Tubular Injury Biomarkers to Predict Chronic Kidney Disease and Hypertension at 3-Months Post-Cisplatin in Children.

BACKGROUND: Urine kidney injury biomarkers measured during cisplatin therapy may identify patients at risk for adverse subsequent kidney outcomes. We examined relationships between tubular injury biomarkers collected early (early visit [EV]: first or second cisplatin cycle) and late (late visit [LV]: last or second-last cisplatin cycle) during cisplatin therapy, with 3-month post-cisplatin chronic kidney disease (CKD) and hypertension. METHODS: We analyzed data from the Applying Biomarkers to Minimize Long-Term Effects of Childhood/Adolescent Cancer Treatment Nephrotoxicity Study: twelve-center prospective cohort study of 159 children receiving cisplatin. We measured urine neutrophil gelatinase-associated lipocalin (NGAL)/creatinine, kidney injury molecule-1 (KIM-1)/creatinine, tissue inhibitor of metalloproteinase-2 (TIMP-2), and insulin-like growth factor-binding protein 7 (IGFBP-7) (TIMP-2 and IGFBP-7 expressed as their product, ng/ml^2/1000) at an EV and LV during cisplatin therapy with pre-infusion, post-infusion, and hospital discharge sampling. Area under the curve (AUC) was calculated for biomarkers to detect 3-month post-cisplatin CKD (KDIGO guidelines: low estimated glomerular filtration rate (eGFR) or elevated uACR for age) and hypertension (three blood pressures; per American Academy of Pediatrics guidelines). RESULTS: At median follow-up of 90 days, 52/118 (44%) and 17/125 (14%) developed CKD and hypertension, respectively. Biomarker prediction for 3-month CKD was low to modest; NGAL combined with KIM-1 at EV discharge yielded the highest AUC (0.67, 95% CI 0.57-0.77). Biomarker prediction of 3-month hypertension was stronger, but modest; the highest AUC was from combining EV pre-infusion NGAL and TIMP-2*IGFBP-7 (0.71, 95% CI 0.62-0.80). When EV pre-infusion NGAL and TIMP-2*IGFBP-7 were added to the 3-month hypertension clinical predictive model, AUCs increased from 0.81 (0.72-0.91) to 0.89 (0.83-0.95) (p<0.05). CONCLUSIONS: Tubular injury biomarkers we studied were individually not strong predictors of 3-month post-cisplatin kidney outcomes. Adding biomarkers to existing clinical prediction models may help predict post-therapy hypertension and identify higher kidney-risk patients.

Trauma, Emotional Regulation, and Coping Styles in Individuals with and without Probable Dissociative Disorders in Hong Kong.

Previous studies showed that dissociation and dissociative disorders (DDs) are prevalent and are associated with considerable individual and social consequences. There are ongoing debates regarding whether dissociation is a response to betrayal trauma across cultures and whether dissociation can be explained by maladaptive coping. Additionally, little is known about the clinical features of individuals with DDs in the Chinese context. This study aimed to investigate the relationship between trauma, emotional regulation, coping, and dissociation. We analyzed baseline data from a randomized controlled trial (N = 101). Participants with dissociative symptoms in Hong Kong completed self-report assessments. Structured interviews were also conducted subsequently. Participants with probable DDs reported more traumatic events (p = .009 to .017) and exhibited significantly higher levels of dysfunctional coping (p < .001) compared to those who reported dissociative symptoms but did not have a DD. Dissociative symptoms were more strongly associated with betrayal trauma than with non-betrayal trauma. Among different emotion regulation and coping strategies, dysfunctional coping was the only significant factor associated with dissociative symptoms (ß = .309, p = .003). Dysfunctional coping was a statistically significant mediator that may explain the relationship between betrayal trauma and dissociative symptoms. Although other mediation paths are also possible and further longitudinal studies are required, our findings highlight the strong link between dysfunctional coping and dissociative symptoms and suggest that coping skills training should be incorporated into interventions for betrayal trauma survivors with dissociative symptoms. Additionally, this study provides evidence for the cross-cultural validity of the betrayal trauma theory. Further studies, however, are required.

