Persistent opioid use after hospital admission due to trauma: a population-based cohort study.

ABSTRACT: Persistent opioid use (POU) is a common marker of harm related to opioid use after trauma. This study determined the incidence and risk factors for POU after hospitalisation due to trauma in New Zealand, among opioid-naïve patients. This was a population-based, retrospective cohort study, using linked data, involving all trauma patients of any age admitted to all NZ hospitals between 2007 and 2019. We included all patients who received opioids after discharge and were considered opioid naïve, defined as not having received opioids or not having a prior diagnosis of opioid-use disorder up to 365 days preceding the discharge date. The primary outcome was the incidence of POU defined as opioid use after discharge between 91 and 365 days. We used a multivariable logistic regression to identify independent risk factors for POU. A total of 177,200 patients were included in this study. Of these, 15.3% (n = 27,060) developed POU based on criteria used for the primary analysis, with sensitivity analyses showing POU incidence ranging from 14.3% to 0.8%. The opioid exposure risk factors associated with POU included switching between different opioids (adjusted odds ratio [aOR] 2.62; 95% confidence interval [CI] 2.51-2.73), prescribed multiple opioids (vs codeine, aOR 1.44; 95% CI 1.37-1.53), slow-release opioid formulations (aOR 1.32; 95% CI 1.26-1.39), and dispensed higher total doses of on the initial discharge prescription (aOR 1.26; 95% CI 1.20-1.33). Overall, 1 in 7 opioid-naïve patients who were exposed to opioids after trauma developed POU. Our findings highlight clinicians should be aware of these factors when continuing opioids on discharge.

Have a little heart (or not): highly minimized skeletal muscle regulatory cassettes with low or no activity in heart.

Adeno-associated virus (AAV)-mediated gene therapies for certain muscle disorders require regulatory cassettes that provide high-level, striated muscle-specific activity. However, cardiotoxicity has emerged as a serious concern in clinical trials for Duchenne muscular dystrophy and X-linked myotubular myopathy. While this may be caused by systemic inflammatory effects of the treatment, high transgene expression in the heart may also play a role. Thus, certain muscle disorders may require a modulated level of therapeutic expression in the heart, while others may not require any cardiac expression at all. Additionally, the size of some cargos requires regulatory cassettes to be small enough that large cDNAs and other therapeutic payloads can be accommodated. Thus, we have performed enhancer/promoter optimization to develop highly minimized regulatory cassettes that are active in skeletal muscles, with either low or no detectable activity in cardiac muscle. Our no-heart (NH) cassette is active in most skeletal muscles, but exhibits only very low activity in extensor digitorum longus (EDL), soleus, and diaphragm, and no activity in heart. By contrast, our have-a-little-heart (HLH) cassette displays high activity in most skeletal muscles, comparable to the ~800-bp CK8 cassette, with increased activity in EDL, soleus, and diaphragm, and low activity in heart. Due to their small size, these cassettes can be used in therapeutic strategies with both flexible (e.g., antisense) and stringent (e.g., CRISPR/Cas or bicistronic) size limitations. Thus, our new cassettes may be useful for gene therapies of muscle disorders in which the need for low or almost no expression in cardiac muscle would outweigh the need for high levels of therapeutic product in certain skeletal muscles.

Crystal structures of four gold(I) complexes [AuL 2]+[AuX 2]- and a by-product (L·LH+)[AuBr2]- (L = substituted pyridine, X = Cl or Br).

