bluuebunny/crossref_metadata_2025 huggingface dataset:
The genetics of Hodgkin lymphoma: an overview and clinical implications
Authors: Borchmann Sven , Engert Andreas
Published: July 2017

Purpose of review

The goal of this review is to give an overview of the genetics of classical Hodgkin lymphoma. Copy number changes, somatic mutations, genome-wide association studies, changes in gene expression, familial classical Hodgkin lymphoma and epigenetic changes will be reviewed. In doing so, special focus is placed on the way recent discoveries have influenced clinical research, diagnostics, treatment and remission monitoring. Furthermore, emphasis is put on how these advances can help to advance the treatment of elderly patients who have a markedly worse prognosis than younger patients.

Recent findings

Frequent amplifications of the 9p24.1 locus in classical Hodgkin lymphoma could be the basis for the success of immune checkpoint inhibitors targeting PD-1 or PD-L1 in this disease. The same amplification also affects the JAK/STAT pathway, which has also been targeted in recent clinical trials. Hodgkin lymphoma-specific copy number alterations and mutations have recently been found to be detectable in cell-free DNA. This could provide the basis for advances in the detection of residual disease during treatment and while monitoring patients in remission.

The advent of new technologies such as massive parallel sequencing has improved our understanding of the genetics of classical Hodgkin lymphoma. Some of these discoveries are now being translated into clinical research in the form of new diagnostics and treatments.
Evaluation and management of vaginoplasty complications
Authors: Amies Oelschlager Anne-Marie , Kirby Anna , Breech Lesley
Published: July 2017

Purpose of review

Indications for vaginoplasty include congenital conditions such as adrenal hyperplasia, cloacal malformations, and Müllerian agenesis, acquired conditions including stenosis from radiation or surgical resection for malignancy, and gender affirmation. All vaginoplasty techniques carry significant risk of both immediate and long-term complications.

Recent findings

The purpose of this study is to provide a review of the evaluation and management of the neovagina, addressing management of human papilloma virus infections and complications including stenosis, fistula, prolapse, and neovaginal colitis.

Gynecologists who care for patients who have had a vaginoplasty need to understand the importance of long-term follow up and care, including evaluation and management of complications.
Comparison of clinical outcomes among users of oral and transdermal estrogen therapy in the Women's Health Initiative Observational Study
Authors: Crandall Carolyn J. , Hovey Kathleen M. , Andrews Christopher , Cauley Jane A. , Stefanick Marcia , Shufelt Chrisandra , Prentice Ross L. , Kaunitz Andrew M. , Eaton Charles , Wactawski-Wende Jean , Manson JoAnn E.
Published: July 2017

Objective:

To examine associations of estrogen preparations with an index of health risks versus benefits.

Methods:

Using data from 45,112 participants of the Women's Health Initiative Observational Study (average follow-up 5.5 years), we examined associations of estrogen type and oral conjugated equine estrogen (CEE) dose with time to first global index event (GIE), defined as coronary heart disease, breast cancer, stroke, pulmonary embolism, hip fracture, colorectal cancer, endometrial cancer, or death.

Results:

Oral CEE less than 0.625 mg/d + progestogen (P) users had a lower risk of a GIE (adjusted hazard ratio 0.74, 95% confidence interval 0.56-0.97) than oral CEE 0.625 mg/d + P users. GIE risk in oral CEE 0.625 mg/d + P users was greater with at least 5-year use (adjusted hazard ratio 1.22, 95% confidence interval 1.06-1.41) than with less than 5-year use. In women with prior hysterectomy, compared with women taking oral CEE 0.625 mg/d for less than 5 years, GIE risk was similar with oral CEE below 0.625 mg/d, oral estradiol (E2), and transdermal E2, whether used for less than 5 years or for at least 5 years. There was no difference in GIE risk between users of the following: oral CEE + P versus oral E2 + P; oral CEE + P versus transdermal E2 + P; oral E2 + P versus transdermal E2 + P. Findings were similar among women with hysterectomy taking estrogen alone.

Conclusions:

The summary index of risks versus benefits was similar for oral CEE versus oral or transdermal E2-containing regimens. CEE + P containing less than 0.625 mg/d of CEE (vs 0.625 mg/d) for less than 5 years appeared safer.
Sleep quality and its association with postural stability and fear of falling among Spanish postmenopausal women
Authors: Hita-Contreras Fidel , Zagalaz-Anula Noelia , Martínez-Amat Antonio , Cruz-Díaz David , Sánchez-Montesinos Indalecio , Aibar-Almazán Agustín , Lomas-Vega Rafael
Published: July 2017

Objective:

To analyze the association of sleep quality with postural balance, as measured with objective stabilometric parameters, and fear of falling (FoF), among Spanish postmenopausal women.

Methods:

In all, 250 women (60 ± 8 years) took part in this cross-sectional study. Sociodemographic and anthropometric data were collected, as well as information concerning history of falls and FoF. Anxiety and depression were assessed using the Hospital Anxiety and Depression Scale, and the Pittsburgh Sleep Quality Index was used to analyze sleep quality. Measurements of sway area (S), velocity (V), and mediolateral (RMSX) and anteroposterior (RMSY) displacements of the center of pressure were obtained with a resistive multisensor platform under both eyes-open (EO) and eyes-closed (EC) conditions to assess postural control. The independent associations of sleep quality with FoF and postural control were evaluated by multivariate linear and logistic regressions, respectively, adjusting for potential confounding variables.

