A Decade of Firearm Injuries: Children Caught in the Crossfire.

INTRODUCTION: Firearm injuries (FIs) are the leading cause of preventable morbidity and mortality in pediatric patients. In this study, we aim to define evolving trends and avenues for prevention. METHODS: Following institutional review board approval, medical records of patients presenting to our two State-Designated Level 1 Pediatric Trauma Centers for treatment of FIs from 2010 to 2019 were retrospectively reviewed. Data was analyzed with Chi-Squared and Student's t-test; P-value <0.05 was significant. RESULTS: 1037 FI encounters from 1005 unique patients aged 0-21 y were included. 70.4% (n = 730) were determined to be assaults, 26.1% (n = 271) unintentional, and 1.7% (n = 18) self-inflicted injuries. Overall mortality was 4.5% (n = 45). FI victims were most commonly African American (n = 836, 80.6%), male (n = 869, 83.8%), aged 13-17 (n = 753, 72.6%), and from single-parent families (n = 647, 62.4%). The incidence of FIs increased significantly over the last 5 y of the study (2010-2014, 6.8 FIs/month), compared to 2015-2019 (averaging 10.6 FIs/month, P < 0.0001). Concurrently, FI related fatality increased from an average of 2.6 deaths/year (2010-2014) to 6.4 deaths/year (2015-2019, P = 0.064). Results were subanalyzed for pediatric patients aged 0-14 y. For the entire cohort, 12.1% (n = 116) recidivists were identified. Geographic patterns of injury were identified, with 75% of all FIs clustered in a single urban region. CONCLUSIONS: Incidence of pediatric FIs is increasing in recent years, with high mortality rates. Violence and recidivism are geographically concentrated, offering an opportunity for targeted interventions.

Factors affecting implant length in primary inflatable penile prosthesis placement.

OBJECTIVES: To evaluate predictors of implant length for men undergoing primary IPP placement. METHODS: A multicenter, retrospective cohort study was performed for men undergoing primary IPP placement at 16 high-volume surgical centers. Patient demographics, comorbidities, operative approach, and implanted cylinder and rear tip extender length were recorded. Associations between potential preoperative and intraoperative predictors of total device length were tested using non-parametric correlation and Kruskal-Wallis tests, followed by multiple regression. RESULTS: Of 3,951 men undergoing primary IPP placement from July 2016 - July 2021, the median implant length was 20 cm (IQR: 19 - 22). Shorter implant length was associated with increasing age in years (ß = -0.01, p=0.009), Asian ethnicity (ß = -2.34, p=0.008), history of radical prostatectomy (ß = -0.35, p=0.001), and use of an infrapubic surgical approach (ß = -1.02, p<0.001). Black or African American ethnicity was associated with the implantation of longer devices (ß = 0.35, p<0.001). No significant associations were recorded with BMI, history of intracavernosal injections, diabetes mellitus, tobacco use, radiation therapy, Peyronie's disease, priapism, or cavernosal dilation technique. CONCLUSIONS: The length of an implanted penile prosthesis was found to be associated with preoperative and intraoperative factors including history of radical prostatectomy and operative approach. The knowledge of these associations may assist in the preoperative counseling of patients receiving IPP and help create accurate postoperative expectations.

Subcellular location of L1 retrotransposon-encoded ORF1p, reverse transcription products, and DNA sensors in lupus granulocytes.

BACKGROUND: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with an unpredictable course of recurrent exacerbations alternating with more stable disease. SLE is characterized by broad immune activation and autoantibodies against double-stranded DNA and numerous proteins that exist in cells as aggregates with nucleic acids, such as Ro60, MOV10, and the L1 retrotransposon-encoded ORF1p. RESULTS: Here we report that these 3 proteins are co-expressed and co-localized in a subset of SLE granulocytes and are concentrated in cytosolic dots that also contain DNA: RNA heteroduplexes and the DNA sensor ZBP1, but not cGAS. The DNA: RNA heteroduplexes vanished from the neutrophils when they were treated with a selective inhibitor of the L1 reverse transcriptase. We also report that ORF1p granules escape neutrophils during the extrusion of neutrophil extracellular traps (NETs) and, to a lesser degree, from neutrophils dying by pyroptosis, but not apoptosis. CONCLUSIONS: These results bring new insights into the composition of ORF1p granules in SLE neutrophils and may explain, in part, why proteins in these granules become targeted by autoantibodies in this disease.

