Psychoeducational group interventions for adults diagnosed with attention-deficit/ hyperactivity disorder: a scoping review of feasibility, acceptability, and outcome measures.

INTRODUCTION: Although psychoeducational group interventions are increasingly used for adults diagnosed with attention-deficit/hyperactivity disorder (ADHD), a comprehensive review focused on the feasibility and acceptability indicators of these interventions remains lacking. Furthermore, although previous research has explored various aspects of psychoeducation for ADHD, such as its definition and approaches, limited research has focused on the synthesis for outcome measures and patients' experiences related to these interventions. Therefore, this scoping review aims to map the existing evidence reported on psychoeducational group interventions for adults diagnosed with ADHD. The objective is to provide a comprehensive overview of feasibility indicators, acceptability, and outcome measures used in psychoeducational group interventions. METHOD: A comprehensive structured literature search on the topic was performed in seven bibliographic databases, and the resulting records were independently screened, and their data extracted by two reviewers. We followed the Preferred Reporting Items for Systematic reviews and Meta-Analyses Extension for Scoping Reviews (PRISMA-S) to ensure the transparency and rigor of this scoping review. RESULTS: The searches yielded 7510 records. Eight studies met the inclusion criteria. These included studies were conducted in European countries and the United States. Among these, six studies used a randomized control design, one an open feasibility trial, and one a pre-post intervention design. All the studies reported some feasibility and acceptability indicators. While all the studies reported on the severity of symptoms of ADHD as an outcome measure, some also reported on outcomes related to psychological or mental-health problems, quality of life, changes in knowledge regarding ADHD, or the level of self-esteem, functioning, and impairment. CONCLUSION: This scoping review revealed that psychoeducational group interventions are generally acceptable for patients in terms of patient satisfaction with the group intervention. All included studies reported some feasibility indicators, with some reporting good attendance and relatively low dropout rates. Most studies reported positive effects on ADHD and mental health symptoms, suggesting that these interventions are beneficial for adults with ADHD. However, several gaps exist regarding the reporting on the feasibility indicators, acceptability, and outcome measures employed across studies.

Non-Canonical Aspects of Antibiotics and Antibiotic Resistance.

The understanding of antibiotic resistance, one of the major health threats of our time, is mostly based on dated and incomplete notions, especially in clinical contexts. The "canonical" mechanisms of action and pharmacodynamics of antibiotics, as well as the methods used to assess their activity upon bacteria, have not changed in decades; the same applies to the definition, acquisition, selective pressures, and drivers of resistance. As a consequence, the strategies to improve antibiotic usage and overcome resistance have ultimately failed. This review gathers most of the "non-canonical" notions on antibiotics and resistance: from the alternative mechanisms of action of antibiotics and the limitations of susceptibility testing to the wide variety of selective pressures, lateral gene transfer mechanisms, ubiquity, and societal factors maintaining resistance. Only by having a "big picture" view of the problem can adequate strategies to harness resistance be devised. These strategies must be global, addressing the many aspects that drive the increasing prevalence of resistant bacteria aside from the clinical use of antibiotics.

Investigating in VigiBase over 6000 cases of pneumonia in clozapine-treated patients in the context of the literature: focus on high lethality and the association with aspiration pneumonia.

BACKGROUND: The literature associates clozapine with pneumonia/aspiration pneumonia. RESEARCH DESIGN AND METHODS: The international pharmacovigilance database (VigiBase™) uses the information component (IC) as statistical signal. VigiBase clozapine reports were analyzed for pneumonia/aspiration pneumonia from introduction to 10 May 2023. RESULTS: There were 6392 cases of all types of pneumonia (5572 cases of pneumonia, 775 of aspiration pneumonia, and 45 combined). The IC was 3.52 for aspiration pneumonia, introduced as a VigiBase label in 2003, and 1.91 for pneumonia. Patients were reclassified as 3628 with no signs of aspiration and 1533 with signs. Signs of aspiration were strongly associated with some co-medications: olanzapine, odds ratio (OR) = 23.8, 95% confidence interval (CI), 14.9-38.0; risperidone OR = 18.6, CI, 11.4-30.4; valproic acid, OR = 5.5, CI, 4.5-6.6; and benzodiazepines OR = 5.5, CI, 4.5-6.6. In 2415 cases with completed data, fatal outcomes made up 45% (signs of aspiration made no difference), but there was wide variability from 0% (females <45 years of age; duration ≤30 days) to 76% (males >64 years of age; duration >1 year). During the first week, pneumonia was associated with 1) very high titration doses, 2) very small doses in Parkinson's disease, and 3) Japan vs other countries. CONCLUSIONS: In clozapine-treated patients: 1) at least 30% of pneumonia cases may be aspiration pneumonia, 2) stopping some co-medications may decrease the risk of aspiration pneumonia, 3) average lethality in pneumonia was 45% but may be around 75% in geriatric patients with long-term treatment, and 4) safer titrations may sometimes require 5-mg tablets.

