Alternative Treatments to Pharmacological Therapy in Pediatric Populations With Attention-Deficit/Hyperactivity Disorder (ADHD): A Scoping Review.

In recent years, there has been an increase in the prevalence of the diagnosis of attention-deficit/hyperactivity disorder (ADHD), a cognitive and behavioral disorder in which individuals present with inattention and impulsivity, in the pediatric population. With an increase in diagnoses, there is also increasing concern regarding overdiagnosis and overtreatment with medications for ADHD. The objective of this study was to map out and compile the recent literature pertaining to alternative therapies (e.g., physical activity, diet, mindfulness, and computer-based interventions) for children and adolescents diagnosed with ADHD in an attempt to reduce or replace the use of pharmacological therapy. This scoping review searched articles from multiple databases (PubMed, ScienceDirect, Web of Science, Directory of Open Access Journals, Scopus, and CINAHL). Using search terms "children with ADHD," "alternative treatment," and "cognitive behavioral therapy," articles were identified that were specific to the research question. The inclusion criteria were patients under the age of 18 with a previous diagnosis of ADHD, no other comorbid illnesses, alternative treatments, and was limited to studies published between 2012 and 2022. After removing duplicates, screening for eligibility criteria, and conducting a critical appraisal of the articles, 16 articles were retained for the final review. The main alternative therapeutic domains that emerged were (1) physical activity, (2) diet, (3) mindfulness, (4) computer-based interventions, and (5) miscellaneous interventions. Seven articles assessed the effect of physical activity on executive and cognitive function in children and adolescents with ADHD. Most findings showed improvement with increased physical activity. Two articles explored the effect of diet on the improvement of ADHD symptoms and reported a positive impact. The two articles that evaluated the effects of mindfulness on ADHD symptoms reported a reduction in ADHD symptoms. Two studies evaluated the use of computer-based interventions as an adjunct treatment in children and adolescents with ADHD; improvements in symptoms were reported. One study each evaluated interventions based on music and nerve stimulation. These showed an improvement in attention, memory, and executive function. With the increasing prevalence of ADHD diagnosis in children and adolescents, alternative and/or adjunctive treatments may be a viable and valuable alternative to pharmaceutical interventions. The findings from this review suggest that multiple non-pharmacological interventions effectively reduce symptoms of ADHD in children and adolescents, including diet, exercise, mindfulness, computer-based interventions, music, and nerve stimulation. While there are implications for alternatives to be used in the future, more research is warranted using larger samples with controlled trials.

Disseminated Intravascular Coagulation in Acute Promyelocytic Leukemia Patients: A Retrospective Analysis of Outcomes and Healthcare Burden in US Hospitals

Objective: Acute promyelocytic leukemia (APL) is associated with an elevated risk of developing disseminated intravascular coagulation (DIC). The purpose of this study was to assess the outcomes of hospitalizations related to DIC in APL and their impact on healthcare. Materials and Methods: This study entailed a cross-sectional and retrospective analysis of the US National Inpatient Sample database. We identified adults with APL and categorized them into groups of patients with and without DIC. Our focus areas included in-hospital mortality, length of stay, charges, and complications associated with DIC. Unadjusted odds ratios/coefficients were computed in univariate analysis, followed by adjusted odds ratios (aOR)/coefficients from multivariate analysis that accounted for confounding factors. Results: Our analysis revealed that APL patients with DIC had a substantially higher aOR for mortality (aOR: 6.68, 95% confidence interval [CI]: 4.76-9.37, p<0.001) and a prolonged length of stay (coefficient: 10.28 days, 95% CI: 8.48-12.09, p<0.001) accompanied by notably elevated total hospital charges (coefficient: $215,512 [95% CI: 177,368-253,656], p<0.001), thereby emphasizing the reality of extended medical care and economic burden. The presence of DIC was associated with increased odds of sepsis, vasopressor support, pneumonia, acute respiratory failure, intubation/mechanical ventilation, and acute kidney injury, reflecting heightened vulnerability to these complications. Patients with DIC demonstrated significantly higher odds ratios for major bleeding, intracranial hemorrhage, gastrointestinal bleeding, red blood cell transfusion, platelet transfusion, fresh frozen plasma transfusion, and cryoprecipitate transfusion, highlighting the pronounced hematological risks posed by DIC. Conclusion: This study has revealed the significant associations between DIC in APL and various outcomes, underscoring the clinical and economic implications of these conditions. The hematological risks further increase patients' vulnerability to bleeding events and the need for transfusions.

Castleman disease- demographics, associations, and outcomes: an analysis of adult 791 cases.

