ISSLS PRIZE IN BIOENGINEERING SCIENCE 2019: biomechanical changes in dynamic sagittal balance and lower limb compensatory strategies following realignment surgery in adult spinal deformity patients.

Study designA longitudinal cohort study.ObjectiveTo define a set of objective biomechanical metrics that are representative of adult spinal deformity (ASD) post-surgical outcomes and that may forecast post-surgical mechanical complications. Current outcomes for ASD surgical planning and post-surgical assessment are limited to static radiographic alignment and patient-reported questionnaires. Little is known about the compensatory biomechanical strategies for stabilizing sagittal balance during functional movements in ASD patients.MethodsWe collected in-clinic motion data from 15 ASD patients and 10 controls during an unassisted sit-to-stand (STS) functional maneuver. Joint motions were measured using noninvasive 3D depth mapping sensor technology. Mathematical methods were used to attain high-fidelity joint-position tracking for biomechanical modeling. This approach provided reliable measurements for biomechanical behaviors at the spine, hip, and knee. These included peak sagittal vertical axis (SVA) over the course of the STS, as well as forces and muscular moments at various joints. We compared changes in dynamic sagittal balance (DSB) metrics between pre- and post-surgery and then separately compared pre- and post-surgical data to controls.ResultsStandard radiographic and patient-reported outcomes significantly improved following realignment surgery. From the DSB biomechanical metrics, peak SVA and biomechanical loads and muscular forces on the lower lumbar spine significantly reduced following surgery (- 19 to - 30%, all p < 0.05). In addition, as SVA improved, hip moments decreased (- 28 to - 65%, all p < 0.05) and knee moments increased (+ 7 to + 28%, p < 0.05), indicating changes in lower limb compensatory strategies. After surgery, DSB data approached values from the controls, with some post-surgical metrics becoming statistically equivalent to controls.ConclusionsLongitudinal changes in DSB following successful multi-level spinal realignment indicate reduced forces on the lower lumbar spine along with altered lower limb dynamics matching that of controls. Inadequate improvement in DSB may indicate increased risk of post-surgical mechanical failure. These slides can be retrieved under Electronic Supplementary Material

#OrthoTwitter: Relationship between author Twitter utilization and academic impact in orthopaedic surgery

Background #OrthoTwitter has evolved to disseminate findings and engage the public. However, the academic impact of Twitter utilization in orthopaedic surgery is unknown. Questions/purposes The purpose of the study was to evaluate relationships between the author and manuscript Twitter activity and citations. Methods Manuscripts in 17 orthopaedic journals from 2018 were identified. Citations, online mentions, impact factors, and subspecialties were obtained. H-index and Twitter account details for authors were obtained for a subset of manuscripts. Relationships between Twitter activity and citations were evaluated. Results 2,473/4,224 (58.5%) manuscripts were mentioned on Twitter (n=29,958 mentions), with Twitter manuscripts cited more frequently (median 10 vs. 7, p\u3c0.0001). Twitter mentions, impact factors, non-open-access status, and subspecialties were associated with citation counts. Articles mentioned in 10, 100, and 1,000 Tweets were observed to have a 1.1-fold, 1.7-fold, and 245-fold increase in citations. In author-level analyses, 156 (20.0%) first and 216 (27.7%) senior authors had Twitter accounts. Citation count was associated with increasing senior author H-index

The Chromosomal High-Affinity Binding Sites for the Drosophila Dosage Compensation Complex

Dosage compensation in male Drosophila relies on the X chromosome–specific recruitment of a chromatin-modifying machinery, the dosage compensation complex (DCC). The principles that assure selective targeting of the DCC are unknown. According to a prevalent model, X chromosome targeting is initiated by recruitment of the DCC core components, MSL1 and MSL2, to a limited number of so-called “high-affinity sites” (HAS). Only very few such sites are known at the DNA sequence level, which has precluded the definition of DCC targeting principles. Combining RNA interference against DCC subunits, limited crosslinking, and chromatin immunoprecipitation coupled to probing high-resolution DNA microarrays, we identified a set of 131 HAS for MSL1 and MSL2 and confirmed their properties by various means. The HAS sites are distributed all over the X chromosome and are functionally important, since the extent of dosage compensation of a given gene and its proximity to a HAS are positively correlated. The sites are mainly located on non-coding parts of genes and predominantly map to regions that are devoid of nucleosomes. In contrast, the bulk of DCC binding is in coding regions and is marked by histone H3K36 methylation. Within the HAS, repetitive DNA sequences mainly based on GA and CA dinucleotides are enriched. Interestingly, DCC subcomplexes bind a small number of autosomal locations with similar features