Results:

SEO was independently associated (adjusted R
2 = 0.073) with sleep duration (P < 0.001) and subjective sleep quality (P = 0.001), VEO (adjusted R
2 = 0.156) with daytime dysfunction (P = 0.006) and sleep duration (P = 0.013), RMSXEO (adjusted R
2 = 0.118) with subjective sleep quality (P = 0.005), and RMSYEO (adjusted R
2 = 0.166) with sleep duration (P = 0.001) and daytime dysfunction (P = 0.046). Under EC condition, SEC (adjusted R
2 = 0.014) was independently related with anxiety (P = 0.034), VEC (adjusted R
2 = 0.148) with daytime dysfunction (P = 0.002) and sleep duration (P = 0.024), RMSXEC (adjusted R
2 = 0.134) with subjective sleep quality (P < 0.001), and RMSYEC (adjusted R
2 = 0.128) with sleep duration (P = 0.013) and daytime dysfunction (P = 0.033). Logistic regression showed that time since menopause (P = 0.003), body mass index (P = 0.001), and anxiety (P < 0.001), unlike sleep quality, were independently associated with FoF. The effect size of the model was medium (adjusted R
2= 0.162).

Conclusions:

In Spanish postmenopausal women, sleep duration, subjective sleep quality, and daytime dysfunction were independent risk factors for worsened postural stability. FoF, anxiety, time since menopause onset, and body mass index, unlike sleep quality, were independently associated with poor postural stability.
The Role of Stigma and Denormalization in Suicide-Prevention Laws in East Asia: A Sociocultural, Historical, and Ethical Perspective
Authors: Chen Justin A. , Courtwright Andrew , Wu Kevin Chien-Chang
Published: July 2017

In many Western countries, the criminalization and stigmatization of suicide has given way to a biomedical approach aimed at destigmatizing suicide and treating underlying mental illness. By contrast, in many East Asian countries, suicide has never historically been criminalized or stigmatized. High rates of suicide in Japan, South Korea, and Taiwan have recently led policy makers in those countries to pursue innovative suicide-prevention strategies. The intentional denormalization of harmful behaviors has been discussed in the public health and ethics literatures, particularly with regard to smoking cessation, and could represent a novel mechanism for preventing suicides in East Asia. Using examples from the sociocultural, historical, and legal discourses surrounding suicide in Western and East Asian contexts, we suggest that denormalization can be a justified, culturally relevant suicide-prevention strategy, but that care must be taken to avoid shaming or stigmatizing suicidal individuals. Specifically, we propose the term weak denormalization to refer to an ethically permissible strategy at the mildest end of a spectrum of denormalizing approaches—milder than the reintegrative shaming described in the criminal justice literature, and diametrically opposed to outright stigmatization, which is generally considered ethically impermissible. Given the severe stigma of mental illness in East Asia, adopting the dominant Western view of suicide as solely a psychiatric concern would not be justified. Weak denormalization strategies in East Asia should be culturally tailored and rigorously tested on a small scale. They should include social supports, praise for the bravery of those of who seek help, and strategies to reduce shame regarding perceived social failure.
Discontinuity of Medicaid Coverage
Authors: Ji Xu , Wilk Adam S. , Druss Benjamin G. , Lally Cathy , Cummings Janet R.
Published: July 2017

Background:

Gaps in Medicaid coverage may disrupt access to and continuity of care. This can be detrimental for beneficiaries with chronic conditions, such as major depression, for whom disruptions in access to outpatient care may lead to increased use of acute care. However, little is known about how Medicaid coverage discontinuities impact acute care utilization among adults with depression.

Objective:

Examine the relationship between Medicaid discontinuities and service utilization among adults with major depression.

Subjects:

A total of 139,164 adults (18–64) with major depression was identified using the 2003–2004 Medicaid Analytic eXtract Files.

Methods:

We used generalized linear and two-part models to examine the effect of Medicaid discontinuity on service utilization. To establish causality in this relationship, we used instrumental variables analysis, relying on exogenous variation in a state-level policy for identification.

Outcome Measures:

Emergency department (ED) visits, inpatient episodes, inpatient days, and Medicaid-reimbursed costs.

Results:

Approximately 29.4% of beneficiaries experienced coverage disruptions. In instrumental variables models, those with coverage disruptions incurred an increase of $650 in acute care costs per-person per Medicaid-covered month compared with those with continuous coverage, evidenced by an increase in ED use (0.1 more ED visits per-person-month) and inpatient days (0.6 more days per-person-month). The increase in acute costs contributed to an overall increase in all-cause costs by $310 per-person-month (all P-values<0.001).

Conclusions:

Among depressed adults, those experiencing coverage disruptions have, on average, significantly greater use of costly ED/inpatient services than those with continuous coverage. Maintenance of continuous Medicaid coverage may help prevent acute episodes requiring high-cost interventions.
Risk of Pancreatic Cancer After a Primary Episode of Acute Pancreatitis
Authors: Rijkers Anton P. , Bakker Olaf J. , Ahmed Ali Usama , Hagenaars Julia C.J.P. , van Santvoort Hjalmar C. , Besselink Marc G. , Bollen Thomas L. , van Eijck Casper H.
Published: July 2017

Objective

Acute pancreatitis may be the first manifestation of pancreatic cancer. The aim of this study was to assess the risk of pancreatic cancer after a first episode of acute pancreatitis.

Methods

Between March 2004 and March 2007, all consecutive patients with a first episode of acute pancreatitis were prospectively registered. Follow-up was based on hospital records audit, radiological imaging, and patient questionnaires. Outcome was stratified based on the development of chronic pancreatitis.

