Short-term effects of transcutaneous auricular vagus nerve stimulation on T-wave alternans in people with focal epilepsy - An exploratory pilot study.

High levels of T-wave alternans (TWA) are linked to an increased risk of sudden cardiac death. People with epilepsy display elevated TWA levels that are decreased by chronic vagus nerve stimulation via implanted devices after 2-4 weeks or later. Our objective was to explore short-term effects of transcutaneous auricular vagus nerve stimulation (tVNS) on TWA. Five patients (3 female) with focal epilepsy undergoing video-EEG monitoring were included. TWA levels were determined using a one-channel modified lead I ECG via an open-source TWA-algorithm on two consecutive days, 1 h before, during and after tVNS via the left auricle. Data are given as mean ± SE. Mean TWA at baseline was 3.8 ± 0.4 µV and 3.0 ± 0.6 µV during stimulation on day 2. Stimulations on the second day were associated with TWA reductions by 22 ± 13 % that exceeded stimulation effects on the first day relative to baseline (p < 0.05). Linear mixed-models revealed effects of both stimulation (p < 0.05) and stimulation number (p < 0.005). Normalized TWA showed reproducible peak reductions at both days within 35 min after the initiation of tVNS (p < 0.05). Our observations suggest that tVNS has short-term effects on TWA, supporting the notion that vagus nerve stimulation has a beneficial impact on electrical cardiac properties.

Atrioventricular Conduction in Mesial Temporal Lobe Seizures.

Purpose: Asymmetric cerebral representation of autonomic function could help to stratify cardiac complications in people with epilepsy, as some seizures are associated with potentially deleterious arrhythmias including bradycardia and atrioventricular (AV) conduction block. We investigated seizure-related changes in AV conduction and ascertained whether these alterations depend on the hemisphere in mesial temporal lobe epilepsy (mTLE). Methods: EEG and ECG data of people with pharmacoresistant mTLE undergoing pre-surgical video-EEG telemetry with seizures independently arising from both hippocampi, as determined by intracranial depths electrodes were reviewed. RR and PR intervals were measured using one-lead ECG. Statistics were done with paired student's t-tests and linear regression analysis. Data are given as mean ± SD. Results: Fifty-six seizures of 14 patients (5 men, age 34.7 ± 9.8 years) were included (2 seizures per hemisphere and patient). There were no differences of absolute PR intervals and HR before and during unilateral ictal activity between left- and right-sided hippocampal seizures. Peri-ictal modulation of AV conduction, however, appeared greater with left-sided seizures, as the slope of the PR/HR correlations was significantly steeper with seizures originating in the left hippocampus. PR lengthening >200 ms or full block did not occur in any seizure. Conclusions: Our data show that on average, PR intervals shortens with mesial temporal lobe seizures with more prominent effects in seizures with left-sided onset, supporting the notion of lateralized cerebral control of cardiac function. The clinical relevance of this subtle finding is unclear but may indicate a lateralized susceptibility to seizure-related AV node dysfunction in mTLE.

Semi-automatic quantification of seizure-related effects on heart activity.

OBJECTIVE: Seizure-related modulation of heart rate (HR) was examined extensively in previous studies. However, the overall effect on HR attributable to epileptic seizures is difficult to determine, given the considerable fluctuations of HR before and during seizures. Here, we developed a semi-automatic procedure allowing quantification of the total impact of seizures on HR and determination of temporal relationships between seizure onset assessed by intracranial EEG (iEEG) and ECG. METHODS: ECG and iEEG data of epilepsy patients undergoing video-EEG telemetry for epilepsy surgery with bilateral hippocampal depth electrodes were analysed retrospectively. Consecutive RR intervals and HR profiles were determined using R detection algorithms. Novel features including the normalized ictal area under the curve (niAUC), as well as the time point of ECG onset (HR breakpoint) were calculated. Selected HR features were compared to widely-used manually acquired measures. Data are given as median ±â€¯SD. RESULTS: Fifteen patients had a total of 34 seizures with left-hippocampal and 37 seizures with right-hippocampal onset. HR increased by 9 ±â€¯19% during seizures. Latency between iEEG seizure-onset to the HR breakpoint was 23 ±â€¯22 s. No significant difference between left- and right-hippocampal seizures was observed with respect to HR increases, latencies and niAUC. A comparison between results of the semi-automatic and manual approach revealed that ictal HR changes showed a higher correlation (r = 0.6) than niAUC (r = 0.4). CONCLUSIONS: The proposed semi-automatic approach to analyze continuous HR data provides useful tools for estimating the overall effect of seizures on HR in greater detail. Our results suggest that the side of hippocampal seizure onset has no significant effect on the latency and extent of ictal HR changes. The algorithms may be of further use in clinical research and the development of seizure detection devices.

