CNS Drugs

Temporal Trends and Predictors of Drug Utilization and Outcomes in First-Ever Stroke Patients: A Population-Based Study Using the Singapore Stroke Registry Abstract Introduction Drug utilization and outcomes research in multi-ethnic Asian stroke populations is lacking. Objectives Our objective was to examine temporal trends and predictors of drug utilization and outcomes in a multi-ethnic Asian stroke population. Methods This registry-based study included ischemic and hemorrhagic first-ever stroke patients hospitalized between 2009 and 2016. Utilization of medications included in-hospital thrombolytic agents, early antithrombotics (antiplatelets, anticoagulants) within 48 h of admission, and antithrombotics and statins at discharge. Outcomes analyzed were in-hospital all-cause mortality; 28-day, 90-day, and 1-year case fatality (CF); and discharge destination. Results Of the 36,615 included patients, 81.6% had ischemic stroke and 18.4% had hemorrhagic stroke (15.5% intracerebral hemorrhage [ICH] and 2.8% subarachnoid hemorrhage [SAH]). For ischemic stroke, the combined use of all three guideline medications (in-hospital thrombolytic therapy, as well as antithrombotics and statins at discharge) increased (P = 0.006). Being on the stroke pathway was associated with prescription of all three guideline medications in ischemic stroke. Decreasing trends for in-hospital mortality, 28-day, 90-day, and 1-year CF and proportion of patients discharged home without rehabilitation appointment were observed in ischemic stroke (P < 0.05) but not in ICH or SAH (apart from 28-day CF). Ischemic stroke patients who received guideline medications were less likely to die or be discharged to nursing homes and chronic sick hospitals. Hemorrhagic stroke patients prescribed statins at discharge were less likely to have 28-day and 1-year CF. Conclusions Prescription of secondary stroke preventive medications (particularly in ischemic stroke) was associated with more favorable outcomes, highlighting the importance of physician adherence to evidence-based pharmacotherapy.

Branched-Chain Amino Acids and Seizures: A Systematic Review of the Literature Abstract Background Up to 40% of patients with epilepsy experience seizures despite treatment with antiepileptic drugs; however, branched-chain amino acid (BCAA) supplementation has shown promise in treating refractory epilepsy. Objectives The purpose of this systematic review was to evaluate all published studies that investigated the effects of BCAAs on seizures, emphasizing therapeutic efficacy and possible underlying mechanisms. Methods On 31 January, 2017, the following databases were searched for relevant studies: MEDLINE (OvidSP), EMBASE (OvidSP), Scopus (Elsevier), the Cochrane Library, and the unindexed material in PubMed (National Library of Medicine/National Institutes of Health). The searches were repeated in all databases on 18 February, 2019. We only included full-length preclinical and clinical studies that were published in the English language that examined the effects of BCAA administration on seizures. Results Eleven of 2045 studies met our inclusion criteria: ten studies were conducted in animal models and one study in human subjects. Seven seizure models were investigated: the strychnine (one study), pentylenetetrazole (two studies), flurothyl (one study), picrotoxin (two studies), genetic absence epilepsy in rats (one study), kainic acid (two studies), and methionine sulfoximine (one study) paradigms. Three studies investigated the effect of a BCAA mixture whereas the other studies explored the effects of individual BCAAs on seizures. In most animal models and in humans, BCAAs had potent anti-seizure effects. However, in the methionine sulfoximine model, long-term BCAA supplementation worsened seizure propagation and caused neuron loss, and in the genetic absence epilepsy in rats model, BCAAs exhibited pro-seizure effects. Conclusions The contradictory effects of BCAAs on seizure activity likely reflect differences in the complex mechanisms that underlie seizure disorders. Some of these mechanisms are likely mediated by BCAA's effects on glucose, glutamate, glutamine, and ammonia metabolism, activation of the mechanistic target of rapamycin signaling pathway, and their effects on aromatic amino acid transport and neurotransmitter synthesis. We propose that a better understanding of mechanisms by which BCAAs affect seizures and neuronal viability is needed to advance the field of BCAA supplementation in epilepsy.

Rotigotine Transdermal Patch: A Review in Parkinson's Disease Abstract Rotigotine (Neupro®), a non-ergolinic dopamine agonist (DA), is administered once daily via a transdermal patch (TP) that delivers the drug over a 24-h period. In the EU, the rotigotine TP is approved as monotherapy for the treatment of early Parkinson's disease (PD) and as combination therapy with levodopa throughout the course of the disease. It is also approved for the treatment of PD in numerous other countries, including Australia, the USA, China and Japan. Rotigotine TP effectively improved motor and overall functioning in clinical trials in Caucasian and Asian patients with early PD (as monotherapy) or advanced PD (in combination with levodopa); treatment benefits appeared to be maintained in open-label extensions that followed patients for up to 6 years. Rotigotine TP was not consistently non-inferior to ropinirole and pramipexole in studies that included these oral non-ergolinic DAs as active comparators. Rotigotine TP variously improved some non-motor symptoms of PD, in particular sleep disturbances and health-related quality of life (HRQOL), based on findings from individual studies and/or a meta-analysis. Rotigotine TP was generally well tolerated, with an adverse event profile characterized by adverse events typical of dopaminergic stimulation and transdermal patch application. Available for more than a decade, rotigotine TP is a well-established, once-daily DA formulation for use in the short- and longer-term treatment of PD. It offers a convenient alternative when non-oral administration of medication is preferred and may be particularly useful in patients with gastrointestinal disturbances that reduce the suitability of oral medication.

Outcome Assessment in Trials of Pharmacological Treatments for Alcohol Use Disorders: Fair and Strict Testing Abstract Outcome assessment in the pharmacological treatment of alcohol use disorders (AUDs) faces specific challenges resulting from low adherence to treatment, high rates of dropout, and the susceptibility of patient self-reports to bias. This review discusses methodological issues in planning, conducting, and interpreting clinical trials on AUD treatment against the background of the principle of 'strictness and fairness' of testing. Threats to fairness include factors that limit the implementation of an intervention, such as low compliance and early treatment termination. In turn, fairness of testing is increased by factors that support the degree to which an intervention is implemented, such as the use of adequate pretreatments and the matching of psychosocial and pharmacological treatment strategies. Furthermore, selecting outcomes on the basis of an intervention's mechanism of action and including continuous outcomes as sensitive measures of drinking change further increases fairness by increasing the likelihood that the data will adequately reflect the effects of the intervention. On the other hand, strictness of testing is increased by all measures that limit the influence of confounders that could potentially lead to an overestimation of effects. The use of a side effect-mimicking placebo to prevent an unmasking of blinding and the repeated assessment of alcohol biomarkers to validate drinking self-reports might be valid strategies to further increase the strictness of testing by limiting risks of bias in trials of AUD treatment.

Long-Term Neuropsychological Outcomes from an Open-Label Phase I/IIa Trial of 2-Hydroxypropyl-β-Cyclodextrins (VTS-270) in Niemann-Pick Disease, Type C1 Abstract Background Niemann-Pick disease, type C1 (NPC1) is a neurodegenerative condition that arises from mutations of NPC1 and is often diagnosed in children. Recently, several drug trials have been implemented to minimize neurodegeneration, including a trial of 2-hydroxypropyl-β-cyclodextrins (VTS-270). Objectives The current study extends findings from a previous report of 18 months of disease severity data by describing neuropsychological outcomes over the course of 36 months post-baseline. Design An open-label, dose-escalation phase I/IIa study of VTS-270 was performed in participants with NPC1 aged 4–23 years. Methods Fourteen participants were sequentially assigned to receive monthly initial intrathecal VTS-270 at doses of 50, 200, 300, or 400 mg per month. After initial dosing, participants were dose-escalated (to 600 or 1200 mg) as tolerated. Participants were evaluated at 6-month intervals using a standardized neuropsychological battery, including tests of cognition and adaptive behavior. A random effects model with restricted maximum likelihood estimation was constructed for each outcome, and the slope was the parameter of interest. Results Findings based on IQ scores and both standard scores and age equivalents of adaptive functioning indicate that there were not meaningful declines in these areas during the study period. The average annualized change in Full Scale IQ was negative: B = − 1.28, standard error (SE) = 0.70, t(34.2) = − 1.83, p = 0.076. The Vineland-II Adaptive Behavior Composite standard score decreased by 1.76 points per year [SE = 0.67, t(59.1) = − 2.62, p = 0.011], but annualized slopes for each of the domain age equivalents were positive: Communication [B = 0.71, SE = 3.12, t(60.7) = 0.23, p = 0.82], Socialization [B = 2.99, SE = 2.92, t(60.4) = 1.03, p = 0.30], Daily Living Skills [B = 2.76, SE = 2.76, t(60.3) = 1.18, p = 0.24], and Motor Skills [B = 1.42, SE = 0.94, t(50.5) = 1.51, p = 0.14], indicating not worsening but slower-than-average acquisition of skills. Conclusion In conjunction with previous findings, these results provide support for the slowing of disease progress up to 36 months post-initiation of intrathecal VTS-270. Registration ClinicalTrials.gov identifier NCT01747135: Hydroxypropyl Beta Cyclodextrin for Niemann-Pick type C1 Disease.

