Heterozygous ZNHIT3 variants within the 17q12 recurrent deletion region are associated with Mayer-Rokitansky-Kuster Hauser (MRKH) syndrome.

The molecular basis of mullerian aplasia, also known as Mayer-Rokitansky-Kuster Hauser (MRKH) or congenital absence of the uterus and vagina, is largely unknown. We applied a multifaceted genetic approach to studying the pathogenesis of MRKH including exome sequencing of trios and duos, genome sequencing of families, qPCR, RT-PCR, and Sanger sequencing to detect intragenic deletions, insertions, splice variants, single nucleotide variants, and rearrangements in 132 persons with MRKH. We identified two heterozygous variants in ZNHIT3 localized to a commonly involved CNV region at chromosome 17q12 in two different families with MRKH. One is a frameshift, truncating variant that is predicted to interfere with steroid hormone binding of the LxxLL sequence of the C-terminal region. The second variant is a double missense/stopgain variant. Both variants impair protein expression in vitro. In addition, four more probands with MRKH harbored the stopgain variant without the nearby missense variant. In total, 6/132 (4.5%) of patients studied, including five with associated anomalies (type 2 MRKH), had ZNHIT3 variants that impair function in vitro. Our findings implicate ZNHIT3 as an important gene associated with MRKH within the 17q12 CNV region.

Generative Adversarial Networks Accurately Reconstruct Pan-Cancer Histology from Pathologic, Genomic, and Radiographic Latent Features.

Artificial intelligence models have been increasingly used in the analysis of tumor histology to perform tasks ranging from routine classification to identification of novel molecular features. These approaches distill cancer histologic images into high-level features which are used in predictions, but understanding the biologic meaning of such features remains challenging. We present and validate a custom generative adversarial network - HistoXGAN - capable of reconstructing representative histology using feature vectors produced by common feature extractors. We evaluate HistoXGAN across 29 cancer subtypes and demonstrate that reconstructed images retain information regarding tumor grade, histologic subtype, and gene expression patterns. We leverage HistoXGAN to illustrate the underlying histologic features for deep learning models for actionable mutations, identify model reliance on histologic batch effect in predictions, and demonstrate accurate reconstruction of tumor histology from radiographic imaging for a 'virtual biopsy'.

Geriatric Motorcycle-Related Outcomes: A Pennsylvania Multicenter Study.

INTRODUCTION: Geriatric patients (GeP) often experience increased morbidity and mortality following traumatic insult and as a result, require more specialized care due to lower physiologic reserve and underlying medical comorbidities. Motorcycle injuries (MCCI) occur across all age groups; however, no large-scale studies evaluating outcomes of GeP exist for this particular subset of patients. Data thus far are limited to elderly participation in recreational activities such as water and alpine skiing, snowboarding, equestrian, snowmobiles, bicycles, and all-terrain vehicles. We hypothesized that GeP with MCCI will have a higher rate of mortality when compared with their younger counterparts despite increased helmet usage. METHODS: We performed a multicenter retrospective review of MCCI patients at three Pennsylvania level I trauma centers from January 2016 to December 2020. Data were extracted from each institution's electronic medical records and trauma registry. GeP were defined as patients aged more than or equal to 65 y. The primary outcome was mortality. Secondary outcomes included ventilator days; hospital, intensive care unit, and intermediate unit length of stays; complications; and helmet use. 3:1 nongeriatric patients (NGeP) to GeP propensity score matching (PSM) was based on sex, abbreviated injury scale (AIS), and injury severity score (ISS). P ≤ 0.05 was considered significant. RESULTS: One thousand five hundred thirty eight patients were included (GeP: 7% [n = 113]; NGP: 93% [n = 1425]). Prior to PSM, GeP had higher median Charlson Comorbidity Index (GeP: 3.0 versus NGeP: 0.0; P ≤ 0.001) and greater helmet usage (GeP: 73.5% versus NGeP: 54.6%; P = 0.001). There was a statistically significant difference between age cohorts in terms of ISS (GeP: 10.0 versus NGeP: 6.0, P = 0.43). There was no significant difference for any AIS body region. Mortality rates were similar between groups (GeP: 1.7% versus NGeP: 2.6%; P = 0.99). After PSM matching for sex, AIS, and ISS, GeP had significantly more comorbidities than NGeP (P ≤ 0.05). There was no difference in trauma bay interventions or complications between cohorts. Mortality rates were similar (GeP: 1.8% versus NGeP: 3.2%; P = 0.417). Differences in ventilator days as well as intensive care unit length of stay, intermediate unit length of stay, and hospital length of stay were negligible. Helmet usage between groups were similar (GeP: 64.5% versus NGeP: 66.8%; P = 0.649). CONCLUSIONS: After matching for sex, ISS, and AIS, age more than 65 y was not associated with increased mortality following MCCI. There was also no significant difference in helmet use between groups. Further studies are needed to investigate the effects of other potential risk factors in the aging patient, such as frailty and anticoagulation use, before any recommendations regarding management of motorcycle-related injuries in GeP can be made.