Cryptic pocket formation underlies allosteric modulator selectivity at muscarinic GPCRs.

Allosteric modulators are highly desirable as drugs, particularly for G-protein-coupled receptor (GPCR) targets, because allosteric drugs can achieve selectivity between closely related receptors. The mechanisms by which allosteric modulators achieve selectivity remain elusive, however, particularly given recent structures that reveal similar allosteric binding sites across receptors. Here we show that positive allosteric modulators (PAMs) of the M1 muscarinic acetylcholine receptor (mAChR) achieve exquisite selectivity by occupying a dynamic pocket absent in existing crystal structures. This cryptic pocket forms far more frequently in molecular dynamics simulations of the M1 mAChR than in those of other mAChRs. These observations reconcile mutagenesis data that previously appeared contradictory. Further mutagenesis experiments validate our prediction that preventing cryptic pocket opening decreases the affinity of M1-selective PAMs. Our findings suggest opportunities for the design of subtype-specific drugs exploiting cryptic pockets that open in certain receptors but not in other receptors with nearly identical static structures.

INI1/SMARCB1-Deficient Carcinoma (Rhabdoid Tumor) of the Lacrimal Gland.

Integrase interactor 1 (INI1) is a tumor suppressor gene that is ubiquitously expressed in all nucleated cells. The loss of INI1 protein activity was first demonstrated in aggressive pediatric tumors, including atypical teratoid/rhabdoid (AT/RT) tumor of the central nervous system and malignant rhabdoid tumor of the kidney. Subsequently, INI1 deficiency was discovered in other pediatric and some adult neoplasms. The spectrum of INI1-negative tumors includes a wide variety of neoplasms that occur over a wide age range, are variably aggressive, and have a variable rhabdoid component on histopathologic evaluation. In this report, the authors describe a 27-year-old gravid woman with INI1-deficient carcinoma of the lacrimal gland, previously not described in this location.

Promoção de saúde na perspectiva da prevenção de doenças parasitárias por meio da educação em saúde com escolares do ensino fundamental / Health promotion in the perspective of the prevention of parasitic diseases through education in health with schools of fundamental education / Promoción de salud en la perspectiva de la prevención de enfermedades parasitarias por medio de la educación en salud con escuelas de la enseñanza fundamental

Objetivos: As doenças parasitárias são recorrentes em populações que vivem em regiões com precárias condições sanitárias, assim o objetivo é relatar a experiência de uma ação de educação em saúde com escolares do ensino fundamental de uma escola pública em zona rural. Descrição do caso: trata-se de um relato de experiência de uma atividade extraclasse do componente curricular Projeto Integrador Científico da Graduação em Enfermagem da Faculdade Verde Norte, realizada em outubro de 2016 na Escola Municipal Odilon Antunes, no Povoado de Poções da cidade de Monte Azul. Foi realizada uma ação de educação em saúde com o envolvimento de 30 alunos, 03 professores e 09 pais. A ação ocorreu nas seguintes etapas: exposição dialógica do conteúdo e exibição de vídeo disparador de discussão; e roda de conversas com público. Conclusão: As crianças estão expostas a risco de contaminação por parasitas, visto as condições sanitárias que habitam, evidenciando a necessidade da ampliação de ações de educação em saúde acerca da importância da prevenção das parasitoses.(AU)

Objectives: Parasitic diseases are recurrent in populations living in regions with poor sanitary conditions, so the objective is to report the experience of a health education action with primary school students of a public school in rural areas. Case Discussion: this is an experience report of an extraclass activity of the curricular component Scientific Integrator Project of the Graduation in Nursing of the Faculdade Verde Norte, held in October 2016 at the Odilon Antunes Municipal School, in the Potions Village of the city of Monte Blue. A health education action was carried out with the participation of 30 students, 03 teachers and 09 parents. The action took place in the following steps: dialogic exposure of the content and video display of discussion trigger; And wheel of conversations with public. Conclusion: Children are at risk of contamination by parasites, given the sanitary conditions they inhabit, evidencing the need to expand health education actions on the importance of parasite prevention.(AU)

Objetivos: Las enfermedades parasitarias son recurrentes en poblaciones que viven en regiones con precarias condiciones sanitarias, así el objetivo es relatar la experiencia de una acción de educación en salud con escolares de la enseñanza fundamental de una escuela pública en zona rural. Descripción del caso: se trata de un relato de experiencia de una actividad extraclase del componente curricular Proyecto Integrador Científico de la Graduación en Enfermería de la Facultad Verde Norte, realizada en octubre de 2016 en la Escuela Municipal Odilon Antunes, en el Pueblo de Pociones de la ciudad de Monte Azul. Se realizó una acción de educación en salud con la participación de 30 alumnos, 03 profesores y 9 padres. La acción ocurrió en las siguientes etapas: exposición dialógica del contenido y visualización de vídeo desencadenador de discusión; y rueda de conversaciones con público. Conclusión: los niños están expuestos a riesgo de contaminación por parásitos, visto las condiciones sanitarias que habitan, evidenciando la necesidad de la ampliación de acciones de educación en salud acerca de la importancia de la prevención de las parasitosis.(AU)

Mental Health Trainees' Explicit and Implicit Attitudes Toward Transracial Adoptive Families Headed by Lesbian, Gay, and Heterosexual Couples.

