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Clinical Cancer Research : An Official... Nov 2023Deregulated metabolism in cancer cells represents a vulnerability that may be therapeutically exploited to benefit patients. One such target is nicotinamide...
PURPOSE
Deregulated metabolism in cancer cells represents a vulnerability that may be therapeutically exploited to benefit patients. One such target is nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in the NAD+ salvage pathway. NAMPT is necessary for efficient NAD+ production and may be exploited in cells with increased metabolic demands. We have identified NAMPT as a dependency in rhabdomyosarcoma (RMS), a malignancy for which novel therapies are critically needed. Here we describe the effect of NAMPT inhibition on RMS proliferation and metabolism in vitro and in vivo.
EXPERIMENTAL DESIGN
Assays of proliferation and cell death were used to determine the effects of pharmacologic NAMPT inhibition in a panel of ten molecularly diverse RMS cell lines. Mechanism of the clinical NAMPTi OT-82 was determined using measures of NAD+ and downstream NAD+-dependent functions, including energy metabolism. We used orthotopic xenograft models to examine tolerability, efficacy, and drug mechanism in vivo.
RESULTS
Across all ten RMS cell lines, OT-82 depleted NAD+ and inhibited cell growth at concentrations ≤1 nmol/L. Significant impairment of glycolysis was a universal finding, with some cell lines also exhibiting diminished oxidative phosphorylation. Most cell lines experienced profound depletion of ATP with subsequent irreversible necrotic cell death. Importantly, loss of NAD and glycolytic activity were confirmed in orthotopic in vivo models, which exhibited complete tumor regressions with OT-82 treatment delivered on the clinical schedule.
CONCLUSIONS
RMS is highly vulnerable to NAMPT inhibition. These findings underscore the need for further clinical study of this class of agents for this malignancy.
Topics: Humans; NAD; Cytokines; Nicotinamide Phosphoribosyltransferase; Pyrazoles; Necrosis; Rhabdomyosarcoma; Cell Line, Tumor
PubMed: 37616468
DOI: 10.1158/1078-0432.CCR-23-0200 -
Epilepsy & Behavior : E&B May 2024A pathogenic variant in SCN1A can result in a spectrum of phenotypes, including Dravet syndrome (DS) and genetic epilepsy with febrile seizures plus (GEFS + )...
BACKGROUND
A pathogenic variant in SCN1A can result in a spectrum of phenotypes, including Dravet syndrome (DS) and genetic epilepsy with febrile seizures plus (GEFS + ) syndrome. Dravet syndrome (DS) is associated with refractory seizures, developmental delay, intellectual disability (ID), motor impairment, and challenging behavior(1,2). GEFS + is a less severe phenotype in which cognition is often normal and seizures are less severe. Challenging behavior largely affects quality of life of patients and their families. This study describes the profile and course of the behavioral phenotype in patients with SCN1A-related epilepsy syndromes, explores correlations between behavioral difficulties and potential risk factors.
METHODS
Data were collected from questionnaires, medical records, and semi-structured interviews. Behavior difficulties were measured using the Adult/Child Behavior Checklist (C/ABCL) and Adult self-report (ASR). Other questionnaires included the Pediatric Quality of Life Inventory (PedsQL), the Functional Mobility Scale (FMS) and the Sleep Behavior Questionnaire by Simonds & Parraga (SQ-SP). To determine differences in behavioral difficulties longitudinally, paired T-tests were used. Pearson correlation and Spearman rank test were used in correlation analyses and multivariable regression analyses were employed to identify potential risk factors.
