IL-10 suppresses T cell expansion while promoting tissue-resident memory cell formation during SARS-CoV-2 infection in rhesus macaques.

The regulation of inflammatory responses and pulmonary disease during SARS-CoV-2 infection is incompletely understood. Here we examine the roles of the prototypic pro- and anti-inflammatory cytokines IFNγ and IL-10 using the rhesus macaque model of mild COVID-19. We find that IFNγ drives the development of 18fluorodeoxyglucose (FDG)-avid lesions in the lungs as measured by PET/CT imaging but is not required for suppression of viral replication. In contrast, IL-10 limits the duration of acute pulmonary lesions, serum markers of inflammation and the magnitude of virus-specific T cell expansion but does not impair viral clearance. We also show that IL-10 induces the subsequent differentiation of virus-specific effector T cells into CD69+CD103+ tissue resident memory cells (Trm) in the airways and maintains Trm cells in nasal mucosal surfaces, highlighting an unexpected role for IL-10 in promoting airway memory T cells during SARS-CoV-2 infection of macaques.

Optimizing Triage of Ambulatory Patients With Advanced Heart Failure: 2-Year Outcomes From REVIVAL.

BACKGROUND: Left ventricular assist device (LVAD) use remains uncommon in advanced heart failure (HF) patients not dependent on inotropes. OBJECTIVES: Before considering a randomized trial comparing a strategy of earlier use of LVAD to continued medical therapy, a better understanding is needed of the clinical trajectory of ambulatory patients with advanced systolic HF on optimal guideline-directed medical therapy (GDMT). METHODS: REVIVAL enrolled 400 patients with advanced ambulatory systolic HF, ≥1 HF mortality risk marker (≥2 HF hospitalizations past year; or HF hospitalization and high natriuretic peptide; or no HF hospitalizations but low peak oxygen consumption, 6-minute walk, serum sodium, HF survival score or Seattle HF model predicted survival), and no LVAD contraindication at 21 LVAD centers from July 2015 to June 2016. Patients were followed for 2 years or until a primary outcome (death, durable ventricular assist device, or urgent transplant). Clinical outcomes and health-related quality of life were evaluated. RESULTS: Mean baseline left ventricular ejection fraction was 21%, median 6-minute walk was 341 m, and 92% were Interagency Registry for Mechanically Assisted Circulatory Support profiles 5 to 7. Adherence to GDMT and electrical device therapies was robust. Composite primary outcome occurred in 22% and 37% at 1 and 2 years, with death alone in 8% and 16%, respectively. Patients surviving for 2 years maintained GDMT intensity and had no decline in health-related quality of life. CONCLUSION: Structured, serial follow-up at programs with expertise in caring for advanced ambulatory systolic HF patients facilitates triage for advanced therapies. Better strategies are still needed to avoid deaths in a small but significant group of patients who die without advanced therapies. REVIVAL patients not selected for VAD or transplant have robust survival and patient-reported outcomes, which challenges advocacy for earlier VAD implantation. (Registry Evaluation of Vital Information for VADs in Ambulatory Life [REVIVAL]; NCT01369407).

Zafirlukast induces DNA condensation and has bactericidal effect on replicating Mycobacterium abscessus.

Mycobacterium abscessus infections are emerging in cystic fibrosis patients, and treatment success rate in these patients is only 33% due to extreme antibiotic resistance. Thus, new treatment options are essential. An interesting target could be Lsr2, a nucleoid-associated protein involved in mycobacterial virulence. Zafirlukast is a Food and Drug Administration (FDA)-approved drug against asthma that was shown to bind Lsr2. In this study, zafirlukast treatment is shown to reduce M. abscessus growth, with a minimal inhibitory concentration of 16 µM and a bactericidal concentration of 64 µM in replicating bacteria only. As an initial response, DNA condensation, a known stress response of mycobacteria, occurs after 1 h of treatment with zafirlukast. During continued zafirlukast treatment, the morphology of the bacteria alters and the structural integrity of the bacteria is lost. After 4 days of treatment, reduced viability is measured in different culture media, and growth of M. abscessus is reduced in a dose-dependent manner. Using transmission electron microscopy, we demonstrated that the hydrophobic multilayered cell wall and periplasm are disorganized and ribosomes are reduced in size and relocalized. In summary, our data demonstrate that zafirlukast alters the morphology of M. abscessus and is bactericidal at 64 µM. The bactericidal concentration of zafirlukast is relatively high, and it is only effective on replicating bacteria but as zafirlukast is an FDA-approved drug, and currently used as an anti-asthma treatment, it could be an interesting drug to further study in in vivo experiments to determine whether it could be used as an antibiotic for M. abscessus infections.

