Treatment Utilization Pattern of Preschool Children With Attention-Deficit/Hyperactivity Disorder.

OBJECTIVE: The aim of this study was to identify patterns of ADHD care, including factors that guide selection and sequencing of treatments in a large nationwide sample of preschool-aged youth over the past 6 years. METHOD: A retrospective cohort study utilizing a large electronic health record (TriNetX) of nearly 24,000 children ages 3 to 6 diagnosed with ADHD. RESULTS: One in three preschoolers with ADHD were prescribed psychotropic medication, most commonly methylphenidate and guanfacine. One in 10 had at least one psychotherapy billing code during the entire assessment with most youth starting medication before psychotherapy. Rates of most treatments, including polypharmacy, increased with comorbid psychiatric disorders or sleep problems and over the course of the coronavirus pandemic. CONCLUSION: Rates of treatment have increased over time but are still largely inconsistent with published care guidelines that advise therapy before medication. Clinicians appear to prioritize psychiatric comorbidity and sleep problems when selecting treatments.

Glucagon-like peptide-1 receptor agonist, liraglutide, reduces heroin self-administration and drug-induced reinstatement of heroin-seeking behaviour in rats.

Drug addiction is a chronic brain disease characterized by the uncontrolled use of a substance. Due to its relapsing nature, addiction is difficult to treat, as individuals can relapse following even long periods of abstinence and, it is during this time, that they are most vulnerable to overdose. In America, opioid overdose has been increasing for decades, making finding new treatments to help patients remain abstinent and prevent overdose deaths imperative. Recently, glucagon-like peptide-1 (GLP-1) receptor agonists have shown promise in reducing motivated behaviours for drugs of abuse. In this study, we test the effectiveness of the GLP-1 analogue, liraglutide (LIR), in reducing heroin addiction-like behaviour, and the potential side effects associated with the treatment. We show that daily treatment with LIR (0.1 mg/kg sc) increases the latency to take heroin, reduces heroin self-administration, prevents escalation of heroin self-administration and reduces drug-induced reinstatement of heroin-seeking behaviour in rats. A 1-h pretreatment time, however, was too short to reduce cue-induced seeking in our study. Moreover, we showed that, while LIR (0.1, 0.3, 0.6 and 1.0 mg/kg sc) supported conditioned taste avoidance of a LIR-paired saccharin cue, it did not elicit intake of the antiemetic kaolin in heroin-naïve or heroin-experienced rats. Further, 0.1 mg/kg LIR did not produce great disruptions in food intake or body weight. Overall, the data show that LIR is effective in reducing heroin taking and heroin seeking at doses that do not cause malaise and have a modest effect on food intake and body weight gain.

Multisite 11-year experience of less-intensive vs intensive therapies in acute myeloid leukemia.

Less-intensive induction therapies are increasingly used in older patients with acute myeloid leukemia (AML). Using an AML composite model (AML-CM) assigning higher scores to older age, increased comorbidity burdens, and adverse cytogenetic risks, we defined 3 distinct prognostic groups and compared outcomes after less-intensive vs intensive induction therapies in a multicenter retrospective cohort (n = 1292) treated at 6 institutions from 2008 to 2012 and a prospective cohort (n = 695) treated at 13 institutions from 2013 to 2017. Prospective study included impacts of Karnofsky performance status (KPS), quality of life (QOL), and physician perception of cure. In the retrospective cohort, recipients of less-intensive therapies were older and had more comorbidities, more adverse cytogenetics, and worse KPS. Less-intensive therapies were associated with higher risks of mortality in AML-CM scores of 4 to 6, 7 to 9, and ≥10. Results were independent of allogeneic transplantation and similar in those age 70 to 79 years. In the prospective cohort, the 2 groups were similar in baseline QOL, geriatric assessment, and patient outcome preferences. Higher mortality risks were seen after less-intensive therapies. However, in models adjusted for age, physician-assigned KPS, and chance of cure, mortality risks and QOL were similar. Less-intensive therapy recipients had shorter length of hospitalization (LOH). Our study questions the survival and QOL benefits (except LOH) of less-intensive therapies in patients with AML, including those age 70 to 79 years or with high comorbidity burdens. A randomized trial in older/medically infirm patients is required to better assess the value of less-intensive and intensive therapies or their combination. This trial was registered at www.clinicaltrials.gov as #NCT01929408.

Vagotomy increases alcohol intake in female rats in diet dependent manner: Implications for increased alcohol use disorder after roux-en-y gastric bypass surgery.

A variety of weight loss surgeries have been developed to fight the obesity epidemic, with Roux-en-Y gastric bypass (RYGB) being one of the most effective and popular procedures. However, the underlying mechanisms behind its efficacy are still not well understood. Furthermore, growing clinical evidence suggests that RYGB may result in increased risk for development of alcohol use disorder (AUD). The vagus nerve is a potentially critical contributor to increased risk of AUD following RYGB due to the potential for significant damage to the vagus during surgery, which has been confirmed in rodent studies. Studies aiming at the mechanisms underlying development of alcohol or substance use disorders following the surgery have exclusively used male rats, despite the majority of RYGB patients being female. Thus, the current study had two objectives: 1) to investigate the effect of RYGB on ethanol (EtOH) intake in female rats using a protocol previously established in male rats, and 2) to test the effect of vagal damage and high fat diet (HFD) on EtOH intake in female rats. In the first study, 22 female rats were maintained on HFD for four weeks and then split into two surgical groups, RYGB (n = 10) and Sham (n = 12). All rats then underwent a two-bottle choice test of increasing EtOH concentrations: 2%, 4%, 6%, 8%. Rats were then forced to abstain from EtOH for two weeks, after which access to 8% EtOH was reinstated. The RYGB female rats significantly increased their intake for low concentrations of EtOH (2% and 4%) and during the reinstatement period for 8%. These results mirror those seen in male rats, and thus, confirms RYGB in female rats as an equally viable model to males. In the second study, 40 female rats were separated into four groups: HFD/Sham, HFD/Vagotomy, normal diet (ND)/Sham, and ND/Vagotomy. All rats then were subjected to the same two-bottle choice test protocol as in the previous study. Rats in the vagotomy condition had significantly greater preference for 2% and 4% EtOH compared with Sham-operated controls. EtOH intake, either in ml or adjusted for body weight, was greater in rats maintained on ND compared with rats maintained on HFD. These data suggest that vagal damage may, at least in part, contribute to increased preference for EtOH. Furthermore, this increase in EtOH preference is counter to the blunting effect of HFD. In conclusion, the data presented here suggest a role for vagal damage in risk of AUD after weight loss surgery.

