The Association Between Repeated Measured Febrile Episodes During Early Childhood and Attention Deficit Hyperactivity Disorder: A Large-Scale Population-Based Study.

OBJECTIVE: We examined the association between the number, magnitude, and frequency of febrile episodes during the 0 to 4 years of life and subsequent diagnosis of ADHD. METHODS: This population-based case-control study in an Israeli HMO, Leumit Health Services (LHS), uses a database for all LHS members aged 5 to 18 years between 1/1/2002 and 1/30/2022. The number and magnitude of measured fever episodes during the 0 to 4 years were recorded in individuals with ADHD (N = 18,558) and individually matched non-ADHD controls in a 1:2 ratio (N = 37,116). RESULTS: A significant, independent association was found between the number and magnitude of febrile episodes during the 0 to 4 years and the probability of a later diagnosis of ADHD. Children who never had a measured temperature >37.5°C had a significantly lower rate of ADHD (OR = 0.834, 95% CI [0.802, 0.866], p < .0001). CONCLUSIONS: Febrile episodes during 0 to 4 years are associated with a significantly increased rate of a later diagnosis of ADHD in a doseresponse relationship.

Increased Rate of Familial Mediterranean Fever in Children With ADHD: A Population-Based Case-Control Study.

OBJECTIVE: There is growing evidence of involvement of inflammatory mechanisms in ADHD. Previous studies found significantly higher rates of ADHD among children with FMF. The present study examined the rate of exposure to FMF in children with a later (within a 5-year period) diagnosis of ADHD compared to non-ADHD children. METHODS: A population-based case-control study of all children (<18 years) registered in Leumit Health Services during 01.01.2006 to 06.30.2021. All cases met ICD-9/10 criteria for ADHD. They were matched by age, sex, and socioeconomic status on a 1:2 rate to randomly selected non-ADHD controls. RESULTS: Fifty-six (0.30%) children with ADHD (N = 18,756) were previously diagnosed with FMF compared to 65 of 37,512 controls (0.17%). A significant, independent association existed between a preceding FMF diagnosis and a later ADHD diagnosis [OR = 1.72 (95% CI 1.18-2.51); p = .003]. CONCLUSIONS: The mechanisms underlying the association w between FMF and later ADHD diagnosis merit further elucidation.

The Association between Glucose 6-Phosphate Dehydrogenase Deficiency and Attention Deficit/Hyperactivity Disorder.

BACKGROUND: Glucose-6-phosphate dehydrogenase (G6PD) deficiency, impacting 4.9% of the population and more prevalent in Mediterranean communities, is a common enzymopathy with potential relevance to Attention Deficit/Hyperactivity Disorder (ADHD). This study investigated this association. METHODS: The clinical characteristics of 7473 G6PD-deficient patients and 29,892 matched case-controls (selected at a 1:4 ratio) from a cohort of 1,031,354 within the Leumit Health Services database were analyzed using Fisher's exact test for categorical variables and the Mann-Whitney U test for continuous variables. RESULTS: In total, 68.7% were male. The mean duration of follow-up was 14.3 ± 6.2 years at a mean age of 29.2 ± 22.3 years. G6PD deficiency was associated with an increased risk of being diagnosed with ADHD (Odds Ratio (OR) = 1.16 [95% CI, 1.08-1.25], p < 0.001), seeking care from adult neurologists (OR = 1.30 [95% CI, 1.22-1.38], p < 0.001), and consulting adult psychiatrists (OR = 1.12 [95% CI, 1.01-1.24], p = 0.048). The use of stimulant medications among G6PD-deficient individuals was 17% higher for the methylphenidate class of drugs (OR = 1.17 [95% CI, 1.08, 1.27], p < 0.001), and there was a 16% elevated risk for amphetamine use (OR = 1.16 [95% CI, 1.03, 1.37], p = 0.047). CONCLUSIONS: G6PD deficiency signals an increased risk of ADHD diagnosis, more severe presentations of ADHD and a greater need for psychiatric medications to treat ADHD.

