Regional Heterogeneity in Intestinal Epithelial Barrier Permeability and Mesenteric Perfusion After Thoracic Spinal Cord Injury.

BACKGROUND: Spinal cord injury (SCI) disrupts intestinal barrier function, thereby increasing antigen permeation and leading to poor outcomes. Despite the intestinal tract's anatomic and physiologic heterogeneity, studies following SCI have not comprehensively addressed intestinal pathophysiology with regional specificity. AIMS AND METHODS: We used an experimental model of high thoracic SCI to investigate (1) regional mucosal oxidative stress using dihydroethidium labeling; (2) regional paracellular permeability to small- and large-molecular probes via Ussing chamber; (3) regional intestinal tight junction (TJ) protein expression; and (4) hindgut perfusion via the caudal mesenteric artery. RESULTS: Dihydroethidium staining was significantly elevated within duodenal mucosa at 3-day post-SCI. Molar flux of [14C]-urea was significantly elevated in duodenum and proximal colon at 3-day post-SCI, while molar flux of [3H]-inulin was significantly elevated only in duodenum at 3-day post-SCI. Barrier permeability was mirrored by a significant increase in the expression of pore-forming TJ protein claudin-2 in duodenum and proximal colon at 3-day post-SCI. Claudin-2 expression remained significantly elevated in proximal colon at 3-week post-SCI. Expression of the barrier-forming TJ protein occludin was significantly reduced in duodenum at 3-day post-SCI. Caudal mesenteric artery flow was unchanged by SCI at 3 days or 3 weeks despite significant reductions in mean arterial pressure. CONCLUSION: These data show that T3-SCI provokes elevated mucosal oxidative stress, altered expression of TJ proteins, and elevated intestinal barrier permeability in the proximal intestine. In contrast, mucosal oxidative stress and intestinal barrier permeability were unchanged in the hindgut after SCI. This regional heterogeneity may result from differential sensitivity to reduced mesenteric perfusion, though further studies are required to establish a causal link. Understanding regional differences in intestinal pathophysiology is essential for developing effective treatments and standards of care for individuals with SCI.

A dynamic microRNA profile that tracks a chemotherapy resistance phenotype in osteosarcoma. Implications for novel therapeutics.

Osteosarcoma is a rare primary bone tumor for which no significant therapeutic advancement has been made since the late 1980s despite ongoing efforts. Overall, the five-year survival rate remains about 65%, and is much lower in patients with tumors unresponsive to methotrexate, doxorubicin, and cisplatin therapy. Genetic studies have not revealed actionable drug targets, but our group, and others, have reported that epigenomic biomarkers, including regulatory RNAs, may be useful prognostic tools for osteosarcoma. We tested if microRNA (miRNA) transcriptional patterns mark the transition from a chemotherapy sensitive to resistant tumor phenotype. Small RNA sequencing was performed using 14 patient matched pre-chemotherapy biopsy and post-chemotherapy resection high-grade osteosarcoma frozen tumor samples. Independently, small RNA sequencing was performed using 14 patient matched biopsy and resection samples from untreated tumors. Separately, miRNA specific Illumina DASL arrays were used to assay an independent cohort of 65 pre-chemotherapy biopsy and 26 patient matched post-chemotherapy resection formalin fixed paraffin embedded (FFPE) tumor samples. mRNA specific Illumina DASL arrays were used to profile 37 pre-chemotherapy biopsy and five post-chemotherapy resection FFPE samples, all of which were also used for Illumina DASL miRNA profiling. The National Cancer Institute Therapeutically Applicable Research to Generate Effective Treatments dataset, including PCR based miRNA profiling and RNA-seq data for 86 and 93 pre-chemotherapy tumor samples, respectively, was also used. Paired differential expression testing revealed a profile of 17 miRNAs with significantly different transcriptional levels following chemotherapy. Genes targeted by the miRNAs were differentially expressed following chemotherapy, suggesting the miRNAs may regulate transcriptional networks. Finally, an in vitro pharmacogenomic screen using miRNAs and their target transcripts predicted response to a set of candidate small molecule therapeutics which potentially reverse the chemotherapy resistance phenotype and synergize with chemotherapy in otherwise treatment resistant tumors. Importantly, these novel therapeutic targets are distinct from targets identified by a similar pharmacogenomic analysis of previously published prognostic miRNA profiles from pre chemotherapy biopsy specimens.

Reproductive health assessment and reports of fertility counseling in pediatric and adolescent patients with sickle cell disease after hematopoietic cell transplantation.

