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Abstract Background The superiority of Enhanced Cognitive Behavior Therapy (CBT-E) with regard to weight gain and improvement of psychopathology of eating disorders for patients with anorexia nervosa (AN) over other psychotherapies and treatment as usual (TAU) has not been demonstrated in randomized controlled trials (RCTs). However, a previous RCT showed that patients with AN whose baseline body mass index (BMI) was less than 17.5 kg/m2 gained more weight when treated with CBT-E than with other psychotherapies. The aim of the study is to compare the efficacy of CBT-E and TAU for patients with AN. It was hypothesized that CBT-E would be superior to TAU, at least in terms of weight gain, as most patients with AN are likely to have a BMI lower than 17.5 kg/m2. Methods/design A randomized parallel-group multicenter trial will be conducted in three teaching hospitals in Japan between January 2023 and March 2026. Patients with DSM-5 AN, aged 16 years and older, with a BMI equal to or above 14.0 and below 18.5 will be eligible to participate. 56 patients will be randomly and evenly assigned to two intervention groups (CBT-E and TAU). Those assigned to CBT-E will be offered 25–40 sessions in accordance with their initial BMI. Patients assigned to TAU will have at least one session every 2 weeks, with the number of sessions and treatment period not fixed in advance. The primary outcome is BMI at 40 weeks after treatment initiation. The secondary outcomes are the results from the Japanese version of the Eating Disorder Examination Questionnaire and Clinical Impairment Assessment questionnaire to measure eating disorder psychopathology and psychological impairment. The follow-up assessment will be performed 6 months after the 40-week assessment. Discussion This multi-center randomized controlled study will probably evaluate the efficacy of CBT-E compared with TAU for patients with more severe AN than in previous studies since Japanese patients are likely to have a lower BMI than those in Western countries. While it may be difficult to generalize the results of a study conducted in Japan, it would be valuable to clarify the efficacy of CBT-E as a treatment package. Trial registration UMIN, UMIN000048847. Registered 12 Sep 2022.

Abstract Background The effectiveness of psychotherapeutic interventions for eating disorders (EDs) is widely studied in Europe, North America, and Australia/New Zealand. However, few controlled studies and no randomized controlled trials (RCTs) have been conducted in Japan despite the relatively high prevalence of EDs in the Japanese population. The aim of this study is to evaluate the effect of enhanced cognitive behavior therapy (CBT-E), an evidence-supported ED-focused form of cognitive behavior therapy (CBT), for the treatment of bulimia nervosa (BN) in Japan. Methods/design This multicenter RCT will compare CBT-E with treatment as usual (TAU), which is widely used in Japan. A group of 140 adult outpatients with a Diagnostic and Statistical Manual of Mental Disorders Fifth Edition (DSM-5) diagnosis of BN, ≥18 years of age, a body mass index (BMI) > 17.5 and

Background: Cognitive–behavioural therapy aims to increase quality of life by changing cognitive and behavioural factors that maintain problematic symptoms. A previous overview of cognitive–behavioural therapy systematic reviews suggested that cognitive–behavioural therapy was effective for many conditions. However, few of the included reviews synthesised randomised controlled trials. Objectives: This project was undertaken to map the quality and gaps in the cognitive–behavioural therapy systematic review of randomised controlled trial evidence base. Panoramic meta-analyses were also conducted to identify any across-condition general effects of cognitive–behavioural therapy. Data sources: The overview was designed with cognitive–behavioural therapy patients, clinicians and researchers. The Cochrane Library, MEDLINE, EMBASE, PsycINFO, Cumulative Index to Nursing and Allied Health Literature, Child Development & Adolescent Studies, Database of Abstracts of Reviews of Effects and OpenGrey databases were searched from 1992 to January 2019. Review methods: Study inclusion criteria were as follows: (1) fulfil the Centre for Reviews and Dissemination criteria; (2) intervention reported as cognitive–behavioural therapy or including one cognitive and one behavioural element; (3) include a synthesis of cognitive–behavioural therapy trials; (4) include either health-related quality of life, depression, anxiety or pain outcome; and (5) available in English. Review quality was assessed with A MeaSurement Tool to Assess systematic Reviews (AMSTAR)-2. Reviews were quality assessed and data were extracted in duplicate by two independent researchers, and then mapped according to condition, population, context and quality. The effects from high-quality reviews were pooled within condition groups, using a random-effect panoramic meta-analysis. If the across-condition heterogeneity was I2

