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Abstract Maize demand in Sub-Saharan Africa is expected to increase 2.3 times during the next 30 years driven by demographic and dietary changes. Over the past two decades, the area cropped with maize has expanded by 17 million hectares in the region, with limited yield increase. Following this trend could potentially result in further maize cropland expansion and the need for imports to satisfy domestic demand. Here, we use data collected from 14,773 smallholder fields in the region to identify agronomic practices that can improve farm yield gains. We find that agronomic practices related to cultivar selection, and nutrient, pest, and crop management can double on-farm yields and provide an additional 82 million tons of maize within current cropped area. Research and development investments should be oriented towards agricultural practices with proven capacity to raise maize yields in the region.

Abstract Background & aims Metallothionein-3 (hMT3) is a structurally unique member of the metallothioneins family of low-mass cysteine-rich proteins. hMT3 has poorly characterized functions, and its importance for hepatocellular carcinoma (HCC) cells has not yet been elucidated. Therefore, we investigated the molecular mechanisms driven by hMT3 with a special emphasis on susceptibility to sorafenib. Methods Intrinsically sorafenib-resistant (BCLC-3) and sensitive (Huh7) cells with or without up-regulated hMT3 were examined using cDNA microarray and methods aimed at mitochondrial flux, oxidative status, cell death, and cell cycle. In addition, in ovo/ex ovo chick chorioallantoic membrane (CAM) assays were conducted to determine a role of hMT3 in resistance to sorafenib and associated cancer hallmarks, such as angiogenesis and metastastic spread. Molecular aspects of hMT3-mediated induction of sorafenib-resistant phenotype were delineated using mass-spectrometry-based proteomics. Results The phenotype of sensitive HCC cells can be remodeled into sorafenib-resistant one via up-regulation of hMT3. hMT3 has a profound effect on mitochondrial respiration, glycolysis, and redox homeostasis. Proteomic analyses revealed a number of hMT3-affected biological pathways, including exocytosis, glycolysis, apoptosis, angiogenesis, and cellular stress, which drive resistance to sorafenib. Conclusions hMT3 acts as a multifunctional driver capable of inducing sorafenib-resistant phenotype of HCC cells. Our data suggest that hMT3 and related pathways could serve as possible druggable targets to improve therapeutic outcomes in patients with sorafenib-resistant HCC.

Abstract Background Understanding the hip adduction and abduction strength in female soccer players is crucial for performance enhancement and injury prevention. This study compares the strength profiles in these muscle groups between elite and sub-elite female soccer players and assesses the impact of leg limb-dominance. Methods A descriptive-comparative study was employed. Eighty-two female soccer players were evaluated. Isometric hip-adduction and abduction strength were measured using a handheld dynamometer. Results Female elite and sub-elite soccer players displayed a mean and standard deviation (SD) on isometric hip-adductor strength for dominant (3.19 Nm/kg ± 0.69 vs. 2.40 Nm/kg ± 0.67) and non-dominant leg (3.32 Nm/kg ± 0.76 versus 2.42 Nm/kg ± 0.70), respectively. For isometric hip-abductor strength in elite and sub-elite players, a mean and SD of dominant (2.86 Nm/kg ± 0.56 vs. 2.07 Nm/kg ± 0.50) and non-dominant (2.80 Nm/kg ± 0.59 vs. 2.04 Nm/kg ± 0.43). In essence, elite players were stronger than sub-elite players on isometric hip-adduction (mean difference [MD] = 0.82 Nm/kg, CI95% = 0.42–1.12) and abduction (MD = 0.83 Nm/kg, CI95% = 0.54- 1.12) both in dominant and non-dominant, leg, whereas no differences existed for hip adduction:abduction ratios between groups and legs. Conclusions Elite female athletes exhibited greater strength than sub-elite female players in both hip adduction and abduction, whereas adduction:abduction ratio values did not differ between the two groups or between different legs.

