The Combined Contributions of Newborn Stress and Parenting Stress on Toddler Language Development.

OBJECTIVE: To examine the longitudinal associations between newborn neurobehavioral stress signs, maternal parenting stress, and several indices of toddler language development. STUDY DESIGN: Participants include 202 mother-infant dyads (104 girls). We measured stress signs in neonates in the hospital at least 24 hours after birth using the Neonatal Intensive Care Unit Network Neurobehavioral Scale. At 7 months, parenting stress (competence, attachment, and role restriction) was assessed using the Parenting Stress Index. At 18 months, mothers completed the Communicative Development Inventories, which measured toddler gesturing, expressive vocabulary, and receptive vocabulary. Longitudinal path modeling was used to estimate associations between neonatal stress signs, parenting stress, and toddler language, and a model was generated for each language outcome. Child sex, birth weight, and family income were included as covariates. RESULTS: Infants who exhibited greater neurobehavioral stress signs at birth produced significantly fewer social-communicative gestures at 18 months of age. Among infants whose mothers reported low (but not high) levels of parenting stress during the first postnatal year, newborn stress signs were negatively associated with 18-month-olds' receptive vocabulary size. Neither newborn stress signs nor parenting stress were significantly related to toddler expressive vocabulary size. CONCLUSIONS: Our findings uncover a negative association between newborn stress signs and toddler gesturing. Furthermore, our results suggest that caregiver stress and neonatal stress signs interact to predict toddler receptive vocabulary. Taken together, these results demonstrate that some neonates who exhibit increased neurobehavioral stress signs may be at heightened risk for experiencing language difficulties. These children may benefit from additional support in infancy.

A Two-dimensional Metal-Organic Framework as Promising Cathode for Advanced Lithium Storage.

Anthraquinone electrode materials are promising candidates for lithium-ion batteries (LIBs) due to the abundance of anthraquinone and the high theoretical capacity, and good reversibility of the anthraquinone electrodes. However, the active anthraquinone materials are soluble in organic electrolytes, resulting in a sharp decay of capacity during the charge and discharge processes. Herein, we report on a two-dimensional calcium anthraquinone 2,3-dicarboxy metal-organic framework (2D CaAQDC MOF) fabricated using a simple hydrothermal method. The 2D CaAQDC MOF not only effectively inhibits the dissolution of active electrode substances into the electrolyte, but also promotes the diffusion of lithium ion into the pores of the MOF. When used as a cathode for the LIBs, the resulting CaAQDC electrode delivers a high specific capacity of ~100 mAh g-1 at a current density of 50 mA g-1 after 200 cycles, demonstrating its good cycle stability. Even at a high current density of 200 mA g-1 , the CaAQDC electrode exhibits a specific capacity of ~60 mAh g-1 . The fabricated 2D coordination polymers effectively restrains the dissolution of anthraquinone into the organic electrolyte and enhances the structural stability, which greatly improves the electrochemical performance of anthraquinone. These research results offer a rational molecular design strategy to address the dissolution of this and other active organic electrode materials.

Maternal psychophysiology profiles: associations with prenatal opioid use, maternal emotion dysregulation, and newborn neurobehavior.

BACKGROUND: Opioid use among pregnant women has more than quadrupled over the past 20 years; however, comorbid risk factors such as emotion dysregulation confound the developmental consequences of prenatal opioid use. Maternal respiratory sinus arrhythmia (RSA) may help to disentangle the comorbid risk factors of prenatal emotion dysregulation and substance use and isolate their consequences on newborn neurobehavior. METHODS: We examined maternal RSA in response to a mild, infant-related stress task in pregnant people (N = 192; 30 on medications for opioid use disorder) recruited from hospitals and a specialty prenatal clinic for substance use disorder. RESULTS: Three latent profiles emerged based on maternal RSA reactivity. Mothers with RSA increasing (Profile 3; more nervous system dysregulation) had higher levels of emotion dysregulation than mothers with RSA decreasing (Profile 1; well-regulated nervous system responses) but were not more likely to use opioids. Additionally, RSA profiles were associated with newborn neurobehavior, including attention, regulation, handling, and arousal. CONCLUSIONS: Given the variability in opioid use across RSA profiles and profile associations with newborn neurodevelopment, future studies should examine protective factors in pregnant individuals using opioids who show more flexible RSA responses. IMPACT: Our study examined maternal psychophysiology and newborn outcomes in a unique population with high levels of emotion dysregulation and opioid use. Three profiles of maternal respiratory sinus arrythmia (RSA) reactivity were identified during pregnancy: decreasing, blunted, and increasing. The RSA increasing and blunted profiles were associated with higher emotion dysregulation than the decreasing profile. Most pregnant people on medications for opioid use disorder (65%) were grouped into the blunted profile, suggesting they might be more at risk for dysregulated RSA reactivity. Differences in RSA profiles were associated with newborn outcomes, with increasing and blunted RSA predicting more newborn neurobehavioral dysregulation.

