"Laser and the Tuber": thermal dynamic and volumetric factors influencing seizure outcomes in pediatric subjects with tuberous sclerosis undergoing stereoencephalography-directed laser ablation of tubers.

PURPOSE: Tuberous sclerosis (TSC) is a well-known cause of medically refractory epilepsy (MRE). Stereoencephalography-directed magnetic resonance-guided laser interstitial thermal therapy (SEEG-directed MRgLITT) is an emerging minimally invasive technique that appears aptly suited for the surgical management of TSC. Our aims are to present our experiences with patients who had undergone SEEG-directed MRgLITT to identify and treat cortical tubers responsible for clinical seizures and to perform an in-depth analysis of volumetric and thermal dynamic factors that may be related to seizure outcomes. METHODS: We studied all pediatric patients with MRE due to TSC who underwent SEEG-directed MRgLITT, investigating seizure outcomes in relation to thermal dynamic and volumetric factors. RESULTS: Eight cortical tubers from three pediatric patients were analyzed. Two of three patients had Engel I outcomes at last follow-up (median 18 months). Average A/T (ablation volume/tuber volume) ratio for Engel I outcomes was 1.28 (variance, 0.16) and 0.84 (variance, < 0.01) for all other outcomes (P = 0.035). There was a moderate positive correlation when comparing ablation energy to ablation volume (R2 = 0.65) in cortical tuber tissue. When the calcified tuber is excluded, the correlation is stronger (R2 = 0.77). Thus, the calculated energy needed to ablate 1 cm3 of cortical tuber tissue is 1263.6 J (calcified tuber) or 1089.5 J (non-calcified tuber). CONCLUSIONS: SEEG-directed MRgLITT appears to be a safe and effective technique in the management of pediatric patients with MRE due to TSC. The A/T ratio may be a useful indicator in predicting seizure outcomes.

Early outcomes of stereoelectroencephalography followed by MR-guided laser interstitial thermal therapy: a paradigm for minimally invasive epilepsy surgery.

OBJECTIVE Stereoelectroencephalography (sEEG) and MR-guided laser interstitial thermal therapy (MRgLITT) have both emerged as minimally invasive alternatives to open surgery for the localization and treatment of medically refractory lesional epilepsy. Although some data are available about the use of these procedures individually, reports are almost nonexistent on their use in conjunction. The authors' aim was to report early outcomes regarding efficacy and safety of sEEG followed by MRgLITT for localization and ablation of seizure foci in the pediatric population with medically refractory lesional epilepsy. METHODS A single-center retrospective review of pediatric patients who underwent sEEG followed by MRgLITT procedures was performed. Demographic, intraoperative, and outcome data were compiled and analyzed. RESULTS Four pediatric patients with 9 total lesions underwent sEEG followed by MRgLITT procedures between January and September 2017. The mean age at surgery was 10.75 (range 2-21) years. Two patients had tuberous sclerosis and 2 had focal cortical dysplasia. Methods of stereotaxy consisted of BrainLab VarioGuide and ROSA robotic guidance, with successful localization of seizure foci in all cases. The sEEG procedure length averaged 153 (range 67-235) minutes, with a mean of 6 (range 4-8) electrodes and 56 (range 18-84) contacts per patient. The MRgLITT procedure length averaged 223 (range 179-252) minutes. The mean duration of monitoring was 6 (range 4-8) days, and the mean total hospital stay was 8 (range 5-11) days. Over a mean follow-up duration of 9.3 (range 5.1-16) months, 3 patients were seizure free (Engel class I, 75%), and 1 patient saw significant improvement in seizure frequency (Engel class II, 25%). There were no complications. CONCLUSIONS These early data demonstrate that sEEG followed by MRgLITT can be used safely and effectively to localize and ablate epileptogenic foci in a minimally invasive paradigm for treatment of medically refractory lesional epilepsy in pediatric populations. Continued collection of data with extended follow-up is needed.

Assessing molecular initiating events (MIEs), key events (KEs) and modulating factors (MFs) for styrene responses in mouse lungs using whole genome gene expression profiling following 1-day and multi-week exposures.

