Estimated effects of reductions in processed meat consumption and unprocessed red meat consumption on occurrences of type 2 diabetes, cardiovascular disease, colorectal cancer, and mortality in the USA: a microsimulation study.

BACKGROUND: High consumption of processed meat and unprocessed red meat is associated with increased risk of multiple chronic diseases, although there is substantial uncertainty regarding the relationship for unprocessed red meat. We developed a microsimulation model to estimate how reductions in processed meat and unprocessed red meat consumption could affect rates of type 2 diabetes, cardiovascular disease, colorectal cancer, and mortality in the US adult population. METHODS: We used data from two versions of the US National Health and Nutrition Examination Survey, one conducted during 2015-16 and one conducted during 2017-18, to create a simulated US population. The starting cohort was restricted to respondents aged 18 years or older who were not pregnant and had 2 days of dietary-recall data. First, we used previously developed risk models to estimate the baseline disease risk of an individual. For type 2 diabetes we used a logistic-regression model and for cardiovascular disease and colorectal cancer we used Cox proportional-hazard models. We then multiplied baseline risk by relative risk associated with individual processed meat and unprocessed red meat consumption. Prevented occurrences of type 2 diabetes, cardiovascular disease, colorectal cancer, and mortality were computed by taking the difference between the incidence in the baseline and intervention scenarios. All stages were repeated for ten iterations to correspond to a 10-year time span. Scenarios were reductions of 5%, 10%, 30%, 50%, 75%, and 100% in grams consumed of processed meat, unprocessed red meat, or both. Each scenario was repeated 50 times for uncertainty analysis. FINDINGS: The total number of individual respondents included in the simulated population was 8665, representing 242 021 876 US adults. 4493 (51·9%) of 8665 individuals were female and 4172 (48·1%) were male; mean age was 49·54 years (SD 18·38). At baseline, weighted mean daily consumption of processed meat was 29·1 g, with a 30% reduction being 8·7 g per day, and of unprocessed red meat was 46·7 g, with a 30% reduction being 14·0 g per day. We estimated that a 30% reduction in processed meat intake alone could lead to 352 900 (95% uncertainty interval 345 500-359 900) fewer occurrences of type 2 diabetes, 92 500 (85 600-99 900) fewer occurrences of cardiovascular disease, 53 300 (51 400-55 000) fewer occurrences of colorectal cancer, and 16 700 (15 300-17 700) fewer all-cause deaths during the 10-year period. A 30% reduction in unprocessed red meat intake alone could lead to 732 600 (725 700-740 400) fewer occurrences of type 2 diabetes, 291 500 (283 900-298 800) fewer occurrences of cardiovascular disease, 32 200 (31 500-32 700) fewer occurrences of colorectal cancer, and 46 100 (45 300-47 200) fewer all-cause deaths during the 10-year period. A 30% reduction in both processed meat and unprocessed red meat intake could lead to 1 073 400 (1 060 100-1 084 700) fewer occurrences of type 2 diabetes, 382 400 (372 100-391 000) fewer occurrences of cardiovascular disease, 84 400 (82 100-86 200) fewer occurrences of colorectal cancer, and 62 200 (60 600-64 400) fewer all-cause deaths during the 10-year period. INTERPRETATION: Reductions in processed meat consumption could reduce the burden of some chronic diseases in the USA. However, more research is needed to increase certainty in the estimated effects of reducing unprocessed red meat consumption. FUNDING: The Wellcome Trust.

A Historical Survey of Key Epidemiological Studies of Ionizing Radiation Exposure.

In this article we review the history of key epidemiological studies of populations exposed to ionizing radiation. We highlight historical and recent findings regarding radiation-associated risks for incidence and mortality of cancer and non-cancer outcomes with emphasis on study design and methods of exposure assessment and dose estimation along with brief consideration of sources of bias for a few of the more important studies. We examine the findings from the epidemiological studies of the Japanese atomic bomb survivors, persons exposed to radiation for diagnostic or therapeutic purposes, those exposed to environmental sources including Chornobyl and other reactor accidents, and occupationally exposed cohorts. We also summarize results of pooled studies. These summaries are necessarily brief, but we provide references to more detailed information. We discuss possible future directions of study, to include assessment of susceptible populations, and possible new populations, data sources, study designs and methods of analysis.