BackgroundBack pain is a common health problem that affects both workers and older people, reducing their quality of life. The primary objective was to assess the effect of dietary supplementation with plant extracts of rosemary, ashwagandha, and sesame consumed for 12 weeks on the intensity of back pain.MethodsA single-center randomized double-blind study with three parallel arms depending on the product consumed. The duration of treatment was 12 weeks. The investigational product, Berelief®, contained a blend of three polyphenolic standardized extracts: rosemary (Rosmarinus officinalis L.), ashwagandha (Withania somnifera L.), and sesame (Sesamum indicum L.) seed. Two doses were tested: low dose (400 mg) and high dose (800 mg). There were 42 subjects in the placebo group, 39 in the low dose and 42 in the high dose groups. Study variables included back pain intensity [VAS score, Patient-Reported Outcomes Measurement Information System (PROMIS-29), and Cornell Musculoskeletal Discomfort Questionnaire; functionality Roland-Morris Disability (RMD) questionnaire]; quality of life (QoL) [36-item Short Form Survey (SF-36), the Beck Depression Inventory-II (BDI-II), the State–Trait Anxiety Inventory (STAI), and the Perceived Stress Scale (PSS)]; sleep quality [accelerometer and Pittsburgh Sleep Quality Index (PSQI)].ResultsThe improvement in back pain recorded by the visual analogue scale (VAS) at the study visits after the beginning of treatment, as well as on a weekly basis recorded in the diary card was significantly higher in the intervention group than in the placebo group (p

Introduction Women experiencing severe perinatal mental health problems require specialized services and care. Perinatal mental disorders are common and can contribute to maternal mortality, affecting neonatal, infant, and child outcomes. Home treatment can prevent hospital admissions and promote strategies within the patient’s support network. Objectives Our aim is to describe a clinical case in perinatal psychiatry managed by a Psychiatric Home Treatment Unit. Methods We present a case of perinatal psychotic depression in a 26-year-old pregnant woman. Results We describe the case of a patient with no prior history of mental health issues. She was 25 weeks pregnant when she first sought psychiatric help in July 2023 and was diagnosed with depressive disorder with psychotic symptoms. She reported symptoms such as low mood, psychomotor inhibition, delusional guilt thoughts, and auditory hallucinations beginning three weeks before her initial visit. Due to her clinical presentation, the patient was admitted to the hospital, where pharmacological treatment was initiated with Olanzapine 5 mg, Sertraline 50 mg, and Lorazepam 1.5 mg. She remained in the hospital for four days, during which she showed gradual improvement but did not achieve full recovery. Considering the improvement observed, home treatment was proposed and accepted by the patient and her relatives. During home treatment, she continued to exhibit persistent depressive and psychotic symptoms, including low mood, inhibition, and delusional thoughts of ruin and catastrophe. Therefore, her treatment was adjusted, with Olanzapine increased to 10 mg, Sertraline raised to 100 mg, and Lorazepam reduced to 0.75 mg. Over time, significant improvement in her clinical symptoms was noted. Throughout the follow-up period, she reported no significant side effects from the pharmacological treatment. After a month of follow-up in our department, she was discharged with outpatient care provided by a specialized community perinatal psychiatric unit. Conclusions We illustrate the possibility of home treatment for perinatal psychiatric disorders. The potential benefits of remaining close to one’s support network and developing coping strategies can be advantageous during the course of illness. Further studies should be conducted to explore these potential benefits. Disclosure of Interest None Declared

Introduction Negative symptoms are present in more than two thirds of schizophrenic patients throughout the evolution of the disorder. These include symptoms related to reduced motivation or pleasure, such as avolition, anhedonia and asociality, and reduced expressivity, including alogia and blunted affect. We present the case of a 24-year-old man who was admitted to our Psychosis Day Hospital after several psychotic episodes, presenting with prominent negative symptomatology that was imbued with mystical delusional beliefs. Objectives 1) To describe the clinical particularities of this case, focusing on the improvement of negative symptoms during the course of treatment at our Day Hospital. 2) To review the available evidence regarding the pharmacological and psychotherapeutic management of negative symptoms of schizophrenia. Methods A review of the patient’s clinical history and complementary tests were carried out. Likewise, we reviewed the available literature in relation to the management of negative symptoms of schizophrenia in an ambulatory setting. Results The patient was admitted to our Day Hospital after four psychiatric hospitalizations due to mystical delusions, ideas of grandiosity and hyper-spirituality, along with prominent negative symptoms at the moment of inclusion at our centre, including social withdrawal, diminished affective response, lack of interest in the academic sphere and poor social drive. Although previous positive symptoms were present in a lesser degree, the patient interpreted the presence of the negative symptoms described above as a “punishment” or “test” from spiritual creatures. Management of negative symptoms represents a major unmet need in schizophrenia. Modest effect size evidence for pharmacological approaches favours the use of antipsychotic in monotherapy and augmentation of antipsychotic treatment with other agents, such as antidepressants. Scarce evidence regarding psychotherapeutic approaches to these symptoms points to the use of cognitive behaviour therapy and social skills training. Conclusions - Clinical identification and characterization of negative symptoms is crucial when treating patients with schizophrenia, as these are associated with important disability and poorer functional outcomes. - Differentiation of primary and secondary negative symptoms is a key aspect in the evaluation and management of schizophrenic patients. - This case outlines the coexistence of positive and negative symptoms, and illustrates the challenges in the pharmacological and psychotherapeutic management of these symptoms at a Psychosis Day Hospital. Disclosure of Interest None Declared

