bluuebunny/crossref_metadata_2025 huggingface dataset:
Pediatric Orthopaedic Workforce in 2014: Current Workforce and Projections for the Future
Authors: Sawyer Jeffrey R. , Jones Kerwyn C. , Copley Lawson A. , Chambers Stephanie
Published: October 2015

Background:

The changing nature of the United States (US) health care system has prompted debate concerning the physician supply. The basic questions are: do we have an adequate number of surgeons to meet current demands and are we training the correct number of surgeons to meet future demands? The purpose of this analysis was to characterize the current pediatric orthopaedic workforce in terms of supply and demand, both present and future.

Methods:

Databases were searched (POSNA, SF Match, KID, MGMA) to determine the current pediatric orthopaedic workforce and workforce distribution, as well as pediatric orthopaedic demand.

Results:

The number of active Pediatric Orthopaedic Society of North America (POSNA) members increased over the past 20 years, from 410 in 1993 to 653 in 2014 (155% increase); however, the density of POSNA members is not equally distributed, but correlates to population density. The number of estimated pediatric discharges, orthopaedic and nonorthopaedic, has remained relatively stable from 6,348,537 in 1997 to 5,850,184 in 2012. Between 2003 and 2013, the number of pediatric orthopaedic fellows graduating from Accreditation Council for Graduate Medical Education and non-Accreditation Council for Graduate Medical Education programs increased from 39 to 50 (29%), with a peak of 67 fellows (71%) in 2009.

Discussion:

Although predicting the exact need for pediatric orthopaedic surgeons (POS) is impossible because of the complex interplay among macroeconomic, governmental, insurance, and local factors, some trends were identified: the supply of POS has increased, which may offset the expected numbers of experienced surgeons who will be leaving the workforce in the next 10 to 15 years; macroeconomic factors influencing demand for physician services, driven by gross domestic product and population growth, are expected to be stable in the near future; expansion of the scope of practice for POS is expected to continue; and further similar assessments are warranted.

Level of Evidence:

Level II—economic and decision analysis.
Arthroscopic Treatment of Traumatic Hip Dislocations in Children and Adolescents: A Preliminary Study
Authors: Morris Andrew C. , Yu Jonathan C. , Gilbert Shawn R.
Published: October 2015

Introduction:

Traumatic hip dislocations in children and adolescents require prompt concentric reduction. Incomplete reduction with or without retained osteochondral fragments has traditionally been addressed with open reduction. We report on the use of arthroscopy to remove loose bodies and reduce enfolded soft tissues to obtain concentric reduction in the pediatric and adolescent population. Specific note is made of underlying pathology and arthroscopic intervention.

Methods:

After obtaining Institutional Review Board approval, we performed a retrospective review of patients under the age of 19 who were treated with hip arthroscopy following hip dislocation reduction at a single children’s hospital from 2006 to 2013. Clinic notes, operative reports, radiographic images, and arthroscopic photographs were reviewed.

Results:

Seven patients were identified (aged 8 to 17) who underwent hip arthroscopy after a posterior hip dislocation. Intra-articular bone fragments were found in 6 of 7 patients and 5 of 7 patients had an incongruent hip joint identified by imaging before surgery. The predominant pathology was avulsion of a small bony fragment attached to the posterior capsular labral soft-tissue complex, which became enfolded and blocked reduction (5 of 7 patients). In all cases, the enfolded soft tissue was reduced without soft tissue or bone repair. Additional loose osteochondral fragments were removed, and in 2 cases an avulsed ligamentum teres was debrided. Average follow-up was 10 months. No avascular necrosis or recurrent instability was identified in any case.

Conclusions:

When incongruent hip joints were arthroscopically evaluated after traumatic dislocation, a consistent pattern of interposition of avulsed posterior bone fragment with attached capsule and labrum was found. Reduction of the capsulolabral complex without repair provided satisfactory short-term outcomes. Arthroscopic treatment of such cases was effective and well tolerated and could lead to considerably less postoperative pain and surgical morbidity than open surgical treatment.

Level of Evidence:

Level IV—case series.
Severity of Asynchronous Slipped Capital Femoral Epiphyses in Skeletally Immature Versus More Skeletally Mature Patients
Authors: Nowicki Philip D. , Silva Selina , Toelle Lisa , Strohmeyer Greg , Wahlquist Trevor , Li Ying , Farley Frances A. , Caird Michelle S.
Published: October 2015

Background:

Routine prophylactic screw fixation for skeletally immature patients with slipped capital femoral epiphysis (SCFE) continues to be debated. The purpose of this study was to assess the slip severity of a second SCFE in skeletally immature versus more mature patients and determine necessity of contralateral hip prophylactic screw fixation.

Methods:

All patients treated for SCFE at 3 pediatric hospitals over a 10-year time period (January 1, 2002 to December 31, 2011) were evaluated. Patients were included if they had a unilateral SCFE and a contralateral asynchronous SCFE, and were divided into immature (Oxford triradiate score 1) versus more mature (Oxford triradiate score 2 and 3) groups. Data evaluation included age, time between slips, body mass index, Southwick angles of first then second SCFEs, and follow-up duration.

