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1.  Comprehensive Renal Function Evaluation in Patients Treated for Synchronous Bilateral Wilms Tumor 
Journal of pediatric surgery  2016;52(1):98-103.
The purpose of this study was to perform a comprehensive assessment of long-term renal function in patients treated at our institution for synchronous bilateral Wilms tumor (BWT) and to determine the optimal method for estimating glomerular filtration rate (eGFR).
Surgical approach, adjuvant therapy, and pathology reports were reviewed for patients with at least six months follow-up from definitive surgery. eGFRs, as assessed by the Schwartz and Chronic Kidney Disease in Children (CKiD) formulas, were compared to measured GFR (mGFR) determined by 99mTc-DTPA scanning. Urine studies, including microalbumin, β-microglobulin, and FENa were also reviewed.
Forty-two patients were identified. Of 36 living patients, 28 (77.8%) had greater than 6 months follow-up, with a median overall follow-up of 5.2 years (range: 1.4-13.4). The median mGFR was 97mL/min/1.73m2, while the median eGFRSchwartz and eGFRCKiD were 103.3mL/min/1.73m2 and 79.7mL/min/1.73m2, respectively, (p=0.13 and p=0.75, compared to mGFR). Eleven (39.3%) patients had at least one abnormal urine study (microalbumin >30μg/g creatinine, n=3; β-2 microglobulin >133μg/g creatinine, n=9; FENa >1%, n=4).
In our series, few patients had an abnormally low GFR. Neither method for estimating GFR gave a significantly different result from measured GFR, suggesting that the Schwartz equation is adequate, although specific urine tests may be more sensitive for detecting subtle renal dysfunction.
PMCID: PMC5218869  PMID: 27856008
renal function; bilateral Wilms tumor; nephron-sparing surgery
2.  Exercise Right Heart Catheterization for Pulmonary Hypertension Identified on Screening Echocardiography in Adult Survivors of Childhood Cancer 
Pediatric blood & cancer  2017;65(1):10.1002/pbc.26769.
Pulmonary hypertension, determined non-invasively by tricuspid regurgitant jet velocity on Doppler echocardiography, was previously identified in 25% of long-term survivors who received chest-directed radiotherapy. To validate non-invasively defined pulmonary hypertension ten survivors (mean age 48 years), exposed to chest radiotherapy underwent right heart catheterization with planned cardiopulmonary exercise testing during catheterization. Eight participants had an elevated mean pulmonary artery pressure at rest (≥25 mm Hg) or with subsequent exercise (>30 mm Hg), evidence of hemodynamically confirmed pulmonary hypertension by right heart catheterization. Cardiopulmonary exercise testing further defined the magnitude and etiology of cardiopulmonary limitations in this life-threatening late-effect.
PMCID: PMC5699937  PMID: 28843055
Pediatric; Cancer; Survivor; Pulmonary Hypertension; Exercise
3.  The Brief Case: Too Beta To Be a “B” 
Journal of Clinical Microbiology  2017;55(6):1604-1607.
PMCID: PMC5442515  PMID: 28536160
Streptococcus pseudoporcinus; adverse obstetrical outcomes; beta-hemolytic streptococci; group B streptococci
4.  Closing the Brief Case: Too Beta To Be a “B” 
Journal of Clinical Microbiology  2017;55(6):1973-1974.
PMCID: PMC5442561  PMID: 28536164
Streptococcus pseudoporcinus; adverse obstetrical outcomes; beta-hemolytic streptococci; group B streptococci
5.  Chronic disease burden and frailty in survivors of childhood HSCT: a report from the St. Jude Lifetime Cohort Study 
Blood Advances  2017;1(24):2243-2246.
Key Points
Childhood HSCT survivors suffer from a higher burden of severe/life-threatening conditions compared to conventional therapy survivors.Seven percent of HSCT survivors exhibit frailty phenotype at early age, placing them at higher risk for early mortality.
Outcomes of hematopoietic stem cell transplantation (HSCT) have markedly improved over the past 2 decades, underscoring a need to better understand the long-term health effects of this intensive treatment modality. We describe the burden of chronic medical conditions and frail health among St. Jude Lifetime Cohort Study participants treated for childhood hematologic malignancies with HSCT (n = 112) or with conventional therapy (n = 1106). Chronic conditions and frail health were ascertained clinically and classified according to a modified version of the Common Terminology Criteria for Adverse Events (version 4.03) and the Fried Frailty Criteria. Seventy-nine transplants were allogeneic (41 from a sibling donor, 34 unrelated, and 4 others from related donor). Twenty-five allogeneic donor recipients had a history of chronic graft-versus-host disease. Compared to those treated with conventional therapy, a higher percentage of HSCT survivors had severe, disabling, or life threatening (grade 3-4) chronic conditions (81.3% vs 69.2%, P = .007). By age 25 years, HSCT survivors experienced 148 grade 3-4 events/100 compared to 60 among conventional therapy survivors (P < .001). Percentages of survivors with second neoplasms (17.0% vs 7.9%, P = .003), grade 3-4 cardiovascular (19.6% vs 10.2%, P = .004) and pulmonary (16.1% vs 4.6%, P < .001) conditions, and frail health (7.1% vs 1.6%, P < .001) were higher after HSCT than conventional therapy. These results underscore the need for clinical follow-up and provide data to guide the development of prevention and/or intervention strategies for this vulnerable population.
Visual Abstract
PMCID: PMC5737129
Journal of pediatric surgery  2013;48(7):1598-1603.
To determine whether performing adrenalectomy at the time of nephrectomy for unilateral Wilms tumor impacts clinical outcome.
We reviewed information on all patients enrolled on National Wilms Tumor Study-4 and -5. Data were abstracted on patient demographics, tumor characteristics, surgical and pathologic status of the adrenal gland, and patient outcomes. The primary endpoints were intraoperative spill and five-year event-free survival (EFS) in patients who did or did not undergo adrenalectomy.
