose steps and 17 formed the PKPPS. Least-squares mean (95% confidence interval) CL/f and V SS /f values were broadly similar across all dose steps (CL/f: 0.5 mg/24 h: 676.86 [408.50–1121.51]; 1 mg/24 h: 671.72 [459.11–982.80]; 2 mg/24 h: 937.56 [658.50–1334.89]; 3 mg/24 h: 1088.77 [723.47–1638.53]; V SS /f: 5403.16 [2850.67–10,241.17]; 6220.79 [3842.05–10,072.28]; 7114.01 [4547.88–11,128.07]; 6037.92 [3598.36–10,131.41]). Among 23 patients with efficacy data, mean IRLS and CGI-1 scores improved at each dosage level. Adverse events reported by ≥3 patients were nausea (seven) and application site reactions (four). Conclusions Key PK properties of rotigotine in adolescent patients with moderate-to-severe idiopathic RLS were comparable to those previously observed in adults. Rotigotine improved RLS symptoms and was well tolerated. ClinicalTrials.gov: NCT01495793.

Restless legs syndrome (RLS) is a sensory-motor neurological disorder characterized by uncomfortable sensations in the extremities, generally at night, which is often relieved by movements. Genome-wide association studies (GWAS) have identified mutations inBTBD9conferring a higher risk of RLS. Knockout of theBTBD9homolog in mice (Btbd9) and fly results in motor restlessness and sleep disruption. Clinical studies have found RLS patients have structural and functional abnormalities in the striatum; however, whether and how striatal pathology contributes to the pathogenesis of RLS is not known. Here, we used fMRI to map regions of altered synaptic activity in basal ganglia of systematicBtbd9knock-out (KO) mice. We further dissected striatal circuits using patch-clamp electrophysiological recordings in brain slices. Two different mouse models were generated to test the effect of specific knockout ofBtbd9in either striatal medium spiny neurons (MSNs) or cholinergic interneurons (ChIs) using the electrophysiological recording, motor and sensory behavioral tests. We found thatBtbd9KO mice showed enhanced neural activity in the striatum, increased postsynaptic currents in the MSNs, and decreased excitability of the striatal ChIs. Knocking outBtbd9specifically in the striatal MSNs, but not the ChIs, led to rest-phase specific motor restlessness, sleep disturbance, and increased thermal sensation in mice, which are consistent with results obtained from theBtbd9KO mice. Our data establish the role ofBtbd9in regulating the activity of striatal neurons. Increased activity of the striatal MSNs, possibly through modulation by the striatal ChIs, contributes to the pathogenesis of RLS.

Restless legs syndrome (RLS) is a sleep disorder that may exacerbate many of the symptoms and consequences of multiple sclerosis (MS), and may have further implications for health-related quality of life (HRQOL). The present study examined the relationships among RLS, symptoms and HRQOL in people with MS. Participants with MS (n = 275) completed the Cambridge-Hopkins Restless Legs Syndrome Questionnaire, the International Restless Legs Syndrome Study Group Scale, the Multiple Sclerosis Impact Scale, the Pittsburgh Sleep Quality Index, the Fatigue Severity Scale, the Hospital Anxiety and Depression Scale and the Patient Determined Disease Steps. There were 74 (26.9%) persons with MS who had RLS (MS + RLS). The MS + RLS group reported worse physical and psychological HRQOL (p = 0.020 and p = 0.017, respectively) and greater perceived fatigue (p = 0.006) and anxiety symptoms (p = 0.042) than the MS-only group. Within the MS + RLS group, RLS severity was associated with physical (r = 0.43) and psychological (r = 0.46) HRQOL, sleep quality (r = 0.38), perceived fatigue (r = 0.28), depression (r = 0.38) and anxiety (r = 0.28). The relationships between RLS severity and the domains of HRQOL were attenuated when accounting for fatigue, depression and/or anxiety. Worse RLS severity was associated with reduced HRQOL, which was accounted for by fatigue, depression and anxiety.

Previous studies have uncovered a potential role of the opioid system in iron hemostasis and dopamine metabolism. Abnormalities in both of these systems have been noted in human RLS. Autopsy studies of human RLS have shown an endogenous opioid deficiency in the thalamus. Opioids, particularly prolonged-release oxycodone/naloxone, have been approved in Europe to be a second-line therapy for severe restless legs syndrome (RLS). To study the role of opioid receptors in the pathogenesis of RLS, we used a triple knockout (KO) mouse strain that lack mu, delta, and kappa opioid receptors and explored the behavioral and biochemical parameters relevant to RLS. The triple KO mice showed hyperactivity and a trend of increased probability of waking during the rest period (day) akin to that in human RLS (night). Surprisingly, triple KO mice also exhibit decreased serum iron concentration, evidence of anemia, a significant dysfunction in dopamine metabolism akin to that noted in human RLS, as well as an increased latency in response to thermal stimuli. To our knowledge, this is the first study to demonstrate that the endogenous opioid system may play a role in iron metabolism and subsequently in the pathogenesis of anemia. It is also the first study showing that opioid receptors are involved in the production of motor restlessness with a circadian predominance. Our findings support the role of endogenous opioids in the pathogenesis of RLS, and the triple KO mice can be used to understand the relationship between iron deficiency, anemia, dopaminergic dysfunction, and RLS.

