Facilitating pathway and network based analysis of RNA-Seq data with pathlinkR.

R package pathlinkR is designed to aid transcriptomic analyses by streamlining and simplifying the process of analyzing and interpreting differentially expressed genes derived from human RNA-Seq data. It provides an integrated approach to performing pathway enrichment and network-based analyses, while also producing publication-quality figures to summarize these results, allowing users to more efficiently interpret their findings and extract biological meaning from large amounts of data. pathlinkR is available to install from the software repository Bioconductor at https://bioconductor.org/packages/pathlinkR/, with support available through the Bioconductor forums. The code, example, and supporting data is available on the GitHub repository at https://github.com/hancockinformatics/pathlinkR, under the GPL-3.0 license, where users may report problems or make suggestions using GitHub's issue system.

DNA Methylation signatures underpinning blood neutrophil to lymphocyte ratio during first week of human life.

Understanding of newborn immune ontogeny in the first week of life will enable age-appropriate strategies for safeguarding vulnerable newborns against infectious diseases. Here we conducted an observational study exploring the immunological profile of infants longitudinally throughout their first week of life. Our Expanded Program on Immunization - Human Immunology Project Consortium (EPIC-HIPC) studies the epigenetic regulation of systemic immunity using small volumes of peripheral blood samples collected from West African neonates on days of life (DOL) 0, 1, 3, and 7. Genome-wide DNA methylation and single nucleotide polymorphism markers are examined alongside matched transcriptomic and flow cytometric data. Integrative analysis reveals that a core network of transcription factors mediates dynamic shifts in neutrophil-to-lymphocyte ratios (NLR), which are underpinned by cell-type specific methylation patterns in the two cell types. Genetic variants are associated with lower NLRs at birth, and healthy newborns with lower NLRs at birth are more likely to subsequently develop sepsis. These findings provide valuable insights into the early-life determinants of immune system development.

Candidate selective sweeps in US wheat populations.

Exploration of novel alleles from ex situ collection is still limited in modern plant breeding as these alleles exist in genetic backgrounds of landraces that are not adapted to modern production environments. The practice of backcross breeding results in preservation of the adapted background of elite parents but leaves little room for novel alleles from landraces to be incorporated. Selection of adaptation-associated linkage blocks instead of the entire adapted background may allow breeders to incorporate more of the landrace's genetic background and to observe and evaluate novel alleles. Important adaptation-associated linkage blocks would have been selected over multiple cycles of breeding and hence are likely to exhibit signatures of positive selection or selective sweeps. We conducted genome-wide scan for candidate selective sweeps (CSS) using Fst, Rsb, and xpEHH in state, regional, spring, winter, and market-class population pairs and reported 446 CSS in 19 population pairs over time and 1033 CSS in 44 population pairs across geography and class. Further validation of these CSS in specific breeding programs may lead to identification of sets of loci that can be selected to restore population-specific adaptation in pre-breeding germplasms.

Comparison of Four Body Composition Methods: Circumference Measurements, Eight-Point Bioelectrical Impedance Analysis up to 500 and 1000 kHz to Dual-Energy X-Ray Absorptiometry to Measure Body Fat Percentage.