BACKGROUND: Conditioning regimens for hematopoietic cell transplant (HCT) in patients with sickle cell disease (SCD) place patients at risk for reproductive health issues. OBJECTIVE: The purpose of this study was to assess reproductive health and reports of fertility counseling in patients with SCD who received a transplant. STUDY DESIGN: This was a secondary analysis of gonadal hormone production, future infertility risk assessment and parent-proxy/patient reports of fertility counseling in SCD transplant recipients who are currently pubertal and were enrolled in the Atlanta sites of the Sickle Cell Transplant Evaluation of Long-term and Late Effects Registry (STELLAR) between May 2017 and October 2023. Clinical information was abstracted from medical records and reproductive health survey data from the STELLAR database. Descriptive statistics were reported as median (IQR) or percentages. RESULTS: There were 20 females and 12 males in the study population. Females were median (IQR) 19.6 (9.4) years old and males 20.8 (11.4) years old at the time of the study. Transplants most commonly occurred in the decade 2010 - 2019 at 10.7 (4.8) years old for females and 11.1 (4.1) years old for males. Most participants received bone marrow stem cells (95.0% females, 100.0% males) from matched sibling donors (90.0% females, 100.0% males). Participants received one of seven HCT conditioning regimens with cyclophosphamide equivalent doses ranging from 3,388mg/m2 to 9,706mg/m2. The majority of females (90.0%) had diminished ovarian reserve with low anti-Mullerian hormone levels, and 61.1% had premature ovarian insufficiency with two follicle-stimulating hormone levels (FSH) ≥ 40 mIU/mL post-HCT. All males had normal testosterone levels, but 63.6% had elevated FSH levels suggestive of impaired spermatogenesis post-HCT. Parent-proxies (for patients < 18 years old) and patients ≥ 18 years old completed surveys 9.0 years (5.2) and 7.9 years (9.3) since HCT in females and males respectively. Twenty five percent of parent-proxies and 45% of patients reported that they had not been informed by a healthcare provider of the risk of infertility post-transplant. CONCLUSION: There are high rates of gonadal dysfunction post-HCT, but many parent-proxies and patients do not recall being told of the risk for future infertility. More effective methods of education are warranted to ensure SCD patients and their families clearly understand the risk for reproductive health issues post-HCT.

Improving health system responses when patients are harmed: a protocol for a multistage mixed-methods study.

INTRODUCTION: At least 10% of hospital admissions in high-income countries, including Australia, are associated with patient safety incidents, which contribute to patient harm ('adverse events'). When a patient is seriously harmed, an investigation or review is undertaken to reduce the risk of further incidents occurring. Despite 20 years of investigations into adverse events in healthcare, few evaluations provide evidence of their quality and effectiveness in reducing preventable harm.This study aims to develop consistent, informed and robust best practice guidance, at state and national levels, that will improve the response, learning and health system improvements arising from adverse events. METHODS AND ANALYSIS: The setting will be healthcare organisations in Australian public health systems in the states of New South Wales, Queensland, Victoria and the Australian Capital Territory. We will apply a multistage mixed-methods research design with evaluation and in-situ feasibility testing. This will include literature reviews (stage 1), an assessment of the quality of 300 adverse event investigation reports from participating hospitals (stage 2), and a policy/procedure document review from participating hospitals (stage 3) as well as focus groups and interviews on perspectives and experiences of investigations with healthcare staff and consumers (stage 4). After triangulating results from stages 1-4, we will then codesign tools and guidance for the conduct of investigations with staff and consumers (stage 5) and conduct feasibility testing on the guidance (stage 6). Participants will include healthcare safety systems policymakers and staff (n=120-255) who commission, undertake or review investigations and consumers (n=20-32) who have been impacted by adverse events. ETHICS AND DISSEMINATION: Ethics approval has been granted by the Northern Sydney Local Health District Human Research Ethics Committee (2023/ETH02007 and 2023/ETH02341).The research findings will be incorporated into best practice guidance, published in international and national journals and disseminated through conferences.

Educating Our Future Medical Leaders: An Innovative Longitudinal Course Across Surgical and Medical Specialties in Graduate Education.

