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Introduction: Knee OA (KOA) can lead to pain, loss of muscle strength, and changes in gait. Knee stiffness is a classic feature of KOA that can increase the risk of falls but has been understudied. Objective: To evaluate the impact of knee stiffness, the factors influencing the severity of stiffness, and the repercussions on participation for patients with KOA. Methods: This qualitative study used an interpretive description approach. Purposeful sampling was used for patients with KOA over 45 years of age, fluent in English, diagnosed with KOA and reported KOA stiffness within the last 6 months. Participants were recruited through social media and Ontario clinics. Semi‐structured interviews were conducted over the phone or using zoom, recorded, and transcribed verbatim. Open, axial, and selective coding were used to identify clinically relevant themes. Results: Twelve participants (5F, 7M) with a mean age of 60 years were included. The five themes identified include elusive and variable perceptions of joint stiffness, inactivity or too much activity exacerbates stiffness, adapting to the ebb and flow of symptoms, risk experiences and safety fears leads to reduced participation, and KOA stiffness impairs quality of life. Conclusion: This study highlights characteristics of knee stiffness, consequences on participation, and quality of life for people with KOA. Monitoring knee stiffness for KOA is recommended for more appropriate treatment intensity, which could improve adherence to a home programme and potentially reduce the risk of falls. [ABSTRACT FROM AUTHOR]

STUDY DESIGN: Experimental laboratory study. OBJECTIVES: To examine how a change in trunk position influences the kinematics, kinetics, and muscle activity of the lead lower extremity during the forward lunge exercise. BACKGROUND: Altering the position of the trunk during the forward lunge exercise is thought to affect the muscular actions of the lead lower extremity. However, no studies have compared the biomechanical differences between the traditional forward lunge and its variations. METHODS AND MEASURES: Ten healthy adults (5 males, 5 females; mean age ± SD, 26.7 ± 3.2 years) participated. Lower extremity kinematics, kinetics, and surface electromyographic (EMG) data were obtained while subjects performed 3 lunge exercises: normal lunge with the trunk erect (NL), lunge with the trunk forward (LTF), and lunge with trunk extension (LTE). A 1-way analysis of variance with repeated measures was used to compare lower extremity kinematics, joint impulse (area under the moment-time curve), and normalized EMG (highest 1-second window of activity for selected lower extremity muscles) among the 3 lunge conditions. RESULTS: During the LTF condition, significant increases were noted in peak hip flexion angle, hip extensor and ankle plantar flexor impulse, as well as gluteus maximus and biceps femoris EMG (P<.015) when compared to the NL condition. During the LTE condition, a significant increase was noted in peak ankle dorsiflexion and a significant decrease was noted in peak hip flexion angle (P<.015) compared to the NL condition. CONCLUSIONS: Performing a lunge with the trunk forward increased the hip extensor impulse and the recruitment of the hip extensors. In contrast, performing a forward lunge with the trunk extended did not alter joint impulse or activation of the lower extremity musculature. LEVEL OF EVIDENCE: Therapy, level 5. [ABSTRACT FROM AUTHOR]

Abstract Background Posterior tibialis tendon dysfunction (PTTD) is a common cause of foot pain and dysfunction in adults. Clinical observations strongly suggest that the condition is progressive. There are currently no controlled studies evaluating the effectiveness of exercise, orthoses, or orthoses and exercise on Stage I or IIA PTTD. Our study will explore the effectiveness of an eccentric versus concentric strengthening intervention to results obtained with the use of orthoses alone. Findings from this study will guide the development of more efficacious PTTD intervention programs and contribute to enhanced function and quality of life in persons with posterior tibialis tendon dysfunction. Methods/design This paper presents the rationale and design for a randomized clinical trial evaluating the effectiveness of a treatment regime for the non-operative management of Stage I or IIA PTTD. Discussion We have presented the rationale and design for an RCT evaluating the effectiveness of a treatment regimen for the non-operative management of Stage I or IIA PTTD. The results of this trial will be presented as soon as they are available.

Objective: The aim of this study was to evaluate whether the configuration of anastomotic doughnuts from upper gastrointestinal surgeries was associated with anastomotic leakage (AL)., Background: AL is a severe postoperative complication after upper gastrointestinal cancer surgeries. AL is associated with an increase in overall and cancer-related morbidity and mortality in patients with esophageal and gastric cancer. New intraoperative biomarkers are needed to predict the risk of AL to implement early preventive measures., Materials and Methods: Anastomotic doughnuts from 102 patients undergoing surgery for esophageal or gastric cancer using circular staplers were examined. The minimal and maximal height and width of the anastomotic doughnuts were measured and correlated with the postoperative AL rate., Results: The AL rate in our study collective was 15,7 %. The minimal width (Wmin) of the oral and aboral anastomotic doughnuts was significantly lower in patients with AL compared to patients without AL (p = 0.002 and p = 0.041 respectively). The Wmin of the esophageal anastomotic doughnut was an independent risk factor for AL in the multivariable analysis (p = 0.034). Negative predictive values for the measurements of anastomotic doughnuts (Wmin) with regard to the risk of AL were higher than for the commonly used postoperative biomarker C-reactive protein., Conclusion: Minimal anastomotic doughnut width was statistically significantly associated with AL. Thus, not only the evaluation of the completeness of the anastomotic doughnuts but also intraoperative measurements could be used to predict the risk of AL to initiate early preventive measures to prevent the development of AL and/or reduce AL-associated morbidity., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Autophagy and lysosomal pathways are involved in the cell entry of SARS-CoV-2 virus. To infect the host cell, the spike protein of SARS-CoV-2 binds to the cell surface receptor angiotensin-converting enzyme 2 (ACE2). To allow the fusion of the viral envelope with the host cell membrane, the spike protein has to be cleaved. One possible mechanism is the endocytosis of the SARS-CoV-2-ACE2 complex and subsequent cleavage of the spike protein, mainly by the lysosomal protease cathepsin L. However, detailed molecular and dynamic insights into the role of cathepsin L in viral cell entry remain elusive. To address this, HeLa cells and iPSC-derived alveolarspheres were treated with recombinant SARS-CoV-2 spike protein, and the changes in mRNA and protein levels of cathepsins L, B, and D were monitored. Additionally, we studied the effect of cathepsin L deficiency on spike protein internalization and investigated the influence of the spike protein on cathepsin L promoters in vitro. Furthermore, we analyzed variants in the genes coding for cathepsin L, B, D, and ACE2 possibly associated with disease progression using data from Regeneron's COVID Results Browser and our own cohort of 173 patients with COVID-19, exhibiting a variant of ACE2 showing significant association with COVID-19 disease progression. Our in vitro studies revealed a significant increase in cathepsin L mRNA and protein levels following exposure to the SARS-CoV-2 spike protein in HeLa cells, accompanied by elevated mRNA levels of cathepsin B and D in alveolarspheres. Moreover, an increase in cathepsin L promoter activity was detected in vitro upon spike protein treatment. Notably, the knockout of cathepsin L resulted in reduced internalization of the spike protein. The study highlights the importance of cathepsin L and lysosomal proteases in the SARS-CoV-2 spike protein internalization and suggests the potential of lysosomal proteases as possible therapeutic targets against COVID-19 and other viral infections., (© 2024 The Author(s). Journal of Cellular Biochemistry published by Wiley Periodicals LLC.)

