Maternal and offspring pools of osteocalcin influence brain development and functions.

The powerful regulation of bone mass exerted by the brain suggests the existence of bone-derived signals modulating this regulation or other functions of the brain. We show here that the osteoblast-derived hormone osteocalcin crosses the blood-brain barrier, binds to neurons of the brainstem, midbrain, and hippocampus, enhances the synthesis of monoamine neurotransmitters, inhibits GABA synthesis, prevents anxiety and depression, and favors learning and memory independently of its metabolic functions. In addition to these postnatal functions, maternal osteocalcin crosses the placenta during pregnancy and prevents neuronal apoptosis before embryos synthesize this hormone. As a result, the severity of the neuroanatomical defects and learning and memory deficits of Osteocalcin(-/-) mice is determined by the maternal genotype, and delivering osteocalcin to pregnant Osteocalcin(-/-) mothers rescues these abnormalities in their Osteocalcin(-/-) progeny. This study reveals that the skeleton via osteocalcin influences cognition and contributes to the maternal influence on fetal brain development.

Harnessing large language models' zero-shot and few-shot learning capabilities for regulatory research.

Large language models (LLMs) are sophisticated AI-driven models trained on vast sources of natural language data. They are adept at generating responses that closely mimic human conversational patterns. One of the most notable examples is OpenAI's ChatGPT, which has been extensively used across diverse sectors. Despite their flexibility, a significant challenge arises as most users must transmit their data to the servers of companies operating these models. Utilizing ChatGPT or similar models online may inadvertently expose sensitive information to the risk of data breaches. Therefore, implementing LLMs that are open source and smaller in scale within a secure local network becomes a crucial step for organizations where ensuring data privacy and protection has the highest priority, such as regulatory agencies. As a feasibility evaluation, we implemented a series of open-source LLMs within a regulatory agency's local network and assessed their performance on specific tasks involving extracting relevant clinical pharmacology information from regulatory drug labels. Our research shows that some models work well in the context of few- or zero-shot learning, achieving performance comparable, or even better than, neural network models that needed thousands of training samples. One of the models was selected to address a real-world issue of finding intrinsic factors that affect drugs' clinical exposure without any training or fine-tuning. In a dataset of over 700 000 sentences, the model showed a 78.5% accuracy rate. Our work pointed to the possibility of implementing open-source LLMs within a secure local network and using these models to perform various natural language processing tasks when large numbers of training examples are unavailable.

Deep learning-enabled natural language processing to identify directional pharmacokinetic drug-drug interactions.

BACKGROUND: During drug development, it is essential to gather information about the change of clinical exposure of a drug (object) due to the pharmacokinetic (PK) drug-drug interactions (DDIs) with another drug (precipitant). While many natural language processing (NLP) methods for DDI have been published, most were designed to evaluate if (and what kind of) DDI relationships exist in the text, without identifying the direction of DDI (object vs. precipitant drug). Here we present a method for the automatic identification of the directionality of a PK DDI from literature or drug labels. METHODS: We reannotated the Text Analysis Conference (TAC) DDI track 2019 corpus for identifying the direction of a PK DDI and evaluated the performance of a fine-tuned BioBERT model on this task by following the training and validation steps prespecified by TAC. RESULTS: This initial attempt showed the model achieved an F-score of 0.82 in identifying sentences as containing PK DDI and an F-score of 0.97 in identifying object versus precipitant drugs in those sentences. DISCUSSION AND CONCLUSION: Despite a growing list of NLP methods for DDI extraction, most of them use a common set of corpora to perform general purpose tasks (e.g., classifying a sentence into one of several fixed DDI categories). There is a lack of coordination between the drug development and biomedical informatics method development community to develop corpora and methods to perform specific tasks (e.g., extract clinical exposure changes due to PK DDI). We hope that our effort can encourage such a coordination so that more "fit for purpose" NLP methods could be developed and used to facilitate the drug development process.

Leukocyte inflammatory phenotype and function in migraine patients compared with matched non-migraine volunteers: a pilot study.

