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Prolyl endopeptidase-like (PREPL) deficiency (MIM#616224) is a rare congenital disorder characterised by neonatal hypotonia and feeding difficulties, growth hormone (GH) deficiency and hypergonadotropic hypogonadism. This syndrome is an autosomal recessive disease resulting from mutations in the PREPL gene (MIM#609557). Herein we report a 7-year-old female patient with biallelic mutations in PREPL (c.1528C>T in one allele and a whole gene deletion in the other) with early growth impairment in infancy. Growth hormone deficiency was confirmed at 20 months of life. Recombinant growth hormone treatment was introduced with a good response. Her clinical features were similar to those of previously reported cases. The description of new patients with PREPL deficiency syndrome is essential to better delineate the phenotypic and genotypic spectrum of the disease.

Left ventricular noncompaction (LVNC) is a heterogeneous entity with uncertain prognosis. This study sought to develop and validate a prediction model of major adverse cardiovascular events (MACE) and to identify LVNC cases without events during long-term follow-up. This is a retrospective longitudinal multicenter cohort study of consecutive patients fulfilling LVNC criteria by echocardiography or cardiovascular magnetic resonance. MACE were defined as heart failure (HF), ventricular arrhythmias (VAs), systemic embolisms, or all-cause mortality. A total of 585 patients were included (45 ± 20 years of age, 57% male). LV ejection fraction (LVEF) was 48% ± 17%, and 18% presented late gadolinium enhancement (LGE). After a median follow-up of 5.1 years, MACE occurred in 223 (38%) patients: HF in 110 (19%), VAs in 87 (15%), systemic embolisms in 18 (3%), and 34 (6%) died. LVEF was the main variable independently associated with MACE (P < 0.05). LGE was associated with HF and VAs in patients with LVEF >35% (P < 0.05). A prediction model of MACE was developed using Cox regression, composed by age, sex, electrocardiography, cardiovascular risk factors, LVEF, and family aggregation. C-index was 0.72 (95% confidence interval: 0.67-0.75) in the derivation cohort and 0.72 (95% confidence interval: 0.71-0.73) in an external validation cohort. Patients with no electrocardiogram abnormalities, LVEF ≥50%, no LGE, and negative family screening presented no MACE at follow-up. LVNC is associated with an increased risk of heart failure and ventricular arrhythmias. LVEF is the variable most strongly associated with MACE; however, LGE confers additional risk in patients without severe systolic dysfunction. A risk prediction model is developed and validated to guide management. The project was partially funded by a grant from the Catalan Society of Cardiology (Barcelona, Spain). Hospital Universitario Virgen de la Arrixaca (Murcia, Spain) was supported by a grant from the Foundation Marató TV3 (218/C/2015) (Barcelona, Spain). Hospital Universitario y Politécnico La Fe (Valencia, Spain) was partially supported by Fondo Europeo de Desarrollo Regional (“Unión Europea, Una forma de hacer Europa”) (Madrid, Spain) and the Instituto de Salud Carlos III (La Fe Biobank PT17/0015/ 0043) (Madrid, Spain). Dr Guala was supported by funding from the Spanish Ministry of Science, Innovation and Universities (IJC2018-037349-I) (Madrid, Spain). Dr La Mura was supported by a research grant from the Cardiopath PhD program (Naples, Italy). Prof de la Pompa was supported by grants PID2019-104776RB-I00 and CB16/11/00399 (CIBER CV) from the Spanish Ministry of Science, Innovation and Universities. Dr Bayes-Genis was supported by grants from CIBER Cardiovascular (CB16/11/00403 and 16/11/00420) (Madrid, Spain) and AdvanceCat 2014-2020 (Barcelona, Spain); and has received advisory board and lecture fees from Novartis, Boehringer Ingelheim, Vifor, Roche Diagnostics, and Critical Diagnostics. Dr Pontone has received speaker honorarium and/or institutional research grants from GE Healthcare, Bracco, Boehringer Ingelheim, and HeartFlow. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Sí

© The Authors., Given its myeloid-restricted expression, myeloperoxidase (MPO) is typically used for lineage assignment (myeloid vs. lymphoid) during acute leukaemia (AL) diagnostics. In the present study, a robust flow cytometric definition for MPO positivity was established based on the standardised EuroFlow protocols, the standardised Acute Leukaemia Orientation Tube and 1734 multicentre AL cases (with confirmed assay stability). The best diagnostic performance was achieved by defining MPO positivity as ≥20% of the AL cells exceeding a lymphocyte-based threshold. The methodology employed should be applicable to any form of standardised flow cytometry., The co-ordination of this study was supported by the EuroFlow Consortium. The EuroFlow Consortium received support from the FP6-2004-LIFESCIHEALTH-5 programme of the European Commission (grant LSHB-CT-2006-018708) as Specific Targeted Research Project (STREP). The EuroFlow Consortium is part of the European Scientific Foundation for Hemato-Oncology (ESLHO), a Scientific Working Group (SWG) of the European Hematology Association (EHA).

