Buddy taping after reduction of displaced extra-articular phalangeal finger fractures in children: a randomized controlled trial.

In this randomized controlled trial, we assessed the non-inferiority of buddy taping to splinting after reduction of displaced extra-articular proximal and middle phalangeal finger fractures in children. The primary outcome was the rate of secondary fracture displacements; the secondary outcomes were patient comfort, analgesic efficacy and total range of active motion 6 months after injury. Eighty-one patients participated: 43 with taping and 38 with splinting. Secondary displacement occurred in eight patients: five in the splinting group and three in the taping group. Risk difference was below the predefined non-inferiority of 10%. Patient comfort was significantly higher in the taping group, with no group differences for other parameters. Our previous study recommended taping for undisplaced finger fractures in children. With the current data, we recommend taping these finger fractures irrespective of displacement or need for reduction. We are encouraged to propose taping as an alternative to splinting for increased patient comfort, lower cost, and shorter application time.Level of evidence: I.

Natural language processing augments comorbidity documentation in neurosurgical inpatient admissions.

OBJECTIVE: To establish whether or not a natural language processing technique could identify two common inpatient neurosurgical comorbidities using only text reports of inpatient head imaging. MATERIALS AND METHODS: A training and testing dataset of reports of 979 CT or MRI scans of the brain for patients admitted to the neurosurgery service of a single hospital in June 2021 or to the Emergency Department between July 1-8, 2021, was identified. A variety of machine learning and deep learning algorithms utilizing natural language processing were trained on the training set (84% of the total cohort) and tested on the remaining images. A subset comparison cohort (n = 76) was then assessed to compare output of the best algorithm against real-life inpatient documentation. RESULTS: For "brain compression", a random forest classifier outperformed other candidate algorithms with an accuracy of 0.81 and area under the curve of 0.90 in the testing dataset. For "brain edema", a random forest classifier again outperformed other candidate algorithms with an accuracy of 0.92 and AUC of 0.94 in the testing dataset. In the provider comparison dataset, for "brain compression," the random forest algorithm demonstrated better accuracy (0.76 vs 0.70) and sensitivity (0.73 vs 0.43) than provider documentation. For "brain edema," the algorithm again demonstrated better accuracy (0.92 vs 0.84) and AUC (0.45 vs 0.09) than provider documentation. DISCUSSION: A natural language processing-based machine learning algorithm can reliably and reproducibly identify selected common neurosurgical comorbidities from radiology reports. CONCLUSION: This result may justify the use of machine learning-based decision support to augment provider documentation.

Comprehensive Genetic Profiling Reveals Frequent Alterations of Driver Genes on the X Chromosome in Extranodal NK/T-cell Lymphoma.

Extranodal NK/T-cell lymphoma (ENKTCL) is an Epstein-Barr virus (EBV)-related neoplasm with male dominance and a poor prognosis. A better understanding of the genetic alterations and their functional roles in ENKTCL could help improve patient stratification and treatments. In this study, we performed a comprehensive genetic analysis of 178 ENKTCL cases to delineate the landscape of mutations, copy number alterations (CNA), and structural variations, identifying 34 driver genes including six previously unappreciated ones, namely, HLA-B, HLA-C, ROBO1, CD58, POT1, and MAP2K1. Among them, CD274 (24%) was the most frequently altered, followed by TP53 (20%), CDKN2A (19%), ARID1A (15%), HLA-A (15%), BCOR (14%), and MSN (14%). Chromosome X losses were the most common arm-level CNAs in females (∼40%), and alterations of four X-linked driver genes (MSN, BCOR, DDX3X, and KDM6A) were more frequent in males and females harboring chromosome X losses. Among X-linked drivers, MSN was the most recurrently altered, and its expression was lost in approximately one-third of cases using immunohistochemical analysis. Functional studies of human cell lines showed that MSN disruption promoted cell proliferation and NF-κB activation. Moreover, MSN inactivation increased sensitivity to NF-κB inhibition in vitro and in vivo. In addition, recurrent deletions were observed at the origin of replication in the EBV genome (6%). Finally, by integrating the 34 drivers and 19 significant arm-level CNAs, nonnegative matrix factorization and consensus clustering identified two molecular groups with different genetic features and prognoses irrespective of clinical prognostic factors. Together, these findings could help improve diagnostic and therapeutic strategies in ENKTCL. Significance: Integrative genetic analyses and functional studies in extranodal NK/T-cell lymphoma identify frequent disruptions of X-linked drivers, reveal prognostic molecular subgroups, and uncover recurrent MSN alterations that confer sensitivity to NF-κB inhibition.

