Small extracellular vesicles: Roles and clinical application in prostate cancer.

Prostate cancer is a significant health problem in the United States. It is remarkably heterogenous, ranging from slow growing disease amenable to active surveillance to highly aggressive forms requiring active treatments. Therefore, being able to precisely determine the nature of disease and appropriately match patients to available and/or novel therapeutics is crucial to improve patients' overall outcome and quality of life. Recently small extracellular vesicles (sEVs), a subset of nanoscale membranous vesicles secreted by various cells, have emerged as important analytes for liquid biopsy and promising vehicles for drug delivery. sEVs contain various biomolecules such as genetic material, proteins, and lipids that recapitulate the characteristics and state of their donor cells. The application of existing and newly developed technologies has resulted in an increased depth of knowledge about biophysical structures, biogenesis, and functions of sEVs. In prostate cancer patients, tumor-derived sEVs can be isolated from biofluids, commonly urine and blood. They mediate intercellular signaling within the tumor microenvironment and distal organ-specific sites, supporting cancer initiation, progression, and metastasis. A mounting body of evidence suggests that sEV components can be potent biomarkers for prostate cancer diagnosis, prognosis, and prediction of disease progression and treatment response. Due to enhanced circulation stability and bio-barrier permeability, sEVs can be also used as effective drug delivery carriers to improve the efficacy and specificity of anti-tumor therapies. This review discusses recent studies on sEVs in prostate cancer and is focused on their role as biomarkers and drug delivery vehicles in the clinical management of prostate cancer.

Targeted degradation of extracellular mitochondrial aspartyl-tRNA synthetase modulates immune responses.

The severity of bacterial pneumonia can be worsened by impaired innate immunity resulting in ineffective pathogen clearance. We describe a mitochondrial protein, aspartyl-tRNA synthetase (DARS2), which is released in circulation during bacterial pneumonia in humans and displays intrinsic innate immune properties and cellular repair properties. DARS2 interacts with a bacterial-induced ubiquitin E3 ligase subunit, FBXO24, which targets the synthetase for ubiquitylation and degradation, a process that is inhibited by DARS2 acetylation. During experimental pneumonia, Fbxo24 knockout mice exhibit elevated DARS2 levels with an increase in pulmonary cellular and cytokine levels. In silico modeling identified an FBXO24 inhibitory compound with immunostimulatory properties which extended DARS2 lifespan in cells. Here, we show a unique biological role for an extracellular, mitochondrially derived enzyme and its molecular control by the ubiquitin apparatus, which may serve as a mechanistic platform to enhance protective host immunity through small molecule discovery.

Lysosome damage triggers acute formation of ER to lysosomes membrane tethers mediated by the bridge-like lipid transport protein VPS13C.

Based on genetic studies, lysosome dysfunction is thought to play a pathogenetic role in Parkinson's disease (PD). Here we show that VPS13C, a bridge-like lipid transport protein and a PD gene, is a sensor of lysosome stress/damage. Upon lysosome membrane perturbation, VPS13C rapidly relocates from the cytosol to the surface of lysosomes where it tethers their membranes to the ER. This recruitment depends on Rab7 and requires release of a brake, most likely an intramolecular interaction within VPS13C, which hinders access of its VAB domain to lysosome-bound Rab7. While another PD protein, LRRK2, is also recruited to stressed/damaged lysosomes, its recruitment occurs at much later stages and by different mechanisms. Given the putative role of VPS13 proteins in bulk lipid transport, these findings suggest lipid delivery to lysosomes by VPS13C is part of an early response to lysosome damage.

Management of Cochlear Implant Electrode Arrays Misplaced in the Internal Auditory Canal: A Systematic Review.