The heavy metal pollution caused by road run-off water constitutes a problem in urban areas. The metallic load associated with road sediment must be determined in order to study its impact in drainage systems and receiving waters, and to perfect the design of prevention systems. This paper presents data regarding the sediment collected on road surfaces in the city of Torrelavega (northern Spain) during a period of 65 days (132 samples). Two sample types were collected: vacuum-dried samples and those swept up following vacuuming. The sediment loading (g m-2), particle size distribution (63-2800 µm) and heavy metal concentrations were determined. The data showed that the concentration of heavy metals tends to increase with the reduction in the particle diameter (exponential tendency). The concentrations of Pb, Zn, Cu, Cr, Ni, Cd, Fe, Mn and Co in the size fraction <63 µm were 350, 630, 124, 57, 56, 38, 3231, 374 and 51 mg kg-1, respectively (average traffic density: 3800 vehicles day-1). By increasing the residence time of the sediment, the concentration increases, whereas the ratio of the concentration between the different size fractions decreases. The concentration across the road diminishes when the distance between the roadway and the sampling siteincreases; when the distance increases, the ratio between size fractions for heavy metal concentrations increases. Finally, the main sources of heavy metals are the particles detached by braking (brake pads) and tyre wear (rubber), and are associated with particle sizes <125 µm. [ABSTRACT FROM AUTHOR]

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To assess whether cognitive behavioural (CB) approaches improve disability, pain, quality of life and/or work disability for patients with low back pain (LBP) of any duration and of any age.Nine databases were searched for randomised controlled trials (RCTs) from inception to November 2014. Two independent reviewers rated trial quality and extracted trial data. Standardised mean differences (SMD) and 95% confidence intervals were calculated for individual trials. Pooled effect sizes were calculated using a random-effects model for two contrasts: CB versus no treatment (including wait-list and usual care (WL/UC)), and CB versus other guideline-based active treatment (GAT).The review included 23 studies with a total of 3359 participants. Of these, the majority studied patients with persistent LBP (>6 weeks; n=20). At long term follow-up, the pooled SMD for the WL/UC comparison was -0.19 (-0.38, 0.01) for disability, and -0.23 (-0.43, -0.04) for pain, in favour of CB. For the GAT comparison, at long term the pooled SMD was -0.83 (-1.46, -0.19) for disability and -0.48 (-0.93, -0.04) for pain, in favour of CB. While trials varied considerably in methodological quality, and in intervention factors such as provider, mode of delivery, dose, duration, and pragmatism, there were several examples of lower intensity, low cost interventions that were effective.CB interventions yield long-term improvements in pain, disability and quality of life in comparison to no treatment and other guideline-based active treatments for patients with LBP of any duration and of any age.PROSPERO protocol registration number: CRD42014010536.

Protein A (PA) is a bacterial cell wall component of Staphylococcus aureus whose function is to bind to Immunoglobulin G (IgG). Given its ability to bind IgG as well as its stability and resistance to harsh acidic and basic cleaning conditions, it is commonly used in the affinity chromotography purification of biotherapeutics. This use can result in levels of PA being present in a drug product and subsequent patient exposure. Interestingly, PA was previously evaluated in clinical trials as well as supporting nonclinical studies, resulting in a database that enables the derivation of a health-based exposure limit (HBEL). Given the widespread use of PA in the pharmaceutical industry, the IQ DruSafe Impurities Safety Working Group (WG) evaluated the available information with the purpose of establishing a harmonized parenteral HBEL for PA. Based on this thorough, collaborative evaluation of nonclinical and clinical data available for PA, a parenteral HBEL of 1.2 μg/kg/dose (60 μg/dose for a 50 kg individual) is expected to be health protective for patients when it is present as an impurity in a biotherapeutic., 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 Inc. All rights reserved.)