Introduction Mental health in the deaf community is a complex issue. Challenges in diagnosis and treatment arise from a lack of experienced interpreters and difficulties in translating Sign Language to spoken language. Deaf individuals, due to auditory limitations, are more vulnerable to abuse, increasing their risk of mental health disorders, including bipolar affective disorder (BPAD). BPAD is a prevalent, debilitating condition with varied prevalence estimates. Managing it is tough due to its lifelong, unpredictable nature. A new approach called Psychiatric Home Hospitalization Unit aims to provide acute mental health care at home as an alternative to hospitalization. Objectives To show the management of severe bipolar disorder with comorbidity from a Psychiatric Home Hospitalization Unit Methods A clinical case of bipolar disorder with deafness attended at the Psychiatric Home Hospitalization Unit of our hospital is presented. Results A 24-year-old deaf woman borned in Pakistan and later moving to Catalonia, she faced educational challenges but ultimately completed her studies with sign language support. Afterward, she struggled to find suitable employment, and her family had a history of bipolar disorder. She exhibited a sudden change in behavior, characterized by irritability, paranoia, and distrust. Communication was challenging due to her speech difficulties, but assessments using sign language and observation were conducted. Her physical examination was normal, but her speech was disorganized and pressured, suggesting possible auditory hallucinations and thought disturbances. She was hospitalized and diagnosed with bipolar disorder with psychotic features. During her initial hospitalization, she received lithium, olanzapine, clotiapine and benzodiacepines. After discharge, she continued treatment through a home hospitalization service during almost 4 month. During follow-up she presented a course with high affective instability, rapid cycling alternating brief periods of stability with other presenting manic and mixed features with high disorganization. Due to the rapid cycling pattern Valproic acid was considered. Valproic acid was introduced up to 700 mg/d (97.1 mcg/mL). Treatment with lithium carbonate 800 mg/d (0.91 mEq/L) was maintained. Previous antipsychotic regimen was changed to quetiapine 400mg/d, olanzapine 5mg/d. Her condition improved significantly with the adjusted treatment regimen. She was discharged to an outpatient service. Conclusions Diagnosing and treating bipolar affective disorder (BPAD) in a deaf and mute patient posed unique challenges. The rapid mood cycling pattern and complexity of her case made treatment challenging. Family information and interpreter support were vital. Cultural factors were considered, and home hospitalization was crucial in managing symptoms that lasted over four months. Disclosure of Interest None Declared

Introduction Hospital at home for psychiatric patients is a new emerging resource of delivering acute mental health care in the community. The main objective of this program is to provide intense care to patients with severe mental disorders at home as an alternative to acute admission. Although home hospitalisation has begun to develop widely in recent years there is a notable lack of studies The CAEM Psychiatric Home Hospitalization Unit (HAD-CAEM) has been operating since 2018 and takes place in Santa Coloma de Gramenet; and from March 2022 also in a part of Badalona. Both are sociodemographically depressed areas near Barcelona. Objectives The aim of this study is to describe the characteristics of patients attended at the Psychiatric Home Hospitalization Unit of our hospital and to study differences according to area and place of referral. Methods Socio-demographic and clinical data were collected retrospectively at admission and discharge of all patients treated at HAD-CAEM between March 2022 to february 2023. Statistical analysis was performed by using SPSS program. Results 85 patients were included in the study. 45.9% were women. The mean age was 45.5 years (SD 15.58 years). The main diagnoses of the sample were psychosis and schizophrenia (38.8%), Bipolar disorder (23.53%), Depressive disorder (21.18%), schizoaffective disorder (8.24%) and others (8,24%). 54 (63.53%) patients were from Santa Coloma area and 35 (41.18%) from Badalona area. The total mean duration of admission was 40.22 days (SD 26.18 days), with a mean follow-up of 10.09 visits (SD 5.39 visits) and 2.41 teleassistence (SD 2.62). The mean duration of admission for Santa Coloma patients was 43.98 days (SD 28.59), and for Badalona patients 33.68 days (SD 20.13). Trend without significance is observed (t= 1.77, p=0.08) We found differences in the mean duration of admission according to referral location. Acute psychiatric unit 33.25 days (SD 18.06), Mental health Center 51.93 days (SD 33.45), Emergencies 34.28 days (SD 19.69) (F=5.1, p=0.008). Conclusions Sociodemografic and clinical característics obtained in our study are consistent with those reported in previous studies. The duration of admission of patients referred from the mental health center is longer than those referred from the acute psychiatric or emergency unit. Home hospitalization teams have been increasing in recent years, being an alternative to traditional hospitalization. Disclosure of Interest None Declared