From prenatal maternal anxiety and respiratory sinus arrhythmia to toddler internalizing problems: The role of infant negative affectivity.

Prenatal maternal anxiety is considered a risk factor for the development of child internalizing problems. However, little is known about potential mechanisms that account for these associations. The current study examined whether prenatal maternal anxiety was indirectly associated with toddler internalizing problems via prenatal maternal physiology and infant negative affectivity. We examined these associations in a longitudinal study of 162 expectant mothers from their third trimester until 18 months postpartum. Path analyses showed that higher prenatal anxiety was associated with higher infant negative affectivity at 7 months, which in turn was associated with higher toddler internalizing problems at 18 months. Prenatal anxiety was not indirectly associated with child outcomes via baseline or task-evoked respiratory sinus arrhythmia (RSA) in response to an infant cry while pregnant. However, pregnant women with greater decreases in task-evoked RSA had toddlers with greater internalizing problems, which was mediated by infant negative affectivity at 7 months. Findings suggest that prenatal anxiety and RSA reactivity to an infant cry may be independent risk factors for the development of infant negative affectivity, which in turn increases risk for toddler internalizing problems. These findings contribute to a growing literature on mechanisms that underlie intergenerational transmission of internalizing problems.

Aging with my family: a grounded theory approach on the role of family when aging as foreign-born.

BACKGROUND: Research indicates that it is the quality of the closest relationships in the mixture of social relations that matters most for older adults. For older foreign-born, especially those who migrate late in life, the family is often the only socioeconomical resource they can lean on. This study aims to explore how older foreign-born perceive the role of family as they age. METHODS: The study design has a grounded theory approach. Data consist of individual open-ended interviews with 15 foreign-born informants aged between 60 and 85 years old who migrated to Sweden as adults from various parts of the world. RESULTS: The findings demonstrate that family was an essential part of the informants' lives as they lived for their families and their families lived for them. Family solidarity was described as a cultural heritage they took over from their original families and a cultural heritage they wished to pass on to their future generations. They found that this was what separated them as foreign-born from native-born. Memories of their parents reminded them of their biological, social, and cultural heritages. The intimate relationship with their spouses in a life course had served as a source of validation of their individual identities and promoted personal growth and self-esteem. The role as a loving and caring parent entailed a sense of accomplishment and satisfaction for the life lived. And now as grandparents, the role as a link between the family's historical heritage and the future generation entailed not only a sense of coherence as they aged but also hope and meaning beyond their own lives. CONCLUSIONS: The older foreign-born experienced life satisfaction as they aged with their families. Family meant community and solidarity. It was in the family that they found their distinct roles that had defined them. Family was an indispensable part of their social identity. The findings highlight the importance of older foreign-born being studied from a family and lifetime perspective.

Interactions among stress, behavioral inhibition, and delta-beta coupling predict adolescent anxiety during the COVID-19 pandemic.

The COVID-19 pandemic brought about unprecedented changes and uncertainty to the daily lives of youth. The range of adjustment in light of a near-universal experience of COVID restrictions highlights the importance of identifying factors that may render some individuals more susceptible to heightened levels of anxiety during stressful life events than others. Two risk factors to consider are temperamental behavioral inhibition (BI) and difficulties in emotion regulation (ER). As such, the current paper focused on BI examined prior to COVID, because of its developmental link to anxiety and ER, as difficulties may be associated with differences in anxiety. We examined a neurocognitive marker of ER processes, delta-beta coupling (DBC). The current paper had two goals: (1) to examine BI in relation to COVID-related worry and social anxiety experienced during the pandemic, and (2) to explore the role of individual differences in early DBC in the relationship between BI and anxiety outcomes 6 months apart during COVID-19 (n = 86; T1 Mage  = 15.95, SD = 1.73; T6 Mage  = 16.43, SD = 1.73). We found support for the moderating role of DBC in the relationship between BI levels and social anxiety disorder (SAD) symptom severity during the pandemic. Here, high BI was predictive of increased SAD symptom levels in adolescents with stronger DBC.

