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Unrecognized gastrointestinal disorders, may contribute to the behavioral problems of the non-verbal autistic patients. The objective of this article is to describe any observations about the possible association between the brain and gastrointestinal dysfunctions in children with autistic disorder. [ABSTRACT FROM AUTHOR]

Introduction: Drotaverine, paracetamol, and peppermint oil are often prescribed for the treatment of gastrointestinal spasm and pain. This study aimed to evaluate the effect of these drugs alone and combined with the well-known antispasmodic hyoscine butylbromide on the human colon., Methods: Colon samples were obtained from macroscopically normal regions of 68 patients undergoing surgery and studied in muscle bath. Drotaverine, paracetamol, and peppermint oil were tested alone and in combination with hyoscine butylbromide on (1) spontaneous contractility induced by isometric stretch (in the presence of 1 µM tetrodotoxin) and (2) contractility induced by 10 -5  M carbachol and after (3) electrical field stimulation-induced selective stimulation of excitatory (in the presence of 1 mM Nω-nitro-L-arginine and 10 µM MRS2179) and (4) inhibitory (under non-adrenergic, non-cholinergic conditions) pathways. (5) Drotaverine alone was also tested on cAMP-dependent pathway activated by forskolin., Results: Compared with the vehicle, drotaverine and paracetamol (10 -9 -10 -5  M) did not modify spontaneous contractions, carbachol-induced contractions, and responses attributed to selective activation of excitatory pathways. The addition of hyoscine butylbromide (10 -7 -10 -5  M), concentration-dependently reduced myogenic contractions and carbachol- and electrical field stimulation-induced contractile responses. The association of paracetamol (10 -4  M) and hyoscine butylbromide (10 -7 -10 -5  M) was not different from hyoscine butylbromide alone (10 -7 -10 -5  M). At higher concentrations (10 -3 M-3*10 -3  M), paracetamol decreased myogenic and carbachol-induced contractions. The adenylate cyclase activator, forskolin, concentration-dependently reduced contractility, leading to smooth muscle relaxation. The effect of forskolin 10 -7  M was concentration-dependently enhanced by drotaverine (10 -6 M-10 -5 M)., Discussion: Peppermint oil reduced myogenic activity and carbachol- and electrical field stimulation-induced contractions. The association of hyoscine butylbromide and peppermint oil was synergistic since the interaction index measured with the isobologram was lower than 1. No effect was seen on the neural-mediated inhibitory responses with any of the drugs studied although peppermint oil reduced the subsequent off-contraction. Drotaverine and hyoscine butylbromide have a complementary effect on human colon motility as one stimulates the cAMP inhibitory pathway and the other inhibits the excitatory pathway. Peppermint oil is synergic with hyoscine butylbromide suggesting that a combination therapy may be more effective in treating patients. In contrast, at therapeutic concentrations, paracetamol does not modify colonic contractility, suggesting that the association of paracetamol and hyoscine butylbromide has independent analgesic and antispasmodic properties., Competing Interests: ST received salary from the Universitat Autònoma de Barcelona, which is funded by a Sanofi grant. MC is a consultant for Sanofi and the co-chief investigator of a Sanofi-sponsored research grant. MJ received a research grant from Sanofi. RL is currently a Sanofi employee and may hold shares and/or stock options in the company. 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. The authors declare that this study received funding from Sanofi. Authors from Sanofi were involved in the study design, data collection, analysis, interpretation, ensuring the accuracy of data and the preparation of the manuscript., (Copyright © 2024 Traserra, Barber, Alcalá-González, Landolfi, Lange, Malagelada, Corsetti and Jimenez.)

Electric power systems with a high penetration of photovoltaic generation and a relevant fleet of electric vehicles face significant stability challenges, particularly in mountainous areas where the variability of photovoltaic resources is pronounced. This study presents a novel methodology to strategically place electric vehicle aggregators along a feeder. This approach considers electrical variables and the dynamics of cloud movements within the study area. This innovative methodology reduces the substation's power load demand and significantly improves the end user's voltage levels. The improvements in voltage regulation and reduced demand on the substation provide clear benefits, including increased system resilience, better integration of renewable energy sources, and enhanced overall efficiency of the electric grid. These advantages are particularly critical in regions with high levels of photovoltaic generation and are important in promoting sustainable electric vehicle charging infrastructure. When analyzing different load scenarios for the IEEE European Low Voltage Test Feeder system, the consideration of distributed aggregators based on cloud movements decreased the power required at the substation by 21.25%, and the voltage drop in loads was reduced from 6.9% to 4.29%. This research underscores the critical need to consider both the variability and geographical distribution of PV resources in the planning and operation of electrical systems with extensive PV generation.

Introduction: Hyoscine butylbromide (HBB) is one of the most used antispasmodics in clinical practice. Recent translational consensus has demonstrated a similarity between human colonic motor patterns studied ex vivo and in vivo, suggesting ex vivo can predict in vivo results. It is unclear whether the mechanism of action of antispasmodics can predict different use in clinical practice. The aim of the present study is to bridge this gap dissecting HBB's role in excitatory and inhibitory neural pathways., Methods: 309 colon samples from 48 patients were studied in muscle bath experiments. HBB was tested on: 1-spontaneous phasic contractions (SPCs); 2-carbachol-induced contractility; electrical field stimulation (EFS)-induced selective stimulation of 3-excitatory and 4-inhibitory pathways and 5- SPCs and EFS-induced contractions enhanced by neostigmine. Atropine, AF-DX116 (M2 blocker) and DAU-5884 (M3 blocker) were used as comparators., Results: In the presence of tetrodotoxin (TTX), HBB and atropine 1 μM reduced SPCs. HBB and atropine concentration-dependently reduced carbachol- and EFS-induced contractions. Inhibitory effects of DAU-5884 on EFS-induced contractions were more potent than of AF-DX116. HBB did not affect the off-response associated to neural inhibitory responses. Neostigmine enhanced both SPCs and EFS-induced contractions. In the presence of TTX and ω-conotoxin (GVIA), neostigmine still enhanced SPCs. Addition of HBB and atropine reduced these responses., Conclusions: This study demonstrates that HBB inhibits neural cholinergic contractions associated to muscarinic (mainly M3) receptors. HBB has a potential role in reducing colonic spasm induced by the release of acetylcholine from enteric motor neurons and from an atypical source including a potential non-neuronal origin., Competing Interests: Declaration of competing interest Sara Traserra received salary from the Universitat Autònoma de Barcelona, which is funded by a Sanofi grant. Luis Gerardo Alcalá-González, Claudia Barber, Stefania Landolfi and Carolina Malagelada declared no conflict of interest. Maura Corsetti is a consultant for Sanofi and co-chief investigator of a Sanofi-sponsored research grant. Marcel Jimenez received a research grant from Sanofi. Robert Lange is currently a Sanofi employee and may hold shares and/or stock options in the company. Sylvie Forestier is a former employee at Sanofi., (Copyright © 2024. Published by Elsevier B.V.)

Cannabidiol (CBD), one of the main Cannabis sativa bioactive compounds, is utilized in the treatment of major epileptic syndromes. Its efficacy can be attributed to a multimodal mechanism of action that includes, as potential targets, several types of ion channels. In the brain, CBD reduces the firing frequency in rat hippocampal neurons, partly prolonging the duration of action potentials, suggesting a potential blockade of voltage-operated K + channels. We postulate that this effect might involve the inhibition of the large-conductance voltage- and Ca 2+ -operated K + channel (BK channel), which plays a role in the neuronal action potential's repolarization. Thus, we assessed the impact of CBD on the BK channel activity, heterologously expressed in HEK293 cells. Our findings, using the patch-clamp technique, revealed that CBD inhibits BK channel currents in a concentration-dependent manner with an IC 50 of 280 nM. The inhibition is through a direct interaction, reducing both the unitary conductance and voltage-dependent activation of the channel. Additionally, the cannabinoid significantly delays channel activation kinetics, indicating stabilization of the closed state. These effects could explain the changes induced by CBD in action potential shape and duration, and they may contribute to the observed anticonvulsant activity of this cannabinoid.