[Optineurin and mitochondrial dysfunction in neurodegeneration]. / L'optineurine et les dysfonctionnements mitochondriaux dans la neurodégénérescence.

Optineurin (OPTN) is a multifunctional protein playing a crucial role as a receptor in selective autophagy. OPTN gene mutations are linked to diseases such as normal-tension glaucoma and amyotrophic lateral sclerosis. Recognized as a critical receptor for mitophagy, OPTN is pivotal in selectively degrading damaged mitochondria. This process is essential to prevent their accumulation, the generation of reactive oxygen species, and the release of pro-apoptotic factors. Mitophagy's quality control is governed by the PINK1 kinase and the cytosolic ubiquitin ligase Parkin, whose mutations are associated with Parkinson's disease. This review highlights recent insights emphasizing OPTN's role in mitophagy and its potential involvement in neurodegenerative diseases.

Title: L'optineurine et les dysfonctionnements mitochondriaux dans la neurodégénérescence. Abstract: L'optineurine (OPTN) est une protéine multifonctionnelle jouant un rôle crucial en tant que récepteur dans l'autophagie sélective. Les mutations du gène OPTN sont liées à des maladies telles que le glaucome à tension normale et la sclérose latérale amyotrophique. L'OPTN exerce une fonction essentielle dans la dégradation sélective des mitochondries endommagées. Ce processus est requis pour empêcher leur accumulation, la production d'espèces réactives de l'oxygène et la libération de facteurs pro-apoptotiques. Le contrôle de la qualité de la mitophagie est orchestré par la kinase PINK1 et la ligase de l'ubiquitine cytosolique Parkin, dont les mutations sont associées à la maladie de Parkinson. Cette revue met en lumière des perspectives récentes soulignant le rôle de l'OPTN dans la mitophagie et son implication potentielle dans les maladies neurodégénératives.

Lumbar Decompression With and Without Fusion for Lumbar Stenosis With Spondylolisthesis: A Cost Utility Analysis.

STUDY DESIGN: Markov model. OBJECTIVE: To compare the cost-effectiveness of lumbar decompression alone (DA) with lumbar decompression with fusion (DF) for the management of adults undergoing surgery for lumbar stenosis with associated degenerative spondylolisthesis. SUMMARY OF BACKGROUND DATA: Rates of lumbar fusion have increased for all indications in the United States over the last 20 years. Recent randomized controlled trial data, however, have suggested comparable functional outcomes and lower reoperation rates for lumbar decompression and fusion as compared with DA in the treatment of lumbar stenosis with degenerative spondylolisthesis. MATERIALS AND METHODS: A multistate Markov model was constructed from the US payer perspective of a hypothetical cohort of patients with lumbar stenosis with associated spondylolisthesis requiring surgery. Data regarding clinical improvement, costs, and reoperation were generated from contemporary randomized trial evidence, meta-analyses of recent prospective studies, and large retrospective cohorts. Base case, one-way sensitivity analysis, and probabilistic sensitivity analyses were conducted, and the results were compared with a WTP threshold of $100,000 (in 2022 USD) over a two-year time horizon. A discount rate of 3% was utilized. RESULTS: The incremental cost and utility of DF relative to DA were $12,778 and 0.00529 aggregated quality adjusted life years. The corresponding incremental cost-effectiveness ratio of $2,416,281 far exceeded the willingness to pay threshold of $100,000. In sensitivity analysis, the results varied the most with respect to rate of improvement after DA, rate of improvement after lumbar decompression and fusion, and odds ratio of reoperation between the two groups. Zero percent of one-way and probabilistic sensitivity analyses achieved cost-effectiveness at the willingness-to-pay threshold. CONCLUSIONS: Within the context of contemporary surgical data, DF is not cost-effective compared with DA in the surgical management of lumbar stenosis with associated spondylolisthesis over a two-year time horizon.

