Citations

Abstract Obesity-related type II diabetes (diabesity) has increased global morbidity and mortality dramatically. Previously, the ancient drug salicylate demonstrated promise for the treatment of type II diabetes, but its clinical use was precluded due to high dose requirements. In this study, we present a nitroalkene derivative of salicylate, 5-(2-nitroethenyl)salicylic acid (SANA), a molecule with unprecedented beneficial effects in diet-induced obesity (DIO). SANA reduces DIO, liver steatosis and insulin resistance at doses up to 40 times lower than salicylate. Mechanistically, SANA stimulated mitochondrial respiration and increased creatine-dependent energy expenditure in adipose tissue. Indeed, depletion of creatine resulted in the loss of SANA action. Moreover, we found that SANA binds to creatine kinases CKMT1/2, and downregulation CKMT1 interferes with the effect of SANA in vivo. Together, these data demonstrate that SANA is a first-in-class activator of creatine-dependent energy expenditure and thermogenesis in adipose tissue and emerges as a candidate for the treatment of diabesity.

Background: There is a wide range of literature on patellar tendon injury, making it increasingly difficult to stay informed on the most influential studies in this field. It is essential to be familiar with the foundational articles of patellar tendon injury research to understand the current state of the literature and deliver high quality care. Purpose: To objectively identify the 50 most influential articles relating to patellar tendon injury and conduct a bibliometric analysis to identify key features of these articles. Study Design: Cross-sectional study. Methods: The Clarivate Analytics Web of Knowledge database was utilized to gather metrics on the 50 most cited articles on patellar tendon injury on June 27, 2022. The information extracted from each article included publication year, number of citations, author information, article type, level of evidence, country of origin, journal name, study focus, and industry influence. Results: The top 50 studies were cited a total of 8543 times and published between 1977 and 2015. The majority of articles were published after 2003, and the majority of citations were accrued after 2011. The most prevalent article types were cohort studies (n = 23), and the majority of studies were of evidence level 2 (n = 14) or 4 (n = 13). Australia and the United States (US) each published the most studies (n = 11). Only 4 (8%) studies focused on patellar tendon rupture, and 12 (24%) of the top 50 studies were associated with industry. Conclusion: The majority of the top 50 most influential articles in patellar tendon injury were published and accumulated citations in the past 10 to 20 years. Non-US countries, institutions, and journals published many of the top 50 studies, reflecting a global interest and commitment to research in this field. Patellar tendon rupture and surgical repair represents a minority of research in the top 50 studies and could be a point of growth in the future.

Abstract Background: DEPendency of association on the number of Top Hits (DEPTH) is an approach to identify candidate susceptibility regions by considering the risk signals from overlapping groups of sequential variants across the genome. Methods: We applied a DEPTH analysis using a sliding window of 200 SNPs to colorectal cancer data from the Colon Cancer Family Registry (CCFR; 5,735 cases and 3,688 controls), and Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO; 8,865 cases and 10,285 controls) studies. A DEPTH score > 1 was used to identify candidate susceptibility regions common to both analyses. We compared DEPTH results against those from conventional genome-wide association study (GWAS) analyses of these two studies as well as against 132 published susceptibility regions. Results: Initial DEPTH analysis revealed 2,622 (CCFR) and 3,686 (GECCO) candidate susceptibility regions, of which 569 were common to both studies. Bootstrapping revealed 40 and 49 candidate susceptibility regions in the CCFR and GECCO data sets, respectively. Notably, DEPTH identified at least 82 regions that would not be detected using conventional GWAS methods, nor had they been identified by previous colorectal cancer GWASs. We found four reproducible candidate susceptibility regions (2q22.2, 2q33.1, 6p21.32, 13q14.3). The highest DEPTH scores were in the human leukocyte antigen locus at 6p21 where the strongest associated SNPs were rs762216297, rs149490268, rs114741460, and rs199707618 for the CCFR data, and rs9270761 for the GECCO data. Conclusions: DEPTH can identify candidate susceptibility regions for colorectal cancer not identified using conventional analyses of larger datasets. Impact: DEPTH has potential as a powerful complementary tool to conventional GWAS analyses for discovering susceptibility regions within the genome.

