Does physical therapy impact clinical outcomes after lumbar decompression surgery?

Objectives: The objectives of our study were to (1) determine if physical therapy (PT) impacts patient-reported outcomes (PROMs) after lumbar decompression surgery and (2) determine if PT impacts postsurgical readmissions or reoperations after lumbar decompression surgery. Methods: Patients >18 years of age who underwent primary one- or two-level lumbar decompression at our institution were identified. Patient demographics, surgical characteristics, surgical outcomes (all-cause 90 days readmissions and 90 days surgical readmissions), and patient-reported outcomes (PROMs) were compared between the groups. Multivariate linear regression was utilized to determine the individual predictors of 90 days readmissions and PROMs at the 1-year postoperative point. Alpha was set at P < 0.05. Results: Of the 1003 patients included, 421 attended PT postoperatively. On univariate analysis, PT attendance did not significantly impact 90-day surgical reoperations (P = 0.225). Although bivariate analysis suggests that attendance of PT is associated with worse improvement in physical function (P = 0.041), increased preoperative Visual Analogue Scale leg pain (0 = 0.004), and disability (P = 0.006), as measured by the Oswestry Disability Index, our multivariate analysis, which accounts for confounding variables found there was no difference in PROM improvement and PT was not an independent predictor of 90-day all-cause readmissions (P = 0.06). Instead, Charlson Comorbidity Index (P = 0.025) and discharge to a skilled nursing facility (P = 0.013) independently predicted greater 90-day all-cause readmissions. Conclusions: Postoperative lumbar decompression PT attendance does not significantly affect clinical improvement, as measured by PROMs or surgical outcomes including all-cause 90 days readmissions and 90-day surgical readmissions.

Immune Cell Abundance and T-cell Receptor Landscapes Suggest New Patient Stratification Strategies in Head and Neck Squamous Cell Carcinoma.

Head and neck squamous cell carcinoma (HNSCC) is a molecularly and spatially heterogeneous disease frequently characterized by impairment of immunosurveillance mechanisms. Despite recent success with immunotherapy treatment, disease progression still occurs quickly after treatment in the majority of cases, suggesting the need to improve patient selection strategies. In the quest for biomarkers that may help inform response to checkpoint blockade, we characterized the tumor microenvironment (TME) of 162 HNSCC primary tumors of diverse etiologic and spatial origin, through gene expression and IHC profiling of relevant immune proteins, T-cell receptor (TCR) repertoire analysis, and whole-exome sequencing. We identified five HNSCC TME categories based on immune/stromal composition: (i) cytotoxic, (ii) plasma cell rich, (iii) dendritic cell rich, (iv) macrophage rich, and (v) immune-excluded. Remarkably, the cytotoxic and plasma cell rich subgroups exhibited a phenotype similar to tertiary lymphoid structures (TLS), which have been previously linked to immunotherapy response. We also found an increased richness of the TCR repertoire in these two subgroups and in never smokers. Mutational patterns evidencing APOBEC activity were enriched in the plasma cell high subgroup. Furthermore, specific signal propagation patterns within the Ras/ERK and PI3K/AKT pathways associated with distinct immune phenotypes. While traditionally CD8/CD3 T-cell infiltration and immune checkpoint expression (e.g., PD-L1) have been used in the patient selection process for checkpoint blockade treatment, we suggest that additional biomarkers, such as TCR productive clonality, smoking history, and TLS index, may have the ability to pull out potential responders to benefit from immunotherapeutic agents. SIGNIFICANCE: Here we present our findings on the genomic and immune landscape of primary disease in a cohort of 162 patients with HNSCC, benefitting from detailed molecular and clinical characterization. By employing whole-exome sequencing and gene expression analysis of relevant immune markers, TCR profiling, and staining of relevant proteins involved in immune response, we highlight how distinct etiologies, cell intrinsic, and environmental factors combine to shape the landscape of HNSCC primary disease.

Disentangling the Impact of Point Defect Density and Carrier Localization-Enhanced Auger Recombination on Efficiency Droop in (In,Ga)N/GaN Quantum Wells.

