Intersectional Hybrids between Darrow's Blueberry (V. darrowii Camp) and Lingonberry (V. vitis-idaea L.).

An initial cross of V. darrowii 'Johnblue' (Darrow's blueberry) × V. vitis-idaea 'Red Sunset' (lingonberry) produced more than 30 true intersectional diploid hybrids as confirmed by molecular markers. The most vigorous of these hybrids was extensively evaluated. This hybrid, US 2535-A, was floriferous and morphologically intermediate to the respective parents. Examination of pollen suggested low male fertility. Numerous crosses using the hybrid as a female reflected similarly low fertility and potential crossing barriers. Stylar examination suggested blockage of pollen tube growth in self-pollinations and significantly retarded growth in backcross pollinations. Nonetheless, two confirmed hybrid offspring were produced using the F1 hybrid as a female in crosses with V. vitis-idaea and V. darrowii, respectively. In a second set of crosses utilizing additional V. darrowii and V. vitis-idaea genotypes, another 23 verified hybrids in seven parental combinations were produced. Hybrids such as the ones presented offer the potential for generating de novo interspecific fruit types in blueberry and/or broadening the adaptation of lingonberry.

A Multidisciplinary Assessment of ChatGPT's Knowledge of Amyloidosis: Observational Study.

BACKGROUND: Amyloidosis, a rare multisystem condition, often requires complex, multidisciplinary care. Its low prevalence underscores the importance of efforts to ensure the availability of high-quality patient education materials for better outcomes. ChatGPT (OpenAI) is a large language model powered by artificial intelligence that offers a potential avenue for disseminating accurate, reliable, and accessible educational resources for both patients and providers. Its user-friendly interface, engaging conversational responses, and the capability for users to ask follow-up questions make it a promising future tool in delivering accurate and tailored information to patients. OBJECTIVE: We performed a multidisciplinary assessment of the accuracy, reproducibility, and readability of ChatGPT in answering questions related to amyloidosis. METHODS: In total, 98 amyloidosis questions related to cardiology, gastroenterology, and neurology were curated from medical societies, institutions, and amyloidosis Facebook support groups and inputted into ChatGPT-3.5 and ChatGPT-4. Cardiology- and gastroenterology-related responses were independently graded by a board-certified cardiologist and gastroenterologist, respectively, who specialize in amyloidosis. These 2 reviewers (RG and DCK) also graded general questions for which disagreements were resolved with discussion. Neurology-related responses were graded by a board-certified neurologist (AAH) who specializes in amyloidosis. Reviewers used the following grading scale: (1) comprehensive, (2) correct but inadequate, (3) some correct and some incorrect, and (4) completely incorrect. Questions were stratified by categories for further analysis. Reproducibility was assessed by inputting each question twice into each model. The readability of ChatGPT-4 responses was also evaluated using the Textstat library in Python (Python Software Foundation) and the Textstat readability package in R software (R Foundation for Statistical Computing). RESULTS: ChatGPT-4 (n=98) provided 93 (95%) responses with accurate information, and 82 (84%) were comprehensive. ChatGPT-3.5 (n=83) provided 74 (89%) responses with accurate information, and 66 (79%) were comprehensive. When examined by question category, ChatGTP-4 and ChatGPT-3.5 provided 53 (95%) and 48 (86%) comprehensive responses, respectively, to "general questions" (n=56). When examined by subject, ChatGPT-4 and ChatGPT-3.5 performed best in response to cardiology questions (n=12) with both models producing 10 (83%) comprehensive responses. For gastroenterology (n=15), ChatGPT-4 received comprehensive grades for 9 (60%) responses, and ChatGPT-3.5 provided 8 (53%) responses. Overall, 96 of 98 (98%) responses for ChatGPT-4 and 73 of 83 (88%) for ChatGPT-3.5 were reproducible. The readability of ChatGPT-4's responses ranged from 10th to beyond graduate US grade levels with an average of 15.5 (SD 1.9). CONCLUSIONS: Large language models are a promising tool for accurate and reliable health information for patients living with amyloidosis. However, ChatGPT's responses exceeded the American Medical Association's recommended fifth- to sixth-grade reading level. Future studies focusing on improving response accuracy and readability are warranted. Prior to widespread implementation, the technology's limitations and ethical implications must be further explored to ensure patient safety and equitable implementation.

Cancer-associated fibroblast-derived acetate promotes pancreatic cancer development by altering polyamine metabolism via the ACSS2-SP1-SAT1 axis.

