Economic and social values in the brain: evidence from lesions to the human ventromedial prefrontal cortex.

Making good economic and social decisions is essential for individual and social welfare. Decades of research have provided compelling evidence that damage to the ventromedial prefrontal cortex (vmPFC) is associated with dramatic personality changes and impairments in economic and social decision-making. However, whether the vmPFC subserves a unified mechanism in the social and non-social domains remains unclear. When choosing between economic options, the vmPFC is thought to guide decision by encoding value signals that reflect the motivational relevance of the options on a common scale. A recent framework, the "extended common neural currency" hypothesis, suggests that the vmPFC may also assign values to social factors and principles, thereby guiding social decision-making. Although neural value signals have been observed in the vmPFC in both social and non-social studies, it is yet to be determined whether they have a causal influence on behavior or merely correlate with decision-making. In this review, we assess whether lesion studies of patients with vmPFC damage offer evidence for such a causal role of the vmPFC in shaping economic and social behavior.

Assessment of Open Probability of the Mitochondrial Permeability Transition Pore in the Setting of Coenzyme Q Excess.

The mitochondrial permeability transition pore (mPTP) is a voltage-gated, nonselective, inner mitochondrial membrane (IMM) mega-channel important in health and disease. The mPTP mediates leakage of protons across the IMM during low-conductance opening and is specifically inhibited by cyclosporine A (CsA). Coenzyme Q (CoQ) is a regulator of the mPTP, and tissue-specific differences have been found in CoQ content and open probability of the mPTP in forebrain and heart mitochondria in a newborn mouse model of fragile X syndrome (FXS, Fmr1 knockout). We developed a technique to determine the voltage threshold for mPTP opening in this mutant strain, exploiting the role of the mPTP as a proton leak channel. To do so, oxygen consumption and membrane potential (ΔΨ) were simultaneously measured in isolated mitochondria using polarography and a tetraphenylphosphonium (TPP+) ion-selective electrode during leak respiration. The threshold for mPTP opening was determined by the onset of CsA-mediated inhibition of proton leak at specific membrane potentials. Using this approach, differences in voltage gating of the mPTP were precisely defined in the context of CoQ excess. This novel technique will permit future investigation for enhancing the understanding of physiological and pathological regulation of low-conductance opening of the mPTP.

ECOCAPTURE@HOME: Protocol for the Remote Assessment of Apathy and Its Everyday-Life Consequences.

Apathy, a common neuropsychiatric symptom associated with dementia, has a strong impact on patients' and caregivers' quality of life. However, it is still poorly understood and hard to define. The main objective of the ECOCAPTURE programme is to define a behavioural signature of apathy using an ecological approach. Within this program, ECOCAPTURE@HOME is an observational study which aims to validate a method based on new technologies for the remote monitoring of apathy in real life. For this study, we plan to recruit 60 couples: 20 patient-caregiver dyads in which patients suffer from behavioral variant Fronto-Temporal Dementia, 20 patient-caregiver dyads in which patients suffer from Alzheimer Disease and 20 healthy control couples. These dyads will be followed for 28 consecutive days via multi-sensor bracelets collecting passive data (acceleration, electrodermal activity, blood volume pulse). Active data will also be collected by questionnaires on a smartphone application. Using a pool of metrics extracted from these passive and active data, we will validate a measurement model for three behavioural markers of apathy (i.e., daytime activity, quality of sleep, and emotional arousal). The final purpose is to facilitate the follow-up and precise diagnosis of apathy, towards a personalised treatment of this condition within everyday life.

Report on the Sixth Pediatric Anesthesia Neurodevelopmental Assessment (PANDA) Symposium, "Anesthesia and Neurodevelopment in Children".

On April 14 and 15, 2018, the Sixth Biennial Pediatric Anesthesia Neurodevelopmental Assessment (PANDA) Symposium convened at Columbia University Medical Center and New York Presbyterian/Morgan Stanley Children's Hospital of New York. Since its inception over 10 years ago, the PANDA Symposium has served as a key forum for clinicians, researchers, and other major stakeholders to gather and review the current state of preclinical and clinical research related to anesthetic neurotoxicity in the developing brain. It has also served as an important venue for participants to gain insight and leverage support from various public and private regulatory bodies. Goals of this year's meeting included assessments of how current knowledge has evolved, endeavors to develop common outcome measures, and formulations of future directions for research and policy. The Symposium program highlighted a diverse body of cutting-edge work, from results of preclinical and clinical studies to updates in clinical practice and policymaking.

