Cancer Incidence and Survival Among Patients Following an Acute Coronary Syndrome.

To examine the role of acute coronary syndrome (ACS) in subsequent cancer incidence and survival, 2 cohorts of patients hospitalized with ACS were matched 1:1 by gender and age (±3 years) to cardiovascular disease (CVD)-free patients from 2 cycles of the Israeli National Health and Nutrition Surveys. Data on all-cause mortality were retrieved from national registries. Cancer incidence with death treated as a competing event, overall survival, and mortality risk associated with incident cancer as a time-dependent variable were compared between the groups. Our cohort included 2,040 cancer-free matched pairs (mean age of 60±14 years, 42.5% women). Despite higher rates of smokers and patients with hypertension and diabetes mellitus, 10-year cumulative cancer incidence was significantly lower in the ACS group compared with CVD-free group (8.0% vs 11.4%, p = 0.02). This decreased risk was more pronounced in women than men (pinteraction = 0.05). Although being free of CVD meant a significant (p <0.001) survival advantage in the general cohort, this advantage faded once a cancer diagnosis was made (p = 0.80). After adjustment for sociodemographic and clinical covariates, the hazard ratios for mortality associated with a cancer diagnosis were 2.96 (95% confidence interval: 2.36 to 3.71) in the ACS group versus 6.41 (95% confidence interval: 4.96 to 8.28) in the CVD-free group (Pinteraction<0.001). In conclusion, in this matched cohort, ACS was associated with a lower risk of cancer and mitigated the excess risk of mortality associated with cancer incidence.

Association between objective measures and parent-reported measures of child tobacco smoke exposure: A secondary data analysis of four trials.

INTRODUCTION: Tobacco smoke exposure (TSE) harms children and adults. Studies of childhood TSE exposure often relies on parental reports, but may benefit from objective measures. The objective of our study was to study the relationship between reported and objective measures of TSE. METHODS: We analyzed data from four intervention trials, conducted in clinical or community settings, to identify objective measures most closely associated with parent-reported measures and the optimal set of parent-reported measures for predicting objective measures. We also assessed whether there was a learning curve in reported exposure over time, and the importance of replicate biomarker measures. RESULTS: Correlations between objective and parent-reported measures of child TSE were modest at best, ranging from zero to 0.41. Serum cotinine and urinary cotinine were most strongly associated with parental reports. Parental questions most closely related to biomarkers were number of cigarettes and home smoking rules; together these formed the best set of predictive questions. No trial included all objective measures and all questions, precluding definitive statements about relative advantages. Within-subject repeatability of biomarker measures varied across studies, suggesting that direct pilot data are needed to assess the benefit of replicate measurements. CONCLUSIONS: Improvements in objective and parent-reported child exposure measurements are needed to accurately monitor child TSE, evaluate efforts to reduce such exposure, and better protect child health.

Gravity-based patterning of osteogenic factors to preserve bone structure after osteochondral injury in a large animal model.

Chondral and osteochondral repair strategies are limited by adverse bony changes that occur after injury. Bone resorption can cause entire scaffolds, engineered tissues, or even endogenous repair tissues to subside below the cartilage surface. To address this translational issue, we fabricated thick-shelled poly(D,L-lactide-co-glycolide) microcapsules containing the pro-osteogenic agents triiodothyronine andß-glycerophosphate, and delivered these microcapsules in a large animal model of osteochondral injury to preserve bone structure. We demonstrate that the developed microcapsules rupturedin vitrounder increasing mechanical loads, and readily sink within a liquid solution, enabling gravity-based patterning along the osteochondral surface. In a large animal, these mechanically-activated microcapsules (MAMCs) were assessed through two different delivery strategies. Intra-articular injection of control MAMCs enabled fluorescent quantification of MAMC rupture and cargo release in a synovial joint setting over timein vivo. This joint-wide injection also confirmed that the MAMCs do not elicit an inflammatory response. In the contralateral hindlimbs, chondral defects were created, MAMCs were patternedin situ, and nanofracture (Nfx), a clinically utilized method to promote cartilage repair, was performed. The Nfx holes enabled marrow-derived stromal cells to enter the defect area and served as repeatable bone injury sites to monitor over time. Animals were evaluated one and two weeks after injection and surgery. Analysis of injected MAMCs showed that bioactive cargo was released in a controlled fashion over two weeks. A bone fluorochrome label injected at the time of surgery displayed maintenance of mineral labeling in the therapeutic group, but resorption in both control groups. Alkaline phosphatase (AP) staining at the osteochondral interface revealed higher AP activity in defects treated with therapeutic MAMCs. Overall, this study develops a gravity-based approach to pattern bioactive factors along the osteochondral interface, and applies this novel biofabrication strategy to preserve bone structure after osteochondral injury.