BACKGROUND: Migraine is a neurological condition characterized by chronic inflammation. However, not much is known about the potential role of peripheral blood immune cells in the pathophysiology of migraine. METHODS: We investigated the status of peripheral blood immune cells of 15 adults with frequent episodic or chronic migraine recruited chronologically from a randomized clinical trial (RCT) on Nutrition for Migraine (NCCIH 5R01AT007813-05) and 15 non-migraine, healthy volunteers (control) matched by age, gender, and Body Mass Index (BMI). Continuous variables were presented as means ± standard deviationas well as medians, and comparisons between patients and healthy volunteers were performed with non-parametric Wilcoxon signed rank tests. Statistical analysis was performed using Stata (StataCorp. 2019. Stata Statistical Software). Fluorescence-Activated Cell Sorting (FACS) data were processed using FlowJo software (Ashland, OR: Becton, Dickenson and Company; 2019). RESULTS: We observed that migraineurs had a significantly lower percentage of non-classical monocytes (CD14+CD16++) in blood circulation, compared to the control group. In addition, Migraineurs also showed a significantly lower percentage of blood CD3+CD4+ helper T cells and CD4+CD25+ regulatory T cells, compared to controls. Differences in leukocyte surface markers between chronic migraine patients and their matched controls were more prominent than those between episodic migraine patients and their matched controls. CONCLUSIONS: Our results suggest that migraine is associated with dysregulated peripheral immune homeostasis and that inflammation and autoimmunity may play a role in its pathophysiology.

Symmetric bis-benzimidazoles as DNA minor groove-binding agents with anti-tumour and antibacterial activity, and the evolution of the drug ridinilazole for the treatment of Clostridium difficile infections.

We report the synthesis of a range of symmetrical bis-benzimidazoles (BBZ) which possess anticancer and antibacterial activities. One of these BBZs has specific activity against Clostridium difficile and is currently in a phase 3 clinical evaluation as the drug ridinilazole. X-ray and computer modelling studies showed that BBZs typically exhibit high specificity for oligonucleotide sequences that occur in the minor groove of DNA.

Ultrasound-Guided Adductor Canal Block Versus Intraoperative Transarticular Saphenous Nerve Block: A Retrospective Analysis.

BACKGROUND: The ultrasound-guided adductor canal block (High-ACB) is an effective option for pain control in total knee arthroplasty (TKA), but its use can add substantial cost and preparatory time to a TKA procedure. An intraoperative adductor canal block (Low-ACB) performed by the operative surgeon has been described as an alternative. The hypothesis of this study is that the Low-ACB would achieve noninferior pain control and opioid utilization postoperatively when compared to the High-ACB. METHODS: This is a retrospective study of a prospectively maintained database comparing the High-ACB vs the Low-ACB. The primary outcome measure was morphine milligram equivalents consumed. Secondary outcome measures included Visual Analog Scale pain scores, postoperative outcomes (Patient-Reported Outcome Measurement Information System, Knee Injury and Osteoarthritis Outcome Score, knee range of motion), length of stay, postoperative speed of mobilization, and complications related to the type of block. RESULTS: There were 139 patients in the study. There was lower opioid use in the first 24 hours in the Low-ACB compared to the High-ACB group respectively (26.3 vs 30, P = .29) but this did not reach statistical significance. There was a statistically significant difference in Visual Analog Scale score on postoperative day 1 in the Low-ACB vs High-ACB groups respectively (4.6 vs 3.7, P = .02) but this did not reach the level of clinical significance. There was no statistical difference in the Patient-Reported Outcome Measurement Information System, Knee Injury and Osteoarthritis Outcome Score, or postoperative range of motion. There were no block-related complications in either group. CONCLUSION: The Low-ACB is a safe, effective, and cost-saving alternative to the traditional High-ACB for pain control in TKA.

Brain cytochrome-c-oxidase as a marker of mitochondrial function: A pilot study in major depression using NIRS.