The ability of tumour cells to thrive in harsh microenvironments depends on the utilization of nutrients available in the milieu. Here we show that pancreatic cancer-associated fibroblasts (CAFs) regulate tumour cell metabolism through the secretion of acetate, which can be blocked by silencing ATP citrate lyase (ACLY) in CAFs. We further show that acetyl-CoA synthetase short-chain family member 2 (ACSS2) channels the exogenous acetate to regulate the dynamic cancer epigenome and transcriptome, thereby facilitating cancer cell survival in an acidic microenvironment. Comparative H3K27ac ChIP-seq and RNA-seq analyses revealed alterations in polyamine homeostasis through regulation of SAT1 gene expression and enrichment of the SP1-responsive signature. We identified acetate/ACSS2-mediated acetylation of SP1 at the lysine 19 residue that increased SP1 protein stability and transcriptional activity. Genetic or pharmacologic inhibition of the ACSS2-SP1-SAT1 axis diminished the tumour burden in mouse models. These results reveal that the metabolic flexibility imparted by the stroma-derived acetate enabled cancer cell survival under acidosis via the ACSS2-SP1-SAT1 axis.

Vitamin B6 Competition in the Tumor Microenvironment Hampers Antitumor Functions of NK Cells.

Nutritional factors play crucial roles in immune responses. The tumor-caused nutritional deficiencies are known to affect antitumor immunity. Here, we demonstrate that pancreatic ductal adenocarcinoma (PDAC) cells can suppress NK-cell cytotoxicity by restricting the accessibility of vitamin B6 (VB6). PDAC cells actively consume VB6 to support one-carbon metabolism, and thus tumor cell growth, causing VB6 deprivation in the tumor microenvironment. In comparison, NK cells require VB6 for intracellular glycogen breakdown, which serves as a critical energy source for NK-cell activation. VB6 supplementation in combination with one-carbon metabolism blockage effectively diminishes tumor burden in vivo. Our results expand the understanding of the critical role of micronutrients in regulating cancer progression and antitumor immunity, and open new avenues for developing novel therapeutic strategies against PDAC. SIGNIFICANCE: The nutrient competition among the different tumor microenvironment components drives tumor growth, immune tolerance, and therapeutic resistance. PDAC cells demand a high amount of VB6, thus competitively causing NK-cell dysfunction. Supplying VB6 with blocking VB6-dependent one-carbon metabolism amplifies the NK-cell antitumor immunity and inhibits tumor growth in PDAC models. This article is featured in Selected Articles from This Issue, p. 5.

Left atrial Thrombus formation after discontinuation of anticoagulation in patient with severe bioprosthetic mitral stenosis.

BACKGROUND: Mitral valve stenosis can be a highly symptomatic condition with significant complications if left untreated. In such cases, mitral valve replacement with a bioprosthetic or mechanical valve may be a viable solution to prevent progressive disease. Current guidelines do not recommend continued anticoagulation beyond 6 months for patients who have undergone bioprosthetic valve replacement without a separate indication for anticoagulation. With this case discussion we aim to 1) Review the current indications for anticoagulation for bioprosthetic mitral valves in patients without atrial fibrillation and 2) Discuss the constellation of comorbidities that may affect the decision to begin anticoagulation therapy. CASE PRESENTATION: We present a case describing a 55-year-old male with end-stage renal disease, coronary artery disease with coronary artery bypass graft surgery, and bioprosthetic mitral valve replacement 2 years prior with rapid degeneration of the replaced valve and on warfarin without a clear indication for anticoagulation. The patient was admitted for symptomatic, severe mitral stenosis and consideration of transcatheter mitral valve-in-valve replacement. During hospital admission, warfarin was discontinued and replaced with prophylactic anticoagulation. However, 8 days after warfarin cessation an intraoperative transesophageal echocardiography revealed a newly developed large left atrial thrombus leading to cancellation of the planned operation. CONCLUSIONS: This patient developed a left atrial thrombus after discontinuing warfarin in the setting of rapidly deteriorating bioprosthetic valve stenosis and vascular comorbidities. The decision to discontinue warfarin was made in concordance with current guidelines, which do not indicate systemic anticoagulation post 3-6 months after bioprosthetic valve replacement without separate indication for anticoagulation. This case identifies the need to investigate rebound hypercoagulability and further risk stratify comorbidities which may independently increase the risk of clot formation in the setting of severe mitral valve stenosis.

Ultrasound Examination Without Axial Imaging is Sufficient for Preoperative Planning in Transcarotid Artery Revascularization (TCAR).

