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The purpose of this review is to outline the most recent understanding of torticollis in the pediatric population.It is important to diagnose the underlying condition of torticollis early in childhood, as some conditions that cause torticollis may result in major developmental delays in early motor milestones. Recent studies have highlighted that many of the rarer causes of torticollis are often misdiagnosed as congenital muscular torticollis, suggesting that physicians should pay close attention to the results of clinical and radiographic examinations when patients present with torticollis.Congenital muscular torticollis is the most common cause of torticollis. Other, less common causes of torticollis include vertebral abnormalities, ocular torticollis, gastrointestinal disorders, soft tissue infections of the neck, posterior fossa tumors, and benign paroxysmal torticollis. Although rare, these differential diagnoses should be considered during a clinical work-up for a patient who presents with torticollis.

Background: With the rise of social media and other web-based platforms, there has been a shift in how medical research findings are disseminated. Questions/Purposes: We sought to investigate how often orthopedic surgeons use different knowledge-seeking methods and how confident they were in their ability to stay up-to-date. Methods: We distributed a 23-question survey to 120 orthopedic surgeons employed at a single tertiary-care metropolitan orthopedic hospital. The survey collected the surgeons’ use of reference managers, RSS feeds, and preferred methods of staying up-to-date. Respondents were asked to report the number of hours they spent staying up-to-date per week and their success with keeping up with orthopedic specialty literature. Results: A total of 85 physicians responded (median age, 52 years); 83% of respondents who spent 3 or more hours a week in keeping up-to-date with the literature said they felt successful in doing so, while 40% of participants who spent less than 1 hour a week said they felt successful. Fifty-five percent of surgeons under the median age used social media, while only 29% of surgeons over the median age used social media. Conclusions: This survey suggests that spending only 1 to 2 hours per week was enough to make the orthopedic surgeons we surveyed feel confident that they were keeping up with the literature in their specialty. These findings also suggest that it may be more important for surgeons to choose a convenient method of literature review that will enable them to maximize time spent reading, rather than attempting to use any one source.

TSC renal cystic disease is poorly understood and has no approved treatment. In a new principal cell-targeted murine model of Tsc cystic disease, the renal cystic epithelium is mostly composed of type A intercalated cells with an intact Tsc2 gene confirmed by sequencing, although these cells exhibit a Tsc-mutant disease phenotype. We used a newly derived targeted murine model in lineage tracing and extracellular vesicle (EV) characterization experiments and a cell culture model in EV characterization and cellular induction experiments to understand TSC cystogenesis. Using lineage tracing experiments, we found principal cells undergo clonal expansion but contribute very few cells to the cyst. We determined that cystic kidneys contain more interstitial EVs than noncystic kidneys, excrete fewer EVs in urine, and contain EVs in cyst fluid. Moreover, the loss of the Tsc2 gene in EV-producing cells greatly changes the effect of EVs on renal tubular epithelium, such that the epithelium develops increased secretory and proliferative pathway activity. We demonstate that the mTORC1 pathway activity is independent form the EV production, and that the EV effects for a single cell line can vary significantly. TSC cystogenesis involves significant contribution from genetically intact cells conscripted to the mutant phenotype by mutant cell derived EVs.

Background: Previous studies have demonstrated that dress style can influence a patient’s impression of a physician’s compassion, trust, and competency. The purpose of this study was to understand the preferences pediatric patients and their caregivers have towards physician attire in the orthopaedic outpatient setting. The authors hypothesized that patients and parents/guardians would have no preference for white coats and would prefer scrubs over other attire options. Methods: Between January and May 2022, patients aged 10 to 21 and their parents/guardians presenting to an outpatient orthopaedic office visit were approached to complete an anonymous, voluntary survey. The survey consisted of preference questions related to white coats, male physicians’ attire, and female physicians’ attire. Categorical variables were analyzed using Pearson Chi-Square with p≤0.05 used as threshold for statistical significance. A kappa analysis was performed to compare agreement between pediatric patients and their respective parents/guardians’ responses. Results: A total of 200 participants surveys were included in analysis; 100 patients and 100 parents/guardians. Patients had an average age of 14.1±2.4 years and were 47.0% female, while parents/guardians had an average age of 47.3±6.0 years and were 76.0% female. A total of 71.5% of participants felt neutral towards the use of white coats in the outpatient office. Scrubs were the most preferred attire option for male physicians for both patients (46%) and parents/guardians (41%), however, significant differences were found in overall attire preference for male and female physicians (p=0.027 and 0.032, respectively). There was discordance in responses between patients and their parents/guardians (kappa=0.15–0.28). Conclusions: After analyzing 200 surveys, this study found that while pediatric patients and parents/guardians have no preference for white coats, both groups were most likely to prefer male and female physicians wear scrubs in outpatient orthopaedic office visits. With the greatest proportion of all participants preferring scrubs to other attire options, the authors suggest pediatric orthopaedic surgeons wear scrubs during outpatient visits.

