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We examined the social and emotional challenges (SEC) of young children and the mental health of their caregivers in areas affected by armed conflict and displacement in Colombia. Anxiety, depression, and PTSD symptoms were assessed in 1,133 caregivers. Caregivers also reported on the SEC of their children aged 21-53 months. A subsample of 487 caregivers (43%) completed a resilience self-report measure. Caregivers reported substantial levels of psychopathology ranging from 12.84% of caregivers with elevated anxiety levels, 24.5% who scored above the cutoff on the PTSD measure, and 44.7% who screened positive for depression. Correlations (r) between child SEC and caregiver psychopathology ranged from 0.15 to 0.33. The association between caregiver depression and child SEC was more substantial for boys (B = 0.56) than girls (B = 0.22). We also found that girls whose caregivers reported elevated levels of psychopathology and low levels of caregiver resilience received the highest ratings of caregiver-reported SEC. The importance of caregiver-child resilience-focused psychosocial support is discussed., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Chloride (Cl - ) is traditionally categorized as an antagonist of nitrate (NO 3 - ) because Cl - hinders plant NO 3 - transport and accumulation. However, we have recently defined Cl - as a beneficial macronutrient for higher plants, due to specific functions that lead to more efficient use of water, nitrogen (N) and CO 2 under optimal N and water supply. When accumulated in leaves at macronutrient levels, Cl - promotes growth through osmotic, physiological, metabolic, anatomical and cellular changes that improve plant performance under optimal NO 3 - nutrition. Nitrate over-fertilization in agriculture can adversely affect crop yield and nature, while its deficiency limits plant growth. To study the relationship between Cl - nutrition and NO 3 - availability, we have characterized different physiological responses such as growth and yield, N-use efficiency, water status, photosynthesis, leaf anatomy, pigments and antioxidants in tomato plants treated with or without 5 mM Cl - salts and increasing NO 3 - treatments (3-15 mM). First, we have demonstrated that 5 mM Cl - application can reduce the use of NO 3 - in the nutrient solution by up to half without detriment to plant growth and yield in tomato and other horticultural plants. Second, Cl - application reduced stress symptoms and improved plant growth under low-NO 3 - conditions. The Cl - -dependent resistance to low-N stress resulted from: more efficient use of the available NO 3 - ; improved plant osmotic and water status regulation; improved stomatal conductance and photosynthetic rate; and better antioxidant response. We proposed that beneficial Cl - levels increase the crop ability to grow better with lower NO 3 - requirements and withstand N deficiency, promoting a more sustainable and resilient agriculture., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Objective: Transition age youth (TAY), aged 18 to 25 years, face barriers to medication treatment for opioid use disorder (MOUD), resulting in lower retention. We evaluated OUD prevalence and MOUD receipt comparing TAY to adults aged 26 or older residing in rural settings., Method: Electronic health records (October 2019 to January 2021) for 36,762 patients across 6 primary care clinics involved in a large feasibility trial in US rural communities were analyzed. All clinics implemented a standardized intervention. Mixed effects logistic/linear regression estimated the odds of OUD diagnosis among all patients, and, among those with OUD, the odds of receiving MOUD and days prescribed MOUD during the 15-month study period, comparing age categories (TAY aged 18-25 years vs adults 26 years or older). Covariates included gender, race, ethnicity, mental health comorbidities, and insurance status., Results: OUD prevalence was 2.82% among TAY (n = 3,122) and 3.24% among adults aged 26 or older (n = 33,208). After adjusting for covariates and clustering, TAY had significantly lower odds of OUD diagnosis compared to adults 26 years or older (odds ratio = 0.58, 95% CI 0.45-0.73). There were no significant differences in MOUD receipt between age groups. Compared to adults aged 26 or older, TAY with OUD had significantly fewer MOUD days during the study, -43.81 days (-76.85 to -10.77)., Conclusion: Although no differences were observed in MOUD prescription receipt between TAY and adults aged 26 or older, TAY with OUD had fewer total days prescribed MOUD, indicating lower retention. Further research generalizable to rural communities is needed to assess retention among rural TAY with OUD., Clinical Trial Registration Information: Rural MOUD Telemedicine in Primary Care Phase 1 (Feasibility); https://clinicaltrials.gov/; NCT04418453., (© 2024 The Author(s).)

Importance: Stimulants (methylphenidate and amphetamines) are often prescribed at unlicensed doses for adults with attention-deficit/hyperactivity disorder (ADHD). Whether dose escalation beyond US Food and Drug Administration recommendations is associated with positive risk benefits is unclear., Objective: To investigate the impact, based on averages, of stimulant doses on treatment outcomes in adults with ADHD and to determine, based on averages, whether unlicensed doses are associated with positive risk benefits compared with licensed doses., Data Sources: Twelve databases, including published (PubMed, Cochrane Library, Embase, Web of Sciences) and unpublished (ClinicalTrials.gov) literature, up to February 22, 2023, without language restrictions., Study Selection: Two researchers independently screened records to identify double-blinded randomized clinical trials of stimulants against placebo in adults (18 years and older) with ADHD., Data Extraction and Synthesis: Aggregate data were extracted and synthesized in random-effects dose-response meta-analyses and network meta-analyses., Main Outcome Measures: Change in ADHD symptoms and discontinuations due to adverse events., Results: A total of 47 randomized clinical trials (7714 participants; mean age, 35 (SD, 11) years; 4204 male [56%]) were included. For methylphenidate, dose-response curves indicated additional reductions of symptoms with increments in doses, but the gains were progressively smaller and accompanied by continued additional risk of adverse events dropouts. Network meta-analyses showed that unlicensed doses were associated with greater reductions of symptoms compared with licensed doses (standardized mean difference [SMD], -0.23; 95% CI, -0.44 to -0.02; very low certainty of evidence), but the additional gain was small and accompanied by increased risk of adverse event dropouts (odds ratio, 2.02; 95% CI, 1.19-3.43; moderate certainty of evidence). For amphetamines, the dose-response curve approached a plateau and increments in doses did not indicate additional reductions of symptoms, but there were continued increments in the risk of adverse event dropouts. Network meta-analysis did not identify differences between unlicensed and licensed doses for reductions of symptoms (SMD, -0.08; 95% CI, -0.24 to 0.08; very low certainty of evidence)., Conclusions and Relevance: Based on group averages, unlicensed doses of stimulants may not have positive risk benefits compared with licensed doses for adults with ADHD. In general, practitioners should consider unlicensed doses cautiously. Practitioners may trial unlicensed doses if needed and tolerated but should be aware that there may not be large gains in the response to the medication with those further increments in dose. However, the findings are averages and will not generalize to every patient.

Increasing irrigation demand has heavily relied on groundwater use, especially in places with highly variable water supplies that are vulnerable to drought. Groundwater management in agriculture is becoming increasingly challenging given the growing effects from overdraft and groundwater depletion worldwide. However, multiple challenges emerge when seeking to develop sustainable groundwater management in irrigated systems, such as trade-offs between the economic revenues from food production and groundwater resources, as well as the broad array of uncertainties in food-water systems. In this study we explore the applicability of Evolutionary Multi-Objective Direct Policy Search (EMODPS) to identify adaptive irrigation policies that water agencies and farmers can implement including operational decisions related to land use and groundwater use controls as well as groundwater pumping fees. The EMODPS framework yields state-aware, adaptive policies that respond dynamically as system state conditions change, for example with variable surface water (e.g., shifting management strategies across wet versus dry years). For this study, we focus on the Semitropic Water Storage district located in the San Joaquin Valley, California to provide broader insights relevant to ongoing efforts to improve groundwater sustainability in the state. Our findings demonstrate that adaptive irrigation policies can achieve sufficiently flexible groundwater management to acceptably balance revenue and sustainability goals across a wide range of uncertain future scenarios. Among the evaluated policy decisions, pumping restrictions and reductions in inflexible irrigation demands from tree crops are actions that can support dry-year pumping while maximizing groundwater storage recovery during wet years. Policies suggest that an adaptive pumping fee is the most flexible decision to control groundwater pumping and land use., Competing Interests: Declaration of competing interest On behalf of all the authors, I declare that we do not have competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Suicide is a public health crisis. We conducted a systematic review and meta-analysis of the effects of psychopharmacologic and somatic therapies on suicide risk., Methods: A systematic search of MEDLINE for studies evaluating the effects of pharmacologic (excluding antidepressants) or somatic interventions on suicide risk was conducted. Studies were included if they used a comparison group, reported on suicide death, assessed a psychopharmacological or somatic intervention, and included adults. Study quality was assessed using the Newcastle-Ottawa scale. Fifty-seven studies were included from 2940 reviewed citations., Results: In bipolar disorder, lithium was associated with a reduction in the odds of suicide compared to active controls (odds ratio [OR] = .58, p = .005; k = 12) and compared to placebo/no lithium (OR = .46, p = .009; k = 9). In mixed diagnostic samples, lithium was associated with a reduction in the odds of suicide compared to placebo/no lithium (OR = .27, p < .001; k = 12), but not compared to active controls (OR = .89, p = .468; k = 7). In psychotic disorders, clozapine was associated with a reduction in the odds of suicide (OR = .46, p = .007; k = 7). Associations between suicide death and electroconvulsive therapy (OR = .77, p = .053; k = 11), non-clozapine antipsychotics in bipolar disorder (OR = .73, p = .090; k = 6) and antipsychotics in psychotic disorders (OR = .39, p = .069; k = 6) were not significant. There was no consistent relationship between antiepileptic mood stabilizers and suicide. There were insufficient studies to meta-analyze associations of suicide risk with vagus nerve stimulation, transcranial magnetic stimulation, magnetic seizure therapy, or transcranial direct current stimulation., Conclusion: Lithium and clozapine have consistent data supporting protective effects against suicide in certain clinical contexts.Reprinted from Depress Anxiety 2022; 39:100-112, with permission from John Wiley and Sons. Copyright © 2022., (Copyright © 2023 by the American Psychiatric Association.)