The discovery of brain therapeutics faces a significant challenge due to the low translatability of preclinical results into clinical success. To address this gap, several efforts have been made to obtain more translatable neuronal models for phenotypic screening. These models allow the selection of active compounds without predetermined knowledge of drug targets. In this review, we present an overview of various existing models within the field, examining their strengths and limitations, particularly in the context of neuropathic pain research. We illustrate the usefulness of these models through a comparative review in three crucial areas: i) the development of novel phenotypic screening strategies specifically for neuropathic pain, ii) the validation of the models for both primary and secondary screening assays, and iii) the use of the models in target deconvolution processes.

Summary: Background: While a low CD4/CD8 ratio during HIV treatment correlates with immunosenescence, its value in identifying patients at an increased risk for clinical events remains unclear. Methods: We analyzed data from the CoRIS cohort to determine whether CD4 count, CD8 count, and CD4/CD8 ratio at year two of antiretroviral therapy (ART) could predict the risk of serious non-AIDS events (SNAEs) during the next five years. These included major adverse cardiovascular events, non-AIDS-defining malignancies, and non-accidental deaths. We used pooled logistic regression with inverse probability weighting to estimate the survival curves and cumulative risk of clinical events. Findings: The study included 4625 participants, 83% male, of whom 200 (4.3%) experienced an SNAE during the follow-up period. A CD4/CD8 ratio

Opioids are the most effective painkillers, but their benefit-risk balance often hinder their therapeutic use. WLB-73502 is a dual, bispecific compound that binds sigma-1 (S1R) and mu-opioid (MOR) receptors. WLB-73502 is an antagonist at the S1R. It behaved as a partial MOR agonist at the G-protein pathway and produced no/unsignificant β-arrestin-2 recruitment, thus demonstrating low intrinsic efficacy on MOR at both signalling pathways. Despite its partial MOR agonism, WLB-73502 exerted full antinociceptive efficacy, with potency superior to morphine and similar to oxycodone against nociceptive, inflammatory and osteoarthritis pain, and superior to both morphine and oxycodone against neuropathic pain. WLB-73502 crosses the blood–brain barrier and binds brain S1R and MOR to an extent consistent with its antinociceptive effect. Contrary to morphine and oxycodone, tolerance to its antinociceptive effect did not develop after repeated 4-week administration. Also, contrary to opioid comparators, WLB-73502 did not inhibit gastrointestinal transit or respiratory function in rats at doses inducing full efficacy, and it was devoid of proemetic effect (retching and vomiting) in ferrets at potentially effective doses. WLB-73502 benefits from its bivalent S1R antagonist and partial MOR agonist nature to provide an improved antinociceptive and safety profile respect to strong opioid therapy.

Abstract Nociplastic pain arises from altered nociception despite no clear evidence of tissue or somatosensory system damage, and fibromyalgia syndrome can be highlighted as a prototype of this chronic pain subtype. Currently, there is a lack of effective treatments to alleviate both reflexive and nonreflexive pain responses associated with fibromyalgia condition, and suitable preclinical models are needed to assess new pharmacological strategies. In this context, although in recent years some remarkable animal models have been developed to mimic the main characteristics of human fibromyalgia, most of them show pain responses in the short term. Considering the chronicity of this condition, the present work aimed to develop two mouse models showing long-lasting reflexive and nonreflexive pain responses after several reserpine (RIM) or intramuscular acid saline solution (ASI) injections. To our knowledge, this is the first study showing that RIM6 and ASI mouse models show reflexive and nonreflexive responses up to 5–6 weeks, accompanied by either astro- or microgliosis in the spinal cord as pivotal physiopathology processes related to such condition development. In addition, acute treatment with pregabalin resulted in reflexive pain response alleviation in both the RIM6 and ASI models. Consequently, both may be considered suitable experimental models of fibromyalgia-like condition, especially RIM6.