The internal quantum efficiency of (In,Ga)N/GaN quantum wells can surpass 90% for blue-emitting structures at moderate drive current densities but decreases significantly for longer emission wavelengths and at higher excitation rates. This latter effect is known as efficiency "droop" and limits the brightness of light-emitting diodes (LEDs) based on such quantum wells. Several mechanisms have been proposed to explain efficiency droop including Auger recombination, both intrinsic and defect-assisted, carrier escape, and the saturation of localized states. However, it remains unclear which of these mechanisms is most important because it has proven difficult to reconcile theoretical calculations of droop with measurements. Here, we first present experimental photoluminescence measurements extending over three orders of magnitude of excitation for three samples grown at different temperatures that indicate that droop behavior is not dependent on the point defect density in the quantum wells studied. Second, we use an atomistic tight-binding electronic structure model to calculate localization-enhanced radiative and Auger rates and show that both the corresponding carrier density-dependent internal quantum efficiency and the carrier density decay dynamics are in excellent agreement with our experimental measurements. Moreover, we show that point defect density, Auger recombination, and the effect of the polarization field on recombination rates only limit the peak internal quantum efficiency to about 70% in the resonantly excited green-emitting quantum wells studied. This suggests that factors external to the quantum wells, such as carrier injection efficiency and homogeneity, contribute appreciably to the significantly lower peak external quantum efficiency of green LEDs.

The Impact of Physical Therapy After Lumbar Fusion Surgery.

STUDY DESIGN: Retrospective Cohort. OBJECTIVE: To determine if outcomes varied between patients based on physical therapy (PT) attendance after lumbar fusion surgery. SUMMARY OF BACKGROUND DATA: The literature has been mixed regarding the efficacy of postoperative PT to improve disability and back pain, as measured by patient-reported outcome measures. Given the prevalence of PT referrals and lack of high-quality evidence, there is a need for additional studies investigating the efficacy of PT after lumbar fusion surgery to aid in developing robust clinical guidelines. METHODS: We retrospectively identified patients receiving lumbar fusion surgery by current procedural terminology codes and separated them into 2 groups based on whether PT was prescribed. Electronic medical records were reviewed for patient and surgical characteristics, PT utilization, and surgical outcomes. Patient-reported outcome measures (PROMs) were identified and compared preoperatively, at 90 days postoperatively and one year postoperatively. RESULTS: The two groups had similar patient characteristics and comorbidities and demonstrated no significant differences between readmission, complication, and revision rates after surgery. Patients that attended PT had significantly more fused levels (1.41 ± 0.64 vs. 1.32 ± 0.54, P =0.027), longer operative durations (234 ± 96.4 vs. 215 ± 86.1 min, P =0.012), and longer postoperative hospital stays (3.35 ± 1.68 vs. 3.00 ± 1.49 days, P =0.004). All groups improved similarly by Oswestry Disability Index, short form-12 physical and mental health subsets, and back and leg pain by Visual Analog Scale at 90-day and 1-year follow-up. CONCLUSION: Our data suggest that physical therapy does not significantly impact PROMs after lumbar fusion surgery. Given the lack of data suggesting clear benefit of PT after lumbar fusion, surgeons should consider more strict criteria when recommending physical therapy to their patients after lumbar fusion surgery. LEVEL OF EVIDENCE: Level-Ⅲ.

The community engagement course and action network: strengthening community and academic research partnerships to advance health equity.

Background: Historically Black Colleges and Universities and Minority Serving Institutions are uniquely positioned to implement community-campus research partnerships based on a history of service, the pursuit of community trustworthiness and student demographics often similar to surrounding marginalized communities. The Morehouse School of Medicine Prevention Research Center collaborates with members of Historically Black Colleges and Universities, Minority Serving Institutes, and community organizations on the Community Engaged Course and Action Network. This network is the first of its kind and aims to strengthen members' ability to implement Community-Based Participatory Research (CBPR) principles and partnerships. Projects address public health priorities including mental health among communities of color, zoonotic disease prevention, and urban food deserts. Materials and methods: To assess the effectiveness of the network, a Participatory Evaluation framework was implemented to conduct process evaluation which included review of partnership structures, operations, project implementation processes, and preliminary outcomes of the research collaborations. A focus group of Community Engagement Course and Action Network members (community and academic) was also conducted to identify benefits and challenges of the network with emphasis on key areas for improvement to further enhance the relationships between partners and to facilitate their subsequent community-campus research. Results: Network improvements were tied to themes strengthening community-academic partnerships including sharing and fellowship, coalition building and collaboration, and greater connections and awareness of community needs through their current community-academic partnerships. The need to conduct ongoing evaluation during and after implementation, for determining the early adoption of CBPR approaches was also identified. Conclusion: Evaluation of the network's processes, infrastructure, and operation provides early lessons learned to strengthen the network. Ongoing assessment is also essential for ensuring continuous quality improvement across partnerships such as determining CBPR fidelity, assessing partnership synergy, and dynamics, and for quality improvement of research protocol. The implications and potential for advancing implementation science through this and similar networks are great towards advancing leadership in modeling how foundations in community service can advance to CBPR partnership formation and ultimately, health equity approaches, that are local defined and assessed.

