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Frontiers in Medicine 2023The blockade of interleukine-1 (anakinra and canakinumab) is a well-known highly effective tool for monogenic autoinflammatory diseases (AIDs), such as familial...
INTRODUCTION
The blockade of interleukine-1 (anakinra and canakinumab) is a well-known highly effective tool for monogenic autoinflammatory diseases (AIDs), such as familial Mediterranean fever, tumor necrosis factor receptor-associated periodic syndrome, hyperimmunoglobulinaemia D syndrome, and cryopyrin-associated periodic syndrome, but this treatment has not been assessed for patients with undifferentiated AIDs (uAIDs). Our study aimed to assess the safety and efficacy of canakinumab for patients with uAIDs.
METHODS
Information on 32 patients with uAIDs was retrospectively collected and analyzed. Next-generation sequencing and Federici criteria were used for the exclusion of the known monogenic AID.
RESULTS
The median age of the first episode was 2.5 years (IQR: 1.3; 5.5), that of the disease diagnosis was 5.7 years (IQR: 2.5;12.7), and that of diagnostic delay was 1.1 years (IQR: 0.4; 6.1). Patients had variations in the following genes: , and . The main clinical features were fever (100%), rash (91%; maculopapular predominantly), joint involvement (72%), splenomegaly (66%), hepatomegaly (59%), lymphadenopathy (50%), myalgia (28%), heart involvement (31%), intestinal involvement (19%); eye involvement (9%), pleuritis (16%), ascites (6%), deafness, hydrocephalia (3%), and failure to thrive (25%). Initial treatment before canakinumab consisted of non-biologic therapies: non-steroidal anti-inflammatory drugs (NSAID) (91%), corticosteroids (88%), methotrexate (38%), intravenous immunoglobulin (IVIG) (34%), cyclosporine A (25%), colchicine (6%) cyclophosphamide (6%), sulfasalazine (3%), mycophenolate mofetil (3%), hydroxychloroquine (3%), and biologic drugs: tocilizumab (62%), sarilumab, etanercept, adalimumab, rituximab, and infliximab (all 3%). Canakinumab induced complete remission in 27 patients (84%) and partial remission in one patient (3%). Two patients (6%) were primary non-responders, and two patients (6%) further developed secondary inefficacy. All patients with partial efficacy or inefficacy were switched to tocilizumab ( = 4) and sarilumab ( = 1). The total duration of canakinumab treatment was 3.6 (0.1; 8.7) years. During the study, there were no reported Serious Adverse Events (SAEs). The patients experienced non-frequent mild respiratory infections at a rate that is similar as before canakinumab is administered. Additionally, one patient developed leucopenia, but it was not necessary to stop canakinumab for this patient.
CONCLUSION
The treatment of patients with uAIDs using canakinumab was safe and effective. Further randomized clinical trials are required to confirm the efficacy and safety.
PubMed: 38034538
DOI: 10.3389/fmed.2023.1257045 -
International Journal of Molecular... Sep 2023HIV-associated neurocognitive disorders (HANDs) still persist despite improved life expectancy, reduced viral loads, and decreased infection severity. The number of... (Review)
Review
HIV-associated neurocognitive disorders (HANDs) still persist despite improved life expectancy, reduced viral loads, and decreased infection severity. The number of patients affected by HANDs ranges from (30 to 50) % of HIV-infected individuals. The pathological mechanisms contributing to HANDs and the most serious manifestation of the disease, HIV-associated dementia (HAD), are not yet well understood. Evidence suggests that these mechanisms are likely multifactorial, producing neurocognitive complications involving disorders such as neurogenesis, autophagy, neuroinflammation, and mitochondrial dysfunction. Over the years, multiple pharmacological approaches with specific mechanisms of action acting upon distinct targets have been approved. Although these therapies are effective in reducing viral loading to undetectable levels, they also present some disadvantages such as common side effects, the need for administration with a very high frequency, and the possibility of drug resistance. Genetic studies on HANDs provide insights into the biological pathways and mechanisms that contribute to cognitive impairment in people living with HIV-1. Furthermore, they also help identify genetic variants that increase susceptibility to HANDs and can be used to tailor treatment approaches for HIV-1 patients. Identification of the genetic markers associated with disease progression can help clinicians predict which individuals require more aggressive management and by understanding the genetic basis of the disorder, it will be possible to develop targeted therapies to mitigate cognitive impairment. The main goal of this review is to provide details on the epidemiological data currently available and to summarise the genetic (specifically, the genetic makeup of the immune system), transcriptomic, and epigenetic studies available on HANDs to date. In addition, we address the potential pharmacological therapeutic strategies currently being investigated. This will provide valuable information that can guide clinical care, drug development, and our overall understanding of these diseases.
