A survey of chromosomal instability measures across mechanistic models.

Chromosomal instability (CIN) is the persistent reshuffling of cancer karyotypes via chromosome mis-segregation during cell division. In cancer, CIN exists at varying levels that have differential effects on tumor progression. However, mis-segregation rates remain challenging to assess in human cancer despite an array of available measures. We evaluated measures of CIN by comparing quantitative methods using specific, inducible phenotypic CIN models of chromosome bridges, pseudobipolar spindles, multipolar spindles, and polar chromosomes. For each, we measured CIN fixed and timelapse fluorescence microscopy, chromosome spreads, six-centromere FISH, bulk transcriptomics, and single-cell DNA sequencing (scDNAseq). As expected, microscopy of tumor cells in live and fixed samples significantly correlated (R = 0.72; P < 0.001) and sensitively detect CIN. Cytogenetics approaches include chromosome spreads and 6-centromere FISH, which also significantly correlate (R = 0.76; P < 0.001) but had limited sensitivity for lower rates of CIN. Bulk genomic DNA signatures and bulk transcriptomic scores, CIN70 and HET70, did not detect CIN. By contrast, scDNAseq detects CIN with high sensitivity, and significantly correlates with imaging methods (R = 0.82; P < 0.001). In summary, single-cell methods such as imaging, cytogenetics, and scDNAseq can measure CIN, with the latter being the most comprehensive method accessible to clinical samples. To facilitate the comparison of CIN rates between phenotypes and methods, we propose a standardized unit of CIN: Mis-segregations per Diploid Division. This systematic analysis of common CIN measures highlights the superiority of single-cell methods and provides guidance for measuring CIN in the clinical setting.

Diverse microtubule-targeted anticancer agents kill cells by inducing chromosome missegregation on multipolar spindles.

Microtubule-targeted agents are commonly used for cancer treatment, though many patients do not benefit. Microtubule-targeted drugs were assumed to elicit anticancer activity via mitotic arrest because they cause cell death following mitotic arrest in cell culture. However, we recently demonstrated that intratumoral paclitaxel concentrations are insufficient to induce mitotic arrest and rather induce chromosomal instability (CIN) via multipolar mitotic spindles. Here, we show in metastatic breast cancer and relevant human cellular models that this mechanism is conserved among clinically useful microtubule poisons. While multipolar divisions typically produce inviable progeny, multipolar spindles can be focused into near-normal bipolar spindles at any stage of mitosis. Using a novel method to quantify the rate of CIN, we demonstrate that cell death positively correlates with net loss of DNA. Spindle focusing decreases CIN and causes resistance to diverse microtubule poisons, which can be counteracted by addition of a drug that increases CIN without affecting spindle polarity. These results demonstrate conserved mechanisms of action and resistance for diverse microtubule-targeted agents. Trial registration: clinicaltrials.gov, NCT03393741.

The reckoning of chromosomal instability: past, present, future.

Quantitative measures of CIN are crucial to our understanding of its role in cancer. Technological advances have changed the way CIN is quantified, offering increased accuracy and insight. Here, we review measures of CIN through its rise as a field, discuss considerations for its measurement, and look forward to future quantification of CIN.

Epidemiology of Homebound Population Among Beneficiaries of a Large National Medicare Advantage Plan.

