The history of chromosomal instability in genome doubled tumors.

Tumors frequently display high chromosomal instability and contain multiple copies of genomic regions. Here, we describe GRITIC, a generic method for timing genomic gains leading to complex copy number states, using single-sample bulk whole-genome sequencing data. By applying GRITIC to 6,091 tumors, we found that non-parsimonious evolution is frequent in the formation of complex copy number states in genome-doubled tumors. We measured chromosomal instability before and after genome duplication in human tumors and found that late genome doubling was followed by an increase in the rate of copy number gain. Copy number gains often accumulate as punctuated bursts, commonly after genome doubling. We infer that genome duplications typically affect the landscape of copy number losses, while only minimally impacting copy number gains. In summary, GRITIC is a novel copy number gain timing framework that permits the analysis of copy number evolution in chromosomally unstable tumors.

Evaluation of deep-learning TSE images in clinical musculoskeletal imaging.

In this study, we compared the fat-saturated (FS) and non-FS turbo spin echo (TSE) magnetic resonance imaging knee sequences reconstructed conventionally (conventional-TSE) against a deep learning-based reconstruction of accelerated TSE (DL-TSE) scans. A total of 232 conventional-TSE and DL-TSE image pairs were acquired for comparison. For each consenting patient, one of the clinically acquired conventional-TSE proton density-weighted sequences in the sagittal or coronal planes (FS and non-FS), or in the axial plane (non-FS), was repeated using a research DL-TSE sequence. The DL-TSE reconstruction resulted in an image resolution that increased by at least 45% and scan times that were up to 52% faster compared to the conventional TSE. All images were acquired on a MAGNETOM Vida 3T scanner (Siemens Healthineers AG, Erlangen, Germany). The reporting radiologists, blinded to the acquisition time, were requested to qualitatively compare the DL-TSE against the conventional-TSE reconstructions. Despite having a faster acquisition time, the DL-TSE was rated to depict smaller structures better for 139/232 (60%) cases, equivalent for 72/232 (31%) cases and worse for 21/232 (9%) cases compared to the conventional-TSE. Overall, the radiologists preferred the DL-TSE reconstruction in 124/232 (53%) cases and stated no preference, implying equivalence, for 65/232 (28%) cases. DL-TSE reconstructions enabled faster acquisition times while enhancing spatial resolution and preserving the image contrast. From these results, the DL-TSE provided added or comparable clinical value and utility in less time. DL-TSE offers the opportunity to further reduce the overall examination time and improve patient comfort with no loss in diagnostic accuracy.

Preceptorship in robotic colorectal surgery: experience from the Australian private sector.

This article describes a post-fellowship preceptorship training program to train sub-specialty colorectal surgeons in gaining proficiency in robotic colorectal surgery using a dual-surgeon model in the Australian private sector. The Australian colorectal surgeon faces challenges in gaining robotic colorectal surgery proficiency with limited exposure and experience in the public setting where the majority of general and colorectal surgery training is currently conducted. This training model uses graded exposure with a range of simulation training, wet lab training, and clinical operative cases to progress through both competency and proficiency in robotic colorectal surgery which is mutually beneficial to surgeons and patients alike. Ongoing audit of practice has shown no adverse impacts.

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.

The family caregiving; A Rogerian concept analysis of Muslim perspective & Islamic sources.

Despite the numerous concepts of caregiving discussed in the literature, there is still no agreed definition and concept of family caregiving from the perspective of Islam. This study aims to comprehensively define family caregiving from Islamic religious and Muslim cultural perspectives. Rodger's evolutionary model was used to generate content by analyzing and redefining concepts. A thorough examination of the relevant literature using Scopus, PubMed, Medline, and CINAHL databases also trusted sources offered a total of 52 articles and 8 books to be reviewed. Our study reveals that family caregiving is viewed as God's gift as important as an essential religious and cultural obligation in Islam, where humans are expected to deliver care for their families although they are unprepared. This can be motivated by aspirations for respect, love, responsibility, and a desire to recompense parents, as well as the belief that by doing so they will be rewarded in the hereafter. The provision of family caregiving leads to positive consequences such as living with hope, gaining rewards and achievement, but at the same time, it also causes devastated life. This research contributes to a new discourse on family caregiving based on Islamic literature which helps in the comprehension of the practices of Muslim communities worldwide.

