Primary Care of Adult Cancer Survivors.

By 2040, there will be an estimated 26 million cancer survivors in the United States. The essential components of survivorship care are (1) surveillance for cancer recurrence, (2) surveillance for new primary cancers, (3) management of physical and psychological long-term effects of treatment, (4) prevention or mitigation of late treatment effects, and (5) coordination of care between the oncology team and primary care clinicians. Recommendations for surveillance to detect recurrence vary with cancer type and stage at diagnosis. Screening for new primary cancers is the same as for the general population. Although many cancer survivors do not undergo recommended surveillance or screening, family physicians can encourage and facilitate adherence. Family physicians should also monitor and manage the physical and psychological effects of cancer diagnosis and treatment, such as depression, lymphedema, pain, and sexual dysfunction. Cardiovascular disease is a leading cause of death for cancer survivors, often as a long-term effect of cancer treatments. Clinicians should counsel patients on cessation of tobacco and alcohol use, participation in recommended levels of physical activity, and adherence to optimal nutrition recommendations. Finally, family physicians should work with the cancer care team to coordinate the care plan and assure that all recommended components are achieved. Written survivorship care plans should be provided to cancer survivors to help them transition from active treatment to posttreatment monitoring. .

Modeling delay of age at natural menopause with planned tissue cryopreservation and autologous transplantation.

BACKGROUND: Ovarian tissue cryopreservation has been proven to preserve fertility against gonadotoxic treatments. It has not been clear how this procedure would perform if planned for slowing ovarian aging. OBJECTIVE: This study aimed to determine the feasibility of cryopreserving ovarian tissue to extend reproductive life span and delay menopause by autotransplantation near menopause. STUDY DESIGN: Based on the existing biological data on follicle loss rates, a stochastic model of primordial follicle wastage was developed to determine the years of delay in menopause (denoted by D) by ovarian tissue cryopreservation and transplantation near menopause. Our model accounted for (1) age at ovarian tissue harvest (21-40 years), (2) the amount of ovarian cortex harvested, (3) transplantation of harvested tissues in single vs multiple procedures (fractionation), and (4) posttransplant follicle survival (40% [conservative] vs 80% [improved] vs 100% [ideal or hypothetical]). RESULTS: Our model predicted that, for most women aged <40 years, ovarian tissue cryopreservation and transplantation would result in a significant delay in menopause. The advantage is greater if the follicle loss after transplant can be minimized. As an example, the delay in menopause (D) for a woman with a median ovarian reserve who cryopreserves 25% of her ovarian cortex at the age of 25 years and for whom 40% of follicles survive after transplantation would be approximately 11.8 years, but this extends to 15.5 years if the survival is 80%. As another novel finding, spreading the same amount of tissue to repetitive transplants significantly extends the benefit. For example, for the same 25-year-old woman with a median ovarian reserve, 25% cortex removal, and 40% follicle survival, fractionating the transplants to 3 or 6 procedures would result in the corresponding delay in menopause (D) of 23 or 31 years. The same conditions (3 or 6 procedures) would delay menopause as much as 47 years if posttransplant follicle survival is improved to 80% with modern approaches. An interactive Web tool was created to test all variables and the feasibility of ovarian tissue freezing and transplantation to delay ovarian aging (here). CONCLUSION: Our model predicts that with harvesting at earlier adult ages and better transplant techniques, a significant menopause postponement and, potentially, fertile life span extension can be achieved by ovarian tissue cryopreservation and transplantation in healthy women.

Recapitulating human ovarian aging using random walks.

