Pediatric attention deficit hyperactivity disorder (ADHD): 2022 updates on pharmacological management.

INTRODUCTION: Pediatric attention-deficit disorder (ADHD) impacts a significant percentage of the population world-wide. Pharmacologic treatments have been shown to be safe and effective for managing symptoms. Various medication formulations exist, and new medication agents are continually approved each year. AREAS COVERED: This article offers an overview of ADHD, an overview of both stimulant and non-stimulant medication options as well as an overview of stimulant misuse. It explores the medication mechanisms of action and side effect profiles, as well as offering an in-depth summary of the novel agents recently approved and soon-to-be approved for use in youth. PubMed and Medline were utilized. Search terms included children, adolescents, ADHD, and medication. FDA package inserts were reviewed for all medications. EXPERT OPINION: New formulations of medications include an evening administered, extended, and delayed-release form of methylphenidate (DR/ER MPH), a methylphenidate pro-drug (serdexmethylphenidate) and an amphetamine patch. The availability of a new SNRI (selective norepinephrine reuptake inhibitor), viloxazine extended-release (VER), and the pending approval of a triple reuptake inhibitor (centanafadine) provides welcome additions to the prescriber's toolbox.

This article is a review of pharmacological treatment options for pediatric attention-deficit disorder (ADHD). It provides an overview of ADHD, an overview of the current stimulant and non-stimulant medication options as well as detailed information on the newer psychopharmacological options to assist in the education of the wide array of medication options for treatment. As ADHD is a heterogeneous illness, a wide array of medication options is helpful in the clinician's toolbox. Learning the mechanisms of action along with the side effect profile for newer medication options is the focus of this review. There are new options for patches and new combinations for long-acting and delayed-release formulations as well as new non-stimulant options which target different receptors.

An Investigation of the Effect of Water Additives on Broiler Growth and the Caecal Microbiota at Harvest.

Campylobacter is the most common foodborne pathogen in developed countries and most cases are associated with poultry. This study investigated the effect of three anti-Campylobacter water additives on broiler growth and on the caecal microbiota at harvest using 16S rRNA amplicon sequencing. Mixtures of organic acids (OA) and essential oils (EO) were administered to broilers for the entirety of the production cycle (35 d) and medium-chain fatty acids (MCFA) for 5 d immediately before harvest, under commercial conditions. Bird weight gain was significantly (p < 0.001) reduced in broilers receiving the OA and EO treatments. While this was most likely due to reduced water intake and corresponding lower feed consumption, changes to the caecal microbiota may also have contributed. Firmicutes made up over 75% of the bacteria regardless of sample type, while the minor phyla included Bacteroidetes, Actinobacteria, Melainabacteria, and Proteobacteria. There were no significant (p > 0.05) differences in the alpha diversity as measured using ACE, Chao1, and Shannon indices, except for control (water) versus MCFA and OA versus MCFA, using the Wilcox test. In contrast, there was a significant (p < 0.05) difference in beta diversity when the treated were compared to the untreated control and main flock samples, while linear discriminant analysis effect size (LeFSe) identified three OTUs that were present in the control but absent in the treated birds. It was concluded that the water additives tested adversely affected broiler performance, which may, at least in part, be due to changes in the caecal microbiota, assuming that the altered microbiota at day 35 is indicative of a change throughout the production cycle.

Genomic diversity, virulence and source of Campylobacter jejuni contamination in Irish poultry slaughterhouses by whole genome sequencing.