Rib-on-Pelvis Deformity and Reported Pain in Neuromuscular Early-Onset Scoliosis.

BACKGROUND: Neuromuscular early-onset scoliosis (N-EOS) often presents with a long sweeping thoracolumbar scoliosis and pelvic obliquity. With severe pelvic obliquity, the ribs come into contact with the high side of the pelvis, termed rib-on-pelvis deformity (ROP). The goal of this study is to evaluate whether ROP is associated with reported pain and other health-related quality of life (HRQOL) measures. We hypothesize that ROP is associated with increased pain and negative HRQOL. METHODS: A multicenter international registry was queried for all nonambulatory patients with N-EOS from 2012 to 2022. Both surgical and nonsurgical patients were included. ROP was classified as a binary radiographic assessment of preoperative (surgical patients) and most recent follow-up (nonsurgical patients) upright radiographs. Reported pain and other HRQOL measures were assessed through the 24-Item Early Onset Scoliosis Questionnaire (EOSQ-24). Patients with nonupright radiographs or EOSQ-24 questionnaires and corresponding radiographs >4 months apart were excluded. RESULTS: Totally, 225 patients (8.4±3.1 y, 55% female) were included. The median major curve was 63.3 (IQR: 40.6 to 81.2) degrees and median pelvic obliquity was 15.5 degrees (IQR: 8.8 to 26.4). Eighty-three patients (37%) had ROP. ROP was associated with both frequency (P<0.001) and severity (P<0.001) of pain. ROP was associated with worse general health (P=0.01), increased difficulty with vocalization (P=0.02), increased frequency of shortness of breath (P=0.002), and increased difficulty sitting upright (P=0.04). Regarding overall EOSQ-24 domains, ROP was associated with worse general health, pain/discomfort, pulmonary function, and physical function (P<0.01). In a subanalysis of 76 patients who underwent surgical intervention with at least 2 years of follow-up, patients with preoperative ROP experienced significantly greater improvements in both frequency (P=0.004) and severity (P=0.001) of pain than the patients without preoperative ROP at 2 years postoperatively. CONCLUSIONS: The overall incidence of ROP in N-EOS is about 37%. ROP is associated with greater pain and worse HRQOL through the EOSQ-24 questionnaire. Furthermore, these patients experienced a greater reduction in pain after surgery. Clinicians and parents must be aware that ROP is possibly a pain generator, but responds positively to surgical intervention. LEVEL OF EVIDENCE: Level III.

Effects of Medicaid managed care on early detection of cancer: Evidence from mandatory Medicaid managed care program in Pennsylvania.

OBJECTIVE: To examine changes in late- versus early-stage diagnosis of cancer associated with the introduction of mandatory Medicaid managed care (MMC) in Pennsylvania. DATA SOURCES AND STUDY SETTING: We analyzed data from the Pennsylvania cancer registry (2010-2018) for adult Medicaid beneficiaries aged 21-64 newly diagnosed with a solid tumor. To ascertain Medicaid and managed care status around diagnosis, we linked the cancer registry to statewide hospital-based facility records collected by an independent state agency (Pennsylvania Health Care Cost Containment Council). STUDY DESIGN: We leveraged a natural experiment arising from county-level variation in mandatory MMC in Pennsylvania. Using a stacked difference-in-differences design, we compared changes in the probability of late-stage cancer diagnosis among those residing in counties that newly transitioned to mandatory managed care to contemporaneous changes among those in counties with mature MMC programs. DATA COLLECTION/EXTRACTION METHODS: N/A. PRINCIPAL FINDINGS: Mandatory MMC was associated with a reduced probability of late-stage cancer diagnosis (-3.9 percentage points; 95% CI: -7.2, -0.5; p = 0.02), particularly for screening-amenable cancers (-5.5 percentage points; 95% CI: -10.4, -0.6; p = 0.03). We found no significant changes in late-stage diagnosis among non-screening amenable cancers. CONCLUSIONS: In Pennsylvania, the implementation of mandatory MMC for adult Medicaid beneficiaries was associated with earlier stage of diagnosis among newly diagnosed cancer patients with Medicaid, especially those diagnosed with screening-amenable cancers. Considering that over half of the sample was diagnosed with late-stage cancer even after the transition to mandatory MMC, Medicaid programs and managed care organizations should continue to carefully monitor receipt of cancer screening and design strategies to reduce barriers to guideline-concordant screening or diagnostic procedures.