Bidirectional Relations Among Maternal Positive Emotion, Infant Positive Emotionality, and Infant Physiological Regulation Across the First 18 Months of Life.

Respiratory sinus arrhythmia (RSA), a marker of self-regulation, has been linked to developmental outcomes in young children. Although positive emotions may have the potential to facilitate physiological self-regulation, and enhanced self-regulation could underlie the development of positive emotions in early childhood, the relation between positive emotions and physiological self-regulation in infancy has been relatively overlooked. The current study examined the bidirectional associations among maternal positive emotion, infant positive emotionality, and infant resting RSA across the first 18 months of life. We used data from the Longitudinal Attention and Temperament Study (LanTs; N = 309 in the current analysis) to test the within- and between-person relations of study variables over time using a random-intercepts cross-lagged panel model. We found that infants with higher overall levels of positive emotionality also displayed greater resting RSA, and their mothers exhibited higher levels of positive emotion. However, there were negative cross-lagged associations within-person; higher than average infant positive emotionality predicted lower levels of infant resting RSA at the subsequent timepoint during early infancy, whereas higher than average infant RSA subsequently predicted decreased levels of infant positive emotionality later in infancy. Results highlight the importance of considering transactional relations between positive emotion and physiological self-regulation in infancy.

How to Harness the Power of Social Media for Quality Drug Information in Infectious Diseases: Perspectives on Behalf of the Society of Infectious Diseases Pharmacists.

Clinicians, researchers, and the public frequently turn to digital channels and social media for up-to-the-minute information on novel therapeutics and vaccines. The value of credible infectious diseases drug information is more apparent in the setting of the coronavirus disease 2019 (COVID-19) pandemic. This viewpoint by the Society of Infectious Diseases Pharmacists (SIDP) provides guidance on utilizing social media platforms to optimize infectious diseases pharmacotherapy. It includes tips for all levels of users but primarily serves a guide for the infectious diseases clinician who has not yet joined social media. It compares various social media platforms and suggests which to begin with based on user needs, recommends efficient curation of social media content, and outlines a stepwise approach (shown below) to increasing engagement over time. This summary will hopefully spur further quality content and engagement regarding drug information from the infectious diseases social media network.

Lymphatic regeneration after implantation of aligned nanofibrillar collagen scaffolds: Preliminary preclinical and clinical results.

BACKGROUND: We tested our hypothesis that implantation of aligned nanofibrillar collagen scaffolds (BioBridge™) can both prevent and reduce established lymphedema in the rat lymphedema model. Our authors report clinical cases that demonstrate new lymphatic formation guided by BioBridge™ as seen by near-infrared (NIR) fluoroscopy and magnetic resonance (MR) lymphography. METHODS: A rat lymphedema model was utilized. A prevention group received implantation of BioBridge™ immediately after lymphadenectomy. A lymphedema group received implantation of BioBridge™ with autologous adipose-derived stem cells (ADSC; treatment group) or remained untreated (control group). All subjects were observed for 4 months after lymphadenectomy. The hindlimb change was evaluated using computed tomography-based volumetric analysis. Lymphagiogenesis was assessed by indocyanine green (ICG) lymphography. RESULTS: Animals in the treatment group showed a reduction in affected limb volume. Animals in the prevention group showed no increase in the affected limb volume. ICG fluoroscopy demonstrated lymph flow and formation of lymphatics toward healthy lymphatics. CONCLUSIONS: In the rat lymphedema model, implantation of BioBridge™ at the time of lymph node removal prevents the development of lymphedema. Treatment of established lymphedema with the BioBridge™ and ADSC reduces lymphedema. New lymphatic vessels are demonstrated by NIR fluoroscopy and MR lymphography. These findings have implications for the treatment of lymphedema in human subjects.