INTRODUCTION: A comparison of body composition assessments using military circumferences to bioelectrical impedance analysis (BIA) and the reference standard dual-energy X-ray absorptiometry (DEXA) can gauge effectiveness of assessments. High-frequency (500 KHz) direct segmental multifrequency bioelectrical impedance analysis (DSM-BIA) accurately calculates total water mass and body fat% (BF%), but it is unknown whether higher frequencies (1,000 KHz) increase measurement accuracy. The purpose was to compare DSM-BIA 500, DSM-BIA 1000, the DoD Circumference Method (CM), and the reference-standard DEXA. MATERIALS AND METHODS: Design: Cross sectional, observational study. Participants/Setting: A total of 62 participants from the military healthcare system (n = 25 males, 38.8 ± 11.4 years, n = 37 females 43.7 ± 15.95 years) were measured in an outpatient clinic setting. Statistical Analysis: BF% was estimated via DEXA, DSM-BIA 500, DSM-BIA 1000, and CM to identify the relationship between methods using Pearson correlation, intraclass correlation coefficients (ICCs), and Bland-Altman plots. The study was approved by the IRB from Walter Reed National Military Medical Center at Bethesda and Concordia University Chicago. RESULTS: Circumference Method BF% was moderately correlated with DSM-BIA 500 (males r = 0.63, ICC = 0.76; females r = 0.77, ICC = 0.85), DSM-BIA 1000 (males r = 0.59, ICC = 0.74; females r = 0.77, ICC = 0.85), and DEXA (males r = 0.62, ICC = 0.62; females r = 0.73, ICC = 0.82). DSM-BIA 500 BF% was strongly correlated with DSM-BIA 1000 (males r = 0.99, ICC = 0.99; females r = 0.99, ICC = 0.99) and DEXA (males r = 0.93, ICC = 0.94; females r = 0.89, ICC = 0.89). Lastly, DSM-BIA 1000 BF% was also strongly correlated with DEXA (males r = 0.93, ICC = 0.94; females r = 0.84, ICC = 0.90) (P for each reported r < 0.01). Bland-Altman analysis confirmed an overall mean bias of -1.72% CM vs. DEXA in females, indicating the tendency of CM to underestimate BF% compared to DEXA limits of agreement from -14.24 to 10.8. There was an upward slope of the linear relationship between the bias and mean of the measures (Beta = 0.34, P = 0.01). In the full cohort, there was an overall mean bias of 1.14% of CM vs. DSM BIA 1000, with CM tending to overestimate BF% compared to DSM BIA 1000 with limits of agreement -11.13 to 13.41%. There is an upward slope line of the linear relationship between the bias and the mean of the measures (Beta = 0.17, P = .03). CONCLUSION: This study found that CM BF% was moderately correlated with DSM-BIA 500 kHz, DSM-BIA 1,000 kHz BIA, and DEXA. Both DSM-BIA 500 and DSM-BIA 1,000 kHz strongly correlated well with DEXA implying that there was no further increase in correlation with increased frequency. Additionally, there was proportional bias in BF% in the female group between CM and DEXA and in the total group between CM and DSM BIA 1000.

Development and Validation of a Bayesian Network Predicting Intubation Following Hospital Arrival Among Injured Children.

BACKGROUND: Inadequate airway management can contribute to preventable trauma deaths. Current machine learning tools for predicting intubation in trauma are limited to adult populations and include predictors not readily available at the time of patient arrival. We developed a Bayesian network to predict intubation in injured children and adolescents using observable data available upon or immediately after patient arrival. METHODS: We obtained patient demographic, injury, resuscitation, and transportation characteristics from trauma registries from four American College of Surgeons-verified level 1 pediatric trauma centers from January 2010 through December 2021. We trained and validated a Bayesian network to predict emergent intubation after pediatric injury. We evaluated model performance using the area under the receiver operating and calibration curves. RESULTS: The final model, TITAN (Timing of Intubation in Trauma Analysis Network), incorporated five factors: Glasgow Coma Scale, mechanism of injury, injury type (e.g., penetrating, blunt), systolic blood pressure, and age. The model achieved an area under the receiver operating characteristic curve of 0.83 (95% CI 0.80, 0.85) and had a calibration curve slope of 0.98 (95% CI 0.67, 1.29). TITAN had high specificity (98%), negative predictive value (97%), and accuracy (96%) at a binary probability threshold of 22.6%. CONCLUSION: The TITAN Bayesian network predicts the risk of intubation in pediatric trauma patients using five factors that are observable early in trauma resuscitation. Prospective validation of the model performance with patient outcomes is needed to assess real-life application benefits and risks. LEVEL OF EVIDENCE: Prognostic and Epidemiological, Level III.

Synaptic imbalance and increased inhibition impair motor function in SMA.