Attention-Deficit/Hyperactivity Disorder Is Associated With Increased Rates of Childhood Infectious Diseases: A Population-Based Case-Control Study.

OBJECTIVE: Infectious diseases (IDs) pose a heavy burden on children. An association between pediatric attention-deficit/hyperactivity disorder (ADHD) and specific IDs has been documented. Our objective was to test the possibility that ADHD is associated with increased likelihood for pediatric IDs at large. METHOD: A population-based case-control study was conducted using Electronic Medical Records (EMRs) of a national Health Maintenance Organization, Leumit Health Services (LHS). ICD-9/10 criteria were used for all diagnoses. The study population consisted of all children and adolescents (aged 5-18 years), members of LHS between January 1, 2006-June 30, 2021. Case patients met International Classification of Diseases (ICD-9/10) criteria for ADHD. Controls included randomly selected persons without ADHD (2:1 ratio), matched individually by demographic indices. The EMRs retrieved 3 exposure categories: pediatric ID, anti-infective medications use, and number of physician visits. The study was approved by the review board of Shamir Medical Center and the Research Committee of LHS. RESULTS: Cases patients comprised 18,756 participants, with a mean age of 8.3 ± 2.6 years and a male/female ratio of 63%:37%. Matched controls comprised 37,512 participants, with a mean age of 8.3 ± 2.6 years and a male/female ratio of 63%:37%. Demographic variables were similar between the groups. The rates of all IDs were significantly higher in participants with ADHD than in controls and were not restricted to a single body system, including acute respiratory infection (OR = 1.4, 95% CI = 1.3-1.4, p < .001), acute gastroenteritis (OR = 1.3,95% CI 1.3-1.4, p < .001), salmonellosis (OR = 2.8, 95% CI = 2.3-3.5, p < .001), and urinary tract infection (OR = 1.3, 95% CI = 1.2-1.4, p < .001). All anti-infective agents were prescribed significantly more often to children with ADHD. There were significantly higher rates of physician visits for participants with ADHD. CONCLUSION: Study findings suggest an association between ID and pediatric ADHD Health care providers should be aware of this potential association. CLINICAL TRIAL REGISTRATION INFORMATION: The Health and Economic Impact of Treated and Untreated ADHD; https://www.shamir.org/; 005-18-LEU.

The Association between Somatotropin Therapy and the Risk of SARS-CoV-2 Infection in Children with Short Stature: A Population-Based Cross-Sectional Study.

COVID-19 is a worldwide pandemic caused by SARS-CoV-2, to which adults are usually more susceptible than children. Growth hormone (GH) levels differ between children and adults and decrease with age. There is bidirectional crosstalk between the GH/insulin-like growth factor-1 (IGF-1) pathway and the immune system that plays a significant role in SARS-CoV-2 infection. We evaluated the association between somatotropin treatment (GH replacement therapy) and the risk for SARS-CoV-2 positivity (a marker for COVID-19 infection) in children with growth hormone issues (GHI): growth hormone deficiency (GHD) and idiopathic short stature (ISS). A population-based cross-sectional study in Leumit Health Services (LHS) was performed using the electronic health record (EHR) database. The rates of SARS-CoV-2 positivity were evaluated among children with GHI, treated or untreated with somatotropin. Higher rates of SARS-CoV-2 positivity were found in GHI children, influenced by the same confounders reported in the pediatric population. A lower prevalence of SARS-CoV-2 PCR positivity was found among the somatotropin-treated children. A multivariate analysis documented that somatotropin treatment was associated with a reduced risk of SARS-CoV-2 positivity (Odds Ratio (OR) = 0.47, Confidence Interval (CI) 0.24-0.94, p = 0.032). Thus, somatotropin might be a protective factor against SARS-CoV-2 infections, possibly related to its immunomodulatory activity.

Clinical and Socio-Demographic Variables Associated with the Diagnosis of Long COVID Syndrome in Youth: A Population-Based Study.

