Motivation and family communication in hereditary prostate cancer genetic testing: Survey of patients from a US tertiary medical center.

Identification of a hereditary prostate cancer in an affected individual can guide treatment and may also impact cancer screening and surveillance for patients and their relatives. This study aimed to determine the factors that are associated with the decision-making process of individuals with prostate cancer regarding whether to pursue genetic testing as well as how, why, and with whom genetic test results are shared. We surveyed 113 patients diagnosed with prostate cancer who received cancer genetic counseling through a United States tertiary medical center, inquiring about genetic testing motivations and family communication about results. Among those who pursued genetic testing, (1) learning about my family's possible cancer risk (98%), (2) learning information that may guide cancer treatment (93%), and (3) learning if I am at risk for future cancers (92%) were most frequently identified as slightly or very important factors in their decision. Participants shared their genetic test results in a higher proportion to male first-degree relatives than female first-degree relatives; however, no significant difference was found (p = 0.103). Our study may suggest sex differences related to family communication about genetic testing results. Such findings indicate a critical need for genetic counselors to clearly communicate the impact of genetic test results on both male and female relatives. Further research on motivation and family communication about genetic test results in diverse cohorts is needed.

Risk of Revision and Complications After Total Hip Arthroplasty for Acute Treatment of Acetabular Fracture.

BACKGROUND: Total hip arthroplasty (THA) for the treatment of acute acetabular fractures may be indicated where there is high risk for failure of open reduction and internal fixation. This study aimed to determine risks of revision and rates of major complications of THA for acute acetabular fractures. METHODS: A retrospective review was performed (all-claims data files of a large national database) by querying International Classification of Disease, 10th revision procedure codes for THA within 14 days of acetabular fracture. We identified all-cause revision and surgical complications including dislocations, mechanical failures (loosenings or broken prostheses), infections, as well as medical complications. Demographic data collected included age, sex, obesity, and Charlson Comorbidity Index (CCI). Multivariate analyses evaluated the association of revision and major surgical complications after adjusting for demographic characteristics and comorbidities. We identified 956 THAs for the treatment of acute acetabular fracture from 2015 to 2020. Of all acute acetabular fractures treated with THA, 241 were concomitant with open reduction and internal fixation (ORIF), and 715 were THA-alone. RESULTS: All-cause revision risk was 18.2%, overall major surgical complication rate 26.9%, and medical complication rate was 13.2%. Women were associated with increased risk of revision (adjusted odds ratio (aOR) 1.8; confidence interval (CI) 1.3 to 2.6, P = .001), dislocation (aOR 2.0; CI 1.5 to 3.1, P < .001), mechanical complication (aOR 2.1; CI 1.4 to 3.2, P < .001), and infection (aOR 1.6; CI 1.0 to 2.5, P = .044). CONCLUSION: We noted risk of all-cause revision of 18.2%, overall major surgical complication rate of 26.9%, and overall major medical complication rate of 13.2% for THA as the treatment of acute acetabular fracture. We caution against broad expansion of THA for treatment of acute acetabular fractures. Furthermore, increased risks of revision and complications in women warrant additional investigation into patient and fracture characteristics that may contribute to this finding.

Delay of fixation increases 30-day complications and mortality in traumatic pelvic ring injuries.

PURPOSE: While decreased time to fixation in femur fractures improves mortality, it remains unclear if the same relationship exists for pelvic fractures. The National Trauma Data Bank (NTDB) is a data repository for trauma hospitals in the United States (injury characteristics, perioperative data, procedures, 30-day complications), and we used this to investigate early, significant complications after pelvic-ring injuries. METHODS: The NTDB (2015-2016) was queried to capture operative pelvic ring injuries in adult patients with injury severity score (ISS) ≥ 15. Complications included medical and surgical complications, as well as 30-day mortality. Multivariable logistic regression was used to investigate the association between days to procedure and complications after adjusting for demographic characteristics and comorbidities. RESULTS: 2325 patients met inclusion criteria. 532 (23.0%) sustained complications, and 72 (3.2%) died within the first 30 days. The most common complications were deep vein thrombosis (DVT) (5.7%), acute kidney injury (AKI) (4.6%), and unplanned intensive care unit (ICU) admission (4.4%). In a multivariate analysis, days to procedure was independently significantly associated with complications, with an adjusted odds ratio (95% confidence interval) of 1.06 (1.03-1.09, P < 0.001), best interpreted as a 6% increase in the odds of complication or death for each additional day. CONCLUSION: Time to pelvic fixation is a significant and modifiable risk factor for major complications and death. This suggests we should prioritize time to pelvic fixation on trauma patients to minimize mortality and major complications.

