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Cognitive effort is an essential part of both forensic and clinical decision-making. Errors occur in both fields because the cognitive process is complex and prone to bias. We performed a selective review of full-text English language literature on cognitive bias leading to diagnostic and forensic errors. Earlier work (1970-2000) concentrated on classifying and raising bias awareness. Recently (2000-2016), the emphasis has shifted toward strategies for "debiasing." While the forensic sciences have focused on the control of misleading contextual cues, clinical debiasing efforts have relied on checklists and hypothetical scenarios. No single generally applicable and effective bias reduction strategy has emerged so far. Generalized attempts at bias elimination have not been particularly successful. It is time to shift focus to the study of errors within specific domains, and how to best communicate uncertainty in order to improve decision making on the part of both the expert and the trier-of-fact., (© 2017 American Academy of Forensic Sciences.)

Purpose: The prolactin (PRL) receptor is over-expressed in breast cancer, and pre-clinical data indicate that it contributes to breast oncogenesis. Cabergoline is a potent dopamine receptor agonist of D2 receptors and has a direct inhibitory effect on pituitary PRL secretion., Methods: A phase II study of cabergoline in patients with metastatic breast cancer was conducted. The primary end point of the study was to determine the clinical benefit rate (CBR) at 2 months. Eligible patients had tumors of any receptor status with no limit of prior lines of therapy. Measurable and unmeasurable diseases were allowed. Cabergoline 1 mg orally, twice weekly (1 cycle = 4 weeks) was given until disease progression or unacceptable toxicity. PRL receptor immunohistochemical staining was performed on available baseline tumor tissue; serial serum PRL levels were assessed., Results: Twenty women were enrolled; 18 were evaluable for CBR. Tumor receptor status was distributed as follows: HR-any/HER2+ 2(10%), HR+/HER2- 18 (90%). The CBR was 33% (6/18), median progression free survival was 1.8 months, and median overall survival was 10.4 months. Two patients experienced disease control for over 12 months. Most common treatment-related adverse events were nausea (30%), fatigue (25%), and elevation in alkaline phosphatase (15%). Nine patients had baseline tissue for analysis; there was no association between baseline tumor PRL receptor expression and clinical benefit (p = 0.24). Change in serum PRL level and response were not correlated after 2 months of treatment (p = 0.64)., Conclusion: Cabergoline was well tolerated, and while the ORR was low, a small subset of patients experienced extended disease control.

Aim: The symptoms of Huntington's disease are well known, yet the symptoms of juvenile Huntington's disease (JHD) are less established due to its rarity. The study examined a cluster of symptoms considered to be common, but under-recognized in JHD: pain, itching, sleeping difficulties, psychosis and tics., Materials & Methods: A symptom survey was constructed using the online tool Qualtrics and dispersed to JHD caregivers through websites., Results: A total of 33 surveys were completed. Disrupted sleep was the most prevalent symptom (87%), followed by tics (78%), pain (69%), itching (60%) and psychosis (39%)., Conclusion: Despite limitations, the study supports that there are symptoms in the JHD population that are not considered classic, however, are common and significant for patients and caregivers.

The Pahrump poolfish (Empetrichthys latos) and White River springfish (Crenichthys baileyi) are small-bodied teleost fishes (order Cyprinodontiformes) endemic to the arid Great Basin and Mojave Desert regions of western North America. These taxa survive as small, isolated populations in remote streams and springs and evolved to tolerate extreme conditions of high temperature and low dissolved oxygen. Both species have experienced severe population declines over the last 50-60years that led to some subspecies being categorized with protected status under the U.S. Endangered Species Act. Here we report the first sequencing of the complete mitochondrial DNA genomes for both E. l. latos and the moapae subspecies of C. baileyi. Complete mitogenomes of 16,546bp nucleotides were obtained from two E. l. latos individuals collected from introduced populations at Spring Mountain Ranch State Park and Shoshone Ponds Natural Area, Nevada, USA, while a single mitogenome of 16,537bp was sequenced for C. b. moapae. The mitogenomes of both species contain 13 protein-encoding genes, twenty-two tRNAs, and two rRNAs (12S and 18S) following the syntenic arrangement typical of Actinopterygiian fish mitogenomes, as well as D-loop control regions of 858bp for E. latos and 842bp for C. baileyi moapae. The two E. latos individuals exhibited only 0.0181% nucleotide sequence divergence across the entire mitogenome, implying little intraspecific mtDNA genetic variation. Comparative phylogenetic analysis of the poolfish and springfish mitochondrial genomes to available mitogenomes of other Cyprinodontoid fishes confirmed the close relationship of these oviparous Empetrichthys and Crenichthys genera to the viviparous goodeid fishes of central Mexico, and showed the combined clade of these fishes to be a sister group to the Profundulidae killifishes. Despite several significant life history and morphological differences between the Empetrichthyinae and Goodienae, estimates of evolutionary genetic distances using two partial regions of mtDNA point to inclusion of the Empetrichthys and Crenichthys genera within the family Goodeidae along with the goodeid fishes of central Mexico., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Hypertensive disorders of pregnancy result in significant maternal morbidity and mortality. State and national guidelines have been proposed to increase treatment of patients with hypertensive emergencies or critically elevated blood pressures. There are limited data available to assess the impact of these recommendations on maternal morbidity., Objective: The purpose of this prospective quality improvement project was to determine if maternal morbidity would be improved using a standardized approach for treatment of critically elevated blood pressures., Study Design: In all, 23 hospitals participated in this project. Treatment recommendations included the use of an intravenous blood pressure medication and magnesium sulfate when there was a sustained blood pressure of ≥160 mm Hg systolic and/or ≥110 mm Hg diastolic. Compliance with the metric recommendations was monitored based on the number of patients treated with an intravenous blood pressure medication, use of magnesium sulfate, and if they received a timely postpartum follow-up appointment. The metric was scored as all or none; missing any of the 3 metric components was considered noncompliant. From January through June 2015 baseline data were collected and hospitals were made aware that ongoing monitoring of compliance would begin in July 2015 through June 2016. The primary outcomes were composite metric compliance, the incidence of eclampsia per 1000 births, and severe maternal morbidity., Results: During the 18 months of this study there were 69,449 births. Within this population, 2034 met criteria for a critically elevated blood pressure, preeclampsia, or superimposed preeclampsia with severe features. Of this group, 1520 had a sustained critical blood elevation. Initial compliance with treatment recommendations was low (50.5%) and increased to >90% after April 2016 (P < .001). Compliance with utilization of intravenous blood pressure medication increased by 33.2%, from a baseline of 57.1-90.3% (P < .01) during the last 6 months of monitoring. Compliance with utilization of magnesium sulfate increased by 10.8%, from a baseline of 85.4-96.2% (P < .01). The incidence of eclampsia declined by 42.6% (1.15 ± 0.15/1000 to 0.62 ± 0.09/1000 births). Severe maternal morbidity decreased by 16.7% from 2.4 ± 0.10% to 2.0 ± 0.15% (P < .01)., Conclusion: We noted 3 important findings: (1) compliance with state and national treatment guidelines is low without monitoring; (2) high levels of compliance can be achieved in a relatively short period of time; and (3) early intervention with intravenous blood pressure medication and magnesium sulfate for verified sustained critical maternal blood pressures resulted in a significant reduction in the rate of eclampsia and severe maternal morbidity. The reduction in the rate of eclampsia could only partially be attributed to the increase in the use of magnesium sulfate, suggesting an additive or synergistic effect of the combined treatment of an antihypertensive medication and magnesium sulfate on the rate of eclampsia and severe maternal morbidity., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Inflammatory breast cancer (IBC) is a rare and aggressive form of breast cancer, which accounts for approximately 3% of cases of breast malignancies. Diagnosis relies largely on its clinical presentation, and despite a characteristic phenotype, underlying molecular mechanisms are poorly understood. Unique clinical presentation indicates that IBC is a distinct clinical and biological entity when compared to non-IBC. Biological understanding of non-IBC has been extrapolated into IBC and targeted therapies for HER2 positive (HER2+) and hormonal receptor positive non-IBC led to improved patient outcomes in the recent years. This manuscript reviews recent discoveries related to the underlying biology of IBC, clinical progress to date and suggests rational approaches for investigational therapies.

