Rat strain differences in seizure frequency and hilar neuron loss after systemic treatment with pilocarpine.

At least 3 months after systemic treatment with pilocarpine to induce status epilepticus, Long-Evans and Sprague-Dawley rats were video-EEG monitored for seizures continuously for 1 month. Rats were then perfused, hippocampi were processed for Nissl staining, and hilar neurons were quantified. Seizure frequency in Long-Evans rats was 1/10th of that in Sprague-Dawley rats, and more variable. Hilar neuron loss was also less severe in Long-Evans rats. However, there was no correlation between hilar neuron loss and seizure frequency in either strain. The low and variable seizure frequency suggests limited usefulness of pilocarpine-treated Long-Evans rats for some epilepsy experiments.

"On the books" yet "off the record"-occupational injury and migrant women: scoping review findings from OECD countries, with implications for New Zealand.

Introduction: Little appears to be known regarding the work-related injury (WRI) experiences of migrants (those born in a country other than their identified host country) and specifically, women migrants. Methods: As part of a wider PhD project investigating the WRI experiences of New Zealand (NZ) migrants, a review of NZ mainstream media coverage of migrants WRIs was undertaken, which identified no representations of migrant women's WRI experiences. In turn, a scoping review was undertaken to identify peer-reviewed publications reporting empirical findings about WRI experiences and outcomes for migrants in Organization for Economic Co-operation and Development (OECD) member countries, including NZ. This paper aims to identify and describe findings for migrant women specifically. From 2,243 potential publications, 383 proceeded to full text review; ultimately 67 were retained. These 67 publications were reviewed to identify findings specifically for occupationally injured migrant women; 22 such publications (from 21 studies) were found. This paper reports: the characteristics of identified studies; characteristics of migrant women within; frameworks and theories used, and knowledge (and gaps) related to occupationally injured migrant women. Results: Publications came from only four OECD countries, the United States, Canada, Australia, and Spain. A range of study designs, and topic areas (working conditions, legal rights, identities, the role of gatekeepers, and precarity), were identified; however, only three studies reported findings for longer-term experiences and outcomes of WRIs. Nine publications considered theoretical models underpinning research, including theories about precarious work, stigmatization, and citizenship. However, there was a paucity of analyses of the WRI experience throughout the life-course, highlighting a gap in understanding of how these experiences are "lived" over the long term by occupationally injured migrant women. Discussion: Scoping review findings were synthesized using a provisional "matryoshka framing narrative" model, to be refined through forthcoming qualitative interviews with occupationally injured NZ migrant women. This model highlights the multitude of influences in WRI experiences, potentially specific to migrant women, suggesting the consequences of WRIs may be uneven, with migrant women experiencing different, and potentially, greater disparities in outcomes. These findings provide an impetus to investigate knowledge gaps and urgently address potential disparities in WRI outcomes for migrant women specifically.

N-(4-Bromo-2,5-Dimethoxyphenethyl)-6-(4-Phenylbutoxy)Hexan-1-Amine (XOB): A Novel Phenylalkylamine Antagonist of Serotonin 2A Receptors and Voltage-Gated Sodium Channels.

Bipolar disorder impacts millions of patients in the United States but the mechanistic understanding of its pathophysiology and therapeutics is incomplete. Atypical antipsychotic serotonin2A (5-HT2A) receptor antagonists, such as quetiapine and olanzapine, and mood-stabilizing voltage-gated sodium channel (VGSC) blockers, such as lamotrigine, carbamazepine, and valproate, show therapeutic synergy and are often prescribed in combination for the treatment of bipolar disorder. Combination therapy is a complex task for clinicians and patients, often resulting in unexpected difficulties with dosing, drug tolerances, and decreased patient compliance. Thus, an unmet need for bipolar disorder treatment is to develop a therapeutic agent that targets both 5-HT2A receptors and VGSCs. Toward this goal, we developed a novel small molecule that simultaneously antagonizes 5-HT2A receptors and blocks sodium current. The new compound, N-(4-bromo-2,5-dimethoxyphenethyl)-6-(4-phenylbutoxy)hexan-1-amine (XOB) antagonizes 5-HT-stimulated, Gq-mediated, calcium flux at 5-HT2A receptors at low micromolar concentrations while displaying negligible affinity and activity at 5-HT1A, 5-HT2B, and 5-HT2C receptors. At similar concentrations, XOB administration inhibits sodium current in heterologous cells and results in reduced action potential (AP) firing and VGSC-related AP properties in mouse prefrontal cortex layer V pyramidal neurons. Thus, XOB represents a new, proof-of-principle tool that can be used for future preclinical investigations and therapeutic development. This polypharmacology approach of developing a single molecule to act upon two targets, which are currently independently targeted by combination therapies, may lead to safer alternatives for the treatment of psychiatric disorders that are increasingly being found to benefit from the simultaneous targeting of multiple receptors. SIGNIFICANCE STATEMENT: The authors synthesized a novel small molecule (XOB) that simultaneously antagonizes two key therapeutic targets of bipolar disorder, 5-HT2A receptors and voltage-gated sodium channels, in heterologous cells, and inhibits the intrinsic excitability of mouse prefrontal cortex layer V pyramidal neurons in brain slices. XOB represents a valuable new proof-of-principle tool for future preclinical investigations and provides a novel molecular approach to the pharmacological treatment of complex neuropsychiatric disease, which often requires a combination of therapeutics for sufficient patient benefit.