Nonclinical safety and pharmacokinetic data for monomethyl auristatin E (MMAE) and 14 vedotin antibody-drug conjugates (ADC) were evaluated to determine patterns of toxicity, consistency of pharmacokinetic results, and species differences between rats and monkeys. Most nonclinical toxicities were antigen-independent, common across ADCs, and included hematologic, lymphoid, and reproductive toxicity related to MMAE pharmacology. Hematologic toxicity was the dose-limiting toxicity (DLT) or predominant toxicity for the majority of vedotin ADCs in both species. Tissue expression of the targeted antigen of an ADC rarely correlated with DLT; only two ADCs had antigen-dependent skin DLTs. For two additional ADCs, antigen-dependent delivery of MMAE in the bone marrow may have exacerbated the antigen-independent hematologic DLT. The highest tolerated doses and pharmacokinetics were similar within a given species, with rats tolerating higher doses than monkeys. Studies longer than 1 month in duration detected the same or fewer toxicities than 1-month studies and had no additional findings that affected the human risk assessment. These data support opportunities to streamline ADC toxicity assessments without compromising human starting dose selection or target organ identification., (©2024 The Authors; Published by the American Association for Cancer Research.)

Introduction: Inguinal hernia is defined as a projection of an organ through the inguinal canal. This can be incarcerated as a consequence of continuous inflammation of the hernial sac, which will prevent its return, causing damage to the venous and lymphatic return of the viscera. The neutrophil-to-lymphocyte ratio (NLR) is an easily accessible inflammatory biomarker obtained from blood cell counts. Therefore, the objective was to determine if the NLR is useful as a predictor of intestinal resection in incarcerated inguinal hernias., Material and Method: An observational, analytical, diagnostic test and retrospective study was carried out in a hospital in northern Peru from January 2013 to August 2019 in the Department of General Surgery and Emergency Surgery and Critical Care. Patients diagnosed with unilateral inguinal hernia with intestinal obstruction were included. For the relationship between the event and the exposure, it was analyzed using Chi square (χ 2 ) and T -Student. The sensitivity, specificity, positive predictive value, negative predictive value of the NLR as well as the area under the ROC curve were found to determine the predictive accuracy., Results: 161 patients with incarcerated inguinal hernia were studied: group I (20 patients with intestinal resection) and group II (141 patients without intestinal resection). The mean age in groups I and II were 69±16 and 60±17 years ( p <0.05); the frequency in males was 70% in group I and 76% in group II ( p >0.05). Intestinal obstruction and duration of incarceration >24 hours and the platelet-to-lymphocyte ratio demonstrated significant differences. With respect to NLR taking a cut-off point ≥6.5, a sensitivity of 75%, a specificity of 93.62%, a positive predictive value of 62.5% and a negative predictive value of 96.35% were observed; In addition, when analyzing with the ROC curve, a value of 5.14 was obtained as a predictor of intestinal resection with a sensitivity of 90% and a specificity of 84.4% ( p <0.001). Therefore, the NLR >5.14 predicts intestinal resection in patients with incarcerated inguinal hernias with an area under the curve of 0.92 at the Belen Hospital of Trujillo., Conclusions: The neutrophil-to-lymphocyte ratio is useful for predicting intestinal resection with a diagnostic accuracy of 92%.