Objective: To evaluate whether a standardized approach to identify pregnant women at risk for shoulder dystocia (SD) is associated with reduced incidence of SD and brachial plexus injury (BPI)., Methods: Between 2011 and 2015, prospective data were collected from 29 community-based hospitals in the USA during implementation of an evidence-based practice bundle, including an admission risk assessment, required "timeout" before operative vaginal delivery (OVD), and low-fidelity SD drills. All women with singleton vertex pregnancies admitted for vaginal delivery were included. Rates of SD, BPI, OVD, and cesarean delivery were compared between a baseline period (January 2011-September 2013) and an intervention period (October 2013-June 2015), during which there was a system-wide average bundle compliance of 90%., Results: There was a significant reduction in the incidence of SD (17.6%; P=0.028), BPI (28.6%; P=0.018), and OVD (18.0%; P<0.001) after implementation of the evidence-based practice bundle. There was a nonsignificant reduction in primary (P=0.823) and total (P=0.396) cesarean rates, but no association between SD drills and incidence of BPI., Conclusion: Implementation of a standard evidence-based practice bundle was found to be associated with a significant reduction in the incidence of SD and BPI. Utilization of low-fidelity drills was not associated with a reduction in BPI., (© 2016 International Federation of Gynecology and Obstetrics.)

Triple negative breast cancer (TNBC) accounts for 10-20% of cases in breast cancer. Despite recent advances in the treatment of hormonal receptor+ and HER2+ breast cancers, there are no targeted therapies available for TNBC. Evidence supports that most patients with TNBC express the transmembrane Epidermal Growth Factor Receptor (EGFR). However, early phase clinical trials failed to demonstrate significant activity of EGFR-targeted monoclonal antibodies and/or tyrosine kinase inhibitors. Here, we review the recent discoveries related to the underlying biology of the EGFR pathway in TNBC, clinical progress to date and suggest rational future approaches for investigational therapies in TNBC., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background and Objectives This pilot study provides a description and evaluation of process-oriented dynamic group psychotherapy for depression as a teaching modality for family medicine residents. The main purpose of using this modality was to teach family medicine residents a variety of psychological clinical skills. A secondary benefit of this modality was to provide in-house, primary care treatment to depressed patients, although the efficacy of this was not evaluated in the present study. Methods A 10-item, self-report, Likert-type questionnaire was administered to a convenience sample of family medicine residents who had participated in the program. Results Completed questionnaires were received from 100% of the family medicine resident participants. Responses to the questionnaires indicate that the residents felt they acquired a variety of clinical skills from the training modality, to include developing active listening and interviewing skills; methods to improve the doctor-patient relationship; increased skills in empathy, intuitive processes, and emotional support; a depth understanding of how intra-psychic conflicts and interpersonal problems contribute to depression; how to give effective feedback that promotes behavioral change; and how to place interventions at the appropriate level of change. Eighty-eight percent of residents indicated they would recommend this learning modality to a family medicine physician colleague. Conclusions The family medicine residents' responses to the questionnaires indicate that they perceived process-oriented dynamic group psychotherapy for depression as a constructive and beneficial modality for both patient care and learning a variety of clinical skills.

Breast cancer is the second-leading cause of metastatic disease in the central nervous system (CNS). Recent advances in the biological understanding of breast cancer have facilitated an unprecedented increase of survival in a subset of patients presenting with metastatic breast cancer. Patients with HER2 positive (HER2+) or triple negative breast cancer are at highest risk of developing CNS metastasis, and typically experience a poor prognosis despite treatment with local and systemic therapies. Among the obstacles ahead in the realm of developmental therapeutics for breast cancer CNS metastasis is the improvement of our knowledge on its biological nuances and on the interaction of the blood–brain barrier with new compounds. This article reviews recent discoveries related to the underlying biology of breast cancer brain metastases, clinical progress to date and suggests rational approaches for investigational therapies.