OBJECTIVE: Misplacement of electrode arrays in the internal auditory canal (IAC) presents a unique clinical challenge. Speech recognition is limited for cochlear implant (CI) users with misplaced arrays, and there are risks with revision surgery including facial and/or cochlear nerve injury. DATABASES REVIEWED: PubMed, Embase, and Scopus. METHODS: A literature search was performed from inception to September 2023. The search terms were designed to capture articles on misplaced arrays and the management options. Articles written in English that described cases of array misplacement into the IAC for children and adults were included. The level of evidence was assessed using Oxford Center for Evidence Based Medicine guidelines. Descriptive statistical analyses were performed. RESULTS: Twenty-eight cases of arrays misplaced in the IAC were identified. Thirteen (46%) were patients with incomplete partition type 3 (IP3), and 7 (25%) were patients with common cavity (CC) malformations. Most misplaced arrays were identified postoperatively (19 cases; 68%). Of these cases, 11 (58%) were managed with array removal. No facial nerve injuries were reported with revision surgery. Eight cases (42%) were left in place. Several underwent mapping procedures in an attempt improve the sound quality with the CI. CONCLUSION: Electrode array misplacement in the IAC is a rare complication that reportedly occurs predominately in cases with IP3 and CC malformations. Removal of misplaced arrays from the IAC reportedly has not been associated with facial nerve injuries. Cases identified with IAC misplacement postoperatively can potentially be managed with modified mapping techniques before proceeding with revision surgery.

A very complicated UTI: malakoplakia following E. coli urinary tract infection.

Malakoplakia is a rare inflammatory disorder believed to result from a defect in macrophage phagocytic function triggering a granulomatous reaction. It can present with genitourinary, gastrointestinal, or cutaneous manifestations in immunocompromised or, less commonly, immunocompetent hosts. We describe a case of renal malakoplakia in a young, otherwise healthy patient presenting with nephromegaly and sepsis following an E. coli urinary tract infection. We discuss diagnosis and management, including antibiotic selection and the decision to pursue nephrectomy. This case highlights the potential for kidney recovery with prolonged antibiotic therapy in conjunction with adjunct immunomodulatory therapies and source control.

Genome-wide association study reveals multiple loci for nociception and opioid consumption behaviors associated with heroin vulnerability in outbred rats.

The increased prevalence of opioid use disorder (OUD) makes it imperative to disentangle the biological mechanisms contributing to individual differences in OUD vulnerability. OUD shows strong heritability, however genetic variants contributing toward vulnerability remain poorly defined. We performed a genome-wide association study using over 850 male and female heterogeneous stock (HS) rats to identify genes underlying behaviors associated with OUD such as nociception, as well as heroin-taking, extinction and seeking behaviors. By using an animal model of OUD, we were able to identify genetic variants associated with distinct OUD behaviors while maintaining a uniform environment, an experimental design not easily achieved in humans. Furthermore, we used a novel non-linear network-based clustering approach to characterize rats based on OUD vulnerability to assess genetic variants associated with OUD susceptibility. Our findings confirm the heritability of several OUD-like behaviors, including OUD susceptibility. Additionally, several genetic variants associated with nociceptive threshold prior to heroin experience, heroin consumption, escalation of intake, and motivation to obtain heroin were identified. Tom1 , a microglial component, was implicated for nociception. Several genes involved in dopaminergic signaling, neuroplasticity and substance use disorders, including Brwd1 , Pcp4, Phb1l2 and Mmp15 were implicated for the heroin traits. Additionally, an OUD vulnerable phenotype was associated with genetic variants for consumption and break point, suggesting a specific genetic contribution for OUD-like traits contributing to vulnerability. Together, these findings identify novel genetic markers related to the susceptibility to OUD-relevant behaviors in HS rats.

A Reproducible Peritonsillar Abscess Incision and Drainage Model for Junior Trainees.

OBJECTIVES: To describe the design and construction of a reproducible, low-cost, peritonsillar abscess (PTA) incision and drainage simulator and assess its impact on trainees' confidence. METHODS: The 2-part simulator we developed consisted of a manikin head with a fixed, partially open mouth and a modular PTA mold. The mold is created by injecting a lotion and water mixture into plastic bubbles, followed by silicone solidification. Neodymium magnets secure the silicone-abscess packet to the manikin's palate. The simulator was utilized during an academic otolaryngology residency training program Annual Otolaryngology Boot Camp. A self-assessment Likert scale questionnaire was used to evaluate participants' confidence before and after simulator training. Fourth-year medical students and junior (first and second year) residents who participated in the boot camp and agreed to complete the evaluation were included. RESULTS: Three medical students, 17 PGY-1, and 10 PGY-2 residents agreed to complete the evaluation. All trainees agreed the model was useful for learning skills. The overall post-training confidence Likert scores of participants, and PGY-1 residents in particular, significantly improved compared to their pre-training scores (P < .001). CONCLUSIONS: Our model offers an affordable and efficient training opportunity for residents to enhance their competence in managing PTAs. This approach, with its simple yet effective design and low production cost, shows potential for scalability on a broader scale.

