T cells and macrophages jointly modulate osteogenesis of mesenchymal stromal cells.

Approximately 5%-10% of fractures go on to delayed healing and nonunion, posing significant clinical, economic, and social challenges. Current treatment methods involving open bone harvesting and grafting are associated with considerable pain and potential morbidity at the donor site. Hence, there is growing interest in minimally invasive approaches such as bone marrow aspirate concentrate (BMAC), which contains mesenchymal stromal cells (MSCs), macrophages (Mφ), and T cells. However, the use of cultured or activated cells for treatment is not yet FDA-approved in the United States, necessitating further exploration of optimal cell types and proportions for effective bone formation. As our understanding of osteoimmunology advances, it has become apparent that factors from anti-inflammatory Mφ (M2) promote bone formation by MSCs. Additionally, M2 Mφ promote T helper 2 (Th2) cells and Treg cells, both of which enhance bone formation. In this study, we investigated the interactions among MSCs, Mφ, and T cells in bone formation and explored the potential of subsets of BMAC. Coculture experiments were conducted using primary MSCs, Mφ, and CD4+ T cells at specific ratios. Our results indicate that nonactivated T cells had no direct influence on osteogenesis by MSCs, while coculturing MSCs with Mφ and T cells at a ratio of 1:5:10 positively impacted bone formation. Furthermore, higher numbers of T cells led to increased M2 polarization and a higher proportion of Th2 cells in the early stages of coculture. These findings suggest the potential for enhancing bone formation by adjusting immune and mesenchymal cell ratios in BMAC. By understanding the interactions and effects of immune cells on bone formation, we can develop more effective strategies and protocols for treating bone defects and nonunions. Further studies are needed to investigate these interactions in vivo and explore additional factors influencing MSC-based therapies.

Slowing lung deflation by increasing the expiratory resistance enhances FRC in preterm rabbits.

BACKGROUND: As very preterm infants have surfactant-deficient and highly incompliant lungs, slowing lung deflation during expiration might help preserve functional residual capacity(FRC) during lung aeration. In this study, we investigated the effect of expiratory resistance(Re) on lung aeration during positive pressure ventilation in preterm rabbits immediately after birth. METHODS: Preterm rabbit pups were delivered at 29 days gestation, mechanically ventilated from birth and simultaneously imaged to measure lung aeration using phase-contrast X-ray. Re was varied by altering the length (0, 60 or 1000 mm) of the expiratory circuit. RESULTS: Increasing Re led to a decrease in lung deflation rates and both peak expiratory flows and flow rates at mid-deflation. As a result, the rate of de-acceleration(slowing) in lung deflation when approaching FRC was markedly reduced with increasing resistance. During lung aeration, FRC was significantly different between resistance groups and was significantly higher over time in the high compared to the low resistance group. While FRC values tended to be higher with higher Re, they were not significantly different at end-ventilation (t = 7 min). CONCLUSION: Increasing Re of the ventilation circuit during lung aeration in preterm rabbits immediately after birth decreased lung deflation rates and increased the accumulation of FRC over time. IMPACT: The expiratory phase of the ventilatory cycle has been largely overlooked as an opportunity to improve ventilation in preterm infants after birth. Increasing the expiratory resistance of the ventilator circuit during lung aeration in preterm rabbits immediately after birth markedly decreased lung deflation rates and increased FRC accumulation, compared to a low expiratory resistance. This indicates that ventilation devices that reduce the "work of breathing" by reducing the expiratory resistance, may have the unintended effect of reducing FRC, particularly in extremely preterm infants that have surfactant deficient highly incompliant lungs.

Drugs Targeting Cough Receptors: New Therapeutic Options in Refractory or Unexplained Chronic Cough.

Refractory chronic cough is a disabling disease with very limited therapeutic options. A better understanding of cough pathophysiology has led to the development of emerging drugs targeting cough receptors. Recent strides have illuminated novel therapeutic avenues, notably centred on modulating transient receptor potential (TRP) channels, purinergic receptors, and neurokinin receptors. By modulating these receptors, the goal is to intervene in the sensory pathways that trigger cough reflexes, thereby providing relief without compromising vital protective mechanisms. These innovative pharmacotherapies hold promise for improvement of refractory chronic cough by offering improved efficacy and potentially mitigating adverse effects associated with current recommended treatments. A deeper comprehension of their precise mechanisms of action and clinical viability is imperative for optimising therapeutic interventions and elevating patient care standards in respiratory health. This review delineates the evolving landscape of drug development in this domain, emphasising the significance of these advancements in reshaping the paradigm of cough management.