Background Context: Cervical interlaminar and transforaminal epidural steroid injections have been increasingly performed as a medical interventional treatment for pain., Purpose: This study aimed to examine if there was increasing proportion of cervical spinal cord injured acute rehabilitation hospital admissions related to cervical epidural injections because of increased use of the procedure. Additionally, this study aimed to determine risk factors that may have made these patients known higher risk premorbidly., Study Design/setting: A retrospective chart review was carried out., Patient Sample: The sample was from a 2001 to 2008 spinal cord-related injuries admitted to Magee Rehabilitation (2,770). A total of 1,343 patients were classified as having acute spinal cord injuries (SCIs). Of these patients, seven cases of SCI occurred after cervical epidural injections., Outcome Measures: Chart data regarding characteristics of patients and proportion of SCI admissions to cervical epidural injections injuries were the outcome measures., Methods: Parameters analyzed included age, sex, American Spinal Injury Association Impairment Scale on admission, mechanism of injury, presenting symptoms, time of onset, and risk factors. Proportion of SCI admissions to cervical epidural injections injuries was also analyzed., Results: From the years 2001 to 2008, there were seven admissions for such injury with no change in the proportion of SCIs from cervical epidural injections relative to all SCIs. All were incomplete and mechanisms included anterior cord infarction (1), intraparenchymal injection (1), epidural abscess (2), contusion (1), epidural hematoma (1), and unknown (1). Presenting symptoms included hypotension, respiratory distress, chest pain, upper limb numbness, paresthesias, weakness, and fever. Symptom onset ranged from minutes to 72 hours after injection., Conclusions: Although there is an increased use of interventional spine procedures to treat pain, this did not increase the proportion of cervical epidural-related SCI admissions. Additional research is needed to advocate reporting complications in all clinical settings., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Significance: Breast cancer is the most common nondermatologic malignancy among women in the United States, among which endocrine receptor-positive breast cancer accounts for up to 80%. Endocrine receptor-positive breast cancers can be categorized molecularly into luminal A and B subtypes, of which the latter is an aggressive form that is less responsive to endocrine therapy with inferior prognosis., Recent Advances: Sirtuin, an aging-related gene involved in mitochondrial metabolism, is associated with life span, and more importantly, murine models lacking Sirt3 spontaneously develop tumors that resemble human luminal B breast cancer. Furthermore, these tumors exhibit aberrant manganese superoxide dismutase (MnSOD) acetylation at lysine 68 and lysine 122 and have abnormally high reactive oxygen species (ROS) levels, which have been observed in many types of breast cancer., Critical Issues: The mechanism of how luminal B breast cancer develops resistance to endocrine therapy remains unclear. MnSOD, a primary mitochondrial detoxification enzyme, functions by scavenging excessive ROS from the mitochondria and maintaining mitochondrial and cellular homeostasis. Sirt3, a mitochondrial fidelity protein, can regulate the activity of MnSOD through deacetylation. In this study, we discuss a possible mechanism of how loss of SIRT3-guided MnSOD acetylation results in endocrine therapy resistance of human luminal B breast cancer., Future Directions: Acetylation of MnSOD and other mitochondrial proteins, due to loss of SIRT3, may explain the connection between ROS and development of luminal B breast cancer and how luminal B breast cancer becomes resistant to endocrine therapy. Antioxid. Redox Signal. 25, 326-336.

Background: Hypertensive diseases of pregnancy are associated with severe maternal morbidity and remain common causes of maternal death. Recently, national guidelines have become available to aid in recognition and management of hypertension in pregnancy to reduce morbidity and mortality. The increased morbidity related to hypertensive disorders of pregnancy is presumed to be associated with the development of severe hypertension. However, there are few data on specific treatment or severe maternal morbidity in women with acute severe intrapartum hypertension as opposed to severe preeclampsia., Objective: The study aimed to characterize maternal morbidity associated with women with acute severe intrapartum hypertension, and to determine whether there was an association between various first-line antihypertensive agents and posttreatment blood pressure., Study Design: This retrospective cohort study of women delivering between July 2012 and August 2014 at 15 hospitals participating in the California Maternal Quality Care Collaborative compared women with severe intrapartum hypertension (systolic blood pressure >160 mm Hg or diastolic blood pressure >105 mm Hg) to women without severe hypertension. Hospital Patient Discharge Data and State of California Birth Certificate Data were used. Severe maternal morbidity using the Centers for Disease Control and Prevention criteria based on International Classification of Diseases-9 codes was compared between groups. The efficacy of different antihypertensive medications in meeting the 1-hour posttreatment goal was determined. Statistical methods included distribution appropriate univariate analyses and multivariate logistic regression., Results: There were 2252 women with acute severe intrapartum hypertension and 93,650 women without severe hypertension. Severe maternal morbidity was significantly more frequent in the women with severe hypertension (8.8%) compared to the control women (2.3%) (P < .0001). Severe maternal morbidity rates did not increase with increasing severity of blood pressures (P = .90 for systolic and .42 for diastolic). There was no difference in severe maternal morbidity between women treated (8.6%) and women not treated (9.5%) (P = .56). Antihypertensive treatment rates were significantly higher in hospitals with a level IV neonatal intensive care unit (85.8%) compared to a level III neonatal intensive care unit (80.2%) (P < .001), and in higher-volume hospitals (84.5%) compared to lower-volume hospitals (69.1%) (P < .001). Severe maternal morbidity rates among severely hypertensive women were significantly higher in hospitals with level III neonatal intensive care unit level compared to hospitals with a level IV neonatal intensive care unit (10.6% vs 5.7%, respectively; P < .001), and significantly higher in low-delivery volume hospitals compared to high-delivery volume hospitals (15.5% vs 7.6%, respectively; P < .001). Only 53% of women treated with oral labetalol as first-line medication met the posttreatment goal of nonsevere hypertension, significantly less than those treated with intravenous hydralazine, intravenous labetalol, or oral nifedipine (68%, 71%, and 82%, respectively) (P = .001). Severe intrapartum hypertension remained untreated in 17% of women., Conclusion: Women with acute severe intrapartum hypertension had a significantly higher risk of severe maternal morbidity compared to women without severe hypertension. Significantly lower antihypertensive treatment rates and higher severe maternal morbidity rates were seen in lower-delivery volume hospitals., (Copyright © 2016 Elsevier Inc. All rights reserved.)

