The noncoding circular RNA circHomer1 regulates developmental experience-dependent plasticity in mouse visual cortex.

Circular RNAs (circRNAs) are noncoding RNAs abundant in brain tissue, and many are derived from activity-dependent, linear mRNAs encoding for synaptic proteins, suggesting that circRNAs may directly or indirectly play a role in regulating synaptic development, plasticity, and function. However, it is unclear if the circular forms of these RNAs are similarly regulated by activity and what role these circRNAs play in developmental plasticity. Here, we employed transcriptome-wide analysis comparing differential expression of both mRNAs and circRNAs in juvenile mouse primary visual cortex (V1) following monocular deprivation (MD), a model of developmental plasticity. Among the differentially expressed mRNAs and circRNAs following 3-day MD, the circular and the activity-dependent linear forms of the Homer1 gene, circHomer1 and Homer1a respectively, were of interest as their expression changed in opposite directions: circHomer1 expression increased while the expression of Homer1a decreased following MD. Knockdown of circHomer1 prevented the depression of closed-eye responses normally observed after 3-day MD. circHomer1-knockdown led to a reduction in average dendritic spine size prior to MD, but critically there was no further reduction after 3-day MD, consistent with impaired structural plasticity. circHomer1-knockdown also prevented the reduction of surface AMPA receptors after 3-day MD. Synapse-localized puncta of the AMPA receptor endocytic protein Arc increased in volume after MD but were smaller in circHomer1-knockdown neurons, suggesting that circHomer1 regulates plasticity through mechanisms of activity-dependent AMPA receptor endocytosis. Thus, activity-dependent circRNAs regulate developmental synaptic plasticity, and our findings highlight the essential role of circHomer1 in V1 plasticity induced by short-term MD.

Targeted muscle reinnervation at the time of amputation to prevent the development of neuropathic pain.

INTRODUCTION: Targeted muscle reinnervation (TMR) is an established modality for the surgical management of neuropathic pain. Although the preventive effect of primary (acute) TMR at the time of amputation has been demonstrated previously, it remains unclear how many and which patients benefit most. Therefore, this study investigated the proportion of patients achieving sustained pain prophylaxis following amputation, as well as factors associated with its efficacy. METHODS: Primary patients who underwent TMR with a minimum follow-up of 6 months between 2018 and 2023 were enrolled. Pain outcomes (numeric rating scale [NRS], 0-10), comorbidities, and surgical factors were collected from chart review. Patients achieving sustained pain prophylaxis (NRS of ≤3 for ≥3 months until final follow-up) were identified. Multilevel mixed-effect models and multivariable regression were used to visualize pain courses and identify associated factors. RESULTS: Seventy-five patients who underwent primary TMR were included (median follow-up: 2.0 years), of whom 57.3% achieved sustained pain prophylaxis whereas 26.7% reported pain disappearance. Distal amputation levels (p = 0.036), a lower Elixhauser Comorbidity Index (p = 0.001), and the absence of psychiatric comorbidities (p = 0.039) were associated with pain prophylaxis. CONCLUSION: This study demonstrates that more than half of all patients undergoing primary TMR achieved sustained pain prophylaxis, and approximately a quarter of patients achieved sustained pain disappearance. Several factors associated with these favorable outcomes are described. These results will aid in preoperative counseling, managing patient expectations, and selecting patients who may benefit most from primary TMR surgery. LEVEL OF EVIDENCE: IV - Therapeutic.

Design, Construction, and Test of Compact, Distributed-Charge, X-Band Accelerator Systems that Enable Image-Guided, VHEE FLASH Radiotherapy.