Nailfold videocapillaroscopy in antineutrophil cytoplasmic antibody-associated vasculitis.

OBJECTIVE: Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a group of illnesses that cause inflammation and alterations to small vessels in the body. Some of the most common and detrimental manifestations, including alveolar hemorrhage and glomerulonephritis, are caused by this capillary inflammation. We sought to clarify whether patients with AAV would have abnormal nailfold capillaries when evaluated with nailfold videocapillaroscopy. METHODS: Patients with a current diagnosis of AAV and a control group were identified for enrollment. Nailfold videocapillaroscopy images were used for a semiquantitative analysis on capillary density, morphology, dilation, and microhemorrhage after review by 2 rheumatologists. Disease characteristics, occurrence of recent disease flare, and presence of ANCA were recorded. RESULTS: Thirty-three patients with a diagnosis of AAV and 21 controls were recruited. The AAV group had a median age of 59 and 17 (52%) were women. Granulomatosis with polyangiitis was the most common diagnosis (19 [58%]), followed by eosinophilic granulomatosis with polyangiitis (7 [21%]) and microscopic polyangiitis (7 [21%]). Twenty-seven patients (82%) had positive ANCA tests. After assessment of capillary density, dilation, morphology, microhemorrhages, and disorganization, there were no statistically significant differences between the 2 groups. CONCLUSION: There was no evidence of differences in nailfold capillaroscopy abnormalities between those diagnosed with AAV and the control group. While this cohort was relatively small, we did not find a high enough prevalence or specific phenotype of capillary abnormalities that could aid in diagnosis or prognostication of these diseases in the clinical setting.

Dermatomyositis in Association With SARS-CoV-2 Infection or COVID-19 Vaccine.

OBJECTIVE: New-onset and relapsed dermatomyositis (DM) has been reported following SARS-CoV-2 infection or COVID-19 vaccination. This study aims to show the characteristics of a DM cohort after COVID-19 infection and vaccination. METHODS: A retrospective review was performed on patients treated for DM between March 1, 2020, and October 31, 2022. Charts were evaluated for the presence of new-onset DM or relapse of preexisting DM following either SARS-CoV-2 infection or COVID-19 vaccination. Data on symptom onset, timing of vaccination, type of vaccination, and disease characteristics were collected. RESULTS: Ninety-eight patients treated for DM at our institution in the Division of Rheumatology were included. In total, 12 of 98 patients (12.2%) experienced DM symptoms (either incident or relapse) following either infection or vaccination. Of the 12 patients who developed incident disease or relapse, 7 (58.3%) developed postinfection symptoms, and 8 (66.7%) developed symptoms after vaccination (3 patients had symptoms following both infection and vaccination). The mean onset of symptoms following COVID-19 infection was 3.2 days (median 0.5 days), and mean onset following COVID-19 vaccination was 5.75 days (median 3.5 days). Nine of 12 patients (75%) had a positive myositis-specific antibody, and the remaining 3 (25%) had myositis-associated antibodies. There was no predominant vaccine associated with the development of postvaccination DM symptoms. CONCLUSION: This retrospective review revealed a strong temporal relationship between DM symptoms and COVID-19 infection or vaccination in 12.2% of all patients with DM evaluated in our clinic during the pandemic. Additional studies are required to understand the possible pathophysiology behind this association.