BACKGROUND: Interest in home-based care is increasing among Medicare Advantage (MA) plans. The epidemiology of homebound MA beneficiaries is unknown. OBJECTIVE: To determine the prevalence, characteristics, predictors, health service use, and mortality outcomes of homebound beneficiaries of a large national MA plan. DESIGN: Cross-sectional. SETTING: National MA plan. PARTICIPANTS: Humana MA beneficiaries in 2022 (n = 2 435 519). MEASUREMENTS: Homebound status was assessed via in-home assessment using previously defined categories: homebound (never or rarely left home in the past month), semihomebound (left home with assistance, had difficulty, or needed help leaving home), and not homebound. Demographic, clinical, health service use, and mortality outcomes were compared by homebound status. RESULTS: In 2022, the overall prevalence of homebound beneficiaries was 22.0% (8.4% of beneficiaries were homebound, and 13.6% were semihomebound). In adjusted models, female sex (odds ratio [OR], 1.36 [95% CI, 1.35 to 1.37), low-income status or dual eligibility for Medicare and Medicaid (OR, 1.56 [CI, 1.55 to 1.57]), dementia (OR, 2.36 [CI, 2.33 to 2.39]), and moderate to severe frailty (OR, 4.32 [CI, 4.19 to 4.45]) were predictive of homebound status. In multivariable logistic regression, homebound status was associated with increased odds of any emergency department visit (OR, 1.14 [ CI, 1.14 to 1.15]), any inpatient hospital admission (OR, 1.44 [CI, 1.42 to 1.46]), any skilled-nursing facility admission (OR, 2.18 [CI, 2.13 to 2.23]), and death (OR, 2.55 [CI, 2.52 to 2.58]). LIMITATION: The study period overlapped the tail end of the COVID-19 pandemic, and data were derived from a single national MA plan, which limits generalizability. CONCLUSION: Overall homebound prevalence in a national MA plan was 22.0% and was independently associated with increased health service use and mortality. Study findings can inform strategic initiatives to identify and manage care for homebound beneficiaries. PRIMARY FUNDING SOURCE: Humana, under a collaborative research agreement with Johns Hopkins University.

Impact of neoadjuvant chemotherapy for locally advanced colon cancer on postoperative complications.

PURPOSE: Although not considered standard therapy, neoadjuvant chemotherapy (NAC) is an encouraging alternative for selected patients with locally advanced colon cancer (LAC). The aim of this study was to compare 30-day postoperative outcomes between patients undergoing upfront surgery and those undergoing NAC for LAC. METHODS: Using the ACS-NSQIP data from 2016 to 2020, 11,498 patients with LAC were divided into those who underwent upfront colectomy (96.2%) and those who received NAC (3.8%). The primary outcome was a composite outcome encompassing 30-day major postoperative complications. Propensity score matched (PSM) analysis and multivariable logistic regression were performed. RESULTS: After PSM analysis, there was no statistically significant difference in the development of a major complication. NAC was not significantly associated with the primary outcome. Risk factors for postoperative complications were T4 stage, older age, male sex, black race, smoking, dependent status, severe COPD, hypoalbuminemia, and preoperative transfusion. Laparoscopic and robotic surgery was protective. CONCLUSION: NAC did not increase the odds of developing a major complication.

Effect of Surgical Humidification on Inflammation and Peritoneal Trauma in Colorectal Cancer Surgery: A Randomized Controlled Trial.

BACKGROUND: Pre-clinical studies indicate that dry-cold-carbon-dioxide (DC-CO2) insufflation leads to more peritoneal damage, inflammation and hypothermia compared with humidified-warm-CO2 (HW-CO2). Peritoneum and core temperature in patients undergoing colorectal cancer (CRC) surgery were compared. METHODS: Sixty-six patients were randomized into laparoscopic groups; those insufflated with DC-CO2 or HW-CO2. A separate group of nineteen patients undergoing laparotomy were randomised to conventional surgery or with the insertion of a device delivering HW-CO2. Temperatures were monitored and peritoneal biopsies and bloods were taken at the start of surgery, at 1 and 3 h. Further bloods were taken depending upon hospital length-of-stay (LOS). Peritoneal samples were subjected to scanning electron microscopy to evaluate mesothelial damage. RESULTS: Laparoscopic cases experienced a temperature drop despite Bair-HuggerTM use. HW-CO2 restored normothermia (≥ 36.5 °C) by 3 h, DC-CO2 did not. LOS was shorter for colon compared with rectal cancer cases and if insufflated with HW-CO2 compared with DC-CO2; 5.0 vs 7.2 days, colon and 11.6 vs 15.4 days rectum, respectively. Unexpectedly, one third of patients had pre-existing damage. Damage increased at 1 and 3 h to a greater extent in the DC-CO2 compared with the HW-CO2 laparoscopic cohort. C-reactive protein levels were higher in open than laparoscopic cases and lower in both matched HW-CO2 groups. CONCLUSIONS: This prospective RCT is in accord with animal studies while highlighting pre-existing damage in some patients. Peritoneal mesothelium protection, reduced inflammation and restoration of core-body temperature data suggest benefit with the use of HW-CO2 in patients undergoing CRC surgery.

