Monogenic conditions that disrupt proper development and/or function of the immune system are termed inborn errors of immunity (IEIs), also known as primary immunodeficiencies. Patients with IEIs ...often suffer from other manifestations in addition to infection, and allergic inflammation is an increasingly recognized feature of these conditions.
We performed a retrospective analysis of IEIs presenting with allergic inflammation as reported in the USIDNET registry. Our inclusion criteria comprised of patients with a reported monogenic cause for IEI where reported lab eosinophil and/or IgE values were available for the patient prior to them receiving potentially curative therapy. Patients were excluded if we were unable to determine the defective gene underlying their IEI. Patients were classified as having eosinophilia or elevated IgE when their record included at least 1 eosinophil count or IgE value that was greater than the age stratified upper limit of normal. We compared the proportion of patients with eosinophilia or elevated IgE with the proportion of samples in a reference population that fall above the upper limit of normal (2.5%).
The query submitted to the USIDNET registry identified 1409 patients meeting inclusion criteria with a monogenic cause for their IEI diagnosis, of which 975 had eosinophil counts and 645 had IgE levels obtained prior to transplantation or gene therapy that were available for analysis. Overall, 18.8% (183/975) of the patients evaluated from the USIDNET registry had eosinophilia and 20.9% (135/645) had an elevated IgE. IEIs caused by defects in 32 genes were found to be significantly associated with eosinophilia and/or an elevated IgE level, spanning 7 of the 10 IEI categories according to the International Union of Immunological Societies classification.
Type 2 inflammation manifesting as eosinophilia or elevated IgE is found in a broad range of IEIs in the USIDNET registry. Our findings suggest that allergic immune dysregulation may be more widespread in IEIs than previously reported.
Epidermal growth factor receptor (EGFR) inhibitors prevent cell growth and have shown benefit in the treatment of metastatic colorectal cancer, whether used as single agents or in combination with ...chemotherapy. Clear benefit has been shown in trials of EGFR monoclonal antibodies (EGFR MAb) but not EGFR tyrosine kinase inhibitors (EGFR TKI). However, there is ongoing debate as to which patient populations gain maximum benefit from EGFR inhibition and where they should be used in the metastatic colorectal cancer treatment paradigm to maximise efficacy and minimise toxicity.
To determine the efficacy, safety profile, and potential harms of EGFR inhibitors in the treatment of people with metastatic colorectal cancer when given alone, in combination with chemotherapy, or with other biological agents.The primary outcome of interest was progression-free survival; secondary outcomes included overall survival, tumour response rate, quality of life, and adverse events.
We searched the Cochrane Central Register of Controlled Trials (CENTRAL), the Cochrane Library, Issue 9, 2016; Ovid MEDLINE (from 1950); and Ovid Embase (from 1974) on 9 September 2016; and ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) on 14 March 2017. We also searched proceedings from the major oncology conferences ESMO, ASCO, and ASCO GI from 2012 to December 2016. We further scanned reference lists from eligible publications and contacted corresponding authors for trials for further information where needed.
We included randomised controlled trials on participants with metastatic colorectal cancer comparing: 1) the combination of EGFR MAb and 'standard therapy' (whether chemotherapy or best supportive care) to standard therapy alone, 2) the combination of EGFR TKI and standard therapy to standard therapy alone, 3) the combination of EGFR inhibitor (whether MAb or TKI) and standard therapy to another EGFR inhibitor (or the same inhibitor with a different dosing regimen) and standard therapy, or 4) the combination of EGFR inhibitor (whether MAb or TKI), anti-angiogenic therapy, and standard therapy to anti-angiogenic therapy and standard therapy alone.
We used standard methodological procedures defined by Cochrane. Summary statistics for the endpoints used hazard ratios (HR) with 95% confidence intervals (CI) for overall survival and progression-free survival, and odds ratios (OR) for response rate (RR) and toxicity. Subgroup analyses were performed by Kirsten rat sarcoma viral oncogene homolog (KRAS) and neuroblastoma RAS viral (V-Ras) oncogene homolog (NRAS) status - firstly by status of KRAS exon 2 testing (mutant or wild type) and also by status of extended KRAS/NRAS testing (any mutation present or wild type).