Typhoon- and pollution-driven enhancement of reactive bromine in the mid-latitude marine boundary layer.

Tropospheric reactive bromine is important for atmospheric chemistry, regional air pollution, and global climate. Previous studies have reported measurements of atmospheric reactive bromine species in different environments, and proposed their main sources, e.g. sea-salt aerosol (SSA), oceanic biogenic activity, polar snow/ice, and volcanoes. Typhoons and other strong cyclonic activities (e.g. hurricanes) induce abrupt changes in different earth system processes, causing widespread destructive effects. However, the role of typhoons in regulating reactive bromine abundance and sources remains unexplored. Here, we report field observations of bromine oxide (BrO), a critical indicator of reactive bromine, on the Huaniao Island (HNI) in the East China Sea in July 2018. We observed high levels of BrO below 500 m with a daytime average of 9.7 ± 4.2 pptv and a peak value of ∼26 pptv under the influence of a typhoon. Our field measurements, supported by model simulations, suggest that the typhoon-induced drastic increase in wind speed amplifies the emission of SSA, significantly enhancing the activation of reactive bromine from SSA debromination. We also detected enhanced BrO mixing ratios under high NOx conditions (ppbv level) suggesting a potential pollution-induced mechanism of bromine release from SSA. Such elevated levels of atmospheric bromine noticeably increase ozone destruction by as much as ∼40% across the East China Sea. Considering the high frequency of cyclonic activity in the northern hemisphere, reactive bromine chemistry is expected to play a more important role than previously thought in affecting coastal air quality and atmospheric oxidation capacity. We suggest that models need to consider the hitherto overlooked typhoon- and pollution-mediated increase in reactive bromine levels when assessing the synergic effects of cyclonic activities on the earth system.

Anthropogenic short-lived halogens increase human exposure to mercury contamination due to enhanced mercury oxidation over continents.

Mercury (Hg) is a contaminant of global concern, and an accurate understanding of its atmospheric fate is needed to assess its risks to humans and ecosystem health. Atmospheric oxidation of Hg is key to the deposition of this toxic metal to the Earth's surface. Short-lived halogens (SLHs) can provide halogen radicals to directly oxidize Hg and perturb the budget of other Hg oxidants (e.g., OH and O3). In addition to known ocean emissions of halogens, recent observational evidence has revealed abundant anthropogenic emissions of SLHs over continental areas. However, the impacts of anthropogenic SLHs emissions on the atmospheric fate of Hg and human exposure to Hg contamination remain unknown. Here, we show that the inclusion of anthropogenic SLHs substantially increased local Hg oxidation and, consequently, deposition in/near Hg continental source regions by up to 20%, thereby decreasing Hg export from source regions to clean environments. Our modeling results indicated that the inclusion of anthropogenic SLHs can lead to higher Hg exposure in/near Hg source regions than estimated in previous assessments, e.g., with increases of 8.7% and 7.5% in China and India, respectively, consequently leading to higher Hg-related human health risks. These results highlight the urgent need for policymakers to reduce local Hg and SLHs emissions. We conclude that the substantial impacts of anthropogenic SLHs emissions should be included in model assessments of the Hg budget and associated health risks at local and global scales.

Revealing the reporting disparity: VigiBase highlights underreporting of clozapine in other Western European countries compared to the UK.