Movement is executed through the balanced action of excitatory and inhibitory neurotransmission in motor circuits of the spinal cord. Short-term perturbations in one of the two types of transmission are counteracted by homeostatic changes of the opposing type. Prolonged failure to balance excitatory and inhibitory drive results in dysfunction at the single neuron, as well as neuronal network levels. However, whether dysfunction in one or both types of neurotransmission leads to pathogenicity in neurodegenerative diseases characterized by select synaptic deficits is not known. Here, we used mouse genetics, functional assays, morphological methods, and viral-mediated approaches to uncover the pathogenic contribution of unbalanced excitation-inhibition neurotransmission in a mouse model of spinal muscular atrophy (SMA). We show that vulnerable motor circuits in the SMA spinal cord fail to respond homeostatically to the reduction of excitatory drive and instead increase inhibition. This imposes an excessive burden on motor neurons and further restricts their recruitment to activate muscle contraction. Importantly, genetic or pharmacological reduction of inhibitory synaptic drive improves neuronal function and provides behavioural benefit in SMA mice. Our findings identify the lack of excitation-inhibition homeostasis as a major maladaptive mechanism in SMA, by which the combined effects of reduced excitation and increased inhibition diminish the capacity of premotor commands to recruit motor neurons and elicit muscle contractions.

Comparison of venturi and peristaltic based phacoemulsification efficiency in routine femtosecond laser cataract surgery.

OBJECTIVE: To compare the efficiency of venturi and peristaltic pump phacoemulsification systems in patients undergoing routine laser cataract surgery. DESIGN: Single center, nonrandomized clinical study. PARTICIPANTS: The study compared consecutive eyes with moderate nuclear sclerosis undergoing routine laser cataract surgery at the Outpatient Eye Center, Mercy Health System, Springfield, MO, USA. METHODS: Each surgery used the same femtosecond laser settings. Surgeries were performed with either a venturi or peristaltic vacuum system by a single surgeon (WJS). The EFX, percent power, ultrasound time (UST), the total time that the phaco tip was in the eye (phaco tip in/out time, PIOT), and the surgery time (speculum in/out time) were recorded. Exclusions and intraoperative complications were also analyzed. RESULTS: 995 eyes were included in the study. The EFX in the venturi eyes (1.7 ± 1.3; n = 521) compared to peristaltic eyes (2.1 ± 1.4; n = 474) was lower (p < 0.0001). Similarly, the UST in the eyes performed with the venturi system versus the peristaltic system was reduced (32.4 ± 22.3 s vs 40.7± 25.7 s; p < 0.0001). The PIOT in the venturi group compared to the peristaltic group was less (71.1 ± 31.1 sec vs 79.1 ± 36.1 s; p = 0.0002). The case time (speculum in/out time) was lower for the venturi eyes (307.2 ± 68.8 s vs. 311.6 ± 53.6 s; p = 0.268). CONCLUSION: In eyes undergoing routine laser cataract surgery, the use of the venturi pump system was more efficient compared to the peristaltic pump system based on energy use and time, and there was no significant difference in complications.

Model of a striatal circuit exploring biological mechanisms underlying decision-making during normal and disordered states.

Decision-making requires continuous adaptation to internal and external contexts. Changes in decision-making are reliable transdiagnostic symptoms of neuropsychiatric disorders. We created a computational model demonstrating how the striosome compartment of the striatum constructs a mathematical space for decision-making computations depending on context, and how the matrix compartment defines action value depending on the space. The model explains multiple experimental results and unifies other theories like reward prediction error, roles of the direct versus indirect pathways, and roles of the striosome versus matrix, under one framework. We also found, through new analyses, that striosome and matrix neurons increase their synchrony during difficult tasks, caused by a necessary increase in dimensionality of the space. The model makes testable predictions about individual differences in disorder susceptibility, decision-making symptoms shared among neuropsychiatric disorders, and differences in neuropsychiatric disorder symptom presentation. The model reframes the role of the striosomal circuit in neuroeconomic and disorder-affected decision-making. Highlights: Striosomes prioritize decision-related data used by matrix to set action values. Striosomes and matrix have different roles in the direct and indirect pathways. Abnormal information organization/valuation alters disorder presentation. Variance in data prioritization may explain individual differences in disorders. eTOC: Beck et al. developed a computational model of how a striatal circuit functions during decision-making. The model unifies and extends theories about the direct versus indirect pathways. It further suggests how aberrant circuit function underlies decision-making phenomena observed in neuropsychiatric disorders.

Improving the diagnostic value of lineup rejections.