Patterns in Decompression and Fusion Procedures for Patients With Lumbar Stenosis After Major Clinical Trial Results, 2016 to 2019.

Importance: Use of lumbar fusion has increased substantially over the last 2 decades. For patients with lumbar stenosis and degenerative spondylolisthesis, 2 landmark prospective randomized clinical trials (RCTs) published in the New England Journal of Medicine in 2016 did not find clear evidence in favor of decompression with fusion over decompression alone in this population. Objective: To assess the national use of decompression with fusion vs decompression alone for the surgical treatment of lumbar stenosis and degenerative spondylolisthesis from 2016 to 2019. Design, Setting, and Participants: This retrospective cohort study included 121 745 hospitalized adult patients (aged ≥18 years) undergoing 1-level decompression alone or decompression with fusion for the management of lumbar stenosis and degenerative spondylolisthesis from January 1, 2016, to December 31, 2019. All data were obtained from the National Inpatient Sample (NIS). Analyses were conducted, reviewed, or updated on June 9, 2023. Main Outcome and Measure: The primary outcome of this study was the use of decompression with fusion vs decompression alone. For the secondary outcome, multivariable logistic regression analysis was used to evaluate factors associated with the decision to perform decompression with fusion vs decompression alone. Results: Among 121 745 eligible hospitalized patients (mean age, 65.2 years [95% CI, 65.0-65.4 years]; 96 645 of 117 640 [82.2%] non-Hispanic White) with lumbar stenosis and degenerative spondylolisthesis, 21 230 (17.4%) underwent decompression alone, and 100 515 (82.6%) underwent decompression with fusion. The proportion of patients undergoing decompression alone decreased from 2016 (7625 of 23 405 [32.6%]) to 2019 (3560 of 37 215 [9.6%]), whereas the proportion of patients undergoing decompression with fusion increased over the same period (from 15 780 of 23 405 [67.4%] in 2016 to 33 655 of 37 215 [90.4%] in 2019). In univariable analysis, patients undergoing decompression alone differed significantly from those undergoing decompression with fusion with regard to age (mean, 68.6 years [95% CI, 68.2-68.9 years] vs 64.5 years [95% CI, 64.3-64.7 years]; P < .001), insurance status (eg, Medicare: 13 725 of 21 205 [64.7%] vs 53 320 of 100 420 [53.1%]; P < .001), All Patient Refined Diagnosis Related Group risk of death (eg, minor risk: 16 900 [79.6%] vs 83 730 [83.3%]; P < .001), and hospital region of the country (eg, South: 7030 [33.1%] vs 38 905 [38.7%]; Midwest: 4470 [21.1%] vs 23 360 [23.2%]; P < .001 for both comparisons). In multivariable logistic regression analysis, older age (adjusted odds ratio [AOR], 0.96 per year; 95% CI, 0.95-0.96 per year), year after 2016 (AOR, 1.76 per year; 95% CI, 1.69-1.85 per year), self-pay insurance status (AOR, 0.59; 95% CI, 0.36-0.95), medium hospital size (AOR, 0.77; 95% CI, 0.67-0.89), large hospital size (AOR, 0.76; 95% CI, 0.67-0.86), and highest median income quartile by patient residence zip code (AOR, 0.79; 95% CI, 0.70-0.89) were associated with lower odds of undergoing decompression with fusion. Conversely, hospital region in the Midwest (AOR, 1.34; 95% CI, 1.14-1.57) or South (AOR, 1.32; 95% CI, 1.14-1.54) was associated with higher odds of undergoing decompression with fusion. Decompression with fusion vs decompression alone was associated with longer length of stay (mean, 2.96 days [95% CI, 2.92-3.01 days] vs 2.55 days [95% CI, 2.49-2.62 days]; P < .001), higher total admission costs (mean, $30 288 [95% CI, $29 386-$31 189] vs $16 190 [95% CI, $15 189-$17 191]; P < .001), and higher total admission charges (mean, $121 892 [95% CI, $119 566-$124 219] vs $82 197 [95% CI, $79 745-$84 648]; P < .001). Conclusions and Relevance: In this cohort study, despite 2 prospective RCTs that demonstrated the noninferiority of decompression alone compared with decompression with fusion, use of decompression with fusion relative to decompression alone increased from 2016 to 2019. A variety of patient- and hospital-level factors were associated with surgical procedure choice. These results suggest the findings of 2 major RCTs have not yet produced changes in surgical practice patterns and deserve renewed focus.