Restless legs syndrome can be a debilitating condition that affects a patient's ability to function and their quality of life. Neuromodulation may represent a potential option for nonpharmacological management of restless legs syndrome. We present 3 patients who have a chronic pain diagnosis and medically refractory restless legs syndrome that warranted neuromodulation. After neuromodulation, all 3 patients had improvement in their restless legs syndrome symptoms and were taking less pain medication, and 2 out of 3 had significantly improved functionality at short-term follow-up. This case series suggests that spinal cord stimulation may be a viable nonpharmacological treatment option for medically refractory restless legs syndrome.

Transboundary collaborations related to international freshwater are critical for ensuring equitable, efficient, and sustainable shared access to our planet's most fundamental resources. Visual artifacts, such as knowledge maps, functioning as boundary objects, are used in hydropolitical contexts to convey understandings and facilitate discussion across scales about challenges and opportunities from multiple perspectives. Such focal points for discussion are valuable in creating shared, socially negotiated priorities and integrating diverse and often disparate cultural perspectives that naturally exist in the context of international transboundary water resources. Visual boundary objects can also represent the collective mental models of the actor countries and transboundary institutions and encompass their perspectives on the complex hydro-social cycles within specific "problem-shed" regions of the shared resources. To investigate and synthesize these multiple concepts, we developed a novel method of eliciting mental models from visual boundary objects in social-ecological contexts by combining content analysis with theoretical frameworks for boundary objects and systems thinking. Using this method, we analyzed visual boundary objects represented in publicly available documents formally related to decision making in the Pilcomayo River Basin in South America. The Pilcomayo River Basin is a unique case for investigating decision making in international collaboration among represented states, given the unique social and biophysical challenges that have plagued the region for over a century. Using our framework, we were able to develop insight into the collective mental models of stakeholders, organizations, and decision-making institutions, related to priorities, vulnerabilities, and adaptation strategies among the various socioeconomic, cultural, political, and biophysical drivers for different regions and scales of the basin.

Background To standardize care and promote early fascial closure among patients undergoing emergent laparotomy and temporary abdominal closure (TAC), we developed a protocol addressing patient selection, operative technique, resuscitation strategies, and critical care provisions. We hypothesized that primary fascial closure rates would increase following protocol implementation with no difference in complication rates. Study design We performed a retrospective cohort analysis of 138 adult trauma and emergency general surgery patients who underwent emergent laparotomy and TAC, comparing protocol patients (n = 60) to recent historic controls (n = 78) who would have met protocol inclusion criteria. The protocol includes low-volume 3% hypertonic saline resuscitation, judicious wound vacuum fluid replacement, and early relaparotomy with sequential fascial closure. Demographics, baseline characteristics, illness severity, resuscitation course, operative management, and outcomes were compared. The primary outcome was fascial closure. Results Baseline characteristics, including age, American Society of Anesthesiologists class, and postoperative lactate levels, were similar between groups. Within 48 hours of initial laparotomy and TAC, protocol patients received significantly lower total intravenous fluid resuscitation volumes (9.7 vs. 11.4 L, p = 0.044) and exhibited higher serum osmolarity (303 vs. 293 mOsm/kg, p = 0.001). The interval between abdominal operations was significantly shorter following protocol implementation (28.2 vs. 32.2 hours, p = 0.027). The incidence of primary fascial closure was significantly higher in the protocol group (93% vs. 81%, p = 0.045, number needed to treat = 8.3). Complication rates were similar between groups. Conclusions Protocol implementation was associated with lower crystalloid resuscitation volumes, a transient hyperosmolar state, shorter intervals between operations, and higher fascial closure rates with no difference in complications. Level of evidence Therapeutic study, level IV.

Telehealth is a reality for health care professionals in the current pandemic-afflicted world Defined as real-time interactive videoconferencing, telehealth involves the provider and patient using technology for treatment when they cannot meet in person Even prior to the pandemic, the number of users of telehealth had grown exponentially It is predicted to reach 266 8 billion by 2026, an increase from 49 8 billion in 2018 (Child Mind Institute 2020)