The design and optimization of laser-Compton x-ray systems based on compact distributed charge accelerator structures can enable micron-scale imaging of disease and the concomitant production of beams of Very High Energy Electrons (VHEEs) capable of producing FLASH-relevant dose rates. The physics of laser-Compton x-ray scattering ensures that the scattered x-rays follow exactly the trajectory of the incident electrons, thus providing a route to image-guided, VHEE FLASH radiotherapy. The keys to a compact architecture capable of producing both laser-Compton x-rays and VHEEs are the use of X-band RF accelerator structures which have been demonstrated to operate with over 100 MeV/m acceleration gradients. The operation of these structures in a distributed charge mode in which each radiofrequency (RF) cycle of the drive RF pulse is filled with a low-charge, high-brightness electron bunch is enabled by the illumination of a high-brightness photogun with a train of UV laser pulses synchronized to the frequency of the underlying accelerator system. The UV pulse trains are created by a patented pulse synthesis approach which utilizes the RF clock of the accelerator to phase and amplitude modulate a narrow band continuous wave (CW) seed laser. In this way it is possible to produce up to 10 {\mu}A of average beam current from the accelerator. Such high current from a compact accelerator enables production of sufficient x-rays via laser-Compton scattering for clinical imaging and does so from a machine of "clinical" footprint. At the same time, the production of 1000 or greater individual micro-bunches per RF pulse enables > 10 nC of charge to be produced in a macrobunch of < 100 ns. The design, construction, and test of the 100-MeV class prototype system in Irvine, CA is also presented.

Evaluation of the Reliability of the CCM-300 Chlorophyll Content Meter in Measuring Chlorophyll Content for Various Plant Functional Types.

Chlorophyll fluorescence is a well-established method to estimate chlorophyll content in leaves. A popular fluorescence-based meter, the Opti-Sciences CCM-300 Chlorophyll Content Meter (CCM-300), utilizes the fluorescence ratio F735/F700 and equations derived from experiments using broadleaf species to provide a direct, rapid estimate of chlorophyll content used for many applications. We sought to quantify the performance of the CCM-300 relative to more intensive methods, both across plant functional types and years of use. We linked CCM-300 measurements of broadleaf, conifer, and graminoid samples in 2018 and 2019 to high-performance liquid chromatography (HPLC) and/or spectrophotometric (Spec) analysis of the same leaves. We observed a significant difference between the CCM-300 and HPLC/Spec, but not between HPLC and Spec. In comparison to HPLC, the CCM-300 performed better for broadleaves (r = 0.55, RMSE = 154.76) than conifers (r = 0.52, RMSE = 171.16) and graminoids (r = 0.32, RMSE = 127.12). We observed a slight deterioration in meter performance between years, potentially due to meter calibration. Our results show that the CCM-300 is reliable to demonstrate coarse variations in chlorophyll but may be limited for cross-plant functional type studies and comparisons across years.

Healthcare Use and Expenditures in Rural Survivors of Hospitalization for Sepsis.

OBJECTIVES: Sepsis survivors have greater healthcare use than those surviving hospitalizations for other reasons, yet factors associated with greater healthcare use in this population remain ill-defined. Rural Americans are older, have more chronic illnesses, and face unique barriers to healthcare access, which could affect postsepsis healthcare use. Therefore, we compared healthcare use and expenditures among rural and urban sepsis survivors. We hypothesized that rural survivors would have greater healthcare use and expenditures. DESIGN, SETTING, AND PATIENTS: To test this hypothesis, we used data from 106,189 adult survivors of a sepsis hospitalization included in the IBM MarketScan Commercial Claims and Encounters database and Medicare Supplemental database between 2013 and 2018. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We identified hospitalizations for severe sepsis and septic shock using the International Classification of Diseases, 9th Edition (ICD-9) or 1CD-10 codes. We used Metropolitan Statistical Area classifications to categorize rurality. We measured emergency department (ED) visits, inpatient hospitalizations, skilled nursing facility admissions, primary care visits, physical therapy visits, occupational therapy visits, and home healthcare visits for the year following sepsis hospitalizations. We calculated the total expenditures for each of these categories. We compared outcomes between rural and urban patients using multivariable regression and adjusted for covariates. After adjusting for age, sex, comorbidities, admission type, insurance type, U.S. Census Bureau region, employment status, and sepsis severity, those living in rural areas had 17% greater odds of having an ED visit (odds ratio [OR] 1.17; 95% CI, 1.13-1.22; p < 0.001), 9% lower odds of having a primary care visit (OR 0.91; 95% CI, 0.87-0.94; p < 0.001), and 12% lower odds of receiving home healthcare (OR 0.88; 95% CI, 0.84-0.93; p < 0.001). Despite higher levels of ED use and equivalent levels of hospital readmissions, expenditures in these areas were 14% (OR 0.86; 95% CI, 0.80-0.91; p < 0.001) and 9% (OR 0.91; 95% CI, 0.87-0.96; p < 0.001) lower among rural survivors, respectively, suggesting these services may be used for lower-acuity conditions. CONCLUSIONS: In this large cohort study, we report important differences in healthcare use and expenditures between rural and urban sepsis survivors. Future research and policy work is needed to understand how best to optimize sepsis survivorship across the urban-rural continuum.