DNA repair genes are frequently mutated in cancer, yet limited data exist regarding the overall genomic landscape and functional implications of these alterations in their entirety. We created comprehensive lists of DNA repair genes and indirect caretakers. Mutation, copy number variation (CNV), and expression frequencies of these genes were analyzed in COSMIC. Mutation co-occurrence, clinical outcomes, and mutation burden were analyzed in TCGA. We report the 20 genes most frequently with mutations (n > 19,689 tumor samples for each gene), CNVs (n > 1,556), or up- or down-regulated (n = 7,998). Mutual exclusivity was observed as no genes displayed both high CNV gain and loss or high up- and down-regulation, and CNV gain and loss positively correlated with up- and down-regulation, respectively. Co-occurrence of mutations differed between cancers, and mutations in many DNA repair genes were associated with higher total mutation burden. Mutation and CNV frequencies offer insights into which genes may play tumor suppressive or oncogenic roles, such as NEIL2 and RRM2B, respectively. Mutual exclusivities within CNV and expression frequencies, and correlations between CNV and expression, support the functionality of these genomic alterations. This study provides comprehensive lists of candidate genes as potential biomarkers for genomic instability, novel therapeutic targets, or predictors of immunotherapy efficacy., Competing Interests: None.

The rise in maternal morbidity and mortality has resulted in national and international attention at optimally organizing systems and teams for pregnancy care. Given that maternal morbidity and mortality can occur unpredictably in any obstetric setting, specialists in general obstetrics and gynecology along with other primary maternal care providers should be integrally involved in efforts to improve the safety of obstetric care delivery. Quality improvement initiatives remain vital to meeting this goal. The evidence-based utilization of triggers, bundles, protocols, and checklists can aid in timely diagnosis and treatment to prevent or limit the severity of morbidity as well as facilitate interdisciplinary, patient-centered care. The purpose of this document is to summarize the pertinent elements from this forum to assist primary maternal care providers in their utilization and implementation of these safety tools., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose of Review: The landscape of genetic diagnostic testing has changed dramatically with the introduction of next-generation clinical exome sequencing (CES), which provides an unbiased analysis of all protein-coding sequences in the roughly 21,000 genes in the human genome. Use of this testing, however, is currently limited in clinical neurologic practice by the lack of a framework for appropriate use and payer coverage., Recent Findings: CES can be cost-effective due to its high diagnostic yield in comparison to other genetic tests in current use and should be utilized as a routine diagnostic test in patients with heterogeneous neurologic phenotypes facing a broad genetic differential diagnosis. CES can eliminate the need for escalating sequences of conventional neurodiagnostic tests., Summary: This review discusses the role of clinical exome sequencing in neurologic disease, including its benefits to patients, limitations, appropriate use, and billing. We also provide a reference template policy for payer use when considering testing requests.

Background: Maternal mortality in the United States has increased unabated for the past 20 years. Maternal morbidity is also affecting an increasingly large number of women in the United States. A number of national and state organizations have recommend the use of maternal early warning tools as a method to combat this problem. There are limited data suggesting that the use of these types of clinical assessment tools can reduce maternal morbidity., Objective: We sought to determine if maternal morbidity could be reduced with the implementation of a clinical pathway-specific Maternal Early Warning Trigger (MEWT) tool., Study Design: The tool was developed internally and prospectively implemented as a pilot project in 6 of 29 hospitals within a large hospital system. The primary goal was early assessment and treatment of patients suspected of clinical deterioration. The tool addressed the 4 most common areas of maternal morbidity: sepsis, cardiopulmonary dysfunction, preeclampsia-hypertension, and hemorrhage. To be considered positive, triggers needed to be sustained for >20 minutes and were defined as severe (single abnormal value): maternal heart rate (HR) >130 beats/min (bpm), respiratory rate >30/min, mean arterial pressure <55 mm Hg, oxygen saturation <90%, or nurse concern; or nonsevere (required 2 abnormal values): temperature >38 or <36°C, blood pressure >160/110 or <85/45 mm Hg, HR >110 or <50 bpm, respiratory rate >24 or <10/min, oxygen saturation <93%, fetal HR >160 bpm, altered mental status, or disproportionate pain. Within each group, recommended management or assessment was also provided. Outcome measures were Centers for Disease Control and Prevention (CDC)-defined severe maternal morbidity, composite maternal morbidity, and intensive care unit (ICU) admissions. Two time intervals were used to analyze the effect of the MEWT tool: a 24-month baseline control period and a 13-month MEWT study period. To determine that the findings noted were not simply changes that would have occurred without the utilization of the early warning tool, we also compared a control population from nonpilot sites during the same baseline and 13-month time periods., Results: There were 36,832 deliveries at the pilot sites (24,221 pre- and 12,611 post-MEWT testing) and 146,359 at the nonpilot sites (95,718 pre- and 50,641 post-MEWT testing) during the 2 study time periods. Use of the MEWT tool resulted in significant reductions in CDC severe maternal morbidity (P < 0.01) and composite morbidity (P < 0.01). ICU admissions were unchanged. At nonpilot sites CDC severe maternal morbidity, composite morbidity, and ICU admissions were unchanged between baseline and the post-MEWT testing time period., Conclusion: The use of the MEWT tool in this study, designed to address 4 of the most common causes of maternal morbidity, as well as provide assessment and management recommendations, resulted in significant improvement in maternal morbidity. The variation in hospital delivery services at the pilot sites suggests that this maternal early warning tool would be suitable for use in the majority of maternity centers in the United States., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose: Aromatase inhibitors can exert unfavorable effects on lipid profiles; however, previous studies have reported inconsistent results. We describe the association of single-nucleotide polymorphisms (SNP) in candidate genes with lipid profiles in women treated with adjuvant aromatase inhibitors., Experimental Design: We conducted a prospective observational study to test the associations between SNPs in candidate genes in estrogen signaling and aromatase inhibitor metabolism pathways with fasting lipid profiles during the first 3 months of aromatase inhibitor therapy in postmenopausal women with early breast cancer randomized to adjuvant letrozole or exemestane. We performed genetic association analysis and multivariable linear regressions using dominant, recessive, and additive models., Results: A total of 303 women had complete genetic and lipid data and were evaluable for analysis. In letrozole-treated patients, SNPs in CYP19A1, including rs4646, rs10046, rs700518, rs749292, rs2289106, rs3759811, and rs4775936 were significantly associated with decreases in triglycerides by 20.2 mg/dL and 39.3 mg/dL (P < 0.00053), respectively, and with variable changes in high-density lipoprotein (HDL-C) from decreases by 4.2 mg/dL to increases by 9.8 mg/dL (P < 0.00053)., Conclusions: Variants in CYP19A1 are associated with decreases in triglycerides and variable changes in HDL-C in postmenopausal women on adjuvant aromatase inhibitors. Future studies are needed to validate these findings, and to identify breast cancer survivors who are at higher risk for cardiovascular disease with aromatase inhibitor therapy., (©2015 American Association for Cancer Research.)