BACKGROUND: Pharmacovigilance studies indicate clozapine history is marked by adverse drug reactions (ADRs). OBJECTIVE: In a 2021 article, the United Kingdom (UK) had >90 % of European clozapine-related fatal outcomes in VigiBase, the World Health Organization's pharmacovigilance database. Two possibly opposing hypotheses could explain this disparity: 1) fewer reported fatal outcomes in other Western European countries mainly reflect underreporting to VigiBase, and 2) the higher number of UK reports reflects higher real relative mortality. METHODS: VigiBase reports from clozapine's introduction to December 31, 2022, were studied for ADRs and the top 10 causes of fatal outcomes. The UK was compared with 11 other top reporting Western countries (Germany, Denmark, France, Finland, Ireland, Italy, Netherlands, Norway, Spain, Sweden and Switzerland). Nine countries (except Ireland and Switzerland) were compared after controlling for population and clozapine prescriptions. RESULTS: The UK accounted for 29 % of worldwide clozapine-related fatal outcomes, Germany 2 % and <1 % in each of the other countries. The nonspecific label "death" was the top cause in the world (46 %) and in the UK (33 %). "Pneumonia" was second in the world (8 %), the UK (12 %), Ireland (8 %) and Finland (14 %). Assuming that our corrections for population and clozapine use are correct, other countries underreported only 1-10 % of the UK clozapine fatal outcome number. CONCLUSIONS: Different Western European countries consistently underreport to VigiBase compared to the UK, but have different reporting/publishing styles for clozapine-related ADRs/fatal outcomes. Three Scandinavian registries suggest lives are saved as clozapine use increases, but this cannot be studied in pharmacovigilance databases.

An expert review of clozapine in Latin American countries: Use, monitoring, and pharmacovigilance.

There is growing interest in clozapine clinical use, monitoring, and research, particularly adverse drug reactions (ADRs) other than agranulocytosis. In this study we focused on clozapine pharmacovigilance. Hence, we contacted clinicians and researchers in Latin America and requested information about local psychiatric services, clozapine availability, clinical use, and ADR monitoring with the VigiBase system. Only two countries have the minimum recommended number of psychiatric beds (15 per 100,000 residents): Uruguay (N = 34.9) and Argentina (N = 17). Bolivia is the only country where clozapine is unavailable. Nine out of twenty countries (45 %) reported ADRs to VigiBase. Argentina, Brazil, Chile, Colombia, and Mexico published national guidelines for schizophrenia treatment. Chile is the sole country with clozapine clinics with drug serum monitoring. Ethnicity-related drug titration in not described in package inserts in any country. We examined in detail the 9 most frequent and important clozapine ADRs in the worldwide database (pneumonia, sudden death, cardiac arrest, agranulocytosis, myocarditis, constipation, arrhythmia, seizure, and syncope). These 9 ADRs led to 294 reports with fatal outcomes in Argentina (N = 3), Brazil (N = 3), Chile (N = 2), and Peru (N = 1). Agranulocytosis was reported from 7 countries: constipation or seizures from 8 countries. Only two countries reported pneumonia and one country reported myocarditis. The number of clozapine reports in VigiBase has no relationship to the country's population. All Latin American countries underreport clozapine associated ADRs. Latin American governments, along with clinicians, researchers, and educators, should optimize clozapine use and monitoring for the benefit of people with severe mental and some neurological disorders.

Clozapine-associated pericarditis and pancreatitis in children and adolescents: A systematic literature review and pharmacovigilance study using the VigiBase database.

BACKGROUND: The literature has paid very little attention to pericarditis, pericardial effusion and pancreatitis during clozapine treatment in children and adolescents. METHODS: Cases of clozapine-associated pericarditis and pancreatitis in children were studied using searches in: 1) PubMed (June 16, 2023), and 2) the World Health Organization's pharmacovigilance database (June 1, 2022), VigiBase. VigiBase uses a logarithmic measure of disproportionality called the information component (IC). RESULTS: The PubMed search yielded 3 clozapine-associated pericarditis cases, 1 pancreatitis case and 1 with both. VigiBase provided a significant clozapine-associated pericarditis IC = 3.6 with an IC025 = 2.9 (only 3 cases were expected while 22 were observed). VigiBase provided a significant clozapine-associated pancreatitis IC = 2.2 with an IC025 = 1.4 (only 3 cases were expected while 16 were observed). In VigiBase clozapine-associated pericarditis and pericardial effusion in youth looked similar and on a continuum with myocarditis, as myocarditis, pericarditis and pancreatitis appeared to occur mainly during clozapine titration. Combining PubMed and VigiBase we identified: 1) 29 cases of at least possible clozapine-associated pericarditis/pericardial effusion (6 probable and 23 possible) including 7 cases with and 22 without myocarditis, and 2) 17 cases of clozapine-associated pancreatitis (1 definite and 16 possible). Two of the pancreatitis cases occurred during overdoses. No fatal outcomes were found in any clozapine-associated pericarditis and pancreatitis cases. CONCLUSIONS: Despite the lack of attention in the literature to clozapine-associated pericarditis and pancreatitis, results demonstrate that they can happen in youth, particularly during titration. Pericarditis and pancreatitis appear to be forms of clozapine-associated inflammation during dose titration.