We investigated 109 (79.8% female; 76% White, and 83.5% Heterosexual) mental health trainees' explicit and implicit attitudes toward heterosexual, lesbian, and gay White couples adopting and raising Black children. To determine explicit attitudes, we used a vignette depicting a Black child ready for adoption and three types of equally qualified White families who were headed by a heterosexual couple, gay couple, or lesbian couple. The trainees were asked to indicate which type of family they preferred to adopt the child. To determine implicit attitudes, we used the computer programed latency-based multifactor implicit association test (IAT) protocol. The IAT data were collected from each participant individually. Explicit data showed that over 80% of the participants indicated no strong preference in terms of which type of family should adopted the child. However, IAT data showed that the trainees implicitly preferred lesbian couples. Overall, the degree of congruence between explicit and implicit was very low. Implications for training were discussed.

Ictal modulation of cardiac repolarization, but not of heart rate, is lateralized in mesial temporal lobe epilepsy.

OBJECTIVES: Human and animal studies provided controversial data on asymmetric cortical representation of cardiac function, which may partially be due to different study designs and inter-individual variability. Here, we investigated whether seizure-related changes in heart rate (HR) and cardiac repolarization depend on the side of seizure-activity in people with mesial temporal lobe epilepsy (mTLE). METHODS: To account for inter-individual variability, EEG and ECG data were reviewed from patients with medically refractory mTLE undergoing pre-surgical video-EEG telemetry with at least 2 seizures arising from each hippocampus as assessed by bilateral hippocampal depths electrodes. RR and QT intervals were determined at different timepoints using a one-lead ECG. QT intervals were corrected for HR (QTc) using 4 established formulas. RESULTS: Eighty-two seizures of 15 patients were analyzed. HR increased by ∼30% during hippocampal activity irrespective of the side (p = 0.411). QTc intervals were lengthened to a significantly greater extent during left hippocampal seizures (e.g. difference of QT intervals between preictal and ictal state using Bazett's formula; left side 32.0±5.3 ms, right side 15.6±7.7 ms; p = 0.016). Abnormal QTc prolongation occurred in 7 of 41 left hippocampal seizures of 4 patients, and only in 2 of 37 right hippocampal seizures of 2 patients. CONCLUSIONS: Seizure-related modulation of cardiac repolarization, but not of HR, appears to depend on the side of ictal activity, strengthening the hypothesis of asymmetric cerebral representation of cardiac function. The clinical relevance of this is unclear, but may indicate an increased risk of abnormal ictal QT prolongation in people with left mTLE.

The relationship between change in therapeutic alliance ratings and improvement in youth symptom severity: whose ratings matter the most?

This paper presents the psychometric evaluation of brief measures of therapeutic alliance (TA) for youths, clinicians and caregivers and a longitudinal analysis of relationships between changes in TA and changes in youth symptom and functioning severity. Psychometric analyses using methods from Classical Test Theory, Item Response Theory, and Factor Analysis indicate that the measures of TA used in this study offer something new for both practice and research. The measures have variability, sensitivity to change over time, brevity and can be used with multiple parties through parallel forms. The longitudinal analyses, employing hierarchical linear modeling with time-varying covariates, found that TA ratings of the clinician correlated with symptom improvement as rated by the clinician, caregiver and youth. Additional analyses showed that decreases in clinician-rated youth TA was most important in predicting a lower rate of youth improvement. Implications for future research and clinical practice are discussed.

Urine drug testing in chronic pain.