Trampolines Versus Playgrounds - A Comparative Assessment of Pediatric Fractures Sustained From Recreational Play.

INTRODUCTION: Using the Pediatric Health Information System, this study compared the relative severity of fractures sustained from trampolines with those from other playground equipment. METHODS: Pediatric patients were identified in the Pediatric Health Information System with trampoline-related injuries (TRIs) or playground-related injuries (PRIs) diagnosed as fractures. Adjustments were made for hospital, year of injury, sex, age, race, median household income, and rurality through propensity score weighting. Four injury-related outcome measures were examined as a proxy for injury severity. RESULTS: A total of 133,232 patients met inclusion criteria. In unadjusted univariate analyses, TRIs were associated with greater odds of severe fracture and lower odds of receiving surgical treatment (OR = 0.954) compared with PRIs. After adjustment, TRIs sustained in late childhood and adolescence were more likely to receive surgical management (OR = 1.092 and OR = 1.192, respectively) while TRIs sustained in younger children were less likely (OR = 0.607) than PRIs. DISCUSSION: Youths in late childhood and adolescence are at increased odds of undergoing surgical management after trampoline fractures. Beyond underscoring the risks of trampoline play, our results highlight the importance of considering age in recreational injury epidemiology and the public health safety initiatives aimed at specific age groups.

Lymph Node Yield is Associated with Improved Overall Survival and Increased Time to Recurrence in Node-Negative Pancreatic Ductal Adenocarcinoma Following Neoadjuvant Therapy.

OBJECTIVE: To determine if lymph node yield (LNY) is associated with improved overall survival (OS) and time to recurrence (TTR) in patients with node-negative pancreatic ductal adenocarcinoma (PDAC) treated with neoadjuvant therapy (NAT). BACKGROUND: Lymph node yield has been associated with survival in solid gastrointestinal cancers, including PDAC. METHODS: Patients with pathological T stage I-III, node-negative (N0), PDAC treated with NAT followed by pancreatoduodenectomy were identified in the Massachusetts General Hospital (MGH) pancreatectomy database and the National Cancer Database (NCDB). A cutoff point of 22 nodes was identified in the NCDB using the point with the optimal (log-rank test) split. Overall survival and TTR were evaluated using univariate and multivariable analyses. RESULTS: In the MGH cohort, 233 node-negative patients following NAT were included. A LNY ≥ 22 was associated with prolonged median OS (59 months vs. 25 months, P<0.001) and prolonged TTR (32 months vs. 14 months, P=0.019). On multivariable analysis, LNY was an independent predictor of survival (HR 0.97, 95% CI 0.95-0.99, P=0.034) per sampled node. In the NCDB, 2,029 node-negative patients following NAT were included. A LNY ≥ 22 was associated with prolonged median OS (49 months vs. 33 months, P<0.001). On multivariable analysis, LNY was an independent predictor of survival (HR 0.99, 95% CI 0.98-0.99, P<0.001) per sampled node. CONCLUSION: Lymph node yield was associated with improved oncologic outcomes in patients treated with NAT followed by pancreatoduodenectomy in two independent datasets. Responsible mechanisms by which LNY impacts the outcomes of node-negative patients following NAT warrant further exploration.