Investigating Patient-Level Radiation Exposure in Hand and Wrist Fracture Surgery.

BACKGROUND: Although occupational exposure to radiation has been previously studied in the hand surgery literature, there is a paucity of studies looking at radiation exposure to the patient during fluoroscopy-guided hand surgery. We aimed to describe the level of radiation experienced by patients undergoing common hand and wrist fracture fixation and to identify risk factors for increased radiation exposure. METHODS: We performed a retrospective review of patients at a single institution who underwent fracture fixation of the hand, wrist, or forearm requiring mini c-arm fluoroscopic guidance from 2016 to 2020. Data points collected included patient demographics, procedural details, and indicators of radiation exposure including dose-area product (DAP), total intraoperative images, and total fluoroscopy time. Effective dose (ED) was calculated using DAP, field size, and a previously established conversion factor. RESULTS: The final sample included 361 patients with an average age of 46 years. Procedures included fixation of forearm fractures (3.3%), distal radius fractures (35.7%), metacarpal fractures (30.8%), and phalangeal fractures (30.2%). The median number of intraoperative images acquired was 36, median total fluoroscopy time was 43 seconds, median DAP was 4.8 cGycm2, and median ED was 0.13 µSv. Distal (metacarpal and phalangeal) fractures required more intraoperative images and longer total fluoroscopy time (49 images, 61 seconds) compared with proximal (forearm and distal radius) fractures (39 images, 47 seconds) (images, P = 0.004; exposure time, P = 0.004). However, distal fractures had a lower average ED compared with proximal fractures (0.15 vs 0.19 µSv, P = 0.020). When compared with open procedures, percutaneous procedures had higher DAPs (8.8 vs 4.9 cGycm2, P < 0.001), higher ED (0.22 vs 0.15 µSv, P < 0.001), more intraoperative images (65 vs 36 images, P < 0.001), and longer total fluoroscopy time (81.9 vs 44.4 seconds, P < 0.001). CONCLUSIONS: Patient-level radiation exposure during fluoroscopy-guided hand and wrist procedures is low relative to other common imaging modalities, such as dental radiographs, chest x-rays, and computed tomography scans, and is comparable with less than a few hours of natural background radiation exposure, highlighting the overall safety of this important technology. Further study should be performed to establish reference ranges, which could lead to improved patient counseling and evidence-based guidelines on patient shielding.

JAK2V617F Is a Risk Factor for TIA/Stroke in Young Patients.

The objective of this study was to assess the risk of arterial thrombosis in patients who harbor the JAK2V617F allele burden ≥1% detected during workup for myeloproliferative neoplasms (MPNs). We conducted a large cross-sectional analysis consisted of 5,220 patients who were tested for JAK2V617F and 1,047,258 people matched in age from health care insurance provider, taking into account age, sex, hypertension, diabetes, atrial fibrillation. Compared with noncarriers, mutation carriers were older, less likely to be current or past smokers and had lower body mass index. There was no significant difference between the groups regarding myocardial infarction and peripheral vascular disease. However, JAK2V617F ≥1% at age 34 to 54 years was associated with eightfold more likely to have transient ischemic attack (TIA)/stroke history unrelated to hypertension, diabetes, or atrial fibrillation. Association of JAK2V617F with TIA/stroke was also observed in the older age group, albeit a weaker association and not statistically significant. Prevalence of TIA/stroke was higher in patients with JAK2V617F negative, with odds ratio of 3.93 when compared with the general population after confounder adjustments. Further research is warranted to verify the relation between allele burden of JAK2V617F mutation and TIA/stroke and the role of JAK2V617F per se as a risk factor for arterial thrombosis in the absence of overt MPN. Also, consideration should be paid to the screened group with JAK2V617F negative due to the high incidence of TIA/stroke among them in comparison to the general population.

