Postural control in childhood: investigating the neurodevelopmental gradient hypothesis

Neurodevelopmental disorders (NDDs) have been suggested to lie on a gradient continuum, all resulting from common brain disturbances, but with different degrees of impairment severity. This case-control study aimed to assess postural stability against such hypothesis in 104 children/adolescents aged 5-17, of whom 81 had NDDs and 23 were healthy controls. Compared to healthy controls, Autism Spectrum Disorder (ASD) resulted in the most severely impaired neurodevelopmental condition, followed by Attention Deficit Hyperactive Disorder (ADHD) and Tourette Syndrome (TS). In particular, while ASD children/adolescents performed worse than healthy controls in a number of sensory conditions across all parameters, ADHD children/adolescents performed worse than healthy controls only in the sway area for the most complex sensory conditions, when their vision and somatosensory functions were both compromised, and performance in Tourette Syndrome (TS) was roughly indistinguishable from that of healthy controls. Finally, differences were also observed between clinical groups, with ASD children/adolescents, and to a much lesser extent ADHD children/adolescents, performing worse than TS children/adolescents, especially when sensory systems were not operationally accurate. Evidence from this study indicates that poor postural control may be a useful biomarker for risk assessment during neurodevelopment, in line with predictions from the gradient hypothesis

Methylation levels of the "long interspersed nucleotide element-1" repetitive sequences predict survival of melanoma patients

Background\ud The prognosis of cutaneous melanoma (CM) differs for patients with identical clinico-pathological stage, and no molecular markers discriminating the prognosis of stage III individuals have been established. Genome-wide alterations in DNA methylation are a common event in cancer. This study aimed to define the prognostic value of genomic DNA methylation levels in stage III CM patients.\ud \ud Methods\ud Overall level of genomic DNA methylation was measured using bisulfite pyrosequencing at three CpG sites (CpG1, CpG2, CpG3) of the Long Interspersed Nucleotide Element-1 (LINE-1) sequences in short-term CM cultures from 42 stage IIIC patients. The impact of LINE-1 methylation on overall survival (OS) was assessed using Cox regression and Kaplan-Meier analysis.\ud \ud Results\ud Hypomethylation (i.e., methylation below median) at CpG2 and CpG3 sites significantly associated with improved prognosis of CM, CpG3 showing the strongest association. Patients with hypomethylated CpG3 had increased OS (P = 0.01, log-rank = 6.39) by Kaplan-Meyer analysis. Median OS of patients with hypomethylated or hypermethylated CpG3 were 31.9 and 11.5 months, respectively. The 5 year OS for patients with hypomethylated CpG3 was 48% compared to 7% for patients with hypermethylated sequences. Among the variables examined by Cox regression analysis, LINE-1 methylation at CpG2 and CpG3 was the only predictor of OS (Hazard Ratio = 2.63, for hypermethylated CpG3; 95% Confidence Interval: 1.21-5.69; P = 0.01).\ud \ud Conclusion\ud LINE-1 methylation is identified as a molecular marker of prognosis for CM patients in stage IIIC. Evaluation of LINE-1 promises to represent a key tool for driving the most appropriate clinical management of stage III CM patients

Risk of psychosis in autism spectrum disorder individuals exposed to psychosocial stressors: A 9-year chart review study