BACKGROUND: Castleman disease (CD), also known as angiofollicular lymph node hyperplasia or large lymph node hyperplasia, is a rare medical condition. Despite its rarity, it exhibits diverse clinical presentations and outcomes, which pose challenges for comprehensive understanding and management. This study aims to shed light on the demographics, associations, and outcomes of CD by conducting a retrospective analysis. METHODS: The National Inpatient Sample (US) was used to identify patients with the diagnosis of Castleman disease using ICD-10 diagnosis code D47.Z2, during the years 2016-2019. Data was collected on demographics, associated diagnoses, treatments and outcomes. Data analysis was performed using STATA Version 17, College Station, TX: Stata Corp LLC. RESULTS: Our study identified 791 hospitalizations involving adult CD patients. The mean age of these patients was 52.4 years, with a male predominance (56.1%). Whites comprised the largest racial group affected (50.1%). Most patients were covered by Medicare (39.6%). The majority received treatment in urban teaching hospitals (84.0%) and large-bed size facilities (62.5%). In-hospital mortality was low at 2.8%, with an average length of stay of 7.5 days and average total charges of $109,308. Common associations included acute kidney injury (27.0%), congestive heart failure (17.1%), sepsis (16.4%), and acute respiratory failure (12.6%). Hematological and lymphatic associations featured anemia (47.5%), thrombocytopenia (12.2%), and other conditions. Red blood cell transfusions were administered to 11.1% of patients. CONCLUSION: This study contributes valuable insights into CD, a rare and clinically heterogeneous disease. It underscores the importance of recognizing its associations and complications. Additionally, it highlights the need for further research and improved diagnostic and treatment guidelines to address the complexity of this condition.

Cytokine Release Syndrome in Patients Treated With Chimeric Antigen Receptor T-cell Therapy: A Retrospective Study Analyzing Risks, Outcomes, and Healthcare Burden.

Background Chimeric antigen receptor T-cell (CAR-T) therapy has emerged as a promising immunotherapy for various malignancies. However, its use is associated with challenges, including cytokine release syndrome (CRS), a potentially severe complication. This retrospective study aims to analyze the risks, outcomes, and healthcare burden of CRS in patients undergoing CAR-T therapy. Method Data from the 2020 National Inpatient Sample (NIS) were utilized, comprising 415 CAR-T-related hospitalizations. They were categorized into those with CRS (n = 68) and those without CRS (n = 347). Baseline characteristics, including age, gender, race, income, insurance status, and comorbidities, were compared. Outcomes of interest included in-hospital mortality, length of stay (LOS), total hospital charges, and access to complications, associations, and interventions. Statistical analyses, including multivariable models, were employed to assess associations. Results Hospitalizations with CRS did not exhibit significant differences in age, gender, race, income, or insurance status compared to those without CRS. The multivariable analysis showed no statistically significant difference in mortality (adjusted odds ratio (aOR) = 2.48, 95% confidence interval (CI): 0.71 to 8.69, p = 0.151), LOS (coefficient = -2.1 days, 95% CI: -5.43 to 1.21, p = 0.207), or total hospital charges (coefficient = $207,456, 95% CI: $6119 to $421,031, p = 0.057) between the two groups. The CRS group had a higher incidence of fever (aOR = 1.91, 95% CI: 1.15 to 3.17, p = 0.014), acute respiratory failure (aOR = 2.10, 95% CI: 1.01 to 4.40, p= 0.049), and the need for intubation/mechanical ventilation (aOR = 2.59, 95% CI: 1.14 to 5.88, p = 0.024). Hemophagocytic lymphohistiocytosis (HLH) was significantly associated with CRS (aOR = 6.72, 95% CI: 2.03 to 22.18, p = 0.002). Conclusion While the development of CRS in CAR-T-treated patients did not significantly increase mortality, LOS, or total hospital charges, it was associated with specific risks and outcomes, including fever, respiratory failure, and HLH. This study emphasizes the importance of vigilance in recognizing and managing CRS in CAR-T therapy to optimize patient outcomes. The findings contribute valuable insights to guide clinical decision-making in the context of CAR-T therapy.

Cytokine and reactivity profiles in SLE patients following anti-CD19 CART therapy.