BACKGROUND: Brain mitochondrial dysfunction is implicated in the pathophysiology of mood disorders. Brain cytochrome-c-oxidase (COX) activity is associated with the mitochondrial function. Near-infrared spectroscopy (NIRS) noninvasively measures oxidized COX (oxCOX) and tissue oxygenation index (TOI) reflecting cerebral blood flow and oxygenation. METHODS: oxCOX and TOI were assessed in prefrontal cortex (Fp1/2, Brodmann area 10) in patients in a major depressive episode (N = 13) with major depressive disorder (MDD; N = 7) and bipolar disorder (BD; N = 6) compared with the controls (N = 10). One patient with MDD and all the patients with BD were taking medications. Computational modeling estimated oxCOX and TOI related indices of mitochondrial function and cerebral blood flow, respectively. RESULTS: oxCOX was lower in patients than controls (p = .014) correlating inversely with depression severity (r = -.72; p = .006), driven primarily by lower oxCOX in BD compared with the controls. Computationally modeled mitochondrial parameters of the electron transport chain, such as the nicotinamide adenine dinucleotide ratio (NAD+ /NADH; p = .001) and the proton leak rate across the inner mitochondrial membrane (klk2 ; p = .008), were also lower in patients and correlated inversely with depression severity. No such effects were found for TOI. CONCLUSIONS: In this pilot study, oxCOX and related mitochondrial parameters assessed by NIRS indicate an abnormal cerebral metabolic state in mood disorders proportional to depression severity, potentially providing a biomarker of antidepressant effect. Because the effect was driven by the medicated BD group, findings need to be evaluated in a larger, medication-free population.

CORRIGENDUM: The expanding clinical phenotype of Bosch-Boonstra-Schaaf optic atrophy syndrome: 20 new cases and possible genotype-phenotype correlations.

This corrects the article DOI: 10.1038/gim.2016.18.

The expanding clinical phenotype of Bosch-Boonstra-Schaaf optic atrophy syndrome: 20 new cases and possible genotype-phenotype correlations.

PURPOSE: Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS) is an autosomal-dominant disorder characterized by optic atrophy and intellectual disability caused by loss-of-function mutations in NR2F1. We report 20 new individuals with BBSOAS, exploring the spectrum of clinical phenotypes and assessing potential genotype-phenotype correlations. METHODS: Clinical features of individuals with pathogenic NR2F1 variants were evaluated by review of medical records. The functional relevance of coding nonsynonymous NR2F1 variants was assessed with a luciferase assay measuring the impact on transcriptional activity. The effects of two start codon variants on protein expression were evaluated by western blot analysis. RESULTS: We recruited 20 individuals with novel pathogenic NR2F1 variants (seven missense variants, five translation initiation variants, two frameshifting insertions/deletions, one nonframeshifting insertion/deletion, and five whole-gene deletions). All the missense variants were found to impair transcriptional activity. In addition to visual and cognitive deficits, individuals with BBSOAS manifested hypotonia (75%), seizures (40%), autism spectrum disorder (35%), oromotor dysfunction (60%), thinning of the corpus callosum (53%), and hearing defects (20%). CONCLUSION: BBSOAS encompasses a broad range of clinical phenotypes. Functional studies help determine the severity of novel NR2F1 variants. Some genotype-phenotype correlations seem to exist, with missense mutations in the DNA-binding domain causing the most severe phenotypes.Genet Med 18 11, 1143-1150.

Superlinear composition-dependent photocurrent in CVD-grown monolayer MoS2(1-x)Se2x alloy devices.

Transition metal dichalcogenides (TMDs) have emerged as a new class of two-dimensional materials that are promising for electronics and photonics. To date, optoelectronic measurements in these materials have shown the conventional behavior expected from photoconductors such as a linear or sublinear dependence of the photocurrent on light intensity. Here, we report the observation of a new regime of operation where the photocurrent depends superlinearly on light intensity. We use spatially resolved photocurrent measurements on devices consisting of CVD-grown monolayers of TMD alloys spanning MoS2 to MoSe2 to show the photoconductive nature of the photoresponse, with the photocurrent dominated by recombination and field-induced carrier separation in the channel. Time-dependent photoconductivity measurements show the presence of persistent photoconductivity for the S-rich alloys, while photocurrent measurements at fixed wavelength for devices of different alloy compositions show a systematic decrease of the responsivity with increasing Se content associated with increased linearity of the current-voltage characteristics. A model based on the presence of different types of recombination centers is presented to explain the origin of the superlinear dependence on light intensity, which emerges when the nonequilibrium occupancy of initially empty fast recombination centers becomes comparable to that of slow recombination centers.