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.

Role of Age as a Predictor of Major Complications After Elective Surgery for Ulcerative Colitis.

BACKGROUND: The incidence of ulcerative colitis (UC) in the elderly population is increasing. The aim of this study was to assess the degree to which age and other factors increase the risk of developing major complications in patients undergoing elective surgery for UC. METHODS: Using the ACS-NSQIP database from 2016 to 2020, patients undergoing elective surgery for UC were divided into four categories: younger than 30, 30-49, 50-69, and 70 or older. A composite outcome was created including major complications and multivariable analysis was performed to identify factors associated with composite major complications. RESULTS: 5946 patients diagnosed with ulcerative colitis who underwent elective surgery were included in the analysis. 14.1% of all patients developed a major complication. For patients with UC, factors associated with the development of a major complication were age 50-69 (OR 1.31, P = .034), male sex (OR 1.38, P < .001), Black race (OR 1.47, P = .049), dependent status (OR 2.06, P = .028), hypoalbuminemia (OR 1.92, P < .001), preoperative steroid treatment (OR 1.27, P = .038), preoperative transfusion (OR 1.91, P < .001), open surgical approach (OR 1.44, P = .002), and partial colectomy (OR 1.51, P = .007). Specifically in patients aged 70 or older, hypoalbuminemia (OR 3.20, P < .001) and preoperative transfusion (OR 2.78, P = .019) were associated with a major complication. CONCLUSION: Age is a risk factor for the development of a major complication in UC patients undergoing elective surgery. However, it is not the only risk factor nor is it the one that increases the risk the most.

Validity of evaluating spinal kinetics without participant-specific kinematics.

Musculoskeletal models are commonly used to estimate in vivo spinal loads under various loading conditions. Typically, participant-specific measured kinematics (PSMK) are coupled with participant-specific models, but obtaining PSMK data can be costly and infeasible in large studies or clinical practice. Thus, we evaluated two alternative methods to estimate spinal loads without PSMK: 1) ensemble average kinematics (EAK) based on kinematics from all participants; and 2) using separately measured individual kinematics (SMIK) from multiple other participants as inputs, then averaging the resulting loads. This study compares the dynamic spine loading patterns and peak loads in older adults performing five lifting tasks using PSMK, EAK and SMIK. Median root mean square errors of EAK and SMIK methods versus PSMK ranged from 18 to 72% body weight for compressive loads and from 2 to 25% body weight for shear loads, with median cross-correlations ranging from 0.931 to 0.991. The root mean square errors and cross-correlations between repeated PSMK trials fell within similar ranges. Compressive peak loads evaluated by EAK and SMIK were not different than PSMK in 12 of 15 cases, while by comparison repeated PSMK trials were not different in 13 of 15 cases. Overall, the resulting spine loading magnitudes and profiles using EAK or SMIK were not notably different than using a PSMK approach, and differences were not greater than between two PSMK trials. Thus, these findings indicate that these approaches may be used to make reasonable estimates of dynamic spinal loading without direct measurement of participant kinematics.

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.

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.

A survey of CIN 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, 6-centromere FISH, bulk transcriptomics, and single cell DNA sequencing (scDNAseq). As expected, microscopy of tumor cells in live and fixed samples correlated well (R=0.77; p<0.01) and sensitively detect CIN. Cytogenetics approaches include chromosome spreads and 6-centromere FISH, which also correlate well (R=0.77; p<0.01) 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, single-cell DNA sequencing (scDNAseq) detects CIN with high sensitivity, and correlates very well with imaging methods (R=0.83; p<0.01). 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 comparison of CIN rates between phenotypes and methods, we propose a standardized unit of CIN: Mis-segregations per Diploid Division (MDD). This systematic analysis of common CIN measures highlights the superiority of single-cell methods and provides guidance for measuring CIN in the clinical setting.