Trichotillomania (hair-pulling disorder) and excoriation (skin-picking) disorder are body-focused repetitive behaviors, which often first present in adolescence and cause distress and impairment into adulthood. Few studies have examined the clinical characteristics of the co-occurrence of these conditions across the lifespan. We examined cross-sectional survey responses collected from April 2018-February 2020 to evaluate the relationship between trichotillomania, excoriation disorder, and their co-occurrence. Responses from individuals with trichotillomania (n = 50), excoriation disorder (n = 52), and both conditions (n = 50) ages 4-67 years old were compared for co-occurring conditions and current symptoms. Self-report measures of hair-pulling and skin-picking severity and subtypes were assessed. Gender, race, and co-occurring conditions were generally similarly distributed across the three groups with high rates of self-reported anxiety (63-82%), depression (34-50%), obsessive-compulsive disorder (16-29%), and attention-deficit/hyperactivity disorder (12-32%). Among individuals with both trichotillomania and excoriation disorder, significant positive correlations were observed between hair-pulling and skin-picking severity scores as well as hair-pulling and skin-picking subtypes. Hair-pulling and skin-picking severity peaked at the transition from adolescence to adulthood and hair-pulling/skin-picking styles appeared to shift across the lifespan. Our results support several similarities between trichotillomania and excoriation disorder, providing new insight into the clinical characteristics of these conditions., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest. M.H.B. has received grant or research support from Therapix Biosciences, Emalex Biosciences, Neurocrine Biosciences, Janssen Pharmaceuticals, Biohaven Pharmaceuticals, NIH, National Alliance for Research on Schizophrenia and Depression (NARSAD), Lesbian Health Fund, Yale Foundation for Lesbian and Gay Studies (FLAGS), and Patterson Foundation. He has served on the advisory board/data monitoring and safety board of Therapix Biosciences. He serves as associate editor of Journal of Child Psychology and Psychiatry and on the editorial boards of Journal of Child and Adolescent Psychopharmacology and Depression & Anxiety. He has received royalties from Wolters Kluwer for Lewis's Child and Adolescent Psychiatry: A Comprehensive Textbook, Fifth Edition. He has received moonlighting pay from the Veteran's Administration., (Copyright © 2023. Published by Elsevier B.V.)

Objective: Winter birth has been hypothesized to be associated with increased schizophrenia risk for nearly a century. Major hypotheses regarding the potential etiological risk factors for schizophrenia such as vitamin D deficiency and virus exposure in utero are predicated based on the observation that risk of schizophrenia is higher in children born in winter months., Methods: We conducted a systematic review and meta-analysis to examine the association between season and month of birth and risk of schizophrenia. We further investigated this relationship stratified by hemisphere., Results: Forty-three studies spanning 30 countries and territories and 440,039 individuals with schizophrenia were included in this meta-analysis. Winter births were associated with a small but statistically significant increased risk of schizophrenia (OR 1.05, 95 % CI 1.03-1.07, p < 0.0001) and summer births were associated with a small but statistically significant decreased risk of schizophrenia (OR 0.96, 95 % CI 0.94-0.98, p = 0.0001). Stratified subgroup analysis demonstrated no significant difference between hemispheres in the risk of schizophrenia for either winter or summer births., Conclusions: Analysis using birth month data demonstrated a clear seasonal trend towards increased risk of schizophrenia being associated with winter birth months and decreased risk of schizophrenia in summer-to-fall months in the Northern but not Southern Hemisphere. These data suggest a small-but-substantial increased risk of schizophrenia in winter birth month. Further research needs to examine potential etiologic causes for this association., Competing Interests: Declaration of competing interest Michael Bloch reports a relationship with Therapix Bioscience that includes: funding grants. Michael Bloch reports a relationship with Emalex Biosciences that includes: funding grants. Michael Bloch reports a relationship with Neurocrine Biosciences Inc. that includes: funding grants. Michael Bloch reports a relationship with Janssen Pharmaceuticals Inc. that includes: funding grants. Michael Bloch reports a relationship with Biohaven Pharmaceuticals Holding Company Ltd. that includes: funding grants. Michael Bloch reports a relationship with National Institutes of Health that includes: funding grants. Michael Bloch reports a relationship with National Alliance for Research on Schizophrenia and Depression (NARSAD) that includes: funding grants. Michael Bloch reports a relationship with Lesbian Health Fund that includes: funding grants. Michael Bloch reports a relationship with Yale Foundation for Lesbian and Gay Studies (FLAGS) that includes: funding grants. Michael Bloch reports a relationship with The Patterson Foundation that includes: funding grants. Corresponding author has served as associate editor of Journal of Child Psychology and Psychiatry and on the editorial boards of Journal of Child and Adolescent Psychopharmacology and Depression and Anxiety. MHB., (Copyright © 2022. Published by Elsevier B.V.)

Low-income, rural frontline communities of California's Central Valley experience environmental and socioeconomic injustice, water insecurity, extremely poor air quality, and lack of fundamental infrastructure (sewage, green areas, health services), which makes them less resilient. Many communities depend financially on agriculture, while water scarcity and associated policy may trigger farmland retirement further hindering socioeconomic opportunities. Here we propose a multi-benefit framework to repurpose cropland in buffers inside and around (400-m and 1600-m buffers) 154 rural disadvantaged communities of the Central Valley to promote socioeconomic opportunities, environmental benefits, and business diversification. We estimate the potential for (1) reductions in water and pesticide use, nitrogen leaching, and nitrogen gas emissions, (2) managed aquifer recharge, and (3) economic and employment impacts associated with clean industries and solar energy. Retiring cropland within 1600-m buffers can result in reductions in water use of 2.18 km 3 /year, nitrate leaching into local aquifers of 105,500 t/year, greenhouse gas emissions of 2,232,000 t CO 2 -equivalent/year, and 5388 t pesticides/year, with accompanying losses in agricultural revenue of US$4213 million/year and employment of 25,682 positions. Buffer repurposing investments of US$27 million/year per community for ten years show potential to generate US$101 million/year per community (total US$15,578 million/year) for 30 years and 407 new jobs/year (total 62,697 jobs/year) paying 67 % more than prior farmworker jobs. In the San Joaquin Valley (southern Central Valley), where groundwater overdraft averages 2.3 km 3 /year, potential water use reduction is 1.8 km 3 /year. We have identified 99 communities with surficial soils adequate for aquifer recharge and canals/rivers within 1600 m. This demonstrates the potential of managed aquifer recharge in buffered zones to substantially reduce overdraft. The buffers framework shows that well-planned land repurposing near disadvantaged communities can create multiple benefits for farmers and industry stakeholders, while improving quality of life in disadvantaged communities and producing positive externalities for society., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Chloride (Cl - ) and nitrate ( NO 3 - ) are closely related anions involved in plant growth. Their similar physical and chemical properties make them to interact in cellular processes like electrical balance and osmoregulation. Since both anions share transport mechanisms, Cl - has been considered to antagonize NO 3 - uptake and accumulation in plants. However, we have recently demonstrated that Cl - provided at beneficial macronutrient levels improves nitrogen (N) use efficiency (NUE). Biochemical mechanisms by which beneficial Cl - nutrition improves NUE in plants are poorly understood. First, we determined that Cl - nutrition at beneficial macronutrient levels did not impair the NO 3 - uptake efficiency, maintaining similar NO 3 - content in the root and in the xylem sap. Second, leaf NO 3 - content was significantly reduced by the treatment of 6 mM Cl - in parallel with an increase in NO 3 - utilization and NUE. To verify whether Cl - nutrition reduces leaf NO 3 - accumulation by inducing its assimilation, we analysed the content of N forms and the activity of different enzymes and genes involved in N metabolism. Chloride supply increased transcript accumulation and activity of most enzymes involved in NO 3 - assimilation into amino acids, along with a greater accumulation of organic N (mostly proteins). A reduced glycine/serine ratio and a greater ammonium accumulation pointed to a higher activity of the photorespiration pathway in leaves of Cl - -treated plants. Chloride, in turn, promoted higher transcript levels of genes encoding enzymes of the photorespiration pathway. Accordingly, microscopy observations suggested strong interactions between different cellular organelles involved in photorespiration. Therefore, in this work we demonstrate for the first time that the greater NO 3 - utilization and NUE induced by beneficial Cl - nutrition is mainly due to the stimulation of NO 3 - assimilation and photorespiration, possibly favouring the production of ammonia, reductants and intermediates that optimize C-N re-utilization and plant growth. This work demonstrates new Cl - functions and remarks on its relevance as a potential tool to manipulate NUE in plants., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Peinado-Torrubia, Álvarez, Lucas, Franco-Navarro, Durán-Gutiérrez, Colmenero-Flores and Rosales.)