BACKGROUND: Duplex ultrasound is frequently used to determine the degree of carotid stenosis. However, axial imaging is typically obtained for operative planning for transcarotid artery revascularization (TCAR). We examined if ultrasound alone is sufficient before TCAR. METHODS: Data from the Vascular Quality Initiative TCAR Surveillance Project registry between 2016 and 2021 was obtained. Patients were divided into 2 groups-those with preoperative ultrasound-alone (US) and those with additional axial imaging (AX). Perioperative outcomes were compared utilizing univariate Chi-square, independent t-test, multivariate logistic regression, and Kaplan-Meier analysis. RESULTS: There were 3,418 patients identified: 682 in the US group and 2,736 in the AX group. More preoperative hypertension was reported in US (16.1% vs. 10.2%, P < 0.001) while cardiovascular disease (23% vs. 28.9%, P = 0.006) and prior ipsilateral stroke (22% vs. 32.7%, P = 0.002) were more prevalent in AX. More patients had history of contralateral carotid endarterectomy (13.6% vs. 16.7%, P = 0.035) or either ipsilateral (2.6% vs. 1.2%, P = 0.002) or contralateral (7.9% vs. 4.9%, P = 0.008) carotid artery stenting in the US group. Lower preoperative creatinine was reported in the US cohort (1.09 ± 0.01 vs. 1.18 ± 0.02, P < 0.001) while more were symptomatic in AX (28.2% vs. 36.2%, P < 0.001). There were no significant differences between lesion characteristics or operative decision making. A slightly higher total procedure time was seen in AX (73.7 ± 0.6 vs. 68.6 ± 1.3 min, P = 0.017). No differences were seen in perioperative transient ischemic attack/stroke or other immediate complications. At 2-year follow-up, both groups reported no significant differences in stroke-free survival (P = 0.750) and independent functional status remained near-identical (97.3% vs. 97.4%, P = 0.921). Kaplan-Meier analysis yielded no significant difference between mortality at 2 years (P = 0.563). Bivariate logistic regression modeling did reveal a statistically significant increase in likelihood of long-term ipsilateral stroke (odds ratio 1.77, P = 0.015) and non stroke-related complication in the postoperative period (odds ratio 4.81, P = 0.005). However, only a statistically significant relationship persisted in non-stroke complication when the model was controlled for between-group differences. CONCLUSIONS: No significant differences in postoperative or long-term complications were noted with additional AX in preoperative TCAR planning. Thus, duplex ultrasound offers a safe and effective alternative for those with contraindication or axial imaging.

Effects of blended learning training for oncology physicians to advise their patients about complementary and integrative therapies: results from the multicenter cluster-randomized KOKON-KTO trial.

BACKGROUND: Many oncology physicians are confronted with the topic of complementary and integrative medicine (CIM) by cancer patients. This study examined whether a blended learning (e-learning and a workshop) to train oncology physicians in providing advice on CIM therapies to their cancer patients, in addition to distributing an information leaflet about reputable CIM websites, had different effects on physician-reported outcomes in regard to consultations compared with only distributing the leaflet. METHODS: In a multicenter, cluster-randomized trial, 48 oncology physicians were randomly allocated to an intervention group (CIM consultation and an information leaflet) or a control group (information leaflet only). After the training, the oncology physicians conducted 297 consultations with their cancer patients. Measurements were assessed at oncology physician, physician-patient-interaction (measured by external reviewers), and patient levels. This analysis focused on the physician outcomes of stress reaction and perceived consultation skill competency. In addition, qualitative interviews were conducted with a subsample of oncology physicians who experienced both, the intervention and control condition. RESULTS: The oncology physicians in the intervention group showed a lower stress reaction in all measured dimensions after CIM consultations than those in the control group. There was no significant difference between oncology physicians in the intervention and control groups regarding the perceived consultation skill competency (overburden: intervention 1.4 [95% CI: 0.7;2.1]; control 2.1 [95% CI: 1.4;2.7], tension: 1.3 [95% CI: 0.7;2.0] vs. 1.9 [95% CI: 1.3;2.5], and discomfort with consultation situations: 1.0 [95% CI: 0.4;1.7]; vs. 1.7 [95% CI: 1.2;2.3]). The qualitative data showed that only providing the leaflet seemed impersonal to oncology physicians, while the training made them feel well prepared to conduct a full conversation about CIM and provide the information leaflet. CONCLUSIONS: In our exploratory study providing structured CIM consultations showed positive effects on the perceived stress of oncology physicians, and the training was subjectively experienced as an approach that improved physician preparation for advising cancer patients about CIM, however no effects regarding perceived consultation skill competency were found. TRIAL REGISTRATION: The trial registration number of the KOKON-KTO study is DRKS00012704 in the German Clinical Trials Register (Date of registration: 28.08.2017).