We identified 33 randomised controlled trials for analysis (15,025 participants), including trials of both EGFR MAb and EGFR TKI. Looking across studies, significant risk of bias was present, particularly with regard to the risk of selection bias (15/33 unclear risk, 1/33 high risk), performance bias (9/33 unclear risk, 9/33 high risk), and detection bias (7/33 unclear risk, 11/33 high risk).The addition of EGFR MAb to standard therapy in the KRAS exon 2 wild-type population improves progression-free survival (HR 0.70, 95% CI 0.60 to 0.82; high-quality evidence), overall survival (HR 0.88, 95% CI 0.80 to 0.98; high-quality evidence), and response rate (OR 2.41, 95% CI 1.70 to 3.41; high-quality evidence). We noted evidence of significant statistical heterogeneity in all three of these analyses (progression-free survival: I
= 76%; overall survival: I
= 40%; and response rate: I
= 77%), likely due to pooling of studies investigating EGFR MAb use in different lines of therapy. Rates of overall grade 3 to 4 toxicity, diarrhoea, and rash were increased (moderate-quality evidence for all three outcomes), but there was no evidence for increased rates of neutropenia.For the extended RAS wild-type population (no mutations in KRAS or NRAS), addition of EGFR MAb improved progression-free survival (HR 0.60, 95% CI 0.48 to 0.75; moderate-quality evidence) and overall survival (HR 0.77, 95% CI 0.67 to 0.88; high-quality evidence). Response rate was also improved (OR 4.28, 95% CI 2.61 to 7.03; moderate-quality evidence). We noted significant statistical heterogeneity in the progression-free survival analysis (I
= 61%), likely due to the pooling of studies combining EGFR MAb with chemotherapy with monotherapy studies.We observed no evidence of a statistically significant difference when EGFR MAb was compared to bevacizumab, in progression-free survival (HR 1.02, 95% CI 0.93 to 1.12; high quality evidence) or overall survival (HR 0.84, 95% CI 0.70 to 1.01; moderate-quality evidence). We noted significant statistical heterogeneity in the overall survival analysis (I
= 51%), likely due to the pooling of first-line and second-line studies.The addition of EGFR TKI to standard therapy in molecularly unselected participants did not show benefit in limited data sets (meta-analysis not performed). The addition of EGFR MAb to bevacizumab plus chemotherapy in people with KRAS exon 2 wild-type metastatic colorectal cancer did not improve progression-free survival (HR 1.04, 95% CI 0.83 to 1.29; very low quality evidence), overall survival (HR 1.00, 95% CI 0.69 to 1.47; low-quality evidence), or response rate (OR 1.20, 95% CI 0.67 to 2.12; very low-quality evidence) but increased toxicity (OR 2.57, 95% CI 1.45 to 4.57; low-quality evidence). We noted significant between-study heterogeneity in most analyses.Scant information on quality of life was reported in the identified studies.
The addition of EGFR MAb to either chemotherapy or best supportive care improves progression-free survival (moderate- to high-quality evidence), overall survival (high-quality evidence), and tumour response rate (moderate- to high-quality evidence), but may increase toxicity in people with KRAS exon 2 wild-type or extended RAS wild-type metastatic colorectal cancer (moderate-quality evidence). The addition of EGFR TKI to standard therapy does not improve clinical outcomes. EGFR MAb combined with bevacizumab is of no clinical value (very low-quality evidence). Future studies should focus on optimal sequencing and predictive biomarkers and collect quality of life data.
Cryptococcosis remains the leading cause of fungal meningitis worldwide, caused primarily by the pathogen Cryptococcus neoformans. Symptomatic cryptococcal infections typically affect ...immunocompromised patients. However, environmental exposure to cryptococcal spores is ubiquitous and most healthy individuals are thought to harbor infections from early childhood onwards that are either resolved, or become latent. Since macrophages are a key host cell for cryptococcal infection, we sought to quantify the extent of individual variation in this early phagocyte response within a small cohort of healthy volunteers with no reported immunocompromising conditions. We show that rates of both intracellular fungal proliferation and non-lytic expulsion (vomocytosis) are remarkably variable between individuals. However, we demonstrate that neither gender, in vitro host inflammatory cytokine profiles, nor polymorphisms in several key immune genes are responsible for this variation. Thus the data we present serve to quantify the natural variation in macrophage responses to this important human pathogen and will hopefully provide a useful "benchmark" for the research community.