BackgroundA proportion of de novo variants in patients affected by genetic disorders, particularly those with autosomal dominant (AD) inheritance, could be the consequence of somatic mosaicism in one of the progenitors. There is growing evidence that germline and somatic mosaicism are more common and play a greater role in genetic disorders than previously acknowledged. In Marfan syndrome (MFS), caused by pathogenic variants in the fibrillin-1 gene (FBN1) gene, approximately 25% of the disease-causing variants are reported as de novo. Only a few cases of parental mosaicism have been reported in MFS.MethodsEmploying an amplicon-based deep sequencing (ADS) method, we carried out a systematic analysis of 60 parents of 30 FBN1 positive, consecutive patients with MFS with an apparently de novo pathogenic variant.ResultsOut of the 60 parents studied (30 families), the majority (n=51, 85%) had a systemic score of 0, seven had a score of 1 and two a score of 2, all due to minor criteria common in the normal population. We detected two families with somatic mosaicism in one of the progenitors, with a rate of 6.6% (2/30) of apparently de novo cases.ConclusionsThe search for parental somatic mosaicism should be routinely implemented in de novo cases of MFS, to offer appropriate genetic and reproductive counselling as well as to reveal masked, isolated clinical signs of MFS in progenitors that may require specific follow-up.

[Purpose] To determine whether the development of levodopa-induced dyskinesia (LID) in Parkinson disease (PD) specifically relates to dopaminergic depletion in sensorimotor-related subregions of the striatum., [Methods] Our primary study sample consisted of 185 locally recruited PD patients, of which 73 (40%) developed LID. Retrospective 123I-FP-CIT SPECT data were used to quantify the specific dopamine transporter (DAT) binding ratio within distinct functionally defined striatal subregions related to limbic, executive, and sensorimotor systems. Regional DAT levels were contrasted between patients who developed LID (PD + LID) and those who did not (PD-LID) using analysis of covariance models controlled for demographic and clinical features. For validation of the findings and assessment of the evolution of LID-associated DAT changes from an early disease stage, we also studied serial 123I-FP-CIT SPECT data from 343 de novo PD patients enrolled in the Parkinson Progression Marker’s Initiative using mixed linear model analysis., [Results] Compared with PD-LID, DAT level reductions in PD + LID patients were most pronounced in the sensorimotor striatal subregion (F = 5.99, P = 0.016) and also significant in the executive-related subregion (F = 5.30, P = 0.023). In the Parkinson Progression Marker’s Initiative cohort, DAT levels in PD + LID (n = 161, 47%) were only significantly reduced compared with PD-LID in the sensorimotor striatal subregion (t = −2.05, P = 0.041), and this difference was already present at baseline and remained largely constant over time., [Conclusion] Measuring DAT depletion in functionally defined sensorimotor-related striatal regions of interest may provide a more sensitive tool to detect LID-associated dopaminergic changes at an early disease stage and could improve individual prognosis of this common clinical complication in PD.

Introduction: Contralateral axillary lymph node metastasis (CAM) is a rare clinical condition in patients with breast cancer. It can be explained from hematogenous spread from the original primary tumor (stage IV) to aberrant regional lymphatic drainage to the contralateral axilla. However, according to the current clinical guidelines, regardless of its origin, CAM is considered as metastatic disease. Case Presentation: A 68-year-old woman presented with relapsed right breast cancer; lymphoscintigraphy showed only one sentinel lymph node (SLN) in the contralateral axilla (left region). Twenty-four hours later, the patient underwent upper internal quadrantectomy and bilateral selective lymph node biopsy. The final pathological analysis revealed one contralateral macrometastasis (>4 mm) in one left SLN. Subsequently, second-level left lymphadenectomy was performed. Currently the patient is being treated with chemotherapy, with appropriate clinical response. Discussion: Our patient was considered to be node-positive rather than having metastatic disease since the preoperative lymphoscintigraphy demonstrated contralateral lymphatic drainage. Through preoperative scan in patients with relapsed breast cancer with clinically negative lymph nodes and CAM, it is possible to identify those cases that would benefit from therapy with curative intention.

This work was supported by project grants of Gobierno de Espana (PSI2017-83893-R and PSI2017-90806-REDT) and Programa "Severo Ochoa" CONSEJERIA DE CULTURA Y DEPORTE del Principado de Asturias (PA-17-PF BP16090) to C. F-B. The authors thank "Asociacion Parkinson Asturias" and "Fundacion AINDACE" (Ayuda a la Investigacion del Dano y Enfermedades Cerebrales) for their collaboration. Also, they express their sincere thanks to all the therapists, patients, and their families for their cooperation.