Drug Treatment of Clinically Isolated Syndrome Abstract Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) that leads to inflammation, demyelination and ultimately axonal degeneration. In most cases, it is preceded by its precursor, clinically isolated syndrome (CIS) with conversion rates to clinically definite MS (CDMS) of roughly 20–75%. Neurologists are therefore faced with the challenge of initiating a disease-modifying therapy (DMT) as early as possible to favorably influence the course of the disease. During the past 20 years, a multitude of drugs have been incorporated into our therapeutic armamentarium for MS and CIS. Choosing the right drug for an individual patient is complex and should be based not only on the drug's overall efficacy to prevent disease progression but also its specific adverse reaction profile, the severity of individual disease courses and, finally, patient compliance in order to adequately weigh associated risks and benefits. Here, we review the available data on the efficacy, safety and tolerability of DMTs tested for CIS and discuss their value regarding a delay of progression to CDMS.

Association Between Statin Use and Depressive Symptoms in a Large Community-Dwelling Older Population Living in Australia and the USA: A Cross-Sectional Study Abstract Background Statin use has been frequently associated with depressive symptoms in an older population. However, the nature of this association is uncertain in the literature. In this study, we aimed to investigate the association of statin intake and the prevalence of depressive symptoms in healthy community-dwelling older adults living in Australia and the USA. Methods We analysed baseline data from 19,114 participants, over 70 years of age (over 65 years of age, if from an ethnic minority). The association of self-reported statin use and prevalence of depressive symptoms, as measured by a validated depression scale [Center for Epidemiological Studies Depression Scale (CES-D 10)], was determined using logistic regression models. Multivariable logistic models were implemented to account for important demographics and other lifestyle and socioeconomic factors, such as sex, age, living status, education and smoking history. Results A total of 5987 individuals were statin users. Of those, 633 (10.6%) had depressive symptoms (CES-D 10 cut-off ≥ 8), compared with 1246 (9.5%) of the non-statin users. In the unadjusted model, statin use was associated with an increase in prevalence of depressive symptoms (odds ratio 1.13, confidence interval 1.02–1.25, p = 0.02). However, after adjusting for important demographic and socioeconomic factors, the use of statins was not significantly associated with depressive symptoms (odds ratio 1.09, confidence interval 0.98–1.20, p = 0.11). In secondary analyses, only simvastatin was marginally associated with an increased prevalence of depressive symptoms. Statins were associated with a decreased prevalence of depressive symptoms in individuals with severe obesity (body mass index > 35 kg/m2) and an increased prevalence in participants between 75 and 84 years of age. Conclusion This study in a large community-dwelling older population did not show any association of statins with late-life depressive symptoms, after accounting for important socioeconomic and demographic factors. Confounding by indication is an important issue to be addressed in future pharmacoepidemiologic studies of statins.

Potential Role of Vitamin D for the Management of Depression and Anxiety Abstract Vitamin D, a fat-soluble vitamin, plays a role not only in calcium and phosphate homeostasis but also in several other functions, including cell growth and neuromuscular and immune function. The deficiency of vitamin D is highly prevalent throughout the world and has been suggested to be associated with an enhanced risk of major depressive disorder (MDD) and anxiety disorders. Therefore, vitamin D supplementation has been investigated for the prevention and treatment of these disorders. This review presents preclinical and clinical evidence of the effects of vitamin D supplementation in these disorders. Although preclinical studies provide limited evidence on the possible mechanisms underlying the beneficial effects of vitamin D for the management of these disorders, most of the clinical studies have indicated that vitamin D supplementation is associated with the reduction of symptoms of depression and anxiety, particularly when the supplementation was carried out in individuals with an MDD diagnosis (of the 13 studies in which MDD diagnosis was established, 12 had positive results with vitamin supplementation). However, some heterogeneity in the outcomes was observed and might be associated with an absence of overt psychiatric symptoms in several studies, genetic polymorphisms that alter vitamin D metabolism and bioavailability, differences in the supplementation regimen (monotherapy, adjunctive therapy, or large bolus dosing), and levels of 25-hydroxyvitamin D3 (25(OH)D) at baseline (individuals with low vitamin D status may respond better) and attained after supplementation. Additionally, factors such as sex, age, and symptom severity also need to be further explored in relation to the effects of vitamin D. Therefore, although vitamin D may hold significant potential for mental health, further preclinical and clinical studies are clearly necessary to better understand its role on mood/affect modulation.

Post-Hoc Analyses of the Effects of Baseline Sleep Quality on SHP465 Mixed Amphetamine Salts Extended-Release Treatment Response in Adults with Attention-Deficit/Hyperactivity Disorder Abstract Objective Sleep problems are common in adults with attention-deficit/hyperactivity disorder (ADHD). The presence of sleep problems at the time of presentation for ADHD treatment could impact the level of improvement in ADHD symptoms or executive function occurring with ADHD pharmacotherapy. Therefore, we examined the influence of baseline sleep quality on the effects of SHP465 mixed amphetamine salts (MAS) extended-release. Methods Adults (18–55 years) with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision-defined ADHD and baseline ADHD Rating Scale IV (ADHD-RS-IV) total scores ≥ 24 were randomized to once-daily SHP465 MAS (12.5–75 mg) or placebo in a 7-week, double-blind, dose-optimization study. Post-hoc analyses evaluated SHP465 MAS treatment effects on ADHD symptoms, using the ADHD-RS-IV, and executive function, using the Brown Attention-Deficit Disorder Scale (BADDS), based on baseline sleep quality as defined by Pittsburgh Sleep Quality Index (PSQI) scores [sleep quality impaired (PSQI total score > 5; PSQI component scores 2 or 3) versus not impaired (PSQI total score ≤ 5; PSQI component scores 0 or 1)]. Analyses were conducted in the intent-to-treat population. Results Of 280 enrolled participants, 272 were randomized (placebo, n = 135; SHP465 MAS, n = 137). The intent-to-treat population consisted of 268 participants (placebo, n = 132; SHP465 MAS, n = 136), and 170 participants (placebo, n = 76; SHP465 MAS, n = 94) completed the study. Treatment differences nominally favored SHP465 MAS over placebo in both sleep impairment groups regarding ADHD-RS-IV total score changes (all nominal p < 0.05), except for those with impairment defined by sleep efficiency (p = 0.2696), and regarding BADDS total score changes (all nominal p < 0.05), except for those with impairment defined by sleep duration (p = 0.1332) and sleep efficiency (p = 0.8226). There were no statistically significant differences in SHP465 MAS treatment effects between sleep impairment groups. Conclusions Improvements in ADHD symptoms and executive function occurred with dose-optimized SHP465 MAS, regardless of baseline impairment in some aspects of sleep in adults with ADHD, with no significant differences observed as a function of sleep impairment. Clinical Trials Registration ClinicalTrials.gov identifier—NCT00150579.

Endolysosome and Autolysosome Dysfunction in Alzheimer's Disease: Where Intracellular and Extracellular Meet Abstract Disturbed proteostasis as reflected by a massive accumulation of misfolded protein aggregates is a central feature in Alzheimer's disease. Proteostatic disturbances may be caused by a shift in protein production and clearance. Whereas rare genetic causes of the disease affect the production side, sporadic cases appear to be directed by dysfunction in protein clearance. This review focusses on the involvement of lysosome-mediated clearance. Autophagy is a degradational system where intracellular components are degraded by lysosomal organelles. In addition, "outside-to-inside" trafficking through the endosomes converges with the autolysosomal pathway, thereby bringing together intracellular and extracellular components. Recent findings demonstrate that disturbance in the endo- and autolysosomal pathway induces "inside-to-outside" communication via induction of unconventional secretion, which may bear relevance to the spreading of disease pathology through the brain. The involvement of these pathways in the pathogenesis of the disease is discussed with an outlook to the opportunities it provides for diagnostics as well as therapeutic interventions.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Clinical Neuropharmacology

Factors Associated With Delirium in Surgical Intensive Care Unit Patients Treated With Supplemental Melatonin: A Case-Cohort Study Objectives Intensive care unit (ICU) delirium is a common neuropsychiatric syndrome that confers significant morbidity and mortality. Melatonin is an endogenous neurohormone involved with regulating sleep-wake cycles and has been found to be disturbed in ICU delirium. We hypothesized that there are independent factors that predict delirium in a cohort of patients on melatonin in the surgical ICU (SICU). Methods A retrospective, observational case-cohort analysis of adult SICU patients was conducted. Cases were defined by testing positive on the Confusion Assessment Method for the ICU (CAM-ICU). Delirioprotective and deliriogenic factors were assessed prior to the studied melatonin administration. Results Forty-one CAM-ICU–positive cases and 59 CAM-ICU–negative controls were included. Higher mean Acute Physiology and Chronic Health Evaluation II scores were associated with delirium in univariable analysis. Stratified analysis found a higher incidence of delirium in baseline CAM-ICU–positive patients who experienced emergency surgery within 24 hours of admission compared with baseline CAM-ICU–negative patients after melatonin administration. Conclusions This study describes the use of melatonin in the SICU and characterizes the patients who receive it. Further research is needed to determine the role of melatonin in deliriogenesis and to clarify its utility as a delirioprotectant for postsurgical, critical care patients.

