About cancer screenings and saving lives: measuring the effects of cancer screening programs through meta-analyses—A comment to the meta-analysis “Estimated Lifetime Gained With Cancer Screening Tests” by Bretthauer et al. (2023)

A meta-analysis of randomized clinical trials conducted by Bretthauer et al. to evaluate the advantage of cancer screening, recently published by Jama Internal Medicine, concluded that “common cancer screenings do not save lives with the possible exception of sigmoidoscopy screening” (1). The Authors derive their conclusion from estimates of lifetime gained with screening by “comparing all-cause mortality in people who underwent screening with those who did not.” They used the relative risk of death from any cause measured from randomized trials of cancer screenings and the average follow-up time of the unscreened group to obtain estimates of lifetime gained with screening. Both Bretthauer et al. in their meta-analysis and a comment paper appeared in the same number of JAMA Internal Medicine express the view that only randomized controlled trials can provide evidence of (cancer) screening efficacy and that a reduction of all-cause mortality is the measure of choice to evaluate efficacy (instead of the commonly used cancer-specific mortality) (1, 2). The reason for their choice is that a reduced risk of cancer specific deaths, if it is not associated with a reduced risk of all- cause mortality, can be considered the consequence of deaths associated with harmful effects of screening counterbalancing the screening benefit or of substitution of cancer specific deaths with death from competing causes. Nevertheless, we contend that the use of too stringent criteria led to an underestimation of the influence of screening on all-cause mortality in the meta-analysis authored by Bretthauer et al. and that the use of all-cause mortality implies small and unreliable estimates of screening efficacy (1). We believe that small estimates of relative risk for all-cause mortality should not be interpreted as minor effect of a cancer screening but indicate the opportunity to investigate the presence of bias in cause of death assignment and eventual harm of screening. With respect to the results published by Bretthauer et al., we also remark that 10–15 years of follow-up are insufficient to fully evaluate the impact of screening. Furthermore, low adherence to screening and uptake of screening in the control arm led to underestimation of screening efficacy in some randomized trials. Finally, evidence from observational studies should not be completely ignored, particularly for cancer screening that reduces incidence of infiltrative cancers

Analysis of Neuropeptide S Receptor Gene (NPSR1) Polymorphism in Rheumatoid Arthritis

Polymorphism in the neuropeptide S receptor gene NPSR1 is associated with asthma and inflammatory bowel disease. NPSR1 is expressed in the brain, where it modulates anxiety and responses to stress, but also in other tissues and cell types including lymphocytes, the lungs, and the intestine, where it appears to be up-regulated in inflammation. We sought to determine whether genetic variability at the NPSR1 locus influences the susceptibility and clinical manifestation of rheumatoid arthritis (RA).From the Epidemiological Investigation of Rheumatoid Arthritis (EIRA) case-control study, 1,888 rheumatoid arthritis patients and 888 controls were genotyped for 19 single-nucleotide polymorphisms (SNPs) spanning the entire NPSR1 gene and 220 KB of DNA on chromosome 7p14. The association between individual genetic markers and their haplotypic combinations, respectively, and diagnosis of RA, presence of autoantibodies to citrullinated proteins (ACPA), and disease activity score based on 28 joints (DAS28) was tested. There was no association between diagnosis of RA and NPSR1 variants. However, several associations of nominal significance were detected concerning susceptibility to ACPA-negative RA and disease activity measures (DAS28). Among these, the association of SNP rs324987 with ACPA-negative RA [(p=0.004, OR=0.674 (95% CI 0.512-0.888)] and that of SNP rs10263447 with DAS28 [p=0.0002, OR=0.380 (95% CI 0.227-0.635)] remained significant after correction for multiple comparisons.NPSR1 polymorphism may be relevant to RA susceptibility and its clinical manifestation. Specific alleles at the NPSR1 locus may represent common risk factors for chronic inflammatory diseases, including RA

The high frequency of manic symptoms in fibromyalgia does influence the choice of treatment?

