Endophthalmitis Rates and Types of Treatments After Intraocular Procedures.

Importance: Long-term trend analyses of overall endophthalmitis rates and treatment patterns are scarce. It is also unknown if the deviation from the recommendations of the Endophthalmitis Vitrectomy Study toward decreased utilization of vitrectomy is associated with different vision outcomes. Objective: To determine whether the rate of endophthalmitis after intraocular procedures or the primary treatment (prompt vitrectomy vs tap and inject) for endophthalmitis has changed over the past 20 years. Design, Setting, and Participants: This cohort study examined data for cohorts created by querying for different intraocular procedures, including intravitreal injections and surgeries for cataract removal, glaucoma, retinal conditions, and corneal transplants from 2000 to 2022. The data source was a US administrative medical claims database comprising commercial and Medicare Advantage insurance plans. Any intraocular procedure with at least 6 months of data available before and 6 weeks after the procedure was eligible. Exclusion criteria consisted of any previous diagnosis of endophthalmitis or another intraocular procedure during the follow-up period. Main Outcome Measure: The main outcomes were rate of postprocedure endophthalmitis and relative rate of prompt vitrectomy (vs tap and inject) as the primary method of treatment. Results: Among 2 124 964 patients, the mean (SD) age was 71.4 (10.2) years; 1 230 320 were female and 894 414 male. Over 22 years, 5 827 809 intraocular procedures were analyzed with 4305 cases of endophthalmitis found for an overall endophthalmitis rate of 0.07%. The yearly rate of endophthalmitis varied but generally declined from a high of 7 cases per 3502 procedures (0.20%) in 2000 to a low of 163 cases per 332 159 procedures (0.05%) in 2022. The percentage of cases treated with prompt vitrectomy also varied but generally declined over time with a high of 17 of 35 (48.6%) in 2003 and a low of 60 of 515 (11.6%) in 2021. Multivariable analysis of the endophthalmitis incidence rate ratio (IRR) showed a per-year decrease of 2.7% (IRR, 0.97; 95% CI, 0.97-0.98; P < .001) over the study period. A similar analysis also showed that the incidence rate of prompt surgical treatment decreased by 3.8% per year throughout the study period (IRR, 0.96; 95% CI, 0.95-0.97; P < .001). Conclusions and Relevance: This study found that the incidence of endophthalmitis following intraocular procedures appears to have decreased substantially over the past 20 years while prompt vitrectomy is being used less frequently as primary treatment than in the past.

Sensor-Assisted Analysis of Autonomic and Cerebrovascular Dysregulation following Concussion in an Individual with a History of Ten Concussions: A Case Study.

INTRODUCTION: Concussion is known to cause transient autonomic and cerebrovascular dysregulation that generally recovers; however, few studies have focused on individuals with an extensive concussion history. METHOD: The case was a 26-year-old male with a history of 10 concussions, diagnosed for bipolar type II disorder, mild attention-deficit hyperactivity disorder, and a history of migraines/headaches. The case was medicated with Valproic Acid and Escitalopram. Sensor-based baseline data were collected within six months of his injury and on days 1-5, 10, and 14 post-injury. Symptom reporting, heart rate variability (HRV), neurovascular coupling (NVC), and dynamic cerebral autoregulation (dCA) assessments were completed using numerous biomedical devices (i.e., transcranial Doppler ultrasound, 3-lead electrocardiography, finger photoplethysmography). RESULTS: Total symptom and symptom severity scores were higher for the first-week post-injury, with physical and emotional symptoms being the most impacted. The NVC response showed lowered activation in the first three days post-injury, while autonomic (HRV) and autoregulation (dCA) were impaired across all testing visits occurring in the first 14 days following his concussion. CONCLUSIONS: Despite symptom resolution, the case demonstrated ongoing autonomic and autoregulatory dysfunction. Larger samples examining individuals with an extensive history of concussion are warranted to understand the chronic physiological changes that occur following cumulative concussions through biosensing devices.

Misophonia reactions in the general population are correlated with strong emotional reactions to other everyday sensory-emotional experiences.

Misophonic experiences are common in the general population, and they may shed light on everyday emotional reactions to multi-modal stimuli. We performed an online study of a non-clinical sample to understand the extent to which adults who have misophonic reactions are generally reactive to a range of audio-visual emotion-inducing stimuli. We also hypothesized that musicality might be predictive of one's emotional reactions to these stimuli because music is an activity that involves strong connections between sensory processing and meaningful emotional experiences. Participants completed self-report scales of misophonia and musicality. They also watched videos meant to induce misophonia, autonomous sensory meridian response (ASMR) and musical chills, and were asked to click a button whenever they had any emotional reaction to the video. They also rated the emotional valence and arousal of each video. Reactions to misophonia videos were predicted by reactions to ASMR and chills videos, which could indicate that the frequency with which individuals experience emotional responses varies similarly across both negative and positive emotional contexts. Musicality scores were not correlated with measures of misophonia. These findings could reflect a general phenotype of stronger emotional reactivity to meaningful sensory inputs. This article is part of the theme issue 'Sensing and feeling: an integrative approach to sensory processing and emotional experience'.