Supracondylar humerus (SCH) fractures are common pediatric injuries, typically requiring closed reduction and percutaneous pinning or open reduction. These injuries are managed frequently by both pediatric-trained (PTOS) and nonpediatric-trained (NTOS) orthopaedic surgeons. However, some literature suggests that complications for pediatric injuries are lower when managed by PTOS. Therefore, this meta-analysis sought to compile existing literature comparing patients treated by PTOS and NTOS to better understand differences in management and clinical outcomes.Using preferred reporting items for systematic reviews and meta-analyses (PRISMA) methodology, a systematic review was conducted for all articles comparing SCH fractures managed by PTOS and NTOS in 4 online databases (PubMed, Embase, CINAHL, Cochrane). Study quality was assessed through the use of the Newcastle-Ottawa Scale. Meta-analyses were then performed for postoperative outcomes using pooled data from the included studies. Statistics were reported as odds ratios and 95% CI.This search strategy yielded 242 unique titles, of which 12 underwent full-text review and 7 met final inclusion. All studies were retrospective and evaluated patients treated in the United States. There were a total of 692 and 769 patients treated by PTOS and NTOS, respectively. PTOS had shorter operative times [mean difference, 13.6 min (CI, -23.9 to -3.4), P=0.01] and less frequently utilized a medial-entry pin [odds ratios, 0.36 (CI, 0.2 to 0.9), P=0.03]. There were no differences in time to treatment, the necessity of open reduction, postoperative Baumann angle, or complications including surgical site infection or iatrogenic nerve injury.Despite shorter operative times and lower frequency of cross-pinning when treated by PTOS, pediatric SCH fracture outcomes are similar when treated by PTOS and NTOS. These findings demonstrate that these fractures may possibly be treated safely by both PTOS and experienced fellowship-trained academic NTOS who are comfortable managing these injuries in pediatric patients.Level III; Meta-analysis.

IntroductionDiagnostic radiology interpretive errors in trauma patients can lead to missed diagnoses, compromising patient care. Due to this, our level II trauma center implemented a reread protocol of all radiographic imaging within 24 hours on our highest trauma activation level (Code T). We sought to determine the efficacy of this reread protocol in identifying missed diagnoses in Code T patients. We hypothesized that a few, but clinically relevant errors, would be identified upon reread.MethodsAll radiographic study findings (initial read and reread) performed for Code T admissions from July 2015 to May 2016 were queried. The reviewed radiological imaging was given one of four designations: agree with interpretation, minor (non-life threatening) nonclinically relevant error(s)—addendum/correction required or clinically relevant error(s) (major [life threatening] and minor)—addendum/correction required, and trauma surgeon notified. The results were compiled, and the number of each type of error was calculated.ResultsOf the 752 radiological imaging studies reviewed on the 121 Code T patients during this period, 3 (0.40%) contained minor clinically relevant errors, 11 (1.46%) contained errors that were not clinically relevant, and 738 (98.1%) agreed with the original interpretation. The three clinically relevant errors included a right mandibular fracture found on X-ray and a temporal bone fracture that crossed the clivus and bilateral rib fractures found on computerized tomography.DiscussionClinically relevant errors, although minimal, were discovered during rereads for Code T patients. Although the clinical errors were significant, none affected patient outcomes. We propose that the implementation of reread protocols should be based upon institution-specific practices.

Die akute Extremitatenischamie (AEI) ist ein potenziell lebensbedrohliches Krankheitsbild mit einer hohen Mortalitats- und Morbiditatsrate. Die sich dem behandelnden Arzt darstellende Klinik ist nicht immer eindeutig. Als diagnostischer Goldstandard sind Doppleruntersuchung und digitale Subtraktionsangiographie etabliert. Eine korrekte Stadieneinteilung der Ischamie nach Rutherford entscheidet uber das therapeutische Vorgehen. Im Laufe der Jahre haben sich in der klinischen Routine neben der chirurgischen Therapie zur Gefasreperfusion zunehmend interventionelle, endovaskulare Behandlungsmoglichkeiten oder deren Kombination mit der Chirurgie etabliert. Im Rahmen dieser Fortbildung wird insbesondere die intraarterielle, kathetergestutzte Fibrinolysetherapie beschrieben. Die interdisziplinare Zusammenarbeit von Radiologie, Gefaschirurgie, Innere Medizin und Intensivmedizin in einem fur Gefasmedizin spezialisierten Krankenhaus optimiert und sichert die Behandlungsablaufe fur den Extremitatenerhalt bei AEI.

High-resolution (1 mm isotropic) diffusion tensor imaging (DTI) of the hippocampus in temporal lobe epilepsy (TLE) patients has shown patterns of hippocampal subfield diffusion abnormalities, which were consistent with hippocampal sclerosis (HS) subtype on surgical histology. The objectives of this longitudinal imaging study were to determine the stability of focal hippocampus diffusion changes over time in TLE patients, compare diffusion and quantitative T2 abnormalities of the sclerotic hippocampus, and correlate presurgical mean diffusivity (MD) and T2 maps with postsurgical histology.Nineteen TLE patients and 19 controls underwent two high-resolution (1 mm isotropic) DTI and 1.1 × 1.1 × 1 mmReduced volume and elevated MD and T2 of sclerotic hippocampi remained unchanged between longitudinal scans. Focal regions of elevated MD and T2 in bilateral hippocampi of HS TLE were detected consistently at both scans. Regions of high MD and T2 correlated and remained consistent over time. Volume, MD, and T2 remained unchanged in postoperative contralateral hippocampus. Regional elevations of MD identified subfield neuron loss on postsurgical histology with 88% sensitivity and 88% specificity. Focal T2 elevations identified subfield neuron loss with 75% sensitivity and 88% specificity.Diffusion and T2 abnormalities in ipsilateral and contralateral hippocampi remained unchanged between the scans suggesting permanent microstructural alterations. MD and T2 demonstrated good sensitivity and specificity to detect hippocampal subfield neuron loss on postsurgical histology, supporting the potential that high-resolution hippocampal DTI and T2 could be used to diagnose HS subtype before surgery.