A pilot integrative genomics study of GABA and glutamate neurotransmitter systems in suicide, suicidal behavior, and major depressive disorder.

Gamma-amino butyric acid (GABA) and glutamate are the major inhibitory and excitatory neurotransmitters in the mammalian central nervous system, respectively, and have been associated with suicidal behavior and major depressive disorder (MDD). We examined the relationship between genotype, brain transcriptome, and MDD/suicide for 24 genes involved in GABAergic and glutamatergic signaling. In part 1 of the study, 119 candidate SNPs in 24 genes (4 transporters, 4 enzymes, and 16 receptors) were tested for associations with MDD and suicidal behavior in 276 live participants (86 nonfatal suicide attempters with MDD and 190 non-attempters of whom 70% had MDD) and 209 postmortem cases (121 suicide deaths of whom 62% had MDD and 88 sudden death from other causes of whom 11% had MDD) using logistic regression adjusting for sex and age. In part 2, RNA-seq was used to assay isoform-level expression in dorsolateral prefrontal cortex of 59 postmortem samples (21 with MDD and suicide, 9 MDD without suicide, and 29 sudden death non-suicides and no psychiatric illness) using robust regression adjusting for sex, age, and RIN score. In part 3, SNPs with subthreshold (uncorrected) significance levels below 0.05 for an association with suicidal behavior and/or MDD in part 1 were tested for eQTL effects in prefrontal cortex using the Brain eQTL Almanac (www.braineac.org). No SNPs or transcripts were significant after adjustment for multiple comparisons. However, a protein coding transcript (ENST00000414552) of the GABA A receptor, gamma 2 (GABRG2) had lower brain expression postmortem in suicide (P = 0.01) and evidence for association with suicide death (P = 0.03) in a SNP that may be an eQTL in prefrontal cortex (rs424740, P = 0.02). These preliminary results implicate GABRG2 in suicide and warrant further investigation and replication in larger samples.

De Novo variants in the KMT2A (MLL) gene causing atypical Wiedemann-Steiner syndrome in two unrelated individuals identified by clinical exome sequencing.

BACKGROUND: Wiedemann-Steiner Syndrome (WSS) is characterized by short stature, a variety of dysmorphic facial and skeletal features, characteristic hypertrichosis cubiti (excessive hair on the elbows), mild-to-moderate developmental delay and intellectual disability. [MIM#: 605130]. Here we report two unrelated children for whom clinical exome sequencing of parent-proband trios was performed at UCLA, resulting in a molecular diagnosis of WSS and atypical clinical presentation. CASE PRESENTATION: For patient 1, clinical features at 9 years of age included developmental delay, craniofacial abnormalities, and multiple minor anomalies. Patient 2 presented at 1 year of age with developmental delay, microphthalmia, partial 3-4 left hand syndactyly, and craniofacial abnormalities. A de novo missense c.4342T>C variant and a de novo splice site c.4086+G>A variant were identified in the KMT2A gene in patients 1 and 2, respectively. CONCLUSIONS: Based on the clinical and molecular findings, both patients appear to have novel presentations of WSS. As the hallmark hypertrichosis cubiti was not initially appreciated in either case, this syndrome was not suspected during the clinical evaluation. This report expands the phenotypic spectrum of the clinical phenotypes and KMT2A variants associated with WSS.

Mechanism-based organization of neural networks to emulate systems biology and pharmacology models.

Deep learning neural networks are often described as black boxes, as it is difficult to trace model outputs back to model inputs due to a lack of clarity over the internal mechanisms. This is even true for those neural networks designed to emulate mechanistic models, which simply learn a mapping between the inputs and outputs of mechanistic models, ignoring the underlying processes. Using a mechanistic model studying the pharmacological interaction between opioids and naloxone as a proof-of-concept example, we demonstrated that by reorganizing the neural networks' layers to mimic the structure of the mechanistic model, it is possible to achieve better training rates and prediction accuracy relative to the previously proposed black-box neural networks, while maintaining the interpretability of the mechanistic simulations. Our framework can be used to emulate mechanistic models in a large parameter space and offers an example on the utility of increasing the interpretability of deep learning networks.