Psychosocial stressors have been suggested to precipitate psychotic episodes in patients with pre-existing psychosis and otherwise healthy subjects. However, such a risk has never been formally investigated in individuals with autism spectrum disorder (ASD). Sixty-nine autistic adolescents hospitalized for psychotic/manic symptoms (PSY) and other mental health issues (NPSY) over a 9-year period were compared with reference to their previous exposure to psychosocial stressors. ASD diagnoses satisfied the International Classification of Diseases (ICD)-10 criteria. Psychotic/manic symptom assessment followed the Kiddie Schedule for Affective Disorders and Schizophrenia (K-SADS). Psychosocial stressor exposure was collected separately at each admission. Preliminarily, univariate between-group comparisons were conducted. Then, a binomial model was adopted to investigate associations with previous exposure to psychosocial stressors. Results were reported with a change in AIC (ΔAIC). PSY patients presented with higher previous exposure to adverse life events (30.43% vs. 6.52%, OR = 6.079 [1.209, 40.926], p = 0.013) and school/work difficulties (30.43% vs. 8.70%, OR = 4.478 [0.984, 23.846], p = 0.034) than NPSY ones. Admissions for psychotic/manic symptoms occurred more likely in the context of family disturbances (OR = 2.275 [1.045, 5.045], p = 0.030) and adverse life events (OR = 3.489 [1.194, 11.161], p = 0.014). The fitted binomial model was found to be significant compared to the random effects model (ΔAIC = -1.962; χ2 10  = 21.96, p = 0.015), with the risk of presenting psychotic/manic symptoms being increased by family disturbances (z = +4.118) and school/work difficulties (z = +2.455). The results suggest a potential psychosis-inducing effect of psychosocial stressors in ASD, which has clinical and policy implications

HIV-1 Gag gene mutations, treatment response and drug resistance to protease inhibitors: a systematic review and meta-analysis protocol

Background: Some mutations in the HIV-1 Gag gene are known to confer resistance to ritonavir-boosted protease inhibitors (PI/r), but their clinical implications remain controversial. This review aims at summarizing current knowledge on HIV-1 Gag gene mutations that are selected under PI/r pressure and their distribution according to viral subtypes. Materials and methods: Randomized and non-randomized trials, cohort and cross-sectional studies evaluating HIV-1 Gag gene mutations and protease resistance associated mutations, will all be included. Searches will be conducted (from January 2000 onwards) in PubMed, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), Latin American and Caribbean Health Sciences Literature (LILAC), Web of Science, African Journals Online, and Cumulative Index to Nursing and Allied Health Literature (CINAHL) databases. Hand searching of the reference lists of relevant reviews and trials will be conducted and we will also look for conference abstracts. Genotypic profiles of both Gag gene and the protease region as well as viral subtypes (especially B vs. non B) will all serve as comparators. Primary outcomes will be the "prevalence of Gag mutations" and the "prevalence of PI/r resistance associated mutations". Secondary outcomes will be the "rate of treatment failure" and the distribution of Gag mutations according to subtypes. Two reviewers will independently screen titles and abstracts, assess the full texts for eligibility, and extract data. If data permits, random effects models will be used where appropriate. This study will be reported according to the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta Analyses. Discussion: This systematic review will help identify HIV-1 Gag gene mutations associated to PI/r-based regimen according to viral subtypes. Findings of this review will help to better understand the implications of the Gag gene mutations in PI/r treatment failure. This may later justify considerations of Gag-genotyping within HIV drug resistance interpretation algorithms in the clinical management of patients receiving PI/r regimens. Systematic review registration: PROSPERO: CRD42019114851

HIV-1 integrase resistance associated mutations and the use of dolutegravir in Sub-Saharan Africa: a systematic review and meta-analysis protocol