An impact of lipid profile and lipid lowering drugs on ≥70 year olds of an upper socioeconomic class: a retrospective cohort study.

BACKGROUND: Life expectancy has greatly increased, generating an improvement in screening programs for disease prevention, lifesaving drugs and medical devices. The impact of lowering low-density lipoprotein cholesterol (LDL-C) in the very elderly is not well-established. Our aim was to explore the association of LDL-C, high density lipoprotein cholesterol (HDL-C) and lipid lowering drugs (LLDs) on cognitive decline, malignancies and overall survival. METHODS: This was a retrospective cohort study. Our study comprised 1498 (72.7%) males and 561 (27.3%) females, aged ≥70 who had attended the Institute for Medical Screening (IMS), Sheba Medical Center, Israel at least twice during 2013-2019. Data were obtained from the computerized database of the IMS. A manual quality control to identify potential discrepancies was performed. RESULTS: Overall, 6.3% of the subjects treated with LLDs (95/1421) versus 4.2% not treated (28/638), cognitively declined during the study years. No statistically significant effects of LDL-C, HDL-C and LLDs on cognitive decline were observed after correcting for age, prior stroke and other vascular risk factors. With regard to cancer, after adjusting for confounders and multiple inferences, no definite relationships were found. CONCLUSIONS: This analysis of an elderly, high socioeconomic status cohort suggests several relationships between the use of LLDs and health outcomes, some beneficial, especially, with regard to certain types of cancer, but with a higher risk of cognitive decline. Further studies are warranted to clarify the health effects of these medications in the elderly.

Pre-diagnosis thyroid hormone dysfunction is associated with cancer mortality.

Research on the association between thyroid hormone levels and cancer mortality remains limited and inconclusive. We determined the relation of thyroid stimulating hormone (TSH), free T4 (FT4), and free T3 (FT3) levels with mortality in overall cancer and specific tumor types. Thyroid hormone levels 1-5 years prior to cancer diagnosis, as well as multiple clinical and demographic parameters, were retrospectively collected for 10,325 Israeli cancer patients, diagnosed between 2000 and 2016. Patients treated with thyroid altering medications were excluded. Cancer diagnosis was determined via the Israel National Cancer Registry. Multivariate-adjusted Cox proportional hazards model was used to assess the hazard ratios (HRs) based on thyroid hormone function for cancer mortality. A total of 5265 patients died during the follow-up period (median of 4.4 years). TSH, FT4, and FT3 levels in the hypothyroid range were associated with increase in overall mortality (adjusted HR 1.20, 1.74, 1.87, respectively). We further analyzed the association between TSH and mortality in 14 cancer subgroups. Specifically, TSH in both the hyperthyroid and hypothyroid range was associated with melanoma mortality (adjusted HR 2.20, 4.47, respectively). In conclusion, pre-diagnosis of thyroid dysfunction is associated with increased cancer mortality, a relation likely driven by specific cancer types. These findings suggest that thyroid hormones may potentially serve as prognostic markers in cancer.

Efficient study design to estimate population means with multiple measurement instruments.