Cerebellofaciodental syndrome (MIM #616202) is an autosomal recessive condition characterized by intellectual disability, microcephaly, cerebellar hypoplasia, dysmorphic features, and short stature. To date, eight patients carrying biallelic BRF1 variants have been reported. Here, we describe two siblings with congenital microcephaly and corpus callosum hypoplasia, pre and postnatal growth retardation, congenital heart defect and severe global developmental delay. We also detected additional findings not previously reported in this syndrome, including bilateral sensorineural hearing impairment and inner ear malformation. Whole exome sequencing identified a novel homozygous missense variant (c.654G>C, p.[Trp218Cys]) in BRF1, predicted to affect the protein structure. Expression assessment showed extremely low BRF1 protein expression caused by the identified variant, supporting its causal involvement. The description of new patients with cerebellofaciodental syndrome is essential to better delineate the phenotypic and genotypic spectrum of the disease.

Dysfunction of the gonadotropin-releasing hormone (GnRH) axis causes a range of reproductive phenotypes resulting from defects in the specification, migration and/or function of GnRH neurons. To identify additional molecular components of this system, we initiated a systematic genetic interrogation of families with isolated GnRH deficiency (IGD). Here, we report 13 families (12 autosomal dominant and one autosomal recessive) with an anosmic form of IGD (Kallmann syndrome) with loss-of-function mutations in TCF12, a locus also known to cause syndromic and non-syndromic craniosynostosis. We show that loss of tcf12 in zebrafish larvae perturbs GnRH neuronal patterning with concomitant attenuation of the orthologous expression of tcf3a/b, encoding a binding partner of TCF12, and stub1, a gene that is both mutated in other syndromic forms of IGD and maps to a TCF12 affinity network. Finally, we report that restored STUB1 mRNA rescues loss of tcf12 in vivo. Our data extend the mutational landscape of IGD, highlight the genetic links between craniofacial patterning and GnRH dysfunction and begin to assemble the functional network that regulates the development of the GnRH axis.

Observational study [Abstract] Background: Infection is a major cause of morbidity and mortality after heart transplantation (HT). Little information about its importance in the immediate post-operative period is available. The aim of this study was to analyze the characteristics, incidence, and outcomes of in-hospital post-operative infections after HT. Methods: We conducted an observational, single-center study based on 677 adults who underwent HT from 1991 to 2015 and who survived the surgical intervention. In-hospital post-operative infections were identified retrospectively according to the medical finding in the clinical records. Results: Over a mean hospital stay of 24.5 days, 239 patients (35.3%) developed 348 episodes of infection (2 episodes per 100 patient-days). The most common sources of infection were those related to invasive procedures (respiratory infections, 115 [33%]; urinary tract infections, 47 [13.5%]; bacteremia, 42 [12.1%]; surgical site infections, 25 [7.2%]), in addition to abdominal focus (33, 9.5%). Enterobacteriaceae (76, 21.8%) and gram-positive cocci (58, 16.7%) were the predominant germs, although opportunistic infections were not infrequent (69, 19.8%). Ninety-five septic episodes were detected with a mean Sequential Organ Failure Assessment Score of 9.5 ± 5.3 points, with hemodynamic failure being the most severe organ dysfunction and renal dysfunction the most frequent one. Management included broad-spectrum antibiotics in 48.8% of episodes and surgical management in 13.8%. The overall antimicrobial success rate was 96.3%. Higher in-hospital mortality was observed among infected patients (15.1% vs. 10.3%), but this difference was not statistically significant (p = 0.067). The one-year survival and events were not different between patients suffering from a post-operative infection and those who did not. Conclusions: In-hospital infections were frequent in the post-operative period after HT and were associated with a poor short-term outcome. Patients who survived sepsis had a similar one-year morbidity and mortality compared with patients who did not develop an infection.

Quetiapine is an atypical antipsychotic widely used for the treatment of schizophrenia and the depressive episodes of bipolar disorder. The aim of this work was to investigate the effect of variants in relevant pharmacogenes in the pharmacokinetics of quetiapine and to exploratorily evaluate adverse drug reaction (ADR) incidence based on genetic polymorphism. Specifically, 49 healthy volunteers enrolled in two bioequivalence clinical trials were included in this study. In addition, 80 variants in 19 relevant pharmacogenes were genotyped, including cytochrome P450 (CYP) genes, catechol-O-methyl transferase (COMT), other enzymes (e.g., UGT1A1 or UGT1A4), and transporters (e.g., SLCO1B1, ABCB1, or ABCG2). The COMT rs13306278 T allele was significantly related to quetiapine-increased exposure. We demonstrated the existence of quetiapine derivatives with a catechol-like structure (7,8-dihydroxi-quetiapine and 7,8-dihydroxi-N-desalkyl-quetiapine), which would be COMT metabolites and would explain quetiapine accumulation through CYP2D6 and CYP3A4 negative feedback. Moreover, CYP3A5 and CYP2B6 phenotypes were related to quetiapine exposure variability, which confirms (for CYP3A5) and suggests (for CYP2B6) that these enzymes play an important role in quetiapine’s metabolism. Finally, the ABCG2 rs2231142 T allele was related to quetiapine accumulation. Further studies are required to confirm the clinical relevance of our findings.