Purpose: Investigate whether adjuvant everolimus, an mTOR inhibitor, improves progression-free survival (PFS) in advanced-stage head and neck squamous cell carcinoma (HNSCC) and provide outcomes related to correlative biological factors associated with disease control., Patients and Methods: This was a prospective, randomized, double-blind phase II trial of patients with advanced-stage HNSCC from 13 institutions who were confirmed disease-free post-definitive therapy and enrolled between December 2010 and March 2015. Patients received adjuvant everolimus or placebo daily (10 mg, oral) for a maximum of 1 year. p16 IHC as a surrogate marker for human papillomavirus infection and whole-exome sequencing were performed. Cox proportional hazard models estimated hazard rates. Log-rank tests evaluated differences in survival. The primary endpoint was PFS. Secondary endpoints and objectives included overall survival (OS) and toxicity assessment., Results: 52 patients [median (range) age, 58 (37-76) years; 43 men (83%), 9 women (17%)] were randomized to placebo (n = 24) or everolimus (n = 28). PFS favored everolimus, but was not significant [log-rank P = 0.093; HR = 0.44; 95% confidence interval (CI), 0.17-1.17]. There was no difference in OS (P = 0.29; HR = 0.57; 95% CI, 0.20-16.2). Everolimus resulted in significant improvement in PFS for p16-negative patients (n = 31; P = 0.031; HR = 0.26; 95% CI, 0.07-0.97), although subgroup analysis showed no difference for p16-positive patients (n = 21; P = 0.93). Further, PFS was significantly higher in TP53-mutated (TP53mut) patients treated with everolimus compared with placebo (log-rank P = 0.027; HR = 0.24; 95% CI, 0.06-0.95). No treatment difference was seen in patients with TP53 wild-type tumors (P = 0.79)., Conclusions: p16-negative and TP53mut patients may benefit from adjuvant treatment with everolimus., (©2022 American Association for Cancer Research.)

The identification of rootstocks of low susceptibility to Verticillium dahliae can become a valuable procedure to achieve effective control of Verticillium wilt in the olive grove. This not only involves the identification of suitable genotypes, but also the study of the interaction between the rootstock and the grafted scion. Thus, a rootstock that prevents or minimizes V. dahliae proliferation (avoidance/resistance strategy) can have very different effects on a susceptible scion compared to a rootstock that shows few or no symptoms despite being infected (tolerance strategy). Both resistance and tolerance mechanisms have been recently identified in wild olive genotypes with low susceptibility to V. dahliae . When used as rootstocks of the highly susceptible variety 'Picual', we found that resistant genotypes, including the cultivar 'Frantoio', were more effective than tolerant genotypes in controlling Verticillium wilt. Furthermore, tolerant genotypes were as ineffective as susceptible or extremely susceptible genotypes in controlling Verticillium wilt. We also identified rootstock-scion combinations with behaviours that were not expected according to the degree of susceptibility previously observed in the non-grafted rootstock. Although the rootstocks were able to control Verticillium wilt according to its degree of susceptibility to V. dahliae , the ability to control the infection was not adequately transferred to the grafted scion. Our results confirmed that: the degree of susceptibility to Verticillium wilt of an olive variety does not predict its performance as a rootstock; to use a very low susceptible genotype as rootstock of a susceptible scion increases the susceptibility of the genotype used as rootstock; in any case, avoidant/resistant rootstocks are more effective than tolerant rootstocks in reducing the susceptibility of the grafted plant to V. dahliae ., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Díaz-Rueda, Peinado-Torrubia, Durán-Gutiérrez, Alcántara-Romano, Aguado, Capote and Colmenero-Flores.)

Objective: Adolescent depression is prevalent and is associated with significant morbidity and mortality. Although intravenous ketamine has shown efficacy in adult treatment-resistant depression, its efficacy in pediatric populations is unknown. The authors conducted an active-placebo-controlled study of ketamine's safety and efficacy in adolescents., Methods: In this proof-of-concept randomized, double-blind, single-dose crossover clinical trial, 17 adolescents (ages 13-17) with a diagnosis of major depressive disorder received a single intravenous infusion of either ketamine (0.5 mg/kg over 40 minutes) or midazolam (0.045 mg/kg over 40 minutes), and the alternate compound 2 weeks later. All participants had previously tried at least one antidepressant medication and met the severity criterion of a score >40 on the Children's Depression Rating Scale-Revised. The primary outcome measure was score on the Montgomery-Åsberg Depression Rating Scale (MADRS) 24 hours after treatment., Results: A single ketamine infusion significantly reduced depressive symptoms 24 hours after infusion compared with midazolam (MADRS score: midazolam, mean=24.13, SD=12.08, 95% CI=18.21, 30.04; ketamine, mean=15.44, SD=10.07, 95% CI=10.51, 20.37; mean difference=-8.69, SD=15.08, 95% CI=-16.72, -0.65, df=15; effect size=0.78). In secondary analyses, the treatment gains associated with ketamine appeared to remain 14 days after treatment, the latest time point assessed, as measured by the MADRS (but not as measured by the Children's Depression Rating Scale-Revised). A significantly greater proportion of participants experienced a response to ketamine during the first 3 days following infusion as compared with midazolam (76% and 35%, respectively). Ketamine was associated with transient, self-limited dissociative symptoms that affected participant blinding, but there were no serious adverse events., Conclusions: In this first randomized placebo-controlled clinical trial of intravenous ketamine in adolescents with depression, the findings suggest that it is well tolerated acutely and has significant short-term (2-week) efficacy in reducing depressive symptoms compared with an active placebo.Reprinted from Am J Psychiatry 2021; 178:352-362 with permission from American Psychiatric Association Publishing., (Copyright © 2022 by the American Psychiatric Association.)

Clinical guidelines currently recommend practitioners titrate stimulant medications, i.e., methylphenidate (MPH) and amphetamines (AMP), to the dose that maximizes symptom control without eliciting intolerable adverse events (AEs) when treating attention-deficit/hyperactivity disorder (ADHD) in school-aged children/adolescents. However, robust evidence-base regarding the effects of doses and dosing strategies of stimulants on clinical outcomes in the treatment of children/adolescents with ADHD is currently lacking and stimulants are often underdosed in clinical practice. To address this gap and provide rigorous evidence-base in relation to the dose and dosing strategy of stimulants, we conducted the largest systematic review and dose-response meta-analysis examining change in ADHD symptoms (efficacy), and treatment discontinuations due to AEs (tolerability) and any reason (acceptability). We conducted one-stage random-effects dose-response meta-analyses examining MPH and AMP separately, stratifying trials based on fixed-dose and flexible-dose design. Daily doses of stimulants were converted to MPH- and AMP-equivalent doses by adjusting for different pharmacokinetics across formulations. We also conducted pairwise meta-analyses to provide indirect comparisons between flexible-dose versus fixed-dose trials. Our study included 65 RCTs involving 7 877 children/adolescents. Meta-analyses of fixed-dose trials for both MPH and AMP demonstrated increased efficacy and increased likelihood of discontinuation due to AEs with increasing doses of stimulants. The incremental benefits of stimulants in terms of efficacy decreased beyond 30 mg of MPH or 20 mg of AMP in fixed-dosed trials. In contrast, meta-analyses of flexible-dose trials for both MPH and AMP demonstrated increased efficacy and reduced likelihood of discontinuations for any reason with increasing stimulant doses. The incremental benefits of stimulants in terms of efficacy remained constant across the FDA-licensed dose range for MPH and AMP in flexible-dose trials. Our results suggest that flexible titration as needed, i.e., considering the presence of ADHD symptoms, and tolerated, i.e., considering the presence of dose-limiting AEs, to higher doses of stimulants is associated with both improved efficacy and acceptability because practitioners can increase/reduce doses based on control of ADHD symptoms/dose-limiting AEs. Although fixed-dose trials that are required by the FDA are valuable to characterize dose-dependency, they may underestimate the true potential benefit of trialing dose-increases of stimulants in clinical practice by not allowing dose adjustment based on response and tolerability. Additional research is required to investigate potential long-term effects of using high doses of stimulants in clinical practice., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Suicide is a public health crisis. We conducted a systematic review and meta-analysis of the effects of psychopharmacologic and somatic therapies on suicide risk., Methods: A systematic search of MEDLINE for studies evaluating the effects of pharmacologic (excluding antidepressants) or somatic interventions on suicide risk was conducted. Studies were included if they used a comparison group, reported on suicide death, assessed a psychopharmacological or somatic intervention, and included adults. Study quality was assessed using the Newcastle-Ottawa scale. Fifty-seven studies were included from 2940 reviewed citations., Results: In bipolar disorder, lithium was associated with a reduction in the odds of suicide compared to active controls (odds ratio [OR] = .58, p = .005; k = 12) and compared to placebo/no lithium (OR = .46, p = .009; k = 9). In mixed diagnostic samples, lithium was associated with a reduction in the odds of suicide compared to placebo/no lithium (OR = .27, p < .001; k = 12), but not compared to active controls (OR = .89, p = .468; k = 7). In psychotic disorders, clozapine was associated with a reduction in the odds of suicide (OR = .46, p = .007; k = 7). Associations between suicide death and electroconvulsive therapy (OR = .77, p = .053; k = 11), non-clozapine antipsychotics in bipolar disorder (OR = .73, p = .090; k = 6) and antipsychotics in psychotic disorders (OR = .39, p = .069; k = 6) were not significant. There was no consistent relationship between antiepileptic mood stabilizers and suicide. There were insufficient studies to meta-analyze associations of suicide risk with vagus nerve stimulation, transcranial magnetic stimulation, magnetic seizure therapy, or transcranial direct current stimulation., Conclusion: Lithium and clozapine have consistent data supporting protective effects against suicide in certain clinical contexts., (© 2021 Wiley Periodicals LLC.)