EMG Validation of a Subject-Specific Thoracolumbar Spine Musculoskeletal Model During Dynamic Activities in Older Adults.

Musculoskeletal models can uniquely estimate in vivo demands and injury risk. In this study, we aimed to compare muscle activations from subject-specific thoracolumbar spine OpenSim models with recorded muscle activity from electromyography (EMG) during five dynamic tasks. Specifically, 11 older adults (mean = 65 years, SD = 9) lifted a crate weighted to 10% of their body mass in axial rotation, 2-handed sagittal lift, 1-handed sagittal lift, and lateral bending, and simulated a window opening task. EMG measurements of back and abdominal muscles were directly compared to equivalent model-predicted activity for temporal similarity via maximum absolute normalized cross-correlation (MANCC) coefficients and for magnitude differences via root-mean-square errors (RMSE), across all combinations of participants, dynamic tasks, and muscle groups. We found that across most of the tasks the model reasonably predicted temporal behavior of back extensor muscles (median MANCC = 0.92 ± 0.07) but moderate temporal similarity was observed for abdominal muscles (median MANCC = 0.60 ± 0.20). Activation magnitude was comparable to previous modeling studies, and median RMSE was 0.18 ± 0.08 for back extensor muscles. Overall, these results indicate that our thoracolumbar spine model can be used to estimate subject-specific in vivo muscular activations for these dynamic lifting tasks.

Presentation and Surgical Management of Multiple Ligament Knee Injuries: A Multicenter Study from the Surgical Timing and Rehabilitation (STaR) Trial for MLKIs Network.

BACKGROUND: Multiple ligament knee injuries (MLKIs) represent a spectrum of injury patterns that are often associated with concomitant musculoskeletal and neurovascular injuries, complex treatment, and postoperative complications. However, there has not been high-level evidence describing the presentation and treatment of MLKIs. The purpose of this multicenter retrospective study was to describe characteristics of MLKIs, their management, and related complications using a pathoanatomic MLKI classification system based on the Schenck Knee Dislocation classification system. METHODS: This review identified and analyzed MLKIs that occurred between 2011 and 2015. Cases with an MLKI were included in this study if there was a complete tear of ≥2 ligaments and at least 1 ligament was repaired or reconstructed. Cases in which a ligament was deemed clinically incompetent due to a partial ligament tear and required surgical repair or reconstruction were considered equivalent to grade-III tears for inclusion and classification. Demographic information, the mechanism of injury, times from injury to presentation to an orthopaedic surgeon and to surgery, the ligament injury pattern, associated injuries, surgical procedures, and complications were captured. Data were analyzed descriptively. RESULTS: A total of 773 individuals from 14 centers who underwent surgery for an MLKI were reviewed. The mean age of the individuals was 30.5 ± 12.7 years, and 74.2% were male. The most common mechanism involved sports (43.2%). The median time from injury to presentation to the orthopaedic surgeon was 11 days (interquartile range [IQR], 3 to 48 days), and the time to initial ligament surgery was 64 days (IQR, 23 to 190 days). While the most common injury patterns were an anterior cruciate ligament tear combined with either a medial-sided (MLK 1-AM, 20.7%) or lateral-sided (MLK 1-AL, 23.2%) injury, one-third (34.7%) were bicruciate injuries. Associated injuries most often involved menisci (55.6%), nerves (18.5%) and tendons (15.6%). The method of surgical intervention (repair versus reconstruction), external fixator use, and staging of procedures varied by MLKI classification. Loss of motion (11.4%) was the most common postoperative complication. CONCLUSIONS: A better understanding of the clinical characteristics and management of the various MLKI patterns can be used to support clinical decision-making and individualized treatment of these complex injuries, and may ultimately lead to enhanced outcomes and reduced associated risks. LEVEL OF EVIDENCE: Therapeutic Level IV . See Instructions for Authors for a complete description of levels of evidence.