Progression and perceptual responses to blood flow restriction resistance training among people with multiple sclerosis.

PURPOSE: Resistance exercise can attenuate muscular impairments associated with multiple sclerosis (MS), and blood flow restriction (BFR) may provide a viable alternative to prescribing heavy training loads. The purpose of this investigation was to examine the progression of upper and lower body low-load (30% of one-repetition maximum [1RM]) resistance training (RT) with BFR applied intermittently during the exercise intervals (RT + BFR) versus volume-matched heavy-load (65% of 1RM) RT. METHODS: Men and women with MS (n = 16) were randomly assigned to low-load RT + BFR (applied intermittently) or heavy-load RT and completed 12 weeks (2 × /week) of RT that consisted of bilateral chest press, seated row, shoulder press, leg press, leg extension, and leg curl exercises. Exercise load, tonnage, and rating of perceived exertion were assessed at baseline and every 6 weeks. RESULTS: Training load increased to a greater extent and sometimes earlier for RT + BFR (57.7-106.3%) than heavy-load RT (42.3-54.3%) during chest press, seated row, and leg curl exercises, while there were similar increases (63.5-101.1%) for shoulder press, leg extension, and leg press exercises. Exercise tonnage was greater across all exercises for RT + BFR than heavy-load RT, although tonnage only increased during the chest press (70.7-80.0%) and leg extension (89.1%) exercises. Perceptions of exertion (4.8-7.2 au) and compliance (97.9-99.0%) were similar for both interventions. CONCLUSION: The training-induced increases in load, high compliance, and moderate levels of exertion suggested that RT + BFR and heavy-load RT are viable interventions among people with MS. RT + BFR may be a preferred modality if heavy loads are not well tolerated and/or to promote early-phase training responses.

Social Deprivation is Associated with Increased Pain in Patients Presenting with Neuropathic Pain.

Background: Neuropathic pain following nerve injury can be debilitating and negatively impact quality of life. Targeted muscle reinnervation (TMR) is an efficacious technique for the management of neuropathic pain. However, this technique may be unequally available for many geographical locations. Therefore, the aim of this study was to evaluate the association between Area Deprivation Index (ADI) and preoperative pain in patients undergoing TMR for treatment of neuropathic pain. Methods: Patients who underwent TMR for neuropathic pain in the lower and upper extremities were prospectively enrolled at our tertiary care clinic. A chart review was conducted to obtain socioeconomic, surgery, and comorbidity parameters. Preoperative pain scores (0-10 pain score index), and the ADI, reflecting deprivation status on a 0-100 scale, were collected. Results: A total of 162 patients from 13 different states were included, of which 119 were amputees (74%). The median ADI was 25 (IQR: 16-41) and the median preoperative pain score was 6 (IQR: 5-8). A higher ADI was independently associated with higher preoperative pain. The time interval from nerve injury to TMR was not associated with ADI. Conclusions: Patients undergoing surgical treatment of neuropathic pain from more socially deprived settings have increased pain experience upon initial evaluation, despite having similar time from nerve injury or amputation to TMR. These findings highlight the importance of identifying patients presenting from socially deprived settings, as this may impact their physical and mental health along with their coping mechanisms, resulting in increased pain.

