Midterm Outcomes After Simultaneous Hip Arthroscopic Surgery for Bilateral Femoroacetabular Impingement.

BACKGROUND: Bilateral hip arthroscopic surgery for the treatment of femoroacetabular impingement (FAI) has demonstrated good outcomes at short-term follow-up, with significant improvements in pain, hip function, and patient-reported outcomes, coupled with a complication rate similar to that of unilateral surgery. PURPOSE: To investigate whether, in patients with bilateral symptomatic FAI, simultaneous bilateral hip arthroscopic surgery is an efficacious option that produces effective midterm outcomes. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: A prospective database of patients who underwent primary hip arthroscopic surgery between August 2012 and October 2020 was used to collect clinical data on 2 groups. Group 1 consisted of patients who underwent simultaneous bilateral hip arthroscopic surgery for the treatment of FAI. Group 2 represented a matched-pair control group of patients selected based on sex and age with signs and symptoms of unilateral FAI and in whom a single side was evaluated and treated. Differences in the International Hip Outcome Tool-12 and Non-Arthritic Hip Score scores were evaluated up to 5 years postoperatively. RESULTS: In total, 171 patients (235 hips) were included, of whom 64 underwent simultaneous bilateral hip arthroscopic surgery (128 hips) and a control group of 107 patients (107 hips) underwent unilateral hip arthroscopic surgery. No significant differences were observed in International Hip Outcome Tool-12 scores between the 2 groups at 6 weeks, 3 months, 1 year, 2 years, and 5 years postoperatively. No significant differences were observed in Non-Arthritic Hip Score scores between the simultaneous bilateral and control groups at 6 weeks, 3 months, 6 months, 1 year, 2 years, and 5 years postoperatively. Overall, 18% of hips in the simultaneous bilateral group reported lateral femoral cutaneous nerve palsy at 2-week follow-up in comparison to 16% of hips in the control group. CONCLUSION: Simultaneous bilateral hip arthroscopic surgery for the treatment of FAI represents a safe treatment option, producing effective midterm outcomes in appropriately selected patients.

Association Between Low-Dose Ketamine After Periacetabular and/or Femoral Osteotomy and Postoperative Opioid Requirements.

Background: Previous studies have sought to determine the effect of inpatient ketamine therapy on postoperative pain in a variety of surgical specialties. Purpose: To determine the effects of postoperative ketamine analgesia after periacetabular osteotomy (PAO) and/or derotational femoral osteotomy (DFO) on opioid requirements, pain, and discharge time. Study Design: Cohort study; Level of evidence, 3. Methods: Prospective data were collected on 145 patients who underwent PAO and/or DFO by the senior author between January 2021 and December 2022. Hip arthroscopy was performed 3 to 10 days before addressing any intra-articular pathology. In 2021, patients (n = 91 procedures; control group) received a traditional postoperative multimodal pain regimen. In 2022, postoperative low-dose ketamine (0.1-1 mg/kg/h) was added to the multimodal analgesic approach until 24 hours before discharge (n = 81 procedures; ketamine group). The ketamine and control groups were matched based on procedure type. Total opioid consumption was collected using milligram morphine equivalents (MMEs) for both groups. Postoperative pain was measured using the Defense and Veterans Pain Rating Scale (DVPRS), which was analyzed as the mean score per day. Data on the mean MME and DVPRS were analyzed for up to 7 days postoperatively. Linear mixed statistical analysis was performed to determine the significance of low-dose postoperative ketamine on postoperative pain and opioid utilization. Results: Patients who did not receive ketamine after PAO and/or DFO utilized a mean of 181 ± 335 MMEs and had a mean DVPRS score of 4.18 ± 1.63. Patients who received postoperative ketamine required a mean of 119 ± 291 MMEs and had a mean DVPRS score of 4.34 ± 1.61. The ketamine group was found to consume a significantly lower total MME dose per day (P < .001). No significant difference was found in the mean DVPRS score between the ketamine and control groups (P = .42). Also, no significant difference was found on the day of discharge (P = .79). Conclusion: Patients who received postoperative ketamine after PAO and/or DFO had a significant decrease in MME dose when compared with a control group of patients who did not receive ketamine. Surgeons should consider adding ketamine to their postoperative multimodal pain control protocol to decrease opioid consumption while adequately addressing postoperative pain.