AIMS: The aim was to exploit whole genome sequencing (WGS) to assess genomic diversity, identify virulence genes and deduce the proportion of Campylobacter colonized broilers that directly contaminate their carcasses. METHODS AND RESULTS: Campylobacter jejuni isolates (107) from caeca and carcass neck skin samples (50 pairs from the same batch plus 7 individual caeca) sampled at three poultry slaughterhouses over a one-year period were selected for sequencing (MiSeq; Illumina). FastQ files were submitted to BioNumerics for analysis using the wgMLST scheme for allele calling. Campylobacter cgMLST and hierarchical clustering was performed by applying the single linkage algorithm. Sequence types (STs) were determined in silico from the WGS data and isolates were assigned into clonal complexes (CCs) using the Campylobacter PubMLST.org database. Virulence genes were determined by downloading core sequences from the virulence factor database (VFDB) and the National Center for Biotechnology Information (NCBI). A high degree of diversity was observed with 23 different STs identified. ST257 and CC-21 were the most common STs and CCs, respectively. cgMLST analysis suggested that 56% of carcass contamination was a direct result of contamination from caeca from the same batch. Virulence genes known to play a role in human C. jejuni infection were identified such as the wlaN gene and the genes associated with lipooligosaccharide synthesis, which were identified in 30% of isolates. CONCLUSIONS: Caecal colonization was the more plausible occurring source of C. jejuni contamination of broiler carcasses, compared with cross-contamination from another batch or the environment. The high rate of genetic diversity observed amongst caecal isolates is consistent with a wide variety of Campylobacter strains circulating in poultry flocks in Ireland. SIGNIFICANCE AND IMPACT OF STUDY: The results will further inform broiler processors and regulators about the influence and importance of on-farm colonization versus slaughterhouse cross-contamination and the relationship between C. jejuni in caeca and carcasses during processing.

Effect of Doxycycline Use in the Early Broiler Production Cycle on the Microbiome.

16S rRNA amplicon sequencing was used to investigate changes in the broiler gastrointestinal tract (GIT) microbiota throughout the rearing period and in combination with antibiotic treatment. Thirty birds (from a commercial flock) were removed at multiple points throughout the rearing period on days 13, 27, and 33, euthanised, and their GIT aseptically removed and divided into upper (the crop, proventriculus, and the gizzard), middle (the duodenum, jejunum, and ileum) and lower (the large intestine, the caeca, and the cloaca) sections. In a separate commercial flock, on the same farm with similar husbandry practices and feed, doxycycline (100 mg/ml per kg body weight) was administered in drinking water between day 8 and 12 (inclusive) of the production cycle. Birds were removed on days, 13, 27, and 33 and GIT samples prepared as above. The contents of three merged samples from each GIT section were pooled (n = 60), the DNA extracted and analysed by 16S rRNA amplicon metagenomic sequencing and analysed. Major changes in the broiler microbiota were observed as the birds aged particularly with the Firmicutes/Bacteroidetes ratio (F:B) of the lower GIT. Moreover, Chao1, ACE, and Shannon indices showed the antibiotic treatment significantly altered the microbiota, and this change persisted throughout the rearing period. Further research is required to investigate the effect of these changes on bird performance, susceptibility to infections and Campylobacter carriage.

Prevalence and levels of Campylobacter in broiler chicken batches and carcasses in Ireland in 2017-2018.

In 2008, an EU wide baseline survey of broilers revealed a high Campylobacter prevalence. To assist with industry-wide controls, updated data were required. The primary objective of this study was to establish up-to-date data on Campylobacter carriage and carcass contamination in Irish broilers. Monthly samples were collected from the three largest broiler processing plants in Ireland over a twelve-month period. Samples were taken from both first and final thin birds (partial and full depopulation) from 358 batches of broilers. From each batch, a composite sample of 10 caecal contents (n = 358) and 5 neck skins (n = 1790) were collected and numbers of Campylobacter in each sample were determined. Of the 1790 neck skin samples tested, 53% were Campylobacter positive. Campylobacter was detected in the caecal contents of 66% of all batches tested. Depopulation and/or age had a significant effect on Campylobacter prevalence with 67% of final thin broilers yielding Campylobacter-positive neck skin samples in contrast to 38% of first thin broilers that yielded positive neck skin samples (P ≤ 0.002). A significant seasonal variation was observed in the rate of Campylobacter-positive caecal samples with higher prevalence seen in July (85%) than the colder months of November (61%), December (50%), January (61%) March (57%) and April (59%). Neck skin samples were 7 times more likely to be Campylobacter positive if the caecal contents from the same batch were positive (odds ratio = 7.1; P ≤ 0.0001). The decrease in Campylobacter prevalence observed in neck skin and caecal contents demonstrates the improvements and progress made in reducing prevalences of this important enteropathogen in the Irish poultry industry since the 2008 EU baseline survey. It also provides further supporting data on the impact of thinning, the processing environment and season on Campylobacter prevalence.