Culturing Primary Cortical Neurons for Live-Imaging.

Primary neuronal cultures allow for in vitro analysis of early developmental processes such as axon pathfinding and growth dynamics. When coupled with methods to visualize and measure microtubule dynamics, this methodology enables an inside look at how the cytoskeleton changes in response to extracellular signaling cues. Here, we describe the culturing conditions and tools required to extract primary cortical neurons from postnatal mouse brains and visualize cytoskeletal components.

Psychosocial and functional impact of successful digital replantation - A cohort study of 36 patients with a median follow-up of 6 years.

INTRODUCTION: This study aims to evaluate the long-term psychosocial and functional outcomes of successful digital replantation following traumatic amputation. METHODS: Patients that underwent successful replantation (i.e. no secondary amputation following replantation) of one or more traumatically amputated digits between January 2009 and April 2019 were invited to participate in this study. In addition to a custom questionnaire on psychosocial and socioeconomic aspects of life, various Patient-Reported Outcomes Measurement Information System (PROMIS) questionnaires regarding global health, upper extremity function, and depressive symptoms were completed. Bivariate analyses were performed to identify significant associations between outcomes and explanatory variables. RESULTS: Thirty-six patients were successfully enrolled and completed the questionnaires at a median follow-up of 6.1 years. The median PROMIS score for Upper Extremity Function (40.6) was considerably different from the score that is typically found in the general population (all PROMIS instruments are calibrated with a control group score of 50.0), but the median PROMIS scores for Global Health - Physical (49.0), Global Health - Mental (50.7), and Depression (45.6) were comparable to those among the general population. Dominant hand injury, a greater number of injured digits, higher age at the time of injury, and the need for neuropathic pain medication were associated with lower Upper Extremity Function scores (all p < 0.05). Additionally, the presence of neuroma was associated with negative changes in both household finances and mental well-being (p < 0.05). CONCLUSIONS: At long-term follow-up, a majority of patients that underwent replantation of traumatically amputated digits seem to cope well based on psychosocial and functional outcomes. However, neuropathic pain and the presence of neuroma are strong negative factors. Specific attention to digital nerves at the time of surgery is crucial in the management of traumatic amputations.

Salmon hatchery strays can demographically boost wild populations at the cost of diversity: quantitative genetic modelling of Alaska pink salmon.

Hatcheries are vital to many salmon fisheries, with inherent risks and rewards. While hatcheries can increase the returns of adult fish, the demographic and evolutionary consequences for natural populations interacting with hatchery fish on spawning grounds remain unclear. This study examined the impacts of stray hatchery-origin pink salmon on natural population productivity and resilience. We explored temporal assortative mating dynamics using a quantitative genetic model that assumed the only difference between hatchery- and natural-origin adults was their return timing to natural spawning grounds. This model was parameterized with empirical data from an intensive multi-generational study of hatchery-wild interactions in the world's largest pink salmon fisheries enhancement program located in Prince William Sound, Alaska. Across scenarios of increasing hatchery fish presence on spawning grounds, our findings underscore a trade-off between demographic enhancement and preservation of natural population diversity. While enhancement bolstered natural population sizes towards local carrying capacities, hatchery introgression reduced variation in adult return timing by up to 20%. Results indicated that hatchery-origin alleles can rapidly assimilate into natural populations, despite the reduced fitness of hatchery fish attributable to phenotypic mismatches. These findings elucidate the potential for long-term demographic and evolutionary consequences arising from specific hatchery-wild interactions, emphasizing the need for management strategies that balance demographic enhancement with the conservation of natural diversity.

