Moral reasoning perspectives of community pharmacists in situations of drug shortages

BACKGROUND: Drug shortages affect health systems worldwide. Research in community pharmacy has focused on the nature, extent and impact of these shortages on patients and pharmacists. However, pharmacists' moral reasoning in situations of drug shortages has not been addressed. OBJECTIVE: To explore the moral reasoning perspectives of Dutch community pharmacists in situations of drug shortages. METHOD: An electronic survey was developed around three drug shortage scenarios with a varying impact on patient outcomes: a Contraceptive, a Parkinson's and an Osteoporosis scenario. Pharmacists rated the likelihood of nine handling options and rated and ranked 13 considerations that may have played a role therein. The considerations represented three moral reasoning perspectives (MRPs): a business orientation (BO), a rules and regulations (RR), and a professional ethics (PE) MRP. Principle component analysis (PCA) was used to investigate construct validity of the MRPs. MRP rating and MRP ranking scores measured the relative importance of the different MRPs of pharmacists in the three shortages. RESULTS: Results from 267 Pharmacists were obtained. They reported mostly similar handling in the three shortages, except for the likelihood to make agreements with prescribers or other pharmacists and regarding the decision to import a product. The PCA analysis confirmed the three MRPs that accounted for 29% of variance in the data. Both the MRP rating and especially the MRP ranking scores indicated that PE-MRP considerations were most influential on pharmacists' intended handling of the shortages. In the Contraceptive and the Osteoporosis scenarios, the relative importance of a BO-MRP was higher than in the Parkinson's scenario. CONCLUSION: Pharmacists predominantly reason with a PE-MRP when handling drug shortages. However, this perspective can be compromised when the drug shortage is perceived to have a lower impact on patient outcomes and when alternative drugs or therapy are expensive

Effects of bumetanide on neurodevelopmental impairments in patients with tuberous sclerosis complex: An open-label pilot study

Background: Tuberous sclerosis complex (TSC) is an autosomal dominant disease that affects multiple organs including the brain. TSC is strongly associated with broad neurodevelopmental disorders, including autism spectrum disorder symptomatology. Preclinical TSC studies have indicated altered neuronal chloride homeostasis affecting the polarity of γ-aminobutyric acid (GABA) ergic transmission as a potential treatment target. Bumetanide, a selective NKCC1 chloride importer antagonist, may attenuate depolarizing GABA action, and in that way reduce disease burden. In this open-label pilot study, we tested the effect of bumetanide on a variety of neurophysiological, cognitive, and behavioral measures in children with TSC. Methods: Participants were treated with bumetanide (2dd 0.5-1.0 mg) for 13 weeks in an open-label trial. The Aberrant Behavior Checklist-Irritability (ABC-I) subscale was chosen as the primary endpoint. Secondary endpoints included other behavioral questionnaires in addition to event-related potentials (ERP) and neuropsychological tests if tolerated. Additionally, the treatment effect on seizure frequency and quality of life was assessed. Endpoint data were collected at baseline, after 91 days of treatment and after a 28-day wash-out period. Results: Fifteen patients (8-21-years old) with TSC were included of which 13 patients completed the study. Treatment was well-tolerated with only expected adverse events due to the diuretic effects of bumetanide. Irritable behavior (ABC-I) showed significant improvement after treatment in 11 out of 13 patients (t(12) = 4.41, p =.001, d =.773). A favorable effect was also found for social behavior (Social Responsiveness Scale) (t(11) = 4.01, p =.002, d =.549) and hyperactive behavior (ABC-hyperactivity subscale) (t(12) = 3.65, p =.003, d =.686). Moreover, patients rated their own health-related quality of life higher after treatment. At baseline, TSC patients showed several atypical ERPs versus typically developing peers of which prepulse inhibition was significantly decreased in the TSC group. Neuropsychological measurements showed no change and bumetanide had no effect on seizure frequency. Limitations: The sample size and open-label design of this pilot study warrant caution when interpreting outcome measures. Conclusions: Bumetanide treatment is a potential treatment to alleviate the behavioral burden and quality of life associated with TSC. More elaborate trials are needed to determine the application and effect size of bumetanide for the TSC population. Trial registration EU Clinical Trial Register, EudraCT 2016-002408-13 (www.clinicaltrialsregister.eu/ctr-search/trial/2016-002408-13/NL). Registered 25 July 2016