CD36 mediates the uptake of long-chain fatty acids (FAs), a major energy substrate for the myocardium. Under excessive FA supply, CD36 can cause cardiac lipid accumulation and inflammation while its deletion reduces heart FA uptake and lipid content and increases glucose utilization. As a result, CD36 was proposed as a therapeutic target for obesity-associated heart disease. However, more recent reports have shown that CD36 deficiency suppresses myocardial flexibility in fuel preference between glucose and FAs, impairing tissue energy balance, while CD36 absence in tissue macrophages reduces efferocytosis and myocardial repair after injury. In line with the latter homeostatic functions, we had previously reported that CD36–/– mice have chronic subclinical inflammation. Lipids are important for the maintenance of tissue homeostasis and there is limited information on heart lipid metabolism in CD36 deficiency. Here, we document in the hearts of unchallenged CD36–/– mice abnormalities in the metabolism of triglycerides, plasmalogens, cardiolipins, acylcarnitines, and arachidonic acid, and the altered remodeling of these lipids in response to an overnight fast. The hearts were examined for evidence of inflammation by monitoring the presence of neutrophils and pro-inflammatory monocytes/macrophages using the respective positron emission tomography (PET) tracers, 64Cu-AMD3100 and 68Ga-DOTA-ECL1i. We detected significant immune cell infiltration in unchallenged CD36–/– hearts as compared with controls and immune infiltration was also observed in hearts of mice with cardiomyocyte-specific CD36 deficiency. Together, the data show that the CD36–/– heart is in a non-homeostatic state that could compromise its stress response. Non-invasive immune cell monitoring in humans with partial or total CD36 deficiency could help evaluate the risk of impaired heart remodeling and disease.

Patients with autosomal dominant polycystic kidney disease (ADPKD) and tuberous sclerosis complex (TSC) are born with normal or near-normal kidneys that later develop cysts and prematurely lose function. Both renal cystic diseases appear to be mediated, at least in part, by disease-promoting extracellular vesicles (EVs) that induce genetically intact cells to participate in the renal disease process. We used centrifugation and size exclusion chromatography to isolate the EVs for study. We characterized the EVs using tunable resistive pulse sensing, dynamic light scattering, transmission electron microscopy, and Western blot analysis. We performed EV trafficking studies using a dye approach in both tissue culture and in vivo studies. We have previously reported that loss of the Tsc2 gene significantly increased EV production and here demonstrate that the loss of the Pkd1 gene also significantly increases EV production. Using a cell culture system, we also show that loss of either the Tsc2 or Pkd1 gene results in EVs that exhibit an enhanced uptake by renal epithelial cells and a prolonged half-life. Loss of the primary cilia significantly reduces EV production in renal collecting duct cells. Cells that have a disrupted Pkd1 gene produce EVs that have altered kinetics and a prolonged half-life, possibly impacting the duration of the EV cargo effect on the recipient cell. These results demonstrate the interplay between primary cilia and EVs and support a role for EVs in polycystic kidney disease pathogenesis.

BACKGROUND AND AIMS With chronic kidney disease (CKD) prevalence rapidly increasing, the need for novel therapies is rising. Sodium glucose co-transporter-2 (SGLT2) inhibitors were originally developed to treat hyperglycemia in patients with type 2 diabetes mellitus. Clinical trials with the SGLT2 inhibitor empagliflozin revealed a marked attenuation of the slope of kidney function decline, also in patients with non-diabetic CKD. The exact mechanism of this kidney sparing effect still remains to be clarified. Interestingly, cells of renin lineage (CoRL), residing in the juxtaglomerular apparatus to regulate blood pressure and fluid balance, have been demonstrated to harbor a stem cell like potential. CoRL have the ability to replenish glomerular cell number by dedifferentiating, migrating and subsequently replacing various glomerular cell types in different kidney injury mouse models. Considering that empagliflozin treatment affects renin plasma levels and electrolyte balance in patients, we hypothesized that empagliflozin could have an effect on CoRL-induced glomerular regeneration. METHOD Experiments were performed in a Ren1cre; tdTomato lineage-trace mouse strain that expresses a tomato fluorescent label in all cells derived from renin lineage. Two kidney injury mouse models were applied; bilateral ischemia reperfusion injury (bIRI) and 5/6 nephrectomy (5/6NTx). Empagliflozin (10 mg/kg) was administered daily via oral gavage for 14 days. Subsequently, mice were sacrificed and kidneys were harvested for histological analysis. RESULTS In both the bIRI and 5/6NTx model, empagliflozin intake led to an increase (>2-fold) of CoRL found in the intraglomerular regions compared with vehicle control littermates. These CoRL seemed to selectively differentiate towards different glomerular cell types per model: bIRI combined with empagliflozin administration resulted in an increase of claudin- (10-fold) and integrin-α8- (1.5-fold) tomato double positive cells, suggesting favored differentiation from CoRL to respectively a parietal epithelial or mesangial cell type. In contrast, in the empagliflozin treated 5/6NTx model, an increase (1.5-fold) in tomato-podocyn double positive cells was observed, implying more restocking of glomerular podocytes by CoRL in this model. CONCLUSION SGLT2 inhibition by empagliflozin treatment leads to increased CoRL-mediated intrinsic regeneration potential and provides the kidney with different replenished cell types in different kidney disease models. Our findings demonstrate a novel mechanism via which SGLT2 inhibition might protect against kidney injury.

