ADHD medicine consumption in Europe after COVID-19: catch-up or trend change?

BACKGROUND: Although the COVID-19 pandemic and its implications have been associated with mental health services utilization and medication consumption, there is no longitudinal study on the long-term impact on ADHD medication use trends. METHODS: This study examines the European ADHD medication consumption in 2020 to 2022 compared to the predicted consumption assuming the persistence of pre-pandemic trends. Predictions are calculated using Seasonal Autoregressive Integrated Moving Average (SARIMA) models. RESULTS: While European ADHD medication sales recorded a drop in 2020, they returned to the predicted level in 2021, even slightly exceeding it. In 2022, we found a clear exceedance of the predicted level by 16.4% on average at country level. Furthermore, the increase in consumption growth in the post-pandemic period (2021-2022) compared to the pre-pandemic period (2014-2019) was significant in 26 of the 28 European countries under consideration. CONCLUSION: There is strong evidence of a trend change in the ADHD medicine consumption growth throughout Europe after the COVID-19 pandemic.

Exosomal evasion of humoral immunotherapy in aggressive B-cell lymphoma modulated by ATP-binding cassette transporter A3.

Targeting the surface of malignant cells has evolved into a cornerstone in cancer therapy, paradigmatically introduced by the success of humoral immunotherapy against CD20 in malignant lymphoma. However, tumor cell susceptibility to immunochemotherapy varies, with mostly a fatal outcome in cases of resistant disease. Here, we show that lymphoma exosomes shield target cells from antibody attack and that exosome biogenesis is modulated by the lysosome-related organelle-associated ATP-binding cassette (ABC) transporter A3 (ABCA3). B-cell lymphoma cells released exosomes that carried CD20, bound therapeutic anti-CD20 antibodies, consumed complement, and protected target cells from antibody attack. ABCA3, previously shown to mediate resistance to chemotherapy, was critical for the amounts of exosomes released, and both pharmacological blockade and the silencing of ABCA3 enhanced susceptibility of target cells to antibody-mediated lysis. Mechanisms of cancer cell resistance to drugs and antibodies are linked in an ABCA3-dependent pathway of exosome secretion.

A Comparison of Virtual Reality Menu Archetypes: Raycasting, Direct Input, and Marking Menus.

We contribute an analysis of the prevalence and relative performance of archetypal VR menu techniques. An initial survey of 108 menu interfaces in 84 popular commercial VR applications establishes common design characteristics. These characteristics motivate the design of raycast, direct, and marking menu archetypes, and a two-experiment comparison of their relative performance with one and two levels of hierarchy using 8 or 24 items. With a single-level menu, direct input is the fastest interaction technique in general, and is unaffected by number of items. With a two-level hierarchical menu, marking is fastest regardless of item number. Menus using raycasting, the most common menu interaction technique, were among the slowest of the tested menus but were rated most consistently usable. Using the combined results, we provide design and implementation recommendations with applications to general VR menu design.

Eukaryotic DNA polymerases require an iron-sulfur cluster for the formation of active complexes.

The eukaryotic replicative DNA polymerases (Pol α, δ and ɛ) and the major DNA mutagenesis enzyme Pol ζ contain two conserved cysteine-rich metal-binding motifs (CysA and CysB) in the C-terminal domain (CTD) of their catalytic subunits. Here we demonstrate by in vivo and in vitro approaches the presence of an essential [4Fe-4S] cluster in the CysB motif of all four yeast B-family DNA polymerases. Loss of the [4Fe-4S] cofactor by cysteine ligand mutagenesis in Pol3 destabilized the CTD and abrogated interaction with the Pol31 and Pol32 subunits. Reciprocally, overexpression of accessory subunits increased the amount of the CTD-bound Fe-S cluster. This implies an important physiological role of the Fe-S cluster in polymerase complex stabilization. Further, we demonstrate that the Zn-binding CysA motif is required for PCNA-mediated Pol δ processivity. Together, our findings show that the function of eukaryotic replicative DNA polymerases crucially depends on different metallocenters for accessory subunit recruitment and replisome stability.

The impact of the COVID-19 pandemic on ADHD medicine consumption in 47 countries and regions.

The objective of this study is to quantify the impact of the COVID-19 pandemic on attention deficit hyperactivity disorder (ADHD) medication consumption globally and nationally using pharmaceutical sales data from 2014 to 2021 across 47 countries and regions. A seasonal autoregressive integrated moving average model (SARIMA) was applied to the time series until the end of 2019 at country level and used for the prediction of the ADHD medication consumption in 2020 and 2021. The deviations from the actual to the forecasted sales, which simulate the development without the emergence of COVID-19, yield estimates for the pandemic's impact. In 36 of the 47 countries and regions, the actual sales in 2020 were lower than predicted, with an average relative drop of 6.2% in defined daily doses (DDD) per 1000 inhabitants per day at country-level. In 2021, most countries recorded actually higher ADHD medication use than predicted at the end of 2019. On average, the consumption increased per country by 1.60%. The deviations strongly correlate with the stringency of anti-pandemic government policies. The findings suggest that the pandemic led to a substantially lower consumption of ADHD medication in 2020. However, in 2021 the pandemic had an accelerating effect as the increasing consumption trends are more pronounced than before the pandemic.