Therapeutic use, overuse, abuse, and diversion of controlled substances in managing chronic non-cancer pain continue to be an issue for physicians and patients. The challenge is to eliminate or significantly curtail abuse of controlled prescription drugs while still assuring the proper treatment of those patients. Some physicians are apprehensive regarding the use of chronic opioid therapy in chronic non-cancer pain due to a perceived lack of proven evidence, the misuse of opioids, tolerance, dependence, and hyperalgesia. However, others have criticized the underuse of opioids, resulting in the undertreatment of pain. It has been the convention that federal, state, and local governments; professional associations; as well as pharmaceutical companies, physicians, accrediting bodies, medical licensure boards, and the public all share responsibility for preventing abuse of controlled prescription drugs. To overcome the critical challenge of eliminating or significantly curtailing abuse of controlled prescription drugs and at the same time assuring the appropriate treatment for those patients who can be helped by these medications, it is crucial to practice adherence or compliance monitoring of opioid therapy. Compliance monitoring has been shown to be crucial in delivering proper opioid therapy and preserving this therapy for the future. Urine drug testing (UDT) is considered one of the mainstays of adherence monitoring in conjunction with prescription monitoring programs and other screening tools, however, UDT is associated with multiple limitations secondary to potential pitfalls related to drug metabolism, reliability of the tests, and the knowledge of the pain physician. UDT is a widely available and familiar method for monitoring opioid use in chronic pain patients. UDT can provide tools for tracking patient compliance and expose possible drug misuse and abuse. UDT is one of the major tools of adherence monitoring in the assessment of the patient's predisposition to, and patterns of, drug misuse/abuse--a vital first step towards establishing and maintaining the safe and effective use of opioid analgesics in the treatment of chronic pain. This comprehensive review provides the role of UDT in monitoring chronic opioid therapy along with reliability and accuracy, appropriate use, overuse, misuse, and abuse.

Opioid guidelines in the management of chronic non-cancer pain.

BACKGROUND: Opioid abuse has increased at an alarming rate. However, available evidence suggests a wide variance in the use of opioids, as documented by different medical specialties, medical boards, advocacy groups, and the Drug Enforcement Administration (DEA). OBJECTIVES: The objective of these opioid guidelines by the American Society of Interventional Pain Physicians (ASIPP) is to provide guidance for the use of opioids for the treatment of chronic non-cancer pain, to bring consistency in opioid philosophy among the many diverse groups involved, to improve the treatment of chronic non-cancer pain, and to reduce the incidence of drug diversion. DESIGN: A policy committee evaluated a systematic review of the available literature regarding opioid use in managing chronic non-cancer pain. This resulted in the formulation of the essentials of guidelines, a series of potential evidence linkages representing conclusions, followed by statements regarding relationships between clinical interventions and outcomes. METHODS: Consistent with the Agency for Healthcare Research and Quality (AHRQ) hierarchical and comprehensive standards, the elements of the guideline preparation process included literature searches, literature synthesis, systematic review, consensus evaluation, open forum presentations, formal endorsement by the Board of Directors of the American Society of Interventional Pain Physicians (ASIPP), and blinded peer review. Evidence was designated based on scientific merit as Level I (conclusive), Level II (strong), Level III (moderate), Level IV (limited), or Level V (indeterminate). RESULTS: After an extensive review and analysis of the literature, the authors utilized two systematic reviews, two narrative reviews, 32 studies included in prior systematic reviews, and 10 additional studies in the synthesis of evidence. The evidence was limited. CONCLUSION: These guidelines evaluated the evidence for the use of opioids in the management of chronic non-cancer pain and recommendations for management. These guidelines are based on the best available scientific evidence and do not constitute inflexible treatment recommendations. Because of the changing body of evidence, this document is not intended to be a "standard of care."

Guidelines for the use of controlled substances in the management of chronic pain.

Controlled substance abuse has increased at an alarming rate. However, available evidence suggests a wide variance in the use of controlled substances, as documented by different medical specialties, medical boards, advocacy groups, and the Drug Enforcement Administration. The primary objective of controlled substance guidelines by American Society of Interventional Pain Physicians (ASIPP) is to provide guidance for the use of controlled substances for the treatment of chronic pain. It is anticipated that these practical guidelines will improve quality of care, patient access, and quality of life. Additional benefits include improved treatment efficiency and efficacy, and cost containment by improving the risk-benefit ratio of treating patients with chronic pain. Further goals of this manuscript are to bring consistency in opioid philosophy among the many diverse groups involved, to improve the treatment of chronic pain patients with medically appropriate controlled substances, and to reduce the incidence of drug diversion. These guidelines also reinforce the need for systematic evaluation and ongoing care of patients with chronic or persistent pain. ASIPP controlled substance guidelines also provide a discussion of the epidemiology of chronic pain, the role of controlled substances in treating chronic pain, various aspects of drug abuse, pharmacological considerations, clinical effectiveness of controlled substances, options for treatment monitoring and drug testing and a review of terminology used in addiction medicine. These guidelines do not constitute inflexible treatment recommendations. It is expected that a provider will establish a plan of care on a case-by-case basis, taking into account an individual patient's medical condition, personal needs, and preferences, and the physician's experience. Based on an individual patient's needs, controlled substance prescribing and treatment different from that outlined here may be warranted. These guidelines do not represent "standard of care."