Styrene increased lung tumors in mice at chronic inhalation exposures of 20ppm and greater. MIEs, KEs and MFs were examined using gene expression in three strains of male mice (the parental C57BL/6 strain, a CYP2F2(-/-) knock out and a CYP2F2(-/-) transgenic containing human CYP2F1, 2A13 and 2B6). Exposures were for 1-day and 1, 4 and 26weeks. After 1-day exposures at 1, 5, 10, 20, 40 and 120ppm significant increases in differentially expressed genes (DEGs) occurred only in parental strain lungs where there was already an increase in DEGs at 5ppm and then many thousands of DEGs by 120ppm. Enrichment for 1-day and 1-week exposures included cell cycle, mitotic M-M/G1 phases, DNA-synthesis and metabolism of lipids and lipoproteins pathways. The numbers of DEGs decreased steadily over time with no DEGs meeting both statistical significance and fold-change criteria at 26weeks. At 4 and 26weeks, some key transcription factors (TFs) - Nr1d1, Nr1d2, Dbp, Tef, Hlf, Per3, Per2 and Bhlhe40 - were upregulated (|FC|>1.5), while others - Npas, Arntl, Nfil3, Nr4a1, Nr4a2, and Nr4a3 - were down-regulated. At all times, consistent changes in gene expression only occurred in the parental strain. Our results support a MIE for styrene of direct mitogenicity from mouse-specific CYP2F2-mediated metabolites activating Nr4a signaling. Longer-term MFs include down-regulation of Nr4a genes and shifts in both circadian clock TFs and other TFs, linking circadian clock to cellular metabolism. We found no gene expression changes indicative of cytotoxicity or activation of p53-mediated DNA-damage pathways.

Moral injury in psychiatric patients with personality and other clinical disorders: development, psychometric properties, and validity of the Moral Injury Events Scale-Civilian Version.

Background: Moral injury emerges when someone perpetrates, fails to prevent, or witnesses acts that violate their own moral or ethical code. Nash et al. [(2013). Psychometric evaluation of the moral injury events scale. Military Medicine, 178(6), 646-652] developed a short measure, the Moral Injury Events Scale (MIES) to facilitate the empirical study of moral injury in the military. Our study aimed to develop a civilian version of the measure (MIES-CV) and examine its psychometric properties in a sample of psychiatric inpatients .Methods: In this cross-sectional study, the sample comprised 240 adult patients (71.7% female) with a mean age of 31.57 (SD = 11.69). The most common diagnoses in the sample were anxiety disorders (58.3%), depressive disorders (53.8%), and borderline personality disorder (39.6%). Participants were diagnosed using structured clinical interviews and filled out psychological questionnaires.Results: Exploratory factor analysis suggested that Nash et al.'s model (Perceived Transgressions, Perceived Betrayals) represents the data well. This two-factor solution showed an excellent fit in the confirmatory factor analysis, as well. Meaningful associations were observed between moral injury and psychopathology dimensions, shame, reflective functioning, well-being, and resilience. The Perceived Betrayals factor was a significant predictor of bipolar disorders, PTSD, paranoid personality disorder, borderline personality disorder, and avoidant personality disorder.Conclusions: Our study demonstrated that this broad version of the MIES is a valid measure of moral injury that can be applied to psychiatric patients.

The Moral Injury Events Scale­Civilian Version is a reliable and valid instrument.The original 2-factor solution (Perceived Transgressions, Perceived Betrayals) yielded a good fit to the data.Moral injury's Perceived Betrayals factor predicted bipolar disorders, PTSD, and three personality disorders (paranoid PD, borderline PD, avoidant PD).

Physio-metabolic and clinical consequences of wearing face masks-Systematic review with meta-analysis and comprehensive evaluation.