Erroneous eyewitness identification evidence is likely the leading cause of wrongful convictions. To minimize this error, scientists recommend collecting confidence. Research shows that eyewitness confidence and accuracy are strongly related when an eyewitness identifies someone from an initial and properly administered lineup. However, confidence is far less informative of accuracy when an eyewitness identifies no one and rejects the lineup instead. In this study, I aimed to improve the confidence-accuracy relationship for lineup rejections in two ways. First, I aimed to find the lineup that yields the strongest confidence-accuracy relationship for lineup rejections by comparing the standard, simultaneous procedure used by police worldwide to the novel "reveal" procedure designed by scientists to boost accuracy. Second, I aimed to find the best method for collecting confidence. To achieve this secondary aim, I made use of machine-learning techniques to compare confidence expressed in words to numeric confidence ratings. First, I find a significantly stronger confidence-accuracy relationship for lineup rejections in the reveal than in the standard procedure regardless of the method used to collect confidence. Second, I find that confidence expressed in words captures unique diagnostic information about the likely accuracy of a lineup rejection separate from the diagnostic information captured by numeric confidence ratings. These results inform models of recognition memory and may improve the criminal-legal system by increasing the diagnostic value of a lineup rejection.

Distinct populations suppress or escalate intake of cocaine paired with aversive quinine.

Background: Only a subset of individuals who encounter drugs of abuse become habitual users. Aversive subjective effects like coughing and unpleasant taste are predictors for continued use. While several preclinical studies have explored self-administration involving aversive cues, none have simultaneously introduced aversion with the initial drug self-administration. We aimed to develop a clinically relevant model by pairing intravenous cocaine with intraoral quinine self-administration from the outset and investigating whether repeated exposure to an aversive stimulus would alter its hedonic value under laboratory conditions. Methods: Twenty-seven male and female Sprague Dawley rats self-administered intravenous/intraoral (cocaine/quinine) for 2 hr/day over 14 days. This was followed by a 1-day quinine-only extinction session, a 3-day return to self-administration, and an intraoral infusion session to assess quinine taste reactivity (TR). Results: We identified three distinct groups. The first self-administered very little cocaine, while the second sharply escalated cocaine intake. Both groups had similar aversive TR to quinine, suggesting that the escalating group did not habituate to the aversive cue but pursued drug despite it. We also identified a third group with high initial intake that decreased over time. This decrease predicted high aversive TR, and we argue this group may represent individuals who "overindulge" on their first use and subsequently find self-administration to be aversive. Conclusions: Our novel model mimics real-world variability in initial interactions with drugs of abuse and yields three distinct groups that differ in self-administration patterns and aversive cue valuation.

RECORD, a high-throughput, customizable system that unveils behavioral strategies leveraged by rodents during foraging-like decision-making.

Translational studies benefit from experimental designs where laboratory organisms use human-relevant behaviors. One such behavior is decision-making, however studying complex decision-making in rodents is labor-intensive and typically restricted to two levels of cost/reward. We design a fully automated, inexpensive, high-throughput framework to study decision-making across multiple levels of rewards and costs: the REward-COst in Rodent Decision-making (RECORD) system. RECORD integrates three components: 1) 3D-printed arenas, 2) custom electronic hardware, and 3) software. We validated four behavioral protocols without employing any food or water restriction, highlighting the versatility of our system. RECORD data exposes heterogeneity in decision-making both within and across individuals that is quantifiably constrained. Using oxycodone self-administration and alcohol-consumption as test cases, we reveal how analytic approaches that incorporate behavioral heterogeneity are sensitive to detecting perturbations in decision-making. RECORD is a powerful approach to studying decision-making in rodents, with features that facilitate translational studies of decision-making in psychiatric disorders.

Local FK506 delivery induces osteogenesis in rat bone defect and rabbit spine fusion models.

