The impact of pregnancy-related hormonal and physiological changes on antiseizure medications: expert perspective.

INTRODUCTION: Epilepsy is a disorder of recurrent, unprovoked seizures affecting approximately 15 million individuals of childbearing potential worldwide. Patients with epilepsy rely on regular daily therapy with antiseizure medications (ASMs). Furthermore, ASMs are also prescribed for other neuropsychiatric indications (e.g. bipolar disorder, pain, migraines) with over 2% of the pregnancies in the United States involving prenatal exposure to ASMs. AREAS COVERED: ASM concentrations are affected by hormonal and physiological changes in pregnancy, including increases in renal and hepatic blood flow, decreased protein binding, and changes in enzyme activity. Clearance changes typically reverse within a few weeks after delivery. During pregnancy, many ASMs, such as lamotrigine, levetiracetam, and oxcarbazepine, should have serum concentrations monitored and doses increased to maintain the individualized target range for seizure control. ASMs metabolized via glucuronidation, primarily lamotrigine, undergo marked increases in clearance throughout pregnancy, requiring about 3-fold the pre-pregnancy daily dose by delivery. Postpartum, ASM doses are usually decreased over several weeks to prevent drug toxicity. EXPERT OPINION: In the future, the development of a physiologically-based pharmacokinetic model for various ASMs may enable empiric dose adjustments in pregnancy without the difficulties of frequent therapeutic drug monitoring.

Pearls & Oy-sters: Two Cases of Stereotactic EEG-Proven Insular Epilepsy With Nonlocalizing Scalp EEG and Interesting Semiologies.

Insular epilepsy is a great mimicker and can be mistaken for seizures originating from other areas of the brain or as nonepileptic spells. The semiology of insular epilepsy can include, but is not limited to, auditory illusions, paresthesias, gastric rising, laryngeal constriction, and hyperkinetic movements. These arise from both the functions of the insula itself and its extensive connections with other regions of the brain. Noninvasive workup can be negative or nonlocalizing because of the insula's location deep within the lateral sulcus. Stereotactic EEG can therefore be an important tool in cases of insular epilepsy so that patients may be appropriately diagnosed and evaluated for potential surgical treatment. We present 2 cases of epilepsy with nonlocalizing scalp EEG and challenging semiologies, the workup undertaken to identify them as cases of insular epilepsy, and subsequent surgical treatments and outcomes.

The Impact of Voluntary Policies on Parents' Ability to Select Healthy Foods in Supermarkets: A Qualitative Study of Australian Parental Views.

Food packaging is used for marketing purposes, providing consumers with information about product attributes at the point-of-sale and thus influencing food choice. The Australian government focuses on voluntary policies to address inappropriate food marketing, including the Health Star Rating nutrition label. This research explored the way marketing via packaging information influences Australian parents' ability to select healthy foods for their children, and who parents believe should be responsible for helping them. Five 90-min focus groups were conducted by an experienced facilitator in Perth, Western Australia. Four fathers and 33 mothers of children aged 2-8 years participated. Group discussions were audio-recorded and transcribed verbatim and inductive thematic content analysis conducted using NVivo11. Seven themes were derived: (1) pressure of meeting multiple demands; (2) desire to speed up shopping; (3) feeding them well versus keeping them happy; (4) lack of certainty in packaging information; (5) government is trusted and should take charge; (6) food manufacturers' health messages are not trusted; (7) supermarkets should assist parents to select healthy foods. Food packaging information appears to be contributing to parents' uncertainty regarding healthy food choices. Supermarkets could respond to parents' trust in them by implementing structural policies, providing shopping environments that support and encourage healthy food choices.

Structured approaches to pain management in the ICU.