Star formation shut down by multiphase gas outflow in a galaxy at a redshift of 2.45.

Large-scale outflows driven by supermassive black holes are thought to have a fundamental role in suppressing star formation in massive galaxies. However, direct observational evidence for this hypothesis is still lacking, particularly in the young universe where star-formation quenching is remarkably rapid1-3, thus requiring effective removal of gas4 as opposed to slow gas heating5,6. Although outflows of ionized gas are frequently detected in massive distant galaxies7, the amount of ejected mass is too small to be able to suppress star formation8,9. Gas ejection is expected to be more efficient in the neutral and molecular phases10, but at high redshift these have only been observed in starbursts and quasars11,12. Here we report JWST spectroscopy of a massive galaxy experiencing rapid quenching at a redshift of 2.445. We detect a weak outflow of ionized gas and a powerful outflow of neutral gas, with a mass outflow rate that is sufficient to quench the star formation. Neither X-ray nor radio activity is detected; however, the presence of a supermassive black hole is suggested by the properties of the ionized gas emission lines. We thus conclude that supermassive black holes are able to rapidly suppress star formation in massive galaxies by efficiently ejecting neutral gas.

Clinical outcomes of outpatient thyroidectomy: A systematic review and single-arm meta-analysis.

BACKGROUND: The aim of this meta-analysis is to investigate the safety of outpatient thyroidectomy based on 24-h and same-day discharge criteria. METHODS: CENTRAL, Embase, PubMed, and Scopus were searched. A meta-analysis of selected studies was performed. The review was registered prospectively with PROSPERO (CRD42022361134). RESULTS: Thirty-one studies met the eligibility criteria, with a total of 74328 patients undergoing thyroidectomy in an outpatient setting based on 24-h discharge criteria. Overall postoperative complications after outpatient thyroidectomies were 5.7% (95%CI: 0.049-0.065; I2 â€‹= â€‹97.3%), consisting of hematoma (0.4%; 95%CI: 0.003-0.005; I2 â€‹= â€‹83.4%), recurrent laryngeal nerve injury (0.4%; 95%CI: 0.003-0.006; I2 â€‹= â€‹93.5%), and hypocalcemia (1.6%; 95%CI: 0.012-0.019; I2 â€‹= â€‹93.7%). The rate of readmission was 1.1% (95%CI: 0.007-0.015; I2 â€‹= â€‹95.4%). Results were similar for same-day criteria. CONCLUSIONS: Our analysis demonstrated that outpatient thyroidectomy is a safe procedure in the management of thyroid disease for selected patients.

A recently quenched galaxy 700 million years after the Big Bang.

Local and low-redshift (z < 3) galaxies are known to broadly follow a bimodal distribution: actively star-forming galaxies with relatively stable star-formation rates and passive systems. These two populations are connected by galaxies in relatively slow transition. By contrast, theory predicts that star formation was stochastic at early cosmic times and in low-mass systems1-4. These galaxies transitioned rapidly between starburst episodes and phases of suppressed star formation, potentially even causing temporary quiescence-so-called mini-quenching events5,6. However, the regime of star-formation burstiness is observationally highly unconstrained. Directly observing mini-quenched galaxies in the primordial Universe is therefore of utmost importance to constrain models of galaxy formation and transformation7,8. Early quenched galaxies have been identified out to redshift z < 5 (refs. 9-12) and these are all found to be massive (M⋆ > 1010 M⊙) and relatively old. Here we report a (mini-)quenched galaxy at z = 7.3, when the Universe was only 700 Myr old. The JWST/NIRSpec spectrum is very blue (U-V = 0.16 ± 0.03 mag) but exhibits a Balmer break and no nebular emission lines. The galaxy experienced a short starburst followed by rapid quenching; its stellar mass (4-6 × 108 M⊙) falls in a range that is sensitive to various feedback mechanisms, which can result in perhaps only temporary quenching.