Iron is a potent catalyst of oxidative stress and cellular proliferation implicated in renal cell carcinoma (RCC) tumorigenesis, yet it also drives ferroptosis that suppresses cancer progression and represents a novel therapeutic target for advanced RCC. The von Hippel Lindau (VHL)/hypoxia-inducible factor-α (HIF-α) axis is a major regulator of cellular iron, and its inactivation underlying most clear cell (cc) RCC tumors introduces both iron dependency and ferroptosis susceptibility. Despite the central role for iron in VHL/HIF-α signaling and ferroptosis, RCC iron levels and their dynamics during RCC initiation/progression are poorly defined. Here, we conducted a large-scale investigation into the incidence and prognostic significance of total tissue iron in ccRCC and non-ccRCC patient primary tumor cancer cells, tumor microenvironment (TME), metastases and non-neoplastic kidneys. Prussian Blue staining was performed to detect non-heme iron accumulation in over 1600 needle-core sections across multiple tissue microarrays. We found that RCC had significantly higher iron staining scores compared with other solid cancers and, on average, >40 times higher than adjacent renal epithelium. RCC cell iron levels correlated positively with TME iron levels and inversely with RCC levels of the main iron uptake protein, transferrin receptor 1 (TfR1/TFRC/CD71). Intriguingly, RCC iron levels, including in the TME, decreased significantly with pathologic (size/stage/grade) progression, sarcomatoid dedifferentiation, and metastasis, particularly among patients with ccRCC, despite increasing TfR1 levels, consistent with an increasingly iron-deficient tumor state. Opposite to tumor iron changes, adjacent renal epithelial iron increased significantly with RCC/ccRCC progression, sarcomatoid dedifferentiation, and metastasis. Lower tumor iron and higher renal epithelial iron each predicted significantly shorter ccRCC patient metastasis-free survival. In conclusion, iron accumulation typifies RCC tumors but declines toward a relative iron-deficient tumor state during progression to metastasis, despite precisely opposite dynamics in adjacent renal epithelium. These findings raise questions regarding the historically presumed selective advantage for high iron during all phases of cancer evolution, suggesting instead distinct tissue-specific roles during RCC carcinogenesis and early tumorigenesis versus later progression. Future study is warranted to determine how the relative iron deficiency of advanced RCC contributes to ferroptosis resistance and/or introduces a heightened susceptibility to iron deprivation that might be therapeutically exploitable.

In recent years, the frequency of anterior cruciate ligament (ACL) tears and ACL reconstruction (ACLR) in skeletally immature patients has increased. Because distal femoral and proximal tibial physes account for the majority of lower-extremity growth, surgical technique and graft selection are crucial to minimize iatrogenic physeal injury. Combined extra- and intra-articular, all-epiphyseal, and transphyseal with soft-tissue grafts are the most common ACLR techniques used in children. Combined extra- and intra-articular ACLR typically is offered to prepubescent patients with ≥2 years of growth remaining. This technique uses iliotibial band (ITB) autograft passed over the lateral femoral condyle and fixed to the anterior tibial periosteum. All-epiphyseal ACLR is similarly used in patients with ≥2 years of growth remaining, provided sufficient epiphyseal maturity to accommodate an all-epiphyseal socket because both the femoral and tibial tunnels are contained within the epiphyses. In postpubertal patients with2 years of growth remaining, transphyseal ACLR using a soft-tissue autograft (typically hamstring or quadriceps tendon) and metaphyseal femoral fixation can be performed. This minimizes risk of physeal injury. In borderline patients with approximately 2 years of growth remaining, an additional option includes partial transphyseal ACLR, which uses a soft-tissue graft and a transphyseal tibial tunnel, but an all-epiphyseal or over-the-top femoral graft trajectory. Recently, transphyseal ITB ACLR and hybrid transphyseal hamstring with combined over-the-top ITB ACLR also have been described. Existing clinical studies focused on pediatric and adolescent ACL reconstructions have reported a wide range of graft rupture rates for these techniques (4.3%-25%), with contralateral ACL injury rates of 2.9% to 15.6%. Ongoing multicenter research is underway to directly compare surgical techniques for this demographic and quantify graft rupture rates and other clinical outcomes.