Bone grafting procedures are commonly used for the repair, regeneration, and fusion of bones in a wide range of orthopaedic surgeries, including large bone defects and spine fusion procedures. Autografts are the clinical gold standard, though recombinant human bone morphogenetic proteins (rhBMPs) are often used, particularly in difficult clinical situations. However, treatment with rhBMPs can have off-target effects and increase surgical costs, adding to patients' already high economic and mental burden. Recent studies have identified that FDA-approved immunosuppressant drug, FK506 (Tacrolimus), can also activate the BMP pathway by binding to its inhibitors. This study tested the hypothesis that FK506, as a standalone treatment, could induce osteogenic differentiation of human mesenchymal stromal cells (hMSCs), as well as functional bone formation in a rat segmental bone defect model and rabbit spinal fusion model. FK506 enhanced osteogenic differentiation and mineralization of hMSCs in vitro. Standalone treatment with FK506 delivered on a collagen sponge produced consistent bone bridging of a critically sized rat femoral defect with functional mechanical properties comparable to naïve bone. In a rabbit single level posterolateral spine fusion model, treatment with FK506 delivered on a collagen sponge successfully fused the L5-L6 vertebrae at rates comparable to rhBMP-2 treatment. These data demonstrate the ability of FK506 to induce bone formation in human cells and two challenging in vivo models, and indicate FK506 can be utilized to treat a variety of spine disorders.

The thin red line: Blood planning factors and the enduring need for a robust military blood system to support combat operations.

ABSTRACT: Battlefield lessons learned are forgotten; the current name for this is the Walker Dip. Blood transfusion and the need for a Department of Defense Blood Program are lessons that have cycled through being learned during wartime, forgotten, and then relearned during the next war. The military will always need a blood program to support combat and contingency operations. Also, blood supply to the battlefield has planning factors that have been consistent over a century. In 2024, it is imperative that we codify these lessons learned. The linchpins of modern combat casualty care are optimal prehospital care, early whole blood transfusion, and forward surgical care. This current opinion comprised of authors from all three military Services, the Joint Trauma System, the Armed Services Blood Program, blood SMEs and the CCC Research Program discuss two vital necessities for a successful military trauma system: (1) the need for an Armed Services Blood Program and (2) Planning factors for current and future deployed military ere is no effective care for wounded soldiers, and by extension there is no effective military medicine.

Feeling the future of eyewitness research.

For decades, eyewitness memory research has had the worthy goal of minimizing the chances that an innocent suspect is falsely identified. However, this is not the only goal. Partial receiver operating characteristic (ROC) curves provide a way to identify lineup procedures that keep the false alarm rate low while also maximizing the hit rate. Recently, there have been attempts to extend the ROC curve into high false alarm rate regions that fair lineups are intentionally designed to avoid. These new full ROCs could provide a way for the police to circumvent the protections offered by fillers in a fair lineup. Moreover, these attempts to extend the ROC curve are not based on a mathematically coherent model of latent diagnostic signals. In this article, we empirically demonstrate how this lack of a solid foundation can lead to dubious conclusions, such as eyewitnesses possessing precognition and being able to reliably identify the person they will see commit a crime in the future.

Polymerase theta is a synthetic lethal target for killing Epstein-Barr virus lymphomas.

Treatment options for Epstein-Barr virus (EBV)-cancers are limited, underscoring the need for new therapeutic approaches. We have previously shown that EBV-transformed cells and cancers lack homologous recombination (HR) repair, a prominent error-free pathway that repairs double-stranded DNA breaks; instead, EBV-transformed cells demonstrate genome-wide scars of the error-prone microhomology-mediated end joining (MMEJ) repair pathway. This suggests that EBV-cancers are vulnerable to synthetic lethal therapeutic approaches that target MMEJ repair. Indeed, we have previously found that targeting PARP, an enzyme that contributes to MMEJ, results in the death of EBV-lymphoma cells. With the emergence of clinical resistance to PARP inhibitors and the recent discovery of inhibitors of Polymerase theta (POLθ), the polymerase essential for MMEJ, we investigated the role of POLθ in EBV-lymphoma cells. We report that EBV-transformed cell lines, EBV-lymphoma cell lines, and EBV-lymphomas in AIDS patients demonstrate greater abundance of POLθ, driven by the EBV protein EBNA1, compared to EBV-uninfected primary lymphocytes and EBV-negative lymphomas from AIDS patients (a group that also abundantly expresses POLθ). We also find POLθ enriched at cellular DNA replication forks and exposure to the POLθ inhibitor Novobiocin impedes replication fork progress, impairs MMEJ-mediated repair of DNA double-stranded breaks, and kills EBV-lymphoma cells. Notably, cell killing is not due to Novobiocin-induced activation of the lytic/replicative phase of EBV. These findings support a role for POLθ not just in DNA repair but also DNA replication and as a therapeutic target in EBV-lymphomas and potentially other EBV-cancers as EBNA1 is expressed in all EBV-cancers.IMPORTANCEEpstein-Barr virus (EBV) contributes to ~2% of the global cancer burden. With a recent estimate of >200,000 deaths a year, identifying molecular vulnerabilities will be key to the management of these frequently aggressive and treatment-resistant cancers. Building on our earlier work demonstrating reliance of EBV-cancers on microhomology-mediated end-joining repair, we now report that EBV lymphomas and transformed B cell lines abundantly express the MMEJ enzyme POLθ that likely protects cellular replication forks and repairs replication-related cellular DNA breaks. Importantly also, we show that a newly identified POLθ inhibitor kills EBV-cancer cells, revealing a novel strategy to block DNA replication and repair of these aggressive cancers.