Introduction: Tafamidis is the only approved transthyretin stabiliser approved for the treatment of variant transthyretin amyloidosis (A-ATTRv) related polyneuropathy (PNP). The aim of this study is to analyse the effectiveness of tafamidis in a real-world setting in Spain., Methods: This is a national multicenter study in which patients with V30M A-ATTR related PN treated with tafamidis for at least 1 year were included. Clinical, demographic, analytical and neurophysiological variables were analysed., Results: 100 patients were recruited. Overall, 47 patients (47%) were classified as complete responders, 32 (32%) as partial responders and 21 (21%) as non-responders. The median duration of treatment with tafamidis was 35 months. Better treatment response was shown in patients with in polyneuropathy disability score (PND) I, lower neuropathy impairment score (NIS), compound muscle action potential (CMAP) and Norfolk QoL questionnaire. Higher albumin levels and lower NTproBNP levels were also associated with better treatment response. A basal NIS≥15 predicts that the patient could be a non-responder with a 60% probability., Conclusions: Our results reinforce the tafamidis efficacy to treat A-ATTRv-PNP if started early in the disease course. Patients with the V30M variant, NIS<15 and PND I are the most appropriate subjects for this treatment., (Copyright © 2024 Elsevier España, S.L.U. All rights reserved.)

Background: Maintenance therapy with niraparib, a poly(ADP-ribose) polymerase inhibitor, has been shown to extend progression-free survival in patients with newly diagnosed advanced ovarian cancer who responded to first-line platinum-based chemotherapy, regardless of biomarker status. However, there are limited data on niraparib's efficacy and safety in the neoadjuvant setting. The objective of Cohort C of the OPAL trial (OPAL-C) is to evaluate the efficacy, safety, and tolerability of neoadjuvant niraparib treatment compared with neoadjuvant platinum-taxane doublet chemotherapy in patients with newly diagnosed stage III/IV ovarian cancer with confirmed homologous recombination-deficient tumors., Methods: OPAL is an ongoing global, multicenter, randomized, open-label, phase 2 trial. In OPAL-C, patients will be randomized 1:1 to receive three 21-day cycles of either neoadjuvant niraparib or platinum-taxane doublet neoadjuvant chemotherapy per standard of care. Patients with a complete or partial response per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) will then undergo interval debulking surgery; patients with stable disease may proceed to interval debulking surgery or alternative therapy at the investigator's discretion. Patients with disease progression will exit the study treatment and proceed to alternative therapy at the investigator's discretion. After interval debulking surgery, all patients will receive up to three 21-day cycles of platinum-taxane doublet chemotherapy followed by niraparib maintenance therapy for up to 36 months. Adult patients with newly diagnosed stage III/IV ovarian cancer eligible to receive neoadjuvant platinum-taxane doublet chemotherapy followed by interval debulking surgery may be enrolled. Patients must have tumors that are homologous recombination-deficient. The primary endpoint is the pre-interval debulking surgery unconfirmed overall response rate, defined as the investigator-assessed percentage of patients with unconfirmed complete or partial response on study treatment before interval debulking surgery per RECIST v1.1., Discussion: OPAL-C explores the use of niraparib in the neoadjuvant setting as an alternative to neoadjuvant platinum-taxane doublet chemotherapy to improve postsurgical residual disease outcomes for patients with ovarian cancer with homologous recombination-deficient tumors. Positive findings from this approach could significantly impact preoperative ovarian cancer therapy, particularly for patients who are ineligible for primary debulking surgery., Trial Registration: ClinicalTrials.gov NCT03574779. Registered on February 28, 2022., (© 2024. The Author(s).)

Leukocyte and Platelet-Rich Fibrin (L-PRF) is part of the second generation of platelet-concentrates. L-PRF derived from nonsmokers has been used in surgical procedures, with its beneficial effects in wound healing being proven to stimulate biological activities such as cell proliferation, angiogenesis, and differentiation. Cigarette smoking exerts detrimental effects on tissue healing and is associated with post-surgical complications; however, evidence about the biological effects of L-PRF derived from smokers is limited. This study evaluated the impact of L-PRF secretome (LPRFS) derived from smokers and nonsmokers on angiogenesis and osteoblast differentiation. LPRFS was obtained by submerging L-PRF membranes derived from smokers or nonsmokers in culture media and was used to treat endothelial cells (HUVEC) or SaOs-2 cells. Angiogenesis was evaluated by tubule formation assay, while osteoblast differentiation was observed by alkaline phosphatase and osterix protein levels, as well as in vitro mineralization. LPRFS treatments increased angiogenesis, alkaline phosphatase, and osterix levels. Treatment with 50% of LPRFS derived from smokers and nonsmokers in the presence of osteogenic factors stimulates in vitro mineralization significantly. Nevertheless, differences between LPRFS derived from smokers and nonsmokers were not found. Both LPRFS stimulated angiogenesis and osteoblast differentiation in vitro; however, clinical studies are required to determine the beneficial effect of LPRFS in smokers.

Chronic intestinal dysmotility is a rare and debilitating digestive disorder characterized by symptoms of mechanical obstruction without an organic lesion. It has diverse causes and involves various pathological mechanisms. Small bowel manometry is the preferred diagnostic method, particularly for patients with severe and progressive symptoms. The condition can be categorized as intestinal pseudo-obstruction and enteric dysmotility, both entities share abnormal small bowel motility, but with important differences in prognosis and management.

The aim of this work was to evaluate possible mechanisms involved in the protective effect of N-acetyl-L-cysteine (NAC) on hepatic endocrine-metabolic, oxidative stress, and inflammatory changes in prediabetic rats. For that, normal male Wistar rats (60 days old) were fed for 21 days with 10% sucrose in their drinking water and 5 days of NAC administration (50 mg/kg, i.p.) and thereafter, we determined: serum glucose, insulin, transaminases, uric acid, and triglyceride levels; hepatic fructokinase and glucokinase activities, glycogen content, lipogenic gene expression; enzymatic and non-enzymatic oxidative stress, insulin signaling pathway, and inflammatory markers. Results showed that alterations evinced in sucrose-fed rats (hypertriglyceridemia, hyperinsulinemia, and high liver fructokinase activity together with increased liver lipogenic gene expression and oxidative stress and inflammatory markers) were prevented by NAC administration. P-endothelial nitric oxide synthase (P-eNOS)/eNOS and pAKT/AKT ratios, decreased by sucrose ingestion, were restored after NAC treatment. In conclusion, the results suggest that NAC administration improves glucose homeostasis, oxidative stress, and inflammation in prediabetic rats probably mediated by modulation of the AKT/NOS pathway. Administration of NAC may be an effective complementary strategy to alleviate or prevent oxidative stress and inflammatory responses observed in type 2 diabetes at early stages of its development (prediabetes).

Objectives. To describe the implementation of a novel disease surveillance model in Puerto Rico, the Municipal Case Investigation and Contact Tracing System for COVID-19, established during the pandemic as the primary response. Methods. We analyzed data from July 2020 to June 2021, including all COVID-19 cases reported by public and private laboratories in Puerto Rico to describe the accomplishments and limitations of the surveillance. Results. During the first year, the system was successfully implemented in all Puerto Rican municipalities, collecting data on more than 132 000 confirmed COVID-19 cases. It improved case investigation coverage, reduced laboratory reporting times, and facilitated community engagement for ongoing response enhancements. Conclusions. Surveillance systems of this scale were new to Puerto Rico's Health System, and there was a steep learning and improvement curve. This approach enabled tailored health education, equitable distribution of testing and treatments, and surveillance by educational institutions. Public Health Implications. Near-real-time epidemiological data publication promoted trust, education, and evidence-based policymaking. ( Am J Public Health . 2024;114(S1):S96-S102. https://doi.org/10.2105/AJPH.2023.307493).