Future demanding scientific space and earth observation missions such as for exoplanet atmospheric spectral analysis or earth climate monitoring will define new benchmarks in technological feasibility and come along with increasingly stringent requirements on instrument subsystems. The requirements imposed on infrared detectors are dependent on the type of optical instrument, the chosen observation approach and the spectral range to be covered. With advanced detector architectures on hand and suitable␣technology approaches in mind, various electrical and electro-optical quantities have to be traded off against each other and possibly be prioritized, reflecting the specific instruments’ needs. From such considerations, implications on the detector material, design and processing arise. In this methodological paper, we will illustrate specific trade-off considerations for focal plane detector arrays (FPAs) based on mercury cadmium telluride (MCT) as detector material, e.g. with respect to modulation transfer function (MTF), detection efficiency (QE), noise level, defect density, etc. As an illustration, we will discuss simulation and implementation approaches and solutions found for a presently ongoing cornerstone pre-development activity in the long wavelength infrared (LWIR) and very long wavelength infrared (VLWIR). In particular, we will consider the thermal infrared (TIR) channels of the European Space Agency (ESA) Land and Surface Temperature Monitoring Mission (LSTM) observation instrument, for which we will present a photodiode array design approach balanced for key electro-optical FPA performance parameters.

Background Extended hospital length of stay (LOS) is widely associated with significant healthcare costs. Since LOS is a known surrogate for cost, we sought to evaluate outliers. We hypothesized that particular characteristics are likely predictive of trauma high resource consumers (THRC) and can be used to more effectively manage care of this population. Methods The Pennsylvania Trauma Outcome Study database was retrospectively queried from 2003-2017 for all adult (age ≥15) trauma patients admitted to accredited trauma centers in Pennsylvania. THRC were defined as patients with hospital LOS two standard deviations above the population mean or ≥22 days (pResults A total of 465,601 patients met inclusion criteria [THRC: 16,818 (3.6%); non-THRC 448,783 (96.4%)]. Compared to non-THRC counterparts, THRC patients were significantly more severely injured (median ISS: 9 vs. 22, pConclusions Reintubation, major surgery, gunshot wound to abdomen, along with injury to the spine, upper or lower extremities are all strongly predictive of THRC. Understanding the profile of the THRC will allow clinicians and case management to proactively put processes in place to streamline care and potentially reduce costs and LOS.

For over a century, the importance of lipid metabolism in biology was recognized but difficult to mechanistically understand due to the lack of sensitive and robust technologies for identification and quantification of lipid molecular species. The enabling technological breakthroughs emerged in the 1980s with the development of soft ionization methods (Electrospray Ionization and Matrix Assisted Laser Desorption/Ionization) that could identify and quantify intact individual lipid molecular species. These soft ionization technologies laid the foundations for what was to be later named the field of lipidomics. Further innovative advances in multistage fragmentation, dramatic improvements in resolution and mass accuracy, and multiplexed sample analysis fueled the early growth of lipidomics through the early 1990s. The field exponentially grew through the use of a variety of strategic approaches, which included direct infusion, chromatographic separation, and charge-switch derivatization, which facilitated access to the low abundance species of the lipidome. In this Thematic Review, we provide a broad perspective of the foundations, enabling advances, and predicted future directions of growth of the lipidomics field.

Background: Compared with male senior authors, female senior authors publish less often in orthopedic journals than expected based on their population proportion. It is unknown whether this trend is also present among orthopedic trainees. Purpose: We sought to determine whether there is a gender discrepancy in the publication volume and authorship status among orthopedic residents. Methods: We conducted a cross-sectional analysis to evaluate the research productivity of male and female orthopedic residents. The top 10 ranked US orthopedic surgery residencies by research output in 2021–2022 were obtained from Doximity. Residents’ names were recorded from each institution’s residency website. We classified each resident as male or female, searched on PubMed, and recorded the number of publications relevant to orthopedic surgery. Resident contribution to each publication was recorded as either a first/last author or a middle author. To assess contributions by postgraduate year, we compared male and female junior residents (PGY1-3) and senior residents (PGY4-5) using the number of total publications, middle author publications, first/last author publications, and the difference between the number of middle and first/last author publications. Results: Among the 335 male and 117 female residents included, male residents had more total publications than female residents. Among PGY4-5, male residents had more total publications and middle author publications. There was no difference in the number of first/last author publications between male and female PGY4-5 residents. Conclusions: Our cross-sectional analysis found that in the 2021–2022 academic year, male orthopedic surgery residents published more often than female residents, although among PGY4-5 residents, we found no gender differences in number of first/last author publications. The difference in total publications among PGY4-5 residents is likely due to differences in middle author publications. Future research should consider residents’ self-identified gender, including non-binary and gender-fluid identity.