The diaphragm muscle is important in both sustaining ventilation and performing higher-force behaviors necessary for maintaining airway patency. Ventilatory behaviors (i.e., eupnea and response to hypoxia-hypercapnia) require only ~20% of maximal force generation, whereas coughing requires forces ~60% of maximal. Existing techniques to measure the full range of forces generated by respiratory muscles are limited by their invasiveness (e.g., balloon manometry for transdiaphragmatic pressure (Pdi) measurements), requirements for training, supervision and subjectivity (e.g., maximal inspiratory and expiratory pressures). Ultrasound-based shear-wave elastography (SWE) assesses muscle stiffness and has shown promising results in being used as a surrogate for Pdi to evaluate diaphragm muscle force. Previous literature has demonstrated a correlation between diaphragm SWE and Pdi at lower force behaviors and the goal of the present study was to evaluate the efficacy of SWE-based measurements of the diaphragm in correlating with Pdi measurements across the range of forces generated by the diaphragm. In this pilot study, we recruited 6 male and 5 female healthy volunteers. Subjects were positioned in a seated position with their torso unsupported. Pdi was measured during graded inspiratory threshold loading trials using a POWERbreathe Plus commercial inspiratory loading device, as well as during maximal inspiratory pressure (MIP). Simultaneously, SWE was performed at the zone of apposition in the right anterior axillary line, and diaphragm Young’s modulus and shear wave speed were subsequently measured. The average Pdi during MIP testing was 149 ± 66 cm H2O. Pdi during inspiratory loading at a low resistance was 39 ± 14 cm H2O and at a high resistance was 78 ± 29 cm H2O. Subjects were able to generate an average Pdi range of 39 ± 19 cm H2O across the graded resistance levels, and the average percent of MIP obtained was 54 ± 13%. Average Young’s modulus as measured with SWE during inspiratory loading at a low resistance was 46 ± 19 kPa and at a high resistance was 104 ± 19 kPa. From low to high resistance, Pdi, Young’s modulus, and shear wave speed increased by an average of 100%, 126%, and 59%, respectively. Taken together, SWE is a promising method of non-invasive assessment of diaphragm muscle forces across a range of voluntary behaviors. Support from NIH grant R21 DA055848 and the Mayo Clinic. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Objective: We report the development and validation of a combined DNA/RNA next-generation sequencing (NGS) platform to improve the evaluation of pancreatic cysts. Background and Aims: Despite a multidisciplinary approach, pancreatic cyst classification, such as a cystic precursor neoplasm, and the detection of high-grade dysplasia and early adenocarcinoma (advanced neoplasia) can be challenging. NGS of preoperative pancreatic cyst fluid improves the clinical evaluation of pancreatic cysts, but the recent identification of novel genomic alterations necessitates the creation of a comprehensive panel and the development of a genomic classifier to integrate the complex molecular results. Methods: An updated and unique 74-gene DNA/RNA-targeted NGS panel (PancreaSeq Genomic Classifier) was created to evaluate 5 classes of genomic alterations to include gene mutations (e.g., KRAS, GNAS, etc.), gene fusions and gene expression. Further, CEA mRNA (CEACAM5) was integrated into the assay using RT-qPCR. Separate multi-institutional cohorts for training (n=108) and validation (n=77) were tested, and diagnostic performance was compared to clinical, imaging, cytopathologic, and guideline data. Results: Upon creation of a genomic classifier system, PancreaSeq GC yielded a 95% sensitivity and 100% specificity for a cystic precursor neoplasm, and the sensitivity and specificity for advanced neoplasia were 82% and 100%, respectively. Associated symptoms, cyst size, duct dilatation, a mural nodule, increasing cyst size, and malignant cytopathology had lower sensitivities (41–59%) and lower specificities (56–96%) for advanced neoplasia. This test also increased the sensitivity of current pancreatic cyst guidelines (IAP/Fukuoka and AGA) by >10% and maintained their inherent specificity. Conclusions: PancreaSeq GC was not only accurate in predicting pancreatic cyst type and advanced neoplasia but also improved the sensitivity of current pancreatic cyst guidelines.