Results:

There were a total of 45 patients: 16 patients in the skeletally immature and 29 patients in the more mature group. Average age at first SCFE in immature patients was 10.9 years and in more mature patients 12.1 years (P=0.70). Age at second SCFE in immature patients was 11.5 years and in more mature patients 13.0 years (P=0.023). Average time between SCFEs was 6.6 months for immature and 11.4 months for more mature patients (P=0.093). Southwick angles for immature patient first and second SCFEs were 25 and 12.9 degrees, respectively, and for more mature patient first and second SCFEs were 31 and 21 degrees, respectively. Southwick angles were higher at first and second slips in the more mature group, significant only at the second slip (P=0.032). SCFE severity at initial event was predictive of severity of second SCFE regardless of maturity (P=0.043). Regression analysis of slip severity against multiple patient factors demonstrated triradiate score was not a factor assessing subsequent SCFE magnitude (P=0.099).

Conclusions:

There was no significant difference between first and second SCFEs regardless of skeletal maturity but severity of initial SCFE did correlate with severity of the second SCFE. Deciding not to prophylactically pin an unaffected hip does not lead to worse deformity if a second SCFE occurs in skeletally immature or more mature patients, unless the initial event is severe. Prophylactic pin fixation in skeletally immature patients should occur as a shared decision between patient, guardians, and treating surgeon.

Level of Evidence:

Level III—retrospective comparative study.
Preoperative Depression, Smoking, and Employment Status are Significant Factors in Patient Satisfaction After Lumbar Spine Surgery
Authors: Chapin Laura , Ward Kelly , Ryken Timothy
Published: October 2015

Study Design:

Prospective cohort study.

Objective:

To determine whether comorbidities and demographics, identified preoperatively, can impact patient outcomes and satisfaction after lumbar spine surgery.

Summary of Background Data:

The surgical treatment of lower back pain does not always eliminate a patient’s pain and symptoms. Revision surgeries are costly and expose the patient to additional risk. We aim to identify patient characteristics that may suggest a greater or lesser likelihood of postsurgical success by examining patient-reported measures and outcomes after surgery.

Methods:

Preoperative smoking status, self-reported depression, prevalence of diabetes, obesity, level of education, and employment status were assessed in the context of patient outcome and satisfaction after lumbar spine surgery. Patients were contacted before surgery, and at 3 and 12 months postoperatively, and responded to Oswestry Disability Index (ODI) and EuroQol-5 Dimensions (EQ-5D) self-assessment examinations, as well as a satisfaction measure.

Results:

A total of 166 patients who underwent lumbar spine surgeries at Iowa Spine and Brain Institute, a department of Covenant Medical Center, and were included in the National Neurosurgery Quality and Outcomes Database were assessed preoperatively, and at 3 and 12 months postoperatively using self-assessment tools. Depression, smoking, and employment status were found to be significant factors in patient satisfaction. Depressed patients, smokers, and patients on disability at the time of surgery have worse ODI and EQ-5D scores at all of the timepoints (baseline, 3 months, and 12 months postsurgery).

Conclusions:

Depression, smoking, and employment status, specifically whether a patient is on disability at the time of surgery, are all significant factors in patient satisfaction after lumbar spine surgery. These factors are also shown in impact ODI and EQ-5D scores. Surgeons should consider these particular characteristics when developing a lower back pain treatment plan involving surgery.
Total Lifetime and Cancer-related Costs for Elderly Patients Diagnosed With Anal Cancer in the United States
Authors: Deshmukh Ashish A. , Zhao Hui , Franzini Luisa , Lairson David R. , Chiao Elizabeth Y. , Das Prajnan , Swartz Michael D. , Giordano Sharon H. , Cantor Scott B.
Published: October 2015

Objective:

To determine the lifetime and phase-specific cost of anal cancer management and the economic burden of anal cancer care in elderly (66 y and older) patients in the United States.

Patients and Methods:

For this study, we used Surveillance Epidemiology and End Results-Medicare linked database (1992 to 2009). We matched newly diagnosed anal cancer patients (by age and sex) to noncancer controls. We estimated survival time from the date of diagnosis until death. Lifetime and average annual cost by stage and age at diagnosis were estimated by combining survival data with Medicare claims. The average lifetime cost, proportion of patients who were elderly, and the number of incident cases were used to estimate the economic burden.

Results:

The average lifetime cost for patients with anal cancer was US$50,150 (N=2227) (2014 US dollars). The average annual cost in men and women was US$8025 and US$5124, respectively. The overall survival after the diagnosis of cancer was 8.42 years. As the age and stage at diagnosis increased, so did the cost of cancer-related care. The anal cancer–related lifetime economic burden in Medicare patients in the United States was US$112 million.

Conclusions:

Although the prevalence of anal cancer among the elderly in the United States is small, its economic burden is considerable.
Hypofractionated Versus Standard Fractionated Proton-beam Therapy for Low-risk Prostate Cancer
Authors: Vargas Carlos E. , Hartsell William F. , Dunn Megan , Keole Sameer R. , Doh Lucius , Eisenbeisz Elaine , Larson Gary L.
Published: October 2015

Objective:

To identify differences in terms of quality of life, the American Urological Association Symptom Index (AUA), or adverse events (AEs) among patients with prostate cancer treated with either standard fractionation or hypofractionation proton-beam therapy.

Materials and Methods:

Patients were prospectively randomized to receive 38 Gy relative biological effectiveness (RBE) in 5 treatments (n=49) or 79.2 Gy RBE in 44 treatments (n=33). All patients had low-risk prostate cancer and were treated with proton therapy using fiducial markers and daily image guidance.