Outcomes from studies assessing exposure often use multiple measurements. In previous work, using a model first proposed by Buonoccorsi (1991), we showed that combining direct (eg, biomarkers) and indirect (eg, self-report) measurements provides a more accurate picture of true exposure than estimates obtained when using a single type of measurement. In this article, we propose a tool for efficient design of studies that include both direct and indirect measurements of a relevant outcome. Based on data from a pilot or preliminary study, the tool, which is available online as a shiny app at https://michalbitan.shinyapps.io/shinyApp/, can be used to compute: (1) the sample size required for a statistical power analysis, while optimizing the percent of participants who should provide direct measures of exposure (biomarkers) in addition to the indirect (self-report) measures provided by all participants; (2) the ideal number of replicates; and (3) the allocation of resources to intervention and control arms. In addition we show how to examine the sensitivity of results to underlying assumptions. We illustrate our analysis using studies of tobacco smoke exposure and nutrition. In these examples, a near-optimal allocation of the resources can be found even if the assumptions are not precise.

Lag Time between Onset of First Symptom and Treatment of Retinoblastoma: An International Collaborative Study of 692 Patients from 10 Countries.

BACKGROUND: The relationship between lag time and outcomes in retinoblastoma (RB) is unclear. In this study, we aimed to study the effect of lag time between onset of symptoms and diagnosis of retinoblastoma (RB) in countries based on their national-income and analyse its effect on the outcomes. METHODS: We performed a prospective study of 692 patients from 11 RB centres in 10 countries from 1 January 2019 to 31 December 2019. RESULTS: The following factors were significantly different among different countries based on national-income level: age at diagnosis of RB (p = 0.001), distance from home to nearest primary healthcare centre (p = 0.03) and mean lag time between detection of first symptom to visit to RB treatment centre (p = 0.0007). After adjusting for country income, increased lag time between onset of symptoms and diagnosis of RB was associated with higher chances of an advanced tumour at presentation (p < 0.001), higher chances of high-risk histopathology features (p = 0.003), regional lymph node metastasis (p < 0.001), systemic metastasis (p < 0.001) and death (p < 0.001). CONCLUSIONS: There is a significant difference in the lag time between onset of signs and symptoms and referral to an RB treatment centre among countries based on national income resulting in significant differences in the presenting features and clinical outcomes.

Opposing effects of thyroid hormones on cancer risk: a population-based study.

OBJECTIVE: The association between dysregulated thyroid hormone function and cancer risk is inconclusive, especially among different age groups and uncommon malignancies. We sought to determine the relation of TSH and free T4 levels with overall cancer risk as well as risk of specific cancer types. DESIGN AND METHODS: Data on thyroid hormone profile was collected from 375 635 Israeli patients with no prior history of cancer. Cancer cases were identified via the Israel National Cancer Registry. Cox proportional hazards model was used to assess hazard ratios for overall cancer as well as 20 cancer subgroups. RESULTS: In this study, 23 808 cases of cancer were detected over median follow up of 10.9 years. Among patients younger than 50 at inclusion, TSH in the hyperthyroid range, elevated free T4 and subclinical hyperthyroidism were associated with increased cancer risk (HR: 1.3, 1.28 and 1.31, respectively). In contrast, patients 50 or older with clinical hyperthyroidism were at lower cancer risk (HR: 0.64). Elevated TSH was associated with decreased risk of prostate cancer (HR: 0.67). Log-TSH elevation was associated with decreased risk of thyroid cancer (HR: 0.82) and increased risk of melanoma (HR: 1.11) and uterine cancer (HR: 1.27). Elevated free T4 was associated with increased lung cancer risk (HR: 1.54), while free T4 levels above the normal range and clinical hyperthyroidism were related to lower colorectal cancer risk (HR: 0.59 and 0.08, respectively). CONCLUSIONS: Thyroid hormones display opposing effects on cancer risk, based on patient age and cancer type.

Optimized Media Volumes Enable Homogeneous Growth of Mesenchymal Stem Cell-Based Engineered Cartilage Constructs.