Differential Components of Bradykinesia in Parkinson Disease Revealed by Deep Brain Stimulation.

Bradykinesia is a term describing several manifestations of movement disruption caused by Parkinson's disease (PD), including movement slowing, amplitude reduction, and gradual decrease of speed and amplitude over multiple repetitions of the same movement. Deep brain stimulation (DBS) of the subthalamic nucleus (STN) improves bradykinesia in patients with PD. We examined the effect of DBS on specific components of bradykinesia when applied at two locations within the STN, using signal processing techniques to identify the time course of amplitude and frequency of repeated hand pronation-supination movements performed by participants with and without PD. Stimulation at either location increased movement amplitude, increased frequency, and decreased variability, though not to the range observed in the control group. Amplitude and frequency showed decrement within trials, which was similar in PD and control groups and did not change with DBS. Decrement across trials, by contrast, differed between PD and control groups, and was reduced by stimulation. We conclude that DBS improves specific aspects of movement that are disrupted by PD, whereas it does not affect short-term decrement that could reflect muscular fatigue.

HER2DX Genomic Assay in HER2-positive Early Breast Cancer Treated with Trastuzumab and Pertuzumab: A Correlative Analysis from PHERGain Phase II Trial.

PURPOSE: To assess the predictive capability of HER2DX assay following (neo)adjuvant trastuzumab-pertuzumab (HP)-based therapy in HER2-positive (HER2+) early breast cancer (EBC). EXPERIMENTAL DESIGN: HER2DX was analyzed in baseline pre-treatment tumors from PHERGain trial. Patients with stage I-IIIA HER2+ EBC were randomized to group A (docetaxel, carboplatin, and HP [TCHP]) and group B (HP ± endocrine therapy). PET response was evaluated after 2 cycles. Group A received TCHP for 6 cycles regardless of PET response. Group B continued with HP ± endocrine therapy for 6 cycles (PET-responders) or with TCHP for 6 cycles (PET-non-responders). The primary objective was to associate HER2DX pCR-score with pathological complete response (pCR). The secondary objective was the association of HER2DX risk-score with 3-year invasive disease-free survival (iDFS). RESULTS: HER2DX was performed on 292 (82.0%) tumors. The overall pCR rate was 38.0%, with pCR rates of 56.4% in group A and 33.8% in group B. In multivariable analysis including treatment and clinicopathological factors, HER2DX pCR-score (continuous variable) significantly correlated with pCR (odds ratio [OR]=1.29, 95% confident interval [CI] 1.10-1.54, p<0.001). HER2DX-defined pCR-high, med, and low groups exhibited pCR rates of 50.4%, 35.8%, and 23.2%, respectively (pCR-high vs pCR-low OR=3.27, CI 1.54-7.09, p<0.001). In patients with residual disease, HER2DX high-risk group demonstrated numerically worse 3-year iDFS than the low-risk group (89.8% vs 100%; HR= 2.70, 95% CI 0.60-12.18, p=0.197). CONCLUSIONS: HER2DX predicts pCR in the context of neoadjuvant HP-based therapy, regardless of chemotherapy addition, and might identify patients at higher risk of recurrence among patients with residual disease.

How Do I Examine Laryngeal Dystonia?

Laryngeal dystonia is a potentially disabling task specific dystonia primarily affecting speech. The evaluation and diagnosis of laryngeal dystonia remain challenging, and often require a multi-disciplinary approach, involving collaboration among speech language pathologists, neurologists and laryngologists (1-5). It is crucial to correctly differentiate between the types of laryngeal dystonia due to the distinct therapeutic approaches and responses to botulinum toxin therapy or speech therapy. For educational purposes, we have divided laryngeal dystonia into two main types: adductor and abductor dystonia. In this article, we describe a series of examination techniques that can assist movement disorders neurologists diagnosing this condition, and appropriately differentiating the most common forms of laryngeal dystonia.

Contributions of Brain Microstructures and Metabolism to Visual Field Loss Patterns in Glaucoma Using Archetypal and Information Gain Analyses.