Pain in patients who are critically ill remains undertreated despite decades of research, guideline development and distribution, and intense educational efforts. By nature of their complex medical conditions, these patients present unique challenges to the delivery of optimal pain treatment. Outdated clinical practices and faulty systems, such as a formulary that allows dangerous prescriptions, present additional obstacles. A multidisciplinary and patient-centered continuous quality improvement process is essential to identifying barriers and implementing evidence-based solutions to the problem of undertreated pain in hospital ICUs. This article addresses barriers common to the ICU setting and presents a number of structured approaches that have been shown to be successful in improving pain treatment in patients who are critically ill.

Pain management within the palliative and end-of-life care experience in the ICU.

In the ICU where critically ill patients receive aggressive life-sustaining interventions, suffering is common and death can be expected in up to 20% of patients. High-quality pain management is a part of optimal therapy and requires knowledge and skill in pharmacologic, behavioral, social, and communication strategies grounded in the holistic palliative care approach. This contemporary review article focuses on pain management within comprehensive palliative and end-of-life care. These key points emerge from the transdisciplinary review: (1) all ICU patients experience opportunities for discomfort and suffering regardless of prognosis or goals, thus palliative therapy is a requisite approach for every patient, of which pain management is a principal component; (2) for those dying in the ICU, an explicit shift in management to comfort-oriented care is often warranted and may be the most beneficial treatment the health-care team can offer; (3) communication and cultural sensitivity with the patient-family unit is a principal approach for optimizing palliative and pain management as part of comprehensive ICU care; (4) ethical and legal misconceptions about the escalation of opiates and other palliative therapies should not be barriers to appropriate care, provided the intention of treatment is alleviation of pain and suffering; (5) standardized instruments, performance measurement, and care delivery aids are effective strategies for decreasing variability and improving palliative care in the complex ICU setting; and (6) comprehensive palliative care should addresses family and caregiver stress associated with caring for critically ill patients and anticipated suffering and loss.

Evaluation of pain in ICU patients.

Pain is a common and distressing symptom in ICU patients. Yet a major challenge exists in assessing and evaluating the pain. Although the patient's self-report of pain is the "gold standard" for pain assessment, other methods must be considered when patients are unable to self-report. Currently only two pain behavior instruments have been tested for their reliability, validity, and feasibility of use in ICUs: the pain behavior scale and the Critical-Care Pain Observation Tool. Other tools, albeit with less validity testing, include the pain assessment, intervention, and notation (PAIN) algorithm and a pain behaviors checklist. When established tools are insufficient to evaluate a patient's pain, alternative methods of augmenting a pain evaluation should be considered. These can include the completion of a pain risk profile, use of surrogates, or performance of an analgesic trial. Meticulous attention to the evaluation of a critically ill patient's pain provides the basis for selection of pain interventions and the subsequent assessment of the intervention's effectiveness.

Pain management principles in the critically ill.

This article addresses conventional pharmacologic and nonpharmacologic treatment of pain in patients in ICUs. For the critically ill patient, opioids have been the mainstay of pain control. The optimal choice of opioid and dosing regimen for a specific patient varies depending on factors such as the pharmacokinetics and physicochemical characteristics of an opioid and the body's handling of the opioid, concomitant sedative regimen, potential or actual adverse drug events, and development of tolerance. The clinician must appreciate that favorable pharmacokinetic properties such as a short-elimination half-life do not necessarily translate into clinical advantages in the ICU setting. A variety of medications have been proposed as alternatives or adjuncts to the opioids for pain control that have unique considerations when contemplated for use in the critically ill patient. Most have been relatively unstudied in the ICU setting, and many have limitations with respect to availability of the GI route of administration in patients with questionable GI absorptive function. Nonpharmacologic, complementary therapies are low cost, easy to provide, and safe, and many clinicians can implement them with little difficulty or resources. However, the evidence base for their effectiveness is limited. At present, insufficient research evidence is available to support a broad implementation of nonpharmacologic therapies in ICUs.

Evaluations of physiologic reactivity and reflexive behaviors during noxious procedures in sedated critically ill patients.