The efficacy of organic acid, medium chain fatty acid and essential oil based broiler treatments; in vitro anti-Campylobacter jejuni activity and the effect of these chemical-based treatments on broiler performance.

AIMS: This research tested the anti-Campylobacter properties of organic acids (OA), medium chain fatty acids (MCFA) and essential oils (EO) in vitro and commenced in vivo suitability testing focused on broiler performance. METHODS AND RESULTS: Nine active compounds were tested at different concentrations and times against Campylobacter jejuni in sterile distilled water, Mueller Hinton broth and grower feed digestate (GFD). Sodium caprate (1.5%, v/v), thymol (0.25% and 2.5%, v/v), carvacrol (1.25%, v/v) and potassium sorbate (1.5%, v/v) each achieved C. jejuni reductions of ≥4.5 log10  CFU per ml in GFD, the matrix most representative of the broiler gut, after 60 s. Similar reductions were achieved after 60 min with lactic acid (1.25%, v/v), formic acid (3.1%, v/v), sodium caprylate (1.5%, v/v) and carvacrol (1.25%, v/v). However, in vivo these compounds adversely affected broiler performance, resulting in dimished water intake and reduced weight. CONCLUSIONS: OA, MFCA and EO based compounds are effective anti-Campylobacter treatments in laboratory model studies but cannot be applied in vivo. SIGNIFICANCE AND IMPACT OF THE STUDY: This study illustrates that OAs, MCFAs and EOs can achieve significant reductions in Campylobacter in vitro but identifies a major issue, inhibition of broiler performance, preventing their use in practice.

Maximising Productivity and Eliminating Campylobacter in Broilers by Manipulating Stocking Density and Population Structure Using 'Biosecurity Cubes'.

This study investigates the effect of stocking density and population dynamics on broiler growth rates and productivity, while further validating the ability of the biosecurity cubes (BC) to protect birds from Campylobacter. In our methodology, six BC were constructed in a commercial broiler house containing approximately 28,500 birds. During three trials, the BC were stocked at densities of 12, 14, 16, 18, 20 and 22 birds/m2, with the main flock (20 birds/m2) considered the control. Periodically, 10 birds per density were weighed and examined. The Campylobacter status of the birds was monitored via faecal samples using the ISO 10272: 2017. The stocking density for maximum calculated yield was 20 (trials 1 and 2) or 22 birds/m2 (trial 3), followed by 18, 16, 14 and 12. At the stocking rate of 20 birds/m2, the birds in the pen grew faster than those at the same density in the main flock achieving 2 Kg 3-6 days faster. Birds in the BC were observed to be generally healthier, and in some cases, remained Campylobacter negative, even after the main flock was infected. Our results conclude that dividing the flock into sub-flocks of approximately 20 birds/m2 using BC could increase productivity up to 20%, while preventing Campylobacter.

The impact of key processing stages and flock variables on the prevalence and levels of Campylobacter on broiler carcasses.

This study examined the impact of key processing stages and flock variables on the prevalence of Campylobacter on broiler carcasses. Overall, the prevalence of Campylobacter was 62% in caeca, and 68%, 65% and 62% in neck skin samples collected after evisceration, final wash and carcass chilling, respectively. Campylobacter were found in 32% of caeca, and 52%, 40% and 32% of neck skin samples collected after evisceration, final wash and carcass chilling, respectively from first thin broiler batches. Final thin broiler batches were more frequently contaminated with prevalences of 83% found in caeca, 80% in neck skin samples collected after evisceration and 83% found in neck skin samples collected after both final wash and carcass chilling stages (p < 0.05). Thinning status had a significant effect on Campylobacter counts with significantly higher counts observed in samples from final thin batches (p < 0.05). Highest Campylobacter concentrations in neck skin samples were observed at the evisceration stage in both first and final thin samples, with counts ranging from 2.0 to 3.8 log10 CFU/g and 2.3 to 4.8 log10 CFU/g in first and final thin batches, respectively. All first thin samples had counts below the European Union (EU) Process Hygiene Criterion threshold level of 3 log10 CFU/g after chilling while 52% of final thin batches had counts above this limit.