An expert review of clozapine in Eastern European countries: Use, regulations and pharmacovigilance.

OBJECTIVES: To compare the prevalence, regulations, and pharmacovigilance practices of clozapine use in Eastern European countries (except Russia). METHODS: Questionnaires and data from administrative databases (2016 and 2021), package inserts and national guidelines were collected from 21 co-authors from 21 countries. Reports of clozapine adverse drug reactions (ADRs) sent to the global pharmacovigilance database (VigiBase™) were analyzed from introduction to December 31, 2022. RESULTS: Clozapine prescription among antipsychotics in 2021 varied six-fold across countries, from 2.8 % in the Czech Republic to 15.8 % in Montenegro. The utilization of antipsychotics in both 2016 and 2021 was highest in Croatia, and lowest in Serbia in 2016, and Montenegro in 2021, which had half the defined daily dose (DDD)/1000/day compared to the Croatian data. From 2016 to 2021, the prevalence of antipsychotic use increased in almost all countries; the proportion of clozapine use mainly remained unchanged. Differences were detected in hematological monitoring requirements and clozapine approved indications. Only a few national schizophrenia guidelines mention clozapine-induced myocarditis or individual titration schemes. The VigiBase search indicated major underreporting regarding clozapine and its fatal outcomes. By comparison, the United Kingdom had less than half the population of these Eastern European countries but reported to VigiBase more clozapine ADRs by 89-fold and clozapine fatal outcomes by almost 300-fold. CONCLUSION: Clozapine is under-utilized in Eastern European countries. Introducing individualized clozapine treatment schedules may help to maximize clozapine benefits and safety. Major improvement is needed in reporting clozapine ADRs and fatal outcomes in Eastern European countries.

Telepsychiatry: The future is already present.

This review paper analyzes the state of knowledge on Telepsychiatry (TP) after the crisis caused by COVID and the resulting need to use new modalities of care. Six essential aspects of TP are addressed: patient's and mental health staff satisfaction, diagnostic reliability, effectiveness of TP interventions, cost-effectiveness in terms of opportunity cost (or efficiency), legal aspects inherent to confidentiality and privacy in particular and the attitude of professionals toward TP. Satisfaction with TP is acceptable among both patients and professionals, the latter being the most reluctant. Diagnostic reliability has been demonstrated, but requires further studies to confirm this reliability in different diagnoses and healthcare settings. The efficacy of TP treatments is not inferior to face-to-face care, as has been proven in specific psychotherapies. Finally, it should be noted that the attitude of the psychiatrist is the most decisive element that limits or facilitates the implementation of TP.

Will ChatGPT3 Substitute for us as Clozapine Experts?

BACKGROUND: ChatGPT3 is a new artificial intelligence program released on February 13, 2023. METHOD: The authors tested ChatGPT3 on February 18, 2023, and repeated the test a week later. They used their expertise on the effects of ethnic ancestry in the stratification of clozapine dosing and the new idea that they published in March 2022 that African-Americans need higher clozapine doses because they have higher clozapine clearance. RESULTS: In the first interaction on February 18, ChatGPT3 provided reasonable and very up-to-date information, which included a comment that patients of African ancestry have higher clozapine metabolism. The other 4 interactions became progressively more concerning as we asked ChatGPT3 to provide references to justify the latter statement. ChatGPT3 provided non-existent "references" using articles from real journals, with real authors, false PubMed identifiers, and false titles. Moreover, ChatGPT3 said that the first author wrote in 2003 that African-Americans had higher CYP1A2 activity when that did not happen until 2022. One week later, the second author repeated the same set of questions. This time ChatGPT3 described the opposite, that African-Americans have "lower" CYP1A2 activity and "slower" metabolism. ChatGPT3 provided another set of articles to justify the information; some were real but did not comment on clozapine metabolism in African-Americans while others did not exist. CONCLUSIONS: ChatGPT3 provided a mixture of truth, twisted reality, and non-existent "facts." Within one week it defended opposite positions regarding a clinically relevant issue such as using higher or lower clozapine doses in African-Americans.