Staging Endovascular Thoracic and Thoracoabdominal Aortic Aneurysm Repairs and the Risk of Post-operative Spinal Cord Ischemia.

OBJECTIVE: Staged aortic aneurysm repair is one method used to decrease the risk of spinal cord ischemia (SCI) following endovascular aortic intervention. Sequential sacrifice of arteries perfusing the spine may allow for improved spinal perfusion through the development of collateral networks over time. To evaluate the impact of staging endovascular aortic aneurysm repairs on SCI, we conducted a conservative analysis of Vascular Quality Initiative (VQI) data. METHODS: De-identified VQI data were queried for cases of endovascular thoracic and thoracoabdominal aneurysm repairs from year 2014 to 2019. Cases were selected based on inclusion criteria: aneurysmal disease, no ruptures, no prior aortic surgeries, no retreatments, and only cases with complete data on aortic zones and SCI. Chi-square, Student's t-tests, and Mann-Whitney U tests were used for univariable analyses, as appropriate. Logistic regression analyses were used to identify independent predictors of outcome. RESULTS: There were 116 staged aortic repairs (SARs) (8.2%) performed out of a total of 1421 endovascular aortic repairs that fit study criteria. The overall rate of SCI within the study cohort was 3.4% (n = 48). The distribution of SARs and SCI events according to aortic zone coverage are displayed in Table 1. Patients who underwent staged endovascular aortic repairs had higher rates of SCI, pre-op spinal drain placement, non-African-American race, COPD, smoking history, positive stress tests, aspirin and statin use, increased estimated blood loss, physician-modified endografts, number of aortic zones covered, lower pre-op hemoglobin levels, larger aneurysm sac size, fusiform aneurysms, and longer total procedure times, Table 2. After adjusting for factors associated with SCI, a priori, and factors with a P < 0.1 univariable analysis, SAR was not associated with SCI (odds ratio [OR] = 1.86, 95% confidence interval [CI] = 0.77-4.50, P = 0.17). Of the six factors associated with SCI on univariable analysis, only procedure time ≥6 hours (OR = 2.49, 95% CI = 1.09-5.70, P = 0.031) and the number of aortic zones covered (OR = 1.15, 95% CI = 1.00-1.32, P = 0.047) were predictive of SCI. Staged repairs had a lower proportion of permanent SCI (38%, 3 of 8 cases) compared with repairs that were not staged (68%, 27 of 40 cases), with a relative risk reduction of 44% for those who developed SCI, P = 0.21. CONCLUSIONS: In a large national data set, SARs were performed for patients with more extensive aortic disease. SARs were only performed in about 8% of cases and the rate of SCI remained low. After adjusting for baseline comorbidities, extent of aortic disease, and other factors that may potentiate SCI, staged aortic aneurysm repair had a similar risk of SCI compared with non-staged repairs. However, there was a trend toward decreased permanent SCI risk in the SAR group.

CD73 induces GM-CSF/MDSC-mediated suppression of T cells to accelerate pancreatic cancer pathogenesis.

Metabolic alterations regulate cancer aggressiveness and immune responses. Given the poor response of pancreatic ductal adenocarcinoma (PDAC) to conventional immunotherapies, we investigated the link between metabolic alterations and immunosuppression. Our metabolic enzyme screen indicated that elevated expression of CD73, an ecto-5'-nucleotidase that generates adenosine, correlates with increased aggressiveness. Correspondingly, we observed increased interstitial adenosine levels in tumors from spontaneous PDAC mouse models. Diminishing CD73 by genetic manipulations ablated in vivo tumor growth, and decreased myeloid-derived suppressor cells (MDSC) in orthotopic mouse models of PDAC. A high-throughput cytokine profiling demonstrated decreased GM-CSF in mice implanted with CD73 knockdowns. Furthermore, we noted increased IFN-γ expression by intratumoral CD4+ and CD8+ T cells in pancreatic tumors with CD73 knockdowns. Depletion of CD4+ T cells, but not CD8+ T cells abrogated the beneficial effects of decreased CD73. We also observed that splenic MDSCs from Nt5e knockdown tumor-bearing mice were incompetent in suppressing T cell activation in the ex vivo assays. Replenishing GM-CSF restored tumor growth in Nt5e knockout tumors, which was reverted by MDSC depletion. Finally, anti-CD73 antibody treatment significantly improved gemcitabine efficacy in orthotopic models. Thus, targeting the adenosine axis presents a novel therapeutic opportunity for improving the anti-tumoral immune response against PDAC.