Referral processes and wait times in primary care.

OBJECTIVE: To evaluate the response times to requests for consultations from FPs and the wait times for patient appointments. DESIGN: Mailed invitation to participate in a survey about non-FP specialist consultation requests from April 28 to May 9, 2014. SETTING: Hamilton, Ont. PARTICIPANTS: All active physicians with community practices from the Department of Family Medicine at St Joseph's Healthcare Hamilton and Hamilton Health Sciences. MAIN OUTCOME MEASURES: All non-FP specialist consultation requests for a 2-week period. RESULTS: Thirty-four practices (9.6% response rate) collected data on 816 consultation requests. Requests for referrals were most commonly made to the following 5 specialties: dermatology, surgery, gastroenterology, orthopedics, and obstetrics and gynecology. Overall, 36.4% of the requests for consultation received no response from the non-FP specialist's office by the end of the follow-up period. The mean wait time for a patient appointment was 60.1 days (range 23.3 to 168.5 days). Five specialties had particularly lengthy wait times of 105.9 to 168.5 days. CONCLUSION: Allowing 5 to 7 weeks for a response from a non-FP specialist, there was still a 36.4% nonresponse rate (similar to a pilot survey administered in 2010). Patient and physician frustration is certainly heightened and more office time and energy is expended when no acknowledgment of a referral is received within 7 weeks. This gives our community wait times much longer than those reported by any of the national bodies.

PDA Single-Use Systems Cross-Organizational Workshop-Meeting Summary, May 14, 2014-PDA Global Headquarters, Bethesda, MD.

UNLABELLED: The application of single-use systems, or disposables, has increased dramatically in the past 10 years. Although some elements of the pharmaceutical and biotech manufacturing process were single-use and therefore disposable and not reused, the majority of the process equipment and fluid path was cleaned and reused by end users. Today, much more of the manufacturing process is composed of single-use systems, and there are some biotech plants that use single-use systems exclusively. Because of this increasing reliance on suppliers, there is an urgent need for more formal standards specifically for single-use system technology. The objective of this PDA-sponsored workshop held on May 14, 2014 was twofold: (1) to promote a harmonized approach to supporting single-use system activities within the industry and in so doing to minimize duplication of efforts, and (2) to communicate ongoing single-use system initiatives among the group. Representatives of ASME, ASTM, BPOG, BPSA, ELSIE, PDA, PQRI, and USP, as well as representatives of CBER and CDER of FDA, attended. LAY ABSTRACT: Today, the majority of pharmaceutical and biotech drug manufacturing equipment is cleaned and reused. However, in the past 10 years, the use of disposable manufacturing systems has increased dramatically; there are even some biotech-derived drugs that are manufactured entirely using single-use technology. This movement toward disposables has placed increased reliance on disposable equipment suppliers, each of which manufactures its products independently to meet customer needs. This fact has led to non-uniformity in design for connectors and similar sub-processes, and has made the need for more formal industry standards. The objective of this PDA-sponsored workshop held on May 14, 2014 was twofold: (1) to promote a harmonized approach to supporting single-use system projects within the industry and in so doing to minimize duplication of efforts, and (2) to communicate ongoing single-use system initiatives among the group. Representatives of industry associations and standard-setting organizations, as well as representatives of the U.S. Food and Drug Administration, attended.

Carbon monoxide pollution and neurodevelopment: A public health concern.