Transcriptional synergy in human aortic endothelial cells is vulnerable to combination p300/CBP and BET bromodomain inhibition.

Combinatorial signaling by proinflammatory cytokines synergizes to exacerbate toxicity to cells and tissue injury during acute infections. To explore synergism at the gene-regulatory level, we investigated the dynamics of transcription and chromatin signaling in response to dual cytokines by integrating nascent RNA imaging mass spectrometry, RNA sequencing, amplification-independent mRNA quantification, assay for transposase-accessible chromatin using sequencing (ATAC-seq), and transcription factor profiling. Costimulation with interferon-gamma (IFNγ) and tumor necrosis factor alpha (TNFα) synergistically induced a small subset of genes, including the chemokines CXCL9, -10, and -11. Gene induction coincided with increased chromatin accessibility at non-coding regions enriched for p65 and STAT1 binding sites. To discover coactivator dependencies, we conducted a targeted chemogenomic screen of transcriptional inhibitors followed by modeling of inhibitor dose-response curves. These results identified high efficacy of either p300/CREB-binding protein (CBP) or bromodomain and extra-terminal (BET) bromodomain inhibitors to disrupt induction of synergy genes. Combination p300/CBP and BET bromodomain inhibition at half-maximal inhibitory concentrations (subIC50) synergistically abrogated IFNγ/TNFα-induced chemokine gene and protein levels.

What is the role of plastic surgery for incisional closures in pediatric spine surgery? Results from a pediatric spine study group survey.

Current best practice guidelines recommend a plastics-style multilayer wound closure for high-risk pediatric spine surgery. However, plastic surgery closure of spinal incisions remains controversial. This study investigates surgeon perceptions and practice patterns regarding plastic surgery multilayered closure (PMC) in pediatric spine surgery. All surgeons in an international pediatric spine study group received a 30-question survey assessing incisional closure practices, frequency of plastic surgery collaboration, and drain management. Relationship to practice size, setting, geographic region, and individual diagnoses were analyzed. 87/178 (49%) surgeons responded from 79% of participating sites. Plastics utilization rates differed by diagnosis: neuromuscular scoliosis 16.9%, early onset scoliosis 7.8%, adolescent idiopathic scoliosis 2.8% (P < 0.0001). Plastics were used more for early onset scoliosis [odds ratio (OR) 18.5, 95% confidence interval (CI): 8.5, 40.2; P < 0.001] and neuromuscular scoliosis [OR 29.2 (12.2, 69.9); P < 0.001] than adolescent idiopathic scoliosis. Plastics use was unrelated to practice size, setting, or geographic region (P ≥ 0.09). Respondents used plastics more often for spina bifida and underweight patients compared to all other indications (P < 0.001). Compared to orthopaedic management, drains were utilized more often by plastic surgery (85 vs. 21%, P = 0.06) and for longer durations (P = 0.001). Eighty-nine percent of surgeons felt plastics increased operative time (58 ±â€…37 min), and 34% felt it increased length of hospitalization. Surgeons who routinely utilize plastics were more likely to believe PMC decreases wound complications (P = 0.007). The perceived benefit of plastic surgery varies, highlighting equipoise among pediatric spine surgeons. An evidence-based guideline is needed to optimize utilization of plastics in pediatric spine surgery.

Cumulative incidence estimates for solid tumors after HCT in the CIBMTR and California Cancer Registry.