Physiologically based modeling reveals different risk of respiratory depression after fentanyl overdose between adults and children.

Despite a rapid increase in pediatric mortality rate from prescription and illicit opioids, there is limited research on the dose-dependent impact of opioids on respiratory depression in children, the leading cause of opioid-associated death. In this article, we extend a previously developed translational model to cover pediatric populations by incorporating age-dependent pharmacokinetic, pharmacodynamic, and physiological changes compared to adults. Our model reproduced previous perioperative clinical findings that adults and children have similar risk of respiratory depression at the same plasma fentanyl concentration when specific endpoints (minute ventilation, CO2 tension in the blood) were used. However, our model points to a potential caveat that, in a perioperative setting, routine use of mechanical ventilation and supplemental oxygen maintained the blood and tissue oxygen partial pressures in patients and prevented the use of oxygen-related endpoints to evaluate the consequences of respiratory depression. In a community setting when such oxygenation procedures are not immediately available, our model suggests that the higher oxygen demand and reduced cerebrovascular reactivity could make children more susceptible to severe hypoxemia and brain hypoxia, even with the same plasma fentanyl concentration as adults. Our work indicates that when developing intervention strategies to protect children from opioid overdose in a community setting, these pediatric-specific factors may need to be considered.

Intranasal Naloxone Repeat Dosing Strategies and Fentanyl Overdose: A Simulation-Based Randomized Clinical Trial.

Importance: Questions have emerged as to whether standard intranasal naloxone dosing recommendations (ie, 1 dose with readministration every 2-3 minutes if needed) are adequate in the era of illicitly manufactured fentanyl and its derivatives (hereinafter, fentanyl). Objective: To compare naloxone plasma concentrations between different intranasal naloxone repeat dosing strategies and to estimate their effect on fentanyl overdose. Design, Setting, and Participants: This unblinded crossover randomized clinical trial was conducted with healthy participants in a clinical pharmacology unit (Spaulding Clinical Research, West Bend, Wisconsin) in March 2021. Inclusion criteria included age 18 to 55 years, nonsmoking status, and negative test results for the presence of alcohol or drugs of abuse. Data analysis was performed from October 2021 to May 2023. Intervention: Naloxone administered as 1 dose (4 mg/0.1 mL) at 0, 2.5, 5, and 7.5 minutes (test), 2 doses at 0 and 2.5 minutes (test), and 1 dose at 0 and 2.5 minutes (reference). Main Outcomes and Measures: The primary outcome was the first prespecified time with higher naloxone plasma concentration. The secondary outcome was estimated brain hypoxia time following simulated fentanyl overdoses using a physiologic pharmacokinetic-pharmacodynamic model. Naloxone concentrations were compared using paired tests at 3 prespecified times across the 3 groups, and simulation results were summarized using descriptive statistics. Results: This study included 21 participants, and 18 (86%) completed the trial. The median participant age was 34 years (IQR, 27-50 years), and slightly more than half of participants were men (11 [52%]). Compared with 1 naloxone dose at 0 and 2.5 minutes, 1 dose at 0, 2.5, 5, and 7.5 minutes significantly increased naloxone plasma concentration at 10 minutes (7.95 vs 4.42 ng/mL; geometric mean ratio, 1.95 [1-sided 97.8% CI, 1.28-∞]), whereas 2 doses at 0 and 2.5 minutes significantly increased the plasma concentration at 4.5 minutes (2.24 vs 1.23 ng/mL; geometric mean ratio, 1.98 [1-sided 97.8% CI, 1.03-∞]). No drug-related serious adverse events were reported. The median brain hypoxia time after a simulated fentanyl 2.97-mg intravenous bolus was 4.5 minutes (IQR, 2.1-∞ minutes) with 1 naloxone dose at 0 and 2.5 minutes, 4.5 minutes (IQR, 2.1-∞ minutes) with 1 naloxone dose at 0, 2.5, 5, and 7.5 minutes, and 3.7 minutes (IQR, 1.5-∞ minutes) with 2 naloxone doses at 0 and 2.5 minutes. Conclusions and Relevance: In this clinical trial with healthy participants, compared with 1 intranasal naloxone dose administered at 0 and 2.5 minutes, 1 dose at 0, 2.5, 5, and 7.5 minutes significantly increased naloxone plasma concentration at 10 minutes, whereas 2 doses at 0 and 2.5 minutes significantly increased naloxone plasma concentration at 4.5 minutes. Additional research is needed to determine optimal naloxone dosing in the community setting. Trial Registration: ClinicalTrials.gov Identifier: NCT04764630.