Postnatal Myelomeningocele Repair in the United States: Rates and Disparities Before and After the Management of Myelomeningocele Study Trial.

BACKGROUND AND OBJECTIVES: Evolving technologies have influenced the practice of myelomeningocele repair (MMCr), including mandatory folic acid fortification, advances in prenatal diagnosis, and the 2011 Management of Myelomeningocele Study (MOMS) trial demonstrating benefits of fetal over postnatal MMCr in select individuals. Postnatal MMCr continues to be performed, especially for those with limitations in prenatal diagnosis, health care access, anatomy, or personal preference. A comprehensive, updated national perspective on the trajectory of postnatal MMCr volumes and patient disparities is absent. We characterize national trends in postnatal MMCr rates before and after the MOMS trial publication (2000-2010 vs 2011-2019) and examine whether historical disparities persist. METHODS: This retrospective, cross-sectional analysis queried Nationwide Inpatient Sample data for postnatal MMCr admissions. Annual and race/ethnicity-specific rates were calculated using national birth registry data. Time series analysis assessed for trends relative to the year 2011. Patient, admission, and outcome characteristics were compared between pre-MOMS and post-MOMS cohorts. RESULTS: Between 2000 and 2019, 12 426 postnatal MMCr operations were estimated nationwide. After 2011, there was a gradual, incremental decline in the annual rate of postnatal MMCr. Post-MOMS admissions were increasingly associated with Medicaid insurance and the lowest income quartiles, as well as increased risk indices, length of stay, and hospital charges. By 2019, race/ethnicity-adjusted rates seemed to converge. The mortality rate remained low in both eras, and there was a lower rate of same-admission shunting post-MOMS. CONCLUSION: National rates of postnatal MMCr gradually declined in the post-MOMS era. Medicaid and low-income patients comprise an increasing majority of MMCr patients post-MOMS, whereas historical race/ethnicity-specific disparities are improving. Now more than ever, we must address disparities in the care of MMC patients before and after birth.

Time of Discharge and 30-Day Re-Presentation to an Acute Care Setting After Elective Lumbar Decompression Surgery.

BACKGROUND: Evidence regarding the consequence of efforts to increase patient throughput and decrease length of stay in the context of elective spine surgery is limited. OBJECTIVE: To evaluate whether early time of discharge results in increased rates of hospital readmission or return to emergency department for patients admitted after elective, posterior, lumbar decompression surgery. METHODS: We conducted a retrospective cohort study of 779 patients admitted to hospital after undergoing elective, posterior, lumbar decompression surgery. Multiple logistic regression evaluated the relationship between time of discharge and the primary outcome of return to acute care within 30 days, while controlling for sociodemographic, procedural, and discharge characteristics. RESULTS: In multiple logistic regression, time of discharge earlier in the day was not associated with increased odds of return to acute care within 30 days (odds ratio [OR] 1.18, 95% CI 0.92-1.52, P = .19). Weekend discharge (OR 1.99, 95% CI 1.04-3.79, P = .04) increased the likelihood of return to acute care. Surgeon experience (<1 year of attending practice, OR 0.43, 95% CI 0.19-1.00, P = .05 and 2-5 years of attending practice, OR 0.50, 95% CI 0.25-1.01, P = .054), weekend discharge (OR 0.49, 95% CI 0.27-0.89, P = .02), and physical therapy evaluation (OR 0.20, 95% CI 0.12-0.33, P < .001) decreased the likelihood of discharge before noon. CONCLUSION: Time of discharge is not associated with risk of readmission or presentation to the emergency department after elective lumbar decompression. Weekend discharge is independently associated with increased risk of readmission and decreased likelihood of prenoon discharge.