Results

We included 731 patients. The median follow-up time was 55 months. Progression to chronic pancreatitis was diagnosed in 51 patients (7.0%). In this group, the incidence rate per 1000 person-years for developing pancreatic cancer was 9.0 (95% confidence interval, 2.3–35.7). In the group of 680 patients who did not develop chronic pancreatitis, the incidence rate per 1000 person-years for developing pancreatic cancer in this group was 1.1 (95% confidence interval, 0.3–3.3). Hence, the rate ratio of pancreatic cancer was almost 9 times higher in patients who developed chronic pancreatitis compared with those who did not (P = 0.049).

Conclusions

Although a first episode of acute pancreatitis may be related to pancreatic cancer, this risk is mainly present in patients who progress to chronic pancreatitis.
Cytomegalovirus Cavitary Pneumonia in Nontransplant Pediatric Acute Lymphoblastic Leukemia: Case Report and Review of the Literature
Authors: De Leonardis Francesco , Perillo Teresa , Daniele Rosa M. , Santoro Nicola
Published: July 2017

Lung cavitary lesions are a rare finding in the nontransplant setting of a patient with acute leukemia. Among viral agents, cytomegalovirus (CMV) may cause pulmonary nodules and cavities in patients undergoing hematopoietic stem cell transplantation, but during pediatric acute lymphoblastic leukemia treatment, CMV disease is less common. Here we report the case of a boy affected by acute lymphoblastic leukemia who suffered severe cavitary CMV pneumonia during chemotherapy, and we review the current literature.
Systemic Epstein-Barr Virus-positive T-Cell Lymphoproliferative Disease of Childhood With Good Response to Steroid Therapy
Authors: Kim Do-Hoon , Kim Myungshin , Kim Yonggoo , Han Kyungja , Han Eunhee , Lee Jae Wook , Chung Nack-Gyun , Cho Bin
Published: July 2017

Systemic Epstein-Barr virus (EBV)-positive T-cell lymphoproliferative disease of childhood is a rare disease and has a very fulminant clinical course with high mortality. A 21-month-old female patient was referred to our hospital with a 1 week history of fever and was subsequently diagnosed with systemic Epstein-Barr virus-positive T-cell lymphoproliferative disease of childhood. After starting treatment with dexamethasone, she showed early defervescence and improvement of laboratory parameters, and has remained disease-free after stopping steroid treatment, although longer follow-up is necessary. Our report underscores the possibility that this disease entity may be heterogenous in terms of prognosis.
Effect of a Training Strategy in Improving Medication Fallacies During Pediatric Cardiopulmonary Resuscitation: A Before-and-After Study From a Developing Country
Authors: Sankar Jhuma , Das Rashmi Ranjan , Mahapatro Samarendra , Sankar M. Jeeva
Published: July 2017

Objective

This study aims to evaluate the effect of structured training on resident performance in improving medication fallacies during pediatric cardiopulmonary resuscitation (CPR).

Methods

This before-and-after study was conducted in the pediatric acute care areas of tertiary care teaching hospitals of a developing country from August to December 2015. Case records of children younger than 18 years who underwent CPR were reviewed. Senior residents rotating through pediatric emergency department and pediatric intensive care unit were evaluated for their knowledge. Incidence of medication fallacies in pediatric CPR and change in the knowledge scores of residents posted in these areas were the main outcome measures.

Results

One-hundred records were evaluated (pre-intervention, 54; post-intervention, 46). In the pre-intervention period, 25 had medication fallacies (documentation, 16; dosing, 9). In the post-intervention period, 7 fallacies pertaining to documentation (not dosing) were found. The incidence of severe fallacies decreased from 20% pretraining to 0% posttraining. The mean (SD) knowledge scores of residents increased from 7.9 (2.9) pretraining to 13 (1.4) posttraining. On univariate analysis, fallacies were found to be less if the resident was formally trained (pediatric advanced life support certified), if the patient was older, and during morning and night shifts as compared with evening shift. On multivariate analysis, however, only status of training (posttraining) (adjusted odds ratio, 0.12; 95% confidence interval, 0.02–0.68) and the morning shift (adjusted odds ratio, 0.03; 95% confidence interval, 0.001–0.72) remained significant with lower incidence of fallacies associated with these variables.

Conclusions

Rates of medication fallacies in pediatric CPR declined with structured training. Documentation fallacies may not be eliminated completely with only 1-time training.
FOXL2 Mutation Analysis of Ovarian Sex Cord-Stromal Tumors: Genotype-Phenotype Correlation With Diagnostic Considerations
Authors: Buza Natalia , Wong Serena , Hui Pei
Published: July 2017