Results:

Median follow-up for both groups was 18 months; 33 patients had follow-up of 2 years or longer. Baseline median (range) AUA was 4.7 (0 to 13) for the 38 Gy RBE arm and 4.8 (0 to 17) for the 79.2 Gy RBE arm. We observed no difference between the groups regarding the Expanded Prostate Index Composite urinary, bowel, or sexual function scores at 3, 6, 12, 18, or 24 months after treatment. The only significant difference was the AUA score at 12 months (8 for the 38 Gy RBE arm vs. 5 for the 79.2 Gy RBE arm; P=0.04); AUA scores otherwise were similar between groups. No grade 3 or higher AEs occurred in either arm.

Conclusions:

Patients treated with proton therapy in this randomized trial tolerated treatment well, with excellent quality-of-life scores, persistent low AUA, and no grade 3 or higher AEs on either arm. We showed no apparent clinical difference in outcomes with hypofractionated proton-beam therapy compared with standard fractionation on the basis of this interim analysis.
Successful Ifosfamide Rechallenge in Soft-Tissue Sarcoma
Authors: Noujaim Jonathan , Constantinidou Anastasia , Messiou Christina , Thway Khin , Miah Aisha , Benson Charlotte , Judson Ian , Jones Robin L.
Published: October 2015

Objectives:

Treatment options for metastatic soft-tissue sarcomas are limited. The aim of this study was to investigate the clinical activity of ifosfamide rechallenge in synovial sarcoma (SS), liposarcoma (LPS), leiomyosarcoma (LMS), and high-grade sarcomas not otherwise specified.

Methods:

A retrospective search of the Royal Marsden Sarcoma Unit Database was performed to identify patients initially treated with ifosfamide (as single agent or in combination) and who were subsequently rechallenged with single-agent ifosfamide. Baseline demographics and response assessment were retrospectively obtained.

Results:

Sixty-seven patients were identified and the median age at diagnosis was 41 years (range, 18 to 71 y). There were 29 cases of SS, 17 of LPS, 12 of LMS, and 9 of sarcomas not otherwise specified. First-line ifosfamide-containing therapy was given to 14 patients as adjuvant therapy (adjuvant group) and 53 patients as palliative therapy (palliative group). Clinical activity (partial response or stable disease) with single-agent ifosfamide rechallenge was documented in 50.0% of patients in the adjuvant group (7 in the second line) and 34.0% of patients in the palliative group (15 in the second line, 1 in third line, and 2 in the fourth line). The median progression-free survival in patients with documented clinical activity was 11.5 months (95% CI, 8.8-12.3) and 6.9 months (95% CI, 5.1-9.0), respectively, in the adjuvant and palliative group. Ifosfamide rechallenge was mostly active in SS patients (49.3%, 14 out of 29 patients with partial remission or stable disease).

Conclusions:

Ifosfamide rechallenge has clinical activity in soft-tissue sarcoma and can be considered a viable option in treating metastatic disease.
Association Between Radiation Dose and Outcomes With Postoperative Radiotherapy for N0-N1 Non–Small Cell Lung Cancer
Authors: Wang Elyn H. , Corso Christopher D. , Park Henry S. , Chen Aileen B. , Wilson Lynn D. , Kim Anthony W. , Decker Roy H. , Yu James B.
Published: October 2015

Purpose:

To review trends in the use of postoperative radiotherapy (PORT) in the modern era for N0-N1 margin-negative non–small cell lung cancer (NSCLC) following surgical resection and evaluate the association between PORT dose and overall survival.

Materials and Methods:

We performed a retrospective study of nonmetastatic stage II and III N0-N1 margin-negative NSCLC surgically treated patients within the National Cancer Data Base from 2003 to 2011. Cox proportional hazards regression was performed for multivariable analyses of overall survival and PORT dose. Radiation modalities included nonconformal beam radiation, 3-dimensional conformal radiation (3D-CRT), and intensity-modulated radiation therapy.

Results:

We identified 2167 (6.7%) and 30,269 (93.3%) patients with surgically resected stage II or III N0-N1 margin-negative NSCLC who were treated with and without PORT, respectively. The proportion of patients treated with PORT (dose range, 45 to 74 Gy) decreased from 8.9% in 2003 to 2006 to 4.1% in 2010 to 2011. Among patients receiving PORT, the use of high-dose (60 to 74 Gy) PORT rose throughout the study period, starting at 34.8% in 2003 to 2006 and rising to 49.3% in 2010 to 2011.

Overall, patients who received PORT had worse survival (hazards ratio=1.30; 95% confidence interval, 1.20-1.40) compared with those not receiving PORT. This association was unchanged when limited to patients receiving modern treatment with 3-CRT or intensity-modulated radiation therapy (hazards ratio=1.35; 95% confidence interval, 1.10-1.65).

Conclusions:

The use of PORT for N0-N1 margin-negative NSCLC decreased from 2003 to 2011. We found no evidence of benefit from PORT for resected N0-N1 margin-negative NSCLC, regardless of dose or technique. PORT should be approached with caution in this group of patients, regardless of radiotherapy technique.
FOLFOX+Nab-Paclitaxel (FOLFOX-A) for Advanced Pancreatic Cancer
Authors: Safran Howard , Charpentier Kevin P. , Perez Kimberly , Mantripragada Kalyan , Miner Thomas , DiPetrillo Thomas , Kuritzky Benjamin , Apor Emmanuel , Bishop Kenneth , Luppe Denise , Mitchell Kristen , Rosati Kayla
Published: October 2015

Background:

The Brown University Oncology Research Group performed a phase I study to remove irinotecan from FOLFIRINOX (5-fluorouracil, oxaliplatin, irinotecan, and leucovorin) and substitute nab-paclitaxel.