(1) Background: Persistent COVID is characterized by the presence of fatigue, mental fog, and sleep problems, among others. We aimed to study cognitive abilities (attention, executive functions, memory, language) and psychological and emotional factors in a group of participants of the population with persistent COVID-19 and asymptomatic or non-COVID-19-infected patients; (2) Methods: A total of 86 participants aged 18 to 66 years (X = 46.76) took part in the study, with 57 individuals (66.27%) in the experimental group and 29 (33.73%) in the control group. A comprehensive assessment included neuropsychological evaluations, evaluations of anxious and depressive symptomatology, assessments of the impact of fatigue, sleep quality, memory failures in daily life, and the perceived general health status of the participants; (3) Results: significant differences between groups were found in incidental learning within the Key Numbers task (U = 462.5; p = 0.001; p = 0.022) and in the Direct Digit Span (U = 562; p = 0.022), but not in the Inverse Digit Span (U = 632.5; p = 0.105). Differences were also observed in the prospective memory task of the Rivermead Prospective Memory Tasks (from the Rivermead Behavioural Memory Test) in the recall of quotations (U = 610; p = 0.020) as well as in the recall of objects (U = 681.5; p = 0.032). Concerning the task of verbal fluency, significant differences were found for both phonological cues ( p - and s-) (t = -2.190; p = 0.031) and semantic cues (animals) (t = -2.277; p = 0.025). In terms of the psychological impact assessment, significant differences were found in the emotional impact across all variables studied (fatigue, quality of sleep, memory lapses, and the perceived general health status), except for quality of life; (4) Conclusions: Our results suggest that the sequelae derived from persistent COVID may have an impact on people's lives, with higher levels of anxiety and depression, worse sleep quality, a greater number of subjective memory complaints, and a greater feeling of fatigue and impact on quality of life. Furthermore, poorer performance was observed in memory and verbal fluency.

Background: Mucopolysaccharidosis (MPS) II is a rare, X-linked lysosomal storage disease. Approximately two-thirds of patients have central nervous system involvement with some demonstrating progressive cognitive impairment (neuronopathic disease). The natural history of cognitive and adaptive function in patients with MPS II is not well-defined. This 2-year, prospective, observational study evaluated the neurodevelopmental trajectories of boys with MPS II aged ≥ 2 years and < 18 years., Results: Overall, 55 patients were enrolled. At baseline, mean (standard deviation [SD]) age was 5.60 (3.32) years; all patients were receiving intravenous idursulfase. Cognitive and adaptive function were assessed using the Differential Ability Scales, Second Edition (DAS-II) General Conceptual Ability (GCA) and the Vineland Adaptive Behavior Scales, Second Edition (VABS-II) Adaptive Behavior Composite (ABC) scores, respectively. Baseline mean (SD) DAS-II GCA and VABS-II ABC scores were 78.4 (19.11) and 83.7 (14.22), respectively, indicating low cognitive function and moderately low adaptive behavior. Over 24 months, modest deteriorations in mean (SD) scores were observed for DAS-II GCA (-3.8 [12.7]) and VABS-II ABC (-2.0 [8.07]). Changes in DAS-II GCA scores varied considerably, and data suggested the existence of four potential patient subgroups: (1) patients with marked early impairment and rapid subsequent decline, (2) patients with marked early impairment then stabilization, (3) patients with mild early impairment then stabilization, and (4) patients without impairment who remained stable. Subgroup analyses revealed numerically greater DAS-II GCA score reductions from baseline in patients aged < 7 years at baseline (vs. those aged ≥ 7 years) and in patients with DAS-II GCA scores ≤ 70 at baseline (vs. those with scores > 70); between-group differences were nonsignificant. No clear subgroups or patterns were identified for individual changes in VABS-II ABC scores. In total, 49 patients (89.1%) reported ≥ 1 adverse event (AE) and nine patients (16.4%) reported serious AEs., Conclusions: Some patients with MPS II had rapid declines in cognitive ability, whereas others remained relatively stable after an initial decline. These insights provide a basis for more detailed analyses of different patient subgroups, which may enhance the definition and understanding of factors that influence cognitive and adaptive function in MPS II., Trial Registration: ClinicalTrials.gov, NCT01822184. Registered retrospectively: April 2, 2013., (© 2023. The Author(s).)

Purpose: We describe the design and development of the European Platform to Promote health and wellbeing in the workplace (EMPOWER) digital intervention that provides an integrative user programme meeting the needs of employees and employers in addressing work stress., Results: A user-centred design process was followed from January 2020 until November 2021. A tailored algorithm was developed to provide support at the individual employee level and the company level. Each element of the digital intervention was developed in English and then translated in Spanish, English, Polish and Finnish. The digital intervention consists of a website and a mobile application (app) that provides algorithm-based personalised content after assessing a user's somatic and psychological symptoms, work functioning, and psychosocial risk factors for work stress. It has a public section and an employer portal that provides recommendations to reduce psychosocial risks in their company based upon clustered input from employees. Usability testing was conducted and showed high ease of use and completion of tasks by participants., Conclusion: The EMPOWER digital intervention is a tailored multimodal intervention addressing wellbeing, work stress, mental and physical health problems, and work productivity. This will be used in a planned RCT in four countries to evaluate its effectiveness., Competing Interests: Christina van der Feltz-Cornelis received honoraries from the Lloyds Register Foundation and Janssen UK. Oriol Borrega Cepa and Laura González Recio have a paid consultancy and development of the Spanish based project “SOM360 - Salud Mental” (https://www.som360.org), participation in the European Project “Share4Rare” as analyst and developer (https://www.share4rare.org), and participation in the European Project “ACADOM” as analyst and language expert (https://www.omada.es/blapp/). All other authors have no conflicts of interest to report., (© 2023 The Authors.)

Background: Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare mitochondrial disease caused by mutations in TYMP, encoding thymidine phosphorylase. Clinically it is characterized by severe gastrointestinal dysmotility associated with cachexia and a demyelinating sensorimotor polyneuropathy. Even though digestive manifestations are progressive and invariably lead to death, the features of gastrointestinal motor dysfunction have not been systematically evaluated. The objective of this study was to describe gastrointestinal motor dysfunction in MNGIE using state-of-the art techniques and to evaluate the relationship between motor abnormalities and symptoms., Methods: Prospective study evaluating gastrointestinal motor function and digestive symptoms in all patients with MNGIE attended at a national referral center in Spain between January 2018 and July 2022., Key Results: In this period, five patients diagnosed of MNGIE (age range 16-46 years, four men) were evaluated. Esophageal motility by high-resolution manometry was abnormal in four patients (two hypoperistalsis, two aperistalsis). Gastric emptying by scintigraphy was mildly delayed in four and indicative of gastroparesis in one. In all patients, small bowel high-resolution manometry exhibited a common, distinctive dysmotility pattern, characterized by repetitive bursts of spasmodic contractions, without traces of normal fasting and postprandial motility patterns. Interestingly, objective motor dysfunctions were detected in the absence of severe digestive symptoms., Conclusions and Inferences: MNGIE patients exhibit a characteristic motor dysfunction, particularly of the small bowel, even in patients with mild digestive symptoms and in the absence of morphological signs of intestinal failure. Since symptoms are not predictive of objective findings, early investigation is indicated., (© 2023 The Authors. Neurogastroenterology & Motility published by John Wiley & Sons Ltd.)

Context: Endocrine complications are common in pediatric brain tumor patients., Objective: To describe hypothalamic-pituitary-gonadal axis (HPGA) function in patients treated in childhood for a primary brain tumor more than 5 years earlier, in order to identify risk factors for HPGA impairment., Methods: We retrospectively included 204 patients diagnosed with a primary brain tumor before 18 years of age and monitored at the pediatric endocrinology unit of the Necker Enfants-Malades University Hospital (Paris, France) between January 2010 and December 2015. Patients with pituitary adenoma or untreated glioma were excluded., Results: Among patients with suprasellar glioma not treated by radiotherapy, the prevalence of advanced puberty was 65% overall and 70% when the diagnosis occurred before 5 years of age. Medulloblastoma chemotherapy caused gonadal toxicity in 70% of all patients and in 87.5% of those younger than 5 years at diagnosis. In the group with craniopharyngioma, 70% of patients had hypogonadotropic hypogonadism, which was consistently accompanied by growth hormone deficiency., Conclusion: Tumor type, location, and treatment were the risk main factors for HPGA impairment. Awareness that onset can be delayed is essential to guide information of parents and patients, patient monitoring, and timely hormone replacement therapy., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The Rad50 interacting protein 1 (Rint1) is a key player in vesicular trafficking between the ER and Golgi apparatus. Biallelic variants in RINT1 cause infantile-onset episodic acute liver failure (ALF). Here, we describe 3 individuals from 2 unrelated families with novel biallelic RINT1 loss-of-function variants who presented with early onset spastic paraplegia, ataxia, optic nerve hypoplasia, and dysmorphic features, broadening the previously described phenotype. Our functional and lipidomic analyses provided evidence that pathogenic RINT1 variants induce defective lipid-droplet biogenesis and profound lipid abnormalities in fibroblasts and plasma that impact both neutral lipid and phospholipid metabolism, including decreased triglycerides and diglycerides, phosphatidylcholine/phosphatidylserine ratios, and inhibited Lands cycle. Further, RINT1 mutations induced intracellular ROS production and reduced ATP synthesis, affecting mitochondria with membrane depolarization, aberrant cristae ultrastructure, and increased fission. Altogether, our results highlighted the pivotal role of RINT1 in lipid metabolism and mitochondria function, with a profound effect in central nervous system development.