Bis(2-methyl-pyridine)-gold(I) di-bromido-aurate(I), [Au(C6H7N)2][AuBr2], (1), crystallizes in space group C2/c with Z = 4. Both gold atoms lie on twofold axes and are connected by an aurophilic contact. A second aurophilic contact leads to infinite chains of alternating cations and anions parallel to the b axis, and the residues are further connected by a short H⋯Au contact and a borderline Br⋯Br contact. Bis(3-methyl-pyridine)-gold(I) di-bromido-aurate(I), [Au(C6H7N)2][AuBr2], (2), crystallizes in space group C2/m with Z = 2. Both gold atoms lie on special positions with symmetry 2/m and are connected by an aurophilic contact; all other atoms except for one methyl hydrogen lie in mirror planes. The extended structure is closely analogous to that of 1, although the structures are formally not isotypic. Bis(3,5-di-methyl-pyridine)-gold(I) di-chlor-ido-aurate(I), [Au(C7H9N)2][AuCl2], (3) crystallizes in space group P with Z = 2. The cation lies on a general position, and there are two independent anions in which the gold atoms lie on inversion centres. The cation and one anion associate via three short H⋯Cl contacts to form a ribbon structure parallel to the b axis; aurophilic contacts link adjacent ribbons. Bis(3,5-di-methyl-pyridine)-gold(I) di-bromido-aurate(I), [Au(C7H9N)2][AuBr2], (4) is isotypic to 3. Attempts to make similar compounds involving 2-bromo-pyridine led instead to 2-bromopyridinium di-bromido-aurate(I)-2-bromo-pyridine (1/1), (C5H5BrN)[AuBr2]·C5H4BrN, (5), which crystallizes in space group P with Z = 2; all atoms lie on general positions. The 2-bromo-pyridinium cation is linked to the 2-bromo-pyridine mol-ecule by an N-H⋯N hydrogen bond. Two formula units aggregate to form inversion-symmetric dimers involving Br⋯Br, Au⋯Br and H⋯Br contacts.

Monitoring Live Mycobacteria in Real-Time Using a Microfluidic Acoustic-Raman Platform.

Tuberculosis (TB) is the most common cause of death from an infectious disease. Although treatment has been available for more than 70 years, it still takes too long and many patients default risking relapse and the emergence of resistance. It is known that lipid-rich, phenotypically antibiotic-tolerant, bacteria are more resistant to antibiotics and may be responsible for relapse necessitating extended therapy. Using a microfluidic system that acoustically traps live mycobacteria, M. smegmatis, a model organism for M. tuberculosis we can perform optical analysis in the form of wavelength-modulated Raman spectroscopy (WMRS) on the trapped organisms. This system can allow observations of the mycobacteria for up to 8 h. By adding antibiotics, it is possible to study the effect of antibiotics in real-time by comparing the Raman fingerprints in comparison to the unstressed condition. This microfluidic platform may be used to study any microorganism and to dynamically monitor its response to many conditions including antibiotic stress, and changes in the growth media. This opens the possibility of understanding better the stimuli that trigger the lipid-rich downregulated and phenotypically antibiotic-resistant cell state.

Early adolescent perceived friendship quality aids affective and neural responses to social inclusion and exclusion in young adults with and without adverse childhood experiences.

Friendships increase mental wellbeing and resilient functioning in young people with childhood adversity (CA). However, the mechanisms of this relationship are unknown. We examined the relationship between perceived friendship quality at age 14 after the experience of CA and reduced affective and neural responses to social exclusion at age 24. Resilient functioning was quantified as psychosocial functioning relative to the degree of CA severity in 310 participants at age 24. From this cohort, 62 young people with and without CA underwent functional Magnetic Resonance Imaging to assess brain responses to social inclusion and exclusion. We observed that good friendship quality was significantly associated with better resilient functioning. Both friendship quality and resilient functioning were related to increased affective responses to social inclusion. We also found that friendship quality, but not resilient functioning, was associated with increased dorsomedial prefrontal cortex responses to peer exclusion. Our findings suggest that friendship quality in early adolescence may contribute to the evaluation of social inclusion by increasing affective sensitivity to positive social experiences and increased brain activity in regions involved in emotion regulation to negative social experiences. Future research is needed to clarify this relationship with resilient functioning in early adulthood.

Internal consistency and temporal stability of the Community Assessment of Psychic Experiences (CAPE): A reliability generalization meta-analysis.

