Proteomic Analysis of the Senescence-Associated Secretory Phenotype: GDF-15, IGFBP-2, and Cystatin-C Are Associated With Multiple Aging Traits.

Cellular senescence, a hallmark of aging, results in a senescence-associated secretory phenotype (SASP) with an increased production of proinflammatory cytokines, growth factors, and proteases. Evidence from nonhuman models demonstrates that SASP contributes to tissue dysfunction and pathological effects of aging. However, there are relatively few human studies on the relationship between SASP and aging-related health outcomes. Proteins from the SASP Atlas were measured in plasma using aptamer-based proteomics (SomaLogic). Regression models were used to identify SASP protein associations with aging-related traits representing multiple aspects of physiology in 1 201 participants from 2 human cohort studies (BLSA/GESTALT and InCHIANTI). Traits examined were fasting glucose, C-reactive protein, interleukin-6, alkaline phosphatase, blood urea nitrogen, albumin, red blood cell distribution width, waist circumference, systolic and diastolic blood pressure, gait speed, and grip strength. Study results were combined with a fixed-effect inverse-variance weighted meta-analysis. In the meta-analysis, 28 of 77 SASP proteins were significantly associated with age. Of the 28 age-associated SASP proteins, 18 were significantly associated with 1 or more clinical traits, and 7 SASP proteins were significantly associated with 3 or more traits. Growth/differentiation factor 15, Insulin-like growth factor-binding protein 2, and Cystatin-C showed significant associations with inflammatory markers and measures of physical function (grip strength or gait speed). These results support the relevance of SASP proteins to human aging, identify specific traits that are potentially affected by SASP, and prioritize specific SASP proteins for their utility as biomarkers of human aging.

Temporal control by cofactors prevents kinetic trapping in retroviral Gag lattice assembly.

For retroviruses like HIV to proliferate, they must form virions shaped by the self-assembly of Gag polyproteins into a rigid lattice. This immature Gag lattice has been structurally characterized and reconstituted in vitro, revealing the sensitivity of lattice assembly to multiple cofactors. Due to this sensitivity, the energetic criterion for forming stable lattices is unknown, as are their corresponding rates. Here, we use a reaction-diffusion model designed from the cryo-ET structure of the immature Gag lattice to map a phase diagram of assembly outcomes controlled by experimentally constrained rates and free energies, over experimentally relevant timescales. We find that productive assembly of complete lattices in bulk solution is extraordinarily difficult due to the large size of this ∼3700 monomer complex. Multiple Gag lattices nucleate before growth can complete, resulting in loss of free monomers and frequent kinetic trapping. We therefore derive a time-dependent protocol to titrate or "activate" the Gag monomers slowly within the solution volume, mimicking the biological roles of cofactors. This general strategy works remarkably well, yielding productive growth of self-assembled lattices for multiple interaction strengths and binding rates. By comparing to the in vitro assembly kinetics, we can estimate bounds on rates of Gag binding to Gag and the cellular cofactor IP6. Our results show that Gag binding to IP6 can provide the additional time delay necessary to support smooth growth of the immature lattice with relatively fast assembly kinetics, mostly avoiding kinetic traps. Our work provides a foundation for predicting and disrupting formation of the immature Gag lattice via targeting specific protein-protein binding interactions.

Functional outcomes of Fournier's gangrene: a multi-institutional experience.

INTRODUCTION: Fournier's gangrene (FG), is a progressive, necrotizing soft tissue infection of the external genitalia, perineum, and/or anorectal region. How treatment and recovery from FG impacts quality of life related to sexual and general health is poorly characterized. Our purpose is to evaluate the long term impact of FG on overall and sexual quality of life using standardized questionnaires through a multi-institutional observational study. MATERIALS AND METHODS: Multi-institutional retrospective data were collected by standardized questionnaires on patient-reported outcome measures including the Changes in Sexual Functioning Questionnaire (CSFQ) and the Veterans RAND 36 (VR-36) survey of general health-related quality of life. Data were collected via telephone call, email, and certified mail, with a 10% response rate. There was no incentive for patient participation. RESULTS: Thirty-five patients responded to the survey, with 9 female and 26 male patients. All patients in the study underwent surgical debridement between 2007-2018 at three tertiary care centers. Further reconstructions were performed for 57% of respondents. Values for respondents with overall lower sexual function were reduced in all component categories (pleasure, desire/ frequency, desire/interest, arousal/excitement, orgasm/ completion), and trended toward male sex, older age, longer time from initial debridement to reconstruction, and poorer self-reported general health-related quality of life metrics. CONCLUSION: FG is associated with high morbidity and significant decreases in quality of life across general and sexual functional domains.