Of 3,825 patients with complete evaluable data, the adrenal was left in situ in 2,264 (57.9%) patients, and was removed completely in 1,367 patients (36.7%) or partially in 194 patients (5.2%). Of the adrenal glands removed, 68 (4.4%) contained tumor. Adrenal involvement was more common in patients with stage 3 (9.8%) than stage 2 disease (1.9%; p<0.0001). After controlling for stage and histopathology, five-year EFS was similar whether or not the adrenal gland was removed (p=0.48), or involved with tumor (p=0.81); however, intraoperative spill rates were higher in patients undergoing adrenalectomy (26.1% vs 15.5%, p<0.0001), likely due to larger tumor size or technical factors. No patient had clinical evidence of adrenal insufficiency or tumor recurrence in the adrenal gland during follow-up (median 9.9 years).
Sparing the adrenal gland during nephrectomy for unilateral Wilms tumor was not associated with a higher incidence of intraoperative spill and was associated with a similar oncologic outcome, on a per-stage basis, with cases where the adrenal was removed. Thus, adrenalectomy should not be considered mandatory during radical nephrectomy for Wilms tumor.
PMCID: PMC5652039  PMID: 23895979
adrenalectomy; Wilms tumor; pediatric renal tumor
7.  Synchrotron imaging and Markov Chain Monte Carlo reveal tooth mineralization patterns 
PLoS ONE  2017;12(10):e0186391.
The progressive character of tooth formation records aspects of mammalian life history, diet, seasonal behavior and climate. Tooth mineralization occurs in two stages: secretion and maturation, which overlap to some degree. Despite decades of study, the spatial and temporal pattern of elemental incorporation during enamel mineralization remains poorly characterized. Here we use synchrotron X-ray microtomography and Markov Chain Monte Carlo sampling to estimate mineralization patterns from an ontogenetic series of sheep molars (n = 45 M1s, 18 M2s). We adopt a Bayesian approach that posits a general pattern of maturation estimated from individual- and population-level mineral density variation over time. This approach converts static images of mineral density into a dynamic model of mineralization, and demonstrates that enamel secretion and maturation waves advance at nonlinear rates with distinct geometries. While enamel secretion is ordered, maturation geometry varies within a population and appears to be driven by diffusive processes. Our model yields concrete expectations for the integration of physiological and environmental signals, which is of particular significance for paleoseasonality research. This study also provides an avenue for characterizing mineralization patterns in other taxa. Our synchrotron imaging data and model are available for application to multiple disciplines, including health, material science, and paleontological research.
PMCID: PMC5648163  PMID: 29049333
8.  Endocrine Abnormalities in Aging Survivors of Childhood Cancer: A Report From the Childhood Cancer Survivor Study 
Journal of Clinical Oncology  2016;34(27):3240-3247.
The development of endocrinopathies in survivors of childhood cancer as they age remains understudied. We characterized endocrine outcomes in aging survivors from the Childhood Cancer Survivor Study on the basis of therapeutic exposures.
Patients and Methods
We analyzed self-reported conditions in 14,290 5-year survivors from the Childhood Cancer Survivor Study, with a median age 6 years (range, < 1 to 20 years) at diagnosis and 32 years (range, 5 to 58 years) at last follow-up. Identification of high-risk therapeutic exposures was adopted from the Children’s Oncology Group Long-Term Follow-Up Guidelines. Cumulative incidence curves and prevalence estimates quantified and regression models compared risks of primary hypothyroidism, hyperthyroidism, thyroid neoplasms, hypopituitarism, obesity, diabetes mellitus, or gonadal dysfunction between survivors and siblings.
The cumulative incidence and prevalence of endocrine abnormalities increased across the lifespan of survivors (P < .01 for all). Risk was significantly higher in survivors exposed to high-risk therapies compared with survivors not so exposed for primary hypothyroidism (hazard ratio [HR], 6.6; 95% CI, 5.6 to 7.8), hyperthyroidism (HR, 1.8; 95% CI, 1.2 to 2.8), thyroid nodules (HR, 6.3; 95% CI, 5.2 to 7.5), thyroid cancer (HR, 9.2; 95% CI, 6.2 to 13.7), growth hormone deficiency (HR, 5.3; 95% CI, 4.3 to 6.4), obesity (relative risk, 1.8; 95% CI, 1.7 to 2.0), and diabetes mellitus (relative risk, 1.9; 95% CI, 1.6 to 2.4). Women exposed to high-risk therapies had six-fold increased risk for premature ovarian insufficiency (P < .001), and men demonstrated higher prevalence of testosterone replacement (P < .001) after cyclophosphamide equivalent dose of 20 g/m2 or greater or testicular irradiation with 20 Gy or greater. Survivors demonstrated an increased risk for all thyroid disorders and diabetes mellitus regardless of treatment exposures compared with siblings (P < .001 for all).
Endocrinopathies in survivors increased substantially over time, underscoring the need for lifelong subspecialty follow-up of those at risk.
PMCID: PMC5024546  PMID: 27382091
9.  Pulmonary Function after Treatment for Childhood Cancer. A Report from the St. Jude Lifetime Cohort Study (SJLIFE) 
Rationale: The relationship between treatment-related impairment of pulmonary function in adult survivors of childhood cancer and subsequent physical function has not been studied.
Objectives: In this prospective evaluation of 606 adult survivors of childhood cancer, we sought to determine the risk factors for, as well as the functional impact of, clinically ascertained pulmonary function impairment.
Methods: We measured FEV1, FVC, total lung capacity (TLC), and single-breath diffusing capacity of the lung for carbon monoxide corrected for hemoglobin (DlCOcorr), expressing the results as percent predicted and lower limit of normal (LLN) values, and we also assessed functional exercise capacity (6-minute-walk distance). Lung radiation exposure was expressed as the estimated percentage of lung tissue that received at least 10 Gy (V10). Associations of clinical and treatment factors with pulmonary function measures were assessed using log-binomial regression to calculate relative risks and 95% confidence intervals.