In a genome-wide association study to identify loci associated with colorectal cancer (CRC) risk, we genotyped 555,510 SNPs in 1,012 early-onset Scottish CRC cases and 1,012 controls (phase 1). In ...phase 2, we genotyped the 15,008 highest-ranked SNPs in 2,057 Scottish cases and 2,111 controls. We then genotyped the five highest-ranked SNPs from the joint phase 1 and 2 analysis in 14,500 cases and 13,294 controls from seven populations, and identified a previously unreported association, rs3802842 on 11q23 (OR = 1.1; P = 5.8 × 10−10), showing population differences in risk. We also replicated and fine-mapped associations at 8q24 (rs7014346; OR = 1.19; P = 8.6 × 10−26) and 18q21 (rs4939827; OR = 1.2; P = 7.8 × 10−28). Risk was greater for rectal than for colon cancer for rs3802842 (P < 0.008) and rs4939827 (P < 0.009). Carrying all six possible risk alleles yielded OR = 2.6 (95% CI = 1.75-3.89) for CRC. These findings extend our understanding of the role of common genetic variation in CRC etiology.
Genome-wide association studies (GWAS) have identified ten loci harboring common variants that influence risk of developing colorectal cancer (CRC). To enhance the power to identify additional CRC ...risk loci, we conducted a meta-analysis of three GWAS from the UK which included a total of 3,334 affected individuals (cases) and 4,628 controls followed by multiple validation analyses including a total of 18,095 cases and 20,197 controls. We identified associations at four new CRC risk loci: 1q41 (rs6691170, odds ratio (OR) = 1.06, P = 9.55 × 10−10 and rs6687758, OR = 1.09, P = 2.27 × 10−9), 3q26.2 (rs10936599, OR = 0.93, P = 3.39 × 10−8), 12q13.13 (rs11169552, OR = 0.92, P = 1.89 × 10−10 and rs7136702, OR = 1.06, P = 4.02 × 10−8) and 20q13.33 (rs4925386, OR = 0.93, P = 1.89 × 10−10). In addition to identifying new CRC risk loci, this analysis provides evidence that additional CRC-associated variants of similar effect size remain to be discovered.
We characterise the evolutionary dynamics of influenza infection described by viral sequence data collected from two challenge studies conducted in human hosts. Viral sequence data were collected at ...regular intervals from infected hosts. Changes in the sequence data observed across time show that the within-host evolution of the virus was driven by the reversion of variants acquired during previous passaging of the virus. Treatment of some patients with oseltamivir on the first day of infection did not lead to the emergence of drug resistance variants in patients. Using an evolutionary model, we inferred the effective rate of reassortment between viral segments, measuring the extent to which randomly chosen viruses within the host exchange genetic material. We find strong evidence that the rate of effective reassortment is low, such that genetic associations between polymorphic loci in different segments are preserved during the course of an infection in a manner not compatible with epistasis. Combining our evidence with that of previous studies we suggest that spatial heterogeneity in the viral population may reduce the extent to which reassortment is observed. Our results do not contradict previous findings of high rates of viral reassortment in vitro and in small animal studies, but indicate that in human hosts the effective rate of reassortment may be substantially more limited.
Online weight control technologies could reduce barriers to treatment, including increased ease and convenience of self-monitoring. Self-monitoring consistently predicts outcomes in behavioral weight ...loss programs; however, little is known about patterns of self-monitoring associated with success.
The current study examines 161 participants (92% women; 31% African American; mean body mass index = 35.7 ± 5.7) randomized to a 6-month online behavioral weight control program that offered weekly group "chat" sessions and online self-monitoring. Self-monitoring log-ins were continuously monitored electronically during treatment and examined in association with weight change and demographics. Weekend and weekday log-ins were examined separately and length of periods of continuous self-monitoring were examined.