Asthma and COVID-19: a controversial relationship.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection induces a spectrum of clinical manifestations that depend on the immune response of the patient, i.e., from an asymptomatic form to an inflammatory response with multiorgan deterioration. In some cases, severe cases of SARS-CoV-2 are characterized by an excessive, persistent release of inflammatory mediators known as a cytokine storm. This phenomenon arises from an ineffective T helper (Th)-1 response, which is unable to control the infection and leads to a reinforcement of innate immunity, causing tissue damage. The evolution of the disease produced by SARS-CoV2, known as COVID-19, has been of interest in several research fields. Asthma patients have been reported to present highly variable outcomes due to the heterogeneity of the disease. For example, the Th2 response in patients with allergic asthma is capable of decreasing Th1 activation in COVID-19, preventing the onset of a cytokine storm; additionally, IL-33 released by damaged epithelium in the context of COVID-19 potentiates either Th1 or T2-high responses, a process that contributes to poor outcomes. IL-13, a T2-high inflammatory cytokine, decreases the expression of angiotensin converting enzyme-2 (ACE2) receptor, hindering SARS-CoV-2 entry; finally, poor outcomes have been observed in COVID-19 patients with severe neutrophilic asthma. In other contexts, the COVID-19 lockdown has had interesting effects on asthma epidemiology. The incidence of asthma in the most populated states in Mexico, including Tamaulipas, which has the highest asthma incidence in the country, showed similar tendencies independent of how strict the lockdown measures were in each state. As described worldwide for various diseases, a decrease in asthma cases was observed during the COVID-19 lockdown. This decrease was associated with a drop in acute respiratory infection cases. The drop in cases of various diseases, such as diabetes, hypertension or depression, observed in 2020 was restored in 2022, but not for asthma and acute respiratory infections. There were slight increases in asthma cases when in-person classes resumed. In conclusion, although many factors were involved in asthma outcomes during the pandemic, it seems that acute respiratory infection is intimately linked to asthma cases. Social distancing during remote learning, particularly school lockdown, appears to be an important cause of the decrease in cases.

The longitudinal relationship between social support and victimization among latino teens.

PURPOSE: This study examines the relationship between social support and victimization of Latino youth over time, utilizing the stress prevention and support deterioration models. METHODS: To address the research questions we utilized data from Waves 1 and 2 (n = 574) of the Dating Violence among Latino Adolescents (DAVILA) study, a national bilingual phone survey of self-identified Latino youth and their caregiver. Cross-lagged panel modeling was used to assess the fit of the two theoretical models to observed patterns of covariance among the victimization and social support variables specified. RESULTS: Results show that victimization at Wave 1 was positively and strongly related to victimization at Wave 2 and social support at Wave 1 was positively and moderately associated with social support at Wave 2. As hypothesized, higher levels of victimization at Wave 1 were significantly related to decreases in social support at Wave 2 (ß = -.15). Wave 1 social support was not significantly related to victimization at Wave 2. CONCLUSIONS: We did not find support for the stress prevention model but did find support for the support deterioration model. Teens who were victimized tended to have lower levels of subsequent social support, highlighting the need to equip peers, family, and significant others to adequately respond to victimization disclosures.

Photocatalytic chlorine atom production on mineral dust-sea spray aerosols over the North Atlantic.

Active chlorine in the atmosphere is poorly constrained and so is its role in the oxidation of the potent greenhouse gas methane, causing uncertainty in global methane budgets. We propose a photocatalytic mechanism for chlorine atom production that occurs when Sahara dust mixes with sea spray aerosol. The mechanism is validated by implementation in a global atmospheric model and thereby explaining the episodic, seasonal, and location-dependent 13C depletion in CO in air samples from Barbados [J.E. Mak, G. Kra, T. Sandomenico, P. Bergamaschi, J. Geophys. Res. Atmos. 108 (2003)], which remained unexplained for decades. The production of Cl can also explain the anomaly in the CO:ethane ratio found at Cape Verde [K. A. Read et al., J. Geophys. Res. Atmos. 114 (2009)], in addition to explaining the observation of elevated HOCl [M. J. Lawler et al., Atmos. Chem. Phys. 11, 7617-7628 (2011)]. Our model finds that 3.8 Tg(Cl) y-1 is produced over the North Atlantic, making it the dominant source of chlorine in the region; globally, chlorine production increases by 41%. The shift in the methane sink budget due to the increased role of Cl means that isotope-constrained top-down models fail to allocate 12 Tg y-1 (2% of total methane emissions) to 13C-depleted biological sources such as agriculture and wetlands. Since 2014, an increase in North African dust emissions has increased the 13C isotope of atmospheric CH4, thereby partially masking a much greater decline in this isotope, which has implications for the interpretation of the drivers behind the recent increase of methane in the atmosphere.