Purpose: To investigate the contributions of the microstructural and metabolic brain environment to glaucoma and their association with visual field (VF) loss patterns by using advanced diffusion magnetic resonance imaging (dMRI), proton magnetic resonance spectroscopy (MRS), and clinical ophthalmic measures. Methods: Sixty-nine glaucoma and healthy subjects underwent dMRI and/or MRS at 3 Tesla. Ophthalmic data were collected from VF perimetry and optical coherence tomography. dMRI parameters of microstructural integrity in the optic radiation and MRS-derived neurochemical levels in the visual cortex were compared among early glaucoma, advanced glaucoma, and healthy controls. Multivariate regression was used to correlate neuroimaging metrics with 16 archetypal VF loss patterns. We also ranked neuroimaging, ophthalmic, and demographic attributes in terms of their information gain to determine their importance to glaucoma. Results: In dMRI, decreasing fractional anisotropy, radial kurtosis, and tortuosity and increasing radial diffusivity correlated with greater overall VF loss bilaterally. Regionally, decreasing intra-axonal space and extra-axonal space diffusivities correlated with greater VF loss in the superior-altitudinal area of the right eye and the inferior-altitudinal area of the left eye. In MRS, both early and advanced glaucoma patients had lower gamma-aminobutyric acid (GABA), glutamate, and choline levels than healthy controls. GABA appeared to associate more with superonasal VF loss, and glutamate and choline more with inferior VF loss. Choline ranked third for importance to early glaucoma, whereas radial kurtosis and GABA ranked fourth and fifth for advanced glaucoma. Conclusions: Our findings highlight the importance of non-invasive neuroimaging biomarkers and analytical modeling for unveiling glaucomatous neurodegeneration and how they reflect complementary VF loss patterns.

Sex differences in the social motivation of rats: Insights from social operant conditioning, behavioural economics, and video tracking.

BACKGROUND: Social behaviour plays a key role in mental health and wellbeing, and developing greater understanding of mechanisms underlying social interaction-particularly social motivation-holds substantial transdiagnostic impact. Common rodent behavioural assays used to assess social behaviour are limited in their assessment of social motivation, whereas the social operant conditioning model can provide unique and valuable insights into social motivation. Further characterisation of common experimental parameters that may influence social motivation within the social operant model, as well as complementary methodological and analytical approaches, are warranted. METHODS: This study investigated the effects of biological sex, housing condition, and time-of-day, on social motivation using the social operant model. This involved training rats to lever press (FR1) for 60-s access to a social reward (same-sex conspecific stimulus). Subjects were male and female Wistar rats, housed under individual or paired conditions, and sessions were conducted either in the mid-late light phase (ZT6-10) or early-mid dark phase (ZT13-17). A behavioural economics approach was implemented to measure social demand and the influence of stimulus partner sex (same- vs. opposite-sex stimulus) on social operant responding. Additionally, video tracking analyses were conducted to assess the degree of convergence between social appetitive and consummatory behaviours. RESULTS: Biological sex, housing conditions, the interaction between sex and housing, and stimulus partner sex potently influenced social motivation, whereas time-of-day did not. Behavioural economics demonstrated that sex, housing, and their interaction influence both the hedonic set-point and elasticity of social demand. Video analysis of social interaction during social operant sessions revealed that social appetitive and consummatory behaviours are not necessarily convergent, and indicate potential social satiety. Lastly, oestrus phase of female experimental and stimulus rats did not impact social motivation within the model. CONCLUSIONS: Social isolation-dependent sex differences exist in social motivation for rats, as assessed by social operant conditioning. The social operant model represents an optimal preclinical assay that comprehensively evaluates social motivation and offers a platform for future investigations of neurobiological mechanisms underlying sex differences in social motivation. These findings highlight the importance of continued consideration and inclusion of sex as a biological variable in future social operant conditioning studies. Humans are social creatures-our everyday interactions with others and the support this provides play a key role in our wellbeing. For those experiencing mental health conditions, people's motivation to engage with others can wane, which can lead them to withdraw from those who support them. Therefore, to develop better treatment strategies for these conditions, we need to gain a deeper understanding of social motivation. Studying social behaviour in animals can facilitate this investigation of social motivation as it allows for a causal understanding of underlying neurobiology that is not possible in human experiments. An optimal way to study social motivation in animals is using the social operant conditioning model, where rats learn to press a lever that opens a door and allows them to interact with another rat for a short time. This study characterised the social operant model by testing whether sex, housing conditions, time-of-day, and the sex of the stimulus partner influence rats' motivation to seek interaction with another rat. We found that female rats were more socially motivated than males, and that rats living alone were more motivated than those living with another rat; interestingly, this effect of housing affected females more than males. Regardless of sex, rats were more motivated to interact with a rat of the opposite sex. These findings provide insights into sex differences in social motivation in rats and new insights into the social operant model which will help guide future research into social motivation and other mental health conditions.