Background: Pancreatic cancer is often accompanied by wasting conditions. While surgery is the primary curative approach, it poses a substantial risk of postoperative complications, hindering subsequent treatments. Therefore, identifying patients at high risk for complications and optimizing their perioperative general condition is crucial. Sarcopenia and other body composition abnormalities have shown to adversely affect surgical and oncological outcomes in various cancer patients. As most pancreatic tumours are located close to the neuronal control centre for the digestive tract, it is possible that neural infiltration in this area deranges bowel functions and contributes to malabsorption and malnutrition and ultimately worsen sarcopenia and weight loss., Methods: A retrospective analysis of CT scans was performed for pancreatic cancer patients who underwent surgical tumour resection at a single high-volume centre from 2007 to 2023. Sarcopenia prevalence was assessed by skeletal muscle index (SMI), and visceral obesity was determined by the visceral adipose tissue area (VAT). Obesity and malnutrition were determined by the GLIM criteria. Sarcopenic obesity was defined as simultaneous sarcopenia and obesity. Postoperative complications, mortality and perineural tumour invasion, were compared among patients with body composition abnormalities., Results: Of 437 patients studied, 46% were female, the median age was 69 (61;74) years. CT analysis revealed 54.9% of patients with sarcopenia, 23.7% with sarcopenic obesity and 45.9% with visceral obesity. Sarcopenia and sarcopenic obesity were more prevalent in elderly and male patients. Postoperative surgical complications occurred in 67.7% of patients, most of which were mild (41.6%). Severe complications occurred in 22.7% of cases and the mortality rate was 3.4%. Severe postoperative complications were significantly more common in patients with sarcopenia or sarcopenic obesity. Visceral obesity or malnutrition based on BMI alone, did not significantly impact complications. Perineural invasion was found in 80.1% of patients and was unrelated to malnutrition or body composition parameters., Conclusions: This is the first and largest study evaluating the associations of CT-based body mass analysis with surgical outcome and histopathological perineural tumour invasion in pancreatic cancer patients. The results suggest that elderly and male patients are at high risk for sarcopenia and should be routinely evaluated by CT before undergoing pancreatic surgery, irrespective of their BMI. Confirmation of the results in prospective studies is needed to assess if pancreatic cancer patients with radiographic sarcopenia benefit from preoperative amelioration of muscle mass and function by exercise and nutritional interventions., (© 2024. The Author(s).)

Prevention of intestinal fibrosis remains an unresolved problem in the treatment of Crohn's disease (CD), as specific antifibrotic therapies are not yet available. Appropriate analysis of fibrosis severity is essential for assessing the therapeutic efficacy of potential antifibrotic drugs. The aim of this study was to develop an observer-independent method to quantify intestinal fibrosis in surgical specimens from patients with CD using structural analysis of the extracellular matrix (ECM). We performed fractal analysis in fibrotic and control histological sections of patients with surgery for CD (n = 28). To specifically assess the structure of the collagen matrix, polarized light microscopy was used. A score to quantify collagen fiber alignment and the color of the polarized light was established. Fractal dimension as a measure for the structural complexity correlated significantly with the histological fibrosis score whereas lacunarity as a measure for the compactness of the ECM showed a negative correlation. Polarized light microscopy to visualize the collagen network underlined the structural changes in the ECM network in advanced fibrosis. In conclusion, observer-independent quantification of the structural complexity of the ECM by fractal analysis is a suitable method to quantify the degree of intestinal fibrosis in histological samples from patients with CD., (© 2024. The Author(s).)

Purpose: Sigmoid diverticulitis is a disease with a high socioeconomic burden, accounting for a high number of left-sided colonic resections worldwide. Modern surgical scheduling relies on accurate prediction of operation times to enhance patient care and optimize healthcare resources. This study aims to develop a predictive model for surgery duration in laparoscopic sigmoid resections, based on preoperative CT biometric and demographic patient data., Methods: This retrospective single-center cohort study included 85 patients who underwent laparoscopic sigmoid resection for diverticular disease. Potentially relevant procedure-specific anatomical parameters recommended by a surgical expert were measured in preoperative CT imaging. After random split into training and test set (75% / 25%) multiclass logistic regression was performed and a Random Forest classifier was trained on CT imaging parameters, patient age, and sex in the training cohort to predict categorized surgery duration. The models were evaluated in the test cohort using established performance metrics including receiver operating characteristics area under the curve (AUROC)., Results: The Random Forest model achieved a good average AUROC of 0.78. It allowed a very good prediction of long (AUROC = 0.89; specificity 0.71; sensitivity 1.0) and short (AUROC = 0.81; specificity 0.77; sensitivity 0.56) procedures. It clearly outperformed the multiclass logistic regression model (AUROC: average = 0.33; short = 0.31; long = 0.22)., Conclusion: A Random Forest classifier trained on demographic and CT imaging biometric patient data could predict procedure duration outliers of laparoscopic sigmoid resections. Pending validation in a multicenter study, this approach could potentially improve procedure scheduling in visceral surgery and be scaled to other procedures., (© 2024. The Author(s).)