A therapeutic small molecule enhances γ-oscillations and improves cognition/memory in Alzheimer's disease model mice.

Brain rhythms provide the timing for recruitment of brain activity required for linking together neuronal ensembles engaged in specific tasks. The γ-oscillations (30 to 120 Hz) orchestrate neuronal circuits underlying cognitive processes and working memory. These oscillations are reduced in numerous neurological and psychiatric disorders, including early cognitive decline in Alzheimer's disease (AD). Here, we report on a potent brain-permeable small molecule, DDL-920 that increases γ-oscillations and improves cognition/memory in a mouse model of AD, thus showing promise as a class of therapeutics for AD. We employed anatomical, in vitro and in vivo electrophysiological, and behavioral methods to examine the effects of our lead therapeutic candidate small molecule. As a novel in central nervous system pharmacotherapy, our lead molecule acts as a potent, efficacious, and selective negative allosteric modulator of the γ-aminobutyric acid type A receptors most likely assembled from α1ß2δ subunits. These receptors, identified through anatomical and pharmacological means, underlie the tonic inhibition of parvalbumin (PV) expressing interneurons (PV+INs) critically involved in the generation of γ-oscillations. When orally administered twice daily for 2 wk, DDL-920 restored the cognitive/memory impairments of 3- to 4-mo-old AD model mice as measured by their performance in the Barnes maze. Our approach is unique as it is meant to enhance cognitive performance and working memory in a state-dependent manner by engaging and amplifying the brain's endogenous γ-oscillations through enhancing the function of PV+INs.

Ancestry-associated co-alteration landscape of KRAS and EGFR-altered non-squamous NSCLC.

Racial/ethnic disparities mar NSCLC care and treatment outcomes. While socioeconomic factors and access to healthcare are important drivers of NSCLC disparities, a deeper understanding of genetic ancestry-associated genomic landscapes can better inform the biology and the treatment actionability for these tumors. We present a comprehensive ancestry-based prevalence and co-alteration landscape of genomic alterations and immunotherapy-associated biomarkers in patients with KRAS and EGFR-altered non-squamous (non-Sq) NSCLC. KRAS was the most frequently altered oncogene in European (EUR) and African (AFR), while EGFR alterations predominated in East Asian (EAS), South Asian (SAS), and Admixed American (AMR) groups, consistent with prior studies. As expected, STK11 and KEAP1 alterations co-occurred with KRAS alterations while showing mutual exclusivity with EGFR alterations. EAS and AMR KRAS-altered non-Sq NSCLC showed lower rates of co-occurring STK11 and KEAP1 alterations relative to other ancestry groups. Ancestry-specific co-alterations included the co-occurrence of KRAS and GNAS alterations in AMR, KRAS, and ARID1A alterations in SAS, and the mutual exclusivity of KRAS and NF1 alterations in the EUR and AFR ancestries. Contrastingly, EGFR-altered tumors exhibited a more conserved co-alteration landscape across ancestries. AFR exhibited the highest tumor mutational burden, with potential therapeutic implications for these tumors.

Health Outcomes around Pregnancy and Exposure to HIV/Antiretrovirals (HOPE) study protocol: a prospective observational cohort study of reproductive-aged women living with HIV.

INTRODUCTION: Over 265 000 women are living with HIV in the USA, but limited research has investigated the physical, mental and behavioural health outcomes among women living with HIV of reproductive age. Health status during the reproductive years before, during and after pregnancy affects pregnancy outcomes and long-term health. Understanding health outcomes among women living with HIV of reproductive age is of substantial public health importance, regardless of whether they experience pregnancy. The Health Outcomes around Pregnancy and Exposure to HIV/Antiretrovirals (HOPE) study is a prospective observational cohort study designed to investigate physical and mental health outcomes of young women living with HIV as they age, including HIV disease course, engagement in care, reproductive health and choices and cardiometabolic health. We describe the HOPE study design, and characteristics of the first 437 participants enrolled as of 1 January 2024. METHODS AND ANALYSIS: The HOPE study seeks to enrol and follow 1630 women living with HIV of reproductive age, including those with perinatally-acquired HIV, at 12 clinical sites across 9 US states and Puerto Rico. HOPE studies multilevel dynamic determinants influencing physical, mental and social well-being and behaviours of women living with HIV across the reproductive life course (preconception, pregnancy, post partum, not or never-pregnant), informed by the socioecological model. Key research areas include the clinical course of HIV, relationship of HIV and antiretroviral medications to reproductive health, pregnancy outcomes and comorbidities and the influence of racism and social determinants of health. HOPE began enrolling in April 2022. ETHICS AND DISSEMINATION: The HOPE study received approval from the Harvard Longwood Campus Institutional Review Board, the single institutional review board of record for all HOPE sites. Results will be disseminated through conference presentations, peer-reviewed journals and lay summaries.