Myogenic bladder dysfunction and ureteral obstruction discovered in an adult patient with neurofibromatosis type 1: A case report.

We present a case of a 44-year-old male with cutaneous manifestations of neurofibromatosis type 1 presenting with long-standing urologic symptoms of uncertain etiology including urinary retention from myogenic bladder failure, chronic kidney disease with evidence of bilateral ureteral obstruction and presenting signs of an obstructing left ureterocele. This patient had a complete urologic evaluation and underwent ileocecocystoplasty with a continent catheterizable channel and bilateral ureteral reimplantation. Surgical excision of a left ureteral mound of tissue demonstrated the presence of a neurofibroma involving the bladder that led to obstruction. To our knowledge, this is the first report of such a presentation.

Antibiotic Prophylaxis for Megaprosthetic Reconstructions: Drug and Dosing May Matter More than Duration.

In orthopedic oncology, the implant of a megaprosthetic device is standard of care after large-scale tumor resection involving segmental removal of bone. Infection remains the leading cause of implant failure, often resulting in major morbidity. Perioperative antibiotic practices for megaprosthetic reconstructions are not standardized and are based on guidelines for conventional joint arthroplasties. This study aims to evaluate the efficacy of current prophylactic strategies for megaprosthetic reconstructions. We conducted a retrospective review of megaprosthetic reconstructions performed at Duke University from 2001 to 2021. Logistic regression with GEE was used to assess whether a prolonged course of postoperative antibiotics is associated with infection risk. We assessed the microbial profile and corresponding susceptibilities of megaprosthetic infections through record review. Additionally, we designed a pharmacokinetic subgroup analysis using liquid chromatography-tandem mass spectrometry to quantify antibiotic concentrations in surgical tissue. Wilcoxon rank-sum tests were used to correlate tissue concentrations with infection risk. Out of 184 cases, 23 (12.5%) developed infection within 1 year. Extended postoperative antibiotics were not significantly associated with infection risk (P = 0.23). Among 18 culture-positive cases, 4 (22.2%) were caused by cefazolin-susceptible organisms. Median bone and muscle concentrations of cefazolin among cases that developed postoperative infection (0.065 ng/mL and 0.2 ng/mL, respectively) were significantly lower than those of cases that did not (0.42 ng/mL and 1.95 ng/mL, P < 0.01 and P = 0.03). This study is the first to comprehensively assess aspects of perioperative prophylaxis for megaprosthetic reconstructions. Extending postoperative antibiotics did not reduce infection risk. We detected a high frequency of cefazolin nonsusceptible organisms among postoperative infections. Additionally, intraoperative antibiotic tissue concentrations may be predictive of later infection. Future studies ought to examine optimal drug choices and dosing strategies.

Genomic characterization of lytic bacteriophages targeting genetically diverse Pseudomonas aeruginosa clinical isolates.

Pseudomonas aeruginosa infections can be difficult to treat and new therapeutics are needed. Bacteriophage therapy is a promising alternative to traditional antibiotics, but large numbers of isolated and characterized phages are lacking. We collected 23 diverse P. aeruginosa isolates from people with cystic fibrosis (CF) and clinical infections, and used them to screen and isolate over a dozen P. aeruginosa-targeting phages from hospital wastewater. Phages were characterized with genome sequencing, comparative genomics, and lytic activity screening against all 23 bacterial host isolates. We evolved bacterial mutants that were resistant to phage infection for four different phages, and used genome sequencing and functional analysis to study them further. We also tested phages for their ability to kill P. aeruginosa grown in biofilms in vitro and ex vivo on CF airway epithelial cells. Overall, this study demonstrates how systematic genomic and phenotypic characterization can be deployed to develop bacteriophages as precision antibiotics.