Data science competition for cross-site individual tree species identification from airborne remote sensing data.

Data on individual tree crowns from remote sensing have the potential to advance forest ecology by providing information about forest composition and structure with a continuous spatial coverage over large spatial extents. Classifying individual trees to their taxonomic species over large regions from remote sensing data is challenging. Methods to classify individual species are often accurate for common species, but perform poorly for less common species and when applied to new sites. We ran a data science competition to help identify effective methods for the task of classification of individual crowns to species identity. The competition included data from three sites to assess each methods' ability to generalize patterns across two sites simultaneously and apply methods to an untrained site. Three different metrics were used to assess and compare model performance. Six teams participated, representing four countries and nine individuals. The highest performing method from a previous competition in 2017 was applied and used as a baseline to understand advancements and changes in successful methods. The best species classification method was based on a two-stage fully connected neural network that significantly outperformed the baseline random forest and gradient boosting ensemble methods. All methods generalized well by showing relatively strong performance on the trained sites (accuracy = 0.46-0.55, macro F1 = 0.09-0.32, cross entropy loss = 2.4-9.2), but generally failed to transfer effectively to the untrained site (accuracy = 0.07-0.32, macro F1 = 0.02-0.18, cross entropy loss = 2.8-16.3). Classification performance was influenced by the number of samples with species labels available for training, with most methods predicting common species at the training sites well (maximum F1 score of 0.86) relative to the uncommon species where none were predicted. Classification errors were most common between species in the same genus and different species that occur in the same habitat. Most methods performed better than the baseline in detecting if a species was not in the training data by predicting an untrained mixed-species class, especially in the untrained site. This work has highlighted that data science competitions can encourage advancement of methods, particularly by bringing in new people from outside the focal discipline, and by providing an open dataset and evaluation criteria from which participants can learn.

PROSPECTIVE POSTMORTEM ASSESSMENT OF THE INCIDENCE OF MAMMARY NEOPLASIA IN CHIMPANZEES (PAN TROGLODYTES).

When evaluating the last 25 yr of morbidity and mortality from adult chimpanzees managed within the Association of Zoo and Aquarium Chimpanzee Species Survival Plan® for North American zoos, only two female chimpanzees were diagnosed with mammary neoplasia: one incidentally antemortem and one with a terminal metastatic neoplasia. When comparing this observation of prevalence of mammary neoplasia to humans, a substantial disparity is apparent. Mammary neoplasia is the second most common cancer in adult female humans, with a lifetime risk of 1:8 in the United States. The reason for the disparity between humans and chimpanzees, as closely related species, is unknown. The true prevalence in chimpanzees may be higher than currently noted, because routine examination of mammary tissue in chimpanzees is generally less complete than for other tissues postmortem, and antemortem assessment is generally limited to mammary palpation. This study was performed on intact, bilateral mammary glands harvested at postmortem examination of adult female chimpanzees (n = 7) from six institutions. With mammography, complete histopathologic sectioning, and genetic evaluation, the risk of mammary neoplasia was evaluated more thoroughly than during a typical postmortem exam in zoo populations during 2017-2019. No chimpanzees in the study were diagnosed with mammary neoplasia. Overall, this study supports the previous impression that chimpanzees do not develop mammary neoplasia at a similar rate as humans, even when comparable diagnostic modalities for evaluation are used.