Firearm screening in pediatric patients.

Introduction: In the United States, firearm-related injuries are the leading cause of death among children and adolescents 1-19 years of age. Although many pediatricians believe addressing firearm safety is important and have guidance from organizations like the American Academy of Pediatrics, few routinely screen and counsel on firearm safety. The goal of this project was to screen all patients presenting to the pediatric emergency department, pediatric floor, and pediatric intensive care unit for the presence of firearms in the home, firearm storage practices, and whether they had previously received any firearm counseling by medical professionals. Methods: A 13-item survey was administered to each participant. Items included demographic information, willingness to answer questions about firearms, practice of asking questions about firearms, previous counseling from medical professionals about the presence of firearms in the home and the presence of firearm in their personal home as well as storage practices. Results: A total of 200 parents responded to the survey. Of those that responded to the survey, 171 (85.5%) did not have a firearm in the home and 28 (14%) did have a firearm in the home. 75% (n = 21) had never had a medical provider discuss firearm safety with them. 100% had never been asked by another parent about the presence of a firearm in their home when a child came over for a playdate. 39% (n = 11) of parents with a firearm in the home had asked other parents whether they have a firearm in the home where their child goes to play. Discussion: Findings from our study highlight a significant lack of screening of our pediatric patients both in the inpatient and outpatient settings, with the majority reporting that they had never been asked by a medical provider about firearm safety. In addition, three quarters of parents with a firearm in the home reported that they did not mind answering questions about firearms yet none had been asked by other parents about firearms. Thus, although firearm possession and safety is considered to be a sensitive topic, many parents are willing to discuss it with their health care providers and other parents.

A software-based observational coding approach for evaluating paediatric dental pain, anxiety, and fear.

BACKGROUND: Dental practitioners desire non-pharmacological methods to alleviate anxiety, fear, and pain in children receiving dental care; high-quality evidence, however, is required to evaluate methods' efficacy. AIM: This study aimed to develop and validate an observation-based coding approach (paediatric dental pain, anxiety, and fear coding approach [PAFCA]) to evaluate non-pharmacological behavior management techniques for anxiety, fear, and pain. DESIGN: Objective (video-based) and subjective (self-reported) anxiety, fear, and pain data were collected from a pilot clinical trial evaluating animal-assisted therapy (AAT) in paediatric dentistry, in which 37 children aged 7-14 were assigned to AAT or control before dental treatment (restorations or extractions). A coding approach utilizing a codebook, a gold standard calibration video, and a user training guide was developed. Trained examiners coded the gold standard video for inter-rater agreement, and masked, calibrated examiners analyzed videos using the Noldus Observer XT software. RESULTS: A novel, software-based coding approach was developed, with moderately high inter-rater agreement. Using PAFCA, we found children reporting higher levels of pain, fear, and anxiety exhibited treatment-interfering behaviors, including crying/moaning, attempts to dislodge instruments, and more upper and lower body movements. CONCLUSION: PAFCA shows promise as a reliable tool for assessing anxiety, pain, and fear in behavioral research for paediatric dentistry.

Summary of ChIP-Seq Methods and Description of an Optimized ChIP-Seq Protocol.