The Dental Aesthetic Index (DAI) was determined in 12- and 15-year-old schoolchildren to ascertain the prevalence of malocclusion and to assess its association with dental caries experience, dental plaque accumulation, and socio-demographic variables. We performed a cross-sectional study with a stratified two-stage sampling design. An oral health survey and oral examination were conducted, and socio-demographic data were recorded. The sample comprised 1453 schoolchildren aged 12 (868) and 15 (585). These two samples were analyzed separately because statistically significant differences were found: the 12-year-old age group displayed a higher frequency of schoolchildren who attended state-run public schools (p = 0.004) and belonged to a lower social class (p = 0.001), the 15-year-old age group registered higher levels of caries (p = 0.001) and lower levels of dental plaque (p &lt, 0.001). The malocclusion was 9.5% higher (p = 0.001), and the global mean DAI score was likewise higher among the 12-year-olds (p &lt, 0.001). The multivariate regression analysis not only showed that caries and dental plaque were the variables that were the most strongly associated with malocclusion, but that caries (OR = 1.5) and dental plaque (OR &gt, 2) were also risk factors for malocclusion in both groups. In conclusion, this study revealed a higher prevalence of malocclusion and dental plaque at age 12. A higher risk of caries and dental plaque was found to be related to the presence of malocclusion in both age groups.

Aymé-Gripp syndrome (AYGRPS) is a recognizable condition caused by a restricted spectrum of dominantly acting missense mutations affecting the transcription factor MAF. Major clinical features of AYGRPS include congenital cataracts, sensorineural hearing loss, intellectual disability, and a distinctive flat facial appearance. Skeletal abnormalities have also been observed in affected individuals, even though these features have not been assessed systematically. Expanding the series with four additional patients, here we provide a more accurate delineation of the molecular aspects and clinical phenotype, particularly focusing on the skeletal features characterizing this disorder. Apart from previously reported malar flattening and joint limitations, we document that carpal/tarsal and long bone defects, and hip dysplasia occur in affected subjects more frequently than formerly appreciated.

Encephalocraniocutaneous lipomatosis (ECCL) is a congenital neurocutaneous disorder. It is characterized by ocular anomalies (epibulbar choristomas), skin lesions (as nevus psiloliparus and subcutaneous lipomas), and central nervous system abnormalities (mostly arachnoid cysts, brain anomalies, vascular defects, and intracranial and spinal lipomas). Mutations in KRAS and fibroblast growth factor receptor gene-1 (FGFR1) are related to ECCL, explaining additional manifestations such as jaw tumors or gliomas. We report a pediatric patient with clinical, radiological, and histological findings consistent with ECCL and a mosaic pathogenic variant in FGFR1 found in the DNA from a non-cultured biopsy of the nevus psiloliparus and absent in blood and DNA from buccal mucosa.

PRMT7 encodes for an arginine methyltransferase that methylates arginine residues on various protein substrates and has been shown to play a role in various developmental processes. Mutations in PRMT7 have been recently shown to be implicated in a phenotype with intellectual disability, short stature and brachydactyly, and considered to be a phenocopy of pseudohypoparathyroidism. We report a patient with short stature, psychomotor delay, hearing loss and brachydactyly, for whom whole exome sequencing detected two mutations in PRMT7 and parental segregation studies detected biallelic mutation inheritance. Few patients with biallelic PRMT7 mutations have been reported so far in the literature. We report a new patient and review all reported cases to date to delineate the clinical manifestations that may help in diagnosis this disorder, known as Short Stature, Brachydactyly, Intellectual Developmental Disability, and Seizures syndrome, allowing appropriate management and genetic counselling.

Background: The relationship between children's sleep and health has been widely examined; however, research focused on the link between sleep and sensory reactivity in children without medical conditions is relatively new and based on studies with small samples. Hence, we aimed at exploring the association between sleep duration and quality and prevalence of sensory reactivity in a population-based sample of children aged 3–7.Methods: We examined data on 579 school-age children from the InProS project, a cross-sectional population-based study. Children's sleep duration was classified as Results: Around a third (32.6%; n = 189) slept Conclusions: In this study, we observed that poor sleep quality was statistically significantly associated with a higher prevalence of sensory reactivity as measured by the total SSP and almost all SSP subscales. To our knowledge, this is the first time that this association has been explored and reported. Further research from prospective studies is required to confirm these findings.