Mechanism(s) that control whether individual human primordial ovarian follicles (PFs) remain dormant, or begin to grow, are all but unknown. One of our groups has recently shown that activation of the Integrated Stress Response (ISR) pathway can slow follicular granulosa cell proliferation by activating cell cycle checkpoints. Those data suggest that the ISR is active and fluctuates according to local conditions in dormant PFs. Because cell cycle entry of (pre)granulosa cells is required for PF growth activation (PFGA), we propose that rare ISR checkpoint resolution allows individual PFs to begin to grow. Fluctuating ISR activity within individual PFs can be described by a random process. In this article, we model ISR activity of individual PFs by one-dimensional random walks (RWs) and monitor the rate at which simulated checkpoint resolution and thus PFGA threshold crossing occurs. We show that the simultaneous recapitulation of (i) the loss of PFs over time within simulated subjects, and (ii) the timing of PF depletion in populations of simulated subjects equivalent to the distribution of the human age of natural menopause can be produced using this approach. In the RW model, the probability that individual PFs grow is influenced by regionally fluctuating conditions, that over time manifests in the known pattern of PFGA. Considered at the level of the ovary, randomness appears to be a key, purposeful feature of human ovarian aging.

New Insights for Tracking Global and Local Trends in Exposure to Air Pollutants.

Over six million people die prematurely each year from exposure to air pollution. Current air quality metrics insufficiently monitor exposure to air pollutants. This gap hinders the ability of decisionmakers to address the public health impacts of air pollution. To spur new emissions control policies and ensure implemented solutions realize meaningful gains in environmental health, we develop a framework of public-health-focused air quality indicators that quantifies over 200 countries' trends in exposure to particulate matter, ozone, nitrogen oxides, sulfur dioxide, carbon monoxide, and volatile organic compounds. We couple population density to ground-level pollutant concentrations to derive population-weighted exposure metrics that quantify the pollutant levels experienced by the average resident in each country. Our analyses demonstrate that most residents in 171 countries experience pollutant levels exceeding international health guidelines. In addition, we find a negative correlation between temporal trends in ozone and nitrogen oxide concentrations, which─when qualitatively interpreted with a simple atmospheric chemistry box model─can help describe the apparent tradeoff between the mitigation of these two pollutants on local scales. These novel indicators and their applications enable regulators to identify their most critical pollutant exposure trends and allow countries to track the performance of their emission control policies over time.

Comorbidities associated with different levels of total cholesterol in male and female acute ischemic stroke patients.

ABSTRACT: Men and women differ in their clinical risk factors with respect to various predictors of severity in acute ischemic stroke (AIS). High cholesterol is a risk factor for AIS and the mechanism by which high cholesterol levels lead to an AIS is well established. However, the specific relationship between demographic, clinical risk factors, total cholesterol, and the resulting gender difference in AIS patients is yet to be investigated. This study recruited AIS patients between January 2000 and June 2016 classified into normal, borderline or high total cholesterol (TC). Normal was defined as ≤200 mg/dl, borderline 200 to 239 mg/dl and high ≥240 mg/dl based on Adult Treatment Panel III (ATP III) Guidelines for the classification of TC levels. The logistic regression model was used to predict clinical risk factors associated within men and women AIS patients with different levels of TC. A total of 3532 AIS patients presented with normal TC, 760 patients with borderline TC and 427 patients with high TC. The high total cholesterol group was more likely to be women with increasing age (OR = 1.028, 95% CI, 1.006-1.052, P = .014), body mass index (BMI) (OR = 1.052, 95% CI, 1.004-1.102, P = .033), and high-density lipoprotein cholesterol (HDL-C) (OR = 1.039, 95% CI, 1.019-1.060, P < .001), while those with coronary artery disease (OR = 0.435, 95% CI, 0.234-0.809, P = .003), history of drug or alcohol abuse (OR = 0.261, 95% CI, 0.079-0.867, P = .028), increasing INR (OR = 0.187, 95% CI, 0.047-0.748, P = .018), and elevated diastolic blood pressure (OR = 0.982, 95% CI, 0.970-0.995, P = .006) were associated with being a male AIS patient. There were disparities in demographic and clinical risk factors associated with high TC levels in men when compared to women and more clinical risk factors were associated with high TC levels in men when compared to women with AIS. It is important to take into account specific clinical risk factors associated with gender-related differences in total cholesterol in AIS population to facilitate personalizing their therapeutic actions.