Background: Carpal tunnel release (CTR) surgery is the most common surgery billed to Medicare by hand surgeons. As such, the purpose of this study was to evaluate trends for CTR surgeries billed to Medicare from 2000 to 2020. Methods: The publicly available Medicare Part B National Summary File from 2000 to 2020 was queried. For both open carpal tunnel release (OCTR) and endoscopic carpal tunnel release (ECTR), the number of procedures and total Medicare reimbursement were extracted. For year 2020, the specialty of the performing surgeon was recorded. Descriptive statistics were reported. Results: A total of 3 429 471 CTR surgeries were performed in the Medicare population from 2000 to 2020. For these procedures, Medicare paid surgeons over $1.23 billion. During this period, there was a 101.8% increase in annual CTR procedures (91 130 in 2000, 183 911 in 2020). Further, annual volume of ECTR increased by 456.2%, and accounted for an increasing percentage of total CTR procedures (9.1% in 2012, 25.2% in 2020). The average adjusted Medicare reimbursement per procedure decreased by 1.5% for OCTR, and decreased by 11.6% for ECTR. In 2020, orthopedic surgeons performed 85.1% of CTR procedures. Conclusions: The volume of CTR surgeries among the Medicare population has increased from 2000 to 2020, and ECTR is accounting for a growing proportion of surgeries. When adjusted for inflation, average reimbursement has decreased, with a greater decrease among ECTR. Orthopedic surgeons perform most of such surgeries. These trends are important to assure adequate resource allocation as treating carpal tunnel becomes more common among the aging Medicare population.

AbstractBackgroundObesity (body mass index [BMI] ≥30 kg/m2) is an important epidemiological risk factor for developing acute myeloid leukemia (AML). Therefore, the authors studied the association of obesity with clinical and genetic phenotype and its impact on outcome in adults with AML.MethodsThe authors analyzed BMI in 1088 adults who were receiving intensive remission induction and consolidation therapy in two prospective, randomized therapeutic clinical trials of the Eastern Cooperative Oncology Group‐American College of Radiology Imaging Network: E1900 (ClinicalTrials.gov identifier NCT00049517; patients younger than 60 years) and E3999 (ClinicalTrials.gov identifier NCT00046930; patients aged 60 years or older).ResultsObesity was prevalent at diagnosis (33%) and, compared with nonobesity, was associated with intermediate‐risk cytogenetics group (p = .008), poorer performance status (p = .01), and a trend toward older age (p = .06). Obesity was not associated with somatic mutations among a selected 18‐gene panel that was tested in a subset of younger patients. Obesity was not associated with clinical outcome (including complete remission, early death, or overall survival), and the authors did not identify any patient subgroup that had inferior outcomes based on BMI. Obese patients were significantly more likely to receive <90% of the intended daunorubicin dose despite protocol specification, particularly in the E1900 high‐dose (90 mg/m2) daunorubicin arm (p = .002); however, this did not correlate with inferior overall survival on multivariate analysis (hazard ratio, 1.39; 95% confidence interval, 0.90–2.13; p = .14).ConclusionsObesity is associated with unique clinical and disease‐related phenotypic features in AML and may influence physician treatment decisions regarding daunorubicin dosing. However, the current study demonstrates that obesity is not a factor in survival, and strict adherence to body surface area‐based dosing is not necessary because dose adjustments do not affect outcomes.