Problem: Increasing healthcare system complexity, multidisciplinary care delivery, and the need to deliver high-quality, cost-effective care drive a critical need for leadership development. Currently, few examples of multidisciplinary leadership development exist in the medical education literature. The Accreditation Council for Graduate Medical Education (ACGME) has identified leadership domains as essential milestones in residency education, encompassing areas such as interpersonal communication, quality improvement, and systems-based practice. Presently, published GME leadership curricula vary widely in content, delivery, and duration and rarely include multispecialty cohorts. Approach: The study authors designed and implemented a longitudinal leadership curriculum for a multispecialty cohort of senior residents and fellows from multiple hospitals within a large integrated GME program. Between July 2022-June 2023, authors delivered 12 monthly sessions on core leadership concepts. Sessions delivered relevant work-based content via large-group didactics with embedded opportunities for small-group interactive experiential and reflective practice, critical thinking, and application. Outcomes: Thirty GME trainees participated in the longitudinal curriculum. Interval pre-/post-session assessments demonstrated significant improvement in composite scores for 6 of 9 sessions assessed. Participants rated each module's overall importance, applicability, and acceptability highly on a summative program evaluation. Next Steps: This longitudinal leadership curriculum adheres to best leadership development practices, demonstrates improvement in knowledge and self-reported attitudes and behaviors related to cognitive, character, and emotional leadership domains, and develops a psychologically safe community of practice for GME participants.

Can white matter hyperintensities based Fazekas visual assessment scales inform about Alzheimer's disease pathology in the population?

BACKGROUND: White matter hyperintensities (WMH) are considered hallmark features of cerebral small vessel disease and have recently been linked to Alzheimer's disease (AD) pathology. Their distinct spatial distributions, namely periventricular versus deep WMH, may differ by underlying age-related and pathobiological processes contributing to cognitive decline. We aimed to identify the spatial patterns of WMH using the 4-scale Fazekas visual assessment and explore their differential association with age, vascular health, AD imaging markers, namely amyloid and tau burden, and cognition. Because our study consisted of scans from GE and Siemens scanners with different resolutions, we also investigated inter-scanner reproducibility and combinability of WMH measurements on imaging. METHODS: We identified 1144 participants from the Mayo Clinic Study of Aging consisting of a population-based sample from Olmsted County, Minnesota with available structural magnetic resonance imaging (MRI), amyloid, and tau positron emission tomography (PET). WMH distribution patterns were assessed on FLAIR-MRI, both 2D axial and 3D, using Fazekas ratings of periventricular and deep WMH severity. We compared the association of periventricular and deep WMH scales with vascular risk factors, amyloid-PET, and tau-PET standardized uptake value ratio, automated WMH volume, and cognition using Pearson partial correlation after adjusting for age. We also evaluated vendor compatibility and reproducibility of the Fazekas scales using intraclass correlations (ICC). RESULTS: Periventricular and deep WMH measurements showed similar correlations with age, cardiometabolic conditions score (vascular risk), and cognition, (p < 0.001). Both periventricular WMH and deep WMH showed weak associations with amyloidosis (R = 0.07, p = < 0.001), and none with tau burden. We found substantial agreement between data from the two scanners for Fazekas measurements (ICC = 0.82 and 0.74). The automated WMH volume had high discriminating power for identifying participants with Fazekas ≥ 2 (area under curve = 0.97) and showed poor correlation with amyloid and tau PET markers similar to the visual grading. CONCLUSION: Our study investigated risk factors underlying WMH spatial patterns and their impact on global cognition, with no discernible differences between periventricular and deep WMH. We observed minimal impact of amyloidosis on WMH severity. These findings, coupled with enhanced inter-scanner reproducibility of WMH data, suggest the combinability of inter-scanner data assessed by harmonized protocols in the context of vascular contributions to cognitive impairment and dementia biomarker research.

Protective Effect of Parental Monitoring on Early-to-Mid Adolescents Displaying High-Level and Increasing Aggressive Behavior.

Studies that distinguish parental monitoring (parent-driven behaviors) from parental knowledge often fail to find protective effects of monitoring on adolescent behavior problems. To answer whether parental monitoring is more strongly associated with adolescent behavior problems among adolescents who may need it most, this study applied group-based trajectory modeling to change in early- to mid-adolescent aggressive behavior problems and examined associations between parental monitoring with different subgroups. Three latent groups of adolescents were found: Low Aggression, Medium-Increasing Aggression, and High-Increasing Aggression. Results show that more maternal and paternal monitoring were associated with fewer adolescent aggressive behavior problems only for adolescents in the High-Increasing Group. This result suggests that parental monitoring is a protective factor against adolescent aggressive behavior problems for subgroups of adolescents who may need it most and less impactful for other adolescents.

Fertility in the Digital Age: A Survey-Based Evaluation of Fertility App Users' Quality of Life.