Background: Microglial dysfunction plays a causative role in Alzheimer's disease (AD) pathogenesis. Here we focus on a germline insertion/deletion variant mapping SIRPβ1, a surface receptor that triggers amyloid-β(Aβ) phagocytosis via TYROBP., Objective: To analyze the impact of this copy-number variant in SIRPβ1 expression and how it affects AD molecular etiology., Methods: Copy-number variant proxy rs2209313 was evaluated in GERALD and GR@ACE longitudinal series. Hippocampal specimens of genotyped AD patients were also examined. SIRPβ1 isoform-specific phagocytosis assays were performed in HEK393T cells., Results: The insertion alters the SIRPβ1 protein isoform landscape compromising its ability to bind oligomeric Aβ and its affinity for TYROBP. SIRPβ1 Dup/Dup patients with mild cognitive impairment show an increased cerebrospinal fluid t-Tau/Aβ ratio (p = 0.018) and a higher risk to develop AD (OR = 1.678, p = 0.018). MRIs showed that Dup/Dup patients exhibited a worse initial response to AD. At the moment of diagnosis, all patients showed equivalent Mini-Mental State Examination scores. However, AD patients with the duplication had less hippocampal degeneration (p < 0.001) and fewer white matter hyperintensities. In contrast, longitudinal studies indicate that patients bearing the duplication allele show a slower cognitive decline (p = 0.013). Transcriptional analysis also shows that the SIRPβ1 duplication allele correlates with higher TREM2 expression and an increased microglial activation., Conclusions: The SIRPβ1 internal duplication has opposite effects over MCI-to-Dementia conversion risk and AD progression, affecting microglial response to Aβ. Given the pharmacological approaches focused on the TREM2-TYROBP axis, we believe that SIRPβ1 structural variant might be considered as a potential modulator of this causative pathway.

The nonhuman primate (NHP) has always been a limited resource for pharmaceutical research with ongoing efforts to conserve. This is due to their inherent biological properties, the growth in biotherapeutics and other modalities, and their use in small molecule drug development. The SARS-CoV-2 pandemic has significantly impacted the availability of NHPs due to the immediate need for NHPs to develop COVID-19 vaccines and treatments and the China NHP export ban; thus, accelerating the need to further replace, reduce and refine (3Rs) NHP use. The impact of the NHP shortage on drug development led DruSafe, BioSafe, and the United States (U.S.) Food and Drug Administration (FDA) Center for Drug Evaluation and Research (CDER) to discuss this issue at their 2021 annual meeting. This meeting identified areas to further the 3Rs in NHP use within the current nonclinical safety evaluation regulatory framework and highlighted the need to continue advancing alternative methods towards the aspirational goal to replace use of NHPs in the long term. Alignment across global health authorities is necessary for implementation of approaches that fall outside existing guidelines. This article captures the proceedings from this meeting highlighting current best practices and areas for 3Rs in NHP use., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: David Ackley, Joanne Birkebak, Jorg Blumel, Christina deZafra, Wendy Halpern, Danuta Herzyk, Sven Kronenberg, Robert Mauthe, Jacintha Shenton and Dana Shuey are employed, respectively, by the following pharmaceutical companies and as employees may hold stock in their respective companies: Eli Lilly, Gilead, Genentech, Seagen, Genentech, Merck, Roche, Pfizer, Amgen, and Incyte.Todd Bourcier, Andrew Goodwin and Ronald Wange are employed by the United States Food and Drug Administration Center for Drug Evaluation and Research., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Behavioral and psychological symptoms of dementia (BPSD) are present in most people with dementia (PwD), including Alzheimer's disease. There is consensus that non-pharmacological therapies represent the first line of treatment to address BPSD., Objective: We explore the efficacy of the use of a rocking chair (Nordic Sensi® Chair, NSC) in the treatment of BPSD in nursing home residents with moderate and severe dementia., Methods: We carried out a 16-week randomized, single-blind, controlled, clinical trial with PwD admitted to nursing homes. Participants were assigned to a treatment group (n = 40) that received three times a week one session per day of 20 minutes in the NSC and a control group (n = 37). The Neuropsychiatric Inventory-Nursing Home (NPI-NH) was used as primary efficacy outcome. Occupational distress for the staff was evaluated using the NPI-NH Occupational Disruptiveness subscale (NPI-NH-OD). Statistical analyses were conducted by means of a Mixed Effects Model Analysis., Results: Treatment with the NSC was associated with a beneficial effect in most of BPSD, as reflected by differences between the treatment and control group on the NPI-NH total score (mean change score -18.87±5.56 versus -1.74±0.67, p = 0.004), agitation (mean change score -2.32±2.02 versus -0.78±1.44, p = 0.003) and irritability (mean change score -3.35±2.93 versus -1.42±1.31, p = 0.004). The NPI-NH-OD total score also improved the most in the treatment group (mean change score -9.67±7.67 versus -7.66±6.08, p = 0.003)., Conclusions: The reduction in overall BPSD along with decreased caregiver occupational disruptiveness represent encouraging findings, adding to the potential of nonpharmacological interventions for nursing home residents living with dementia.