Identifying Modifiable and Non-modifiable Risk Factors of Readmission and Short-Term Mortality in Chondrosarcoma: A National Cancer Database Study.

BACKGROUND: Limited data are available to inform the risk of readmission and short-term mortality in musculoskeletal oncology. The goal of this study was to identify factors independently associated with 30-day readmission and 90-day mortality following surgical resection of chondrosarcoma. METHODS: We retrospectively reviewed 6653 patients following surgical resection of primary chondrosarcoma in the National Cancer Database (2004-2017). Both demographic and clinicopathologic variables were assessed for correlation with readmission and short-term mortality utilizing univariate and multivariate logistic regression modeling. RESULTS: Of 220 readmissions (3.26%), risk factors independently associated with an increased risk of unplanned 30-day readmission included Charlson-Deyo Comorbidity Index (CDCC) (odds ratio [OR] 1.31; p = 0.027), increasing American Joint Committee on Cancer (AJCC) stage (OR 1.31; p = 0.004), undergoing major amputation (OR 2.38; p = 0.001), and axial skeletal location (OR 1.51; p = 0.028). A total of 137 patients died within 90 days of surgery (2.25%). Risk factors associated with increased mortality included the CDCC (OR 1.60; p = 0.001), increasing age (OR 1.06; p < 0.001), having Medicaid insurance status (OR 3.453; p = 0.005), living in a zip code with a higher educational attainment (OR 1.59; p = 0.003), increasing AJCC stage (OR 2.32; p < 0.001), longer postoperative length of stay (OR 1.015; p = 0.033), and positive surgical margins (OR 2.75; p = 0.001). Although a majority of the cohort did not receive radiation therapy (88.8%), receiving radiotherapy (OR 0.132; p = 0.010) was associated with a decreased risk of short-term mortality. CONCLUSIONS: Several tumor, treatment, and patient factors can help inform the risk of readmission and short-term mortality in patients with surgically treated chondrosarcoma.

Cross-Sectional and Prospective Associations of Rest-Activity Rhythms With Circulating Inflammatory Markers in Older Men.

Chronic increases in pro-inflammatory cytokines in older adults, known as inflammaging, are an important risk factor for morbidity and mortality in the aging population. It has been suggested that circadian disruption may play a role in chronic inflammation, but there has been limited study that investigated the overall profile of 24-hour rest-activity rhythms in relation to inflammation using longitudinal data. In the Outcomes of Sleep Disorders in Older Men Study, we applied the extended cosine model to derive multiple rest-activity rhythm characteristics using multiday actigraphy, and examined their associations with 6 inflammatory markers (ie, C-reactive protein [CRP], interleukin 6 [IL-6], tumor necrosis factor alpha [TNF-α], tumor necrosis factor alpha soluble receptor II [TNF-α-sRII], interleukin-1ß [IL-1ß], interferon gamma [IFN-γ]) measured from fasting blood. We assessed both the cross-sectional association between rest-activity rhythms and inflammatory markers measured at baseline, and the prospective association between baseline rest-activity rhythms and changes in inflammatory markers over 3.5 years of follow-up. We found that multiple rest-activity characteristics, including lower amplitude and relative amplitude, and decreased overall rhythmicity, were associated with higher levels of CRP, IL-6, TNF-α, and TNF-α-sRII, but not IL-1ß and IFN-γ at baseline. Moreover, the lowest quartile of these 3 rest-activity characteristics was associated with an approximately 2-fold increase in the odds of having elevated inflammation (ie, having 3 or more markers in the highest quartile) at baseline. However, we found little evidence supporting a relationship between rest-activity rhythm characteristics and changes in inflammatory markers. Future studies should clarify the dynamic relationship between rest-activity rhythms and inflammation in different populations, and evaluate the effects of improving rest-activity profiles on inflammation and related disease outcomes.

Use of a 5-item modified Fragility Index for risk stratification in patients undergoing surgical management of distal humerus fractures.