An economic evaluation of cabazitaxel versus a second androgen receptor-targeted agent (ARTA) for patients with metastatic castration-resistant prostate cancer previously treated with docetaxel and an ARTA: the United States payer perspective.

BACKGROUND: Cabazitaxel significantly improves clinical outcomes compared with a second androgen receptor-targeted agent (ARTA) in patients with metastatic castration-resistant prostate cancer (mCRPC) previously treated with docetaxel and an ARTA (abiraterone or enzalutamide), as demonstrated in the CARD trial (NCT02485691). We aimed to estimate healthcare costs avoided with the use of cabazitaxel as a third-line (3 L) treatment versus a second ARTA from a US payer perspective. METHODS: Model inputs were based on the CARD trial, published sources, and estimates of typical clinical care patterns by genitourinary oncologists (n = 3). Assessed time points were 6, 12, 18, and 24 months. Outcomes included progression-free survival (PFS), radiographic PFS (rPFS), and overall survival (OS); hospitalization and intensive care unit (ICU) days; and costs (reported in 2020 US dollar [USD] and converted into Euro) to manage symptomatic skeletal events (SSEs), adverse events (AEs), and end-of-life care. RESULTS: At 18 months, in a cohort of 100 patients, the use of cabazitaxel was estimated to result in 9 more patients achieving rPFS, 2 more patients achieving PFS, and 17 more survivors versus a second ARTA. The costs of SSEs, AEs, and end-of-life care were $498,909 (€424,073), $276,198 (€234,768), and $808,785 (€687,468), respectively, for cabazitaxel and $627,569 (€533,434), $251,124 (€213,455), and $1,028,294 (€874,050), respectively, for a second ARTA. Cabazitaxel was estimated to be associated with a 21% reduction in both SSE management and end-of-life care costs. Hospitalization cost was $1,442,870 (€1,226,440) for cabazitaxel and $1,728,394 (€1,469,135) for a second ARTA, representing an estimated 17% reduction in these costs. Cabazitaxel, as compared with a second ARTA, was associated with 58 fewer hospitalization days and 2 fewer ICU days and was estimated to avoid $323,095 (€274,630, 17%) in total costs, driven by SSEs management and end-of-life care. CONCLUSION: The use of cabazitaxel as a 3 L treatment after docetaxel and an ARTA in patients with mCRPC is estimated to result in clinical benefits (longer rPFS, PFS, and OS) and lower healthcare resource utilization (fewer hospitalization and ICU days), compared with a second ARTA.

Autonomic nervous system activity moderates associations between temperament and externalizing behaviors in early childhood.

Temperamental risk, such as surgency, negative affect, and poor effortful control, has been posited as a predictor of externalizing symptom development. However, autonomic nervous system (ANS) activity underlying processes of reactivity and regulation may moderate associations between early temperament and later externalizing behaviors during early childhood. The aim of the present study was to examine how interactions between resting sympathetic (SNS) and parasympathetic (PNS) activity at age 5 may moderate associations between temperamental risk at age 3 and externalizing behavior at age 6 (n = 87). Results demonstrate different interactions between resting ANS activity and temperamental risk to predict externalizing behaviors. For children with lower SNS activation at rest, surgency was positively associated with externalizing behaviors. Negative affect was positively associated with externalizing behaviors except when there were either high levels of SNS and PNS activity or low levels of SNS and PNS activity. Effortful control was not associated with externalizing behaviors, though SNS and PNS activity interacted to predict externalizing behaviors after accounting for effortful control. Taken together, the results highlight the importance to examine multisystem resting physiological activity as a moderator of associations between temperamental risk and the development of externalizing  behaviors.

Bidirectional effects of toddler temperament and maternal overprotection on maternal and child anxiety symptoms across preschool.