Assessing midbrain neuromelanin and its relationship to reward learning in anorexia nervosa: Stage 1 of a registered report.

INTRODUCTION: Anorexia nervosa (AN) is a debilitating and potentially chronic eating disorder, characterized by low hedonic drive toward food, which has been linked with perturbations in both reward processing and dopaminergic activity. Neuromelanin-sensitive magnetic resonance imaging (MRI) is an emerging method to index midbrain neuromelanin-a by-product of dopaminergic synthesis. The assessment of midbrain neuromelanin, and its association with AN psychopathology and reward-related processes, may provide critical insights into reward circuit function in AN. METHODS: This study will incorporate neuromelanin-sensitive MRI into an existing study of appetitive conditioning in those with AN. Specifically, those with acute and underweight AN (N = 30), those with weight-restored AN (N = 30), and age-matched healthy controls (N = 30) will undergo clinical assessment of current and previous psychopathology, in addition to structural neuromelanin-sensitive MRI, diffusion MRI, and functional MRI (fMRI) during appetitive conditioning. CONCLUSION: This study will be among the first to interrogate midbrain neuromelanin in AN-a disorder characterized by altered dopaminergic activity. Results will help establish whether abnormalities in the midbrain synthesis of dopamine are evident in those with AN and are associated with symptomatic behavior and reduced ability to experience pleasure and reward.

Changing-state irrelevant speech disrupts visual-verbal but not visual-spatial serial recall.

In an influential article, Jones et al. (1995) provide evidence that auditory distraction by changing relative to repetitive auditory distracters (the changing-state effect) did not differ between a visual-verbal and visual-spatial serial recall task, providing evidence for an amodal mechanism for the representation of serial order in short-term memory that transcends modalities. This finding has been highly influential for theories of short-term memory and auditory distraction. However, evidence vis-à-vis the robustness of this result is sorely lacking. Here, two high-powered replications of Jones et al.'s (1995) crucial Experiment 4 were undertaken. In the first partial replication (n = 64), a fully within-participants design was adopted, wherein participants undertook both the visual-verbal and visual-spatial serial recall tasks under different irrelevant sound conditions, without a retention period. The second near-identical replication (n = 128), incorporated a retention period and implemented the task-modality manipulation as a between-participants factor, as per the original Jones et al. (1995; Experiment 4) study. In both experiments, the changing-state effect was observed for visual-verbal serial recall but not for visual-spatial serial recall. The results are consistent with modular and interference-based accounts of distraction and challenge some aspects of functional equivalence accounts. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Relationship between sex biases in gene expression and sex biases in autism and Alzheimer's disease.

BACKGROUND: Sex differences in the brain may play an important role in sex-differential prevalence of neuropsychiatric conditions. METHODS: In order to understand the transcriptional basis of sex differences, we analyzed multiple, large-scale, human postmortem brain RNA-Seq datasets using both within-region and pan-regional frameworks. RESULTS: We find evidence of sex-biased transcription in many autosomal genes, some of which provide evidence for pathways and cell population differences between chromosomally male and female individuals. These analyses also highlight regional differences in the extent of sex-differential gene expression. We observe an increase in specific neuronal transcripts in male brains and an increase in immune and glial function-related transcripts in female brains. Integration with single-nucleus data suggests this corresponds to sex differences in cellular states rather than cell abundance. Integration with case-control gene expression studies suggests a female molecular predisposition towards Alzheimer's disease, a female-biased disease. Autism, a male-biased diagnosis, does not exhibit a male predisposition pattern in our analysis. CONCLUSION: Overall, these analyses highlight mechanisms by which sex differences may interact with sex-biased conditions in the brain. Furthermore, we provide region-specific analyses of sex differences in brain gene expression to enable additional studies at the interface of gene expression and diagnostic differences.