INTRODUCTION: We hypothesized that the modified Fragility Index (mFI), which predicts surgical complications, would be applicable to surgical complications in patients older than 50 years with distal humerus fractures (DHF). METHODS: We retrospectively reviewed the American College of Surgeons National Surgery Quality Improvement Program database, including patients older than 50 years who underwent open reduction and internal fixation of a DHF. A 5-item mFI score was calculated. Postoperative complications, readmission and reoperation rates, and length of stay were recorded. Univariate as well as a multivariable statistical analysis was performed, controlling for age, sex, body mass index, length of stay, and operative time. RESULTS: We identified 864 patients (mean age, 68.6 years ± 10.4), and 74.1% were female. As the mFI increased from 0 to 2 or greater, 30-day readmission rate increased from 3% to 10% (P value = .01), rate of discharge to rehabilitation facility increased from 12% to 32% (P value = .0), and any complication rate increased from 4% to 19% (P value = .0). Rates of pulmonary complications increased significantly in patients with the mFI of 2 or greater (P value = .047). Patients with the mFI of 2 or greater were nearly 4 times more likely to be readmitted within 30 days (odds ratio [OR] = 3.5, P value = .007) and had an increased OR of 30-day reoperation and any complication (OR = 3.7, P value = .02; OR = 4.5, P value = .00, respectively) on multivariate analysis. CONCLUSION: A fragility state is predictive of postoperative complications, readmission, and reoperation after surgical management of DHF. Our data suggest that a fragility evaluation can help inform surgical decision-making in patients older than 50 years with DHF.

Identifying Modifiable and Non-modifiable Risk Factors of Readmission and Short-Term Mortality in Osteosarcoma: A National Cancer Database Study.

BACKGROUND: There are limited data to inform risk of readmission and short-term mortality in musculoskeletal oncology. The goal of this study was to identify factors independently associated with 30-day readmission and 90-day mortality following surgical resection of osteosarcoma. METHODS: We retrospectively reviewed patients (n = 5293) following surgical resection of primary osteosarcoma in the National Cancer Database (2004-2015). Univariate and multivariate methods were used to correlate variables with readmission and short-term mortality. RESULTS: Of 210 readmissions (3.97%), risk factors independently associated with unplanned 30-day readmission included comorbidity burden (odds ratio [OR] 2.4, p = 0.042), Medicare insurance (OR 1.9, p = 0.021), and axial skeleton location (OR 1.5, p = 0.029). A total of 91 patients died within 90 days of their surgery (1.84%). Risk factors independently associated with mortality included age (hazard ratio 1.1, p < 0.001), increasing comorbidity burden (OR 6.6, p = 0.001), higher grade (OR 1.7, p = 0.007), increasing tumor size (OR 2.2, p = 0.03), metastatic disease at presentation (OR 8.5, p < 0.001), and amputation (OR 2.0, p = 0.04). Chemotherapy was associated with a decreased risk of short-term mortality (p < 0.001). CONCLUSIONS: Several trends were clear: insurance status, tumor location and comorbidity burden were independently associated with readmission rates, while age, amputation, grade, tumor size, metastatic disease, and comorbidity burden were independently associated with short-term mortality.

Use of a 5-item modified Fragility Index for risk stratification in patients undergoing surgical management of proximal humerus fractures.