Background: Sub-Saharan Africa carries the greatest burden of HIV-infection with increasing drug resistance burden, which requires improved patient management and monitoring. Current WHO recommendations suggest transitioning to dolutegravir-based (adults) or raltegravir-based-regimens (neonates) for initial antiretroviral therapy (ART) and as a suitable alternative in cases of multi-resistance in resource-limited settings. This review aims at synthesizing the current knowledge on dolutegravir use and integrase resistance-associated mutations found before the wide use of dolutegravir-based regimens. Methods: This systematic review will include randomized and non-randomized trials, cohort, and cross-sectional studies published on dolutegravir use or integrase resistance-associated mutations in Sub-Saharan Africa. Searches will be conducted (from 2007 onwards) in PubMed, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), Latin American and Caribbean Health Sciences Literature (LILAC), Web of Science, African Journals Online, and Cumulative Index to Nursing and Allied Health Literature (CINAHL) databases. Hand searching of the reference lists of relevant reviews and trials will be conducted and we will also look for conference abstracts. We will include studies of adults and/or children exposed to integrase inhibitors-based therapies; especially dolutegravir or raltegravir (which is our intervention of interest as compared to other antiretroviral regimens). We will exclude studies of patients with specific co-morbidities such as tuberculosis or opportunistic infections. Primary outcomes will be "the rate of viral suppression" and "the level of drug resistance" on integrase inhibitor-based regimens among patients in Sub-Saharan Africa. Secondary outcomes will be "the effect of baseline viremia on viral suppression," "the effect of treatment duration on viral suppression," "the proportion of patients with immune recovery," "the rate of non-adherence," "rate of adverse events;" "drug resistance according to different integrase inhibitor-based regimens," and "drug resistance according to viral subtypes/recombinants." Two reviewers will independently screen titles and abstracts, assess the full texts for eligibility, and extract data. If data permits, random effects models will be used where appropriate. Subgroup and additional analyses will be conducted to explore the potential sources of heterogeneity (e.g., age, sex, baseline viremia, CD4 following treatment, treatment duration, and adherence level). Discussion: This review will help to strengthen evidence on the effectiveness of integrase strand transfer inhibitors by contributing to current knowledge on the use of dolutegravir and/or raltegravir (especially for neonates) in Sub-Saharan Africa. Results will therefore help in setting-up baseline data for an optimal management of people living with HIV as Sub-Saharan African countries are transitioning to dolutegravir-based regimens. Evidence will also support HIV/AIDS programs in identifying gaps and actions to be undertaken for improved long-term care and treatment of people living with HIV in Sub-Saharan Africa. Systematic review registration: PROSPERO CRD42019122424

Baseline integrase drug resistance mutations and conserved regions across HIV-1 clades in Cameroon: implications for transition to dolutegravir in resource-limited settings

Background: Transition to dolutegravir-based regimens in resource-limited settings (RLS) requires prior understanding of HIV-1 integrase variants and conserved regions. Therefore, we evaluated integrase drug resistance mutations (DRMs) and conserved regions amongst integrase strand transfer inhibitor (INSTI)-naive patients harbouring diverse HIV-1 clades in Cameroon. Methods: A cross-sectional study was conducted amongst 918 INSTI-naive patients from Cameroon (89 ART-naive and 829 ART-experienced patients). HIV-1 sequences were interpreted regarding INSTI-DRMs using the Stanford HIVdb v8.9-1 and the 2019 IAS-USA list. Amino acid positions with <1% variability were considered as highly conserved. Subtyping was performed by phylogeny. Results: Overall prevalence (95% CI) of INSTI-DRMs was 0.8% (0.4-1.7), with 0.0% (0.0-4.0) amongst ART-naive versus 0.9% (0.5-1.9) amongst ART-experienced patients; P = 0.44. Accessory mutations (95% CI) were found in 33.8% (30.9-37.0), with 38.2% (28.1-49.1) amongst ART-naive versus 33.4% (30.4-36.7) amongst ART-experienced patients; P = 0.21. Of 288 HIV-1 integrase amino acid positions, 58.3% were highly conserved across subtypes in the following major regions: V75-G82, E85-P90, H114-G118, K127-W132, E138-G149, Q168-L172, T174-V180, W235-A239 and L241-D253. Wide genetic diversity was found (37 clades), including groups M (92.3%), N (1.4%), O (6.2%) and P (0.1%). Amongst group M, CRF02_AG was predominant (47.4%), with a significantly higher frequency (95% CI) of accessory mutations compared with non-AG [41.4% (36.8-46.0) versus 27.1% (23.3-31.2) respectively; P < 0.001]. Conclusions: The low baseline of INSTI-DRMs (<1%) in Cameroon suggests effectiveness of dolutegravir-based regimens. In spite of high conservation across clades, the variability of accessory mutations between major circulating strains underscores the need for monitoring the selection of INSTI-DRMs while scaling up dolutegravir-based regimens in RLS

Antibody dependent cellular cytotoxicity-inducing anti-EGFR antibodies as effective therapeutic option for cutaneous melanoma resistant to BRAF inhibitors