INTRODUCTION The primary goal of this study was to compare gastrointestinal symptom reduction in patients on bismuth-containing quadruple eradication therapy supplemented with Lactobacillus reuteri strains (DSM 17938 and ATCC PTA 6475) or placebo. MATERIALS AND METHODS This was randomized, double-blind, parallel-arm, placebo-controlled clinical trial. Patients received first-line an eradication regimen based on bismuth subcitrate potassium, metronidazole, tetracycline hydrochloride (three-in-one capsules), and omeprazole 40 mg twice a day for ten days, plus a probiotic or placebo tablet for 30 days. During follow-up gastrointestinal symptoms were assessed using an evaluation scale (GSRS), and adverse events were collected at 0, 14, 28, and 56 days. RESULTS A total of 80 patients were included from February 2018 to May 2019 at a single site. Eradication therapy was effective for 85% of patients, with no differences between treatment arms. In the group receiving the probiotic, abdominal pain decreased in 42% of patients, compared with 19% in the control group (OR: 0.27; CI, 0.13-0.58; p < 0.001), and abdominal distension decreased in 25% versus 17% in the control group (OR: 0.24; IC, 0.19-0.84; p < 0.001); Conclusions: Treatment with L. reuteri only reduced abdominal pain and distension. Further studies are needed to establish the role of probiotics as adjuvant therapy in H. pylori eradication.

Acute myocarditis is an inflammatory disease of the myocardium, and it can present as severe heart failure in children. Differential diagnosis with genetic cardiomyopathy can be difficult. The objective of this study is to identify patterns of clinical presentation and to assess invasive and non-invasive measures to differentiate patients with acute myocarditis from patients with dilated genetic cardiomyopathy. We performed a retrospective descriptive study of all paediatric patients (0–16 years old) that presented with new-onset heart failure with left ventricle ejection fraction

Background: Hepatocellular carcinoma (HCC) is a highly recurrent tumor after resection and has been closely related to hypoxia. Hypoxia-inducible factors 1α and 2α (HIF-1α and HIF-2α) have been shown to contribute to tumor progression and therapy resistance in HCC. We evaluated the prognostic and clinicopathological significance of HIF-1α and HIF-2α in HCC patients. Methods: We systematically searched Embase, Cochrane, PubMed, Scopus and Web of Science (WOS) from inception to 1 June 2020 for studies evaluating HIF-1α and/or HIF-2α expression in HCC. Selected articles evaluate at least one factor by immunohistochemistry (IHC) in HCC patients who underwent surgical resection, and its relationship with prognosis and/or clinicopathological features. Study protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO; CDR42020191977). We meta-analyzed the data extracted or estimated according to the Parmar method employing STATA software. We evaluated the overall effect size for the hazard ratio (HR) and odds ratio (OR) with 95% confidence interval (CI), as well as heterogeneity across studies with the I2 statistic and chi-square-based Q test. Moreover, we conducted subgroup analysis when heterogeneity was substantial. Publication bias was assessed by funnel plot asymmetry and Egger’s test. Results: HIF-1α overexpression was correlated with overall survival (OS), disease-free survival (DFS)/recurrence-free survival (RFS) and clinicopathological features including Barcelona Clinic Liver Cancer (BCLC), capsule infiltration, intrahepatic metastasis, lymph node metastasis, tumor–node–metastasis (TNM), tumor differentiation, tumor number, tumor size (3 cm), vascular invasion and vasculogenic mimicry. We also detected a possible correlation of HIF-1α with alpha-fetoprotein (AFP), cirrhosis, histological grade, tumor size (5 cm) and albumin after subgroup analysis. Initially, only DFS/RFS appeared to be associated with HIF-2α overexpression. Subgroup analysis denoted that HIF-2α overexpression was related to OS and capsule infiltration. Conclusions: HIF-1α and HIF-2α overexpression is related to poor OS, DFS/RFS and some clinicopathological features of HCC patients, suggesting that both factors could be useful HCC biomarkers.

Background Infections are among the leading causes of maternal mortality and morbidity. The Global Maternal Sepsis and Neonatal Initiative, launched in 2016 by WHO and partners, sought to reduce the burden of maternal infections and sepsis and was the basis upon which the Global Maternal Sepsis Study (GLOSS) was implemented in 2017. In this Article, we aimed to describe the availability of facility resources and services and to analyse their association with maternal outcomes. Methods GLOSS was a facility-based, prospective, 1-week inception cohort study implemented in 713 health-care facilities in 52 countries and included 2850 hospitalised pregnant or recently pregnant women with suspected or confirmed infections. All women admitted for or in hospital with suspected or confirmed infections during pregnancy, childbirth, post partum, or post abortion at any of the participating facilities between Nov 28 and Dec 4 were eligible for inclusion. In this study, we included all GLOSS participating facilities that collected facility-level data (446 of 713 facilities). We used data obtained from individual forms completed for each enrolled woman and their newborn babies by trained researchers who checked the medical records and from facility forms completed by hospital administrators for each participating facility. We described facilities according to country income level, compliance with providing core clinical interventions and services according to women's needs and reported availability, and severity of infection-related maternal outcomes. We used a logistic multilevel mixed model for assessing the association between facility characteristics and infection-related maternal outcomes. Findings We included 446 facilities from 46 countries that enrolled 2560 women. We found a high availability of most services and resources needed for obstetric care and infection prevention. We found increased odds for severe maternal outcomes among women enrolled during the post-partum or post-abortion period from facilities located in low-income countries (adjusted odds ratio 1middot84 [95% CI 1middot05-3middot22]) and among women enrolled during pregnancy or childbirth from non-urban facilities (adjusted odds ratio 2middot44 [1middot02-5middot85]). Despite compliance being high overall, it was low with regards to measuring respiratory rate (85 [24%] of 355 facilities) and measuring pulse oximetry (184 [57%] of 325 facilities). Interpretation While health-care facilities caring for pregnant and recently pregnant women with suspected or confirmed infections have access to a wide range of resources and interventions, worse maternal outcomes are seen among recently pregnant women located in low-income countries than among those in higher-income countries; this trend is similar for pregnant women. Compliance with cost-effective clinical practices and timely care of women with particular individual characteristics can potentially improve infection-related maternal outcomes. Funding UNDP/UNFPA/UNICEF/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction, WHO, Merck for Mothers, and US Agency for International Development. Copyright (c) 2021 World Health Organization; licensee Elsevier. This is an Open Access article under the CC BY 3.0 IGO license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. In any use of this article, there should be no suggestion that WHO endorses any specific organisation, products, or services. The use of the WHO logo is not permitted. This notice should be preserved along with the article's original URL.