External fixation increases complications following surgical treatment of multiple ligament knee injuries.

PURPOSE: The purpose of this study was to review post-operative complications after surgical intervention of MLKIs within the first 6 months to be better able to counsel patients before surgical intervention. METHODS: All patients who underwent surgical reconstruction for a MLKI at one institution from 2009 to 2018 were included in this study. A retrospective review was performed of all patients and post-operative complications were recorded, including motion loss (which included > 10 degree flexion loss or > 3 degree extension loss), hematoma formation, infection, iatrogenic vascular or nerve injury, deep vein thrombosis (DVT), pulmonary embolism (PE), skin lesions, symptomatic hardware, recurrent ligamentous laxity, and need for additional surgery. Knee ligament injuries were classified based on the Schenck Knee Dislocation (KD) Classification. RESULTS: A total of 136 patients were included in this study, 83 with KD I injuries, 40 with KD III injuries, 9 with KD IV injuries, and 4 with KD V injuries. Of these total patients, 48 (35.5%) sustained a post-operative complication: 11 out of 133 (8.3%) from 0 to 1 week, 46 out of 132 (34.8%) from 1 week to 1 month, 28 out of 124 (22.6%) from 1 to 3 months, and 26 out of 121 (21.5%) from 3 to 6 months. Out of the total complications, 99 (78.5%) occurred at 1 week-3 months post-operation. Patients who had an external fixator placed at initial injury were more likely to sustain a post-operative complication. The most common complication was motion loss in 39 (28.6%) patients. There was a significant difference in mean number of complications between the KD I and KD III groups, as well as the KD III and KD IV-V groups. There was no significant difference in the overall prevalence of post-operative complications or occurrence of motion loss with KD grade. CONCLUSION: The main finding of this study was 48 (35.5%) patients sustained a complication after surgical treatment of MLKIs, with 99 (78.5% of all complications) complications occurring at 1 week-3 months post-operation. Patients who had an external fixator placed at initial injury were more likely to sustain a post-operative complication. The most common post-operative complication was motion loss in 39 (28.6%) patients. The KD grade was not associated with post-operative development of motion loss, but KD III had a significantly greater mean number of complications than KD I or KD IV-V grades. LEVEL OF EVIDENCE: IV.

Return to preinjury sports after anterior cruciate ligament reconstruction is predicted by five independent factors.

PURPOSE: To determine factors that predict return to the same frequency and type of sports participation with similar activity demands as before injury. METHODS: Individuals 1 to 5 years after primary ACL reconstruction completed a comprehensive survey related to sports participation and activity before injury and after surgery. Patient characteristics, injury variables, and surgical variables were extracted from the medical record. Return to preinjury sports (RTPS) was defined as: "Returning to the same or more demanding type of sports participation, at the same or greater frequency with the same or better Marx Activity Score as before injury." Variables were compared between individuals that achieved comprehensive RTPS and those that did not with univariate and multivariate logistic regression models. RESULTS: Two-hundred and fifty-one patients (mean age 26.1 years, SD 9.9) completed the survey at an average of 3.4 years (SD 1.3) after ACL reconstruction. The overall rate of RTPS was 48.6%. Patients were more likely to RTPS if they were younger than 19 years old (OR = 4.07; 95%CI 2.21-7.50; p < 0.01) or if they were competitive athletes (OR = 2.07; 95%CI 1.24-3.46; p = 0.01). Patients were less likely to RTPS if surgery occurred more than 3 months after injury (OR = 0.31, 95%CI 0.17-0.58; p < 0.01), if there was a concomitant cartilage lesion (OR = 0.38; 95%CI 0.21-0.70; p < 0.01), and if cartilage surgery was performed (OR = 0.17; 95%CI 0.04-0.80; p = 0.02). CONCLUSION: Five variables best predicted RTPS including age at time of surgery. Only time from injury to surgery is a potentially modifiable factor to improve RTPS; however, the reasons for which patients delayed surgery may also contribute to them not returning to sports. Regardless, younger patients, those that partake in sports on a competitive level, those that undergo surgery sooner, or do not have a cartilage injury or require cartilage surgery are more likely to return to pre-injury sports participation. LEVEL OF EVIDENCE: III.