Effect of Duloxetine for the Treatment of Chronic Central Poststroke Pain Objectives Central poststroke pain (CPSP) is the neuropathic pain in areas of the body corresponding to stroke lesions. It is often refractory to treatment, reduces quality of life, and impedes rehabilitation. The pharmacological treatment of CPSP is challenging. Duloxetine, a serotonin-norepinephrine reuptake inhibitor, is known to be effective against neuropathic pain. The current study describes the efficacy of duloxetine in reducing pain severity in CPSP patients. Subjects and Methods For the purpose of this study, CPSP was defined as spontaneous pain within an area of the body corresponding to the brain lesion that emerged at or after stroke onset. Any previously prescribed medical therapy for the patients was not changed or stopped; duloxetine 30 mg was added to their ongoing treatment. Pain was assessed at baseline and thereafter at 1 and 3 weeks using Numeric Rating Scale (NRS) and Short-form MC Gill Pain Questionnaire scores. At the first follow-up, scores were reviewed and dose was doubled if no improvement or adverse effects were observed. Results From a total of 37 patients, 4 were withdrawn because of adverse effects including nausea, agitation, and somnolence. The mean elapsed time of observed symptoms since stroke onset was 3.1 ± 4.1 years. There was a significant difference between the mean values of Short-form MC Gill Pain Questionnaire and NRS scores at baseline and those at the follow-up assessment. Twenty-six (70.3%) of the patients showed at least 30% reduction of NRS compared with baseline at the third week. Conclusions Our findings suggest that duloxetine can be effective for managing CPSP.

The Dopamine Receptor Antagonism of Opipramol: Relevance to Parkinsonism? Drug-induced Parkinsonism (DIP) represents the second most-frequent etiology of Parkinson syndromes after neurodegenerative disorders. It has been described mainly for antipsychotics, Ca++-channel blockers, antiemetics, and gastrointestinal prokinetics. In this article, we present a clinical case series of 10 patients, retrieved within our movement disorders hospital, with DIP under intake of opipramol. Symptoms completely resolved after drug withdrawal, and associated risk factors were old age, high doses, and presence of cortical atrophy. This frequently prescribed anxiolytic drug has so far not been associated with DIP. Our objective is to raise awareness of DIP as an adverse effect of opipramol.

Chronotherapeutics: Recognizing the Importance of Timing Factors in the Treatment of Disease and Sleep Disorders This review describes the characteristics of a number of pathologies, which are considered from the point of view of chronobiology, that is, the way in which biological processes are expressed throughout the 24-hour day. This perspective is a relatively new way of thinking about disease and additionally about how to treat diseases. It has called attention to the importance of not only the quantity of a drug that is administered but also when it is administered. In addition, the review presents an overview of the emerging clinical strategies known as chronotherapeutics, that is, the effects of the daily scheduling of drug administration and the consequences of the activity and efficacy of therapies that are applied in this manner. This article also reviews innovative ways in which physicians are applying time-specified drug treatment (chronopharmacology) for sleep disorders. Here, we present a systematic description of chronopharmacology as well as definitions of key terms that, we believe, will be helpful for newcomers to the field. It is hoped that greater awareness of this new perspective on pharmacology will promote its adoption by researchers and clinicians.

An Option to Consider for Alternating Hemiplegia of Childhood: Aripiprazole Alternating hemiplegia of childhood (AHC) is an infrequent neurological disorder characterized by recurrent transient attacks of hemiplegia that last minutes to days and impress either side of the body, dystonic or tonic attacks, and nystagmus. Cognitive or neurological deficits with progressive course are another findings. Epileptic seizures may occur in some patients. We report the medical treatment in a case of AHC in a-12-year-old male patient with convulsions. The patient did not respond to available therapies for AHC, except for aripiprazole. After the initiation of aripiprazole therapy, duration and frequency of hemiplegia episodes were decreased. Also, he is currently seizure-free with topiramate treatment for 3 months. On follow-up, a compound heterozygous ATP1A3 mutation c.868C > T (p.R290C)/c.684 + 1G > A was determined. Aripiprazole may reduce the attacks of AHC, which are resistant to other available therapies.

Gabapentin-Associated Urinary Incontinence: A Case Verified by Rechallenge Introduction Gabapentin (GBP) is an analog of γ-aminobutyric acid and was originally designed as an anticonvulsant. Because its mechanism of action is unclear, assumed to have no abuse potential, and apparent lack of toxicity, GBP is used widely off-label to treat an array of disorders, including essential tremor. Case Report We present a case of an elderly woman diagnosed with essential tremor, in which GBP was initiated. In the following day, she complained of urinary incontinence with the absence of dysuria and urgency. It was not worse with movement, coughing, sneezing, or laughing. The vaginal parity of the patient was one. Laboratory tests and urinalysis were within normal limits. Assuming that the urinary symptom was an adverse drug reaction, the GBP was withdrawn and the patient's incontinence completely resolved within 2 days. Several weeks later, a rechallenge with GBP was tried. In the day 1 of GBP use, the subject reported intermittent urinary incontinence. Medication was discontinued and her continence returned. One year later, in the follow-up, the subject remained continent. Conclusions Only a few cases with GBP-associated urinary incontinence have been reported in the literature. To the authors' knowledge, these cases described individuals with only 1 attempt of the use of GBP. In this way, the present case was the first to describe a subject with the recurrence of urinary incontinence with the GBP rechallenge. This adverse effect, although not potentially fatal, can be very embarrassing to patients and lead to poor compliance with therapy.

Drug-Induced Parkinsonism Manifesting as Gait Freezing in a Patient With Traumatic Brain Injury: A Case Report Background Among the neuropsychiatric complications commonly induced by traumatic brain injury (TBI), behavioral disorders, such as agitation and aggression, can hinder neurological recovery and deteriorate rehabilitation outcomes. Pharmacological treatment for behavioral disorders might be beneficial but could lead to drug-induced parkinsonism. We report a case of a patient with drug-induced parkinsonism manifested as freezing of gait after TBI, which improved with the cessation of the offending drugs and comprehensive rehabilitation. Case Presentation A 35-year-old male patient left with a TBI after a car accident was referred to our hospital. He had been on many neuropsychiatric medications, including atypical antipsychotics, for his agitated behaviors. He could walk independently but showed freezing of gait at the initiation of his gait, when turning to the side, when reaching his destination, and passing through narrow corridors. Under the impression of drug-induced parkinsonism, we gradually tapered the patient off his neuropsychiatric medications. He also underwent comprehensive rehabilitation, including gait training under visual and auditory cues and balance training. Five weeks after admission to the hospital, the patient's freezing of gait improved, with disappearance of his hesitation at gait initiation and a decreased freezing duration while turning around. Conclusions This is a rare report of drug-induced parkinsonism manifested as freezing of gait, which showed improvement after discontinuation of the causative drugs and subsequent rehabilitation.

Levetiracetam-Related Mania-Like Symptoms: An Adolescent Case Levetiracetam is an antiepileptic agent that is used for partial and generalized epilepsy. Although it is well tolerated in most cases, behavioral and nonbehavioral adverse effects may be observed. Among behavioral symptoms, depression, hostility, and agitation have been frequently reported. However, mania or mania-like symptoms are relatively rare, especially in children and adolescents. Hereby, we report mania-like symptoms with levetiracetam use in a 15-year-old boy. Mania-like symptoms emerged 3 weeks after starting levetiracetam and disappeared after adding risperidone to ongoing levetiracetam treatment.

Sertraline-Related Amenorrhea in an Adolescent Amenorrhea is one of the clinical consequences of hyperprolactinemia. Although symptomatic hyperprolactinemia is among the well-described adverse reactions of antipsychotic agents, it may also be reported with the use of selective serotonin reuptake inhibitors. Hereby, we present a case of sertraline-related hyperprolactinemic amenorrhea in an adolescent. Amenorrhea occurred 2 months after starting sertraline, and menstrual cycle restored after stopping the treatment.