Methods:

Patients with newly diagnosed advanced pancreatic adenocarcinoma were eligible. Patients received oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, and 5-fluorouracil 2400 mg/m2 with 3 dose levels of nab-paclitaxel (125, 150, and 175 mg/m2) every 2 weeks. Dose-limiting toxicities were assessed in the first 2 cycles of treatment. The final dose level was expanded to assess cumulative neurotoxicity.

Results:

Thirty-five patients were entered; 24 with metastatic and 11 with locally advanced pancreatic cancer. The maximum tolerated dose of nab-paclitaxel was 150 mg/m2 every 2 weeks with FOLFOX. Cumulative neuropathy was the most important toxicity. Grade 3 neuropathy developed in 2 of the first 6 patients at 10 and 11 cycles of FOLFOX-A. Following an amendment to reduce oxaliplatin to 65 mg/m2 if grade 2 neuropathy developed, no additional patients developed grade 3 neurotoxicity. Twenty-one of 35 patients (60%) had a partial response. The median survival for patients with metastatic disease was 15 months.

Conclusions:

The maximum tolerated dose of nab-paclitaxel is 150 mg/m2 every 2 weeks with FOLFOX. The regimen of FOLFOX-A represents a promising treatment for pancreatic cancer.
Orbital Complication Following Calcium Hydroxylapatite Filler Injection
Authors: Dagi Glass Lora R. , Choi Catherine J. , Lee Nahyoung Grace
Published: October 2015

Cosmetic facial fillers have gained immense popularity in recent years. Although some patients opt to undergo an injection over surgery in light of the risks of an operation, there have been numerous reports of complications from these injections, including blindness. It is thought that filler particles can migrate within an artery and become emboli within small vessels. This case of focal orbital inflammation and dysmotility as a consequence of calcium hydroxylapatite filler injection in the face has not yet been documented in the literature.
Predicted VO2max and effectiveness of external chest compression by Chinese nurses
Authors: Ho Leo S.T. , Jones Alice Y.M. , Rainer Timothy H.
Published: October 2015

Objectives

The aims of this study were to assess the influence of sex and body position on external chest compression (ECC) to a manikin by Chinese nurses and to determine the relationship between rescuer’s predicted VO2max and ECC depth.

Participants and methods

A total of 40 nurses performed ECC on a manikin for 5 min in the standing (S) and bed-mount kneeling (K) position, then completed a Chester step-test, in 3 separate days. The rate and depth of compressions and oxygen consumption during ECC were measured.

Results

Mean compression rate recorded was above 100/min in both positions throughout ECC. Mean compression depth for male participants was more than 38 mm for 5 min in the K-position but only 3 min in the S-position. Female participants achieved this compression depth for less than 90 s in the K-position but not at all in the S-position.

Conclusion

Irrespective of sex, the K-position appears to facilitate effective ECC. The relationship between aerobic fitness of female nurses and their ability to perform effective cardiopulmonary resuscitation warrants further investigation.
The SPEED (sepsis patient evaluation in the emergency department) score: a risk stratification and outcome prediction tool
Authors: Bewersdorf Jan Philipp , Hautmann Oliver , Kofink Daniel , Abdul Khalil Alizan , Zainal Abidin Imran , Loch Alexander
Published: October 2015

Objectives

The aim of the study was to identify covariates associated with 28-day mortality in septic patients admitted to the emergency department and derive and validate a score that stratifies mortality risk utilizing parameters that are readily available.

Methods

Patients with an admission diagnosis of suspected or confirmed infection and fulfilling at least two criteria for severe inflammatory response syndrome were included in this study. Patients’ characteristics, vital signs, and laboratory values were used to identify prognostic factors for mortality. A scoring system was derived and validated. The primary outcome was the 28-day mortality rate.

Results

A total of 440 patients were included in the study. The 28-day hospital mortality rate was 32.4 and 25.2% for the derivation (293 patients) and validation (147 patients) sets, respectively. Factors associated with a higher mortality were immune-suppressed state (odds ratio 4.7; 95% confidence interval 2.0–11.4), systolic blood pressure on arrival less than 90 mmHg (3.8; 1.7–8.3), body temperature less than 36.0°C (4.1; 1.3–12.9), oxygen saturation less than 90% (2.3; 1.1–4.8), hematocrit less than 0.38 (3.1; 1.6–5.9), blood pH less than 7.35 (2.0; 1.04–3.9), lactate level more than 2.4 mmol/l (2.27; 1.2–4.2), and pneumonia as the source of infection (2.7; 1.5–5.0). The area under the receiver operating characteristic curve was 0.81 (0.75–0.86) in the derivation and 0.81 (0.73–0.90) in the validation set. The SPEED (sepsis patient evaluation in the emergency department) score performed better (P=0.02) than the Mortality in Emergency Department Sepsis score when applied to the complete study population with an area under the curve of 0.81 (0.76–0.85) as compared with 0.74 (0.70–0.79).