BACKGROUND With the recent birth of the Pennsylvania TQIP Collaborative, statewide data identified unplanned admissions to the intensive care unit (ICU) as an overarching issue plaguing the state trauma community. To better understand the impact of this unique population, we sought to determine the effect of unplanned ICU admission/readmission on mortality to identify potential predictors of this population. We hypothesized that ICU bounceback (ICUBB) patients would experience increased mortality compared with non-ICUBB controls and would likely be associated with specific patterns of complications. METHODS The Pennsylvania Trauma Outcome Study database was retrospectively queried from 2012 to 2015 for all ICU admissions. Unadjusted mortality rates were compared between ICUBB and non-ICUBB counterparts. Multilevel mixed-effects logistic regression models assessed the adjusted impact of ICUBB on mortality and the adjusted predictive impact of 8 complications on ICUBB. RESULTS A total of 58,013 ICU admissions were identified from 2012 to 2015. From these, 53,715 survived their ICU index admission. The ICUBB rate was determined to be 3.82% (2,054/53,715). Compared with the non-ICUBB population, ICUBB patients had a significantly higher mortality rate (12% vs. 8%; p < 0.001). In adjusted analysis, ICUBB was associated with a 70% increased odds ratio for mortality (adjusted odds ratio, 1.70; 95% confidence interval, 1.44-2.00; p < 0.001). Adjusted analysis of predictive variables revealed unplanned intubation, sepsis, and pulmonary embolism as the strongest predictors of ICUBB. CONCLUSION Intensive care unit bouncebacks are associated with worse outcomes and are disproportionately burdened by respiratory complications. These findings emphasize the importance of the TQIP Collaborative in identifying statewide issues in need of performance improvement within mature trauma systems. LEVEL OF EVIDENCE Epidemiological study, level III.

PURPOSE To describe clinical characteristics and visual outcomes of non-traumatic open globe injuries. SETTING A level 1 trauma centre in a large urban medical centre. DESIGN Retrospective study. METHODS Charts of non-traumatic open globe patients admitted to MHH-TMC from 1/2010 to 3/2015 were reviewed for demographics, cause, clinical characteristics, visual acuity (VA) and enucleation. RESULTS Thirty eyes were included: 15 (50%) were males with a mean age of 47 (±28) years. All presented with zone 1 injury. Twenty-five (83%) had a perforated corneal ulcer. Presenting VA was count fingers (n = 3, 10%) to NLP (n = 6, 20%). Twenty-four (80%) involved infection, 5 (17%) congenital, 3 (10%) chemical burn and 2 (7%) neurotrophic. Conjunctival injection (n = 22, 77%), corneal opacification (n = 20, 71%) and relative afferent pupillary defect (n = 9, 44%) were common. After treatment, 23 (88%) were worse than 6/60 (20/200), 9 (35%) were NLP and 8 (27%) required enucleation. CONCLUSIONS Often non-traumatic open globe injuries are zone 1 and due to perforated infectious ulcers. Compared to previously reported traumatic injuries, these have higher rates of enucleation (27% vs 8%) and poorer final VA (88% vs 68% worse than 6/60 20/200).

Avelumab is an IgG1 anti–programmed death ligand 1 (anti–PD-L1) monoclonal antibody that has been approved as a monotherapy for metastatic Merkel cell carcinoma and advanced urothelial carcinoma, and in combination with axitinib for advanced renal cell carcinoma. Avelumab is cleared faster and has a shorter half-life than other anti–PD-L1 antibodies, such as atezolizumab and durvalumab, but the mechanisms underlying these differences are unknown. IgG antibodies can be cleared through receptor-mediated endocytosis after binding of the antibody Fab region to target proteins, or via Fcγ receptor (FcγR)-mediated endocytosis. Unlike other approved anti–PD-L1 antibodies, avelumab has a native Fc region that retains FcγR binding capability. We hypothesized that the rapid clearance of avelumab might be due to the synergistic effect of both FcγR-mediated and PD-L1 target–mediated internalization. To investigate this, we performed in vitro and in vivo studies that compared engineered variants of avelumab and atezolizumab to determine mechanisms of cellular internalization. We found that both FcγR and PD-L1 binding contribute to avelumab internalization. While FcγR binding was the dominant mechanism of avelumab internalization in vitro, with CD64 acting as the most important FcγR, studies in mice and cynomolgus monkeys showed that both FcγR and PD-L1 contribute to avelumab elimination, with PD-L1 binding playing a greater role. These studies suggest that the rapid internalization of avelumab might be due to simultaneous binding of both PD-L1 and FcγR in trans. Our findings also provide a basis to alter the clearance and half-life of monoclonal antibodies in therapeutic development.

In tuberous sclerosis complex (TSC), Tsc2 mutations are associated with more severe disease manifestations than Tsc1 mutations and the role of extracellular vesicles (EVs) in this context is not yet studied. We report a comparative analysis of EVs derived from isogenic renal cells except for Tsc1 or Tsc2 gene status and hypothesized that in spite of having similar physical characteristics, EVs modulate signaling pathways differently, thus leading to TSC heterogenicity. We used mouse inner medullary collecting duct (mIMCD3) cells with the Tsc1 (T1G cells) or Tsc2 (T2J cells) gene disrupted by CRISPR/CAS9. EVs were isolated from the cell culture media by size-exclusion column chromatography followed by detailed physical and chemical characterization. Physical characterization of EVs was accessed by tunable resistive pulse sensing and dynamic light scattering, revealing similar average sizes and zeta potentials (at pH 7.4) for EVs from mIMCD3 (123.5 ± 5.7 nm and −16.3 ± 2.1 mV), T1G cells (131.5 ± 8.3 nm and −19.8 ± 2.7 mV), and T2J cells (127.3 ± 4.9 nm and −20.2 ± 2.1 mV). EVs derived from parental mIMCD3 cells and both mutated cell lines were heterogeneous (>90% of EVs < 150 nm) in nature. Immunoblotting detected cilial Hedgehog signaling protein Arl13b; intercellular proteins TSG101 and Alix; and transmembrane proteins CD63, CD9, and CD81. Compared to Tsc2 deletion, Tsc1 deletion cells had reduced EV production and release rates. EVs from Tsc1 mutant cells altered mTORC1, autophagy, and β-catenin pathways differently than EVs from Tsc2-mutated cells. Quantitative PCR analysis revealed the down regulation of miR-212a-3p and miR-99a-5p in EVs from Tsc2-mutated cells compared to EVs from Tsc1-mutant cells. Thus, EV-derived miR-212-3p and mIR-99a-5p axes may represent therapeutic targets or biomarkers for TSC disease.