Automated Quantification of the Behaviour of Beef Cattle Exposed to Heat Load Conditions.

Cattle change their behaviour in response to hot temperatures, including by engaging in stepping that indicates agitation. The automated recording of these responses would be helpful in the timely diagnosis of animals experiencing heat loading. Behavioural responses of beef cattle to hot environmental conditions were studied to investigate whether it was possible to assess behavioural responses by video-digitised image analysis. Open-source automated behavioural quantification software was used to record pixel changes in 13 beef cattle videorecorded in a climate-controlled chamber during exposure to a simulated typical heat event in Queensland, Australia. Increased digitised movement was observed during the heat event, which was related to stepping and grooming/scratching activities in standing animals. The 13 cattle were exposed in two cohorts, in which the first group of cattle (n = 6) was fed a standard finisher diet based on a high percentage of cereal grains, and the second group of cattle (n = 7) received a substituted diet in which 8% of the grains were replaced by lucerne hay. The second group displayed a smaller increase in digitised movements on exposure to heat than the first, suggesting less discomfort under hot conditions. The results suggest that cattle exposed to heat display increased movement that can be detected automatically by video digitisation software, and that replacing some cereal grain with forage in the diet of feedlot cattle may reduce the measured activity responses to the heat.

Diffuse alveolar hemorrhage secondary to sarcoidosis.

Diffuse alveolar hemorrhage (DAH) is a pulmonary condition that can be caused by autoimmune disorders such as lupus, small vessel vasculitis, and antiphospholipid syndrome. Sarcoidosis as a cause of DAH has been reported; however, the literature remains limited. We performed a chart review for patients with a diagnosis of both sarcoidosis and DAH. Seven patients met inclusion criteria. Mean (range) patient age was 54 years (39-72), and 3 patients had a history of tobacco use. Diagnosis of DAH and sarcoidosis were concurrent for 3 patients. Corticosteroids were used for treatment of DAH in all patients; 2 (including 1 with refractory DAH) were successfully treated with rituximab. We believe sarcoidosis-associated DAH is more common than previously reported. It is essential to consider sarcoidosis in the differential diagnosis of immune-mediated DAH. Key Points • Sarcoidosis can cause diffuse alveolar hemorrhage (DAH); more extensive studies are needed to estimate this condition's prevalence. • BMI of 25 or higher appears to be a risk factor for the development of sarcoidosis-associated DAH.

Programmed Death Ligand-1 Combined Positive Score Concordance and Interrater Reliability in Primary Tumors and Synchronous Lymph Node Metastases in Resected Cases of p16+ Oropharyngeal Squamous Cell Carcinoma.

CONTEXT.­: Pembrolizumab is used in patients with metastatic head and neck squamous cell carcinoma contingent upon the programmed death ligand-1 (PD-L1) combined positive score (CPS). OBJECTIVE.­: To compare PD-L1 CPS scores derived from paired resected primary tumors (PTs) and lymph node metastases (LMs) in patients with p16+ oropharyngeal squamous cell carcinoma (OPSCC). DESIGN.­: We identified 38 resected p16+ OPSCCs for which paired PTs and LMs were available. PD-L1 immunohistochemistry using the SP263 antibody clone was done on both the PT and the LM. CPS scoring was performed by 4 observers, and data were analyzed at the CPS cut points of greater than or equal to 1 and 20 in regard to interobserver and interspecimen agreement. RESULTS.­: Overall agreement between consensus CPS scoring of PT and LM was seen in 76% of paired specimens (κ = 0.53). No specimen received a negative consensus score. Interobserver agreement for both PT and LM was fair to substantial (κ = 0.54 and 0.51, respectively) and was inferior to that seen in a prospective series of unselected head and neck squamous carcinoma cases evaluated at our institution (κ = 0.84). CONCLUSIONS.­: Given the high rates of interobserver and interspecimen variability, evaluation of additional material or by additional observers may be of value in performing CPS scoring in cases of p16+ OPSCC. This is particularly the case when a negative or low-positive result is being evaluated in a patient who is otherwise a good candidate for immunotherapy.