RESULTS
A cohort of 147 participants, including 107 participants with DS and 40 with genetic epilepsy with febrile seizures plus (GEFS + ), was evaluated. Forty-six DS participants (43.0 %) and three GEFS + participants (7.5 %) showed behavioral problems in the clinical range on the A/CBCL total problems scale. The behavioral profile in DS exists out of withdrawn behavior, aggressive behavior, and attention problems. In DS patients, sleep disturbances (β = 1.15, p < 0.001) and a lower age (β = -0.21, p = 0.001) were significantly associated with behavioral difficulties. Between 2015 and 2022, behavioral difficulties significantly decreased with age (t = -2.24, CI = -6.10 - -0.15, p = 0.04) in DS participants aging from adolescence into adulthood. A decrease in intellectual functioning (β = 3.37, p = 0.02) and using less antiseizure medications in 2022 than in 2015, (β = -1.96, p = 0.04), were identified as possible risk factors for developing (more) behavioral difficulties.
CONCLUSIONS
These findings suggest that, in addition to epilepsy, behavioral difficulties are a core feature of the DS phenotype. Behavioral problems require personalized management and treatment strategies. Further research is needed to identify effective interventions.
Topics: Humans; Male; Female; NAV1.1 Voltage-Gated Sodium Channel; Adult; Child; Adolescent; Young Adult; Child, Preschool; Epilepsies, Myoclonic; Quality of Life; Epileptic Syndromes; Neurodevelopmental Disorders; Seizures, Febrile; Problem Behavior; Epilepsy
PubMed: 38513571
DOI: 10.1016/j.yebeh.2024.109726 -
NeuroImage Jan 2024Early-onset Schizophrenia (EOS) is a profoundly progressive psychiatric disorder characterized by both positive and negative symptoms, whose pathogenesis is influenced...
Early-onset Schizophrenia (EOS) is a profoundly progressive psychiatric disorder characterized by both positive and negative symptoms, whose pathogenesis is influenced by genes, environment and brain structure development. In this study, the MIND (Morphometric Inverse Divergence) network was employed to explore the relationship between morphological similarity and specific transcriptional expression patterns in EOS patients. This study involved a cohort of 187 participants aged between 7 and 17 years, consisting of 97 EOS patients and 90 healthy controls (HC). Multiple morphological features were used to construct the MIND network for all participants. Furthermore, we explored the associations between MIND network and brain-wide gene expression in EOS patients through partial least squares (PLS) regression, shared genetic predispositions with other psychiatric disorders, functional enrichment of PLS weighted genes, as well as transcriptional signature assessment of cell types, cortical layers, and developmental stages. The MIND showed similarity differences in the orbitofrontal cortex, pericalcarine cortex, lingual gyrus, and multiple networks in EOS patients compared to HC. Moreover, our exploration revealed a significant overlap of PLS2 weighted genes linking to EOS-related MIND differences and the dysregulated genes reported in other psychiatric diseases. Interestingly, genes correlated with MIND changes (PLS2-) exhibited a significant enrichment not only in metabolism-related pathways, but also in specific astrocytes, cortical layers (specifically layer I and III), and posterior developmental stages (late infancy to young adulthood stages). However, PLS2+ genes were primarily enriched in synapses signaling-related pathways and early developmental stages (from early-mid fetal to neonatal early infancy) but not in special cell types or layers. These findings provide a novel perspective on the intricate relationship between macroscopic morphometric structural abnormalities and microscopic transcriptional patterns during the onset and progression of EOS.
Topics: Infant, Newborn; Humans; Young Adult; Adult; Child; Adolescent; Schizophrenia; Magnetic Resonance Imaging; Brain; Prefrontal Cortex; Occipital Lobe
PubMed: 38086496
DOI: 10.1016/j.neuroimage.2023.120493 -
Obstetrics and Gynecology Dec 2023To compare contraceptive provision to women with and without intellectual and developmental disabilities enrolled in North Carolina Medicaid.
OBJECTIVE
To compare contraceptive provision to women with and without intellectual and developmental disabilities enrolled in North Carolina Medicaid.