Chromosome-Biased Binding and Gene Regulation by the Caenorhabditis elegans DRM Complex

DRM is a conserved transcription factor complex that includes E2F/DP and pRB family proteins and plays important roles in development and cancer. Here we describe new aspects of DRM binding and function revealed through genome-wide analyses of the Caenorhabditis elegans DRM subunit LIN-54. We show that LIN-54 DNA-binding activity recruits DRM to promoters enriched for adjacent putative E2F/DP and LIN-54 binding sites, suggesting that these two DNA–binding moieties together direct DRM to its target genes. Chromatin immunoprecipitation and gene expression profiling reveals conserved roles for DRM in regulating genes involved in cell division, development, and reproduction. We find that LIN-54 promotes expression of reproduction genes in the germline, but prevents ectopic activation of germline-specific genes in embryonic soma. Strikingly, C. elegans DRM does not act uniformly throughout the genome: the DRM recruitment motif, DRM binding, and DRM-regulated embryonic genes are all under-represented on the X chromosome. However, germline genes down-regulated in lin-54 mutants are over-represented on the X chromosome. We discuss models for how loss of autosome-bound DRM may enhance germline X chromosome silencing. We propose that autosome-enriched binding of DRM arose in C. elegans as a consequence of germline X chromosome silencing and the evolutionary redistribution of germline-expressed and essential target genes to autosomes. Sex chromosome gene regulation may thus have profound evolutionary effects on genome organization and transcriptional regulatory networks.National Institutes of Health (U.S.) (grant GM24663)National Institutes of Health (U.S.) (grant DK068429)National Institutes of Health (U.S.) (grant GM082971)National Institutes of Health (U.S.) (grant GM076378

Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial

Background: Glucagon-like peptide 1 receptor agonists differ in chemical structure, duration of action, and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. We aimed to determine the safety and efficacy of albiglutide in preventing cardiovascular death, myocardial infarction, or stroke. Methods: We did a double-blind, randomised, placebo-controlled trial in 610 sites across 28 countries. We randomly assigned patients aged 40 years and older with type 2 diabetes and cardiovascular disease (at a 1:1 ratio) to groups that either received a subcutaneous injection of albiglutide (30–50 mg, based on glycaemic response and tolerability) or of a matched volume of placebo once a week, in addition to their standard care. Investigators used an interactive voice or web response system to obtain treatment assignment, and patients and all study investigators were masked to their treatment allocation. We hypothesised that albiglutide would be non-inferior to placebo for the primary outcome of the first occurrence of cardiovascular death, myocardial infarction, or stroke, which was assessed in the intention-to-treat population. If non-inferiority was confirmed by an upper limit of the 95% CI for a hazard ratio of less than 1·30, closed testing for superiority was prespecified. This study is registered with ClinicalTrials.gov, number NCT02465515. Findings: Patients were screened between July 1, 2015, and Nov 24, 2016. 10 793 patients were screened and 9463 participants were enrolled and randomly assigned to groups: 4731 patients were assigned to receive albiglutide and 4732 patients to receive placebo. On Nov 8, 2017, it was determined that 611 primary endpoints and a median follow-up of at least 1·5 years had accrued, and participants returned for a final visit and discontinuation from study treatment; the last patient visit was on March 12, 2018. These 9463 patients, the intention-to-treat population, were evaluated for a median duration of 1·6 years and were assessed for the primary outcome. The primary composite outcome occurred in 338 (7%) of 4731 patients at an incidence rate of 4·6 events per 100 person-years in the albiglutide group and in 428 (9%) of 4732 patients at an incidence rate of 5·9 events per 100 person-years in the placebo group (hazard ratio 0·78, 95% CI 0·68–0·90), which indicated that albiglutide was superior to placebo (p<0·0001 for non-inferiority; p=0·0006 for superiority). The incidence of acute pancreatitis (ten patients in the albiglutide group and seven patients in the placebo group), pancreatic cancer (six patients in the albiglutide group and five patients in the placebo group), medullary thyroid carcinoma (zero patients in both groups), and other serious adverse events did not differ between the two groups. There were three (<1%) deaths in the placebo group that were assessed by investigators, who were masked to study drug assignment, to be treatment-related and two (<1%) deaths in the albiglutide group. Interpretation: In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. Evidence-based glucagon-like peptide 1 receptor agonists should therefore be considered as part of a comprehensive strategy to reduce the risk of cardiovascular events in patients with type 2 diabetes. Funding: GlaxoSmithKline