Self-Determination Theory and Workplace Outcomes: A Conceptual Review and Future Research Directions.

Adaptive workplace outcomes, such as employee work engagement, job performance, and satisfaction are positively associated with physical and psychological well-being, while maladaptive workplace outcomes, including work-related disengagement, dissatisfaction, stress, boredom, fatigue, and burnout, are negatively associated with well-being. Researchers have applied self-determination theory to identify key motivational correlates of these adaptive work-related determinants and outcomes. Research applying the theory has consistently indicated that autonomous forms of motivation and basic psychological need satisfaction are related to better employee performance, satisfaction, and engagement, while controlled forms of motivation and need frustration are associated with increased employee burnout and turnover. Forms of motivation have also been shown to mediate relations between need satisfaction and adaptive workplace outcomes. Despite support for these associations, a number of limitations in research in the field have been identified, which place limits on the inferences that can be drawn. Noted limitations encompass an over-reliance on single-occasion, correlational data; few fit-for-purpose tests of theory mechanisms; and a lack of consideration of key moderating variables. In the current conceptual review, we discuss these limitations in turn, with specific reference to examples from the extant research applying the theory in workplace contexts, and provide a series of recommendations we expect will set the agenda for future studies applying the theory in the workplace. Based on our review, we make three key recommendations: we stress the need for studies adopting experimental and longitudinal designs to permit better inferences (i.e., causal and directional), highlight the need for intervention research to explicitly test mediation effects to provide evidence for theory mechanisms, and outline some candidate moderators of theory effects, including workplace context, job type, pay structure, and causality orientations. We expect these recommendations to set an agenda for future research applying self-determination theory in workplace contexts with a view to filling the current evidence gaps and improving evidential quality.

Testing the Effect of Cue Consistency on the Past Behavior-Habit-Physical Activity Relationship.

Behavior performed in the presence of consistent cues is a core element for successful habit development, with the repeated presence of consistent cues facilitating the activation of automatic responses in future. Yet, little is known about the effects of different cue types on habit. Using a two-wave prospective PLS-SEM model with a sample of 68 undergraduate students, we assessed the mediating effects of habit on the past-behavior-to-physical-activity relationship, and how the mediating effects of habit were moderated by the consistent presence of different forms of cues. Habit mediated the effects of past behavior on physical activity, with a significantly stronger mediating effect of habit in those reporting undertaking physical activity at the same time of day, doing the same activity, and in the same mood. Consistent place, people, and part of routine did not moderate the effects of habit. The results provide formative evidence for a key assertion of the habit theory that consistent contextual and internal cues are a cornerstone of habitual development and action, but they also indicate the importance of examining different forms of cues and their impact on the formation and enaction of habits as some cues may be more relevant than others.

Multiple Vertebral Compression Fractures Secondary to Pregnancy-induced Osteoporosis: A Case Report.

Introduction: Although rare in incidence, pregnancy-induced osteoporosis (PIO)-associated OVCFs represent a significant cause of morbidity for the young, peri-partum female population. Case Report: We present the case of a 27-year-old nulliparous lady who suffered seven osteoporosis vertebral compression fractures (OVCFs) with associated sagittal imbalance, the challenges posed to the attending physician or surgeon in treating this rare condition, as well as an in-depth discussion of previous literature reported on pregnancy-induced osteoporosis (PLIO) to date. Although rare in incidence, PLIO-associated OVCFs represent a significant cause of morbidity for the young, peripartum female. Conclusion: This case demonstrates how multiple PLIO-associated OVCFs may be managed successfully, with careful consideration of sagittal imbalance, using a combination of medical and non-operative orthopedic therapies at medium-term follow-up.

Simultaneous bilateral total hip arthroplasty-a survey of Irish orthopaedic surgeons' practice.