Exploring the generative capabilities of the multimodal GPT-4, our study uncovered significant differences between radiological assessments and automatic evaluation metrics for chest x-ray impression generation and revealed radiological bias., (©Sebastian Ziegelmayer, Alexander W Marka, Nicolas Lenhart, Nadja Nehls, Stefan Reischl, Felix Harder, Andreas Sauter, Marcus Makowski, Markus Graf, Joshua Gawlitza. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 22.12.2023.)

Percutaneous CT-guided biopsy is a frequently performed procedure for the confirmation and molecular workup of hepatic metastases of pancreatic ductal adenocarcinoma (PDAC). Tumor necrosis of primary PDAC has shown a negative prognostic impact in recent studies. This study aims to examine predictability in CT scans and the prognostic impact of necrosis in hepatic metastases of PDAC. In this tertiary-center retrospective cohort study, we included 36 patients with hepatic metastases of PDAC who underwent CT-guided hepatic biopsies. Normalized attenuation of the biopsied metastasis was determined in venous phase contrast-enhanced planning scans obtained prior to biopsy by automatic, threshold-based 3D segmentation and manual, blinded 2D segmentation. A board-certified pathologist specialized in hepatic pathology histologically quantified the tumor necrosis and cellularity of the biopsy cylinders. We found a significant inverse-linear correlation between normalized attenuation and the fraction of necrosis (Pearson's r = 0.51, p < 0.001 for automatic 3D segmentation or Pearson's r = 0.52, p < 0.001 for manual 2D segmentation), whereas no correlation was found with tumor cellularity. Additionally, we discovered that patients with a fraction of necrosis ≥ 20% in metastases had a significantly shorter overall survival ( p < 0.035). In summary, tumor necrosis of PDAC metastases can be estimated from contrast-enhanced CT scans, which could help to improve biopsy sample pattern planning. In addition, liver metastatic necrosis may serve as a prognostic biomarker in PDAC.

Purpose: Evaluation of dual-layer spectral computed tomography (CT) for contrast enhancement during image-guided biopsy of liver lesions using virtual monoenergetic images (VMI) and virtual non-contrast (VNC) images., Methods: Spectral CT data of 20 patients receiving CT-guided needle biopsy of focal liver lesions were used to generate VMI at energy levels from 40 to 200 keV and VNC images. Images were analyzed objectively regarding contrast-to-noise ratio between lesion center (CNR cent ) or periphery (CNR peri ) and normal liver parenchyma. Lesion visibility and image quality were evaluated on a 4-point Likert scale by two radiologists., Results: Using VMI/VNC images, readers reported an increased visibility of the lesion compared to the conventional CT images in 18/20 cases. In 75% of cases, the highest visibility was derived by VMI-40. Showing all reconstructions simultaneously, VMI-40 offered the highest visibility in 75% of cases, followed by VNC in 12.5% of cases. Either CNR cent (17/20) or/and CNR peri (17/20) was higher (CNR increase > 50%) in 19/20 cases for VMI-40 or VNC images compared to conventional CT images. VMI-40 showed the highest CNR cent in 14 cases and the highest CNR peri in 12 cases. High image quality was present for all reconstructions with a minimum median of 3.5 for VMI-40 and VMI-50., Conclusions: When implemented in the CT scanner software, automated contrast enhancement of liver lesions during image-guided biopsy may facilitate the procedure., (© 2023. The Author(s).)

Background and Aims: High-dose glucocorticoid treatment has been identified as a risk factor for anastomotic leakage in patients with inflammatory bowel disease [IBD] undergoing bowel resection surgery. By contrast, active disease during surgery is also associated with elevated morbidity. Perioperative low-dose treatment might be beneficial regarding postoperative outcomes by controlling disease activity. The present study is the first to investigate the dose-dependent effect of perioperative prednisolone therapy in a murine IBD model combining dextran sodium sulphate [DSS] colitis with intestinal anastomosis surgery., Methods: In 84 10-week-old wild-type mice, a colorectal anastomosis was performed using a microsurgical technique. Half the animals received induction of chemical colitis with 2% DSS via drinking water prior to surgery. In both groups, one-third of the animals received daily oral administration of high-dose [0.533 mg/kg] and one-third low-dose [0.133 mg/kg] prednisolone. Evaluation was performed on postoperative days 3 and 7., Results: While high-dose prednisolone treatment led to an increased anastomotic leakage rate in mice under colitis, low-dose prednisolone treatment limited preoperative disease activity and did not influence the leakage rate. Histological examination showed a beneficial effect of low-dose prednisolone treatment on microscopic abscess formation at the anastomotic site in DSS mice as well as an increased anastomotic healing score., Conclusions: We demonstrate a beneficial effect of perioperative short-term low-dose prednisolone treatment on intestinal anastomotic healing in the context of colitis. Perioperative use of short-term low-dose prednisolone treatment might be beneficial in IBD patients who need to undergo surgery during active disease., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Purpose: To critically appraise randomized controlled trials (RCTs) on Instrument-Assisted Soft Tissue Mobilisation (IASTM) and quantify the effects of IASTM compared with other treatment in individuals with or without pathologies on function, pain, and range of motion., Materials and Methods: We search four electronic databases from January 1999 to January 2022 and included RCTs of healthy participants/athletes and people with upper, lower, or spinal conditions, who received IASTM versus other active treatment for clinical outcomes (function, pain, and range of motion)., Results: Forty-six RCTs were considered eligible for data analysis. Effects of IASTM plus other treatment versus other treatment on function and pain intensity were not statistically significant or clinically meaningful (very low quality, SMD -0.28, 95% CI -0.66 to 0.09) and (very low quality, SMD -0.05, 95% CI -0.53 to 0.43) at up to one-year follow-up respectively. No clinically meaningful improvements were found on range of motion outcomes. Out of the 46 included RCTs, only 10 assessed and reported IASTM-related adverse events., Conclusion: Evidence of very low-quality certainty does not support the efficacy of IASTM in individuals with or without various pathologies on function, pain, and range of motion in the management of upper body, lower body, or spinal conditions. IMPLICATIONS FOR REHABILITATIONThe included RCTs had a high risk of bias and were assessed as very-low quality evidence for all the included outcomes.IASTM does not lead to clinically meaningful improvements in function, pain, or range of motion in individuals with upper body, lower body, and spinal conditions.The publication of IASTM trials in suspected predatory journals is increasing.The available evidence on IASTM does not support its use to improve function, pain, or range of motion in individuals with upper body, lower body, and spinal conditions.Health care practitioners should consider other evidence-based management strategies (physical activity and exercise) to improve function, pain, or range of motion in individuals with musculoskeletal injuries and disorders.Given the rise of publications on IASTM in suspected predatory journals, health care practitioners should be judicious to examine the legitimacy of a journal when searching for evidence on IASTM treatment technique.