The Role of Pharmacogenomics in Rare Diseases.

Rare diseases have become an increasingly important public health priority due to their collective prevalence and often life-threatening nature. Incentive programs, such as the Orphan Drug Act have been introduced to increase the development of rare disease therapeutics. While the approval of these therapeutics requires supportive data from stringent pre-market studies, these data lack the ability to describe the causes of treatment response heterogeneity, leading to medications often being more harmful or less effective than predicted. If a Goal Line were to be used to describe the multifactorial continuum of phenotypic variations occurring in response to a medication, the 'Goal Posts', or the two defining points of this continuum, would be (1) Super-Response, or an extraordinary therapeutic effect; and (2) Serious Harm. Investigation of the pharmacogenomics behind these two extreme phenotypes can potentially lead to the development of new therapeutics, help inform rational use criteria in drug policy, and improve the understanding of underlying disease pathophysiology. In the context of rare diseases where cohort sizes are smaller than ideal, 'small data' and 'big data' approaches to data collection and analysis should be combined to produce the most robust results. This paper presents the importance of studying drug response in parallel to other research initiatives in rare diseases, as well as the need for international collaboration in the area of rare disease pharmacogenomics.

Systemic delivery of proteins using novel peptides via the sublingual route.

Therapeutic proteins often require needle-based injections, which compromise medication adherence especially for those with chronic diseases. Sublingual administration provides a simple and non-invasive alternative. Herein, two novel peptides (lipid-conjugated protamine and a protamine dimer) were synthesized to enable sublingual delivery of proteins through simple physical mixing with the payloads. It was found that the novel peptides promoted intracellular delivery of proteins via increased pore formation on the cell surface. Results from in vitro models of cell spheroids and human sublingual tissue substitute indicated that the novel peptides enhanced protein penetration through multiple cell layers compared to protamine. The novel peptides were mixed with insulin or semaglutide and sublingually delivered to mice for blood glucose (BG) control. The effects of these sublingual formulations were comparable to the subcutaneous preparations and superior to protamine. In addition to peptide drugs, the novel peptides were shown to enable sublingual absorption of larger proteins with molecular weights from 22 to 150 kDa in mice, including human recombinant growth hormone (rhGH), bovine serum albumin (BSA) and Immunoglobulin G (IgG). The novel peptides given sublingually did not induce any measurable toxicities in mice.

CIAO1 and MMS19 deficiency: A lethal neurodegenerative phenotype caused by cytosolic Fe-S cluster protein assembly disorders.

PURPOSE: The functionality of many cellular proteins depends on cofactors; yet, they have only been implicated in a minority of Mendelian diseases. Here, we describe the first 2 inherited disorders of the cytosolic iron-sulfur protein assembly system. METHODS: Genetic testing via genome sequencing was applied to identify the underlying disease cause in 3 patients with microcephaly, congenital brain malformations, progressive developmental and neurologic impairments, recurrent infections, and a fatal outcome. Studies in patient-derived skin fibroblasts and zebrafish models were performed to investigate the biochemical and cellular consequences. RESULTS: Metabolic analysis showed elevated uracil and thymine levels in body fluids but no pathogenic variants in DPYD, encoding dihydropyrimidine dehydrogenase. Genome sequencing identified compound heterozygosity in 2 patients for missense variants in CIAO1, encoding cytosolic iron-sulfur assembly component 1, and homozygosity for an in-frame 3-nucleotide deletion in MMS19, encoding the MMS19 homolog, cytosolic iron-sulfur assembly component, in the third patient. Profound alterations in the proteome, metabolome, and lipidome were observed in patient-derived fibroblasts. We confirmed the detrimental effect of deficiencies in CIAO1 and MMS19 in zebrafish models. CONCLUSION: A general failure of cytosolic and nuclear iron-sulfur protein maturation caused pleiotropic effects. The critical function of the cytosolic iron-sulfur protein assembly machinery for antiviral host defense may well explain the recurrent severe infections occurring in our patients.