Observing the Dynamics of an Electrochemically Driven Active Material with Liquid Electron Microscopy.

Electrochemical liquid electron microscopy has revolutionized our understanding of nanomaterial dynamics by allowing for direct observation of their electrochemical production. This technique, primarily applied to inorganic materials, is now being used to explore the self-assembly dynamics of active molecular materials. Our study examines these dynamics across various scales, from the nanoscale behavior of individual fibers to the micrometer-scale hierarchical evolution of fiber clusters. To isolate the influences of the electron beam and electrical potential on material behavior, we conducted thorough beam-sample interaction analyses. Our findings reveal that the dynamics of these active materials at the nanoscale are shaped by their proximity to the electrode and the applied electrical current. By integrating electron microscopy observations with reaction-diffusion simulations, we uncover that local structures and their formation history play a crucial role in determining assembly rates. This suggests that the emergence of nonequilibrium structures can locally accelerate further structural development, offering insights into the behavior of active materials under electrochemical conditions.

Automated Seizure Detection Based on State-Space Model Identification.

In this study, we developed a machine learning model for automated seizure detection using system identification techniques on EEG recordings. System identification builds mathematical models from a time series signal and uses a small number of parameters to represent the entirety of time domain signal epochs. Such parameters were used as features for the classifiers in our study. We analyzed 69 seizure and 55 non-seizure recordings and an additional 10 continuous recordings from Thomas Jefferson University Hospital, alongside a larger dataset from the CHB-MIT database. By dividing EEGs into epochs (1 s, 2 s, 5 s, and 10 s) and employing fifth-order state-space dynamic systems for feature extraction, we tested various classifiers, with the decision tree and 1 s epochs achieving the highest performance: 96.0% accuracy, 92.7% sensitivity, and 97.6% specificity based on the Jefferson dataset. Moreover, as the epoch length increased, the accuracy dropped to 94.9%, with a decrease in sensitivity to 91.5% and specificity to 96.7%. Accuracy for the CHB-MIT dataset was 94.1%, with 87.6% sensitivity and 97.5% specificity. The subject-specific cases showed improved results, with an average of 98.3% accuracy, 97.4% sensitivity, and 98.4% specificity. The average false detection rate per hour was 0.5 ± 0.28 in the 10 continuous EEG recordings. This study suggests that using a system identification technique, specifically, state-space modeling, combined with machine learning classifiers, such as decision trees, is an effective and efficient approach to automated seizure detection.

Health-related quality of life following trauma: Prevalence of problems and factors associated with six-month outcomes in a New Zealand cohort.

Injury is a leading cause of health loss in Aotearoa me Te Waipounamu (New Zealand; NZ). The NZ Trauma Registry was established in 2015 to monitor outcomes in those experiencing severe injury and to identify ways of improving the quality of care for these patients. Few NZ studies have assessed outcomes in trauma patients using patient-reported outcome measures (PROMs) despite increasing recognition that the impacts of injury are better understood through PROMs. Our aim was to estimate the prevalence of self-reported problems with health-related quality of life (HRQoL) outcomes six months post-injury, and identify factors associated with these, in a cohort of Maori (the Indigenous population of NZ) and non-Maori individuals who had experienced major trauma. HRQoL outcomes were measured according to the five dimensions of the EQ-5D-5L. This information, along with sociodemographic data, was collected via structured telephone interviews. Participants (n = 870), aged 16 years or more, were recruited following admission to a trauma hospital in one of three (of NZ's four) trauma regions. Multivariable models were developed using modified Poisson Regression to identify factors associated with outcomes for both Maori and non-Maori patients. The prevalence and severity of problems across each of the five EQ-5D-5L dimensions was similar for Maori and non-Maori except for Anxiety/Depression. The prevalence and severity of problems with Anxiety/Depression was greater for Maori. Factors associated with HRQoL problems at six-months were also largely similar for each cohort. Those commonly associated with outcomes were age, hospital length of stay, adequacy of household income, and participants' expectations regarding recovery from injury. Further research examining recovery expectations in trauma patients to determine which factors contribute to formulating recovery expectations, and the potential impact of recovery expectations on treatment and rehabilitation, would be of value. Should expectations, at least in part, influence HRQoL outcomes, then routinely collecting data on patients' recovery expectations, adequacy of household income and potential barriers to treatment and rehabilitation, could help inform post-hospital treatment plans, and identify those who may require additional support following discharge from hospital.

CIAO1 and MMS19 deficiency: A lethal neurodegenerative phenotype caused by cytosolic Fe-S cluster protein assembly disorders.