A microfluidic approach to study variations in Chlamydomonas reinhardtii alkaline phosphatase activity in response to phosphate availability.

Algal growth depends strongly on phosphorus (P) as a key nutrient, underscoring the significance of monitoring P levels. Algal species display a sensitive response to fluctuations in P availability, notably through the expression of alkaline phosphatase (AP) when challenged with P-depletion. As such, alkaline phosphatase activity (APA) serves as a valuable metric for P availability, offering insights into how algae utilize and fix available P resources. However, current APA quantification methods lack single cell resolution, while also being time- and reagent consuming. Microfluidics offers a promising cost-effective solution to these limitations, providing a platform for precise single-cell analysis. In this study, a trap-based microfluidic device was integrated with a commercially available AP live stain to study the single cell APA response of a model algae strain, Chlamydomonas reinhardtii, when exposed to different exogenous P levels. A three-step culture-starve-spike process was used to induce APA in cells cultured under two different basal P levels (1 and 21 mM). When challenged with different spiked P levels (ranging from 0.1-41 mM), C. reinhardtii cells demonstrated a highly heterogeneous APA response. Two-way ANOVA confirmed that this response is influenced by both spiked and basal P levels. Utilizing an unsupervised machine learning approach (HDBSCAN), distinct subpopulations of C. reinhardtii cells were identified exhibiting varying levels of APA at the single-cell level. These subpopulations encompass significant groups of individual cells with either notably high or low APA, contributing to the overall behavior of the cohorts. Considerable intrapopulation differences in APA were observed across cohorts with similar average behavior. For instance, while some cohorts exhibited a concentrated distribution around the overall average APA, others displayed subpopulations dispersed across a wider range of APA levels. This underscores the potential bias introduced by analyzing a small number of cells in bulk, which may skew results by overrepresenting extreme behavioral subpopulations. The findings if this study highlight the need for analytical approaches that account for single cell heterogeneity in APA and demonstrate the utility of microfluidics as a well-suited means for such investigations. This study illuminates the complexities of APA regulation at the single cell level, providing crucial insights that advance our understanding of algal phosphorus metabolism and environmental responses.

Perinatal substance use disorder: Examining the impact on adverse pregnancy outcomes.

