Autoantibodies neutralizing type I interferons (IFN-Is) can underlie infection severity. Here, we trace the development of these autoantibodies at high-resolution using longitudinal samples from 1,876 well-treated individuals living with HIV over a 35-year period. Similar to general populations, ∼1.9% of individuals acquired anti-IFN-I autoantibodies as they aged (median onset ∼63 years). Once detected, anti-IFN-I autoantibodies persisted lifelong, and titers increased over decades. Individuals developed distinct neutralizing and non-neutralizing autoantibody repertoires at discrete times that selectively targeted combinations of IFNα, IFNβ, and IFNω. Emergence of neutralizing anti-IFNα autoantibodies correlated with reduced baseline IFN-stimulated gene levels and was associated with subsequent susceptibility to severe COVID-19 several years later. Retrospective measurements revealed enrichment of pre-existing autoreactivity against other autoantigens in individuals who later developed anti-IFN-I autoantibodies, and there was evidence for prior viral infections or increased IFN at the time of anti-IFN-I autoantibody triggering. These analyses suggest that age-related loss of self-tolerance prior to IFN-I immune-triggering poses a risk of developing lifelong functional IFN-I deficiency.
<p>Figure 1 Mean ({plus minus}SD) serum lumretuzumab profiles following multiple ascending doses from 100 mg up to 2000 mg Figure 2 Percentage change in standardized uptake value maximum from baseline as assessed by FDG-PET at (a) Cycle 1 Day 14 and (b) Cycle 4 Day 14 Table 1 Summary of baseline and change in HER3 expression measured by IHC in skin and tumor biopsy samples pre and post treatment with lumretuzumab Table 2 Summary of change in expression of HER3, HER2, EGFR and cMET in fresh tumor biopsies compared to primary archival samples Table 3 Peripheral blood immunophenotyping (T, B and NK cells and NK subsets) from patients dosed with 2000 mg lumretuzumab Table 4 Ex-vivo activation potential of peripheral NK lymphocytes for all patients at ba seline and following exposure to lumretuzumab in the 2000 mg dose cohort Table 5 Summary of tumor immune effector cell infiltration Table 6 Tumor response to treatment (RECIST)</p>
These are pseudo-anonymised data from the eFASH randomised trial: "Ultrasound in managing extrapulmonary tuberculosis: A randomised, controlled, parallel, superiority, open-label trial". There is one dataset, containing baseline and outcome data (one row per participant). The data dictionary explains the data available. Between September 2018 and October 2020, 701 eligible and consenting participants were enrolled from two health facilities in Tanzania, and followed up for six months. The protocol was published, DOI: 10.1186/s12879-020-05073-9.
PCR-based detection of Mucorales species could improve diagnosis of suspected invasive fungal infection, leading to a better patient outcome. This study describes two independent probe-based real-time PCR tests for detection of clinically relevant Mucorales, targeting specific fragments of the 18S and the 28S rRNA genes. Both assays have a short turnaround time, allow fast, specific and very sensitive detection of clinically relevant Mucorales and have the potential to be used as quantitative tests. They were validated on various clinical samples (fresh and formalin-fixed paraffin-embedded specimens, mainly biopsies, n = 17). The assays should be used as add-on tools to complement standard techniques; a combined approach of both real-time PCR assays has 100 % sensitivity. Genus identification by subsequent sequencing is possible for amplicons of the 18S PCR assay. In conclusion, combination of the two independent Mucorales assays described in this study, 18S and 28S, detected all clinical samples associated with proven Mucorales infection (n = 10). Reliable and specific identification of Mucorales is a prerequisite for successful antifungal therapy as these fungi show intrinsic resistance to voriconazole and caspofungin.