PURPOSE: The functionality of many cellular proteins depends on cofactors; yet, they have only been implicated in a minority of Mendelian diseases. Here, we describe the first 2 inherited disorders of the cytosolic iron-sulfur protein assembly system. METHODS: Genetic testing via genome sequencing was applied to identify the underlying disease cause in 3 patients with microcephaly, congenital brain malformations, progressive developmental and neurologic impairments, recurrent infections, and a fatal outcome. Studies in patient-derived skin fibroblasts and zebrafish models were performed to investigate the biochemical and cellular consequences. RESULTS: Metabolic analysis showed elevated uracil and thymine levels in body fluids but no pathogenic variants in DPYD, encoding dihydropyrimidine dehydrogenase. Genome sequencing identified compound heterozygosity in 2 patients for missense variants in CIAO1, encoding cytosolic iron-sulfur assembly component 1, and homozygosity for an in-frame 3-nucleotide deletion in MMS19, encoding the MMS19 homolog, cytosolic iron-sulfur assembly component, in the third patient. Profound alterations in the proteome, metabolome, and lipidome were observed in patient-derived fibroblasts. We confirmed the detrimental effect of deficiencies in CIAO1 and MMS19 in zebrafish models. CONCLUSION: A general failure of cytosolic and nuclear iron-sulfur protein maturation caused pleiotropic effects. The critical function of the cytosolic iron-sulfur protein assembly machinery for antiviral host defense may well explain the recurrent severe infections occurring in our patients.

Effect of Milling Speed on the Properties of Zirconia Restorations.

Background: The purpose of this study was to evaluate the effect of milling speed on the surface roughness, marginal gap, marginal gap volume, marginal offset, and fracture load of zirconia restorations. Material and Methods: A mandibular molar #30 typodont tooth was digitally scanned and an ideal crown preparation for a zirconia restoration was digitally created. A single master model die of the crown preparation was milled out of a resin material. The master die was scanned, and a final restoration was designed using the bio-copy feature of the typodont tooth. Ten zirconia restorations were milled (CEREC Primemill, Dentsply Sirona) per each of three milling speeds (super-fast, fine, and extra-fine), sintered, and seated on the master die. Surface roughness, marginal gap, marginal gap volume, and marginal offset were measured using a non-contact profilometer. Then, all restorations were cemented to the dies and loaded to failure in a material testing device. Data were analyzed with one-way ANOVA and Tukey's post hoc tests per property (alpha=0.05). Results: Super-fast milling speed resulted in restorations with statistically significant greater surface roughness and marginal gap volume compared to fine and extra-fine milling speeds. No significant difference in marginal gap, marginal offset, and fracture load were found based on milling speed. Conclusions: Zirconia restorations milled at slower speeds may result in similar or slightly better properties compared to super-fast speed. Key words:Milling speed, properties, zirconia restorations.

New Zealand's Prospective Outcomes of Injury Study-10 years on (POIS-10): descriptive outcomes to 12 years post-injury.

BACKGROUND: The 'Prospective Outcomes of Injury Study-10 years on' (POIS-10) aims to contribute to improving long-term disability, health and well-being outcomes for injured New Zealanders. This brief report describes recruitment, characteristics and key outcomes to 12 years post-injury. METHODS: Between 2007 and 2009, the study recruited 2856 people, including 566 Maori, from New Zealand's Accident Compensation Corporation's entitlement claims register. People experienced a range of injury types, causes and settings; 25% had been hospitalised for their injury. POIS-10 data were primarily collected via interviewer-administered structured questionnaires. RESULTS: Of the original participants, 2068 (92%) were eligible for follow-up in POIS-10. Of these, 1543 (75%) people participated between March 2020 and July 2021, including 240 Maori. Half of the participants (n=757; 50%) reported ongoing problems attributed to their injury 12 years earlier. Most reported difficulties with items assessing disability (WHO Disability Assessment Schedule II). For health-related quality of life (HRQoL), measured using the EQ-5D-5L, the prevalence of problems was higher 12 years post-injury compared with 12 months post-injury for four of five dimensions. Importantly, the prevalence of problems did not reduce to pre-injury levels for any HRQoL dimension. DISCUSSION: POIS-10 highlights the importance of early post-injury interventions to improve health, disability and well-being outcomes of injured New Zealanders.

Tazocin: piperacilina sódica, tazobactamna sódica / Tazocin: sodium piperacillin, sodium tazobactam

Mostra a biodisponibilidade, a farmacinética, a atividade in vitro, os estudos clínicos, a segurança, os efeitos colaterias, a posologia e a relação custo/benfício da junção da pipericilina sódica com a tazobactama sódica

Tazocin: piperacilina sódica, tazobactamna sódica / Tazocin: sodium piperacillin, sodium tazobactam

Mostra a biodisponibilidade, a farmacinética, a atividade in vitro, os estudos clínicos, a segurança, os efeitos colaterias, a posologia e a relação custo/benfício da junção da pipericilina sódica com a tazobactama sódica