Psychotic experiences (PE) are prevalent in general and clinical populations and can increase the risk for mental disorders in young people. The Community Assessment of Psychic Experiences (CAPE) is a widely used measure to assess PE in different populations and settings. However, the current knowledge on their overall reliability is limited. We examined the reliability of the CAPE-42 and later versions, testing the role of age, sex, test scores, and clinical status as moderators. A systematic search was conducted on the Scopus, Web of Science, PubMed, EBSCOhost, ProQuest, and GoogleScholar databases. Internal consistency and temporal stability indices were examined through reliability generalization meta-analysis (RGMA). Moderators were tested through meta-regression analysis. From a pool of 1,015 records, 90 independent samples were extracted from 71 studies. Four versions showed quantitative evidence for inclusion: CAPE-42, CAPE-20, CAPE-P15, and CAPE-P8. Internal consistency indices were good (α/ω≈.725-0.917). Temporal stability was only analyzed for the CAPE-P15, yielding a moderate but not-significant effect (r=0.672). The evidence for temporal stability is scant due to the limited literature, and definitive conclusions cannot be drawn. Further evidence on other potential moderators such as adverse experiences or psychosocial functioning is required.

Conserved epigenetic hallmarks of T cell aging during immunity and malignancy.

Chronological aging correlates with epigenetic modifications at specific loci, calibrated to species lifespan. Such 'epigenetic clocks' appear conserved among mammals, but whether they are cell autonomous and restricted by maximal organismal lifespan remains unknown. We used a multilifetime murine model of repeat vaccination and memory T cell transplantation to test whether epigenetic aging tracks with cellular replication and if such clocks continue 'counting' beyond species lifespan. Here we found that memory T cell epigenetic clocks tick independently of host age and continue through four lifetimes. Instead of recording chronological time, T cells recorded proliferative experience through modification of cell cycle regulatory genes. Applying this epigenetic profile across a range of human T cell contexts, we found that naive T cells appeared 'young' regardless of organism age, while in pediatric patients, T cell acute lymphoblastic leukemia appeared to have epigenetically aged for up to 200 years. Thus, T cell epigenetic clocks measure replicative history and can continue to accumulate well-beyond organismal lifespan.

Efficient activation of hundreds of LTR12C elements reveals cis-regulatory function determined by distinct epigenetic mechanisms.

Long terminal repeats (LTRs), which often contain promoter and enhancer sequences of intact endogenous retroviruses (ERVs), are known to be co-opted as cis-regulatory elements for fine-tuning host-coding gene expression. Since LTRs are mainly silenced by the deposition of repressive epigenetic marks, substantial activation of LTRs has been found in human cells after treatment with epigenetic inhibitors. Although the LTR12C family makes up the majority of ERVs activated by epigenetic inhibitors, how these epigenetically and transcriptionally activated LTR12C elements can regulate the host-coding gene expression remains unclear due to genome-wide alteration of transcriptional changes after epigenetic inhibitor treatments. Here, we specifically transactivated >600 LTR12C elements by using single guide RNA-based dCas9-SunTag-VP64, a site-specific targeting CRISPR activation (CRISPRa) system, with minimal off-target events. Interestingly, most of the transactivated LTR12C elements acquired the H3K27ac-marked enhancer feature, while only 20% were co-marked with promoter-associated H3K4me3 modifications. The enrichment of the H3K4me3 signal was intricately associated with downstream regions of LTR12C, such as internal regions of intact ERV9 or other types of retrotransposons. Here, we leverage an optimized CRISPRa system to identify two distinct epigenetic signatures that define LTR12C transcriptional activation, which modulate the expression of proximal protein-coding genes.

Crystal structures of fourteen halochalcogenylphos-pho-nium tetra-halogenidoaurates(III).