A new subcutaneous formulation of the infliximab biosimilar CT-P13 has recently been developed for the treatment of inflammatory bowel disease (IBD), providing response rates similar to intravenous treatment. In an effort to limit patient attendance at intravenous infusion centers and to maintain biological treatment during the COVID-19 pandemic, the use of this new formulation was requested. The objective of this observational, retrospective, and descriptive study was to assess CT-P13 efficacy and safety after switching from intravenous to subcutaneous formulation in patients with IBD receiving maintenance therapy. This article shows preliminary results after six months of follow-up.

Melatonin (N-acetyl-5-methoxytryptamine) is an indoleamine with antioxidant, chronobiotic and anti-inflammatory properties; reduced levels of this hormone are associated with higher risk of cancer. Several beneficial effects of melatonin have been described in a broad number of tumors, including liver cancers. In this work we systematically reviewed the publications of the last 15 years that assessed the underlying mechanisms of melatonin activities against liver cancers, and its role as coadjuvant in the treatment of these tumors. Literature research was performed employing PubMed, Scopus and Web of Science (WOS) databases and, after screening, 51 articles were included. Results from the selected studies denoted the useful actions of melatonin in preventing carcinogenesis and as a promising treatment option for the primary liver tumors hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), either alone or in combination with other compounds. Different processes were modulated by the indole, such as inhibition of oxidative stress, proliferation, angiogenesis and invasion, promotion of immune system response, cell cycle arrest and apoptosis, as well as recovery of circadian rhythms and autophagy modulation. Taken together, the present systematic review highlights the evidence that document the potential role of melatonin in improving the landscape of liver tumor treatment.

The acquisition of scientific competencies for the application of evidence-based practice (EBP) is considered an essential part of healthcare education programs in order to improve clinical effectiveness. An examination of scientific skills in occupational therapists may be helpful in understanding their current practice as well as being useful in providing a basis for applying suitable approaches to the development and implementation of EBP. Hence, this study was designed with a double main objective: (1) to describe the level of acquisition of scientific skills and academic achievement in Spanish-speaking occupational therapists; (2) to examine the factors associated with these skills. The screening for Scientific Skills in Occupational Therapists (HAbilidades Científicas en Terapeutas Ocupacionales), the HACTO-Screen, is an online cross-sectional survey divided into five sections: sociodemographic data, academic and professional background; assessment of scientific skills; research training and development needs; experience as a researcher and/or academic. A total sample of 1159 occupational therapists finally participated. Main associations will be analyzed using multiple linear and/or Poisson regression models with/without robust variance. Our findings will provide valuable insights on the research skills and associated factors in a large sample of Spanish-speaking occupational therapists. The results will also be helpful to enhance research training and research career development in occupational therapy in order to promote the use of EBP.

We report the case of a 67-year-old male who was referred to our hospital due to severe abdominal pain and fever. His past medical history included a total gastrectomy surgery for stomach cancer. Abdominal examination showed intense pain on deep palpation in the epigastric region. Laboratory test revealed elevated C-reactive protein (235 mg/l) and amylase (1,789 U/l). Computerized tomography reported a pancreatic collection with the presence of air bubbles inside and areas of necrotic pancreatic parenchyma.