The combination of in ovo and ex ovo chorioallantoic membrane (CAM) assay provides an excellent platform which extends its relevance in studying carcinogenesis to the field of screening of anticancer activity of platinum nanoparticles (PtNPs) and further study of the amino acids’ fluctuations in liver and brain. PtNPs are promising candidates for replacing cisplatin (CDDP); however, insufficient data of their antitumor efficiency and activity on the cancer-related amino acid metabolism are available, and the assessment of the in vivo performance has barely scratched the surface. Herein, we used CAM assay as in vivo model for screening of novel therapeutic modalities, and we conducted a comparative study of the effects of CDDP and polyvinylpyrrolidone coated PtNPs on MDA-MB-231 breast cancer xenograft. PtNPs showed a higher efficiency to inhibit the tumor growth and metastasis compared to CDDP. The amino acids profiling in the MDA-MB-231 ​cells revealed that the PtNPs had an overall depleting effect on the amino acids content. Noteworthy, more side effects to amino acid metabolism were deduced from the depletion of the amino acids in tumor, brain, and liver upon CDDP treatment. Different sets of enzymes of the tricarboxylic acid (TCA) cycle were targeted by PtNPs and CDDP, and while mRNA encoding multiple enzymes was downregulated by PtNPs, the treatment with CDDP affected only two TCA enzymes, indicating a different mechanism of action. Taken together, CAM assay represents and invaluable model, demonstrating the PtNPs capability of repressing angiogenesis, decrease amino acid contents and disrupt the TCA cycle.

Introduction Bipolar disorder is one of the top 10 medical causes of disability according to the WHO and despite this, its diagnosis can be delayed up to 10 years after the appearance of the first symptoms of the disease. A major reason for the difficult diagnosis is the challenge of differentiating bipolar disorder type II from unipolar depression and borderline personality disorder, especially in those patients with no clear history of hypomania. Objectives To present a case report of a bipolar disorder undiagnosed for years to remark the importance of recognizing premorbid symptoms of the disease in order to implement an early intervention that potentially improves the prognosis of patients. Methods We compiled the patient’s complete medical history and we carried out a non-systematic review of literature containing the key-words “bipolar disorder type II” and “diagnosis”. Results We present the case of a 48-year-old woman going through a depressive episode, multiple suicide attempts and more than 10 admissions in the Acute Inpatient Psychiatric Unit. For 3 years, the evolution was torpid with a significant multidomain cognitive impairment in a previously functional patient. Different antidepressant treatments were tested, however they were not tolerated due to adverse effects such as anxiety, insomnia and nervousness. After considering multiple differential diagnoses, bipolar disorder type II was finally diagnosed. A hypomanic episode that took place after 3 sessions of electroconvulsive therapy during an admission for depression, allowed to guide the diagnosis and after the introduction of Lithium and Quetiapine as treatment, the patient experienced a complete remission of the symptoms. Conclusions 1. It is important to consider the differential diagnosis of bipolar disorder type II due to its impact on the patient´s life. 2. An early diagnosis improves the course and prognosis of the disease. 3. Patients resistant or intolerant to antidepressant treatment could have undiagnosed bipolar disorder. Disclosure of Interest None Declared

Introduction We present the case of a 43 year-old woman that, following the sudden death of his brother in 2015, begins with symptoms of anxiety, irritability and emotional instability, with a tendency to social isolation. Thereafter, she starts the development of persecutory delusions focused on the work and family environment that evolve into inappropriate behaviors to the point of abandoning her professional life. Objectives (1) We will carry out a complete review about persecutory delusions and its relationship with affective disorders, based on the severity of our patient’s case. (2) We will study the different lines of treatment in delusional disorder (DD) and its course and prognosis in relation to the intervention performed. Methods A review of the patient’s history will be conducted, taking into account her biography, clinical evolution and response to the treatments received. Likewise, a bibliographic review of the available scientific literature in relation to DD treatment strategies will be carried out. Results (1) DD is more common in middle-aged women. People who tend to be socially isolated are more likely to develop DD. (2) Acute onset, in young women with identifiable precipitating factors, suggests a better prognosis. (3) In the long term, 50% of patients recover and a further 20% experience some improvement. (4) The combination of antipsychotic medications and psychological therapies such as cognitive behavioral therapy (CBT) is fundamental in the management of DD patients. Conclusions The prognosis for patients with DD varies depending on various factors, including the type and severity of the delusional ideas, and their own life circumstances. It is often possible to eliminate the behavioral alterations derived from the DD, allowing the patient to function normally. However, delusions often persist and become encapsulated. Disclosure of Interest None Declared

A Rectangular Dielectric Resonator Antenna (RDRA) design for mmWave-frequency-band MIMO metrics is proposed, with a compact, low-complexity, high-gain structure that is easy to fabricate and offers reduced inter–port isolation. The RDRA operates in the mmWave spectrum, featuring a compact size of 1.307 λ 0 × 1.307 λ 0 , an impedance bandwidth of 6%, and a resonant frequency of 28 GHz, with a peak gain of 7 dBi. A four element MIMO system iteration was developed while maintaining the performance of the single element antenna. Additionally, a simple, low-complexity slot-etching technique was applied to achieve an average inter-port element isolation of 14 dB. The design also achieved a novel four-beam petal-splitting radiation pattern. The MIMO metrics, with an envelope correlation coefficient (ECC) of <0.5 and a diversity gain (DG) < 10, were successfully met. The simulated and measured results are in good agreement. [ABSTRACT FROM AUTHOR]