The structures of fourteen halochalcogenyl-phospho-nium tetra-halogen-ido-aurates(III), phosphane chalcogenide derivatives with general formula [R 1 3- nR 2 nPEX][AuX 4] (R 1 = t-butyl; R 2 = isopropyl; n = 0 to 3; E = S or Se; X = Cl or Br) are presented. The eight possible chlorido derivatives are: 17 a, n = 3, E = S; 18 a, n = 2, E = S; 19 a, n = 1, E = S; 20 a, n = 0, E = S; 21 a, n = 3, E = Se; 22 a, n = 2, E = Se; 23 a, n = 1, E = Se; and 24 a, n = 0, E = Se, and the corresponding bromido derivatives are 17 b-24 b in the same order. Structures were obtained for all compounds except for the tri-t-butyl derivatives 24 a and 24 b. Isotypy is observed for 18 a/18 b/22 a/22 b, 19 a/23 a, 17 b/21 b and 19 b/23 b. In eleven of the compounds, X⋯X contacts (mostly very short) are observed between the cation and anion, whereby the E-X⋯X groups are approximately linear and the X⋯X-Au angles approximately 90°. The exceptions are 17 a, 19 a and 23 a, which instead display short E⋯X contacts. Bond lengths in the cations correspond to single bonds P-E and E-X. For each group with constant E and X, the P-E-X bond-angle values increase monotonically with the steric bulk of the alkyl groups. The packing is analysed in terms of E⋯X, X⋯X (some between anions alone), H⋯X and H⋯Au contacts. Even for isotypic compounds, some significant differences can be discerned.

Crystal structure of (E)-N-(4-bromo-phen-yl)-2-cyano-3-[3-(2-methyl-prop-yl)-1-phenyl-1H-pyrazol-4-yl]prop-2-enamide.

The structure of the title compound, C23H21BrN4O, contains two independent mol-ecules connected by hydrogen bonds of the type Namide-H⋯N≡C to form a dimer. The configuration at the exocyclic C=C double bond is E. The mol-ecules are roughly planar except for the isopropyl groups. There are minor differences in the orientations of these groups and the phenyl rings at N1. The dimers are further linked by 'weak' hydrogen bonds, two each of the types Hphen-yl⋯O=C (H⋯O = 2.50, 2.51 Å) and Hphen-yl⋯Br (H⋯Br = 2.89, 2.91 Å), to form ribbons parallel to the b and c axes, respectively. The studied crystal was a non-merohedral twin.

Crystal structures of tri-chlorido-(4-methyl-piperidine)gold(III) and two polymorphs of tri-bromido(4-methyl-piperidine)-gold(III).

Tri-chlorido-(4-methyl-piperidine)-gold(III), [AuCl3(C6H13N)], 1, crystallizes in Pbca with Z = 8. Tri-bromido-(4-methyl-piperidine)-gold(III), [AuBr3(C6H13N)], 2, crystallizes as two polymorphs, 2a in Pnma with Z = 4 (imposed mirror symmetry) and 2b, which is isotypic to 1. The Au-N bonds trans to Cl are somewhat shorter than those trans to Br, and the Au-Cl bonds trans to N are longer than those cis to N, whereas the Au-Br bonds trans to N are slightly shorter than the cis bonds. The methyl and AuX 3 groups (X = halogen) occupy equatorial positions at the six-membered ring. The packing of all three structures involves chains of mol-ecules with offset stacking of the AuX 3 moieties associated with short Au⋯X contacts; for 1 and 2b these are reinforced by N-H⋯X hydrogen bonds, whereas for 2a there are no classical hydrogen bonds and the chains are inter-connected by Br⋯Br contacts.

The Role of Social Deprivation and Cannabis Use in Explaining Variation in the Incidence of Psychotic Disorders: Findings From the EU-GEI Study.

BACKGROUND AND HYPOTHESIS: Recent findings suggest the incidence of first-episode psychotic disorders (FEP) varies according to setting-level deprivation and cannabis use, but these factors have not been investigated together. We hypothesized deprivation would be more strongly associated with variation in FEP incidence than the prevalence of daily or high-potency cannabis use between settings. STUDY DESIGN: We used incidence data in people aged 18-64 years from 14 settings of the EU-GEI study. We estimated the prevalence of daily and high-potency cannabis use in controls as a proxy for usage in the population at-risk; multiple imputations by chained equations and poststratification weighting handled missing data and control representativeness, respectively. We modeled FEP incidence in random intercepts negative binomial regression models to investigate associations with the prevalence of cannabis use in controls, unemployment, and owner-occupancy in each setting, controlling for population density, age, sex, and migrant/ethnic group. STUDY RESULTS: Lower owner-occupancy was independently associated with increased FEP (adjusted incidence rate ratio [aIRR]: 0.76, 95% CI: 0.61-0.95) and non-affective psychosis incidence (aIRR: 0.68, 95% CI: 0.55-0.83), after multivariable adjustment. Prevalence of daily cannabis use in controls was associated with the incidence of affective psychoses (aIRR: 1.53, 95% CI: 1.02-2.31). We found no association between FEP incidence and unemployment or high-potency cannabis use prevalence. Sensitivity analyses supported these findings. CONCLUSIONS: Lower setting-level owner-occupancy and increased prevalence of daily cannabis use in controls independently contributed to setting-level variance in the incidence of different psychotic disorders. Public health interventions that reduce exposure to these harmful environmental factors could lower the population-level burden of psychotic disorders.