Aim: Anastomotic leakage (AL) is one of the most dreaded complications in colorectal surgery. In 2013, the International Classification of Diseases code K91.83 for AL was introduced in Germany, allowing nationwide analysis of AL rates and associated parameters. The aim of this population-based study was to investigate the current incidence, risk factors, mortality, clinical management, and associated costs of AL in colorectal surgery., Methods: A data query was performed based on diagnosis-related group data of all hospital cases of inpatients undergoing colon or sphincter-preserving rectal resections between 2013 and 2018 in Germany., Results: A total number of 690,690 inpatient cases were included in this study. AL rates were 6.7% for colon resections and 9.2% for rectal resections in 2018. Regarding the treatment of AL, the application of endoluminal vacuum therapy increased during the studied period, while rates of relaparotomy, abdominal vacuum therapy, and terminal enterostomy remained stable. AL was associated with significantly increased in-house mortality (7.11% vs. 20.11% for colon resections and 3.52% vs. 11.33% for rectal resections in 2018) and higher socioeconomic costs (mean hospital reimbursement volume per case: 14,877€ (no AL) vs. 37,521€ (AL) for colon resections and 14,602€ (no AL) vs. 30,606€ (AL) for rectal resections in 2018)., Conclusions: During the studied time period, AL rates did not decrease, and associated mortality remained at a high level. Our study provides updated population-based data on the clinical and economic burden of AL in Germany. Focused research in the field of AL is still urgently necessary to develop targeted strategies to prevent AL, improve patient care, and decrease socioeconomic costs., (© 2023. The Author(s).)

Importance: Differentiating between malignant and benign etiology in large-bowel wall thickening on computed tomography (CT) images can be a challenging task. Artificial intelligence (AI) support systems can improve the diagnostic accuracy of radiologists, as shown for a variety of imaging tasks. Improvements in diagnostic performance, in particular the reduction of false-negative findings, may be useful in patient care., Objective: To develop and evaluate a deep learning algorithm able to differentiate colon carcinoma (CC) and acute diverticulitis (AD) on CT images and analyze the impact of the AI-support system in a reader study., Design, Setting, and Participants: In this diagnostic study, patients who underwent surgery between July 1, 2005, and October 1, 2020, for CC or AD were included. Three-dimensional (3-D) bounding boxes including the diseased bowel segment and surrounding mesentery were manually delineated and used to develop a 3-D convolutional neural network (CNN). A reader study with 10 observers of different experience levels was conducted. Readers were asked to classify the testing cohort under reading room conditions, first without and then with algorithmic support., Main Outcomes and Measures: To evaluate the diagnostic performance, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated for all readers and reader groups with and without AI support. Metrics were compared using the McNemar test and relative and absolute predictive value comparisons., Results: A total of 585 patients (AD: n = 267, CC: n = 318; mean [SD] age, 63.2 [13.4] years; 341 men [58.3%]) were included. The 3-D CNN reached a sensitivity of 83.3% (95% CI, 70.0%-96.6%) and specificity of 86.6% (95% CI, 74.5%-98.8%) for the test set, compared with the mean reader sensitivity of 77.6% (95% CI, 72.9%-82.3%) and specificity of 81.6% (95% CI, 77.2%-86.1%). The combined group of readers improved significantly with AI support from a sensitivity of 77.6% to 85.6% (95% CI, 81.3%-89.3%; P < .001) and a specificity of 81.6% to 91.3% (95% CI, 88.1%-94.5%; P < .001). Artificial intelligence support significantly reduced the number of false-negative and false-positive findings (NPV from 78.5% to 86.4% and PPV from 80.9% to 90.8%; P < .001)., Conclusions and Relevance: The findings of this study suggest that a deep learning model able to distinguish CC and AD in CT images as a support system may significantly improve the diagnostic performance of radiologists, which may improve patient care.

The rate of abdominal surgical interventions and associated postoperative complications in inflammatory bowel disease (IBD) patients is still substantially high. There is an ongoing debate as to whether or not patients who undergo treatment with anti-tumor necrosis factor-alpha (TNF-α) agents may have an increased risk for general and surgical postoperative complications. Therefore, a systematic review and meta-analysis was conducted in order to assess the effect of anti-TNF-α treatment within 12 weeks (washout period) prior to abdominal surgery on 30-day postoperative complications in patients with IBD. The results of previously published meta-analyses examining the effect of preoperative anti-TNF-α treatment on postoperative complications reported conflicting findings which is why we specifically focus on the effect of anti-TNF-α treatment within 12 weeks prior to surgery. PubMed, Cochrane, Scopus, Web of Science, World Health Organization Trial Registry, ClinicalTrials.gov and reference lists were searched (June 1995−February 2022) to identify studies, investigating effects of anti-TNF-α treatment prior to abdominal surgery on postoperative complications in IBD patients. Pooled odds ratios (OR) with 95% confidence intervals (CI) were calculated and subgroup analyses were performed. In this case, 55 cohort studies (22,714 patients) were included. Overall, postoperative complications (OR, 1.23; 95% CI, 1.04−1.45; p = 0.02), readmission (OR, 1.39; 95% CI, 1.11−1.73; p = 0.004), and intra-abdominal septic complications (OR, 1.89; 95% CI, 1.44−2.49; p < 0.00001) were significantly higher for anti-TNF-α-treated patients. Significantly higher intra-abdominal abscesses and readmission were found for anti-TNF-α-treated CD patients (p = 0.05; p = 0.002). Concomitant treatment with immunosuppressives in <50% of anti-TNF-α-treated patients was associated with significantly lower mortality rates (OR, 0.32; 95% CI, 0.12−0.83; p = 0.02). Anti-TNF-α treatment within 12 weeks prior to surgery is associated with higher short-term postoperative complication rates (general and surgical) for patients with IBD, especially CD.