Despite marked advances in the field of cartilage tissue engineering, it remains a challenge to engineer cartilage constructs with homogeneous properties. Moreover, for engineered cartilage to make it to the clinic, this homogeneous growth must occur in a time-efficient manner. In this study we investigated the potential of increased media volume to expedite the homogeneous maturation of mesenchymal stem cell (MSC) laden engineered constructs over time in vitro. We assessed the MSC-laden constructs after 4 and 8 weeks of chondrogenic culture using bulk mechanical, histological, and biochemical measures. These assays were performed on both the intact total constructs and the construct cores to elucidate region-dependent differences. In addition, local strain transfer was assessed to quantify depth-dependent mechanical properties throughout the constructs. Our findings suggest that increased media volume enhances matrix deposition early in culture and ameliorates unwanted regional heterogeneities at later time points. Taken together, these data support the use of higher media volumes during in vitro culture to hasten tissue maturation and increase the core strength of tissue constructs. These findings will forward the field of cartilage tissue engineering and the translation of tissue engineered constructs.

Fabrication and maturation of integrated biphasic anatomic mesenchymal stromal cell-laden composite scaffolds for osteochondral repair and joint resurfacing.

Articular cartilage injury can lead to joint-wide erosion and the early onset of osteoarthritis. To address this, we recently developed a rapid fabrication method to produce patient-specific engineered cartilage tissues to replace an entire articular surface. Here, we extended that work by coupling a mesenchymal stromal cell-laden hydrogel (methacrylated hyaluronic acid) with the porous polycaprolactone (PCL) bone integrating phase and assessed the composition and mechanical performance of these constructs over time. To improve initial construct stability, PCL/hydrogel interface parameters were first optimized by varying PCL pretreatment (with sodium hydroxide before ethanol) before hydrogel infusion. Next, cylindrical osteochondral constructs were formed and cultured in media containing transforming growth factor ß3 for up to 8 weeks, with constructs evaluated for viability, histological features, and biochemical content. Mechanical properties were also assessed in axial compression and via an interface shear strength assay. Results showed that the fabrication process was compatible with cell viability, and that construct biochemical content and mechanical properties increased with time. Interestingly, compressive properties peaked at 5 weeks, while interfacial shear properties continued to improve beyond this time point. Finally, these fabrication methods were combined with a custom mold developed from limb-specific computed tomography imaging data to create an anatomic implantable cell-seeded biologic joint surface, which showedmaturation similar to the osteochondral cylinders. Future work will apply these advances in large animal models of critically sized osteochondral defects to study repair and whole joint resurfacing.

Flexor Pollicis Longus Tendon Wear Associated With Volar Plating: A Cadaveric Study.

PURPOSE: This study examined the effect of low-profile volar rim plates (VR), proximally placed standard variable-angle locking plates (pVA-LCP), and distally placed standard variable-angle locking plates (dVA-LCP) on the flexor pollicis longus (FPL) tendon in a cadaver model. We hypothesized that tendons from the VR and pVA-LCP groups would exhibit similar contact pressures, wear patterns, and post-fatigue testing mechanical properties, whereas dVA-LCP tendons would exhibit higher contact pressures, increased tendon wear patterns, and decreased mechanical properties. METHODS: Nine matched pairs of cadaveric specimens were used in this study. Thin-film pressure sensors were used to measure the initial contact loads between plates and FPL tendons. Specimens were cyclically loaded for 10,000 cycles by actuating the FPL tendon. Cycled tendons were harvested, photographed with a stereomicroscope, and graded for wear on a Likert scale by 5 observers who were blinded to the study protocol. Uniaxial tensile testing measured mechanical properties of the tendon: ultimate failure load, ultimate stress, percent stress relaxation, elastic modulus, and stiffness. RESULTS: With regard to the cadaveric FPL tendon, VR and dVA-LCP had increased contact pressure and tendon wear compared with pVA-LCP. There were no significant differences in contact pressure or tendon wear between dVA-LCP and VR. There was no major difference in the tested mechanical properties of the FPL tendon among any of the groups. CONCLUSIONS: Plates placed directly on or beyond the volar rim demonstrate increased contact pressures and increased tendon wear in a cadaveric model. CLINICAL RELEVANCE: Although low-profile plates allow for fixation of smaller volar fragments in the distal radius, they cause substantial contact with the FPL tendon, which may rupture if the plate is not removed.