Behavioral Responses of Sea Lamprey to Varying Application Rates of a Synthesized Pheromone in Diverse Trapping Scenarios.

Use of the first fish pheromone biopesticide, 3-keto petromyzonol sulfate (3kPZS) in sea lamprey (Petromyzon marinus) control requires an understanding of both how the amount 3kPZS applied to a trap relates to catch, and how that relationship varies among stream types. By conducting 3kPZS dose-response experiments over two years and across six varied trapping contexts, we conclude (1) that 3kPZS application is best standardized by how much is emitted from the trap instead of the fully mixed concentration achieved downstream, and (2) that 3kPZS is more effective in wide streams (>30 m). In wide streams, emission of 3kPZS at 50 mg hr.-1 from the trap increased capture rate by 10-15% as sea lamprey were 25-50% more likely to enter the trap after encounter. However, in narrow streams (< 15 m), 50 mg hr.-1 3kPZS generally reduced probabilities of upstream movement, trap encounter, and entrance. While 3kPZS significantly influenced upstream movement, encounter, and capture probabilities, these behaviors were also highly influenced by water temperature, stream width, sea lamprey length, and sex. This study highlights that a pheromone component in a stream environment does not ubiquitously increase trap catch in all contexts, but that where, how, and when the pheromone is applied has major impacts on whether it benefits or hinders trapping efforts.

Mitigation of lampricide toxicity to juvenile lake sturgeon: the importance of water alkalinity and life stage.

The pesticide, 3-trifluoromethyl-4-nitrophenol (TFM), is used to control invasive sea lamprey (Petromyzon marinus) populations in the Laurentian Great Lakes. Applied to infested tributaries, it is most toxic to larval sea lamprey, which have a low capacity to detoxify TFM. However, TFM can be toxic to lake sturgeon (Acipenser fulvescens), whose populations are at risk throughout the basin. They are most vulnerable to TFM in early life stages, with the greatest risk of non-target mortality occurring in waters with high alkalinity. We quantified TFM toxicity and used radio-labelled TFM (14C-TFM) to measure TFM uptake rates in lake sturgeon in waters of different pH and alkalinity. Regardless of pH or alkalinity, TFM uptake was 2-3-fold higher in young-of-the-year (YOY) than in age 1-year-plus (1+) sturgeon, likely due to higher mass-specific metabolic rates in the smaller YOY fish. As expected, TFM uptake was highest at lower (pH 6.5) versus higher (pH 9.0) pH, indicating that it is taken up across the gills by diffusion in its unionized form. Uptake decreased as alkalinity increased from low (~50 mg L-1 as CaCO3) to moderate alkalinity (~150 mg L-1 as CaCO3), before plateauing at high alkalinity (~250 mg L-1 as CaCO3). Toxicity curves revealed that the 12-h LC50 and 12-h LC99.9 of TFM to lake sturgeon were in fact higher (less toxic) than in sea lamprey, regardless of alkalinity. However, in actual treatments, 1.3-1.5 times the minimum lethal TFM concentration (MLC = LC99.9) to lamprey is applied to maximize mortality, disproportionately amplifying TFM toxicity to sturgeon at higher alkalinities. We conclude that limiting TFM treatments to late summer/early fall in waters of moderate-high alkalinity, when lake sturgeon are larger with lower rates of TFM uptake, would mitigate non-target TFM effects and help conserve populations of these ancient, culturally important fishes.

A portable trap with electric lead catches up to 75% of an invasive fish species.

A novel system combining a trap and pulsed direct current electricity was able to catch up to 75% of tagged invasive sea lamprey Petromyzon marinus in free-flowing streams. Non-target mortality was rare and impacts to non-target migration were minimal; likely because pulsed direct current only needed to be activated at night (7 hours of each day). The system was completely portable and the annual cost of the trapping system was low ($4,800 U.S. dollars). Use of the technology is poised to substantially advance integrated control of sea lamprey, which threaten a fishery valued at 7 billion U.S. dollars annually, and help restore sea lamprey populations in Europe where they are native, but imperiled. The system may be broadly applicable to controlling invasive fishes and restoring valued fishes worldwide, thus having far reaching effects on ecosystems and societies.