A novel approach to surviving an acute aorto-oesophageal fistula: A case report.

INTRODUCTION AND IMPORTANCE: Acute aorto-oesophageal fistula poses a significant mortality risk, requiring immediate and decisive medical intervention. This report highlights the critical need for innovation in emergency surgical responses. CASE PRESENTATION: A 57-year-old male, with a history of aortic repair, presented with chronic anaemia and dysphagia. He suffered a cardiac arrest from massive hematemesis during surgery for an infected thoracic hematoma. Lacking a Stengsten-Blackmore tube, a 26Fr Foley catheter was used to control the bleeding. This measure stabilized the patient enough for a definitive endovascular repair with aortic stents, which successfully managed the bleeding. CLINICAL DISCUSSION: The treatment objectives for this condition include initial control of oesophageal bleeding, followed by endovascular management to further control the bleeding, subsequently releasing the oesophageal control, and ultimately preventing infection through the administration of intravenous antibiotics. CONCLUSION: This case illustrates the importance of adaptability and the use of unconventional methods in emergency situations, demonstrating that innovative solutions can be lifesaving in critical surgical emergencies.

Impact of endophyte-infected tall fescue seed consumption on endocrine changes associated with intake regulation and post-absorptive metabolism in growing steers.

Fescue toxicosis is a syndrome occurring from the consumption of endophyte-infected tall fescue and results in substantial economic losses to the beef industry primarily from reduced growth accompanied by decreased dry matter intake (DMI); however, the associations characterizing this reduction in DMI have yet to be elucidated. The objective of this experiment was to identify endocrine changes associated with intake regulation post-consumption of endophyte-infected tall fescue seed (E+). Twelve Holstein steers were stratified by body weight and assigned to 1 of 3 treatments (n=4): 0 ppm ergovaline (ERV), 1.8 ppm ERV, or 2.7 ppm ERV. Treatments were achieved by combining differing proportions of ground E+ and non-endophyte-infected tall fescue seed. Steers were adapted to their diets for 7 d followed by a 7 d DMI collection period. Within treatment, steers were assigned to a sampling day (d 16 or d 17). Blood samples were collected every 20 min for 8 h, beginning 1 h before feeding. Intake data was analyzed using the MIXED procedure of SAS 9.4 (SAS Inst. Inc., Cary, NC) with treatment, day, and the interaction as fixed effects. Hormone and metabolite data were analyzed with the fixed effect of treatment, time, and the interaction including time as a repeated measure and orthogonal contrasts. Dry matter intake was linearly decreased with increasing ERV in the diet (P < 0.001). Insulin and leptin concentrations exhibited a quadratic effect (P = 0.018 and P = 0.005) with insulin concentrations highest for the 2.7 ppm treatment and leptin concentrations highest for the 1.8 ppm treatment. No differences were detected for active ghrelin or ß-hydroxybuytrate concentrations among treatment groups. Further, steers consuming both the 1.8 and 2.7 ppm ERV treatments had lower prolactin concentrations compared to the 0 ppm treatment (quadratic, P= 0.019). Glucose concentrations had a tendency for a linear increase as ERV concentrations increased (P = 0.091). A treatment × time interaction (P = 0.002) was noted in NEFA concentrations, with the 1.8 ppm ERV treatment showing increased pre-feeding concentrations, and the 2.7 ppm ERV treatment exhibiting elevated NEFA concentrations as time post-feeding progressed. The results suggest that E+ consumption reduces intake likely through alterations in intake-related hormones and post-absorptive metabolism and contributes to our current understanding of E+ effects on intake reduction while providing avenues for future research.

Parathyroid Adenoma Orientation for Gland Embryologic Origin on Ultrasonography.