Are Treatment Patterns for Endophthalmitis After Cataract Surgery Following the EVS Trial Recommendations? An IRIS® Registry Analysis.

OBJECTIVE: Evaluate whether treatment patterns for endophthalmitis after cataract surgery in American Academy of Ophthalmology IRIS® Registry (Intelligent Research in Sight) patients are in line with evidence-based guidelines established by the 1995 Endophthalmitis Vitrectomy Treatment Study (EVS), which showed that patients who present with light perception vision (LP) have better visual outcomes with immediate vitrectomy (VIT) compared with vitreous tap with antibiotic injection (TAP). DESIGN: Retrospective cohort study SUBJECTS: IRIS Registry patients undergoing cataract surgery between 2014 and 2022 (identified by CPT codes), presenting with endophthalmitis (identified by ICD 10 codes) within 42 days post-cataract surgery, and having a record of being treated with VIT or TAP on the same or one day following endophthalmitis diagnosis were identified. METHODS: Potential covariates of age, sex, race, ethnicity, geographic region, insurance status, and visual acuity on the day of endophthalmitis diagnosis were evaluated using multivariable logistic regression. MAIN OUTCOME MEASURE: Treatment with VIT or TAP RESULTS: Of the 2425 patients who met the inclusion criteria, 14% (345) underwent VIT and 86% (2080) underwent TAP. 80% of patients (1946) presented with endophthalmitis within 14 days from cataract surgery (median = 6 days). Notably, 66% (173/263) of the patients presenting with LP vision underwent TAP instead of VIT. In a multivariable logistic regression model, receiving VIT instead of TAP was positively associated with poor vision at endophthalmitis presentation (LP - OR, 5.3 [CI: 2.9-10.5]; Counting Fingers, Hand Motion - OR 1.8 [CI: 1.0-3.6]) vs. [20/20-20/40] vision; Asian vs. White race (OR, 2.6 [CI: 1.2-5.1]); Hispanic vs. Non-Hispanic ethnicity (OR, 1.9 [CI, 1.0-3.2]); living in the West (OR, 1.5 [CI, 1.1-2.2]) and Midwest (OR- 1.4 [CI, 1.0-2.0]) (vs. South), but not with age, sex, and insurance coverage (P>0.05). CONCLUSIONS: In the IRIS Registry, treatment patterns for post-cataract surgery endophthalmitis did not match evidence-based recommendations of the EVS, a randomized controlled clinical trial. More work is needed to evaluate whether the current treatment patterns are optimal for patients with post-cataract surgery endophthalmitis.

A gene for all seasons: The evolutionary consequences of HIF-1 in carcinogenesis, tumor growth and metastasis.

Oxygen played a pivotal role in the evolution of multicellularity during the Cambrian Explosion. Not surprisingly, responses to fluctuating oxygen concentrations are integral to the evolution of cancer-a disease characterized by the breakdown of multicellularity. Poorly organized tumor vasculature results in chaotic patterns of blood flow characterized by large spatial and temporal variations in intra-tumoral oxygen concentrations. Hypoxia-inducible growth factor (HIF-1) plays a pivotal role in enabling cells to adapt, metabolize, and proliferate in low oxygen conditions. HIF-1 is often constitutively activated in cancers, underscoring its importance in cancer progression. Here, we argue that the phenotypic changes mediated by HIF-1, in addition to adapting the cancer cells to their local environment, also "pre-adapt" them for proliferation at distant, metastatic sites. HIF-1-mediated adaptations include a metabolic shift towards anaerobic respiration or glycolysis, activation of cell survival mechanisms like phenotypic plasticity and epigenetic reprogramming, and formation of tumor vasculature through angiogenesis. Hypoxia induced epigenetic reprogramming can trigger epithelial to mesenchymal transition in cancer cells-the first step in the metastatic cascade. Highly glycolytic cells facilitate local invasion by acidifying the tumor microenvironment. New blood vessels, formed due to angiogenesis, provide cancer cells a conduit to the circulatory system. Moreover, survival mechanisms acquired by cancer cells in the primary site allow them to remodel tissue at the metastatic site generating tumor promoting microenvironment. Thus, hypoxia in the primary tumor promoted adaptations conducive to all stages of the metastatic cascade from the initial escape entry into a blood vessel, intravascular survival, extravasation into distant tissues, and establishment of secondary tumors.

Effects of rate of body weight gain during the first trimester of gestation on beef heifer and offspring performance, concentrations of hormones and metabolites, and response to vaccination.