State Responses to Alcohol Use and Pregnancy: Findings From the Alcohol Policy Information System (APIS).

This article describes U.S. state policies related to alcohol use during pregnancy, using data from the National Institute on Alcohol Abuse and Alcoholism (NIAAA) Alcohol Policy Information System (APIS). Specifically, this study examines trends in policies enacted by states over time and types of policies enacted across states in the U.S., with a focus on whether laws were supportive or punitive toward women. Findings revealed substantial variability in characteristics of policies (19 primarily supportive, 12 primarily punitive, 12 with a mixed approach, and 8 with no policies). Findings underscore the need to examine possible consequences of policies, especially of punitive policies and "mixed" approaches.

Musical hallucinations associated with pontine lacunar lesions.

Three elderly patients experienced musical hallucinations (MH) in the context of hearing loss. In at least two of the cases, the onset was sudden. All three patients had pontine T2/FLAIR hyperintense foci on MR scan after the onset of the MH.

BCR-ABL1 kinase domain mutation analysis in an Irish cohort of chronic myeloid leukemia patients.

While tyrosine kinase inhibitor (TKI) therapy is the mainstay of modern management of chronic myeloid leukemia (CML), a significant proportion of CML patients may be refractory or lose their initial response to TKI therapy through a number of cellular and molecular mechanisms of which acquired mutations in the BCR-ABL1 kinase domain (KD) are the most common. BCR-ABL1 KD mutations were prospectively identified in order to inform clinical decisions on subsequent therapy. Direct sequencing of the BCR-ABL1 KD was performed in 85 CML patients that were either TKI refractory or displayed increasing BCR-ABL1 transcript levels by serial monitoring after an initial molecular response. Twenty-three BCR-ABL1 KD mutations were detected in 21 CML patients and were detected across the KD. Mutations were associated with specific TKI resistance, indicating change and enabling rational selection of subsequent therapy. Serial molecular monitoring of BCR-ABL1 transcripts in CML patients allows appropriate selection of CML patients for BCR-ABL1 KD mutation analysis associated with acquired TKI resistance. Identification of these KD mutations is essential in order to direct alternative treatment strategies in such CML patients.

In silico analysis and DHPLC screening strategy identifies novel apoptotic gene targets of aberrant promoter hypermethylation in prostate cancer.

BACKGROUND: Aberrant DNA methylation has been implicated as a key survival mechanism in cancer, whereby promoter hypermethylation silences genes essential for many cellular processes including apoptosis. Limited data is available on the methylation profile of apoptotic genes in prostate cancer (CaP). The aim of this study was to profile methylation of apoptotic-related genes in CaP using denaturing high performance liquid chromatography (DHPLC). METHODS: Based on an in silico selection process, 13 genes were screened for methylation in CaP cell lines using DHPLC. Quantitative methylation specific PCR was employed to determine methylation levels in prostate tissue specimens (n = 135), representing tumor, histologically benign prostate, high-grade prostatic intraepithelial neoplasia and benign prostatic hyperplasia. Gene expression was measured by QRT-PCR in cell lines and tissue specimens. RESULTS: The promoters of BIK, BNIP3, cFLIP, TMS1, DCR1, DCR2, and CDKN2A appeared fully or partially methylated in a number of malignant cell lines. This is the first report of aberrant methylation of BIK, BNIP3, and cFLIP in CaP. Quantitative methylation analysis in prostate tissues identified 5 genes (BNIP3, CDKN2A, DCR1, DCR2 and TMS1) which were frequently methylated in tumors but were unmethylated in 100% of benign tissues. Furthermore, 69% of tumors were methylated in at least one of the five-gene panel. In the case of all genes, except BNIP3, promoter hypermethylation was associated with concurrent downregulation of gene expression. CONCLUSION: Future examination of this "CaP apoptotic methylation signature" in a larger cohort of patients is justified to further evaluate its value as a diagnostic and prognostic marker.