Compared with the general population, hematopoietic cell transplantation (HCT) survivors are at elevated risk for developing solid subsequent neoplasms (SNs). The Center for International Blood and Marrow Transplant Research (CIBMTR) is a key resource for quantifying solid SN incidence following HCT, but the completeness of SN ascertainment is uncertain. Within a cohort of 18,450 CIBMTR patients linked to the California Cancer Registry (CCR), we evaluated the completeness of solid SN data reported to the CIBMTR during 1991-2018 to understand the implications of using CIBMTR data alone or combined with CCR data to quantify the burden of solid SNs post-HCT. We estimated the cumulative incidence of developing a solid SN, accounting for the competing risk of death. Within the cohort, solid SNs were reported among 724 patients; 15.6% of these patients had an SN reported by CIBMTR-only, 36.9% by CCR-only, and 47.5% by both. The corresponding cumulative incidence of developing a solid SN at 10 years following a first HCT was 4.0% (95% CI=3.5% to 4.4%) based on CIBMTR data only, 5.3% (95% CI=4.9% to 5.9%) based on CCR data only, and 6.3% (95% CI=5.7% to 6.8%) based on both sources combined. The patterns were similar for allogeneic and autologous HCT recipients. Linking detailed HCT information from CIBMTR with comprehensive SN data from cancer registries provides an opportunity to optimize SN ascertainment for informing follow-up care practices and evaluating risk factors in the growing population of HCT survivors.

Changes in sex-specific incidence of lymphoid neoplasms across the lifespan.

Not available.

Hip Surgery is Not More Painful Than Spine Surgery in Children With Cerebral Palsy.

BACKGROUND: Posterior spinal fusion (PSF) and hip reconstruction are commonly indicated surgeries in children with cerebral palsy (CP), particularly those functioning at GMFCS levels IV and V. These are large and often painful procedures, and previous literature suggests that hip surgery is more painful than spine surgery in this patient population. The purpose of this study is to investigate pain scores and opioid use following hip and spine surgery in a large cohort of children with CP, including many patients who have undergone both types of surgery. METHODS: A retrospective chart review was performed to identify children with CP who underwent hip reconstruction and/or PSF at a tertiary children's hospital between 2004 and 2022. Charts were reviewed for demographic data, pain scores, pain medication usage, duration of hospital stay, and complications. RESULTS: Data were collected for 200 patients (101 male, 99 female) who met inclusion criteria. Eighty-seven patients underwent hip reconstruction, 62 spinal fusion, and 51 both hip and spine surgery asynchronously. Median (interquartile range) age at the time of surgery was significantly older for spinal fusion compared with hip surgery [13.1 (4.9) vs. 8.1 (5.7) y, P<0.0001]. Length of stay was significantly longer after PSF, with a median of 6 (4) days compared with 2 (1) days after hip surgery (P<0.0001). Both maximum and average daily pain scores were similar following hip and spine surgery, with the exception that average pain scores for hip surgery were slightly higher on postoperative day 1, hip=1.73 vs. spine=1.0 (P<0.0001). The amount of opioids used, expressed as morphine milligram equivalents (MME)/kg were similar in the hip and spine surgery groups; however, it was significantly lower in the hip surgery group on postoperative day 0, hip=0.06 versus spine=0.17 (P<0.0001). For the 51 patients who underwent both hip and spine surgery, the amount of opioids used mirrored that for the entire group (similar MME/kg, though only statistically significantly less on POD 0 and 3), and pain scores were not significantly different between the 2 groups except in 2 circumstances. The 2 exceptions in these 51 patients both demonstrated lower pain scores in patients after hip surgery, including lower maximum pain scores on POD 1 (P=0.041), and lower average pain scores on POD3 (P=0.043). CONCLUSIONS: This is the largest series to date comparing postoperative pain in children with CP after hip and spine surgery, including 51 of 200 patients who underwent both types of surgery. The results of this study demonstrate that hip surgery is not more painful than spine surgery in children with CP, and conflict with the traditional belief that hip surgery is more painful. This is important information for health care providers when counseling patients and families regarding these surgeries in children with CP. LEVEL OF EVIDENCE: Level 3.