T-Cell/B-Cell Interactions in Atherosclerosis.

Atherosclerosis is a complex inflammatory disease in which the adaptive immune response plays an important role. While the overall impact of T and B cells in atherosclerosis is relatively well established, we are only beginning to understand how bidirectional T-cell/B-cell interactions can exert prominent atheroprotective and proatherogenic functions. In this review, we will focus on these T-cell/B-cell interactions and how we could use them to therapeutically target the adaptive immune response in atherosclerosis.

Impact of the COVID-19 pandemic on young adults' mental health and beyond: a qualitative investigation nested within an ongoing general population cohort study.

PURPOSE: Initial discussions about the COVID-19 pandemic often overlooked its impact on young adults. By employing a qualitative approach nested within an ongoing general population cohort study, we seek to fill a gap in the literature by providing insights into the longer-term impact on this demographic. METHODS: Data collection involved the use of in-depth semi-structured interviews. Using a pre-determined sampling frame, we purposively recruited 30 participants based on age, gender, ethnicity, and deprivation from the Neuroscience in Psychiatry Network (NSPN). The NSPN cohort, established in 2012, consists of 2403 young people aged 14-24 at baseline, recruited from Greater London and Cambridgeshire. Interviews were conducted in Autumn 2022; data were analysed using the framework method. RESULTS: Participants were on average 28 years old (SD = 3 years, range 24-34 years; 53.3% female). The sample comprised individuals from diverse ethnic backgrounds, with 40% from non-White ethnic groups. Many young adults reported profound personal growth and a stronger sense of resilience, a perception observed across varying levels of anxiety or depression. Nevertheless, we observed substantial disruptions to their personal and professional lives such as returning to their parents' homes, often deferring other life plans, lacking mental health support, and encountering significant career challenges. CONCLUSION: Our findings highlight the complexity of pandemic impacts, demonstrating the need for supportive policies and further research to understand the circumstances under which genuine personal growth occurs, whether it is enduring or transient, and which factors influence it.

Linear Amine-Linked Oligo-BODIPYs: Convergent Access via Buchwald-Hartwig Coupling.

A convergent route toward nitrogen-bridged BODIPY oligomers has been developed. The synthetic key step is a Buchwald-Hartwig cross-coupling reaction of an α-amino-BODIPY and the respective halide. Not only does the selective synthesis provide control of the oligomer size, but the facile preparative procedure also enables easy access to these types of dyes. Furthermore, functionalized examples were accessible via brominated derivatives.

Regulation of cardiomyocyte t-tubule structure by preload and afterload: Roles in cardiac compensation and decompensation.