Treatment after ACL injury: Panther Symposium ACL Treatment Consensus Group.

Treatment strategies for ACL injuries continue to evolve. Evidence supporting best practice guidelines to manage ACL injury is largely based on studies with low-level evidence. An international consensus group of experts was convened determine consensus regarding best available evidence on operative versus non-operative treatment for ACL injury. The purpose of this study is to report the consensus statements on operative versus non-operative treatment of ACL injuries developed at the ACL Consensus Meeting Panther Symposium 2019. Sixty-six international experts on the management of ACL injuries, representing 18 countries, convened and participated in a process based on the Delphi method of achieving consensus. Proposed consensus statements were drafted by the Scientific Organising Committee and Session Chairs. Panel participants reviewed preliminary statements prior to the meeting and provided initial agreement and comments on the statement via online survey. During the meeting, discussion and debate occurred for each statement, after which a final vote was then held. Eighty per cent agreement was defined a priori as consensus. A total of 11 of 13 statements on operative versus non-operative treatment of ACL injury reached consensus during the Symposium. Nine statements achieved unanimous support, two reached strong consensus, one did not achieve consensus, and one was removed due to redundancy in the information provided. In highly active patients engaged in jumping, cutting and pivoting sports, early anatomical ACL reconstruction is recommended due to the high risk of secondary meniscus and cartilage injuries with delayed surgery, although a period of progressive rehabilitation to resolve impairments and improve neuromuscular function is recommended. For patients who seek to return to straight plane activities, non-operative treatment with structured, progressive rehabilitation is an acceptable treatment option. However, with persistent functional instability, or when episodes of giving way occur, anatomical ACL reconstruction is indicated. The consensus statements derived from international leaders in the field may assist clinicians in deciding between operative and non-operative treatment with patients after an ACL injury Level of evidence: Level V.

Interaction Energetics and Druggability of the Protein-Protein Interaction between Kelch-like ECH-Associated Protein 1 (KEAP1) and Nuclear Factor Erythroid 2 Like 2 (Nrf2).

Development of small molecule inhibitors of protein-protein interactions (PPIs) is hampered by our poor understanding of the druggability of PPI target sites. Here, we describe the combined application of alanine-scanning mutagenesis, fragment screening, and FTMap computational hot spot mapping to evaluate the energetics and druggability of the highly charged PPI interface between Kelch-like ECH-associated protein 1 (KEAP1) and nuclear factor erythroid 2 like 2 (Nrf2), an important drug target. FTMap identifies four binding energy hot spots at the active site. Only two of these are exploited by Nrf2, which alanine scanning of both proteins shows to bind primarily through E79 and E82 interacting with KEAP1 residues S363, R380, R415, R483, and S508. We identify fragment hits and obtain X-ray complex structures for three fragments via crystal soaking using a new crystal form of KEAP1. Combining these results provides a comprehensive and quantitative picture of the origins of binding energy at the interface. Our findings additionally reveal non-native interactions that might be exploited in the design of uncharged synthetic ligands to occupy the same site on KEAP1 that has evolved to bind the highly charged DEETGE binding loop of Nrf2. These include π-stacking with KEAP1 Y525 and interactions at an FTMap-identified hot spot deep in the binding site. Finally, we discuss how the complementary information provided by alanine-scanning mutagenesis, fragment screening, and computational hot spot mapping can be integrated to more comprehensively evaluate PPI druggability.

Pelvic Exenteration for Anal and Urogenital Squamous Cell Carcinoma: Experience and Outcomes from an Exenteration Unit Over 12 Years.