Four-Year Follow-Up of the World's First Pediatric Bilateral Hand-Forearm Transplants: Do They Grow as Expected?

BACKGROUND: In 2015, the first bilateral pediatric hand-forearm transplant was performed in an 8-year-old boy. The growth rate of the transplanted upper extremities was unknown at the time. METHODS: Forearm and hand radiographs were obtained annually. Radius and ulna measurements were performed by multiple coauthors and mathematically normalized using a standardized methodology. The Greulich and Pyle atlas was used to estimate hand bone age. RESULTS: From July of 2015 to July of 2019, unadjusted bone length (metaphysis to metaphysis) increased 38.8 and 39.6 mm for the left radius and ulna, and 39.5 and 35.8 mm for the right radius and ulna, respectively. Distal physes of the donor limbs increasingly contributed to overall bone length relative to proximal physes. Normalized growth between the two limbs was statistically similar. At each annual follow-up, the bone age increased by 1 year. CONCLUSIONS: Successful pediatric hand-forearm transplantation offers the advantage of growth similar to that of nontransplanted pediatric patients. The transplanted distal physes contributes more to the overall growth, paralleling normal pediatric growth patterns. Chronologic age parallels the increase in bone age. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, V.

Preexisting coronary heart disease and susceptibility to long-term effects of traffic-related air pollution: A matched cohort analysis.

BACKGROUND: Individuals with coronary heart disease are considered susceptible to traffic-related air pollution exposure. Yet, cohort-based evidence on whether preexisting coronary heart disease modifies the association of traffic-related air pollution with health outcomes is lacking. AIM: Using data of four Israeli cohorts, we compared associations of traffic-related air pollution with mortality and cancer between coronary heart disease patients and matched controls from the general population. METHODS: Subjects hospitalized with acute coronary syndrome from two patient cohorts (inception years: 1992-1993 and 2006-2014) were age- and sex-matched to coronary heart disease-free participants of two cycles of the Israeli National Health and Nutrition Surveys (inception years: 1999-2001 and 2005-2006). Ambient concentrations of nitrogen oxides at the residential place served as a proxy for traffic-related air pollution exposure across all cohorts, based on a high-resolution national land use regression model (50 m). Data on all-cause mortality (last update: 2018) and cancer incidence (last update: 2016) were retrieved from national registries. Cox-derived stratum-specific hazard ratios with 95% confidence intervals were calculated, adjusted for harmonized covariates across cohorts, including age, sex, ethnicity, neighborhood socioeconomic status, smoking, diabetes, hypertension, prior stroke and prior malignancy (the latter only in the mortality analysis). Effect-modification was examined by testing nitrogen oxides-by-coronary heart disease interaction term in the entire matched cohort. RESULTS: The cohort (mean (standard deviation) age 61.5 (14) years; 44% women) included 2393 matched pairs, among them 2040 were cancer-free at baseline. During a median (25th-75th percentiles) follow-up of 13 (10-19) and 11 (7-17) years, 1458 deaths and 536 new cancer cases were identified, respectively. In multivariable-adjusted models, a 10-parts per billion nitrogen oxides increment was positively associated with all-cause mortality among coronary heart disease patients (hazard ratio = 1.13, 95% confidence interval 1.05-1.22), but not among controls (hazard ratio = 1.00, 0.93-1.08) (pinteraction = 0.003). A similar pattern was seen for all-cancer incidence (hazard ratioCHD = 1.19 (1.03-1.37), hazard ratioCHD-Free = 0.93 (0.84-1.04) (pinteraction = 0.01)). Associations were robust to multiple sensitivity analyses. CONCLUSIONS: Coronary heart disease patients might be at increased risk for traffic-related air pollution-associated mortality and cancer, irrespective of their age and sex. Patients and clinicians should be more aware of the adverse health effects on coronary heart disease patients of chronic exposure to vehicle emissions.