This study sought to characterize fertility app use among women seen for infertility care and to investigate the association between fertility app use and quality of life. This survey-based study was conducted at an academic infertility clinic. Surveys were administered to patients who presented for a new infertility visit. One survey collected information regarding app use and the second survey was FertiQoL, an internationally validated instrument measuring quality of life in those with infertility. Descriptive statistics were used to characterize the patient population regarding app use and FertiQoL scores. Comparisons between those who did and didn't use an app were evaluated using t-tests and Cochran Armitage test for trend. 149 surveys were collected. Most (75.5%) participants reported using a fertility app. Most participants (85.1%) used a free app and nearly all (97.2%) found their app helpful. There was a significant difference (p = 0.0034) in satisfaction with one's quality of life between app users and non-app users with app users demonstrating higher satisfaction. There were no significant differences between app users and non-app users with their overall FertiQoL scores however there was a statistically significant difference (p = 0.031) in Relational sub-scores with app users displaying higher scores. While overall quality of life, measured by standardized measures, did not differ, self-perceived satisfaction with quality of life improved with more satisfaction reported in those using an app. This self-perceived satisfaction and increased quality of life surrounding relationships carries important implications, especially when one may face the stress of infertility and its treatment.

Allogeneic hematopoietic cell transplant for bone marrow failure or myelodysplastic syndrome in dyskeratosis congenita/telomere biology disorders: Single-center single-arm open-label trial of reduced intensity conditioning without radiation.

BACKGROUND: Dyskeratosis congenita/Telomere biology disorders (DC/TBD) often manifest as bone marrow failure (BMF) or myelodysplastic syndrome (MDS). Allogeneic hematopoietic cell transplant (alloHCT) rescues hematologic complications, but radiation and alkylator-based conditioning regimens cause diffuse whole-body toxicity and may expedite DC/TBD-specific non-hematopoietic complications. Optimization of conditioning intensity in DC/TBD to allow for donor hematopoietic cell engraftment with the least amount of toxicity remains a critical goal of the alloHCT field. OBJECTIVES/STUDY DESIGN: We report prospectively collected standard alloHCT outcomes from a single-center single-arm open-label clinical trial of bone marrow or peripheral blood stem cell alloHCT for DC/TBD-associated BMF or MDS. Conditioning was reduced intensity (RIC) including alemtuzumab 1mg/kg, fludarabine 200 mg/m2, and cyclophosphamide 50 mg/kg. A previous single-arm open-label phase II clinical trial for the same patient population conducted at the same center, differing only by inclusion of 200 centigray of total body irradiation (TBI), served as a control cohort. RESULTS: The Non-TBI cohort included 10 patients (ages 1.7-65.9 years, median follow-up of 3.9 years) compared to the control TBI cohort which included 12 patients (ages 2.2-52.2 years, median follow-up of 10.5 years). Baseline characteristics differed only in total CD34+ cells received, with a median of 5.6 (Non-TBI) compared to 2.6 (TBI) x 106/kg (p=0.02; no difference in total nucleated cells). The cumulative incidence of day +100 grade II-IV acute and 4-year chronic graft-versus-host disease (GvHD) were low at 0 and 10% (Non-TBI) and 8 and 17% (TBI), respectively (acute, p=0.36; chronic, p=0.72). Primary graft failure was absent. Secondary non-neutropenic graft failure occurred in one (Non-TBI cohort). The Non-TBI cohort demonstrated delayed achievement of full donor chimerism but superior lymphocyte recovery. There was no difference in 4-year overall survival at 80% (Non-TBI) and 75% (TBI; p=0.78). MDS as an indication for alloHCT was uncommon, but overall associated with poor outcomes. There were 3 MDS patients in the Non-TBI cohort: 1 relapsed and died at day+387; 1 relapsed at day+500 and is alive 5.5 years later following salvage with a 2nd alloHCT; 1 relapsed at day+1093 and is alive at day +100 after a 2nd alloHCT. There was 1 MDS patient in the TBI cohort who achieved 100% donor myeloid engraftment without relapse but died at day+827 from a bacterial infection in the setting of immune mediated cytopenia. CONCLUSION: Elimination of TBI from the RIC regimen for DC/TBD was not associated with significant changes in rates of graft failure, GvHD, and overall survival, but was associated with delayed achievement of full donor chimerism and improved lymphocyte reconstitution. For DC/TBD-associated BMF, TBI appears to be dispensable. Optimal approaches to DC/TBD-associated MDS remain unclear. Larger cohorts are needed to better assess the unique contribution of TBI and donor CD34+ cell dose. Longer follow-up is required to assess differences in DC/TBD complications and late effects.

The effect of pharmacist-led interventions on the appropriateness and clinical outcomes of anticoagulant therapy: a systematic review and meta-analysis.