The Impact of COVID-19 on Routine Medical Care and Cancer Screening.

BACKGROUND: COVID-19 restrictions and fear dramatically changed the use of medical care. Understanding the magnitude of cancelled and postponed appointments and associated factors can help identify approaches to mitigate unmet need. OBJECTIVE: To determine the proportion of medical visits cancelled or postponed and for whom. We hypothesized that adults with serious medical conditions and those with higher anxiety, depressive symptoms, and avoidance-oriented coping would have more cancellations/postponements. DESIGN: Four nationally representative cross-sectional surveys conducted online in May, July, October, and December 2020. PARTICIPANTS: 59,747 US adults who completed 15-min online surveys. 69% cooperation rate. MEASURES: Physical and mental health visits and cancer screening cancelled or postponed over prior 2 months. Plan to cancel or postpone visits over the next 2 months. Relationship with demographics, medical conditions, local COVID-19 death rate, anxiety, depressive symptoms, coping, intolerance of uncertainty, and perceived COVID-19 risk. KEY RESULTS: Of the 58% (N = 34,868) with a medical appointment during the 2 months before the survey, 64% had an appointment cancelled or postponed in May, decreasing to 37% in December. Of the 41% of respondents with scheduled cancer screening, 20% cancelled/postponed, which was stable May to December. People with more medical conditions were more likely to cancel or postpone medical visits (OR 1.19 per condition, 95% CI 1.16, 1.22) and cancer screening (OR 1.20, 95% CI 1.15, 1.24). Race, ethnicity, and income had weak associations with cancelled/postponed visits, local death rate was unrelated, but anxiety and depressive symptoms were strongly related to cancellations, and this grew between May and December. CONCLUSIONS: Cancelled medical care and cancer screening were more common among persons with medical conditions, anxiety and depression, even after accounting for COVID-19 deaths. Outreach and support to ensure that patients are not avoiding needed care due to anxiety, depression and inaccurate perceptions of risk will be important.

Contemporary rates of inferior vena cava filter thrombosis and risk factors.

OBJECTIVE: Inferior vena cava (IVC) thrombosis is an uncommon complication associated with IVC filters (IVCFs), with studies reporting rates ranging from 1% to 31%. Few observational studies have described the risk factors associated with IVCF thrombosis, despite the significant clinical sequelae such as post-thrombotic syndrome, venous claudication, and venous ulceration. To better describe IVCF thrombosis and the risk factors, data were queried from Vascular Quality Initiative (VQI) participating centers. METHODS: IVCF data were obtained from the international VQI database from 2013 to 2019. The patients included in the present analysis had 2 years of follow-up data available. The baseline demographics, medical comorbidities, medication, and procedural, anatomic, and postoperative variables were assessed using Kaplan-Meier survival curves with log-rank tests, Student's t tests, or Mann-Whitney U tests for IVCF thrombosis at 2 years. Cox regression analyses were used to identify independent predictors of IVCF thrombosis. A subgroup analysis of those who had presented with venous thromboembolism (VTE) was also performed. RESULTS: A total of 62 U.S. and Canadian VQI-participating centers included 12,874 cases of IVCF placement. Of the 5780 cases with 2 years of follow-up available, 78 (1.3%) had developed IVCF thrombosis. Those who had experienced IVCF thrombosis had had significantly lower rates of diabetes, coronary artery disease, preoperative antiplatelet medications, preoperative statin use, and lower rates of discharge and follow-up antiplatelet medications. On univariable analysis, the cases of IVCF thrombosis also had higher rates of pulmonary embolism and VTE on admission, internal jugular venous access (vs femoral vein access), temporary IVCF use, follow-up anticoagulation, follow-up IVCF complication, follow-up access site thrombosis, and rates of new or propagated deep vein thrombosis at follow-up, and longer postoperative hospital stays. Multivariable analysis demonstrated that the independent predictors of IVCF thrombosis included new or propagated deep vein thrombosis at follow-up (hazard ratio [HR], 16.3; 95% confident interval [CI], 9.8-27.3; P < .001), no antiplatelet therapy at follow-up (HR, 4.8; 95% CI, 1.9-12.5; P = .001), internal jugular venous access (HR, 2.2; 95% CI, 1.4-3.5; P = .001), the presence of VTE on admission (HR, 2.7; 95% CI, 1.4-5.1; P = .002), and temporary IVCF placement (HR, 2.5; 95% CI, 1.1-5.6; P = .031). In an analysis of the subgroup of patients with VTE on admission, similar predictive factors were identified in a multivariable model. Massive pulmonary embolism was also predictive of IVCF thrombosis in this subgroup. CONCLUSIONS: The rate of IVCF thrombosis remained low in a contemporary international database. The results from the present study of >5000 patients with IVCFs suggest that antiplatelet therapy should be administered after IVCF placement to decreased the risk of IVCF thrombosis.