Objective: To determine whether predefined maternal early warning triggers (MEWTs) can predict pregnancy morbidity., Methods: In a retrospective case-control study, obstetric patients admitted to the intensive care unit (ICU) between 2012 and 2013 at seven pilot US hospitals were compared with control patients who had a normal delivery outcome. Six MEWTs were assessed., Results: The case and control groups each contained 50 patients. Hemorrhage (15/50, 30%), sepsis (12/50, 24%), cardiac dysfunction (8/50, 16%), and pre-eclampsia (6/50, 12%) were the most common reasons for ICU admission. Significant associations were recorded between ICU admission and tachycardia (OR 5.0, 95% CI 2.1-11.7), mean arterial pressure less than 65 mm Hg (OR 4.5, 95% CI 1.9-10.8), temperature of at least 38°C (OR 44.1, 95% CI 13.0-839.1), and altered mental state (OR 44.1, 95% CI 13.1-839.0). Two or more triggers were persistent for 30 minutes or more in 36 (72%) ICU patients versus 2 (4%) controls (OR 61.7, 95% CI 13.2-288.0). Earlier medical intervention might have led to a lesser degree of maternal morbidity for 31 (62%) ICU patients with at least one MEWT., Conclusion: Persistent MEWTs were present in most obstetric ICU cases. Retrospectively, MEWTs in this cohort seemed to separate normal obstetric patients from those for whom ICU admission was indicated; their use might reduce maternal morbidity., (Copyright © 2015 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.)

Human epidermal growth factor receptor 2 (HER2)/neu-positive breast cancer has changed from being an aggressive disease with a poor prognosis to a disease that is highly treatable, with prolonged survival possible even in patients with metastatic disease. A better understanding of HER2 biology has led to the development of powerful targeted therapies, and four drugs are already approved by the US Food and Drug Administration for treatment in the metastatic setting (trastuzumab, pertuzumab, lapatinib, and trastuzumab emtansine). Optimizing how these drugs are delivered and in what sequence is an important part of modern management of HER2-positive breast cancer. However, while the prognosis has improved, metastatic disease is still not curable; newer, better drugs are needed. This review will summarize the current standard of care; key issues that arise when treating patients with HER2-positive disease; and developments in novel therapeutics, including small-molecule inhibitors, nanoparticles, immunotherapy, and agents targeting resistance pathways.

Telehealth programs for congestive heart failure have been shown to be clinically effective. This study assesses clinical and economic consequences of providing telehealth programs for CHF patients. A Markov model was developed and presented in the context of a home-based telehealth program on CHF. Incremental life expectancy, hospital admissions, and total healthcare costs were examined at periods ranging up to five years. One-way and two-way sensitivity analyses were also conducted on clinical performance parameters. The base case analysis yielded cost savings ranging from $2832 to $5499 and 0.03 to 0.04 life year gain per patient over a 1-year period. Applying telehealth solution to a low-risk cohort with no prior admission history would result in $2502 cost increase per person over the 1-year time frame with 0.01 life year gain. Sensitivity analyses demonstrated that the cost savings were most sensitive to patient risk, baseline cost of hospital admission, and the length-of-stay reduction ratio affected by the telehealth programs. In sum, telehealth programs can be cost saving for intermediate and high risk patients over a 1- to 5-year window. The results suggested the economic viability of telehealth programs for managing CHF patients and illustrated the importance of risk stratification in such programs.

Research in the fields of surgical, medical, and radiation oncology has changed the landscape of neoadjuvant therapy in breast cancer, yet many areas of controversy still exist. When considering whether a patient is a candidate for neoadjuvant therapy, ideally the initial assessment should be multidisciplinary in nature and should include clinical, radiographic, and pathologic evaluation. Optimization of systemic therapy is dependent upon identifying the patient's breast cancer subtype; the best approach may include targeted agents, as well as the determination of eligibility for enrollment into clinical trials that incorporate novel therapeutics or predictive biomarkers. This article will review a variety of surgical and radiation-based strategies for management of early-stage breast cancer, including surgical options involving the breast and axilla, and the role of radiation based on response to systemic therapy. Key areas of controversy include the ideal systemic treatment for different breast cancer subtypes, the surgical and radiotherapeutic approaches for management of the axilla, and the role of pathologic response rates as a surrogate for survival in drug development.

In medicine, cognitive errors form the basis of bias in clinical practice. Several types of bias are common and pervasive, and may lead to inaccurate diagnosis or treatment. Forensic and clinical neurology, even when aided by current technologies, are still dependent on cognitive interpretations, and therefore prone to bias. This article discusses 4 common biases that can lead the clinician astray. They are confirmation bias (selective gathering of and neglect of contradictory evidence); base rate bias (ignoring or misusing prevailing base rate data); hindsight bias (oversimplification of past causation); and good old days bias (the tendency for patients to misremember and exaggerate their preinjury functioning). We briefly describe strategies adopted from the field of psychology that could minimize bias. While debiasing is not easy, reducing such errors requires awareness and acknowledgment of our susceptibility to these cognitive distortions.