AIM: Although pharmacist-led interventions in anticoagulant (AC) therapy are widely accepted, there is a lack of evidence comparing their effectiveness to usual care in terms of AC therapy appropriateness and clinical outcomes. We aimed to estimate the comparative effectiveness of pharmacist-led interventions on the appropriateness and clinical outcomes of AC therapy. METHODS AND RESULTS: Adhering to the PRISMA guidelines, we searched PubMed, EMBASE, and Scopus databases to identify randomised controlled trials and quasi-experimental and cohort studies published between 2010 and 2023. A random-effects model was used to calculate pooled intervention effects. We assessed heterogeneity (using Higgins' I2 and Cochran's Q) and publication bias (using Egger's test, the trim-and-fill method and visualisation of the funnel plot). In total, 35 studies involving 10 374 patients in the intervention groups and 11 840 in the control groups were included. The pharmacist-led interventions significantly improved the appropriateness of AC therapy (odds ratio [OR]: 3.43; 95% confidence interval [CI]: 2.33-5.06, p < 0.01). They significantly decreased total bleeding (relative risk [RR]: 0.75, 95% CI: 0.58-0.96, p = 0.03) and hospitalisation or readmission (RR: 0.64, 95% CI: 0.41-0.99, P = 0.04). However, the impact of the pharmacist-led interventions on thromboembolic events (RR: 0.69, 95% CI: 0.46-1.02, p = 0.07) and mortality (RR: 0.76, 95% CI: 0.51-1.13, p = 0.17) were not significant. CONCLUSION: Pharmacist-led interventions demonstrated superior outcomes in optimising AC therapy compared to usual care. Further research is needed to evaluate pharmacist-led interventions' cost-effectiveness and long-term sustainability.PROSPERO registration number CRD42023487362.

Symmetry-Guided Inverse Design of Self-Assembling Multiscale DNA Origami Tilings.

Recent advances enable the creation of nanoscale building blocks with complex geometries and interaction specificities for self-assembly. This nearly boundless design space necessitates design principles for defining the mutual interactions between multiple particle species to target a user-specified complex structure or pattern. In this article, we develop a symmetry-based method to generate the interaction matrices that specify the assembly of two-dimensional tilings, which we illustrate using equilateral triangles. By exploiting the allowed 2D symmetries, we develop an algorithmic approach by which any periodic 2D tiling can be generated from an arbitrarily large number of subunit species, notably addressing an unmet challenge of engineering 2D crystals with periodicities that can be arbitrarily larger than the subunit size. To demonstrate the utility of our design approach, we encode specific interactions between triangular subunits synthesized by DNA origami and show that we can guide their self-assembly into tilings with a wide variety of symmetries, using up to 12 unique species of triangles. By conjugating specific triangles with gold nanoparticles, we fabricate gold-nanoparticle supracrystals whose lattice parameter spans up to 300 nm. Finally, to generate economical design rules, we compare the design economy of various tilings. In particular, we show that (1) higher symmetries allow assembly of larger unit cells with fewer subunits and (2) linear supracrystals can be designed more economically using linear primitive unit cells. This work provides a simple algorithmic approach to designing periodic assemblies, aiding in the multiscale assembly of supracrystals of nanostructured "meta-atoms" with engineered plasmonic functions.

Shape equilibria of vesicles with rigid planar inclusions.

Motivated by recent studies of two-phase lipid vesicles possessing 2D solid domains integrated within a fluid bilayer phase, we study the shape equilibria of closed vesicles possessing a single planar, circular inclusion. While 2D solid elasticity tends to expel Gaussian curvature, topology requires closed vesicles to maintain an average, non-zero Gaussian curvature leading to an elementary mechanism of shape frustration that increases with inclusion size. We study elastic ground states of the Helfrich model of the fluid-planar composite vesicles, analytically and computationally, as a function of planar fraction and reduced volume. Notably, we show that incorporation of a planar inclusion of only a few percent dramatically shifts the ground state shapes of vesicles from predominantly prolate to oblate, and moreover, shifts the optimal surface-to-volume ratio far from spherical shapes. We show that for sufficiently small planar inclusions, the elastic ground states break symmetry via a complex variety of asymmetric oblate, prolate, and triaxial shapes, while inclusion sizes above about 8% drive composite vesicles to adopt axisymmetric oblate shapes. These predictions cast useful light on the emergent shape and mechanical responses of fluid-solid composite vesicles.

Saturation genome editing maps the functional spectrum of pathogenic VHL alleles.