Chloride (Cl-), traditionally considered harmful for agriculture, has recently been defined as a beneficial macronutrient with specific roles that result in more efficient use of water (WUE), nitrogen (NUE), and CO2 in well-watered plants. When supplied in a beneficial range of 1-5 mM, Cl- increases leaf cell size, improves leaf osmoregulation, and reduces water consumption without impairing photosynthetic efficiency, resulting in overall higher WUE. Thus, adequate management of Cl- nutrition arises as a potential strategy to increase the ability of plants to withstand water deficit. To study the relationship between Cl- nutrition and drought resistance, tobacco plants treated with 0.5-5 mM Cl- salts were subjected to sustained water deficit (WD; 60% field capacity) and water deprivation/rehydration treatments, in comparison with plants treated with equivalent concentrations of nitrate, sulfate, and phosphate salts. The results showed that Cl- application reduced stress symptoms and improved plant growth during water deficit. Drought resistance promoted by Cl- nutrition resulted from the simultaneous occurrence of water deficit avoidance and tolerance mechanisms, which improved leaf turgor, water balance, photosynthesis performance, and WUE. Thus, it is proposed that beneficial Cl- levels increase the ability of crops to withstand drought, promoting a more sustainable and resilient agriculture., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Experimental Biology.)

The clinical features and neurobiology of pain and opioid use disorder (OUD) are inextricably linked. Despite emerging evidence supporting the negative impact of ongoing pain in the treatment of OUD, the pharmacological management of pain in the presence of OUD has received limited attention. We sought to systematically review the studies investigating pharmacotherapies for pain among persons with OUD. Eligible studies had participants with OUD and outcomes including evoked or spontaneous pain. We searched Scopus, Cochrane Database of Systematic Reviews, Medline, and Embase. Out of 1,097 studies that met the search criteria, 12 studies provided data relevant to the research question-five laboratory studies and seven clinical trials. Random effects pooled estimates suggested no significant difference between groups at baseline but a response favoring the active treatment group over placebo, with nonsignificant heterogeneity between studies. Findings from these studies provide preliminary evidence for analgesic and antihyperalgesic effects of gabapentin, GABA agonists, and NMDA antagonists among persons with OUD. To establish the tradeoffs between the analgesic effects and abuse liability of these compounds, further well-controlled clinical trials are required among persons with OUD. This review also underscores the need for methodological enhancement in drug development for pain in OUD. Future research should address the clinical and neurobiological overlap between pain- and addiction-related phenomena. Transdisciplinary approaches may identify biomarkers of these shared phenomena and their neural substrates. The development of novel therapeutics for pain in OUD may be accelerated by such integration of pain and addiction research., (© 2020 Society for the Study of Addiction.)

Resistance to the defoliating pathotype of Verticillium dahliae has been evaluated in a pool of 68 wild genotypes of olive belonging to the SILVOLIVE collection. Resistance was evaluated by assessing symptom severity using a 0-4 rating scale, estimating the relative area under the disease progress curve (RAUDPC), determining the percentage of dead plants (PDP), and measuring the evolution of morphological parameters in inoculated plants over time. In addition, the density levels of V. dahliae in the stem of root-inoculated genotypes have been quantified by means of quantitative real-time PCR at 35 and 120 days after inoculation (dai). Fifteen genotypes (22%) were cataloged as resistant to V. dahliae (i.e., disease parameters did not significantly differ from those of the resistant cultivar Frantoio, or were even lower). Resistant genotypes are characterized by presenting fewer symptoms and a lower amount of V. dahliae DNA at 120 dai than at 35 dai, indicating their ability to control the disease and reduce the density of the pathogen. The rest of the evaluated genotypes showed variable levels of susceptibility. Overall analysis of all genotypes showed high correlation between symptomatology and the amount of V. dahliae DNA in the stem of inoculated genotypes at 120 dai, rather than at 35 dai. However, correlation at 120 dai was not observed in the set of resistant genotypes, suggesting that resistance to defoliating V. dahliae in olive is based on the occurrence of different mechanisms such as avoidance or tolerance. These mechanisms are valuable for designing breeding programs and for the identification of target genes and resistant rootstocks to better control Verticillium wilt in the olive grove., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Díaz-Rueda, Aguado, Romero-Cuadrado, Capote and Colmenero-Flores.)

Objective: Adolescent depression is prevalent and is associated with significant morbidity and mortality. Although intravenous ketamine has shown efficacy in adult treatment-resistant depression, its efficacy in pediatric populations is unknown. The authors conducted an active-placebo-controlled study of ketamine's safety and efficacy in adolescents., Methods: In this proof-of-concept randomized, double-blind, single-dose crossover clinical trial, 17 adolescents (ages 13-17) with a diagnosis of major depressive disorder received a single intravenous infusion of either ketamine (0.5 mg/kg over 40 minutes) or midazolam (0.045 mg/kg over 40 minutes), and the alternate compound 2 weeks later. All participants had previously tried at least one antidepressant medication and met the severity criterion of a score >40 on the Children's Depression Rating Scale-Revised. The primary outcome measure was score on the Montgomery-Åsberg Depression Rating Scale (MADRS) 24 hours after treatment., Results: A single ketamine infusion significantly reduced depressive symptoms 24 hours after infusion compared with midazolam (MADRS score: midazolam, mean=24.13, SD=12.08, 95% CI=18.21, 30.04; ketamine, mean=15.44, SD=10.07, 95% CI=10.51, 20.37; mean difference=-8.69, SD=15.08, 95% CI=-16.72, -0.65, df=15; effect size=0.78). In secondary analyses, the treatment gains associated with ketamine appeared to remain 14 days after treatment, the latest time point assessed, as measured by the MADRS (but not as measured by the Children's Depression Rating Scale-Revised). A significantly greater proportion of participants experienced a response to ketamine during the first 3 days following infusion as compared with midazolam (76% and 35%, respectively). Ketamine was associated with transient, self-limited dissociative symptoms that affected participant blinding, but there were no serious adverse events., Conclusions: In this first randomized placebo-controlled clinical trial of intravenous ketamine in adolescents with depression, the findings suggest that it is well tolerated acutely and has significant short-term (2-week) efficacy in reducing depressive symptoms compared with an active placebo.