Struthanthusibe-dzi sp. nov. is a new species described and illustrated from the cloud and pine-oak forests of the Sierra Madre del Sur in Oaxaca, Mexico. This species shares similarities of leaf shape and inflorescence type with S.deppeanus , S.quercicola , and S.ramiro-cruzii . However, S.ibe-dzi can be recognized by its glaucous branches, leaves and inflorescences; compressed nodes; convoluted distal half of styles in pistillate flowers; and staminate flowers with asymmetrical thecae and an extended connective forming an apiculate horn in both anther series. A distribution map and an identification key are provided to separate S.ibe-dzi from morphologically similar congeners present in the region., (Maria Guadalupe Maldonado-Borja, Rosa Cerros-Tlatilpa, Luis Gil Galván-González.)

Background: The last version of the Chicago Criteria for high resolution esophageal manometry proposes an expanded protocol including complementary maneuvers to improve the diagnostic yield of the exploration. Our aim was to determine the diagnostic gain of the CCv4.0 protocol compared to the CCv3.0 protocol., Methods: All manometry recordings performed in 4 reference centers during the first 10 months after the implementation of the new protocol were retrospectively reviewed. The time spent to complete the protocol was measured, and the changes in diagnosis resulting from the new CCv4.0 were compared to CCv3.0., Key Results: From a total of 756 HRM performed, 606 studies could be properly analyzed. The duration of the studies was 18.3 ± 4.3 min. From these, 11.3 ± 3.4 min were spent to complete the CCv3.0 protocol, and 7.4 ± 3.6 min were spent for the remaining maneuvers. A discordant diagnosis between CCv3.0 and CCv4.0 was obtained in 12% of patients: 32% of patients with ineffective esophageal motility turned to normal motility; 24% of patients with esophagogastric junction outlet obstruction (EGJOO) turned to a non-obstructive disorder; and 1% of patients with an apparently normal EGJ relaxation, turned to an obstructive disorder. EGJOO according to CCv4.0 was more prevalent in patients referred for dysphagia (11%) than those referred for GERD (4%; p = 0.003)., Conclusions and Inferences: Prolongation of the time spent to complete the CCv4.0 protocol leads to a change in the diagnosis of 12% of patients. Clinically relevant changes are mainly related to the evaluation of EGJOO., (© 2022 John Wiley & Sons Ltd.)

Background/aims: Absent contractility is considered a disorder of peristalsis. The literature about the etiology and clinical characteristics is scarce and the evidence on systemic diseases associated with this esophageal disorder is limited. Therefore, we aimed to determine the etiology of absent contractility in our population using the clinical algorithm recently described in the literature., Methods: We conducted a retrospective, descriptive study at a single tertiary hospital of all patients diagnosed of absent contractility between May 2018 and February 2020. Data on demographic characteristics, medication, comorbidities, and laboratory and paraclinical tests were recorded from clinical records., Results: A total of 72 patients with absent contractility were included for analysis. There was a predominance of female sex (n=43, 59.7%), with a mean age of 55.4 (±15.0) years. We identified a systemic disorder associated with absent contractility in 64 (88.9%) patients. From these, 31 (43.1%) patients were diagnosed with a systemic autoimmune disease, 26 (36.1%) patients were considered to have absent contractility secondary to pathological exposure to acid-reflux and 15 (20.8%) patients were diagnosed with other non-autoimmune systemic disorders. In the remaining eight (11.1%) patients, there were no underlying systemic disorders that could justify the diagnosis of absent contractility., Conclusions: A systematic approach to search for an underlying cause in patients diagnosed with absent contractility is warranted. Up to 90% of patients with absent contractility have a systemic disorder associated with this condition., (Copyright © 2022 Elsevier España, S.L.U. All rights reserved.)

Introduction: Minute rhythm and prolonged simultaneous contractions are patterns of postprandial small bowel contractile activity that historically have been considered as suggestive of mechanical intestinal obstruction; however, these patterns have been also encountered in patients with motility-like symptoms in the absence of bowel obstruction. The objective of this study was to determine the current diagnostic outcome of patients with these intestinal manometry patterns., Methods: Retrospective study of patients with chronic digestive symptoms evaluated by intestinal manometry at our center between 2010 and 2018., Results: The minute rhythm (MRP) or prolonged simultaneous contractions (PSC) postprandial patterns were detected in 61 of 488 patients (55 MRP and 6 PSC). Clinical work-up detected a previously non-diagnosed partial mechanical obstruction of the distal intestine in 10 (16%) and a systemic disorder causing intestinal neuropathy in 32 (53%). In the remaining 19 patients (31%, all with MRP), the origin of the contractile pattern was undetermined, but in 16, substantial fecal retention was detected within 7 days of the manometric procedure by abdominal imaging, and in 6 of them colonic cleansing completely normalized intestinal motility on a second manometry performed within 39 ± 30 days., Conclusion and Inference: Currently, the most frequent origin of MRP and PSC encountered on small bowel manometry is intestinal neuropathy, while a previously undetected mechanical obstruction is rare. Still, in a substantial proportion of patients, no underlying disease can be identified, and in them, colonic fecal retention might play a role, because in a subgroup of these patients, manometry normalized after colonic cleansing. Hence, colonic preparation may be considered prior to intestinal manometry., (© 2022 The Authors. Neurogastroenterology & Motility published by John Wiley & Sons Ltd.)

Bioaerosol capture and analysis is emerging as a non-invasive diagnostic method for the detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In this proof-of-concept study conducted in Lesotho, we evaluated the novel and simple AL2 bioaerosol detection device in comparison to conventional nasopharyngeal sampling methods. We demonstrated for the first time that SARS-CoV-2 can be detected using the AL2 bioaerosol capture device. However, studies with a larger sample size are needed to further evaluate this bioaerosol capture device for the detection of SARS-CoV-2., Competing Interests: 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. AL2 Impact and 3M Company provided the bioaerosol capture devices and gave technical advice, but were not involved in data analysis., (© 2022 Published by Elsevier Ltd on behalf of International Society for Infectious Diseases.)

Background: Gastrointestinal bleeding (GIB) is a common adverse event related to anticoagulation therapy. However, evidence comparing the severity, etiology and outcome of GIB in patients taking direct oral anticoagulants (DOAC) vs. vitamin K antagonists (VKA) is scarce., Aims: To evaluate the severity, etiology and outcomes of GIB in patients under DOACs compared to VKA., Methods: Patients under oral anticoagulant therapy admitted to the emergency department with acute GIB were prospectively recruited from July 2016 to January 2018 at a tertiary referral hospital. Demographic and clinical outcome were obtained from medical records. Severity of the GIB event was classified as mild, major or severe according to clinical presentation and the type of support needed. Etiology and location of bleeding, number of packed red blood cells transfused (PRBC) and length of hospital stay were recorded until discharge or in-hospital death., Results: A total of 208 patients with acute GIB under oral anticoagulant treatment were recruited: 119 patients were on VKA and 89 patients on DOAC with similar characteristics. Thirty-one patients had severe GIB; 134 major and 43 mild, with no differences in severity, number of PRBC and length of hospital stay between the groups. Peptic disease was the most frequent etiology of GIB in patients on VKA (20.2 % vs. 13.6%, p=0.20). Diverticular bleeding was the most frequent adverse event in patients on DOAC (14.3% vs. 24.8%, p= 0.056)., Conclusions: Severity and clinical outcomes of GIB are similar between patients on DOAC and patients on VKA, regardless of etiology of GIB.