INTRODUCTION: Existing research highlights interactions among child temperament, parents' own anxiety symptoms, and parenting in predicting increased risk for anxiety symptom development. Theoretical models of child-elicited effects on parents have proposed that parents' behaviors are likely not independent of children's temperament; fearful children likely elicit more protective responses from parents and these parenting behaviors reinforces child anxiety and parents' own anxiety. METHOD: The current study tests this model and examines whether there are bidirectional influences between early fearful temperament (i.e., dysregulated fear [DF]), maternal overprotection, and subsequent trajectories of maternal and child anxiety symptoms across early childhood. A total of 166 children and mothers participated in a multimethod, longitudinal study of temperament risk from 2 to 6 years. RESULTS: Results largely support our hypotheses, replicating and extending the prior literature. DF was associated with more maternal overprotective behavior, subsequent child anxiety symptoms, and maternal anxiety symptoms. Moreover, there were indirect (mediated) associations through maternal overprotective behavior and both child and mother anxiety symptoms. CONCLUSION: Results support the hypothesis that intergenerational transmission of anxiety was meditated through maternal behaviors and that the child-driven temperament effects are central to trajectories of child and maternal anxiety trajectories.

CDK4/6 inhibitors in HR+/HER2- advanced/metastatic breast cancer: a systematic literature review of real-world evidence studies.

Background: This review aims to qualitatively summarize the published real-world evidence (RWE) for CDK4/6 inhibitors (CDK4/6i) approved for treating HR+, HER2-negative advanced/metastatic breast cancer (HR+/HER2- a/mBC). Materials & methods: A systematic literature review was conducted to identify RWE studies of CDK4/6i in HR+/HER2- a/mBC published from 2015 to 2019. Results: This review identified 114 studies, of which 85 were only presented at scientific conferences. Most RWE studies investigated palbociclib and demonstrated improved outcomes. There are limited long-term and comparative data between CDK4/6i and endocrine monotherapy, and within the CDK4/6i class. Conclusion: Available RWE suggests that CDK4/6i are associated with improved outcomes in HR+/HER2- a/mBC, although additional studies with longer follow-up periods are needed.

Trajectories of internalizing symptoms in early childhood: Associations with maternal internalizing symptoms and child physiology.

Research has shown that children's internalizing symptom development during early childhood are shaped by biopsychosocial processes including physiology and parental symptoms. However, associations between maternal internalizing symptoms, child physiology and trajectories of child internalizing symptoms are not well understood. We used growth curve models to examine how maternal internalizing symptoms, child physiology and the interaction between maternal internalizing symptoms and child physiology may be associated with trajectories of internalizing symptoms during early childhood. Mothers reported their children's internalizing symptoms when children were 3, 4, 5 and 6 years of age, and mothers self-reported their own internalizing symptoms when children were 3. Respiratory Sinus Arrhythmia (RSA) was collected when children were 3.5-years-old. Results showed that there is a non-linear, quadratic trajectory across all participants from age 3 to 6. Maternal internalizing symptoms were not associated with children's internalizing symptoms at age 6, but were associated with both linear and quadratic change. Lower resting RSA was associated with greater increases in children's internalizing symptoms over time. Interactions between maternal internalizing symptoms and RSA were not associated with children's internalizing symptom development. The findings demonstrate that maternal internalizing symptoms and child physiology are independently associated with internalizing symptom development during early childhood.

Sensory restoration of breast reconstruction - The search for the ideal approach continues.

Contemporary reconstructive modalities focus on breast anatomy and attempt to reconstruct breasts that are soft, of adequate shape, size, and symmetry. However, a functional component, i.e. sensation, has largely been ignored. Flap neurotization addresses this shortcoming. While we are still in search of the ideal surgical technique to achieve this goal, a novel approach that limits nerve harvest to the sensory branch only, thus, minimizing abdominal donor-site morbidity, is presented.

Association between TPMT*3C and decreased thiopurine S-methyltransferase activity in patients with neuromyelitis optica spectrum disorders in China.