Ketamine, a medication traditionally used as an anesthetic, has increasingly been recognized as an effective treatment for psychiatric disorders. At sub-anesthetic doses (defined here as ≤ 0.5 mg/kg), ketamine treatment has been studied in patients with treatment-resistant depression (TRD), obsessive-compulsive disorder (OCD), post-traumatic stress disorder (PTSD), and social anxiety disorder (SAD). Transient increases in hemodynamic activity have been reported during and after ketamine treatment, which may be desirable properties in some anesthesia settings, but are generally undesirable in psychiatric settings. While ketamine doses used in psychiatry are lower than those used in anesthesia, there are published instances of early termination of psychiatric ketamine infusions due to elevations in blood pressure and heart rate. No unifying study has been conducted to examine the impact of sub-anesthetic ketamine doses on hemodynamic parameters [systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate (HR)] in psychiatric populations and to evaluate these changes across adult age groups. Here, data from 15 articles comprising a total N = 2,252 ketamine or esketamine treatments in adult participants were used to conduct a meta-analysis of treatment-induced hemodynamic changes. Ketamine/esketamine produced modest but significant increases in the variables of interest with an average SBP increase of 12.61 mm Hg (95% CI 10.40-14.82 mm Hg, z = 11.18, p < 0.0001), average DBP increase of 8.49 mm Hg (95% CI 6.89-10.09 mmHg, z = 10.41, p < 0.0001), and average heart rate increase of 4.09 beats per minute (95% CI 0.55-7.63 BPM), z = 2.27, p = 0.0235). Stratified subgroup analysis indicated no significant differences between ketamine and esketamine effects on blood pressure. Further analysis indicated that there was no significant effect of age on ketamine-induced changes in SBP, DBP, and HR. Taken together these data show that sub-anesthetic ketamine and esketamine induce small but significant increases in hemodynamic parameters that are transient in nature in adult psychiatric populations. While these data are reassuring, it is important for each treatment case to fully explore potential cardiovascular risks prior to initiating treatment., Competing Interests: JF receives financial support for his research from NIH (T32MH018268). MB receives research support from Therapix Biosciences, Neurocrine Biosciences, Janssen Pharmaceuticals and Biohaven Pharmaceuticals, but none provided support for the current manuscript. MB gratefully acknowledges additional research support from NIH. JD receives consulting income from Axsome Therapeutics and research support from the Klingenstein Third Generation Foundation, the AACAP Junior Investigator Award, the National Institutes of Mental Health, and the Brain and Behavior Foundation. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Vankawala, Naples, Avila-Quintero, Ramírez, Flores, Bloch and Dwyer.)

Varroa mite is the major threat to the western honey bee, Apis mellifera, and the cause of significant economic losses in the apiculture industry. Varroa destructor feeds on brood and adult bees being responsible for vectoring virus infections and other diseases. This study analyses the role of Varroa and other associated pathogens, such as viruses or the fungus Nosema ceranae, and their relationships regarding the viability of the bee colony. It has been carried out during one beekeeping season, with the subspecies A. m. iberiensis, commonly used in the apiculture industry of Spain. Our study shows a significant relationship between the presence of Varroa destructor and viral infection by deformed wing virus and acute bee paralysis virus. Nosema ceranae behaved as an opportunistic pathogen. In addition, this study explored a potential naturally occurring subset of peptides, responsible for the humoral immunity of the bees. The expression of the antimicrobial peptides abaecin and melittin showed a significant relationship with the levels of Varroa mite and the deformed wing virus., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objective: Racial and ethnic disparities are well documented in psychiatry, yet suboptimal understanding of underlying mechanisms of these disparities undermines diversity, inclusion, and education efforts. Prior research suggests that implicit associations can affect human behavior, which may ultimately influence healthcare disparities. This study investigated whether racial implicit associations exist among medical students and psychiatric physicians and whether race/ethnicity, training level, age, and gender predicted racial implicit associations., Methods: Participants completed online demographic questions and 3 race Implicit Association Tests (IATs) related to psychiatric diagnosis (psychosis vs. mood disorders), patient compliance (compliance vs. non-compliance), and psychiatric medications (antipsychotics vs. antidepressants). Linear and logistic regression models were used to identify demographic predictors of racial implicit associations., Results: The authors analyzed data from 294 medical students and psychiatric physicians. Participants were more likely to pair faces of Black individuals with words related to psychotic disorders (as opposed to mood disorders), non-compliance (as opposed to compliance), and antipsychotic medications (as opposed to antidepressant medications). Among participants, self-reported White race and higher level of training were the strongest predictors of associating faces of Black individuals with psychotic disorders, even after adjusting for participant's age., Conclusions: Racial implicit associations were measurable among medical students and psychiatric physicians. Future research should examine (1) the relationship between implicit associations and clinician behavior and (2) the ability of interventions to reduce racial implicit associations in mental healthcare.

Objective: In March 2018, the American Association of Directors of Psychiatric Residency Training (AADPRT) formed the Diversity and Inclusion (D&I) Committee. One of the committee's goals was to understand the AADPRT membership's composition and their perceptions of D&I. This study's objective was to identify the demographic characteristics of the AADPRT membership., Methods: Program directors were invited by email to participate in an anonymous survey. The survey collected participants' demographic information including gender, race/ethnicity, training background, age, disability/differently abled status, job role, geographic region where their program is located, type of program, and their program's community setting., Results: Two hundred fifty six of 657 AADPRT members (39%) completed the survey. Respondents were mostly White (64.5%) followed by Asian/Southeast Asian (17.6%), Hispanic/Latinx (4.3%), and Black (1.6%). Only 13.3% of the participants were international medical graduates. Women were more prevalent (61.7%) than men (37.5%), and 9.4% self-identified as members of the LGBTQ+ Community., Conclusions: This study represents the first systematic investigation into the diversity among psychiatry program directors throughout the USA and Canada. Future qualitative studies are needed to better understand the reasons behind this initial study's findings. Potential concerns requiring exploration include the possibility of the program director role serving as a "glass ceiling" for some women and a "leaky pipeline" in academia for groups underrepresented in medicine.

Despite the restriction of the use of neonicotinoids in the EU, including thiamethoxam and clothianidin, the debate over their risk on honey bees has not been fully settled. This study presents results of a three-year study working with 180 honey bee colonies in ten replicates. Colonies were sorted into three treatments (60 colonies per treatment) exposed to sunflower blooms grown from seeds treated with thiamethoxam, clothianidin and a non-treated control. Each colony was assessed at six moments: one before to exposition to sunflower, two during the exposition (short-time risk), two after exposition (medium-time risk) and one after wintering (long-time risk). The health and development of the colonies were assessed by monitoring adult bee population, brood development, status of the queen, food reserves and survival. No significant difference among treatments when raw data was considered. However, when evolution from initial status of the colony was evaluated, a significant difference was observed from the first week of exposure to sunflower blooms. In this period, the number of adult bees and the amount of brood were slightly lower in the bee hives exposed to neonicotinoids, although such differences disappeared in subsequent evaluations. The concentration of residues in samples of beebread and adult bees was at the level of ng·g -1 . Magnitude of the effect of the treatment factor on the variability of colony health and development related parameters was low. The most important factor was the hive, followed by the replicate and year, and to a lesser extent the initial strength of the colonies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Introduction: Current cigarette smoking rates among older women remain problematic, especially given that this population experiences increased smoking-related health consequences. Despite these increased health concerns, little research to date has explored smoking patterns across the menopausal transition (pre-, early-peri-, late-peri-, and postmenopausal) or the effect of unique factors such as sex hormones and depression during this transition., Methods: This study used 10 yearly waves of data from the Study of Women's Health Across the Nation, a longitudinal dataset. Data included 1397 women endorsing ever smoking regularly at baseline. Random-effects logistic regression models were used to examine smoking transitions., Results: Although there were no associations between menopausal transition stage and smoking behavior, increased estradiol was associated with an increased likelihood of quitting regular smoking (eg, transitioning from regular smoking to non-regular or no smoking; odds ratio [OR] = 1.28), whereas increased testosterone was associated with an increased likelihood of relapsing to regular smoking (eg, transitioning from former or nonregular smoking to regular smoking OR = 2.56). Depression was associated with increased likelihood of continued smoking (OR = 0.97) and relapse (OR = 1.03)., Conclusions: The results emphasize the need to develop interventions to target initiated or continued smoking among women across the menopausal transition and specifically highlight the importance of developing treatments that target depressive symptoms in this population. In addition, although singular hormone measures were associated with smoking behavior, there is a need for future study of dynamic changes in hormones, as well as the impact of progesterone on smoking behaviors across the menopausal transition., Implications: To date, no studies have examined smoking behaviors across the menopausal transition. In this study, although menopausal transition status was not significantly related to transitions in smoking behavior, important relationships between sex hormones and depression were observed. Increased estradiol was associated with an increased likelihood of quitting regular smoking, whereas increased testosterone was associated with an increased likelihood of relapsing to regular smoking behavior. Higher depression scores were related to continued smoking and relapse to regular smoking behavior. These results highlight the need to develop interventions to target smoking cessation among women across the menopausal transition., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved.For permissions, please e-mail: journals.permissions@oup.com.)

