La violencia como problema de salud

Violencia; Maltrato infantilViolence; Child abuseViolència; Maltractament infantilViolence is a public health problem, and when it affects childhood, it can cause illness throughout the individual’s life. Apart from being able to cause damage in the physical, mental and social spheres, it represents a violation of the rights of the affected children, and a high consumption of resources, both economic and social. A multitude of investigations have improved attention to this violence. However, these advances are not consistent with the practical management of victims, both in Primary and Hospital Care. There is a significant area of improvement for paediatric care. Through this article, different professionals from all established paediatric health care facilities develop general lines of knowledge and action regarding violence against children. An overview is taken of the legislation related to childhood, the different types of abuse that exist, their effects, management and prevention. It concludes with an epilogue, through which we aim to move sensibilities. In summary, this work aims to promote the training and awareness of all professionals specialized in children’s health, so that they pursue the goal of achieving their patients’ greatest potential in life, and in this way, to help create a healthier society, with less disease, and more justice.La violencia es un problema de salud pública. Esta, cuando afecta a la infancia, puede generar enfermedad a lo largo de toda la vida del individuo. Aparte de poder producir daños en la esfera física, psíquica y social, supone una vulneración de los derechos de los niños afectados y un elevado consumo de recursos tanto económicos como sociales. Multitud de investigaciones han mejorado la atención a esta violencia. Sin embargo, estos avances no son parejos con el manejo práctico que se realiza a las víctimas tanto en la atención primaria como en la hospitalaria. Existe una significativa área de mejora para la atención pediátrica. A través de este artículo, distintos profesionales de todas las áreas sanitarias pediátricas establecidas desarrollan líneas generales de conocimiento y actuación con respecto a la violencia contra la infancia. Se hace un recorrido a través de la legislación relacionada con la infancia, las distintas tipologías de maltrato que existen, sus efectos, manejo y prevención. Concluye con un epílogo, a través del cual pretendemos mover sensibilidades. En resumen, este es un trabajo que pretende fomentar la formación y sensibilización de todos los profesionales especializados en la salud infantil, para que persigan como objetivo el que sus pacientes alcancen su mayor potencial en la vida y, de esa manera, ayudar a crear una sociedad más sana, con menos enfermedad y más justa.BBQL has received a Río Hortega Grant from the Carlos III Health Institute - Ministry of Health, co-financed by Feder Funds from the European Union (CM23/00057). TS has received a grant from the European Society of Paediatric Infectious Diseases (ESPID Springboard Award)

Risk factors for antibiotic-resistant bacteria colonisation in children with chronic complex conditions

To assess drug-resistant bacterial colonisation rates and associated risk factors in children with complex chronic conditions admitted to a national reference unit in Spain. Cross-sectional study that included all children admitted to our unit from September 2018 to July 2019. Rectal swabs were obtained to determine multidrug-resistant Gram-negative bacilli (MR-GNB) colonisation, and nasal swab to determine S. aureus and methicillin-resistant S. aureus (MRSA) colonisation. Medical records were reviewed. 100 children were included, with a median of four complex chronic conditions. Sixteen percent had S. aureus colonisation, including two MRSA. S. aureus colonisation was associated with technology-dependent children, while being on antibiotic prophylaxis or having undergone antibiotic therapy in the previous month were protective factors. The prevalence of MR-GNB colonisation was 27%, which was associated with immunosuppressive therapy (aOR 31; 2.02-47]; p = 0.01), antibiotic prophylaxis (aOR 4.56; 1.4-14.86; p = 0.012), previously treated skin-infections (aOR 2.9; 1.07-8.14; p = 0.03), surgery in the previous year (aOR 1.4; 1.06-1.8; p = 0.014), and hospital admission in the previous year (aOR 1.79; [1.26-2.56]; p = 0.001). The rate of S. aureus nasal colonisation in this series was not high despite the presence of chronic conditions, and few cases corresponded to MRSA. Antibiotic prophylaxis, immunosuppressive therapies, history of infections, previous surgeries, and length of admission in the previous year were risk factors for MR-GNB colonisation.This study was supported by Te Spanish Ministry of Science and Innovation-Carlos III Health Institute, and European Regional Development Funds; Grant No. PI18CIII/00372 [Fondo de Investigaciones Sanitarias-Spanish Health Research Fund (ISCIII)]; Grant Award “Jose María Corretger” from the Spanish Society for Paediatric Infectious Diseases; Grant Research Award from the Spanish Association of Paediatric Primary Care; and a small grant award from the European Society for Paediatric Infectious Diseases.S