Genomic characterization of cervical lymph node metastases in papillary thyroid carcinoma following the Chornobyl accident.

Childhood radioactive iodine exposure from the Chornobyl accident increased papillary thyroid carcinoma (PTC) risk. While cervical lymph node metastases (cLNM) are well-recognized in pediatric PTC, the PTC metastatic process and potential radiation association are poorly understood. Here, we analyze cLNM occurrence among 428 PTC with genomic landscape analyses and known drivers (131I-exposed = 349, unexposed = 79; mean age = 27.9 years). We show that cLNM are more frequent in PTC with fusion (55%) versus mutation (30%) drivers, although the proportion varies by specific driver gene (RET-fusion = 71%, BRAF-mutation = 38%, RAS-mutation = 5%). cLNM frequency is not associated with other characteristics, including radiation dose. cLNM molecular profiling (N = 47) demonstrates 100% driver concordance with matched primary PTCs and highly concordant mutational spectra. Transcriptome analysis reveals 17 differentially expressed genes, particularly in the HOXC cluster and BRINP3; the strongest differentially expressed microRNA also is near HOXC10. Our findings underscore the critical role of driver alterations and provide promising candidates for elucidating the biological underpinnings of PTC cLNM.

The effectiveness of social prescribing in the management of long-term conditions in community-based adults: A systematic review and meta-analysis.

OBJECTIVE: The objective of this systematic review and meta-analysis was to evaluate the effectiveness of social prescribing interventions in the management of long-term conditions in adults. DATA SOURCES: Eleven electronic databases were searched for randomised and quasi-randomised controlled trials. REVIEW METHODS: Outcomes of interest were quality of life, physical activity, psychological well-being and disease-specific measures. Bias was assessed with the Cochrane Risk of Bias 2 tool. A narrative synthesis and meta-analysis were performed. RESULTS: Twelve studies (n = 3566) were included in this review. Social prescribing interventions were heterogeneous and the most common risks of bias were poor blinding and high attrition. Social prescribing interventions designed to target specific long-term conditions i.e., cancer and diabetes demonstrated significant improvements in quality of life (n = 2 studies) and disease-specific psychological outcomes respectively (n = 3 studies). There was some evidence for improvement in physical activity (n = 2 studies) but most changes were within group only (n = 4 studies). Social prescribing interventions did not demonstrate any significant changes in general psychological well-being. CONCLUSION: Social prescribing interventions demonstrated some improvements across a range of outcomes although the quality of evidence remains poor.

The Fate of The Broken Tether: How Do Curves Treated with Vertebral Body Tethering Behave After Tether Breakage?

STUDY DESIGN: Retrospective, Multicenter. OBJECTIVE: Assess curve progression and occurrence of revision surgery following tether breakage after vertebral body tethering (VBT). SUMMARY OF BACKGROUND DATA: Tether breakage after VBT is common with rates up to 50% reported. In these cases, it remains unknown whether the curve will progress or remain stable. METHODS: Adolescent and juvenile idiopathic scoliosis patients in a multicenter registry with ≥2 year-follow-up after VBT were reviewed. Broken tethers were listed as postoperative complications and identified by increased screw divergence of >5° on serial radiographs. Revision procedures and curve magnitude at subsequent visits were recorded. RESULTS: Of 186 patients who qualified for inclusion, 84 (45.2%) patients with tether breakage were identified with a mean age at VBT of 12.4±1.4 years and mean curve magnitude at index procedure of 51.8°±8.1°. Tether breakage occurred at a mean of 30.3±11.8 months and mean curve of 33.9°±13.2°. Twelve patients (12/84, 14.5%) underwent 13 revision procedures after VBT breakage, including 6 tether revisions and 7 conversions to fusion. All tether revisions occurred within 5 months of breakage identification. No patients with curves <35° after breakage underwent revision. Revision rate was greatest in skeletally immature (Risser 0-3) patients with curves ≥35° at time of breakage (Risser 0-3: 9/17, 53% vs. Risser 4-5: 3/23, 13%, P=0.01).Curves increased by 3.1° and 3.7° in the first and second year, respectively. By two years, 15/30 (50%) progressed >5° and 8/30 (26.7%) progressed greater than 10°. Overall, 66.7% (40/60) reached a curve magnitude >35° at their latest follow-up, and 14/60 (23.3%) reached a curve magnitude greater than 45°. Skeletal maturity did not affect curve progression after tether breakage (P>0.26), but time to rupture did (P=0.048). CONCLUSION: While skeletal immaturity and curve magnitude were not independently associated with curve progression, skeletally immature patients with curves ≥35° at time of rupture are most likely to undergo additional surgery. Most patients can expect progression at least 5° in the first two years after tether breakage, though longer-term behavior remains unknown. LEVEL OF EVIDENCE: III.

