Nevin Manimala

Autoimmun Rev. 2021 Sep 8:102941. doi: 10.1016/j.autrev.2021.102941. Online ahead of print.

ABSTRACT

Although vaccination represents the most promising way to stop or contain the coronavirus disease 2019 (COVID-19) pandemic and safety and effectiveness of available vaccines were proven, a small number of individuals who received anti-SARS-CoV-2 vaccines developed a prothrombotic syndrome. Vaccine-induced immune thrombotic thrombocytopenia (VITT) can be triggered by the adenoviral vector-based vaccine, whereas lipid nanoparticle-mRNA-based vaccines can induce rare cases of deep vein thrombosis (DVT). Although the main pathogenic mechanisms behind this rare phenomenon have not yet been identified, both host and vaccine factors might be involved, with pathology at least in part being related to the vaccine-triggered autoimmune reaction. In this review, we are considering some aspects related to pathogenesis, major risk factors, as well as peculiarities of diagnosis and treatment of this rare condition.

PMID:34508917 | DOI:10.1016/j.autrev.2021.102941

J Natl Cancer Inst. 2021 Sep 11:djab177. doi: 10.1093/jnci/djab177. Online ahead of print.

ABSTRACT

Some concerns have been raised about potential bias in patient-reported outcome (PRO) results from open-label cancer randomized controlled trials (RCTs). We investigated if open-label trials favor the experimental treatment over the standard treatment more frequently than blinded trials. We also examined if the effect of treatment concealment differs for distal vs more proximal PROs. We assessed 538 RCTs with a PRO endpoint conducted in the most prevalent cancers, of which 366 (68.0%) were open-label, 148 (27.5%) were blinded, and 24 (4.5%) were categorized as unclear. In our multivariable logistic regression model, we did not observe a statistically significant association of the independent variable treatment concealment (open-label vs blinded) on the dependent variable measuring the proportion of trials favoring the experimental treatment (adjusted odds ratio = 1.19, 95% confidence interval = 0.79 to 1.79, 2-sided P = .40. This was also the case when comparing distal and proximal PROs. Our findings provide novel evidence-based data that support the validity of PRO results from open label cancer RCTs.

PMID:34508610 | DOI:10.1093/jnci/djab177

J Natl Cancer Inst. 2021 Sep 11:djab186. doi: 10.1093/jnci/djab186. Online ahead of print.

ABSTRACT

BACKGROUND: Incidence of estrogen receptor (ER)-negative breast cancer, an aggressive subtype, is highest in United States (US) African American women and in southern residents but has decreased overall since 1992. We assessed whether ER-negative breast cancer is decreasing in all age groups and cancer registries among non-Hispanic White (NHW), non-Hispanic Black (NHB), and Hispanic White (HW) women.

METHODS: We analyzed 17 Surveillance, Epidemiology, and End-Results Program registries (twelve for 1992-2016; five for 2000-2016) to assess NHW, NHB, and HW trends by ER status and age group (30-39, 40-49, 50-69, 70-84 years). We used hierarchical age-period-cohort models that account for sparse data, which improve estimates to quantify between-registry heterogeneity in mean incidence rates and age-adjusted trends versus SEER overall.

RESULTS: Overall, ER-negative incidence was highest in NHB, then NHW and HW women, and decreased from 1992-2016 in each age group and racial/ethnic group. The greatest decrease was for HW women ages 40-49 years with an annual percent change of -3.5%/year (95% credible interval = -4.4%, -2.7%), averaged over registries. The trend heterogeneity was statistically significant in every race/ethnic and age group. Furthermore, the incidence relative risks by race/ethnicity compared to the race-specific SEER average were also statistically significantly heterogeneous across the majority of registries and age groups (62 of 68 strata). The greatest heterogeneity was seen in HW women, followed by NHB women, and the least in NHW women.