The expanded role of the transplant pharmacist: A 10-year follow-up.

The role of the transplant pharmacist is recognized by transplant programs, governmental groups, and professional organizations as an essential part of the transplant multidisciplinary team. This role has evolved drastically over the last decade with the advent of major advances in the science of transplantation and the growth of the field, which necessitate expanded pharmacy services to meet the needs of patients. Data now exist within all realms of the phases of care for a transplant recipient regarding the utility and benefit of a solid organ transplant (SOT) pharmacist. Furthermore, governing bodies now have the opportunity to use Board Certification in Solid Organ Transplant Pharmacotherapy as a mechanism to identify and recognize specialty knowledge and expertise within the field of SOT pharmacotherapy. The purpose of this paper is to provide an overarching review of the current and future state of SOT pharmacy while also identifying major changes to the profession, forthcoming challenges, and expected areas of growth.

The Hendra virus vaccine: perceptions regarding the role of antibody titre testing.

OBJECTIVES: To elucidate veterinarians' and horse owners' perceptions towards the use of Hendra virus (HeV) antibody titre testing and how it influences veterinary advice. METHODS: Six semi-structured phone interviews were conducted with veterinarians who have submitted samples for HeV antibody titre testing. Interviews were recorded, transcribed and thematically analysed to identify and report common themes within the data. RESULTS: Veterinarians are predominantly using the titre tests as an alternative to vaccination due to clients' fear of vaccine reactions. The high cost of titre testing, the difficulty interpreting titre results and a lack of titre test recognition by authorities were the major barriers reported to using this test. Some veterinarians detailed difficulties communicating titre test procedures and results to their clients. The majority of veterinarians accepted titres of 64 or greater as evidence of protective immunity and would rely on those results for 12 months. However, there was discrepancy of these values and the level of confidence veterinarians had in interpreting the results of HeV antibody titre tests varied. CONCLUSION: This study has provided an overview of the attitudes of horse owners and veterinarians towards HeV antibody titre testing. Although evidence for HeV vaccination titres as an indication of protective immunity is still inadequate, it will assist veterinarians in interpreting and communicating titre results.

Hemispheric asymmetry in ocean change and the productivity of ecosystem sentinels.

Climate change and other human activities are causing profound effects on marine ecosystem productivity. We show that the breeding success of seabirds is tracking hemispheric differences in ocean warming and human impacts, with the strongest effects on fish-eating, surface-foraging species in the north. Hemispheric asymmetry suggests the need for ocean management at hemispheric scales. For the north, tactical, climate-based recovery plans for forage fish resources are needed to recover seabird breeding productivity. In the south, lower-magnitude change in seabird productivity presents opportunities for strategic management approaches such as large marine protected areas to sustain food webs and maintain predator productivity. Global monitoring of seabird productivity enables the detection of ecosystem change in remote regions and contributes to our understanding of marine climate impacts on ecosystems.

Patient Outcomes Following Short-segment Lumbar Fusion Are Not Affected by PI-LL Mismatch.