BACKGROUND: Pelvic exenteration has increasingly been shown to improve disease-free and overall survival for patients with locally advanced pelvic malignancies. Squamous cell carcinoma (SCC) is the second most common pelvic malignancy requiring exenteration. OBJECTIVE: The aim of this study was to report the clinical and oncological outcomes from patients treated with pelvic exenteration for anal and urogenital SCC from a single, high-volume unit. METHODS: A review of a prospectively maintained database from 1991 to 2018 at a high-volume specialised institution was performed. Primary endpoints included R0 resection rates, local recurrence and overall survival (OS) rates. RESULTS: From January 1999 to July 2018, 361 patients underwent pelvic exenteration of which 31 patients were identified with SCC (15 anal SCC, 16 urogenital SCC). The majority of patients were females (n = 24, 77.4%). Median age was 59 (range 35-81). Twenty-seven patients underwent resection with curative intent with an R0 resection rate of 81.5%. Four patients underwent a palliative procedure [R1 = 3 (8%), R2 = 1 (3.3%)]. Mean hospital length of stay was 32 days (range 8-122 days). Disease-free survival was significantly increased in anal SCC with no significant difference in OS compared to urogenital SCC (p = 0.03, p = 0.447 respectively). Advanced pathological T stage was associated with decreased OS (p = 0.023). In the curative intent group the disease-free survival and OS rate was 59.3% and 70% at 24 months, respectively. CONCLUSION: Complete R0 resection is achievable in a high proportion of patients. Urogenital SCC is associated with significantly worse disease-free survival, and advanced T-stage was a significant prognostic factor for OS.

Germline whole exome sequencing of a family with appendiceal mucinous tumours presenting with pseudomyxoma peritonei.

BACKGROUND: Familial cases of appendiceal mucinous tumours (AMTs) are extremely rare and the underlying genetic aetiology uncertain. We identified potential predisposing germline genetic variants in a father and daughter with AMTs presenting with pseudomyxoma peritonei (PMP) and correlated these with regions of loss of heterozygosity (LOH) in the tumours. METHODS: Through germline whole exome sequencing, we identified novel heterozygous loss-of-function (LoF) (i.e. nonsense, frameshift and essential splice site mutations) and missense variants shared between father and daughter, and validated all LoF variants, and missense variants with a Combined Annotation Dependent Depletion (CADD) scaled score of ≥10. Genome-wide copy number analysis was performed on tumour tissue from both individuals to identify regions of LOH. RESULTS: Fifteen novel variants in 15 genes were shared by the father and daughter, including a nonsense mutation in REEP5. None of these germline variants were located in tumour regions of LOH shared by the father and daughter. Four genes (EXOG, RANBP2, RANBP6 and TNFRSF1B) harboured missense variants that fell in a region of LOH in the tumour from the father only, but none showed somatic loss of the wild type allele in the tumour. The REEP5 gene was sequenced in 23 individuals with presumed sporadic AMTs or PMP; no LoF or rare missense germline variants were identified. CONCLUSION: Germline exome sequencing of a father and daughter with AMTs identified novel candidate predisposing genes. Further studies are required to clarify the role of these genes in familial AMTs.

Membrane association of monotopic phosphoglycosyl transferase underpins function.

Polyprenol phosphate phosphoglycosyl transferases (PGTs) catalyze the first membrane-committed step in assembly of essential glycoconjugates. Currently there is no structure-function information to describe how monotopic PGTs coordinate the reaction between membrane-embedded and soluble substrates. We describe the structure and mode of membrane association of PglC, a PGT from Campylobacter concisus. The structure reveals a unique architecture, provides mechanistic insight and identifies ligand-binding determinants for PglC and the monotopic PGT superfamily.

Modes of carbon dioxide delivery during laparoscopy generate distinct differences in peritoneal damage and hypoxia in a porcine model.