Conclusion

The SPEED score predicts 28-day mortality in septic patients. It is simple and its predictive value is comparable to that of other scoring systems.
Medically Serious Suicide Attempters With or Without Plan in Rural China
Authors: Sun Long , Zhang Jie
Published: October 2015

Although previous studies have discussed the risk factors of unplanned suicide behavior in several countries, the unplanned suicide attempt in China was not explored in a large sample. We aim to look into the characteristics of unplanned suicide attempters in China and compare them with those suicide attempters with plans. Subjects were 791 medically serious suicide attempters aged 15–54 years in rural China. The sixth item of Beck's Suicide Intent Scale was used to estimate the planned and unplanned suicide attempt. Logistic regression analysis was performed to examine the factors related to planned or unplanned suicide attempt. The results showed that the planned suicide attempts were associated with higher education, hopelessness, and previous suicide act. The unplanned suicide attempt tends to be suicide by pesticide and store pesticide at home. A ban of lethal pesticides may be a method for suicide prevention in rural China.
Predictors of Cognitive and Functional Decline in Patients With Alzheimer Disease Dementia From Brazil
Authors: Oliveira Fabricio F. , Chen Elizabeth S. , Smith Marilia C. , Bertolucci Paulo H.F.
Published: October 2015

Little is known on how risk factors for Alzheimer disease (AD) dementia affect disease progression, much less for populations with low mean schooling, whereas the transcription of APOE may be regulated by nongenetic factors. In this 44-month cohort study, 214 consecutive outpatients with late-onset AD were assessed for rates of cognitive and functional decline by way of Clinical Dementia Rating and Mini-Mental State Examination (MMSE) scores, keeping blinded assessment of APOE haplotypes. Subjects were evaluated for sex, schooling, age of dementia onset, and cerebrovascular risk factors (including Framingham risk scores). Of the 214 patients, there were 146 (68.2%) women and 113 (52.8%) APOE4+ carriers. The mean age of AD onset was 73.4±6.5 years-old, negatively correlated with time to Clinical Dementia Rating >1.0 (β=−0.132; ρ<0.001), MMSE=20 (β=−0.105; ρ<0.001), and MMSE=15 (β=−0.124; ρ=0.003), more significantly for women and APOE4+ carriers. Mean schooling was 4.18±3.7 years, correlated with time to MMSE=20 and MMSE=15 for women and APOE4+ carriers. Body mass index was correlated with time to MMSE=20 only for men (ρ=0.006). The 10-year coronary heart disease risk was correlated with time to MMSE=20 only for APOE4+ carriers (ρ=0.015). These outcomes suggest interactions among genomic effects of cognitive reserve, cerebral perfusion, and hormonal changes over mechanisms of neurodegeneration.
Detection and Differentiation of Frontotemporal Dementia and Related Disorders From Alzheimer Disease Using the Montreal Cognitive Assessment
Authors: Coleman Kristy K.L. , Coleman Brenda L. , MacKinley Julia D. , Pasternak Stephen H. , Finger Elizabeth C.
Published: October 2015

The Montreal Cognitive Assessment (MoCA) is a cognitive screening tool used by practitioners worldwide. The efficacy of the MoCA for screening frontotemporal dementia (FTD) and related disorders is unknown. The objectives were: (1) to determine whether the MoCA detects cognitive impairment (CI) in FTD subjects; (2) to determine whether Alzheimer disease (AD) and FTD subtypes and related disorders can be parsed using the MoCA; and (3) describe longitudinal MoCA performance by subtype. We extracted demographic and testing data from a database of patients referred to a cognitive neurology clinic who met criteria for probable AD or FTD (N=192). Logistic regression was used to determine whether dementia subtypes were associated with overall scores, subscores, or combinations of subscores on the MoCA. Initial MoCA results demonstrated CI in the majority of FTD subjects (87%). FTD subjects (N=94) performed better than AD subjects (N=98) on the MoCA (mean scores: 18.1 vs. 16.3; P=0.02). Subscores parsed many, but not all subtypes. FTD subjects had a larger decline on the MoCA within 13 to 36 months than AD subjects (P=0.02). The results indicate that the MoCA is a useful tool to identify and track progression of CI in FTD. Further, the data informs future research on scoring models for the MoCA to enhance cognitive screening and detection of FTD patients.
The Strength of Selection Against Neanderthal Introgression
Authors: Juric Ivan , Aeschbacher Simon , Coop Graham
Published: October 2015

Hybridization between humans and Neanderthals has resulted in a low level of Neanderthal ancestry scattered across the genomes of many modern-day humans. After hybridization, on average, selection appears to have removed Neanderthal alleles from the human population. Quantifying the strength and causes of this selection against Neanderthal ancestry is key to understanding our relationship to Neanderthals and, more broadly, how populations remain distinct after secondary contact. Here, we develop a novel method for estimating the genome-wide average strength of selection and the density of selected sites using estimates of Neanderthal allele frequency along the genomes of modern-day humans. We confirm that East Asians had somewhat higher initial levels of Neanderthal ancestry than Europeans even after accounting for selection. We find that the bulk of purifying selection against Neanderthal ancestry is best understood as acting on many weakly deleterious alleles. We propose that the majority of these alleles were effectively neutral—and segregating at high frequency—in Neanderthals, but became selected against after entering human populations of much larger effective size. While individually of small effect, these alleles potentially imposed a heavy genetic load on the early-generation human–Neanderthal hybrids. This work suggests that differences in effective population size may play a far more important role in shaping levels of introgression than previously thought.