STUDY DESIGN: This is a retrospective cohort study. OBJECTIVE: The objective of this study was to further elucidate the relationship between pelvic incidence-lumbar lordosis (PI-LL) mismatch and surgical outcomes in patients undergoing short segment lumbar fusions for degenerative lumbar disease. SUMMARY OF BACKGROUND DATA: There are few studies examining the relationship between spinopelvic parameters and patient reported outcome measurements (PROMs) in short segment lumbar degenerative disease. MATERIALS AND METHODS: A retrospective review was conducted at single academic institution. Patients undergoing 1- or 2-level lumbar fusion were retrospectively identified and separated into 2 groups based on postoperative PI-LL mismatch ≤10 degrees (NM) or PI-LL mismatch >10 degrees (M). Outcomes including the Physical Component Score (PCS)-12, Mental Component Score (MCS)-12, Oswestry Disability Index (ODI), Visual Analog Scale (VAS) back and leg scores were analyzed. Absolute PROM scores, the recovery ratio and the percentage of patients achieving minimum clinically important difference between groups were compared and a multiple linear regression analysis was performed. RESULTS: A total of 306 patients were included, with 59 patients in the NM group and 247 patients in the M group. Patients in the M group started with a higher degree of PI-LL mismatch compared with the NM group (22.2 vs. 7.6 degrees, P<0.001) and this difference increased postoperatively (24.7 vs. 2.5 degrees, P<0.001). There were no differences between the 2 groups in terms of baseline, postoperative, or Δ outcome scores (P>0.05). In addition, having a PI-LL mismatch was not found to be an independent predictor of any PROM on multivariate analysis (P>0.05). CONCLUSION: The findings in this study show that even though patients in the M group had a higher degree of mismatch preoperatively and postoperatively, there was no difference in PROMs. LEVEL OF EVIDENCE: Level III.

Discovery of Novel Gain-of-Function Mutations Guided by Structure-Based Deep Learning.

Despite the promise of deep learning accelerated protein engineering, examples of such improved proteins are scarce. Here we report that a 3D convolutional neural network trained to associate amino acids with neighboring chemical microenvironments can guide identification of novel gain-of-function mutations that are not predicted by energetics-based approaches. Amalgamation of these mutations improved protein function in vivo across three diverse proteins by at least 5-fold. Furthermore, this model provides a means to interrogate the chemical space within protein microenvironments and identify specific chemical interactions that contribute to the gain-of-function phenotypes resulting from individual mutations.

Machine learning methods to support personalized neuromusculoskeletal modelling.

Many biomedical, orthopaedic, and industrial applications are emerging that will benefit from personalized neuromusculoskeletal models. Applications include refined diagnostics, prediction of treatment trajectories for neuromusculoskeletal diseases, in silico design, development, and testing of medical implants, and human-machine interfaces to support assistive technologies. This review proposes how physics-based simulation, combined with machine learning approaches from big data, can be used to develop high-fidelity personalized representations of the human neuromusculoskeletal system. The core neuromusculoskeletal model features requiring personalization are identified, and big data/machine learning approaches for implementation are presented together with recommendations for further research.

Individuals with mild-to-moderate hip osteoarthritis walk with lower hip joint contact forces despite higher levels of muscle co-contraction compared to healthy individuals.

OBJECTIVE: To compare hip joint contact forces (HJCF), hip muscle forces, and hip muscle co-contraction levels between individuals with mild-to-moderate hip osteoarthritis (OA) and healthy controls during walking. DESIGN: Eighteen participants with mild-to-moderate hip OA and 23 healthy controls walked at a self-selected speed while motion capture and electromyographic data were synchronously collected. HJCF were computed using a calibrated electromyography-informed neuromusculoskeletal model. Hip joint contact forces, muscle forces, and co-contraction indices for flexor/extensor and adductor/abductor muscle groups were compared between groups using independent sample t-tests (P < 0.05). RESULTS: There was no between-group difference in self-selected walking speed. On average, participants with hip OA walked with 11% lower first peak (mean difference 235 [95% confidence interval (CI) 57-413] N) and 22% lower second peak (mean difference 574 [95%CI 304-844] N) HJCF compared to controls. Hip muscle forces were also significantly lower in the hip OA compared to control group at first (mean difference 224 [95%CI 66-382] N) and second (mean difference 782 [95%CI 399-1164] N) peak HJCF. Participants with hip OA exhibited higher levels of hip muscle co-contraction in both flexor/extensor and adductor/abductor muscle groups. Consistent with existing literature, hip joint angles (extension, adduction) and external moments (flexion, extension, adduction) were lower in hip OA compared to controls. CONCLUSION: Lower HJCF were detected in mild-to-moderate hip OA, primarily due to lower hip muscle force production, and despite higher levels of hip muscle co-contraction. Findings suggest that lower loading of the hip joint during walking is a feature of mild-to-moderate hip OA, which could have implications for the pathogenesis of hip OA and/or disease progression.