We sought to understand why females have higher rates of Alzheimer's disease, and males have higher rates of autism. One idea was that the female brain at baseline may be more similar to an Alzheimer's brain, so it is easier for them to shift into that state (likewise, males may be more similar to autism). To test this, we examined gene expression differences between brains of biological males and biological females. While all people have the same ~ 25,000 genes, each gene can be on or off ('expressed') to different extents. Overall, we found that there were differences in gene expression between males and females in all brain regions tested but more differences in some brain regions than others. By looking at the role of these genes we estimate that female immune system processes might be more active in the brain. We also found female brain gene expression looked slightly more like people with Alzheimer's compared to people without Alzheimer's, which may explain why females get Alzheimer's disease more easily. However, the male brain gene expression did not look more like autism, suggesting that the reason males have higher rates of autism is complex and needs further investigation.

Knee-to-chest flexion manoeuvre to reduce respiratory distress after planned caesarean birth: a feasibility study.

BACKGROUND: Planned caesarean section (CS) is a risk factor for neonatal respiratory distress caused by a greater volume of airway liquid in the absence of uterine contractions.Performing a newly conceptualised knee-to-chest flexion (KCF) manoeuvre at birth, mimicking uterine contraction-induced flexion may aid in expelling excess lung liquid. OBJECTIVES: To test whether performing a KCF manoeuvre at birth is feasible in infants born after planned CS and to test whether KCF leads to visible expulsion of lung liquid. METHODS: Single-centre prospective interventional study in term infants born by planned CS at Leiden University Medical Centre, Netherlands. KCF was performed for a maximum of 45 s. Baseline characteristics were collected, primary outcome was ability to perform KCF and secondary outcome was any visible expulsion of fluid. RESULTS: In 39 infants (mean (SD) gestational age 38.0 (0.7) weeks, birth weight 3537 (440) g), KCF could be performed in 21/39 (54%), whereas 18/39 (46.2%) starting vigorous breathing before KCF could be performed. Notably, visible lung liquid expulsion occurred in 9/21 (43%) infants. KCF duration averaged 29 (18) s. In 13/21 (62 %), KCF was not performed as per standard operating procedure. No adverse events were reported. CONCLUSION: It is feasible to perform KCF at birth in a large proportion of term infants born by planned CS, with visible expulsion of liquid in a significant proportion of these infants. Training healthcare providers to perform a standardised KCF could increase feasibility and success. Further studies are needed to assess feasibility and effectiveness of KCF. TRIAL REGISTRATION NUMBER: NL74285.058.20.

Morphological Species Delimitation in The Western Pond Turtle (Actinemys): Can Machine Learning Methods Aid in Cryptic Species Identification?

As the discovery of cryptic species has increased in frequency, there has been an interest in whether geometric morphometric data can detect fine-scale patterns of variation that can be used to morphologically diagnose such species. We used a combination of geometric morphometric data and an ensemble of five supervised machine learning methods (MLMs) to investigate whether plastron shape can differentiate two putative cryptic turtle species, Actinemys marmorata and Actinemys pallida. Actinemys has been the focus of considerable research due to its biogeographic distribution and conservation status. Despite this work, reliable morphological diagnoses for its two species are still lacking. We validated our approach on two datasets, one consisting of eight morphologically disparate emydid species, the other consisting of two subspecies of Trachemys (T. scripta scripta, T. scripta elegans). The validation tests returned near-perfect classification rates, demonstrating that plastron shape is an effective means for distinguishing taxonomic groups of emydids via MLMs. In contrast, the same methods did not return high classification rates for a set of alternative phylogeographic and morphological binning schemes in Actinemys. All classification hypotheses performed poorly relative to the validation datasets and no single hypothesis was unequivocally supported for Actinemys. Two hypotheses had machine learning performance that was marginally better than our remaining hypotheses. In both cases, those hypotheses favored a two-species split between A. marmorata and A. pallida specimens, lending tentative morphological support to the hypothesis of two Actinemys species. However, the machine learning results also underscore that Actinemys as a whole has lower levels of plastral variation than other turtles within Emydidae, but the reason for this morphological conservatism is unclear.

Expert Consensus on Pediatric Urodynamics Reporting Using Modified Delphi Technique.

