Dolutegravir-Based or Low-Dose Efavirenz-Based Regimen for the Treatment of HIV-1.

BACKGROUND: An efavirenz-based regimen (with a 600-mg dose of efavirenz, known as EFV600) was the World Health Organization preferred first-line treatment for human immunodeficiency virus type 1 (HIV-1) infection until June 2018. Given concerns about side effects, dolutegravir-based and low-dose efavirenz-based combinations have been considered as first-line treatments for HIV-1 in resource-limited settings. METHODS: We conducted an open-label, multicenter, randomized, phase 3 noninferiority trial in Cameroon. Adults with HIV-1 infection who had not received antiretroviral therapy and had an HIV-1 RNA level (viral load) of at least 1000 copies per milliliter were randomly assigned to receive either dolutegravir or the reference treatment of low-dose efavirenz (a 400-mg dose, known as EFV400), combined with tenofovir and lamivudine. The primary end point was the proportion of participants with a viral load of less than 50 copies per milliliter at week 48, on the basis of the Food and Drug Administration snapshot algorithm. The difference between treatment groups was calculated, and noninferiority was tested with a margin of 10 percentage points. RESULTS: A total of 613 participants received at least one dose of the assigned regimen. At week 48, a viral load of less than 50 copies per milliliter was observed in 231 of 310 participants (74.5%) in the dolutegravir group and in 209 of 303 participants (69.0%) in the EFV400 group, with a difference of 5.5 percentage points (95% confidence interval [CI], -1.6 to 12.7; P<0.001 for noninferiority). Among those with a baseline viral load of at least 100,000 copies per milliliter, a viral load of less than 50 copies per milliliter was observed in 137 of 207 participants (66.2%) in the dolutegravir group and in 123 of 200 participants (61.5%) in the EFV400 group, with a difference of 4.7 percentage points (95% CI, -4.6 to 14.0). Virologic failure (a viral load of >1000 copies per milliliter) was observed in 3 participants in the dolutegravir group (with none acquiring drug-resistance mutations) and in 16 participants in the EFV400 group. More weight gain was observed in the dolutegravir group than in the EFV400 group (median weight gain, 5.0 kg vs. 3.0 kg; incidence of obesity, 12.3% vs. 5.4%). CONCLUSIONS: In HIV-1-infected adults in Cameroon, a dolutegravir-based regimen was noninferior to an EFV400-based reference regimen with regard to viral suppression at week 48. Among participants who had a viral load of at least 100,000 copies per milliliter when antiretroviral therapy was initiated, fewer participants than expected had viral suppression. (Funded by Unitaid and the French National Agency for AIDS Research; NAMSAL ANRS 12313 ClinicalTrials.gov number, NCT02777229.).

Primary immune thrombocytopenia (ITP) treated with romiplostim in routine clinical practice: retrospective study from the United Kingdom ITP Registry.

BACKGROUND: Romiplostim is a thrombopoietin-mimetic peptibody for adult refractory chronic immune thrombocytopenia (ITP). We aimed to describe ITP patients receiving romiplostim, platelet counts and romiplostim usage in UK clinical practice. METHODS: This was a retrospective cohort study of patients in the UKITP Registry who received romiplostim between October 2009 and January 2015, including data up to 6 months before romiplostim initiation through follow-up. RESULTS: Of 1440 patients in the UKITP Registry, 118 adults with primary ITP were eligible. Before romiplostim, 22% had splenectomy, 12% received platelet transfusion, 97% received ≥ 1 different ITP medication and 77% received ≥ 3. Most patients (73%) initiated romiplostim ≥ 1 year after ITP diagnosis (chronic phase). The mean duration of romiplostim treatment was 5.7 (SE 0.9) months, and the median was 1.4 months (IQR: 0.2, 6.5). Mean platelet count before romiplostim was 38 × 109 /L, rising to 103 × 109 /L within 1 month, and remaining 50-150 × 109 /L through up to 3 years of follow-up. After romiplostim, 4% of patients had splenectomy, 6% received platelet transfusion, and 57% received just one ITP medication other than romiplostim. CONCLUSION: The study provides valuable insights into the real-world use of romiplostim in primary ITP in routine practice and highlighted the timing of romiplostim initiation at different ITP disease phases.