Correlation of FOXL2 mutation status with morphologic features and reticulin staining patterns was performed in a comprehensive single-institutional cohort of ovarian sex cord-stromal tumors. Fifty-one cases were included, 35 of which were morphologically diagnosed as adult granulosa cell tumor, 4 as Sertoli-Leydig cell tumor, 11 as fibroma/fibrothecoma and 1 as a thecoma. Of the adult granulosa cell tumors, 31 (88.6%) harbored FOXL2 mutation. Abundant pale cytoplasm was seen in 51.6% (16/31) of FOXL2 mutated tumors, compared with 6.7% (1/15) among FOXL2 wild type tumors (P=0.003). Nearly half of FOXL2 negative tumors showed individual pericellular reticulin staining pattern, while none of the FOXL2 positive cases demonstrated this feature (P=0.0001). Nested reticulin pattern was observed in 67.7% of FOXL2 positive tumors, compared with 20% of FOXL2 negative cases (P=0.004). Indeterminate reticulin staining pattern was seen in nearly one third of cases in both groups. Nested reticulin pattern was 87.5% specific and 67.7% sensitive for FOXL2 mutation, while individual reticulin pattern was 100% specific for absence of FOXL2 mutation. No statistical significance was observed between the 2 groups in tumor size, mitotic activity, nuclear atypia, and nuclear grooves. Follow-up was available for 44 patients ranging from 0.3 to 259 months (mean: 67.5 mo). Two patients developed recurrence, both of them harbored FOXL2 mutation. In conclusion, the pathology diagnosis of sex cord-stromal tumors continues to be difficult, and reticulin staining remains a valuable tool as an initial step in the diagnostic work-up. Individual pericellular reticulin pattern essentially rules out adult granulosa cell tumor, while cases with indeterminate or nested patterns can be subjected to FOXL2 mutation testing to aid the diagnosis.
Medication Simulation Affects Health Provider Students' Attitudes About Adherence and Concordance
Authors: Perdue Tamara O. , Jackson J. Todd , Herring Christine , Garren Kathryn , Yocum R. Anthony , Swanson Melvin , Nye Ann Marie
Published: July 2017

Introduction

Assisting polypharmacy patients with complex health regimens is a part of health provider responsibilities. The concepts of adherence and concordance contrast the traditional emphasis on patient compliance. However, health provider students may not be able to empathize with polypharmacy patients. The purpose of this study was to measure the effect of a medication simulation on medical, nursing, and pharmacy students' beliefs about adherence and concordance.

Methods

A prospective, quasi-experimental, pretest, and posttest design was used with institutional review board approval. The participants (N = 62) took four simulated medications (varied dosing schedules) for 1 week. Attitudes toward adherence and concordance were assessed before and after the intervention.

Results

Subjects averaged 24.6 years (SD = 4.32), 72.6% female, and 79% white. Most were medical students (n = 33, 53%), followed by nursing (n = 21, 34%) and pharmacy students (n = 8, 13%). There were significant changes [t(61) = 3.92, P < 0.001] in beliefs about adherence from time 1 (mean = 25.13, SD = 5.77) to time 2 (mean = 22.05, SD = 6.06), and about concordance (mean = 41.85, SD = 5.58 time 1) to (mean = 44.29, SD = 6.32 time 2) [t(61) = 3.31, P < 0.05], for the entire group. Most students (84%) predicted that they would be able to take four medications correctly for 1 week. Fifty-eight students (94%) found that adherence was ‘much harder’ or ‘a little harder’ than anticipated. Most (89%) felt that the simulation will impact their patient care.

Conclusions

Participation in a medication simulation exercise affected health provider students' attitudes toward adherence and concordant behaviors. These experiences may influence future patient interactions.
Design and Early Experience With a Real-World Surgical Registry
Authors: Weber LeBrun Emily E. , Lynch Lauren D. , Peterson Hanna V. , Pena Savannah Rose , Ruder Kara , Vasilopoulos Terrie
Published: July 2017

Objectives

We describe the rationale, design, and methods and 6-year experience with a real-world surgical registry for female pelvic reconstructive and incontinence procedures and postoperative outcomes.

Methods

The primary goal of creating this registry was to establish the feasibility of prospective data capture for all urogynecologic procedures. Data captured included baseline demographics, surgical procedures, perioperative complications, and subjective and objective findings up to 36 months after surgery.

Results

The Pelvic Reconstruction and Incontinence Surgery ± Mesh Registry was developed over 3 years to include 194 unique variables for prospective data capture. The registry was implemented in December 2010, and data from 924 separate case events from a single surgeon were recorded, comprising 100% surgical case capture. Cases included a variety of procedures representing a comprehensive urogynecology practice on 804 unique patients. Patients who were asked to participate in long-term follow-up (n = 299) returned with attendance of 96% at 6 weeks, 64% at 6 months, 51% at 12 months, 39% at 24 months, and 22% at 36 months.

Conclusions

The Pelvic Reconstruction and Incontinence Surgery ± Mesh Registry effectively captured all urogynecologic procedures for the purpose of quality improvement. This real-world tool demonstrates that 100% case capture is feasible and provides valuable information for the highly motivated surgeon, although adequate long-term follow-up is limited. Additional research is needed to better understand the role of surgical registries for quality improvement and development of patient-centered strategies to increase long-term follow-up.
Good news, bad news: An analysis of 11,294 gunshot wounds (GSWs) over two decades in a single center
Authors: Manley Nathan R. , Fabian Timothy C. , Sharpe John P. , Magnotti Louis J. , Croce Martin A.
Published: July 2017

INTRODUCTION

Gun violence is a substantial public health problem accounting for significant physical, psychological, and financial costs. Although aggregate data sources demonstrate decreasing rates of firearm violence, analyses from individual trauma centers have shown that mortality and injury severity from gunshot wounds (GSWs) are increasing. To evaluate the evolving characteristics of gun violence in our region, we studied all GSWs admitted to our trauma center over a 20-year period.

METHODS

A retrospective analysis of all newly admitted patients with GSWs was performed from 1996 to 2016. Our trauma registry was used to collect data on demographics, mortality, injury severity, body regions injured, and geographic location of injury. Homicide data were obtained from local law enforcement.