A consensus reverse docking approach for identification of a competitive inhibitor of acetyltransferase enhanced intracellular survival protein from Mycobacterium tuberculosis.

Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis (Mtb), which remains a significant global health challenge. The emergence of multidrug-resistant (MDR) Mtb strains imposes the development of new therapeutic strategies. This study focuses on the identification and evaluation of potential inhibitors against Mtb H37Ra through a comprehensive screening of an in-house chemolibrary. Subsequently, a promising pyrimidine derivative (LQM495) was identified as promising and then further investigated by experimental and in silico approaches. In this context, computational techniques were used to elucidate the potential molecular target underlying the inhibitory action of LQM495. Then, a consensus reverse docking (CRD) protocol was used to investigate the interactions between this compound and several Mtb targets. Out of 98 Mtb targets investigated, the enhanced intracellular survival (Eis) protein emerged as a target for LQM495. To gain insights into the stability of the LQM495-Eis complex, molecular dynamics (MD) simulations were conducted over a 400 ns trajectory. Further insights into its binding modes within the Eis binding site were obtained through a Quantum mechanics (QM) approach, using density functional theory (DFT), with B3LYP/D3 basis set. These calculations shed light on the electronic properties and reactivity of LQM495. Subsequently, inhibition assays and kinetic studies of the Eis activity were used to investigate the activity of LQM495. Then, an IC50 value of 11.0 ± 1.4 µM was found for LQM495 upon Eis protein. Additionally, its Vmax, Km, and Ki parameters indicated that it is a competitive inhibitor. Lastly, this study presents LQM495 as a promising inhibitor of Mtb Eis protein, which could be further explored for developing novel anti-TB drugs in the future.

Results from the ENJOY MAP for HEALTH: a quasi experiment evaluating the impact of age-friendly outdoor exercise equipment to increase older people's park visitations and physical activity.

BACKGROUND: Recreational parks can play a significant role in older people's health, with emerging evidence suggesting that changes in the physical environment, such as refurbishments of local parks, can increase park visitations and physical activity engagement. The ENJOY MAP for HEALTH aimed to evaluate the impact of Seniors Exercise Park installations and associated capacity building activities on older people's park visitation, and park-based physical activity. METHOD: The ENJOY MAP for HEALTH was a quasi-experiment study design that involved the installation of specialised Seniors Exercise Park equipment as part of park refurbishment, supported by promotion and community capacity building activities in six municipalities in Victoria, Australia. Direct observations of park users took place prior to park upgrades, one-month post upgrade and 12-months from baseline. The overall number and characteristics of park visitors, and the type and level of physical activity undertaken, were summarised descriptively. Generalised linear models were used to examine the impact of park refurbishment (equipment installation and site activation) on the total number of older people observed in the park, and their engagement in physical activity, accounting for site and seasonal effects. RESULTS: Overall number of visits increased following park upgrades, with the largest number of visitors observed one-month post upgrade (n = 12,501). The proportion of older people observed at the parks remained relatively low prior to and one-month post upgrade compared to other age groups. However, after adjusting for site and seasonal effects, the number of older people observed in the parks increased significantly post upgrade and site activation compared to prior to the refurbishment (incidence rate ratios (IRR) 3.55; 95% CI 2.68, 4.70). The number of older people observed to be exercising at the Seniors Exercise Park also increased by 100% at 12-months post-installation relative to one-month post upgrade (IRR 2.00; 95% CI 1.26, 3.17). CONCLUSION: Installation of the Seniors Exercise Parks and the supportive programs and activities following six park upgrades resulted in an increase in older people's park visitation and engagement in physical activity. Community engagement and training of volunteers with the support of local governments are likely to contribute to the increased park usage by older people. TRIAL REGISTRATION: This trial was registered with the Australian New Zealand Clinical Trials Registry. Trial registration number ACTRN12621000965808. https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=380745&isReview=true .

Do Complications After Pancreatoduodenectomy Have an Impact on Long-Term Quality of Life and Functional Outcomes?