Importance Hypertension is the primary cardiovascular risk factor in Africa. Recently revised World Health Organization guidelines recommend starting antihypertensive dual therapy; clinical efficacy and tolerability of low-dose triple combination remain unclear. Objectives To compare the effect of 3 treatment strategies on blood pressure control among persons with untreated hypertension in Africa. Design, Setting, and Participants This was an open-label, parallel, 3-arm randomized clinical trial to evaluate noninferiority of a strategy starting 2 pills vs full-dose monotherapy with stepped escalation (noninferiority margin 10%) and superiority of starting low-dose 3 pills vs monotherapy allowing for monthly up titration. Recruitment lasted from March 5, 2020, to March 30, 2022. The setting was 2 hospitals in rural Lesotho and Tanzania. Participants included nonpregnant Black African individuals 18 years and older with uncomplicated, untreated hypertension (standardized office blood pressure ≥140 mm Hg systolic or ≥90 mm Hg diastolic). Interventions Participants were randomized 2:2:1 to stepped monotherapy (amlodipine, 10 mg, with escalation to add hydrochlorothiazide if needed), 2-pill strategy (amlodipine, 5 mg; losartan, 25 mg), or 3-pill strategy (amlodipine, 2.5 mg; losartan, 12.5 mg; hydrochlorothiazide, 6.25 mg). Drugs were up titrated monthly until reaching the target blood pressure (≤ 130/80 mm Hg for participants aged &lt;65 years; ≤140/90 mm Hg for those aged ≥65 years). Main Outcomes and Measures Proportion of participants reaching target blood pressure at 12 weeks. Results Of 1761 participants screened, 1268 were enrolled (median [IQR] age, 54 [45-65] years; 914 female [72%]), with 505 in the monotherapy cohort, 510 in the 2-pill cohort, and 253 in the 3-pill cohort. In noninferiority analyses, 207 of 370 participants (56%) receiving the 2-pill strategy and 173 of 338 participants (51%) receiving the stepped monotherapy strategy achieved the blood pressure target (adjusted odds ratio [aOR], 1.18; 95% CI, 0.87-1.61), fulfilling noninferiority. In superiority analyses after multiple imputation for missing outcome data, 57% of participants receiving the 3-pill strategy, 55% receiving the 2-pill strategy, and 49% receiving the stepped monotherapy strategy reached the target blood pressure (aOR, 1.24; 95% CI, 0.94-1.63; P = .12 and aOR, 1.28; 95% CI, 0.91-1.79; P = .16 for the 2-pill and 3-pill vs stepped monotherapy strategies, respectively). Conclusions and Relevance Results of this randomized clinical trial show that in 2 African settings, for adults with uncomplicated untreated hypertension, a strategy starting a 2-pill low-dose treatment was noninferior to starting stepped monotherapy. Two-pill and 3-pill low-dose strategies were not superior to stepped monotherapy. Wide CIs preclude the ability to rule out potentially clinically important effects of the additional pill strategies for hypertension control. Trial Registration ClinicalTrials.gov Identifier: NCT04129840
11095 Background: Human epidermal growth factor receptor 3 (HER3) can play a critical role in tumor growth, proliferation and progression. The glycoengineered humanized monoclonal HER3-targeting antibody RG7116 is currently in phase I development (NCT01482377). Knowledge about whole body target expression, drug biodistribution and organ pharmacokinetics is lacking from many phase I designs. The aim of this imaging study is to determine in vivo biodistribution and tumor targeting characteristics of RG7116 by means of immunoPET using 89Zr-RG7116. Methods: Patients with HER3-positive metastatic or locally advanced solid tumors underwent 89Zr-RG7116-PET before treatment with RG7116. To determine optimal tracer dose and imaging schedule patients received 89Zr-RG7116 with increasing doses of unlabeled RG7116 followed by up to 3 PET scans until 7 days post injection (pi). Tracer uptake in organs of interest and tumor lesions was quantified as standardized uptake value (SUV) and tumor-to-background ratios (TBR) were calculated. Results: 13 patients participated without experiencing major safety issues. Initially, 7 patients received 37 MBq 89Zr-RG7116 containing 10, 50 or 100 mg unlabeled RG7116. The optimal dose was 100 mg and PET 2 days pi did not add valuable information. Subsequent patients (n=6) were evaluated at the 100 mg dose with PET scans 4 and 7 days pi. In all 13 patients tracer uptake in tumor lesions was seen, including in 12/13 biopsied HER3-positive lesions. In 3 of the 13 patients previously unknown brain and bone metastases were also detected. At the 100 mg dose 37 tumor lesions (9 patients) were quantifiable, with mean SUVmax 4 days pi of 4.2 (±1.8 SD). Normal antibody tissue distribution was seen with mean SUVmax 4 days pi for liver 8.1, intestine 6.5, blood pool 6.2, kidney 5.0, spleen 4.9, and low uptake in the vertebrae 2.7, lung 1.4, muscle 1.1 and brain 0.5, resulting in mean TBR of 3.60 (range 1.10-9.53). Conclusions: With 89Zr-RG7116-PET biodistribution of RG7116 was determined and tumor specific uptake of 89Zr-RG7116 was shown in patients with HER3-positive metastatic cancer. Analysis of HER3 saturation by repeated 89Zr-RG7116-PET scanning is ongoing. Clinical trial information: NCT01482377.