Reliability and Mental Health Correlates of a Single-Item Measure of Self-Rated Mental Health (SRMH) in the Chinese Context.

The use of single-item measures of self-rated mental health (SRMH) has been increasingly valued in epidemiologic research. However, little is known about the reliability and mental health correlates of SRMH in Chinese populations. This study examined the reliability and mental health correlates of SRMH in three Chinese samples. We analyzed data collected from two convenience samples of Chinese adults from Hong Kong and/or Taiwan (Sample 1: N = 205; Sample 2: N = 377), and a random sample of Taiwan psychiatric inpatients (Sample 3: N = 100). Our results showed that the single-item measure of SRMH had moderate to good test-retest reliability (intraclass correlation [ICC] = 0.75) in Sample 1 and acceptable reliability between the self-report and interviewer-administered versions (ICC = 0.58) in Sample 3. It had a high positive correlation with self-esteem and a moderately high negative correlation with depression. It also had a consistently negative correlation with borderline personality disorder symptoms and post-traumatic stress disorder symptoms. The SRMH score was also associated with psychiatric service usage. These findings contribute to the body of knowledge regarding the use of a single-item measure of SRMH to assess overall self-perceived mental health in Chinese communities.

COULD FAMILY WELL-BEING MODERATE THE RELATIONSHIP BETWEEN ADVERSE CHILDHOOD EXPERIENCES AND SOMATOFORM DISSOCIATION? A PRELIMINARY INVESTIGATION.

The impacts of adverse childhood experiences (ACEs) have been well documented. One possible consequence of ACEs is dissociation, which is a major feature of post-traumatic psychopathology and is also associated with considerable impairment and health care costs. Although ACEs are known to be associated with both psychoform and somatoform dissociation, much less is known about the mechanisms behind this relationship. Little is known about whether social and interpersonal factors such as family environments would moderate the relationship between ACEs and somatoform dissociation. This paper discusses the importance of having a positive and healthy family environment in trauma recovery. We then report the findings of a preliminary study in which we examined whether the association between ACEs and somatoform dissociation would be moderated by family well-being in a convenience sample of Hong Kong adults (N = 359). The number of ACEs was positively associated with somatoform dissociative symptoms, but this association was moderated by the level of family well-being. The number of ACEs was associated with somatoform dissociation only when the family well-being scores were low. These moderating effects were medium. The findings point to the potential importance of using family education and intervention programs to prevent and treat trauma-related dissociative symptoms, but further investigation is needed.

Effects of pharmacogenetic profiles on pediatric pain relief and adverse events with ibuprofen and oxycodone.

Introduction: Individual genetic variation may influence clinical effects for pain medications. Effects of CYP2C9, CYP3A4, and CYP2D6 polymorphisms on clinical effectiveness and safety for ibuprofen and oxycodone were studied. Objective: Primary objectives were to AU2 evaluate if allelic variations would affect clinical effectiveness and adverse events (AEs) occurrence. Methods: This pragmatic prospective, observational cohort included children aged 4 to 16 years who were seen in a pediatric emergency department with an acute fracture and prescribed ibuprofen or oxycodone for at-home pain management. Saliva samples were obtained for genotyping of allelic variants, and daily telephone follow-up was conducted for 3 days. Pain was measured using the Faces Pain Scale-Revised. Results: We included 210 children (n = 140 ibuprofen and n = 70 oxycodone); mean age was 11.1 (±SD 3.5) years, 33.8% were female. Median pain reduction on day 1 was similar between groups [ibuprofen 4 (IQR 2,4) and oxycodone 4 (IQR 2,6), P = 0.69]. Over the 3 days, the oxycodone group experienced more AE than the ibuprofen group (78.3% vs 53.2%, P < 0.001). Those with a CYP2C9*2 reduced function allele experienced less adverse events with ibuprofen compared with those with a normal functioning allele CYP2C9*1 (P = 0.003). Neither CYP3A4 variants nor CYP2D6 phenotype classification affected clinical effect or AE. Conclusion: Although pain relief was similar, children receiving oxycodone experienced more AE, overall, than those receiving ibuprofen. For children receiving ibuprofen or oxycodone, pain relief was not affected by genetic variations in CYP2C9 or CYP3A4/CYP2D6, respectively. For children receiving ibuprofen, the presence of CYP2C9*2 was associated with less adverse events.