Objective: Our aim was to assess whether complications after pancreatoduodenectomy (PD) impact long-term quality of life (QoL) and functional outcomes. Background: There is an increasing number of long-term post-PD survivors, but few studies have evaluated long-term QoL outcomes. Methods: The EORTC QLQ-C30 and QLQ-PAN26 questionnaires were administered to patients who survived >5 years post-PD. Clinical relevance (CR) was scored as small (5-10), moderate (10-20), or large (>20). Patients were stratified based on whether they experienced a complication during the index hospitalization. Results: Of 305 patients >5 years post-PD survivors, with valid contact information, 248 completed the questionnaires, and 231 had complication data available. Twenty-nine percent of patients experienced a complication, of which 17 (7.4%) were grade 1, 27 (11.7%) were grade 2, and 25 (10.8%) were grade 3. Global health status and functional domain scores were similar between both groups. Patients experiencing complications reported lower fatigue (21.4 vs 28.1, P < 0.05, CR small) and diarrhea (15.9 vs 23.1, P < 0.05, CR small) symptom scores when compared to patients without complications. Patients experiencing complications also reported lower pancreatic pain (38.2 vs 43.4, P < 0.05, CR small) and altered bowel habits (30.1 vs 40.7, P < 0.01, CR moderate) symptom scores. There was a lower prevalence of worrying (36.2% vs 60.5%, P < 0.05) and bloating (42.0% vs 56.2%, P < 0.05) among PD survivors with complications. Conclusions: Post-PD complication rates were not associated with long-term global QoL or functionality, and may be associated with less severe pancreas-specific symptoms.

The significant others' responses to trauma scale (SORTS): applying factor analysis and item response theory to a measure of PTSD symptom accommodation.

Background: Symptom accommodation by family members (FMs) of individuals with posttraumatic stress disorder (PTSD) includes FMs' participation in patients' avoidance/safety behaviours and constraining self-expression to minimise conflict, potentially maintaining patients' symptoms. The Significant Others' Responses to Trauma Scale (SORTS) is the only existing measure of accommodation in PTSD but has not been rigorously psychometrically tested.Objective: We aimed to conduct further psychometric analyses to determine the factor structure and overall performance of the SORTS. Method: We conducted exploratory and confirmatory factor analyses using a sample of N = 715 FMs (85.7% female, 62.1% White, 86.7% romantic partners of individuals with elevated PTSD symptoms).Results: After dropping cross-loading items, results indicated good fit for a higher-order model of accommodation with two factors: an anger-related accommodation factor encompassed items related largely to minimising conflict, and an anxiety-related accommodation factor encompassed items related primarily to changes to the FM's activities. Accommodation was positively related to PTSD severity and negatively related to relationship satisfaction, although the factors showed somewhat distinct associations. Item Response Theory analyses indicated that the scale provided good information and robust coverage of different accommodation levels.Conclusions: SORTS data should be analysed as both a single score as well as two factors to explore the factors' potential differential performance across treatment and relationship outcomes.

We examined the Significant Others' Responses to Trauma Scale (SORTS), a measure of symptom accommodation in PTSD, among a large sample of family members.As measured by the SORTS, accommodation in PTSD could be broken down into two aspects: anger-related accommodation and anxiety-related accommodation.Accommodation was positively related to PTSD severity and negatively related to relationship satisfaction.

Inner core backtracking by seismic waveform change reversals.