BACKGROUND: Insufflation with CO2 can employ continuous flow, recirculated gas and/or additional warming and humidification. The ability to compare these modes of delivery depends upon the assays employed and opportunities to minimize subject variation. The use of pigs to train colorectal surgeons provided an opportunity to compare three modes of CO2 delivery under controlled circumstances. METHODS: Sixteen pigs were subjected to rectal resection, insufflated with dry-cold CO2 (DC-CO2) (n = 5), recirculated CO2 by an AirSeal device (n = 5) and humidification and warming (HW-CO2) by a HumiGard device (n = 6). Peritoneal biopsies were harvested from the same region of the peritoneum for fixation for immunohistochemistry for hypoxia-inducible factor 1 alpha (HIF-1α) and scanning electron microscopy (SEM) to evaluate hypoxia induction or tissue/cellular damage, respectively. RESULTS: DC-CO2 insufflation by both modes leads to significant damage to mesothelial cells as measured by cellular bulging and retraction as well as microvillus shortening compared with HW-CO2 at 1 to 1.5 h. DC-CO2 also leads to a rapid and significant induction of HIF-1α compared with HW-CO2. CONCLUSIONS: DC-CO2 insufflation induces substantive cellular damage and hypoxia responses within the first hour of application. The use of HW-CO2 insufflation ameliorates these processes for the first one to one and half hours in a large mammal used to replicate surgery in humans.

Appraising the relevance of DNA copy number loss and gain in prostate cancer using whole genome DNA sequence data.

A variety of models have been proposed to explain regions of recurrent somatic copy number alteration (SCNA) in human cancer. Our study employs Whole Genome DNA Sequence (WGS) data from tumor samples (n = 103) to comprehensively assess the role of the Knudson two hit genetic model in SCNA generation in prostate cancer. 64 recurrent regions of loss and gain were detected, of which 28 were novel, including regions of loss with more than 15% frequency at Chr4p15.2-p15.1 (15.53%), Chr6q27 (16.50%) and Chr18q12.3 (17.48%). Comprehensive mutation screens of genes, lincRNA encoding sequences, control regions and conserved domains within SCNAs demonstrated that a two-hit genetic model was supported in only a minor proportion of recurrent SCNA losses examined (15/40). We found that recurrent breakpoints and regions of inversion often occur within Knudson model SCNAs, leading to the identification of ZNF292 as a target gene for the deletion at 6q14.3-q15 and NKX3.1 as a two-hit target at 8p21.3-p21.2. The importance of alterations of lincRNA sequences was illustrated by the identification of a novel mutational hotspot at the KCCAT42, FENDRR, CAT1886 and STCAT2 loci at the 16q23.1-q24.3 loss. Our data confirm that the burden of SCNAs is predictive of biochemical recurrence, define nine individual regions that are associated with relapse, and highlight the possible importance of ion channel and G-protein coupled-receptor (GPCR) pathways in cancer development. We concluded that a two-hit genetic model accounts for about one third of SCNA indicating that mechanisms, such haploinsufficiency and epigenetic inactivation, account for the remaining SCNA losses.

Quadriceps tendon anterior cruciate ligament reconstruction.

Quadriceps tendon is a promising alternative graft option for anterior cruciate ligament (ACL) reconstruction, which can be harvested with or without a bone block as well as a full or partial thickness graft. Therefore, quadriceps tendon graft could be used in primary and revision ACL reconstruction based on the requirements (tunnel size, tunnel position, etc.). The all soft tissue, partial thickness quadriceps tendon graft in detail and pitfalls of the harvest are described in the present review. After quadriceps tendon harvest, especially in soccer players, who need a strong quadriceps to strike a ball with power, the postoperative rehabilitation may need to be adapted. LEVEL OF EVIDENCE: V.

Treatment after anterior cruciate ligament injury: Panther Symposium ACL Treatment Consensus Group.