Mentalizing in and out of awareness: A meta-analytic review of implicit and explicit mentalizing.

BACKGROUND: Mentalizing, making sense of mental states, is hypothesized to have a central role in self-organization and social learning. Findings support this notion, but the extent of the association between mentalizing and various correlates has not been meta-analyzed. Furthermore, mentalizing presumably occurs with (explicit) and without (implicit) awareness but few studies have attempted to disentangle these aspects. We conducted a meta-analysis of implicit and explicit mentalizing in relation to the domains of attachment security, personality, affect, psychopathology, and functioning. METHODS: We searched for studies of adult mentalizing in PsycINFO and in related reviews. Overall, 511 studies (N = 78,733) met criteria and were analyzed using multi-level meta-analysis. RESULTS: Implicit (r = 0.19-0.29) and explicit (r = 0.26-0.40) mentalizing were moderately correlated with psychopathology, functioning, personality, affect, and attachment security. The correlations of implicit mentalizing were stronger with more objectively measured correlates (b = 0.02, p < .001) while the correlations of explicit mentalizing were not (b = -0.07, p = .21). CONCLUSIONS: Mentalizing is associated with better intra- and interpersonal functioning. Implicit mentalizing is more strongly associated with objectively measured correlates. These findings underscore the importance of an integrative approach considering both implicit and explicit mentalizing.

BISCUIT: an efficient, standards-compliant tool suite for simultaneous genetic and epigenetic inference in bulk and single-cell studies.

Data from both bulk and single-cell whole-genome DNA methylation experiments are under-utilized in many ways. This is attributable to inefficient mapping of methylation sequencing reads, routinely discarded genetic information, and neglected read-level epigenetic and genetic linkage information. We introduce the BISulfite-seq Command line User Interface Toolkit (BISCUIT) and its companion R/Bioconductor package, biscuiteer, for simultaneous extraction of genetic and epigenetic information from bulk and single-cell DNA methylation sequencing. BISCUIT's performance, flexibility and standards-compliant output allow large, complex experimental designs to be characterized on clinical timescales. BISCUIT is particularly suited for processing data from single-cell DNA methylation assays, with its excellent scalability, efficiency, and ability to greatly enhance mappability, a key challenge for single-cell studies. We also introduce the epiBED format for single-molecule analysis of coupled epigenetic and genetic information, facilitating the study of cellular and tissue heterogeneity from DNA methylation sequencing.

Perlecan (HSPG2) promotes structural, contractile, and metabolic development of human cardiomyocytes.

Perlecan (HSPG2), a heparan sulfate proteoglycan similar to agrin, is key for extracellular matrix (ECM) maturation and stabilization. Although crucial for cardiac development, its role remains elusive. We show that perlecan expression increases as cardiomyocytes mature in vivo and during human pluripotent stem cell differentiation to cardiomyocytes (hPSC-CMs). Perlecan-haploinsuffient hPSCs (HSPG2+/-) differentiate efficiently, but late-stage CMs have structural, contractile, metabolic, and ECM gene dysregulation. In keeping with this, late-stage HSPG2+/- hPSC-CMs have immature features, including reduced ⍺-actinin expression and increased glycolytic metabolism and proliferation. Moreover, perlecan-haploinsuffient engineered heart tissues have reduced tissue thickness and force generation. Conversely, hPSC-CMs grown on a perlecan-peptide substrate are enlarged and display increased nucleation, typical of hypertrophic growth. Together, perlecan appears to play the opposite role of agrin, promoting cellular maturation rather than hyperplasia and proliferation. Perlecan signaling is likely mediated via its binding to the dystroglycan complex. Targeting perlecan-dependent signaling may help reverse the phenotypic switch common to heart failure.

A Cost-Effectiveness Analysis of Wittmann Patch-Assisted Abdominal Closure Compared to Planned Ventral Hernia in Management of the Open Abdomen.