Two-thirds of patients with mucopolysaccharidosis II (MPS II; Hunter syndrome) have cognitive impairment. This phase 2/3, randomized, controlled, open-label, multicenter study (NCT02055118) investigated the effects of intrathecally administered idursulfase-IT on cognitive function in patients with MPS II. Children older than 3 years with MPS II and mild-to-moderate cognitive impairment (assessed by Differential Ability Scales-II [DAS-II], General Conceptual Ability [GCA] score) who had tolerated intravenous idursulfase for at least 4 months were randomly assigned (2:1) to monthly idursulfase-IT 10 mg (n = 34) via an intrathecal drug delivery device (IDDD; or by lumbar puncture) or no idursulfase-IT treatment (n = 15) for 52 weeks. All patients continued to receive weekly intravenous idursulfase 0.5 mg/kg as standard of care. Of 49 randomized patients, 47 completed the study (two patients receiving idursulfase-IT discontinued). The primary endpoint (change from baseline in DAS-II GCA score at week 52 in a linear mixed-effects model for repeated measures analysis) was not met: although there was a smaller decrease in DAS-II GCA scores with idursulfase-IT than with no idursulfase-IT at week 52, this was not significant (least-squares mean treatment difference [95% confidence interval], 3.0 [-7.3, 13.3]; p = 0.5669). Changes from baseline in Vineland Adaptive Behavioral Scales-II Adaptive Behavior Composite scores at week 52 (key secondary endpoint) were similar in the idursulfase-IT (n = 31) and no idursulfase-IT (n = 14) groups. There were trends towards a potential positive effect of idursulfase-IT across DAS-II composite, cluster, and subtest scores, notably in patients younger than 6 years at baseline. In a post hoc analysis, there was a significant (p = 0.0174), clinically meaningful difference in change from baseline in DAS-II GCA scores at week 52 with idursulfase-IT (n = 13) versus no idursulfase-IT (n = 6) among those younger than 6 years with missense iduronate-2-sulfatase gene variants. Overall, idursulfase-IT reduced cerebrospinal glycosaminoglycan levels from baseline by 72.0% at week 52. Idursulfase-IT was generally well tolerated. These data suggest potential benefits of idursulfase-IT in the treatment of cognitive impairment in some patients with neuronopathic MPS II. After many years of extensive review and regulatory discussions, the data were found to be insufficient to meet the evidentiary standard to support regulatory filings., Competing Interests: Declaration of Competing Interest Joseph Muenzer has received consulting fees/other remuneration from Denali Therapeutics, JCR Pharmaceuticals, REGENXBIO, Sangamo Therapeutics, Sanofi Genzyme, and Takeda (Shire); has participated in advisory boards for BioMarin Pharmaceutical, Denali Therapeutics, JCR Pharmaceuticals, Sanofi Genzyme, and Takeda; and has received research support from BioMarin Pharmaceutical, Denali Therapeutics, and Takeda. Barbara K. Burton has received consulting fees/other remuneration from Alexion Pharmaceuticals, Applied Therapeutics, BioMarin Pharmaceutical, Capsida Biotherapeutics, Denali Therapeutics, Horizon Therapeutics, JCR Pharmaceuticals, Moderna, Passage Bio, Sanofi Genzyme, Sio Gene Therapies, Takeda, and Ultragenyx Pharmaceutical; has participated in advisory boards or similar committees for Alexion Pharmaceuticals, BioMarin Pharmaceutical, and Takeda; and has received research support from Alexion Pharmaceuticals, BioMarin Pharmaceutical, Denali Therapeutics, Homology Medicines, JCR Pharmaceuticals, Sangamo Therapeutics, Takeda, and Ultragenyx Pharmaceutical. Paul Harmatz has received consulting fees/other remuneration from Aeglea, Alexion Pharmaceuticals, ArmaGen, AVROBIO, Audentes, BioMarin Pharmaceutical, Capsida Biotherapeutics, Chiesi, Denali Therapeutics, Enzyvant, Fondazione Telethon, Inventiva Pharma, JCR Pharmaceuticals, Orphazyme, Paradigm, PTC Therapeutics, REGENXBIO, Sangamo Therapeutics, Sanofi Genzyme, Takeda, and Ultragenyx Pharmaceutical; and has received research support from Alexion Pharmaceuticals, ArmaGen, BioMarin Pharmaceutical, Denali Therapeutics, Enzyvant, Inventiva Pharma, JCR Pharmaceuticals, Orphazyme, QED Therapeutics, REGENXBIO, Sangamo Therapeutics, Swedish Orphan Biovitrum, Takeda, and Ultragenyx Pharmaceutical. Luis González Gutiérrez-Solana has received consulting fees/other remuneration from BioMarin Pharmaceutical, Sanofi Genzyme, Takeda, and Ultragenyx Pharmaceutical; and has received research support from Takeda. Matilde Ruiz-Garcia has received consulting fees/other remuneration and research support from Takeda. Simon A. Jones has received consulting fees/other remuneration from Alexion Pharmaceuticals, AVROBIO, BioMarin Pharmaceutical, Denali Therapeutics, Orchard Therapeutics, REGENXBIO, Sanofi Genzyme, Takeda, and Ultragenyx Pharmaceutical; and has received research support from Takeda. Nathalie Guffon has received research support from BioMarin Pharmaceutical, Chiesi, Sanofi Genzyme, Takeda, and Ultragenyx Pharmaceutical. Michal Inbar-Feigenberg has received consulting fees from Takeda; has participated in advisory boards for Sanofi Genzyme, Takeda, and Ultragenyx Pharmaceutical; is a member of the medical advisory board for the Canadian MPS Society and Allied Diseases; is Chair of the Garrod Association Guideline Committee; and has received research support from the Canadian Institute for Health Research, Sanofi Genzyme, Takeda, and Ultragenyx Pharmaceutical. Drago Bratkovic has received research support from Takeda. Michael Hale was an employee of Takeda Development Center Americas, Inc. at the time of this study, and is a stockholder of Takeda Pharmaceuticals Company Limited. Yuna Wu is an employee of Takeda Development Center Americas, Inc.; and is a stockholder of Takeda Pharmaceuticals Company Limited. Karen S. Yee is an employee of Takeda Development Center Americas, Inc.; a stockholder of Takeda Pharmaceuticals Company Limited, and is an unpaid member of the Critical Path Institute PRO consortium and Rare Disease COA consortium, sponsored by Takeda. David A.H. Whiteman is an employee of Takeda Development Center Americas, Inc. and a stockholder of Takeda Pharmaceuticals Company Limited. David Alexanderian was an employee of Takeda Development Center Americas, Inc. at the time of this study and of the writing of the manuscript, and is a stockholder of Takeda Pharmaceuticals Company Limited., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Enzyme replacement therapy with weekly infused intravenous (IV) idursulfase is effective in treating somatic symptoms of mucopolysaccharidosis II (MPS II; Hunter syndrome). A formulation of idursulfase for intrathecal administration (idursulfase-IT) is under investigation for the treatment of neuronopathic MPS II. Here, we report 36-month data from the open-label extension (NCT02412787) of a phase 2/3, randomized, controlled study (HGT-HIT-094; NCT02055118) that assessed the safety and efficacy of monthly idursulfase-IT 10 mg in addition to weekly IV idursulfase on cognitive function in children older than 3 years with MPS II and mild-to-moderate cognitive impairment. Participants were also enrolled in this extension from a linked non-randomized sub-study of children younger than 3 years at the start of idursulfase-IT therapy. The extension safety population comprised 56 patients who received idursulfase-IT 10 mg once a month (or age-adjusted dose for sub-study patients) plus IV idursulfase (0.5 mg/kg) once a week. Idursulfase-IT was generally well tolerated over the cumulative treatment period of up to 36 months. Overall, 25.0% of patients had at least one adverse event (AE) related to idursulfase-IT; most treatment-emergent AEs were mild in severity. Of serious AEs (reported by 76.8% patients), none were considered related to idursulfase-IT treatment. There were no deaths or discontinuations owing to AEs. Secondary efficacy analyses (in patients younger than 6 years at phase 2/3 study baseline; n = 40) indicated a trend for improved Differential Ability Scale-II (DAS-II) General Conceptual Ability (GCA) scores in the early idursulfase-IT versus delayed idursulfase-IT group (treatment difference over 36 months from phase 2/3 study baseline: least-squares mean, 6.8 [90% confidence interval: -2.1, 15.8; p = 0.2064]). Post hoc analyses of DAS-II GCA scores by genotype revealed a clinically meaningful treatment effect in patients younger than 6 years with missense variants of the iduronate-2-sulfatase gene (IDS) (least-squares mean [standard error] treatment difference over 36 months, 12.3 [7.24]). These long-term data further suggest the benefits of idursulfase-IT in the treatment of neurocognitive dysfunction in some patients with MPS II. After many years of extensive review and regulatory discussions, the data were found to be insufficient to meet the evidentiary standard to support regulatory filings., Competing Interests: Declaration of Competing Interest Joseph Muenzer has received consulting fees/other remuneration from Denali Therapeutics, JCR Pharmaceuticals, REGENXBIO, Sangamo Therapeutics, Sanofi Genzyme, and Takeda (Shire); has participated in advisory boards for BioMarin Pharmaceutical, Denali Therapeutics, JCR Pharmaceuticals, Sanofi Genzyme, and Takeda; and has received research support from BioMarin Pharmaceutical, Denali Therapeutics, and Takeda. Barbara K. Burton has received consulting fees/other remuneration from Alexion Pharmaceuticals, Applied Therapeutics, BioMarin Pharmaceutical, Capsida Biotherapeutics, Denali Therapeutics, Horizon Therapeutics, JCR Pharmaceuticals, Moderna, Passage Bio, Sanofi Genzyme, Sio Gene Therapies, Takeda, and Ultragenyx Pharmaceutical; has participated in advisory boards or similar committees for Alexion Pharmaceuticals, BioMarin Pharmaceutical, and Takeda; and has received research support from Alexion Pharmaceuticals, BioMarin Pharmaceutical, Denali Therapeutics, Homology Medicines, JCR Pharmaceuticals, Sangamo Therapeutics, Takeda, and Ultragenyx Pharmaceutical. Paul Harmatz has received consulting fees/other remuneration from Aeglea, Alexion Pharmaceuticals, ArmaGen, AVROBIO, Audentes, BioMarin Pharmaceutical, Capsida Biotherapeutics, Chiesi, Denali Therapeutics, Enzyvant, Fondazione Telethon, Inventiva Pharma, JCR Pharmaceuticals, Orphazyme, Paradigm, PTC Therapeutics, REGENXBIO, Sangamo Therapeutics, Sanofi Genzyme, Takeda, and Ultragenyx Pharmaceutical; and has received research support from Alexion Pharmaceuticals, ArmaGen, BioMarin Pharmaceutical, Denali Therapeutics, Enzyvant, Inventiva Pharma, JCR Pharmaceuticals, Orphazyme, QED Therapeutics, REGENXBIO, Sangamo Therapeutics, Swedish Orphan Biovitrum, Takeda, and Ultragenyx Pharmaceutical. Luis González Gutiérrez-Solana has received consulting fees/other remuneration from BioMarin Pharmaceutical, Sanofi Genzyme, Takeda, and Ultragenyx Pharmaceutical; and has received research support from Takeda. Matilde Ruiz-Garcia has received consulting fees/other remuneration and research support from Takeda. Simon A. Jones has received consulting fees/other remuneration from Alexion Pharmaceuticals, AVROBIO, BioMarin Pharmaceutical, Denali Therapeutics, Orchard Therapeutics, REGENXBIO, Sanofi Genzyme, Takeda, and Ultragenyx Pharmaceutical; has participated in advisory boards or similar committees for Takeda; and has received research support from Takeda. Nathalie Guffon has received research support from BioMarin Pharmaceutical, Chiesi, Sanofi Genzyme, Takeda, and Ultragenyx Pharmaceutical. Michal Inbar-Feigenberg has received consulting fees from Takeda; has participated in advisory boards for Sanofi Genzyme, Takeda, and Ultragenyx Pharmaceutical; is a member of the medical advisory board for the Canadian MPS Society and Allied Diseases; is Chair of the Garrod Association Guideline Committee; and has received research support from the Canadian Institute for Health Research, Sanofi Genzyme, Takeda, and Ultragenyx Pharmaceutical. Drago Bratkovic has received research support from Takeda. Michael Hale was an employee of Takeda Development Center Americas, Inc. at the time of this study. Yuna Wu is an employee of Takeda Development Center Americas, Inc.; is a stockholder of Takeda Pharmaceuticals Company Limited; and is an unpaid member of the Critical Path Institute PRO consortium and Rare Disease COA consortium, sponsored by Takeda. Karen S. Yee is an employee of Takeda Development Center Americas, Inc. and a stockholder of Takeda Pharmaceuticals Company Limited. David A.H. Whiteman is an employee of Takeda Development Center Americas, Inc. and a stockholder of Takeda Pharmaceuticals Company Limited. David Alexanderian was an employee of Takeda Development Center Americas, Inc. at the time of this study and the writing of the manuscript, and is a stockholder of Takeda Pharmaceuticals Company Limited., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Colorectal cancer (CRC) is one of the most lethal cancers worldwide. If detected on time, surgery can expand life expectations of patients up to five more years. However, if metastasis has grown deliberately, the use of chemotherapy can play a crucial role in CRC control. Moreover, the lack of selectivity of current anticancer drugs, plus mutations that occur in cancerous cells, demands the development of new chemotherapeutic agents. Several steroids have shown their potentiality as anticancer agents, while some other compounds, such as Taxol and its derivatives bearing a carbamate functionality, have reached the market. In this article, the synthesis, characterization, and antiproliferative activity of four steroidal carbamates on mouse colon carcinoma CT26WT cells are described. Carbamate synthesis occurred via direct reaction between diosgenin, its B-ring modified derivative, and testosterone with phenyl isocyanate under a Brønsted acid catalysis. All obtained compounds were characterized by 1 H and 13 C Nuclear Magnetic Resonance (NMR), High Resolution Mass Spectroscopy (HRMS); their melting points are also reported. Results obtained from antiproliferative activity assays indicated that carbamates compounds have inhibitory effects on the growth of this colon cancer cell line. A molecular docking study carried out on Human Prostaglandin E Receptor (EP4) showed a high affinity between carbamates and protein, thus providing a valuable theoretical explanation of the in vitro results.