The lncRNA ALPHA specifically targets chikungunya virus to control infection.

Arthropod-borne viruses, including the alphavirus chikungunya virus (CHIKV), cause acute disease in millions of people and utilize potent mechanisms to antagonize and circumvent innate immune pathways including the type I interferon (IFN) pathway. In response, hosts have evolved antiviral counterdefense strategies that remain incompletely understood. Recent studies have found that long noncoding RNAs (lncRNAs) regulate classical innate immune pathways; how lncRNAs contribute to additional antiviral counterdefenses remains unclear. Using high-throughput genetic screening, we identified a cytoplasmic antiviral lncRNA that we named antiviral lncRNA prohibiting human alphaviruses (ALPHA), which is transcriptionally induced by alphaviruses and functions independently of IFN to inhibit the replication of CHIKV and its closest relative, O'nyong'nyong virus (ONNV), but not other viruses. Furthermore, we showed that ALPHA interacts with CHIKV genomic RNA and restrains viral RNA replication. Together, our findings reveal that ALPHA and potentially other lncRNAs can mediate non-canonical antiviral immune responses against specific viruses.

Identification of genetic loci shared between Alzheimer's disease and hypertension.

Alzheimer's disease (AD) and high blood pressure (BP) are prevalent age-related diseases with significant unexplained heritability. A thorough analysis of genetic pleiotropy between AD and BP will lay a foundation for the study of the associated molecular mechanisms, leading to a better understanding of the development of each phenotype. We used the conditional false discovery rate (cFDR) method to identify novel genetic loci associated with both AD and BP. The cFDR approach improves the effective sample size for association testing by combining GWAS summary statistics for correlated phenotypes. We identified 50 pleiotropic SNPs for AD and BP, 7 of which are novel and have not previously been reported to be associated with either AD or BP. The novel SNPs located at STK3 are particularly noteworthy, as this gene may influence AD risk via the Hippo signaling network, which regulates cell death. Bayesian colocalization analysis demonstrated that although AD and BP are associated, they do not appear to share the same causal variants. We further performed two sample Mendelian randomization analysis, but could not detect a causal effect of BP on AD. Despite the inability to establish a causal link between AD and BP, our findings report some potential novel pleiotropic loci that may influence disease susceptibility. In summary, we identified 7 SNPs that annotate to 4 novel genes which have not previously been reported to be associated with AD nor with BP and discuss the possible role of one of these genes, STK3 in the Hippo signaling network.

Most Facial Fractures Do Not Require Surgical Intervention.

PURPOSE: Literature describing the number of patients that had a facial fracture that required surgical intervention in the United States is very limited. The purpose of this study was to evaluate the percentage of patients who required surgical intervention after presenting to a Level 1 Trauma Center with 1 or more facial fractures. MATERIALS AND METHODS: This was a retrospective cross-sectional study of all patients who presented with facial fracture(s) to University Hospital, a Level 1 Trauma Center (San Antonio, Texas), over a 5-year period from July 2015 to July 2020. Patients' charts that had 1 or more International Classification of Diseases 10 codes pertaining to facial fractures were collected. Cases were subdivided by fracture location: mandible, midface, upper face, or a combination of any of the aforementioned locations (predictor variables). After subdividing based on location, each chart was then reviewed and separated based on whether or not surgical intervention was provided (primary outcome variable). Data were tabulated and analyzed with descriptive and inferential statistics. RESULTS: Over the 5-year period, 3,416 patients presented with facial fractures. Of the 3,126 patients who survived their injuries and were not lost to follow-up, the vast majority (80.9%) did not require surgical intervention for their facial fractures. Mandible fractures required surgical intervention, whether isolated or in combination, much more frequently than in patients who did not have any type of mandible fracture (RR 8.01, 95% CI 6.92-9.27, P < .05 and RR 4.60, 95% CI 3.42-6.18, P < .05, respectively). Patients aged 50 years or less were also more likely to receive surgical intervention than those aged 51 years and more (RR 1.98 95% CI 1.63-2.41, P < .05). CONCLUSIONS: The vast majority of facial fractures that present to a Level 1 Trauma Center do not require surgical intervention. Patients who present with any type of mandible fracture and are aged 50 years or less are more likely to need surgical intervention.