Although an association between air pollution and adverse systemic health effects has been known for years, the effect of pollutants on neurodevelopment has been underappreciated. Recent evidence suggests a possible link between air pollution and neurocognitive impairment and behavioral disorders in children, however, the exact nature of this relationship remains poorly understood. Infants and children are uniquely vulnerable due to the potential for exposure in both the fetal and postnatal environments during critical periods in development. Carbon monoxide (CO), a common component of indoor and outdoor air pollution, can cross the placenta to gain access to the fetal circulation and the developing brain. Thus, CO is of particular interest as a known neurotoxin and a potential public health threat. Here we review overt CO toxicity and the policies regulating CO exposure, detail the evidence suggesting a potential link between CO-associated ambient air pollution, tobacco smoke, and learning and behavioral abnormalities in children, describe the effects of subclinical CO exposure on the brain during development, and provide mechanistic insight into a potential connection between CO exposure and neurodevelopmental outcome. CO can disrupt a number of critical processes in the developing brain, providing a better understanding of how this specific neurotoxin may impair neurodevelopment. However, further investigation is needed to better define the effects of perinatal CO exposure on the immature brain. Current policies regarding CO standards were established based on evidence of cardiovascular risk in adults with pre-existing comorbidities. Thus, recent and emerging data highlighted in this review regarding CO exposure in the fetus and developing child may be important to consider when the standards and guidelines are evaluated and revised in the future.

Progressive burden of myelofibrosis in untreated patients: assessment of patient-reported outcomes in patients randomized to placebo in the COMFORT-I study.

Patient-reported outcomes (PROs) and spleen size in patients not receiving therapy (N=154) in COMFORT-I, a randomized, double-blind study of the JAK1/JAK2 inhibitor ruxolitinib in patients with intermediate-2 or high-risk myelofibrosis were evaluated. Baseline PROs indicated considerable disease burden. European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 scores, modified Myelofibrosis Symptom Assessment Form v2.0 Total Symptom Score, and Patient Reported Outcome Measurement Information System Fatigue scores worsened from baseline through week 24. At weeks 4 and 24, 18.3 and 40.2% of patients evaluated their condition as having worsened from baseline on the Patient Global Impression of Change questionnaire. Spleen volume and palpable length increased in most patients. These results demonstrate the progressive and debilitating effects of myelofibrosis. The consequences of delayed intervention should be assessed in the management of patients with myelofibrosis and treatment should be considered as clinically indicated for symptomatic relief or splenomegaly control.

The SEA (Social cognition and Emotional Assessment): a clinical neuropsychological tool for early diagnosis of frontal variant of frontotemporal lobar degeneration.

OBJECTIVE: The frontal variant of frontotemporal degeneration (fvFTD) is characterized by a predominant behavioral syndrome, which is mostly attributable to an orbital-medial prefrontal dysfunction. The orbital and ventral medial prefrontal functions in humans are difficult to assess in clinical practice. Here, we propose a new tool, the SEA (Social cognition and Emotional Assessment), for use in evaluating the functions of the orbital and ventral-medial portions of the prefrontal cortex. METHOD: The SEA is composed of five subtests, each assessing a specific orbitofrontal-related function: a test of identification of facial emotions, a reversal/extinction task, a behavioral control task, a theory of mind test, and an apathy scale. The maximum score is 55. Three groups have been tested: 22 fvFTD patients, 22 patients with Alzheimer's disease (AD) or amnesic mild cognitive impairment (aMCI), and 30 healthy control subjects, all matched for age and educational level. RESULTS: FvFTD patients showed significantly lower performances in all subtests of the SEA. A cut-off score of 39.4/55 was proposed to separate normal controls from fvFTD patients, with a maximum sensitivity and specificity of 100%. A very high specificity (88.5%) was obtained using the same cut-off with AD/aMCI patients and normal controls versus fvFTD patients. FvFTD patients' performance in the SEA did not correlate with any other neuropsychological scores, particularly the classical cognitive executive tests. CONCLUSIONS: The SEA is a new and useful tool for diagnosing fvFTD and, more generally, all of the diseases affecting the orbital and medial prefrontal functions.

Evaluating the serial use of the Myelofibrosis Symptom Assessment Form for measuring symptomatic improvement: performance in 87 myelofibrosis patients on a JAK1 and JAK2 inhibitor (INCB018424) clinical trial.

