Citations

Background Hyperkalemia has been associated with increased mortality in patients with myocardial infarction, but few data exist regarding hyperkalemia in cardiac intensive care unit ( CICU ) patients. We hypothesize that hyperkalemia is associated with increased mortality in unselected CICU patients. Methods and Results We retrospectively reviewed a historical cohort of 9681 CICU patients admitted from January 2007 to December 2015. Hyperkalemia was defined as admission potassium ≥5.0 mEq/L and hypokalemia as admission potassium <3.5 mEq/L. Multivariate logistic regression was used to determine predictors of in‐hospital mortality. Postdischarge survival was assessed using Kaplan–Meier analysis and Cox proportional hazards models. The mean age of included patients was 67±15 years, with 36% females, and in‐hospital mortality was 9%. Hyperkalemia occurred in 1187 (12.3%) and hypokalemia occurred in 719 (7.4%) patients. Both patients with hyperkalemia (unadjusted odds ratio, 2.85; 95% CI, 2.40–3.39; P <0.001) and patients with hypokalemia (unadjusted odds ratio, 2.31; 95% CI, 1.85–2.88; P <0.001) were at increased risk of unadjusted in‐hospital mortality. After adjustment for illness severity and renal function, only patients with hyperkalemia demonstrated increased risk of in‐hospital death (adjusted odds ratio, 1.44; 95% CI, 1.11–1.87; P =0.006). Among hospital survivors, only patients with hyperkalemia had lower postdischarge survival by Kaplan–Meier analysis ( P <0.001). After adjustment for illness severity and renal function, hospital survivors with admission hyperkalemia remained at increased risk for postdischarge mortality (adjusted hazard ratio, 1.20; 95% CI, 1.08–1.34; P <0.001). Conclusions Hyperkalemia on CICU admission is associated with higher in‐hospital and postdischarge mortality, independent of renal function and illness severity. These findings emphasize the importance of potassium abnormalities as a risk predictor in patients admitted to the CICU .

ABSTRACT Estrogen deficiency is a seminal mechanism in the pathogenesis of osteoporosis. Mounting evidence, however, establishes that cellular senescence, a fundamental mechanism that drives multiple age-related diseases, also causes osteoporosis. Recently, we systematically identified an accumulation of senescent cells, characterized by increased p16Ink4a and p21Cip1 levels and development of a senescence-associated secretory phenotype (SASP), in mouse bone/marrow and human bone with aging. We then demonstrated that elimination of senescent cells prevented age-related bone loss using multiple approaches, eg, treating old mice expressing a “suicide” transgene, INK-ATTAC, with AP20187 to induce apoptosis of p16Ink4a-senescent cells or periodically treating old wild-type mice with “senolytics,” ie, drugs that eliminate senescent cells. Here, we investigate a possible role for estrogen in the regulation of cellular senescence using multiple approaches. First, sex steroid deficiency 2 months after ovariectomy (OVX, n = 15) or orchidectomy (ORCH, n = 15) versus sham surgery (SHAM, n = 15/sex) in young adult (4-month-old) wild-type mice did not alter senescence biomarkers or induce a SASP in bone. Next, in elderly postmenopausal women, 3 weeks of estrogen therapy (n = 10; 74 ± 5 years) compared with no treatment (n = 10; 78 ± 5 years) did not alter senescence biomarkers or the SASP in human bone biopsies. Finally, young adult (4-month-old) female INK-ATTAC mice were randomized (n = 17/group) to SHAM+Vehicle, OVX+Vehicle, or OVX+AP20187 for 2 months. As anticipated, OVX+Vehicle caused significant trabecular/cortical bone loss compared with SHAM+Vehicle. However, treatment with AP20187, which eliminates senescent cells in INK-ATTAC mice, did not rescue the OVX-induced bone loss or alter senescence biomarkers. Collectively, our data establish independent roles of estrogen deficiency and cellular senescence in the pathogenesis of osteoporosis, which has important implications for testing novel senolytics for skeletal efficacy, as these drugs will need to be evaluated in preclinical models of aging as opposed to the current FDA model of prevention of OVX-induced bone loss. © 2019 American Society for Bone and Mineral Research.

Background: Professional baseball pitchers are at high risk for tears of the ulnar collateral ligament (UCL) of the elbow, often requiring surgical reconstruction. Despite acceptable published return-to-play outcomes, multiple techniques and graft types have been described. Purpose: This study compares UCL reconstruction (UCLR) outcomes based on tunnel configuration and graft type. Study Design: Cohort study; Level of evidence, 3. Methods: After approval from our institutional review board and Major League Baseball (MLB), 566 professional baseball pitchers who underwent UCLR between 2010 and 2014 were identified and included. The following patient characteristics were analyzed: age, pitching role (starter vs reliever), level of play (MLB vs Minor League Baseball [MiLB]), and throwing side dominance. Surgical factors analyzed included reconstruction technique, graft type, and concomitant procedures. Primary outcome measures consisted of the ability to return to play at any level (RTP), ability to return to the same level of play (RSL), time to return, subsequent elbow injuries, and need for subsequent or revision elbow surgery. The effects of patient and surgical factors on outcomes were analyzed using multivariate linear and logistic regression modeling. Results: The RTP rate was 79.9%, and the RSL rate was 71.2%. Grafts used to reconstruct the UCL included the palmaris longus autograft (n = 361, 63.7%), the gracilis autograft (n = 135, 23.8%), and other grafts (n = 70, 12.5%). Surgical techniques utilized were the docking technique (n = 171, 30.2%), the modified Jobe technique (n = 290, 51.2%), and other techniques (n = 105, 18.6%). There were no significant differences in the time to RTP or RSL based on reconstruction technique or graft type. RTP rates were similar for the docking versus modified Jobe technique (80.1% vs 82.4%, respectively; P = .537) and for the 2 primary graft types (83.1% for palmaris longus vs 80.7% for gracilis; P = .596). The rate of subsequent elbow surgery was 10.5% for the docking technique versus 14.8% for the modified Jobe technique ( P = .203), and the rate of revision UCLR was 2.9% versus 6.2% for the docking versus modified Jobe technique, respectively ( P = .128). Significant trends toward an increasing use of the palmaris longus autograft ( P = .023) and the docking technique ( P = .006) were observed. MLB pitchers were more likely than MiLB pitchers to RTP ( P < .001) and RSL ( P < .001), but they required a longer time to return (mean difference, 35 days; P = .039) and had a higher likelihood of subsequent elbow (odds ratio [OR], 3.58 [95% CI, 2.06-6.23]; P < .001) and forearm injuries (OR, 5.70 [95% CI, 1.99-16.30]; P = .004) but not subsequent elbow surgery. No specific variables correlated with the rates of subsequent elbow surgery or revision UCLR in the multivariate analysis. The use of concomitant ulnar nerve transposition did not affect outcomes. Conclusion: Surgical outcomes in professional baseball players are not significantly influenced by UCLR technique or graft type. There was a high rate (46.3%) of subsequent throwing elbow injuries. MLB pitchers were more likely to RTP and RSL, but they had a higher frequency of subsequent elbow and forearm injuries than MiLB pitchers. Both the docking technique and the palmaris longus autograft are increasing in popularity among surgeons treating professional baseball players.