PURPOSE: Urodynamic testing (UDS) is an important tool in the management of pediatric lower urinary tract conditions. There have been notable efforts to standardize pediatric UDS nomenclature and technique, but no formal guidelines exist on essential elements to include in a clinical report. We sought to identify ideal structure and elements of a pediatric UDS assessment based on expert consensus. MATERIALS AND METHODS: Pediatric urologists regularly performing UDS were queried using a Delphi process. Participants were invited representing varied geographic, experience, and societal involvement. Participants underwent 3 rounds of questionnaires between November 2022 and August 2023 focusing on report organization, elements, definitions, and automated electronic health record clinical decision support. Professional billing requirements were also considered. Consensus was defined as 80% agreeing either in favor of or against a topic. Elements without consensus were discussed in subsequent rounds. RESULTS: A diverse sample of 30 providers, representing 27 institutions across 21 US states; Washington, District of Columbia; and Canada completed the study. Participants reported interpreting an average number of 5 UDS reports per week (range 1-22). The finalized consensus report identifies 93 elements that should be included in a pediatric UDS report based on applicable study conditions and findings. CONCLUSIONS: This consensus report details the key elements and structure agreed upon by an expert panel of pediatric urologists. Further standardization of documentation should aid collaboration and research for patients undergoing UDS. Based on this information, development of a standardized UDS report template using electronic health record implementation principles is underway, which will be openly available for pediatric urologists.

Updates in the treatment of eating disorders in 2023: a year in review in eating disorders: the Journal of treatment & Prevention.

Empirical evidence is unequivocal in illustrating that the majority of patients with eating disorders will not fully recover during treatment. To that end, the need for optimized treatment approaches and improved patient outcomes cannot be overstated. While empirical efforts are underway to optimize outcomes, this article reviews treatment-related research findings published in Eating Disorders: The Journal of Treatment & Prevention during 2023. Importantly, this review encapsulates research addressing (i) between-session patient behaviors, (ii) the integration of technology into treatment approaches, (iii) methods to augment emotional regulation in the context of eating disorder treatment, (iv) methods to measure progress, and potentially risk markers for patient dropout, during treatment, (v) optimizing treatment approaches for inpatient settings, and (vi) augmenting family therapy-based approaches. Incorporating novel technological advances may be critical in enhancing the scalability of eating disorder treatments, since treatment uptake remains an ongoing challenge for the field. Moreover, expanding the scope of non-outpatient eating disorder treatment settings, while ensuring fidelity to theoretical models developed in outpatient settings, is critical as treatment is effectively administer across the spectrum of levels of patient care.

Associations between memory performance and Bifidobacterium pseudolongum abundance in the canine gut microbiome.

Memory has been identified as the least heritable cognitive trait in canines, suggesting a significant influence of non-genetic factors. We observed a trend that overall memory scores (OMS) improve with age in a cohort of 27 young dogs, but considerable plasticity exists. Employing linear discriminant analysis of gut microbiome data from dogs exhibiting low and high OMS, a single bacterial species, Bifidobacterium pseudolongum, was identified and confirmed to be correlated with elevated OMS. Subsequent analysis using a random forest regression model revealed that sex, litter, and breed identity had minimal predictive importance. Age had some predictive value but failed to achieve statistical significance in this dataset. In sharp contrast, the abundance of 17 bacterial taxa in the microbiome showed a stronger predictive capacity for memory performance. Our findings provide insights into microbiome underpinnings of mammalian cognitive functions and suggest avenues for developing psychobiotics to enhance canine memory and learning.

The outcome of revision total hip arthroplasty for instability.