Prognostic factors of a lower CD4/CD8 ratio in long term viral suppression HIV infected children

CoRISpe (Cohorte Nacional de VIH pediátrica de la RED RIS).[Background] Combination antiretroviral therapy (cART) is associated with marked immune reconstitution. Although a long term viral suppression is achievable, not all children however, attain complete immunological recovery due to persistent immune activation. We use CD4/CD8 ratio like a marker of immune reconstitution.[Methods] Perinatal HIV-infected children who underwent a first-line cART, achieved viral suppression in the first year and maintained it for more than 5 years, with no viral rebound were included. Logistic models were applied to estimate the prognostic factors, clinical characteristics at cART start, of a lower CD4/CD8 ratio at the last visit.[Results] 146 HIV-infected children were included: 77% Caucasian, 45% male and 28% CDC C. Median age at cART initiation was 2.3 years (IQR: 0.5–6.2). 42 (30%) children received mono-dual therapy previously to cART. Time of undetectable viral load was 9.5 years (IQR: 7.8, 12.5). 33% of the children not achieved CD4/CD8 ratio >1. Univariate analysis showed an association between CD4/CD8 1 was not achieved in 33% of the children. Lower CD4 nadir and previous exposure to suboptimal therapy, before initiating cART, are factors showing independently association with a worse immune recovery (CD4/CD8 < 1).Peer reviewe

Characterization of methicillin-resistant Staphylococcus aureus strains colonizing the nostrils of Spanish children

Objective: To characterize the Staphylococcus aureus strains colonizing healthy Spanish children. Methods: Between March and July 2018, 1876 Spanish children younger than 14 years attending primary healthcare centers were recruited from rural and urban areas. Staphylococcus aureus colonization of the anterior nostrils was analyzed. MecA and mecC genes, antibiotic susceptibility, and genotyping according to the spa were determined in all strains, and the following toxins were examined: Panton-Valentine leucocidin (pvl), toxic shock syndrome toxin (tst), and exfoliative toxins (eta, etb, etd). Multilocus sequence typing (MLST) and staphylococcal cassette chromosome (SCCmec) typing were performed on methicillin-resistant Staphylococcus aureus (MRSA) strains, as well as pulsed-field gel electrophoresis (PFGE). Results: 619 strains were isolated in 1876 children (33%), and 92% of them were sent for characterization to the Spanish National Centre of Microbiology (n = 572). Twenty (3.5%) of these strains were mecA-positive. Several spa types were detected among MRSA, being t002 the most frequently observed (30%), associating with SCCmec IVc. Among MSSA, 33% were positive for tst, while only 0.73% were positive for pvl. The 20 MRSA strains were negative for pvl, and 6 (30%) harbored the tst gene. Conclusions: methicillin-resistant Staphylococcus aureus nasal colonization in Spanish children is rare, with t002 being the most observed spa type, associated with SCCmec IVc. None of the MRSA strains produced pvl, but up to 30% of S. aureus strains were positive for tst

Characterization of methicillin-resistant Staphylococcus aureus strains colonizing the nostrils of Spanish children

Objective: To characterize the Staphylococcus aureus strains colonizing healthy Spanish children. Methods: Between March and July 2018, 1876 Spanish children younger than 14 years attending primary healthcare centers were recruited from rural and urban areas. Staphylococcus aureus colonization of the anterior nostrils was analyzed. MecA and mecC genes, antibiotic susceptibility, and genotyping according to the spa were determined in all strains, and the following toxins were examined: Panton-Valentine leucocidin (pvl), toxic shock syndrome toxin (tst), and exfoliative toxins (eta, etb, etd). Multilocus sequence typing (MLST) and staphylococcal cassette chromosome (SCCmec) typing were performed on methicillin-resistant Staphylococcus aureus (MRSA) strains, as well as pulsed-field gel electrophoresis (PFGE). Results: 619 strains were isolated in 1876 children (33%), and 92% of them were sent for characterization to the Spanish National Centre of Microbiology (n = 572). Twenty (3.5%) of these strains were mecA-positive. Several spa types were detected among MRSA, being t002 the most frequently observed (30%), associating with SCCmec IVc. Among MSSA, 33% were positive for tst, while only 0.73% were positive for pvl. The 20 MRSA strains were negative for pvl, and 6 (30%) harbored the tst gene. Conclusions: methicillin-resistant Staphylococcus aureus nasal colonization in Spanish children is rare, with t002 being the most observed spa type, associated with SCCmec IVc. None of the MRSA strains produced pvl, but up to 30% of S. aureus strains were positive for tst.Sociedad Española Infectologia Pediatrica, Grant/Award Number: José María Corretger. Grant 2018; Spanish Association of Paediatric Primary Care, Grant/Award Number: Grant 2018; European Society for Paediatric Infectious Diseases, Grant/Award Number: Small Grant Award 2018; Instituto de Salud Carlos III, Grant/Award Number: PI18CIII/00372S