Treatment strategies for anterior cruciate ligament (ACL) injuries continue to evolve. Evidence supporting best practice guidelines for the management of ACL injury is to a large extent based on studies with low-level evidence. An international consensus group of experts was convened to collaboratively advance toward consensus opinions regarding the best available evidence on operative vs. non-operative treatment for ACL injury. The purpose of this study is to report the consensus statements on operative vs. non-operative treatment of ACL injuries developed at the ACL Consensus Meeting Panther Symposium 2019. Sixty-six international experts on the management of ACL injuries, representing 18 countries, were convened and participated in a process based on the Delphi method of achieving consensus. Proposed consensus statements were drafted by the Scientific Organizing Committee and Session Chairs for the three working groups. Panel participants reviewed preliminary statements prior to the meeting and provided the initial agreement and comments on the statement via an online survey. During the meeting, discussion and debate occurred for each statement, after which a final vote was then held. Eighty percent agreement was defined a-priori as consensus. A total of 11 of 13 statements on operative v. non-operative treatment of ACL injury reached the consensus during the Symposium. Nine statements achieved unanimous support, two reached strong consensus, one did not achieve consensus, and one was removed due to redundancy in the information provided. In highly active patients engaged in jumping, cutting, and pivoting sports, early anatomic ACL reconstruction is recommended due to the high risk of secondary meniscus and cartilage injuries with delayed surgery, although a period of progressive rehabilitation to resolve impairments and improve neuromuscular function is recommended. For patients who seek to return to straight plane activities, non-operative treatment with structured, progressive rehabilitation is an acceptable treatment option. However, with persistent functional instability, or when episodes of giving way occur, anatomic ACL reconstruction is indicated. The consensus statements derived from international leaders in the field will assist clinicians in deciding between operative and non-operative treatments with patients after an ACL injury.Level of evidence V.

A Portable System for Remote Rehabilitation Following a Total Knee Replacement: A Pilot Randomized Controlled Clinical Study.

Rehabilitation has been shown to improve functional outcomes following total knee replacement (TKR). However, its delivery and associated costs are highly variable. The authors have developed and previously validated the accuracy of a remote (wearable) rehabilitation monitoring platform (interACTION). The present study's objective was to assess the feasibility of utilizing interACTION for the remote management of rehabilitation after TKR and to determine a preliminary estimate of the effects of the interACTION system on the value of rehabilitation. Specifically, we tested post-operative outpatient rehabilitation supplemented with interACTION (n = 13) by comparing it to a standard post-operative outpatient rehabilitation program (n = 12) using a randomized design. Attrition rates were relatively low and not significantly different between groups, indicating that participants found both interventions acceptable. A small (not statistically significant) decrease in the number of physical therapy visits was observed in the interACTION Group, therefore no significant difference in total cost could be observed. All patients and physical therapists in the interACTION Group indicated that they would use the system again in the future. Therefore, the next steps are to address the concerns identified in this pilot study and to expand the platform to include behavioral change strategies prior to conducting a full-scale randomized controlled trial. Trial registration: ClinicalTrials.gov NCT02646761 "interACTION: A Portable Joint Function Monitoring and Training System for Remote Rehabilitation Following TKA" 6 January 2016.

Verification of a Portable Motion Tracking System for Remote Management of Physical Rehabilitation of the Knee.

Rehabilitation following knee injury or surgery is critical for recovery of function and independence. However, patient non-adherence remains a significant barrier to success. Remote rehabilitation using mobile health (mHealth) technologies have potential for improving adherence to and execution of home exercise. We developed a remote rehabilitation management system combining two wireless inertial measurement units (IMUs) with an interactive mobile application and a web-based clinician portal (interACTION). However, in order to translate interACTION into the clinical setting, it was first necessary to verify the efficacy of measuring knee motion during rehabilitation exercises for physical therapy and determine if visual feedback significantly improves the participant's ability to perform the exercises correctly. Therefore, the aim of this study was to verify the accuracy of the IMU-based knee angle measurement system during three common physical therapy exercises, quantify the effect of visual feedback on exercise performance, and understand the qualitative experience of the user interface through survey data. A convenience sample of ten healthy control participants were recruited for an IRB-approved protocol. Using the interACTION application in a controlled laboratory environment, participants performed ten repetitions of three knee rehabilitation exercises: heel slides, short arc quadriceps contractions, and sit-to-stand. The heel slide exercise was completed without feedback from the mobile application, then all exercises were performed with visual feedback. Exercises were recorded simultaneously by the IMU motion tracking sensors and a video-based motion tracking system. Validation showed moderate to good agreement between the two systems for all exercises and accuracy was within three degrees. Based on custom usability survey results, interACTION was well received. Overall, this study demonstrated the potential of interACTION to measure range of motion during rehabilitation exercises for physical therapy and visual feedback significantly improved the participant's ability to perform the exercises correctly.