Lipid Nanoparticle-Mediated Hit-and-Run Approaches Yield Efficient and Safe In Situ Gene Editing in Human Skin.

Despite exciting advances in gene editing, the efficient delivery of genetic tools to extrahepatic tissues remains challenging. This holds particularly true for the skin, which poses a highly restrictive delivery barrier. In this study, we ran a head-to-head comparison between Cas9 mRNA or ribonucleoprotein (RNP)-loaded lipid nanoparticles (LNPs) to deliver gene editing tools into epidermal layers of human skin, aiming for in situ gene editing. We observed distinct LNP composition and cell-specific effects such as an extended presence of RNP in slow-cycling epithelial cells for up to 72 h. While obtaining similar gene editing rates using Cas9 RNP and mRNA with MC3-based LNPs (10-16%), mRNA-loaded LNPs proved to be more cytotoxic. Interestingly, ionizable lipids with a pKa ∼ 7.1 yielded superior gene editing rates (55%-72%) in two-dimensional (2D) epithelial cells while no single guide RNA-dependent off-target effects were detectable. Unexpectedly, these high 2D editing efficacies did not translate to actual skin tissue where overall gene editing rates between 5%-12% were achieved after a single application and irrespective of the LNP composition. Finally, we successfully base-corrected a disease-causing mutation with an efficacy of ∼5% in autosomal recessive congenital ichthyosis patient cells, showcasing the potential of this strategy for the treatment of monogenic skin diseases. Taken together, this study demonstrates the feasibility of an in situ correction of disease-causing mutations in the skin that could provide effective treatment and potentially even a cure for rare, monogenic, and common skin diseases.

The symptom criteria for the dissociative subtype of posttraumatic stress disorder.

OBJECTIVE: The dissociative subtype of posttraumatic stress disorder (PTSD) was incorporated into the diagnostic criteria for PTSD in Diagnostic and Statisical Manual of Mental Disorders, Fifth Edition (DSM-5). The subtype requires the presence of persistent or recurrent depersonalization or derealization; however, several authors have suggested that a broader array of dissociative symptoms could be included in the criteria. The objective of the present study was to gather data on a wide range of dissociative symptoms in a sample of highly traumatized individuals. METHOD: The authors administered a set of measures to 62 inpatients in a private psychiatric inpatient program specializing in PTSD and dissociative disorders. RESULTS: Almost every participant met International Classification of Diseases, 11th Edition criteria for complex PTSD, DSM-5 criteria for the dissociative subtype of PTSD, and DSM-5 criteria for dissociative identity disorder or other specified dissociative disorder; these four diagnoses seem to identify largely the same patients and may not be separate disorders. CONCLUSIONS: A broad range of dissociative symptoms was endorsed on the Dissociative Experiences Scale and the Dissociative Disorders Interview Schedule. The results support a recommendation that a broad array of symptoms be included in the criteria for the dissociative subtype of PTSD in future editions of the Diagnostic and Statistical Manual of Mental Disorders. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Dissociative symptoms among community health service users in Hong Kong: a longitudinal study of clinical course and consequences.