This study examines the demographic, clinical and socioeconomic factors associated with diagnosis of long COVID syndrome (LCS). Data of 20,601 COVID-19-positive children aged 5 to 18 years were collected between 2020 and 2021 in an Israeli database. Logistic regression analysis was used to evaluate the adjusted odds ratio for the characteristics of the COVID-19 infection and pre-COVID-19 morbidities. Children with LCS were significantly more likely to have been severely symptomatic, required hospitalization, and experienced recurrent acute infection within 180 days. In addition, children with LCS were significantly more likely to have had ADHD, chronic urticaria, and allergic rhinitis. Diagnosis of LCS is significantly associated with pre-COVID-19 ADHD diagnosis, suggesting clinicians treating ADHD children who become infected with COVID-19 remain vigilant for the possibility of LCS. Although the risk of severe COVID-19 infection and LCS in children is low, further research on possible morbidity related to LCS in children is needed.

Differential Impact of Work Overload on Physicians' Attention: A Comparison Between Residential Fields.

OBJECTIVES: Medical errors cause tens of thousands of deaths annually and have a major impact on quality of care and management; however, it receives scant research and public awareness. This study aimed to examine the relation between workload-induced lack of sleep and attention failure, as indications for medical errors risk, among young residents. METHODS: We performed an evaluation of young physicians by the Test of Variables of Attention, before and after a 24-hour shift. RESULTS: Workload was manifested by 13% overall attention impairment at baseline, which increased to 34% with deficiencies below the normal range after the shift. Attention measures differed between physicians of each residential field at baseline, but to greater extent after the shift. CONCLUSIONS: Traditional working schedule is strongly associated with attention failure. Based on the literature linking attention failures to medical errors, we suggest a regulatory change regarding residents' shift duration to decrease preventable errors.

The Association between ADHD and the Severity of COVID-19 Infection.

OBJECTIVE: Patients with ADHD are at increased risk of acquiring COVID-19. The present study assessed the possibility that ADHD also increases the risk of severe COVID-19 infection. METHOD: We assessed 1,870 COVID-19 positive patients, aged 5 to 60 years, registered in the database of Leumit Health Services (LHS, Israel), February to -June 2020, of whom 231 with ADHD. Logistic regression analysis models evaluated the association between ADHD and the dependent variables of being symptomatic/referral to hospitalization, controlling for demographic and medical variables. RESULTS: Age, male sex, and BMI were confirmed to be significant risk factors for increased COVID-19 severity. ADHD was found to be associated with increased severity of COVID-19 symptoms (OR = 1.81, 95% CI [1.29, 2.52], p < .05) and referral to hospitalization (OR =1.93, 95% CI [1.06, 3.51], p = .03). CONCLUSION: ADHD is associated with poorer outcomes in COVID-19 infection.

Polygenic association between attention-deficit/hyperactivity disorder liability and cognitive impairments.

BACKGROUND: A recent genome-wide association study (GWAS) identified 12 independent loci significantly associated with attention-deficit/hyperactivity disorder (ADHD). Polygenic risk scores (PRS), derived from the GWAS, can be used to assess genetic overlap between ADHD and other traits. Using ADHD samples from several international sites, we derived PRS for ADHD from the recent GWAS to test whether genetic variants that contribute to ADHD also influence two cognitive functions that show strong association with ADHD: attention regulation and response inhibition, captured by reaction time variability (RTV) and commission errors (CE). METHODS: The discovery GWAS included 19 099 ADHD cases and 34 194 control participants. The combined target sample included 845 people with ADHD (age: 8-40 years). RTV and CE were available from reaction time and response inhibition tasks. ADHD PRS were calculated from the GWAS using a leave-one-study-out approach. Regression analyses were run to investigate whether ADHD PRS were associated with CE and RTV. Results across sites were combined via random effect meta-analyses. RESULTS: When combining the studies in meta-analyses, results were significant for RTV (R2 = 0.011, ß = 0.088, p = 0.02) but not for CE (R2 = 0.011, ß = 0.013, p = 0.732). No significant association was found between ADHD PRS and RTV or CE in any sample individually (p > 0.10). CONCLUSIONS: We detected a significant association between PRS for ADHD and RTV (but not CE) in individuals with ADHD, suggesting that common genetic risk variants for ADHD influence attention regulation.