Moving Toward a Standardized National Family Medicine Subinternship Curriculum: Results From a CERA Clerkship Directors Survey.

BACKGROUND AND OBJECTIVES: Although the subinternship (sub-I) is considered integral in many medical schools' curricula, family medicine does not have standardized course recommendations. Given the variable nature of this clinical experience, this study investigated the potential role of a standardized sub-I curriculum in family medicine. METHODS: Questions about sub-Is were created and data were gathered and analyzed as part of the 2019 Council of Academic Family Medicine's (CAFM) Educational Research Alliance (CERA) survey of family medicine clerkship directors. The survey was distributed via email to 126 US and 16 Canadian recipients between June 19, 2019 and August 2, 2019 through the online program SurveyMonkey. RESULTS: A total of 101 (71.1%) of 142 clerkship directors responded to the survey. Most (84.2%) schools require sub-Is. There was a positive association between students matching into family medicine and having family medicine sub-Is at residency programs (P<.001). There was no relationship between higher family medicine match rates and the presence of family medicine sub-Is at nonresidency sites (P=.48) or having an advanced ambulatory rotation requirement (P=.16). CONCLUSIONS: A sub-I is a way to further expose students to family medicine, and increasing sub-I positions at residency programs may influence the number who pursue the specialty. Creation of a standardized sub-I curriculum presents an opportunity to enhance a critical educational experience in family medicine.

Design and Implementation of a Lifestyle Medicine Curriculum in Undergraduate Medical Education.

While scientific evidence demonstrates conclusive associations between unhealthy lifestyle behaviors and increased morbidity and mortality related to noncommunicable chronic diseases (NCDs), most physicians are not formally taught the root causes of NCDs nor how to counsel patients regarding their lifestyle behaviors for disease prevention and treatment. Since its inception in 2012, the University of South Carolina School of Medicine Greenville has designed, developed, and implemented an innovative, formalized lifestyle medicine curriculum to provide required undergraduate medical student training with a graduating program-level goal to "Deliver total health care using lifestyle medicine to prevent and treat morbidity and mortality related to chronic diseases." The process was guided by the Association of American Medical Colleges' Core Entrustable Professional Activities (required for graduates entering residency) and aimed to satisfy the Quadruple Aim components of better outcomes, lower cost, improved patient experience, and improved physician experience. Four essential instructional design phases, Analysis, Design, Development, and Evaluation, were used as systematic steps to create and deploy the curriculum. This article describes the evidence-based approach used and offers guidance to other undergraduate medical schools that may wish to implement lifestyle medicine training to improve physicians' medical knowledge and clinical skills for optimum health care.

Estimated Placental Volume and Gestational Age.

OBJECTIVE: The objective of this study was to validate estimated placental volume (EPV) across a range of gestational ages (GAs). STUDY DESIGN: Three hundred sixty-six patients from 2009 to 2011 received ultrasound scans between 11 + 0 and 38 + 6 weeks GA to assess EPV. An EPV versus GA best fit curve was generated and compared with published normative curves of EPV versus GA in a different population. A subanalysis was performed to explore the relationship between EPV and birth weight (BW). RESULTS: Analysis of EPV versus GA revealed a parabolic curve with the following best fit equation: EPV = (0.372 GA - 0.00364 GA2)3. EPV was weakly correlated with BW, and patients with an EPV in the bottom 50th percentile had 2.42 times the odds of having a newborn with a BW in the bottom 50th percentile (95% confidence interval: 1.27-4.68). Microscopic evaluation of two placentas corresponding to the smallest EPV outliers revealed significant placental pathology. CONCLUSION: Placental volume increases throughout gestation and follows a predictable parabolic curve, in agreement with the existing literature. Further validation is required, but EPV may have the potential for clinical utility as a screening tool in a variety of settings.