Global environmental implications of atmospheric methane removal through chlorine-mediated chemistry-climate interactions.

Atmospheric methane is both a potent greenhouse gas and photochemically active, with approximately equal anthropogenic and natural sources. The addition of chlorine to the atmosphere has been proposed to mitigate global warming through methane reduction by increasing its chemical loss. However, the potential environmental impacts of such climate mitigation remain unexplored. Here, sensitivity studies are conducted to evaluate the possible effects of increasing reactive chlorine emissions on the methane budget, atmospheric composition and radiative forcing. Because of non-linear chemistry, in order to achieve a reduction in methane burden (instead of an increase), the chlorine atom burden needs to be a minimum of three times the estimated present-day burden. If the methane removal target is set to 20%, 45%, or 70% less global methane by 2050 compared to the levels in the Representative Concentration Pathway 8.5 scenario (RCP8.5), our modeling results suggest that additional chlorine fluxes of 630, 1250, and 1880 Tg Cl/year, respectively, are needed. The results show that increasing chlorine emissions also induces significant changes in other important climate forcers. Remarkably, the tropospheric ozone decrease is large enough that the magnitude of radiative forcing decrease is similar to that of methane. Adding 630, 1250, and 1880 Tg Cl/year to the RCP8.5 scenario, chosen to have the most consistent current-day trends of methane, will decrease the surface temperature by 0.2, 0.4, and 0.6 °C by 2050, respectively. The quantity and method in which the chlorine is added, its interactions with climate pathways, and the potential environmental impacts on air quality and ocean acidity, must be carefully considered before any action is taken.

Psychiatric Patients' Perceived Health Control and Reactance: Implications for Medication Adherence.

Adherence to prescribed treatment is a major challenge in psychiatry, with non-adherence rates estimated to be as high as 50%. Two factors that have been suggested to influence medication adherence in psychiatric patients are perceived health control and psychological reactance. Perceived health control refers to the belief that one can control their own health outcomes, while psychological reactance refers to the negative response that occurs when individuals perceive their freedom or autonomy to be threatened. The aim of this review is to explore the possible relevance and interaction of perceived health control and psychological reactance in the adherence of psychiatric patients to their treatment. Several studies have suggested that higher levels of perceived health control are associated with better medication adherence, while higher levels of psychological reactance are associated with poorer adherence. Moreover, it has been suggested that patients with high levels of perceived health control may be more likely to experience psychological reactance if they feel that their autonomy is threatened by the treatment regimen. Taken together, these findings suggest that perceived health control and psychological reactance may interact to influence medication adherence in psychiatric patients. Future research could explore ways to enhance patients' perceived health control while minimizing psychological reactance in order to improve treatment adherence in this population.

Exoprotease exploitation and social cheating in a Pseudomonas aeruginosa environmental lysogenic strain with a noncanonical quorum sensing system.

Social cheating is the exploitation of public goods that are costly metabolites, like exoproteases. Exoprotease exploitation in Pseudomonas aeruginosa has been studied in reference strains. Experimental evolution with reference strains during continuous growth in casein has demonstrated that nonexoprotease producers that are lasR mutants are selected while they behave as social cheaters. However, noncanonical quorum-sensing systems exist in P. aeruginosa strains, which are diverse. In this work, the exploitation of exoproteases in the environmental strain ID4365 was evaluated; ID4365 has a nonsense mutation that precludes expression of LasR. ID4365 produces exoproteases under the control of RhlR, and harbors an inducible prophage. As expected, rhlR mutants of ID4365 behave as social cheaters, and exoprotease-deficient individuals accumulate upon continuous growth in casein. Moreover, in all continuous cultures, population collapses occur. However, this also sometimes happens before cheaters dominate. Interestingly, during growth in casein, ID4565's native prophage is induced, suggesting that the metabolic costs imposed by social cheating may increase its induction, promoting population collapses. Accordingly, lysogenization of the PAO1 lasR mutant with this prophage accelerated its collapse. These findings highlight the influence of temperate phages in social cheating.