Reliable markers to predict or diagnose anastomotic leakage (AL) of stapled circular anastomoses following colorectal resections are an important clinical need. Here, we aim to quantitatively investigate the morphology of anastomotic rings as an early available prognostic marker for AL and compare them to established inflammatory markers. We perform a prospective single-center cohort study, including patients undergoing stapled circular anastomosis between August 2020 and August 2021. The predictive value of the anastomotic ring configuration and the neutrophil-to-lymphocyte ratio (NLR) regarding anastomotic leakage is examined by ROC analyses and compared to the C-reactive protein (CRP) as an established marker. We included 204 patients, of which 19 suffered from anastomotic leakage (LEAK group), while in 185 patients the anastomoses healed well (HEAL group). The minimal height of the anastomotic rings as a binary classifier had a good ROC-AUC of 0.81 but was inferior to the NLR at postoperative day (POD) 5, with an excellent ROC-AUC of 0.93. Still, it was superior to the NLR at POD 3 (0.74) and the CRP at POD 3 (ROC-AUC 0.54) and 5 (ROC-AUC 0.70). The minimal height of the anastomotic rings as indicator for technically insufficient anastomoses is a good predictor of AL, while postoperatively the NLR was superior to the CRP in prediction of AL.

Huntington's disease (HD) is a neurodegenerative disorder caused by poly-Q expansion in the Huntingtin (HTT) protein. Here, we delineate elevated mutant HTT (mHTT) levels in patient-derived cells including fibroblasts and iPSC derived cortical neurons using mesoscale discovery (MSD) HTT assays. HD patients' fibroblasts and cortical neurons recapitulate aberrant alternative splicing as a molecular fingerprint of HD. Branaplam is a splicing modulator currently tested in a phase II study in HD (NCT05111249). The drug lowers total HTT (tHTT) and mHTT levels in fibroblasts, iPSC, cortical progenitors, and neurons in a dose dependent manner at an IC 50 consistently below 10 nM without inducing cellular toxicity. Branaplam promotes inclusion of non-annotated novel exons. Among these Branaplam-induced exons, there is a 115 bp frameshift-inducing exon in the HTT transcript. This exon is observed upon Branaplam treatment in Ctrl and HD patients leading to a profound reduction of HTT RNA and protein levels. Importantly, Branaplam ameliorates aberrant alternative splicing in HD patients' fibroblasts and cortical neurons. These findings highlight the applicability of splicing modulators in the treatment of CAG repeat disorders and decipher their molecular effects associated with the pharmacokinetic and -dynamic properties in patient-derived cellular models., (© 2022. The Author(s).)

Background: Patients with complicated appendicitis frequently develop postoperative septic complications. There are no uniform standards for the choice of perioperative antibiotic prophylaxis and the duration of postoperative antibiotic treatment. The purpose of this study was to investigate associations between microbiological samples and postoperative complications., Methods: Patients with appendectomy and positive intraoperative swabs during 2013-2018 were included in this case-control study. Pathogen classes and their resistance patterns were evaluated in initial and follow-up swabs and compared in each of the groups with and without complications., Results: A total of 870 patients underwent surgery during the period studied. Pathogen detection succeeded in 102 of 210 cases (48.6%) with suspected bacterial peritoneal contamination. Conversion from laparoscopic to open intra-abdominal perforation and the presence of an abscess were independent risk factors for wound infections in the multivariate analysis. The combination of different classes of pathogens resulted in significantly increased overall resistance to ampicillin/sulbactam in both the initial swabs (57%) and the follow-up swabs (73%). Resistant E. coli strains combined with certain anaerobes were also regularly detected in postoperative intra-abdominal abscesses. Piperacillin/tazobactam was effective against 83% of positive swabs in our resistance tests., Conclusion: Surgical treatment for complicated appendicitis remains the central therapeutic column. A regular review of the existing resistance patterns in perforated appendicitis can help to adjust and improve antibiotic treatment. Piperacillin/tazobactam should be used cautiously as a reserve antibiotic. A valid alternative is second or third generation cephalosporins in combination with metronidazole., (© 2022. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Amyotrophic lateral sclerosis (ALS) is a fatal disease characterized by aberrant alternative splicing (AS). Nuclear loss and cytoplasmic accumulation of the splicing factor TDP-43 in motor neurons (MN) are hallmarks of ALS at late stages of the disease. However, it is unknown if altered AS is present before TDP-43 pathology occurs. Here, we investigate altered AS and its origins in early stages of ALS using human induced pluripotent stem cell-derived motor neurons (MNs) from sporadic and familial ALS patients. We find high levels of the RNA-binding proteins NOVA1, NOVA2, and RBFOX2 in the insoluble protein fractions and observe that AS events in ALS-associated MNs are enriched for binding sites of these proteins. Our study points to an early disrupted function of NOVA1 that drives AS changes in a complex fashion, including events caused by a consistent loss of NOVA1 function. NOVA1 exhibits increased cytoplasmic protein levels in early stage MNs without TDP-43 pathology in ALS postmortem tissue. As nuclear TDP-43 protein level depletes, NOVA1 is reduced. Potential indications for a reduction of NOVA1 also came from mice over-expressing TDP-43 lacking its nuclear localization signal and iPSC-MN stressed with puromycin. This study highlights that additional RBP-RNA perturbations in ALS occur in parallel to TDP-43., (© 2022. The Author(s).)