Aims: Instability is a common indication for revision total hip arthroplasty (THA). However, even after the initial revision, some patients continue to have recurrent dislocation. The aim of this study was to assess the risk for recurrent dislocation after revision THA for instability. Methods: Between 2009 and 2019, 163 patients underwent revision THA for instability at Stanford University Medical Center. Of these, 33 (20.2%) required re-revision due to recurrent dislocation. Cox proportional hazard models, with death and re-revision surgery for periprosthetic infection as competing events, were used to analyze the risk factors, including the size and alignment of the components. Paired t-tests or Wilcoxon signed-rank tests were used to assess the outcome using the Veterans RAND 12 (VR-12) physical and VR-12 mental scores, the Harris Hip Score (HHS) pain and function, and the Hip disability and Osteoarthritis Outcome score for Joint Replacement (HOOS, JR). Results: The median follow-up was 3.1 years (interquartile range 2.0 to 5.1). The one-year cumulative incidence of recurrent dislocation after revision was 8.7%, which increased to 18.8% at five years and 31.9% at ten years postoperatively. In multivariable analysis, a high American Society of Anesthesiologists (ASA) grade (hazard ratio (HR) 2.72 (95% confidence interval (CI) 1.13 to 6.60)), BMI between 25 and 30 kg/m2 (HR 4.31 (95% CI 1.52 to 12.27)), the use of specialized liners (HR 5.39 (95% CI 1.97 to 14.79) to 10.55 (95% CI 2.27 to 49.15)), lumbopelvic stiffness (HR 6.03 (95% CI 1.80 to 20.23)), and postoperative abductor weakness (HR 7.48 (95% CI 2.34 to 23.91)) were significant risk factors for recurrent dislocation. Increasing the size of the acetabular component by > 1 mm significantly decreased the risk of dislocation (HR 0.89 (95% CI 0.82 to 0.96)). The VR-12 physical and HHS (pain and function) scores improved significantly at mid term. Conclusion: Patients requiring revision THA for instability are at risk of recurrent dislocation. Higher ASA grades, being overweight, a previous lumbopelvic fusion, the use of specialized liners, and postoperative abductor weakness are significant risk factors.

The influence of chorioamnionitis on respiratory drive and spontaneous breathing of premature infants at birth: a narrative review.

Most very premature infants breathe at birth but require respiratory support in order to stimulate and support their breathing. A significant proportion of premature infants are affected by chorioamnionitis, defined as an umbrella term for antenatal inflammation of the foetal membranes and umbilical vessels. Chorioamnionitis produces inflammatory mediators that potentially depress the respiratory drive generated in the brainstem. Such respiratory depression could maintain itself by delaying lung aeration, hampering respiratory support at birth and putting infants at risk of hypoxic injury. This inflammatory-mediated respiratory depression may contribute to an association between chorioamnionitis and increased requirement of neonatal resuscitation in premature infants at birth. This narrative review summarises mechanisms on how respiratory drive and spontaneous breathing could be influenced by chorioamnionitis and provides possible interventions to stimulate spontaneous breathing.  Conclusion: Chorioamnionitis could possibly depress respiratory drive and spontaneous breathing in premature infants at birth. Interventions to stimulate spontaneous breathing could therefore be valuable. What is Known: • A large proportion of premature infants are affected by chorioamnionitis, antenatal inflammation of the foetal membranes and umbilical vessels. What is New: • Premature infants affected by chorioamnionitis might be exposed to higher concentrations of respiratory drive inhibitors which could depress breathing at birth. • Premature infants affected by chorioamnionitis seem to be associated with a higher and more extensive requirement of resuscitation at birth.

Evidence for vagal sensory neural involvement in influenza pathogenesis and disease.

Influenza A virus (IAV) is a common respiratory pathogen and a global cause of significant and often severe morbidity. Although inflammatory immune responses to IAV infections are well described, little is known about how neuroimmune processes contribute to IAV pathogenesis. In the present study, we employed surgical, genetic, and pharmacological approaches to manipulate pulmonary vagal sensory neuron innervation and activity in the lungs to explore potential crosstalk between pulmonary sensory neurons and immune processes. Intranasal inoculation of mice with H1N1 strains of IAV resulted in stereotypical antiviral lung inflammation and tissue pathology, changes in breathing, loss of body weight and other clinical signs of severe IAV disease. Unilateral cervical vagotomy and genetic ablation of pulmonary vagal sensory neurons had a moderate effect on the pulmonary inflammation induced by IAV infection, but significantly worsened clinical disease presentation. Inhibition of pulmonary vagal sensory neuron activity via inhalation of the charged sodium channel blocker, QX-314, resulted in a moderate decrease in lung pathology, but again this was accompanied by a paradoxical worsening of clinical signs. Notably, vagal sensory ganglia neuroinflammation was induced by IAV infection and this was significantly potentiated by QX-314 administration. This vagal ganglia hyperinflammation was characterized by alterations in IAV-induced host defense gene expression, increased neuropeptide gene and protein expression, and an increase in the number of inflammatory cells present within the ganglia. These data suggest that pulmonary vagal sensory neurons play a role in the regulation of the inflammatory process during IAV infection and suggest that vagal neuroinflammation may be an important contributor to IAV pathogenesis and clinical presentation. Targeting these pathways could offer therapeutic opportunities to treat IAV-induced morbidity and mortality.