Introduction: About 50% of cutaneous melanoma (CM) patients present activating BRAF mutations that can be effectively targeted by BRAF inhibitors (BRAFi). However, 20% of CM patients exhibit intrinsic drug resistance to BRAFi, while most of the others develop adaptive resistance over time. The mechanisms involved in BRAFi resistance are disparate and globally seem to rewire the cellular signaling profile by up-regulating different receptor tyrosine kinases (RTKs), such as the epidermal growth factor receptor (EGFR). RTKs inhibitors have not clearly demonstrated anti-tumor activity in BRAFi resistant models. To overcome this issue, we wondered whether the shared up-regulated RTK phenotype associated with BRAFi resistance could be exploited by using immune weapons as the antibody-dependent cell cytotoxicity (ADCC)-mediated effect of anti-RTKs antibodies, and kill tumor cells independently from the mechanistic roots. Methods and results: By using an in vitro model of BRAFi resistance, we detected increased membrane expression of EGFR, both at mRNA and protein level in 4 out of 9 BRAFi-resistant (VR) CM cultures as compared to their parental sensitive cells. Increased EGFR phosphorylation and AKT activation were observed in the VR CM cultures. EGFR signaling appeared dispensable for maintaining resistance, since small molecule-, antibody- and CRISPR-targeting of EGFR did not restore sensitivity of VR cells to BRAFi. Importantly, immune-targeting of EGFR by the anti-EGFR antibody cetuximab efficiently and specifically killed EGFR-expressing VR CM cells, both in vitro and in humanized mouse models in vivo, triggering ADCC by healthy donors' and patients' peripheral blood cells. Conclusion: Our data demonstrate the efficacy of immune targeting of RTKs expressed by CM relapsing on BRAFi, providing the proof-of-concept supporting the assessment of anti-RTK antibodies in combination therapies in this setting. This strategy might be expected to concomitantly trigger the crosstalk of adaptive immune response leading to a complementing T cell immune rejection of tumors

Pre-Treatment HIV Drug Resistance and Genetic Diversity in Cameroon: Implications for First-Line Regimens

the efficacy of first-line antiretroviral therapy (ART) may be hampered by the presence of HIV drug resistance (HIVDR). we described HIV-1 pre-treatment drug resistance (PDR) patterns, effect of viral clades on PDR, and programmatic implications on first-line regimens in cameroon. a sentinel surveillance of PDR was conducted from 2014 to 2019. sequencing of HIV-1 protease and reverse transcriptase was performed, and HIVDR was interpreted using stanford HIVdb.v.9.4. In total, 379 sequences were obtained from participants (62% female, mean age 36 +/- 10 years). the overall PDR rate was 15.0% [95% CI: 11.8-19.0] nationwide, with significant disparity between regions (p = 0.03). NNRTI PDR was highest (12.4%), of which 7.9% had DRMs to EFV/NVP. two regions had EFV/NVP PDR above the 10% critical threshold, namely the far north (15%) and east (10.9%). Eighteen viral strains were identified, predominated by CRF02_AG (65.4%), with no influence of genetic diversity PDR occurrence. TDF-3TC-DTG predictive efficacy was superior (98.4%) to TDF-3TC-EFV (92%), p < 0.0001. the overall high rate of PDR in cameroon, not substantially affected by the wide HIV-1 genetic diversity, underscores the poor efficacy of EFV/NVP-based first-line ART nationwide, with major implications in two regions of the country. this supports the need for a rapid transition to NNRTI-sparing regimens, with TDF-3TC-DTG having optimal efficacy at the programmatic level

Inflammatory profile of vertically HIV-1 infected adolescents receiving ART in Cameroon: a contribution toward optimal pediatric HIV control strategies