OctoPocus in VR: Using a Dynamic Guide for 3D Mid-Air Gestures in Virtual Reality.

Bau and Mackays OctoPocus dynamic guide helps novices learn, execute, and remember 2D surface gestures. We adapt OctoPocus to 3D mid-air gestures in Virtual Reality (VR) using an optimization-based recognizer, and by introducing an optional exploration mode to help visualize the spatial complexity of guides in a 3D gesture set. A replication of the original experiment protocol is used to compare OctoPocus in VR with a VR implementation of a crib-sheet. Results show that despite requiring 0.9s more reaction time than crib-sheet, OctoPocus enables participants to execute gestures 1.8s faster with 13.8 percent more accuracy during training, while remembering a comparable number of gestures. Subjective ratings support these results, 75 percent of participants found OctoPocus easier to learn and 83 percent found it more accurate. We contribute an implementation and empirical evidence demonstrating that an adaptation of the OctoPocus guide to VR is feasible and beneficial.

A double-blind, placebo-controlled pilot study of quetiapine for depressed adolescents with bipolar disorder.

OBJECTIVE: To conduct a pilot study comparing the effects of quetiapine and placebo for the treatment of depressive episodes in adolescents with bipolar I disorder. METHOD: Thirty-two adolescents (ages 12-18 years) with a depressive episode associated with bipolar I disorder were randomized to eight weeks of double-blind treatment with quetiapine, 300-600 mg/day, or placebo. This two-site study was conducted from March 2006 through August 2007. The primary efficacy measure was change in Children's Depression Rating Scale-Revised Version (CDRS-R) scores from baseline to endpoint. Secondary efficacy measures included change in CDRS-R scores over the eight-week study period (PROC MIXED), changes from baseline to endpoint in Hamilton Anxiety Rating Scale (HAM-A), Young Mania Rating Scale (YMRS), and Clinical Global Impression-Bipolar Version Severity (CGI-BP-S) scores, as well as response and remission rates. Safety and tolerability were assessed weekly. RESULTS: There was no statistically significant treatment group difference in change in CDRS-R scores from baseline to endpoint (p = 0.89, effect size =-0.05, 95% confidence interval: -0.77-0.68), nor in the average rate of change over the eight weeks of the study (p = 0.95). Additionally, there were no statistically significant differences in response (placebo =67% versus quetiapine = 71%) or remission (placebo = 40% versus quetiapine = 35%) rates, or change in HAM-A, YMRS, or CGI-BP-S scores (all p > 0.7) between treatment groups. Dizziness was more commonly reported in the quetiapine (41%) than in the placebo (7%) group (Fisher's exact test, p = 0.04). CONCLUSIONS: The results suggest that quetiapine monotherapy is no more effective than placebo for the treatment of depression in adolescents with bipolar disorder. However, limitations of the study, including the high placebo response rate, may have contributed to our findings and should be considered in the design of future investigations of pharmacological interventions for this population.

Evaluating authentication options for mobile health applications in younger and older adults.

OBJECTIVE: Apps promoting patient self-management may improve health outcomes. However, methods to secure stored information on mobile devices may adversely affect usability. We tested the reliability and usability of common user authentication techniques in younger and older adults. METHODOLOGY: Usability testing was conducted in two age groups, 18 to 30 years and 50 years and older. After completing a demographic questionnaire, each participant tested four authentication options in random order: four-digit personal identification number (PIN), graphical password (GRAPHICAL), Android pattern-lock (PATTERN), and a swipe-style Android fingerprint scanner (FINGERPRINT). Participants rated each option using the Systems Usability Scale (SUS). RESULTS: A total of 59 older and 43 younger participants completed the study. Overall, PATTERN was the fastest option (3.44s), and PIN had the fewest errors per attempt (0.02). Participants were able to login using PIN, PATTERN, and GRAPHICAL at least 98% of the time. FINGERPRINT was the slowest (26.97s), had an average of 1.46 errors per attempt, and had a successful login rate of 85%. Overall, PIN and PATTERN had higher SUS scores than FINGERPRINT and GRAPHICAL. Compared to younger participants, older participants were also less likely to find PATTERN to be tiring, annoying or time consuming and less likely to consider PIN to be time consuming. Younger participants were more likely to rate GRAPHICAL as annoying, time consuming and tiring than older participants. CONCLUSIONS: On mobile devices, PIN and pattern-lock outperformed graphical passwords and swipe-style fingerprints. All participants took longer to authenticate using the swipe-style fingerprint compared to other options. Older participants also took two to three seconds longer to authenticate using the PIN, pattern and graphical passwords though this did not appear to affect perceived usability.

