The role of adrenergic neurotransmitter reuptake inhibitors in the ADHD armamentarium.

INTRODUCTION: Adrenergic neurotransmitter reuptake inhibitors are gaining attention in treatment for attention-deficit hyperactivity disorder (ADHD). Due to their effects on norepinephrine, dopamine, and serotonin neurotransmission, they benefit both ADHD and comorbid disorders and have some other advantages including longer duration of action and fewer adverse effects compared to stimulants. There is continued interest in these agents with novel mechanisms of action in treatment of ADHD. AREAS COVERED: The authors conducted a PubMed literature search using the following key words: 'ADHD' AND 'adrenergic reuptake inhibitors' OR 'nonstimulants' OR 'atomoxetine' OR 'Viloxazine' OR 'Dasotraline' OR 'Centanafadine' OR 'PDC-1421' OR 'Reboxetine' OR 'Edivoxetine' OR 'Bupropion' OR 'Venlafaxine' OR 'Duloxetine.' They reviewed FDA fact sheets of available medications for safety/tolerability studies and reviewed published clinical studies of these medications for treatment of ADHD. EXPERT OPINION: Adrenergic neurotransmitter reuptake inhibitors fit the diverse needs of children and adolescents with ADHD with 1) poor tolerability to stimulants (e.g. due to growth suppression, insomnia, rebound irritability, co-morbid depression, anxiety and tic disorders, substance abuse or diversion concerns), 2) cardiac risks, and/or 3) need for extended duration of action. Their differences in receptor affinities and modulating effects support the unique benefits of individual agents.

Challenging the Diagnostic Value of Theta/Beta Ratio: Insights From an EEG Subtyping Meta-Analytical Approach in ADHD.

The frequently reported high theta/beta ratio (TBR) in the electroencephalograms (EEGs) of children with attention-deficit/hyperactivity disorder (ADHD) has been suggested to include at least two distinct neurophysiological subgroups, a subgroup with high TBR and one with slow alpha peak frequency, overlapping the theta range. We combined three large ADHD cohorts recorded under standardized procedures and used a meta-analytical approach to leverage the large sample size (N = 417; age range: 6-18 years), classify these EEG subtypes and investigate their behavioral correlates to clarify their brain-behavior relationships. To control for the fact that slow alpha might contribute to theta power, three distinct EEG subgroups (non-slow-alpha TBR (NSAT) subgroup, slow alpha peak frequency (SAF) subgroup, not applicable (NA) subgroup) were determined, based on a halfway cut-off in age- and sex-normalized theta and alpha, informed by previous literature. For the meta-analysis, Cohen's d was calculated to assess the differences between EEG subgroups for baseline effects, using means and standard deviations of baseline inattention and hyperactivity-impulsivity scores. Non-significant, small Grand Mean effect sizes (-0.212 < d < 0.218) were obtained when comparing baseline behavioral scores between the EEG subgroups. This study could not confirm any association of EEG subtype with behavioral traits. This confirms previous findings suggesting that TBR has no diagnostic value for ADHD. TBR could, however, serve as an aid to stratify patients between neurofeedback protocols based on baseline TBR. A free online tool was made available for clinicians to calculate age- and sex-corrected TBR decile scores (Brainmarker-IV) for stratification of neurofeedback protocols.

Developing the Diagnostic Interview for Adolescents and Adults with Mild/Moderate Intellectual Disabilities: An interview schedule of mental disorders (DIAAID).

Introduction: Young people with intellectual disabilities (ID) are at an increased risk for experiencing mental health issues compared to their peers without disabilities. Further, there are limited resources available to help accurately assess mental health disorders and that are accessible for adolescents with ID. Method: This paper describes the iterative development and pilot testing of the Diagnostic Interview for Adolescents and Adults with Intellectual Disabilities (DIAAID). The authors utilized Evidence Center Design and Universal Design principals to develop the DIAAID; a multi-informant diagnostic interview. Results: The DIAAID development resulted in the creation of 15 adolescents disorder interviews and 24 caregiver disorder interviews. Preliminary results suggest that the DIAAID is a feasible and accessible diagnostic interview for adolescents with ID and their caregivers. Discussion: Lessons learned from DIAAID implementation and future areas research are discussed.