HYPOTHESIS: We hypothesized that the modified Fragility Index (mFI) would predict complications in patients older than 50 years who underwent operative intervention for a proximal humerus fracture. METHODS: We retrospectively reviewed the American College of Surgeons National Surgery Quality Improvement Program database, including patients older than 50 years who underwent open reduction and internal fixation of a proximal humerus fracture. A 5-item mFI score was then calculated for each patient. Postoperative complications, readmission and reoperation rates as well as length of stay (LOS) were recorded. Univariate as well as multivariable statistical analyses were performed, controlling for age, sex, body mass index, LOS, and operative time. RESULTS: We identified 2,004 patients (median age, 66 years; interquartile range: 59-74), of which 76.2% were female. As mFI increased from 0 to 2 or greater, 30-day readmission rate increased from 2.8% to 6.7% (P-value = .005), rate of discharge to rehabilitation facility increased from 7.1% to 25.3% (P-value < .001), and rates of any complication increased from 6.5% to 13.9% (P-value < .001). Specifically, the rates of renal and hematologic complications increased significantly in patients with mFI of 2 or greater (P-value = .042 and P-value < .001, respectively). Compared with patients with mFI of 0, patients with mFI of 2 or greater were 2 times more likely to be readmitted within 30 days (odds ratio = 2.2, P-value .026). In addition, patients with mFI of 2 or greater had an increased odds of discharge to a rehabilitation center (odds ratio = 2.3, P-value < .001). However, increased fragility was not significantly associated with an increased odds of 30-day reoperation or any complication after controlling for demographic data, LOS, and operative time. CONCLUSION: An increasing level of fragility is predictive of readmission and discharge to a rehabilitation center after open reduction and internal fixation of proximal humerus fractures. Our data suggest that a simple fragility evaluation can help inform surgical decision-making and counseling in patients older than 50 years with proximal humerus fractures.

The effects of restricted glenohumeral horizontal adduction motion on shoulder and elbow forces in collegiate baseball pitchers.

BACKGROUND: Decreased glenohumeral (GH) horizontal adduction range of motion (ROM) among baseball pitchers has been associated with the development of various shoulder and elbow pathologies. No research has examined how this tightness may affect the forces placed on the shoulder and elbow during the pitching motion. METHODS: Fifty-five asymptomatic National Collegiate Athletic Association Division I baseball pitchers participated. Twenty-five participants had -10° or less horizontal adduction ROM in their throwing shoulder. The remaining 30 participants had greater than -10° of horizontal adduction. A digital inclinometer was used to measure GH horizontal adduction, internal rotation, and external rotation ROM while in 90° of shoulder abduction. Forces produced in the throwing shoulder and elbow were assessed with a 3-dimension, high-speed video capture system and based on the sum of angular momenta of the kinetic chain segments around the center of gravity. Separate 2-tailed t tests were run to determine significant differences between groups (P < .05). RESULTS: Both groups presented with significant bilateral differences in their total arcs of motion (P < .04). This suggests that the loss of horizontal adduction in these groups was at least partially due to soft tissue tightness. There were no significant between-group differences for shoulder external rotation torque or shoulder and elbow distraction (P > .10). The restricted ROM group had significantly more shoulder abduction torque (P = .04), shoulder horizontal abduction torque (P = .004), elbow flexion torque (P = .002), and elbow valgus torque (P = .02) compared with the control group. CONCLUSIONS: These results demonstrate that collegiate pitchers with -10° or less of horizontal adduction ROM in their throwing shoulder create significantly more shoulder abduction and horizontal abduction torque, as well as more elbow flexion and valgus torque, during the pitching motion than those with more ROM.

Needle in a haystack: Robotic removal of a retroperitoneal wire.

Retroperitoneal foreign bodies are rare indications for exploratory surgery. We present a case of a 19-year-old male with abdominal pain after a fall who was found to have a linear metallic object adjacent to the right ureter and inferior vena cava. Given the patient's pain and discomfort, he elected for robotic exploration of the retroperitoneum, which was carried out successfully with the Da Vinci Si® robot. This case demonstrates the feasibility of robotic retroperitoneal exploration and foreign body retrieval for a very small object.

Limb salvage versus amputation in patients with osteosarcoma of the extremities: an update in the modern era using the National Cancer Database.