BACKGROUND: Inability to achieve primary fascial closure after damage control laparotomy is a frequently encountered problem by acute care and trauma surgeons. This study aims to compare the cost-effectiveness of Wittmann patch-assisted closure to the planned ventral hernia closure. METHODS: A literature review was performed to determine the probabilities and outcomes for Wittmann patch-assisted primary closure and planned ventral hernia closure techniques. Average utility scores were obtained by a patient-administered survey for the following: rate of successful surgeries (uncomplicated abdominal wall closure), surgical site infection, wound dehiscence, abdominal hernia and enterocutaneous fistula. A visual analogue scale (VAS) was utilized to assess the survey responses and then converted to quality-adjusted life years (QALYs). Total cost for each strategy was calculated using Medicare billing codes. A decision tree was generated with rollback and incremental cost-utility ratio (ICUR) analyses. Sensitivity analyses were performed to account for uncertainty. RESULTS: Wittmann patch-assisted closure was associated with higher clinical effectiveness of 19.43 QALYs compared to planned ventral hernia repair (19.38), with a relative cost reduction of US$7777. Rollback analysis supported Wittmann patch-assisted closure as the more cost-effective strategy. The resulting negative ICUR of -156,679.77 favored Wittmann patch-assisted closure. Monte Carlo analysis demonstrated a confidence of 96.8% that Wittmann patch-assisted closure was cost-effective. CONCLUSIONS: This study demonstrates using the Wittmann patch-assisted closure strategy as a more cost-efficient management of the open abdomen compared to the planned ventral hernia approach.

Coherent olfactory bulb gamma oscillations arise from coupling independent columnar oscillators.

Spike timing-based representations of sensory information depend on embedded dynamical frameworks within neuronal networks that establish the rules of local computation and interareal communication. Here, we investigated the dynamical properties of olfactory bulb circuitry in mice of both sexes using microelectrode array recordings from slice and in vivo preparations. Neurochemical activation or optogenetic stimulation of sensory afferents evoked persistent gamma oscillations in the local field potential. These oscillations arose from slower, GABA(A) receptor-independent intracolumnar oscillators coupled by GABA(A)-ergic synapses into a faster, broadly coherent network oscillation. Consistent with the theoretical properties of coupled-oscillator networks, the spatial extent of zero-phase coherence was bounded in slices by the reduced density of lateral interactions. The intact in vivo network, however, exhibited long-range lateral interactions that suffice in simulation to enable zero-phase gamma coherence across the olfactory bulb. The timing of action potentials in a subset of principal neurons was phase-constrained with respect to evoked gamma oscillations. Coupled-oscillator dynamics in olfactory bulb thereby enable a common clock, robust to biological heterogeneities, that is capable of supporting gamma-band spike synchronization and phase coding across the ensemble of activated principal neurons.NEW & NOTEWORTHY Odor stimulation evokes rhythmic gamma oscillations in the field potential of the olfactory bulb, but the dynamical mechanisms governing these oscillations have remained unclear. Establishing these mechanisms is important as they determine the biophysical capacities of the bulbar circuit to, for example, maintain zero-phase coherence across a spatially extended network, or coordinate the timing of action potentials in principal neurons. These properties in turn constrain and suggest hypotheses of sensory coding.

Tibial Spine Fractures in the Child and Adolescent Athlete: A Systematic Review and Meta-analysis.