Evaluating Mineral Biomarkers as Mediators and Moderators of Behavioural Improvements in a Randomized Controlled Trial of Multinutrients for Children with ADHD.

Essential minerals are cofactors for synthesis of neurotransmitters supporting cognition and mood. An 8-week fully-blind RCT of multinutrients for ADHD demonstrated three times as many children (age 6-12) had significantly improved behavior ("treatment responders") on multinutrients (54%) compared to placebo (18%). The aim of this secondary study was to evaluate changes in fasted plasma and urinary mineral concentrations following the intervention, and their role as mediators and moderators of treatment response. Fourteen essential or trace minerals were measured in plasma and/or urine at baseline and week 8 from 86 participants (49 multinutrient, 37 placebo). Two-sample t-tests/Mann-Whitney U-tests compared 8-week change between treatment and placebo groups, which were also evaluated as potential mediators. Baseline levels were evaluated as potential moderators, using logistic regression models with clinical treatment response as the outcome. After 8 weeks, plasma boron, chromium (in females only), lithium, molybdenum, selenium, and vanadium, and urinary iodine, lithium, and selenium increased more with multinutrients than placebo, while plasma phosphorus decreased. These changes did not mediate treatment response. However, baseline urinary lithium trended toward moderation: participants with lower baseline urinary lithium were more likely to respond to multinutrients (p=0.058). Additionally, participants with higher baseline iron were more likely to be treatment responders regardless of treatment group (p=0.036.) These results show that multinutrient treatment response among children with ADHD is independent of their baseline plasma mineral levels, while baseline urinary lithium levels show potential as a non-invasive biomarker of treatment response requiring further study.

Problems most concerning to parents of children with ADHD and emotional dysregulation in a randomized controlled trial of multinutrients: MADDY secondary analysis.

OBJECTIVE: With dual focus on structured, objective quantification of parent observations of child's behavior and identifying behaviors most amenable to change, this report examines Parent Target Problems (PTP) as a secondary outcome in a randomized clinical trial (RCT) of children with attention-deficit/ hyperactivity disorder (ADHD) in which one primary outcome, Clinical Global Impression-Improvement, showed a significant advantage of multinutrients over placebo and the other, Likert-type parent ratings, showed significant improvement in both groups, without significant difference between them. METHOD: In a multisite 8-week RCT of broad-spectrum micronutrients ("multinutrients"), parents of children ages 6-12 (N = 126, 73% male, 88% white) with ADHD and emotional dysregulation nominated their child's most concerning problem(s) at baseline and quantified them by frequency, duration, impairment, and consequences. At subsequent visits, parents re-quantified the problem(s). Blinded child psychiatrists independently reviewed the PTPs and rated change at two timepoints compared to baseline. PTPs were grouped into 9 categories. Mean ratings were compared between active and placebo groups and explored by category. RESULTS: By week 8, a significant separation favored multinutrients: 38% of the multinutrient group were "definitely improved" or better, compared to 25% of the placebo group, and ratings of "no change" or "worse" occurred in 35% with placebo versus 23% with multinutrients (p = 0.04). Inattention (72.2%) and emotional dysregulation (69.1%) were the most frequently reported PTP categories. Inattention and internalizing symptoms improved more with multinutrients than placebo (p = 0.01, d = 0.55; p = 0.03, d = 0.80, respectively). The multinutrient advantage was not significant for 7 other symptoms, including hyperactivity/impulsivity, aggression, autistic symptoms, or emotional dysregulation/irritable oppositionality. CONCLUSIONS: This secondary analysis found that the multinutrients, compared to placebo, were associated with improvements in parental concerns overall, and in two domains specifically: inattention and internalizing symptoms (anxiety/depression), but not in seven domains: hyperactivity/impulsivity, aggression, autistic symptoms or physiological symptoms, peer relationships or emotional dysregulation/irritable oppositionality.

Assessment of Iron-Based Spin-Orbit Coupling Effects in Pt-Fe Heterobimetallic Lantern Complexes via 57Fe Mössbauer Spectroscopy.