Cationic antimicrobial peptides are molecules with potential applications for treating infections due to their antimicrobial and immunomodulatory properties. The aim of this work was to explore the antimicrobial activity and mechanisms of action of a porcine neutrophil cathelicidin mixture (MPPN). Gram-positive and Gram-negative bacteria were used to determine the minimum inhibitory concentration (MIC) and experiments of both time–kill kinetics and effects on growth curves were performed. Planar black lipid bilayer conductance was measured to analyze the interaction of MPPN with lipid bilayers. Visualization of bacterial surfaces and membrane alterations was achieved using atomic force microscopy and transmission electron microscopy. The effects on the activity of efflux pumps (EPs) were studied with an intracellular accumulation of acridine orange (AO) assay. In E. coli, MPPN behaves as a bactericide at high concentrations and as a bacteriostatic at lower concentrations. The bacteriostatic effect was also observed for slightly shorter periods in S. enterica. The mixture was not active on S. aureus. The increase in AO accumulation in the presence of MPPN indicates that, at least in E. coli, the mixture causes inhibition of the EP function. Observed and detected variable conductance events demonstrate a strong MPPN effect on lipid bilayers. Damage to the structure of treated E. coli indicates that MPPN induces alterations in the bacterial surface. The use of AMPs capable of inhibiting EP can be seen as a good tool to combat antimicrobial resistance since they could be used alone or in combination with other conventional antibiotics to which bacteria have become resistant.

Objective This study aimed to determine the association of health determinants, lifestyle and socioeconomic variables on healthcare use in people with diabetes in Europe.Design A cross-sectional study was conducted using data from the European Health Interview Survey wave 2 (ie, secondary analysis).Setting The sample included data from 25 European countries.Participants The sample included 16 270 patients with diabetes aged 15 years or older (49.1% men and 50.9% women).Results The survey data showed that 58.2% of respondents had seen their primary care physician in the past month and 22.6% had been admitted to the hospital in the past year. Use of primary care was associated with being retired (prevalence ratio (PR) 1.13, 95% CI 1.07 to 1.19) and having very poor self-perceived health (PR 1.80, 95% CI 1.51 to 2.15), long-standing health problems (PR 1.14, 95% CI 1.04 to 1.24), high blood pressure (PR 1.06, 95% CI 1.03 to 1.10) and chronic back pain (PR 1.07, 95% CI 1.04 to 1.11). Hospital admission was associated with very poor self-perceived health (PR 3.03, 95% CI 2.14 to 4.31), accidents at home (PR 1.54, 95% CI 1.40 to 1.69), chronic obstructive pulmonary disease (COPD) (PR 1.34, 95% CI 1.22 to 1.47), high blood pressure (PR 1.08, 95% CI 1.01 to 1.17), chronic back pain (PR 0.91, 95% CI 0.84 to 0.98), moderate difficulty walking (PR 1.33, 95% CI 1.21 to 1.45) and severe difficulty walking (PR 1.67, 95% CI 1.51 to 1.85).Conclusions In the European diabetic population, the high cumulative incidences of primary care visits and hospital admissions are associated with labour status, alcohol consumption, self-perceived health, long-standing health problems, high blood pressure, chronic back pain, accidents at home, COPD and difficulty walking.

Cisplatin (cis-diamminedichloroplatinum II; CDDP) is a widely used cytostatic agent; however, it tends to promote kidney and liver disease, which are a major signs of drug-induced toxicity. Platinum compounds are often presented as alternative therapeutics and subsequently easily dispersed in the environment as contaminants. Due to the major roles of the liver and kidneys in removing toxic materials from the human body, we performed a comparative study of the amino acid profiles in chicken liver and kidneys before and after the application of CDDP and platinum nanoparticles (PtNPs-10 and PtNPs-40). The treatment of the liver with the selected drugs affected different amino acids; however, Leu and Arg were decreased after all treatments. The treatment of the kidneys with CDDP mostly affected Val; PtNPs-10 decreased Val, Ile and Thr; and PtNPs-40 affected only Pro. In addition, we tested the same drugs on two healthy cell lines, HaCaT and HEK-293, and ultimately explored the amino acid profiles in relation to the tricarboxylic acid cycle (TCA) and methionine cycle, which revealed that in both cell lines, there was a general increase in amino acid concentrations associated with changes in the concentrations of the metabolites of these cycles.