Background: Previous studies have demonstrated the high prevalence of dissociative symptoms and their association with considerable healthcare costs. However, there is a lack of studies that describe whether dissociative symptoms persist and lead to other clinical outcomes over time in the community.Objectives: This study investigated the persistence, predictors, and consequences of dissociative symptoms in the community.Methods: We analyzed longitudinal data in a sample of community health service users in Hong Kong (N = 173).Results: A relatively high proportion (63.6%) of participants with baseline dissociative symptoms continued to exhibit dissociative symptoms after approximately 9 months. Baseline non-betrayal trauma predicted subsequent dissociative symptoms (ß = .141, p = .024). Participants with baseline dissociative symptoms were more likely to have received subsequent emergency mental health services (9.1% vs 0.7%, p = .005). Baseline dissociative symptoms significantly predicted subsequent post-traumatic symptoms (ß = .165 to .191, p < .05) and difficulty in social and occupational participation (ß = -.152 to -.182, p < .05) even after controlling for baseline scores, trauma exposure, and use of professional support. The predictive role of dissociative symptoms on subsequent disturbances in self-organization symptoms and social participation difficulty remained significant after applying the Bonferroni correction.Conclusions: This is one of the very few studies showing that dissociative symptoms are persistent to a certain degree and could predict other symptoms and subsequent impairments even in community settings. Factors that affect the trajectory of dissociative symptoms should be further investigated. Regular screening for dissociative symptoms is recommended. Considering its prevalence, persistence, and clinical and social consequences, dissociation should be given greater public health attention.

Dissociative symptoms have been linked to considerable healthcare costs.The persistence and consequences of dissociation in the community had not been previously reported.This study showed that dissociative symptoms persisted to a certain degree and predicted subsequent impairments after approximately 9 months.Dissociation should be given greater public health attention.

Systematic Critical Review of Genetic Factors Associated with Cisplatin-induced Ototoxicity: Canadian Pharmacogenomics Network for Drug Safety 2022 Update.

BACKGROUND: Cisplatin is commonly used to treat solid tumors; however, its use can be complicated by drug-induced hearing loss (ie, ototoxicity). The presence of certain genetic variants has been associated with the development/occurrence of cisplatin-induced ototoxicity, suggesting that genetic factors may be able to predict patients who are more likely to develop ototoxicity. The authors aimed to review genetic associations with cisplatin-induced ototoxicity and discuss their clinical relevance. METHODS: An updated systematic review was conducted on behalf of the Canadian Pharmacogenomics Network for Drug Safety, based on the Preferred Reporting Items for Systematic reviews and Meta-Analyses 2020 statement. Pharmacogenomic studies that reported associations between genetic variation and cisplatin-induced ototoxicity were included. The evidence on genetic associations was summarized and evaluated, and knowledge gaps that can be used to inform future pharmacogenomic studies identified. RESULTS: Overall, 40 evaluated reports, considering 47 independent patient populations, captured associations involving 24 genes. Considering GRADE criteria, genetic variants in 2 genes were strongly (ie, odds ratios ≥3) and consistently (ie, replication in ≥3 independent populations) predictive of cisplatin-induced ototoxicity. Specifically, an ACYP2 variant has been associated with ototoxicity in both children and adults, whereas TPMT variants are relevant in children. Encouraging evidence for associations involving several other genes also exists; however, further research is necessary to determine potential clinical relevance. CONCLUSIONS: Genetic variation in ACYP2 and TPMT may be helpful in predicting patients at the highest risk of developing cisplatin-induced ototoxicity. Further research (including replication studies considering diverse pediatric and adult patient populations) is required to determine whether genetic variation in additional genes may help further identify patients most at risk.

Implementation of pharmacogenetic testing in oncology: DPYD-guided dosing to prevent fluoropyrimidine toxicity in British Columbia.