Topics: Humans; HIV Infections; Genomics; Neurocognitive Disorders; HIV-1; AIDS Dementia Complex
PubMed: 37762667
DOI: 10.3390/ijms241814364 -
Pediatric Rheumatology Online Journal Oct 2023Monogenic autoinflammatory diseases (AIDs) are rare inflammatory diseases caused by genetic variants. The pathogenesis is complex and treatment options are limited. This...
BACKGROUND
Monogenic autoinflammatory diseases (AIDs) are rare inflammatory diseases caused by genetic variants. The pathogenesis is complex and treatment options are limited. This study aimed to describe the safety and efficacy of thalidomide in the treatment of monogenic AIDs.
METHODS
This was a single-center, single-arm, real-world study. From September 2016 to August 2021, patients with monogenic AIDs who met the inclusion and exclusion criteria were given thalidomide for 12 months. There was a 3-month run-in period before dosing. The efficacy and adverse events were evaluated and recorded every 3 months. After 3 and 12 months of thalidomide treatment, clinical manifestations, disease activity score, inflammatory markers, and background medication adjustments were compared with baseline for efficacy analyses.
RESULTS
A total of 16 patients entered this study, including 3 with Aicardi-Goutières syndrome (AGS), 4 Blau syndrome, 2 chronic infantile neurologic cutaneous articular syndrome (CINCA), 2 A20 haploinsufficiency (HA20), 1 adenosine deaminase 2 deficiency(DADA2), 1 familial Mediterranean fever (FMF),1 tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS), 1 PLCγ2-associated antibody deficiency and immune dysregulation (PLAID), and 1 stimulator of interferon genes-associated vasculopathy with onset in infancy(SAVI). The efficacy rate in the 16 patients after 3-month and 12-month thalidomide treatment in patients was 56.3%. Twelve patients completed the study, the fever improved in all of them, rash improved in 7 patients, and 5 patients stopped using glucocorticoids or other immunosuppressive agents. C-reactive protein was normal in 8 patients and erythrocyte sedimentation rate was normal in 11 patients. Anorexia and nausea occurred in 2 cases, with no other reported drug-related adverse reactions.
CONCLUSION
The largest cohort of monogenic AIDs with the treatment of thalidomide demonstrated that thalidomide can help reduce disease activity and inflammation, reduce the dosage of glucocorticoids, and improve clinical outcomes. Thalidomide is relatively safe in monogenic AIDs.
Topics: Humans; Child; Thalidomide; Adenosine Deaminase; Intercellular Signaling Peptides and Proteins; Hereditary Autoinflammatory Diseases; Familial Mediterranean Fever; Cryopyrin-Associated Periodic Syndromes
PubMed: 37848905
DOI: 10.1186/s12969-023-00881-0 -
Resuscitation Plus Sep 2024To compare the effectiveness of cognitive aid use during resuscitation with no use of cognitive aids on cardiopulmonary resuscitation quality and performance. (Review)
Review
OBJECTIVES
To compare the effectiveness of cognitive aid use during resuscitation with no use of cognitive aids on cardiopulmonary resuscitation quality and performance.