Punitive laws, key population size estimates, and Global AIDS Response Progress Reports: An ecological study of 154 countries

INTRODUCTION: UN global plans on HIV/AIDS have committed to reducing the number of countries with punitive laws criminalizing key populations. This study explores whether punitive laws are associated with countries' performance on targets set in the global plans. METHODS: The study used chi-square tests of independence to explore associations between legal status, key population size estimates, and HIV service coverage for 193 countries from 2007 to 2014. We used data reported by countries on United Nations Global AIDS Progress Report (GARPR) indicators, and legal data from UNAIDS, UNDP, and civil society organizations. Due to lack of sufficiently reliable legal data, only men who have sex with men (MSM) could be studied. The study utilized public data aggregated at the national level. Correspondence with individual experts in a subset of countries stated the purpose of the study, and all responses were anonymized. RESULTS AND DISCUSSION: A significantly larger proportion of countries that criminalize same-sex sexual behaviour reported implausibly low size estimates or no size estimates for MSM. This is consistent with findings in qualitative research that MSMs are marginalized and reluctant to be studied in countries where same-sex sexuality is criminalized. Size estimates are often used as the denominators for national HIV service coverage reports. Initially, countries that criminalized same-sex sexuality appeared to have higher HIV testing coverage among MSM than did countries where it is not criminalized. However, investigation of a subset of countries that have reported 90-100% HIV testing coverage among MSM found that most were based on implausibly low or absent size estimates. CONCLUSION: Criminalization of same-sex sexuality is associated with implausibly low or absent MSM size estimates. Low size estimates may contribute to official denial of the existence of MSM; to failure to adequately address their needs; and to inflated HIV service coverage reports that paint a false picture of success. To enable and measure progress in the HIV response, UN agencies should lead a collaborative process to systematically, independently and rigorously gather data on laws and their enforcement.

Development of downstream processing to minimize beta-glucan impurities in GMP-manufactured therapeutic antibodies.

The presence of impurities or contaminants in biological products such as monoclonal antibodies (mAb) could affect efficacy or cause adverse reactions in patients. ICH guidelines (Q6A and Q6B) are in place to regulate the level of impurities within clinical drug products. An impurity less often reported and, therefore, lacking regulatory guideline is beta-glucan. Beta-glucans are polysaccharides of d-glucose monomers linked by (1-3) beta-glycosidic bonds, and are produced by prokaryotic and eukaryotic organisms, including plants. They may enter manufacturing processes via raw materials such as cellulose-based membrane filters or sucrose. Here we report the detection of beta-glucan contamination of a monoclonal IgE antibody (MOv18), manufactured in our facility for a first-in-human, first-in-class clinical trial in patients with cancer. Since beta-glucans have potential immunostimulatory properties and can cause symptomatic infusion reactions, it was of paramount importance to identify the source of beta-glucans in our product and to reduce the levels to clinically insignificant concentrations. We identified beta-glucans in sucrose within the formulation buffer and within the housing storage buffer of the virus removal filter. We also detected low level beta-glucan contamination in two of four commercially available antibodies used in oncology. Both formulation buffers contained sucrose. We managed to reduce levels of beta-glucan in our product 10-fold, by screening all sucrose raw material, filtering the sucrose by Posidyne® membrane filtration, and by incorporating extra wash steps when preparing the virus removal filter. The beta-glucan levels now lie within a range that is unlikely to cause clinically significant immunological effects. © 2016 American Institute of Chemical Engineers Biotechnol. Prog., 32:1494-1502, 2016.

A Multidisciplinary Intervention Utilizing Virtual Communication Tools to Reduce Health Disparities: A Pilot Randomized Controlled Trial.