Analysis of ATG8 Family Members Using LC3-Interacting Regions (LIR)-Based Molecular Traps.

The ATG8 family of proteins regulates the autophagy process from the autophagosome maturation and cargo recruitment up to degradation. Autophagy dysfunction is involved in the development of multiple diseases. The LC3 interacting region (LIR)-based molecular traps have been designed to isolate endogenous ATG8 proteins and their interactors in order to facilitate the study of selective autophagy events. Here, we summarize protocols describing LC3 traps and sample preparation as well as adaptations for the analysis of ATG8 proteins in different biological models. This protocol was optimized to prepare affinity columns, reduce background, and improve the protein recovery to be analyzed by immunodetection with antibodies recognizing proteins of interest.

Neighborhood-level socioeconomic status, extended length of stay, and discharge disposition following elective lumbar spine surgery.

Background: In the context of increased attention afforded to hospital efficiency and improved but safe patient throughput, decreasing unnecessary hospital length of stay (LOS) is imperative. Given that lumbar spine procedures may be among a hospital's most profitable services, identifying patients at risk of increased healthcare resource utilization prior to surgery is a valuable opportunity to develop targeted pre- and peri-operative intervention and quality improvement initiatives. The purpose of the present investigation was to examine patient factors that predict prolonged LOS as well as discharge disposition following elective, posterior, lumbar spine surgery. Methods: We employed a retrospective cohort analysis on 779 consecutive patients treated with lumbar surgery without fusion. Our primary outcome measures were extended LOS (three or more midnights) and discharge disposition. Patient sociodemographic, procedural, and discharge characteristics were adjusted for in our analysis. Sociodemographic variables included Area of Deprivation Index (ADI), a comprehensive metric of socioeconomic status, utilizing income, education, employment, and housing quality based on patient zip code. Multivariable logistic regression and ordinal logistic regression analyses were performed to assess whether covariates were independently predictive of extended LOS and discharge disposition, respectively. Results: 779 patients were studied, with a median age of 66 years (±15) and a median LOS of 1 midnight (range, 1-10 midnights). Patients in the most disadvantaged ADI quintile (adjusted odds ratio, aOR 2.48 95% CI 1.15-5.47), those who underwent a minimally-invasive or tubular retractor surgery (aOR 3.03 95% CI 1.02-8.56), those who had an intra-operative drain placed (aOR 4.46 95% CI 2.53-7.26), who had a cerebrospinal fluid leak (aOR 3.46 95% CI 1.55-7.58), who were discharged anywhere but home (aOR 17.11 95% CI 9.24-33.00), and those who were evaluated by physical therapy (aOR 7.23 95% CI 2.13-45.30) or OT (aOR 2.20 95% CI 1.13-4.22) had a significantly increased chance of an extended LOS. Preoperative opioid use was not associated with an increased LOS following surgery (aOR 1.12 95% CI 0.56-1.46). Extended LOS was not associated with post-discharge emergency department representation or unplanned readmission within 90 days following discharge (p=0.148). Patients who were older (aOR 1.99 95% CI 1.62-2.48), in higher quintiles on ADI (3rd quintile; aOR 1.90 95% CI 1.12-3.23, 4th quintile; aOR 1.79, 95% CI 1.05-3.05, 5th quintile; aOR 2.16 95% CI 1.26-3.75), who had a CSF leak (aOR 2.18 95% CI 1.22-3.86), or who had a longer procedure duration (aOR 1.38 95% CI 1.17-1.62) were more likely to require additional services or be sent to a subacute facility upon discharge. Conclusions: Patient sociodemographics, along with procedural factors, and discharge disposition were all associated with an increased likelihood of prolonged LOS and resource intensive discharges following elective lumbar spine surgery. Several of these factors could be reliably identified pre-operatively and may be amenable to targeted preoperative intervention. Improving discharge disposition planning in the peri-operative period may allow for more efficient use of hospitalization and inpatient and post-acute resources.