Dimension of pain-related quality of life and self-reported mental health in men and women of the European Prospective Investigation into Cancer-Norfolk cohort: a population-based cross-sectional study.

Both cognitive and behavioural factors are linked to the experience of pain as well as its interference with quality of life. Psychological distress has been shown to be associated to several emotional and social impairments. Although, the association between pain and mental health has been widely discussed, the understanding of life interference and outcome is not fully understood. This study examined the association of pain dimension and mental health domain in 16,051 participants of the EPIC-Norfolk cohort (mean age = 58.9 ± 9.1 years). Study outcomes were depressive or anxious behaviour and limitations due to emotional problems and impairments in social functioning (mental functional health components of the Short Form-36 (SF-36)). Logistic regression models were constructed controlling for the potentially confounding factors including socio-economic variables (occupational social class, deprivation, marital status, education), lifestyle behaviour (physical activity, smoking, alcohol, dietary) and previous medical history. Strong interference in quality of life due to pain (bottom 20% of pain dimension score of SF-36) was significantly associated with poor MH in men and women (odds ratios (ORs) (95% confidence intervals (CIs)): 1.35 (1.19, 1.54) and 1.39 (1.25, 1.55), respectively; p < 0.0001) in fully adjusted models. Moreover, strong interference due to pain was also significantly associated with poor overall MH including emotional and social functioning (ORs (95% CIs): 1.42 (1.25, 1.62) and 1.39 (1.25, 1.55) respectively; p < 0.0001) in fully adjusted models; subsidiary analysis using linear regression models demonstrated similar results for these domains. Although a strong association has been shown, further research is needed to provide information on the different site and/or causes of pain which would allow stratification. Moreover, assuming a bi-directional nature of both domains, systematic assessment and management of pain have a lot of potential to improve the MH-related quality of life in the general population and vice versa.

Five-year follow-up of the Argentine randomized trial of coronary angioplasty with stenting versus coronary bypass surgery in patients with multiple vessel disease (ERACI II).

OBJECTIVES: The purpose of the present study is to report the five-year follow-up results of the ERACI II trial. BACKGROUND: Immediate and one-year follow-up results of the ERACI II study showed a prognosis advantage of percutaneous coronary intervention (PCI) with stents over coronary artery bypass grafting (CABG). METHODS: A total of 450 patients were randomly assigned to undergo either PCI (n = 225); or CABG (n = 225). Only patients with multi-vessel disease were enrolled. Clinical follow-up during five years was obtained in 92% of the total population after hospital discharge. The primary end point of the study was to compare freedom from major adverse cardiovascular events (MACE) at 30 days, 1 year, 3 years, and 5 years of follow-up. RESULTS: At five years of follow-up, patients initially treated with PCI had similar survival and freedom from non-fatal acute myocardial infarction than those initially treated with CABG (92.8% vs. 88.4% and 97.3% vs. 94% respectively, p = 0.16). Freedom from repeat revascularization procedures (PCI/CABG) was significantly lower with PCI compared with CABG (71.5% vs. 92.4%, p = 0.0002). Freedom from MACE was also significantly lower with PCI compared with CABG (65.3% vs. 76.4%; p = 0.013). At five years similar numbers of patients randomized to each revascularization procedure were asymptomatic or with class I angina. CONCLUSIONS: At five years of follow-up, in the ERACI II study, there were no survival benefits from any revascularization procedure; however patients initially treated with CABG had better freedom from repeat revascularization procedures and from MACE.

Nuclear Trapping through Inhibition of Exosomal Export by Indomethacin Increases Cytostatic Efficacy of Doxorubicin and Pixantrone.