The solid inner core, suspended within the liquid outer core and anchored by gravity, has been inferred to rotate relative to the surface of Earth or change over years to decades based on changes in seismograms from repeating earthquakes and explosions1,2. It has a rich inner structure3-6 and influences the pattern of outer core convection and therefore Earth's magnetic field. Here we compile 143 distinct pairs of repeating earthquakes, many within 16 multiplets, built from 121 earthquakes between 1991 and 2023 in the South Sandwich Islands. We analyse their inner-core-penetrating PKIKP waves recorded on the medium-aperture arrays in northern North America. We document that many multiplets exhibit waveforms that change and then revert at later times to match earlier events. The matching waveforms reveal times at which the inner core re-occupies the same position, relative to the mantle, as it did at some time in the past. The pattern of matches, together with previous studies, demonstrates that the inner core gradually super-rotated from 2003 to 2008, and then from 2008 to 2023 sub-rotated two to three times more slowly back through the same path. These matches enable precise and unambiguous tracking of inner core progression and regression. The resolved different rates of forward and backward motion suggest that new models will be necessary for the dynamics between the inner core, outer core and mantle.

Standardised definitions and diagnostic criteria for extranodal extension detected on histopathological examination in head and neck cancer: Head and Neck Cancer International Group consensus recommendations.

Detection of extranodal extension on histopathology in surgically treated head and neck squamous cell carcinoma indicates poor prognosis. However, there is no consensus on the diagnostic criteria, interpretation, and reporting of histology detected extranodal extension, which has contributed to conflicting evidence in the literature, and likely clinical inconsistency. The Head and Neck Cancer International Group conducted a three-round modified Delphi process with a group of 19 international pathology experts representing 15 national clinical research groups to generate consensus recommendations for histology detected extranodal extension diagnostic criteria. The expert panel strongly agreed on terminology and diagnostic features for histology detected extranodal extension and soft tissue metastasis. Moreover, the panel reached consensus on reporting of histology detected extranodal extension and on nodal sampling. These consensus recommendations, endorsed by 19 organisations representing 34 countries, are a crucial development towards standardised diagnosis and reporting of histology detected extranodal extension, and more accurate data collection and analysis.

Predicting the direction of phenotypic difference.

Predicting phenotypes from genomic data is a key goal in genetics, but for most complex phenotypes, predictions are hampered by incomplete genotype-to-phenotype mapping. Here, we describe a more attainable approach than quantitative predictions, which is aimed at qualitatively predicting phenotypic differences. Despite incomplete genotype-to-phenotype mapping, we show that it is relatively easy to determine which of two individuals has a greater phenotypic value. This question is central in many scenarios, e.g., comparing disease risk between individuals, the yield of crop strains, or the anatomy of extinct vs extant species. To evaluate prediction accuracy, i.e., the probability that the individual with the greater predicted phenotype indeed has a greater phenotypic value, we developed an estimator of the ratio between known and unknown effects on the phenotype. We evaluated prediction accuracy using human data from tens of thousands of individuals from either the same family or the same population, as well as data from different species. We found that, in many cases, even when only a small fraction of the loci affecting a phenotype is known, the individual with the greater phenotypic value can be identified with over 90% accuracy. Our approach also circumvents some of the limitations in transferring genetic association results across populations. Overall, we introduce an approach that enables accurate predictions of key information on phenotypes - the direction of phenotypic difference - and suggest that more phenotypic information can be extracted from genomic data than previously appreciated.

Multigenerational spaces: the usage and activities of different age groups within six community parks in Victoria, Australia.

BACKGROUND: This study investigated how different spaces within multigenerational local parks are being used by older people and other age groups. METHODS: Observation of park visitors occurred in six Victorian parks one month after park refurbishment. Parks were classified into six spaces based on equipment/amenities and associated expected activity. Observations were summarized descriptively, and negative binomial regression models were used to examine the association between visitor counts and classified targeted areas. RESULTS: A total of 12 501 people visited the parks with 4.1% older visitors. The number of older visitors in each park area was consistently less than other age groups, with counts of older visitors being 50% less in mixed spaces (95% confidence interval [CI] 0.38, 0.65), 40% less in adult exercise equipment areas (95% CI 0.46, 0.77) and 59% less in walking paths (95% CI 0.31, 0.55). The number of older visitors engaging in physical activity were significantly greater in walking paths (incidence rate ratios 1.75; 95% CI 1.16, 2.64) compared with children's play spaces. CONCLUSION: The number of visitors across different age groups varied significantly between the park targeted areas. Most spaces were mainly used by the intended target age group/user, with no particular area used by all age groups in similar proportions.