A series of heterobimetallic lantern complexes, [PtFe(SOCR)4(pyX)] where R = Me, X = H (1), X = NH2 (2), X = SMe (3); R = Ph, X = H (4), X = NH2 (5), X = SMe (6), have been prepared and characterized spectroscopically. Compounds 1, 4, and 5 are reported herein for the first time. The high-spin iron(II) sites of 1-6 have been investigated using 57Fe Mössbauer spectroscopy. Although the isomer shift of these species is nearly identical, their quadrupole splitting exhibits a much larger variation. Moreover, the zero-field Mössbauer spectra of 3-5 show surprising changes over time which are likely indicative of small structural distortions. The field dependent Mössbauer study of 1 and 6 revealed a zero field splitting (ZFS) characterized by a relatively large and positive D value. The combined Density Functional Theory (DFT) and ab initio Complete Active Space Self-Consistent Field (CASSCF) investigation of 1-6 indicates that their ground state is best described using a linear combination of {|xz⟩, |yz⟩} states. Our theoretical analysis suggests that the ZFSs and magnitude of the quadrupole splitting of 1-6 are determined by the spin-orbit coupling of the three lowest orbital states which have a T2g parentage.

Ultrafast Au(III)-Mediated Arylation of Cysteine.

Through mechanistic work and rational design, we have developed the fastest organometallic abiotic Cys bioconjugation. As a result, the developed organometallic Au(III) bioconjugation reagents enable selective labeling of Cys moieties down to picomolar concentrations and allow for the rapid construction of complex heterostructures from peptides, proteins, and oligonucleotides. This work showcases how organometallic chemistry can be interfaced with biomolecules and lead to a range of reactivities that are largely unmatched by classical organic chemistry tools.

Impact of electrophysiologists at daily multidisciplinary report in a paediatric cardiac care unit.

BACKGROUND: Paediatric cardiac electrophysiologists are essential in CHD inpatient care, but their involvement is typically limited to consultation with individual patients. In our integrated heart centre, an electrophysiologist reviews all cardiac inpatient telemetry over the preceding 24 hours and participates in daily multidisciplinary morning report. This study investigates the impact of the strategy of consistent, formalised electrophysiologist presence at multidisciplinary morning report. METHODS: This is a single-centre, prospective, observational study of electrophysiologist participation in patient encounters during heart centre multidisciplinary morning report from 10/20/2021 to 10/31/2022. Multidisciplinary morning report includes discussion of all intensive care and non-intensive care cardiac patients. An encounter was defined as reporting on one patient for one day. Electrophysiologists were initially blinded to observations. RESULTS: Two electrophysiologists were observed over 215 days encompassing 6413 patient encounters. Electrophysiologists made comments on 581(9.1%) encounters in 234 unique patients with diverse diagnoses, equating to a median of 3[interquartile range:1-4] encounters per day. These included identifications of arrhythmias and describing electrocardiographic findings. Recommendation to change management occurred in 282(48.5%) encounters, most commonly regarding medications (n = 142, 24.4%) or pacemaker management (n = 48, 8.3%). Of the 581 encounters, there were 61(10.5%) in which they corrected another physician's interpretation of rhythm or electrocardiogram. CONCLUSION: Routine electrophysiologist involvement in multidisciplinary morning report provides significant, frequent, and timely input in patient management by identifying precise rhythm-related diagnoses and allowing nuanced, patient-specific medication and pacemaker management of all cardiac patients, not just those consulted. Electrophysiologist presence at multidisciplinary morning report is a vital resource and this practice should be considered at integrated paediatric cardiac centres.

Demographic and Clinical Factors Associated With Health-Related Quality-of-Life Profiles Among Prostate Cancer Survivors.