BACKGROUND: Bilateral total hip arthroplasty may be performed simultaneously (SIMTHA) or in two staged operations. AIM: To assess attitudes towards and utilization of SIMTHA in Irish orthopaedic practice, and to assess patient and surgeon factors which are associated with the management of bilateral hip arthritis. METHODS: A 16-question electronic survey (Google Forms) was distributed via email to consultant Irish orthopaedic surgeons who perform total hip arthroplasty, followed by a reminder 1 month later. A p value < 0.05 was considered significant. RESULTS: There were 53 responses from arthroplasty surgeons, with 28% reporting they never perform SIMTHA, 26% have performed ≤ 5 SIMTHA, and 46% do ≥ 1 SIMTHA per year. Amongst the 15 surgeons who do not do SIMTHA, 60% reported a preference for staged arthroplasty, 20% felt it was not feasible in their institution, and a third reported a lack of experience with SIMTHA. There was a significant association between not performing SIMTHA and years of consultant experience (p = 0.002). There were no institutional guidelines on eligibility criteria for SIMTHA. The most common time interval for staged bilateral arthroplasty was 6-12 weeks (60%). Overall, 56% of surgeons felt SIMTHA is underutilised in the Irish healthcare system; this was associated with greater SIMTHA volume (p = 0.023). CONCLUSION: Half of the Irish arthroplasty surgeons report SIMTHA is a regular aspect of their practice. Performing SIMTHA is associated with greater arthroplasty volume, more recent consultant appointments, and a perception that the operation is underutilised.

Exploring the Ocular Surface Microbiome and Tear Proteome in Glaucoma.

Although glaucoma is a leading cause of irreversible blindness worldwide, its pathogenesis is incompletely understood, and intraocular pressure (IOP) is the only modifiable risk factor to target the disease. Several associations between the gut microbiome and glaucoma, including the IOP, have been suggested. There is growing evidence that interactions between microbes on the ocular surface, termed the ocular surface microbiome (OSM), and tear proteins, collectively called the tear proteome, may also play a role in ocular diseases such as glaucoma. This study aimed to find characteristic features of the OSM and tear proteins in patients with glaucoma. The whole-metagenome shotgun sequencing of 32 conjunctival swabs identified Actinobacteria, Firmicutes, and Proteobacteria as the dominant phyla in the cohort. The species Corynebacterium mastitidis was only found in healthy controls, and their conjunctival microbiomes may be enriched in genes of the phospholipase pathway compared to glaucoma patients. Despite these minor differences in the OSM, patients showed an enrichment of many tear proteins associated with the immune system compared to controls. In contrast to the OSM, this emphasizes the role of the proteome, with a potential involvement of immunological processes in glaucoma. These findings may contribute to the design of new therapeutic approaches targeting glaucoma and other associated diseases.

The Role of Chromatic Aberration in Vision.

The study of biological optics would be complicated enough if light only came in a single wavelength. However, altering the wavelength (or distribution of wavelengths) of light has multiple effects on optics, including on diffraction, scattering (of various sorts), transmission through and reflection by various media, fluorescence, and waveguiding properties, among others. In this review, we consider just one wavelength-dependent optical effect: longitudinal chromatic aberration (LCA). All vertebrate eyes that have been tested have significant LCA, with shorter (bluer) wavelengths of light focusing closer to the front of the eye than longer (redder) wavelengths. We consider the role of LCA in the visual system in terms of both how it could degrade visual acuity and how biological systems make use of it.

Analysis of optical coherence tomography biomarker probability detection in central serous chorioretinopathy by using an artificial intelligence-based biomarker detector.