METHODS
This systematic review followed the PICOST format. All randomised controlled trials and non-randomised studies evaluating cognitive aid use during (simulated) resuscitation were included in any setting. Unpublished studies were excluded. We did not include studies that reported cognitive aid use during training for resuscitation alone. Medline, Embase and Cochrane databases were searched from inception until July 2019 (updated August 2022, November 2023, and 23 April 2024). We did not search trial registries. Title and abstract screening, full-text screening, data extraction, risk of bias assessment (using RoB2 and ROBINS-I), and certainty of evidence (using GRADE) were performed by two researchers. PRISMA reporting standards were followed, and registration (PROSPERO CRD42020159162, version 19 July 2022) was performed. No funding has been obtained.
RESULTS
The literature search identified 5029 citations. After removing 512 duplicates, reviewing the titles and abstracts of the remaining articles yielded 103 articles for full-text review. Hand-searching identified 3 more studies for full-text review. Of these, 29 studies were included in the final analysis. No clinical studies involving patients were identified. The review was limited to indirect evidence from simulation studies only. The results are presented in five different populations: healthcare professionals managing simulated resuscitations in neonates, children, adult advanced life support, and other emergencies; as well as lay providers managing resuscitations. Main outcomes were adherence to protocol or process, adherence to protocol or process assessed by performance score, CPR performance and retention, and feasibility of chatbot guidance. The risk of bias assessment ranged from low to high. Studies in neonatal, paediatric and adult life support delivered by healthcare professionals showed benefits of using cognitive aids, however, some studies evaluating resuscitations by lay providers reported undesirable effects. The performance of a -analysis was not possible due to significant methodological heterogeneity. The certainty of evidence was rated as moderate to very low due to serious indirectness, (very) serious risk of bias, serious inconsistency and (very) serious imprecision.
CONCLUSION
Because of the very low certainty evidence from simulation studies, we suggest that cognitive aids should be used by healthcare professionals during resuscitation. In contrast, we do not suggest use of cognitive aids for lay providers, based on low certainty evidence.
PubMed: 38873274
DOI: 10.1016/j.resplu.2024.100675 -
MMWR. Morbidity and Mortality Weekly... Feb 2024In the United States, annual influenza vaccination is recommended for all persons aged ≥6 months. Using data from four vaccine effectiveness (VE) networks during the...
In the United States, annual influenza vaccination is recommended for all persons aged ≥6 months. Using data from four vaccine effectiveness (VE) networks during the 2023-24 influenza season, interim influenza VE was estimated among patients aged ≥6 months with acute respiratory illness-associated medical encounters using a test-negative case-control study design. Among children and adolescents aged 6 months-17 years, VE against influenza-associated outpatient visits ranged from 59% to 67% and against influenza-associated hospitalization ranged from 52% to 61%. Among adults aged ≥18 years, VE against influenza-associated outpatient visits ranged from 33% to 49% and against hospitalization from 41% to 44%. VE against influenza A ranged from 46% to 59% for children and adolescents and from 27% to 46% for adults across settings. VE against influenza B ranged from 64% to 89% for pediatric patients in outpatient settings and from 60% to 78% for all adults across settings. These findings demonstrate that the 2023-24 seasonal influenza vaccine is effective at reducing the risk for medically attended influenza virus infection. CDC recommends that all persons aged ≥6 months who have not yet been vaccinated this season get vaccinated while influenza circulates locally.
Topics: Adolescent; Adult; Humans; Child; Influenza Vaccines; Influenza, Human; Seasons; Case-Control Studies; Vaccine Efficacy
PubMed: 38421935
DOI: 10.15585/mmwr.mm7308a3 -
PLoS Medicine Sep 2023• Human immunodeficiency virus (HIV) drug resistance has implications for antiretroviral treatment strategies and for containing the HIV pandemic because the...