Glycemic Control and Diabetes Related Complications in Adults with Type 1 Diabetes Mellitus and ADHD.

OBJECTIVE: To assess the correlation of co-morbid ADHD and diabetes-related complications in patients with type-1-diabetes-mellitus (T1DM). METHODS: A retrospective cross-sectional study was conducted during 2018 using the Leumit-Health-Services(LHS) database. Diabetes-related complications were assessed in patients with T1DM and ADHD (T1DM-ADHD+) and compared with patients with T1DM alone (T1DM-ADHD-). RESULTS: Out of 789 adult-patients with T1DM, 75 (9.5%) were T1DM-ADHD+, matched to 225 T1DM-ADHD-. HbA1C levels were higher in T1DM-ADHD+ patients (8.1% ± 1.6 vs. 7.4% ± 1.2, p < .01), as well as diabetes-related complications: neuropathy (22.7% vs. 5.8%, p < .01), ulcers (8% vs. 0.9%, p < .05), limb amputation (5.3% vs. 0.9%, p < .05), albuminuria (15.5% vs. 2.8%, p < .01), chronic renal failure (10.6% vs. 2.5%, p = .01), and emergency room admissions rate (26.7% vs. 15.1%, p < .05). In sub-analysis, lower average HbA1C levels and diabetic ulcer rates were found among ADHD patients treated with stimulants, all p < .05. CONCLUSION: Co-morbidity of ADHD and T1DM is associated with poor glycemic control and higher complication rates.

Higher rates of allergies, autoimmune diseases and low-grade inflammation markers in treatment-resistant major depression.

Only 30% of patients with major depressive disorder (MDD) reach full recovery or remission. Treatment-resistant depression (TRD) is MDD that does not respond to adequate treatment attempts with at least two antidepressants. TRD is associated more with immune activation than with treatment responsive depression. The current retrospective population-based cross-sectional study, utilizing data from a large nation-wide health maintenance organization in Israel which provides services to estimated 725,000 members, aimed to assess the clinical signs and laboratory markers of autoimmune comorbidity and low-grade inflammation, in patients with TRD. Included were participants aged 18-70 years, diagnosed twice within one year with ICD-9-CM MDD and two control groups, MDD responders (MDD-r) consisting of people with MDD and no TRD and a non-MDD group that included people with no MDD or TRD. The case (570 subjects in TRD group) to control ratio in both control groups (2850 subjects in MDD-r and 2850 subjects in non-MDD control group) was 1:5. Compared to MDD-r, the overall proportion of allergic diseases was higher among the TRD than among the MDD-r [OR 1.52 (1.19-1.94); p â€‹< â€‹0.001]. Any systemic autoimmune disease was associated with increased likelihood of MDD-r [OR 1.52 (1.04-2.24); p â€‹= â€‹0.03] or TRD [OR 2.22 (1.30-3.78); p â€‹= â€‹0.003]. Higher rates of positive (>1:80) antinuclear antibodies [33 (5.79%)] were found among the TRD than among the MDD-r [98 (3.44%); p â€‹= â€‹0.011). More allergy and autoimmune comorbidities and presence of low-grade inflammation biomarkers, were found mainly in TRD.

The World Federation of ADHD International Consensus Statement: 208 Evidence-based conclusions about the disorder.

BACKGROUND: Misconceptions about ADHD stigmatize affected people, reduce credibility of providers, and prevent/delay treatment. To challenge misconceptions, we curated findings with strong evidence base. METHODS: We reviewed studies with more than 2000 participants or meta-analyses from five or more studies or 2000 or more participants. We excluded meta-analyses that did not assess publication bias, except for meta-analyses of prevalence. For network meta-analyses we required comparison adjusted funnel plots. We excluded treatment studies with waiting-list or treatment as usual controls. From this literature, we extracted evidence-based assertions about the disorder. RESULTS: We generated 208 empirically supported statements about ADHD. The status of the included statements as empirically supported is approved by 80 authors from 27 countries and 6 continents. The contents of the manuscript are endorsed by 366 people who have read this document and agree with its contents. CONCLUSIONS: Many findings in ADHD are supported by meta-analysis. These allow for firm statements about the nature, course, outcome causes, and treatments for disorders that are useful for reducing misconceptions and stigma.