RESULTS

A total of 11,294 patients with GSWs were reviewed. The number of GSWs treated per biennium increased from 1,349 in 1996–1997 to 1,484 in 2014–2015, with a 59% increase occurring from 2010–2011 to 2014–2015. Overall mortality was 14.6% and decreased from 15.8% in 1996–1997 to 10.2% in 2014–2015 (p < 0.0001). Mean Injury Severity Score was 12.6 and the percentage of patients who suffered GSWs to ≥3 Abbreviated Injury Scale body regions increased from 2.5% in 1996–1997 to 7.7% in 2014–2015 (p < 0.0001). Local firearm homicide data show a 118% increase from 2010 to 2016.

CONCLUSIONS

In contrast to other recent studies, we found that mortality decreased whereas the number of patients treated for GSWs and those with multicompartmental injuries increased. The decrease in mortality suggests improved trauma systems as well as an increase in nonfatal GSWs that dilutes overall mortality. Wounding in multiple body regions suggests more effective weaponry, including increased magazine size. The recent increase in local homicides parallels trends in registry data and illustrates worsening gun violence in our region. Further research is needed to understand local and regional determinants of increased gun violence to better guide prevention strategies.

LEVEL OF EVIDENCE

Epidemiological study, level III.
The renaissance man of burn surgery: Basil A. Pruitt, Jr.
Authors: Capek Karel D. , Foncerrada Guillermo , Clayton R. Patrick , Sljivich Michaela , Voigt Charles D. , Hundeshagen Gabriel , Cambiaso-Daniel Janos , Porter Craig , Guillory Ashley , Herndon David N.
Published: July 2017

Dr. Basil A. Pruitt Jr., a consummate clinical and translational surgeon-scientist, has spent over half a century at the forefront of an advancing standard of burn care. Commanding the US Army Institute for Surgical Research in San Antonio, he trained generations of leading burn clinicians and allied scientists. At his direction, there were forged discoveries in resuscitation from shock, treatment of inhalation injury, control of burn-related infections, prevention of iatrogenic complications, and understanding the sympathetic, endocrine, and immune responses to burn injury. Most consequentially, this team was among the first to recognize and define alterations in the basal metabolic rate and thermoregulation consequent to burn injury. These investigations prompted groundbreaking insights into the coordinated nervous, autonomic, endocrine, immune, and metabolic outflows that a severely burned patient uses to remain alive and restore homeostasis. Marking his scientific consequence, many of his reports continue to bear fruit when viewed through a contemporary lens. This article summarizes some of the major findings of his career thus far and is intended to complement a Festschrift recently held in his honor.
Risk factors for deep vein thrombosis and pulmonary embolism after traumatic injury: A competing risks analysis
Authors: Van Gent Jan-Michael , Calvo Richard Yee , Zander Ashley L. , Olson Erik J. , Sise C. Beth , Sise Michael J. , Shackford Steven R.
Published: July 2017

BACKGROUND

Venous thromboembolism, including deep vein thrombosis (DVT) and pulmonary embolism (PE), is typically reported as a composite measure of the quality of trauma center care. Given that recent data suggesting postinjury DVT and PE are distinct clinical processes, a better understanding may result from analyzing them as independent, competing events. Using competing risks analysis, we evaluated our hypothesis that the risk factors and timing of postinjury DVT and PE are different.

METHODS

We examined all adult trauma patients admitted to our Level I trauma center from July 2006 to December 2011 who received at least one surveillance duplex ultrasound of the lower extremities and who were at high risk or greater for DVT. Outcomes included DVT and PE events, and time-to-event from admission. We used competing risks analysis to evaluate risk factors for DVT while accounting for PE as a competing event, and vice versa.

RESULTS

Of 2,370 patients, 265 (11.2%) had at least one venous thromboembolism event, 235 DVT only, 19 PE only, 11 DVT and PE. Within 2 days of admission, 38% of DVT cases had occurred compared with 26% of PE. Competing risks modeling of DVT as primary event identified older age, severe injury (Injury Severity Score, ≥ 15), mechanical ventilation longer than 4 days, active cancer, history of DVT or PE, major venous repair, male sex, and prophylactic enoxaparin and prophylactic heparin as associated risk factors. Modeling of PE as the primary event showed younger age, nonsevere injury (Injury Severity Score, < 15), central line placement, and prophylactic heparin as relevant factors.

CONCLUSION

The risk factors for PE and DVT after injury were different, suggesting that they are clinically distinct events that merit independent consideration. Many DVT events occurred early despite prophylaxis, bringing into question the preventability of postinjury DVT. We recommend trauma center quality reporting program measures be revised to account for DVT and PE as unique events.

LEVEL OF EVIDENCE

Epidemiologic, level III.
DprA from Neisseria meningitidis: properties and role in natural competence for transformation
Authors: Hovland Eirik , Beyene Getachew Tesfaye , Frye Stephan A. , Homberset Håvard , Balasingham Seetha V. , Gómez-Muñoz Marta , Derrick Jeremy P. , Tønjum Tone , Ambur Ole H.
Published: July 2017