Our study objectives were to evaluate the effects of divergent rates of body weight (BW) gain during early gestation in beef heifers on F0 performance, metabolic and endocrine status, colostrum immunoglobulins, and subsequent F1 calf characteristics, growth performance, concentrations of hormones and metabolites, and response to vaccination. Angus-based heifers (n = 100; BW = 369 ± 2.5 kg) were adapted to individual feeding for 14 d and bred using artificial insemination with female-sexed semen. Heifers were ranked by BW assigned to either a basal diet targeting 0.28 kg/d gain (LG, n = 50) or the basal diet plus an energy/protein supplement targeting 0.79 kg/d gain (MG, n = 50) until d 84 of gestation. Dam BW and blood samples were collected at 6 time points during gestation; body composition was evaluated at d -10 and 84; and fetal measurements were taken on d 42, 63, and 84. At calving (LG, n = 23; MG, n = 23), dam and calf BW were recorded; and colostrum, calf body measurements, and blood samples were collected. Cow-calf pairs were managed on a common diet from calving to weaning, followed by a common postnatal development period for all F1 female offspring. Growth performance, hormone and metabolite profiles, feeding behavior, and reproductive performance were assessed from birth to pre-breeding in F1 heifers. Offspring were vaccinated against respiratory disease and bovine viral diarrhea pathogens on d 62.3 ± 4.13 and 220.3 ± 4.13 post-calving. By design, MG dams were heavier (P < 0.0001) than LG at d 84, and the BW advantage persisted until subsequent weaning of F1 calves. Concentrations of serum IGF-1 and glucose were increased throughout gestation (P < 0.001) for MG dams, whereas concentrations of NEFA were decreased (P < 0.001) in LG dams. Calves from MG dams were 2.14 kg heavier (P = 0.03) and had larger chest circumference (P = 0.04) at birth compared with LG cohorts. Heifers from MG dams continued to have greater (P ≤ 0.03) BW gain and feed efficiency during the development period, but no differences were observed (P ≥ 0.13) in body composition, concentrations of hormones and metabolites, feeding behavior, puberty attainment, and response to vaccination in F1 offspring. Hence, early gestation rate of gain impacted BW and concentrations of glucose and IGF-1 throughout gestation in the F0 dam, resulting in altered F1 calf BW and measurements at birth and increased gain and efficiency during the development period.

One-carbon metabolite supplementation increases vitamin B12, folate, and methionine cycle metabolites in beef heifers and fetuses in an energy dependent manner at day 63 of gestation.

One-carbon metabolites (OCM) are metabolites and cofactors which include folate, vitamin B12, methionine, and choline that support methylation reactions. The objectives of this study were to investigate the effects of moderate changes in maternal body weight gain in combination with OCM supplementation during the first 63 days of gestation in beef cattle on (1) B12 and folate concentrations in maternal serum (2) folate cycle intermediates in maternal and fetal liver, allantoic fluid (ALF), and amniotic fluid (AMF) and (3) metabolites involved in one-carbon metabolism and related metabolic pathways in maternal and fetal liver. Heifers were either intake restricted (RES) and fed to lose 0.23 kg/d, or fed to gain 0.60 kg/d (CON). Supplemented (+OCM) heifers were given B12 and folate injections weekly and fed rumen protected methionine and choline daily, while non-supplemented (-OCM) heifers were given weekly saline injections. These two treatments were combined in a 2 × 2 factorial arrangement resulting in four treatments: CON-OCM, CON+OCM, RES-OCM, and RES+OCM. Samples of maternal serum, maternal and fetal liver, ALF, and AMF were collected at slaughter on day 63 of gestation. Restricted maternal nutrition most notably increased (P ≤ 0.05) the concentration of: vitamin B12 in maternal serum, 5,10-methylenetetrahydrofolate and 5,10-methenyltetrahydrofolate in maternal liver, and of cystathionine in fetal liver; conversely, maternal restriction decreased (P = 0.05) 5,10-methylenetetrahydrofolate concentration in fetal liver. Supplementing OCM increased (P ≤ 0.05) the concentrations of: maternal serum B12, folate and folate intermediates, ALF and AMF 5-methyltetrahydrofolate concentration, and altered (P ≤ 0.02) other maternal liver intermediates including S-adenosylmethionine, dimethylglycine, cystathionine Glutathione reduced, glutathione oxidized, taurine, serine, sarcosine, and pyridoxine. These data demonstrate that OCM supplementation was effective at increasing maternal OCM status. Furthermore, these data are similar to previously published literature where restricted maternal nutrition also affected maternal OCM status. Altering OCM status in both the dam and fetus could impact fetal developmental outcomes and production efficiencies. Lastly, these data demonstrate that fetal metabolite abundance is highly regulated, although the changes required to maintain homeostasis may program altered metabolism postnatally.

Type II innate lymphoid cell plasticity contributes to impaired reconstitution after allogeneic hematopoietic stem cell transplantation.