AIM OF THE STUDY: Thiopurines are effective drugs in treating neuromyelitis optica spectrum disorders and other diseases. Thiopurines' toxicity is mainly imputed to thiopurine S-methyltransferase activity. In Chinese population, the most common and important variation of thiopurine S-methyltransferase is TPMT*3C (rs1142345). This study aims to reveal the association between thiopurine S-methyltransferase activity and genetic polymorphisms of thiopurine S-methyltransferase in patients with neuromyelitis optica spectrum disorders in China. MATERIAL AND METHODS: A liquid chromatography tandem mass/mass method was used to evaluate the thiopurine S-methyltransferase activity by using 6-mercapthioprine as the substrate in human erythrocyte haemolysate via 1 h incubation at 37 °C to form its methylated product 6-methylmercaptopurine. The amount of 6-methylmercaptopurine was adjusted by haematocrit and normalized to 8 × 108 erythrocytes. The selected polymorphisms of thiopurine S-methyltransferase were identified using MassARRAY system (Sequenom) and multiple SNaPshot technique. RESULTS: In 69 patients with neuromyelitis optica spectrum disorders, thiopurine S-methyltransferase activity was 80.29-154.53 (127.51 ± 16.83) pmol/h/8 × 108 erythrocytes. TPMT*3C (rs1142345) was associated with lower thiopurine S-methyltransferase activity (BETA = -25.37, P = 0.011). Other selected variants were not associated with thiopurine S-methyltransferase activity. CONCLUSIONS: TPMT*3C affects TPMT activity in Chinese patients with neuromyelitis optica spectrum disorders. Further studies are warranted to confirm the results. ABBREVIATIONS: TPRs = thiopurines; NMOSD = neuromyelitis optica spectrum disorders; TPMT = thiopurine S-methyltransferase; LC-MS/MS = liquid chromatography tandem mass/mass; 6-MMP = 6-methylmercaptopurine; IS = internal standard; SNP = single nucleotide polymorphism; MAF = minor allele frequency; HWE = Hardy-Weinberg equilibrium; BETA = regression coefficients; UTR-3 = untranslated region 3.

Detecting the Formation and Transformation of Oligomers during Insulin Fibrillation by a Dendrimer Conjugated with Aggregation-Induced Emission Molecule.

The fibrillation of protein is harmful and impedes the use of protein drugs. It also relates to various debilitating diseases such as Alzheimer's diseases. Thus, investigating the protein fibrillation process is necessary. In this study, poly(amido amine) dendrimers (PAMAM) of generation 3 (G3) and generation 4 (G4) were synthesized and conjugated with 4-aminobiphenyl, an aggregation-induced emission (AIE) moiety, at varied grafting ratios. Among them, one fluorescence probe named G3-biph-3 that was grafted average 3.25 4-aminobiphenyl to the G3, can detect the transformations both from native insulin to oligomers and from oligomers to fibrils. The size difference of native insulin, oligomers, and fibrils was proposed to be the main factor leading to the detection of the above transformations. Different molecular weights of sodium polyacrylate (PAAS) were also applied as a model to interact with G3-biph-3 to further reveal the mechanism. The results indicated that PAMAM with a certain generation and grafted with appropriate AIE groups can detect the oligomer formation and transformation during the insulin fibrillation process.

LC-MS/MS Analysis of Erythrocyte Thiopurine Nucleotides and Their Association With Genetic Variants in Patients With Neuromyelitis Optica Spectrum Disorders Taking Azathioprine.

BACKGROUND: Azathioprine is a first-line drug in treating neuromyelitis optica spectrum disorders (NMOSD). To exhibit its bioactivity, azathioprine needs to be converted to thiopurine nucleotides (TPNs) including 6-thioguanine nucleotides (6-TGNs) and 6-methylmercaptopurine nucleotides (6-MMPNs) that are affected by genetic polymorphisms. This study aims to develop an LC-MS/MS method for the analysis of erythrocyte concentrations of TPNs and to evaluate their associations with variants of various genes (MTHFR, TPMT, HLA, SLC29A1, SLC28A2, SLC28A3, ABCB1, and ABCC4) in patients with NMOSD. METHODS: Erythrocyte 6-TGNs and 6-MMPNs were converted to their free bases 6-thioguanine and 6-methylmercaptopurine derivative by 1-hour acid hydrolysis at 95°C. An LC-MS/MS method was developed, validated, and used to study 32 patients with NMOSD to determine these free bases. Genetic variants were identified by MassARRAY (Sequenom) and multiple SNaPshot techniques. The associations between genetic variants and the concentrations of TPNs or the 6-MMPNs:6-TGNs ratio were evaluated by PLINK software using linear regression. RESULTS: Methanol and water were used for separation with a total run time of 6.5 minutes. The lowest limit of quantification was 0.1 µmol/L with an injection volume of 10 µL. rs10868138 (SLC28A3) was associated with a higher erythrocyte concentration of 6-TGNs (P = 0.031), whereas rs12378361 (SLC28A3) was associated with a lower erythrocyte concentration of 6-TGNs (P = 0.0067). rs507964 (SLC29A1) was significantly associated with a lower erythrocyte concentration of 6-MMPNs (P = 0.024) and a lower 6-MMPNs:6-TGNs ratio (P = 0.029). CONCLUSIONS: An LC-MS/MS method for the analysis of erythrocyte TPNs was developed, validated, and used to study 32 patients with NMOSD. SLC29A1 and SLC28A3 were associated with the erythrocyte concentrations of TPNs and 6-MMPNs:6-TGNs ratio. Further studies are needed to confirm these results.