Chimeric antigen receptor (CAR) T cells targeting CD19+ B cells have demonstrated efficacy in refractory systemic lupus erythematosus (SLE). Although initial clinical data suggest that anti-CD19 CAR T cell therapy is well tolerated and highly effective, the immunologic consequences of CAR T cell therapy in SLE patients remain unclear. We profiled serum in six refractory SLE patients prior to and 3 months following CAR T cell infusion. Three months post T cell infusion, the inflammatory cytokines IL-6 and TNFα decreased in patient sera. This was accompanied by elevations in serum IL-7 and BAFF. Furthermore, SLE-associated antibodies dropped profoundly in five of six patients. Last, consistent with other reports of CD19 CAR T therapy in B cell malignancies, we were able to show marginal impact of anti-CD19 CART therapy on pre-existing humoral immune responses in SLE patients. Together, these results provide insights into the mechanisms of efficacy of anti-CD19 CAR T cell therapy in SLE.

Precision targeting of autoantigen-specific B cells in muscle-specific tyrosine kinase myasthenia gravis with chimeric autoantibody receptor T cells.

Muscle-specific tyrosine kinase myasthenia gravis (MuSK MG) is an autoimmune disease that causes life-threatening muscle weakness due to anti-MuSK autoantibodies that disrupt neuromuscular junction signaling. To avoid chronic immunosuppression from current therapies, we engineered T cells to express a MuSK chimeric autoantibody receptor with CD137-CD3ζ signaling domains (MuSK-CAART) for precision targeting of B cells expressing anti-MuSK autoantibodies. MuSK-CAART demonstrated similar efficacy as anti-CD19 chimeric antigen receptor T cells for depletion of anti-MuSK B cells and retained cytolytic activity in the presence of soluble anti-MuSK antibodies. In an experimental autoimmune MG mouse model, MuSK-CAART reduced anti-MuSK IgG without decreasing B cells or total IgG levels, reflecting MuSK-specific B cell depletion. Specific off-target interactions of MuSK-CAART were not identified in vivo, in primary human cell screens or by high-throughput human membrane proteome array. These data contributed to an investigational new drug application and phase 1 clinical study design for MuSK-CAART for the treatment of MuSK autoantibody-positive MG.

Transcriptomics of angiotensin II-induced long noncoding and coding RNAs in endothelial cells.

OBJECTIVE: Angiotensin II (Ang II)-induced endothelial dysfunction plays an important role in the pathogenesis of cardiovascular diseases such as systemic hypertension, cardiac hypertrophy and atherosclerosis. Recently, long noncoding RNAs (lncRNAs) have been shown to play an essential role in the pathobiology of cardiovascular diseases; however, the effect of Ang II on lncRNAs and coding RNAs expression in endothelial cells has not been evaluated. Accordingly, we sought to evaluate the expression profiles of lncRNAs and coding RNAs in endothelial cells following treatment with Ang II. METHODS: Human umbilical vein endothelial cells (HUVECs) were cultured and treated with Ang II (10-6 mol/l) for 24 h. The cells were then profiled for the expression of lncRNAs and mRNAs using the Arraystar Human lncRNA Expression Microarray V3.0. RESULTS: In HUVECs following Ang II treatment, from a total of 30 584 lncRNA targets screened, 25 targets were significantly upregulated, while 69 were downregulated. In the same HUVECs samples, from 26 106 mRNA targets screened, 28 targets were significantly upregulated and 67 were downregulated. Of the differentially expressed lncRNAs, RP11-354P11.2 and RP11-360F5.1 were the most upregulated (11-fold) and downregulated (three-fold) lncRNAs, respectively. Assigning the differentially regulated genes into functional groups using bioinformatics reveals numerous genes involved in the nucleotide excision repair and ECM-receptor interaction. CONCLUSION: This is the first study to profile the Ang II-induced differentially expressed lncRNAs and mRNAs in human endothelial cells. Our results reveal novel targets and substantially extend the list of potential candidate genes involved in Ang II-induced endothelial dysfunction and cardiovascular diseases.

Age-based disparities in telehealth use in an urban, underserved population in cancer and pulmonary clinics: A need for policy change.

BACKGROUND: During the COVID-19 pandemic, telehealth rapidly emerged as an essential health care service and became particularly important for patients with cancer and chronic conditions. However, the benefits of telehealth have not been fully realized for some of the most vulnerable populations due to inequitable access to telehealth capable technology. PURPOSE: This study aimed to assess accessibility and satisfaction with telehealth technology by vulnerable patients with cancer and pulmonary disease. METHODOLOGY: A paper survey and internet-based survey were developed and administered to adult (≥18 years) cancer and pulmonary clinic patients (July 1, 2020 to October 30, 2020). RESULTS: Descriptive statistics and Fisher exact test were performed. Two hundred eleven patients completed the survey. Adults ≥50 years old (older) had reduced access to smartphone video capability and internet connection compared with adults less than 50 years old (59% vs. 90%, p < .01). Older adults reported more challenges with telehealth visits compared with younger adults (50.3%, 28.6%; p < .01). No difference in access to technology and preferences for telehealth versus in-person care was found by race, gender, or education level. CONCLUSIONS: Nearly all patients (95%) who had a previous experience with a telehealth visit felt confident in the quality of care they received via telehealth. Younger adults preferred video visits compared with older adults (75% vs. 50.6%, p < .01). Older adults were less likely to have access to smartphones with internet access, have more challenges with telehealth visits, and were less likely to prefer audio-video telehealth visits compared with younger adults. IMPLICATIONS: Ensuring equitable access to all health care delivery modalities by telehealth, including audio-only visits for patients across the age continuum, is paramount.