Chromatin immunoprecipitation (ChIP) is an invaluable method to characterize interactions between proteins and genomic DNA, such as the genomic localization of transcription factors and post-translational modification of histones. DNA and proteins are reversibly and covalently crosslinked using formaldehyde. Then the cells are lysed to release the chromatin. The chromatin is fragmented into smaller sizes either by micrococcal nuclease (MN) or sonication and then purified from other cellular components. The protein-DNA complexes are enriched by immunoprecipitation (IP) with antibodies that target the epitope of interest. The DNA is released from the proteins by heat and protease treatment, followed by degradation of contaminating RNAs with RNase. The resulting DNA is analyzed using various methods, including polymerase chain reaction (PCR), quantitative PCR (qPCR), or sequencing. This protocol outlines each of these steps for both yeast and human cells. This chapter includes a contextual discussion of the combination of ChIP with DNA analysis methods such as ChIP-on-Chip, ChIP-qPCR, and ChIP-Seq, recent updates on ChIP-Seq data analysis pipelines, complementary methods for identification of binding sites of DNA binding proteins, and additional protocol information about ChIP-qPCR and ChIP-Seq.

Prediction error determines how memories are organized in the brain.

How is new information organized in memory? According to latent state theories, this is determined by the level of surprise, or prediction error, generated by the new information: a small prediction error leads to the updating of existing memory, large prediction error leads to encoding of a new memory. We tested this idea using a protocol in which rats were first conditioned to fear a stimulus paired with shock. The stimulus was then gradually extinguished by progressively reducing the shock intensity until the stimulus was presented alone. Consistent with latent state theories, this gradual extinction protocol (small prediction errors) was better than standard extinction (large prediction errors) in producing long-term suppression of fear responses, and the benefit of gradual extinction was due to updating of the conditioning memory with information about extinction. Thus, prediction error determines how new information is organized in memory, and latent state theories adequately describe the ways in which this occurs.

Understanding attrition of early career midwives in Australia.

PROBLEM: There is a lack of understanding of the experiences of early career midwives which lead to workforce attrition. BACKGROUND: In the Australian midwifery setting, workforce attrition in conjunction with the ageing profile of the workforce is of increasing concern. Midwives in the earliest stages of their career are most vulnerable to career attrition, however limited research specifically engages with this cohort. AIM: To understand the professional and social circumstances that led early career midwives to leave clinical practice, how their midwifery background influenced career trajectories, and what would compel them to return to clinical practice. METHODS: Semi-structured interviews were conducted with 11 early career midwives who had left the profession within 5 years of qualification. Transcripts underwent thematic analysis. FINDINGS: Three themes described early career midwives' experiences: transition to professional practice, an untenable workplace culture, mental health impacts of early clinical midwifery practice. Two further themes emerged about experiences post-midwifery careers: influence of midwifery on subsequent career, and conditions for re-entry. DISCUSSION: Challenges with transitioning to professional midwifery practice in conjunction with untenable workplace culture led to such deterioration in wellbeing that remaining within the profession became unfeasible for early career midwives. Desire to remain within health care was apparent, however re-entry to the profession was deemed by most to be out of the question. CONCLUSION: Early workforce retention strategies should be the focus of future workforce planning and policy. Larger scale inquiry foregrounding early career midwives is necessary to inform strategies for midwifery workforce retention in Australia.

Accuracy and Interpretation of Transcutaneous Carbon Dioxide Monitoring in Critically Ill Children.

OBJECTIVES: Transcutaneous carbon dioxide (Tcco2) monitoring can noninvasively assess ventilation by estimating carbon dioxide (CO2) levels in the blood. We aimed to evaluate the accuracy of Tcco2 monitoring in critically ill children by comparing it to the partial pressure of arterial carbon dioxide (Paco2). In addition, we sought to determine the variation between Tcco2 and Paco2 acceptable to clinicians to modify patient care and to determine which patient-level factors may affect the accuracy of Tcco2 measurements. DESIGN: Retrospective observational cohort study. SETTING: Single, quaternary care PICU from July 1, 2012, to August 1, 2020. PATIENTS: Included participants were admitted to the PICU and received noninvasive ventilation support (i.e., continuous or bilevel positive airway pressure), conventional mechanical ventilation, or high-frequency oscillatory or percussive ventilation with Tcco2 measurements obtained within 15 minutes of Paco2 measurement. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Three thousand four hundred seven paired arterial blood gas and Tcco2 measurements were obtained from 264 patients. Bland-Altman analysis revealed a bias of -4.4 mm Hg (95% CI, -27 to 18.3 mm Hg) for Tcco2 levels against Paco2 levels on the first measurement pair for each patient, which fell within the acceptable range of ±5 mm Hg stated by surveyed clinicians, albeit with wide limits of agreement. The sensitivity and specificity of Tcco2 to diagnose hypercarbia were 93% and 71%, respectively. Vasoactive-Infusion Score (VIS), age, and self-identified Black/African American race confounded the relationship between Tcco2 with Paco2 but percent fluid overload, weight-for-age, probe location, and severity of illness were not significantly associated with Tcco2 accuracy. CONCLUSIONS: Tcco2 monitoring may be a useful adjunct to monitor ventilation in children with respiratory failure, but providers must be aware of the limitations to its accuracy.