Two Cases of De Novo Pathological Gambling Associated With Aripiprazole Objectives Pathological gambling can be potentiated by treatment with dopamine agonists. Aripiprazole, bearing a partial agonist activity at dopamine D2 and D3 receptors, has also been linked to such a behavioral aberration, usually on subjects predisposed with tendency of impulsive or addictive behaviors. Methods Review of patient's medical records and literature review. Results Two young patients' pathological gambling emerged simply due to exposure to aripiprazole, neither related to manic or psychotic symptoms nor with history of addictive or impulsive behaviors. Their pathological gambling disappeared soon after switching aripiprazole to other antipsychotics. One patient has tested such a relationship by reexposure to aripiprazole while his compulsion to gamble recurred. Conclusions In addition to previously recognized risk factors, pathological gambling might occur in young patients whose history did not reveal an addictive tendency while they were sensitive to the pharmacological effect, as well as adverse effects, of psychotropic agents.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Therapeutic Drug Monitoring

Official International Association for Therapeutic Drug Monitoring and Clinical Toxicology Guideline: Development and Validation of Dried Blood Spot–Based Methods for Therapeutic Drug Monitoring Abstract: Dried blood spot (DBS) analysis has been introduced more and more into clinical practice to facilitate Therapeutic Drug Monitoring (TDM). To assure the quality of bioanalytical methods, the design, development and validation needs to fit the intended use. Current validation requirements, described in guidelines for traditional matrices (blood, plasma, serum), do not cover all necessary aspects of method development, analytical- and clinical validation of DBS assays for TDM. Therefore, this guideline provides parameters required for the validation of quantitative determination of small molecule drugs in DBS using chromatographic methods, and to provide advice on how these can be assessed. In addition, guidance is given on the application of validated methods in a routine context. First, considerations for the method development stage are described covering sample collection procedure, type of filter paper and punch size, sample volume, drying and storage, internal standard incorporation, type of blood used, sample preparation and prevalidation. Second, common parameters regarding analytical validation are described in context of DBS analysis with the addition of DBS-specific parameters, such as volume-, volcano- and hematocrit effects. Third, clinical validation studies are described, including number of clinical samples and patients, comparison of DBS with venous blood, statistical methods and interpretation, spot quality, sampling procedure, duplicates, outliers, automated analysis methods and quality control programs. Lastly, cross-validation is discussed, covering changes made to existing sampling- and analysis methods. This guideline of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology on the development, validation and evaluation of DBS-based methods for the purpose of TDM aims to contribute to high-quality micro sampling methods used in clinical practice.

Optimizing Pediatric Dosing Recommendations and Treatment Management of Antiretroviral Drugs Using Therapeutic Drug Monitoring Data in Children Living With HIV Introduction: This review summarizes the current dosing recommendations for antiretroviral (ARV) drugs in the international pediatric guidelines of the World Health Organization (WHO), US Department of Health and Human Services (DHHS), and Pediatric European Network for Treatment of AIDS (PENTA), and evaluates the research that informed these approaches. We further explore the role of data generated through therapeutic drug monitoring in optimizing the dosing of ARVs in children. Methods: A PubMed search was conducted for the literature on ARV dosing published in English. In addition, the registration documentation of European Medicines Agency and the US Food and Drug Administration for currently used ARVs and studies referenced by the WHO, DHHS, and EMA guidelines were screened. Resulting publications were screened for papers containing data on the area under the concentration–time curve, trough concentration, and peak concentration. Studies with enrolled participants with a median or mean age of ≥18 years were excluded. No restriction on publishing date was applied. Discussion and conclusion: Pediatric ARV dosing is frequently based on data obtained from small studies and is often simplified to facilitate dosing in the context of a public health approach. Pharmacokinetic parameters of pediatric ARVs are subject to high interpatient variation and this leads to a potential risk of underdosing or overdosing when drugs are used in real life. To ensure optimal use of ARVs and validate dosing recommendations for children, it is essential to monitor ARV dosing more thoroughly with larger sample sizes and to include diverse subpopulations. Therapeutic drug monitoring data generated in children, where available and affordable, have the potential to enhance our understanding of the appropriateness of simplified pediatric dosing strategies recommended using a public health approach and to uncover suboptimal dosing or other unanticipated issues postmarketing, further facilitating the ultimate goal of optimizing pediatric ARV treatment.

Dolutegravir Population Pharmacokinetics in a Real-Life Cohort of People Living With HIV Infection: A Covariate Analysis Background: There are growing concerns about dolutegravir (DTG)-related neuropsychiatric adverse events and about differences in the characteristics of people living with HIV infection (PLWH) potentially associated with higher risks of said side effects. Several studies have shown that DTG was stopped more frequently among women, older PLWH, and PLWH who initiated abacavir (ABC) at the same time. This study aimed to clarify the factors affecting the pharmacokinetics (PKs) of DTG in a real-life cohort of PLWH using a population PK approach. Methods: The model-building strategy was based on a previously published model developed from premarketing trials (1-compartment model with first-order absorption and a lag time). Sparse therapeutic drug monitoring data were obtained from a real-life cohort of 279 PLWH, and population PK analysis was performed using Monolix software. A stepwise covariate model-building strategy was used to evaluate any relevant effects of age, body weight, gender, total bilirubin, smoking status, formulations of DTG, morning versus evening dosing, backbone therapy, and other comedications including CYP/UGT inducers/inhibitors. Results: For a typical 70-kg PLWH, the apparent clearance (CL/F) and apparent volume of distribution (V/F) were 0.748 L/h and 14.6 L, respectively. Of the demographic factors evaluated, body weight was a significant covariate for CL/F and for V/F. Smokers had a 17% higher CL/F relative to nonsmokers. Both strong enzyme inhibitors (eg, atazanavir) and inducers (eg, rifampicin) had marked effects on DTG exposure, with potential clinical implications. Ritonavir-boosted darunavir was found to moderately increase clearance of DTG by 23%. No significant effect of ABC-based backbone therapy was observed on the PK parameters of DTG. Conclusions: Our results did not support the hypothesis that ABC, by competing with the DTG metabolic pathway, may significantly increase DTG exposure leading to potential drug toxicity.

Sources of Variability and Accuracy of Performance Assessment in the Clinical Pharmacology Quality Assurance Proficiency Testing Program for Antiretrovirals Background: The Clinical Pharmacology Quality Assurance (CPQA) program provides semiannual proficiency testing (PT) of antiretroviral analytes for 11 US and international clinical pharmacology laboratories (CPLs) to ensure interlaboratory comparability. In this article, we provide estimates of the main sources of variability and assess the accuracy of the algorithm for the assessment of performance. Methods: Descriptive statistics are reported from 13 PT rounds from 2010 to 2016. Eight of the most common antiretroviral analytes were examined. Variance components analysis was used to rank the relative contributions of CPLs, antiretroviral analyte, and concentration category (low, medium, and high) to bias and variability using mixed models. Binary classification metrics of the PT assessment algorithm are calculated in comparison with a model using 95% prediction limits around estimated regression equations. Results: CPLs provided 4109 reported concentrations of 65 unique samples for each of the 8 antiretroviral analytes across 13 PT rounds. Individual CPL accounted for the greatest amount of total variability (4.4%). Individual CPL and analyte combination (interaction) accounted for the greatest amount of bias (8.1%). Analyte alone accounted for 0.5% or less for total variability and bias. Overall, using a ±20% acceptance window around the final target, 97% of individual reported concentrations were scored acceptable, and 96% of antiretroviral/round scores were deemed satisfactory. Comparison with the regression model gave 100% sensitivity but only 34.47% specificity. Narrowing the acceptance window to ±15% improved specificity to 84.47% while maintaining a 99.17% sensitivity. Conclusions: The current CPQA PT scoring algorithm that use a ±20% acceptance window seems to suffer from a low specificity and may be too lenient. A stricter ±15% acceptance window would increase specificity and overall accuracy while lowering the overall pass rate by only 3%.

Comparison of Immunoassays for Measuring Serum Levels of Golimumab and Antibodies Against Golimumab in Ulcerative Colitis: A Retrospective Observational Study Background: Golimumab is a monoclonal anti–tumor necrosis factor alpha antibody, which is used in ulcerative colitis with an exposure–response relationship. The goal of this study was to compare results obtained with different immunoassays (golimumab and antigolimumab antibodies trough levels). Methods: This study was based on samples from 78 ulcerative colitis patients on golimumab treatment. Golimumab was quantified by either an anti-IgG detection antibody (Theradiag, Marne la Vallée, France) or an antibody directed against golimumab (Sanquin, Amsterdam, The Netherlands, KU Leuven, Leuven, Belgium, and Janssen R&D, San Diego, CA). Bridging drug-sensitive enzyme-linked immunosorbent assays (Theradiag, Janssen R&D, and KU Leuven), a bridging drug-tolerant enzyme-linked immunosorbent assay (Janssen R&D), and a radioimmunoassay (Sanquin) were used to quantify antidrug antibody. Results: Median serum golimumab levels were 4.5, 3.5, 4.9, and 2.4 mcg/mL with Theradiag, Sanquin, KU Leuven, and Janssen R&D assay, respectively (P < 0.05). Correlation coefficients between assays ranged from 0.9 to 0.97. When using the KU Leuven and Janssen R&D assays, 86% of samples were in the same quartile of distribution of values, and for Sanquin and Janssen R&D assays, this overlap was 80%. The concordance observed for the other pairs was 83% (Sanquin/KU Leuven R&D), 71% (Theradiag/KU Leuven), and 68% (Theradiag/Janssen R&D and Theradiag/Sanquin). The specificity of assays for golimumab was demonstrated. Antidrug antibodies were detected in 28.2% of the samples with the Janssen R&D drug-tolerant assay and in the same 2 patients by the 3 other assays. Conclusions: Performances of these immunoassays were similar in terms of quality, but differences in the quantitative results point to the importance of using the same assay consistently to monitor a patient's treatment.