Type II innate lymphoid cells (ILC2s) maintain homeostasis and barrier integrity in mucosal tissues. In both mice and humans, ILC2s poorly reconstitute after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Determining the mechanisms involved in their impaired reconstitution could improve transplant outcomes. By integrating single-cell chromatin and transcriptomic analyses of transplanted ILC2s, we identify a previously unreported population of converted ILC1-like cells in the mouse small intestine post-transplant. Exposure of ILC2s to proinflammatory cytokines resulted in a mixed ILC1-ILC2 phenotype but was able to convert only a small population of ILC2s to ILC1s, which were found post-transplant. Whereas ILC2s protected against acute graft-versus-host disease (aGVHD) mediated mortality, infusion of proinflammatory cytokine-exposed ILC2s accelerated aGvHD. Interestingly, murine ILC2 reconstitution post-HSCT is decreased in the presence of alloreactive T cells. Finally, peripheral blood cells from human patients with aGvHD have an altered ILC2-associated chromatin landscape compared to transplanted controls. These data demonstrate that following transplantation ILC2s convert to a pro-pathogenic population with an ILC1-like chromatin state and provide insights into the contribution of ILC plasticity to the impaired reconstitution of ILC2 cells, which is one of several potential mechanisms for the poor reconstitution of these important cells after allo-HSCT.

Differing planes of nutrition alter serum and histotroph amino acid composition in nonpregnant, multiparous beef cows on day three of the estrous cycle.

Endometrial-derived uterine histotroph is a critical component of nutrient supply to a growing conceptus throughout gestation; however, the effect of nutritional plane on histotroph nutrient composition remains unknown in multiparous cows. We hypothesized that differing planes of nutrition would alter histotroph and serum nutrient composition in beef cattle. Thus, we evaluated serum and histotroph amino acid and glucose composition, and serum non-esterified fatty acids (NEFA) and blood urea nitrogen (BUN) in cows individually fed to maintain body weight (0 kd/d, n = 9; CON) compared with those losing moderate body weight (-0.7 kg/d, n = 9; NEG). After 49 d of differing nutritional planes, cows were subjected to the 7-d CoSynch + CIDR estrus synchronization protocol and then slaughtered on d 62. Blood serum (d 0 and 62) and uterine histotroph [d 62; from uterine horns ipsilateral and contralateral to the corpus luteum (CL)] were collected and analyzed for concentrations of amino acids, glucose, and NEFA. Performance characteristics, body composition via ultrasound (d 0 and 62), and carcass characteristics were collected. Body condition score, change in body weight, average daily gain (ADG), dry matter intake (DMI), and gain:feed (G:F) were decreased (P ≤ 0.05) in NEG vs. CON cows. There were no differences in body composition or carcass characteristics, except an increase (P ≤ 0.05) in dressing percentage in NEG cows due to differences in gut fill, consistent with study design. Serum NEFA increased (P ≤ 0.05) in the NEG group, but there were no differences between NEG vs. CON in glucose or BUN. Serum histidine increased (P ≤ 0.05) and alanine, isoleucine and tryptophan decreased (P ≤ 0.05) in NEG vs. CON cows. Compared with that of the uterine horn ipsilateral to the CL, histotroph from the uterine horn contralateral to the CL had increased (P ≤ 0.05) isoleucine, asparagine, and proline concentrations in NEG cows, and decreased (P ≤ 0.05) tryptophan as a proportion of essential and total amino acids. There were no differences in glucose concentrations of histotroph contralateral or ipsilateral to the CL. Cow nutritional plane does alter serum and histotroph amino acid composition, although the presence of an embryo may be necessary to fully elucidate these changes. Differences in serum and histotroph tryptophan should be given consideration in future studies due to its importance as an essential amino acid in protein synthesis and bioactive affects.

Mitigation of Fetal Radiation Injury from Mid-Gestation Total-body Irradiation by Maternal Administration of Mitochondrial-Targeted GS-Nitroxide JP4-039.