Time to Switch to Second-line Antiretroviral Therapy in Children With Human Immunodeficiency Virus in Europe and Thailand.

Background: Data on durability of first-line antiretroviral therapy (ART) in children with human immunodeficiency virus (HIV) are limited. We assessed time to switch to second-line therapy in 16 European countries and Thailand. Methods: Children aged <18 years initiating combination ART (≥2 nucleoside reverse transcriptase inhibitors [NRTIs] plus nonnucleoside reverse transcriptase inhibitor [NNRTI] or boosted protease inhibitor [PI]) were included. Switch to second-line was defined as (i) change across drug class (PI to NNRTI or vice versa) or within PI class plus change of ≥1 NRTI; (ii) change from single to dual PI; or (iii) addition of a new drug class. Cumulative incidence of switch was calculated with death and loss to follow-up as competing risks. Results: Of 3668 children included, median age at ART initiation was 6.1 (interquartile range (IQR), 1.7-10.5) years. Initial regimens were 32% PI based, 34% nevirapine (NVP) based, and 33% efavirenz based. Median duration of follow-up was 5.4 (IQR, 2.9-8.3) years. Cumulative incidence of switch at 5 years was 21% (95% confidence interval, 20%-23%), with significant regional variations. Median time to switch was 30 (IQR, 16-58) months; two-thirds of switches were related to treatment failure. In multivariable analysis, older age, severe immunosuppression and higher viral load (VL) at ART start, and NVP-based initial regimens were associated with increased risk of switch. Conclusions: One in 5 children switched to a second-line regimen by 5 years of ART, with two-thirds failure related. Advanced HIV, older age, and NVP-based regimens were associated with increased risk of switch

Postoperative Outcomes of a Digital Rehabilitation Program After Total Knee Arthroplasty: Retrospective, Observational Feasibility Study.