To maximize the impact of precision medicine approaches, it is critical to identify genetic variants underlying disease and to accurately quantify their functional effects. A gene exemplifying the challenge of variant interpretation is the von Hippel-Lindautumor suppressor (VHL). VHL encodes an E3 ubiquitin ligase that regulates the cellular response to hypoxia. Germline pathogenic variants in VHL predispose patients to tumors including clear cell renal cell carcinoma (ccRCC) and pheochromocytoma, and somatic VHL mutations are frequently observed in sporadic renal cancer. Here we optimize and apply saturation genome editing to assay nearly all possible single-nucleotide variants (SNVs) across VHL's coding sequence. To delineate mechanisms, we quantify mRNA dosage effects and compare functional effects in isogenic cell lines. Function scores for 2,268 VHL SNVs identify a core set of pathogenic alleles driving ccRCC with perfect accuracy, inform differential risk across tumor types and reveal new mechanisms by which variants impact function. These results have immediate utility for classifying VHL variants encountered clinically and illustrate how precise functional measurements can resolve pleiotropic and dosage-dependent genotype-phenotype relationships across complete genes.

Biogeographic and seasonal differences in consumer pressure underlie strong predation in the tropics.

Biotic interactions play a critical role in shaping patterns of global biodiversity. While several macroecological studies provide evidence for stronger predation in tropical regions compared with higher latitudes, results are variable even within the tropics, and the drivers of this variability are not well understood. We conducted two complementary standardized experiments on communities of sessile marine invertebrate prey and their associated predators to test for spatial and seasonal differences in predation across the tropical Atlantic and Pacific coastlines of Panama. We further tested the prediction that higher predator diversity contributes to stronger impacts of predation, using both direct observations of predators and data from extensive reef surveys. Our results revealed substantially higher predation rates and stronger effects of predators on prey in the Pacific than in the Atlantic, demonstrating striking variation within tropical regions. While regional predator diversity was high in the Atlantic, functional diversity at local scales was markedly low. Peak predation strength in the Pacific occurred during the wet, non-upwelling season when ocean temperatures were warmer and predator communities were more functionally diverse. Our results highlight the importance of regional biotic and abiotic drivers that shape interaction strength and the maintenance of tropical communities, which are experiencing rapid environmental change.

A comparative cohort study of surgical approaches for adult spinal deformity at a minimum 2-year follow-up.

STUDY DESIGN: This study was a retrospective multi-center comparative cohort study. MATERIALS AND METHODS: A retrospective institutional database of operative adult spinal deformity patients was utilized. All fusions > 5 vertebral levels and including the sacrum/pelvis were eligible for inclusion. Revisions, 3 column osteotomies, and patients with < 2-year clinical follow-up were excluded. Patients were separated into 3 groups based on surgical approach: 1) posterior spinal fusion without interbody (PSF), 2) PSF with interbody (PSF-IB), and 3) anteroposterior (AP) fusion (anterior lumbar interbody fusion or lateral lumbar interbody fusion with posterior screw fixation). Intraoperative, radiographic, and clinical outcomes, as well as complications, were compared between groups with ANOVA and χ2 tests. RESULTS: One-hundred and thirty-eight patients were included for study (PSF, n = 37; PSF-IB, n = 44; AP, n = 57). Intraoperatively, estimated blood loss was similar between groups (p = 0.171). However, the AP group had longer operative times (547.5 min) compared to PSF (385.1) and PSF-IB (370.7) (p < 0.001). Additionally, fusion length was shorter in PSF-IB (11.4) compared to AP (13.6) and PSF (12.9) (p = 0.004). There were no differences between the groups in terms of change in alignment from preoperative to 2 years postoperative. There were no differences in clinical outcomes. While postoperative complications were largely similar between groups, operative complications were higher in the AP group (31.6%) compared to the PSF (5.4%) and PSF-IB (9.1) groups (p < 0.001). CONCLUSION: While there were differences in intraoperative outcomes (operative time and fusion length), there were no differences in postoperative clinical or radiographic outcomes. AP fusion was associated with a higher rate of operative complications.

Hip Osteoarthritis in Patients Undergoing Surgery for Severe Adult Spinal Deformity: Prevalence and Impact on Spine Surgery Outcomes.