Victims of a radiation terrorist event will include pregnant women and unborn fetuses. Mitochondrial dysfunction and oxidative stress are key pathogenic factors of fetal radiation injury. The goal of this preclinical study is to investigate the efficacy of mitigating fetal radiation injury by maternal administration of the mitochondrial-targeted gramicidin S (GS)-nitroxide radiation mitigator JP4-039. Pregnant female C57BL/6NTac mice received 3 Gy total-body irradiation (TBI) at mid-gestation embryonic day 13.5 (E13.5). Using novel time-and-motion-resolved 4D in utero magnetic resonance imaging (4D-uMRI), we found TBI caused extensive injury to the fetal brain that included cerebral hemorrhage, loss of cerebral tissue, and hydrocephalus with excessive accumulation of cerebrospinal fluid (CSF). Histopathology of the fetal mouse brain showed broken cerebral vessels and elevated apoptosis. Further use of novel 4D Oxy-wavelet MRI capable of probing in vivo mitochondrial function in intact brain revealed a significant reduction of mitochondrial function in the fetal brain after 3 Gy TBI. This was validated by ex vivo Oroboros mitochondrial respirometry. One day after TBI (E14.5) maternal administration of JP4-039, which passes through the placenta, significantly reduced fetal brain radiation injury and improved fetal brain mitochondrial respiration. Treatment also preserved cerebral brain tissue integrity and reduced cerebral hemorrhage and cell death. JP4-039 administration following irradiation resulted in increased survival of pups. These findings indicate that JP4-039 can be deployed as a safe and effective mitigator of fetal radiation injury from mid-gestational in utero ionizing radiation exposure.

Standardization and clinical applications of retinal imaging biomarkers for cardiovascular disease: a Roadmap from an NHLBI workshop.

The accessibility of the retina with the use of non-invasive and relatively low-cost ophthalmic imaging techniques and analytics provides a unique opportunity to improve the detection, diagnosis and monitoring of systemic diseases. The National Heart, Lung, and Blood Institute conducted a workshop in October 2022 to examine this concept. On the basis of the discussions at that workshop, this Roadmap describes current knowledge gaps and new research opportunities to evaluate the relationships between the eye (in particular, retinal biomarkers) and the risk of cardiovascular diseases, including coronary artery disease, heart failure, stroke, hypertension and vascular dementia. Identified gaps include the need to simplify and standardize the capture of high-quality images of the eye by non-ophthalmic health workers and to conduct longitudinal studies using multidisciplinary networks of diverse at-risk populations with improved implementation and methods to protect participant and dataset privacy. Other gaps include improving the measurement of structural and functional retinal biomarkers, determining the relationship between microvascular and macrovascular risk factors, improving multimodal imaging 'pipelines', and integrating advanced imaging with 'omics', lifestyle factors, primary care data and radiological reports, by using artificial intelligence technology to improve the identification of individual-level risk. Future research on retinal microvascular disease and retinal biomarkers might additionally provide insights into the temporal development of microvascular disease across other systemic vascular beds.

Defining the Regulatory Logic of Breast Cancer Using Single-Cell Epigenetic and Transcriptome Profiling.

Annotation of the cis-regulatory elements that drive transcriptional dysregulation in cancer cells is critical to improving our understanding of tumor biology. Herein, we present a compendium of matched chromatin accessibility (scATAC-seq) and transcriptome (scRNA-seq) profiles at single-cell resolution from human breast tumors and healthy mammary tissues processed immediately following surgical resection. We identify the most likely cell-of-origin for luminal breast tumors and basal breast tumors and then introduce a novel methodology that implements linear mixed-effects models to systematically quantify associations between regions of chromatin accessibility (i.e. regulatory elements) and gene expression in malignant cells versus normal mammary epithelial cells. These data unveil regulatory elements with that switch from silencers of gene expression in normal cells to enhancers of gene expression in cancer cells, leading to the upregulation of clinically relevant oncogenes. To translate the utility of this dataset into tractable models, we generated matched scATAC-seq and scRNA-seq profiles for breast cancer cell lines, revealing, for each subtype, a conserved oncogenic gene expression program between in vitro and in vivo cells. Together, this work highlights the importance of non-coding regulatory mechanisms that underlie oncogenic processes and the ability of single-cell multi-omics to define the regulatory logic of BC cells at single-cell resolution.

Development of Chronic Pain Conditions Among Women in the Military Health System.