Reestablishment of spermatogenesis after more than 20 years of cryopreservation of rat spermatogonial stem cells reveals an important impact in differentiation capacity.

Treatment of cancer in children is increasingly successful but leaves many prepubertal boys suffering from infertility or subfertility later in life. A current strategy to preserve fertility in these boys is to cryopreserve a testicular biopsy prior to treatment with the expectation of future technologies allowing for the reintroduction of stem cells and restoration of spermatogenesis. Spermatogonial stem cells (SSCs) form the basis of male reproduction, differentiating into all germ cell types, including mature spermatozoa and can regenerate spermatogenesis following transplantation into an infertile testis. Here, we demonstrate that rat SSCs frozen for more than 20 years can be transplanted into recipient mice and produce all differentiating germ cell types. However, compared with freshly isolated cells or those frozen for a short period of time, long-frozen cells do not colonize efficiently and showed reduced production of spermatids. Single-cell RNA sequencing revealed similar profiles of gene expression changes between short- and long-frozen cells as compared with fresh immediately after thawing. Conversely, following transplantation, long-frozen samples showed enhanced stem cell signaling in the undifferentiated spermatogonia compartment, consistent with self-renewal and a lack of differentiation. In addition, long-frozen samples showed fewer round spermatids with detectable protamine expression, suggesting a partial block of spermatogenesis after meiosis resulting in a lack of elongating spermatids. These findings strongly suggest that prolonged cryopreservation can impact the success of transplantation to produce spermatogenesis, which may not be revealed by analysis of the cells immediately after thawing. Our analysis uncovered persistent effects of long-term freezing not found in other cryopreservation studies that lacked functional regeneration of the tissue and this phenomenon must be accounted for any future therapeutic application.

Elliptical and linear relationships with rumen temperature support a homeorhetic trajectory for DMI during recovery of feedlot cattle exposed to moderate heat load.

Most feedlot animals in Australia experience 2 to 3 moderate heat waves during summer. This study aimed to gain understanding of the physiological drivers in response to and during recovery from such events with a view to designing strategies to ensure rapid and safe recovery. Two hypotheses were tested during thermal challenge and recovery in climate-controlled rooms (CCR): firstly, the feedlot steer on a grain-based diet mounts appropriate physiological responses during moderate heat load and in recovery so that its performance and physiology state after recovery is not different to the feed restricted thermoneutral (FRTN) steer. Secondly, commonly used indicators of increased heat load, e.g., respiration rate (RR), panting score (PS), body surface temperatures (ST), and water consumption (WC), reflect rumen temperature (RT) during thermal challenge and recovery at the level of daily means. In this study, 36 Angus steers (live weight (LW) 451.5 ± 22.6 kg) made up 3 cohorts of 12 animals that sequentially underwent the CCR phase. For this 18-d phase, the steers were allocated to either a moderate heat load treatment (thermally challenged, TC, n = 18) or a FRTN treatment (n = 18). The TC group underwent 3 periods, Pre-Challenge (4 d, temperature humidity index (THI) range of 68 to 71), Challenge (7 d, THI 73 to 84 with diurnal cycling), and Recovery (7 d, THI 68 to 71). The FRTN group were held at thermoneutral conditions in the CCR (THI 66.9 ± 0.3), and each animal was offered an amount of feed was based on the feed intake of its LW matched TC pair. Thus, as DMI fell in the TC group during Challenge, feed restriction was imposed on the FRTN group. The data were collected by trained observers were DMI, RT, RR, PS, body STs (forehead, shoulder, leg, rump), and WC. Challenge induced a heat stress response in the TC group with reduced DMI and LW, and elevated RT, RR, PS, body STs, and WC (P < 0.001). These measures were unchanged or reduced in the FRTN group (P < 0.001). At the end of Recovery, the TC and FRTN groups had converged on most measures including LW. Daily mean RT of both groups showed strong linear relationships with THI, RR, PS, head ST, and WC (P ≤ 0.0022) but opposing elliptical relationships with DMI; that is, as DMI fell with increasing RT for the TC group, DMI increased with rising RT for the FRTN group. In all, the feedlot steers in this study demonstrated sufficient homeorhetic capacity to adjust to moderate heat load and recover from it.