Possible Age-Related Progression of Attentional Impairment in ADHD and Its Attenuation by Past Diagnosis and Treatment.

Objective: The aim of the study is to evaluate attentional impairment in different age groups with ADHD. Method: In all, 58 children, 73 adolescents, and 104 adults with ADHD were evaluated using the Test of Variables of Attention (TOVA). Subjects with comorbidities or psychotropic treatment were not included. Results: Considering Response Time Variability (RTV), adults were 10.6 and 4.0 times more likely to be severely impaired (standard score < 40) than children and adolescents, respectively. Adults were twice as likely as adolescents to be very impaired (standard score< 70) in Omissions. Considering d' (decrement of attentional performance over time), all severely impaired participants were adults. Age predicted impairment in Attention Performance Index (API), RTV, and d', but not Omissions or Commissions. Past treatment with stimulants predicted less impairment in d', past diagnosis predicted less impairment in RTV, and each predicted less impairment in Omissions and API. Conclusion: Adults had more attentional impairment than children and adolescents. Past diagnosis and treatment were associated with less ADHD-related attentional impairment.

The Placebo Response in Adult ADHD as Objectively Assessed by the TOVA Continuous Performance Test.

Objective: We compared the placebo response (PR) as measured by the Test of Variables of Attention (TOVA) and the Conners' Adult ADHD Rating Scale (CAARS) scores. Method: A retrospective data analysis from a double-blind placebo-controlled study of metadoxine-ER in adults with ADHD. An additional database was used for comparison to TOVA response after methylphenidate challenge (TOVA-MPH-R). Results: PR was highest when calculated from the TOVA-Attention Composite Score (ACS). The PR showed significantly fewer variables improving concomitantly compared with MPH-R. The most prominent correlation between the CAARS-PR and the TOVA-PR was in the Omissions score (p = .032), which was age-dependent (b = .0007, p <.001). Discussion: TOVA-PR has an index-specific profile compared with CAARS-PR and TOVA-MPH-R. The partial correlation of TOVA-PR with CAARS-PR suggests that a composite score of TOVA specific indices and CAARS could have a synergic impact to improve the reliability of the response assessment in adult ADHD.

ADHD as a Risk Factor for Infection With Covid-19.

Background: ADHD limits the ability to comply with Covid-19 prevention recommendations. We hypothesized that ADHD constitutes a risk factor for Covid-19 infection and that pharmacotherapy may lower that risk. Methods: Study population included all subjects (N = 14,022) registered with Leumit Health Services between February 1st and April 30, 2020, who underwent at least one Covid-19 test. Data were collected from the electronic health records. Purchasing consecutively at least three ADHD-medication-prescriptions during past year was considered drug-treatment. Results: A total of 1,416 (10.1%) subjects (aged 2 months-103 years) were Covid-19-positive.They were significantly younger, and had higher rates of ADHD (adjOR 1.58 (95% CI 1.27-1.96, p < .001) than Covid-19-negative subjects. The risk for Covid-19-Positive was higher in untreated-ADHD subjects compared to non-ADHD subjects [crudeOR 1.61 (95% CI 1.36-1.89, p < .001)], while no higher risk was detected in treated ones [crudeOR 1.07 (95% CI 0.78-1.48, p = .65)]. Conclusion: Untreated ADHD seems to constitute a risk factor for Covid-19 infection while drug-treatment ameliorates this effect.

Contrasting effects of music on reading comprehension in preadolescents with and without ADHD.