CONCLUSION: Decreasing ER-negative breast cancer incidence differs meaningfully by US region and age among NHB and HW women. Analytical studies including minority women from higher and lower incidence areas may provide insights into breast cancer racial disparities.

PMID:34508608 | DOI:10.1093/jnci/djab186

Syst Biol. 2021 Sep 11:syab075. doi: 10.1093/sysbio/syab075. Online ahead of print.

ABSTRACT

The historical signal in nucleotide sequences becomes eroded over time by substitutions occurring repeatedly at the same sites. This phenomenon, known as substitution saturation, is recognized as one of the primary obstacles to deep-time phylogenetic inference using genome-scale data sets. We present a new test of substitution saturation and demonstrate its performance in simulated and empirical data. For some of the 36 empirical phylogenomic data sets that we examined, we detect substitution saturation in around 50% of loci. We found that saturation tends to be flagged as problematic in loci with highly discordant phylogenetic signals across sites. Within each data set, the loci with smaller numbers of informative sites are more likely to be flagged as containing problematic levels of saturation. The entropy saturation test proposed here is sensitive to high evolutionary rates relative to the evolutionary timeframe, while also being sensitive to several factors known to mislead phylogenetic inference, including short internal branches relative to external branches, short nucleotide sequences, and tree imbalance. Our study demonstrates that excluding loci with substitution saturation can be an effective means of mitigating the negative impact of multiple substitutions on phylogenetic inferences.

PMID:34508605 | DOI:10.1093/sysbio/syab075

J Natl Cancer Inst. 2021 Sep 11:djab171. doi: 10.1093/jnci/djab171. Online ahead of print.

ABSTRACT

BACKGROUND: Trials of immune checkpoint inhibitors (ICIs) have published patient-reported quality of life (QOL), but the size and heterogeneity of this literature can make patient education difficult. This meta-analysis aimed to describe change in QOL and symptomatology in patients receiving ICIs for cancer.

METHODS: Following PRISMA guidelines, databases were searched through November 2019 for articles or abstracts of prospective, original studies reporting longitudinal QOL in adult cancer patients treated with ICIs. The prespecified primary outcomes were change in global QOL among patients treated with ICIs and difference in change since baseline in global QOL between patients treated with ICI vs. non-ICI active treatment. Secondary outcomes included physical functioning and symptomatology. All statistical tests were 2-sided.

RESULTS: Twenty-six of 20,323 publications met inclusion criteria. Global QOL did not change over time in patients treated with ICIs (k = 26, n = 6,974, P = .19). Larger improvements in global QOL was observed in patients receiving ICI vs. non-ICI regimens (k = 16, ICI n = 3,588, non-ICI n = 2,948, P < .001). Physical functioning did not change in patients treated with ICIs (k = 14, n = 3,169, P=.47); there were no differences in mean change between ICI vs. non-ICI regimens (k = 11, n = 4,630, P=.94. Regarding symptoms, appetite loss, insomnia, and pain severity decreased but dyspnea severity increased in patients treated with ICIs (k = 14, n = 3,243-3,499) (Ps < 0.001). Insomnia severity was higher in patients treated with ICIs than non-ICI regimens (k = 11, n = 4,791) (P < .001).

CONCLUSIONS: This study is among the first to quantitatively summarize QOL in patients treated with ICIs. Findings suggest ICI recipients report no change in global QOL and higher QOL than patients treated with non-ICI regimens.

PMID:34508604 | DOI:10.1093/jnci/djab171

J Natl Cancer Inst. 2021 Sep 11:djab172. doi: 10.1093/jnci/djab172. Online ahead of print.

ABSTRACT

BACKGROUND: The symptom burden associated with cancer and its treatment can negatively impact patients’ quality of life and survival. Symptom-focused collaborative care model (CCM) interventions can improve outcomes, but only if patients engage with them. We assessed the receptivity of severely symptomatic oncology patients to a remote nurse-led CCM intervention.