Commercially available heart valves have many limitations, such as a lack of remodeling, risk of calcification, and thromboembolic problems. Many state-of-the-art tissue-engineered heart valves (TEHV) rely on recellularization to allow remodeling and transition to mechanical behavior of native tissues. Current in vitro testing is insufficient in characterizing a soon-to-be living valve due to this change in mechanical response; thus, it is imperative to understand the performance of an in situ valve. However, due to the complex in vivo environment, this is difficult to accomplish. Finite element (FE) analysis has become a standard tool for modeling mechanical behavior of heart valves; yet, research to date has mostly focused on commercial valves. The purpose of this study has been to evaluate the mechanical behavior of a TEHV material before and after 6 months of implantation in a rat subdermis model. This model allows the recellularization and remodeling potential of the material to be assessed via a simple and inexpensive means prior to more complex ovine orthotropic studies. Biaxial testing was utilized to evaluate the mechanical properties, and subsequently, constitutive model parameters were fit to the data to allow mechanical performance to be evaluated via FE analysis of a full cardiac cycle. Maximum principal stresses and strains from the leaflets and commissures were then analyzed. The results of this study demonstrate that the explanted tissues had reduced mechanical strength compared to the implants but were similar to the native tissues. For the FE models, this trend was continued with similar mechanical behavior in explant and native tissue groups and less compliant behavior in implant tissues. Histology demonstrated recellularization and remodeling although remodeled collagen had no clear directionality. In conclusion, we observed successful recellularization and remodeling of the tissue giving confidence to our TEHV material; however, the mechanical response indicates the additional remodeling would likely occur in the aortic/pulmonary position.

Cells establish and sustain structural and functional integrity of the genome to support cellular identity and prevent malignant transformation. In this review, we present a strategic overview of epigenetic regulatory mechanisms including histone modifications and higher order chromatin organization (HCO) that are perturbed in breast cancer onset and progression. Implications for dysfunctions that occur in hormone regulation, cell cycle control, and mitotic bookmarking in breast cancer are considered, with an emphasis on epithelial‐to‐mesenchymal transition and cancer stem cell activities. The architectural organization of regulatory machinery is addressed within the contexts of translating cancer‐compromised genomic organization to advances in breast cancer risk assessment, diagnosis, prognosis, and identification of novel therapeutic targets with high specificity and minimal off target effects.

Background: Achilles tendon tears are potentially career-ending injuries for professional athletes. For players in the National Football League (NFL), return requires not only surgery and extensive rehabilitation but also the ability to compete in a market with limited positions that annually introduces new recruits. Purpose/Hypothesis: We authors sought to evaluate factors related to return to play (RTP) and changes in performance following a primary Achilles tear. Our hypothesis was that “skilled” position players and those drafted in later rounds would return at a lower rate as compared with “unskilled” position players and higher draft-round players. Study Design: Case-control study; Level of evidence, 3. Methods: From a previously established database, 80 NFL players were identified as having primary Achilles tendon tears between the 2009 and 2014 seasons. RTP was defined as playing in a regular season or postseason game following injury. Probability of RTP was modeled as a function of time after injury in Kaplan-Meier analysis with demographic variables assessed via generalized linear models. Twelve players (15%) experienced a subsequent Achilles tendon tear during or after the study period and were included in the overall RTP rate but were excluded from performance analyses owing to the confounding effects of an ipsilateral retear or contralateral tear. Results: The overall RTP rate was 61.3%. Age, number of prior seasons, position type, or draft round status did not significantly affect RTP when evaluated with Kaplan-Meier analysis. In the season before their injury, players who did RTP played in a significantly greater number of regular season games (13.7) compared with players who did not RTP (8.71) ( P = .011). Players who did not RTP exhibited a significant decrease in performance in the season preceding injury (12.7 regular season games played 2 seasons preinjury vs 8.71 regular season games played 1 season prior preinjury;, P = .019). Players who returned did not display a significant change in the number of games played or started in seasons following injury when >1 season after return was evaluated. Conclusion: Rate of RTP following primary Achilles tendon tears may be lower than previously published. However, for those able to return, performance only in the season immediately following injury appears to be affected; players return to preinjury levels if given the opportunity to play >1 season after injury.