BACKGROUND: Historically, amputation was the primary surgical treatment for osteosarcoma of the extremities; however, with advancements in surgical techniques and chemotherapies limb salvage has replaced amputation as the dominant treatment paradigm. This study assessed the type of surgical resection chosen for osteosarcoma patients in the twenty-first century. METHODS: Utilizing the largest registry of primary osteosarcoma, the National Cancer Database (NCDB), we retrospectively analyzed patients with high grade osteosarcoma of the extremities from 2004 through 2015. Differences between patients undergoing amputation and patients undergoing limb salvage are described. Unadjusted five-year overall survival between patients who received limb salvage and amputation was assessed utilizing Kaplan Meier curves. A multivariate Cox proportional hazard model and propensity matched analysis was used to determine the variables independently correlated with survival. RESULTS: From a total of 2442 patients, 1855 underwent limb salvage and 587 underwent amputation. Patients undergoing amputation were more likely to be older, male, uninsured, and live in zip codes associated with lower income. Patients undergoing amputation were also more likely to have larger tumors, more comorbid conditions, and metastatic disease at presentation. After controlling for confounders, limb salvage was associated with a significant survival benefit over amputation (HR: 0.70; p < 0.001). Although this may well reflect underlying biases impacting choice of treatment, this survival benefit remained significant after propensity matched analysis of all significantly different independent variables (HR: 0.71; p < 0.01). CONCLUSION: Among patients in the NCDB, amputation for osteosarcoma is associated with advanced age, advanced stage, larger tumors, greater comorbidities, and lower income. Limb salvage is associated with a significant survival benefit, even when controlling for significant confounding variables and differences between cohorts.

Development of a polygenic risk score to improve screening for fracture risk: A genetic risk prediction study.

BACKGROUND: Since screening programs identify only a small proportion of the population as eligible for an intervention, genomic prediction of heritable risk factors could decrease the number needing to be screened by removing individuals at low genetic risk. We therefore tested whether a polygenic risk score for heel quantitative ultrasound speed of sound (SOS)-a heritable risk factor for osteoporotic fracture-can identify low-risk individuals who can safely be excluded from a fracture risk screening program. METHODS AND FINDINGS: A polygenic risk score for SOS was trained and selected in 2 separate subsets of UK Biobank (comprising 341,449 and 5,335 individuals). The top-performing prediction model was termed "gSOS", and its utility in fracture risk screening was tested in 5 validation cohorts using the National Osteoporosis Guideline Group clinical guidelines (N = 10,522 eligible participants). All individuals were genome-wide genotyped and had measured fracture risk factors. Across the 5 cohorts, the average age ranged from 57 to 75 years, and 54% of studied individuals were women. The main outcomes were the sensitivity and specificity to correctly identify individuals requiring treatment with and without genetic prescreening. The reference standard was a bone mineral density (BMD)-based Fracture Risk Assessment Tool (FRAX) score. The secondary outcomes were the proportions of the screened population requiring clinical-risk-factor-based FRAX (CRF-FRAX) screening and BMD-based FRAX (BMD-FRAX) screening. gSOS was strongly correlated with measured SOS (r2 = 23.2%, 95% CI 22.7% to 23.7%). Without genetic prescreening, guideline recommendations achieved a sensitivity and specificity for correct treatment assignment of 99.6% and 97.1%, respectively, in the validation cohorts. However, 81% of the population required CRF-FRAX tests, and 37% required BMD-FRAX tests to achieve this accuracy. Using gSOS in prescreening and limiting further assessment to those with a low gSOS resulted in small changes to the sensitivity and specificity (93.4% and 98.5%, respectively), but the proportions of individuals requiring CRF-FRAX tests and BMD-FRAX tests were reduced by 37% and 41%, respectively. Study limitations include a reliance on cohorts of predominantly European ethnicity and use of a proxy of fracture risk. CONCLUSIONS: Our results suggest that the use of a polygenic risk score in fracture risk screening could decrease the number of individuals requiring screening tests, including BMD measurement, while maintaining a high sensitivity and specificity to identify individuals who should be recommended an intervention.

Evolution of vancomycin-resistant Enterococcus faecium during colonization and infection in immunocompromised pediatric patients.