BACKGROUND: Symptomatic burden from constitutional symptoms, anemia, and splenomegaly-related symptoms are common and morbidity inducing in patients with myelofibrosis (MF). The authors previously developed a MF-specific instrument for capturing the burden of MF-associated disease-related symptoms, the Myelofibrosis Symptom Assessment Form. METHODS: The authors evaluated the usefulness of serial administration of the Myelofibrosis Symptom Assessment Form as an instrument for the assessment of symptomatic burden and improvement in conjunction with the therapeutic clinical trial of the open label phase 2 trial of the JAK1 and JAK2 inhibitor INCB018424 in patients with MF. RESULTS: The analysis cohort of 87 patients treated in this trial demonstrated that the instrument was comprehensive and sensitive to symptoms present at trial enrollment. In addition, baseline Myelofibrosis Symptom Assessment Form symptom scores correlated well with objective parameters such as splenomegaly and impaired performance status assessed by the 6-minute walk test. Serial administration while on therapy with INCB018424 demonstrated the instrument to be sensitive to symptomatic change, and that improvements in symptoms correlated well with objective improvements in both weight loss and performance status (6-minute walk test). CONCLUSIONS: The use of the Myelofibrosis Symptom Assessment Form in this phase 2 trial helped characterize the symptomatic improvements observed with use of INCB018424 in MF patients. In an era of many targeted therapies undergoing testing for MF with potential symptomatic benefit, the Myelofibrosis Symptom Assessment Form may provide a useful tool for objective symptomatic assessment and potentially allow some nonrandomized comparison between therapeutic agents.

Toward a 21st-century health care system: recommendations for health care reform.

The coverage, cost, and quality problems of the U.S. health care system are evident. Sustainable health care reform must go beyond financing expanded access to care to substantially changing the organization and delivery of care. The FRESH-Thinking Project (www.fresh-thinking.org) held a series of workshops during which physicians, health policy experts, health insurance executives, business leaders, hospital administrators, economists, and others who represent diverse perspectives came together. This group agreed that the following 8 recommendations are fundamental to successful reform: 1. Replace the current fee-for-service payment system with a payment system that encourages and rewards innovation in the efficient delivery of quality care. The new payment system should invest in the development of outcome measures to guide payment. 2. Establish a securely funded, independent agency to sponsor and evaluate research on the comparative effectiveness of drugs, devices, and other medical interventions. 3. Simplify and rationalize federal and state laws and regulations to facilitate organizational innovation, support care coordination, and streamline financial and administrative functions. 4. Develop a health information technology infrastructure with national standards of interoperability to promote data exchange. 5. Create a national health database with the participation of all payers, delivery systems, and others who own health care data. Agree on methods to make de-identified information from this database on clinical interventions, patient outcomes, and costs available to researchers. 6. Identify revenue sources, including a cap on the tax exclusion of employer-based health insurance, to subsidize health care coverage with the goal of insuring all Americans. 7. Create state or regional insurance exchanges to pool risk, so that Americans without access to employer-based or other group insurance could obtain a standard benefits package through these exchanges. Employers should also be allowed to participate in these exchanges for their employees' coverage. 8. Create a health coverage board with broad stakeholder representation to determine and periodically update the affordable standard benefit package available through state or regional insurance exchanges.

Personalized treatment with atypical antipsychotic medications.

The considerable pharmacologic differences among atypical antipsychotic agents and the specific clinical circumstances of individual patients with psychiatric illness require the availability of a full range of agents in this class. Restrictions in the availability of atypical agents may prove to be counterproductive, both clinically and economically. Elderly individuals and those from minority groups may be particularly disadvantaged by restrictions placed on these agents. Additional clinical studies in large populations with different forms of schizophrenia and varied clinical histories are required to determine the appropriateness of specific atypical agents in patient subgroups. Advances in knowledge of the molecular genetics of schizophrenia and the receptor properties of individual drugs will help the clinician determine which drug and dosage are best for each individual patient. This will eventually replace the "hit or miss" process that characterizes current practice. Because of variations in response to atypical agents, the clinical vulnerability of patients with psychiatric illness, the difficulties they have in adapting to changes and adhering to medication regimens, and our poor understanding of the molecular basis of schizophrenia and its treatment, prescription insurance plans should provide access to a broad range of atypical agents.

Urinary incontinence: economic burden and new choices in pharmaceutical treatment.