Background: As face masks became mandatory in most countries during the COVID-19 pandemic, adverse effects require substantiated investigation. Methods: A systematic review of 2,168 studies on adverse medical mask effects yielded 54 publications for synthesis and 37 studies for meta-analysis (on n = 8,641, m = 2,482, f = 6,159, age = 34.8 ± 12.5). The median trial duration was only 18 min (IQR = 50) for our comprehensive evaluation of mask induced physio-metabolic and clinical outcomes. Results: We found significant effects in both medical surgical and N95 masks, with a greater impact of the second. These effects included decreased SpO2 (overall Standard Mean Difference, SMD = -0.24, 95% CI = -0.38 to -0.11, p < 0.001) and minute ventilation (SMD = -0.72, 95% CI = -0.99 to -0.46, p < 0.001), simultaneous increased in blood-CO2 (SMD = +0.64, 95% CI = 0.31-0.96, p < 0.001), heart rate (N95: SMD = +0.22, 95% CI = 0.03-0.41, p = 0.02), systolic blood pressure (surgical: SMD = +0.21, 95% CI = 0.03-0.39, p = 0.02), skin temperature (overall SMD = +0.80 95% CI = 0.23-1.38, p = 0.006) and humidity (SMD +2.24, 95% CI = 1.32-3.17, p < 0.001). Effects on exertion (overall SMD = +0.9, surgical = +0.63, N95 = +1.19), discomfort (SMD = +1.16), dyspnoea (SMD = +1.46), heat (SMD = +0.70), and humidity (SMD = +0.9) were significant in n = 373 with a robust relationship to mask wearing (p < 0.006 to p < 0.001). Pooled symptom prevalence (n = 8,128) was significant for: headache (62%, p < 0.001), acne (38%, p < 0.001), skin irritation (36%, p < 0.001), dyspnoea (33%, p < 0.001), heat (26%, p < 0.001), itching (26%, p < 0.001), voice disorder (23%, p < 0.03), and dizziness (5%, p = 0.01). Discussion: Masks interfered with O2-uptake and CO2-release and compromised respiratory compensation. Though evaluated wearing durations are shorter than daily/prolonged use, outcomes independently validate mask-induced exhaustion-syndrome (MIES) and down-stream physio-metabolic disfunctions. MIES can have long-term clinical consequences, especially for vulnerable groups. So far, several mask related symptoms may have been misinterpreted as long COVID-19 symptoms. In any case, the possible MIES contrasts with the WHO definition of health. Conclusion: Face mask side-effects must be assessed (risk-benefit) against the available evidence of their effectiveness against viral transmissions. In the absence of strong empirical evidence of effectiveness, mask wearing should not be mandated let alone enforced by law. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021256694, identifier: PROSPERO 2021 CRD42021256694.

Possible toxicity of chronic carbon dioxide exposure associated with face mask use, particularly in pregnant women, children and adolescents - A scoping review.

Introduction: During the SARS-CoV-2-pandemic, face masks have become one of the most important ubiquitous factors affecting human breathing. It increases the resistance and dead space volume leading to a re-breathing of CO2. So far, this phenomenon and possible implications on early life has not been evaluated in depth. Method: As part of a scoping review, literature was systematically reviewed regarding CO2 exposure and facemask use. Results: Fresh air has around 0.04% CO2, while wearing masks more than 5 min bears a possible chronic exposure to carbon dioxide of 1.41% to 3.2% of the inhaled air. Although the buildup is usually within the short-term exposure limits, long-term exceedances and consequences must be considered due to experimental data. US Navy toxicity experts set the exposure limits for submarines carrying a female crew to 0.8% CO2 based on animal studies which indicated an increased risk for stillbirths. Additionally, mammals who were chronically exposed to 0.3% CO2 the experimental data demonstrate a teratogenicity with irreversible neuron damage in the offspring, reduced spatial learning caused by brainstem neuron apoptosis and reduced circulating levels of the insulin-like growth factor-1. With significant impact on three readout parameters (morphological, functional, marker) this chronic 0.3% CO2 exposure has to be defined as being toxic. Additional data exists on the exposure of chronic 0.3% CO2 in adolescent mammals causing neuron destruction, which includes less activity, increased anxiety and impaired learning and memory. There is also data indicating testicular toxicity in adolescents at CO2 inhalation concentrations above 0.5%. Discussion: There is a possible negative impact risk by imposing extended mask mandates especially for vulnerable subgroups. Circumstantial evidence exists that extended mask use may be related to current observations of stillbirths and to reduced verbal motor and overall cognitive performance in children born during the pandemic. A need exists to reconsider mask mandates.

Is a Mask That Covers the Mouth and Nose Free from Undesirable Side Effects in Everyday Use and Free of Potential Hazards?

Many countries introduced the requirement to wear masks in public spaces for containing SARS-CoV-2 making it commonplace in 2020. Up until now, there has been no comprehensive investigation as to the adverse health effects masks can cause. The aim was to find, test, evaluate and compile scientifically proven related side effects of wearing masks. For a quantitative evaluation, 44 mostly experimental studies were referenced, and for a substantive evaluation, 65 publications were found. The literature revealed relevant adverse effects of masks in numerous disciplines. In this paper, we refer to the psychological and physical deterioration as well as multiple symptoms described because of their consistent, recurrent and uniform presentation from different disciplines as a Mask-Induced Exhaustion Syndrome (MIES). We objectified evaluation evidenced changes in respiratory physiology of mask wearers with significant correlation of O2 drop and fatigue (p < 0.05), a clustered co-occurrence of respiratory impairment and O2 drop (67%), N95 mask and CO2 rise (82%), N95 mask and O2 drop (72%), N95 mask and headache (60%), respiratory impairment and temperature rise (88%), but also temperature rise and moisture (100%) under the masks. Extended mask-wearing by the general population could lead to relevant effects and consequences in many medical fields.