Условия формирования зон скопления метана в углепородном массиве

Розглянуті основні геологічні чинники, які впливають на формування зон скупчення метану у вуглепородному масиві. Виділені, найбільш ефективні показники для середнього катагенеза порід – опосередковані локальні структури, зони тріщинуватості порід, стрижневі ділянки пісковиків (палеопотоки). Для виділених показників виконаний розрахунок дисперсійного аналізу по альтернативній ознаці. На основі розрахунків встановлено вплив кожного фактора на формування зон скупчення метану у вуглепродному масиві.Basic geological factors, which influence on forming of zone of accumulation of methane in coalrock massif, are presented. The most effective indexes for middle katagenesis of rock are determinated - medial local structures, zone of jointing of rock, race areas of sandstones (paleocurrent). For determinated indexes calculation of dispersion on an alternative character is executed. On the basis of calculations influence of every factor on forming of zone of accumulation of methane in a coalrock massif is definited

Assessing the genetic association between vitamin B6 metabolism and genetic generalized epilepsy

Altered vitamin B6 metabolism due to pathogenic variants in the gene PNPO causes early onset epileptic encephalopathy, which can be treated with high doses of vitamin B6. We recently reported that single nucleotide polymorphisms (SNPs) that influence PNPO expression in the brain are associated with genetic generalized epilepsy (GGE). However, it is not known whether any of these GGE-associated SNPs influence vitamin B6 metabolite levels. Such an influence would suggest that vitamin B6 could play a role in GGE therapy. Here, we performed genome-wide association studies (GWAS) to assess the influence of GGE associated genetic variants on measures of vitamin B6 metabolism in blood plasma in 2232 healthy individuals. We also asked if SNPs that influence vitamin B6 were associated with GGE in 3122 affected individuals and 20,244 controls. Our GWAS of vitamin B6 metabolites reproduced a previous association and found a novel genome-wide significant locus. The SNPs in these loci were not associated with GGE. We found that 84 GGE-associated SNPs influence expression levels of PNPO in the brain as well as in blood. However, these SNPs were not associated with vitamin B6 metabolism in plasma. By leveraging polygenic risk scoring (PRS), we found suggestive evidence of higher catabolism and lower levels of the active and transport forms of vitamin B6 in GGE, although these findings require further replication.Peer reviewe

Clinical characteristics and diagnoses of 1213 children referred to a first seizure clinic

Objective: New-onset seizure-like events (SLEs) are common in children, but differentiating between epilepsy and its mimics is challenging. This study provides an overview of the clinical characteristics, diagnoses, and corresponding etiologies of children evaluated at a first seizure clinic (FSC), which will be helpful for all physicians involved in the care of children with SLEs. Methods: We included 1213 children who were referred to the FSC of a Dutch tertiary children's hospital over a 13-year period and described their clinical characteristics, first routine EEG recording results, and the distribution and specification of their eventual epilepsy and non-epilepsy diagnoses. The time interval to correct diagnosis and the diagnostic accuracy of the FSC were evaluated. Results: “Epilepsy” was eventually diagnosed in 407 children (33.5%), “no epilepsy” in 737 (60.8%), and the diagnosis remained “unclear” in 69 (5.7%). Epileptiform abnormalities were seen in 60.9% of the EEG recordings in the “epilepsy” group, and in 5.7% and 11.6% of the “no epilepsy” and “unclear” group, respectively. Of all children with final “epilepsy” and “no epilepsy” diagnoses, 68.6% already received their diagnosis at FSC consultation, and 2.9% of the children were initially misdiagnosed. The mean time to final diagnosis was 2.0 months, and 91.3% of all children received their final diagnosis within 12 months after the FSC consultation. Significance: We describe the largest pediatric FSC cohort to date, which can serve as a clinical frame of reference. The experience and expertise built at FSCs will improve and accelerate diagnosis in children with SLEs. Plain language summary: Many children experience events that resemble but not necessarily are seizures. Distinguishing between seizures and seizure mimics is important but challenging. Specialized first-seizure clinics can help with this. Here, we report data from 1213 children who were referred to the first seizure clinic of a Dutch children's hospital. One-third of them were diagnosed with epilepsy. In 68.8% of all children—with and without epilepsy—the diagnosis was made during the first consultation. Less than 3% were misdiagnosed. This study may help physicians in what to expect regarding the diagnoses in children who present with events that resemble seizures

High-resolution electric source imaging for presurgical evaluation of tuberous sclerosis complex patients

Objective: We retrospectively assessed the localizing value of patient-history-based semiology (PHS), video-based semiology (VS), long-term monitoring video electroencephalography (LTM-VEEG) and interictal high resolution electric source imaging (HR-ESI) in the presurgical workup of patients with tuberous sclerosis complex (TSC). Methods: Data from 24 consecutive TSC surgical candidates who underwent both HR-ESI and LTM-VEEG was retrospectively collected. PHS and VS were analyzed to hypothesize the symptomatogenic zone localization. LTM-VEEG and HR-ESI localization results were extracted from the diagnostic reports. Localizing value was compared between modalities, taken the resected/disconnected area of surgical patients in consideration. HR-ESI's impact on the epileptogenic zone hypothesis and surgical workup was evaluated. Results: Semiology, interictal EEG, ictal EEG and HR-ESI were localizing in 25%, 54%, 63% and 79% of patients. Inter-modality concordance ranged between 33–89%. In good surgical outcome patients, PHS, VS, interictal EEG, ictal EEG and HR-ESI showed concordance with resected area in 1/9 (11%), 0/9 (0%), 4/9 (44%), 3/9 (33%) and 6/9 patients (67%). HR-ESI positively impacts clinical management in 50% of patients. Conclusions: In presurgical evaluation of TSC patients, semiology often has limited localizing value. Presurgical work-up benefits from HR-ESI. Significance: Our findings may advice future presurgical epilepsy workup of TSC patients with the ultimate aim to improve outcome