Determination of Cetuximab in Plasma by Liquid Chromatography–High-Resolution Mass Spectrometry Orbitrap With a Stable Labeled 13C,15N-Cetuximab Internal Standard Background: Cetuximab (CTX) is a chimeric IgG1 Kappa monoclonal antibody used to treat head and neck cancer and colorectal cancer. Previous clinical studies indicated that the pharmacokinetics of CTX influences patient survival. Thus, individualizing CTX treatment by measuring trough levels of the drug in plasma could have a major impact on clinical efficacy. Methods: To measure these levels, a full-length stable isotope-labeled CTX standard was used in a generic, rapid, and high-throughput sample preparation protocol based on IgG capture followed by trypsin digestion, on-line solid-phase extraction cleanup, and liquid chromatography–high resolution mass spectrometry (LC-HRMS). Results: The optimized method displayed good analytical performance and was linear over a range from 5 to 150 mcg/mL. The within-run and between-run imprecision of the assay were equal to or less than 10%, for 6 replicates at 3 different concentrations and for runs performed on 5 separate days. The plasma CTX concentrations in 19 patients were also determined. Conclusions: The results showed that quantification of mAb in clinical samples does not strictly require a tandem mass spectrometry system, and LC-HRMS is also relevant in this context. This first study implementing a quantitative LC-HRMS assay with a specific stable isotope-labeled mAb internal standard paves the way for more robust clinical monitoring of anticancer mAbs.

Development and Validation of a Fast Ultra-High Performance Liquid Chromatography–Fluorescent Method for the Quantification of Hydroxychloroquine and Its Metabolites in Patients With Lupus Background: Hydroxychloroquine (HCQ) is approved for the treatment of systemic lupus erythematosus (SLE). Therapeutic drug monitoring of HCQ is necessary to detect nonadherence and to improve treatment efficacy in patients with SLE. Liquid chromatographic–tandem mass spectroscopy and high performance liquid chromatography (HPLC)–fluorescent methods are currently used to measure whole blood concentrations of HCQ and its 2 main metabolites desethylhydroxychloroquine and desethylchloroquine in patients with SLE. This study reports the development and validation of an ultra-HPLC (U-HPLC) method with fluorescence detection for the simultaneous quantification of HCQ and its metabolites in whole blood. Methods: After adding chloroquine (internal standard) to the samples, a single-step protein precipitation and a subsequent filtration were used for blood sample preparation. Analytes were separated under isocratic elution on a U-HPLC RP18 column with a total run time of 7 minutes. The mobile phase consisted of piperazine buffer (46.4 mM, pH = 9.8) and acetonitrile (68:32, vol/vol), which was delivered at a flow rate of 0.4 mL/min. Fluorescence excitation and emission wavelengths were 335 and 390 nm, respectively. Assay performance parameters were evaluated per FDA bioanalytical guidelines. Results: The calibration curve was linear from 125 to 4000 ng/mL for HCQ. The lower limit of quantification was 10 ng/mL for all analytes. For HCQ, desethylchloroquine, and desethylhydroxychloroquine, accuracies and imprecisions ranged from −7.90% to 7.85% and 1.14% to 8.78%, respectively. Conclusions: A sensitive, accurate, and fast U-HPLC–fluorescent method was validated and successfully applied to quantify whole blood concentrations to perform therapeutic drug monitoring of HCQ in pediatric and adult lupus patients.

Examining the Relationship Between Vancomycin Area Under the Concentration Time Curve and Serum Trough Levels in Adults With Presumed or Documented Staphylococcal Infections Background: Investigations of the relationship between vancomycin trough concentrations and area under the concentration time curve (AUC) are growing, but still limited. The authors sought to determine vancomycin exposure among hospitalized adults with presumed or confirmed invasive staphylococcal infections using 2-level pharmacokinetic monitoring to inform changes to an institutional vancomycin dosing protocol. Methods: This was a retrospective observational study performed in 2 acute care hospitals. Adults prescribed vancomycin (therapeutic trough 15–20 mg/L) for a presumed or documented invasive staphylococcal infection were evaluated. Two steady-state serum vancomycin levels were used to determine each patient's 24-hour AUC to minimum inhibitory concentration ratio (AUC/MIC) using a non-Bayesian, equation-based approach. Patient demographics and crude clinical outcomes were also collected. Results: Thirty-four patients were included in the study, with 2 patients having vancomycin levels drawn twice (36 sets of levels). Most patients were located in an intensive care unit (91.2%), and 85.3% of patients were prescribed vancomycin for bacteremia, pneumonia, or endocarditis. The mean ± SD vancomycin Cmin was 16.6 ± 6.1 mg/L, and the mean AUC/MIC was 588 ± 156 mg/L × hour. The rate of 24-hour vancomycin AUC/MIC target attainment was 91.2% (n = 31/34). Of the patients with a Cmin > 9 mg/L, 100% (n = 33) achieved AUC/MIC values >400 mg/L × hour and 93.9% were >500 mg/L × hour. There was a strong correlation between vancomycin Cmin and AUC24 hr (R2 = 0.731; P < 0.001). Conclusions: Targeting a vancomycin trough between 15 and 20 mg/L frequently resulted in an AUC/MIC greater than that thought to be necessary for efficacy optimization. Considering these findings alongside the practical challenges associated with wide-scale implementation of AUC monitoring, reducing the target trough as a means to prevent vancomycin overexposure warrants clinical consideration and further evaluation.

Quantification of the Plasma Concentration of Apatinib by 2-Dimensional Liquid Chromatography Background: Apatinib is a new oral micromolecular tyrosine kinase inhibitor, which is mainly used as a third-line treatment for chemotherapy-refractory advanced metastatic gastric cancer patients. However, apatinib has shown dose titration and severe adverse reactions in clinical practice. Quantification of plasma concentrations of apatinib may be an effective method to balance the clinical efficacy and adverse reactions. The purpose of this study was to develop and validate a 2-dimensional liquid chromatography method for the measurement of apatinib in plasma. Methods: The analysis of apatinib was performed using a 2-dimensional high-performance liquid chromatography system. We precipitated the proteins with acetonitrile. The mobile phases consisted of a first-dimensional mobile phase (acetonitrile:methanol:25 mmol·L−1 ammonium phosphate = 25:25:50, V/V/V, pH adjusted to 7.2 using phosphoric acid) and a second-dimensional mobile phase (acetonitrile:10 mmol·L−1 ammonium phosphate = 28:72, vol/vol, pH adjusted to 3.7 using phosphoric acid). The ultraviolet detection wavelength was set at 340 nm. The temperature of the detector cell was 40°C, and the injection volume was 500 μL. Results: The range of calibration curve was 15.27–1491.48 ng/mL. The accuracy and imprecision were within ±2.23% and less than 10.22%, respectively (intraday and interday). The range of recovery was 97.45%–108.92%. The intraday and interday relative SDs (reproducibility) of high-performance liquid chromatography retention times were less than 0.18% and 0.46%, respectively. In the clinical assessment, the dose range of apatinib mesylate for patients with gastric cancer was 250–500 mg every day (2–60 days), resulting in trough plasma concentrations between 272.7 and 727.8 ng/mL. Conclusions: A simple, convenient, accurate, and robust 2-dimensional liquid chromatography method was developed and verified, which successfully determined the plasma concentrations of apatinib in patients with gastric cancer.

Tolerability of Erythrocyte Ribavirin Triphosphate Concentrations Depends on the ITPA Genotype Background: Ribavirin (RBV) is an antiviral drug that is part of the current standard therapy for chronic hepatitis C (CHC). It is enzymatically converted to ribavirin triphosphate (RTP) that inhibits the activity of viral RNA polymerase, thereby preventing viral replication. However, one of its adverse effects includes hemolytic anemia that limits its application. The variant of ITPA (inosine triphosphatase), which dephosphorylates inosine triphosphate to inosine monophosphate, is a protective factor for RBV-induced anemia. RTP is an important metabolite required for ribavirin action. This study evaluated the time-dependent association of RTP concentrations in erythrocytes, RBV-induced toxicity, and virological response to RBV treatment for hepatitis C. Methods: A total of 28 Japanese patients with CHC were treated with RBV/peg-interferon/simeprevir or RBV/sofosbuvir and were genotyped for ITPA variants (rs1127354 and rs7270101). We measured RTP concentrations in erythrocytes in a total of 76 samples collected at 4, 8, and 12 weeks from the initiation of treatment. Results: The ITPA rs1127354 variant was found in 7 patients. This was associated with significantly higher RTP concentrations in erythrocytes than in the wild-type patients (P < 0.001). Moreover, a significant correlation was observed between RTP concentrations and decline in hemoglobin (Hb) levels from baseline values in ITPA wild type and rs1127354 variant 12 weeks after treatment initiation (P < 0.01; r = −0.618 and −0.967, respectively). Multiple regression analysis revealed that ITPA genotype and erythrocyte RTP concentrations were major factors associated with reduced Hb levels in RBV therapy for CHC. However, we did not find any association between erythrocyte concentrations and virological response. Conclusions: The increased tolerability to RTP concentrations in erythrocytes in the ITPA variant rs1127354 plays a role in preventing RBV-induced severe anemia in this ITPA variant.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Nursing Research