Author Summary

A small percentage of Neanderthal DNA is present in the genomes of many contemporary human populations due to hybridization tens of thousands of years ago. Much of this Neanderthal DNA appears to be deleterious in humans, and natural selection is acting to remove it. One hypothesis is that the underlying alleles were not deleterious in Neanderthals, but rather represent genetic incompatibilities that became deleterious only once they were introduced to the human population. If so, reproductive barriers must have evolved rapidly between Neanderthals and humans after their split. Here, we show that oberved patterns of Neanderthal ancestry in modern humans can be explained simply as a consequence of the difference in effective population size between Neanderthals and humans. Specifically, we find that on average, selection against individual Neanderthal alleles is very weak. This is consistent with the idea that Neanderthals over time accumulated many weakly deleterious alleles that in their small population were effectively neutral. However, after introgressing into larger human populations, those alleles became exposed to purifying selection. Thus, rather than being the result of hybrid incompatibilities, differences between human and Neanderthal effective population sizes appear to have played a key role in shaping our present-day shared ancestry.
Comprehensive Cross-Population Analysis of High-Grade Serous Ovarian Cancer Supports No More Than Three Subtypes
Authors: Way Gregory P. , Rudd James , Wang Chen , Hamidi Habib , Fridley Brooke L. , Konecny Gottfried , Goode Ellen L. , Greene Casey S. , Doherty Jennifer A.
Published: October 2015

Four gene expression subtypes of high-grade serous ovarian cancer (HGSC) have been previously described. In these studies, a fraction of samples that did not fit well into the four subtype classifications were excluded. Therefore, we sought to systematically determine the concordance of transcriptomic HGSC subtypes across populations without removing any samples. We created a bioinformatics pipeline to independently cluster the five largest mRNA expression datasets usingk-means and non-negative matrix factorization (NMF). We summarized differential expression patterns to compare clusters across studies. While previous studies reported four subtypes, our cross-population comparison does not support four. Because these results contrast with previous reports, we attempted to reproduce analyses performed in those studies. Our results suggest that early results favoring four subtypes may have been driven by including serous borderline tumors. In summary, our analysis suggests that either two or three, but not four, gene expression subtypes are most consistent across datasets.

CONFLICTS OF INTEREST

The authors do not declare any conflicts of interest.

OTHER PRESENTATIONS

Aspects of this study were presented at the 2015 AACR Conference and the 2015 Rocky Mountain Bioinformatics Conference.
Sporadic, global linkage disequilibrium between unlinked segregating sites
Authors: Skelly Daniel A. , Magwene Paul M. , Stone Eric A.
Published: October 2015

Demographic, genetic, or stochastic factors can lead to perfect linkage disequilibrium (LD) between alleles at two loci without respect to the extent of their physical distance, a phenomenon that Lawrenceet al. (2005a) refer to as “genetic indistinguishability”. This phenomenon can complicate genotype-phenotype association testing by hindering the ability to localize causal alleles, but has not been thoroughly explored from a theoretical perspective or using large, dense whole-genome polymorphism datasets. We derive a simple theoretical model of the prevalence of genetic indistinguishability between unlinked loci, and verify its accuracy via simulation. We show that sample size and minor allele frequency are the major determinants of the prevalence of perfect LD between unlinked loci but that demographic factors, such as deviations from random mating, can produce significant effects as well. Finally, we quantify this phenomenon in three model organisms and find thousands of pairs of moderate-frequency (> 5%) genetically indistinguishable variants in relatively large datasets. These results clarify a previously underexplored population genetic phenomenon with important implications for association studies, and define conditions under which it is likely to manifest.
IMO-HIP 2015 Report: An Evolutionary Game Theory Approach to evolutionary-enlightened application of chemotherapy in bone metastatic prostate cancer
Authors: Warman Pranav , Araujo Arturo , Lynch Conor , Basanta David
Published: October 2015

Prostate cancer metastasis to the bone is predominantly lethal and results from the ability of successful metastatic prostate cancer cells to co-opt microenvironmental cells and processes involved in bone remodelling. Understanding how the interactions between tumour and stromal cells determine successful metastases and how metastatic tumours respond to treatment is an emergent process that is hard to asses biologically and thus can benefit from mathematical models. In this work we describe a mathematical model of bone remodelling and the establishment of a prostate cancer metastasis in the bone using evolutionary game theory. We have mathematically recapitulated the current paradigm of a vicious cycle driving the tumor growth and we have used this tool to investigate the key interactions between the tumour and the bone stroma. Crucially, the model sheds light on the role that the interactions of heterogeneous tumor cells with the bone microenvironment have in the treatment of cancer. Our results show that resistant populations naturally become dominant in the metastases under a number treatment schemes and that schedules designed by an evolutionary game theory approach could be used to better control the tumour and the associated bone growth than the current standard of care.
Frequency and complexity of de novo structural mutation in autism
Authors: Brandler William M , Antaki Danny , Gujral Madhusudan , Noor Amina , Rosanio Gabriel , Chapman Timothy R , Barrera Daniel J , Lin Guan Ning , Malhotra Dheeraj , Watts Amanda C , Wong Lawrence C , Estabillo Jasper A , Gadomski Therese E , Hong Oanh , Fuentes Fajardo Karin V , Bhandari Abhishek , Owen Renius , Baughn Michael , Yuan Jeffrey , Solomon Terry , Moyzis Alexandra G , Sanders Stephan J , Reiner Gail E , Vaux Keith K , Strom Charles M , Zhang Kang , Muotri Alysson R , Akshoomoff Natacha , Leal Suzanne M , Pierce Karen , Courchesne Eric , Iakoucheva Lilia M , Corsello Christina , Sebat Jonathan
Published: October 2015