Measurements and Main Results: The participants’ median age at evaluation was 34.2 years, and the median elapsed time from diagnosis was 21.9 years. Among the sample population, 50.7% had an FEV1 percent predicted less than 80%, 47.2% had an FVC percent predicted less than 80%, 31.2% had a TLC percent predicted less than 75%, and 44.6% had DlCOcorr percent predicted less than 75%. Also, 49.0% had FEV1 less than the LLN on the basis of the Global Lung Function Initiative (GLI) criteria, and 45.4% had FVC less than LLN. Obstructive lung defects (FEV1/FVC, <0.7) were found in 0.8%, but none had obstructive lung defects on the basis of the GLI criterion of FEV1/FVC less than the LLN. Restrictive lung defects (TLC, <75%) were found in 31.2% of participants. V10 and elapsed time since diagnosis were associated with abnormal FEV1 and FVC based on the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03 criteria, and with abnormal FEV1 using the GLI criterion. Age at diagnosis was an additional risk factor for abnormal FVC based on the GLI criteria. Age at diagnosis and V10 were associated with abnormal TLC. Increased body mass index, V10, and elapsed time since diagnosis were risk factors for abnormal DlCOcorr. Abnormal pulmonary function tests were associated with decreased 6-minute walk distance.
Conclusions: Impaired pulmonary function in adult survivors of childhood cancer is associated with decreased physical function. These patients may benefit from interventions designed to preserve and/or improve pulmonary function.
PMCID: PMC5059496  PMID: 27391297
lung injury; radiation pneumonitis; metastasectomy; thoracic surgical procedures
10.  Clinical Outcome Reporting in Youth ACL Literature Is Widely Variable 
Orthopaedic Journal of Sports Medicine  2017;5(8):2325967117724431.
Advances in anterior cruciate ligament (ACL) reconstruction procedures in pediatric and adolescent patients have resulted in an increase in recent clinical studies on this topic. However, the consistency with which outcome measures are reported in this demographic is unknown.
To document outcome reporting patterns of youth ACL reconstruction studies in high-impact journals.
Study Design:
Systematic review; Level of evidence, 4.
All articles published in 5 high-impact orthopaedic journals from 2010 to 2016 were reviewed to identify those reporting clinical outcomes of young patients who underwent ACL reconstruction. Studies that were nonclinical, reported on patients older than 18 years, or included fewer than 10 patients were excluded. Outcome measures used in all included studies were recorded.
Seventeen studies encompassing 772 subjects (mean age, 14.3 years; range, 6.3-18.0 years) were analyzed. Eight studies (47%) reported on Tanner stage of subjects, while 1 study reported skeletal age. Ten studies (59%) clearly documented the presence or absence of surgical complications. Range of motion was reported in 65% of studies. Leg-length discrepancy and angular deformity were each reported in 76% of studies, with 12% quantifying results through radiographic measurements. Ligament testing was variably defined by inclusion of instrumented testing (65%), Lachman test (53%), and pivot-shift test (53%). Fourteen studies (82%) explicitly reported on the rate of ACL rerupture, while 71% reported on the rate of revision surgery. Rate of return to preinjury activity was reported in 8 studies (47%), of which 2 defined criteria for return to sport and 3 defined the level of competitive sport. Patient-reported outcome measures (PROMs) were used variably. For the 3 most commonly reported PROMs (Lysholm, International Knee Documentation Committee, and Tegner), 24% of studies reported all 3 PROMs, 35% of studies reported 2 PROMs, and 6% of studies reported 1 PROM in isolation. A pediatric-specific PROM was reported in 1 of the 17 studies.
Studies on pediatric ACL reconstruction published in high-impact journals unreliably defined subjects’ skeletal maturity, inconsistently reported on objective outcome measures, and used disparate adult-validated PROMs to assess subjective outcomes. These findings highlight the need for standardized, pediatric-specific outcome measures to be applied in future studies evaluating ACL reconstruction in children and adolescents.
PMCID: PMC5555504
ACL reconstruction; outcomes; pediatric; adolescents; clinical assessment
11.  Pulmonary fibrosis on the lateral chest radiograph: Kerley D lines revisited 
Insights into Imaging  2017;8(5):483-489.
The retrosternal clear space (RCS) is a lucent area on the lateral chest radiograph located directly behind the sternum. The two types of pathology classically addressed in the RCS are anterior mediastinal masses and emphysema. Diseases of the pulmonary interstitium are a third type of pathology that can be seen in the RCS. Retrosternal reticular opacities, known as Kerley D lines, were initially described in the setting of interstitial oedema. Pulmonary fibrosis is another aetiology of Kerley D lines, which may be more easily identified in the RCS than elsewhere on the chest radiograph.
Teaching points
• The RCS is one of three lucent spaces on the lateral chest radiograph.
• Reticular opacities in the RCS are known as Kerley D lines.
• Pulmonary fibrosis can be seen in the RCS as Kerley D lines.
• Kerley D lines should be further evaluated with chest CT.
PMCID: PMC5621990  PMID: 28786002
Pulmonary fibrosis; Lung diseases, interstitial; Thoracic radiography; Multidetector computed tomography; Pulmonary emphysema
12.  Is Pre-Injury Leg Length Discrepancy A Risk Factor for Anterior Cruciate Ligament Injury in the Skeletally Immature Athlete? 
Orthopaedic Journal of Sports Medicine  2017;5(7 suppl6):2325967117S00437.
Recognition of modifiable and non-modifiable risk factors for anterior cruciate ligament (ACL) injuries in children and adolescent athletes is paramount to develop effective strategies for prevention and treatment. We hypothesize that the intrinsic risk factors leg length discrepancy (LLD) and lateral mechanical axis deviation (MAD) are not uncommon in skeletally immature athletes that suffered an acute ACL injury.