Thoracic Endovascular Aortic Repair for Iatrogenic Injury of the Thoracic Aorta.

PURPOSE: Address iatrogenic injury to the descending thoracic aorta by breached spinal screws through a novel approach of concomitant spinal screw removal and thoracic endovascular repair (TEVAR) placement. CASE REPORT: A 36-year-old female with idiopathic scoliosis underwent T4 to L3 bilateral pedicle instrumentation with spinal fusion and correction of scoliosis deformity. Ten months post-operative, she continued to complain of mid-thoracic pain; computed tomography (CT) angiography revealed protrusion of the left T5 and T6 transpedicular screws into her descending thoracic aorta by 3 and 5 mm, respectively. She was taken to the odds ratio (OR) in a combination case with vascular and neurosurgery. Positioned in the right lateral decubitus position, TEVAR was successfully deployed while neurosurgery concurrently removed the invading spinal screws via posterior spinal exposure. Neurosurgery then completely revised the spinal hardware during the same operation. The patient progressed well throughout the remainder of her hospital stay and was discharged on postoperative day 4. Two-year angiography demonstrated a well-placed TEVAR with no extravasation or aortic abnormality. CONCLUSIONS: In the setting of iatrogenic aortic injury due to pedicle screws, concomitant TEVAR and spinal screw removal is a safe and feasible treatment option that allows for spinal reconstruction to occur without multiple trips to the operating room.

The cholesterol pathway: impact on immunity and cancer.

Cholesterol is a multifaceted metabolite that is known to modulate processes in cancer, atherosclerosis, and autoimmunity. A common denominator between these diseases appears to be the immune system, in which many cholesterol-associated metabolites impact both adaptive and innate immunity. Many cancers display altered cholesterol metabolism, and recent studies demonstrate that manipulating systemic cholesterol metabolism may be useful in improving immunotherapy responses. However, cholesterol can have both proinflammatory and anti-inflammatory roles in mammals, acting via multiple immune cell types, and depending on context. Gaining mechanistic insights into various cholesterol-related metabolites can improve our understanding of their functions and extensive effects on the immune system, and ideally will inform the design of future therapeutic strategies against cancer and/or other pathologies.

Rapidly Destructive Hip Disease Following Intra-Articular Corticosteroid Injection of the Hip.

BACKGROUND: While recent reports have suggested that hip corticosteroid injections can hasten joint degeneration, there are few published data on the topic. The purpose of the present study was to evaluate for an association between corticosteroid injection and rapidly destructive hip disease (RDHD) and to determine the rate of, and risk factors for, occurrence. METHODS: This study was conducted in 2 parts. First, to assess for a potential association between hip corticosteroid injection and RDHD, a case-control analysis was performed. Patients who developed RDHD between 2013 and 2016 served as cases, whereas those who underwent total hip arthroplasty for diagnoses other than RDHD during the same period served as controls, and the exposure of interest was prior intra-articular hip corticosteroid injection. Second, in a retrospective cohort analysis, we analyzed all patients who received a fluoroscopically guided intra-articular hip corticosteroid injection at our institution from 2013 to 2016. The rate of post-injection RDHD was determined, and logistic regression was used to identify risk factors for occurrence. RESULTS: In the case-control analysis, hip corticosteroid injection was associated with the development of RDHD (adjusted odds ratio, 8.56 [95% confidence interval, 3.29 to 22.3], p < 0.0001). There was evidence of a dose-response curve, with the risk of RDHD increasing with injection dosage as well as with the number of injections received. In the retrospective cohort analysis, the rate of post-injection RDHD was 5.4% (37 of 688). Cases of post-injection RDHD were diagnosed at an average of 5.1 months following injection and were characterized by rapidly progressive joint-space narrowing, osteolysis, and collapse of the femoral head. CONCLUSIONS: This study documents an association between hip corticosteroid injection and RDHD. While the risk of RDHD following a single low-dose (≤40 mg) triamcinolone injection is low, the risk is higher following high-dose (≥80 mg) injection and multiple injections. These findings provide information that can be used to counsel patients about the risks associated with this common procedure. In addition, caution should be taken with intra-articular hip injections utilizing ≥80 mg of corticosteroid and multiple injections. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Live cell tagging tracking and isolation for spatial transcriptomics using photoactivatable cell dyes.