A Path to High-Value Gastric Cancer Surgery Care Delivery.

Objective: To evaluate the feasibility, safety, and effectiveness of a comprehensive regional program, including the Minimally Invasive Recovery and Empowerment Care (MIREC) pathway, that can significantly reduce hospital stays after laparoscopic gastrectomy without increasing adverse events. Background: Cost-effectiveness and improving patient outcomes are crucial in providing quality gastric cancer care worldwide. Methods: To compare the outcomes of gastric cancer surgery using 2 different models of care within an integrated healthcare system from February 2012 to March 2023. The primary endpoint was the length of hospital stay. The secondary endpoints were the need for intensive care unit care, emergency room (ER) visits, readmission, reoperation, and death within 30 days after surgery. Results: There were 553 patients, 167 in the pre-(February 2012-April 2016) and 386 in the post-MIREC period (May 2016-March 2023). Perioperative chemotherapy utilization increased from 31.7% to 76.4% (P < 0.0001). Laparoscopic gastrectomy increased from 17.4% to 97.7% (P < 0.0001). Length of hospitalization decreased from 7 to 2 days (P < 0.0001), with 32.1% and 88% of patients discharged home on postoperative day 1 and postoperative day 2, respectively. When comparing pre- and post-MIREC, intensive care unit utilization (10.8% vs. 2.9%, P < 0.0001), ER visits (34.7% vs. 19.7%, P = 0.0002), and readmission (18.6% vs. 11.1%, P = 0.019) at 30 days were also considerably lower. In addition, more patients received postoperative adjuvant chemotherapy (31.4% to 63.5%, P < 0.0001), and the time between gastrectomy and starting adjuvant chemotherapy was also less (49-41 days; P = 0.002). Conclusion: This comprehensive regional program, which encompasses regionalization care, laparoscopic approach, modern oncologic care, surgical subspecialization, and the MIREC pathway, can potentially improve gastric cancer surgery outcomes. These benefits include reduced hospital stays and lower complication rates. As such, this program can revolutionize how gastric cancer surgery is delivered, leading to a higher quality of care and increased value to patients.

What makes a stimulus worthy of attention: Cue-outcome correlation and choice relevance in the learned predictiveness effect.

The learned predictiveness effect refers to the tendency for predictive cues to attract greater attention and show faster learning in subsequent tasks. However, in typical designs, the predictiveness of each cue (its objective cue-outcome correlation) is confounded with the degree to which it is informative for making the correct response on each trial (a feature we term choice relevance). In four experiments, we tested the unique contributions of cue-outcome correlation and choice relevance to the learned predictiveness effect by manipulating the outcome choices available on each trial. Experiments 1A and 1B compared two sets of partially predictive cues and found that participants learned more in a transfer phase about the set of cues that were previously choice-relevant. Experiments 2A and 2B used a design in which the cue-outcome correlation was stronger for one set of cues (perfect predictors) than the other set (imperfect predictors). Manipulating the choice relevance of the imperfect predictors in this design did not influence the magnitude of the learning bias toward the perfect predictor. Unlike cue-outcome correlation, choice relevance did not seem to correspond to biases in eye-gaze, suggesting that it operates via a distinct mechanism. Simulations with a modified EXIT model successfully predicted cue-outcome correlation and choice relevance effects by assuming that participants update learning for present outcomes only, but incorrectly predicted additive effects. We conclude that cue-outcome correlation and choice relevance are important factors that can lead to biases in future learning; both were individually sufficient but neither was necessary. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

The Forgotten Flap: The Pedicled Trapezius Flap's Utility in Pediatric Head and Neck Reconstruction-A Systematic Review.