Purpose: To identify, critically appraise, and synthesise the measurement properties of Patient-Specific Functional Scale (PSFS) in patients with upper extremity musculoskeletal disorders., Methods: Medline, Embase, PubMed, and Google Scholar databases from January 1999 to November 2020 were searched. Prospective measurement studies that included patients with upper extremity musculoskeletal disorders, that reported on the psychometric properties of PSFS were included. We used the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) 2018 guideline for systematic reviews to appraise the studies., Results: Fourteen eligible studies were included. Three studies with adequate-very good quality and sufficient properties indicated excellent intra-class correlation coefficients (ICC) (≥0.75) in patients with shoulder pain (mean age 48 ± 11 years), multiple shoulder disorders (mean age 55 ± 16 years), and hand osteoarthritis (mean age 64 ± 9 years). The construct validity estimates of PSFS were moderate, when compared with Upper Extremity Functional Index (UEFI) ( r  = 0.50) and Numeric Pain Rating Scale (NPRS) ( r  = 0.51) in patients with combined upper extremity musculoskeletal disorders (shoulder/upper arm, wrist/hand and elbow/forearm)., Conclusions: The patient-specific functional scale can be considered as a reliable, valid, and responsive tool in assessing functional change in patients with shoulder disorders/pain.Implications for rehabilitationThe Patient-Specific Functional Scale (PSFS) can be considered as: • a reliable outcome measure in assessing functional change in patients with shoulder pain and hand osteoarthritis; • a valid measure in assessing functional limitation in patients with upper extremity disorders; • a measure that is sensitive to change (displays longitudinal validity) in assessing functional change in patients with upper extremity disorders and in patients with shoulder pain; and • a responsive outcome measure in assessing functional change in patients with upper extremity disorders.

Purpose: Maintaining balance during static standing postures requires the coordination of many neuromuscular mechanisms. The role of the intrinsic and extrinsic foot muscles in this paradigm has yet to be clearly defined. The purpose of this study was to explore foot muscle activation during static phases on common weight-bearing tasks of varying loads and balance demands., Methods: Twenty healthy young adults performed 6 standing postures (single-limb and double-limb stand, squat, and heel raise) with one foot on a force plate. Muscle activity was recorded from the abductor hallucis, flexor hallucis longus and brevis, and tibialis posterior using intramuscular electrodes; surface electrodes were used to record activity from the peroneus longus and tibialis anterior. Two-way repeated measures ANOVA (2 loading conditions × 3 postures) were run to compare muscle activation and center of pressure velocity., Results: Intrinsic foot muscle activity increased as loading and postural demand increased; however, the specific effects varied for each of the extrinsic foot muscles., Conclusions: These results suggest that the intrinsic foot muscles play an important role in maintaining static balance. Strengthening intrinsic and extrinsic foot muscles may help increase stability in people who have weak toe flexors or who suffer from a variety of foot pathologies., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2022 Sarah T. Ridge et al.)

Background: For several decades, scientific efforts have been taken to develop strategies and medical aids for the reduction of anastomotic complications after intestinal surgery. Still, anastomotic leakage (AL) represents a frequently occurring postoperative complication with serious consequences on health, quality of life, and economic aspects. Approaches using collagen and/or fibrin-based sealants to cover intestinal anastomoses have shown promising effects toward leak reduction; however, they have not reached routine use yet. To assess the effects of covering intestinal anastomoses with collagen and/or fibrin-based sealants on postoperative leakage, a systematic review and meta-analysis were conducted., Method: PubMed, Web of Science, Cochrane Library, and Scopus (01/01/1964 to 17/01/2022) were searched to identify studies investigating the effects of coating any intestinal anastomoses with collagen and/or fibrin-based sealants on postoperative AL, reoperation rates, Clavien-Dindo major complication, mortality, and hospitalization length. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated., Results: Overall, 15 studies (five randomized controlled trials, three nonrandomized intervention studies, six observational cohort studies) examining 1,387 patients in the intervention group and 2,243 in the control group were included. Using fixed-effects meta-analysis ( I 2  < 50%), patients with coated intestinal anastomoses presented significantly lower AL rates (OR = 0.37; 95% CI 0.27-0.52; p  < 0.00001), reoperation rates (OR, 0.21; 95% CI, 0.10-0.47; p  = 0.0001), and Clavien-Dindo major complication rates (OR, 0.54; 95% CI, 0.35-0.84; p  = 0.006) in comparison to controls, with results remaining stable in sensitivity and subgroup analyses (stratified by study design, age group, intervention used, location of anastomoses, and indication for surgery). The length of hospitalization was significantly shorter in the intervention group (weighted mean difference (WMD), -1.96; 95% CI, -3.21, -0.71; p  = 0.002) using random-effects meta-analysis ( I 2  ≥ 50%), especially for patients with surgery of upper gastrointestinal malignancy (WMD, -4.94; 95% CI, -7.98, -1.90; p  = 0.001)., Conclusion: The application of collagen-based laminar biomaterials or fibrin sealants on intestinal anastomoses can significantly reduce postoperative rates of AL and its sequelae. Coating of intestinal anastomoses could be a step toward effective and sustainable leak prevention. To assess the validity and robustness of these findings, further clinical studies need to be conducted., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Cira, Stocker, Reischl, Obermeier, Friess, Burgkart and Neumann.)