Leisure-Time Physical Activity and Cancer Risk Among Older Adults: A Cohort Study.

OBJECTIVE: To examine the association between leisure-time physical activity (LTPA) and long-term cancer risk in a nationwide cohort of older adults. PARTICIPANTS AND METHODS: The cohort comprised participants of a national survey conducted between July 2005 and December 2006, constituting a random sample of Israeli community-dwelling adults aged 65 years or older. Based on self-reported LTPA habits, participants were classified as sufficiently active, insufficiently active, or inactive according to published guidelines. Cancer diagnosis was assessed via the Israeli National Cancer Registry through September 2015. Inverse probability weighted hazard ratios for incident cancer, based on propensity score, were estimated for LTPA categories. RESULTS: Analysis included 1542 participants with no history of cancer at baseline (median [25th-75th percentile] age, 73 years [69-78 years]; 826 [53.6%] women). Inactive participants (n=641 [41.6%]) were more likely to be female, of lower socioeconomic status, and with higher body mass index and poorer perceived health compared with their insufficiently active (n=443 [28.7%]) and sufficiently active (n=458 [29.7%]) counterparts. In the propensity score-weighted synthetic sample, the distribution of measured baseline covariates was similar across LTPA categories. Over a median follow-up of 9 years, 254 new cancer cases (16.5%) were diagnosed. Leisure-time physical activity was inversely associated with incident cancer, with adjusted hazard ratios (95% CIs) of 0.66 (0.46-0.93) in insufficiently active and 0.59 (0.42-0.82) in sufficiently active participants compared with inactive individuals (P value for trend = .002). CONCLUSION: Among older adults, engaging in LTPA, even at lower levels than officially recommended, may have a beneficial effect on primary prevention of cancer.

Cancer and mortality in relation to traffic-related air pollution among coronary patients: Using an ensemble of exposure estimates to identify high-risk individuals.

BACKGROUND: Moderate correlations were previously observed between individual estimates of traffic-related air pollution (TRAP) produced by different exposure modeling approaches. This induces exposure misclassification for a substantial fraction of subjects. AIM: We used an ensemble of well-established modeling approaches to increase certainty of exposure classification and reevaluated the association with cancers previously linked to TRAP (lung, breast and prostate), other cancers, and all-cause mortality in a cohort of coronary patients. METHODS: Patients undergoing percutaneous coronary interventions in a major Israeli medical center from 2004 to 2014 (n = 10,627) were followed for cancer (through 2015) and mortality (through 2017) via national registries. Residential exposure to nitrogen oxides (NOx) -a proxy for TRAP- was estimated by optimized dispersion model (ODM) and land use regression (LUR) (rPearson = 0.50). Mutually exclusive groups of subjects classified as exposed by none of the methods (high-certainty low-exposed), ODM alone, LUR alone, or both methods (high-certainty high-exposed) were created. Associations were examined using Cox regression models. RESULTS: During follow-up, 741 incident cancer cases were diagnosed and 3051 deaths occurred. Using a ≥25 ppb cutoff, compared with high-certainty low exposed, the multivariable-adjusted hazard ratios (95% confidence intervals) for lung, breast and prostate cancer were 1.56 (1.13-2.15) in high-certainty exposed, 1.27 (0.86-1.86) in LUR-exposed alone, and 1.13 (0.77-1.65) in ODM-exposed alone. The association of the former category was strengthened using more extreme NOx cutoffs. A similar pattern, albeit less strong, was observed for mortality, whereas no association was shown for cancers not previously linked to TRAP. CONCLUSIONS: Use of an ensemble of TRAP exposure estimates may improve classification, resulting in a stronger association with outcomes.

A Subperiosteal Proximal Phalanx Osteoid Osteoma: A Challenging Diagnosis.