Regimen-intensity per count-recovery and hospitalization index: A new tool to assign regimen intensity for AML.

BACKGROUND: Low-intensity regimens have been increasingly used to treat older patients with acute myeloid leukemia (AML). Recent studies, however, suggest older patients can tolerate and potentially benefit from intensive chemotherapeutic regimens. The ability to compare the utility of varying regimen intensities in AML is hindered by the lack of a standardized definition of "regimen intensity." METHODS: We conducted a survey asking AML physicians which of 38 regimens they would consider intensive vs less-intensive. Electronic medical records of 592 patients receiving many of these regimens were used to design a model characterizing regimens as intensive vs less-intensive as identified by ≥75% physician consensus. Variables included frequency and length of hospitalizations, intensive care unit admissions, severe gastrointestinal toxicities, time to nadir, and recovery of neutrophil/platelet count. RESULTS: Physicians agreed at a rate of 75%-100% on the assignment of degree of intensity to the majority (n = 28) of these regimens, while the level of agreement was <75% for the remaining 10 regimens (26%). Logistic regression analyses identified number and length of hospitalizations to be significantly associated with intensive regimens and count recovery with less-intensive regimens. We created the "regimen-intensity per count-recovery and hospitalization" (RICH) index with an AUC of 0.87. Independent model validation yielded an AUC of 0.75. CONCLUSIONS: We were able to generate a novel model that defines regimen intensity for many therapies used to treat AML. Results facilitate a future randomized study comparing intensive vs less-intensive regimens.

Genetic variant rs3750625 in the 3'UTR of ADRA2A affects stress-dependent acute pain severity after trauma and alters a microRNA-34a regulatory site.

α2A adrenergic receptor (α2A-AR) activation has been shown in animal models to play an important role in regulating the balance of acute pain inhibition vs facilitation after both physical and psychological stress. To our knowledge, the influence of genetic variants in the gene encoding α2A-AR, ADRA2A, on acute pain outcomes in humans experiencing traumatic stress has not been assessed. In this study, we tested whether a genetic variant in the 3'UTR of ADRA2A, rs3750625, is associated with acute musculoskeletal pain (MSP) severity following motor vehicle collision (MVC, n = 948) and sexual assault (n = 84), and whether this influence was affected by stress severity. We evaluated rs3750625 because it is located in the seed binding region of miR-34a, a microRNA (miRNA) known to regulate pain and stress responses. In both cohorts, the minor allele at rs3750625 was associated with increased musculoskeletal pain in distressed individuals (stress*rs3750625 P = 0.043 for MVC cohort and P = 0.007 for sexual assault cohort). We further found that (1) miR-34a binds the 3'UTR of ADRA2A, (2) the amount of repression is greater when the minor (risk) allele is present, (3) miR-34a in the IMR-32 adrenergic neuroblastoma cell line affects ADRA2A expression, (4) miR-34a and ADRA2A are expressed in tissues known to play a role in pain and stress, (5) following forced swim stress exposure, rat peripheral nerve tissue expression changes are consistent with miR-34a regulation of ADRA2A. Together, these results suggest that ADRA2A rs3750625 contributes to poststress musculoskeletal pain severity by modulating miR-34a regulation.

Transplantation of human retinal pigment epithelial cells in the nucleus accumbens of cocaine self-administering rats provides protection from seeking.

Chronic exposure to drugs and alcohol leads to damage to dopaminergic neurons and their projections in the 'reward pathway' that originate in the ventral tegmental area (VTA) and terminate in the nucleus accumbens (NAc). This damage is thought to contribute to the signature symptom of addiction: chronic relapse. In this study we show that bilateral transplants of human retinal pigment epithelial cells (RPECs), a cell mediated dopaminergic and trophic neuromodulator, into the medial shell of the NAc, rescue rats with a history of high rates of cocaine self-administration from drug-seeking when returned, after 2 weeks of abstinence, to the drug-associated chamber under extinction conditions (i.e., with no drug available). Excellent survival was noted for the transplant of RPECs in the shell and/or the core of the NAc bilaterally in all rats that showed behavioral recovery from cocaine seeking. Design based unbiased stereology of tyrosine hydroxylase (TH) positive cell bodies in the VTA showed better preservation (p<0.035) in transplanted animals compared to control animals. This experiment shows that the RPEC graft provides beneficial effects to prevent drug seeking in drug addiction via its effects directly on the NAc and its neural network with the VTA.

State of the science review: Advances in pain management in wounded service members over a decade at war.

The pain conditions and comorbidities experienced by injured service members and the challenge of pain management by the military medical system offer a unique opportunity to inform pain management and medical research. In this article, acute and chronic pain issues, current treatment options and limitations, as well as novel approaches to pain management are discussed within the context of combat casualty care, from the battlefield to hospitalization and rehabilitation. This review will also highlight the current pain management limitations that need to be addressed in future clinical and basic science research to improve care for our nation's injured service members.