Genetic studies of Autism Spectrum Disorder (ASD) have established thatde novoduplications and deletions contribute to risk. However, ascertainment of structural variation (SV) has been restricted by the coarse resolution of current approaches. By applying a custom pipeline for SV discovery, genotyping andde novoassembly to genome sequencing of 235 subjects, 71 cases, 26 sibling controls and their parents, we present an atlas of 1.2 million SVs (5,213/genome), comprising 11 different classes. We demonstrate a high diversity ofde novomutations, a majority of which were undetectable by previous methods. In addition, we observe complex mutation clusters where combinations ofde novoSVs, nucleotide substitutions and indels occurred as a single event. We estimate a high rate of structural mutation in humans (20%). Genetic risk for ASD is attributable to an elevated frequency of gene-disruptingde novoSVs but not an elevated rate of genome rearrangement.
SimpleSBML: A Python package for creating and editing SBML models
Authors: Cannistra Caroline , Medley Kyle , Sauro Herbert M.
Published: October 2015

In this technical report we describe a simple extension to python-libSBML that allows users of Python to more easily construct SBML based models. The most commonly used package for constructing SBML models in Python is python-libSBML based on the C/C++ library libSBML. python-libSBML supports a comprehensive set of model types, but is difficult for new users to learn and requires long scripts to create even the simplest models. We present SimpleSBML, a package that allows users to add species, parameters, reactions, events, and rules to a libSBML model with only one command for each. Models can be exported to SBML format, and SBML files can be imported and converted to SimpleSBML commands that creates each element in a new model. This allows users to create new models and edit existing models for use with other software.

Accessibility and Implementation

SimpleSBML is publicly available and licensed under the liberal Apache 2.0 open source license. It supports SBML levels 2 and 3. Its only dependency is libSBML. It is supported on Windows and Mac OS X. All code has been deposited at the GitHub sitehttps://github.com/sys-bio/simplesbml

Contact

carolc24@u.washington.eduorhsauro@u.washington.edu
Analysis of protein-coding genetic variation in 60,706 humans
Authors:   Exome Aggregation Consortium, Lek Monkol , Karczewski Konrad J , Minikel Eric V , Samocha Kaitlin E , Banks Eric , Fennell Timothy , O’Donnell-Luria Anne H , Ware James S , Hill Andrew J , Cummings Beryl B , Tukiainen Taru , Birnbaum Daniel P , Kosmicki Jack A , Duncan Laramie E , Estrada Karol , Zhao Fengmei , Zou James , Pierce-Hoffman Emma , Berghout Joanne , Cooper David N , Deflaux Nicole , DePristo Mark , Do Ron , Flannick Jason , Fromer Menachem , Gauthier Laura , Goldstein Jackie , Gupta Namrata , Howrigan Daniel , Kiezun Adam , Kurki Mitja I , Moonshine Ami Levy , Natarajan Pradeep , Orozco Lorena , Peloso Gina M , Poplin Ryan , Rivas Manuel A , Ruano-Rubio Valentin , Rose Samuel A , Ruderfer Douglas M , Shakir Khalid , Stenson Peter D , Stevens Christine , Thomas Brett P , Tiao Grace , Tusie-Luna Maria T , Weisburd Ben , Won Hong-Hee , Yu Dongmei , Altshuler David M , Ardissino Diego , Boehnke Michael , Danesh John , Donnelly Stacey , Elosua Roberto , Florez Jose C , Gabriel Stacey B , Getz Gad , Glatt Stephen J , Hultman Christina M , Kathiresan Sekar , Laakso Markku , McCarroll Steven , McCarthy Mark I , McGovern Dermot , McPherson Ruth , Neale Benjamin M , Palotie Aarno , Purcell Shaun M , Saleheen Danish , Scharf Jeremiah M , Sklar Pamela , Sullivan Patrick F , Tuomilehto Jaakko , Tsuang Ming T , Watkins Hugh C , Wilson James G , Daly Mark J , MacArthur Daniel G
Published: October 2015

Large-scale reference data sets of human genetic variation are critical for the medical and functional interpretation of DNA sequence changes. Here we describe the aggregation and analysis of high-quality exome (protein-coding region) sequence data for 60,706 individuals of diverse ethnicities generated as part of the Exome Aggregation Consortium (ExAC). The resulting catalogue of human genetic diversity contains an average of one variant every eight bases of the exome, and provides direct evidence for the presence of widespread mutational recurrence. We show that this catalogue can be used to calculate objective metrics of pathogenicity for sequence variants, and to identify genes subject to strong selection against various classes of mutation; we identify 3,230 genes with near-complete depletion of truncating variants, 72% of which have no currently established human disease phenotype. Finally, we demonstrate that these data can be used for the efficient filtering of candidate disease-causing variants, and for the discovery of human “knockout” variants in protein-coding genes.
DBSIM: A Platform of Simulation Resources for Genetic Epidemiology Studies
Authors: Yao Po-Ju , Chung Ren-Hua
Published: October 2015