Headspace analysis of E-cigarette fluids using comprehensive two dimensional GC×GC-TOF-MS reveals the presence of volatile and toxic compounds.

The analysis of electronic cigarrete (E-cigarette) fluids by high performance liquid chromatography or gas chromatography (GC) coupled to mass spectrometry (MS), GC hyphenated to flame-ionisation detection, or nuclear magnetic resonance spectroscopy poses many challenges due to the complex matrix and extremely high number of compounds present. In order to overcome these challenges, this study focused on the detection of the multiple complex compounds classes produced by the pyrolysis of E-cigarette liquids using comprehensive two dimensional gas chromatography (GCxGC) coupled to time of flight (TOF)-MS. Gas samples were prepared by heating E-liquids inside aluminium tins for 5 min. The tins were placed in a sand bath, which was temperature controlled at 200 °C. The samples were collected using thermal desorption tubes connected to volatile organic compound (VOC) sampling pump attached and subsequently analysed using GCxGC-TOF-MS. The greater peak resolution obtained when using GCxGC-TOF-MS allowed to distinguish many toxic compounds and VOCs that could not be detected by the other methods mentioned above. As a result, a comprehensive list of volatile compounds emitted from E-cigarette fluids when heated was established, which might allow a better understanding of potential health effects of vaping. Heating E-liquids to moderate temperature results in the emission of over 1000 volatile compounds of which over 150 are toxic. These compounds are either present in the liquid or can be formed during storage or heating leading to a more complex volatile profile of E-cigarette liquids than previously assumed. The application of GCxGC-TOF-MS allows the elucidation of this profile and therefore a better understanding of possible health implications.

ISMP Adverse Drug Reactions: Longitudinal Thumbnail Fissures Due to Erlotinib Priapism Associated With the Use of ExtenZe Blindness From a Nevirapine-Based HAART Regimen Hyperprolactinemia and Galactorrhea Due to Aripiprazole Trypophobia Associated With Gabapentin Coadministered Linezolid and Methadone Cause Serotonin Syndrome.

The purpose of this feature is to heighten awareness of specific adverse drug reactions (ADRs), discuss methods of prevention, and promote reporting of ADRs to the US Food and Drug Administration's (FDA) MedWatch program (800-FDA-1088). If you have reported an interesting, preventable ADR to MedWatch, please consider sharing the account with our readers. E-mail Dr. Mancano at michael.mancano@temple.edu. Your report will be published anonymously unless otherwise requested. This feature is provided by the Institute for Safe Medication Practices (ISMP) in cooperation with the FDA's MedWatch program and Temple University School of Pharmacy. ISMP is an FDA MedWatch partner.

A tough row to hoe: when replication forks encounter DNA damage.

Eukaryotic cells continuously experience DNA damage that can perturb key molecular processes like DNA replication. DNA replication forks that encounter DNA lesions typically slow and may stall, which can lead to highly detrimental fork collapse if appropriate protective measures are not executed. Stabilization and protection of stalled replication forks ensures the possibility of effective fork restart and prevents genomic instability. Recent efforts from multiple laboratories have highlighted several proteins involved in replication fork remodeling and DNA damage response pathways as key regulators of fork stability. Homologous recombination factors such as RAD51, BRCA1, and BRCA2, along with components of the Fanconi Anemia pathway, are now known to be crucial for stabilizing stalled replication forks and preventing nascent strand degradation. Several checkpoint proteins have additionally been implicated in fork protection. Ongoing work in this area continues to shed light on a sophisticated molecular pathway that balances the action of DNA resection and fork protection to maintain genomic integrity, with important implications for the fate of both normal and malignant cells following replication stress.

ISMP Adverse Drug Reactions: Adalimumab-Induced Aseptic Meningitis Pill Desiccant -Induced Acute Hypoxic Respiratory Failure Rivastigmine Patch -Induced Angioedema Acute Liver Failure Due to Etodolac Severe Cognitive Impairment Due to High Free Valproic Acid Levels.