Purpose: Glutamine addiction in c-MYC-overexpressing breast cancer is targeted by the aminotransferase inhibitor, aminooxyacetate (AOA). However, the mechanism of ensuing cell death remains unresolved., Experimental Design: A correlation between glutamine dependence for growth and c-MYC expression was studied in breast cancer cell lines. The cytotoxic effects of AOA, its correlation with high c-MYC expression, and effects on enzymes in the glutaminolytic pathway were investigated. AOA-induced cell death was assessed by measuring changes in metabolite levels by magnetic resonance spectroscopy (MRS), the effects of amino acid depletion on nucleotide synthesis by cell-cycle and bromodeoxyuridine (BrdUrd) uptake analysis, and activation of the endoplasmic reticulum (ER) stress-mediated pathway. Antitumor effects of AOA with or without common chemotherapies were determined in breast cancer xenografts in immunodeficient mice and in a transgenic MMTV-rTtA-TetO-myc mouse mammary tumor model., Results: We established a direct correlation between c-MYC overexpression, suppression of glutaminolysis, and AOA sensitivity in most breast cancer cells. MRS, cell-cycle analysis, and BrdUrd uptake measurements indicated depletion of aspartic acid and alanine leading to cell-cycle arrest at S-phase by AOA. Activation of components of the ER stress-mediated pathway, initiated through GRP78, led to apoptotic cell death. AOA inhibited growth of SUM159, SUM149, and MCF-7 xenografts and c-myc-overexpressing transgenic mouse mammary tumors. In MDA-MB-231, AOA was effective only in combination with chemotherapy., Conclusions: AOA mediates its cytotoxic effects largely through the stress response pathway. The preclinical data of AOA's effectiveness provide a strong rationale for further clinical development, particularly for c-MYC-overexpressing breast cancers., (©2015 American Association for Cancer Research.)

Advances in understanding tumor biology, particularly signaling pathways, have led to the development and approval of many novel agents and have changed the landscape of therapy for patients with metastatic breast cancer. This review highlights some of the recent successes and failures in breast cancer drug development, including strategies to overcome endocrine and human epidermal growth factor 2-neu (HER2) resistance, targeting triple-negative breast cancers (which do not express the HER2, estrogen, and progesterone receptors) through novel receptors, harnessing the immune system, and new ways of targeting angiogenesis. For patients with metastatic breast cancer, expanding therapeutic options through clinical trial participation is a crucial part of modern oncology practice. As we continue to learn how to use targeted therapies in the context of genomic medicine, analysis of the tumor in real-time may become increasingly important, giving researchers the information needed to start combining therapies in a biologically informed manner.

The optimal adjuvant endocrine therapy in premenopausal women with early-stage breast cancer is yet to be elucidated. Studies have demonstrated that women who experience cessation of ovarian function after chemotherapy (chemotherapy-induced amenorrhea) may experience improved survival. These findings, however, have not been replicated when pharmacologic or surgical interventions have been used to stop ovarian function (eg, gonadotropin-releasing hormone agonists, oophorectomy, or ovarian irradiation) in combination with an endocrine agent such as tamoxifen or an aromatase inhibitor. Recent large phase III clinical trials, including the Austrian Breast and Colorectal Cancer Study Group trial (ABCSG-12), Suppression of Ovarian Function Trial (SOFT), and Tamoxifen and Exemestane Trial (TEXT), did not demonstrate an improvement in disease-free survival with ovarian suppression in the overall population. However, subgroup analyses suggest that women at high risk for recurrence, including very young women or those who have received chemotherapy, may benefit from the addition of ovarian suppression. Still, toxicity and adverse effects on patient-reported outcomes were more frequent in patients who received ovarian suppression; these included more menopausal and sexual dysfunction symptoms, diabetes, hypertension, and osteoporosis. This review will summarize the experience with ovarian suppression in the adjuvant setting for the treatment of premenopausal early-stage breast cancer and offer recommendations for clinical management.

Background: Obese women with estrogen receptor (ER)-positive breast cancer may experience worse disease-free and overall survival. We hypothesize that this observation is due to intrinsically aggressive disease and that obesity will be associated with higher histologic grade and Ki67., Methods: A sequential cohort of women with breast cancer diagnosed over 2 years was assembled from institutional tumor registries. Patient and tumor characteristics were abstracted from medical records; those with non-invasive tumors, or lacking body mass index (BMI), Ki67 or histologic grade data, were excluded. Univariate and multivariate analysis was performed to investigate the relationship between markers of aggressive disease (grade and Ki67) and multiple variables associated with obesity. A subgroup analysis was performed to investigate further whether ER and menopausal status influenced associations between BMI and aggressive phenotypes., Results: Of the 1007 patients initially identified, 668 (68 %) met the eligibility criteria. In univariate analysis, histologic grade and Ki67 were strongly associated with increased BMI, younger age, and African-American race, but less so with diabetes, hypertension, and hyperlipidemia. Multivariate analysis confirmed that higher histologic grade was associated with increased BMI (p = 0.02), and that increased Ki67 was associated with younger age (p = 0.0003) and African-American race (p = 0.002). Additional analysis found that the association between increased BMI and higher-grade tumors was particularly significant in premenopausal women with ER-positive disease., Conclusion: This study concludes that increased BMI is associated with aggressive-phenotype breast cancer and may be particularly relevant to ER-positive breast cancer developing in premenopausal African-American women.

The purpose of this study was to assess the effectiveness of instituting a comprehensive protocol for the treatment of maternal hemorrhage within a large health care system. A comprehensive maternal hemorrhage protocol was initiated within a health care system with 29 different delivery units and with >60,000 annual births. Compliance with key elements of the protocol was assessed monthly by a dedicated perinatal safety nurse at each site and validated during site visits by system perinatal nurse specialist. Outcome variables were the total number of units of blood transfused and the number of puerperal hysterectomies. Three time points were assessed: (1) 2 months before implementation of the protocol, (2) a 2-month period that was measured at 5 months after implementation of the protocol, and (3) a 2-month period at 10 months after implementation. There were 32,059 deliveries during the 3 study periods. Relative to baseline, there was a significant reduction in blood product use per 1000 births (-25.9%; P < .01) and a nonsignificant reduction (-14.8%; P = .2) in the number of patients who required puerperal hysterectomy. Within a large health care system, the application of a standardized method to address maternal hemorrhage significantly reduced maternal morbidity, based on the need for maternal transfusion and peripartum hysterectomy. These data support implementation of standardized methods for postpartum care and treatment of maternal hemorrhage and support that this approach will reduce maternal morbidity., (Copyright © 2015 Elsevier Inc. All rights reserved.)