BACKGROUND: When free tissue transfer is precluded or undesired, the pedicled trapezius flap is a viable alternative for adults requiring complex head and neck (H&N) defect reconstruction. However, the application of this flap in pediatric reconstruction is underexplored. This systematic review aimed to describe the use of the pedicled trapezius flap and investigate its efficacy in pediatric H&N reconstruction. METHODS: A systematic review was performed using Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Articles describing the trapezius flap for H&N reconstruction in pediatric patients were included. Patient demographics, surgical indications, wound characteristics, flap characteristics, complications, and functional outcomes were abstracted. RESULTS: A systematic review identified 22 articles for inclusion. Studies mainly consisted of case reports (n = 11) and case series (n = 8). In total, 67 pedicled trapezius flaps were successfully performed for H&N reconstruction in 63 patients. The most common surgical indications included burn scar contractures (n = 46, 73.0%) and chronic wounds secondary to H&N masses (n = 9, 14.3%). Defects were most commonly located in the neck (n = 28, 41.8%). The mean flap area and arc of rotation were 326.4 ± 241.7 cm2 and 157.6 ± 33.2 degrees, respectively. Most flaps were myocutaneous (n = 48, 71.6%) and based on the dorsal scapular artery (n = 32, 47.8%). Complications occurred in 10 (14.9%) flaps. The flap's survival rate was 100% (n = 67). No instances of functional donor site morbidity were reported. The mean follow-up was 2.2 ± 1.8 years. CONCLUSION: This systematic review demonstrated the reliability of the pedicled trapezius flap in pediatric H&N reconstruction, with a low complication rate, no reports of functional donor site morbidity, and a 100% flap survival rate. The flap's substantial surface area, bulk, and arc of rotation contribute to its efficacy in covering soft tissue defects ranging from the proximal neck to the vertex of the scalp. The pedicled trapezius flap is a viable option for pediatric H&N reconstruction.

Pediatric skull inflammatory myofibroblastic tumor: a rare case report and literature review.

Inflammatory myofibroblastic tumors (IMTs) represent rare neoplasms, particularly infrequent in the pediatric skull. We present a novel case of a newborn male with a 5 cm right temporal mass and discuss current diagnostic and treatment options for IMTs. A multidisciplinary effort to surgically remove the lesion was successful, and the patient's skull defect healed without neurological deficits. The etiology of IMTs remains elusive, with proposed associations with chromosomal mutations in the anaplastic lymphoma kinase (ALK) gene. Surgical excision remains the primary treatment for IMTs. Promising pharmacological treatments, like Crizotinib, warrant further research into understanding potential alternatives in IMT management.

A second space age spanning omics, platforms and medicine across orbits.

The recent acceleration of commercial, private and multi-national spaceflight has created an unprecedented level of activity in low Earth orbit, concomitant with the largest-ever number of crewed missions entering space and preparations for exploration-class (lasting longer than one year) missions. Such rapid advancement into space from many new companies, countries and space-related entities has enabled a 'second space age'. This era is also poised to leverage, for the first time, modern tools and methods of molecular biology and precision medicine, thus enabling precision aerospace medicine for the crews. The applications of these biomedical technologies and algorithms are diverse, and encompass multi-omic, single-cell and spatial biology tools to investigate human and microbial responses to spaceflight. Additionally, they extend to the development of new imaging techniques, real-time cognitive assessments, physiological monitoring and personalized risk profiles tailored for astronauts. Furthermore, these technologies enable advancements in pharmacogenomics, as well as the identification of novel spaceflight biomarkers and the development of corresponding countermeasures. In this Perspective, we highlight some of the recent biomedical research from the National Aeronautics and Space Administration, Japan Aerospace Exploration Agency, European Space Agency and other space agencies, and detail the entrance of the commercial spaceflight sector (including SpaceX, Blue Origin, Axiom and Sierra Space) into aerospace medicine and space biology, the first aerospace medicine biobank, and various upcoming missions that will utilize these tools to ensure a permanent human presence beyond low Earth orbit, venturing out to other planets and moons.