METHODS
Our retrospective cohort study used 2019 North Carolina Medicaid claims to identify women aged 15-44 years with and without intellectual and developmental disabilities at risk for pregnancy who were continuously enrolled during 2019 or had Family Planning Medicaid with at least one claim. We calculated the proportion in each cohort who received 1) most or moderately effective contraception, 2) long-acting reversible contraception, 3) short-acting contraception, and 4) individual methods. We classified contraceptive receipt by procedure type and disaggregated across sociodemographic characteristics. Adjusting for age, race, ethnicity, and urban or rural setting, we constructed logistic regression models to estimate most or moderately effective contraceptive provision odds by intellectual and developmental disability status and by level or type of intellectual and developmental disability. We performed subanalyses to estimate co-occurrence of provision and menstrual disorders.
RESULTS
Among 9,508 women with intellectual and developmental disabilities and 299,978 without, a significantly smaller proportion with intellectual and developmental disabilities received most or moderately effective contraception (30.1% vs 36.3%, P <.001). With the exception of injectable contraception, this trend was consistent across all measures and remained statistically significant after controlling for race, ethnicity, age, and urban or rural status (adjusted odds ratio 0.75, 95% CI 0.72-0.79; P <.001). Among those who received most or moderately effective contraception, a significantly greater proportion of women with intellectual and developmental disabilities had co-occurring menstrual disorders (31.3% vs 24.3%, P <.001).
CONCLUSION
These findings suggest disparities in contraceptive provision and potential differences in clinical indication by intellectual and developmental disability status. Future studies should investigate reasons for and barriers to contraceptive use among women with intellectual and developmental disabilities.
Topics: Pregnancy; United States; Child; Female; Humans; Contraceptive Agents; Medicaid; Developmental Disabilities; Retrospective Studies; Contraception
PubMed: 38051293
DOI: 10.1097/AOG.0000000000005421 -
BMC Pediatrics May 2024Sleep has been known to affect childhood development. Sleep disturbance is likely more common in children with developmental delay (DD) than in typical development....
BACKGROUND
Sleep has been known to affect childhood development. Sleep disturbance is likely more common in children with developmental delay (DD) than in typical development. There are few studies on the correlation between sleep disturbance and developmental features in children with DD. Therefore, this study aimed to evaluate the associations between the two in children with DD.
METHODS
A total of 45 children (age range 27.0 ± 11.1) with DD were recruited and evaluated using the Sleep Disturbance Scale for Children (SDSC) and Bayley Scales of Infant and Toddler Development (BSID-III). The outcomes are expressed as means and standard deviations. The correlation between SDSC and BSID-III was assessed using Spearman's rank correlation test. Multiple regression analysis was performed to investigate the relationship between BSID-III domains and SDSC questionnaire subscales. Statistical significance was set at p < 0.05.
RESULTS
Based on the correlation analysis and subsequent hierarchical regression analysis, cognition and socio-emotional domains of BSID-III were significantly associated with the DOES subscale of the SDSC questionnaire. In addition, the expressive language domain of the BSID-III was found to be associated with the DA subscale of the SDSC questionnaire. It seems that excessive daytime sleepiness might negatively affect emotional and behavioral problems and cognitive function. Also, arousal disorders seem to be related to memory consolidation process, which is thought to affect language expression.
CONCLUSION
This study demonstrated that DA and DOES subscales of the SDSC questionnaire were correlated with developmental aspects in preschool-aged children with DD. Sleep problems in children with DD can negatively affect their development, thereby interfering with the effectiveness of rehabilitation. Identifying and properly managing the modifiable factors of sleep problems is also crucial as a part of comprehensive rehabilitation treatment. Therefore, we should pay more attention to sleep problems, even in preschool-aged children with DD.
Topics: Humans; Child, Preschool; Male; Female; Developmental Disabilities; Sleep Wake Disorders; Child Development; Cognition; Infant
PubMed: 38811876
DOI: 10.1186/s12887-024-04857-1 -
Health Science Reports Dec 2023Preterm birth (PTB) accompanies with morbidities and mortality among newborns. This study aimed to show that different factors such as economic (adjusted net national...