Development of Consensus-Based Best Practice Guidelines for the Peri- and Post-operative Care of Pediatric Patients with Spinal Deformity and Programmable Implanted Devices.

STUDY DESIGN: Modified Delphi consensus study. OBJECTIVE: To develop consensus-based best practices for the care of pediatric patients who have implanted programmable devices (IPDs) and require spinal deformity surgery. SUMMARY OF BACKGROUND DATA: Implanted programmable devices (IPDs) are often present in patients with neuromuscular or syndromic scoliosis who require spine surgery. Guidelines for monitoring and interrogating these devices during the peri-operative period are not available. METHODS: A panel was assembled consisting of 25 experts (i.e., spinal deformity surgeons, neurosurgeons, neuro-electrophysiologists, cardiologists, and otolaryngologists). Initial postulates were based on literature review and results from a prior survey. Postulates addressed the following IPDs: vagal nerve stimulators (VNS), programmable ventriculo-peritoneal shunts (VPS), intrathecal baclofen pumps (ITBP), cardiac pacemakers and implantable cardioverter-defibrillators (ICD), deep brain stimulators (DBS), and cochlear implants. Cardiologist and otolaryngologists participants responded only to postulates on cardiac pacemakers or cochlear implants, respectively. Consensus was defined as ≥80% agreement, items that did not reach consensus were revised and included in subsequent rounds. A total of three survey rounds and one virtual meeting were conducted. RESULTS: Consensus was reached on 39 total postulates across six IPD types. Postulates addressed general spine surgery considerations, use of intraoperative monitoring and cautery, use of magnetically-controlled growing rods (MCGRs), and use of an external remote controller to lengthen MCGRs. Across IPD types, consensus for the final postulates ranged from 94.4-100%. Overall, experts agreed that MCGRs can be surgically inserted and lengthened in patients with a variety of IPDs and provided guidance for the use of intraoperative monitoring and cautery, which varied between IPD types. CONCLUSION: Spinal deformity correction surgery often benefits from the use of intraoperative monitoring, monopolar and bipolar cautery, and MCGRs. Final postulates from this study can inform the peri- and post-operative practices of spinal deformity surgeons who treat patients with both scoliosis and IPDs. LEVEL OF EVIDENCE: V- Expert opinion.

Impact of the Affordable Care Act on access to accredited facilities for cancer treatment.

OBJECTIVE: To examine differential changes in receipt of surgery at National Cancer Institute (NCI)-designated comprehensive cancer centers (NCI-CCC) and Commission on Cancer (CoC) accredited hospitals for patients with cancer more likely to be newly eligible for coverage under Affordable Care Act (ACA) insurance expansions, relative to those less likely to have been impacted by the ACA. DATA SOURCES AND STUDY SETTING: Pennsylvania Cancer Registry (PCR) for 2010-2019 linked with discharge records from the Pennsylvania Health Care Cost Containment Council (PHC4). STUDY DESIGN: Outcomes include whether cancer surgery was performed at an NCI-CCC or a CoC-accredited hospital. We conducted a difference-in-differences analysis, estimating linear probability models for each outcome that control for residence in a county with above median county-level pre-ACA uninsurance and the interaction between county-level baseline uninsurance and cancer treatment post-ACA to capture differential changes in access between those more and less likely to become newly eligible for insurance coverage (based on area-level proxy). All models control for age, sex, race and ethnicity, cancer site and stage, census-tract level urban/rural residence, Area Deprivation Index, and year- and county-fixed effects. DATA COLLECTION/EXTRACTION METHODS: We identified adults aged 26-64 in PCR with prostate, lung, or colorectal cancer who received cancer-directed surgery and had a corresponding surgery discharge record in PHC4. PRINCIPAL FINDINGS: We observe a differential increase in receiving care at an NCI-CCC of 6.2 percentage points (95% CI: 2.6-9.8; baseline mean = 9.8%) among patients in high baseline uninsurance areas (p = 0.001). Our estimate of the differential change in care at the larger set of CoC hospitals is positive (3.9 percentage points [95% CI: -0.5-8.2; baseline mean = 73.7%]) but not statistically significant (p = 0.079). CONCLUSIONS: Our findings suggest that insurance expansions under the ACA were associated with increased access to NCI-CCCs.