BACKGROUND: Tibial spine fractures (TSFs) are uncommon injuries that may result in substantial morbidity in children. A variety of open and arthroscopic techniques are used to treat these fractures, but no single standardized operative method has been identified. PURPOSE: To systematically review the literature on pediatric TSFs to determine the current treatment approaches, outcomes, and complications. STUDY DESIGN: Meta-analysis; Level of evidence, 4. METHODS: A systematic review of the literature was performed in accordance with the PRISMA (Preferred Reporting Items for Systematic Review and Meta-Analyses) guidelines using PubMed, Embase, and Cochrane databases. Studies evaluating treatment and outcomes of patients <18 years old were included. Patient demographic characteristics, fracture characteristics, treatments, and outcomes were abstracted. Descriptive statistics were used to summarize categorical and quantitative variables, and a meta-analytic technique was used to compare observational studies with sufficient data. RESULTS: A total of 47 studies were included, totaling 1922 TSFs in patients (66.4% male) with a mean age of 12 years (range, 3-18 years). The operative approach was open reduction and internal fixation in 291 cases and arthroscopic reduction and internal fixation in 1236 cases; screw fixation was used in 411 cases and suture fixation, in 586 cases. A total of 13 nonunions were reported, occurring most frequently in Meyers and McKeever type III fractures (n = 6) and in fractures that were treated nonoperatively (n = 10). Arthrofibrosis rates were reported in 33 studies (n = 1700), and arthrofibrosis was present in 190 patients (11.2%). Range of motion loss occurred significantly more frequently in patients with type III and IV fractures (P < .001), and secondary anterior cruciate ligament (ACL) injury occurred most frequently in patients with type I and II fractures (P = .008). No statistically significant differences were found with regard to rates of nonunion, arthrofibrosis, range of motion loss, laxity, or secondary ACL injury between fixation methods (screw vs suture). CONCLUSION: Despite variation in TSF treatment, good overall outcomes have been reported with low complication rates in both open and arthroscopic treatment and with both screw and suture fixation. Arthrofibrosis remains a concern after surgical treatment for TSF, but no significant difference in incidence was found between the analysis groups. Larger studies are necessary to compare outcomes and form a consensus on how to treat and manage patients with TSFs.

The discovery and evaluation of [18F]BMS-986229, a novel macrocyclic peptide PET radioligand for the measurement of PD-L1 expression and in-vivo PD-L1 target engagement.

PURPOSE: A same-day PET imaging agent capable of measuring PD-L1 status in tumors is an important tool for optimizing PD-1 and PD-L1 treatments. Herein we describe the discovery and evaluation of a novel, fluorine-18 labeled macrocyclic peptide-based PET ligand for imaging PD-L1. METHODS: [18F]BMS-986229 was synthesized via copper mediated click-chemistry to yield a PD-L1 PET ligand with picomolar affinity and was tested as an in-vivo tool for assessing PD-L1 expression. RESULTS: Autoradiography showed an 8:1 binding ratio in L2987 (PD-L1 (+)) vs. HT-29 (PD-L1 (-)) tumor tissues, with >90% specific binding. Specific radioligand binding (>90%) was observed in human non-small-cell lung cancer (NSCLC) and cynomolgus monkey spleen tissues. Images of PD-L1 (+) tissues in primates were characterized by high signal-to-noise, with low background signal in non-expressing tissues. PET imaging enabled clear visualization of PD-L1 expression in a murine model in vivo, with 5-fold higher uptake in L2987 (PD-L1 (+)) than in control HT-29 (PD-L1 (-)) tumors. Moreover, this imaging agent was used to measure target engagement of PD-L1 inhibitors (peptide or mAb), in PD-L1 (+) tumors as high as 97%. CONCLUSION: A novel 18F-labeled macrocyclic peptide radioligand was developed for PET imaging of PD-L1 expressing tissues that demonstrated several advantages within a nonhuman primate model when compared directly to adnectin- or mAb-based ligands. Clinical studies are currently evaluating [18F]BMS-986229 to measure PD-L1 expression in tumors.

Cell State of Origin Impacts Development of Distinct Endometriosis-Related Ovarian Carcinoma Histotypes.

Clear cell ovarian carcinoma (CCOC) and endometrioid ovarian carcinoma (ENOC) are ovarian carcinoma histotypes, which are both thought to arise from ectopic endometrial (or endometrial-like) cells through an endometriosis intermediate. How the same cell type of origin gives rise to two morphologically and biologically different histotypes has been perplexing, particularly given that recurrent genetic mutations are common to both and present in nonmalignant precursors. We used RNA transcription analysis to show that the expression profiles of CCOC and ENOC resemble those of normal endometrium at secretory and proliferative phases of the menstrual cycle, respectively. DNA methylation at the promoter of the estrogen receptor (ER) gene (ESR1) was enriched in CCOC, which could potentially lock the cells in the secretory state. Compared with normal secretory-type endometrium, CCOC was further defined by increased expression of cysteine and glutathione synthesis pathway genes and downregulation of the iron antiporter, suggesting iron addiction and highlighting ferroptosis as a potential therapeutic target. Overall, these findings suggest that while CCOC and ENOC arise from the same cell type, these histotypes likely originate from different cell states. This "cell state of origin" model may help to explain the presence of histologic and molecular cancer subtypes arising in other organs. SIGNIFICANCE: Two cancer histotypes diverge from a common cell of origin epigenetically locked in different cell states, highlighting the importance of considering cell state to better understand the cell of origin of cancer.