Malaria is an infectious illness, affecting vulnerable populations in Third World countries. Inspired by natural products, indole alkaloids have been used as a nucleus to design new antimalarial drugs. So, eighteen oxindole derivatives, aza analogues were obtained with moderate to excellent yields. Also, the saturated derivatives of oxindole and aza derivatives via H 2 /Pd/C reduction were obtained in good yields, leading to racemic mixtures of each compound. Next, the inhibitory activity against P. falciparum of 18 compounds were tested, founding six compounds with IC 50 < 20 µM. The most active of these compounds was 8c ; however, their unsaturated derivative 7c was inactive. Then, a structure-activity relationship analysis was done, founding that focused LUMO lobe on the specific molecular zone is related to inhibitory activity against P. falciparum . Finally, we found a potential inhibition of lactate dehydrogenase by oxindole derivatives, using molecular docking virtual screening.

Background: Arterial hypertension (aHT) is the leading cardiovascular disease (CVD) risk factor in sub-Saharan Africa; it remains, however, underdiagnosed, and undertreated. Community-based care services could potentially expand access to aHT diagnosis and treatment in underserved communities. In this scoping review, we catalogued, described, and appraised community-based care models for aHT in sub-Saharan Africa, considering their acceptability, engagement in care and clinical outcomes. Additionally, we developed a framework to design and describe service delivery models for long-term aHT care., Methods: We searched relevant references in Embase Elsevier, MEDLINE Ovid, CINAHL EBSCOhost and Scopus. Included studies described models where substantial care occurred outside a formal health facility and reported on acceptability, blood pressure (BP) control, engagement in care, or end-organ damage. We summarized the interventions' characteristics, effectiveness, and evaluated the quality of included studies. Considering the common integrating elements of aHT care services, we conceptualized a general framework to guide the design of service models for aHT., Results: We identified 18,695 records, screened 4,954 and included twelve studies. Four types of aHT care models were identified: services provided at community pharmacies, out-of-facility, household services, and aHT treatment groups. Two studies reported on acceptability, eleven on BP control, ten on engagement in care and one on end-organ damage. Most studies reported significant reductions in BP values and improved access to comprehensive CVDs services through task-sharing. Major reported shortcomings included high attrition rates and their nature as parallel, non-integrated models of care. The overall quality of the studies was low, with high risk of bias, and most of the studies did not include comparisons with routine facility-based care., Conclusions: The overall quality of available evidence on community-based aHT care is low. Published models of care are very heterogeneous and available evidence is insufficient to recommend or refute further scale up in sub-Sahara Africa. We propose that future projects and studies implementing and assessing community-based models for aHT care are designed and described according to six building blocks: providers, target groups, components, location, time of service delivery, and their use of information systems., (© 2022. The Author(s).)