Over any summer, most feedlot steers in Australia will encounter 2 to 3 moderate heat waves lasting 5 to 6 d. The ability of these animals to adjust to the hot conditions and recovery from them is not well understood. The advent of obtaining near real-time body (rumen) temperature from feedlot steers has the potential to help feedlot managers, veterinarians and nutritionists make decisions on the handling of feedlots animals during and after heatwaves. Using climate-controlled rooms, this study demonstrated that feedlot steers are physiologically capable of dealing with moderate heatwave conditions. The co-ordinated increases in respiration rate, sweating rate, body surface temperature, and water consumption alongside reduction in feed intake as heat load increases limits the rise in body temperature. By the end of a 7-d recovery period in thermoneutral conditions, the heat stressed steers were not different physiologically and performance-wise from thermoneutral counterparts feeding on a similar amount of food. However, during the recovery period, all animals appeared to be metabolically and physiologically constrained, and did not return to their pre-heatwave feed intake, body temperature or respiration rate. These findings will assist the management of feedlot animals through recovery after a heat wave.

Trampoline Injuries in a Statewide Trauma System.

INTRODUCTION: It is well known that trampolines can be a particular source of danger, especially in children. We sought to examine the profile of those patients with trampoline injuries. We hypothesized there would be certain injury patterns predicative of trampoline injuries. METHODS: All patients submitted to Pennsylvania Trauma Outcome Study database from 2016 to 2018 were analyzed. Trampoline injury was determined by ICD-10 activity code. Injury patterns in the form of abbreviated injury scale body regions were examined. Patient demographics and clinical variables were compared between those with trampoline injury vs those without. RESULTS: There were 107 patients with a trampoline injury. All of these patients were discharged alive and had a blunt mechanism of injury. The most common injury type was injury to the extremities (n=90,[84.1%]) with 54(50.5%) upper extremity injuries and 36(33.6%) lower extremity injuries. Ten (9.35%) patients had injury to the spine and five (4.67%) had head injury. Those with trampoline injuries were significantly younger (13y vs. 48.6y) and more likely to be white or of Hispanic ethnicity. Almost half of the patients injured (49.5%) were under 10 years. Patients with trampoline injuries had significantly lower Injury Severity Scores and significantly higher shock index. DISCUSSION: The majority of patients with trampoline injuries had injury to an extremity. These results help better understand the demographic, physiologic, and anatomic patterns surrounding trampoline injuries. Current government standards recommend that no child under age six should use a full-sized trampoline; however, based of this study, we advise that this age be increased to ten.

Spontaneous and Naloxone-Precipitated Withdrawal Behaviors From Chronic Opiates are Accompanied by Changes in N-Oleoylglycine and N-Oleoylalanine Levels in the Brain and Ameliorated by Treatment With These Mediators.