Children and adolescents with attention-deficit/hyperactivity disorder (ADHD) are advised to study in quiet settings; yet, many professionals assert that environments devoid of external stimulus, are often unnecessary to facilitate optimal learning conditions. Empirical controlled trials examining this assertion are scarce. This study explored whether music improves reading performance of preadolescents with ADHD compared with typically developed (TD) peers, and its correlation with changes in heart rate variability (HRV), an autonomic nervous system indicator. After a pilot phase (N = 20; age = 12.05), additional independent sample of ADHD (n = 25; age = 10.28) and TD (n = 25; age = 10.44) preadolescents completed reading tasks under four conditions: without background music, with calm music without lyrics, calm music with lyrics, and rhythmic music with lyrics. Reading comprehension and mean-levels of HRV changes (before and during each task) were assessed using validated instruments. Reading comprehension significantly improved under the music conditions in ADHD group and deteriorated among TD. Differences in HRV changes were significant between groups, and explained reading performance. These findings suggest that music may improve attentive skills of preadolescents with ADHD, but not TD, and urge the need to identify an optimal fit between individual and contextual characteristics.

Levels of Proneness to Boredom in Children with Attention-Deficit/Hyperactivity Disorder On and Off Methylphenidate Treatment.

Objective: To evaluate the relationship between attention-deficit/hyperactivity disorder (ADHD) severity and propensity for boredom in children with ADHD, both on and off methylphenidate (MPH). Methods: A group of children and adolescents with ADHD (n = 30), aged 7-18 years, were assessed using the Parent-Reported-ADHD Rating Scale-5 (PR-ADHD-RS-5) and Short Boredom Proneness Scale (SBPS), at baseline, after 3 months of MPH treatment, and again after 3 weeks of MPH treatment discontinuation. Results: Significant correlation was found at baseline between PR-ADHD-RS-5 and SBPS scores [n = 30, r = 0.40 (95% confidence interval {CI} = 0.048-0.67), p = 0.027]. Both ADHD and boredom levels decreased significantly after 3 months of MPH treatment. Significant correlation was found between the reductions in PR-ADHD-RS-5 and SBPS scores at this time [n = 30, r = 0.39 (95% CI = 0.035-0.66), p = 0.045]. MPH discontinuation for 3 weeks resulted in mild but statistically significant increases in ADHD and SBPS levels. No significant correlation was detected between the changes in PR-ADHD-RS-5 and SBPS scores after 3 weeks of MPH discontinuation. Conclusions: Three months of MPH treatment resulted in parallel improvement in ADHD severity and in the level of proneness to boredom (PtB), whereas discontinuation of MPH administration is associated with increases in the two parameters, causing them to approach pretreatment levels. Clinicians and parents should be aware of the possibility of increased PtB in children with ADHD who discontinue MPH treatment. Structured daily activity and continuation of MPH treatment may preserve the beneficial effects of MPH on academic and leisure activities and may prevent aggravation of subjective boredom sensations that could lead to risky sensation-seeking behaviors and overuse of electronic devices.

Characterizing the Placebo Response in Adults With ADHD.

Objective: Several ADHD pharmacological trials reported high placebo response (PR) rates. This study aims to characterize the PR in adult ADHD. Method: A retrospective cohort analysis of the placebo arm (140 adults with ADHD, 18-55 yrs, M:F 46.4%-53.6%) of a 6-week randomized, multicenter, double-blind metadoxine study, using Conners' Adult ADHD Rating Scale (CAARS) and the Adult ADHD Self-Report Scale (ASRS), was conducted. Results: Pre-post changes in placebo-treated adults were significant for both the CAARS and ASRS, F(2.9, 404.5) = 61.2, p < .00001, F(2.8, 383.0) = 43.1, p < .00001, respectively. Less than half of the participants had a PR which began early in treatment and persisted; almost 50% had a variable, inconsistent PR. Conclusion: In the current sample, PR in adult ADHD was prominent on both symptom scales and the investigator-rater instrument. Therefore, using investigator ratings as a primary endpoint does not necessarily attenuate PR. Of note, about half of the PR is variable, suggesting unreliable determination of efficacy.