Exploring low clozapine C/D ratios, inverted clozapine-norclozapine ratios and undetectable concentrations as measures of non-adherence in clozapine patients: A literature review and a case series of 17 patients from 3 studies.

BACKGROUND: Up to 1/2 of outpatients prescribed clozapine may be partially/fully non-adherent, based on therapeutic drug monitoring (TDM). Three indices for measuring partial/full non-adherence are proposed a: 1) clozapine concentration/dose (C/D) ratio which drops to half or more of what is expected in the patient; 2) clozapine/norclozapine ratio that becomes inverted; and 3) clozapine concentration that becomes non-detectable. METHODS: These 3 proposed indices are based on a literature review and 17 cases of possible non-adherence from 3 samples: 1) an inpatient study in a Chinese hospital, 2) an inpatient randomized clinical trial in a United States hospital, and 3) and a Uruguayan outpatient study. RESULTS: The first index of non-adherence is a clozapine C/D ratio which is less than half the ratio corresponding to the patient's specific ancestry group and sex-smoking subgroup. Knowing the minimum therapeutic dose of the patient based on repeated TDM makes it much easier to establish non-adherence. The second index is inverted clozapine/norclozapine ratios in the absence of alternative explanations. The third index is undetectable concentrations. By using half-lives, the chronology of the 3 indices of non-adherence was modeled in two patients: 1) the clozapine C/D ratio dropped to ≥1/2 of what is expected from the patient (around day 2); 2) the clozapine/norclozapine ratio became inverted (around day 3); and 3) the clozapine concentration became undetectable by the laboratory (around days 9-11). CONCLUSION: Prospective studies should further explore these proposed clozapine indices in average patients, poor metabolizers (3 presented) and ultrarapid metabolizers (2 presented).

Natural short-lived halogens exert an indirect cooling effect on climate.

Observational evidence shows the ubiquitous presence of ocean-emitted short-lived halogens in the global atmosphere1-3. Natural emissions of these chemical compounds have been anthropogenically amplified since pre-industrial times4-6, while, in addition, anthropogenic short-lived halocarbons are currently being emitted to the atmosphere7,8. Despite their widespread distribution in the atmosphere, the combined impact of these species on Earth's radiative balance remains unknown. Here we show that short-lived halogens exert a substantial indirect cooling effect at present (-0.13 ± 0.03 watts per square metre) that arises from halogen-mediated radiative perturbations of ozone (-0.24 ± 0.02 watts per square metre), compensated by those from methane (+0.09 ± 0.01 watts per square metre), aerosols (+0.03 ± 0.01 watts per square metre) and stratospheric water vapour (+0.011 ± 0.001 watts per square metre). Importantly, this substantial cooling effect has increased since 1750 by -0.05 ± 0.03 watts per square metre (61 per cent), driven by the anthropogenic amplification of natural halogen emissions, and is projected to change further (18-31 per cent by 2100) depending on climate warming projections and socioeconomic development. We conclude that the indirect radiative effect due to short-lived halogens should now be incorporated into climate models to provide a more realistic natural baseline of Earth's climate system.

Ascorbate and Antibiotics, at Concentrations Attainable in Urine, Can Inhibit the Growth of Resistant Strains of Escherichia coli Cultured in Synthetic Human Urine.

There are conflicting reports on the antibacterial activity of ascorbate; all at concentrations much higher than the typical in human plasma, but that can be reached in urine. The effect of 10 mM ascorbate (in itself not inhibitory) along with antibiotics, was tested both in Mueller-Hinton broth (MHb) and in synthetic human urine (SHU), against resistant isolates of Escherichia coli from lower urinary infections. The activity of nitrofurantoin and sulfamethoxazole was higher in SHU than in MHb; minimal inhibitory concentrations (MICs) in SHU with ascorbate were below typical urinary concentrations. For other antibiotics, MICs were the same in MHb vs. SHU, with no effect of ascorbate in MHb; but in SHU with ascorbate, MICs of ciprofloxacin and gentamicin also went below reported urinary concentrations, with a lesser effect with norfloxacin and trimethoprim, and none with ampicillin. The effect of ascorbate was independent of oxygen and not related to the susceptibility of each strain to oxidative stress. Ascorbate oxidizes during incubation in SHU, and bacterial growth partially prevented oxidation. These results suggest that 10 mM ascorbate can enhance the inhibitory activity of antibiotics upon resistant strains in urine. Clinical experimentation with ascorbate-antibiotic combinations against urinary infections caused by resistant bacteria is warranted.