Background: Fluoropyrimidine toxicity is often due to variations in the gene (DPYD) encoding dihydropyrimidine dehydrogenase (DPD). DPYD genotyping can be used to adjust doses to reduce the likelihood of fluoropyrimidine toxicity while maintaining therapeutically effective drug levels. Methods: A multiplex QPCR assay was locally developed to allow genotyping for six DPYD variants. The test was offered prospectively for all patients starting on fluoropyrimidines at the BC Cancer Centre in Vancouver and then across B.C., Canada as well as retrospectively for patients suspected to have had an adverse reaction to therapy. Dose adjustments were made for variant carriers. The incidence of toxicity in the first three cycles was compared between DPYD variant allele carriers and non-variant carriers. Subsequent to an initial implementation phase, this test was made available province-wide. Results: In 9 months, 186 patients were tested and 14 were found to be heterozygous variant carriers. Fluoropyrimidine-related toxicity was higher in DPYD variant carriers. Of 127 non-variant carriers who have completed chemotherapy, 18 (14%) experienced severe (grade ≥3, Common Terminology Criteria for Adverse Events version 5.0). Of note, 22% (3 patients) of the variant carriers experienced severe toxicity even after DPYD-guided dose reductions. For one of these carriers who experienced severe thrombocytopenia within the first week, DPYD testing likely prevented lethal toxicity. In DPYD variant carriers who tolerate reduced doses, a later 25% increase led to chemotherapy discontinuation. As a result, a recommendation was made to clinicians based on available literature and expert opinion specifying that variant carriers who tolerated two cycles without toxicity can have a dose escalation of only 10%. Conclusion: DPYD-guided dose reductions were a feasible and acceptable method of preventing severe toxicity in DPYD variant carriers. Even with dose reductions, there were variant carriers who still experienced severe fluoropyrimidine toxicity, highlighting the importance of adhering to guideline-recommended dose reductions. Following the completion of the pilot phase of this study, DPYD genotyping was made available province-wide in British Columbia.

Preclinical Development and Characterization of Novel Adeno-Associated Viral Vectors for the Treatment of Lipoprotein Lipase Deficiency.

Lipoprotein lipase deficiency (LPLD) results from mutations within the lipoprotein lipase (LPL) gene that lead to a complete lack of catalytically active LPL protein. Glybera was one of the first adeno-associated virus (AAV) gene replacement therapy to receive European Medicines Agency regulatory approval for the treatment of LPLD. However, Glybera is no longer marketed potentially due to a combination of economical, manufacturing, and vector-related issues. The aim of this study was to develop a more efficacious AAV gene therapy vector for LPLD. Following preclinical biodistribution, efficacy and non-Good Laboratory Practice toxicity studies with novel AAV1 and AAV8-based vectors in mice, we identified AAV8 pVR59. AAV8 pVR59 delivered a codon-optimized, human gain-of-function hLPLS447X transgene driven by a CAG promoter in an AAV8 capsid. AAV8 pVR59 was significantly more efficacious, at 10- to 100-fold lower doses, compared with an AAV1 vector based on Glybera, when delivered intramuscularly or intravenously, respectively, in mice with LPLD. Efficient gene transfer was observed within the injected skeletal muscle and liver following delivery of AAV8 pVR59, with long-term correction of LPLD phenotypes, including normalization of plasma triglycerides and lipid tolerance, for up to 6 months post-treatment. While intramuscular delivery of AAV8 pVR59 was well tolerated, intravenous administration augmented liver pathology. These results highlight the feasibility of developing a superior AAV vector for the treatment of LPLD and provide critical insight for initiating studies in larger animal models. The identification of an AAV gene therapy vector that is more efficacious at lower doses, when paired with recent advances in production and manufacturing technologies, will ultimately translate to increased safety and accessibility for patients.

Generation of a human induced pluripotent stem cell line from a patient with hypomyelinating leukodystrophy 22 (HLD22).

Hypomyelinating Leukodystrophy 22 (HLD22) is caused by a stoploss mutation in CLDN11. To study the molecular mechanisms underlying HLD22, human induced pluripotent stem cells (hiPSCs) were generated from patient fibroblasts carrying the stop-loss mutation in CLDN11.

RBL2 Regulates Cardiac Sensitivity to Anthracycline Chemotherapy.