We prospectively obtained full-length hip-to-ankle radiographs in a consecutive cohort of skeletally immature athletes that suffered an acute ACL injury and underwent surgical reconstruction. Using computer software, we measured standing hip to ankle radiographs for LLD including the individual segments (femur length and tibia length). (Fig.1 ) We also measured coronal mechanical alignment of the entire leg [MAD, mechanical tibio-femoral angle (mTFA)] and the segments [mechanical lateral distal femoral angle (mLDFA) and medial proximal tibial angle (MPTA)].
A total of 108 pediatric patients (mean age 13.4, range 7-14 years) were included (79 boys and 29 girls). Fifty (46.3%) patients had a LLD of ≥5 mm of which 33 (66%) sustained ACL injury of their shorter leg and 17 (34%) of their longer leg. Twelve (11.1%) patients had a LLD of ≥10 mm of which 9 (75%) had ACL injury of the shorter leg and 3 (25%) of their longer leg. Thirty-five (32.4%) and thirty-four (31.5%) patients had ≥ 5 mm of length discrepancy between the femurs and tibias, respectively. Three (2.8%) and nine (8.3%) patients had ≥10 mm of length discrepancy between the femurs and tibias, respectively. When comparing the coronal alignment of the injured leg with the contralateral leg, it was noted that the MAD was displaced 6.6±9.4mm lateral (valgus) with ACL injury vs. 1.4±8.1mm lateral without injury (p<0.001). (Table 1) The mTFA and mLDFA of the injured leg had a greater valgus alignment than the non-injury leg (2.4°±2.7 and 85.2°±2.2 vs. 0.9°±2.3 and 86.1°±1.82; p<0.001). Stratifying results by gender, similar findings were seen when comparing the leg with ACL injury versus the leg without ACL injury for MAD (boys: 6.9±9.2mm lateral vs. 1.7±8.3mm lateral, respectively, p<0.001; girls: 6.0±9.7mm lateral vs. 0.9±7.8mm lateral, respectively, p=0.031). Pelvic width was larger in girls when compared to boys (166±17mm vs. 155±18mm, respectively, p=0.005).
A LLD>5mm was present in 46% of our pediatric ACL patients (the majority sustained the ACL tear in the shorter leg). This high rate suggests a possible association of mild LLD with ACL tear in the active immature athlete. Growth disturbance is a major concern when surgically treating pediatric patients with ACL injury. Recognizing these abnormalities preoperatively is crucial to adequately evaluate for growth disturbance (LLD and/or Malalignment) following ACL reconstruction. Strategies to prevent ACL injury should also consider LLD of the lower limb.
PMCID: PMC5564985
13.  Sequential MRI Study of Graft Integrity and Signal Following Pediatric All-epiphyseal ACL Reconstruction: Does the “Sharp Turn” at the Socket of the Distal Femoral Aperture Matter? 
Orthopaedic Journal of Sports Medicine  2017;5(7 suppl6):2325967117S00431.
To analyze graft structure and signal with particular emphasis on the distal femoral socket aperture following all-epiphyseal ACLR using hamstring autografts with sequential MRI in skeletally immature athletes.
Retrospective cohort study of 23 skeletally immature patients who underwent ACLR by the same surgical team at a tertiary center during 2011-2013. Athletes had at least two follow-up MRIs, the first MRI 6-12 months after surgery and the second MRI >18 months, were included. Exclusion criteria included those athletes with inMRI follow-up (6) or with a failure of their reconstructions (1). All athletes were treated with an arthroscopic all-inside, all-epiphyseal ACLR, using hamstring autograft, secured with adjustable loop cortical buttons on both tibia and femur. MRI images were analyzed independently and blinded by an orthopaedic surgery fellow and a musculoskeletal radiology fellow. Using a GE Functional Analysis Software, the signal intensity (SI) of the graft was measured in 5 different locations: 1) femoral tunnel, 2) intra-articular proximal turn, 3) midsubstance, 4) intra-articular distal turn, and 5) tibial tunnel. Values were normalized to cortical bone density. The amount of perigraft scarring and synovitis was analyzed. An intraclass correlation coefficient was used to quantify inter-rater reliability, non-parametric Wilcoxon test for perigraft scarring and synovitis, one-way ANOVA to test if significant differences of SI were seen between the different graft locations, and a 2-tailed student t-test for SI changes from 1st to 2nd MRI.
The study included 16 patients (5 girls and 11 boys), with an average age at surgery of 11.9 years (range 10-15). The first follow-up MRI was on average at 8.4 months (range 6-12 months), while the 2nd MRI was on average 30.7 months (range 18-40) after surgery. Intra-class correlation coefficients were above 0.7 for all measurements, indicating an excellent concordance between observers. Perigraft scarring tended to reduce with follow-up (p=0.057) though not significantly, while synovitis had a significant reduction over time (p=0.01). On average, normalized SI showed no significant differences between measurements taken in different regions of the graft (p=0.58). When comparing the graft SI from 1st to 2nd MRI, no significant differences were found in any of the locations: femoral tunnel (p=0.14), proximal turn (p=0.11), midsubstance (p=0,29), intra-articular distal (p=0.10), or tibial tunnel (p=0.15). All 16 athletes returned to their prior sport at the same level of performance without re-injury.
ACL grafts in skeletally immature patients with all-epiphyseal reconstructions maintain a stable intensity signaling at long term MRI follow-up, with no significant signal reduction over time. Despite the sharp turn created at the distal femoral socket aperture in physeal-sparing reconstructions, no particular anatomic location of the graft presents significantly different signal intensity over others. This is the first sequential mri study in pediatric epiphyseal acl reconstructions demonstrating postoperative maintenance of graft integrity and graft signal.
PMCID: PMC5564986
14.  Impact of temporal changes in therapeutic exposure on self-reported health status in childhood cancer survivors 
Annals of internal medicine  2016;166(2):89-98.
The impact of temporal changes in cancer therapy on health status among childhood cancer survivors has not been evaluated.
Compare proportions of self-report of adverse health status outcomes across three decades among childhood cancer survivors.