Cortisol, Stress, and Disease-Bidirectional Associations; Role for Corticosteroid-Binding Globulin?

Selye described stress as a unified neurohormonal mechanism maintaining homeostasis. Acute stress system activation is adaptive through neurocognitive, catecholaminergic, and immunomodulation mechanisms, followed by a reset via cortisol. Stress system components, the sympathoadrenomedullary system, hypothalamic-pituitary-adrenal axis, and limbic structures are implicated in many chronic diseases by establishing an altered homeostatic state, allostasis. Consequent "primary stress system disorders" were popularly accepted, with phenotypes based on conditions such as Cushing syndrome, pheochromocytoma, and adrenal insufficiency. Cardiometabolic and major depressive disorders are candidates for hypercortisolemic etiology, contrasting the "hypocortisolemic symptom triad" of stress sensitivity, chronic fatigue, and pain. However, acceptance of chronic stress etiology requires cause-and-effect associations, and practical utility such as therapeutics altering stress system function. Inherent predispositions to stress system perturbations may be relevant. Glucocorticoid receptor (GR) variants have been associated with metabolic/neuropsychological states. The SERPINA6 gene encoding corticosteroid-binding globulin (CBG), was the sole genetic factor in a single-nucleotide variation-genome-wide association study linkage study of morning plasma cortisol, a risk factor for cardiovascular disease, with alterations in tissue-specific GR-related gene expression. Studies showed genetically predicted high cortisol concentrations are associated with hypertension and anxiety, and low CBG concentrations/binding affinity, with the hypocortisolemic triad. Acquired CBG deficiency in septic shock results in 3-fold higher mortality when hydrocortisone administration produces equivocal results, consistent with CBG's role in spatiotemporal cortisol delivery. We propose some stress system disorders result from constitutional stress system variants rather than stressors themselves. Altered CBG:cortisol buffering may influence interstitial cortisol ultradian surges leading to pathological tissue effects, an example of stress system variants contributing to stress-related disorders.

Narrative analysis in individuals with Parkinson's disease following intensive voice treatment: secondary outcome variables from a randomized controlled trial.

Communication is often impaired in individuals with Parkinson's disease (PD), typically secondary to sensorimotor deficits impacting voice and speech. Language may also be diminished in PD, particularly for production and comprehension of verbs. Evidence exists that verb processing is influenced by motor system modulation suggesting that verb deficits in PD are underpinned by similarities in the neural representations of actions that span motor and semantic systems. Conversely, subtle differences in cognition in PD may explain difficulty in processing of complex syntactic forms, which increases cognitive demand and is linked to verb use. Here we investigated whether optimizing motor system support for vocal function (improving loudness) affects change in lexical semantic, syntactic, or informativeness aspects of spoken discourse. Picture description narratives were compared for 20 Control participants and 39 with PD, 19 of whom underwent Lee Silverman Voice Treatment (LSVT LOUD®). Treated PD narratives were also contrasted with those of untreated PD and Control participants at Baseline and after treatment. Controls differed significantly from the 39 PD participants for verbs per utterance, but this difference was largely driven by untreated PD participants who produced few utterances but with verbs, inflating their verbs per utterance. Given intervention, there was a significant increase in vocal loudness but no significant changes in language performance. These data do not support the hypothesis that targeting this speech motor system results in improved language production. Instead, the data provide evidence of considerable variability in measures of language production across groups, particularly in verbs per utterance.

ACAD9 treatment with bezafibrate and nicotinamide riboside temporarily stabilizes cardiomyopathy and lactic acidosis.

Pathogenic ACAD9 variants cause complex I deficiency. Patients presenting in infancy unresponsive to riboflavin have high mortality. A six-month-old infant presented with riboflavin unresponsive lactic acidosis and life-threatening cardiomyopathy. Treatment with high dose bezafibrate and nicotinamide riboside resulted in marked clinical improvement including reduced lactate and NT-pro-brain type natriuretic peptide levels, with stabilized echocardiographic measures. After a long stable period, the child succumbed from cardiac failure with infection at 10.5 months. Therapy was well tolerated. Peak bezafibrate levels exceeded its EC50. The clinical improvement with this treatment illustrates its potential, but weak PPAR agonist activity of bezafibrate limited its efficacy.