Antiretroviral therapy (ART) has improved the lifespan of people living with HIV. However, their immune system remains in a state of sustained activation/inflammation, which favors viral replication and depletion of helper T-cells with varying profiles according to ART-response. We herein sought to ascertain the inflammatory profile of adolescents living with perinatal HIV-1 infection (ALPHI) receiving ART in an African context. In this cross-sectional and comparative study among ART-experienced ALPHI in Yaoundé-Cameroon, HIV-1 RNA was measured by Abbott Real-time PCR; CD4 cells were enumerated using flow cytometry; serum cytokines were measured by ELISA; HIV-1 proviral DNA was genotyped by Sanger-sequencing; and archived drug resistance mutations (ADRMs) were interpreted using Stanford HIVdb.v9.0.1. Overall, 73 adolescents were enrolled (60 ALPHI and 13 HIV-1 negative peers) aged 15 (13-18) years; 60.00% were female. ART median duration was 92 (46-123) months; median viral load was 3.99 (3.17-4.66) RNA Log10 (copies)/mL and median CD4 count was 326 (201-654) cells/mm3. As compared to HIV-negative adolescents, TNFα was highly expressed among ALPHI (p<0.01). Following a virological response, inflammatory cytokines (IFNγ and IL-12), anti-inflammatory cytokines (IL-4 and IL-10) and inflammation-related cytokines (IL-6 and IL-1β) were highly expressed with viral suppression (VS) vs. virological failure (VF), while the chemokine CCL3 was highly expressed with VF (p<0.01). Regarding the immune response, the inflammatory cytokine TNFα was highly expressed in those that are immunocompetent (CD4≥500 cell/mm3) vs. immunocompromised (CD4<500 cell/mm3), p ≤ 0.01; while chemokine CCL2 was highly expressed in the immunocompromised (p<0.05). In the presence of ADRMs, IL-4 and CCL3 were highly expressed (p=0.027 and p=0.043 respectively). Among ART-experienced ALPHI in Cameroon, the TNFα cytokine was found to be an inflammatory marker of HIV infection; IFNγ, IL-1β, IL-6, and IL-12 are potential immunological markers of VS and targeting these cytokines in addition to antiretroviral drugs may improve management. Moreover, CCL3 and CCL2 are possible predictors of VF and/or being immunocompromised and could serve as surrogates of poor ART response

Inflammatory profile of vertically HIV-1 infected adolescents receiving ART in Cameroon: a contribution toward optimal pediatric HIV control strategies

Antiretroviral therapy (ART) has improved the lifespan of people living with HIV. However, their immune system remains in a state of sustained activation/inflammation, which favors viral replication and depletion of helper T-cells with varying profiles according to ART-response. We herein sought to ascertain the inflammatory profile of adolescents living with perinatal HIV-1 infection (ALPHI) receiving ART in an African context. In this cross-sectional and comparative study among ART-experienced ALPHI in Yaoundé-Cameroon, HIV-1 RNA was measured by Abbott Real-time PCR; CD4 cells were enumerated using flow cytometry; serum cytokines were measured by ELISA; HIV-1 proviral DNA was genotyped by Sanger-sequencing; and archived drug resistance mutations (ADRMs) were interpreted using Stanford HIVdb.v9.0.1. Overall, 73 adolescents were enrolled (60 ALPHI and 13 HIV-1 negative peers) aged 15 (13-18) years; 60.00% were female. ART median duration was 92 (46-123) months; median viral load was 3.99 (3.17-4.66) RNA Log10 (copies)/mL and median CD4 count was 326 (201-654) cells/mm3. As compared to HIV-negative adolescents, TNFα was highly expressed among ALPHI (p<0.01). Following a virological response, inflammatory cytokines (IFNγ and IL-12), anti-inflammatory cytokines (IL-4 and IL-10) and inflammation-related cytokines (IL-6 and IL-1β) were highly expressed with viral suppression (VS) vs. virological failure (VF), while the chemokine CCL3 was highly expressed with VF (p<0.01). Regarding the immune response, the inflammatory cytokine TNFα was highly expressed in those that are immunocompetent (CD4≥500 cell/mm3) vs. immunocompromised (CD4<500 cell/mm3), p ≤ 0.01; while chemokine CCL2 was highly expressed in the immunocompromised (p<0.05). In the presence of ADRMs, IL-4 and CCL3 were highly expressed (p=0.027 and p=0.043 respectively). Among ART-experienced ALPHI in Cameroon, the TNFα cytokine was found to be an inflammatory marker of HIV infection; IFNγ, IL-1β, IL-6, and IL-12 are potential immunological markers of VS and targeting these cytokines in addition to antiretroviral drugs may improve management. Moreover, CCL3 and CCL2 are possible predictors of VF and/or being immunocompromised and could serve as surrogates of poor ART response