Using static postures to estimate spinal loading during dynamic lifts with participant-specific thoracolumbar musculoskeletal models.

Static biomechanical simulations are sometimes used to estimate in vivo kinetic demands because they can be solved efficiently, but this ignores any potential inertial effects. To date, comparisons between static and dynamic analyses of spinal demands have been limited to lumbar joint differences in young males performing sagittal lifts. Here we compare static and dynamic vertebral compressive and shear force estimates during axial, lateral, and sagittal lifting tasks across all thoracic and lumbar vertebrae in older men and women. Participant-specific thoracolumbar full-body musculoskeletal models estimated vertebral forces from recorded kinematics both with and without consideration of dynamic effects, at an identified frame of peak vertebral loading. Static analyses under-predicted dynamic compressive and resultant shear forces, by an average of about 16% for all three lifts across the thoracic and lumbar spine but were highly correlated with dynamic forces (average r2 > .95). The study outcomes have the potential to enable standard clinical and occupational estimates using static analyses.

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.

Quantifying chromosomal instability from intratumoral karyotype diversity using agent-based modeling and Bayesian inference.

Chromosomal instability (CIN)-persistent chromosome gain or loss through abnormal mitotic segregation-is a hallmark of cancer that drives aneuploidy. Intrinsic chromosome mis-segregation rate, a measure of CIN, can inform prognosis and is a promising biomarker for response to anti-microtubule agents. However, existing methodologies to measure this rate are labor intensive, indirect, and confounded by selection against aneuploid cells, which reduces observable diversity. We developed a framework to measure CIN, accounting for karyotype selection, using simulations with various levels of CIN and models of selection. To identify the model parameters that best fit karyotype data from single-cell sequencing, we used approximate Bayesian computation to infer mis-segregation rates and karyotype selection. Experimental validation confirmed the extensive chromosome mis-segregation rates caused by the chemotherapy paclitaxel (18.5 ± 0.5/division). Extending this approach to clinical samples revealed that inferred rates fell within direct observations of cancer cell lines. This work provides the necessary framework to quantify CIN in human tumors and develop it as a predictive biomarker.

DNA contains all the information that cells need to function. The DNA inside cells is housed in structures called chromosomes, and most healthy human cells contain 23 pairs. When a cell divides, all chromosomes are copied so that each new cell gets a complete set. However, sometimes the process of separating chromosomes is faulty, and new cells may get incorrect numbers of chromosomes during cell division. Cancer cells frequently exhibit this behavior, which is called chromosomal instability', or CIN. Chromosomal instability affects many cancer cells with varying severity. In cancers with high chromosomal instability, the number of chromosomes may change almost every time the cells divide. These cancers are often the most aggressive and difficult to treat. Scientists can estimate chromosomal instability by counting differences in the number of chromosomes across many cells. However, many cells that are missing chromosomes die, resulting in inaccurate measures of chromosomal instability. To find a solution to this problem, Lynch et al. counted chromosomes in human cells with different levels of chromosomal instability and created a computer model to work out the relationship between chromosomal instability and chromosome number. The model could account for both living and dead cells, which gave more accurate results. Lynch et al. then confirmed the accuracy of their approach by using it on a group of cells treated with a chemotherapy drug that causes a known level of chromosomal instability. They also used existing data from breast and bowel cancer, which revealed that levels of chromosomal instability varied between one mistake per three to twenty cell divisions. Lower levels of chromosomal instability can be linked to a better prognosis for cancer patients, but it currently cannot be measured reliably. These results may help to reveal the causes of chromosomal instability and the role it has in cancer. If this method is successfully applied to patient samples, it could also improve our ability to predict how each cancer will progress and may lead to better treatments.

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.