Impact of processing load on analogical mapping with visual sequences in children with developmental language disorders (DLD).

BACKGROUND: Analogical mapping is a domain-general cognitive process used notably in language development, and particularly in the abstraction of construction schemas. Children with developmental language disorders (DLD) display an impairment in linguistic productivity and creativity, which can be linked to a lack of generalization of construction schemas. AIMS: To investigate analogical mapping in children with DLD, and especially the influence of processing load, as it could explain the lack of creativity observed in children with DLD. It was hypothesized that analogical mapping is altered in children with DLD and that greater cognitive load (sequential presentation and no perceptual support) would be linked to poorer performance in these children. METHODS & PROCEDURES: Fifteen children with DLD and their age-matched peers were administrated a visual analogical reasoning task where they had to complete a sequence sharing the same relational structure as previously presented sequences. Two factors influencing processing load were studied: the modality of presentation (sequential versus simultaneous) and the perceptual support (with versus without). OUTCOMES & RESULTS: Results showed an expected group effect with poorer performance in children with DLD compared with children with typical language development (TLD). Results corroborated hypotheses according to which children with DLD have difficulties with analogical mapping, which could hinder their abstraction of construction schemas. Results about the influence of processing load were mixed. While the difference between the two groups was more marked for the items without perceptual support than for those with perceptual support, children with DLD were not more affected by the sequential presentation than children with TLD. CONCLUSIONS & IMPLICATIONS: Children with DLD have impaired analogical mapping competences, especially when the relational similarities are not supported by perceptual cues. This impairment may be the cause of their difficulties in abstracting construction schemas, thus provoking their poor linguistic productivity and creativity. However, more studies are needed to confirm this hypothesis, as the influence of analogical reasoning on language development could also be reversed or could be linked to another external factor.

A Time-Based Analysis of Inflammation in Infants at Risk of Bronchopulmonary Dysplasia.

OBJECTIVE: To precisely delineate the timing and contribution of inflammation to bronchopulmonary dysplasia (BPD) in preterm infants during the neonatal period. STUDY DESIGN: Longitudinal study of blood inflammatory biomarkers (interleukin [IL]-6, IL-8, and granulocyte colony-stimulating factor) measured between birth and 42 days of age, at high temporal (daily) resolution, in infants born at or below 30 weeks of gestation. Cytokine predictors of BPD at 36 weeks postmenstrual age were adjusted for infant-specific and time-dependent factors, using hierarchical mixed effects regressions models. RESULTS: A total of 1518 data points were obtained in 62 infants (mean gestational age of 27 weeks). Infants who developed BPD later on presented increased inflammation after birth compared with infants without BPD. Inflammation was sustained, with gradual attenuation over 2 weeks (IL-8: OR: 6.5 [95% CI: 1.8-24]; granulocyte colony-stimulating factor: 3.3 [1.5-7.6]) and was higher in boys and in infants of lower birth weight. This inflammation preceded the clinical increased requirement in supplemental oxygen characteristic of BPD, and preceded the peak occurrence of neonatal sepsis or necrotizing enterocolitis. CONCLUSIONS: Systemic inflammation occurs early in the neonatal period and precedes clinical symptoms in infants with BPD. These data provide a discrete vulnerability window period, supporting a role for targeted intensive care interventions during the early phase of BPD.

Dynamics of Ebola RNA Persistence in Semen: A Report From the Postebogui Cohort in Guinea.

This study modeled the presence of Ebola virus RNA in the semen of male Ebola survivors participating in the Postebogui study in Guinea. The median time of reverse-transcription polymerase chain reaction negativity was 46.4 days after symptom onset (95% confidence interval, 11-82.6). The results emphasize the importance of the World Health Organization recommendations for survivors' management.

SCID patients with ARTEMIS vs RAG deficiencies following HCT: increased risk of late toxicity in ARTEMIS-deficient SCID.