A cell's phenotype and function are influenced by dynamic interactions with its microenvironment. To examine cellular spatiotemporal activity, we developed SPACECAT-Spatially PhotoActivatable Color Encoded Cell Address Tags-to annotate, track, and isolate cells while preserving viability. In SPACECAT, samples are stained with photocaged fluorescent molecules, and cells are labeled by uncaging those molecules with user-patterned near-UV light. SPACECAT offers single-cell precision and temporal stability across diverse cell and tissue types. Illustratively, we target crypt-like regions in patient-derived intestinal organoids to enrich for stem-like and actively mitotic cells, matching literature expectations. Moreover, we apply SPACECAT to ex vivo tissue sections from four healthy organs and an autochthonous lung tumor model. Lastly, we provide a computational framework to identify spatially-biased transcriptome patterns and enriched phenotypes. This minimally perturbative and broadly applicable method links cellular spatiotemporal and/or behavioral phenotypes with diverse downstream assays, enabling insights into the connections between tissue microenvironments and (dys)function.

Age-based outcomes of autogenous fistulas for hemodialysis access.

BACKGROUND: Hemodialysis (HD) dependence and autogenous fistula use for HD span the spectrum of age. This study examines age-related outcomes of autogenous fistulas for HD access in a large population-based cohort of patients. METHODS: A retrospective cohort study of all patients who initiated HD in the United States Renal Database System (2007-2014). χ2 tests, t tests, Kaplan-Meier, log-rank tests, multivariable logistic, and Cox regression analyses were employed to evaluate access maturation, interventions, patency, and mortality. RESULTS: Of the 303,281 patients studied, 48,892 (16.1%) were younger than 50 years, 55,817 (18.4%) were 50 to 59 years, 79,138 (26.1%) were 60 to 69 years, 75,200 (24.8%) were 70 to 79 years, and 44,234 (14.6%) were 80 years or older. There was a decrease in autogenous fistula maturation with increasing age. Primary patency at 5 years comparing patients <50 vs 50 to 59 vs 60 to 69 vs 70 to 79 vs 80+ years was 24% vs 23% vs 21% vs 20% vs 18% (P < .001). Primary assisted patency at 5 years was 38% vs 40% vs 37% vs 35% vs 33% (P < .001). Secondary patency at 5 years was 48% vs 50% vs 47% vs 45% vs 42% (P < .001). The risk-adjusted analyses revealed a progressive decrease in primary, primary assisted, and secondary patency with increasing age. As expected, patient survival decreased with increasing age. CONCLUSIONS: In this population-based cohort of HD patients, there was a decrease in autogenous fistula maturation, primary patency, primary assisted patency, secondary patency, and patient survival with increasing age. Despite the relative decline in outcomes associated with older age, decisions about arteriovenous access creation in older patients should be individualized, taking overall clinical status and outcomes of alternatives modes of access into consideration.

Metabolic Rewiring by Loss of Sirt5 Promotes Kras-Induced Pancreatic Cancer Progression.