Patients with hematological malignancies or undergoing hematopoietic stem cell transplantation are vulnerable to colonization and infection with multidrug-resistant organisms, including vancomycin-resistant Enterococcus faecium (VREfm). Over a 10-y period, we collected and sequenced the genomes of 110 VREfm isolates from gastrointestinal and blood cultures of 24 pediatric patients undergoing chemotherapy or hematopoietic stem cell transplantation for hematological malignancy at St. Jude Children's Research Hospital. We used patient-specific reference genomes to identify variants that arose over time in subsequent gastrointestinal and blood isolates from each patient and analyzed these variants for insight into how VREfm adapted during colonization and bloodstream infection within each patient. Variants were enriched in genes involved in carbohydrate metabolism, and phenotypic analysis identified associated differences in carbohydrate utilization among isolates. In particular, a Y585C mutation in the sorbitol operon transcriptional regulator gutR was associated with increased bacterial growth in the presence of sorbitol. We also found differences in biofilm-formation capability between isolates and observed that increased biofilm formation correlated with mutations in the putative E. faecium capsular polysaccharide (cps) biosynthetic locus, with different mutations arising independently in distinct genetic backgrounds. Isolates with cps mutations showed improved survival following exposure to lysozyme, suggesting a possible reason for the selection of capsule-lacking bacteria. Finally, we observed mutations conferring increased tolerance of linezolid and daptomycin in patients who were treated with these antibiotics. Overall, this study documents known and previously undescribed ways that VREfm evolve during intestinal colonization and subsequent bloodstream infection in immunocompromised pediatric patients.

18F-fluciclovine PET CT detection of biochemical recurrent prostate cancer at specific PSA thresholds after definitive treatment.

OBJECTIVES: To evaluate various Prostate-Specific Antigen (PSA) thresholds at which a 18F-fluciclovine PET scan could be considered in the setting of biochemical recurrent prostate cancer after definitive treatment. METHODS: We analyzed available records of men who underwent a 18F-fluciclovine PET scan after definitive therapy at a single academic institution between November 2016 to May 2018. The primary outcome was the rate of positive imaging findings at specific PSA thresholds. We then employed empiric strategies including a ROC curve and decision curve analysis to identify a specific threshold for which obtaining a positive result would be optimized. RESULTS: A total of 115 men underwent imaging with 18F-fluciclovine PET. No concerning lesions were identified in 25 (21.7%) patients, 32 (27.8%) had a solitary lesion identified, 45 (39.1%) had 2 to 5 lesions, and 13 (11.3%) had greater than 5 suspicious lesions identified. At PSA thresholds of less than 0.5, 0.5 to 2.0, and greater than 2, lesions were detected in 55.5% (12/22), 70.6% (24/34), and 91.5% (54/59) of patients respectively [P < 0.001]. Our ROC analysis yielded a PSA threshold of 2.10 while our decision curve analysis provided a PSA cutoff of 1.38. CONCLUSION: This study constitutes an early single institution series evaluating the use of 18F-fluciclovine PET scans in the assessment of biochemically recurrent prostate cancer after definitive treatment. The probability of having positive imaging findings and increasing numbers of suspicious lesions rises with increasing PSA. Utilization of a lower PSA threshold of 0.5 may allow earlier intervention with salvage therapies in biochemical recurrence. However, using a threshold below 1 carries a higher risk of negative scans. Employing a higher PSA threshold of 1 to 2 carries greater sensitivity and specificity and may maximize identifying individuals with early BCR who may benefit from early intervention, while minimizing negative scans.

Sequencing Analysis at 8p23 Identifies Multiple Rare Variants in DLC1 Associated with Sleep-Related Oxyhemoglobin Saturation Level.

Average arterial oxyhemoglobin saturation during sleep (AvSpO2S) is a clinically relevant measure of physiological stress associated with sleep-disordered breathing, and this measure predicts incident cardiovascular disease and mortality. Using high-depth whole-genome sequencing data from the National Heart, Lung, and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) project and focusing on genes with linkage evidence on chromosome 8p23,1,2 we observed that six coding and 51 noncoding variants in a gene that encodes the GTPase-activating protein (DLC1) are significantly associated with AvSpO2S and replicated in independent subjects. The combined DLC1 association evidence of discovery and replication cohorts reaches genome-wide significance in European Americans (p = 7.9 × 10-7). A risk score for these variants, built on an independent dataset, explains 0.97% of the AvSpO2S variation and contributes to the linkage evidence. The 51 noncoding variants are enriched in regulatory features in a human lung fibroblast cell line and contribute to DLC1 expression variation. Mendelian randomization analysis using these variants indicates a significant causal effect of DLC1 expression in fibroblasts on AvSpO2S. Multiple sources of information, including genetic variants, gene expression, and methylation, consistently suggest that DLC1 is a gene associated with AvSpO2S.