• Human immunodeficiency virus (HIV) drug resistance has implications for antiretroviral treatment strategies and for containing the HIV pandemic because the development of HIV drug resistance leads to the requirement for antiretroviral drugs that may be less effective, less well-tolerated, and more expensive than those used in first-line regimens. • HIV drug resistance studies are designed to determine which HIV mutations are selected by antiretroviral drugs and, in turn, how these mutations affect antiretroviral drug susceptibility and response to future antiretroviral treatment regimens. • Such studies collectively form a vital knowledge base essential for monitoring global HIV drug resistance trends, interpreting HIV genotypic tests, and updating HIV treatment guidelines. • Although HIV drug resistance data are collected in many studies, such data are often not publicly shared, prompting the need to recommend best practices to encourage and standardize HIV drug resistance data sharing. • In contrast to other viruses, sharing HIV sequences from phylogenetic studies of transmission dynamics requires additional precautions as HIV transmission is criminalized in many countries and regions. • Our recommendations are designed to ensure that the data that contribute to HIV drug resistance knowledge will be available without undue hardship to those publishing HIV drug resistance studies and without risk to people living with HIV.
Topics: Humans; HIV Infections; Phylogeny; HIV-1; Drug Resistance, Viral; Anti-Retroviral Agents; Mutation; Anti-HIV Agents
PubMed: 37738247
DOI: 10.1371/journal.pmed.1004293 -
The Lancet. Digital Health Dec 2023Extremely preterm infants (<28 weeks of gestation) are at great risk of long-term neurodevelopmental impairments. Early amplitude-integrated electroencephalogram (aEEG)...
Early qualitative and quantitative amplitude-integrated electroencephalogram and raw electroencephalogram for predicting long-term neurodevelopmental outcomes in extremely preterm infants in the Netherlands: a 10-year cohort study.
BACKGROUND
Extremely preterm infants (<28 weeks of gestation) are at great risk of long-term neurodevelopmental impairments. Early amplitude-integrated electroencephalogram (aEEG) accompanied by raw EEG traces (aEEG-EEG) has potential for predicting subsequent outcomes in preterm infants. We aimed to determine whether and which qualitative and quantitative aEEG-EEG features obtained within the first postnatal days predict neurodevelopmental outcomes in extremely preterm infants.
METHODS
This study retrospectively analysed a cohort of extremely preterm infants (born before 28 weeks and 0 days of gestation) who underwent continuous two-channel aEEG-EEG monitoring during their first 3 postnatal days at Wilhelmina Children's Hospital, Utrecht, the Netherlands, between June 1, 2008, and Sept 30, 2018. Only infants who did not have genetic or metabolic diseases or major congenital malformations were eligible for inclusion. Features were extracted from preprocessed aEEG-EEG signals, comprising qualitative parameters grouped in three types (background pattern, sleep-wake cycling, and seizure activity) and quantitative metrics grouped in four categories (spectral content, amplitude, connectivity, and discontinuity). Machine learning-based regression and classification models were used to evaluate the predictive value of the extracted aEEG-EEG features for 13 outcomes, including cognitive, motor, and behavioural problem outcomes, at 2-3 years and 5-7 years. Potential confounders (gestational age at birth, maternal education, illness severity, morphine cumulative dose, the presence of severe brain injury, and the administration of antiseizure, sedative, or anaesthetic medications) were controlled for in all prediction analyses.
FINDINGS
369 infants were included and an extensive set of 339 aEEG-EEG features was extracted, comprising nine qualitative parameters and 330 quantitative metrics. The machine learning-based regression models showed significant but relatively weak predictive performance (ranging from r=0·13 to r=0·23) for nine of 13 outcomes. However, the machine learning-based classifiers exhibited acceptable performance in identifying infants with intellectual impairments from those with optimal outcomes at age 5-7 years, achieving balanced accuracies of 0·77 (95% CI 0·62-0·90; p=0·0020) for full-scale intelligence quotient score and 0·81 (0·65-0·96; p=0·0010) for verbal intelligence quotient score. Both classifiers maintained identical performance when solely using quantitative features, achieving balanced accuracies of 0·77 (95% CI 0·63-0·91; p=0·0030) for full-scale intelligence quotient score and 0·81 (0·65-0·96; p=0·0010) for verbal intelligence quotient score.
INTERPRETATION
These findings highlight the potential benefits of using early postnatal aEEG-EEG features to automatically recognise extremely preterm infants with poor outcomes, facilitating the development of an interpretable prognostic tool that aids in decision making and therapy planning.
FUNDING
European Commission Horizon 2020.