The vascular targeting agent combretastatin-A4 and a novel cis-Restricted {beta}-Lactam Analogue, CA-432, induce apoptosis in human chronic myeloid leukemia cells and ex vivo patient samples including those displaying multidrug resistance.

Combretastatin-A4 (CA-4) is a natural derivative of the African willow tree Combretum caffrum. CA-4 is one of the most potent antimitotic components of natural origin, but it is, however, intrinsically unstable. A novel series of CA-4 analogs incorporating a 3,4-diaryl-2-azetidinone (ß-lactam) ring were designed and synthesized with the objective to prevent cis -trans isomerization and improve the intrinsic stability without altering the biological activity of CA-4. Evaluation of selected ß-lactam CA-4 analogs demonstrated potent antitubulin, antiproliferative, and antimitotic effects in human leukemia cells. A lead ß-lactam analog, CA-432, displayed comparable antiproliferative activities with CA-4. CA-432 induced rapid apoptosis in HL-60 acute myeloid leukemia cells, which was accompanied by depolymerization of the microtubular network, poly(ADP-ribose) polymerase cleavage, caspase-3 activation, and Bcl-2 cleavage. A prolonged G(2)M cell cycle arrest accompanied by a sustained phosphorylation of mitotic spindle checkpoint protein, BubR1, and the antiapoptotic proteins Bcl-2 and Bcl-x(L) preceded apoptotic events in K562 chronic myeloid leukemia (CML) cells. Molecular docking studies in conjunction with comprehensive cell line data rule out CA-4 and ß-lactam derivatives as P-glycoprotein substrates. Furthermore, both CA-4 and CA-432 induced significantly more apoptosis compared with imatinib mesylate in ex vivo samples from patients with CML, including those positive for the T315I mutation displaying resistance to imatinib mesylate and dasatinib. In summary, synthetic intrinsically stable analogs of CA-4 that display significant clinical potential as antileukemic agents have been designed and synthesized.

Preventing unsafe alcohol consumption on the 21st birthday: roles for nurses.

Because of its legal significance, the 21st birthday is considered a milestone event. Research reveals that turning 21 is an occasion that is often marked by the ingestion of excessive, perhaps even lethal, amounts of alcohol. Peer pressure and lack of knowledge about the potentially life-threatening effects of alcohol overconsumption can make this birthday a perilous event. Birthday rituals have developed that encourage reckless consumption. Literature addressing the prevalence of excessive drinking among college students is abundant. However, the authors found minimal literature addressing the potential contribution of nurses toward the reduction of unsafe alcohol consumption among young adults celebrating their 21st birthday. This article provides a brief review of the physiological effects of alcohol and practical suggestions for promoting safety among young adults celebrating this milestone birthday.

Sexual and physical victimization as predictors of HIV risk among felony drug offenders.

Injection and other drug use and high-risk sexual behaviors put criminal offenders at increased risk for HIV infection. Studies in other populations, especially females, have found that a history of sexual or physical victimization increases engagement in HIV-risk behaviors, and drug-involved offenders have high rates of such prior victimization. However, there has been little research among male offenders. In a sample of 247 male felony drug offenders in New York City, prior sexual victimization was related to a higher number of sex partners and lower proportion of protected sex acts in the 30 days before arrest. Prior physical abuse was related to cocaine injection, but not heroin injection or high-risk sex behaviors. These results suggest a complex relationship between sexual and physical abuse and HIV risk among male offenders. Assessing for specific prior abuse histories of offenders and providing targeted interventions may be useful for developing more effective primary and secondary HIV prevention services for this high-risk population.

"Nothing about me without me": leading the way to collaborative relationships with families.

This article discusses the National Center on Addiction and Substance Abuse's CASA Safe Haven, an evidence-based, community-driven intervention program for children and families in child welfare whose lives have been adversely affected by substance abuse, and for staff in the agencies that work with them. CASA Safe Haven builds collaborative relationships that feature a blend of multidisciplinary teams that share responsibility for helping families; family group conferencing, in which families are equal and welcome participants in designing and driving a service plan; and the influence of family court to hold families and service providers accountable for progress. CASA Safe Haven is a framework for collaboration.