PURPOSE: Although R-CHOP-based immunochemotherapy cures significant proportions of patients with aggressive B-cell lymphoma, tumor cell susceptibility to chemotherapy varies, with mostly fatal outcome in cases of resistant disease. We and others have shown before that export of cytostatic drugs contributes to drug resistance. Now we provide a novel approach to overcome exosome-mediated drug resistance in aggressive B-cell lymphomas. EXPERIMENTAL DESIGN: We used well-established centrifugation protocols to purify exosomes from DLBCL cell lines and detected anthracyclines using FACS and HPLC. We used shRNA knockdown of ABCA3 to determine ABCA3 dependence of chemotherapy susceptibility and monitored ABCA3 expression after indomethacin treatment using qPCR. Finally, we established an in vivo assay using a chorioallantoic membrane (CAM) assay to determine the synergy of anthracycline and indomethacin treatment. RESULTS: We show increased efficacy of the anthracycline doxorubicin and the anthracenedione pixantrone by suppression of exosomal drug resistance with indomethacin. B-cell lymphoma cells in vitro efficiently extruded doxorubicin and pixantrone, in part compacted in exosomes. Exosomal biogenesis was critically dependent on the expression of the ATP-transporter A3 (ABCA3). Genetic or chemical depletion of ABCA3 augmented intracellular retention of both drugs and shifted the subcellular drug accumulation to prolonged nuclear retention. Indomethacin increased the cytostatic efficacy of both drugs against DLBCL cell lines in vitro and in vivo in a CAM assay. CONCLUSIONS: We propose pretreatment with indomethacin toward enhanced antitumor efficacy of anthracyclines and anthracenediones.

The management of pediatric subtrochanteric femur fractures with a statically locked intramedullary nail.

OBJECTIVES: To evaluate locked intramedullary (IM) fixation as an alternative treatment method for children with subtrochanteric fractures. DESIGN: Retrospective review. SETTING: Level 1 trauma center in a Children's Hospital. PATIENTS/PARTICIPANTS: Pediatric patients with subtrochanteric femur fractures with open growth plates. INTERVENTION: All patients were treated with a lateral entry IM locking nail. OUTCOME MEASUREMENTS: Patients were followed until full fracture consolidation or until implant removal. Data on time to full weight bearing, return to full activity, residual pain, any form of gait abnormality, and any other complication from follow-up visits were collected. RESULTS: There were 9 males and 1 female patient with an average age of 12 years and average follow-up of 22 months. Most of the fractures occurred secondary to high-energy trauma. Partial weight bearing was started at 24 days and full at 66 days. Implants were removed on average at 11 months after implantation. There were neither intraoperative complications nor major complications in the postoperative period recorded after removal. Two patients presented with a longer limb on the affected side, both 8 mm, and 2 presented with asymptomatic grade I heterotopic ossification. CONCLUSIONS: The use of a statically locked lateral entry IM nail for subtrochanteric femur fractures in children is a safe and efficacious method of treatment with few complications and risks and satisfactory outcomes in children over the age of 8 years. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Glucagon-like peptide-1 is involved in sodium and water homeostasis in humans.

UNLABELLED: In previous studies with glucagon-like peptide-1 (GLP-1) we have observed that this peptide modulates fluid intake and increases renal sodium excretion in healthy volunteers and in patients with diabetes mellitus type 2. The effect of GLP-1 on thirst, water intake and on osmoregulation has, however, not been examined in detail in humans. METHODS: Seventeen healthy male subjects were enrolled in two double-blind, placebo-controlled studies. In study part A, 8 volunteers participated in a protocol with an intravenous salt load of 26.7 +/- 0.9 g comparing the effect of an infusion of GLP-1 (1.5 pmol/kg x min) to isotonic saline (placebo). Sodium excretion and water intake were measured. In part B, 9 volunteers were challenged with an oral salt load of 27.7 +/- 0.5 g; sodium excretion and water intake were determined comparing an infusion of GLP-1 (1.5 pmol/kg x min) to isotonic saline (placebo). In part C, intestinal biopsies along the gastrointestinal tract were obtained from 14 healthy subjects. Expression of human GLP-1 receptor mRNA was measured by real-time polymerase chain reaction. RESULTS: In study part A, an increase in renal sodium excretion was demonstrated: FeNa rose from 1.6 +/- 0.3 (placebo) to 2.7 +/- 0.2% (GLP-1; p = 0.0005). There was no difference in water consumption between the two treatments: 1,291 +/- 69 (saline) vs. 1,228 +/- 74 ml (GLP-1; p = 0.49). In part B, an oral salt challenge of 27.7 +/- 0.5 g led to an increased renal excretion of sodium during GLP-1: FeNa increased from 1.6 +/- 0.2% (placebo) to 2.0 +/- 0.2% (GLP-1; p = 0.012). In contrast to part A, oral water intake was reduced by 36% under GLP-1 treatment: 1,848 +/- 331 ml (placebo) vs. 1,181 +/- 177 ml (GLP-1; p = 0.0414). Three subjects in part B did not finish treatment with GLP-1 because of diarrhea. Human GLP-1 receptor mRNA expression was highest in the proximal human small intestine compared to terminal ileum and colon (p < 0.02). CONCLUSIONS: GLP-1 acts on renal tissue reducing sodium absorption, probably via similar sodium transporters, which also may be localized in the gastrointestinal tract. This hypothesis needs to be confirmed by further studies.