Topics: Infant; Child; Humans; Infant, Newborn; Child, Preschool; Infant, Extremely Premature; Cohort Studies; Retrospective Studies; Netherlands; Electroencephalography
PubMed: 37940489
DOI: 10.1016/S2589-7500(23)00198-X -
Antimicrobial Agents and Chemotherapy Nov 2023Physiological changes during pregnancy may alter the pharmacokinetics (PK) of antituberculosis drugs. The International Maternal Pediatric Adolescent AIDS Clinical...
Pharmacokinetics and safety of first-line tuberculosis drugs rifampin, isoniazid, ethambutol, and pyrazinamide during pregnancy and postpartum: results from IMPAACT P1026s.
Physiological changes during pregnancy may alter the pharmacokinetics (PK) of antituberculosis drugs. The International Maternal Pediatric Adolescent AIDS Clinical Trials Network P1026s was a multicenter, phase IV, observational, prospective PK and safety study of antiretroviral and antituberculosis drugs administered as part of clinical care in pregnant persons living with and without HIV. We assessed the effects of pregnancy on rifampin, isoniazid, ethambutol, and pyrazinamide PK in pregnant and postpartum (PP) persons without HIV treated for drug-susceptible tuberculosis disease. Daily antituberculosis treatment was prescribed following World Health Organization-recommended weight-band dosing guidelines. Steady-state 12-hour PK profiles of rifampin, isoniazid, ethambutol, and pyrazinamide were performed during second trimester (2T), third trimester (3T), and 2-8 of weeks PP. PK parameters were characterized using noncompartmental analysis, and comparisons were made using geometric mean ratios (GMRs) with 90% confidence intervals (CI). Twenty-seven participants were included: 11 African, 9 Asian, 3 Hispanic, and 4 mixed descent. PK data were available for 17, 21, and 14 participants in 2T, 3T, and PP, respectively. Rifampin and pyrazinamide AUC and in pregnancy were comparable to PP with the GMR between 0.80 and 1.25. Compared to PP, isoniazid AUC was 25% lower and was 23% lower in 3T. Ethambutol AUC was 39% lower in 3T but limited by a low PP sample size. In summary, isoniazid and ethambutol concentrations were lower during pregnancy compared to PP concentrations, while rifampin and pyrazinamide concentrations were similar. However, the median AUC for rifampin, isoniazid, and pyrazinamide met the therapeutic targets. The clinical impact of lower isoniazid and ethambutol exposure during pregnancy needs to be determined.
Topics: Adolescent; Female; Humans; Pregnancy; Antitubercular Agents; Ethambutol; HIV Infections; Isoniazid; Postpartum Period; Prospective Studies; Pyrazinamide; Rifampin; Tuberculosis; Multicenter Studies as Topic; Clinical Trials, Phase IV as Topic; Observational Studies as Topic
PubMed: 37882552
DOI: 10.1128/aac.00737-23 -
Journal of the International AIDS... Aug 2023Common mental disorders (CMDs) are highly prevalent among people with HIV. Integrating mental healthcare into HIV care may improve mental health and HIV treatment...
Availability of screening and treatment for common mental disorders in HIV clinic settings: data from the global International epidemiology Databases to Evaluate AIDS (IeDEA) Consortium, 2016-2017 and 2020.
INTRODUCTION
Common mental disorders (CMDs) are highly prevalent among people with HIV. Integrating mental healthcare into HIV care may improve mental health and HIV treatment outcomes. We describe the reported availability of screening and treatment for depression, anxiety and post-traumatic stress disorder (PTSD) at global HIV treatment centres participating in the International epidemiology Databases to Evaluate AIDS (IeDEA) Consortium in 2020 and changes in availability at sites in low- or middle-income countries (LMICs) between 2016/2017 and 2020.
METHODS
In 2020, 238 sites contributing individual-level data to the IeDEA Consortium and in 2016/2017 a stratified random sample of IeDEA sites in LMICs were eligible to participate in site surveys on the availability of screening and treatment for CMDs. We assessed trends over time for 68 sites across 27 LMICs that participated in both surveys.