There is a growing body of literature studying changes in hippocampal subfields in a variety of different neurological conditions, but this work has mainly focused on the hippocampal body given challenges in visualization of hippocampal anatomy in the head and tail when sectioned in the typical coronal image plane. Curved multiplanar reformatting (CMPR) is an image reconstruction method that can improve visualization of complex three‐dimensional structures. The objective of this study was to determine whether CMPR could facilitate visualization of the human hippocampal anatomy along the entire caudal–rostral axis. CMPR was applied to high‐resolution magnetic resonance imaging acquired ex vivo on four cadaveric hippocampal specimens at 4.7 T (T2‐weighted, 0.2 × 0.2 × 0.5 mm3). CMPR provided clear visualization of the classic “interlocking C” appearance of the dentate gyrus and cornu ammonis along the entire caudal–rostral axis including the head and tail, which otherwise show complex anatomy on the standard coronal slices. CMPR facilitated visualization of hippocampal anatomy providing the impetus to develop simplified approaches to delineate subfields along the entire hippocampus including the usually neglected head and tail.

ZusammenfassungEin 47-jähriger Mann wurde mit Fieber, Gewichtsverlust und radiologisch nachgewiesenen flächenhaften Konsolidierungen mit Kavernenbildung vorstellig. Nachdem in der umfangreichen Diagnostik pulmonale epitheloidzellige Granulome festgestellt wurden, erhielt er unter dem Verdacht einer Sarkoidose eine immunsuppressive Therapie. Im weiteren Verlauf kam es zu einem Progress der pulmonalen Infiltrate und Nachweis von zerebralen und abdominalen Abszessen, deren mikrobiologische Untersuchung Nocardia farcinica ergab. Trotz antibiogrammgerechter Therapie verstarb der Patient im Rahmen eines septischen Schocks mit Multiorganversagen.Die Nokardiose ist eine seltene granulomatöse bakterielle Infektionskrankheit. Als Risikofaktoren gelten die Immunsuppression und strukturelle Lungenerkrankungen. Typisches Krankheitsmerkmal ist eine Abszessbildung, die in jedem Organ auftreten kann, wobei der pulmonale Beginn häufig ist. Der Fall veranschaulicht die Relevanz, seltene Differenzialdiagnosen bei Nachweis von pulmonalen epitheloidzelligen Granulomen in Betracht zu ziehen.

BACKGROUND The effect of Level IV trauma center (TC) accreditation within an existing trauma network remains understudied. This study compared preaccreditation to postaccreditation data from Level IV TCs within a mature trauma system in Pennsylvania to determine whether TC designation affected time to and/or rate of transfer to definitive care. Level IV TCs were hypothesized to have a decreased time to transfer following accreditation and improved mortality. METHODS The Pennsylvania Trauma Systems Foundation collects predesignation and postdesignation data from hospitals pursuing accreditation. Data from Pennsylvania Trauma Systems Foundation between 2012 and 2017 were analyzed. Variables of interest included patient demographics, injury severity, mortality, and incidence of surgical interventions precredentialingto postcredentialing. A multilevel mixed-effects logistic regression model assessed the adjusted impact of Level IV TC accreditation on transfer rate. ArcGIS Desktop was used for geospatial mapping of lives and geographic area covered by the addition of Level IV TCs in Pennsylvania. RESULTS Five hospitals underwent Level IV credentialing from 2012 to 2017, providing data on 5,076 cases (pre, 2,395 [47.2%]; post, 2,681 [52.8%]). No significant difference in age, admission Glasgow Coma Scale score, or shock index was observed preaccreditation to postaccreditation. A difference in transfer rate was observed after credentialing in unadjusted (62.7% vs. 63.3%; p < 0.014) and adjusted analyses (adjusted odds ratios, 1.13, p = 0.389). There was a trend toward reduced odds of mortality postcredentialing (adjusted odds ratios, 0.59, p = 0.261). Major surgical intervention decreased (Pre, 0.42%; Post, 0.04%; p = 0.004). CONCLUSION Level IV TC accreditation has beneficial effects on increased transfer rates and may improve mortality. It is important to continue to observe the impact of Level IV TCs on patient outcomes within a mature trauma system. LEVEL OF EVIDENCE Prognostic and epidemiological, level III.