STAT3 and STAT5B (STAT3/STAT5B) mutations are the most common mutations in T-cell large granular lymphocytic leukemia (T-LGLL) and chronic lymphoproliferative disorders of NK cells (CLPD-NK), but their clinical impact remains unknown. We investigated the frequency and type of STAT3/STAT5B mutations in FACS-sorted populations of expanded T/NK-LGL from 100 (82 clonal, 6 oligoclonal, 12 polyclonal) patients, and its relationship with disease features. Seventeen non-LGL T-CLPD patients and 628 age-matched healthy donors were analyzed as controls. STAT3 (n = 30) and STAT5B (n = 1) mutations were detected in 28/82 clonal T/NK-LGLL patients (34%), while absent (0/18, 0%) among oligoclonal/polyclonal LGL-lymphocytosis. Mutations were found across all diagnostic subgroups: TCD8+-LGLL, 36%, CLPD-NK, 38%, TCD4+-LGLL, 7%, T&alpha, &beta, +DP-LGLL, 100%, +DN-LGLL, 50%, T&gamma, &delta, +-LGLL, 44%. STAT3-mutated T-LGLL/CLPD-NK showed overall reduced (p &lt, 0.05) blood counts of most normal leukocyte subsets, with a higher rate (vs. nonmutated LGLL) of neutropenia (p = 0.04), severe neutropenia (p = 0.02), and cases requiring treatment (p = 0.0001), together with a shorter time-to-therapy (p = 0.0001), particularly in non-Y640F STAT3-mutated patients. These findings confirm and extend on previous observations about the high prevalence of STAT3 mutations across different subtypes of LGLL, and its association with a more marked decrease of all major blood-cell subsets and a shortened time-to-therapy.

We assessed the association between body mass index (BMI) and sensory processing in 445 Spanish children aged 3&ndash, 7 from the InProS project. Child sensory processing was measured using the short sensory profile (SSP), an atypical sensory performance was defined as an SSP total score &lt, 155 and scores of tactile sensitivity &lt, 30, taste/smell sensitivity &lt, 15, movement sensitivity &lt, 13, under-responsive/seeks sensation &lt, 27, auditory filtering &lt, 23, low energy/weak &lt, 26, and visual/auditory sensitivity &lt, 19. The BMI was calculated according to the cutoffs by the World Health Organization for children aged 0&ndash, 5 and 5&ndash, 19 years. We used multiple Poisson regression models with robust variance to obtain prevalence ratios (PR). No associations between children&rsquo, s overweight and obesity and the prevalence of atypical sensory outcomes were observed. A one-point increase in BMI was significantly associated with a higher prevalence of atypical tactile sensitivity (PR = 1.07, 95% CI: 1.02, 1.12). A statistically marginal association was also observed for atypical total SSP (PR = 1.03, 95% CI: 1.00, 1.07) and atypical movement sensitivity (PR = 1.05, 95% CI: 1.00, 1.10). To our knowledge, this is the first time the association between children&rsquo, s BMI and sensory processing has been reported. Our findings suggest that sensory processing issues may play a part in the complex context of childhood obesity. Further research is required to confirm these findings.

Congenital adrenal hyperplasia (CAH) consists of several autosomal recessive disorders that inhibit steroid biosynthesis. We describe a case report diagnosed with adrenal insufficiency due to low adrenal steroids and adrenocorticotropic hormone excess due to lack of cortisol negative feedback signaling to the pituary gland. Genetic work up revealed two missense variants, p.Thr204Arg and p.Leu260Arg in the STAR gene, inherited by both parents (non-consanguineous). The StAR protein supports CYP11A1 enzyme to cleave the side chain of cholesterol and synthesize pregnenolone which is metabolized to all steroid hormones. We used bioinformatics to predict the impact of the variants on StAR activity and then we performed functional tests to characterize the two novel variants. In a cell system we tested the ability of variants to support cholesterol conversion to pregnenolone and measured their mRNA and protein expression. For both variants, we observed loss of StAR function, reduced protein expression and categorized them as pathogenic variants according to guidelines of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. These results fit the phenotype of the girl during diagnosis. This study characterizes two novel variants and expands the list of missense variants that cause CAH.