This article identifies payment policy perspectives of the American Academy of Neurology's guideline on complementary and alternative medicine (CAM) in multiple sclerosis (MS). The guideline is a reliable repository of information for advocating or not recommending certain CAM treatments in MS. It eases the burden of searching for information on each separate CAM treatment. It frequently emphasizes the need for patient counseling. To provide such generally undervalued, but needed, cognitive services, neurologists could use advanced practice providers and patient-friendly visual aids during or between visits. They should also rely on evaluation and management codes that recognize time spent predominantly on counseling or coordination of care. The guideline's categorization of probable effectiveness of certain therapies will not influence coverage decisions because payers do not generally cover CAM therapies.

Neurologists often evaluate patients whose symptoms cannot be readily explained even after thorough clinical and diagnostic testing. Such medically unexplained symptoms are common, occurring at a rate of 10%-30% among several specialties. These patients are frequently diagnosed as having somatoform, functional, factitious, or conversion disorders. Features of these disorders may include symptom exaggeration and inadequate effort. Symptom validity tests (SVTs) used by psychologists when assessing the validity of symptoms and impairments are structured, validated, and objectively scored. They could detect poor effort, underperformance, and exaggeration. In settings with appropriate prior probabilities, detection rates for symptom exaggeration have diagnostic utility. SVTs may help in moderating expensive diagnostic testing and redirecting treatment plans. This article familiarizes practicing neurologists with their merits, shortcomings, utility, and applicability in practice.

While breast cancer has not historically been considered an immunogenic cancer, recent data demonstrating the powerful anti-cancer effects of immune checkpoints in many cancers, including breast cancer, has reinvigorated the field. Although the responses are generally low with single agents, some patients experience disease control for a long period of time. Selecting appropriate patients for immunotherapy is an important area of research, and many biomarkers are under investigation. Although immunotherapies are still in their early stages of development, learning how to use them in combination with other agents that can alter antigen presentation or other immune elements will be crucial. This review aims to summarize efforts in immune-related biomarker and drug development, particularly as it pertains to breast cancer.

Despite advances in knowledge about human lactation, clinicians face many problems when advising mothers who are experiencing breastfeeding difficulties that do not respond to normal management strategies. Primary insufficient milk production is now being acknowledged, but incidence rates have not been well studied. Many women have known histories of infertility, polycystic ovary syndrome, obesity, hypertension, insulin resistance, thyroid dysfunction, hyperandrogenism or other hormonal imbalances, while others have no obvious risk factors. Some present with obviously abnormal breasts that are pubescent, tuberous/tubular or asymmetric in shape, raising the question of insufficient mammary gland tissue. Other women have breasts that appear within normal limits yet do not lactate normally. Endocrine disruptors may underlie some of these cases but their impact on human milk production has not been well explored. Similarly, any problem with prolactin such as a deficiency in serum prolactin or receptor number, receptor resistance, or poor bioavailability or bioactivity could underlie some cases of insufficient lactation, yet these possibilities are rarely investigated. A weak or suppressed milk ejection reflex, often assumed to be psychosomatic, could be related to thyroid dysfunction or caused by downstream post-receptor pathway problems. In the absence of sufficient data regarding these situations, desperate mothers may turn to non-evidence-based remedies, sometimes at considerable cost and unknown risk. Research targeted to these clinical dilemmas is critical in order to develop evidence-based strategies and increase breastfeeding duration and success rates.

Objectives: Optimal treatment strategies in frail and/or elderly patients with metastatic colorectal cancer have not been well defined. Using data from a prospective, phase II study of elderly patients with metastatic colorectal cancer treated with bevacizumab and capecitabine, we explored the differences in functional measure and quality of life (QoL) between patients with ECOG performance status (PS) 1 and 2., Materials and Methods: Geriatric functional measures included patient reported limitations in ADLs and IADLs, ECOG PS, 3-item recall, hearing acuity, and the "Get up and Go" test. QoL was assessed by means of the FACT-C questionnaire and the EQ-5D questionnaire. The prognostic impact of baseline characteristics on survival was studied using univariate Cox regression analysis., Results: The majority (62%) of the 45 patients had an ECOG PS of 2. The ECOG PS 2 group had more limitations in IADLs, lower baseline QoL, and a lower patient-rated health score. For all participants, QoL significantly improved from baseline to the start of cycle 2 (FACT-C: 99.9 vs. 105.4, p=0.01) and did not deteriorate when baseline scores were compared to when participants went off study (FACT-C: 99.9 vs. 98.6, p=0.59). In the Cox-regression analysis, a positive "Get up and Go" test was prognostic for improved survival (HR=0.31, p=0.01)., Conclusion: There is significant heterogeneity in functional measures and quality of life among elderly patients with metastatic colorectal cancer with ECOG PS 1 and 2. The "Get up and Go" test may be a useful prognostic indicator for survival in this population., (Copyright © 2014 Elsevier Inc. All rights reserved.)

In this open-label, intra-patient phase I/II trial, bortezomib was replaced with carfilzomib (escalated from 20 to 45 mg/m(2) on days 1, 2, 8, 9, 15 and 16 of a 28-day cycle) for multiple myeloma (MM) patients who progressed while on or within 12 weeks of receiving a bortezomib-containing combination regimen. Study objectives included determination of the maximum tolerated dose (MTD), overall response rate (ORR), clinical benefit rate (CBR), time to progression, time to response, duration of response, progression-free survival and overall survival (OS). Of 38 registered patients, 37 were treated and evaluable for efficacy and safety. Thirty-one carfilzomib-based regimens using 14 different drug combinations were tested. One regimen (carfilzomib (45 mg/m(2)), ascorbic acid (1000 mg) and cyclophosphamide (2.2 mg/kg)) reached MTD. ORR and CBR were 43.2 and 62.2%, respectively. Median progression-free survival, time to progression and OS were 8.3, 9.9 and 15.8 months, respectively. Hematologic adverse events (AEs; ⩾grade 3) included lymphopenia (35.1%), thrombocytopenia (24.3%), anemia (10.8%) and neutropenia (10.8%). Nonhematologic AEs (⩾grade 3) included fever (5.4%) and hypokalemia (5.4%). These results demonstrate that replacing bortezomib with carfilzomib is safe and can be effective for MM patients failing bortezomib-containing combination regimens. This trial was registered at http://www.clinicaltrials.gov (#NCT01365559).