PURPOSE: Our purpose was to describe the prevalence and predictors of symptom and function clusters related to physical, emotional, and social components of general health-related quality of life (HRQOL) in a population-based sample of prostate cancer (PCa) survivors. METHODS: Participants (N = 1,162) completed a baseline survey at a median of 9 months after diagnosis to ascertain the co-occurrence of eight symptom and functional domains that are common across all cancers and not treatment-specific. We used latent profile analysis (LPA) to identify subgroup profiles of survivors with low, moderate, or high HRQOL levels. Multinomial logistic regression models were used to identify clinical and sociodemographic factors associated with survivors' membership in the low versus moderate or high HRQOL profile. RESULTS: The LPA identified 16% of survivors who were categorized in the low HRQOL profile at baseline, indicative of the highest symptom burden and lowest functioning. Factors related to survivors' membership in the low versus higher HRQOL profile groups included less than age 65 years at diagnosis, identifying as non-Hispanic Black race, not working, being a former versus never smoker, systemic therapy, less companionship, more comorbidities, lower health care financial well-being, or less spirituality. Several factors remained associated with remaining in the low versus higher HRQOL profiles on the follow-up survey (n = 699), including younger age, Black race, comorbidity, and lower financial and spiritual well-being. CONCLUSION: About one of six PCa survivors experienced elevated physical and psychosocial symptoms that were independent of local curative therapy, but with younger age, race, comorbidity, and lower financial and spiritual well-being as stable risk factors for poor HRQOL over time.

Circum-Antarctic bottom water formation mediated by tides and topographic waves.

The downslope plumes of dense shelf water (DSW) are critical for the formation of Antarctic Bottom Water (AABW), and thus to the exchange of heat and carbon between surface and abyssal ocean. Previous studies have shown that tides and overflow-forced topographic Rossby waves (TRWs) may have strong impact on the downslope transport of DSW, but it remains unclear how the combined action of these two processes influence the descent processes of DSW, and of the resulting AABW properties. Here, with a synthesis of historical in situ observations and a set of numerical model experiments, we show that tides and TRWs play comparable roles in AABW formation: they both act to accelerate DSW descent to the abyss, leading to the formation of colder and denser AABW. Yet, tides have little impact on AABW formation unless the continental slope is steep enough to suppress TRW generation. We further characterize the dynamical regimes of dense overflows around the entire Antarctic continent based on the relative importance of TRWs versus tides. These findings highlight the pervasive role of high-frequency processes, which are not well represented in the present climate models, in the formation of AABW, and thus in the global overturning circulation.

Rilparencel (Renal Autologous Cell Therapy-REACT®) for Chronic Kidney Disease and Type 1 and Type 2 Diabetes: Phase 2 Trial Design Evaluating Bilateral Kidney Dosing and Redosing Triggers.

INTRODUCTION: Autologous cell-based therapies (CBT) to treat chronic kidney disease (CKD) with diabetes are novel and can potentially preserve renal function and decelerate disease progression. CBT dosing schedules are in early development and may benefit from individual bilateral organ dosing and kidney-dependent function to improve efficacy and durability. The objective of this open-label, phase 2 randomized controlled trial (RCT) is to evaluate participants' responses to rilparencel (Renal Autologous Cell Therapy-REACT®) following bilateral percutaneous kidney injections into the kidney cortex with a prescribed dosing schedule versus redosing based on biomarker triggers. METHODS: Eligible participants with type 1 or 2 diabetes and CKD, eGFR 20-50 mL/min/1.73 m2, urine albumin-to-creatinine ratio (UACR) 30-5,000 mg/g, hemoglobin >10 g/dL, and glycosylated hemoglobin <10% were enrolled. After a percutaneous kidney biopsy and bioprocessing ex vivo expansion of selected renal cells, participants were randomized 1:1 into two cohorts determined by the dosing scheme. Cohort 1 receives 2 cell injections, one in each kidney 3 months apart, and cohort 2 receives one injection and the second dose only if there is a sustained eGFR decline of ≥20 mL/min/1.73 m2 and/or UACR increase of ≥30% and ≥30 mg/g, confirmed by re-testing. CONCLUSION: The trial is fully enrolled with fifty-three participants. Cell injections and follow-up clinical visits are ongoing. This multicenter phase 2 RCT is designed to investigate the efficacy and safety of rilparencel with bilateral kidney dosing and compare two injection schedules with the potential of preserving or improving kidney function and delaying kidney disease progression among patients with stages 3a-4 CKD with diabetes.

High Salinity Shelf Water production rates in Terra Nova Bay, Ross Sea from high-resolution salinity observations.