METHODS: In a pragmatic, cluster-randomized, stepped wedge trial conducted as part of the NCI IMPACT Consortium (E2C2, NCT03892967), patients receiving cancer care were asked to rate their sleep disturbance, pain, anxiety, emotional distress, fatigue, and limitations in physical function. Patients reporting at least one severe symptom (≥7/10) were offered phone consultation with a nurse symptom care manager (RN SCM). Initially, patients had to “opt-in” to receive a call, but the protocol was later modified so they had to “opt-out” if they did not want a call. We assessed the impact of opt-in vs. opt-out framing and patient characteristics on receptiveness to RN SCM calls. All statistical tests were 2-sided.

RESULTS: Of the 1204 symptom assessments (from 864 patients) on which at least one severe symptom was documented, 469 (39.0%) indicated receptivity to an RN SCM phone call. The opt-out period (odds ratio [OR] = 1.61, 95% confidence interval [CI] = 1.12 to 2.32, p=.01), receiving care at a tertiary care center (OR = 3.59, 95% CI = 2.18 to 5.91, p<.001), and having severe pain (OR = 1.80, 95% CI = 1.24 to 2.62, p=.002), were associated with statistically significantly greater willingness to receive a call.

CONCLUSION: Many severely symptomatic patients were not receptive to an RN SCM phone call. Better understanding of reasons for refusal and strategies for improving patient receptivity are needed.

PMID:34508602 | DOI:10.1093/jnci/djab172

J Clin Endocrinol Metab. 2021 Sep 11:dgab671. doi: 10.1210/clinem/dgab671. Online ahead of print.

ABSTRACT

CONTEXT: Obesity prevalence has increased in type 1 diabetes (T1D). However, the relationship between body composition and severe diabetic eye disease (SDED) is unknown.

OBJECTIVE: To investigate the associations between body composition and SDED in adults with T1D.

METHODS: From 5401 adults with T1D in the Finnish Diabetic Nephropathy Study, we assessed 3468, and 437 underwent dual-energy-X-ray-absorptiometry for body composition analysis. The composite outcome was SDED, defined as proliferative retinopathy, laser treatment, anti-VEGF treatment, diabetic maculopathy, vitreous hemorrhage, and vitrectomy. Logistic regression analysis evaluated the associations between body composition and SDED. Multivariable Cox regression analysis assessed the associations between the anthropometric measures and SDED. Subgroup analysis was performed by stages of albuminuria. The relevance ranking of each variable was based on the z statistic.

RESULTS: During a median follow-up of 14.5 (IQR 7.8-17.5) years, 886 SDED events occurred. Visceral/android fat ratio was associated with SDED (OR 1.40, z=3.13), as well as the percentages of visceral (OR 1.80, z=2.45) and android fat (OR 1.28, z=2.08), but not the total body fat percentage. Waist-height ratio showed the strongest association with the SDED risk (HR=1.28, z= 3.73), followed by the waist (HR 1.01, z=3.03), body mass index (HR 1.03, z=2.33), and waist-hip ratio (HR 1.15, z=2.22). The results were similar in normo- and microalbuminuria, but not significant in macroalbuminuria. A WHtR ≥ 0.5 increased the SDED risk by 28% at the normo- and microalbuminuria stages.

CONCLUSIONS: WHtR, a hallmark of central obesity, is associated with SDED in individuals with type 1 diabetes.

PMID:34508598 | DOI:10.1210/clinem/dgab671

Hum Mol Genet. 2021 Sep 11:ddab261. doi: 10.1093/hmg/ddab261. Online ahead of print.