Background: prescription opioid use is on the rise. There has been an increasing recognition that chronic opioid consumption can result in esophageal motility disorders, and this association has been named opioid-induced esophageal dysfunction (OIED)., Aims: to analyze the prevalence of chronic opioid consumption in patients referred for esophageal motility testing in a European center; to describe the clinical characteristics and the association of opioid consumption with esophageal motility disorders., Methods: a retrospective, descriptive study in patients who had undergone an HRM in a single center. The clinical history in the electronic medical records was reviewed., Results: the prevalence of opioid prescription in patients referred to our institution was 10.1 %, and 4.8 % of them were chronic active opioid users. There was a 32 % prevalence of OIED. Comparing chronic active opioid users (CAOU) with OIED and CAOU patients without OIED, there was a higher prevalence of males (43.8 % vs 8.8 %; p-value = 0.007). Converting the different opioid medications to morphine milligram equivalent daily dose (MMED), CAOU patients with OIED had a higher MMED than CAOU patients without OIED (125.2 ± 31.3 vs 33.4 ± 5.7 MME; p = 0.041). Dysphagia was the most common indication for performing an HRM in 60.0 % of CAOU patients. Furthermore, dysphagia was more frequent in CAOU patients with OIED (87.5 % vs 47.0 %; p = 0.019)., Conclusions: chronic opioid users with OIED complained mostly of dysphagia. There was an association of male sex and a higher dose of opioids in CAOU patients with esophageal motility disorders.

Clubroot, caused by Plasmodiophora brassicae Woronin, is a significant threat to the canola ( Brassica napus L.) industry in Canada. Clubroot resistance has been overcome in more than 200 fields since 2013, representing one of the biggest challenges to sustainable canola production. The genetic structure of 36 single-spore isolates derived from 12 field isolates of P. brassicae collected before and after the introduction of clubroot resistant (CR) canola cultivars (2005-2014) was evaluated by simple sequence repeat (SSR) marker analysis. Polymorphisms were detected in 32 loci with the identification of 93 distinct alleles. A low level of genetic diversity was found among the single-spore isolates. Haploid linkage disequilibrium and number of migrants suggested that recombination and migration were rare or almost absent in the tested P. brassicae population. A relatively clear relationship was found between the genetic structure and virulence phenotypes of the pathogen as defined on the differential hosts of Somé et al., Williams, and the Canadian Clubroot Differential (CCD) set. Although genetic variability within each pathotype group, as classified on each differential system, was low, significant genetic differentiation was observed among the pathotypes. The highest correlation between genetic structure and virulence was found among matrices produced with genetic data and the hosts of the CCD set, with a threshold index of disease of 50% to distinguish susceptible from resistant reactions. Genetically homogeneous single-spore isolates provided a more complete and clearer picture of the population genetic structure of P. brassicae , and the results suggest some promise for the development of pathotype-specific primers.

Background: The objective of this study was to describe the most common medical complications in simultaneous pancreas-kidney recipients in our center., Methods: Retrospective and descriptive study of complications observed in a series of 73 simultaneous pancreas-kidney transplant recipients, which included 54 men and 19 women with an average age of 40.6 years, between February 2009 and April 2019. The study assessed the incidence of cytopenia, viral infections, tumors, and graft rejection. Frequency tables were created for each complication in the analysis., Results: Cytopenia was the most common complication, either by itself or associated with a different complication, and it was found in 23.3% of all patients. The most common infection was cytomegalovirus, which was in 55.6% of all 9 patients who presented infections in spite of universal prophylaxis with valganciclovir, followed by herpes virus (11.1%), papillomavirus (11.1%), and polyoma BK virus (22.2%). Regarding tumors, the number of patients who presented this complication was low; 2 gynecologic tumors were detected (cervical intracellular neoplasia and one ovarian tumor), and 1 case of skin tumor was also observed. There were 3 cases of acute rejection, which represents 4.1% of all patients. Rejection was cellular and steroid-sensitive except for 1 case that was humoral, with good response to treatment., Conclusions: In spite of the doses of immunosuppressive drugs received by these patients, the incidence of infections was low, and cytomegalovirus was the most common infection. As a consequence of the drugs administered, virtually all patients developed cytopenia. The number of tumors observed in this series was low in spite of the immunosuppressive treatment., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Introduction: Obesity is a chronic disease associated with other comorbidities, including atherogenic dyslipidemia (AD). Bariatric surgery (BS) has shown to reduce cardiovascular risk (CVR) by achieving a significant weight reduction and improving the lipid profile. Different surgical techniques may have a different effect on the lipoprotein profile., Purpose: To evaluate the lipid profile at 3 years after BS according to the surgical technique used and to determine which variables predict variation in the lipid profile at 3 years after BS., Methods: Retrospective observational study of 206 patients who underwent BS between 2010 and 2019. We analyzed the variation of lipid parameters in the 3 years of follow-up according to the surgical technique, including a group analysis of patients according to whether they had dyslipidemia and whether they were treated or untreated and determined which variables predict variation in the lipid profile at 3 years after BS., Results: There was a significant increase in high-density lipoprotein cholesterol (HDL-c) with sleeve gastrectomy (SG) and a significant decrease in total cholesterol (TC), LDL-cholesterol (LDL-c), non-HDL, and LDL/non-HDL with biliopancreatic diversion (BPD). Variables predicting lipid profile variation were surgical technique and pre-surgery lipoprotein level., Conclusions: Malabsorptive techniques achieve a greater decrease in TC and LDL-c throughout follow-up and could also improve residual cardiovascular risk (non-HDL and LDL/non-HDL). The type of surgical technique and the presurgery lipid profile predict variation after 3 years of BS., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: The high incidence of idiopathic scoliosis worldwide as well as the serious health problems it can cause in adulthood, make it necessary to seek effective treatments to prevent the progression of the disease to more aggressive treatments such as surgery and improve patients' quality of life. The use of night braces, besides a less severe influence on the patient's quality of life, is effective in stopping the progression of the curve in idiopathic scoliosis., Methods: A longitudinal study was performed with an experimental population of 108 participants who attended orthotic treatment at the University Hospital of Barcelona, with ages between 4 and 15 years old, with a main curvature greater than 25 degrees and a Risser between 0 and 3. The participants received treatment with Providence ISJ-3D night braces until their pubertal change (mean duration of 2.78 years for males and 1.97 years for females)., Results: The implementation of night-time orthotic treatment in children with idiopathic scoliosis is effective in slowing the progression of the curve and in the prevention of more aggressive treatments such as surgery, maintaining the patient's quality of life., Conclusions: The use of night braces is efficacious in the treatment of idiopathic scoliosis, although new studies including more sociodemographic data as well as curves from 20 degrees of progression are necessary.