BACKGROUND: Mood disorders were found associated with fibromyalgia (FM) and clinical studies have revealed the efficacy of antidepressant drugs in the treatment of FM. However no specific instruments to identify manic symptoms were used. OBJECTIVES: To assess the frequency of anxiety and mood disorders (particularly bipolar disorders and manic symptoms) in a consecutive sample of women affected by FM using standardized diagnostic tools and to compare the prevalence of these disorders with that observed in a sample of healthy controls from the general population. METHODS: Cases: consecutive series of women (N = 37, mean age 50.1 ± 21.0) attending a Rheumatology outpatient Unit at the University of Cagliari. Controls: 148 women, drawn from the data bank of an epidemiological study matched for sex and age with controls according to a randomisation "after blocks" method. The Italian version of the Composite International Diagnostic Interview Simplified were carried out by physicians. Psychiatric diagnosis was formulated according to DSM-IV criteria. The Italian version of the Mood Disorder Questionnaire (MDQ) was administered to identify manic symptoms and bipolar disorders. Diagnosis of FM were carried out by rheumatologist according to the criteria of American College of Rheumatology. RESULTS: Subjects with FM showed a higher comorbidity with Generalised Anxiety Disorder, Panic Disorder and Major Depressive Disorder than controls. The study showed a high frequency of manic symptoms (MDQ positive) in the sample of fibromyalgic patients (59%), approximately double that found in the control sample (P < 0.001). DISCUSSION: Clinical studies have shown the efficacy of antidepressants, especially tricyclic antidepressants, in the treatment of FM. The clinical difficulty in identifying hypomanic episodes is well known particularly where previous and not present episodes are concerned as in depressive patients. These data would suggest further studies on the subject are needed and more caution also in prescribing antidepressants in a population apparently at high risk for bipolar disorders

The asthma candidate gene NPSR1 mediates isoform specific downstream signalling

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An explainable model of host genetic interactions linked to COVID-19 severity

We employed a multifaceted computational strategy to identify the genetic factors contributing to increased risk of severe COVID-19 infection from a Whole Exome Sequencing (WES) dataset of a cohort of 2000 Italian patients. We coupled a stratified k-fold screening, to rank variants more associated with severity, with the training of multiple supervised classifiers, to predict severity based on screened features. Feature importance analysis from tree-based models allowed us to identify 16 variants with the highest support which, together with age and gender covariates, were found to be most predictive of COVID-19 severity. When tested on a follow-up cohort, our ensemble of models predicted severity with high accuracy (ACC = 81.88%; AUCROC = 96%; MCC = 61.55%). Our model recapitulated a vast literature of emerging molecular mechanisms and genetic factors linked to COVID-19 response and extends previous landmark Genome-Wide Association Studies (GWAS). It revealed a network of interplaying genetic signatures converging on established immune system and inflammatory processes linked to viral infection response. It also identified additional processes cross-talking with immune pathways, such as GPCR signaling, which might offer additional opportunities for therapeutic intervention and patient stratification. Publicly available PheWAS datasets revealed that several variants were significantly associated with phenotypic traits such as "Respiratory or thoracic disease", supporting their link with COVID-19 severity outcome.A multifaceted computational strategy identifies 16 genetic variants contributing to increased risk of severe COVID-19 infection from a Whole Exome Sequencing dataset of a cohort of Italian patients

A genome-wide association study for survival from a multi-centre European study identified variants associated with COVID-19 risk of death

: The clinical manifestations of SARS-CoV-2 infection vary widely among patients, from asymptomatic to life-threatening. Host genetics is one of the factors that contributes to this variability as previously reported by the COVID-19 Host Genetics Initiative (HGI), which identified sixteen loci associated with COVID-19 severity. Herein, we investigated the genetic determinants of COVID-19 mortality, by performing a case-only genome-wide survival analysis, 60 days after infection, of 3904 COVID-19 patients from the GEN-COVID and other European series (EGAS00001005304 study of the COVID-19 HGI). Using imputed genotype data, we carried out a survival analysis using the Cox model adjusted for age, age2, sex, series, time of infection, and the first ten principal components. We observed a genome-wide significant (P-value < 5.0 × 10-8) association of the rs117011822 variant, on chromosome 11, of rs7208524 on chromosome 17, approaching the genome-wide threshold (P-value = 5.19 × 10-8). A total of 113 variants were associated with survival at P-value < 1.0 × 10-5 and most of them regulated the expression of genes involved in immune response (e.g., CD300 and KLR genes), or in lung repair and function (e.g., FGF19 and CDH13). Overall, our results suggest that germline variants may modulate COVID-19 risk of death, possibly through the regulation of gene expression in immune response and lung function pathways