A subgroup of severe combined immunodeficiencies (SCID) is characterized by lack of T and B cells and is caused by defects in genes required for T- and B-cell receptor gene rearrangement. Several of these genes are also involved in nonhomologous end joining of DNA double-strand break repair, the largest subgroup consisting of patients with T(-)B(-)NK(+)SCID due to DCLRE1C/ARTEMIS defects. We postulated that in patients with ARTEMIS deficiency, early and late complications following hematopoietic cell transplantation might be more prominent compared with patients with T(-)B(-)NK(+)SCID caused by recombination activating gene 1/2 (RAG1/2) deficiencies. We analyzed 69 patients with ARTEMIS and 76 patients with RAG1/2 deficiencies who received transplants from either HLA-identical donors without conditioning or from HLA-nonidentical donors without or with conditioning. There was no difference in survival or in the incidence or severity of acute graft-versus-host disease regardless of exposure to alkylating agents. Secondary malignancies were not observed. Immune reconstitution was comparable in both groups, however, ARTEMIS-deficient patients had a significantly higher occurrence of infections in long-term follow-up. There is a highly significant association between poor growth in ARTEMIS deficiency and use of alkylating agents. Furthermore, abnormalities in dental development and endocrine late effects were associated with alkylation therapy in ARTEMIS deficiency.

B-cell reconstitution for SCID: should a conditioning regimen be used in SCID treatment?

Bone marrow transplantation has resulted in life-saving sustained T-cell reconstitution in many infants with severe combined immunodeficiency (SCID), but correction of B-cell function has been more problematic. At the annual meeting of the Primary Immunodeficiency Treatment Consortium held in Boston, Massachusetts, on April 27, 2012, a debate was held regarding the use of pretransplantation conditioning versus no pretransplantation conditioning in an effort to address this problem. Reviews of the literature were made by both debaters, and there was agreement that there was a higher rate of B-cell chimerism and a lower number of patients who required ongoing immunoglobulin replacement therapy in centers that used pretransplantation conditioning. However, there were still patients who required immunoglobulin replacement in those centers, and therefore pretransplantation conditioning did not guarantee development of B-cell function. Dr Rebecca H. Buckley presented data on B-cell function according to the molecular defect of the patient, and showed that patients with IL-7 receptor α, ADA, and CD3 chain gene mutations can have normal B-cell function after transplantation with only host B cells. Dr Elie Haddad presented a statistical analysis of B-cell function in published reports and showed that only a conditioning regimen that contained busulfan was significantly associated with better B-cell function after transplantation. The question is whether the risk of immediate and long-term toxicity with use of busulfan is justified, particularly in patients with SCID with DNA repair defects and in very young newborns with SCID who will be detected by using newborn screening.

Prediction of steroid-sparing agent use in childhood idiopathic nephrotic syndrome.

BACKGROUND: About half of children with steroid-sensitive idiopathic nephrotic syndrome (INS) will develop steroid dependency or a frequently relapsing course requiring steroid-sparing agents (SSA). Because of the adverse effects of prolonged steroid treatment, the early identification of children at high risk of requiring SSA may be a useful diagnostic tool to tailor the therapeutic strategy. The aim of this study was to identify predictors of the need for SSA and derive a predictive model. METHODS: This was a retrospective hospital-based cohort study which included all children with steroid-responsive INS followed for at least 4.5 months. Cox regression modeling and decision curve analysis were performed. RESULTS: A total of 120 children (81 boys) with INS were included and followed up for a median time of 6.7 (range 0.4-24.1) years. Median age at diagnosis was 3.4 years. Seventy-two (60 %) children required a SSA after a median time of 10 months following initial diagnosis. Male children, age at disease onset, methylprednisolone pulse use, and time to achieve first remission were significantly associated with the outcome. Time to achieve remission only remained significant after adjustment: hazard ratio (HR) =1.9 [95 % confidence interval (CI) 1.5-2.5] if considered as a continuous variable, and HR=4.1 (95 % CI 1.9-8.6) when dichotomized using the 9-day threshold. The area under the receiver operating curve of the related predictive model was 0.81 (95 % CI 0.74-0.89), and the decision curve analysis demonstrated that this model performed better than any other strategy. CONCLUSIONS: Time to first remission is a strong predictor of the need for SSA in pediatric INS. Further prospective and impact studies are warranted to confirm the accuracy and benefit of our prediction model.

The influence of the frequency of functional markers on repetitive imitation of syntactic constructions in children with specific language impairment, from their own language productions.