Importance: The incidence of chronic pain has been increasing over the last decades and may be associated with the stress of deployment in active-duty servicewomen (ADSW) as well as women civilian dependents whose spouse or partner served on active duty. Objective: To assess incidence of chronic pain among active-duty servicewomen and women civilian dependents with service during 2006 to 2013 compared with incidence among like individuals at a time of reduced combat exposure and deployment intensity (2014-2020). Design, Setting, and Participants: This cohort study used claims data from the Military Health System data repository to identify ADSW and dependents who were diagnosed with chronic pain. The incidence of chronic pain among individuals associated with service during 2006 to 2013 was compared with 2014 to 2020 incidence. Data were analyzed from September 2023 to April 2024. Main Outcomes and Measures: The primary outcome was the diagnosis of chronic pain. Multivariable logistic regression analyses were used to adjust for confounding, and secondary analyses were performed to account for interactions between time period and proxies for socioeconomic status and combat exposure. Results: A total of 3 473 401 individuals (median [IQR] age, 29.0 [22.0-46.0] years) were included, with 644 478 ADSW (18.6%). Compared with ADSW in 2014 to 2020, ADSW in 2006 to 2013 had significantly increased odds of chronic pain (odds ratio [OR], 1.53; 95% CI, 1.48-1.58). The odds of chronic pain among dependents in 2006 to 2013 was also significantly higher compared with dependents from 2014 to 2020 (OR, 1.96; 95% CI, 1.93-1.99). The proxy for socioeconomic status was significantly associated with an increased odds of chronic pain (2006-2013 junior enlisted ADSWs: OR, 1.95; 95% CI, 1.83-2.09; 2006-2013 junior enlisted dependents: OR, 3.05; 95% CI, 2.87-3.25). Conclusions and Relevance: This cohort study found significant increases in the diagnosis of chronic pain among ADSW and civilian dependents affiliated with the military during a period of heightened deployment intensity (2006-2013). The effects of disparate support structures, coping strategies, stress regulation, and exposure to military sexual trauma may apply to both women veterans and civilian dependents.

The Central Role of Cytogenetics in Radiation Biology.

Radiation cytogenetics has a rich history seldom appreciated by those outside the field. Early radiobiology was dominated by physics and biophysical concepts that borrowed heavily from the study of radiation-induced chromosome aberrations. From such studies, quantitative relationships between biological effect and changes in absorbed dose, dose rate and ionization density were codified into key concepts of radiobiological theory that have persisted for nearly a century. This review aims to provide a historical perspective of some of these concepts, including evidence supporting the contention that chromosome aberrations underlie development of many, if not most, of the biological effects of concern for humans exposed to ionizing radiations including cancer induction, on the one hand, and tumor eradication on the other. The significance of discoveries originating from these studies has widened and extended far beyond their original scope. Chromosome structural rearrangements viewed in mitotic cells were first attributed to the production of breaks by the radiations during interphase, followed by the rejoining or mis-rejoining among ends of other nearby breaks. These relatively modest beginnings eventually led to the discovery and characterization of DNA repair of double-strand breaks by non-homologous end joining, whose importance to various biological processes is now widely appreciated. Two examples, among many, are V(D)J recombination and speciation. Rapid technological advancements in cytogenetics, the burgeoning fields of molecular radiobiology and third-generation sequencing served as a point of confluence between the old and new. As a result, the emergent field of "cytogenomics" now becomes uniquely positioned for the purpose of more fully understanding mechanisms underlying the biological effects of ionizing radiation exposure.

Clinical Outcomes Following Operative and Nonoperative Management of Odontoid Fractures Among Elderly Individuals with Dementia.

BACKGROUND: The incidence of odontoid fractures among the elderly population has been increasing in recent years. Elderly individuals with dementia may be at increased risk for inferior outcomes following such fractures. Although surgical intervention has been maintained to optimize survival and recovery, it is unclear if this benefit extends to patients with dementia. We hypothesized that patients with dementia who were treated operatively for odontoid fractures would experience improved survival and lower rates of hospice admission but higher rates of delirium and of intensive interventions. METHODS: We used Medicare claims data (2017 to 2018) to identify community-dwelling individuals with dementia who sustained type-II odontoid fractures. We considered treatment strategy (operative or nonoperative) as the primary predictor and survival as the primary outcome. The secondary outcomes consisted of post-treatment delirium, hospice admission, post-treatment intensive intervention, and post-discharge admission to a nursing home or a skilled nursing facility. In all models, we controlled for age, biological sex, race, Elixhauser Comorbidity Index, Frailty Index, admission source, treating hospital, and dual eligibility. Adjusted analyses for survival were conducted using Cox proportional hazards regression. Adjusted analyses for secondary outcomes were performed using generalized estimating equations. To address confounding by indication, we performed confirmatory analyses using inverse probability of treatment weighting. RESULTS: In this study, we included 1,030 patients. The median age of the cohort was 86.5 years (interquartile range, 80.9 to 90.8 years), 60.7% of the patients were female, and 90% of the patients were White. A surgical procedure was performed in 19.8% of the cohort. Following an adjusted analysis, patients treated surgically had a 28% lower hazard of mortality (hazard ratio, 0.72 [95% confidence interval (CI), 0.53 to 0.98]), but higher odds of delirium (odds ratio, 1.64 [95% CI, 1.10 to 2.44]). These findings were preserved in the inverse probability weighted analysis. CONCLUSIONS: We found that, among individuals with dementia who sustain a type-II odontoid fracture, surgical intervention may confer a survival benefit. A surgical procedure may be an appropriate treatment strategy for individuals with dementia whose life-care goals include life prolongation and maximizing quality of life in the short term following an injury. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.