The multidisciplinary pancreatic cyst clinic: A collaborative approach to streamlined management.

BACKGROUND: Pancreatic cysts are often incidentally detected on routine imaging studies. Of these, mucinous cysts have a malignant potential. Several guidelines propose different management strategies, and implementation in patient care is inconsistent in the absence of dedicated infrastructure. METHODS: To address the challenges of pancreatic cyst diagnosis and management, we established a multidisciplinary pancreas cyst clinic (PCC) within our health system. This clinic encompasses both tertiary care academic centers and community hospitals, with leadership from surgical oncology, gastroenterology, and radiology. Our PCC's primary goal is to provide accurate diagnosis and tailored management recommendations for all patients with pancreatic cysts. Additionally, we maintain a prospective database to study the disease's natural history and the outcomes of various treatment strategies. CLINIC INFRASTRUCTURE: The clinic meets once per week for 45 min virtually via Zoom in the mornings. Patients are referred via electronic medical record (EMR) order, telephone call, or email from patient or referring provider. A dedicated advanced practice provider reviews referrals several times per day, calls patients to gather clinical data, ensures imaging is uploaded, and coordinates logistical aspects of the meeting during the dedicated time. Conferences are attended by representatives from surgery, radiology, medical pancreatology, and interventional gastroenterology. Each patient case is reviewed in detail and recommendations are submitted to referring providers and patients via an EMR message and letter. For patients requiring imaging surveillance, patients are followed longitudinally by the referring provider, gastroenterology team, or surgical team. For patients requiring endoscopic ultrasound (EUS) or surgical consultation, expedited referral to these services is made with prompt subsequent evaluation. RESULTS: A total of 1052 patients from our health system were evaluated between 2020 and 2021. Of these, 196 (18.6 %) underwent EUS, 41 (3.9 %) underwent upfront surgical resection, and the remainder were referred to gastroenterology (141-13.4 %), surgery (314-29.8 %), or back to their referring provider (597-56.7 %) for ongoing surveillance in collaboration with their primary care provider (PCP). Of cysts under surveillance, 61.3 % remained stable, 13.2 % increased in size, and 2 % decreased in size. A total of 2.3 % of patients were recommended to discontinue surveillance. CONCLUSIONS: The PCC provides infrastructure that has served to provide multidisciplinary review and consensus recommendations to patients with pancreatic cysts. This has served to improve the application of guidelines while providing individualized recommendations to each patient, while aiding non-expert referring providers throughout the region.

Self-management Programs Within Rehabilitation Yield Positive Health Outcomes at a Small Increased Cost Compared With Usual Care: A Systematic Review and Meta-analysis.

OBJECTIVE: To determine if self-management programs, supported by a health professional, in rehabilitation are cost effective. DATA SOURCES: Six databases were searched until December 2023. STUDY SELECTION: Randomized controlled trials with adults completing a supported self-management program while participating in rehabilitation or receiving health professional input in the hospital or community settings were included. Self-management programs were completed outside the structured, supervised therapy and health professional sessions. Included trials had a cost measure and an effectiveness outcome reported, such as health-related quality of life or function. Grading of Recommendations, Assessment, Development, and Evaluations was used to determine the certainty of evidence across trials included in each meta-analysis. Incremental cost-effectiveness ratios were calculated based on the mean difference from the meta-analyses of contributing health care costs and quality of life. DATA EXTRACTION: After application of the search strategy, two independent reviewers determined eligibility of identified literature, initially by reviewing the title and/or abstract before full-text review. Using a customized form, data were extracted by one reviewer and checked by a second reviewer. DATA SYNTHESIS: Forty-three trials were included, and 27 had data included in meta-analyses. Where self-management was a primary intervention, there was moderate certainty of a meaningful positive difference in quality-of-life utility index of 0.03 units (95% confidence interval, 0.01-0.06). The cost difference between self-management as the primary intervention and usual care (comprising usual intervention/therapy, minimal intervention [including education only], or no intervention) potentially favored the comparison group (mean difference=Australian dollar [AUD]90; 95% confidence interval, -AUD130 to AUD310). The cost per quality-adjusted life year (QALY) gained for self-management programs as a stand-alone intervention was AUD3000, which was below the acceptable willingness-to-pay threshold in Australia per QALY gained (AUD50,000/QALY gained). CONCLUSIONS: Self-management as an intervention is low cost and could improve health-related quality of life.