Importance: Accurate preoperative localization is critical to success in targeted parathyroidectomy for primary hyperparathyroidism. Objective: To determine if the association between the long axis of a parathyroid adenoma (PTA) candidate and strap musculature on sagittal ultrasonography (US) can be used to predict the embryologic origin of the gland. Design, Setting, and Participants: This diagnostic study was performed using the Stanford Research Repository. Patients 18 years or older with primary hyperparathyroidism who underwent parathyroidectomy between January 2009 and October 2021 were considered. Additional inclusion criteria were having clear sagittal view of the adenoma candidate on US, confirmation of the gland of origin intraoperatively, and confirmation of hypercellular parathyroid on final pathology. Data were analyzed from October 2021 to June 2022. Exposures: B-mode US and surgical parathyroidectomy. Main Outcomes and Measures: The index test was using US to measure the angle between the long axis of an adenoma candidate and the strap musculature in the sagittal plane. This angle was used to test whether inferior and superior PTAs could be accurately assigned. The hypothesis was formulated prior to data collection. Results: A total of 426 patients (mean [range] age, 61.1 [20-96] years; 316 [74.2%] female) with 442 adenomas met inclusion criteria. Of the 442 adenomas, 314 (71.0%) had measurable angles, of which 204 (46.2%) were assigned a superior origin, 238 (53.8%) were assigned an inferior origin, and 128 (29%) were indeterminate. Of the surgically identified superior PTAs, 144 (70.6%) had a definable angle, and of the surgically identified inferior PTAs, 170 (71.4%) had a definable angle. The receiver operating characteristic analysis found 94° as the optimized angle for differentiating true negatives from true positives, with an overall sensitivity of 74% and specificity of 72%. This supported using 90° as a break point for US review. True positives were considered superior adenomas with an angle greater than 90°; true negatives were inferior adenomas with an angle less than 90°. Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of angulation analysis for determining PTA origin were 72.2% (95% CI, 64.9%-79.5%), 73.5% (95% CI, 66.9%-80.1%), 69.8% (95% CI, 62.5%-77.1%), 75.8% (95% CI, 69.3%-82.3%), and 72.9%, respectively. A subgroup analysis of 426 adenomas using the posterior carotid artery border on transverse US as a surrogate for predicting gland origin showed the following for sensitivity, specificity, positive predictive value, negative predictive value, and accuracy: 49.5% (95% CI, 42.6%-56.4%), 82.3% (95% CI, 77.3%-87.3%), 71.4% (95% CI, 63.9%-78.9%), 64.6% (95% CI, 59.1%-70.1%), and 66.9%, respectively. Conclusions and Relevance: This diagnostic study showed that PTA angulation on sagittal plane US can be used to predict gland of origin and guide surgery. The relationship between adenoma and posterior carotid artery border on transverse US can also be used to predict gland origin. These easy-to-apply US-based tests can be used in conjunction with other imaging modalities to guide targeted parathyroidectomy.

Evidence for Reproductive Health Effects Following Exposures to Hydraulic Fracturing Chemical Mixtures.

Unconventional oil and natural gas (UOG) operations have emerged over the last four decades to transform oil and gas production in the United States and globally by unlocking previously inaccessible hydrocarbon deposits. UOG development utilizes many compounds associated with conventional oil and gas, as well as some specific to UOG extraction, particularly during hydraulic fracturing (HF). While research is increasing on UOG chemicals and their mixtures, this review discusses the current evidence for reproductive toxicity following exposures to UOG/HF mixtures. These complex chemical mixtures have been demonstrated to interact with numerous mechanisms known to influence reproductive health. A growing number of environmental and controlled laboratory testing studies have reported adverse reproductive health effects in animals exposed to various UOG chemical mixtures. An expanding body of epidemiological literature has assessed adverse birth outcomes, although none has directly examined reproductive measures such as time to pregnancy, semen quality, and other direct measures of fertility. The existing literature provides moderate evidence for decreased birth weights, increased risk of small for gestational age and/or preterm birth, increased congenital abnormalities, and increased infant mortality, though importantly, studies are widely variable in methods used. Most studies utilized distance from UOG operations as an exposure proxy and did not measure actual chemical exposures experienced by those living near these operations. As such, while there is growing evidence for effects on births in these regions and good mechanistic evidence for reproductive toxicity, there is much research still needed to make firm conclusions about UOG development and reproductive health.