Several studies provide considerable insight into the role that frequency plays in language development. However, no study has investigated the direct relationship between frequency and grammatical acquisition in children with specific language impairment (SLI). In this study, we focus specifically on the influence of the frequency of functional words on the ability of children with SLI to produce grammatical constructions based on the children's own previous production but containing previously unused functional words. To test our hypothesis, the children were administered an imitative repetition task, tailored to their current level of language development. Results showed that children with SLI performed more poorly than language-matched children with typical language development. The difference between the two groups was more marked when the previously unused functional words were infrequent rather than frequent. Consequently, it would seem that the token frequency of functional words influences grammatical acquisition in children with SLI. The results and their implications for linguistic theories are discussed.

Prediction of moderate and high grade vesicoureteral reflux after a first febrile urinary tract infection in children: construction and internal validation of a clinical decision rule.

PURPOSE: Urinary tract infection leads to a diagnosis of moderate or high grade (III or higher) vesicoureteral reflux in approximately 15% of children. Predicting reflux grade III or higher would make it possible to restrict cystography to high risk cases. We aimed to derive a clinical decision rule to predict vesicoureteral reflux grade III or higher in children with a first febrile urinary tract infection. MATERIALS AND METHODS: We conducted a secondary analysis of prospective series including all children with a first febrile urinary tract infection from the 8 European participating university hospitals. RESULTS: A total of 494 patients (197 boys, reflux grade III or higher in 11%) were included. Procalcitonin and ureteral dilatation on ultrasound were significantly associated with reflux grade III or higher and then combined into a prediction model with an ROC AUC of 0.75 (95% CI 0.69-0.81). Given the prespecified constraint of achieving at least 85% sensitivity, our model led to the clinical decision rule, for children with a first febrile urinary tract infection cystography should be performed in cases with ureteral dilatation and serum procalcitonin level 0.17 ng/ml or higher, or without ureteral dilatation (ie ureter not visible) when serum procalcitonin level is 0.63 ng/ml or higher. The rule had 86% sensitivity (95% CI 74-93) with 47% specificity (95% CI 42-51). Internal cross-validation produced 86% sensitivity (95% CI 79-93) and 43% specificity (95% CI 39-47). CONCLUSIONS: A clinical decision rule was derived to enable a selective approach to cystography in children with urinary tract infection. The rule predicts high grade vesicoureteral reflux with approximately 85% sensitivity and avoids half of the cystograms that do not find reflux grade III or higher. Further validation is needed before its widespread use.

Centropontine myelinolysis related to refeeding syndrome in an adolescent suffering from anorexia nervosa.

Centropontine myelinolysis (CPM) is a rare neurologic disorder defined by symmetric demyelination in the central pons, mostly due to alcoholism, malnutrition, or water-electrolyte abnormalities. We report an unusual case of CPM likely due to hypophosphatemia, related to a refeeding syndrome in the context of mental anorexia. A 15-year-old girl with mental anorexia presented with hypophosphatemia in the following days of enteral refeeding, and then suffered from confusion, neurological signs, and typical MRI lesions of CPM. Hypophosphoremia may be considered as a causative agent in CPM related to refeeding syndrome. This clinical observation also highlights the importance of recognizing patients at high risk of refeeding syndrome to initiate a balanced nutrition with careful monitoring.

Analogical reasoning in children with specific language impairment.

Usage-based theory considers analogical reasoning as a cognitive process required in language development. We hypothesized that difficulties with analogical reasoning could hinder the abstraction of construction schemas, thus slowing down morphosyntactic development for children with specific language impairment (SLI). We also hypothesized, in accordance with usage-based theory, that the same analogy mechanism is shared by linguistic and non-linguistic processes. The current study investigated the performance of 15 children with SLI in comparison with age-matched peers on a non-linguistic analogical reasoning task. Our experimental setting targeted two prerequisites of analogical reasoning: structural alignment and the discovery of relational similarity in comparison with perceptual similarity. The results obtained are compatible with our hypotheses according to which children with SLI would encounter problems building more abstract construction schemas, related to difficulties with analogical reasoning. The study also shows that children with SLI have specific cognitive difficulties regardless of their linguistic development.

Safety of macitentan for the treatment of pulmonary hypertension: Real-world experience from the OPsumit® USers Registry (OPUS) and OPsumit® Historical USers cohort (OrPHeUS).