Predictors of Substance Use Initiation by Early Adolescence.

OBJECTIVE: Substance use initiation during early adolescence is associated with later development of substance use and mental health disorders. This study used various domains to predict substance use initiation, defined as trying any nonprescribed substance (e.g., alcohol, tobacco, cannabis), by age 12, using a large longitudinal data set. METHODS: Substance-naive youths from the Adolescent Brain Cognitive Development Study (ages 9-10; N=6,829) were followed for 3 years. A total of 420 variables were examined as predictors of substance use initiation, using a penalized logistic regression with elastic net; domains spanned demographic characteristics, self and peer involvement with substance use, parenting behaviors, mental and physical health, culture and environment, hormones, neurocognitive functioning, and structural neuroimaging. RESULTS: By age 12, 982 (14.4%) children reported substance initiation, with alcohol being the most common. Models with only self-report predictors had similar prediction performance to models adding hormones, neurocognitive factors, and neuroimaging predictors (AUCtest=0.66). Sociodemographic factors were the most robust predictors, followed by cultural and environmental factors, physical health factors, and parenting behaviors. The top predictor was a religious preference of Mormon (coefficient=-0.87), followed by a religious preference for Jewish (coefficient=0.32), and by Black youths (coefficient=-0.32). CONCLUSIONS: Sociodemographic variables were the most robust predictors of substance use initiation. Adding resource-intensive measures, including hormones, neurocognitive assessment, and structural neuroimaging, did not improve prediction of substance use initiation. The application of these large-scale findings in clinical settings could help to streamline and tailor prevention and early intervention efforts.

Combination and Optimal Sequencing of Systemic and Locoregional Therapies in Hepatocellular Carcinoma: Proceedings from the Society of Interventional Radiology Foundation Research Consensus Panel.

Hepatocellular carcinoma, historically, has had a poor prognosis with very few systemic options. Furthermore, most patients at diagnosis are not surgical candidates. Therefore, locoregional therapy (LRT) has been widely used, with strong data supporting its use. Over the last 15 years, there has been progress in the available systemic agents. This has led to the updated Barcelona Clinic Liver Cancer (BCLC) algorithm's inclusion of these new systemic agents, with advocacy of earlier usage in those who progress on LRT or have tumor characteristics that make them less likely to benefit from LRT. However, neither the adjunct of LRT nor the specific sequencing of combination therapies is addressed directly. This Research Consensus Panel sought to highlight research priorities pertaining to the combination and optimal sequencing of LRT and systemic therapy, assessing the greatest needs across BCLC stages.

Gross Tumor and Intracranial Control Benefits with Fractionated Radiotherapy Compared with Stereotactic Radiosurgery for Patients with WHO Grade 2 Meningioma.