PURPOSE: Sedated patients' responses to noxious stimulation are not well characterized. A standardized measure of nociception for use in the intensive care unit (ICU) is elusive. The study aimed to describe cardiovascular and pupil reactivity and behavioral responses between noxious and nonnoxious procedures in sedated ICU patients. MATERIALS AND METHODS: This prospective, descriptive study performed repeated measures using within-subject and crossover techniques. Forty-eight sedated, ventilated cardiac surgery patients from 2 institutions were included. Pupil sizes, heart rate, blood pressure, cortical arousal changes per the bispectral index, and behaviors were recorded at baseline, during, and after a noxious procedure (endotracheal suctioning or turning), and gentle touch. RESULTS: The majority of patients was deeply sedated with propofol infusion and were unresponsive or responsive only to physical stimulation. Significant changes in heart rate, pupil size, and bispectral index occurred with the noxious procedure but not with the nonnoxious procedure (P < .01). Reflexive behaviors were not evident during both procedures. CONCLUSIONS: Certain physiologic reactions and pupil size changes may be potentially useful nociceptive indicators in ICU settings. Further research is needed to determine the clinical parameters of physiologic response change and to evaluate the effects of opioids and sedatives on these physiologic responses.

Ensuring cross-cultural equivalence in translation of research consents and clinical documents: a systematic process for translating English to Chinese.

The aim of this article is to describe a formal process used to translate research study materials from English into traditional Chinese characters. This process may be useful for translating documents for use by both research participants and clinical patients. A modified Brislin model was used as the systematic translation process. Four bilingual translators were involved, and a Flaherty 3-point scale was used to evaluate the translated documents. The linguistic discrepancies that arise in the process of ensuring cross-cultural congruency or equivalency between the two languages are presented to promote the development of patient-accessible cross-cultural documents.

A review of objective pain measures for use with critical care adult patients unable to self-report.

UNLABELLED: Critically ill patients experience significant levels of pain and discomfort from multiple intrinsic and extrinsic sources while in the intensive care unit (ICU). The use of objective pain measures in nonverbal patients is an essential alternative approach for pain assessment when self-reports are unavailable. This paper provides a critical review of the psychometric properties of 6 objective pain measures that were developed to assess pain in nonverbal adult patients in the ICU. The strengths and weaknesses of these objective measures are evaluated, as well as their applicability for use with this patient population. Although 2 of the 6 objective pain measures showed good evidence of validity and reliability, none has undergone vigorous validation or has been accepted as a standardized measure. Findings from the available studies of objective pain measures provide useful information to direct future research to develop and validate clinically useful pain measures for use with critically ill patients unable to self-report. PERSPECTIVE: This review provides clinicians with a summary of the psychometric properties of 6 objective pain measures and discusses their applicability for use to assess pain in critically ill adult patients unable to self-report.

A pilot study on coexisting symptoms in intensive care patients.

Little is known about the symptoms of patients in the intensive care unit (ICU). This pilot study prospectively evaluated the perceptions on nine symptoms (pain, dyspnea, thirst, nausea, hunger, tiredness, anxiety, generalized discomfort, and depressed feelings) of ICU patients receiving ventilation and examined their relationships. Patients' symptoms were assessed by a numeric rating scale. The study found that many symptoms existed at substantial levels and that there was evidence of association among symptoms. It suggests that attention to the multiple symptoms that ICU patients experience is needed to improve their overall comfort. Further research is needed to evaluate and validate the relationships among these symptoms and their impact on the health outcomes of ICU patients.

Cytohesin binder and regulator (cybr) is not essential for T- and dendritic-cell activation and differentiation.