Radiographic bladder shift is a harbinger of intraoperative blood loss in acetabular surgical fixation.

PURPOSE: The purpose of this study was to characterize the relationship between a novel radiographic measurement on initial AP pelvis radiograph (termed "bladder shift," BS) to intraoperative blood loss (IBL) during acetabular surgical fixation. METHODS: All adult patients receiving unilateral acetabular fixation (Level 1 academic trauma; 2008-18) were reviewed. AP pelvis radiographs were reviewed for visible bladder outlines and then measured to determine the percentage deformation toward the midline. Hemoglobin & hematocrit data were then used to calculate quantitative blood loss between pre- and post- operative blood counts for data analysis. RESULTS: 371 patients with unilateral traumatic acetabular fractures requiring fixation were reviewed; 99 of these had visible bladder outlines, complete blood count and transfusion data (2008-2018; 66% associated patterns). Median bladder shift (BS) was 13.3%. Every 10% of bladder shift was associated with 123 mL greater IBL. Patients with full bladder shift to midline sustained a median 1.5L IBL (interquartile range [IQR] 0.8 to 1.6). Associated patterns had a threefold greater median BS (associated: 16.5% [15.4 to 45.9] vs. elementary: 5.6% [1.1 to 15.4], p < 0.05) and received intraoperative pRBC twice as frequently (57% vs. 24%, p < 0.01). CONCLUSIONS: Radiographic bladder shift is an easily available visual marker, in patients sustaining acetabular fractures, that may predict intraoperative hemorrhage and need for transfusions.

Socioeconomic factors and outcomes from exercise-related sudden cardiac arrest in high school student-athletes in the USA.

OBJECTIVE: Minority student-athletes have a lower survival rate from sudden cardiac arrest (SCA) than non-minority student-athletes. This study examined the relationship between high school indicators of socioeconomic status (SES) and survival in student-athletes with exercise-related SCA. METHODS: High school student-athletes in the USA with exercise-related SCA on school campuses were prospectively identified from 1 July 2014 to 30 June 2018 by the National Center for Catastrophic Sports Injury Research. High school indicators of SES included the following: median household and family income, proportion of students on free/reduced lunch and percent minority students. Resuscitation details included witnessed arrest, presence of an athletic trainer, bystander cardiopulmonary resuscitation and use of an on-site automated external defibrillator (AED). The primary outcome was survival to hospital discharge. Differences in survival were analysed using risk ratios (RR) and univariate general log-binomial regression models. RESULTS: Of 111 cases identified (mean age 15.8 years, 88% male, 49% white non-Hispanic), 75 (68%) survived. Minority student-athletes had a lower survival rate compared with white non-Hispanic student-athletes (51.1% vs 75.9%; RR 0.67, 95% CI 0.49 to 0.92). A non-significant monotonic increase in survival was observed with increasing median household or family income and with decreasing percent minority students or proportion on free/reduced lunch. The survival rate was 83% if an athletic trainer was on-site at the time of SCA and 85% if an on-site AED was used. CONCLUSIONS: Minority student-athletes with exercise-related SCA on high school campuses have lower survival rates than white non-Hispanic athletes, but this difference is not fully explained by SES markers of the school.

The emerging role of Janus kinase inhibitors in the treatment of autoimmune and inflammatory diseases.

Autoimmune and inflammatory diseases are common and diverse, and they can affect nearly any organ system. Much of the pathogenesis of these diseases is related to dysregulated cytokine activity. Historically, autoimmune and inflammatory diseases have been treated with medications that nonspecifically suppress the immune system. mAbs that block the action of pathogenic cytokines emerged 2 decades ago and have become widely useful. More recently, agents that simultaneously block multiple pathogenic cytokines via inhibition of the downstream Janus kinase (JAK)-signal transducer and activator of transcription pathway have emerged and are becoming increasingly important. These small-molecule inhibitors, collectively termed JAK inhibitors, are US Food and Drug Administration-approved in a few autoimmune/inflammatory disorders and are being evaluated in many others. Here, we review the biology of the JAK-signal transducer and activator of transcription pathway and the use of JAK inhibitors to treat autoimmune and inflammatory diseases across medical subspecialties.

Treatment of granuloma annulare and suppression of proinflammatory cytokine activity with tofacitinib.