Chloride (Cl - ) has traditionally been considered harmful to agriculture because of its toxic effects in saline soils and its antagonistic interaction with nitrate (NO 3 - ), which impairs NO 3 - nutrition. It has been largely believed that Cl - antagonizes NO 3 - uptake and accumulation in higher plants, reducing crop yield. However, we have recently uncovered that Cl - has new beneficial macronutrient, functions that improve plant growth, tissue water balance, plant water relations, photosynthetic performance, and water-use efficiency. The increased plant biomass indicates in turn that Cl - may also improve nitrogen use efficiency (NUE). Considering that N availability is a bottleneck for the plant growth, the excessive NO 3 - fertilization frequently used in agriculture becomes a major environmental concern worldwide, causing excessive leaf NO 3 - accumulation in crops like vegetables and, consequently, a potential risk to human health. New farming practices aimed to enhance plant NUE by reducing NO 3 - fertilization should promote a healthier and more sustainable agriculture. Given the strong interaction between Cl - and NO 3 - homeostasis in plants, we have verified if indeed Cl - affects NO 3 - accumulation and NUE in plants. For the first time to our knowledge, we provide a direct demonstration which shows that Cl - , contrary to impairing of NO 3 - nutrition, facilitates NO 3 - utilization and improves NUE in plants. This is largely due to Cl - improvement of the N-NO 3 - utilization efficiency (NU T E), having little or moderate effect on N-NO 3 - uptake efficiency (NU P E) when NO 3 - is used as the sole N source. Clear positive correlations between leaf Cl - content vs. NUE/NU T E or plant growth have been established at both intra- and interspecies levels. Optimal NO 3 - vs. Cl - ratios become a useful tool to increase crop yield and quality, agricultural sustainability and reducing the negative ecological impact of NO 3 - on the environment and on human health., (Copyright © 2020 Rosales, Franco-Navarro, Peinado-Torrubia, Díaz-Rueda, Álvarez and Colmenero-Flores.)

Chloride (Cl - ) has traditionally been considered a micronutrient largely excluded by plants due to its ubiquity and abundance in nature, its antagonism with nitrate (NO 3 - ), and its toxicity when accumulated at high concentrations. In recent years, there has been a paradigm shift in this regard since Cl - has gone from being considered a harmful ion, accidentally absorbed through NO 3 - transporters, to being considered a beneficial macronutrient whose transport is finely regulated by plants. As a beneficial macronutrient, Cl - determines increased fresh and dry biomass, greater leaf expansion, increased elongation of leaf and root cells, improved water relations, higher mesophyll diffusion to CO 2 , and better water- and nitrogen-use efficiency. While optimal growth of plants requires the synchronic supply of both Cl - and NO 3 - molecules, the NO 3 - /Cl - plant selectivity varies between species and varieties, and in the same plant it can be modified by environmental cues such as water deficit or salinity. Recently, new genes encoding transporters mediating Cl - influx ( ZmNPF6.4 and ZmNPF6.6 ), Cl - efflux ( AtSLAH3 and AtSLAH1 ), and Cl - compartmentalization ( AtDTX33 , AtDTX35 , AtALMT4, and GsCLC2 ) have been identified and characterized. These transporters have proven to be highly relevant for nutrition, long-distance transport and compartmentalization of Cl - , as well as for cell turgor regulation and stress tolerance in plants.

Chloride (Cl - ) has been recently described as a beneficial macronutrient, playing specific roles in promoting plant growth and water-use efficiency (WUE). However, it is still unclear how Cl - could be beneficial, especially in comparison with nitrate (NO 3 - ), an essential source of nitrogen that shares with Cl - similar physical and osmotic properties, as well as common transport mechanisms. In tobacco plants, macronutrient levels of Cl - specifically reduce stomatal conductance (g s ) without a concomitant reduction in the net photosynthesis rate (A N ). As stomata-mediated water loss through transpiration is inherent in the need of C 3 plants to capture CO 2 , simultaneous increase in photosynthesis and WUE is of great relevance to achieve a sustainable increase in C 3 crop productivity. Our results showed that Cl - -mediated stimulation of larger leaf cells leads to a reduction in stomatal density, which in turn reduces g s and water consumption. Conversely, Cl - improves mesophyll diffusion conductance to CO 2 (g m ) and photosynthetic performance due to a higher surface area of chloroplasts exposed to the intercellular airspace of mesophyll cells, possibly as a consequence of the stimulation of chloroplast biogenesis. A key finding of this study is the simultaneous improvement of A N and WUE due to macronutrient Cl - nutrition. This work identifies relevant and specific functions in which Cl - participates as a beneficial macronutrient for higher plants, uncovering a sustainable approach to improve crop yield., (© 2019 The Authors The Plant Journal © 2019 John Wiley & Sons Ltd.)

Chloroquine (CQ) is an old antimalarial drug currently being investigated for its anti-tumor properties. As chloroquine has been shown to inhibits several potassium channels, we decided to study its effect on the tumor-related Kv10.1 channel by using patch-clamp electrophysiology and cell migration assays. We found that chloroquine inhibited Kv10.1 channels transiently expressed in HEK-293 cells in a concentration- and voltage-dependent manner acting from the cytoplasmic side of the plasma membrane. Chloroquine also inhibited the outward potassium currents from MDA-MB-231 cells, which are mainly carried through Kv10.1 channels as was confirmed using astemizole. Additionally, chloroquine decreased MDA-MB-231 cell migration in the in vitro scratch wound healing assay. In conclusion, our data suggest that chloroquine decreases MDA-MB-231 cell migration by inhibiting Kv10.1 channels. The inhibition of Kv10.1 channels could represent another mechanism of the antitumoral action of chloroquine, besides autophagy inhibition and tumor vessel normalization., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Honey bee plays the leading role in the pollination of many wild plants and crops, but it currently faces serious threats. Climate change is pointed out as one of the causes of the colony collapse disorder. Understanding the response of bees to the new climate change scenario is essential to face this challenge. Especially in the most sensitive bioclimatic zones, such as the Mediterranean areas. In this work, we remotely monitored the weight of the hives with an electronic device during a flowering period in the beekeeping seasons of 2016 and 2017, marked by extreme episodes of drought and high temperatures. We assessed bee colonies at the beginning, middle and at the end of the flowering as well, considering the adult bee population, bee brood, and pollen and honey reserves. The results showed that the flowering was reduced in three weeks in 2017 in comparison to 2016. In those years weight gain was 7.67 kg and 18.92 kg, respectively. The adverse conditions affected the evolution of the populations of bees and the reserves of honey and pollen in a meaningful way, increasing food stress for bees. It also affected the pollen spectrum and commercial characteristics of honey. Our results provide objective data about the effect of climate change on bees, but it also proved the relevant role of bees in the study of changes in the environment., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Venous thromboembolism (VTE) has been studied in lower extremity fractures but little is known of its relation with upper extremity (UE) fractures. As an often overlooked but serious complication, VTE may compromise patient outcomes., Methods: Using data on inpatients (aged ≥ 18 years) at a level-I trauma center and patients in the National Surgical Quality Improvement Program database who sustained UE fractures (clavicle, humerus, or radius/ulna) and VTE in the same hospitalization between 2007 and 2014, the authors analyzed data on demographic characteristics, fracture type, VTE location (pulmonary embolism, lower extremity, or UE), VTE onset, polytrauma, operative or nonoperative management, comorbidities, and mortality., Results: Of 1984 inpatients with UE fractures at 1 instution, 9 experienced VTE on admission, and 17 (15 received thromboprophylaxis) experienced VTE during hospitalization, for an overall VTE rate of 1.3%. VTE occurred most often in patients with fractures of the proximal humerus (3.0%) followed by the clavicle (2.0%), midshaft humerus (1.9%), distal radius/ulna (0.95%), and distal humerus/elbow (0.36%) (p = 0.0035). There were no significant trends in the incidence of PE (p = 0.33) over the study period, but there was a sharp rise since 2011. In the national database, 42 of 11570 (0.36%) patients with UE fracture had VTE, with incidence by fracture location ranging from 0.14% (radius/ulna) to 0.98% (proximal humerus) (p = 0.00001). Predictors were chronic steroid use (odds ratio [OR] = 6.22, p = .030), inpatient status (OR = 4.09, p = .002), and totally disabled functional status (OR = 3.31, p = .021)., Conclusions: VTE incidence was highest following proximal humerus or clavicle fractures and are rarely associated with radius/ulna fractures. There may have been a rise in the incidence of PE since 2007, warranting further investigation.