PeakQC: A Software Tool for Omics-Agnostic Automated Quality Control of Mass Spectrometry Data.

Mass spectrometry is broadly employed to study complex molecular mechanisms in various biological and environmental fields, enabling 'omics' research such as proteomics, metabolomics, and lipidomics. As study cohorts grow larger and more complex with dozens to hundreds of samples, the need for robust quality control (QC) measures through automated software tools becomes paramount to ensure the integrity, high quality, and validity of scientific conclusions from downstream analyses and minimize the waste of resources. Since existing QC tools are mostly dedicated to proteomics, automated solutions supporting metabolomics are needed. To address this need, we developed the software PeakQC, a tool for automated QC of MS data that is independent of omics molecular types (i.e., omics-agnostic). It allows automated extraction and inspection of peak metrics of precursor ions (e.g., errors in mass, retention time, arrival time) and supports various instrumentations and acquisition types, from infusion experiments or using liquid chromatography and/or ion mobility spectrometry front-end separations and with/without fragmentation spectra from data-dependent or independent acquisition analyses. Diagnostic plots for fragmentation spectra are also generated. Here, we describe and illustrate PeakQC's functionalities using different representative data sets, demonstrating its utility as a valuable tool for enhancing the quality and reliability of omics mass spectrometry analyses.

The neuroma map: A systematic review of the anatomic distribution, etiologies, and surgical treatment of painful traumatic neuromas.

BACKGROUND: This study analyzed all reported cases of painful traumatic neuromas to better understand their anatomic distribution, etiologies, and surgical treatment. METHODS: PubMed, Embase, Cochrane, and Web of Science were searched in October 2023 for articles describing painful traumatic neuromas. RESULTS: In total, 414 articles reporting 5,562 neuromas were included and categorized into head/neck, trunk, upper extremity, lower extremity, and autonomic nerves. Distribution was as follows: Head/neck: 82 articles reported on 393 neuromas (93.2% iatrogenic) most frequently involving the lingual (44.3%), cervical plexus (14.9%), great auricular (8.5%), inferior/superior alveolar (8.3%), and occipital (7.2%) nerves. Trunk: 47 articles reported on 554 neuromas (92.9% iatrogenic) most commonly involving the intercostal (35.4%), genitofemoral (14.3%), and pudendal (12.9%) nerves. Upper extremity: 159 articles reported on 2079 neuromas (53.3% after amputation) most frequently involving the digital (46.9%), superficial radial (18.3%), and median (7.0%) nerves. Lower extremity: 128 articles reported on 2,531 neuromas (53.0% after amputation) most commonly involving the sural (17.9%), superficial peroneal (17.3%), and saphenous (16.0%) nerves. Autonomic nerves: 15 articles reported on 53 neuromas (100% iatrogenic) most frequently involving the biliary tract (73.9%) and vagus nerve (14.9%). Compared with the extremities, neuromas in the head/neck and trunk had significantly longer symptom duration before surgical treatment and the nerve end was significantly less frequently reconstructed after neuroma excision. CONCLUSION: Painful neuromas are predominantly reported in the extremities yet may occur throughout the body primarily after iatrogenic injury. Knowledge of their anatomic distribution from head to toe will encourage awareness to avoid injury and expedite diagnosis to prevent treatment delay.

Knockdown of microglial iron import gene, DMT1, worsens cognitive function and alters microglial transcriptional landscape in a sex-specific manner in the APP/PS1 model of Alzheimer's disease.