Objective: Substance use disorder is a growing concern in the USA, especially among pregnant women. This study was undertaken to assess the impact of substance use disorder on adverse pregnancy outcomes using a nationwide sample of inpatient pregnancy hospitalizations in the USA, and to elucidate the influence on each type of adverse pregnancy outcome. Study design: A cross-sectional analysis of inpatient pregnancy hospitalizations in the USA from the Healthcare Cost and Utilization Project National Inpatient Sample from 2016 to 2020 was conducted. International Classification of Diseases - 10th revision and diagnosis-related group codes were used to identify inpatient pregnancy-related delivery hospitalizations with a substance use disorder and/or adverse pregnancy outcomes. Propensity score matching and multiple logistic regression analyses were undertaken to predict the likelihood of adverse pregnancy outcomes among pregnancy hospitalizations with and without substance use disorder. Subgroup analyses were performed to estimate the impact of substance use disorder on each adverse pregnancy outcome. Results: From 3,238,558 hospitalizations, the prevalence of adverse pregnancy outcomes was substantially higher among pregnancy hospitalizations with substance use disorder (35.6 %) compared with pregnancy hospitalizations without substance use disorder (25.1 %, p < 0.001). After matching and model adjustment for sociodemographic covariates, substance use disorder was identified as an independent predictor of adverse pregnancy outcomes [adjusted odds ratio (aOR) 1.47, 95 % confidence interval (CI) 1.45-1.49]. In subgroup analyses based on type of adverse pregnancy outcome, the greatest exposure risks were fetal growth restriction (aOR 1.96, 95 % CI 1.91-2.01), antepartum hemorrhage (aOR 1.79, 95 % CI 1.73-1.85) and preterm birth (aOR 1.65, 95 % CI 1.62-1.68). Conclusion: Patients with substance use disorder are at higher risk of adverse pregnancy outcomes, particularly fetal growth restriction, antepartum hemorrhage and preterm birth.

Moral injury, race-related stress and post-traumatic stress disorder in a trauma-exposed Black population.

BACKGROUND: Race-related stress (RRS) is an unrecognized source of moral injury (MI)-or the emotional and/or spiritual suffering that may emerge after exposure to events that violate deeply held beliefs. Additionally, MI has not been explored as a mechanism of risk for post-traumatic stress disorder (PTSD) in trauma-exposed civilians. We examined relations among exposure to potentially morally injurious events (moral injury exposure, MIE), related distress (moral injury distress, MID), and RRS in Black Americans. Potential indirect associations between RRS and PTSD symptoms via MID were also examined. METHODS: Black Americans (n = 228; 90.4% female; Mage = 31.6 years. SDage = 12.8 years) recruited from an ongoing study of trauma completed measures assessing civilian MIE and MID, RRS, and PTSD. Bivariate correlations were conducted with MIE and MID, and mediation analysis with MID, to examine the role of MI in the relationship between RRS and PTSD symptom severity. RESULTS: MIE was significantly correlated with cultural (r = 0.27), individual (r = 0.29), and institutional (r = 0.25) RRS; MID also correlated with cultural (r = 0.31), individual (r = 0.31), and institutional (r = 0.26) RRS (ps < 0.001). We found an indirect effect of RRS on PTSD symptoms via MID (ß = 0.10, p < 0.005). CONCLUSIONS: All types of RRS were associated with facets of MI, which mediated the relationship between RRS and current PTSD symptoms. MI may be a potential mechanism through which RRS increases the risk for PTSD in Black individuals.

Local FK506 delivery induces osteogenesis in in vivo rat bone defect and rabbit spine fusion models.

Bone grafting procedures are commonly used for the repair, regeneration, and fusion of bones in in a wide range of orthopaedic surgeries, including large bone defects and spine fusion procedures. Autografts are the clinical gold standard, though recombinant human bone morphogenetic proteins (rhBMPs) are often used, particularly in difficult clinical situations. However, treatment with rhBMPs can have off-target effects and significantly increase surgical costs, adding to patients' already high economic and mental burden. Recent studies have identified that FDA-approved immunosuppressant drug, FK506 (Tacrolimus), can also activate the BMP pathway by binding to its inhibitors. This study tested the hypothesis that FK506, as a standalone treatment, could induce osteogenic differentiation of human mesenchymal stromal cells (hMSCs), as well as functional bone formation in a rat segmental bone defect model and rabbit spinal fusion model. FK506 potentiated the effect of low dose BMP-2 to enhance osteogenic differentiation and mineralization of hMSCs in vitro. Standalone treatment with FK506 delivered on a collagen sponge, produced consistent bone bridging of a rat critically-sized femoral defect with functional mechanical properties comparable to naïve bone. In a rabbit single level posterolateral spine fusion model, treatment with FK506 delivered on a collagen sponge successfully fused the L5-L6 vertebrae at rates comparable to rhBMP-2 treatment. These data demonstrate the ability of FK506 to induce bone formation in human cells and two challenging in vivo models, and indicate FK506 can be utilized either as a standalone treatment or in conjunction with rhBMP to treat a variety of spine disorders.