The purpose of this feature is to heighten awareness of specific adverse drug reactions (ADRs), discuss methods of revention, and promote reporting of ADRs to the US Food and Drug Administration's (FDA) MedWatch program (800-ßDA-1088). If you have reported an interesting, preventable ADR to MedWatch, please consider sharing the account with ur readers. E-mail Dr.Mancanomichael.mancano@temple.edu). Your report will be published anonymously unless otherwise requested. This feature is provided by the Institute for Safe Medication Practices (ISMP) in cooperation with the FDA's MedWatch program and Temple University School of Pharmacy. ISMP is an FDA MedWatch partner.

Oncoprotein Stathmin Modulates Sensitivity to Apoptosis in Hepatocellular Carcinoma Cells During Hepatitis C Viral Replication.

Patients with chronic hepatitis C virus (HCV) infection risk complications of cirrhosis, liver failure, and hepatocellular carcinoma (HCC). Previously, our proteomic examination of hepatocytes carrying a HCV-replicon revealed that deregulation of cytoskeletal dynamics may be a potential mechanism of viral-induced HCC growth. Here, we demonstrate the effect of HCV replication on the microtubule regulator stathmin (STMN1) in HCC cells. We further explore how the altered activity or synthesis of stathmin affects cellular proliferation and sensitivity to apoptosis in control HCC cells (Huh7.5) and experimental HCV-replicon harboring HCC cells (R-Huh7.5). The HCV-replicon harboring HCC cells (R-Huh 7.5) lack viral structural genes/proteins for acute infectivity and thus is the standard model for in vitro chronic infection study. Knockdown of endogenous stathmin reduced sensitivity to apoptosis in replicon cells. Meanwhile, constitutively active stathmin increased sensitivity to apoptosis in replicon cells. In addition, overexpression of constitutively active stathmin reduced cell proliferation in both control and replicon cells. These findings implicate, for the first time, a novel role for stathmin in viral replication-related apoptosis. Stathmin's potential role in HCV replication and HCC make it a candidate for the future study of viral-induced malignancies.

Phospho-Network Analysis Identifies and Quantifies Hepatitis C Virus (HCV)-induced Hepatocellular Carcinoma (HCC) Proteins Regulating Viral-mediated Tumor Growth.

BACKGROUND: Patients with chronic hepatitis C virus (HCV) infection are at risk of serious complications of cirrhosis and hepatocellular carcinoma (HCC). Mass spectrometry (MS) is a versatile methodology that produces a global proteomic landscape for analysis of cancer mechanisms. MATERIALS AND METHODS: Using multiplex peptide stable isotopic labeling and immobilized metal affinity chromatography (IMAC), we enriched and quantified the phosphoproteome of HCC, with and without HCV. While raw data identified protein targets based on expression alone, we also used abundance groups for comprehensive functional analysis. RESULTS: Analysis of functional differences highlighted deregulated phosphoprotein networks. This uncovered additional candidates that could be directly derived from the MS data. Cellular processes and pathways that may differ with HCV infection include: cytoskeletal dynamics, insulin response, gene expression, and PI3K/AKT oncogenesis. CONCLUSION: This function-focused workflow provides a simple framework to analyze MS data. Phosphoproteome quantitation with inclusive functional analysis can generate hypotheses for liver cancer research to improve early screening and identification of molecular targets for therapy.

Genome Protection by the 9-1-1 Complex Subunit HUS1 Requires Clamp Formation, DNA Contacts, and ATR Signaling-independent Effector Functions.

The RAD9A-HUS1-RAD1 (9-1-1) complex is a heterotrimeric clamp that promotes checkpoint signaling and repair at DNA damage sites. In this study, we elucidated HUS1 functional residues that drive clamp assembly, DNA interactions, and downstream effector functions. First, we mapped a HUS1-RAD9A interface residue that was critical for 9-1-1 assembly and DNA loading. Next, we identified multiple positively charged residues in the inner ring of HUS1 that were crucial for genotoxin-induced 9-1-1 chromatin localization and ATR signaling. Finally, we found two hydrophobic pockets on the HUS1 outer surface that were important for cell survival after DNA damage. Interestingly, these pockets were not required for 9-1-1 chromatin localization or ATR-mediated CHK1 activation but were necessary for interactions between HUS1 and its binding partner MYH, suggesting that they serve as interaction domains for the recruitment and coordination of downstream effectors at damage sites. Together, these results indicate that, once properly loaded onto damaged DNA, the 9-1-1 complex executes multiple, separable functions that promote genome maintenance.