Mechanical load is a potent regulator of cardiac structure and function. Although high workload during heart failure is associated with disruption of cardiomyocyte t-tubules and Ca2+ homeostasis, it remains unclear whether changes in preload and afterload may promote adaptive t-tubule remodelling. We examined this issue by first investigating isolated effects of stepwise increases in load in cultured rat papillary muscles. Both preload and afterload increases produced a biphasic response, with the highest t-tubule densities observed at moderate loads, whereas excessively low and high loads resulted in low t-tubule levels. To determine the baseline position of the heart on this bell-shaped curve, mice were subjected to mildly elevated preload or afterload (1 week of aortic shunt or banding). Both interventions resulted in compensated cardiac function linked to increased t-tubule density, consistent with ascension up the rising limb of the curve. Similar t-tubule proliferation was observed in human patients with moderately increased preload or afterload (mitral valve regurgitation, aortic stenosis). T-tubule growth was associated with larger Ca2+ transients, linked to upregulation of L-type Ca2+ channels, Na+-Ca2+ exchanger, mechanosensors and regulators of t-tubule structure. By contrast, marked elevation of cardiac load in rodents and patients advanced the heart down the declining limb of the t-tubule-load relationship. This bell-shaped relationship was lost in the absence of electrical stimulation, indicating a key role of systolic stress in controlling t-tubule plasticity. In conclusion, modest augmentation of workload promotes compensatory increases in t-tubule density and Ca2+ cycling, whereas this adaptation is reversed in overloaded hearts during heart failure progression. KEY POINTS: Excised papillary muscle experiments demonstrated a bell-shaped relationship between cardiomyocyte t-tubule density and workload (preload or afterload), which was only present when muscles were electrically stimulated. The in vivo heart at baseline is positioned on the rising phase of this curve because moderate increases in preload (mice with brief aortic shunt surgery, patients with mitral valve regurgitation) resulted in t-tubule growth. Moderate increases in afterload (mice and patients with mild aortic banding/stenosis) similarly increased t-tubule density. T-tubule proliferation was associated with larger Ca2+ transients, with upregulation of the L-type Ca2+ channel, Na+-Ca2+ exchanger, mechanosensors and regulators of t-tubule structure. By contrast, marked elevation of cardiac load in rodents and patients placed the heart on the declining phase of the t-tubule-load relationship, promoting heart failure progression. The dependence of t-tubule structure on preload and afterload thus enables both compensatory and maladaptive remodelling, in rodents and humans.

Empowering School Staff to Support Pupil Mental Health Through a Brief, Interactive Web-Based Training Program: Mixed Methods Study.

BACKGROUND: Schools in the United Kingdom and elsewhere are expected to protect and promote pupil mental health. However, many school staff members do not feel confident in identifying and responding to pupil mental health difficulties and report wanting additional training in this area. OBJECTIVE: We aimed to explore the feasibility of Kognito's At-Risk for Elementary School Educators, a brief, interactive web-based training program that uses a simulation-based approach to improve school staff's knowledge and skills in supporting pupil mental health. METHODS: We conducted a mixed methods, nonrandomized feasibility study of At-Risk for Elementary School Educators in 6 UK primary schools. Our outcomes were (1) school staff's self-efficacy and preparedness to identify and respond to pupil mental health difficulties, (2) school staff's identification of mental health difficulties and increased risk of mental health difficulties, (3) mental health support for identified pupils (including conversations about concerns, documentation of concerns, in-class and in-school support, and referral and access to specialist mental health services), and (4) the acceptability and practicality of the training. We assessed these outcomes using a series of questionnaires completed at baseline (T1), 1 week after the training (T2), and 3 months after the training (T3), as well as semistructured qualitative interviews. Following guidance for feasibility studies, we assessed quantitative outcomes across time points by comparing medians and IQRs and analyzed qualitative data using reflexive thematic analysis. RESULTS: A total of 108 teachers and teaching assistants (TAs) completed T1 questionnaires, 89 (82.4%) completed T2 questionnaires, and 70 (64.8%) completed T3 questionnaires; 54 (50%) completed all 3. Eight school staff members, including teachers, TAs, mental health leads, and senior leaders, participated in the interviews. School staff reported greater confidence and preparedness in identifying and responding to mental health difficulties after completing the training. The proportion of pupils whom they identified as having mental health difficulties or increased risk declined slightly over time (medianT1=10%; medianT2=10%; medianT3=7.4%), but findings suggested a slight increase in accuracy compared with a validated screening measure (the Strengths and Difficulties Questionnaire). In-school mental health support outcomes for identified pupils improved after the training, with increases in formal documentation and communication of concerns as well as provision of in-class and in-school support. Referrals and access to external mental health services remained constant. The qualitative findings indicated that school staff perceived the training as useful, practical, and acceptable. CONCLUSIONS: The findings suggest that brief, interactive web-based training programs such as At-Risk for Elementary School Educators are a feasible means to improve the identification of and response to mental health difficulties in UK primary schools. Such training may help address the high prevalence of mental health difficulties in this age group by helping facilitate access to care and support.