ABSTRACT

The use of external controls in genome-wide association study (GWAS) can significantly increase the size and diversity of the control sample, enabling high-resolution ancestry matching and enhancing the power to detect association signals. However, the aggregation of controls from multiple sources is challenging due to batch effects, difficulty in identifying genotyping errors, and the use of different genotyping platforms. These obstacles have impeded the use of external controls in GWAS and can lead to spurious results if not carefully addressed. We propose a unified data harmonization pipeline that includes an iterative approach to quality control (QC) and imputation, implemented before and after merging cohorts and arrays. We apply this harmonization pipeline to aggregate 27 517 European control samples from 16 collections within dbGaP. We leverage these harmonized controls to conduct a GWAS of Crohn’s disease. We demonstrate a boost in power over using the cohort samples alone, and that our procedure results in summary statistics free of any significant batch effects. This harmonization pipeline for aggregating genotype data from multiple sources can also serve other applications where individual level genotypes, rather than summary statistics, are required.

PMID:34508597 | DOI:10.1093/hmg/ddab261

Int J Epidemiol. 2021 Sep 11:dyab180. doi: 10.1093/ije/dyab180. Online ahead of print.

ABSTRACT

BACKGROUND: Research documents social and economic antecedents of adverse birth outcomes, which may include involuntary job loss. Previous work on job loss and adverse birth outcomes, however, lacks high-quality individual data on, and variation in, plausibly exogenous job loss during pregnancy and therefore cannot rule out strong confounding.

METHODS: We analysed unique linked registries in Denmark, from 1980 to 2017, to examine whether a father’s involuntary job loss during his spouse’s pregnancy increases the risk of a low-weight (i.e. <2500 grams) and/or preterm (i.e. <37 weeks of gestational age) birth. We applied a matched-sibling design to 743 574 sibling pairs.

RESULTS: Results indicate an increased risk of a low-weight birth among infants exposed in utero to fathers’ unexpected job loss [odds ratio (OR) = 1.37, 95% confidence interval (CI): 1.07, 1.75]. Sex-specific analyses show that this result holds for males (OR = 1.70, 95% CI: 1.14, 2.53) but not females (OR = 1.24, 95% CI: 0.80, 1.91). We find no relation with preterm birth.

CONCLUSIONS: Findings support the inference that a father’s unexpected job loss adversely affects the course of pregnancy, especially among males exposed in utero.

PMID:34508593 | DOI:10.1093/ije/dyab180

Rheumatology (Oxford). 2021 Sep 11:keab629. doi: 10.1093/rheumatology/keab629. Online ahead of print.

ABSTRACT

OBJECTIVES: To explore the efficacy of plasma exchange (PE) therapy in refractory idiopathic inflammatory myopathy (IIM) patients with positive anti-signal recognition particle (SRP) antibody.

METHODS: Nine refractory IIM patients with positive anti-SRP antibody were enrolled, who received PE therapy at Ruijin Hospital from Octobor 2017 to December 2020. The clinical manifestations, laboratory tests, chest CT and lower extremity MRI images before and after PE therapy were compared. The treatment response was evaluated by the 2016 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) myositis response criteria.

RESULTS: 88.9% (8/9) subjects had achieved improvement by 3 weeks after PE therapy, with 55.6% (5/9) minimal improvement and 33.3% (3/9) moderate improvement. There were statistically significant improvements between baseline and after PE therapy at 3 weeks on the core set measures: physician global activity, patient global activity, Health Assessment Questionnaire (HAQ), manual muscle testing (MMT), extramuscular disease activity, and muscle enzymes activity including creatine kinase (CK), lactate dehydrogenase (LDH), aspartate transaminase (AST), except for alanine transaminase (ALT). Moreover, the chest CT showed regression of ground glass opacities and irregular linear opacities after PE therapy in four patients with interstitial lung disease. The MRI images of lower extremity in four patients showed reduction of muscle oedema after the therapy.

CONCLUSION: PE therapy is effective for refractory IIM patients with positive anti-SRP antibody. It should be considered as an alternative treatment for those patients who are resistant to the combined therapy of glucocorticoids and immunosuppressive agents.

PMID:34508561 | DOI:10.1093/rheumatology/keab629