High Salinity Shelf Water (HSSW) formed in the Ross Sea of Antarctica is a precursor to Antarctic Bottom Water (AABW), a water mass that constitutes the bottom limb of the global overturning circulation. HSSW production rates are poorly constrained, as in-situ observations are scarce. Here, we present high-vertical-and-temporal-resolution salinity time series collected in austral winter 2017 from a mooring in Terra Nova Bay (TNB), one of two major sites of HSSW production in the Ross Sea. We calculate an annual-average HSSW production rate of ~0.4 Sv (106 m3 s-1), which we use to ground truth additional estimates across 2012-2021 made from parametrized net surface heat fluxes. We find sub-seasonal and interannual variability on the order of [Formula: see text] [Formula: see text], with a strong dependence on variability in open-water area that suggests a sensitivity of TNB HSSW production rates to changes in the local wind regime and offshore sea ice pack.

The stability and persistence of symptoms in childhood-onset ADHD.

The course of childhood-onset attention deficit hyperactivity disorder (ADHD) varies across individuals; some will experience persistent symptoms while others' symptoms fluctuate or remit. We describe the longitudinal course of ADHD symptoms and associated clinical characteristics in adolescents with childhood-onset ADHD. Participants (aged 6-12 at baseline) from the Longitudinal Assessment of Manic Symptoms (LAMS) study who met DSM criteria for ADHD prior to age 12 were evaluated annually with the Kiddie Schedule for Affective Disorders and Schizophrenia for eight years. At each timepoint, participants were categorized as meeting ADHD criteria, subthreshold criteria, or not having ADHD. Stability of course was defined by whether participants experienced consistent ADHD symptoms, fluctuating symptoms, or remission. The persistence of the symptoms was defined by symptom status at the final two follow-ups (stable ADHD, stable remission, stable partial remission, unstable). Of 685 baseline participants, 431 had childhood-onset ADHD and at least two follow-ups. Half had a consistent course of ADHD, nearly 40% had a remitting course, and the remaining participants had a fluctuating course. More than half of participants met criteria for ADHD at the end of their participation; about 30% demonstrated stable full remission, 15% had unstable symptoms, and one had stable partial remission. Participants with a persistent course and stable ADHD outcome reported the highest number of symptoms and were most impaired. This work builds on earlier studies that describe fluctuating symptoms in young people with childhood-onset ADHD. Results emphasize the importance of ongoing monitoring and detailed assessment of factors likely to influence course and outcome to help young people with childhood-onset ADHD.

Treatment response to supplemental nutrients for ADHD is independent of diet quality: the MADDY Study RCT.

OBJECTIVES: The 8-week Micronutrients for ADHD in Youth (MADDY) randomized controlled trial (N = 126, age 6-12) of broad-spectrum multinutrients for ADHD with emotional dysregulation found 3 times as many responders with multinutrients (54%) compared to placebo (18%) by Clinical Global Impression-Improvement (CGI-I). Our primary aim for this analysis tests the hypothesis that those with poor overall diet quality at baseline benefit more. The second aim is to explore whether specific components of diet quality moderate treatment response. METHODS: 124 children (69 multinutrients, 55 placebo) had diet quality assessed using the Healthy Eating Index-2015 (HEI-2015). For each potential moderator, the outcome CGI-I at week 8 (RCT-end), was modeled two ways: (1) as a dichotomous variable: responder/non-responder, with responders defined by a rating of 1 or 2 'very much' or 'much improved,' all else equals non-responder using logistic regression, and (2) as a dimensional improvement outcome from 1 = very much improved to 7 = very much worse, using linear regression. RESULTS: HEI-2015 total score did not moderate treatment response [odds ratio = 1.00 (95% CI: 0.90,1.10), p = 0.984] or improvement [ß = -0.01 (95% CI: -0.06,0.04), p = 0.648]. However, total vegetable intake moderated level of improvement in exploratory analysis [ß = -0.48 (95% CI: -0.82, -0.13), p = 0.007]: those with higher baseline vegetable intake showed greater benefit from multinutrients compared to placebo. CONCLUSIONS: Multinutrients may benefit children with ADHD and irritability regardless of overall diet quality. The finding that higher baseline vegetable intake may improve response to multinutrients deserves further exploration, including dietary effect on gut microbiota and absorption of multinutrients and parental factors.