Diversity of immune responses in children highly exposed to SARS-CoV-2

Background: Children are less susceptible than adults to symptomatic COVID‐19 infection, but very few studies addressed their underlying cause. Moreover, very few studies analyzed why children highly exposed to the virus remain uninfected. Methods: We analyzed the serum levels of ACE2, angiotensin II, anti-spike and anti-N antibodies, cytokine profiles, and virus neutralization in a cohort of children at high risk of viral exposure, cohabiting with infected close relatives during the lockdown in Spain. Results: We analyzed 40 children who were highly exposed to the virus since they lived with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)-infected relatives during the lockdown for several months without taking preventive measures. Of those, 26 reported mild or very mild symptoms. The induced immune response to the virus was analyzed 3 months after the household infection. Surprisingly, only 15 children had IgG anti-S (IgG+) determined by a sensitive method indicative of a past infection. The rest, negative for IgG anti-N or S in various tests, could be further subdivided, according to IgM antibodies, into those having IgM anti-S and IgM anti-N (IgG−IgMhigh) and those having only IgM anti-N (IgG−IgMlow). Interestingly, those two subgroups of children with IgM antibodies have strikingly different patterns of cytokines. The IgMhigh group had significantly higher IFN-α2 and IFN-γ levels as well as IL-10 and GM-CSF than the IgMlow group. In contrast, the IgMlow group had low levels of ACE2 in the serum. Both groups have a weaker but significant capacity to neutralize the virus in the serum than the IgG+ group. Two children were negative in all immunological antibody tests. Conclusions: A significant proportion of children highly exposed to SARS-CoV-2 did not develop a classical adaptive immune response, defined by the production of IgG, despite being in close contact with infected relatives. A large proportion of those children show immunological signs compatible with innate immune responses (as secretion of natural antibodies and cytokines), and others displayed very low levels of the viral receptor ACE2 that may have protected them from the virus spreading in the body despite high and constant viral exposure.This research was funded by grants from “Ministerio de Ciencia e Innovación” (PID-2019104760RB-100); “Comunidad de Madrid” (S2017/BMD-3671. INFLAMUNE-CM; FEDER and COTRAVI-19-CM) to MF; Consejo Superior de Investigaciones Científica, CSIC (CSIC-COV19-108, SGL210235) to MF and UB; CRUE-Supera COVID; the European Development Regional Fund “A way to achieve Europe” (ERDF); Merck, Sharp and Dohme Investigator Studies Program (code MISP# IIS 60257); and Fondo Supera COVID-19 (2020–001) to SSV. The study also received institutional grants from “Fundación Ramón Areces” and “Banco de Santander.”Peer reviewe

Effects of Combined CCR5/Integrase Inhibitors-Based Regimen on Mucosal Immunity in HIV-Infected Patients Naïve to Antiretroviral Therapy: A Pilot Randomized Trial

Whether initiation of antiretroviral therapy (ART) regimens aimed at achieving greater concentrations within gut associated lymphoid tissue (GALT) impacts the level of mucosal immune reconstitution, inflammatory markers and the viral reservoir remains unknown. We included 12 HIV- controls and 32 ART-naïve HIV patients who were randomized to efavirenz, maraviroc or maraviroc+raltegravir, each with fixed-dose tenofovir disoproxil fumarate/emtricitabine. Rectal and duodenal biopsies were obtained at baseline and at 9 months of ART. We performed a comprehensive assay of T-cell subsets by flow cytometry, T-cell density in intestinal biopsies, plasma and tissue concentrations of antiretroviral drugs by high-performance liquid chromatography/mass spectroscopy, and plasma interleukin-6 (IL-6), lipoteichoic acid (LTA), soluble CD14 (sCD14) and zonulin-1 each measured by ELISA. Total cell-associated HIV DNA was measured in PBMC and rectal and duodenal mononuclear cells. Twenty-six HIV-infected patients completed the follow-up. In the duodenum, the quadruple regimen resulted in greater CD8+ T-cell density decline, greater normalization of mucosal CCR5+CD4+ T-cells and increase of the naïve/memory CD8+ T-cell ratio, and a greater decline of sCD14 levels and duodenal HIV DNA levels (P = 0.004 and P = 0.067, respectively), with no changes in HIV RNA in plasma or tissue. Maraviroc showed the highest drug distribution to the gut tissue, and duodenal concentrations correlated well with other T-cell markers in duodenum, i.e., the CD4/CD8 ratio, %CD4+ and %CD8+ HLA-DR+CD38+ T-cells. Maraviroc use elicited greater activation of the mucosal naïve CD8+ T-cell subset, ameliorated the distribution of the CD8+ T-cell maturational subsets and induced higher improvement of zonulin-1 levels. These data suggest that combined CCR5 and integrase inhibitor based combination therapy in ART treatment naïve patients might more effectively reconstitute duodenal immunity, decrease inflammatory markers and impact on HIV persistence by cell-dependent mechanisms, and show unique effects of MVC in duodenal immunity driven by higher drug tissue penetration and possibly by class-dependent effects