ObjectiveTo determine the optimal ultrasound (US) cut-off values for cranial and extracranial arteries intima media thickness (IMT) to discriminate between patients with and without giant cell arteritis (GCA).MethodsRetrospective observational study including patients referred to an US fast-track clinic. All patients underwent bilateral US examination of the cranial and extracranial arteries including the IMT measurement. Clinical confirmation of GCA after 6 months was considered the gold standard for diagnosis. A receiver operating characteristic (ROC) analysis was performed to select the cut-off values on the basis of the best tradeoff values between sensitivity and specificity.ResultsA total of 157 patients were included, 47 (29.9%) with clinical confirmation of GCA after 6 months. 41 (87.2%) of patients with GCA had positive US findings (61.7% had cranial and 44.7% extracranial involvement). The best threshold IMT values were 0.44 mm for the common temporal artery; 0.34 mm for the frontal branch; 0.36 mm for the parietal branch; 1.1 mm for the carotid artery and 1 mm for the subclavian and axillary arteries. The areas under the ROC curves were greater for axillary arteries 0.996 (95% CI 0.991–1), for parietal branch 0.991 (95% CI 0.980–1), for subclavian 0.990 (95% CI 0.979–1), for frontal branch 0.989 (95% CI 0.976–1), for common temporal artery 0.984 (95% CI 0.959–1) and for common carotid arteries 0.977 (95% CI 0.961–0.993).ConclusionIMT cut-off values have been identified for each artery. These proposed IMT cut-off values may help to improve the diagnostic accuracy of US in clinical practice.

Cet article rend compte de la présence du motif du jardin d’Éden et de sa signification dans deux romans d’Antonio Muñoz Molina, Beatus ille (1986) et La noche de los tiempos (2009). Il propose une approche descriptive qui répertorie les occurrences de ce motif et ses ramifications – la rencontre amoureuse, la métaphore de l’île et du refuge, l’expulsion et l’exil – avant de proposer une interprétation idéologique de cette poétique qui montre que ce motif s’inscrit dans des structures narratives polarisées autour de la triade paradis/expulsion/exil qui font écho à la mémoire dominante du passé récent de l’Espagne contemporaine qui fait de la Transition un moment de réconciliation et de rédemption collective.

Abstract Metallothionein-3 has poorly characterized functions in neuroblastoma. Cisplatin-based chemotherapy is a major regimen to treat neuroblastoma, but its clinical efficacy is limited by chemoresistance. We investigated the impact of human metallothionein-3 (hMT3) up-regulation in neuroblastoma cells and the mechanisms underlying the cisplatin-resistance. We confirmed the cisplatin-metallothionein complex formation using mass spectrometry. Overexpression of hMT3 decreased the sensitivity of neuroblastoma UKF-NB-4 cells to cisplatin. We report, for the first time, cisplatin-sensitive human UKF-NB-4 cells remodelled into cisplatin-resistant cells via high and constitutive hMT3 expression in an in vivo model using chick chorioallantoic membrane assay. Comparative proteomic analysis demonstrated that several biological pathways related to apoptosis, transport, proteasome, and cellular stress were involved in cisplatin-resistance in hMT3 overexpressing UKF-NB-4 cells. Overall, our data confirmed that up-regulation of hMT3 positively correlated with increased cisplatin-chemoresistance in neuroblastoma, and a high level of hMT3 could be one of the causes of frequent tumour relapses.

Abstract Background Patients with Hailey-Hailey and Darier diseases present with disabling inflammatory lesions located in large skin folds, which are often exacerbated or induced by sweating. Quality of life is highly impaired because of pain and recurrent skin infections. An improvement in skin lesions after botulinum toxin A injections has previously been reported in some patients but no prospective interventional studies are available. The aim of this open-label, 6-month, interventional pilot study (NCT02782702) was to evaluate the effectiveness and safety of botulinum toxin A for patients with moderate to very severe skin lesions located in folds. Results Thirty patients (26 Hailey-Hailey/4 Darier) were included. Botulinum toxin A proved effective within the first month in two-thirds of patients, taking all study parameters (itchiness, cutaneous pain, sweating and odour, infections, psychosocial impairment and quality of life) into account and persisted during the 6-month follow-up period. No patient was classed as a BtxA non-responder, but 11 (37%) Hailey-Hailey patients (the most severe ones), experienced a relapse during the study. No serious side effects were reported. Mild transient clear fluid discharge at the site of the injections was reported for 27% of patients. Conclusions Botulinic toxin seems to be an effective and safe treatment for Hailey-Hailey and Darier diseases. Nevertheless, it may prove insufficient for the severest of Hailey-Hailey cases and could be considered as supplementary to other conventional treatments. Further studies are required to confirm our results on larger Darier cohorts.