Advances in technology are likely to provide new approaches to address healthcare disparities for high-risk populations. This study explores the feasibility of a new approach to health disparities research using a multidisciplinary intervention and advanced communication technology to improve patient access to care and chronic disease management. A high-risk cohort of uninsured, poorly-controlled diabetic patients was identified then randomized pre-consent with stratification by geographic region to receive either the intervention or usual care. Prior to enrollment, participants were screened for readiness to make a behavioral change. The primary outcome was the feasibility of protocol implementation, and secondary outcomes included the use of patient-centered medical home (PCMH) services and markers of chronic disease control. The intervention included a standardized needs assessment, individualized care plan, intensive management by a multidisciplinary team, including health coach-facilitated virtual visits, and the use of a cloud-based glucose monitoring system. One-hundred twenty-seven high-risk, potentially eligible participants were randomized. Sixty-one met eligibility criteria after an in-depth review. Due to limited resources and time for the pilot, we only attempted to contact 36 participants. Of these, we successfully reached 20 (32%) by phone and conducted a readiness to change screen. Ten participants screened in as ready to change and were enrolled, while the remaining 10 were not ready to change. Eight enrolled participants completed the final three-month follow-up. Intervention feasibility was demonstrated through successful implementation of 13 out of 14 health coach-facilitated virtual visits, and 100% of participants indicated that they would recommend the intervention to a friend. Protocol feasibility was demonstrated as eight of 10 participants completed the entire study protocol. At the end of the three-month intervention, participants had a median of nine total documented contacts with PCMH providers compared to four in the control group. Three intervention and two control participants had controlled diabetes (hemoglobin A1C <9%). Multidisciplinary care that utilizes health coach-facilitated virtual visits is an intervention that could increase access to intensive primary care services in a vulnerable population. The methods tested are feasible and should be tested in a pragmatic randomized controlled trial to evaluate the impact on patient-relevant outcomes across multiple chronic diseases.

A multivariate distance-based analytic framework for connectome-wide association studies.

The identification of phenotypic associations in high-dimensional brain connectivity data represents the next frontier in the neuroimaging connectomics era. Exploration of brain-phenotype relationships remains limited by statistical approaches that are computationally intensive, depend on a priori hypotheses, or require stringent correction for multiple comparisons. Here, we propose a computationally efficient, data-driven technique for connectome-wide association studies (CWAS) that provides a comprehensive voxel-wise survey of brain-behavior relationships across the connectome; the approach identifies voxels whose whole-brain connectivity patterns vary significantly with a phenotypic variable. Using resting state fMRI data, we demonstrate the utility of our analytic framework by identifying significant connectivity-phenotype relationships for full-scale IQ and assessing their overlap with existent neuroimaging findings, as synthesized by openly available automated meta-analysis (www.neurosynth.org). The results appeared to be robust to the removal of nuisance covariates (i.e., mean connectivity, global signal, and motion) and varying brain resolution (i.e., voxelwise results are highly similar to results using 800 parcellations). We show that CWAS findings can be used to guide subsequent seed-based correlation analyses. Finally, we demonstrate the applicability of the approach by examining CWAS for three additional datasets, each encompassing a distinct phenotypic variable: neurotypical development, Attention-Deficit/Hyperactivity Disorder diagnostic status, and L-DOPA pharmacological manipulation. For each phenotype, our approach to CWAS identified distinct connectome-wide association profiles, not previously attainable in a single study utilizing traditional univariate approaches. As a computationally efficient, extensible, and scalable method, our CWAS framework can accelerate the discovery of brain-behavior relationships in the connectome.

The effects of edema and self-adherent wrap on the work of flexion in a cadaveric hand.