We found that 91% of participants logged in to the self-monitoring webpage at least once. Over 6 months, these participants monitored on an average of 28% of weekdays and 17% of weekend days, with most log-ins earlier in the program. Women were less likely to log-in, and there were trends for greater self-monitoring by older participants. Race, education, and marital status were not significant predictors of self-monitoring. Both weekday and weekend log-ins were significant independent predictors of weight loss. Patterns of consistent self-monitoring emerged early for participants who went on to achieve greater than a 5% weight loss.
Patterns of online self-monitoring were strongly associated with weight loss outcomes. These results suggest a specific focus on consistent self-monitoring early in a behavioral weight control program might be beneficial for achieving clinically significant weight losses.
Cryptococcus gattii is an emerging intracellular pathogen and the cause of the largest primary outbreak of a life-threatening fungal disease in a healthy population. Outbreak strains share a unique ...mitochondrial gene expression profile and an increased ability to tubularize their mitochondria within host macrophages. However, the underlying mechanism that causes this lineage of C. gattii to be virulent in immunocompetent individuals remains unexplained. Here we show that a subpopulation of intracellular C. gattii adopts a tubular mitochondrial morphology in response to host reactive oxygen species. These fungal cells then facilitate the rapid growth of neighbouring C. gattii cells with non-tubular mitochondria, allowing for effective establishment of the pathogen within a macrophage intracellular niche. Thus, host reactive oxygen species, an essential component of the innate immune response, act as major signalling molecules to trigger a 'division of labour' in the intracellular fungal population, leading to increased pathogenesis within this outbreak lineage.
Standard behavioral weight loss interventions often set uniform physical activity (PA) goals and promote PA self-monitoring; however, adherence remains a challenge, and recommendations may not ...accommodate all individuals. Identifying patterns of PA goal attainment and self-monitoring behavior will offer a deeper understanding of how individuals adhere to different types of commonly prescribed PA recommendations (ie, minutes of moderate-to-vigorous physical activity MVPA and daily steps) and guide future recommendations for improved intervention effectiveness.
This study examined weekly patterns of adherence to step-based and minute-based PA goals and self-monitoring behavior during a 6-month online behavioral weight loss intervention.
Participants were prescribed weekly PA goals for steps (7000-10,000 steps/day) and minutes of MVPA (50-200 minutes/week) as part of a lifestyle program. Goals gradually increased during the initial 2 months, followed by 4 months of fixed goals. PA was self-reported daily on the study website. For each week, participants were categorized as adherent if they self-monitored their PA and met the program PA goal, suboptimally adherent if they self-monitored but did not meet the program goal, or nonadherent if they did not self-monitor. The probability of transitioning into a less adherent status was examined using multinomial logistic regression.
Participants (N=212) were predominantly middle-aged females with obesity, and 67 (31.6%) self-identified as a racial/ethnic minority. Initially, 73 (34.4%) participants were categorized as adherent to step-based goals, with 110 51.9% suboptimally adherent and 29 13.7% nonadherent, and there was a high probability of either remaining suboptimally adherent from week to week or transitioning to a nonadherent status. However, 149 (70.3%) participants started out adherent to minute-based goals (34 16% suboptimally adherent and 29 13.7% nonadherent), with suboptimally adherent seen as the most variable status. During the graded goal phase, participants were more likely to transition to a less adherent status for minute-based goals (odds ratio OR 1.39, 95% CI 1.31-1.48) compared to step-based goals (OR 1.24, 95% CI 1.17-1.30); however, no differences were seen during the fixed goal phase (minute-based goals: OR 1.06, 95% CI 1.05-1.08; step-based goals: OR 1.07, 95% CI 1.05-1.08).
States of vulnerability to poor PA adherence can emerge rapidly and early in obesity treatment. There is a window of opportunity within the initial 2 months to bring more people toward adherent behavior, especially those who fail to meet the prescribed goals but engage in self-monitoring. Although this study describes the probability of adhering to step- and minute-based targets, it will be prudent to determine how individual characteristics and contextual states relate to these behavioral patterns, which can inform how best to adapt interventions.
ClinicalTrials.gov NCT02688621; https://clinicaltrials.gov/ct2/show/NCT02688621.
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