BACKGROUND AND AIM
Preterm birth (PTB) accompanies with morbidities and mortality among newborns. This study aimed to show that different factors such as economic (adjusted net national income and gross domestic product [GDP] per capita), human developmental (human developmental index), and health (overall health performance, pregnancy prenatal care rate, and modeled estimated maternal mortality rate) indexes might influence the prevalence of PTB.
METHODS
To this, the top 10 countries with the highest and lowest prevalence of PTB were extracted from the Global Burden of Disease report for PTB. Then, we have gathered some common indexes for economic (adjusted net national income and GDP per capita), health-related (overall health performance, pregnancy prenatal care rate, and modeled estimated maternal mortality rate), and combined developmental (human developmental index) factors from different resources including World Bank and United Nations for those countries. The truncated Bayesian linear regression model, decision tree, and k-means clustering algorithms were used for data analysis.
RESULTS
The results showed Pregnancy Prenatal Care Rate index has a significant effect on the PTB rate in the top 10 countries with the highest prevalence of PTB. Also, for the top 10 less prevalent countries for PTB, it was shown that modeled estimated maternal mortality rate, human developmental index rank, and pregnancy prenatal care rate have significant effects on PTB rate. In addition, the clustering based on the similarities in socioeconomic, human developmental, and health indexes were approximately like with the clustering of the countries based on the PTB rates (Rand index = 0.823).
CONCLUSION
The results showed studies on the epidemiology of PTB (either worldwide or nation-based) should consider these confounder factors to obtain accurate results.
PubMed: 38078305
DOI: 10.1002/hsr2.1746 -
Journal of Graduate Medical Education Aug 2023The Clinical Competency Committee (CCC) provides accountability to the general public that physicians completing a training program have achieved competence. CCC...
BACKGROUND
The Clinical Competency Committee (CCC) provides accountability to the general public that physicians completing a training program have achieved competence. CCC processes and features that best identify resident outcomes along a developmental spectrum are not well described.
OBJECTIVE
This study sought to describe CCC features associated with effective and efficient CCC performance.
METHODS
The study was conducted as part of the 2022 Council of Academic Family Medicine Educational Research Alliance survey of family medicine residency program directors. The survey assessed CCC methods, policies, faculty development, structure, and overall CCC time required. The outcomes were identification of residents along a spectrum of development, from failing to exceeding expectations. Ordinal logistic regressions were used to explore the relationship between CCC characteristics and CCC outcomes.
RESULTS
The response rate was 43.3% (291 of 672). Eighty-nine percent (258 of 291) of program directors reported their CCC is successful in identifying residents not meeting expectations; 69.3% (201 of 290) agree their CCC identifies residents who are exceeding expectations. Programs with written policies for synthesizing data (OR=2.53; 95% CI 1.22-5.22; =.012) and written policies for resident feedback (OR=19.91; 95% CI 3.72-106.44; <.001) were more likely to report successfully identifying residents below expectations. Programs whose members spent fewer than 3 hours per 6-month interval on CCC meetings were less likely to report being able to identify failing residents (OR=0.37; 95% CI 0.19-0.72; =.004).
CONCLUSIONS
This survey of family medicine program directors suggests that formal policies, faculty development, and adequate time for CCC faculty are associated with an effective CCC, especially if goals beyond "identifying failure" are desired.
Topics: Humans; Clinical Competence; Internship and Residency; Faculty; Family Practice; Physicians
PubMed: 37637335
DOI: 10.4300/JGME-D-22-00756.1 -
Genes Feb 2024Infantile epileptic spasms syndrome (IESS) is a devastating developmental epileptic encephalopathy (DEE) consisting of epileptic spasms, as well as one or both of... (Review)
Review
Infantile epileptic spasms syndrome (IESS) is a devastating developmental epileptic encephalopathy (DEE) consisting of epileptic spasms, as well as one or both of developmental regression or stagnation and hypsarrhythmia on EEG. A myriad of aetiologies are associated with the development of IESS; broadly, 60% of cases are thought to be structural, metabolic or infectious in nature, with the remainder genetic or of unknown cause. Epilepsy genetics is a growing field, and over 28 copy number variants and 70 single gene pathogenic variants related to IESS have been discovered to date. While not exhaustive, some of the most commonly reported genetic aetiologies include trisomy 21 and pathogenic variants in genes such as , , , , , and . Understanding the genetic mechanisms of IESS may provide the opportunity to better discern IESS pathophysiology and improve treatments for this condition. This narrative review presents an overview of our current understanding of IESS genetics, with an emphasis on animal models of IESS pathogenesis, the spectrum of genetic aetiologies of IESS (i.e., chromosomal disorders, single-gene disorders, trinucleotide repeat disorders and mitochondrial disorders), as well as available genetic testing methods and their respective diagnostic yields. Future opportunities as they relate to precision medicine and epilepsy genetics in the treatment of IESS are also explored.