Differences in saliva ACE2 activity among infected and non-infected adult and pediatric population exposed to SARS-CoV-2

Background Variations in the ACE2 activity in saliva could explain the striking differences of susceptibility to infection and risk of severe disease. Methods We analyze the activity of ACE2 in saliva in different population groups across a wide age range and disease status during April to June 2020, before SARS-CoV-2 vaccine implementation, and we establish differences between infected people and participants considered resistant (highly exposed healthcare workers and children who cohabited with parents with COVID-19 without isolation and remain IgG negative). Results We included 74 adults, of which 47 (64%) were susceptible and 27 (36%) were resistant, and 79 children, of which 41 (52%) were susceptible and 38 (48%) were resistant. Resistant adults have significantly lower ACE2 activity in saliva than susceptible adults and non-significant higher values than susceptible and resistant children. ACE2 activity is similar in the susceptible and resistant pediatric population (p = 0.527). In contrast, we observe an increase in activity as the disease's severity increases among the adult population (mild disease vs. severe disease, 39 vs. 105 FU, p = 0.039; severe disease vs. resistant, 105 vs. 31 FU, p < 0.001). Conclusions using an enzymatic test, we show that ACE2 activity in saliva correlates with the susceptibility to SARS-Cov-2 infection and disease severity. Children and adults with low-susceptibility to SARS-Cov-2 infection showed the lowest ACE2 activity. These findings could inform future strategies to identify at-risk individuals.This work was supported by Instituto de Salud Carlos III (AC17/00019, PI18/00154, COV20/00349, ICI20/00058), CRUE-Supera COVID, cofinanced by the European Development Regional Fund ‘‘A way to achieve Europe’’ (ERDF), Merck, Sharp & Dohme Investigator Studies Program (code MISP# IIS 60257), Fondo Supera COVID-19 (2020-001), and SEIMC (becas SEIMC).Peer reviewe

Dolutegravir twice-daily dosing in children with HIV-associated tuberculosis: a pharmacokinetic and safety study within the open-label, multicentre, randomised, non-inferiority ODYSSEY trial

Background: Children with HIV-associated tuberculosis (TB) have few antiretroviral therapy (ART) options. We aimed to evaluate the safety and pharmacokinetics of dolutegravir twice-daily dosing in children receiving rifampicin for HIV-associated TB. Methods: We nested a two-period, fixed-order pharmacokinetic substudy within the open-label, multicentre, randomised, controlled, non-inferiority ODYSSEY trial at research centres in South Africa, Uganda, and Zimbabwe. Children (aged 4 weeks to <18 years) with HIV-associated TB who were receiving rifampicin and twice-daily dolutegravir were eligible for inclusion. We did a 12-h pharmacokinetic profile on rifampicin and twice-daily dolutegravir and a 24-h profile on once-daily dolutegravir. Geometric mean ratios for trough plasma concentration (Ctrough), area under the plasma concentration time curve from 0 h to 24 h after dosing (AUC0–24 h), and maximum plasma concentration (Cmax) were used to compare dolutegravir concentrations between substudy days. We assessed rifampicin Cmax on the first substudy day. All children within ODYSSEY with HIV-associated TB who received rifampicin and twice-daily dolutegravir were included in the safety analysis. We described adverse events reported from starting twice-daily dolutegravir to 30 days after returning to once-daily dolutegravir. This trial is registered with ClinicalTrials.gov (NCT02259127), EudraCT (2014–002632-14), and the ISRCTN registry (ISRCTN91737921). Findings: Between Sept 20, 2016, and June 28, 2021, 37 children with HIV-associated TB (median age 11·9 years [range 0·4–17·6], 19 [51%] were female and 18 [49%] were male, 36 [97%] in Africa and one [3%] in Thailand) received rifampicin with twice-daily dolutegravir and were included in the safety analysis. 20 (54%) of 37 children enrolled in the pharmacokinetic substudy, 14 of whom contributed at least one evaluable pharmacokinetic curve for dolutegravir, including 12 who had within-participant comparisons. Geometric mean ratios for rifampicin and twice-daily dolutegravir versus once-daily dolutegravir were 1·51 (90% CI 1·08–2·11) for Ctrough, 1·23 (0·99–1·53) for AUC0–24 h, and 0·94 (0·76–1·16) for Cmax. Individual dolutegravir Ctrough concentrations were higher than the 90% effective concentration (ie, 0·32 mg/L) in all children receiving rifampicin and twice-daily dolutegravir. Of 18 children with evaluable rifampicin concentrations, 15 (83%) had a Cmax of less than the optimal target concentration of 8 mg/L. Rifampicin geometric mean Cmax was 5·1 mg/L (coefficient of variation 71%). During a median follow-up of 31 weeks (IQR 30–40), 15 grade 3 or higher adverse events occurred among 11 (30%) of 37 children, ten serious adverse events occurred among eight (22%) children, including two deaths (one tuberculosis-related death, one death due to traumatic injury); no adverse events, including deaths, were considered related to dolutegravir. Interpretation: Twice-daily dolutegravir was shown to be safe and sufficient to overcome the rifampicin enzyme-inducing effect in children, and could provide a practical ART option for children with HIV-associated TB