RESULTS
Among the 238 sites eligible to participate in the 2020 site survey, 227 (95%) participated, and mental health screening and treatment data were available for 223 (98%) sites across 41 countries. A total of 95 sites across 29 LMICs completed the 2016/2017 survey. In 2020, 68% of sites were in urban settings, and 77% were in LMICs. Overall, 50%, 14% and 12% of sites reported screening with a validated instrument for depression, anxiety and PTSD, respectively. Screening plus treatment in the form of counselling was available for depression, anxiety and PTSD at 46%, 13% and 11% of sites, respectively. Screening plus treatment in the form of medication was available for depression, anxiety and PTSD at 36%, 11% and 8% of sites, respectively. Among sites that participated in both surveys, screening for depression was more commonly available in 2020 than 2016/2017 (75% vs. 59%, respectively, p = 0.048).
CONCLUSIONS
Reported availability of screening for depression increased among this group of IeDEA sites in LMICs between 2016/2017 and 2020. However, substantial gaps persist in the availability of mental healthcare at HIV treatment sites across global settings, particularly in resource-constrained settings. Implementation of sustainable strategies to integrate mental health services into HIV care is needed.
Topics: Humans; Acquired Immunodeficiency Syndrome; HIV Infections; Stress Disorders, Post-Traumatic; Anxiety Disorders; Ambulatory Care Facilities
PubMed: 37535703
DOI: 10.1002/jia2.26147 -
JCI Insight Mar 2024BACKGROUNDNovel biomarkers to identify infectious patients transmitting Mycobacterium tuberculosis are urgently needed to control the global tuberculosis (TB) pandemic....
BACKGROUNDNovel biomarkers to identify infectious patients transmitting Mycobacterium tuberculosis are urgently needed to control the global tuberculosis (TB) pandemic. We hypothesized that proteins released into the plasma in active pulmonary TB are clinically useful biomarkers to distinguish TB cases from healthy individuals and patients with other respiratory infections.METHODSWe applied a highly sensitive non-depletion tandem mass spectrometry discovery approach to investigate plasma protein expression in pulmonary TB cases compared to healthy controls in South African and Peruvian cohorts. Bioinformatic analysis using linear modeling and network correlation analyses identified 118 differentially expressed proteins, significant through 3 complementary analytical pipelines. Candidate biomarkers were subsequently analyzed in 2 validation cohorts of differing ethnicity using antibody-based proximity extension assays.RESULTSTB-specific host biomarkers were confirmed. A 6-protein diagnostic panel, comprising FETUB, FCGR3B, LRG1, SELL, CD14, and ADA2, differentiated patients with pulmonary TB from healthy controls and patients with other respiratory infections with high sensitivity and specificity in both cohorts.CONCLUSIONThis biomarker panel exceeds the World Health Organization Target Product Profile specificity criteria for a triage test for TB. The new biomarkers have potential for further development as near-patient TB screening assays, thereby helping to close the case-detection gap that fuels the global pandemic.FUNDINGMedical Research Council (MRC) (MR/R001065/1, MR/S024220/1, MR/P023754/1, and MR/W025728/1); the MRC and the UK Foreign Commonwealth and Development Office; the UK National Institute for Health Research (NIHR); the Wellcome Trust (094000, 203135, and CC2112); Starter Grant for Clinical Lecturers (Academy of Medical Sciences UK); the British Infection Association; the Program for Advanced Research Capacities for AIDS in Peru at Universidad Peruana Cayetano Heredia (D43TW00976301) from the Fogarty International Center at the US NIH; the UK Technology Strategy Board/Innovate UK (101556); the Francis Crick Institute, which receives funding from UKRI-MRC (CC2112); Cancer Research UK (CC2112); and the NIHR Biomedical Research Centre of Imperial College NHS.
Topics: Humans; Biomarkers; Proteomics; Male; Female; Adult; Tuberculosis, Pulmonary; Mycobacterium tuberculosis; Middle Aged; Peru; South Africa; Case-Control Studies; Sensitivity and Specificity
PubMed: 38512356
DOI: 10.1172/jci.insight.173273