27 North American institutions
14,566 adults, ≥5 year survivors (median age 27, range 18-48 years) treated 1970-1999
Patient-report of poor general or mental health, functional impairment, activity limitation, cancer-related anxiety or pain were evaluated as a function of treatment decade, cancer treatment exposures, chronic health conditions, demographics, and health habits.
Despite reductions in late-mortality and proportions with severe, disabling or life threatening chronic health conditions (33.4% among survivors treated 1970-79, 21.0% among those treated 1990-99), proportions reporting adverse health status did not decrease by treatment decade. When compared to those diagnosed 1970-79, survivors diagnosed 1990-99 were more likely to report poor general health (11.2% vs. 13.7%, p < 0.001) and cancer-related anxiety (13.3% vs. 15.0%, p < 0.001). From 1970-79 to 1990-99, the proportions reporting adverse outcomes were higher (p < 0.001) among leukemia (9.5% vs. 13.9%, poor general health) and osteosarcoma (23.9% vs. 36.6%, pain) survivors. Temporal changes in treatment exposures were not associated with changes in proportions reporting adverse health status. However, smoking, not meeting physical activity guidelines, and being either underweight or obese were associated with poor health status.
The considerable improvement in survival among children diagnosed with cancer in the 1990s compared to those diagnosed in the 1970s makes it difficult to definitively determine the impact of risk factors on later self-reported health status without considering their impact on mortality itself.
Because survival rates following a diagnosis of childhood cancer have improved substantially over the past thirty years, this population now includes persons who would have died in earlier eras. Unfortunately, self-reported health status among those that do survive has not improved. This is despite evolution of treatment designed to reduce toxicities, and is an important reminder that even in the modern era, cancer cure is not without consequences.”
PMCID: PMC5239750  PMID: 27820947
15.  Predictors of oxidative stress in heart failure patients with Cheyne–Stokes respiration 
Cheyne–Stokes respiration during sleep is associated with increased mortality in heart failure. The magnitude of oxidative stress is a marker of disease severity and a valuable predictor of mortality in heart failure. Increased oxidative stress associated with periodic breathing during Cheyne–Stokes respiration may mediate increased mortality in these patients. We hypothesized that the presence of Cheyne–Stokes respiration is associated with oxidative stress by increasing the formation of reactive oxygen species in patients with heart failure.
Methods and results
Twenty-three patients with heart failure [left ventricular ejection fraction 30.2±9% (mean±standard deviation)] and 11 healthy controls underwent nocturnal polysomnography. Subjects with obstructive sleep apnea were excluded. The majority (88%) of patients with heart failure had Cheyne–Stokes respiration during sleep. The intensity of oxidative stress in neutrophils was greater in patients with heart failure (4,218±1,706 mean fluorescence intensity/cell vs. 1,003±348 for controls, p<0.001) and correlated with the duration of Cheyne–Stokes respiration. Oxidative stress was negatively correlated with SaO2 nadir during sleep (r=−0.43, p=0.039). The duration of Cheyne–Stokes respiration predicted severity of oxidative stress in patients with heart failure (beta=483 mean fluorescence intensity/cell, p<0.02).
Levels of oxidative stress are increased in patients with heart failure and Cheyne–Stokes respiration during sleep compared with healthy controls. The duration of Cheyne–Stokes respiration predicts the magnitude of oxidative stress in heart failure. Increased oxidative stress may mediate increased mortality associated with Cheyne–Stokes respiration in patients with heart failure.
PMCID: PMC5470639  PMID: 21103943
Oxidative stress; Heart failure; Cheyne-stokes respiration; Periodic breathing; Hypoxemia; Sleep apnea
16.  Prevalence and Predictors of Human Papillomavirus (HPV) Vaccination among Young Women Surviving Childhood Cancer 
Human papillomavirus (HPV) is a sexually transmitted infection and the cause of cervical and other cancers. Vaccination is available to protect against genital HPV and is recommended for individuals aged 9-26 years. This study aimed to estimate the prevalence of HPV vaccination among childhood cancer survivors and to identify factors associated with vaccine outcomes.
Young adult females with (n = 114; M age =21.18 years, SD =2.48) and without (n = 98; M age = 20.65 years, SD = 2.29) a childhood cancer history completed surveys querying HPV vaccination initiation/completion, as well as sociodemographic, medical, and health belief factors. Multivariable logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CI) for vaccine outcomes.
Among survivors, 38.6% (44/114) and 26.3% (30/114) initiated or completed vaccination compared to 44.9% (44/98) and 28.6% (28/98) among controls, respectively. In the combined survivor/control group, physician recommendation (OR = 11.24, 95% CI, 3.15 – 40.14), and familial HPV communication (OR = 7.28, 95% CI, 1.89 – 28.05) associated with vaccine initiation. Perceptions of vaccine benefit associated with vaccine completion (OR = 10.55, 95% CI, 1.59 – 69.92), whereas perceptions of HPV-related severity associated with non-completion (OR = 0.14, 95% CI, 0.03 – 0.71).
Despite their increased risk for HPV-related complication, a minority of childhood cancer survivors have initiated or completed HPV vaccination. Modifiable factors associating with vaccine outcomes were identified.
HPV vaccination is a useful tool for cancer prevention in survivorship, and interventions to increase vaccine uptake are warranted.
PMCID: PMC4864112  PMID: 26572902
Oncology; Young Adults; Human Papillomavirus; Vaccination
17.  Monocyte and interferon based therapy for the treatment of ovarian cancer 
Cytokines and cells of the innate immune system have been shown to be critical regulators in the elimination, equilibrium and escape of malignant cells. Despite in vitro and in vivo evidence, components of the innate immune system have shown limited efficacy in the treatment of ovarian cancer. Intraperitoneal immunotherapies are a promising field that has not yet been fully explored in ovarian cancer. Cytokine immunotherapy using interferon alpha (IFN-α) and interferon gamma (IFN-γ) has predominantly been used intraperitoneally in ovarian cancer, with promising results. Early studies also showed that autologous monocytes infused into the peritoneum have anti-tumor properties. Combination therapies have been shown to be more effective in treating cancer than monotherapies. Based on these observations the combination of cell therapy with cytokine therapy may provide a unique strategy for the treatment of chemotherapy resistant solid cancers.