In the year 2000, an estimated 17 million community-dwelling adults in the United States had daily urinary incontinence (UI), and an additional 33 million suffered from the overlapping condition, overactive bladder. Estimates of the total annual cost of these conditions range up to 32 billion US dollar; the largest components are management costs and the expenses associated with nursing home admissions attributable to UI. In most cases, patients with UI can be treated with pharmaceutical agents, in addition to behavioral therapy. Until recently, pharmaceutical therapy for UI has been limited, especially because the adverse effects of available agents resulted in poor adherence to treatment regimens. Recent innovations in molecular design and new dosage forms of UI medications offer the promise of fewer and less severe adverse effects and, thus, better treatment outcomes for patients. Additionally, the availability of multiple agents within a therapeutic class offers health care providers a spectrum of choices with which to personalize treatment for each individual patient. New pharmacologic treatment options for UI have the potential to allow greater independence for older persons who reside at home and to delay or avoid the costs of admission to long-term care facilities. Alternate dosage forms, which include patches and sustained-release formulations, may benefit patients who have difficulty chewing, swallowing, or remembering to take medications. Although these newer products are generally more expensive than older forms of therapy, they typically have more favorable cost-effectiveness ratios. Access to these new medications for patients enrolled in public and private health care plans may help to reduce the economic and social burden of UI care.

Fraction of nursing home admissions attributable to urinary incontinence.

OBJECTIVE: To calculate the proportion of nursing home admissions of the elderly that is attributable to urinary incontinence (UI). METHODS: The fraction of nursing home admissions attributable to UI was computed from published values for the prevalence of UI and relative risks corrected for variables independently associated with nursing home admission. RESULTS: The attributable fraction of nursing home admissions due to UI in the elderly population was 0.10 (95% confidence interval [CI] 0.08-0.13) for men and 0.06 (95% CI 0.05-0.09) for women. Extrapolation to the US population in 2000 suggests an annualized cost of nursing home admissions due to UI of 6.0 billion dollars (3.0 billion dollars each for elderly men and women). CONCLUSIONS: The estimates of the fraction of nursing home admissions attributable to UI exceed those previously assumed and show an imbalance between the sexes. Policies that support reimbursement for treatments of UI in the community might help prevent or delay institutionalization and offset some of the costs.

Drug delivery systems improve pharmaceutical profile and facilitate medication adherence.

Innovations in dosage forms and dose delivery systems across a wide range of medications offer substantial clinical advantages, including reduced dosing frequency and improved patient adherence; minimized fluctuation of drug concentrations and maintenance of blood levels within a desired range; localized drug delivery; and the potential for reduced adverse effects and increased safety. The advent of new large-molecule drugs for previously untreatable or only partially treatable diseases is stimulating the development of suitable delivery systems for these agents. Although advanced formulations may be more expensive than conventional dosage forms, they often have a more favorable pharmacologic profile and can be cost-effective. Inclusion of these dosage forms on drug formulary lists may help patients remain on therapy and reduce the economic and social burden of care.

Costs and benefits of pharmaceuticals: the value equation for older Americans.

Recent increases in drug expenditures are primarily due to the availability of more and better therapy rather than price inflation. Investment in new drugs generates savings throughout the health care system. Increased use of drugs, especially newer agents, has also resulted in increased longevity and reduced disability. Benefits from new pharmaceuticals for outweigh their costs for many key diseases of the elderly. Even incremental improvements in drug therapies contribute substantially to improved care. Chronic illness, disability, and an aging population will drive future health care spending. Pharmaceutical innovation will be an integral part of effective strategies to address this challenge. The availability of individualized therapy for the elderly will soon increase based on our rapidly growing understanding of the molecular and genetic basis of disease. This is expected to result in major advances in preventing, treating, and perhaps even curing many of the costly, life-threatening, and disabling diseases afflicting older Americans. The adequacy of drug benefit programs for elderly patients depends on the extent to which the range of drug therapies necessary for appropriate care are covered. Policies that foster the availability of unique pharmaceuticals can have important implications for treatment outcomes, quality of life, cost containment, and ongoing research investment in newer and more effective medicines. Such policies increase the diversity of agents within drug classes and thereby enable differentiated, individualized therapy. A wide range of choices is especially important for elderly patients, who have the greatest need for individualized care and are at greatest risk for compromised outcomes if choices are overly circumscribed.