Computer simulations are routinely conducted to evaluate new statistical methods, to compare the properties among different methods, and to mimic the real data in genetic epidemiology studies. Conducting simulation studies can become a complicated task as several challenges can occur, such as the selection of an appropriate simulation tool and the specification of parameters in the simulation model. Although abundant simulated data have been generated for human genetic research, currently there is no public database designed specifically as a repository for these simulated data. With the lack of such database, for similar studies, similar simulations may have been repeated, which resulted in redundant works. We created an online platform, DBSIM, for simulation data sharing and discussion of simulation techniques for human genetic studies. DBSIM has a database containing simulation scripts, simulated data, and documentations from published manuscripts, as well as a discussion forum, which provides a platform for discussion of the simulated data and exchanging simulation ideas. DBSIM will be useful in three aspects. Moreover, summary statistics such as the simulation tools that are most commonly used and datasets that are most frequently downloaded are provided. The statistics will be very informative for researchers to choose an appropriate simulation tool or select a common dataset for method comparisons. DBSIM can be accessed athttp://dbsim.nhri.org.tw.
The Genetic cost of Neanderthal introgression
Authors: Harris Kelley , Nielsen Rasmus
Published: October 2015

Approximately 2-4% of genetic material in human populations outside Africa is derived from Neanderthals who interbred with anatomically modern humans. Recent studies have shown that this Neanderthal DNA is depleted around functional genomic regions; this has been suggested to be a consequence of harmful epistatic interactions between human and Neanderthal alleles. However, using published estimates of Neanderthal inbreeding and the distribution of mutational fitness effects, we infer that Neanderthals had at least 40% lower fitness than humans on average; this increased load predicts the reduction in Neanderthal introgression around genes without the need to invoke epistasis. We also predict a residual Neanderthal mutational load in non-Africans, leading to a fitness reduction of at least 0.5%. This effect of Neanderthal admixture has been left out of previous debate on mutation load differences between Africans and non-Africans. We also show that if many deleterious mutations are recessive, the Neanderthal admixture fraction could increase over time due to the protective effect of Neanderthal haplotypes against deleterious alleles that arose recently in the human population. This might partially explain why so many organisms retain gene flow from other species and appear to derive adaptive benefits from introgression.
Phylogenomic evidence for ancient hybridization in the genomes of living cats (Felidae)
Authors: Li Gang , Davis Brian W. , Eizirik Eduardo , Murphy William J.
Published: October 2015

Inter-species hybridization has been recently recognized as potentially common in wild animals, but the extent to which it shapes modern genomes is still poorly understood. Distinguishing historical hybridization events from other processes leading to phylogenetic discordance among different markers requires a well-resolved species tree that considers all modes of inheritance and overcomes systematic problems due to rapid lineage diversification by sampling large genomic character sets. Here, we assessed genome-wide phylogenetic variation across a diverse mammalian family, Felidae (cats). We combined genotypes from a genome-wide SNP array with additional autosomal, X- and Y-linked variants to sample ∼150 kb of nuclear sequence, in addition to complete mitochondrial genomes generated using light-coverage Illumina sequencing. We present the first robust felid time tree that accounts for unique maternal, paternal, and biparental evolutionary histories. Signatures of phylogenetic discordance were abundant in the genomes of modern cats, in many cases indicating hybridization as the most likely cause. Comparison of big cat whole-genome sequences revealed a substantial reduction of X-linked divergence times across several large recombination cold spots, which were highly enriched for signatures of selection-driven post-divergence hybridization between the ancestors of the snow leopard and lion lineages. These results highlight the mosaic origin of modern felid genomes and the influence of sex chromosomes and sex-biased dispersal in post-speciation gene flow. A complete resolution of the tree of life will require comprehensive genomic sampling of biparental and sex-limited genetic variation to identify and control for phylogenetic conflict caused by ancient admixture and sex-biased differences in genomic transmission.
High mutational rates of large-scale duplication and deletion in Daphnia pulex
Authors: Keith Nathan , Tucker Abraham E. , Jackson Craig E. , Sung Way , Lucas Lledó José Ignacio , Schrider Daniel R. , Schaack Sarah , Dudycha Jeffry L. , Ackerman Matthew , Younge Andrew J. , Shaw Joseph R. , Lynch Michael
Published: October 2015

Knowledge of the genome-wide rate and spectrum of mutations is necessary to understand the origin of disease and the genetic variation driving all evolutionary processes. Here, we provide a genome-wide analysis of the rate and spectrum of mutations obtained in two Daphnia pulex genotypes via separate mutation-accumulation (MA) experiments. Unlike most MA studies that utilize haploid, homozygous, or self-fertilizing lines, D. pulex can be propagated ameiotically while maintaining a naturally heterozygous, diploid genome, allowing the capture of the full spectrum of genomic changes that arise in a heterozygous state. While base-substitution mutation rates are similar to those in other multicellular eukaryotes (about 4 × 10−9 per site per generation), we find that the rates of large-scale (>100 kb) de novo copy-number variants (CNVs) are significantly elevated relative to those seen in previous MA studies. The heterozygosity maintained in this experiment allowed for estimates of gene-conversion processes. While most of the conversion tract lengths we report are similar to those generated by meiotic processes, we also find larger tract lengths that are indicative of mitotic processes. Comparison of MA lines to natural isolates reveals that a majority of large-scale CNVs in natural populations are removed by purifying selection. The mutations observed here share similarities with disease-causing, complex, large-scale CNVs, thereby demonstrating that MA studies in D. pulex serve as a system for studying the processes leading to such alterations.