Frailty independently predicts unfavorable discharge in non-operative traumatic brain injury: A retrospective single-institution cohort study.

BACKGROUND: Frailty is associated with adverse outcomes in traumatically injured geriatric patients but has not been well-studied in geriatric Traumatic Brain Injury (TBI). OBJECTIVE: To assess relationships between frailty and outcomes after TBI. METHODS: The records of all patients aged 70 or older admitted from home to the neurosurgical service of a single institution for non-operative TBI between January 2020 and July 2021 were retrospectively reviewed. The primary outcome was adverse discharge disposition (either in-hospital expiration or discharge to skilled nursing facility (SNF), hospice, or home with hospice). Secondary outcomes included major inpatient complication, 30-day readmission, and length of stay. RESULTS: 100 patients were included, 90% of whom presented with Glasgow Coma Score (GCS) 14-15. The mean length of stay was 3.78 days. 7% had an in-hospital complication, and 44% had an unfavorable discharge destination. 49% of patients attended follow-up within 3 months. The rate of readmission within 30 days was 13%. Patients were characterized as low frailty (FRAIL score 0-1, n = 35, 35%) or high frailty (FRAIL score 2-5, n = 65, 65%). In multivariate analysis controlling for age and other factors, frailty category (aOR 2.63, 95CI [1.02, 7.14], p = 0.005) was significantly associated with unfavorable discharge. Frailty was not associated with increased readmission rate, LOS, or rate of complications on uncontrolled univariate analyses. CONCLUSION: Frailty is associated with increased odds of unfavorable discharge disposition for geriatric patients admitted with TBI.

Cranial Irradiation for Childhood Cancers and Adult Risk of Meningioma.

INTRODUCTION: Following cranial irradiation, there is an increased risk of developing secondary neoplasms, especially meningiomas. Despite childhood cancer survivors who have undergone cranial irradiation having an increased risk of acquiring radiation-induced meningioma (RIM), there is no widely used standard guideline for meningioma screening. METHODS: At a single institution, we reviewed three adult survivors of childhood cancer who were treated for RIM between 2010 and 2020. We recorded age at diagnosis for the primary lesion, the radiation dose, age at RIM diagnosis, and tumor characteristics including treatment, pathology, and outcome. Two had had T-cell acute lymphocytic leukemia and one a rhabdomyosarcoma. The age of diagnosis of the RIM ranged from 20 to 40 years, with latencies ranging from 18 to 33 years. All lesions were classified as WHO Grade I meningiomas, and only 1 patient had a subsequent recurrence. A literature search identified articles that address RIM: a total of 684 cases were identified in 36 publications. RESULTS: Mean radiation doses ranged from 1.4 gray to 70 gray. Mean age of diagnosis for secondary meningioma ranged from 8 to 53.4 years old, with latency periods ranging from 2.8 to 44 years. Given variability in the way that investigators have published their results, it is difficult to make a single recommendation for RIM screening. Using our experience and the literature, we devised two different screening protocols and calculated their expense. CONCLUSIONS: We recommend that data be standardized in a registry to provide greater insight into the clinical and resource allocation questions, especially as long-term survival of children with pediatric cancer into full adulthood becomes more commonplace worldwide.

The FDA-approved drug Auranofin has a dual inhibitory effect on SARS-CoV-2 entry and NF-κB signaling.