DNA processing chain A (DprA) is a DNA-binding protein that is ubiquitous in bacteria and expressed in some archaea. DprA is active in many bacterial species that are competent for transformation of DNA, but its role in Neisseriameningitidis (Nm) is not well characterized. An Nm mutant lacking DprA was constructed, and the phenotypes of the wild-type and ΔdprA mutant were compared. The salient feature of the phenotype of dprA null cells is the total lack of competence for genetic transformation shown by all of the donor DNA substrates tested in this study. Here, Nm wild-type and dprA null cells appeared to be equally resistant to genotoxic stress. The gene encoding DprANm was cloned and overexpressed, and the biological activities of DprANm were further investigated. DprANm binds ssDNA more strongly than dsDNA, but lacks DNA uptake sequence-specific DNA binding. DprANm dimerization and interaction with the C-terminal part of the single-stranded binding protein SSBNmwere demonstrated. dprA is co-expressed with smg, a downstream gene of unknown function, and the gene encoding topoisomerase 1, topA.
Dissecting causal pathways using Mendelian randomization with summarized genetic data: application to age at menarche and risk of breast cancer
Authors: Burgess Stephen , Thompson Deborah J , Rees Jessica MB , Day Felix R , Perry John R , Ong Ken K
Published: July 2017

Mendelian randomization is the use of genetic variants as instrumental variables to estimate causal effects of risk factors on outcomes. The total causal effect of a risk factor is the change in the outcome resulting from intervening on the risk factor. This total causal effect may potentially encompass multiple mediating mechanisms. For a proposed mediator, the direct effect of the risk factor is the change in the outcome resulting from a change in the risk factor keeping the mediator constant. A difference between the total effect and the direct effect indicates that the causal pathway from the risk factor to the outcome acts at least in part via the mediator (an indirect effect). Here, we show that Mendelian randomization estimates of total and direct effects can be obtained using summarized data on genetic associations with the risk factor, mediator, and outcome, potentially from different data sources. We perform simulations to test the validity of this approach when there is unmeasured confounding and/or bidirectional effects between the risk factor and mediator. We illustrate this method using the relationship between age at menarche and risk of breast cancer, with body mass index (BMI) as a potential mediator. We show an inverse direct causal effect of age at menarche on risk of breast cancer (independent of BMI) and a positive indirect effect via BMI. In conclusion, multivariable Mendelian randomization using summarized genetic data provides a rapid and accessible analytic strategy that can be undertaken using publicly-available data to better understand causal mechanisms.
PIP30/FAM192A is a novel regulator of the nuclear proteasome activator PA28γ
Authors: Jonik-Nowak Beata , Menneteau Thomas , Fesquet Didier , Baldin Véronique , Bonne-Andrea Catherine , Méchali Francisca , Fabre Bertrand , Boisguerin Prisca , de Rossi Sylvain , Henriquet Corinne , Pugnière Martine , Ducoux-Petit Manuelle , Burlet-Schiltz Odile , Lamond Angus I. , Fort Philippe , Boulon Séverine , Bousquet Marie-Pierre , Coux Olivier
Published: July 2017

PA28γ is a nuclear activator of the 20S proteasome involved in the regulation of several essential cellular processes, such as cell proliferation, apoptosis, nuclear dynamics and cellular stress response. Unlike the 19S regulator of the proteasome, which specifically recognizes ubiquitylated proteins, PA28γ promotes the degradation of several substrates by the proteasome in an ATP- and ubiquitin-independent manner. However its exact mechanisms of action are unclear and likely to involve additional partners that remain to be identified. Here we report the identification of the first cofactor of PA28γ, PIP30/FAM192A. PIP30 binds directly and specifically via its C-terminal end and in an interaction stabilized by casein kinase 2 phosphorylation to both free and 20S proteasome-associated PA28γ. Its recruitment to proteasome-containing complexes depends on PA28γ and its expression increases the association of PA28γ with the 20S proteasome in cells. Further dissection of its possible roles shows that PIP30 alters PA28γ-dependent activation of peptide degradation by the 20S proteasomein vitroand negatively controls in cells the presence of PA28γ in Cajal Bodies by inhibition of its association with the key Cajal body component coilin. Altogether, our data show that PIP30 deeply affects PA28γ interactions with cellular proteins, including 20S proteasome, demonstrating that it is an important regulator of PA28γ in cells and thus a new player in the control of the multiple functions of the proteasome within the nucleus.

Significance Statement

The 20S proteasome is a key actor of the control of protein levels and integrity in cells. To perform its multiple functions, it works with a series of regulators, among which a nuclear complex called PA28γ. In particular, PA28γ participates in the regulation of cell proliferation and nuclear dynamics. We describe here the characterization of a novel protein, PIP30/FAM192A, which binds tightly to PA28γ and favors its interaction with the 20S proteasome while inhibiting its association with coilin, a central component of nuclear Cajal bodies. Thus PIP30/FAM192A critically controls the interactome and consequently the functions of PA28γ, and appears to be a new player in the fine regulation of intracellular proteostasis in the cell nucleus.
Computational correction of copy-number effect improves specificity of CRISPR-Cas9 essentiality screens in cancer cells
Authors: Meyers Robin M. , Bryan Jordan G. , McFarland James M. , Weir Barbara A. , Sizemore Ann E. , Xu Han , Dharia Neekesh V. , Montgomery Phillip G. , Cowley Glenn S. , Pantel Sasha , Goodale Amy , Lee Yenarae , Ali Levi D. , Jiang Guozhi , Lubonja Rakela , Harrington William F. , Strickland Matthew , Wu Ting , Hawes Derek C. , Zhivich Victor A. , Wyatt Meghan R. , Kalani Zohra , Chang Jaime J. , Okamoto Michael , Golub Todd R. , Boehm Jesse S. , Vazquez Francisca , Root David E. , Hahn William C. , Tsherniak Aviad
Published: July 2017