Materials and Methods: Imaging phantoms were scanned twice on 3 computed tomography scanners from 2 different manufactures with varying tube voltages and currents. Phantoms were segmented, and features were extracted using PyRadiomics and a pretrained CNN. After standardization the concordance correlation coefficient (CCC), mean feature variance, feature range, and the coefficient of variant were calculated to assess feature robustness. In addition, the cosine similarity was calculated for the vectorized activation maps for an exemplary phantom. For the in vivo comparison, the radiomics and CNN features of 30 patients with hepatocellular carcinoma (HCC) and 30 patients with hepatic colon carcinoma metastasis were compared., Results: In total, 851 radiomics features and 256 CNN features were extracted for each phantom. For all phantoms, the global CCC of the CNN features was above 98%, whereas the highest CCC for the radiomics features was 36%. The mean feature variance and feature range was significantly lower for the CNN features. Using a coefficient of variant ≤0.2 as a threshold to define robust features and averaging across all phantoms 346 of 851 (41%) radiomics features and 196 of 256 (77%) CNN features were found to be robust. The cosine similarity was greater than 0.98 for all scanner and parameter variations. In the retrospective analysis, 122 of the 256 CNN (49%) features showed significant differences between HCC and hepatic colon metastasis., Discussion: Convolutional neural network features were more stable compared with radiomics features against technical variations. Moreover, the possibility of tumor entity differentiation based on CNN features was shown. Combined with visualization methods, CNN features are expected to increase reproducibility of quantitative image representations. Further studies are warranted to investigate the impact of feature stability on radiological image-based prediction of clinical outcomes., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: This systematic review and meta-analysis identifies, critically appraises, synthesizes, and meta-analyses the reported psychometric properties of the Patient-Specific Functional Scale (PSFS) in patients with low back pain or pathology. Method: The MEDLINE, Embase, PubMed, and Google Scholar databases were searched from their inception to September 2019. We included prospective measurement studies that reported on the psychometric properties (reliability, validity, responsiveness) of the PSFS in people with low back pain or pathology. We followed the COnsensus-based Standards for the selection of health Measurement INstruments 2018 guideline for systematic reviews. We performed both quantitative and qualitative syntheses in which the results were summarized on the basis of the reported measurement properties and study quality. Results: Ten eligible studies were included. The pooled PSFS reliability measure was excellent (intra-class correlation coefficient = 0.89; 95% CI: 0.75, 0.95). Validity measures displayed correlations that ranged from -0.47 to 0.69 when compared with other patient-reported outcome measures (PROMs) or other tests. Eight studies had assessed the responsiveness of the PSFS. Effect sizes reported were large (≥ 0.91). Conclusions: The PSFS is a reliable, valid, and responsive PROM for patients with low back pain or pathology., (© Canadian Physiotherapy Association.)

Purpose: Despite primary conservative therapy for Crohn's disease, a considerable proportion of patients ultimately needs to undergo surgery. Presumably, due to the increased use of biologics, the number of surgeries might have decreased. This study aimed to delineate current case numbers and trends in surgery in the era of biological therapy for Crohn's disease., Methods: Nationwide standardized hospital discharge data (diagnosis-related groups statistics) from 2010 to 2017 were used. All patients who were admitted as inpatient Crohn's disease cases in Germany were included. Time-related development of admission numbers, rate of surgery, morbidity, and mortality of inpatient Crohn's disease cases were analyzed., Results: A total number of 201,165 Crohn's disease cases were included. Within the analyzed time period, the total number of hospital admissions increased by 10.6% (n = 23,301 vs. 26,069). While gender and age distribution remained comparable, patients with comorbidities such as stenosis formation (2010: 10.1%, 2017: 13.4%) or malnutrition (2010: 0.8%, 2017: 3.2%) were increasingly admitted. The total number of all analyzed operations for Crohn's disease increased by 7.5% (2010: n = 1567; 2017: n = 1694). On average, 6.8 ± 0.2% of all inpatient patients received ileocolonic resections. Procedures have increasingly been performed minimally invasive (2010: n = 353; 2017: n = 687). The number of postoperative complications remained low., Conclusion: Despite the development of novel immunotherapeutics, the number of patients requiring surgery for Crohn's disease remains stable. Interestingly, patients have been increasingly hospitalized with stenosis and malnutrition. The trend towards more minimally invasive operations has not relevantly changed the rate of overall complications., (© 2021. The Author(s).)

Purpose: Modern non-operative management of diverticulitis consists of a complex therapeutic regimen and is successful in most cases even of complicated diverticulitis. Still, a certain proportion of patients requires urgent surgery due to failure of the conservative approach. This study aims to identify predictors for failure of conservative treatment of complicated diverticulitis with the need for subsequent urgent resection during the acute episode., Methods: A single-centre retrospective cohort study was performed at our tertiary centre including cases of acute complicated diverticulitis (characterized by localized abscess formation and/or pericolic air) between 2007 and 2019 that were treated guideline-conform by multimodal conservative treatment. Radiologic characteristics of disease in CT scans upon admission were analysed by uni- and multivariable logistic regression to determine predictors for resection within 30 days after onset of the conservative therapy approach., Results: A total of 669 cases of acute diverticulitis were identified, of which 141 patients met the inclusion criteria. Overall, 13% (n = 19) of patients were operated within 30 days despite initial conservative management. Multivariable logistic regression identified length of inflamed bowel greater than 7 cm (p < 0.011) and abscess formations >1 cm (p < 0.001) as significant risk factors for failure of conservative treatment., Conclusion: Patients with length of inflamed bowel >7 cm or abscess formation >1 cm have increased risk for failure of conservative treatment of acute episodes of diverticulitis with contained perforations with subsequent need for urgent surgery. Therefore, conservative treatment of those patients should be monitored with special caution., (© 2021. The Author(s).)