PMCID: PMC4899185  PMID: 27026228
Monocyte; Interferon Alpha; Interferon Gamma; Ovarian Cancer; immunotherapy
18.  Clinical Utility of On-Demand Multiplex Respiratory Pathogen Testing among Adult Outpatients 
Journal of Clinical Microbiology  2016;54(12):2950-2955.
Multiplex tests for respiratory tract infections include up to 20 targets for common pathogens, predominantly viruses. A specific therapeutic intervention is available for individuals testing positive for influenza viruses (oseltamivir), and it is potentially beneficial to identify non-influenza viruses to avoid unnecessary antibiotic use. We evaluated antimicrobial prescriptions following respiratory pathogen testing among outpatients at a large Veterans Administration (VA) medical center. Results of the FilmArray respiratory panel (BioFire, Salt Lake City, UT) from 15 December 2014 to 15 April 2015 were evaluated among 408 outpatients, and patient medical records were reviewed. Differences in antibiotic and oseltamivir prescription rates were analyzed. Among 408 patients tested in outpatient centers (emergency departments, urgent care clinics, and outpatient clinics), 295 (72.3%) were managed as outpatients. Among these 295 outpatients, 105 (35.6%) tested positive for influenza virus, 109 (36.9%) tested positive for a non-influenza virus pathogen, and 81 (27.5%) had no respiratory pathogen detected. Rates of oseltamivir and antibiotic prescriptions were significantly different among the three test groups (chi-squared values of 167.6 [P < 0.0001] and 10.48 [P = 0.005], respectively), but there was no significant difference in antibiotic prescription rates between the non-influenza virus pathogen group and those who tested negative (chi-square value, 0; P = 1.0). Among adult outpatients, testing positive for influenza virus was associated with receiving fewer antibiotic prescriptions, but no such effect was seen for those who tested positive for a non-influenza virus. These data suggest that testing for influenza viruses alone may be sufficient and more cost-effective than multiplex pathogen testing for outpatients.
PMCID: PMC5121384  PMID: 27654334
19.  Differential impact of water immersion on arterial blood flow and shear stress in the carotid and brachial arteries of humans 
Physiological Reports  2017;5(10):e13285.
Arterial shear stress is a potent stimulus to vascular adaptation in humans. Typically, increases in retrograde shear have been found to acutely impair vascular function while increases in antegrade shear enhance function. We hypothesized that blood flow and shear stress through the brachial and carotid arteries would change in a similar manner in response to water immersion, an intervention which modifies hemodynamics. Nine healthy young male subjects were recruited to undergo controlled water immersion in a standing upright position to the level of the right atrium in 30°C water. Diameters were continuously and simultaneously recorded in the brachial and common carotid arteries along with mean arterial pressure (MAP), cardiac output (CO), and heart rate before, during, and after 10 min of immersion. MAP and CO increased during water immersion (baseline vs. 8–10 min; 80 ± 9 vs. 91 ± 12 mmHg; and 4.8 ± 0.7 vs. 5.1 ± 0.6 L/min, P < 0.01 and P < 0.05, respectively). We observed a differential regulation of flow and shear stress patterns in the brachial and carotid arteries in response to water immersion; brachial conductance decreased markedly in response to immersion (1.25 ± 0.56 vs. 0.57 ± 0.30 mL.min/mmHg, P < 0.05), whereas it was unaltered in the carotid artery (5.82 ± 2.14 vs. 5.60 ± 1.59). Our findings indicate that adaptations to systemic stimuli and arterial adaptation may be vessel bed specific in humans, highlighting the need to assess multiple vascular sites in future studies.
PMCID: PMC5449564
Arteries; mean arterial pressure; shear stress; water immersion
20.  Relationship between monocyte‐platelet aggregation and endothelial function in middle‐aged and elderly adults 
Physiological Reports  2017;5(10):e13189.
Low‐grade inflammation, endothelial dysfunction, and platelet hyper‐reactivity to agonists are associated with an increased risk of cardiovascular events. In vitro and animal studies infer an inverse mechanistic relationship between platelet activation and the production of endothelium‐derived nitric oxide and prostacyclin. This concept is supported by evidence of an inverse relationship between endothelial function and platelet activation in high‐risk cardiac patients. The aim of this study was to investigate what relationship, if any, exists between platelet and endothelial function in healthy, middle‐aged, and elderly adults. In 51 participants (18 male, 33 post menopausal female), endothelial function was assessed by flow‐mediated dilation (FMD). Platelet function was assessed by flow cytometric determination of glycoprotein IIb/IIIa activation (measured by PAC‐1 binding), granule exocytosis (measured by surface P‐selectin expression), and monocyte‐platelet aggregates (MPAs), with and without stimulation by canonical platelet agonists adenosine diphosphate (ADP), arachidonic acid (AA), and collagen. Correlation analysis indicated there was no significant (all P => 0.05) relationship between FMD and any marker of in vivo platelet activation (MPAs R = 0.193, PAC‐1 R = −0.113, anti‐CD62P R = −0.078) or inducible platelet activation by ADP (MPA R = −0.128, anti‐CD62P R = −0.237), AA (MPA R = −0.122, PAC‐1 R = −0.045, anti‐CD62P R = −0.142), or collagen (MPA R = 0.136, PAC‐1 R = 0.174, anti‐CD62P R = −0.077). Our findings contrast with two previous studies performed in high‐risk cardiac patients, which reported inverse relationships between platelet activation and endothelial function, suggesting that some compensatory redundancy may exist in the relationship between platelet and endothelial function in preclinical populations.