The CRISPR-Cas9 system has revolutionized gene editing both on single genes and in multiplexed loss-of-function screens, enabling precise genome-scale identification of genes essential to proliferation and survival of cancer cells. However, previous studies reported that an anti-proliferative effect of Cas9-mediated DNA cleavage confounds such measurement of genetic dependency, particularly in the setting of copy number gain1-4. We performed genome-scale CRISPR-Cas9 essentiality screens on 342 cancer cell lines and found that this effect is common to all lines, leading to false positive results when targeting genes in copy number amplified regions. We developed CERES, a computational method to estimate gene dependency levels from CRISPR-Cas9 essentiality screens while accounting for the copy-number-specific effect, as well as variable sgRNA activity. We applied CERES to sets of screens performed with different sgRNA libraries and found that it reduces false positive results and provides meaningful estimates of sgRNA activity. As a result, the application of CERES improves confidence in the interpretation of genetic dependency data from CRISPR-Cas9 essentiality screens of cancer cell lines.
Hospitalizations associated with respiratory syncytial virus (RSV) and influenza in children, including children having a diagnosis of asthma
Authors: Goldstein E. , Finelli L. , O’Halloran A. , Liu P. , Karaca Z. , Steiner C. , Viboud C. , Lipsitch M.
Published: July 2017

Background

There is uncertainty about the burden of hospitalization associated with RSV and influenza in children, including those with underlying medical conditions.

Methods

We applied previously developed methodology (Goldstein et al., Epidemiology 2012) to HealthCare Cost and Utilization Project (HCUP) hospitalization data and additional data related to asthma diagnosis/previous history in hospitalized children to estimate RSV and influenza-associated hospitalization rates in different subpopulations of US children between 2003-2010.

Results

The estimated average annual rates (per 100,000 children) of RSV-associated hospitalization with a respiratory cause (ICD-9 codes 460-519) present anywhere in the discharge diagnosis were 2381 (95% CI(2252,2515)) in age <1y; 710.6(609.1,809.2) (age 1y); 395(327.7,462.4) (age 2y); 211.3(154.6,266.8) (age 3y); 111.1(62.4,160.1) (age 4y); 72.3(29.3,116.4) (ages 5-6y); 35.6(9.9,62.2) (ages 7-11y); and 39(17.5,60.6) (ages 12-17y).

The corresponding rates of influenza-associated hospitalization were lower, ranging from 181(142.5,220.3) in age <1y to 17.9(11.7,24.2) in ages 12-17y. The relative risks for RSV-related hospitalization associated with a prior diagnosis of asthma in age groups under 5y ranged between 3.1(2.1,4.7) (age <1y) to 6.7(4.2,11.8) (age 2y); the corresponding risks for influenza-related hospitalization ranged from 2.8(2.1,4) (age <1y) to 4.9(3.8,6.4) (age 3y).

Conclusions

RSV-associated hospitalization rates in young children are high and decline rapidly with age. Young children with an asthma diagnosis should be target groups for RSV and influenza-related mitigation efforts, possibly including RSV prophylaxis for the youngest children.
Virtual Reality system for freely-moving rodents
Authors: Del Grosso Nicholas A. , Graboski Justin J. , Chen Weiwei , Blanco-Hernández Eduardo , Sirota Anton
Published: July 2017

Spatial navigation, active sensing, and most cognitive functions rely on a tight link between motor output and sensory input. Virtual reality (VR) systems simulate the sensorimotor loop, allowing flexible manipulation of enriched sensory input. Conventional rodent VR systems provide 3D visual cues linked to restrained locomotion on a treadmill, leading to a mismatch between visual and most other sensory inputs, sensory-motor conflicts, as well as restricted naturalistic behavior. To rectify these limitations, we developed a VR system (ratCAVE) that provides realistic and low-latency visual feedback directly to head movements of completely unrestrained rodents. Immersed in this VR system, rats displayed naturalistic behavior by spontaneously interacting with and hugging virtual walls, exploring virtual objects, and avoiding virtual cliffs. We further illustrate the effect of ratCAVE-VR manipulation on hippocampal place fields. The newly-developed methodology enables a wide range of experiments involving flexible manipulation of visual feedback in freely-moving behaving animals.
Relevance learning via inhibitory plasticity and its implications for schizophrenia
Authors: Insel Nathan , Richards Blake A.
Published: July 2017

Symptoms of schizophrenia may arise from a failure of cortical circuits to filter-out irrelevant inputs. Schizophrenia has also been linked to disruptions to cortical inhibitory interneurons, consistent with the possibility that in the normally functioning brain, these cells are in some part responsible for determining which inputs are relevant and which irrelevant. Here, we develop an abstract but biologically plausible neural network model that demonstrates how the cortex may learn to ignore irrelevant inputs through plasticity processes affecting inhibition. The model is based on the proposal that the amount of excitatory output from a cortical circuit encodes expected magnitude of reward or punishment (”relevance”), which can be trained using a temporal difference learning mechanism acting on feed-forward inputs to inhibitory interneurons. The model exhibits learned irrelevance and blocking, which become impaired following disruptions to inhibitory units. When excitatory units are connected to a competitive-learning output layer, the relevance code is capable of modulating learning and activity. Accordingly, the combined network is capable of recapitulating published experimental data linking inhibition in frontal cortex with fear learning and expression. Finally, the model demonstrates how relevance learning can take place in parallel with other types of learning, through plasticity rules involving inhibitory and excitatory components respectively. Altogether, this work offers a theory of how the cortex learns to selectively inhibit inputs, providing insight into how relevance-assignment problems may emerge in schizophrenia.
Disrupted modular organization of primary sensory brain areas in schizophrenics
Authors: Bordier Cécile , Nicolini Carlo , Bifone Angelo
Published: July 2017