Patterns of genetic diversity in three plant lineages endemic to the Cape Verde Islands.

Conservation of plant diversity on islands relies on a good knowledge of the taxonomy, distribution and genetic diversity of species. In recent decades, a combination of morphology- and DNA-based approaches has become the standard for investigating island plant lineages and this has led, in some cases, to the discovery of previously overlooked diversity, including 'cryptic species'. The flora of the Cape Verde archipelago in the North Atlantic is currently thought to comprise ∼740 vascular plant species, 92 of them endemics. Despite the fact that it is considered relatively well known, there has been a 12 % increase in the number of endemics in the last two decades. Relatively few of the Cape Verde plant lineages have been included in genetic studies so far and little is known about the patterns of diversification in the archipelago. Here we present an updated list for the endemic Cape Verde flora and analyse diversity patterns for three endemic plant lineages (Cynanchum, Globularia and Umbilicus) based on one nuclear (ITS) and four plastid DNA regions. In all three lineages, we find genetic variation. In Cynanchum, we find two distinct haplotypes with no clear geographical pattern, possibly reflecting different ploidy levels. In Globularia and Umbilicus, differentiation is evident between populations from northern and southern islands. Isolation and drift resulting from the small and fragmented distributions, coupled with the significant distances separating the northern and southern islands, could explain this pattern. Overall, our study suggests that the diversity in the endemic vascular flora of Cape Verde is higher than previously thought and further work is necessary to characterize the flora.

Towards a non-animal risk assessment for anti-androgenic effects in humans.

Toxicology testing is undergoing a transformation from a system based on high-dose studies in laboratory animals to one founded primarily on in vitro methods that evaluate changes in normal cellular signalling pathways using human-relevant cells or tissues. We review the tools and approaches that could be used to develop a non-animal safety assessment for anti-androgenic effects in humans, with a focus on the molecular initiating events (MIEs) that human disorders indicate critical for normal functioning of the hypothalamus-pituitary-testicular (HPT) axis. In vitro test systems exist which can be used to characterize the effects of test chemicals on some MIEs such as androgen receptor antagonism, inhibition of steroidogenic enzymes or 5α-reductase inhibition. When used alongside information describing the pharmacokinetics of a specific chemical exposure, these could be used to inform a pathways-based safety assessment. However, some parts of the HPT axis such as events occurring in the hypothalamus or pituitary are not well represented by accepted in vitro methods. In vitro tools to characterize perturbations in these events need to be developed before a fully integrated model of the HPT axis can be described. Knowledge gaps also exist which prevent us from using in vitro data to predict the type and severity of in vivo effect(s) that could arise from a given level of in vitro anti-androgenic activity. This means that more work is needed to reliably link an MIE with an adverse outcome. However, especially for chemicals with low anti-androgenic activity, human exposure data can be used to put in vitro mode of action data into context for risk-based safety decision-making.

Role of endoscopic sphincterotomy of the minor papilla in pancreas divisum.

BACKGROUND: Pancreas divisum (PD) is a common anatomical variant of the pancreatic duct system. Only a little percentage of patients with this altered anatomy develop symptoms: acute recurrent pancreatitis (ARP), chronic pancreatitis (CP) and pancreatic-type pain alone. These have been supposed to arise from an obstruction to outflow of the pancreatic dorsal duct due to a stenosis of the minor papilla. Endoscopic sphincterotomy of the minor papilla (MiES) can be considered an effective treatment for patients with PD and ARP supported by stenosis or obstruction of the minor papilla. On the other hand, the access through the minor papilla is essential for therapeutic pancreatic endoscopy in patients with PD and CP, but the effectiveness of MiES in these patients is extremely controversial. MATERIALS AND METHODS: Aim of this brief review has been to evaluate the short and long-term effects of endoscopic pancreatic interventions in patients affected by symptomatic PD who underwent therapeutic endoscopic retrograde cholangiopancreatography (ERCP) with pancreatic sphincterotomy of the minor papilla (MiES). The main literature database was Medline (1966-2013). RESULTS: Data come from a personal overview of articles emerging from the same search strategy. CONCLUSIONS: Nowadays, when endoscopic pancreatic drainage is indicated in patient with symptomatic PD, access through the minor papilla (MiP) is required. Therapeutic endoscopic interventions provide less invasive alternatives to the surgical approach.