Patients with severe COVID-19 show an altered immune response that fails to control the viral spread and suffer from exacerbated inflammatory response, which eventually can lead to death. A major challenge is to develop an effective treatment for COVID-19. NF-κB is a major player in innate immunity and inflammatory process. By a high-throughput screening approach, we identified FDA-approved compounds that inhibit the NF-κB pathway and thus dampen inflammation. Among these, we show that Auranofin prevents post-translational modifications of NF-κB effectors and their recruitment into activating complexes in response to SARS-CoV-2 infection or cytokine stimulation. In addition, we demonstrate that Auranofin counteracts several steps of SARS-CoV-2 infection. First, it inhibits a raft-dependent endocytic pathway involved in SARS-CoV-2 entry into host cells; Second, Auranofin alters the ACE2 mobility at the plasma membrane. Overall, Auranofin should prevent SARS-CoV-2 infection and inflammatory damages, offering new opportunities as a repurposable drug candidate to treat COVID-19.

Exploring selective autophagy events in multiple biologic models using LC3-interacting regions (LIR)-based molecular traps.

Autophagy is an essential cellular pathway that ensures degradation of a wide range of substrates including damaged organelles or large protein aggregates. Understanding how this proteolytic pathway is regulated would increase our comprehension on its role in cellular physiology and contribute to identify biomarkers or potential drug targets to develop more specific treatments for disease in which autophagy is dysregulated. Here, we report the development of molecular traps based in the tandem disposition of LC3-interacting regions (LIR). The estimated affinity of LC3-traps for distinct recombinant LC3/GABARAP proteins is in the low nanomolar range and allows the capture of these proteins from distinct mammalian cell lines, S. cerevisiae and C. elegans. LC3-traps show preferences for GABARAP/LGG1 or LC3/LGG2 and pull-down substrates targeted to proteaphagy and mitophagy. Therefore, LC3-traps are versatile tools that can be adapted to multiple applications to monitor selective autophagy events in distinct physiologic and pathologic circumstances.

Human OTULIN haploinsufficiency impairs cell-intrinsic immunity to staphylococcal α-toxin.

The molecular basis of interindividual clinical variability upon infection with Staphylococcus aureus is unclear. We describe patients with haploinsufficiency for the linear deubiquitinase OTULIN, encoded by a gene on chromosome 5p. Patients suffer from episodes of life-threatening necrosis, typically triggered by S. aureus infection. The disorder is phenocopied in patients with the 5p- (Cri-du-Chat) chromosomal deletion syndrome. OTULIN haploinsufficiency causes an accumulation of linear ubiquitin in dermal fibroblasts, but tumor necrosis factor receptor-mediated nuclear factor κB signaling remains intact. Blood leukocyte subsets are unaffected. The OTULIN-dependent accumulation of caveolin-1 in dermal fibroblasts, but not leukocytes, facilitates the cytotoxic damage inflicted by the staphylococcal virulence factor α-toxin. Naturally elicited antibodies against α-toxin contribute to incomplete clinical penetrance. Human OTULIN haploinsufficiency underlies life-threatening staphylococcal disease by disrupting cell-intrinsic immunity to α-toxin in nonleukocytic cells.

Targeting selenoprotein H in the nucleolus suppresses tumors and metastases by Isovalerylspiramycin I.

BACKGROUND: Compared to normal cells, cancer cells exhibit a higher level of oxidative stress, which primes key cellular and metabolic pathways and thereby increases their resilience under oxidative stress. This higher level of oxidative stress also can be exploited to kill tumor cells while leaving normal cells intact. In this study we have found that isovalerylspiramycin I (ISP I), a novel macrolide antibiotic, suppresses cancer cell growth and tumor metastases by targeting the nucleolar protein selenoprotein H (SELH), which plays critical roles in keeping redox homeostasis and genome stability in cancer cells. METHODS: We developed ISP I through genetic recombination and tested the antitumor effects using primary and metastatic cancer models. The drug target was identified using the drug affinity responsive target stability (DARTS) and mass spectrum assays. The effects of ISP I were assessed for reactive oxygen species (ROS) generation, DNA damage, R-loop formation and its impact on the JNK2/TIF-IA/RNA polymerase I (POLI) transcription pathway. RESULTS: ISP I suppresses cancer cell growth and tumor metastases by targeting SELH. Suppression of SELH induces accumulation of ROS and cancer cell-specific genomic instability. The accumulation of ROS in the nucleolus triggers nucleolar stress and blocks ribosomal RNA transcription via the JNK2/TIF-IA/POLI pathway, causing cell cycle arrest and apoptosis in cancer cells. CONCLUSIONS: We demonstrated that ISP I links cancer cell vulnerability to oxidative stress and RNA biogenesis by targeting SELH. This suggests a potential new cancer treatment paradigm, in which the primary therapeutic agent has minimal side-effects and hence may be useful for long-term cancer chemoprevention.