Chagas disease causes more deaths in the Americas than any other parasitic disease. Initially confined to the American continent, it is increasingly becoming a global health problem. In fact, it is considered to be an "exotic" disease in Europe, being virtually undiagnosed. Benznidazole, the only drug approved for treatment, effectively treats acute-stage Chagas disease, but its effectiveness for treating indeterminate and chronic stages remains uncertain. Previously, our research group demonstrated that 4-thiazolidinones presented anti-T. cruzi activity including in the in vivo assays in mice, making this fragment appealing for drug development. The present work reports the synthesis and anti-T. cruzi activities of a novel series of 4-thiazolidinones derivatives that resulted in an increased anti-T. cruzi activity in comparison to thiosemicarbazones intermediates. Compounds 2c, 2e, and 3a showed potent inhibition of the trypomastigote form of the parasite at low cytotoxicity concentrations in mouse splenocytes. Besides, all the 2c, 2e, and 3a tested concentrations showed no cytotoxic activity on macrophages cell viability. When macrophages were submitted to T. cruzi infection and treated with 2c and 3a, compounds reduced the release of trypomastigote forms. Results also showed that the increased trypanocidal activity induced by 2c and 3a is independent of nitric oxide release. Flow cytometry assay showed that compound 2e was able to induce necrosis and apoptosis in trypomastigotes. Parasites treated with the compounds 2e, 3a, and 3c presented flagellum shortening, retraction and curvature of the parasite body, and extravasation of the internal content. Together, these data revealed a novel series of 4-thiazolidinones fragment-based compounds with potential effects against T. cruzi and lead-like characteristics., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Patients with Prader-Willi syndrome (PWS) often have comorbidities, especially obesity, that may constitute a risk factor for severe forms of COVID-19. We aimed to assess prevalence and medical course of SARS-CoV-2 infection in children and adults with PWS. From November 2020 to January 2021, we performed a detailed medical survey on 342 adults and 305 children with PWS followed in the French reference center., Results: We obtained responses from 288 adults (84%) and 239 children (78%). From March 2020 to January 2021, 38 adults (13.2%) and 13 children (5.4%) with PWS had SARS-CoV-2 infection. Mean age of adults was 34.1 ± 11.9 years and mean body mass index was 40.6 ± 12.7 kg/m 2 ; 82% had obesity and 37% had diabetes. Only 3 children (23%) had obesity and none had diabetes. Similar to the general population, the most frequent symptoms of COVID-19 were asthenia, fever, cough, headache and shortness of breath. All patients had a favorable outcome., Conclusion: PWS itself is not a risk factor for severe COVID-19 in children and adults. On the contrary, evolution of SARS-CoV-2 infection in adults with PWS seems more favorable than expected, given their comorbidities., (© 2021. The Author(s).)

The aim of this study was to evaluate the efficacy and safety of outpatient antimicrobial therapy with piperacillin-tazobactam in continuous infusion using elastomeric pumps and to evaluate the economic impact compared with conventional hospital treatment in patients with Pseudomonas aeruginosa (PA) infections. This is an observational study. Patients with PA infection treated with continuous piperacillin-tazobactam infusion using elastomeric pumps in our hospital between January 2015 and December 2017 were included. Primary outcomes were mortality during antibiotic treatment and mortality at 30 days. Secondary outcomes were reinfection or relapse at 30 days and clinical cure rate. The cost of each episode was compared with theoretical cost of the same treatment using conventional hospitalization. 35 patients were included. One patient (2.9%) died during the treatment. Overall 30-day mortality was 5.7%. No death was related to infection by PA. One patient (2.9%) had a reinfection at 30 days. Cure was achieved in 93% of patients at the end of treatment. There were no severe complications related to elastomeric pumps. Treatment cost with outpatient antimicrobial therapy was 67% lower than theoretical cost with conventional hospital treatment. Oupatient antimicrobial therapy with piperacillin-tazobactam in continuous infusion using elastomeric pumps in patients with PA infections is safe and effective with lower costs.

Among the different biomarkers predicting response in chronic lymphocytic leukemia (CLL), the most influential parameters are the mutational status of the IGHV genes and the presence of TP53 gene disruptions. Nevertheless, these important assessments are not readily available in most centers dealing with CLL patients. To provide this molecular testing across the country, the Spanish Cooperative Group on CLL (GELLC) established a network of four analytical reference centers. A total of 2153 samples from 256 centers were analyzed over a period of 30 months. In 9% of the patients, we found pathological mutations in the TP53 gene, whereas 48.96% were classified as IGHV unmutated. Results of the satisfaction survey of the program showed a Net Promoter Score of 85.15. Building a national network for molecular testing in CLL allowed the CLL population a broad access to complex biomarkers analysis that should translate into a more accurate and informed therapeutic decision-making.

Background: Little is known about radiofrequency electromagnetic fields (RF) from mobile technology and resulting dose in young people. We describe modeled integrated RF dose in European children and adolescents combining own mobile device use and surrounding sources., Methods: Using an integrated RF model, we estimated the daily RF dose in the brain (whole-brain, cerebellum, frontal lobe, midbrain, occipital lobe, parietal lobe, temporal lobes) and the whole-body in 8358 children (ages 8-12) and adolescents (ages 14-18) from the Netherlands, Spain, and Switzerland during 2012-2016. The integrated model estimated RF dose from near-field sources (digital enhanced communication technology (DECT) phone, mobile phone, tablet, and laptop) and far-field sources (mobile phone base stations via 3D-radiowave modeling or RF measurements)., Results: Adolescents were more frequent mobile phone users and experienced higher modeled RF doses in the whole-brain (median 330.4 mJ/kg/day) compared to children (median 81.8 mJ/kg/day). Children spent more time using tablets or laptops compared to adolescents, resulting in higher RF doses in the whole-body (median whole-body dose of 81.8 mJ/kg/day) compared to adolescents (41.9 mJ/kg/day). Among brain regions, temporal lobes received the highest RF dose (medians of 274.9 and 1786.5 mJ/kg/day in children and adolescents, respectively) followed by the frontal lobe. In most children and adolescents, calling on 2G networks was the main contributor to RF dose in the whole-brain (medians of 31.1 and 273.7 mJ/kg/day, respectively)., Conclusion: This first large study of RF dose to the brain and body of children and adolescents shows that mobile phone calls on 2G networks are the main determinants of brain dose, especially in temporal and frontal lobes, whereas whole-body doses were mostly determined by tablet and laptop use. The modeling of RF doses provides valuable input to epidemiological research and to potential risk management regarding RF exposure in young people., (Copyright © 2020. Published by Elsevier Inc.)

Aims: The aims of this study were (a) to know the kinetics of antitumor necrosis factor (TNF) drug serum levels during the induction phase in patients with Crohn's disease; (b) to identify variables associated with these levels; and (c) to assess the relation between these levels and short-term effectiveness in Crohn's disease patients., Methods: Patients with Crohn's disease naïve to anti-TNF treatment were prospectively included. Remission was defined as a Crohn's disease activity index (CDAI) score <150 after 14 weeks of treatment. Blood samples were obtained at baseline and at weeks 4, 8, and 14. Adalimumab and infliximab levels were measured, receiver operating characteristic (ROC) curves were constructed, and the area under the ROC curve was calculated., Results: One-hundred fifty patients with Crohn's disease were included, 79 (53%) received infliximab and 71 (47%) had CDAI > 150 at study entry. At week 14, 52 out of 71 patients with CDAI > 150 at baseline (73%) had clinical remission. There were no differences in infliximab levels between patients with and without remission (8 vs. 9.1 μg/mL, P > 0.05) or with and without response (7 vs. 11 μg/mL, P > 0.05) at week 14. There was a trend to higher levels of adalimumab concentration in responders in comparison with nonresponders (13 vs. 6.7 μg/mL, P = 0.05) and in patients who achieved remission in comparison with nonremitters (13.5 vs. 8.4 μg/mL, P = 0.06). In the multivariate analysis, no variable was predictive of short-term remission, including infliximab and adalimumab serum levels., Conclusion: Determining anti-TNF serum levels during the induction phase is not useful for predicting short-term remission in patients with Crohn's disease.

Niemann-Pick type C (NP-C) disease is a neurovisceral atypical lysosomal lipid storage disorder with a poor prognosis. We present the 5-year neuropsychological follow-up of a patient with juvenile onset NP-C, spanning the pre-diagnostic stage to the period after treatment with miglustat (Actelion Pharmaceuticals Inc., CA, US). In the initial stages of the disease, the patient presented behavioral dysexecutive symptoms resembling those frequently observed in adult-onset forms and frontotemporal dementia, which frequently makes early diagnosis difficult in children. After 4 years of treatment, the impaired cognitive function and behavioral dysexecutive syndrome had been completely reversed. The variability of NP-C disease makes early diagnosis challenging. Evaluations of long-term neuropsychological development can help diagnose this neurodegenerative disease and document its progression.