PMCID: PMC5449553  PMID: 28533260
Cardiovascular disease; endothelial function; platelet function
21.  Detection of mcr-1-Carrying Escherichia coli Causing Bloodstream Infection in a New York City Hospital: Avian Origins, Human Concerns? 
Open Forum Infectious Diseases  2017;4(3):ofx115.
The spread of mcr-1 in the United States remains poorly defined. mcr-1-producing Escherichia coli that also carried blaSHV-12 was detected in a hospitalized patient. No additional cases were identified during screening of 801 Gram-negative isolates. Genomic sequencing identified an IncX4 mcr-1- harboring plasmid and ST117 clonal background associated with avian pathogenic E coli.
PMCID: PMC5508776
avian pathogenic E coli; colistin; IncX4 plasmid; mcr-1; polymyxin B.
22.  Sedentary behavior as a risk factor for cognitive decline? A focus on the influence of glycemic control in brain health 
Cognitive decline leading to dementia represents a global health burden. In the absence of targeted pharmacotherapy, lifestyle approaches remain the best option for slowing the onset of dementia. However, older adults spend very little time doing moderate to vigorous exercise and spend a majority of time in sedentary behavior. Sedentary behavior has been linked to poor glycemic control and increased risk of all-cause mortality. Here, we explore a potential link between sedentary behavior and brain health. We highlight the role of glycemic control in maintaining brain function and suggest that reducing and replacing sedentary behavior with intermittent light-intensity physical activity may protect against cognitive decline by reducing glycemic variability. Given that older adults find it difficult to achieve current exercise recommendations, this may be an additional practical strategy. However, more research is needed to understand the impact of poor glycemic control on brain function and whether practical interventions aimed at reducing and replacing sedentary behavior with intermittent light intensity physical activity can help slow cognitive decline.
•Older adults spend a majority of time in sedentary behavior.•Sedentary behavior may be linked to cognitive decline via glycemic control.•Replacing sitting with intermittent light activity can improve glycemic control.•Future research should determine if light activity can forestall cognitive decline.•Engaging in more light activity may be an achievable public health target.
PMCID: PMC5651418
Dementia; Alzheimer's disease; Cognitive function; Diabetes; Glucose metabolism; Exercise; Physical activity; Light-intensity activity; Sitting; Sedentary behavior; Breaks in sedentary time
23.  Pregnancy after chemotherapy in male and female survivors of childhood cancer treated between 1970 and 1999: a report from the Childhood Cancer Survivor Study cohort 
The Lancet. Oncology  2016;17(5):567-576.
The effect of many contemporary chemotherapeutic drugs on pregnancy and livebirth is not well established. We aimed to establish the effects of these drugs on pregnancy in male and female survivors of childhood cancer not exposed to pelvic or cranial radiotherapy.
We used data from a subset of the Childhood Cancer Survivor Study cohort, which followed 5-year survivors of the most common types of childhood cancer who were diagnosed before age 21 years and treated at 27 institutions in the USA and Canada between 1970 and 1999. We extracted doses of 14 alkylating and similar DNA interstrand crosslinking drugs from medical records. We used sex-specific Cox models to establish the independent effects of each drug and the cumulative cyclophosphamide equivalent dose of all drugs in relation to pregnancies and livebirths occurring between ages 15 years and 44 years. We included siblings of survivors as a comparison group.
We included 10 938 survivors and 3949 siblings. After a median follow-up of 8 years (IQR 4–12) from cohort entry or at age 15 years, whichever was later, 4149 (38%) survivors reported having or siring a pregnancy, of whom 3453 (83%) individuals reported at least one livebirth. After a median follow-up of 10 years (IQR 6–15), 2445 (62%) siblings reported having or siring a pregnancy, of whom 2201 (90%) individuals reported at least one livebirth. In multivariable analysis, survivors had a decreased likelihood of siring or having a pregnancy versus siblings (male survivors: hazard ratio [HR] 0·63, 95% CI 0·58–0·68; p<0·0001; female survivors: 0·87, 0·81–0·94; p<0·0001) or of having a livebirth (male survivors: 0·63, 0·58–0·69; p<0·0001; female survivors: 0·82, 0·76–0·89; p<0·0001). In male survivors, reduced likelihood of pregnancy was associated with upper tertile doses of cyclophosphamide (HR 0·60, 95% CI 0·51–0·71; p<0·0001), ifosfamide (0·42, 0·23–0·79; p=0·0069), procarbazine (0·30, 0·20–0·46; p<0·0001) and cisplatin (0·56, 0·39–0·82; p=0·0023). Cyclophosphamide equivalent dose in male survivors was significantly associated with a decreased likelihood of siring a pregnancy (per 5000 mg/m2 increments: HR 0·82, 95% CI 0·79–0·86; p<0·0001). However, in female survivors, only busulfan (<450 mg/m2 HR 0·22, 95% CI 0·06–0·79; p=0·020; ≥450 mg/m2 0·14, 0·03–0·55; p=0·0051) and doses of lomustine equal to or greater than 411 mg/m2 (0·41, 0·17–0·98; p=0·046) were significantly associated with reduced pregnancy; cyclophosphamide equivalent dose was associated with risk only at the highest doses in analyses categorised by quartile (upper quartile vs no exposure: HR 0·85, 95% CI 0·74–0·98; p=0·023). Results for livebirth were similar to those for pregnancy.
Greater doses of contemporary alkylating drugs and cisplatin were associated with a decreased likelihood of siring a pregnancy in male survivors of childhood cancer. However, our findings should provide reassurance to most female survivors treated with chemotherapy without radiotherapy to the pelvis or brain, given that chemotherapy-specific effects on pregnancy were generally few. Nevertheless, consideration of fertility preservation before cancer treatment remains important to maximise the reproductive potential of all adolescents newly diagnosed with cancer.
National Cancer Institute, National Institutes of Health, and the American Lebanese–Syrian Associated Charities.