Neighborhood-Level Socioeconomic Status Predicts Extended Length of Stay After Elective Anterior Cervical Spine Surgery.

BACKGROUND: A significant portion of health care spending is driven by a small percentage of the overall population. Understanding risk factors predisposing patients to disproportionate use of health care resources is critical. Our objective was to identify risk factors leading to a prolonged length of stay (LOS) after cervical spine surgery. METHODS: A single-center cohort analysis was performed on patients who underwent elective anterior spine surgery from 2015 to 2021. Multivariate logistic regression evaluated the effects of sociodemographic factors including Area of Deprivation Index (quantifies income, education, employment, and housing quality), procedural, and discharge characteristics on postoperative LOS. Extended LOS was defined as greater than the 90th percentile in midnights for the study population (≥3 midnights). RESULTS: A total of 686 patients were included in the study, with a mean age of 57 years (range, 26-92 years), median of 1 level (1-4) fused, and median LOS of 1 midnight (interquartile range, 1-2). After adjusting for confounders, patients had increased odds of extended LOS if they were highly disadvantaged on the Area of Deprivation Index (odds ratio [OR], 2.24; 95% confidence interval [CI], 1.04-4.82; P = 0.039); had surgery on Thursday or Friday (OR, 1.94; 95% CI, 1.01-3.72; P = 0.046); had a corpectomy performed (OR, 2.81; 95% CI, 1.26-6.28; P = 0.012); or discharged not to home (OR, 8.24; 95% CI, 2.88-23.56; P < 0.001). Patients with extended LOS were more likely to present to the emergency department or be readmitted within 30 days after discharge (P = 0.024). CONCLUSIONS: After adjusting for potential cofounders, patients most disadvantaged on Area of Deprivation Index were more likely to have an extended LOS.

Influence of Time of Discharge and Length of Stay on 30-Day Outcomes After Elective Anterior Cervical Spine Surgery.

BACKGROUND: Encouraging early time of discharge (TOD) for medical inpatients is commonplace and may potentially improve patient throughput. It is unclear, however, whether early TOD after elective spine surgery achieves this goal without a consequent increase in re-presentations to the hospital. OBJECTIVE: To evaluate whether early TOD results in increased rates of hospital readmission or return to the emergency department after elective anterior cervical spine surgery. METHODS: We analyzed 686 patients who underwent elective uncomplicated anterior cervical spine surgery at a single institution. Logistic regression was used to evaluate the relationship between sociodemographic, procedural, and discharge characteristics, and the outcomes of readmission or return to the emergency department and TOD. RESULTS: In multiple logistic regression, TOD was not associated with increased risk of readmission or return to the emergency department within 30 days of surgery. Weekend discharge (odds ratio [OR] 0.33, 95% CI 0.21-0.53), physical therapy evaluation (OR 0.44, 95% CI 0.28-0.71), and occupational therapy evaluation (OR 0.32, 95% CI 0.17-0.63) were all significantly associated with decreased odds of discharge before noon. Disadvantaged status, as measured by area of deprivation index, was associated with increased odds of readmission or re-presentation (OR 1.86, 95% CI 0.95-3.66), although this result did not achieve statistical significance. CONCLUSION: There does not appear to be an association between readmission or return to the emergency department and early TOD after elective spine surgery. Overuse of inpatient physical and occupational therapy consultations may contribute to decreased patient throughput in surgical admissions.