Cybr (also known as Cytip, CASP, and PSCDBP) is an interleukin-12-induced gene expressed exclusively in hematopoietic cells and tissues that associates with Arf guanine nucleotide exchange factors known as cytohesins. Cybr levels are dynamically regulated during T-cell development in the thymus and upon activation of peripheral T cells. In addition, Cybr is induced in activated dendritic cells and has been reported to regulate dendritic cell (DC)-T-cell adhesion. Here we report the generation and characterization of Cybr-deficient mice. Despite the selective expression in hematopoietic cells, there was no intrinsic defect in T- or B-cell development or function in Cybr-deficient mice. The adoptive transfer of Cybr-deficient DCs showed that they migrated efficiently and stimulated proliferation and cytokine production by T cells in vivo. However, competitive stem cell repopulation experiments showed a defect in the abilities of Cybr-deficient T cells to develop in the presence of wild-type precursors. These data suggest that Cybr is not absolutely required for hematopoietic cell development or function, but stem cells lacking Cybr are at a developmental disadvantage compared to wild-type cells. Collectively, these data demonstrate that despite its selective expression in hematopoietic cells, the role of Cybr is limited or largely redundant. Previous in vitro studies using overexpression or short interfering RNA inhibition of the levels of Cybr protein appear to have overestimated its immunological role.

Stat5a/b are essential for normal lymphoid development and differentiation.

Cytokines that use the common gamma chain gammac are critical for lymphoid development and function. Mutations of the IL-7 receptor, gammac, or its associated kinase, Jak3, are the major cause of human severe combined immunodeficiency. Although activated by IL-7, Stat5a/b (Stat, signal transducer and activator of transcription) have been thought to play limited roles in lymphoid development. However, we now show that mice completely deficient in Stat5a/b have severely impaired lymphoid development and differentiation. Absence of Stat5 also abrogates T cell receptor gamma rearrangement and survival of peripheral CD8(+) T cells. Thus, deficiency of Stat5 results in severe combined immunodeficiency, similar in many respects to deficiency of IL-7R, gammac, and Jak3.

What is the current evidence on pain and sedation assessment in nonresponsive patients in the intensive care unit?

Assessing pain and sedation in nonresponsive patients is challenging. A major challenge is the confounding effect of sedation on objective indicators of pain. Clinicians might infer that adequate sedation means different patient states: promotion of amnesia, sleep/rest, patient safety, ventilator synchrony, and hemodynamic stability. Hence, an ideal measure that can adequately address the complexity and individualize the nature of the goals of pain and sedation therapy remains elusive. Furthermore, the behavioral responses to pain and anxiety/agitation (eg, restlessness, ventilator dyssynchrony, and movement) have many similarities. Tolerance to mechanical ventilation has been suggested to have validity in both an ICU pain scale and a sedation scale. Additional research is needed to establish the validity, sensitivity, and specificity of these pain indicators in sedated patients. In the meantime, in circumstances where patients are nonresponsive to external stimuli, clinicians should integrate other information such as actual or potential risks of pain (eg, extensiveness of injury, invasive therapies, intubation) and risks of pain-related functional impairment into their pain assessment in nonresponsive, sedated patients.

Jak3 and the pathogenesis of severe combined immunodeficiency.

The discovery that Jak3 mutations are a significant cause of severe combined immunodeficiency (SCID), a rare inherited defect characterized by lymphopenia, has provided valuable insights into the functions of Jak3 in lymphoid development and function. The current therapy for patients suffering from Jak3 SCID is hematopoetic stem cell transplantation, although gene therapy trials have also been performed. In lieu of crystal structure data, these patient-derived mutations have aided in the elucidation of the functions of various structural components of Jak3. By virtue of its requirement for lymphoid functions, Jak3 makes a tantalizing target for immunosuppression and anti-cancer therapy. Herein, we discuss the normal actions of the gammac cytokines, the pathogenesis and treatment protocols for SCID, and finally, the production of a new, selective Jak3 inhibitor capable of preventing transplant rejection in two animal models. Further study of Jak3 will hopefully provide insights into the clinical treatment of patients suffering from immune-mediated diseases.