BACKGROUND: Granuloma annulare (GA) is a common cutaneous inflammatory disorder characterized by macrophage accumulation and activation in skin. Its pathogenesis is poorly understood, and there are no effective treatments. The potential health implications of severe GA are unknown. OBJECTIVE: We sought to better understand GA pathogenesis and evaluate a molecularly targeted treatment approach for this disease. METHODS: We used single-cell RNA sequencing to study the immunopathogenesis of GA and also evaluated the efficacy of tofacitinib (a Janus kinase 1/3 inhibitor) in 5 patients with severe, long-standing GA in an open-label clinical trial. RESULTS: Using single-cell RNA sequencing, we found that in GA lesions IFN-γ production by CD4+ T cells is upregulated and is associated with inflammatory polarization of macrophages and fibroblasts. In particular, macrophages upregulate oncostatin M, an IL-6 family cytokine, which appears to act on fibroblasts to alter extracellular matrix production, a hallmark of GA. IL-15 and IL-21 production appears to feed back on CD4+ T cells to sustain inflammation. Treatment of 5 patients with recalcitrant GA with tofacitinib inhibited IFN-γ and oncostatin M, as well as IL-15 and IL-21, activity and resulted in clinical and histologic disease remission in 3 patients and marked improvement in the other 2. Inhibition of these effects at the molecular level paralleled the clinical improvement. Evidence of systemic inflammation is also present in some patients with severe GA and is mitigated by tofacitinib. CONCLUSIONS: The Janus kinase-signal transducer and activator of transcription pathway is activated in GA, likely in part through the activity of IFN-γ and oncostatin M, and Janus kinase inhibitors appear to be an effective treatment.

Aetiology and incidence of sudden cardiac arrest and death in young competitive athletes in the USA: a 4-year prospective study.

OBJECTIVE: To investigate the aetiology and incidence of sudden cardiac arrest and death (SCA/D) in US competitive athletes. METHODS: Prospective surveillance was conducted from 1 July 2014 to 30 June 2018 through the National Center for Catastrophic Sports Injury Research in collaboration with national sports organisations. Autopsy reports, death certificates, and medical records were reviewed by an expert panel to determine aetiology. Athlete participation statistics from the National Federation of State High School Associations and the National Collegiate Athletic Association (NCAA) were used to calculate incidence rates per athlete-years (AY). Comparisons of incidence rates were calculated using incidence rate ratios (IRR) with 95% CIs. RESULTS: 331 cases of confirmed SCA/D (158 survivors; 173 fatalities) were identified; 15.4% in middle school, 61.6% in high school and 16.6% in college and professional athletes. Average age was 16.7 (11-29) years, and the majority were in male (83.7%), basketball (28.7%) or American football (25.4%) athletes. Common causes included hypertrophic cardiomyopathy (20.6%), idiopathic left ventricular hypertrophy (13.4%), coronary artery anomalies (12.0%) and autopsy-negative sudden unexplained death (9.6%). Coronary anomalies were more common in middle school athletes (28%), while cardiomyopathies (hypertrophic, arrhythmogenic, dilated, non-compaction or restricted) accounted for 47% of cases in college and professional athletes. Incidence was higher in male versus female athletes at the high school (1:43 932 AY (95% CI 1:38 101 to 1:50 907) vs 1:203 786 AY (95% CI 1:145 251 to 1:293 794); IRR 4.6 (95% CI 3.1 to 7.2)) and NCAA (1:34 906 AY (95% CI 1:25 385 to 1:49 173) vs 1:123 278 AY (95% CI 1:66 078 to 1:249 853); IRR 3.5 (95% CI 1.5 to 9.5)) levels. African American male NCAA Division I basketball players had the highest annual incidence rate of SCA/D (1:2087 AY (95% CI 1:1073 to 1:4 450)). CONCLUSIONS: Cardiomyopathies account for nearly half of SCA/D cases in college and professional athletes, while coronary artery anomalies play a more prominent role than expected in middle school athletes. Over half of SCA cases in athletes result in sudden death, calling for improved prevention strategies.

Etiology of Sudden Cardiac Arrest and Death in US Competitive Athletes: A 2-Year Prospective Surveillance Study.