Background: Although in most patients with inflammatory bowel diseases, conservative therapy is successful, a significant proportion of patients still require surgery once in their lifetime. Development of a safe perioperative treatment to dampen colitis activity without disturbance of anastomotic healing is an urgent and unmet medical need. Annexin A1 (ANXA1) has been shown to be effective in reducing colitis activity. Herein, a nanoparticle-based perioperative treatment approach was used for analysis of the effects of ANXA1 on the resolution of inflammation after surgery for colitis., Methods: Anxa1-knockout mice were used to delineate the effects of ANXA1 on anastomotic healing. A murine model of preoperative dextran sodium sulfate colitis was performed. Collagen-IV-targeted polymeric nanoparticles, loaded with the ANXA1 biomimetic peptide Ac2-26 (Ac2-26-NPs), were synthesized and administered perioperatively during colitis induction. The effects of the Ac2-26-NPs on postoperative recovery and anastomotic healing were evaluated using the disease activity index, histological healing scores, and weight monitoring. Ultimately, whole-genome RNA sequencing of the anastomotic tissue was performed to unravel underlying molecular mechanisms., Results: Anxa1-knockout exacerbated the inflammatory response in the healing anastomosis. Treatment with Ac2-26-NPs improved preoperative colitis activity (P < 0.045), postoperative healing scores (P < 0.018), and weight recovery (P < 0.015). Whole-genome RNA sequencing revealed that the suppression of proinflammatory cytokine and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling was associated with the treatment effects and a phenotypic switch toward anti-inflammatory M2 macrophages., Conclusions: Proresolving therapy with Ac2-26-NPs promises to be a potent perioperative therapy because it improves colitis activity and even intestinal anastomotic healing by the suppression of proinflammatory signaling., (© 2021 Crohn’s & Colitis Foundation. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The cell biology of circadian clocks is still in its infancy. Here, we describe an efficient strategy for generating knock-in reporter cell lines using CRISPR technology that is particularly useful for genes expressed transiently or at low levels, such as those coding for circadian clock proteins. We generated single and double knock-in cells with endogenously expressed PER2 and CRY1 fused to fluorescent proteins allowing us to simultaneously monitor the dynamics of CRY1 and PER2 proteins in live single cells. Both proteins are highly rhythmic in the nucleus of human cells with PER2 showing a much higher amplitude than CRY1. Surprisingly, CRY1 protein is nuclear at all circadian times indicating the absence of circadian gating of nuclear import. Furthermore, in the nucleus of individual cells CRY1 abundance rhythms are phase-delayed (~5 hours), and CRY1 levels are much higher (>5 times) compared to PER2 questioning the current model of the circadian oscillator.

Purpose: In most cases, traditional techniques to perform an anastomosis following gastrointestinal resections lead to successful healing. However, despite focused research in the field, in certain high-risk situations leakage rates remain almost unchanged. Here, additional techniques may help the surgeon to protect the anastomosis and prevent leakage. We give an overview of some of the latest developments on experimental and clinical techniques for induction of anastomotic healing., Methods: We performed a review of the current literature on approaches to improve anastomotic healing., Results: Many promising approaches with a high clinical potential are in the developmental pipeline. Highly experimental approaches like inhibition of matrix metalloproteinases, stem cell therapy, hyperbaric oxygen therapy, induction of the hypoxic adaptive response, and the administration of growth factors are still in the preclinical phase. Other more clinical developments aim to strengthen the anastomotic suture line mechanically while shielding it from the influence of the microbiome. Among them are gluing, seaming the staple line, attachment of laminar biomaterials, and temporary intraluminal tubes. In addition, individualized bowel preparation, selectively reducing certain detrimental microbial populations could become the next stage of bowel preparation. Compression anastomoses are evolving as an equivalent technique additional to established hand-sewn and stapled anastomoses. Fluorescence angiography and flexible endoscopy could complement intraoperative quality control additionally to the air leak tests. Virtual ileostomy is a concept to prepare the bowel for the easy formation of a stoma in case of leakage., Conclusion: A variety of promising diagnostic and prophylactic measures that may support the surgeon in identifying high-risk anastomoses and support them according to their potential deficits is currently in development.

Recent advances in genomics unraveled several actionable mutational drivers in lung cancer, leading to promising therapies such as tyrosine kinase inhibitors and immune checkpoint inhibitors. However, the tumors' acquired resistance to the newly-developed as well as existing therapies restricts life quality improvements. Therefore, we investigated the noncoding portion of the human transcriptome in search of alternative actionable targets. We identified an antisense transcript, LY6K-AS, with elevated expression in lung adenocarcinoma (LUAD) patients, and its higher expression in LUAD patients predicts poor survival outcomes. LY6K-AS abrogation interfered with the mitotic progression of lung cancer cells resulting in unfaithful chromosomal segregation. LY6K-AS interacts with and stabilizes 14-3-3 proteins to regulate the transcription of kinetochore and mitotic checkpoint proteins. We also show that LY6K-AS regulates the levels of histone H3 lysine 4 trimethylation (H3K4me3) at the promoters of kinetochore members. Cisplatin treatment and LY6K-AS silencing affect many common pathways enriched in cell cycle-related functions. LY6K-AS silencing affects the growth of xenografts derived from wildtype and cisplatin-resistant lung cancer cells. Collectively, these data indicate that LY6K-AS silencing is a promising therapeutic option for LUAD that inhibits oncogenic mitotic progression.

Neuroblastoma has a low mutation rate for the p53 gene. Alternative ways of p53 inactivation have been proposed in neuroblastoma, such as abnormal cytoplasmic accumulation of wild-type p53. However, mechanisms leading to p53 inactivation via cytoplasmic accumulation are not well investigated. Here we show that the neuroblastoma risk-associated locus 6p22.3-derived tumor suppressor NBAT1 is a p53-responsive lncRNA that regulates p53 subcellular levels. Low expression of NBAT1 provided resistance to genotoxic drugs by promoting p53 accumulation in cytoplasm and loss from mitochondrial and nuclear compartments. Depletion of NBAT1 altered CRM1 function and contributed to the loss of p53-dependent nuclear gene expression during genotoxic drug treatment. CRM1 inhibition rescued p53-dependent nuclear functions and sensitized NBAT1 -depleted cells to genotoxic drugs. Combined inhibition of CRM1 and MDM2 was even more effective in sensitizing aggressive neuroblastoma cells with p53 cytoplasmic accumulation. Thus, our mechanistic studies uncover an NBAT1 -dependent CRM1/MDM2-based potential combination therapy for patients with high-risk neuroblastoma. SIGNIFICANCE: This study shows how a p53-responsive lncRNA mediates chemotherapeutic response by modulating nuclear p53 pathways and identifies a potential treatment strategy for patients with high-risk neuroblastoma., (©2020 American Association for Cancer Research.)