Background: Maternal infections are an important cause of maternal mortality and severe maternal morbidity. We report the main findings of the WHO Global Maternal Sepsis Study, which aimed to assess the frequency of maternal infections in health facilities, according to maternal characteristics and outcomes, and coverage of core practices for early identification and management. Methods: We did a facility-based, prospective, 1-week inception cohort study in 713 health facilities providing obstetric, midwifery, or abortion care, or where women could be admitted because of complications of pregnancy, childbirth, post-partum, or post-abortion, in 52 low-income and middle-income countries (LMICs) and high-income countries (HICs). We obtained data from hospital records for all pregnant or recently pregnant women hospitalised with suspected or confirmed infection. We calculated ratios of infection and infection-related severe maternal outcomes (ie, death or near-miss) per 1000 livebirths and the proportion of intrahospital fatalities across country income groups, as well as the distribution of demographic, obstetric, clinical characteristics and outcomes, and coverage of a set of core practices for identification and management across infection severity groups. Findings: Between Nov 28, 2017, and Dec 4, 2017, of 2965 women assessed for eligibility, 2850 pregnant or recently pregnant women with suspected or confirmed infection were included. 70·4 (95% CI 67·7–73·1) hospitalised women per 1000 livebirths had a maternal infection, and 10·9 (9·8–12·0) women per 1000 livebirths presented with infection-related (underlying or contributing cause) severe maternal outcomes. Highest ratios were observed in LMICs and the lowest in HICs. The proportion of intrahospital fatalities was 6·8% among women with severe maternal outcomes, with the highest proportion in low-income countries. Infection-related maternal deaths represented more than half of the intrahospital deaths. Around two-thirds (63·9%, n=1821) of the women had a complete set of vital signs recorded, or received antimicrobials the day of suspicion or diagnosis of the infection (70·2%, n=1875), without marked differences across severity groups. Interpretation: The frequency of maternal infections requiring management in health facilities is high. Our results suggest that contribution of direct (obstetric) and indirect (non-obstetric) infections to overall maternal deaths is greater than previously thought. Improvement of early identification is urgently needed, as well as prompt management of women with infections in health facilities by implementing effective evidence-based practices. Fil: Althabe, Fernando. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones en Epidemiología y Salud Pública. Instituto de Efectividad Clínica y Sanitaria. Centro de Investigaciones en Epidemiología y Salud Pública; Argentina Fil: Espinoza, Marisa Mabel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones en Epidemiología y Salud Pública. Instituto de Efectividad Clínica y Sanitaria. Centro de Investigaciones en Epidemiología y Salud Pública; Argentina Fil: Pasquale, Julia. No especifíca; Fil: Hernández Muñoz, Rosalinda. No especifíca; Fil: Carvajal, Javier. No especifíca; Fil: Escobar, María Fernanda. No especifíca; Fil: Cecatti, José Guilherme. No especifíca; Fil: Ribeiro Do Valle, Carolina C.. No especifíca; Fil: Mereci, Wilson. No especifíca; Fil: Vélez, Paola. No especifíca; Fil: Pérez, Aquilino M.. No especifíca; Fil: Vitureira, Gerardo. No especifíca; Fil: Leroy, Charlotte. No especifíca; Fil: Roelens, Kristien. No especifíca; Fil: Vandenberghe, Griet. No especifíca; Fil: Aguemon, Christiane Tshabu. No especifíca; Fil: Cisse, Kadari. No especifíca; Fil: Ouedraogo, Henri Gautier. No especifíca; Fil: Kannitha, Cheang. No especifíca; Fil: Rathavy, Tung. No especifíca; Fil: Tebeu, Pierre Marie. No especifíca; Fil: Bustillo, Carolina. No especifíca; Fil: Bredy, Lara. No especifíca; Fil: Herrera Maldonado, Nazarea. No especifíca; Fil: Abdosh, Abdulfetah Abdulkadir. No especifíca; Fil: Teklu, Alula M.. No especifíca; Fil: Kassa, Dawit Worku. No especifíca; Fil: Kumar, Vijay. No especifíca; Fil: Suri, Vanita. No especifíca; Fil: Trikha, Sonia. No especifíca

Alzheimer’s disease (AD) is a neurodegenerative disease with as yet no efficient therapies, the pathophysiology of which is still largely unclear. Many drugs and therapies have been designed and developed in the past decade to stop or slow down this neurodegenerative process, although none has successfully terminated a phase-III clinical trial in humans. Most therapies have been inspired by the amyloid cascade hypothesis, which has more recently come under question due to the almost complete failure of clinical trials of anti-amyloid/tau therapies to date. To shift the perspective for the design of new AD therapies, membrane lipid therapy has been tested, which assumes that brain lipid alterations lie upstream in the pathophysiology of AD. A hydroxylated derivative of docosahexaenoic acid was used, 2-hydroxy-docosahexaenoic acid (DHA-H), which has been tested in a number of animal models and has shown efficacy against hallmarks of AD pathology. Here, for the first time, DHA-H is shown to undergo α-oxidation to generate the heneicosapentaenoic acid (HPA, C21:5, n-3) metabolite, an odd-chain omega-3 polyunsaturated fatty acid that accumulates in cell cultures, mouse blood plasma and brain tissue upon DHA-H treatment, reaching higher concentrations than those of DHA-H itself. Interestingly, DHA-H does not share metabolic routes with its natural analog DHA (C22:6, n-3) but rather, DHA-H and DHA accumulate distinctly, both having different effects on cell fatty acid composition. This is partly explained because DHA-H α-hydroxyl group provokes steric hindrance on fatty acid carbon 1, which in turn leads to diminished incorporation into cell lipids and accumulation as free fatty acid in cell membranes. Finally, DHA-H administration to mice elevated the brain HPA levels, which was directly and positively correlated with cognitive spatial scores in AD mice, apparently in the absence of DHA-H and without any significant change in brain DHA levels. Thus, the evidence presented in this work suggest that the metabolic conversion of DHA-H into HPA could represent a key event in the therapeutic effects of DHA-H against AD.