BackgroundSurgery can sometimes be the best solution for chronic musculoskeletal pain, but presurgical preparation and postsurgical rehabilitation are often required to achieve the maximum benefits. A digital musculoskeletal surgical care program was developed to support the population of patients undergoing total knee arthroplasty.ObjectiveWe aimed to demonstrate safety, engagement, and acceptability and explore clinical outcomes, health care use, and satisfaction among participants of a digital musculoskeletal surgical care program who were undergoing total knee arthroplasty.MethodsA retrospective, observational feasibility study comparing digital musculoskeletal surgical care program participants to a comparison group was conducted. The intervention group registered for a digital musculoskeletal surgical care program, which included health coaches, physical therapists, and tailored exercises and&nbsp;educational articles to provide preoperative and postoperative support to patients who had recently undergone total knee arthroplasty. Comparison group members received standard-of-care treatment. Engagement (number of exercise therapy sessions and educational articles accessed per week) and acceptability (Net Promoter Score) were examined among intervention group participants. Descriptive statistics for postoperative outcomes, including safety (postoperative complications), clinical improvement&nbsp;(pain, function, anxiety, and depression), and health care use and experiences (length of hospital stay, surgery satisfaction, and physical therapy adherence), were reported for both groups. Differences among postoperative results were compared by using the independent samples 2-tailed t test or Mann-Whitney test for continuous outcomes and the Fisher exact test or chi-square test for categorical outcomes.ResultsOf the 53 participants (intervention group: n=22; comparison group: n=31) who were included in this study, 35 (66%) were female and 25 (47%) were aged from 45 to 60 years. On average, the intervention group completed 23 exercise sessions, read 2.7 educational articles, sent 45.5 texts to their health coaches, and were actively engaged for 6 weeks after their operation. Among 21 participants, 14 (67%) self-reported as promoters on the Net Promoter Score scale. Intervention group members reported fewer postoperative complications (6/22, 27%) than the comparison group (15/31, 48%), and they experienced better outcomes with regard to function (Knee Injury and Osteoarthritis Outcome Score-Physical Function Short Form-intervention group: mean 23.0; comparison group: mean 32.5), depression (Patient Health Questionnaire 2-Item-intervention group: mean 0.4; comparison group: mean 1.6), anxiety (General Anxiety Disorder 2-Item-intervention group: mean 0.6; comparison group: mean 1.5), and impressions of change (Patient Global Impression of Change-intervention group: median 7.0; comparison group: median 6.0). Intervention group participants&nbsp;also reported less health care use, better adherence to their physical therapy exercises, and higher surgery satisfaction.ConclusionsOur digital musculoskeletal surgical care program shows promising levels of engagement and acceptability among those who recently underwent total knee arthroplasty. The surgical care program may also help with improving postsurgical complications and clinical outcomes and lowering health care use

Effects of a Digital Musculoskeletal Acute Care Program on Chronic Pain Prevention: An Observational Study with Nonparticipant Comparison Group

BackgroundThere is limited research on whether digital interventions can prevent acute or subacute pain from developing into chronic pain. This observational study's primary objective examined whether chronic pain was more likely to be prevented in digital acute MSK program participants than nonparticipants. An exploratory objective was time to pain relief for program participants versus nonparticipants.Patients and methodsThe intervention group participants conducted video visits with physical therapists and were recommended exercise therapies and educational articles delivered through an app dedicated to addressing musculoskeletal (MSK) needs. This study used a multidimensional approach incorporating pain, function, depression, and anxiety scores to determine whether chronic pain prevention was achieved at 12 weeks. Descriptive analyses, unadjusted, and adjusted logistic regression were conducted. Time-to-event analysis was performed to compare the time to pain relief between groups.ResultsA total of 171 participants (intervention: 75, nonparticipants: 96) with baseline and 3, 6, and 12 week follow-up data were included in the sample. Baseline mean (SD) age was 44.2 (11.8) years and mean VAS pain was 43.3 (22.9), out of 100. Results showed significantly higher odds of achieving chronic pain prevention at 12 weeks in the intervention participants versus nonparticipants. After adjusting for age, pain region, registration month, number of weeks of pain experienced, and healthcare service use at 12 weeks, 20.5% of the intervention group and 5.5% of the nonparticipant group achieved chronic pain prevention. At 91 days, the probability of developing chronic pain was 77.7% for nonparticipants and 46.5% for intervention participants (p&lt;0.001; Log rank test).ConclusionA digital acute MSK program may help to prevent chronic pain from developing among those with acute and subacute MSK needs. Study results also suggest that program participants achieve chronic pain relief sooner compared to nonparticipants

Clinical outcomes one year after a digital musculoskeletal (MSK) program: an observational, longitudinal study with nonparticipant comparison group.