In this study, honeybee colonies were monitored in a field study conducted on sunflowers grown from seeds treated with the systemic neonicotinoids thiamethoxam or clothianidin. This field trial was carried out in different representative growing areas in Spain over a beekeeping season. The health and development of the colonies was assessed by measuring factors that have a significant influence on their strength and overwintering ability. The parameters assessed were: colony strength (adult bees), brood development, amount of pollen and honey stores and presence and status of the queen. The concentration of residues (clothianidin and thiamethoxam) in samples of beebread and in adult bees was at the level of ng.g -1 ; in the ranges of 0.10-2.89 ng g -1 and 0.05-0.12 ng g -1 ; 0.10-0.37 ng g -1 and 0.01-0.05 ng g -1 , respectively. Multivariate models were applied to evaluate the interaction among factors. No significant differences were found between the honeybee colonies of the different treatment groups, either exposed or not to the neonicotinoids. The seasonal development of the colonies was affected by the environmental conditions which, together with the initial strength of the bee colonies and the characteristics of the plots, had a significant effect on the different variables studied., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Background: Neoadjuvant radiotherapy (NRT) enhances breast-conserving surgery outcomes, reducing local recurrence of breast cancer and increasing median survival. However, its effect on postoperative morbidity remains under-studied. We sought to assess the impact of NRT on 30-day postoperative morbidity after mastectomy., Methods: We analyzed data from women undergoing mastectomy (with or without immediate reconstruction) using the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) 2005-2011 datasets. ACS-NSQIP is a prospective, risk-adjusted, outcomes-based registry. Data included demographic and perioperative factors. Outcomes studied included surgical site (wound and prosthesis/flap complications), systemic (cardiac, respiratory, neurological, urinary, and venous thromboembolism events), and overall morbidity. Logistic regression was used to estimate the unadjusted odds ratio (uOR) and adjusted odds ratio (aOR) between NRT and postoperative 30-day morbidity., Results: The study population included 77,902 women, of which 61,039 (78.4%) underwent mastectomy only and 16,863 (21.6%) underwent mastectomy with immediate breast reconstruction. NRT was administered to 266 (0.4%) mastectomy-only and 75 (0.4%) immediate breast reconstruction patients. In the mastectomy-only group, there were no significant differences in the rates of postoperative surgical site morbidity (aOR = 1.41; 95% confidence interval (CI): 0.76-2.63; P = 0.276), systemic morbidity (aOR = 0.72; 95% CI: 0.40-1.26; P = 0.252), and overall morbidity (aOR = 0.85; 95% CI: 0.54-1.33; P = 0.477) between NRT and control groups. Similarly, no significant differences were found for these three outcomes in the immediate breast reconstruction population. Statistical power for every comparison was >80%., Conclusions: This study suggests that NRT is not associated with significantly higher 30-day postoperative complications among breast cancer patients undergoing mastectomy with or without immediate breast reconstruction.

Background: Medicaid and uninsured patients anecdotally incur higher cost and length of stay because of nonmedical, discharge-related factors. The purpose of this study was to investigate the association between primary payer and length of stay and cost, controlling for comorbidities and complications, in patients undergoing total laryngectomy., Methods: The sample included 4128 patients who underwent total laryngectomy in the 2005 to 2010 National Inpatient Sample (NIS). Patients were categorized into 4 subgroups based on payer status: Medicare, Medicaid, uninsured, and private insurance. Using multilevel modeling, we examined differences in length of stay and hospitalization costs., Results: The odds of being in the top quartile of length of stay increased for Medicaid patients by 41% (odds ratio [OR] = 1.41; 95% confidence interval [CI] = 1.03-1.92) compared with privately insured patients., Conclusion: After controlling for medical factors, Medicaid patients had increased lengths of stay. Overall costs were highest for those with public insurance, but no difference was seen for the adjusted cost. © 2016 Wiley Periodicals, Inc. Head Neck 39: 311-319, 2017., (© 2016 Wiley Periodicals, Inc.)

Higher plants take up nutrients via the roots and load them into xylem vessels for translocation to the shoot. After uptake, anions have to be channeled toward the root xylem vessels. Thereby, xylem parenchyma and pericycle cells control the anion composition of the root-shoot xylem sap [1-6]. The fact that salt-tolerant genotypes possess lower xylem-sap Cl(-) contents compared to salt-sensitive genotypes [7-10] indicates that membrane transport proteins at the sites of xylem loading contribute to plant salinity tolerance via selective chloride exclusion. However, the molecular mechanism of xylem loading that lies behind the balance between NO3(-) and Cl(-) loading remains largely unknown. Here we identify two root anion channels in Arabidopsis, SLAH1 and SLAH3, that control the shoot NO3(-)/Cl(-) ratio. The AtSLAH1 gene is expressed in the root xylem-pole pericycle, where it co-localizes with AtSLAH3. Under high soil salinity, AtSLAH1 expression markedly declined and the chloride content of the xylem sap in AtSLAH1 loss-of-function mutants was half of the wild-type level only. SLAH3 anion channels are not active per se but require extracellular nitrate and phosphorylation by calcium-dependent kinases (CPKs) [11-13]. When co-expressed in Xenopus oocytes, however, the electrically silent SLAH1 subunit gates SLAH3 open even in the absence of nitrate- and calcium-dependent kinases. Apparently, SLAH1/SLAH3 heteromerization facilitates SLAH3-mediated chloride efflux from pericycle cells into the root xylem vessels. Our results indicate that under salt stress, plants adjust the distribution of NO3(-) and Cl(-) between root and shoot via differential expression and assembly of SLAH1/SLAH3 anion channel subunits., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Chloride (Cl(-)) is a micronutrient that accumulates to macronutrient levels since it is normally available in nature and actively taken up by higher plants. Besides a role as an unspecific cell osmoticum, no clear biological roles have been explicitly associated with Cl(-) when accumulated to macronutrient concentrations. To address this question, the glycophyte tobacco (Nicotiana tabacum L. var. Habana) has been treated with a basal nutrient solution supplemented with one of three salt combinations containing the same cationic balance: Cl(-)-based (CL), nitrate-based (N), and sulphate+phosphate-based (SP) treatments. Under non-saline conditions (up to 5 mM Cl(-)) and no water limitation, Cl(-) specifically stimulated higher leaf cell size and led to a moderate increase of plant fresh and dry biomass mainly due to higher shoot expansion. When applied in the 1-5 mM range, Cl(-) played specific roles in regulating leaf osmotic potential and turgor, allowing plants to improve leaf water balance parameters. In addition, Cl(-) also altered water relations at the whole-plant level through reduction of plant transpiration. This was a consequence of a lower stomatal conductance, which resulted in lower water loss and greater photosynthetic and integrated water-use efficiency. In contrast to Cl(-), these effects were not observed for essential anionic macronutrients such as nitrate, sulphate, and phosphate. We propose that the abundant uptake and accumulation of Cl(-) responds to adaptive functions improving water homeostasis in higher plants., (© The Author 2015. Published by Oxford University Press on behalf of the Society for Experimental Biology.)

Background: Multiple perfusion assessment technologies exist to identify compromised microvascular free flaps. The effectiveness, operability, and cost of each technology vary. The authors investigated surgeon preference and clinical behavior with several perfusion assessment technologies., Methods: A questionnaire was sent to members of the American Society for Reconstructive Microsurgery concerning perceptions and frequency of use of several technologies in varied clinical situations. Demographic information was also collected. Adjusted odds ratios were calculated using multinomial logistic regression accounting for clustering of similar practices within institutions/regions., Results: The questionnaire was completed by 157 of 389 participants (40.4 percent response rate). Handheld Doppler was the most commonly preferred free flap-monitoring technology (56.1 percent), followed by implantable Doppler (22.9 percent) and cutaneous tissue oximetry (16.6 percent). Surgeons were significantly more likely to opt for immediate take-back to the operating room when presented with a concerning tissue oximetry readout compared with a concerning handheld Doppler signal (OR, 2.82; p < 0.01), whereas other technologies did not significantly alter postoperative management more than simple handheld Doppler. Clinical decision making did not significantly differ by demographics, training, or practice setup., Conclusions: Although most surgeons still prefer to use standard handheld Doppler for free flap assessment, respondents were significantly more likely to opt for immediate return to the operating room for a concerning tissue oximetry reading than an abnormal Doppler signal. This suggests that tissue oximetry may have the greatest impact on clinical decision making in the postoperative period.