End-tidal CO2 Monitoring is Available in Most Community Hospitals in a Rural State: A Health System Survey.

INTRODUCTION: Procedural sedation and analgesia (PSA) provides safe and effective relief for pain, anxiety and discomfort during procedures performed in the emergency department (ED). Our objective was to identify hospital-level factors associated with routine PSA capnography use in the ED. METHODS: This study was a cross-sectional telephone survey of ED nurse managers and designees in a Midwestern state. Respondents identified information about hospital infrastructure, physician staffing, family practice (FP) physicians only, board-certified emergency physicians (EPs) only (or both), and critical intervention capabilities. Additional characteristics including ED volume and hospital designation (i.e., rural-urban classification) were obtained from the Centers for Medicare and Medicaid Services and the state hospital association database, respectively. The primary outcome was reported use of PSA capnography. We conducted univariate analyses (relative risks, 95% confidence interval [CI]) to identify associations between hospital-level characteristics and PSA capnography use. RESULTS: We had an overall response rate of 98% (n=118 participating hospitals). The majority of EDs were in rural settings (78%), with a median of 5,057 visits per year (interquartile range 2,823-14,322). Nearly half of the EDs were staffed by FP physicians only, while 16% had board-certified EPs only. Nearly all hospitals (n=114, 97%), reported using continuous capnography for ventilated patients, and 74% reported use of capnography during PSA. Urban hospitals were more likely to use PSA capnography than critical access hospitals (relative risk 1.45; 95% CI, 1.22-1.73), and PSA capnography use increased with each ED volume quartile. Facilities with only EPs were 1.46 (95% CI, 1.15-1.87) times more likely to use PSA capnography than facilities with FP physicians only. CONCLUSION: Continuous capnography was available in nearly all EDs, independent of size, location or patient volume. The implementation of capnography during PSA was less penetrant. Smaller, rural departments were less likely than their larger, urban counterparts to implement these national guidelines. Rurality and hospital size may be potential institutional barriers to capnography implementation.

Identification of Novel Loci Associated With Hip Shape: A Meta-Analysis of Genomewide Association Studies.

We aimed to report the first genomewide association study (GWAS) meta-analysis of dual-energy X-ray absorptiometry (DXA)-derived hip shape, which is thought to be related to the risk of both hip osteoarthritis and hip fracture. Ten hip shape modes (HSMs) were derived by statistical shape modeling using SHAPE software, from hip DXA scans in the Avon Longitudinal Study of Parents and Children (ALSPAC; adult females), TwinsUK (mixed sex), Framingham Osteoporosis Study (FOS; mixed), Osteoporotic Fractures in Men study (MrOS), and Study of Osteoporotic Fractures (SOF; females) (total N = 15,934). Associations were adjusted for age, sex, and ancestry. Five genomewide significant (p < 5 × 10-9 , adjusted for 10 independent outcomes) single-nucleotide polymorphisms (SNPs) were associated with HSM1, and three SNPs with HSM2. One SNP, in high linkage disequilibrium with rs2158915 associated with HSM1, was associated with HSM5 at genomewide significance. In a look-up of previous GWASs, three of the identified SNPs were associated with hip osteoarthritis, one with hip fracture, and five with height. Seven SNPs were within 200 kb of genes involved in endochondral bone formation, namely SOX9, PTHrP, RUNX1, NKX3-2, FGFR4, DICER1, and HHIP. The SNP adjacent to DICER1 also showed osteoblast cis-regulatory activity of GSC, in which mutations have previously been reported to cause hip dysplasia. For three of the lead SNPs, SNPs in high LD (r2 > 0.5) were identified, which intersected with open chromatin sites as detected by ATAC-seq performed on embryonic mouse proximal femora. In conclusion, we identified eight SNPs independently associated with hip shape, most of which were associated with height and/or mapped close to endochondral bone formation genes, consistent with a contribution of processes involved in limb growth to hip shape and pathological sequelae. These findings raise the possibility that genetic studies of hip shape might help in understanding potential pathways involved in hip osteoarthritis and hip fracture. © 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals, Inc.