Background: Microglial cell iron load and inflammatory activation are significant hallmarks of late-stage Alzheimer's disease (AD). In vitro, microglia preferentially upregulate the iron importer, divalent metal transporter 1 (DMT1, gene name Slc11a2) in response to inflammatory stimuli, and excess iron can augment cellular inflammation, suggesting a feed-forward loop between iron import mechanisms and inflammatory signaling. However, it is not understood whether microglial iron import mechanisms directly contribute to inflammatory signaling and chronic disease in vivo. These studies determined the effects of microglial-specific knockdown of Slc11a2 on AD-related cognitive decline and microglial transcriptional phenotype. Methods: In vitro experiments and RT-qPCR were used to assess a role for DMT1 in amyloid-ß-associated inflammation. To determine the effects of microglial Slc11a2 knockdown on AD-related phenotypes in vivo, triple-transgenic Cx3cr1 Cre - ERT2 ;Slc11a2 flfl;APP/PS1 + or - mice were generated and administered corn oil or tamoxifen to induce knockdown at 5-6 months of age. Both sexes underwent behavioral analyses to assess cognition and memory (12-15 months of age). Hippocampal CD11b + microglia were magnetically isolated from female mice (15-17 months) and bulk RNA-sequencing analysis was conducted. Results: DMT1 inhibition in vitro robustly decreased Aß-induced inflammatory gene expression and cellular iron levels in conditions of excess iron. In vivo, Slc11a2 KD APP/PS1 female, but not male, mice displayed a significant worsening of memory function in Morris water maze and a fear conditioning assay, along with significant hyperactivity compared to control WT and APP/PS1 mice. Hippocampal microglia from Slc11a2 KD APP/PS1 females displayed significant increases in Enpp2, Ttr, and the iron-export gene, Slc40a1, compared to control APP/PS1 cells. Slc11a2 KD cells from APP/PS1 females also exhibited decreased expression of markers associated with disease-associated microglia (DAMs), such as Apoe, Ctsb, Csf1, and Hif1α. Conclusions: This work suggests a sex-specific role for microglial iron import gene Slc11a2 in propagating behavioral and cognitive phenotypes in the APP/PS1 model of AD. These data also highlight an association between loss of a DAM-like phenotype in microglia and cognitive deficits in Slc11a2 KD APP/PS1 female mice. Overall, this work illuminates an iron-related pathway in microglia that may serve a protective role during disease and offers insight into mechanisms behind disease-related sex differences.

Remotely sensed crown nutrient concentrations modulate forest reproduction across the contiguous United States.

Global forests are increasingly lost to climate change, disturbance, and human management. Evaluating forests' capacities to regenerate and colonize new habitats has to start with the seed production of individual trees and how it depends on nutrient access. Studies on the linkage between reproduction and foliar nutrients are limited to a few locations and few species, due to the large investment needed for field measurements on both variables. We synthesized tree fecundity estimates from the Masting Inference and Forecasting (MASTIF) network with foliar nutrient concentrations from hyperspectral remote sensing at the National Ecological Observatory Network (NEON) across the contiguous United States. We evaluated the relationships between seed production and foliar nutrients for 56,544 tree-years from 26 species at individual and community scales. We found a prevalent association between high foliar phosphorous (P) concentration and low individual seed production (ISP) across the continent. Within-species coefficients to nitrogen (N), potassium (K), calcium (Ca), and magnesium (Mg) are related to species differences in nutrient demand, with distinct biogeographic patterns. Community seed production (CSP) decreased four orders of magnitude from the lowest to the highest foliar P. This first continental-scale study sheds light on the relationship between seed production and foliar nutrients, highlighting the potential of using combined Light Detection And Ranging (LiDAR) and hyperspectral remote sensing to evaluate forest regeneration. The fact that both ISP and CSP decline in the presence of high foliar P levels has immediate application in improving forest demographic and regeneration models by providing more realistic nutrient effects at multiple scales.