Natural products in cancer chemotherapy: past, present and future.

Natural products have been the mainstay of cancer chemotherapy for the past 30 years. However, the quickening pace of (aberrant) gene identification, and the new technologies of combinatorial chemistry and high-throughput screening, should provide access to a wide range of new, totally synthetic drugs. Will these new approaches sound the death knell for therapies based on natural products? In reality, natural products are likely to provide many of the lead structures, and these will be used as templates for the construction of novel compounds with enhanced biological properties.

Effect of Tibial Slope on Coronal Alignment in Total Knee Arthroplasty.

Malalignment of total knee arthroplasty (TKA) components affects function and survivorship. Common practice is to set coronal alignment prior to adjusting slope. With improper jig placement, adjustment of the slope may alter coronal alignment. The purpose of this study was to quantify the change in coronal alignment with increasing posterior tibial slope while comparing two methods of jig fixation. A prospective consecutive series of 100 patients underwent TKA using computer navigation. Fifty patients had the extramedullary cutting jig secured proximally with one pin and 50 patients had the jig secured proximally with two pins. Coronal alignment (CA) was recorded with each increasing degree of posterior slope (PS) from 0 to 7 degrees. Mean CA and change in CA were compared between cohorts. Utilizing one pin, osteotomies drifted into varus with an average change in CA of 0.34 degrees per degree PS. At 4 degrees PS, patients started to have >3 degrees of varus with 12.0% having >3 degrees of varus at 7 degrees PS. Utilizing two pins, osteotomies drifted into valgus with an average change of 0.04 degrees in CA per degree PS. No patients in the two-pin cohort fell outside 3 degrees varus/valgus CA. CA was significantly different at all degrees of PS between the cohorts. Changes in PS influenced CA making verification of tibial cut intraoperative critical. Use of >1 pin and computer navigation were beneficial to prevent coronal plane malalignment. This relationship may explain why computer navigation has been shown to improve alignment as well as survivorship and outcomes in some patients, especially those <65 years.

Comorbidity and healthcare utilization in patients with treatment resistant depression: A large-scale retrospective cohort analysis using electronic health records.

BACKGROUND: Medical comorbidity and healthcare utilization in patients with treatment resistant depression (TRD) is usually reported in convenience samples, making estimates unreliable. There is only limited large-scale clinical research on comorbidities and healthcare utilization in TRD patients. METHODS: Electronic Health Record data from over 3.3 million patients from the INSIGHT Clinical Research Network in New York City was used to define TRD as initiation of a third antidepressant regimen in a 12-month period among patients diagnosed with major depressive disorder (MDD). Age and sex matched TRD and non-TRD MDD patients were compared for anxiety disorder, 27 comorbid medical conditions, and healthcare utilization. RESULTS: Out of 30,218 individuals diagnosed with MDD, 15.2 % of patients met the criteria for TRD (n = 4605). Compared to MDD patients without TRD, the TRD patients had higher rates of anxiety disorder and physical comorbidities. They also had higher odds of ischemic heart disease (OR = 1.38), stroke/transient ischemic attack (OR = 1.57), chronic kidney diseases (OR = 1.53), arthritis (OR = 1.52), hip/pelvic fractures (OR = 2.14), and cancers (OR = 1.41). As compared to non-TRD MDD, TRD patients had higher rates of emergency room visits, and inpatient stays. In relation to patients without MDD, both TRD and non-TRD MDD patients had significantly higher levels of anxiety disorder and physical comorbidities. LIMITATIONS: The INSIGHT-CRN data lack information on depression severity and medication adherence. CONCLUSIONS: TRD patients compared to non-TRD MDD patients have a substantially higher prevalence of various psychiatric and medical comorbidities and higher health care utilization. These findings highlight the challenges of developing interventions and care coordination strategies to meet the complex clinical needs of TRD patients.