PURPOSE: Early motion protocols after flexor tendon repair often require hand therapy in edematous digits. Self-adherent wraps are used in the postoperative period to reduce edema. The purpose of this study was to determine whether the presence of a self-adherent wrap affected the work of flexion during early motion protocols. METHODS: In an unpreserved cadaveric hand, the flexor digitorum profundus and flexor pollicis longus tendons were identified and attached to a tensile testing machine to measure work of flexion (WoF). We simulated subcutaneous edema by injecting normal saline into the digits. Moderate and severe edema was simulated by 10% and 20% increases in circumference of the digits, respectively. We evaluated 2 commonly used products: 2.5-cm Coban self-adherent wrap (3M, St. Paul, MN) and 2.5-cm Co-Wrap cohesive bandage (Hartmann, Rock Hill, SC). Statistical analyses include analysis of variance, 95% confidence intervals for average responses, and graphical display of both data and model predictions. RESULTS: In digits without edema or wraps, WoF ranged from 0.0114 J (small finger) to 0.0710 J (thumb). Without wraps, simulated moderate and severe edema was predicted to increase WoF by an average of 23% and 71%, respectively. Application of self-adherent wrap increased WoF values significantly in all digits. In the majority of conditions tested, application of self-adherent wrap increased WoF more significantly than moderate edema did. The effects of edema and self-adherent wrap were additive, producing WoF values 4 times the baseline values. CONCLUSIONS: Edema and self-adherent wrap increased WoF in this model. Therapists and surgeons should be aware of increased stress placed on tendons when early motion protocols are initiated in the presence of edema and self-adherent wrap. CLINICAL RELEVANCE: We recommend removal of self-adherent wrap before starting a therapy session.

Cone-beam reconstruction for the two-circles-plus-one-line trajectory.

The Kodak Image Station In-Vivo FX has an x-ray module with cone-beam configuration for radiographic imaging but lacks the functionality of tomography. To introduce x-ray tomography into the system, we choose the two-circles-plus-one-line trajectory by mounting one translation motor and one rotation motor. We establish a reconstruction algorithm by applying the M-line reconstruction method. Numerical studies and preliminary physical phantom experiment demonstrate the feasibility of the proposed design and reconstruction algorithm.

Reference regions for beat-to-beat ECG data.

The QT interval is regarded as an important biomarker for the assessment of arrhythmia liability, and evidence of QT prolongation has led to the withdrawal and relabeling of numerous compounds. Traditional methods of assessing QT prolongation correct the QT interval for the length of the RR interval (which varies inversely with heart-rate) in a variety of ways. These methods often disagree with each other and do not take into account changes in autonomic state. Correcting the QT interval for RR reduces a bivariate observation (RR, QT) to a univariate observation (QTc). The development of automatic electrocardiogram (ECG) signal acquisition systems has made it possible to collect continuous (so called 'beat-to-beat') ECG data. ECG data collected prior to administration of a compound allow us to define a region for (RR, QT) values that encompasses typical activity. Such reference regions are used in clinical applications to define the 'normal' region of clinical or laboratory measurements. This paper motivates the need for reference regions of (RR, QT) values from beat-to-beat ECG data, and describes a way of constructing these. We introduce a measure of agreement between two reference regions that points to the reliability of 12-lead digital Holter data. We discuss the use of reference regions in establishing baselines for ECG parameters to assist in the evaluation of cardiac risk and illustrate using data from two methodological studies.

Accelerated solvent extraction of lignin from Aleurites moluccana (Candlenut) nutshells.

Lignin from candlenut shells was isolated using an ethanol-water accelerated solvent extraction method. Yields (based on Klason lignin) increased from about 14 to 33% as temperature increased from 100 to 195 °C and were also influenced by the amount of aqueous acid used to precipitate lignin from the extraction liquor. These yields were higher than could be obtained using a conventional dioxane-water acidolysis method. The resulting lignin was characterized by IR, 31P NMR, and 1H-13C HMQC NMR spectroscopic techniques. The lignin contained predominantly guaiacyl units, and both the total hydroxyl group content and phenolic hydroxyl group content were high.

Quantitative assessment of tissue biomarkers and construction of a model to predict outcome in breast cancer using multiple imputation.

Missing data pose one of the greatest challenges in the rigorous evaluation of biomarkers. The limited availability of specimens with complete clinical annotation and quality biomaterial often leads to underpowered studies. Tissue microarray studies, for example, may be further handicapped by the loss of data points because of unevaluable staining, core loss, or the lack of tumor in the histospot. This paper presents a novel approach to these common problems in the context of a tissue protein biomarker analysis in a cohort of patients with breast cancer. Our analysis develops techniques based on multiple imputation to address the missing value problem. We first select markers using a training cohort, identifying a small subset of protein expression levels that are most useful in predicting patient survival. The best model is obtained by including both protein markers (including COX6C, GATA3, NAT1, and ESR1) and lymph node status. The use of either lymph node status or the four protein expression levels provides similar improvements in goodness-of-fit, with both significantly better than a baseline clinical model. Using the same multiple imputation strategy, we then validate the results out-of-sample on a larger independent cohort. Our approach of integrating multiple imputation with each stage of the analysis serves as an example that may be replicated or adapted in future studies with missing values.