To investigate effects of soil moisture heterogeneity on plant physiology and gene expression in roots and leaves, three treatments were implemented in sunflower plants growing with roots split between two compartments: a control (C) treatment supplying 100% of plant evapotranspiration, and two treatments receiving 50% of plant evapotranspiration, either evenly distributed to both compartments (deficit irrigation - DI) or unevenly distributed to ensure distinct wet and dry compartments (partial rootzone drying - PRD). Plants receiving the same amount of water responded differently under the two irrigation systems. After 3 days, evapotranspiration was similar in C and DI, but 20% less in PRD, concomitant with decreased leaf water potential (Ψleaf) and increased leaf xylem ABA concentration. Six water-stress responsive genes were highly induced in roots growing in the drying soil compartment of PRD plants, and their expression was best correlated with local soil water content. On the other hand, foliar gene expression differed significantly from that of the root and correlated better with xylem ABA concentration and Ψleaf. While the PRD irrigation strategy triggered stronger physiological and molecular responses, suggesting a more intense and systemic stress reaction due to local dehydration of the dry compartment of PRD plants, the DI strategy resulted in similar water savings without strongly inducing these responses. Correlating physiological and molecular responses in PRD/DI plants may provide insights into the severity and location of water deficits and may enable a better understanding of long-distance signalling mechanisms., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Importance: Neoadjuvant chemotherapy (NC) is increasingly being used in patients with breast cancer, and evidence-based reports related to its independent effects on morbidity after mastectomy with immediate breast reconstruction are limited., Objective: To determine the effect of NC on 30-day postoperative morbidity in women undergoing mastectomy with or without immediate breast reconstruction., Design, Setting, and Participants: All women undergoing mastectomy with or without immediate breast reconstruction from January 1, 2005, through December 31, 2011, at university and private hospitals internationally were analyzed using the American College of Surgeons National Surgical Quality Improvement Program 2005-2011 databases. Patients who received NC were compared with those without a history of NC to estimate the relative odds of 30-day postoperative overall, systemic, and surgical site morbidity using model-wise multivariable logistic regression., Exposure: Neoadjuvant chemotherapy., Main Outcomes and Measures: Thirty-day postoperative morbidity (overall, systemic, and surgical site)., Results: Of 85,851 women, 66,593 (77.6%) underwent mastectomy without breast reconstruction, with 2876 (4.3%) receiving NC; 7893 patients were excluded because of missing exposure data. The immediate breast reconstruction population included 19,258 patients (22.4%), with 820 (4.3%) receiving NC. After univariable analysis, NC was associated with a 20% lower odds of overall morbidity in the group undergoing mastectomy without breast reconstruction (odds ratio [OR], 0.80; 95% CI, 0.71-0.91) but had no significant effect in the immediate breast reconstruction group (OR, 0.98; 95% CI, 0.79-1.23). After adjustment for confounding, NC was independently associated with lower overall morbidity in the group undergoing mastectomy without breast reconstruction (OR, 0.61; 95% CI, 0.51-0.73) and the immediate tissue expander reconstruction subgroup (OR, 0.49; 95% CI, 0.30-0.84). Neoadjuvant chemotherapy was associated with decreased odds of systemic morbidity in 4 different populations: complete sample (OR, 0.59; 95% CI, 0.49-0.71), mastectomy without breast reconstruction (OR, 0.59; 95% CI, 0.48-0.72), any immediate breast reconstruction (OR, 0.57; 95% CI, 0.37-0.88), and the tissue expander subgroup (OR, 0.41; 95% CI, 0.23-0.72)., Conclusions and Relevance: Our study supports the safety of NC in women undergoing mastectomy with or without immediate breast reconstruction. Neoadjuvant chemotherapy is associated with lower overall morbidity in the patients undergoing mastectomy without breast reconstruction and in those undergoing tissue expander breast reconstruction. In addition, the odds of systemic morbidity were decreased in patients undergoing mastectomy with and without immediate breast reconstruction. The mechanisms behind the protective association of NC remain unknown and warrant further investigation.

Background: Continuing advances in cranioplasty have enabled repair of increasingly complicated cranial defects. However, the optimal materials and approaches for particular clinical scenarios remain unclear. This study examines outcomes following cranioplasty for a variety of indications in patients treated with alloplastic material, autogenous tissue, or a combination of both., Methods the Authors Conducted: a retrospective analysis on 180 patients who had 195 cranioplasties performed between 1993 and 2010., Results: Materials used for cranioplasty included alloplastic for 42.6 percent (83 of 195), autologous for 19.0 percent (37 of 195), and both combined for 38.5 percent (75 of 195). Mean defect size was 70.5 cm. A subset of patients had undergone previous irradiation (12.2 percent; 22 of 180) or had preoperative infections (30.6 percent; 55 of 180). The most common complication was postoperative infection (15.9 percent; 31 of 195). Factors that significantly predisposed to complications included preoperative radiation, previous infection, and frontal location. Preoperative radiation was the strongest predictor of having any postoperative complications, with an adjusted odds ratio of 6.91 (p < 0.005). Irradiated patients (OR, 7.96; p < 0.05) and patients undergoing frontal cranioplasties (OR, 2.83; p < 0.05) were more likely to require repeated operation. Preoperative infection predisposed patients to exposure of hardware in alloplastic reconstructions (OR, 3.13; p < 0.05)., Conclusions: Despite the evolution of cranioplasty techniques and materials, complications are not uncommon. The choice of reconstructive material may modify the risk of developing postoperative complications but appears less important than the clinical history in affecting outcome., Clinical Question/level of Evidence: Risk, III.

Purpose: The aim of this article was to assess how regional facial fracture patterns predict mortality and occult intracranial injury after blunt trauma., Methods: Retrospective chart review was performed for blunt-mechanism craniofacial fracture patients who presented to an urban trauma center from 1998 to 2010. Fractures were confirmed by author review of computed tomographic imaging and then grouped into 1 of 5 patterns of regional involvement representing all possible permutations of facial-third injury. Mortality and the presence of occult intracranial injury, defined as those occurring in patients at low risk at presentation for head injury by Canadian CT Head Rule criteria, were evaluated. Relative risk estimates were obtained using multivariable regression., Results: Of 4540 patients identified, 338 (7.4%) died, and 171 (8.1%) had intracranial injury despite normal Glasgow Coma Scale at presentation. Cumulative mortality reached 18.8% for isolated upper face fractures, compared with 6.9% and 4.0% for middle and lower face fractures (P < 0.001), respectively. Upper face fractures were independently associated with 4.06-, 3.46-, and 3.59-fold increased risk of death for the following fracture patterns: isolated upper, combined upper, panfacial, respectively (P < 0.001). Patients who were at low risk for head injury remained 4 to 6 times more likely to suffer an occult intracranial injury if they had involvement of the upper face., Conclusions: The association between facial fractures, intracranial injury, and death varies by regional involvement, with increasing insult in those with upper face fractures. Cognizance of the increased risk for intracranial injury in patients with upper face fractures may supplement existing triage tools and should increase suspicion for underlying or impending neuropathology, regardless of clinical picture at presentation.

Background: Preoperative anemia is independently associated with adverse outcomes after general and cardiac surgery. Outcomes after breast reconstruction are not established. We assessed the effect of preoperative anemia on 30-day postoperative morbidity and length of hospital stay (LOS) in patients undergoing immediate breast reconstruction., Methods: We identified patients undergoing immediate breast reconstruction from 2008 to 2010 from the American College of Surgeons' National Surgical Quality Improvement Program database (a prospective outcomes-based registry from hospitals worldwide). De-identified data were obtained for demographics, preoperative risk factors, 30-day morbidity, and LOS. Morbidity variables included flap/graft/prosthesis, cardiac, respiratory, neurological, urinary, wound, and venous thromboembolism outcomes. Logistic regression assessed the crude and adjusted effect of anemia (hematocrit <36%) on postoperative 30-day morbidity. Measures of central tendency of LOS were compared across increasing severities of anemia in patients developing adverse events versus controls., Results: The study population included 10,958 patients; 1556 (16.74%) had preoperative anemia. Crude odds ratio for 30-day morbidity was significantly higher in anemic patients, unadjusted odds ratio = 1.33 (P < 0.008). This prevailed after extensive adjustment for confounding, yielding an adjusted odds ratio = 1.38 (P < 0.03). Patients who experienced adverse effects had protracted LOS, and the presence of anemia significantly amplified this effect., Conclusions: These data provide new insight into the effect of anemia in immediate breast reconstruction, demonstrating an independent association between preoperative anemia and 30-day morbidity. These findings suggest treating anemia when possible; however, prospective studies should explore the efficacy, safety, and cost-effectiveness of such treatments.

Purpose: To investigate whether complex midface fractures have a greater association with death and intracranial injury than simple midface fractures., Materials and Methods: A retrospective chart review was performed for patients with blunt-mechanism midface fractures who had presented to an urban trauma center from 1998 to 2010. The survival and intracranial injury status was evaluated for patients with simple and complex midface fractures, including Le Fort, naso-orbitoethmoid, and/or zygomaticomaxillary fractures. Intracranial injury included hemorrhage and brainstem injury. Patients with upper face fractures were excluded to minimize confounding. Adjusted relative risk estimates were obtained using multivariate regression analysis., Results: Of 3,291 patients with midface fractures, 213 (6.3%) died and 693 (21.3%) had an intracranial injury. The cumulative mortality reached 11.6% in patients with complex midface fractures and 5.1% in those with simple midface fractures (P < .001). Patients with complex midface fractures were 57% more likely to die (relative risk = 1.57; P < .005). Specifically, Le Fort II fractures independently conferred a 94% increased risk of death (relative risk = 1.94; P < .01), but Le Fort I and III fractures were not significantly associated with death. Among patients presenting without neurologic impairment, those with Le Fort II and III fractures remained 2.88-fold (P < .01) and 2.54-fold (P < .001) more likely to have an underlying intracranial injury, respectively., Conclusions: Le Fort II fractures are associated with increased mortality. Furthermore, Le Fort II and III fractures are associated with serious intracranial injury, even in the absence of alterations in consciousness. These patients should be monitored with heightened vigilance and followed up closely during hospitalization, regardless of the presenting clinical findings., (Copyright © 2013 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.)