Status epilepticus in Auckland, New Zealand: Treatment patterns and determinants of outcome in a prospective population-based cohort.

OBJECTIVE: Determination of the real-world performance of a health care system in the treatment of status epilepticus (SE). METHODS: Prospective, multicenter population-based study of SE in Auckland, New Zealand (NZ) over 1 year, with data recorded in the EpiNet database. Focus on treatment patterns and determinants of SE duration and 30-day mortality. The incidence, etiology, ethnic discrepancies, and seizure characteristics of this cohort have been published previously. RESULTS: A total of 365 patients were included in this treatment cohort; 326 patients (89.3%) were brought to hospital because of SE, whereas 39 patients (10.7%) developed SE during a hospital admission for another reason. Overall, 190 (52.1%) had a known history of epilepsy and 254 (70.0%) presented with SE with prominent motor activity. The mean Status Epilepticus Severity Score (STESS) was 2.15 and the mean SE duration of all patients was 44 min. SE self-terminated without any treatment in 84 patients (22.7%). Earlier administration of appropriately dosed benzodiazepine in the pre-hospital setting was a major determinant of SE duration. Univariate analysis demonstrated that mortality was significantly higher in older patients, patients with longer durations of SE, higher STESS, and patients who developed SE in hospital, but these did not maintain significance with multivariate analysis. There was no difference in the performance of the health care system in the treatment of SE across ethnic groups. SIGNIFICANCE: When SE was defined as 10 continuous minutes of seizure, overall mortality was lower than expected and many patients had self-limited presentations for which no treatment was required. Although there were disparities in the incidence of SE across ethnic groups there was no difference in treatment or outcome. The finding highlights the benefit of a health care system designed to deliver universal health care.

Silver Organometallics that are Highly Potent Thioredoxin and Glutathione Reductase Inhibitors: Exploring the Correlations of Solution Chemistry with the Strong Antibacterial Effects.

The antibacterial activity of silver species is well-established; however, their mechanism of action has not been adequately explored. Furthermore, issues of low-molecular silver compounds with cytotoxicity, stability, and solubility hamper their progress to drug leads. We have investigated silver N-heterocyclic carbene (NHC) halido complexes [(NHC)AgX, X = Cl, Br, and I] as a promising new type of antibacterial silver organometallics. Spectroscopic studies and conductometry established a higher stability for the complexes with iodide ligands, and nephelometry indicated that the complexes could be administered in solutions with physiological chloride levels. The complexes showed a broad spectrum of strong activity against pathogenic Gram-negative bacteria. However, there was no significant activity against Gram-positive strains. Further studies clarified that tryptone and yeast extract, as components of the culture media, were responsible for this lack of activity. The reduction of biofilm formation and a strong inhibition of both glutathione and thioredoxin reductases with IC50 values in the nanomolar range were confirmed for selected compounds. In addition to their improved physicochemical properties, the compounds with iodide ligands did not display cytotoxic effects, unlike the other silver complexes. In summary, silver NHC complexes with iodide secondary ligands represent a useful scaffold for nontoxic silver organometallics with improved physicochemical properties and a distinct mechanism of action that is based on inhibition of thioredoxin and glutathione reductases.

Crystal structure of 2,4-di-amino-5-(4-hy-droxy-3-meth-oxy-phen-yl)-8,8-dimethyl-6-oxo-6,7,8,9-tetra-hydro-5H-chromeno[2,3-b]pyridine-3-carbo-nitrile-di-methyl-formamide-water (1/1/1).

In the structure of the title compound, C22H22N4O4·C3H7NO·H2O, the entire tricyclic system is approximately planar except for the carbon atom bearing the two methyl groups; the meth-oxy-phenyl ring is approximately perpendicular to the tricycle. All seven potential hydrogen-bond donors take part in classical hydrogen bonds. The main mol-ecule and the DMF combine to form broad ribbons parallel to the a axis and roughly parallel to the ab plane; the water mol-ecules connect the residues in the third dimension.