Toward responsible clinical n-of-1 strategies for rare diseases

N-of-1 strategies can provide high-quality evidence of treatment efficacy at the individual level and optimize evidence-based selection of off-label treatments for patients with rare diseases. Given their design characteristics, n-of-1 strategies are considered to lay at the intersection between medical research and clinical care. Therefore, whether n-of-1 strategies should be governed by research or care regulations remains a debated issue. Here, we delineate differences between medical research and optimized clinical care, and distinguish the regulations which apply to either. We also set standards for responsible optimized clinical n-of-1 strategies with (off-label) treatments for rare diseases. Implementing clinical n-of-1 strategies as defined here could aid in optimized treatment selection for such diseases

Fetal brain magnetic resonance imaging findings predict neurodevelopment in children with tuberous sclerosis complex

Objective: To correlate fetal brain magnetic resonance imaging (MRI) findings with epilepsy characteristics and neurodevelopment at 2 years of age in children with tuberous sclerosis complex (TSC) to improve prenatal counseling. Study design: This retrospective cohort study was performed in a collaboration between centers of the EPISTOP consortium. We included children with definite TSC, fetal MRIs, and available follow-up data at 2 years of age. A pediatric neuroradiologist masked to the patient's clinical characteristics evaluated all fetal MRIs. MRIs were categorized for each of the 10 brain lobes as score 0: no (sub)cortical lesions or doubt; score 1: a single small lesion; score 2: more than one small lesion or at least one large lesion (&gt;5 mm). Neurologic manifestations were correlated to lesion sum scores. Results: Forty-one children were included. Median gestational age at MRI was 33.3 weeks; (sub)cortical lesions were detected in 97.6%. Mean lesion sum score was 4.5. At 2 years, 58.5% of patients had epilepsy and 22% had drug-resistant epilepsy. Cognitive, language, and motor development were delayed in 38%, 81%, and 50% of patients, respectively. Autism spectrum disorder (ASD) was diagnosed in 20.5%. Fetal MRI lesion sum scores were significantly associated with cognitive and motor development, and with ASD diagnosis, but not with epilepsy characteristics. Conclusions: Fetal cerebral lesion scores correlate with neurodevelopment and ASD at 2 years in children with TSC.</p

The epileptogenic zone in children with tuberous sclerosis complex is characterized by prominent features of focal cortical dysplasia

OBJECTIVE: Patients with tuberous sclerosis complex (TSC) present with drug-resistant epilepsy in about 60% of cases, and evaluation for epilepsy surgery may be warranted. Correct delineation of the epileptogenic zone (EZ) among multiple dysplastic lesions on MRI represents a challenging step in pre-surgical evaluation. METHODS: Two experienced neuroradiologists evaluated pre- and post-surgical MRIs of 28 epilepsy surgery patients with TSC, assessing characteristics of tubers, cysts, calcifications, and focal cortical dysplasia (FCD)-resembling lesions. Utilizing multiple metrics, we compared MRI features of the EZ-defined as the resected area in TSC patients who achieved seizure-freedom 2 years after epilepsy surgery-with features of other brain areas. Using combinatorial analysis, we identified combinations of dysplastic features that are most frequently observed in the epileptogenic zone in TSC patients. RESULTS: All TSC-associated dysplastic features were more frequently observed in the EZ than in other brain areas (increased cortical thickness, gray-white matter blurring, transmantle sign, calcifications, and tubers; Kendal's tau 0.35, 0.25, 0.27, 0.26, and 0.23, respectively; P value <.001 in all). No single feature could reliably and independently indicate the EZ in all patients. Conversely, the EZ was indicated by the presence of the combination of three of the following features: tubers, transmantle sign, increased cortical thickness, calcifications, and the largest FCD-affected area. Out of these, the largest FCD-affected area emerged as the most reliable indicator of the EZ, combined either with calcifications or tubers. SIGNIFICANCE: The epileptogenic zone in TSC patients harbors multiple dysplastic features, consistent with focal cortical dysplasia. A specific combination of these features can indicate the EZ and aid in pre-surgical MRI evaluation in epilepsy surgery candidates with TSC