Macitentan is an oral endothelin receptor antagonist for the management of pulmonary arterial hypertension (PAH). The OPsumit® USers Registry (OPUS) and the OPsumit® Historical USers cohort (OrPHeUS) medical chart review provide real-world data for patients newly initiating macitentan. This study aims to describe the characteristics, safety profile, and clinical outcomes of PAH patients newly treated with macitentan in the combined OPUS/OrPHeUS data set. OPUS was a prospective, multicenter, long-term, observational drug registry from April 2014 to June 2020. OrPHeUS was a retrospective, US, multicenter chart review: observation period October 2013 to March 2017. All analyses were descriptive. At registry closure in June 2020, the combined population consisted of 5654 patients, of whom 81.9% were diagnosed with PAH. For these 4626 patients, median duration of macitentan exposure observed was 14.5 (Q1 = 5.2, Q3 = 29.0) months; idiopathic PAH (54.8%) was the most common form of PAH; macitentan was initiated as monotherapy (37.9%), or as part of double (48.0%) or triple therapy (14.1%); discontinuation due to nonhepatic/hepatic adverse events occurred in 17.1%/0.3% of patients; 9.9% of patients experienced ≥1 hepatic adverse events; Kaplan-Meier estimates showed that at 1 year 59.9% (95% confidence interval: 58.3, 61.5) of patients were free from hospitalization and survival was 90.4% (89.3, 91.3). This analysis of real-world data from the combined OPUS and OrPHeUS populations demonstrated that macitentan is well tolerated in a large, diverse population of PAH patients, with overall and hepatic safety profiles consistent with previous macitentan clinical trials.

Procalcitonin is a predictor for high-grade vesicoureteral reflux in children: meta-analysis of individual patient data.

OBJECTIVE: To assess the predictive value of procalcitonin, a serum inflammatory marker, in the identification of children with first urinary tract infection (UTI) who might have high-grade (≥3) vesicoureteral reflux (VUR). STUDY DESIGN: We conducted a meta-analysis of individual data, including all series of children aged 1 month to 4 years with a first UTI, a procalcitonin (PCT) level measurement, cystograms, and an early dimercaptosuccinic acid scan. RESULTS: Of the 152 relevant identified articles, 12 studies representing 526 patients (10% with VUR ≥3) were included. PCT level was associated with VUR ≥3 as a continuous (P = .001), and as a binary variable, with a 0.5 ng/mL preferred threshold (adjusted OR, 2.5; 95% CI, 1.1 to 5.4). The sensitivity of PCT ≥0.5 ng/mL was 83% (95% CI, 71 to 91) with 43% specificity rate (95% CI, 38 to 47). In the subgroup of children with a positive results on dimercaptosuccinic acid scan, PCT ≥0.5 ng/mL was also associated with high-grade VUR (adjusted OR, 4.8; 95% CI, 1.3 to 17.6). CONCLUSIONS: We confirmed that PCT is a sensitive and validated predictor strongly associated with VUR ≥3, regardless of the presence of early renal parenchymal involvement in children with a first UTI.

Long-term outcome after hematopoietic stem cell transplantation of a single-center cohort of 90 patients with severe combined immunodeficiency.

Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative treatment for severe combined immunodeficiency (SCID). Detailed assessment of the long-term outcome of HSCT, ie, the occurrence of clinical events and the quality and stability of immune reconstitution, is now required. We performed a single-center retrospective analysis of the long-term outcome of HSCT in 90-patient cohort followed for between 2 and 34 years (median, 14 years). Clinical events and immune reconstitution data were collected. Almost half the patients have experienced one or more significant clinical events, including persistent chronic graft-versus-host disease (GVHD), autoimmune and inflammatory manifestations, opportunistic and nonopportunistic infections, chronic human papilloma virus (HPV) infections, and a requirement for nutritional support. With the notable exception of severe HPV infection, these complications tend to become less common 15 years later after HSCT. A multivariate analysis showed that the occurrence of these events correlated with non-genoidentical donors, diagnosis of Artemis SCID, and quality of immune reconstitution. In most cases, HSCT enables long-term survival with infrequent sequelae. However, the occurrence of relatively late-onset complications is a concern that requires specific means of prevention and justifies careful patient follow-up.