Neuropsychiatric manifestations and sleep disturbances with dolutegravir-based antiretroviral therapy versus standard of care in children and adolescents: a secondary analysis of the ODYSSEY trial

BACKGROUND: Cohort studies in adults with HIV showed that dolutegravir was associated with neuropsychiatric adverse events and sleep problems, yet data are scarce in children and adolescents. We aimed to evaluate neuropsychiatric manifestations in children and adolescents treated with dolutegravir-based treatment versus alternative antiretroviral therapy. METHODS: This is a secondary analysis of ODYSSEY, an open-label, multicentre, randomised, non-inferiority trial, in which adolescents and children initiating first-line or second-line antiretroviral therapy were randomly assigned 1:1 to dolutegravir-based treatment or standard-of-care treatment. We assessed neuropsychiatric adverse events (reported by clinicians) and responses to the mood and sleep questionnaires (reported by the participant or their carer) in both groups. We compared the proportions of patients with neuropsychiatric adverse events (neurological, psychiatric, and total), time to first neuropsychiatric adverse event, and participant-reported responses to questionnaires capturing issues with mood, suicidal thoughts, and sleep problems. FINDINGS: Between Sept 20, 2016, and June 22, 2018, 707 participants were enrolled, of whom 345 (49%) were female and 362 (51%) were male, and 623 (88%) were Black-African. Of 707 participants, 350 (50%) were randomly assigned to dolutegravir-based antiretroviral therapy and 357 (50%) to non-dolutegravir-based standard-of-care. 311 (44%) of 707 participants started first-line antiretroviral therapy (ODYSSEY-A; 145 [92%] of 157 participants had efavirenz-based therapy in the standard-of-care group), and 396 (56%) of 707 started second-line therapy (ODYSSEY-B; 195 [98%] of 200 had protease inhibitor-based therapy in the standard-of-care group). During follow-up (median 142 weeks, IQR 124–159), 23 participants had 31 neuropsychiatric adverse events (15 in the dolutegravir group and eight in the standard-of-care group; difference in proportion of participants with ≥1 event p=0·13). 11 participants had one or more neurological events (six and five; p=0·74) and 14 participants had one or more psychiatric events (ten and four; p=0·097). Among 14 participants with psychiatric events, eight participants in the dolutegravir group and four in standard-of-care group had suicidal ideation or behaviour. More participants in the dolutegravir group than the standard-of-care group reported symptoms of self-harm (eight vs one; p=0·025), life not worth living (17 vs five; p=0·0091), or suicidal thoughts (13 vs none; p=0·0006) at one or more follow-up visits. Most reports were transient. There were no differences by treatment group in low mood or feeling sad, problems concentrating, feeling worried or feeling angry or aggressive, sleep problems, or sleep quality. INTERPRETATION: The numbers of neuropsychiatric adverse events and reported neuropsychiatric symptoms were low. However, numerically more participants had psychiatric events and reported suicidality ideation in the dolutegravir group than the standard-of-care group. These differences should be interpreted with caution in an open-label trial. Clinicians and policy makers should consider including suicidality screening of children or adolescents receiving dolutegravir