AIM: To adopt a novel artificial intelligence (AI) optical coherence tomography (OCT)-based program to identify the presence of biomarkers associated with central serous chorioretinopathy (CSC) and whether these can differentiate between acute and chronic central serous chorioretinopathy (aCSC and cCSC). METHODS: Multicenter, observational study with a retrospective design enrolling treatment-naïve patients with aCSC and cCSC. The diagnosis of aCSC and cCSC was established with multimodal imaging and for the current study subsequent follow-up visits were also considered. Baseline OCTs were analyzed by an AI-based platform (Discovery® OCT Fluid and Biomarker Detector, RetinAI AG, Switzerland). This software allows to detect several different biomarkers in each single OCT scan, including subretinal fluid (SRF), intraretinal fluid (IRF), hyperreflective foci (HF) and flat irregular pigment epithelium detachment (FIPED). The presence of SRF was considered as a necessary inclusion criterion for performing biomarker analysis and OCT slabs without SRF presence were excluded from the analysis. RESULTS: Overall, 160 eyes of 144 patients with CSC were enrolled, out of which 100 (62.5%) eyes were diagnosed with cCSC and 60 eyes (34.5%) with aCSC. In the OCT slabs showing presence of SRF the presence of biomarkers was found to be clinically relevant (> 50%) for HF and FIPED in aCSC and cCSC. HF had an average percentage of 81% (± 20) in the cCSC group and 81% (± 15) in the aCSC group (p = 0.4295) and FIPED had a mean percentage of 88% (± 18) in cCSC vs. 89% (± 15) in the aCSC (p = 0.3197). CONCLUSION: We demonstrate that HF and FIPED are OCT biomarkers positively associated with CSC when present at baseline. While both HF and FIPED biomarkers could aid in CSC diagnosis, they could not distinguish between aCSC and cCSC at the first visit. AI-assisted biomarker detection shows promise for reducing invasive imaging needs, but further validation through longitudinal studies is needed.

Effect of Treatment of Residual Disease After Immunotherapy-Based Combinations on Complete Response Rate of Patients With Metastatic Renal Cell Carcinomas.

INTRODUCTION: Immune checkpoint inhibitor (ICI)-based combinations have revolutionized the management of first-line metastatic renal cell carcinoma (mRCC) by improving patient survival. Large phase 3 randomized trials assessing ICI-based combinations have reported complete response (CR) rates of 10% to 18% in the first-line setting. However, there is a scarcity of data about the effect of treatment of residual disease regarding CR rates improvement. MATERIALS AND METHODS: We included retrospectively all consecutive mRCC patients treated in first-line setting at the Institut de Cancérologie Strasbourg Europe with an ICI-based combination involving ICI or TKI, either alone or with added local treatment of residual disease. Patients were characterized according to IMDC risk. Radiologic response was defined according to RECIST v1.1. RESULTS: We enrolled 80 mRCC patients treated with ICI-based combinations between May 2015 and May 2022. The median age was 63 years. Regarding IMDC risk, there were 12 favourable (15%), 50 intermediate (63%), and 18 poor-risk (22%) patients. Forty-seven patients (59%) received ICI + ICI, 24 (30%) received ICI + TKI, and 9 (11%) received another ICI-based therapy. In total, 8 achieved CR (10%), 36 patients (45%) achieved partial response, 23 (29%) achieved stable disease and 12 achieved progressive disease (15%) as the best response with systemic therapy alone. By adding local treatment of residual disease, 11 additional patients (14%) achieved radiological NED. Residual disease resected sites included kidney (n = 6), lymph nodes (n = 5), lung metastases (n = 2) and liver metastases (n = 1). CONCLUSIONS: The resection of residual disease after first-line ICI-based therapy is associated with improved CR rate (CR + NED) in patients with mRCC. These results need to be validated in prospective trial. PATIENT SUMMARY: In recent years, the advent of immunotherapy has radically changed the management of patients with metastatic kidney cancer. Approximately 10% to 18% of these patients using immune checkpoint inhibitor (ICI)-based combinations no longer have detectable disease on CT scans (complete response). There are currently few data on the use of treatment of residual disease to increase the number of patients in complete response. In this retrospective study, the complete response rate with ICI-based treatment was 10%. When local treatment was added, the number of patients with a complete response increased to 24%. This strategy could increase the number of patients with a prolonged complete response in the future.

Diversity and phage sensitivity to phages of porcine enterotoxigenic Escherichia coli.