Background: Ganglion cysts are benign soft-tissue tumors that are most commonly found in the wrist. Within the wrist, 60% to 70% of ganglion cysts occur on the dorsal side and 20% to 30% occur on the volar side 1 . Although ganglia arise from multiple sites over the dorsal wrist, dorsal ganglia most commonly originate at the scapholunate joint 2,3 . Open excision is the standard surgical treatment for dorsal wrist ganglia. This procedure is considered when symptoms such as pain and range-of-motion deficits begin to impact activities of daily living. Description: Open excision of a dorsal wrist ganglion is commonly performed with the patient under general anesthesia or a regional block. The patient is placed in the supine position, and a tourniquet is applied on the affected upper limb. After outlining the periphery of the palpable ganglion, the surgeon makes a transverse or longitudinal incision over the ganglion. The surgeon then begins a deep dissection, dissecting through the subcutaneous tissue and isolating the ganglion while avoiding any rupture, if possible. Once the cyst has been identified, extensor tendons surrounding the cyst are retracted and the cyst and stalk are mobilized. The cyst and stalk are subsequently excised, and the wound is closed 4 . Alternatives: Alternative treatments for dorsal wrist ganglia include nonoperative interventions such as observation, aspiration, controlled rupture, and injection. Operative treatments include arthroscopic and open dorsal wrist ganglion resections. Rationale: Although nonoperative treatment can produce successful outcomes, the various modalities have been associated with recurrence rates ranging from 15% to 90% 4 . As a result, surgical excision remains the gold standard of treatment and is typically indicated when weakness, pain, and limited range of motion interfere with activities of daily living. Among surgical interventions, arthroscopic excision is a minimally invasive procedure that has become more common because of the reduced scarring and faster recovery 5 . However, open excision, which does not involve complex equipment, is regarded as the standard among surgical treatments. Although the rates of recurrence for arthroscopic versus open dorsal ganglion excision are similar, arthroscopic excision is less effective with regard to pain relief 5,6 . This difference in pain relief could potentially be the result of the neurectomy of the posterior interosseous nerve in an open excision. In contrast, an arthroscopic procedure may provide less relief of pain from the posterior interosseous nerve stump attaching to the scarred capsule 5 . Expected Outcomes: Open excision of a dorsal wrist ganglion is a safe, reliable procedure. The recurrence rate after open excision is similar to that after arthroscopic excision and significantly lower recurrence than that after ganglion cyst aspiration 6,7 . Additionally, not all ganglion cysts can be aspirated. In a retrospective study assessing the risk of recurrence after open excision of ganglion cysts in 628 patients, researchers reported a recurrence rate of 4.1% among the 341 who underwent open dorsal ganglion excision. Furthermore, the authors reported male sex and less surgeon experience as significant risk factors for cyst recurrence 8 . In a study assessing outcomes of open dorsal ganglion excision in 125 active-duty military personnel, researchers reported a recurrence rate of 9%. More notably, the researchers found persistent pain at 4 weeks postoperatively in 14% of the participants. The authors recommended that patients whose daily activities require forceful wrist extension, such as athletes and military personnel, should be counseled on the potential functional limitations and residual pain from open dorsal wrist ganglion excision 9 . Important Tips: When conducting an open excision, it is beneficial to identify the stalk of the cyst, allowing the surgeon to excise the complete ganglion complex and prevent recurrence. For large cysts that adhere to the surrounding soft tissue, it is helpful to rupture the ganglion in order to facilitate an easier deep dissection. Excising the scapholunate interosseous ligament could possibly lead to scapholunate dissociation and instability. The posterior interosseous nerve courses past the 4th dorsal compartment and may be resected during the deep dissection.

HCC recurrence following liver transplantation (LT) is highly morbid and occurs despite strict patient selection criteria. Individualized prediction of post-LT HCC recurrence risk remains an important need. Clinico-radiologic and pathologic data of 4981 patients with HCC undergoing LT from the US Multicenter HCC Transplant Consortium (UMHTC) were analyzed to develop a REcurrent Liver cAncer Prediction ScorE (RELAPSE). Multivariable Fine and Gray competing risk analysis and machine learning algorithms (Random Survival Forest and Classification and Regression Tree models) identified variables to model HCC recurrence. RELAPSE was externally validated in 1160 HCC LT recipients from the European Hepatocellular Cancer Liver Transplant study group. Of 4981 UMHTC patients with HCC undergoing LT, 71.9% were within Milan criteria, 16.1% were initially beyond Milan criteria with 9.4% downstaged before LT, and 12.0% had incidental HCC on explant pathology. Overall and recurrence-free survival at 1, 3, and 5 years was 89.7%, 78.6%, and 69.8% and 86.8%, 74.9%, and 66.7%, respectively, with a 5-year incidence of HCC recurrence of 12.5% (median 16 months) and non-HCC mortality of 20.8%. A multivariable model identified maximum alpha-fetoprotein (HR = 1.35 per-log SD, 95% CI,1.22–1.50, p < 0.001), neutrophil-lymphocyte ratio (HR = 1.16 per-log SD, 95% CI,1.04–1.28, p < 0.006), pathologic maximum tumor diameter (HR = 1.53 per-log SD, 95% CI, 1.35–1.73, p < 0.001), microvascular (HR = 2.37, 95%–CI, 1.87–2.99, p < 0.001) and macrovascular (HR = 3.38, 95% CI, 2.41–4.75, p < 0.001) invasion, and tumor differentiation (moderate HR = 1.75, 95% CI, 1.29–2.37, p < 0.001; poor HR = 2.62, 95% CI, 1.54–3.32, p < 0.001) as independent variables predicting post-LT HCC recurrence (C-statistic = 0.78). Machine learning algorithms incorporating additional covariates improved prediction of recurrence (Random Survival Forest C-statistic = 0.81). Despite significant differences in European Hepatocellular Cancer Liver Transplant recipient radiologic, treatment, and pathologic characteristics, external validation of RELAPSE demonstrated consistent 2- and 5-year recurrence risk discrimination (AUCs 0.77 and 0.75, respectively). We developed and externally validated a RELAPSE score that accurately discriminates post-LT HCC recurrence risk and may allow for individualized post-LT surveillance, immunosuppression modification, and selection of high-risk patients for adjuvant therapies.