Blood pressure and cerebral oxygenation with physiologically-based cord clamping: sub-study of the BabyDUCC trial.

BACKGROUND: Cord-clamping strategies may modify blood pressure (BP) and cerebral tissue oxygen saturation (rStO2) immediately after birth. METHODS: We conducted a sub-study nested within the Baby-Directed Umbilical Cord-Clamping trial. Infants ≥32+0 weeks' gestation assessed as requiring resuscitation were randomly allocated to either physiologically-based cord clamping (PBCC), where resuscitation commenced prior to umbilical cord clamping, or standard care where cord clamping occurred early (ECC). In this single-site sub-study, we obtained additional measurements of pre-ductal BP and rStO2. In a separate observational arm, non-randomised vigorous infants received 2 min of deferred cord clamping (DCC) and contributed data for reference percentiles. RESULTS: Among 161 included infants, n = 55 were randomly allocated to PBCC (n = 30) or ECC (n = 25). The mean (SD) BP at 3-4 min after birth (primary outcome) in the PBCC group was 64 (10) mmHg compared to 62 (10) mmHg in the ECC group, mean difference 2 mmHg (95% confidence interval -3-8 mmHg, p = 0.42). BP and rStO2 were similar across both randomised arms and the observational arm (n = 106). CONCLUSION: We found no difference in BP or rStO2 with the different cord clamping strategies. We report reference ranges for BP and rStO2 for late-preterm and full-term infants receiving DCC. IMPACT: Among late-preterm and full-term infants receiving varying levels of resuscitation, blood pressure (BP, at 3-4 minutes and 6 min) and cerebral tissue oxygen saturation (rStO2) are not influenced by timing of cord clamping in relation to establishment of ventilation. Infants in this study did not require advanced resuscitation, where cord clamping strategies may yet influence BP and rStO2. The reference ranges for BP and rStO2 represent the first, to our knowledge, for vigorous late-preterm and full-term infants receiving deferred cord clamping. rStO2 > 90% (~90th percentile) may be used to define cerebral hyperoxia, for instance when studying oxygen supplementation after birth.

Neuromodulation of Eating Disorders: A Review of Underlying Neural Network Activity and Neuromodulatory Treatments.

Eating disorders are a group of psychiatric conditions that involve pathological relationships between patients and food. The most prolific of these disorders are anorexia nervosa, bulimia nervosa, and binge eating disorder. The current standard of care involves psychotherapy, pharmacotherapy, and the management of comorbid conditions, with nutritional rehabilitation reserved for severe cases of anorexia nervosa. Unfortunately, many patients often fail to respond, leaving a concerning treatment gap between the current and requisite treatments for eating disorders. To better understand the neurobiology underlying these eating disorders, investigations have been undertaken to characterize the activity of various neural networks, primarily those activated during tasks of executive inhibition, reward processing, and self-reference. Various neuromodulatory techniques have been proposed to stimulate these networks with the goal of improving patients' BMI and mental health. The aim of this review is to compile a comprehensive summarization of the current literature regarding the underlying neural connectivity of anorexia nervosa, bulimia nervosa, and binge eating disorder as well as the numerous neuromodulatory modalities that have been investigated. Importantly, we aimed to summarize the most significant clinical trials to date as well as to provide an updated assessment of the role of deep brain stimulation, summarizing numerous recently published clinical studies that have greatly contributed to the literature. In this review, we found therapeutic evidence for transcranial magnetic stimulation and transcranial direct current stimulation in treating individuals suffering from anorexia nervosa, bulimia nervosa, and binge eating disorder. We also found significant evidence for the role of deep brain stimulation, particularly as an escalatory therapy option for the those who failed standard therapy. Finally, we hope to provide promising directions for future clinical investigations.