Intestinal permeability and inflammatory features of juvenile age correlate with the eventual systemic autoimmunity in lupus-prone female SWR × NZB F1 (SNF1) mice.

The incidence of systemic lupus erythematosus (SLE) is about nine times higher in women than in men, and the underlying mechanisms that contribute to this gender bias are not fully understood. Previously, using lupus-prone (SWR × NZB)F1 (SNF1) mice, we have shown that the intestinal immune system could play a role in the initiation and progression of disease in SLE, and depletion of gut microbiota produces more pronounced disease protection in females than in males. Here, we show that the gut permeability features of lupus-prone female SNF1 mice at juvenile ages directly correlate with the expression levels of pro-inflammatory factors, faecal IgA abundance and nAg reactivity and the eventual systemic autoantibody levels and proteinuria onset. Furthermore, we observed that the disease protection achieved in female SNF1 mice upon depletion of gut microbiota correlates with the diminished gut inflammatory protein levels, intestinal permeability and circulating microbial DNA levels. However, faecal microbiota transplant from juvenile male and females did not result in modulation of gut inflammatory features or permeability. Overall, these observations suggest that the early onset of intestinal inflammation, systemic autoantibody production and clinical stage disease in lupus-prone females is linked to higher gut permeability in them starting at as early as juvenile age. While the higher gut permeability in juvenile lupus-prone females is dependent on the presence of gut microbes, it appears to be independent of the composition of gut microbiota.

Genu Valgum in Pediatric Patients Presenting With Patellofemoral Instability.

BACKGROUND: Lower extremity valgus is a commonly described factor associated with patellofemoral instability (PFI) and, if identified before skeletal maturity, can be treated with guided growth. The prevalence of valgus alignment in the pediatric and adolescent PFI population is largely unknown. PURPOSE: The aim of this study was to report the prevalence of valgus alignment in adolescent patients presenting with PFI; with secondary assessment of high-grade valgus (zone II or III), coronal asymmetry, and associations of these findings with body mass index (BMI). STUDY DESIGN: A retrospective cohort study. METHODS: A total of 279 consecutive patients (349 knees) with a diagnosis of PFI presenting to a single orthopedic pediatric sport medicine surgeon were identified. A retrospective chart review was performed to collect demographic and clinical data, chronologic and bone age, sex, BMI, mechanism of injury, and the presence of osteochondral fracture. Full-length standing hip-to-ankle alignment radiographs were graded for knee alignment mechanical zone utilizing standard linear femoral head center to talar center assessment. In addition, mechanical axis deviation, mechanical lateral distal femoral angle and medial proximal tibial angle (MPTA) were also calculated. RESULTS: Mean patient age was 14.0±2.5 years. There were 162 (58.1%) females and mean BMI was 24.3±6.4. Seventy patients (25.1%) had bilateral PFI. Standing alignment radiographs were available for 81.4% of knees (n=284). Valgus alignment was present in 172 knees with PFI (60.6%). High-grade valgus, defined as zone 2 or greater, was present in 66 knees (23.3%). Overall, 48.9% had asymmetry of coronal alignment (n=139). The mean mechanical lateral distal femoral angle was 85.4±2.8 and the mean MPTA was 88.2±2.6. There was a greater MPTA in female patients (88.8±2.4 vs. 87.5±2.7, P <0.001). A higher BMI (24.87±6.95, P =0.03) was associated with valgus alignment. CONCLUSIONS: There is a high (60%) prevalence of lower extremity valgus in adolescent patients presenting with PFI, with nearly 1 in 4 presenting with high-grade valgus. The treatment team should be aware of this association as it may be an important consideration in the pediatric and adolescent PFI populations. LEVEL OF EVIDENCE: Level III.