Maintaining and Improving Psychological Well-Being No abstract available

Mediating Effects of Social Support on Depression and Suicidal Ideation in Older Korean Adults With Hypertension Who Live Alone Background: Older adults who live alone are less physically and emotionally healthy and report higher levels of depression relative to those who do not live alone. Suicide is the most problematic health issue reported by older adults who live alone. In particular, vulnerable older adults who live alone experience difficulty obtaining self-care and medical services; therefore, early detection of depression is difficult, and there are few opportunities to implement suicide prevention strategies in this population. In addition, social support for depression is an important factor affecting illness and economic vulnerability in older adults who live alone. Purpose: This study aimed to examine the relationship between depression and suicidal ideation in vulnerable older Korean adults with hypertension and to explore the mediating effect of social support on this relationship. Methods: The study used a cross-sectional design. Vulnerable older adults who were 65 years old or older with hypertension and who received home visit services from a public health center were invited to participate. The participants completed structured questionnaires, including the 15-item Short-Form Geriatric Depression Scale, 12-item Multidimensional Scale of Perceived Social Support, and 19-item Scale for Suicidal Ideation, and provided information regarding their demographic characteristics, health status, and economic status. Descriptive and correlation analyses were performed to examine the correlations among these variables. The three-step regression analysis method proposed by Baron and Kenny was used to examine the mediating effect of social support. Results: The mean depression, social support, and suicidal ideation scores of participants were 23.64 (± 2.04), 35.94 (± 15.40), and 7.80 (± 7.73), respectively. In addition, depression was negatively correlated with social support (r = −.27) and positively correlated with suicidal ideation (r = .21), whereas social support was negatively correlated with suicidal ideation (r = −.35). Social support mediated the relationship between depression and suicidal ideation (Z = 2.69). Conclusions: Social support was identified as an important variable for older adults with chronic illness who lived alone. Interventions that include social support hold the potential to reduce depression and suicidal ideation in this population.

Comparisons of Health Promoting Behavior, Depression, and Life Satisfaction Between Older Adults in Rural Areas in South Korea Living in Group Homes and at Home Background: In South Korea, population aging is advancing at a more rapid rate in rural areas than urban areas, leading to a particularly high percentage of rural-dwelling older adults. Purpose: The aim of this study was to examine and compare health promoting behaviors, depression, and life satisfaction between rural-dwelling older adults who live, respectively, in group homes and at home. Methods: A cross-sectional descriptive study design was employed. Study participants included 160 older adults aged 65 years and older who were living in group homes (n = 80) and at home (n = 80) in Gyeonggi province, South Korea. The Health Promotion Lifestyle Profile-II was used to examine health promoting behaviors, the Korean Geriatric Depression Screening Scale was used to examine depression, and the Life Satisfaction Index was used to examine life satisfaction. Data were analyzed using SPSS Version 21.0. Results: The data showed significant differences between the two groups in terms of health promoting behaviors (t = −9.035, p < .001), depression (t = 20.861, p < .001), and life satisfaction (t = −12.153, p < .001). Conclusions/Implications for Practice: The mean scores for health promotion behaviors and life satisfaction were higher, and the mean score for depression was lower in the group-home group than the at-home group. The findings from this study may be employed as basic data for establishing residence-appropriate nursing intervention protocols for older adults living in rural areas.

Investigation of the Experiences of Mothers Living Through Prenatal Loss Incidents: A Qualitative Study Background: Fetal death causes women to experience negative feelings after the loss. These lived experiences influence the future pregnancies and maternal health of women negatively. Purpose: The aim of this study was to investigate the experiences of women whose pregnancies were terminated because of medical indications. Methods: A "design for definitive status study" type of qualitative research design was used. Ten women who were hospitalized between April and July 2017 at the Akdeniz University Clinic of Obstetrics and Gynecology and had subsequently experienced pregnancy loss during their hospitalization were enrolled as participants. Thematic analysis was used to analyze the data. Results: The pregnancy loss experiences of participants were investigated under the five main themes of (a) lived experiences before the termination of pregnancy, (b) lived experiences after pregnancy termination, (c) willingness to see the baby after termination, (d) posttermination care requirements, and (e) physical condition of hospital rooms during hospitalization. The participants expressed feelings of hope, fear, and worry over being unsuccessful before fetal death and feelings of loneliness, disappointment, blame, and avoidance after fetal death. Conclusions/Implications for Practice: In the aftermath of fetal death, health professionals should use insightful and empathic communication skills to help mothers cope with their loss. In addition, some of the participants wanted to see their babies, and some did not. Thus, individualized care is very important for women who experience pregnancy loss.

Alcohol Consumption as a Moderator of Anxiety and Sleep Quality Background: Although people who sleep poorly may attempt to relieve anxiety for better sleep quality, whether daily alcohol consumption is a factor that moderates anxiety and sleep disturbance is not known. Purpose: The aim of the study was to explore (a) the association between anxiety and sleep quality and (b) whether daily alcohol consumption acted as a moderator between anxiety and sleep quality in those who reported sleeping poorly. Methods: Eighty-four participants aged 20–80 years who reported poor sleep (Pittsburgh Sleep Quality Index > 5) in northern Taiwan were enrolled in this cross-sectional study. A structured questionnaire covering demographics (including daily alcohol consumption), level of anxiety, level of depression, and perceived sleep quality was used to collect data. Results: The participants were mostly women (72.6%). The mean age was 41.81 (SD = 12.62) years; 51.2%, 19.0%, 13.1%, and 14.3%, respectively, had minimal, mild, moderate, and severe anxiety. After adjusting for factors related to sleep quality using multiple regression analysis, receiving sleep therapy, consuming alcohol on a daily basis, and having anxiety were found to be predictors of poor sleep quality. Moreover, daily alcohol consumption was found to moderate the relationship between anxiety and sleep quality. Conclusions/Implications for Practice: People who sleep poorly should avoid misusing alcohol to self-treat poor sleep quality or anxiety and should instead utilize sleep hygiene education and mental healthcare. Daily alcohol consumption may be a moderator between anxiety status and sleep quality.

Predictors of Caregiver Burden in Caregivers of Bedridden Patients Background Caregivers are at risk of experiencing caregiver burden. It is therefore important to determine the caregiver burden of caregivers who provide care to bedridden patients and related factors. Purpose The aim of this study was to determine the caregiver burden of caregivers who provide care to bedridden patients and the factors that impact this burden. Methods This cross-sectional study was executed at a state hospital in Istanbul, Turkey, on bedridden patients registered in the home healthcare unit and their caregivers. During study period, the researchers made 312 visits to patients and their caregivers. A sociodemographic questionnaire, the Burden Interview, and the Katz Index of Independence in Activities of Daily Living were used to collect data. Descriptive statistics, an independent sample t test, one-way analysis of variance, and stepwise multiple regression analysis were used for data analysis. Results The participants reported a moderate level of caregiver burden. Existing caregiver health problems, caregiver employment status, the ability of the caregiver to maintain his or her own good health, type of home, and the degree of patient dependence in terms of activities of daily living were each found to be significant predictors of caregiver burden. Conclusions/Implications of Practice The support provided to caregivers by home healthcare units is important in terms of protecting the physical, mental, and social health conditions of caregivers and preventing the exacerbation of caregiver burden.

The Relationship Between the Quality of Work and Organizational Commitment of Prison Nurses Background: Nurses working in prisons are exposed to security problems while serving those who may be uninterested in their own healthcare, face high risks of drug and alcohol addiction, and may have aggressive personalities. For this reason, nurses working in prisons may have more problems with work-related quality of life than their non-prison-nurse peers. Purpose: This descriptive research study was conducted to evaluate the work-related quality of life and organizational commitment of nurses who work at prisons and detention centers. Methods: According to 2015 data, approximately 513 nurses currently work in prisons in Turkey. The study group consisted of 224 nurses who currently work in prisons or detention centers. The data were collected by sending a created link address to the e-mail addresses of nurses who work in these facilities. A 13-item sociodemographic information form, including a demographics datasheet, a work-related quality of life scale, and an organizational commitment scale, was used to collect data. Results: The participants reported a moderate level of work-related quality of life and organizational commitment. Moreover, work-related quality of life was shown to affect organizational commitment, with 20% of the total variance in organizational commitment explained by work-related quality of life. Conclusions/Implications for Practice: This study supports that work-related quality of life affects organizational commitment positively. Therefore, regulating working conditions by taking into consideration employee security will positively affect job satisfaction in terms of both the institution and the employee. Moreover, as nurses do not only work in hospitals, taking this action should also work in different settings. Administrators should ensure the work-related quality of life of the prison nurses by understanding the difficulties of prison nursing.