Rationale: The endocannabinoidome mediators, N-Oleoylglycine (OlGly) and N-Oleoylalanine (OlAla), have been shown to reduce acute naloxone-precipitated morphine withdrawal affective and somatic responses. Objectives: To determine the role and mechanism of action of OlGly and OlAla in withdrawal responses from chronic exposure to opiates in male Sprague-Dawley rats. Methods: Opiate withdrawal was produced: 1) spontaneously 24 h following chronic exposure to escalating doses of morphine over 14 days (Experiments 1 and 2) and steady-state exposure to heroin by minipumps for 12 days (Experiment 3), 2) by naloxone injection during steady-state heroin exposure (Experiment 4), 3) by naloxone injection during operant heroin self-administration (Experiment 5). Results: In Experiment 1, spontaneous morphine withdrawal produced somatic withdrawal reactions. The behavioral withdrawal reactions were accompanied by suppressed endogenous levels of OlGly in the nucleus accumbens, amygdala, and prefrontal cortex, N-Arachidonylglycerol and OlAla in the amygdala, 2-arachidonoylglycerol in the nucleus accumbens, amygdala and interoceptive insular cortex, and by changes in colonic microbiota composition. In Experiment 2, treatment with OlAla, but not OlGly, reduced spontaneous morphine withdrawal responses. In Experiment 3, OlAla attenuated spontaneous steady-state heroin withdrawal responses at both 5 and 20 mg/kg; OlGly only reduced withdrawal responses at the higher dose of 20 mg/kg. Experiment 4 demonstrated that naloxone-precipitated heroin withdrawal from steady-state exposure to heroin (7 mg/kg/day for 12 days) is accompanied by tissue-specific changes in brain or gut endocannabinoidome mediator, including OlGly and OlAla, levels and colonic microbiota composition, and that OlAla (5 mg/kg) attenuated behavioural withdrawal reactions, while also reversing some of the changes in brain and gut endocannabinoidome and gut microbiota induced by naloxone. Experiment 5 demonstrated that although OlAla (5 mg/kg) did not interfere with operant heroin self-administration on its own, it blocked naloxone-precipitated elevation of heroin self-administration behavior. Conclusion: These results suggest that OlAla and OlGly are two endogenous mediators whose brain concentrations respond to chronic opiate treatment and withdrawal concomitantly with changes in colon microbiota composition, and that OlAla may be more effective than OlGly in suppressing chronic opiate withdrawal responses.

Intra-articular therapy with methotrexate or tumor necrosis factor inhibitors in rheumatoid arthritis: a systematic review.

BACKGROUND: Persistent monoarthritis in otherwise well-controlled rheumatoid arthritis presents a therapeutic challenge. Intra-articular (IA) steroids are a mainstay of treatment, though some have queried whether IA disease modifying anti-rheumatic drugs (DMARD) and biologics can be used in those who fail steroid injections. METHODS: A systematic literature review was conducted using four medical databases to identify randomized, controlled trials assessing IA therapies in RA patients. Included studies underwent Cochrane Risk of Bias 2 assessment for quality. RESULTS: Twelve studies were included, 6 of which examined intra-articular (IA) TNF inhibitors (TNFi), and 6 studies evaluating IA methotrexate. Of those evaluating IA TNFi, one study reported statistical improvement in TNFi therapy when compared with placebo. The remaining 5 studies compared IA TNFi therapy with steroid injections. IA TNFi had statistically improved symptom scores and clinical assessments comparable with IA steroid treatments. In the 6 studies evaluating IA methotrexate, the addition of methotrexate to steroid intra-articular therapy was not found to be beneficial, and singular methotrexate injection was not superior to the control arms (saline or triamcinolone). Risk-of-bias (ROB) assessment with the Revised Cochrane ROB tool indicated that 2 of 6 TNFi studies were at some risk or high risk for bias, compared with 5 out of 6 methotrexate studies. CONCLUSION: For persistent monoarthritis in rheumatoid arthritis, IA methotrexate was not found to have clinical utility. Intra-articular TNFi therapy appears to have equal efficacy to IA steroids, though the optimal dose and frequency of injections is yet unknown.