BACKGROUND & AIMS: SIRT5 plays pleiotropic roles via post-translational modifications, serving as a tumor suppressor, or an oncogene, in different tumors. However, the role SIRT5 plays in the initiation and progression of pancreatic ductal adenocarcinoma (PDAC) remains unknown. METHODS: Published datasets and tissue arrays with SIRT5 staining were used to investigate the clinical relevance of SIRT5 in PDAC. Furthermore, to define the role of SIRT5 in the carcinogenesis of PDAC, we generated autochthonous mouse models with conditional Sirt5 knockout. Moreover, to examine the mechanistic role of SIRT5 in PDAC carcinogenesis, SIRT5 was knocked down in PDAC cell lines and organoids, followed by metabolomics and proteomics studies. A novel SIRT5 activator was used for therapeutic studies in organoids and patient-derived xenografts. RESULTS: SIRT5 expression negatively regulated tumor cell proliferation and correlated with a favorable prognosis in patients with PDAC. Genetic ablation of Sirt5 in PDAC mouse models promoted acinar-to-ductal metaplasia, precursor lesions, and pancreatic tumorigenesis, resulting in poor survival. Mechanistically, SIRT5 loss enhanced glutamine and glutathione metabolism via acetylation-mediated activation of GOT1. A selective SIRT5 activator, MC3138, phenocopied the effects of SIRT5 overexpression and exhibited antitumor effects on human PDAC cells. MC3138 also diminished nucleotide pools, sensitizing human PDAC cell lines, organoids, and patient-derived xenografts to gemcitabine. CONCLUSIONS: Collectively, we identify SIRT5 as a key tumor suppressor in PDAC, whose loss promotes tumorigenesis through increased noncanonic use of glutamine via GOT1, and that SIRT5 activation is a novel therapeutic strategy to target PDAC.

Metabolic and Immunological Subtypes of Esophageal Cancer Reveal Potential Therapeutic Opportunities.

BACKGROUND: Esophageal cancer has the sixth highest rate of cancer-associated deaths worldwide, with many patients displaying metastases and chemotherapy resistance. We sought to find subtypes to see if precision medicine could play a role in finding new potential targets and predicting responses to therapy. Since metabolism not only drives cancers but also serves as a readout, metabolism was examined as a key reporter for differences. METHODS: Unsupervised and supervised classification methods, including hierarchical clustering, partial least squares discriminant analysis, k-nearest neighbors, and machine learning techniques, were used to discover and display two major subgroups. Genes, pathways, gene ontologies, survival, and immune differences between the groups were further examined, along with biomarkers between the groups and against normal tissue. RESULTS: Esophageal cancer had two major unique metabolic profiles observed between the histological subtypes esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC). The metabolic differences suggest that ESCC depends on glycolysis, whereas EAC relies more on oxidative metabolism, catabolism of glycolipids, the tricarboxylic acid (TCA) cycle, and the electron transport chain. We also noted a robust prognostic risk associated with COQ3 expression. In addition to the metabolic alterations, we noted significant alterations in key pathways regulating immunity, including alterations in cytokines and predicted immune infiltration. ESCC appears to have increased signature associated with dendritic cells, Th17, and CD8 T cells, the latter of which correlate with survival in ESCC. We bioinformatically observed that ESCC may be more responsive to checkpoint inhibitor therapy than EAC and postulate targets to enhance therapy further. Lastly, we highlight correlations between differentially expressed enzymes and the potential immune status. CONCLUSION: Overall, these results highlight the extreme differences observed between the histological subtypes and may lead to novel biomarkers, therapeutic strategies, and differences in therapeutic response for targeting each esophageal cancer subtype.

Development and validation of a multivariable model and online decision-support calculator to aid in preoperative discrimination of benign from malignant splenic masses in dogs.

OBJECTIVE: To develop a multivariable model and online decision-support calculator to aid in preoperative discrimination of benign from malignant splenic masses in dogs. ANIMALS: 522 dogs that underwent splenectomy because of splenic masses. PROCEDURES: A multivariable model was developed with preoperative clinical data obtained retrospectively from the records of 422 dogs that underwent splenectomy. Inclusion criteria were the availability of complete abdominal ultrasonographic examination images and splenic histologic slides or histology reports for review. Variables considered potentially predictive of splenic malignancy were analyzed. A receiver operating characteristic curve was created for the final multivariable model, and area under the curve was calculated. The model was externally validated with data from 100 dogs that underwent splenectomy subsequent to model development and was used to create an online calculator to estimate probability of splenic malignancy in individual dogs. RESULTS: The final multivariable model contained 8 clinical variables used to estimate splenic malignancy probability: serum total protein concentration, presence (vs absence) of ≥ 2 nRBCs/100 WBCs, ultrasonographically assessed splenic mass diameter, number of liver nodules (0, 1, or ≥ 2), presence (vs absence) of multiple splenic masses or nodules, moderate to marked splenic mass inhomogeneity, moderate to marked abdominal effusion, and mesenteric, omental, or peritoneal nodules. Areas under the receiver operating characteristic curves for the development and validation populations were 0.80 and 0.78, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: The online calculator (T-STAT.net or T-STAT.org) developed in this study can be used as an aid to estimate the probability of malignancy in dogs with splenic masses and has potential to facilitate owners' decisions regarding splenectomy.