BACKGROUND: Hip osteoarthritis (OA) is common in patients with adult spinal deformity (ASD). Limited data exist on the prevalence of hip OA in patients with ASD, or on its impact on baseline and postoperative alignment and patient-reported outcome measures (PROMs). Therefore, this paper will assess the prevalence and impact of hip OA on alignment and PROMs. METHODS: Patients with ASD who underwent L1-pelvis or longer fusions were included. Two independent reviewers graded hip OA with the Kellgren-Lawrence (KL) classification and stratified it by severity into non-severe (KL grade 1 or 2) and severe (KL grade 3 or 4). Radiographic parameters and PROMs were compared among 3 patient groups: Hip-Spine (hip KL grade 3 or 4 bilaterally), Unilateral (UL)-Hip (hip KL grade 3 or 4 unilaterally), or Spine (hip KL grade 1 or 2 bilaterally). RESULTS: Of 520 patients with ASD who met inclusion criteria for an OA prevalence analysis, 34% (177 of 520) had severe bilateral hip OA and unilateral or bilateral hip arthroplasty had been performed in 8.7% (45 of 520). A subset of 165 patients had all data components and were examined: 68 Hip-Spine, 32 UL-Hip, and 65 Spine. Hip-Spine patients were older (67.9 ± 9.5 years, versus 59.6 ± 10.1 years for Spine and 65.8 ± 7.5 years for UL-Hip; p < 0.001) and had a higher frailty index (4.3 ± 2.6, versus 2.7 ± 2.0 for UL-Hip and 2.9 ± 2.0 for Spine; p < 0.001). At 1 year, the groups had similar lumbar lordosis, yet the Hip-Spine patients had a worse sagittal vertebral axis (SVA) measurement (45.9 ± 45.5 mm, versus 25.1 ± 37.1 mm for UL-Hip and 19.0 ± 39.3 mm for Spine; p = 0.001). Hip-Spine patients also had worse Veterans RAND-12 Physical Component Summary scores at baseline (25.7 ± 9.3, versus 28.7 ± 9.8 for UL-Hip and 31.3 ± 10.5 for Spine; p = 0.005) and 1 year postoperatively (34.5 ± 11.4, versus 40.3 ± 10.4 for UL-Hip and 40.1 ± 10.9 for Spine; p = 0.006). CONCLUSIONS: This study of operatively treated ASD revealed that 1 in 3 patients had severe hip OA bilaterally. Such patients with severe bilateral hip OA had worse baseline SVA and PROMs that persisted 1 year following ASD surgery, despite correction of lordosis. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Economical routes to size-specific assembly of self-closing structures.

Programmable self-assembly has seen an explosion in the diversity of synthetic crystalline materials, but developing strategies that target "self-limiting" assemblies has remained a challenge. Among these, self-closing structures, in which the local curvature defines the finite global size, are prone to polymorphism due to thermal bending fluctuations, a problem that worsens with increasing target size. Here, we show that assembly complexity can be used to eliminate this source of polymorphism in the assembly of tubules. Using many distinct components, we prune the local density of off-target geometries, increasing the selectivity of the tubule width and helicity to nearly 100%. We further show that by reducing the design constraints to target either the pitch or the width alone, fewer components are needed to reach complete selectivity. Combining experiments with theory, we reveal an economical limit, which determines the minimum number of components required to create arbitrary assembly sizes with full selectivity.

Proximal foundation anchor variations and their correlation with unplanned return to the operating room (UPROR) in children with EOS treated with magnetically controlled growing rods (MCGR).

INTRODUCTION: The evolution of MCGR technique has led to modifications in the configuration of the proximal construct to decrease the incidence of implant-related complications (IRC) and revision surgeries. However, there is no data characterizing the performance of the most used configurations reducing the risk of complications. METHODS: 487 patients were identified from an international multicenter EOS database. INCLUSION CRITERIA: EOS patients, primary dual MCGR, complete radiographs, and minimum of 2-year follow-up. 76 patients had incomplete X-rays, 5 had apical fusions, and 18 had inconclusive complications, leaving 388 patients for review. A digital spine template was created to document UIV; number of levels; number, type, and location of anchors; as well as implant configuration. First available postoperative and latest follow-up radiographs were reviewed by two senior surgeons and two spine fellows. UPROR due to IRC was defined as any change in proximal anchors between the postoperative and final follow-up radiographs. RESULTS: The most common proximal construct configuration: UIV at T2 (50.0%) with 17.5% UPROR, followed by T3 (34.0%) with 12.1% UPROR; number of levels was three (57.1%) with 16.8% UPROR and two (26.0%) with 17.0% UPROR; number of proximal anchors was six (49.9%) with 14.1% UPROR and four (27.0%) with 18.3% UPROR. The most common anchors were all screws (42.0%) with 9.9% UPROR, and all hooks (26.4%) with 31.4% UPROR (P < 0.001). The construct with the lowest rate of UPROR was a UIV at T2, with six anchors (all screws) across three levels (42 cases), with 0% UPROR. Other construct combinations that yielded 0% UPROR rates were UIV of T3, six anchors (all screws) across three levels (25 cases), and a UIV of T3 with six anchors (screws and hooks) across three3 levels (9 cases). CONCLUSION: Proximal anchor configuration impacts the incidence of UPROR due to IRC in MCGR. UIV at T2 and T3 compared to T4, and the use of all screws or combination of screws and hooks compared to all hooks were associated with a lower UPROR rate. The most common construct configuration was T2 UIV, three levels, six anchors, and all screws. The use of a combination of six anchors (screws or screws and hooks) across three levels with a UIV at T2 or T3 was associated with a lower UPROR rate. Additional research is needed to further evaluate the variables contributing to configuration selection and their association with IRC.