Abnormal brain resting-state functional connectivity has been consistently observed in patients affected by Schizophrenia (SCZ) using functional MRI and other neuroimaging methods. Graph theoretical methods provide a framework to investigate these defective functional interactions and their effects on the modular organization of brain connectivity networks. A few studies have shown abnormal distribution of connectivity within and between functional modules, an indication of imbalanced functional segregation ad integration in SCZ patients. However, no major alterations in the modular structure of functional connectivity networks in patients have been reported, and unambiguous identification of the neural substrates involved remains elusive. Recently, it has been demonstrated that current modularity analysis methods suffer from a fundamental and severe resolution limit, as they fail to detect features that are smaller than a scale determined by the size of the entire connectivity network. This resolution limit is likely to have hampered the ability to resolve differences between patients and controls in previous cross-sectional studies. Here, we apply a novel, resolution limit-free approach to study the modular organization of resting state functional connectivity networks in a large cohort of SCZ patients, and in matched healthy controls. Leveraging these important methodological advances, we find new evidence of substantial fragmentation and reorganization involving primary sensory, auditory and visual areas in SCZ patients. Conversely, frontal and prefrontal areas, typically associated with higher cognitive functions, appear to be largely unaffected, with changes selectively involving language and speech processing areas. Our findings provide support to the hypothesis that cognitive dysfunction in SCZ may arise from deficits occurring already at early stages of sensory processing.
Large-Scale Uniform Analysis of Cancer Whole Genomes in Multiple Computing Environments
Authors: Yung Christina K. , O’Connor Brian D. , Yakneen Sergei , Zhang Junjun , Ellrott Kyle , Kleinheinz Kortine , Miyoshi Naoki , Raine Keiran M. , Royo Romina , Saksena Gordon B. , Schlesner Matthias , Shorser Solomon I. , Vazquez Miguel , Weischenfeldt Joachim , Yuen Denis , Butler Adam P. , Davis-Dusenbery Brandi N. , Eils Roland , Ferretti Vincent , Grossman Robert L. , Harismendy Olivier , Kim Youngwook , Nakagawa Hidewaki , Newhouse Steven J. , Torrents David , Stein Lincoln D. ,   on behalf of the PCAWG Technical Working Group, Rodriguez Javier Bartolomé , Boroevich Keith A. , Boyce Rich , Brooks Angela N. , Buchanan Alex , Buchhalter Ivo , Byrne Niall J. , Cafferkey Andy , Campbell Peter J. , Chen Zhaohong , Cho Sunghoon , Choi Wan , Clapham Peter , De La Vega Francisco M. , Demeulemeester Jonas , Dow Michelle T. , Dursi Lewis J. , Eils Juergen , Farcas Claudiu , Favero Francesco , Fayzullaev Nodirjon , Flicek Paul , Fonseca Nuno A. , Gelpi Josep L.l. , Getz Gad , Gibson Bob , Heinold Michael C. , Hess Julian M. , Hofmann Oliver , Hong Jongwhi H. , Hudson Thomas J. , Huebschmann Daniel , Hutter Barbara , Hutter Carolyn M. , Imoto Seiya , Ivkovic Sinisa , Jeon Seung-Hyup , Jiao Wei , Jung Jongsun , Kabbe Rolf , Kahles Andre , Kerssemakers Jules , Kim Hyunghwan , Kim Hyung-Lae , Kim Jihoon , Korbel Jan O. , Koscher Michael , Koures Antonios , Kovacevic Milena , Lawerenz Chris , Leshchiner Ignaty , Livitz Dimitri G. , Mihaiescu George L. , Mijalkovic Sanja , Lazic Ana Mijalkovic , Miyano Satoru , Nahal Hardeep K. , Nastic Mia , Nicholson Jonathan , Ocana David , Ohi Kazuhiro , Ohno-Machado Lucila , Omberg Larsson , Francis Ouellette B.F. , Paramasivam Nagarajan , Perry Marc D. , Pihl Todd D. , Prinz Manuel , Puiggròs Montserrat , Radovic Petar , Rheinbay Esther , Rosenberg Mara W. , Short Charles , Sofia Heidi J. , Spring Jonathan , Struck Adam J. , Tiao Grace , Tijanic Nebojsa , Loo Peter Van , Vicente David , Wala Jeremiah A. , Wang Zhining , Werner Johannes , Williams Ashley , Woo Youngchoon , Wright Adam J. , Xiang Qian ,   the PCAWG Network
Published: July 2017

The International Cancer Genome Consortium (ICGC)’s Pan-Cancer Analysis of Whole Genomes (PCAWG) project aimed to categorize somatic and germline variations in both coding and non-coding regions in over 2,800 cancer patients. To provide this dataset to the research working groups for downstream analysis, the PCAWG Technical Working Group marshalled ~800TB of sequencing data from distributed geographical locations; developed portable software for uniform alignment, variant calling, artifact filtering and variant merging; performed the analysis in a geographically and technologically disparate collection of compute environments; and disseminated high-quality validated consensus variants to the working groups. The PCAWG dataset has been mirrored to multiple repositories and can be located using the ICGC Data Portal. The PCAWG workflows are also available as Docker images through Dockstore enabling researchers to replicate our analysis on their own data.