Background: Anthracycline chemotherapies cause heart failure in a subset of cancer patients. We previously reported that the anthracycline doxorubicin (DOX) induces cardiotoxicity through the activation of cyclin-dependent kinase 2 (CDK2). Objectives: The aim of this study was to determine whether retinoblastoma-like 2 (RBL2/p130), an emerging CDK2 inhibitor, regulates anthracycline sensitivity in the heart. Methods: Rbl2-/- mice and Rbl2+/+ littermates received DOX (5 mg/kg/wk for 4 weeks intraperitoneally, 20 mg/kg cumulative). Heart function was monitored with echocardiography. The association of RBL2 genetic variants with anthracycline cardiomyopathy was evaluated in the SJLIFE (St. Jude Lifetime Cohort Study) and CPNDS (Canadian Pharmacogenomics Network for Drug Safety) studies. Results: The loss of endogenous Rbl2 increased basal CDK2 activity in the mouse heart. Mice lacking Rbl2 were more sensitive to DOX-induced cardiotoxicity, as evidenced by rapid deterioration of heart function and loss of heart mass. The disruption of Rbl2 exacerbated DOX-induced mitochondrial damage and cardiomyocyte apoptosis. Mechanistically, Rbl2 deficiency enhanced CDK2-dependent activation of forkhead box O1 (FOXO1), leading to up-regulation of the proapoptotic protein Bim. The inhibition of CDK2 desensitized Rbl2-depleted cardiomyocytes to DOX. In wild-type cardiomyocytes, DOX exposure induced Rbl2 expression in a FOXO1-dependent manner. Importantly, the rs17800727 G allele of the human RBL2 gene was associated with reduced anthracycline cardiotoxicity in childhood cancer survivors. Conclusions: Rbl2 is an endogenous CDK2 inhibitor in the heart and represses FOXO1-mediated proapoptotic gene expression. The loss of Rbl2 increases sensitivity to DOX-induced cardiotoxicity. Our findings suggest that RBL2 could be used as a biomarker to predict the risk of cardiotoxicity before the initiation of anthracycline-based chemotherapy.

Borderline personality disorder features and their relationship with trauma and dissociation in a sample of community health service users.

BACKGROUND: Previous studies have indicated that borderline personality disorder (BPD) is closely associated with trauma and dissociation. Nevertheless, BPD is a heterogeneous condition, and not all people with BPD have severe dissociation. This study examined whether the relationship of BPD features with trauma and dissociation would remain significant after controlling for some general non-specific mental health distress. We also made the first attempt to explore which specific BPD features would be particularly associated with dissociation. METHODS: We analyzed survey data from a sample of community health service users in Hong Kong (N = 376). Hierarchical multiple regression and data-driven network analysis were used. RESULTS: The lifetime prevalence of DSM-5 BPD was 16.0% in our sample. Of participants who met criteria for BPD, 43.3% scored above cutoff on the dissociation measures, thus possibly having clinically significant dissociative symptoms. BPD features were associated with adulthood trauma and psychoform dissociation even after controlling for age, depression and self-esteem. Network analysis showed that some BPD features - including impulsivity, identity disturbance and suicidal/self-mutilation behaviors - were particularly associated with dissociation; other BPD features such as interpersonal-related problems had relatively weak to no connection with dissociation. CONCLUSIONS: Our results suggested that some particular BPD features might be dissociative in nature, although further longitudinal research is required. We argue that a trauma-informed perspective should be employed when working with clients presenting with BPD features despite these features being commonly stigmatized. Further research on the intervention needs of the people with BPD who suffer from high levels of dissociation is required.

Intravenous N-Acetylcysteine to Prevent Cisplatin-Induced Hearing Loss in Children: A Nonrandomized Controlled Phase I Trial.

PURPOSE: Cisplatin-induced hearing loss (CIHL) is common and permanent. As compared with earlier otoprotectants, we hypothesized N-acetylcysteine (NAC) offers potential for stronger otoprotection through stimulation of glutathione (GSH) production. This study tested the optimal dose, safety, and efficacy of NAC to prevent CIHL. PATIENTS AND METHODS: In this nonrandomized, controlled phase Ia/Ib trial, children and adolescents newly diagnosed with nonmetastatic, cisplatin-treated tumors received NAC intravenously 4 hours post-cisplatin. The trial performed dose-escalation across three dose levels to establish a safe dose that exceeded the targeted peak serum NAC concentration of 1.5 mmol/L (as identified from preclinical models). Patients with metastatic disease or who were otherwise ineligible were enrolled in an observation-only/control arm. To evaluate efficacy, serial age-appropriate audiology assessments were performed. Integrated biology examined genes involved in GSH metabolism and post-NAC GSH concentrations. RESULTS: Of 52 patients enrolled, 24 received NAC and 28 were in the control arm. The maximum tolerated dose was not reached; analysis of peak NAC concentration identified 450 mg/kg as the recommended phase II dose (RP2D). Infusion-related reactions were common. No severe adverse events occurred. Compared with the control arm, NAC decreased likelihood of CIHL at the end of cisplatin therapy [OR, 0.13; 95% confidence interval (CI), 0.021-0.847; P = 0.033] and recommendations for hearing intervention at end of study (OR, 0.082; 95% CI, 0.011-0.60; P = 0.014). NAC increased GSH; GSTP1 influenced risk for CIHL and NAC otoprotection. CONCLUSIONS: NAC was safe at the RP2D, with strong evidence for efficacy to prevent CIHL, warranting further development as a next-generation otoprotectant.