Author Correction: Nanofocusing of hard X-ray free electron laser pulses using diamond based Fresnel zone plates.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Single-Molecule Mechanistic Study of Enzyme Hysteresis.

Hysteresis is an important feature of enzyme-catalyzed reactions, as it reflects the influence of enzyme regulation in the presence of ligands such as substrates or allosteric molecules. In typical kinetic studies of enzyme activity, hysteretic behavior is observed as a "lag" or "burst" in the time course of the catalyzed reaction. These lags and bursts are due to the relatively slow transition from one state to another state of the enzyme molecule, with different states having different kinetic properties. However, it is difficult to understand the underlying mechanism of hysteresis by observing bulk reactions because the different enzyme molecules in the population behave stochastically. In this work, we studied the hysteretic behavior of mutant ß-glucuronidase (GUS) using a high-throughput single-molecule array platform and investigated the effect of thermal treatment on the hysteresis.

Employing 25-Residue Docking Motifs from Modular Polyketide Synthases as Orthogonal Protein Connectors.

The proteins of trans-acyltransferase modular polyketide synthases (PKSs) self-organize into assembly lines, enabling the multienzyme biosynthesis of complex organic molecules. Docking domains comprised of ∼25 residues at the C- and N-termini of these polypeptides (CDDs and NDDs) help drive this association through the formation of four-helix bundles. Molecular connectors like these are desired in synthetic contexts, such as artificial biocatalytic systems and biomaterials, to orthogonally join proteins. Here, the ability of six CDD/NDD pairs to link non-PKS proteins is examined using green fluorescent protein (GFP) variants. As observed through size-exclusion chromatography and Förster resonance energy transfer (FRET), matched but not mismatched pairs of Venus+CDD and NDD+mTurquoise2 fusion proteins associate with low micromolar affinities.

Fusion technique does not affect short-term patient-reported outcomes for lumbar degenerative disease.

BACKGROUND/CONTEXT: Degenerative lumbar disease can be addressed via an anterior or posterior approach, and with or without the use of an interbody cage. Although several studies have compared the type of approach and technique, there is a lack of literature assessing patient-reported outcome measures (PROMs) and radiographic parameters between different fusion techniques. PURPOSE: To determine whether the surgical approach and fusion technique for lumbar degenerative disease had an effect on short-term PROMs and radiographic parameters. STUDY DESIGN/SETTING: Retrospective Cohort Study. PATIENT SAMPLE: Three hundred and ninety-one patients who underwent a 1-3 level lumbar spine fusion procedure at a high-volume academic center were retrospectively identified. Patients were divided into three groups based on the type of fusion they underwent: posterolateral fusion (PLF), anterior lumbar interbody fusion (ALIF), or transforaminal lumbar interbody fusion (TLIF). OUTCOME MEASURES: PROMs: Short Form-12 (SF-12) Physical Component Score (PCS) and Mental Component Score (MCS), Oswestry Disability Index (ODI), Visual Analog Score (VAS) Back, VAS Leg. Spinopelvic measurements: Pelvic Tilt (PT), Sacral Slope (SS), Pelvic Incidence (PI), Lumbar Lordosis (LL), Segmental Lordosis (SL), PI-LL mismatch. METHODS: Patients with less than 1-year follow-up were excluded from the cohort. Pre- and postoperative spinopelvic measurements were obtained for all patients. Univariate analysis (Chi-squared/Fisher's exact test or ANOVA test with post-hoc Bonferroni test) was used to compare among the three groups in the PROMs and radiographic spinopelvic parameters. Multiple linear regression was used to determine if fusion technique was an independent predictor of change in each patient outcome. RESULTS: Two hundred and sixteen patients were included in the PLF group, 33 patients in the ALIF group, and 142 patients in the TLIF group. The PLF group was significantly older at baseline (p<.001) and had lower preoperative diagnosis rates of degenerative scoliosis and disc herniations (p<.001), whereas the ALIF group underwent a higher proportion of three-level fusions (p<.001). There was no significant difference in spinopelvic parameters preoperatively, however the ALIF group showed significantly more improvement in SL postoperatively (p=.004) than the PLF and TLIF groups. Within each group, SL improved for the PLF and ALIF groups (p=.002 for both), but not for the TLIF group (p=.238). Comparing patient outcomes, the ALIF group reported lower preoperative VAS Leg scores (p=.031), however, this difference resolved postoperatively. Stratifying for preoperative diagnosis, there were no significant differences in outcomes, except for a greater improvement in VAS Leg scores for degenerative scoliosis patients undergoing ALIF. Using multivariate analysis, fusion technique was not found to be a significant predictor of change in any patient outcome or in odds of revision. CONCLUSIONS: Lumbar degenerative disease can be treated with several different fusion techniques, however, the relationship between type of fusion and PROMs is not established. Based on the findings in this study, the ALIF group showed greater improvement in SL compared with the PLF and TLIF groups, however, there was no difference noted in overall LL, PI-LL mismatch or other spinopelvic parameters. Despite these radiographic findings, patient outcome measures remained similar between all three fusion types.