Carriers of ADAMTS13 Rare Variants Are at High Risk of Life-Threatening COVID-19

Thrombosis of small and large vessels is reported as a key player in COVID-19 severity. However, host genetic determinants of this susceptibility are still unclear. Congenital Thrombotic Thrombocytopenic Purpura is a severe autosomal recessive disorder characterized by uncleaved ultra-large vWF and thrombotic microangiopathy, frequently triggered by infections. Carriers are reported to be asymptomatic. Exome analysis of about 3000 SARS-CoV-2 infected subjects of different severities, belonging to the GEN-COVID cohort, revealed the specific role of vWF cleaving enzyme ADAMTS13 (A disintegrin-like and metalloprotease with thrombospondin type 1 motif, 13). We report here that ultra-rare variants in a heterozygous state lead to a rare form of COVID-19 characterized by hyper-inflammation signs, which segregates in families as an autosomal dominant disorder conditioned by SARS-CoV-2 infection, sex, and age. This has clinical relevance due to the availability of drugs such as Caplacizumab, which inhibits vWF-platelet interaction, and Crizanlizumab, which, by inhibiting P-selectin binding to its ligands, prevents leukocyte recruitment and platelet aggregation at the site of vascular damage

Gain- and Loss-of-Function CFTR Alleles Are Associated with COVID-19 Clinical Outcomes

Carriers of single pathogenic variants of the CFTR (cystic fibrosis transmembrane conductance regulator) gene have a higher risk of severe COVID-19 and 14-day death. The machine learning post-Mendelian model pinpointed CFTR as a bidirectional modulator of COVID-19 outcomes. Here, we demonstrate that the rare complex allele [G576V;R668C] is associated with a milder disease via a gain-of-function mechanism. Conversely, CFTR ultra-rare alleles with reduced function are associated with disease severity either alone (dominant disorder) or with another hypomorphic allele in the second chromosome (recessive disorder) with a global residual CFTR activity between 50 to 91%. Furthermore, we characterized novel CFTR complex alleles, including [A238V;F508del], [R74W;D1270N;V201M], [I1027T;F508del], [I506V;D1168G], and simple alleles, including R347C, F1052V, Y625N, I328V, K68E, A309D, A252T, G542*, V562I, R1066H, I506V, I807M, which lead to a reduced CFTR function and thus, to more severe COVID-19. In conclusion, CFTR genetic analysis is an important tool in identifying patients at risk of severe COVID-19

The polymorphism L412F in TLR3 inhibits autophagy and is a marker of severe COVID-19 in males

The polymorphism L412F in TLR3 has been associated with several infectious diseases. However, the mechanism underlying this association is still unexplored. Here, we show that the L412F polymorphism in TLR3 is a marker of severity in COVID-19. This association increases in the sub-cohort of males. Impaired macroautophagy/autophagy and reduced TNF/TNFα production was demonstrated in HEK293 cells transfected with TLR3L412F-encoding plasmid and stimulated with specific agonist poly(I:C). A statistically significant reduced survival at 28 days was shown in L412F COVID-19 patients treated with the autophagy-inhibitor hydroxychloroquine (p = 0.038). An increased frequency of autoimmune disorders such as co-morbidity was found in L412F COVID-19 males with specific class II HLA haplotypes prone to autoantigen presentation. Our analyses indicate that L412F polymorphism makes males at risk of severe COVID-19 and provides a rationale for reinterpreting clinical trials considering autophagy pathways. Abbreviations: AP: autophagosome; AUC: area under the curve; BafA1: bafilomycin A1; COVID-19: coronavirus disease-2019; HCQ: hydroxychloroquine; RAP: rapamycin; ROC: receiver operating characteristic; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; TLR: toll like receptor; TNF/TNF-α: tumor necrosis factor

Multiple Polymorphisms Affect Expression and Function of the Neuropeptide S Receptor (NPSR1)

Peer reviewe