Topics: Animals; Precision Medicine; Spasms, Infantile; Epilepsy; Epileptic Syndromes; Spasm
PubMed: 38540325
DOI: 10.3390/genes15030266 -
JAMA Psychiatry Sep 2023People with a severe mental illness (SMI) have a life expectancy reduced by 10 to 20 years compared with the general population, primarily attributable to... (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
People with a severe mental illness (SMI) have a life expectancy reduced by 10 to 20 years compared with the general population, primarily attributable to cardiometabolic disorders. Lifestyle interventions for people with SMI can improve health and reduce cardiometabolic risk.
OBJECTIVE
To evaluate the effectiveness of a group-based lifestyle intervention among people with SMI in outpatient treatment settings compared with treatment as usual (TAU).
DESIGN, SETTING, AND PARTICIPANTS
The Severe Mental Illness Lifestyle Evaluation (SMILE) study is a pragmatic cluster randomized clinical trial performed in 8 mental health care centers with 21 flexible assertive community treatment teams in the Netherlands. Inclusion criteria were SMI, age of 18 years or older, and body mass index (calculated as weight in kilograms divided by height in meters squared) of 27 or greater. Data were collected from January 2018 to February 2020, and data were analyzed from September 2020 to February 2023.
INTERVENTIONS
Weekly 2-hour group sessions for 6 months followed by monthly 2-hour group sessions for another 6 months, delivered by trained mental health care workers. The intervention targeted overall lifestyle changes, emphasizing establishing a healthy diet and promoting physical activity. TAU (control) did not include structured interventions or advice on lifestyle.
MAIN OUTCOMES AND MEASURES
Crude and adjusted linear mixed models and multivariable logistic regression analyses were performed. The main outcome was body weight change. Secondary outcomes included changes in body mass index, blood pressure, lipid profiles, fasting glucose level, quality of life, self-management ability, and lifestyle behaviors (physical activity and health, mental health, nutrition, and sleep).
RESULTS
The study population included 11 lifestyle intervention teams (126 participants) and 10 TAU teams (98 participants). Of 224 included patients, 137 (61.2%) were female, and the mean (SD) age was 47.6 (11.1) years. From baseline to 12 months, participants in the lifestyle intervention group lost 3.3 kg (95% CI, -6.2 to -0.4) more than those in the control group. In the lifestyle intervention group, people with high attendance rates lost more weight than participants with medium and low rates (mean [SD] weight loss: high, -4.9 [8.1] kg; medium, -0.2 [7.8] kg; low, 0.8 [8.3] kg). Only small or no changes were found for secondary outcomes.
CONCLUSIONS AND RELEVANCE
In this trial, the lifestyle intervention significantly reduced weight from baseline to 12 months in overweight and obese adults with SMI. Tailoring lifestyle interventions and increasing attendance rates might be beneficial for people with SMI.
TRIAL REGISTRATION
Netherlands Trial Register Identifier: NTR6837.
Topics: Adult; Humans; Female; Adolescent; Middle Aged; Male; Quality of Life; Mental Health; Outpatients; Mental Disorders; Life Style; Cardiovascular Diseases
PubMed: 37342055
DOI: 10.1001/jamapsychiatry.2023.1566