Introduction: The objective is to analyze the impact of the COVID-19 pandemic on the pediatric emergencies and hospital admissions., Methods: Retrospective cohort study of patients treated in a tertiary hospital, from March 14 to April 26, 2020, compared to the same period of the previous 3 years., Results: A notable overall reduction in emergency room visits and admissions is observed in all pediatric areas, maintaining care in neonatology and scheduled admissions in oncology., Discussion: The reduction in global activity in pediatric emergencies is not only explained by the decrease in contagious diseases. The decrease in inadequate demand and inappropriate income may have contributed. The availability of pediatric beds would make the reduction of programmed surgical activity unnecessary and would allow the redistribution of resources to areas with greater healthcare pressure., (Copyright © 2021 Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica. Published by Elsevier España, S.L.U. All rights reserved.)

The IQ Consortium NHP Reuse Working Group (WG) comprises members from 15 pharmaceutical and biotechnology companies. In 2020, the WG developed and distributed a detailed questionnaire on protein non-naïve NHP reuse to the WG member companies. The WG received responses from key stakeholders including principal investigators, facility managers, animal welfare officers and research scientists. This paper's content reflects the consolidated opinion of the WG members and the questionnaire responses on the subject of NHP reuse within nonclinical programs at all stages of research and development. Many of the pharmaceutical companies represented in the working group or participating in the questionnaire have already achieved some level of NHP reuse in their nonclinical programs, but the survey results suggested that there is significant potential to increase NHP reuse further and a need to understand the considerations involved in reuse more clearly. The WG has also focused carefully on the inherent concerns and risks of implementing protein non-naive NHP reuse and has evaluated the best methods of risk assessment and decision-making. This paper presents a discussion on the challenges and opportunities surrounding protein non-naïve NHP reuse and aims to stimulate further industry dialogue on the subject and provide guidance for pharmaceutical companies to establish roadmaps and decision trees enabling increased protein non-naïve NHP reuse. In addition, this paper represents a solid basis for collaborative engagement between pharmaceutical and biotechnology companies with contract research organizations (CROs) to discuss how the availability of protein non-naïve NHP within CROs can be better leveraged for their use within nonclinical studies.

Integral membrane proteins (MPs) are important drug targets across most fields of medicine, but historically have posed a major challenge for drug discovery due to difficulties in producing them in functional forms. We review the state of the art in drug discovery strategies using recombinant multipass MPs, and outline methods to successfully express, stabilize, and formulate them for small-molecule and monoclonal antibody therapeutics development. Advances in structure-based drug design and high-throughput screening are allowing access to previously intractable targets such as ion channels and transporters, propelling the field towards the development of highly specific therapies targeting desired conformations., Competing Interests: Declaration of interests All authors are employees of TetraGenetics Inc., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Introduction: The objective is to analyze the impact of the COVID-19 pandemic on the pediatric emergencies and hospital admissions., Methods: Retrospective cohort study of patients treated in a tertiary hospital, from March 14 to April 26, 2020, compared to the same period of the previous 3 years., Results: A notable overall reduction in emergency room visits and admissions is observed in all pediatric areas, maintaining care in neonatology and scheduled admissions in oncology., Discussion: The reduction in global activity in pediatric emergencies is not only explained by the decrease in contagious diseases. The decrease in inadequate demand and inappropriate income may have contributed. The availability of pediatric beds would make the reduction of programmed surgical activity unnecessary and would allow the redistribution of resources to areas with greater healthcare pressure., (Copyright © 2021 Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica. Publicado por Elsevier España, S.L.U. All rights reserved.)