Role of Cisplatin Dose Intensity and TPMT Variation in the Development of Hearing Loss in Children.

BACKGROUND: Cisplatin, widely used in the treatment of solid tumors, causes permanent hearing loss in more than 60% of treated children. Previous studies have implicated several clinical factors in the development of ototoxicity, including cumulative cisplatin dose. However, the role of cisplatin dose intensity in the development of hearing loss in children remains unclear. Pharmacogenetic studies have also identified genetic variants in TPMT that increase the risk of cisplatin-induced hearing loss. This study aims to determine whether cisplatin dose intensity contributes to the risk of hearing loss in children and whether genetic variations in TPMT further modifies the risk of cisplatin-induced hearing loss. METHODS: The authors genotyped 371 cisplatin-treated children for the presence of any 3 TPMT -risk variants. Patients were categorized into high-, moderate-, and low-intensity cisplatin dosing groups according to the cisplatin dose administered per unit time. Kaplan-Meier curves were plotted to compare the cumulative incidence of hearing loss between the genotype and dose intensity groups. RESULTS: Patients receiving cisplatin at high dose intensity experienced significantly higher incidences of ototoxicity than those receiving cisplatin at low dose intensity ( P = 9 × 10 -7 ). Further stratification by TPMT genotype revealed that carriers of ≥1 TPMT variants receiving high-intensity cisplatin developed ototoxicity sooner and more often than their wild-type counterparts (93.8% vs. 56.6% at 12 months; P = 5 × 10 -5 ) and noncarriers receiving low-intensity cisplatin (21.2% at 12 months). CONCLUSIONS: Cisplatin dose intensity is strongly associated with ototoxicity development in children, and this risk is further increased by the presence of TPMT -risk alleles.

A luciferase reporter mouse model to optimize in vivo gene editing validated by lipid nanoparticle delivery of adenine base editors.

The rapid development of CRISPR genome editing technology has provided the potential to treat genetic diseases effectively and precisely. However, efficient and safe delivery of genome editors to affected tissues remains a challenge. Here, we developed luminescent ABE (LumA), a luciferase reporter mouse model containing the R387X mutation (c.A1159T) in the luciferase gene located in the Rosa26 locus of the mouse genome. This mutation eliminates luciferase activity but can be restored upon A-to-G correction by SpCas9 adenine base editors (ABEs). The LumA mouse model was validated through intravenous injection of two FDA-approved lipid nanoparticle (LNP) formulations consisting of either MC3 or ALC-0315 ionizable cationic lipids, encapsulated with ABE mRNA and LucR387X-specific guide RNA (gRNA). Whole-body bioluminescence live imaging showed consistent restoration of luminescence lasting up to 4 months in treated mice. Compared with mice carrying the wild-type luciferase gene, the ALC-0315 and MC3 LNP groups showed 83.5% ± 17.5% and 8.4% ± 4.3% restoration of luciferase activity in the liver, respectively, as measured by tissue luciferase assays. These results demonstrated successful development of a luciferase reporter mouse model that can be used to evaluate the efficacy and safety of different genome editors, LNP formulations, and tissue-specific delivery systems for optimizing genome editing therapeutics.