A phase 2 study of a brachyury-targeting vaccine in combination with radiation therapy for the treatment of advanced chordoma.

BACKGROUND: This was a single-arm, phase 2 clinical trial of Bavarian Nordic (BN)-Brachyury vaccine plus radiotherapy (RT) designed to determine the objective response rate (ORR), progression-free survival (PFS), and safety of the combination in chordoma. METHODS: A total of 29 adult patients with advanced chordoma were treated with two subcutaneous priming vaccine doses of modified vaccinia Ankara-Bavarian Nordic (MVA-BN)-Brachyury and one vaccine dose of fowlpox virus (FPV)-Brachyury before RT. After RT, booster vaccinations were given with FPV-Brachyury every 4 weeks for 4 doses, then every 12 weeks (week 110). A minimum RT dose of >8 Gy in one fraction for each target was required. Response was evaluated by modified Response Evaluation Criteria in Solid Tumors 1.1 (mRECIST), where only radiated lesions were considered targets, and by standard RECIST 1.1 in a subset of patients. RESULTS: Two of 26 evaluable patients experienced durable partial response (PR) (ORR of 7.7%; 90% confidence interval [CI], 2.6-20.8]) by mRECIST 1.1. A total of 21 patients (80.8%; 90% CI, 65.4-90.3) had stable disease, and three patients (11.5%; 90% CI, 4.7-25.6) had progressive disease as best response per mRECIST 1.1. Median PFS was not reached during the study. CONCLUSIONS: This trial confirms the safety of BN-Brachyury and RT. Although the study did not meet the predefined study goal of four responses in 29 patients, we did observe two PRs and a PFS of greater than 2 years. For a vaccine-based study in chordoma, an ultra-rare disease where response rates are low, a randomized study or novel trial designs may be required to confirm activity.

Comparative analysis of mechanical thrombectomy outcomes of middle cerebral artery M1, M2 superior and M2 inferior occlusion strokes.

BACKGROUND: The M1 middle cerebral artery (MCA) commonly bifurcates into an M2 superior and an M2 inferior segment. However, MCA anatomy is highly variable rendering classification for mechanical thrombectomy (MT) trials difficult. Safety and effectiveness of M2 MCA stroke thrombectomy stratified by M2 MCA anatomy remains to be explored. METHODS: Large vessel occlusion strokes undergoing MT between 02/2016-08/2022 were reviewed (n=784). M1 (n=431) and M2 MCA (n=118) occlusions were assessed. Among M2 MCA occlusions only prototypical MCA bifurcation anatomy cases were included (n=99). Dominance was assessed based on angiography. Procedural and outcome data was compared between M1, M2 superior and M2 inferior MCA occlusions. RESULTS: Baseline demographics and periprocedural criteria of M2 superior (n=56) and M2 inferior (n=43) occlusion MTs were comparable. Among M2 inferior cases, the occluded branch was dominant in 41/43 (95.3%) but only in 37/56 (66.1%) among M2 superior cases (p<0.001). The 90-day favorable functional outcome (mRS 0-2) and mortality (mRS 6) rates were 60.0% and 8.9% in the M2 superior, 42.9% and 32.6% in the M2 inferior, and 44.1% and 26.0% in the M1 group (n=431). Compared to M2 superior, M2 inferior favorable outcome rates were lower (p=0.094) and mortality rates were higher (p=0.003) and resembled M1 outcome rates (p=0.750 and p=0.355, respectively). CONCLUSION: In setting of prototypical MCA bifurcation anatomy, thrombectomy of dominant M2 inferior occlusions had outcome rates like M1 occlusions. In contrast, M2 superior occlusions had significantly lower mortality rates and a trend towards better favorable functional outcome rates.