Enterotoxigenic Escherichia coli (ETEC) is a diverse and poorly characterized E. coli pathotype that causes diarrhea in humans and animals. Phages have been proposed for the veterinary biocontrol of ETEC, but effective solutions require understanding of porcine ETEC diversity that affects phage infection. Here, we sequenced and analyzed the genomes of the PHAGEBio ETEC collection, gathering 79 diverse ETEC strains isolated from European pigs with post-weaning diarrhea (PWD). We identified the virulence factors characterizing the pathotype and several antibiotic resistance genes on plasmids, while phage resistance genes and other virulence factors were mostly chromosome encoded. We experienced that ETEC strains were highly resistant to Enterobacteriaceae phage infection. It was only by enrichment of numerous diverse samples with different media and conditions, using the 41 ETEC strains of our collection as hosts, that we could isolate two lytic phages that could infect a large part of our diverse ETEC collection: vB_EcoP_ETEP21B and vB_EcoS_ETEP102. Based on genome and host range analyses, we discussed the infection strategies of the two phages and identified components of lipopolysaccharides ( LPS) as receptors for the two phages. Our detailed computational structural analysis highlights several loops and pockets in the tail fibers that may allow recognition and binding of ETEC strains, also in the presence of O-antigens. Despite the importance of receptor recognition, the diversity of the ETEC strains remains a significant challenge for isolating ETEC phages and developing sustainable phage-based products to address ETEC-induced PWD.IMPORTANCEEnterotoxigenic Escherichia coli (ETEC)-induced post-weaning diarrhea is a severe disease in piglets that leads to weight loss and potentially death, with high economic and animal welfare costs worldwide. Phage-based approaches have been proposed, but available data are insufficient to ensure efficacy. Genome analysis of an extensive collection of ETEC strains revealed that phage defense mechanisms were mostly chromosome encoded, suggesting a lower chance of spread and selection by phage exposure. The difficulty in isolating lytic phages and the molecular and structural analyses of two ETEC phages point toward a multifactorial resistance of ETEC to phage infection and the importance of extensive phage screenings specifically against clinically relevant strains. The PHAGEBio ETEC collection and these two phages are valuable tools for the scientific community to expand our knowledge on the most studied, but still enigmatic, bacterial species-E. coli.

Discrete measurements of RNA polymerase and reverse transcriptase fidelity reveal evolutionary tuning.

Direct methods for determining the fidelity of DNA polymerases are robust, with relatively little sample manipulation before sequencing. In contrast, methods for measuring RNA polymerase and reverse transcriptase fidelities are complicated by additional preparation steps that introduce ambiguity and error. Here, we describe a sequencing method, termed Roll-Seq, for simultaneously determining the individual fidelities of RNA polymerases and reverse transcriptases (RT) using Pacific Biosciences Single Molecule Real-Time sequencing. By employing reverse transcriptases with high rolling-circle activity, Roll-Seq generates long concatemeric cDNA from a circular RNA template. To discern the origin of a mutation, errors are recorded and determined to occur within a single concatemer (reverse transcriptase error) or all concatemers (RNA polymerase error) over the cDNA strand. We used Roll-Seq to measure the fidelities of T7 RNA polymerases, a Group II intron-encoded RT (Induro), and two LINE RTs (Fasciolopsis buski R2-RT and human LINE-1). Substitution rates for Induro and R2-RT are the same for cDNA and second strand synthesis while LINE-1 has 2.5-fold lower fidelity when performing second strand synthesis. Deletion and insertion rates increase for all RTs during second strand synthesis. In addition, we find that a structured RNA template impacts fidelity for both RNA polymerase and RT. The accuracy and precision of Roll-Seq enable this method to be applied as a complementary analysis to structural and mechanistic characterization of RNA polymerases and reverse transcriptases or as a screening method for RNAP and RT fidelity.

Larger Tumor Size and Elevated Serum Chromogranin A Levels Predict Metastatic Disease on DOTATATE Imaging in Patients with Gastroenteropancreatic Neuroendocrine Tumors.