A relatively rare tumor, osteoid osteoma most commonly affects the lower extremity. In 10% of the cases, it can affect the hand and wrist. We present a case of osteoid osteoma in the proximal phalanx of ring finger that was initially misdiagnosed as a soft tissue lesion. The soft tissue lesion was resected, but the symptoms recurred shortly thereafter, leading to repeat diagnostic workup. Despite X-rays, magnetic resonance imaging, and tissue biopsy, the diagnosis remained elusive until surgical re-exploration. Based on the lessons learned from this case and the experience reported in literature, we discuss the intricate nature of osteoid osteoma diagnosis in the hand, the obstacles often encountered, and how to approach these challenging patients in a stepwise and critical fashion.

The Saline Load Test is Effective at Diagnosing Traumatic Arthrotomies of the Wrist.

BACKGROUND: The saline load test has previously been shown to be an effective tool to diagnose traumatic arthrotomies, but no studies have assessed the test's efficacy in the wrist. The purpose of this study was to investigate the amount of fluid required during a saline load test to detect intra-articular wrist involvement of traumatic wounds with high sensitivity. METHODS: A cadaveric study was conducted using 7 thawed, fresh-frozen forequarter amputations from 7 different donors (3 male, 4 female). Specimen age (mean: 67.7 y, range: 52 to 80 y), laterality (1 right, 6 left), body weight (mean: 164.3 lbs, range: 100 to 223 lbs), and wrist range of motion (ROM) was assessed before testing. The wrist capsule was punctured with an 11-blade scalpel through the 6R radiocarpal portal site under fluoroscopic guidance to ensure the injury was intra-articular. A 19-G needle was then placed through the 3,4 radiocarpal portal site and confirmed with fluoroscopy to ensure intra-articular placement. Normal saline was then injected at a steady rate into the 3,4 radiocarpal portal site until extravasation of the saline was observed from the 6R radiocarpal arthrotomy site. The volume of saline required for extravasation from the 6R radiocarpal arthrotomy was recorded as the volume required to detect the arthrotomy. A plot of saline volumes (by percentile) was created, and a logarithmic distribution was calculated. A Wilcoxon rank-sum test was used to compare injection volumes between male and female specimens, and Pearson Coefficients were used to determine any correlations between injection volume and ROM. RESULTS: The average amount of saline that resulted in extravasation was 4 mL (range: 2 to 7 mL). In order to identify 75%, 90%, 95%, and 99% of the simulated wrist arthrotomies, 5 (95% confidence interval: 3-7), 6 (4-9), 7 (4-10), and 9 (5-14) mL were required, respectively. Pretest ROM did not correlate with saline volume. CONCLUSIONS: This study demonstrates the efficacy of the saline load test in detecting traumatic arthrotomies of the wrist joint with 95% sensitivity after loading 7 mL of saline. Prompt and accurate diagnosis of traumatic arthrotomies is paramount to guide management and optimize postinjury outcomes.

Extracellular vesicles mediate improved functional outcomes in engineered cartilage produced from MSC/chondrocyte cocultures.

Several recent studies have demonstrated that coculture of chondrocytes (CHs) with bone marrow-derived mesenchymal stem cells (MSCs) improves their chondrogenesis. This implies that intercellular communication dictates fate decisions in recipient cells and/or reprograms their metabolic state to support a differentiated function. While this coculture phenomenon is compelling, the differential chondroinductivity of zonal CHs on MSC cocultures, the nature of the molecular cargo, and their transport mechanisms remains undetermined. Here, we demonstrate that juvenile CHs in coculture with adult MSCs promote functional differentiation and improved matrix production. We further demonstrate that close proximity between the two cell types is a prerequisite for this response and that the outcome of this interaction improves viability, chondrogenesis, matrix formation, and homeostasis in the recipient MSCs. Furthermore, we visualized the transfer of intracellular contents from CHs to nearby MSCs and showed that inhibition of extracellular vesicle (EV) transfer blocks the synergistic effect of coculture, identifying EVs as the primary mode of communication in these cocultures. These findings will forward the development of therapeutic agents and more effective delivery systems to promote cartilage repair.