Stitching techniques for measuring X-ray synchrotron mirror topography.

Optical metrology and polishing techniques are continuously evolving to satisfy the increasingly stringent specifications required for X-ray optical components for synchrotron and free-electron laser light source beamlines. For both spherical and aspherical geometries, the most demanding applications may have target residual figure errors close to 1 nm. To achieve such specifications and maintain them in the optomechanical mount, it is critical to develop methods capable of measuring the topography of the optical surface over the clear aperture of the mirror. The European Synchrotron Radiation Facility optical metrology laboratory has developed a stitching tool initially aimed at measuring long flat mirrors up to 1 m long with a Fizeau interferometer. The system is routinely used providing 2D maps of the optical surface. The instrument capabilities have been extended to characterize moderately curved optics using a transmission flat element, and results obtained on a high quality spherical mirror with 120 m of radius of curvature are presented. As a novel approach of stitching application, the technique has been used to improve the measurement accuracy of the Fizeau interferometer when measuring short plane mirrors. Acquisition of 2D topographies on a short plane mirror by micro-stitching interferometry is also presented and discussed.

Supercharging enables organized assembly of synthetic biomolecules.

Symmetrical protein oligomers are ubiquitous in biological systems and perform key structural and regulatory functions. However, there are few methods for constructing such oligomers. Here we have engineered completely synthetic, symmetrical oligomers by combining pairs of oppositely supercharged variants of a normally monomeric model protein through a strategy we term 'supercharged protein assembly' (SuPrA). We show that supercharged variants of green fluorescent protein can assemble into a variety of architectures including a well-defined symmetrical 16-mer structure that we solved using cryo-electron microscopy at 3.47 Å resolution. The 16-mer is composed of two stacked rings of octamers, in which the octamers contain supercharged proteins of alternating charges, and interactions within and between the rings are mediated by a variety of specific electrostatic contacts. The ready assembly of this structure suggests that combining oppositely supercharged pairs of protein variants may provide broad opportunities for generating novel architectures via otherwise unprogrammed interactions.

Orthogonal Comparison of Four Plasma NGS Tests With Tumor Suggests Technical Factors are a Major Source of Assay Discordance.

PURPOSE: Discordance between plasma and tumor variant calling has been attributed primarily to tumor heterogeneity, whereas technical variables remain largely unexplored. MATERIALS AND METHODS: To measure these variables, we tested four next-generation sequencing (NGS) gene panel assays for mutations in circulating tumor DNA (ctDNA) using replicate sets of 24 plasma samples and compared the results with matched tumor-normal tissue pairs. RESULTS: Our orthogonal approach identified false-negative (FN) and false-positive (FP) variants with high confidence and revealed substantial variability among the ctDNA assays, with a range of sensitivity (38% to 89%) and positive predictive value (36% to 80%). Most discordance in our cross-vendor study was observed below 1% variant allele frequency. FP variants displayed mutational biases and tended to be novel variants not found in somatic databases. Of the 56 unique variants called by all four ctDNA assays, 41 (68%) resulted from technical discordance. CONCLUSION: These findings suggest that most NGS assay discordance is a result of technical variations and, to a lesser extent, biologic factors such as clonal hematopoiesis of indeterminate potential and tumor heterogeneity.