Sensorimotor impairment of the tongue has the potential to affect speech and swallowing. The purpose of this study was to critically examine the effects of nerve preservation and reinnervation after reconstruction of the base of tongue on patient-perceived outcomes of quality of life (QoL) related to speech and swallowing through completion of the EORTC QLQ-H&N35 standardised questionnaire. Thirty participants with a diagnosis of base of tongue cancer underwent primary resection and reconstruction with a radial forearm free flap, which may or may not have included nerve repair to the lingual nerve, hypoglossal nerve or both. Eight QoL domains sensitive to changes in motor and sensory nerve function were included in the analysis. Transected lingual and hypoglossal nerves were associated with difficulty in swallowing, social eating, dry mouth and social contact. There were fewer problems reported when these nerves were either repaired or left intact. There were no significant differences between patient nerve status and QoL outcomes for speech, sticky saliva and use of feeding tubes. This study was the first to examine the impact of sensory or motor nerve transection and reconstruction on health-related QoL outcomes., (© 2013 John Wiley & Sons Ltd.)

The basis of the Fracture Liaison Service is to identify and treat those patients at highest risk of suffering a second fracture. The execution of this type of program poses unique challenges in open healthcare settings that lack a central coordination of patient care. This invited editorial reviews the establishment and operation of The Marian Osteoporosis Center at Marian Medical Center in Santa Maria, California.

This article is presented as a companion to the recent American Academy of Neurology (AAN) guideline update on use of vagus nerve stimulation (VNS) for treating epilepsy. The guideline update reaffirms the efficacy of VNS for intractable epilepsy. Whereas it upholds the value of VNS for its originally approved indications, the guideline reminds us of existing evidence gaps and unmet research needs. This companion identifies ambiguities in the definition of intractable epilepsies and discusses the use of VNS in children under age 12 years and in persons with intellectual disabilities (mental retardation). Many payers require prior authorization and fulfillment of criteria for coverage of VNS. This article provides guidance and background information to reduce obstacles for coverage, especially where uncertainties exist and levels of evidence are lower.

Objectives: This study aims to determine the efficacy and tolerability of capecitabine (CAP) plus bevacizumab (BEV) as treatment for frontline metastatic colorectal cancer (mCRC) in frail and/or elderly patients., Materials and Methods: This was an open label, multi-site, single arm, phase II study in frontline mCRC. In this study, patients (pts) who were frail (ECOG 2) or older patients with ECOG 1 performance status (PS) received CAP (1000 mg/m(2) bid, 14 days of every 21 days) plus BEV (7.5mg/kg iv once every 21 days). The primary objective was progression free survival (PFS). Secondary objectives were overall response rate (ORR) and toxicity., Results: In terms of patients: 50 were enrolled; 5 withdrew consent prior to treatment; 45 were treated, and 41 were evaluable. The mean age was 75.9 (range 54-93) and 62% had an ECOG 2 PS. The median PFS was 6.87 months (95% CI, 5.1-11.5 months) and median overall survival was 12.7 months (95% CI, 6.9-12.7 months). The most common grades 3-4 toxicities were: diarrhea (17.8%), fatigue (13.3%), hand-foot syndrome (13.3%), dehydration (8.9%), hypertension (6.7%) and vomiting (6.7%)., Conclusions: The results of this trial support the use of CAP plus BEV as first-line treatment for frail/elderly patients with metastatic CRC. The ORR (40%) is comparable to pooled data in elderly on fluorouracil (5-FU)+BEV. The median PFS (7.2 months) in this study is slightly lower than that seen with 5-FU+BEV but this study had a high percentage of ECOG PS 2 patients. Side effects were manageable with no new safety signals., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Given the high incidence, morbidity and mortality associated with breast cancer, developing effective chemopreventive strategies is crucial. Clinicians must carefully identify both populations at risk who would benefit from chemoprevention, and interventions that are effective and safe. Tamoxifen and raloxifene, the two agents approved for breast cancer chemoprevention, and third generation aromatase inhibitors reduce only the incidence of hormone receptor-positive tumors. 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMG-CoAR) inhibitors, or statins, are well tolerated and approved for prevention of cardiovascular disease. In preclinical breast cancer models statins carry potent anti-neoplastic activity. Results from epidemiological and clinical studies, however, are conflicting and have not identified a strong relationship between statin use and reduced breast cancer incidence. These studies have several limitations and were not designed to detect modest effects in high-risk populations. Additional focused epidemiological and translational studies in high-risk populations are needed to justify and guide definitive large prospective trials.

Health insurers look for reliable, published evidence such as evidence-based guidelines put forth by medical specialty societies to craft their coverage policies. These guidelines generate both beneficial and controversial consequences on policies. Coverage policies aim to address the most typical clinical presentations. The American Academy of Neurology guideline for IV immunoglobulin strengthens the case for coverage when it is used to treat Guillain-Barré syndrome and chronic inflammatory demyelinating polyradiculoneuropathy. The guideline is less likely to strengthen coverage for several other diagnoses with lower levels of evidence. The responsibility to clarify specific situations when patient need falls outside of what is considered to be routine evaluation or treatment rests heavily on the physician. Advice on appealing an unfavorable coverage decision is also provided to the reader.

Scientific, evidence-based clinical practice guidelines (CPGs) differ from coverage/policy statements. The latter incorporate values and priorities and translate evidence into human benefit. They assist provider and payer decisions, and abide by extant laws and regulations. Payers have set internal processes for balancing and integrating the intent of CPGs into their coverage/payment policies. Recently, however, their efforts to reach out to respected medical specialty societies for input are increasing. In response, the American Academy of Neurology (AAN) has taken the following steps: 1) it is reacting to, and providing input to, payer requests for policy reviews; 2) it is taking a proactive approach by developing AAN guideline companion documents that describe potential provider impacts and policy implications; and 3) it is commencing an initiative to write its own template policies. This new involvement has met with initial positive outcomes. The AAN will continue to expand efforts to fulfill a growing need in this area.