Relationship between Azathioprine metabolites and therapeutic efficacy in Chinese patients with neuromyelitis optica spectrum disorders.

BACKGROUND: Neuromyelitis optica spectrum disorders (NMOSD) are demyelinating autoimmune diseases in the central nervous system (CNS) that are characterized by a high relapse rate and the presence of anti-aquaporin 4 antibodies (AQP4-IgG) in the serum. Azathioprine (AZA) is a first-line immunomodulatory drug that is widely used for the treatment of patients with NMOSD. However, the efficacy and safety of AZA vary in different individuals. METHOD: Thirty-two patients with NMOSD who regularly took AZA were enrolled in the study at Beijing Tiantan Hospital, Capital Medical University. The efficacy of AZA was evaluated using the expanded disability status scale (EDSS) and the annual relapse rate (ARR). The erythrocyte concentrations of AZA metabolites were detected using an LC-MS/MS method. RESULTS: The erythrocyte concentrations of 6-thioguanine nucleotides (6-TGNs) and 6-methylmercaptopurine nucleotides (6-MMPNs) were 202.03 ± 63.35 pmol/8*108 RBC and 1618.90 ± 1607.06 pmol/8*108 RBC, respectively. After the patients had received AZA therapy for more than one year, the EDSS score decreased from 5.21 ± 0.24 to 2.57 ± 0.33 (p < 0.0001), and the ARR decreased from 1.41 ± 0.23 to 0.36 ± 0.09 (p < 0.0001). The 6-TGN and 6-MMPN levels were significantly different between the non-relapsed and relapsed groups (p < 0.0001, p = 0.006, respectively). A higher ARR was significantly correlated with higher erythrocyte concentrations of 6-TGNs (p < 0.0001) and 6-MMPNs (p = 0.004). CONCLUSION: AZA can reduce the EDSS score and ARR in NMOSD patients. Additionally, the efficacy of AZA is significantly related to the erythrocyte concentrations of 6-TGNs and 6-MMPNs. Within the safe upper limits, a higher concentration of 6-TGNs is associated with better efficacy of AZA. TRIAL REGISTRATION NUMBER: ISRCTN16551495 , retrospectively registered on May 22, 2017.

Comparison of 6-mercaptopurine with 6-thioguanine for the analysis of thiopurine S-methyltransferase activity in human erythrocyte by LC-MS/MS.

Thiopurines (TPDs) are first-line drugs in treating neuromyelitis optica spectrum disorders (NMOSD). Evaluation of thiopurine S-methyltransferase activity (TPMT), a major determinant of TPD toxicity, before TPD treatment using 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG) as substrate was suggested. However, the equivalent of the two substrates in TPMT activity evaluation was unknown, and an alternative substrate was required in TPMT activity evaluation in patients who were already taking 6-MP or 6-TG. Before evaluating the agreement of 6-MP and 6-TG in TPMT activity measurement in patients with NMOSD, the affinity of the two substrates for the active center of TPMT should be established. A computer-based simulation indicated that 6-MP and 6-TG had similar affinities for the two active sites of TPMT. According to the guidelines, an LC-MS/MS method was developed and validated to evaluate the TPMT activity in human erythrocyte hemolysate using 6-MP or 6-TG as substrates via 1 h incubation at 37°C. The method was applied in 81 patients with NMOSD. Evaluated by Bland-Altman plot, 6-methylmercaptopurine and 6-methylthioguanine represented TPMT activities were in agreement with each other. Further studies are warranted to confirm the results.