PURPOSE: DOTATATE PET/CT (DOTATATE) is superior to conventional imaging in detecting metastasis for gastroenteropancreatic neuroendocrine tumors (GEP-NETs). However, limited availability, high-cost, and additive radiation exposure necessitate guidelines for its use. This study seeks to investigate the relationship between clinical characteristics and metastasis on DOTATATE. METHODS: This was a retrospective analysis of 815 patients who underwent DOTATATE at UCLA from 2014 to 2022. After applying inclusion and exclusion criteria, the study cohort consisted of 163 patients with pathologically diagnosed GEP-NETs, who either underwent primary tumor resection within 1-year prior, or had not undergone resection at the time of DOTATATE imaging. The presence of metastasis was determined using DOTATATE. Fisher's exact test, chi-squared test, and Mann-Whitney test were conducted to compare intergroup difference. Multivariate analysis was performed to identify clinical characteristics associated with metastasis on DOTATATE. RESULTS: Of patients with GEP-NETs, 40.5% (n = 66) were diagnosed with metastases by using DOTATATE. Those with metastatic disease were more likely to exhibit a larger primary tumor size (median 3.4 vs. 1.2, cm, P < 0.001), elevated serum chromogranin A level (CgA, median 208 vs. 97, mg/ml, P = 0.005), and higher tumor grade (P < 0.001). Primary tumor size ≥2 cm and serum CgA level ≥150 ng/mL for metastatic disease had a sensitivity and specificity of 64% and 89%, and 72% and 59%, respectively. Multivariate analysis demonstrated that primary tumor size (≥2/<2, cm, odds ratio [OR] 47.90, P < 0.001), tumor functionality (functional/nonfunctional, adjusted OR 10.17 P = 0.008), serum CgA level (≥150/<150, ng/ml, OR 6.25, P = 0.005), and tumor grade G2 (G2/G1, OR 9.6, P < 0.001) were independently associated with metastases on DOTATATE. CONCLUSIONS: Among patients with GEP-NETs, primary tumor size ≥2 cm, serum CgA level ≥150 ng/mL, and tumor grade G2 are associated with an increased risk of metastases on DOTATATE, and these predictors may be helpful to identify patients where DOTATATE is indicated for complete staging.

Strand-resolved mutagenicity of DNA damage and repair.

DNA base damage is a major source of oncogenic mutations1. Such damage can produce strand-phased mutation patterns and multiallelic variation through the process of lesion segregation2. Here we exploited these properties to reveal how strand-asymmetric processes, such as replication and transcription, shape DNA damage and repair. Despite distinct mechanisms of leading and lagging strand replication3,4, we observe identical fidelity and damage tolerance for both strands. For small alkylation adducts of DNA, our results support a model in which the same translesion polymerase is recruited on-the-fly to both replication strands, starkly contrasting the strand asymmetric tolerance of bulky UV-induced adducts5. The accumulation of multiple distinct mutations at the site of persistent lesions provides the means to quantify the relative efficiency of repair processes genome wide and at single-base resolution. At multiple scales, we show DNA damage-induced mutations are largely shaped by the influence of DNA accessibility on repair efficiency, rather than gradients of DNA damage. Finally, we reveal specific genomic conditions that can actively drive oncogenic mutagenesis by corrupting the fidelity of nucleotide excision repair. These results provide insight into how strand-asymmetric mechanisms underlie the formation, tolerance and repair of DNA damage, thereby shaping cancer genome evolution.

Human mitochondrial carriers of the SLC25 family function as monomers exchanging substrates with a ping-pong kinetic mechanism.

Members of the SLC25 mitochondrial carrier family link cytosolic and mitochondrial metabolism and support cellular maintenance and growth by transporting compounds across the mitochondrial inner membrane. Their monomeric or dimeric state and kinetic mechanism have been a matter of long-standing debate. It is believed by some that they exist as homodimers and transport substrates with a sequential kinetic mechanism, forming a ternary complex where both exchanged substrates are bound simultaneously. Some studies, in contrast, have provided evidence indicating that the mitochondrial ADP/ATP carrier (SLC25A4) functions as a monomer, has a single substrate binding site, and operates with a ping-pong kinetic mechanism, whereby ADP is imported before ATP is exported. Here we reanalyze the oligomeric state and kinetic properties of the human mitochondrial citrate carrier (SLC25A1), dicarboxylate carrier (SLC25A10), oxoglutarate carrier (SLC25A11), and aspartate/glutamate carrier (SLC25A13), all previously reported to be dimers with a sequential kinetic mechanism. We demonstrate that they are monomers, except for dimeric SLC25A13, and operate with a ping-pong kinetic mechanism in which the substrate import and export steps occur consecutively. These observations are consistent with a common transport mechanism, based on a functional monomer, in which a single central substrate-binding site is alternately accessible.