OBJECTIVE: To determine the etiology of sudden cardiac arrest and death (SCA/D) in competitive athletes through a prospective national surveillance program. DESIGN: Sudden cardiac arrest and death cases in middle school, high school, college, and professional athletes were identified from July 2014 to June 2016 through traditional and social media searches, reporting to the National Center for Catastrophic Sports Injury Research, communication with state and national high school associations, review of the Parent Heart Watch database, and search of student-athlete deaths on the NCAA Resolutions List. Autopsy reports and medical records were reviewed by a multidisciplinary panel to determine the underlying cause. SETTING AND PARTICIPANTS: US competitive athletes with SCA/D. MAIN OUTCOME MEASURES: Etiology of SCA/D. RESULTS: A total of 179 cases of SCA/D were identified (74 arrests with survival, 105 deaths): average age 16.6 years (range 11-29), 149 (83.2%) men, 94 (52.5%) whites, and 54 (30.2%) African American. One hundred seventeen (65.4%) had an adjudicated diagnosis, including 83 deaths and 34 survivors. The most common etiologies included hypertrophic cardiomyopathy (19, 16.2%), coronary artery anomalies (16, 13.7%), idiopathic left ventricular hypertrophy/possible cardiomyopathy (13, 11.1%), autopsy-negative sudden unexplained death (8, 6.8%), Wolff-Parkinson-White (8, 6.8%), and long QT syndrome (7, 6.0%). Hypertrophic cardiomyopathy was more common in male basketball (23.3%), football (25%), and African American athletes (30.3%). An estimated 56.4% of cases would likely demonstrate abnormalities on an electrocardiogram. CONCLUSIONS: The etiology of SCA/D in competitive athletes involves a wide range of clinical disorders. More robust reporting mechanisms, standardized autopsy protocols, and accurate etiology data are needed to better inform prevention strategies.

Organohalogen Contaminants and Vitamins in Northern Fur Seals (Callorhinus ursinus) Collected During Subsistence Hunts in Alaska.

During native subsistence hunts from 1987 to 2007, blubber and liver samples from 50 subadult male northern fur seals (Callorhinus ursinus) were collected on St. Paul Island, Alaska. Samples were analyzed for legacy persistent organic pollutants (POPs), recently phased-out/current-use POPs, and vitamins. The legacy POPs measured from blubber samples included polychlorinated biphenyl congeners, DDT (and its metabolites), chlorobenzenes, chlordanes, and mirex. Recently phased-out/current-use POPs included in the blubber analysis were the flame retardants, polybrominated diphenyl ethers, and hexabromocyclododecanes. The chemical surfactants, perfluorinated alkyl acids, and vitamins A and E were assessed in the liver samples. Overall, concentrations of legacy POPs are similar to levels seen in seal samples from other areas of the North Pacific Ocean and the Bering Sea. Statistically significant correlations were seen between compounds with similar functions (pesticides, flame retardants, vitamins). With sample collection spanning two decades, the temporal trends in the concentrations of POPs and vitamins were assessed. For these animals, the concentrations of the legacy POPs tend to decrease or stay the same with sampling year; however, the concentrations of the current-use POPs increased with sampling year. Vitamin concentrations tended to stay the same across the sampling years. With the population of northern fur seals from St. Paul Island on the decline, a detailed assessment of exposure to contaminants and the correlations with vitamins fills a critical gap for identifying potential population risk factors that might be associated with health effects.

Sodium-dependent phosphate cotransporters and phosphate-induced calcification of vascular smooth muscle cells: redundant roles for PiT-1 and PiT-2.

OBJECTIVE: Elevated serum phosphate has emerged as a major risk factor for vascular calcification. The sodium-dependent phosphate cotransporter, PiT-1, was previously shown to be required for phosphate-induced osteogenic differentiation and calcification of cultured human vascular smooth muscle cells (VSMCs), but its importance in vascular calcification in vivo and the potential role of its homologue, PiT-2, have not been determined. We investigated the in vivo requirement for PiT-1 in vascular calcification using a mouse model of chronic kidney disease and the potential compensatory role of PiT-2 using in vitro knockdown and overexpression strategies. APPROACH AND RESULTS: Mice with targeted deletion of PiT-1 in VSMCs were generated (PiT-1(Δsm)). PiT-1 mRNA levels were undetectable, whereas PiT-2 mRNA levels were increased 2-fold in the vascular aortic media of PiT-1(Δsm) compared with PiT-1(flox/flox) control. When arterial medial calcification was induced in PiT-1(Δsm) and PiT-1(flox/flox) by chronic kidney disease followed by dietary phosphate loading, the degree of aortic calcification was not different between genotypes, suggesting compensation by PiT-2. Consistent with this possibility, VSMCs isolated from PiT-1(Δsm) mice had no PiT-1 mRNA expression, increased PiT-2 mRNA levels, and no difference in sodium-dependent phosphate uptake or phosphate-induced matrix calcification compared with PiT-1(flox/flox) VSMCs. Knockdown of PiT-2 decreased phosphate uptake and phosphate-induced calcification of PiT-1(Δsm) VSMCs. Furthermore, overexpression of PiT-2 restored these parameters in human PiT-1-deficient VSMCs. CONCLUSIONS: PiT-2 can mediate phosphate uptake and calcification of VSMCs in the absence of PiT-1. Mechanistically, PiT-1 and PiT-2 seem to serve redundant roles in phosphate-induced calcification of VSMCs.