A simplified method is proposed for determining the potential load of heavy metals (HMs) derived from the wash-off caused by surface runoff on road-deposited sediment (RDS). The method consists of three phases: (i) characterization of RDS load wash-off, (ii) assessment of HM load in dry weather, and (iii) application of a wash-off equation. Two processes were included in the wash-off equation: HM transport (solid fraction) and HM leaching (dissolved fraction). The average wash-off of HMs ranges from 16.6 to 46.3%, relative to the total mass of HMs associated with dry-weather RDS (Pb, Zn, Cu, Cr, Ni, Cd, Fe, Mn, Co, and Ba). Cd, Mn, and Zn presented the highest wash-off in the areas studied. The size fraction below 250μm contributed an average of 86.7% of potential HM load washed-off from RDS. Based on the phenomena included in the wash-off equation, it was observed the following order of precedence: transport of RDS<250μm, leaching of RDS<250μm, and leaching of RDS≥250μm. Solid and dissolved fractions contributed 70.7 and 29.3% of the potential HM load washed-off by runoff from RDS, respectively. The proposed method serves as a management tool for road HM pollution during rain., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background/aims: Sinusoidal endothelial dysfunction with decreased nitric oxide (NO) production contributes to increased hepatic resistance in cirrhosis. Statins improve endothelial dysfunction in peripheral vasculature. This study was designed to characterize the hemodynamic and molecular effects of statins in cirrhotic rats., Methods: Systemic and splanchnic hemodynamics were evaluated in CCl(4) ascitic cirrhotic rats treated with placebo or simvastatin (25 mg/kg/day, for 3 days), at baseline and after volume expansion. Vascular responses of liver vasculature were evaluated after isolation and perfusion of the liver., Results: There were no differences in baseline hemodynamics in rats treated with simvastatin or placebo. However, in rats treated with simvastatin the increase in portal pressure induced by volume expansion was significantly attenuated. In isolated and perfused cirrhotic livers simvastatin pre-treatment significantly attenuated the pressure response to methoxamine, and significantly improved paradoxical vasoconstriction induced by acetylcholine. These effects were not observed in the presence of a nitric oxide synthase inhibitor. Simvastatin increased eNOS expression, Akt-dependent eNOS phosphorylation and cGMP liver content., Conclusions: The administration of simvastatin might constitute a new way to selectively increase NO availability in the cirrhotic liver circulation and, therefore improve the vascular disturbances that contribute to portal hypertension.

Mesalazine is an aminosalicillic derivative considered as a safe alternative to the relative frequency (5-55%) of adverse effects observed with sulfasalazine. The well known hepatoxicity associated with sulfasalazine and attributed to its sulfamidic fraction is limited to few cases described in the treatment with mesalazine. We herein present a new case of hepatoxicity by mesalazine in a patient with lymphocytic colitis. The possible pathogenic mechanism is also commented upon.

Sex differences in GABA neurotransmitter have been described. We have studied the involvement of the GABAA receptor in sex differences in the brain and reproductive behaviour. Neonatal administration of the GABAA agonist diazepam to male rats facilitated the induction of maternal behaviour in adults, while the antagonist picrotoxin disrupted it in females. Sex differences in the accessory olfactory bulb were also reversed, but gonadal function remained unaltered in both sexes. This suggests that neonatal changes in neuronal membrane permeability to Cl- ions may play a role in the organization of sex differences. Our study constitutes a new model for understanding the early neurobiological organization of sex differences.

The appearance of cellular associations between macrophages and lymphocytes--which we have denominated macrophage-lymphocyte rosettes--and their kinetic formation in the presence of phytohemagglutinin (PHA) have been studied in B10 A (4R) mice. The greatest number of macrophage-lymphocyte rosettes was found from 6 to 12 hours after incubation with PHA. During this time, 42.38 +/- 10.70 of the total number of macrophages had lymphocytes attached to their membranes. This percentage decreased to 17.33 +/- 2.07% after 24 hours. The activation of macrophages after PHA treatment was tested by the phagocytic capacity of these cells. This activity increased significantly 24 hours after incubation. In our assay, an increase in the appearance of multinucleated giant cells when compared to controls was also observed. When the macrophages were lymphocyte depleted, the appearance of the multinucleated giant cells was significantly lower. The kinetics for these formations are also discussed.

The activity of a new synthetic C-nucleoside upon cell proliferation was tested using mouse Ehrlich ascites tumor cells and PHA-stimulated human blood T lymphocytes. The product did not modify the cancer cells reproduction. Contrarily, it inhibited T lymphocytes proliferation.