Stress, Workplace Violence, and Burnout in Nurses Working in King Abdullah Medical City During Al-Hajj Season Background: The Hajj pilgrimage to Mecca, one of the largest mass gatherings in the world, is associated with various challenges for nurses. One of these challenges is increased levels of workplace violence. Therefore, handling and mitigating workplace violence against nurses during Hajj, when nurses face a higher risk of violence and most experience stress and burnout, is of particular importance. Purpose: The aims of this study were to identify the types and sources of workplace violence, examine the relationship between burnout in nurses and the variables of stress and workplace violence, and identify from the perspective of nurses measures to effectively handle and mitigate these issues during Hajj season. Methods: This study used a descriptive correlational design. A convenience sample of 118 nurses completed the Perceived Stress Scale, the Maslach Burnout Inventory, and the modified version of the Joint Programme on Workplace Violence in the Health Sector published by the International Labour Office in Geneva. Data analysis was done using an independent samples t test and Pearson product–moment correlation. Results: One hundred eighteen nurses completed the study. Over two thirds (65%) were female, and 56% reported experiencing at least one type of violence, of which bullying/mobbing, racial harassment, threats, and physical violence accounted for 61%, 15%, 12%, and 12%, respectively. Nurse managers displayed violent behaviors against 54% of the participants. Participants reported high levels of stress and burnout. A positive relationship was found between stress and emotional exhaustion (r = .387, p < .01). Providing effective security measures and staff training regarding how to deal with violence at the workplace were the main measures identified to help reduce workplace violence. Conclusions: Providing effective security measures and tailored intervention programs addressing how to deal with violence in the workplace may enable nurses to handle violent behaviors more effectively.

Using a Text Mining Approach to Explore the Recording Quality of a Nursing Record System Background: Most nursing records in Taiwan have been computerized, resulting in a large amount of unstructured text data. The quality of these records has rarely been discussed. Purpose: This study used a text mining method to analyze the quality of a nursing record system to establish an auditing model and associated tools for nursing records, with the ultimate objective of improving the quality of electronic nursing records. Methods: This study utilized a retrospective method to collect the electronic nursing records of 6,277 patients who had been discharged from the internal medicine departments of a medical center in northern Taiwan from January to June 2014. SAS Enterprise Guide Version 6.1 and SAS Text Miner Version 13.2 software were used to perform text mining. Nursing experts were invited to examine the electronic nursing records. The text mining results were compared against a benchmark that was developed by the experts, and the efficiency of SAS Text Miner was examined using the criteria of specificity, sensitivity, and accuracy. Results: In this study, 27,356 nurse-formulated events were used in the analysis. The results of the nurse-formulated events showed an 8.08% similar error with system-formulated events, 29.72% were identified as necessary and appropriate names, 17.53% were retained, 10.15% involved error event names, and 34.52% were not classified. In this study, the sensitivity of SAS text mining in the training (testing) data set was 96% (95%), and the specificity and accuracy were both 99% (99%). Conclusions: The results of this study show that text mining is an effective approach to auditing the quality of electronic nursing records. SAS Text Miner software was shown to identify inappropriate nursing record content quickly and efficiently. Furthermore, the results of this study may be included in in-service education teaching materials to promote the writing of better nursing records to improve the quality of electronic nursing records.

Frail Phenotype and Disability Prediction in Community-Dwelling Older People: A Systematic Review and Meta-Analysis of Prospective Cohort Studies Background: The World Health Organization has identified frailty as a crucial factor affecting successful aging. Systematic literature reviews have yet to focus on the relationship between stages of frailty and disability in community-dwelling older adults. Purpose: The purpose of this study was to investigate the relationships between various frailty types and disability in community-dwelling older adults and to explore how various frailty criteria have been used to assess disability in this population. Methods: A systematic literature review and meta-analysis were conducted on articles from the following databases: Cochrane Library, CINAHL, PubMed, and Ovid. Database search criteria included articles that were published between January 2001 and July 2017 and study samples that included community-dwelling adults aged 60 years and older. We excluded studies that were conducted in institutions or hospitals and experimental studies on frailty. Two reviewers independently assessed eligibility and extracted data. A random-effects model was used to analyze the literature and to calculate the pooled disability of frailty. Results: In total, nine studies with a total sample of 32,998 participants that recorded 8,666 disabilities and a mean follow-up time of 30.4 months (SD = 29.26) were pooled for the meta-analysis. Using various indicators to predict the risk of disability compared with robust older adults, those with frailty faced a higher risk of disability, followed by older adults at risk of frailty. Conclusions/Implications for Practice: Frailty is a crucial health consideration among older adults. Those who are frail have the highest relative risk of disability, followed by those at risk of frailty. Early assessment of frailty may effectively prevent the occurrence of frailty-induced disability in older adults.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Dermatitis

SELF-ASSESSMENT No abstract available

Poison Ivy, Oak, and Sumac Dermatitis: What Is Known and What Is New? Poison ivy, poison oak, and poison sumac are the most common causes of clinically diagnosed allergic contact dermatitis in North America. Approximately 50% to 75% of the US adult population is clinically sensitive to poison ivy, oak, and sumac. We reviewed the botany and history of these plants; urushiol chemistry and pathophysiology, clinical features, and the prevalence of allergic contact dermatitis caused by these plants; and current postexposure treatment and preventive methods, including ongoing investigations in the development of a vaccine (immunotherapy). Although extensive efforts have been made to develop therapies that prevent and treat contact dermatitis to these plants, there lacks an entirely effective method, besides complete avoidance. There is a need for a better therapy to definitively prevent allergic contact dermatitis to these plants.

Bathing Additives for Atopic Dermatitis — A Systematic Review Bathing additives are regularly used for a range of inflammatory dermatoses that affect a large body surface area. Emerging evidence demonstrates that certain bathing additives have anti-inflammatory, skin barrier repair, antimicrobial, and antioxidative properties, all pertinent to atopic dermatitis. This review summarizes the mechanism and effects of Dead Sea salt, hard water, commercial baby cleansers, oatmeal, rice, and natural oils as bathing additives for the treatment of atopic dermatitis. The use of these compounds seems to augment the benefit of traditional treatments while also reducing the need for and side effects of prescription modalities. Bathing additives are useful adjuvant treatments for atopic dermatitis. Benefits of these compounds are derived from anti-inflammatory, antimicrobial, antioxidative, and skin barrier repair properties.

Effects of Merino Wool on Atopic Dermatitis Using Clinical, Quality of Life, and Physiological Outcome Measures Background Wool clothing may be perceived as a poor choice for use by individuals with sensitive skin or atopic dermatitis. Objectives The aims of the study were to evaluate the effect on atopic dermatitis of wearing fine Merino wool clothing versus standard clothing and to assess the effect of Merino wool clothing on quality of life in children and adults with atopic dermatitis 5 years and older. Methods Subjects with mild to moderate atopic dermatitis were assessed in a crossover fashion after wearing Merino wool clothing for 6 weeks and standard clothing for 6 weeks, for Eczema Area and Severity Index, Dermatology Life Quality Index, static Investigator's Global Assessment, and skin hydration. Results While wearing Merino wool clothing, compared with standard clothing, statistically significant improvements were seen in mean Eczema Area and Severity Index scores, Dermatology Life Quality Index scores, and static Investigator's Global Assessment scores. No significant difference was seen with skin hydration. Wearing Merino wool clothing did not produce any negative cutaneous effects compared with wearing standard clothing. Conclusions Merino wool clothing compared with standard clothing provided improvements in severity of atopic dermatitis as well as quality of life in atopic patients.

Formaldehyde Release From Baby Wipes: Analysis Using the Chromotropic Acid Method Background Formaldehyde is a common preservative and strong sensitizer. Objective The aim of the study was to evaluate the release of formaldehyde from baby/toddler wet wipes using the chromotropic acid method (CAM). Methods An online search of best-selling baby wipes was conducted. None declared formaldehyde or formaldehyde-releasing preservatives. Standard CAM procedures were used: a 1 × 1-in square of fresh wipe was placed in a bottle with an open vial of 4 mg/1 mL of chromotropic acid and sulfuric acid solution, sealed, and stored for 48 hours. Formalin and water served as controls. A blinded investigator graded color change (negative, indeterminate, mild, moderate, or strong). For quality control, 20% of all samples as well as all positives were retested. Results Fifty-one popular and highly reviewed baby and toddler wet wipe products were tested using CAM. Twelve wipes (24%) released formaldehyde (8 mild, 4 moderate/strong). Chromotropic acid method testing of 9 wipes (18%) was indeterminate and 30 (59%) were negative. Conclusions Almost one quarter of baby/toddler wet wipes released formaldehyde when evaluated with CAM. Patients and clinicians should be aware of this potentially undeclared source of this common allergen.

Cross-sectional Survey of Nickel Allergy Management in the Context of Intracardiac Device Implantation Background The occlusion devices used for repair of atrial septal defect and patent foramen ovale commonly contain nitinol, an alloy containing nickel. There are reports of nickel allergy in the context of intracardiac device implantation. Type IV delayed-type reactions likely predominate in intracardiac metal hypersensitivity, but there are potentially other mechanisms such as cytotoxic or innate immunity. Based on available literature to date, the significance of nickel allergy in intracardiac occluders remains unclear. Objective The aim of the study was to investigate nickel allergy management strategies in intracardiac occluders. Methods The American Contact Dermatitis Society facilitated distribution of a survey via e-mail to the members of its association, which included dermatologists and allergists/immunologists. A total of 70 individuals answered the survey. Conclusions There was no consensus regarding the ability of patch testing to accurately determine allergic reactions within cardiac tissue. There was also no agreement on the criteria for patch testing in patients undergoing intracardiac implantation. However, most would inquire about a history of contact sensitivity to previously implanted devices. With a positive patch test, nickel-based intracardiac devices should be avoided, or the decision should be left to the discretion of the cardiologist.