The assessment of cervical foramina with oblique radiographs: the effect of film angle on foraminal area.

STUDY DESIGN: Radiographic evaluation of cadaveric cervical spine specimens. OBJECTIVE: Assess reliability and reproducibility of foraminal dimensions obtained from cervical radiographs of varying obliquity and determine optimal angles for visualizing foramina at each cervical spine level. SUMMARY OF BACKGROUND DATA: Oblique radiographs may be considered to assess cervical foraminal dimensions and are generally obtained 45 degrees from the anteroposterior (AP) orientation. Previous reports have suggested that foraminal area observed on these radiographs may be influenced by changes in obliquity so that certain film angles may be better suited for accurately assessing foramen size, depending on which level is being evaluated. METHODS: Radiographs of 4 human cadaveric cervical spines were obtained at 5-degree increments from 20 to 70 degrees relative to AP orientation, using both left and right sides of each specimen. Foraminal area was estimated by measuring height and width of each foramen and also with a freehand area measurement tool. Reliabilities of both methods were calculated. At each level, foraminal area was plotted against film angle and quadratic best-fit curves were used to determine the maximum area observed and the optimal angle of obliquity for assessment. RESULTS: Assessment of foraminal area using the height and width values was associated with good interobserver reliability, whereas the freehand method exhibited excellent reliability. The optimal film angles for calculating foraminal area increased from 46.3 degrees for C2-C3 to 56.1 degrees for C7-T1. The ideal film angle that minimized the overall error of measurement across the entire cervical spine was estimated to be 52.4 degrees. CONCLUSIONS: Optimal angles for visualizing lower cervical foramina are larger than those for upper cervical spine. To minimize overall loss of foraminal area throughout the entire cervical spine, oblique cervical radiographs should be obtained at an angle of approximately 52 degrees from the AP orientation.

Macrophages directly contribute to the exaggerated inflammatory response in cystic fibrosis transmembrane conductance regulator-/- mice.

Pulmonary infection with an exaggerated inflammatory response is the major cause of morbidity and mortality in cystic fibrosis (CF). The objective of this study was to determine whether differences in the innate immune system underlie the exaggerated immune response in CF. We established a model that recapitulates the exaggerated immune response in a CF mouse model by exposure to Pseudomonas aeruginosa LPS and assessed the pulmonary cellular and cytokine responses of wild-type (WT) and CF mice. Compared with WT mice, CF mice had increased numbers of neutrophils and increased proinflammatory cytokines in their bronchoalveolar lavage fluid after LPS exposure. Based on the increased levels of IL-1alpha, IL-6, granulocyte colony-stimulating factor (G-CSF), and keratinocyte chemoattractant, all of which are known to be produced by macrophages, we tested whether two populations of macrophages, bone marrow-derived macrophages and alveolar macrophages, directly contribute to the elevated cytokine response of CF mice to LPS. After in vitro stimulation of bone marrow-derived macrophages and alveolar macrophages with LPS, IL-1alpha, IL-6, G-CSF, and monocyte chemoattractant protein-1 were higher in CF compared with WT cell supernatants. Quantitative analyses for IL-6 and keratinocyte chemoattractant revealed that LPS-stimulated CF macrophages have higher mRNA and intracellular protein levels compared with WT macrophages. Our data support the hypothesis that macrophages play a role in the exuberant cytokine production and secretion that characterizes CF, suggesting that the macrophage response may be an important therapeutic target for decreasing the morbidity of CF lung disease.