Firearm violence in the United States knows no age limit. This study compares the survival of children younger than five years to children and adolescents of age 5–19 years who presented to an ED for gunshot wounds (GSWs) in the United States to test the hypothesis of higher GSW mortality in very young children. A study of GSW patients aged 19 years and younger who survived to reach medical care was performed using the Nationwide ED Sample for 2010–2015. Hospital survival and incidence of fatal and nonfatal GSWs in the United States were the study outcomes. A multilevel logistic regression model estimated the strength of association among predictors of hospital mortality. The incidence of ED presentation for GSW is as high as 19 per 100,000 population per year. Children younger than five years were 2.7 times as likely to die compared with older children (15.3% vs 5.6%). Children younger than one year had the highest hospital mortality, 33.1 per cent. The mortality from GSW is highest among the youngest children compared with older children. This information may help policy makers and the public better understand the impact of gun violence on the youngest and most vulnerable Americans.

With its foundation in 1945, UNESCO declared as its main purpose the promotion of international cultural exchange UNESCO Constitution 1945, Art. I, 2 (c) . A number of legal instruments (Conventions, Recommendations and Declarations) should duly help to substantiate that general purpose and make it work in practice. In this process, the regulation of the international exchange of cultural property plays a key role. However, the proper regulation of cultural property exchange has been a highly controversial issue. This paper focus on UNESCO's guiding ideas and conceptions of cultural property, international exchange and regulation. The central question is: Are the regulations codified in UNESCO’s Conventions and Recommendations helpful in encouraging international cultural exchange or are we faced, due to the neglect of private agents and the roles they play in cultural exchange, with some sort of one-sided regulation running counter to that aim? The author argues that UNESCO's legal instruments are driven by and express a strong anti-private and anti-market bias, which produce problematic economic incentives in the art and antiquities world to the disadvantage of the international exchange of cultural property.

BackgroundBintrafusp alfa (BA) is a bifunctional fusion protein designed for colocalized, simultaneous inhibition of two immunosuppressive pathways, transforming growth factor-β (TGF-β) and programmed death-ligand 1 (PD-L1), within the tumor microenvironment (TME). We hypothesized that targeting PD-L1 to the tumor by BA colocalizes the TGF-β trap (TGF-βRII) to the TME, enabling it to sequester TGF-β in the tumor more effectively than systemic TGF-β blockade, thereby enhancing antitumor activity.MethodsMultiple technologies were used to characterize the TGF-β trap binding avidity. BA versus combinations of anti-PD-L1 and TGF-β trap or the pan-TGF-β antibody fresolimumab were compared in proliferation and two-way mixed lymphocyte reaction assays. Immunophenotyping of tumor-infiltrating lymphocytes (TILs) and RNA sequencing (RNAseq) analysis assessing stromal and immune landscape following BA or the combination therapy were performed in MC38 tumors. TGF-β and PD-L1 co-expression and their associated gene signatures in MC38 tumors and human lung carcinoma tissue were studied with single-cell RNAseq (scRNAseq) and immunostaining. BA-induced internalization, degradation, and depletion of TGF-β were investigated in vitro.ResultsBA and fresolimumab had comparable intrinsic binding to TGF-β1, but there was an ~80× avidity-based increase in binding affinity with BA. BA inhibited cell proliferation in TGF-β-dependent and PD-L1-expressing cells more potently than TGF-β trap or fresolimumab. Compared with the combination of anti-PD-L1 and TGF-β trap or fresolimumab, BA enhanced T cell activation in vitro and increased TILs in MC38 tumors, which correlated with efficacy. BA induced distinct gene expression in the TME compared with the combination therapy, including upregulation of immune-related gene signatures and reduced activities in TGF-β-regulated pathways, such as epithelial-mesenchymal transition, extracellular matrix deposition, and fibrosis. Regulatory T cells, macrophages, immune cells of myeloid lineage, and fibroblasts were key PD-L1/TGF-β1 co-expressing cells in the TME. scRNAseq analysis suggested BA modulation of the macrophage phenotype, which was confirmed by histological assessment. PD-L1/TGF-β1 co-expression was also seen in human tumors. Finally, BA induced TGF-β1 internalization and degradation in the lysosomes.ConclusionBA more effectively blocks TGF-β by targeting TGF-β trap to the tumor via PD-L1 binding. Such colocalized targeting elicits distinct and superior antitumor responses relative to single agent combination therapy.

On December 31, 2018, the White Earth Reservation Business Committee, or tribal council, passed Resolution Number 001-19-009 recognizing the inherent rights of wild rice. The resolution also includes a regulation entitled “Rights of Manoomin,” meaning the regulation is enforceable under tribal law (White Earth Reservation Business Committee, 2019, pp. 19–21). The Rights of Manoomin lays out the legal protections afforded to wild rice under the resolution. The Reservation Business Committee passed Resolution Number 001-19-010 the same day to support the previous resolution (White Earth Reservation Business Committee, 2019, pp. 22–26). The resolution to recognize the inherent rights of wild rice is part of a larger international movement to recognize the rights of nature (Bouayad, 2020, pp. 39–40). However, the case of the White Earth Anishinaabeg (pl.) and wild rice is different for two reasons. First, the Rights of Manoomin regulation is the first to recognize the inherent rights of a plant (LaDuke, 2019). Second, the resolution claims protection for wild rice in all the territories the Anishinaabeg ceded under the 1867 treaty with the United States government that established the reservation. In this paper, I will argue that the importance of wild rice to the Anishinaabeg and the threats it is currently under served as an impetus for the White Earth Reservation Business Committee to pass the resolutions in question.