Screening for Gold Sensitization in Consecutive Eczema Patients: Prevalence, Relevance, and Sources of Exposure Background Since the 1990s, gold has been recognized as an important contact allergen. Objectives Based on our results with gold sodium thiosulfate (GST) in the TRUE Test patch test system in the baseline series, the aims of the study were to evaluate baseline testing with gold salts worldwide and to discuss relevance. Methods Patients with positive patch test reactions to GST were questioned on exposure at day 7 reading. Results In a 1-year period, 89 (18.5%) of 480 patients tested positive to GST, making this the most frequent contact allergy. The 89 patients comprised 18 males and 71 females. The reaction was considered relevant in 21%; this is a minimum figure because 2 patients were withdrawn because of unknown relevance and because clinical features suggestive of gold contact allergy at distant sites, such as the face, were not taken into account. Altogether, 88% had been exposed. Worldwide, the prevalence of gold sensitization ranges between 0.78% and 30.7%, and relevance, in larger studies, has been between 15% and 20% of patients. The use of earrings and the presence of dental gold were important sources of exposure. Conclusions Because it may be difficult to diagnose gold allergy, screening may be recommended when history taken suggests gold exposure.

Allergic Contact Dermatitis to Licorice Root Extract No abstract available

Oh My Glucosides! Occult Sources in Medical Products No abstract available

Allergic Contact Dermatitis Due to Benzoyl Peroxide From an Unlikely Source No abstract available

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Anaesthesia

Retrieval of a Esophageal pH Monitoring Probe Dislodged Into the Laryngopharynx: A Case Report Esophageal pH monitoring via wireless probes is used to evaluate chest pain and atypical symptoms and diagnose gastroesophageal reflux. These probes are commonly placed during esophagogastroduodenoscopy performed by gastroenterologists in an ambulatory anesthesia setting. Dislodgment and aspiration of these probes can cause morbidity, require surgical removal, and involve the anesthesia provider in prolonged emergency care. We present a case of a probe dislodgment where aspiration was avoided and describe how retrieval of this device is different from typical hypopharyngeal foreign body removal.

Urgent Complex Intraoperative Reintubation in a Known Difficult Airway After Endotracheal Tube Damage: A Case Report Treacher Collins syndrome is an inherited disorder resulting in maldevelopment of the first and second branchial arches. Patients have complex orofacial anatomy often requiring airway interventions from birth. A 17-year-old boy with Treacher Collins syndrome and history of difficult ventilation and intubation presented for elective maxillofacial reconstruction. After uneventful awake nasal fiberoptic intubation, the nasotracheal tube was damaged intraoperatively. Due to the patient's unique anatomy, a fiberoptic bronchoscope and ventilating exchange catheter were utilized together to facilitate a nasotracheal tube exchange. This case demonstrates the utilization of a combination of advanced airway techniques in an urgent perioperative setting.

Supraglottic Airway Rescue After Failed Fiberoptic Intubation in a Patient With Osteogenesis Imperfecta: A Case Report We describe the management of a pregnant patient with osteogenesis imperfecta with a history of numerous fractures, severe scoliosis, and anticipated difficult airway. Her pregnancy was complicated by progressive shortness of breath and a fetal diagnosis of osteogenesis imperfecta. Spine anatomy precluded neuraxial anesthesia. Cesarean delivery was performed under general anesthesia at 34 weeks. Immediately after awake fiberoptic intubation and induction of general anesthesia, capnography waveform was lost with rapid profound oxygen desaturation. A supraglottic airway device was placed, oxygenation maintained with supraglottic airway and positive pressure ventilation throughout case, and the baby was delivered with Apgars of 8 and 9.

Successful Use of Cangrelor and Heparin for Cardiopulmonary Bypass in a Patient With Heparin-Induced Thrombocytopenia and End-Stage Renal Disease: A Case Report Heparin is the only well-established anticoagulant medication for cardiopulmonary bypass making selecting an alternative anticoagulant challenging in patients with heparin-induced thrombocytopenia. Other anticoagulant medications can cause significant postoperative bleeding, especially in patients with end-stage renal disease. We present a case of a 63-year-old woman requiring aortic valve replacement with a history of heparin-induced thrombocytopenia and end-stage renal disease. Cangrelor and heparin were successfully used during cardiopulmonary bypass, offering an option for anticoagulation management for a uniquely challenging patient population.

Extraluminal Use of a Pediatric Bronchial Blocker With Confirmation by Point-of-Care Ultrasound: A Case Report Lung isolation for pediatric thoracic surgery is especially challenging in a patient with chronic lung infection and need to protect the nonoperative lobes from the spread of infection during anesthesia and surgery. Typically, for pediatric thoracic surgery, a mainstem intubation or placement of an intraluminal bronchial blocker is sufficient for lung isolation. The patient whose case is reported here suffered from a pleuropulmonary blastoma compressing the left lower lobe bronchus and resultant chronic infection involving the left lower lobe. In this unusual situation, to isolate the chronic lung infection and to provide the needed adequate operative conditions, endobronchial intubation of the right, nonoperative lung and placement of an endobronchial blocker into the left lower lobe bronchus were performed. Intraoperative point-of-care ultrasound was then used to confirm ventilation of the right lung segments and absence of air movement in the left upper lobe.

Efficacy of Sugammadex in Preventing Skin Test Reaction in a Patient With Confirmed Rocuronium Anaphylaxis: A Case Report The curative role of sugammadex has been challenged in several observations of rocuronium-induced anaphylaxis because sugammadex may not completely encapsulate the molecule of rocuronium. In such conditions, rocuronium remains able to cause immunoglobulin E cross-linkage and the anaphylaxis mechanism can continue. We describe a case of rocuronium-induced anaphylaxis in which clinical improvement followed sugammadex administration. Intradermic skin tests confirmed rocuronium immunoglobulin E–mediated anaphylaxis but also showed intradermal injection of mixing in equal molecular ratio of sugammadex with rocuronium preventing rocuronium anaphylactic skin reaction. This observation demonstrates the efficacy of sugammadex to prevent rocuronium interaction with the skin immune system.

Nebulized Lidocaine in the Treatment of Refractory Postoperative Laryngospasm: A Case Report Intraoperative laryngospasm occurs in <1% of cases. Recurrent laryngospasm is rarer. Some risk factors include shared airway and pediatric surgery, secretions, pungent volatile anesthetics, and patient factors, such as smoking and asthma. Conventional management includes the application of positive airway pressure, jaw thrust, the removal of any offending stimuli, deepening anesthesia, or administering muscle relaxants. Nebulized lidocaine is used to anesthetize the vocal cords before awake fiberoptic intubation. This case highlights the novel use of nebulized lidocaine to successfully treat refractory postoperative laryngospasm in a fully conscious adult patient after conventional measures were unsuccessful.

Failed Awake Intubation for Critical Airway Obstruction Rescued With the Ventrain Device and an Arndt Exchange Catheter: A Case Report A 71-year-old man with advanced vocal cord carcinoma presented with severe airway obstruction. Therapeutic anticoagulation with enoxaparin complicated management. Failure of an oral awake bronchoscopic intubation was rescued by passing a guidewire through the working channel and threading an Arndt exchange catheter into the trachea under videoscopic vision. Ventilation with the Ventrain device lasting 40 minutes (15 L/min, inspiration/expiration 1:1, 15 breaths/min), during IV anesthesia with muscle paralysis, resulted in excellent blood gas values until placement of the tracheal cannula. This case report highlights the effectiveness of a novel ventilation technique that should be considered as back-up when bronchoscopic intubation fails.

Localized Corticosteroid Injections for Malignant Joint Pain in the Oncologic Population: A Case Series Pain is a common issue that is present in cancer survivors as well as those with active malignant processes. Despite opioid analgesics and adjuvant therapies such as systemic corticosteroids, many patients have persistent localized pain. We describe a case series of 3 cancer patients who have concurrent hip- and greater trochanteric–related pain. We performed a single-insertion-site, ultrasound-guided injection to target both the intra-articular hip and greater trochanteric bursa for each patient. All patients reported an improvement in pain symptoms and function with no major complications. Targeted corticosteroid injections provide a potential for relief of malignant joint pain.

Low-Dose Intrathecal Ziconotide for Spasticity From Primary Lateral Sclerosis: A Case Report Spasticity can be very debilitating and painful. We present a case of severe spasticity from primary lateral sclerosis refractory to intrathecal baclofen in doses up to 1100 μg/d. Baclofen was weaned down and switched to intrathecal ziconotide at 0.6 μg/d. The dose was then titrated up to 3 μg/d with excellent control of spasticity. This case suggests that low-dose intrathecal ziconotide should be considered in patients with lower extremity spasticity refractory to intrathecal baclofen.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com