BackgroundThe evidence base for the impact of digital health on musculoskeletal (MSK) outcomes is growing, but it is unclear how much digital MSK programs address pain and function in the intermediate and long term.MethodsThis observational study of digital MSK program participants versus nonparticipants (n = 2570) examined pain, function, depression, and anxiety at 3, 6, and 12 months, and health care use at 12 months. The intervention group engaged in a digital MSK program that included exercise, education, and coaching for at least 3 months. The nonparticipant group registered, but never started the program. We collected data in app or by emailed survey at 3, 6, and 12 months after registering for the program. We conducted descriptive analyses and unadjusted and adjusted regression modeling.ResultsThe odds ratio of achieving a minimally clinically important difference (MCID) in pain improvement for the intervention versus the nonparticipant group was 1.97 (95% CI: 1.28, 3.02; p = .002) at 3 months, 1.44 (95% CI: 0.91, 2.25; p = .11) at 6 months, and 2.06 (95% CI: 1.38, 3.08; p = .004) at 12 months in adjusted models. The odds ratio of achieving a MCID in functional improvement for the intervention versus the nonparticipant group was 1.56 (95% CI: 1.03, 2.38; p = .01) at 3 months, 1.55 (95% CI: 1.02, 2.37; p = .04) at 6 months, and 1.35 (95% CI: 0.89, 2.06, p = 0.16) at 12 months in adjusted models. For those with moderate to severe depression or anxiety at baseline, we observed statistically significant lower odds of moderate to severe depression or anxiety at 3 months, 6 months, and 12 months for the intervention versus the nonparticipant group in adjusted models (p &lt; .05). At 12 months, the percentage with invasive, imaging, and conservative services was higher for the nonparticipant versus intervention group by 5.7, 8.1, and 16.7 percentage points, respectively (p &lt; 0.05).ConclusionsA digital MSK program may offer participants sustained improvement in pain, depression, and anxiety with concomitant decreases in health care use

Clinical Outcomes After a Digital Musculoskeletal Program for Acute and Subacute Pain: Observational, Longitudinal Study With Comparison Group.

BackgroundTelerehabilitation for musculoskeletal (MSK) conditions may produce similar or better outcomes than usual care, but most telerehabilitation studies address only chronic or postsurgical pain.ObjectiveWe aimed to examine pain and function at 3, 6, and 12 weeks for individuals with acute and subacute MSK pain who took part in a digital MSK program versus a nonparticipant comparison group.MethodsWe conducted an observational, longitudinal study with a nonparticipant comparison group. The intervention group had video visits with physical therapists who recommended exercise therapies and educational articles delivered via an app. Nonparticipants were those who were registered but unable to participate because their benefit coverage had not yet begun. We collected pain and function outcomes through surveys delivered at 3-, 6-, and 12-week follow-ups. We conducted descriptive analyses, unadjusted regression, and mixed effects regression adjusting for baseline characteristics, time as fixed effects, and a time*group interaction term.ResultsThe analysis included data from 675 nonparticipants and 262 intervention group participants. Compared to baseline, the intervention group showed significantly more pain improvement at 3, 6, and 12 weeks versus nonparticipants after adjusting for baseline factors. Specifically, the intervention group's pain scores decreased by 55.8% at 3 weeks versus baseline, 69.1% at 6 weeks, and 73% at 12 weeks. The intervention group's adjusted pain scores decreased from 43.7 (95% CI 41.1-46.2) at baseline to 19.3 (95% CI 16.8-21.8) at 3 weeks to 13.5 (95% CI 10.8-16.2) at 6 weeks to 11.8 (95% CI 9-14.6) at 12 weeks. In contrast, nonparticipants' pain scores decreased by 30.8% at 3 weeks versus baseline, 45.8% at 6 weeks, and 46.7% at 12 weeks. Nonparticipants' adjusted pain scores decreased from 43.8 (95% CI 42-45.5) at baseline to 30.3 (95% CI 27.1-33.5) at 3 weeks to 23.7 (95% CI 20-27.5) at 6 weeks to 23.3 (95% CI 19.6-27) at 12 weeks. After adjustments, the percentage of participants reporting that pain was better or much better at follow-up was significantly higher by 40.6% at 3 weeks, 31.4% at 6 weeks, and 31.2% at 12 weeks for intervention group participants versus nonparticipants. After adjustments, the percentage of participants with meaningful functional improvement at follow-up was significantly higher by 15.2% at 3 weeks and 24.6% at 12 weeks for intervention group participants versus nonparticipants.ConclusionsA digital MSK program may help to improve pain and function in the short term among those with acute and subacute MSK pain