The determinants of proxy treadmilling in evolutionary models of reliable signals.

Identifying the conditions of proxy treadmilling is crucial for determining whether reliable signals can persist over time. I present a framework that maps evolutionary models of reliable signals according to their assumptions regarding the effects of Goodhart's law. This framework can explain the contrasting outcomes of different modelling approaches, and identify in which models proxy treadmilling is expected to occur.

DORA: an interactive map for the visualization and analysis of ancient human DNA and associated data.

The ability to sequence ancient genomes has revolutionized the way we study evolutionary history by providing access to the most important aspect of evolution-time. Until recently, studying human demography, ecology, biology, and history using population genomic inference relied on contemporary genomic datasets. Over the past decade, the availability of human ancient DNA (aDNA) has increased rapidly, almost doubling every year, opening the way for spatiotemporal studies of ancient human populations. However, the multidimensionality of aDNA, with genotypes having temporal, spatial and genomic coordinates, and integrating multiple sources of data, poses a challenge for developing meta-analyses pipelines. To address this challenge, we developed a publicly-available interactive tool, DORA, which integrates multiple data types, genomic and non-genomic, in a unified interface. This web-based tool enables browsing sample metadata alongside additional layers of information, such as population structure, climatic data, and unpublished samples. Users can perform analyses on genotypes of these samples, or export sample subsets for external analyses. DORA integrates analyses and visualizations in a single intuitive interface, resolving the technical issues of combining datasets from different sources and formats, and allowing researchers to focus on the scientific questions that can be addressed through analysis of aDNA datasets.

How do implants overlying the spine influence "The Law of Diminishing Returns" in early-onset scoliosis patients?

PURPOSE: The "law of diminishing returns" (LODR) in early-onset scoliosis (EOS) is well-known. We hypothesized that previously observed variations between constructs may be related to the lateral distance that each construct lies from the spine. We therefore sought to determine whether the curve magnitude improvement and spinal length gains for distraction-based constructs in EOS are positively correlated with the collinearity of the spine and the convex-sided implant on posteroanterior radiographs. METHODS: A prospectively-collected, multicenter EOS registry was queried for all patients who underwent non-fusion, distraction-based instrumentation surgery. Post-index radiographs were graded from 1 to 5 based on amount of overlap between the convex-sided rod and the apical vertebra. Grade 1: convex rod is lateral to convex-sided pedicle; Grade 2: overlaps the convex-sided pedicle; Grade 3: lies between pedicles; Grade 4: overlaps concave-sided pedicle; Grade 5: medial to concave-sided pedicle. ANOVA assessed the correlations between post-index overlap grade and change in (a) curve magnitude and (b) T1-T12 height. Multivariable regression modeling further assessed these associations. RESULTS: 284 patients met all selection criteria and were included. On ANOVA, post-index grade was associated with curve magnitude (p <0.001) and T1-12 height (p = 0.028) change. Better curve correction and height change were associated with higher grade. On regression modeling, curve correction (R = 0.574) and T1-T12 height change (R = 0.339) remained significantly associated with grade when controlling for time, anchor locations, age, underlying diagnosis, and pre-index curve magnitude. CONCLUSION: More apical overlap by the convex rod was associated with better spinal deformity control and improved height gain. LEVEL OF EVIDENCE III: Therapeutic.