Abstract The Sigma-1 receptor (σ1R) has emerged as an interesting pharmacological target because it inhibits analgesia mediated by mu-opioid receptors (MOR), and also facilitates the development of neuropathic pain. Based on these findings, the recent cloning of the Sigma-2 receptor (σ2R) led us to investigate its potential role as a regulator of opioid analgesia and of pain hypersensitivity in σ2R knockout mice. In contrast to σ1R deficient mice, σ2R knockout mice developed mechanical allodynia following establishment of chronic constriction injury-induced neuropathic pain, which was alleviated by the σ1R antagonist S1RA. The analgesic effects of morphine, [D-Ala, N-MePhe, Gly-ol]-encephalin (DAMGO) and β-endorphin increased in σ1R−/− mice and diminished in σ2R−/− mice. The analgesic effect of morphine was increased in σ2R−/− mice by treatment with S1RA. However, σ2R−/− mice and wild-type mice exhibited comparable antinociceptive responses to the delta receptor agonist [D-Pen2,5]-encephalin (DPDPE), the cannabinoid type 1 receptor agonist WIN55,212-2 and the α2-adrenergic receptor agonist clonidine. Therefore, while σR1 inhibits and σ2R facilitates MOR-mediated analgesia these receptors exchange their roles when regulating neuropathic pain perception. Our study may help identify new pharmacological targets for diminishing pain perception and improving opioid detoxification therapies.

Neuronal differentiation is a complex process through which newborn neurons acquire the morphology of mature neurons and become excitable. We employed a combination of functional and transcriptomic approaches to deconvolute and identify key regulators of the differentiation process of a DRG neuron-derived cell line, and we focused our study on the NaV1.5 ion channel (encoded by Scn5a) as a channel involved in the acquisition of DRG neuronal features. Overexpression of Scn5a enhances the acquisition of neuronal phenotypic features and increases the KCl-elicited hyperexcitability response in a DRG-derived cell line. Moreover, pharmacologic inhibition of the NaV1.5 channel during differentiation hinders the acquisition of phenotypic features of neuronal cells and the hyperexcitability increase in response to changes in the extracellular medium ionic composition. Taken together, these data highlight the relevance of sodium transients in regulating the neuronal differentiation process in a DRG neuron-derived cell line.

Abstract Background Currently, the diagnosis and treatment of neuroblastomas—the most frequent solid tumors in children—exploit the norepinephrine transporter (hNET) via radiolabeled norepinephrine analogs. We aim to develop a nanomedicine-based strategy towards precision therapy by targeting hNET cell-surface protein with hNET-derived homing peptides. Results The peptides (seq. GASNGINAYL and SLWERLAYGI) were shown to bind high-resolution homology models of hNET in silico. In particular, one unique binding site has marked the sequence and structural similarities of both peptides, while most of the contribution to the interaction was attributed to the electrostatic energy of Asn and Arg (

[This corrects the article DOI: 10.1371/journal.pone.0163983.].

Introducción: La intubación traqueal, además de formar parte de la atención a pacientes críticos, puede conllevar diferentes complicaciones. Una presión inadecuada dentro del manguito del tubo endotraqueal es el principal factor de riesgo. Objetivo: Evaluar la presión del neumotaponamiento del tubo en los pacientes adultos en el servicio de urgencias. Métodos: Diseño observacional, analítico. Se analizaron 60 procedimientos de intubación endotraqueal por personal médico de urgencias. La presión del neumotaponamiento fue calculada de forma empírica, posteriormente registrada con un manómetro en cmH2O. Se compararon las diferentes categorías con la presión de insuflado. Se utilizó análisis descriptivo, chi cuadrada de Pearson y ANOVA de un factor. Se consideró significativo un grado de significación (p) menor a 0.05. Resultados: Se incluyeron 60 pacientes. El 77% fueron neumotaponamientos suprainsuflados y el 23% normoinsuflados. El 64% de las intubaciones las realizaron residentes de 3.er año de urgencias. El volumen administrado al neumotaponamiento fue entre 4 y 10 ml. La presión de insuflado fue de 22 a 45 cmH2O, sin diferencia significativa entre el personal que manipuló el globo. Conclusiones: La presión del neumotaponamiento del tubo endotraqueal insuflado de manera empírica en los pacientes adultos en el servicio de urgencias es mayor al límite normal.