A diffusion decision model analysis of the cognitive effects of neurofeedback for ADHD.

OBJECTIVE: To examine cognitive effects of neurofeedback (NF) for attention-deficit hyperactivity disorder (ADHD) as a secondary outcome of a randomized clinical trial. METHOD: In a double-blind randomized clinical trial (NCT02251743), 133 7-10-year olds with ADHD received either 38 sessions of NF (n = 78) or control treatment (n = 55) and performed an integrated visual and auditory continuous performance test at baseline, mid- and end-treatment. We used the diffusion decision model to decompose integrated visual and auditory continuous performance test performance at each assessment into cognitive components: efficiency of integrating stimulus information (v), context sensitivity (cv), response cautiousness (a), response bias (z/a), and nondecision time for perceptual encoding and response execution (Ter). Based on prior findings, we tested whether the components known to be deficient improved with NF and explored whether other cognitive components improved using linear mixed modeling. RESULTS: Before NF, children with ADHD showed main deficits in integrating stimulus information (v), which led to less accurate and slower responses than healthy controls (p = .008). The NF group showed significantly more improvement in integrating auditory stimulus information (v) than control treatment (significant group-by-time-by-modality effect: p = .044). CONCLUSIONS: NF seems to improve v, deficient in ADHD. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Relationship between area-level socioeconomic status and health-related quality of life among cancer survivors.

Area-level socioeconomic status (SES) impacts cancer outcomes, such as stage at diagnosis, treatments received, and mortality. However, less is known about the relationship between area-level SES and health-related quality of life (HRQOL) for cancer survivors. To assess the additive value of area-level SES data and the relative contribution of area- and individual-level SES for estimating cancer survivors' HRQOL, we conducted a secondary analysis of data from a population-based survey study of cancer survivors (the Measuring Your Health [MY-Health] Study). Multilevel multinomial logistic regression models were used to examine the relationships between individual-level SES, area-level SES as measured by the Centers for Disease Control and Prevention's Social Vulnerability Index, and HRQOL group membership (high, average, low, or very low HRQOL). Area-level SES did not significantly increase model estimation accuracy compared to models using only individual-level SES. However, area-level SES could be an appropriate proxy when the individual-level SES is missing.

Association of metabolic syndrome conditions with risk of second primary uterine cancer in breast cancer survivors.

PURPOSE: Uterine cancer risk is high in breast cancer survivors. Although breast cancer and uterine cancer share some common epidemiological risk factors, association of metabolic syndrome with incident uterine cancer in breast cancer survivors is under-studied. We evaluated the association of metabolic syndrome conditions with second primary uterine cancer in breast cancer survivors. METHODS: In this retrospective cohort study, 37,303 breast cancer patients diagnosed between 2008 and 2020 at Kaiser Permanente Southern California, an integrated healthcare system, were included. Data on cancer-related variables, sociodemographic, and clinical variables were extracted from KPSC's Surveillance, Epidemiology, and End Results (SEER)-affiliated cancer registry and electronic health records, as appropriate. Patients were followed from breast cancer diagnosis until 12/31/2021 for incident uterine cancer. Proportional hazards regression was used to report association [HR (95% CI)] between metabolic conditions and uterine cancer. RESULTS: More than half (53.1%) of the breast cancer survivors had 1-2 metabolic conditions; 19.4% had 3 + , while 27. 5% had no metabolic conditions. Median time to follow-up was 5.33 years and 185 (0.5%) patients developed second primary uterine cancer. Obesity was associated with an elevated uterine cancer risk in the adjusted model [HR (95% CI) 1.64 (1.20-2.25)]. Having 1-2 metabolic conditions (versus none) was not associated with increased uterine cancer risk [adjusted HR (95% CI) 1.24 (0.85-1.82)]; however, there was an increased uterine cancer risk with 3 + metabolic conditions [adjusted HR (95% CI) 1.82 (1.16-2.87)]. CONCLUSION: Although not statistically significant, we found a trend demonstrating greater uterine cancer risk by increasing numbers of metabolic syndrome conditions in breast cancer survivors.