PMCID: PMC4907859  PMID: 27020005
24.  Return to Sport for Skeletally Immature Athletes After ACL Reconstruction: Preventing a Second Injury Using a Quality of Movement Assessment and Quantitative Measures to Address Modifiable Risk Factors 
Orthopaedic Journal of Sports Medicine  2017;5(4):2325967117700599.
Reinjury rates after anterior cruciate ligament reconstruction (ACLR) are highest among young athletes, who consequently suffer from low rates of return to play. Historically, quantitative measures have been used to determine readiness to return to sport; however, they do not assess modifiable risk factors related to the quality of movement.
To determine the effectiveness of a criteria-based rehabilitation progression and return-to-sport criteria on efficient return to activity and prevention of second injury in young athletes post-ACLR.
Study Design:
Case series; Level of evidence, 4.
Between December 2010 and 2013, 42 skeletally immature athletes (mean chronologic age, 12 years; range, 10-15 years) who underwent ACLR using ipsilateral hamstring tendon autograft were prospectively evaluated. All athletes progressed through a criteria-based rehabilitation progression; were assessed at specific time frames for strength, biomechanical, and neuromuscular risk factors predictive of injury; and were provided targeted interventions. The final return to sport phase consisted of quantitative testing as well as a quality of movement assessment of several functional movements with progressive difficulty and sports-specific loading. Clearance for unrestricted activity was determined by achieving satisfactory results on both qualitative and quantitative assessments with consideration for the demands of each sport.
The mean time for return to unrestricted competitive activity was 12 months. All but 3 (7%) athletes returned to their primary sport. Thirty-five athletes (83%) returned to unrestricted activity. Of the 6 (14%) who sustained a second injury, 3 (50%) were injured in sports they were not cleared for. All ACL reinjuries occurred in a cutting sport. Half of reinjuries occurred within 1 year of surgery, while the remaining occurred between 1 and 2 years. Eighty-three percent of reinjuries involved highly competitive cutting athletes.
In our cohort, the combination of qualitative and quantitative data served as a good indicator for reducing risk and determining readiness to return to sport.
PMCID: PMC5400136
ACL injury; skeletally immature; young athletes; ACL prevention
25.  The effects of implementing a point-of-care electronic template to prompt routine anxiety and depression screening in patients consulting for osteoarthritis (the Primary Care Osteoarthritis Trial): A cluster randomised trial in primary care 
PLoS Medicine  2017;14(4):e1002273.
This study aimed to evaluate whether prompting general practitioners (GPs) to routinely assess and manage anxiety and depression in patients consulting with osteoarthritis (OA) improves pain outcomes.
Methods and findings
We conducted a cluster randomised controlled trial involving 45 English general practices. In intervention practices, patients aged ≥45 y consulting with OA received point-of-care anxiety and depression screening by the GP, prompted by an automated electronic template comprising five questions (a two-item Patient Health Questionnaire–2 for depression, a two-item Generalized Anxiety Disorder–2 questionnaire for anxiety, and a question about current pain intensity [0–10 numerical rating scale]). The template signposted GPs to follow National Institute for Health and Care Excellence clinical guidelines for anxiety, depression, and OA and was supported by a brief training package. The template in control practices prompted GPs to ask the pain intensity question only. The primary outcome was patient-reported current pain intensity post-consultation and at 3-, 6-, and 12-mo follow-up. Secondary outcomes included pain-related disability, anxiety, depression, and general health.
During the trial period, 7,279 patients aged ≥45 y consulted with a relevant OA-related code, and 4,240 patients were deemed potentially eligible by participating GPs. Templates were completed for 2,042 patients (1,339 [31.6%] in the control arm and 703 [23.1%] in the intervention arm). Of these 2,042 patients, 1,412 returned questionnaires (501 [71.3%] from 20 intervention practices, 911 [68.0%] from 24 control practices). Follow-up rates were similar in both arms, totalling 1,093 (77.4%) at 3 mo, 1,064 (75.4%) at 6 mo, and 1,017 (72.0%) at 12 mo. For the primary endpoint, multilevel modelling yielded significantly higher average pain intensity across follow-up to 12 mo in the intervention group than the control group (adjusted mean difference 0.31; 95% CI 0.04, 0.59). Secondary outcomes were consistent with the primary outcome measure in reflecting better outcomes as a whole for the control group than the intervention group. Anxiety and depression scores did not reduce following the intervention. The main limitations of this study are two potential sources of bias: an imbalance in cluster size (mean practice size 7,397 [intervention] versus 5,850 [control]) and a difference in the proportion of patients for whom the GP deactivated the template (33.6% [intervention] versus 27.8% [control]).
In this study, we observed no beneficial effect on pain outcomes of prompting GPs to routinely screen for and manage comorbid anxiety and depression in patients presenting with symptoms due to OA, with those in the intervention group reporting statistically significantly higher average pain scores over the four follow-up time points than those in the control group.
Trial registration
ISRCTN registry ISRCTN40721988
Christian Mallen and colleagues report on a cluster-randomized trial investigating screening for anxiety and depression in patients presenting with osteoarthritis.
Author summary
Why was this study done?
Patients with painful conditions, such as osteoarthritis, are at higher risk of experiencing depression and anxiety.
People with pain and coexisting mood problems are more likely to have a poorer long-term outcome.
Routine screening for anxiety and depression in higher risk patients is controversial, with conflicting evidence.
What did the researchers do and find?
We conducted a large cluster randomised trial to investigate the impact on pain of screening and treating people with osteoarthritis for depression and anxiety in the general practice consultation.
General practices were randomised either to routinely screen patients consulting with osteoarthritis for depression and anxiety or to not screen.
We found that those screened for depression and anxiety had worse pain outcomes over the following 12 months than those not screened.
What do these findings mean?
Our findings do not support the implementation of routine screening of patients with osteoarthritis for depression and anxiety in primary care.
Further work is needed to determine the potential benefit of screening patients with different musculoskeletal disorders.
PMCID: PMC5388468  PMID: 28399129

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