OBJECTIVE: Surgical resection is the mainstay of treatment for WHO grade 2 meningioma. Fractionated radiation therapy (RT) is frequently used after surgery, though many centers utilize stereotactic radiosurgery (SRS) for recurrence or progression. Herein, we report disease control outcomes from an institutional cohort with adjuvant fractionated RT versus salvage SRS. METHODS: We identified 32 patients from an institutional database with WHO grade 2 meningioma and residual/recurrent tumor treated with either SRS or fractionated RT. Patients were treated between 2007 and 2021 and had at least 1 year of follow-up. Kaplan-Meier estimators were used to determine gross tumor control (GTC) and intracranial control (IC). Univariate Cox proportional hazards models using biologically effective dose (BED) as a continuous parameter were used to assess for dose responses. RESULTS: With a median follow-up of 5.5 years, 13 patients (41%) received SRS to a recurrent or progressive nodule, 2 (6%) fractionated RT to a recurrent or progressive nodule, and 17 (53%) adjuvant fractionated RT following subtotal resection. Five-year GTC was higher with fractionated RT versus SRS (82% vs. 38%, P = 0.03). Five-year IC was also better with fractionated RT versus SRS (82% vs. 11%, P < 0.001). On univariate analysis, increasing BED10 was significantly associated with better GTC (P = 0.039); increasing BED3 was not (P = 0.82). CONCLUSIONS: In this patient cohort, GTC and IC were significantly higher in patients treated with adjuvant fractionated RT compared with salvage SRS. Increasing BED10 was associated with better GTC. Fractionated RT may provide a better therapeutic ratio than SRS for grade 2 meningiomas.

Gene editing for latent herpes simplex virus infection reduces viral load and shedding in vivo.

Anti-HSV therapies are only suppressive because they do not eliminate latent HSV present in ganglionic neurons, the source of recurrent disease. We have developed a potentially curative approach against HSV infection, based on gene editing using HSV-specific meganucleases delivered by adeno-associated virus (AAV) vectors. Gene editing performed with two anti-HSV-1 meganucleases delivered by a combination of AAV9, AAV-Dj/8, and AAV-Rh10 can eliminate 90% or more of latent HSV DNA in mouse models of orofacial infection, and up to 97% of latent HSV DNA in mouse models of genital infection. Using a pharmacological approach to reactivate latent HSV-1, we demonstrate that ganglionic viral load reduction leads to a significant decrease of viral shedding in treated female mice. While therapy is well tolerated, in some instances, we observe hepatotoxicity at high doses and subtle histological evidence of neuronal injury without observable neurological signs or deficits. Simplification of the regimen through use of a single serotype (AAV9) delivering single meganuclease targeting a duplicated region of the HSV genome, dose reduction, and use of a neuron-specific promoter each results in improved tolerability while retaining efficacy. These results reinforce the curative potential of gene editing for HSV disease.

Incidental dural tears during pediatric posterior spinal fusions.

PURPOSE: To characterize the frequency of incidental dural tears in pediatric spine surgery, their treatment, complications, and results of long-term follow-up. METHODS: A retrospective review of all pediatric patients who underwent a posterior spinal fusion (PSF) between 2004-2019 at a tertiary children's hospital was conducted. Electronic medical records were reviewed for patient demographics, intra-operative data, presence of an incidental dural tear, repair method, and patient outcomes. RESULTS: 3043 PSFs were reviewed, with 99 dural tears identified in 94 patients (3.3% overall incidence). Mean follow-up was 35.7 months (range 0.1-142.5). When the cause of the dural tear was specified, 69% occurred during exposure, 5% during pedicle screw placement, 4% during osteotomy, 2% during removal of implants, and 2% during intra-thecal injection of morphine. The rate of dural tears during primary PSF was significantly lower than during revision PSF procedures (2.6% vs. 6.2%, p < 0.05). 86.9% of dural tears were repaired and/or sealed intraoperatively, while 13.1% had spontaneous resolution. Postoperative headaches developed in 13.1% of patients and resolved at a mean of 7.6 days. There was no difference in the incidence of headaches in patients that were ordered bedrest vs. no bedrest (p > 0.99). Postoperative infections occurred in 9.5% of patients and 24.1% patients were identified to have undergone a revision surgery. CONCLUSIONS: Incidence of intra-operative dural tears in pediatric spine surgery is 3.3%. Although complications associated with the dural tear occur, most resolve over time and there were no long-term sequelae in patients with 2 years of follow up. LEVEL OF EVIDENCE: Level IV.