The results show that our regimen has strong immunologic and antitumor activity in colorectal cancer patients and deserves to be investigated in phase III trials.

Exfoliation syndrome (XFS) is the commonest known risk factor for secondary glaucoma and a significant cause of blindness worldwide. Variants in two genes, LOXL1 and CACNA1A have been previously associated with XFS. To further elucidate the genetic basis of XFS, we collected a global sample of XFS cases to refine the association at LOXL1, which previously showed inconsistent results between populations, and to identify new variants associated with XFS. We identified a rare, protective allele at LOXL1 (p.407Phe, OR = 25, P =2.9 × 10−14) through deep resequencing of XFS cases and controls from 9 countries. This variant results in increased cellular adhesion strength compared to the wild-type (p.407Tyr) allele. A genome-wide association study (GWAS) of XFS cases and controls from 24 countries followed by replication in 18 countries identified seven genome-wide significant loci (P < 5 × 10−8). Index variants at the new loci map to chromosomes 13q12 (POMP), 11q23.3 (TMEM136), 6p21 (AGPAT1), 3p24 (RBMS3) and 5q23 (near SEMA6A). These findings provide biological insights into the pathology of XFS, and highlight a potential role for naturally occurring rare LOXL1 variants in disease biology.

To the Editor: Whether or not persons who have already been infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) should be vaccinated is unclear. Only a few studies have shown that vaccinees who were previously infected with SARS-CoV-2 had a significantly higher antibody response than previously uninfected vaccinees. [1][2][3][4] In an observational cohort study, we enrolled 100 health care workers, including 38 (9 men and 29 women) with a documented history of SARS-CoV-2 infection (mean duration between infection and vaccination, 111 days). The mean age of these previously infected participants was 35.1 years (95% confidence interval [CI], 31.7 to 38.6). Our study also included 62 participants (25 men and 37 women) who had not been previously infected. The mean age of those participants was 44.7 years (95% CI, 41.0 to 47.6).Both groups of participants received the messenger RNA vaccine BNT162b2 (Pfizer-BioNTech). Serum samples were obtained from the previously infected participants 10 days after the administration of the first dose and from the previously uninfected participants 10 days after the administration of the second dose. Thereafter, all the participants were screened for the presence of specific anti-SARS-CoV-2 spike IgG by means of a chemiluminescence microparticle immunoassay.No significant difference in circulating antispike IgG antibody titers was observed between the samples from previously infected participants (mean level, 20,120 arbitrary units per milliliter; 95% CI, 16,400 to 23,800) and those from previously uninfected participants (mean level, 22,639 arbitrary units per milliliter; 95% CI, 19,400 to 25,900) (median levels are shown in Fig. 1A). Circulating anti-spike IgG antibodies were not detected in only one previously infected participant; that participant did not have an antibody response to natural infection with SARS-CoV-2.

The presence of the endogenous Leishmania RNA virus 1 (LRV1) replicating stably within some parasite species has been associated with the development of more severe forms of leishmaniasis and relapses after drug treatment in humans. Here, we show that the disease-exacerbatory role of LRV1 relies on type I IFN (type I IFNs) production by macrophages and signaling in vivo. Moreover, infecting mice with the LRV1-cured Leishmania guyanensis (LgyLRV1 − ) strain of parasites followed by type I IFN treatment increased lesion size and parasite burden, quantitatively reproducing the LRV1-bearing (LgyLRV1 + ) infection phenotype. This finding suggested the possibility that exogenous viral infections could likewise increase pathogenicity, which was tested by coinfecting mice with L. guyanensis and lymphocytic choriomeningitis virus (LCMV), or the sand fly-transmitted arbovirus Toscana virus (TOSV). The type I IFN antiviral response increased the pathology of L. guyanensis infection, accompanied by down-regulation of the IFN-γ receptor normally required for antileishmanial control. Further, LCMV coinfection of IFN-γ-deficient mice promoted parasite dissemination to secondary sites, reproducing the LgyLRV1 + metastatic phenotype. Remarkably, LCMV coinfection of mice that had healed from L. guyanensis infection induced reactivation of disease pathology, overriding the protective adaptive immune response. Our findings establish that type I IFN-dependent responses, arising from endogenous viral elements (dsRNA/LRV1), or exogenous coinfection with IFN-inducing viruses, are able to synergize with New World Leishmania parasites in both primary and relapse infections. Thus, viral infections likely represent a significant risk factor along with parasite and host factors, thereby contributing to the pathological spectrum of human leishmaniasis.Leishmania RNA virus 1 | Totiviridae | arboviruses | trypanosomatid protozoan parasite | Leishmania subgenus Viannia

Impact of recently discovered viruses on epidemiology of acute respiratory tract infections (ARTI) is still unclear. We studied the impact of recently discovered human metapneumovirus (hMPV), human bocavirus (HBoV), and new coronaviruses (HCoV-NL63 and HKU1) on the global epidemiology of ARTI. From October 2006 to April 2007, 237 pediatric patients affected by ARTI were enrolled in our study. Specimens were tested for respiratory viruses by polymerase chain reaction. One hundred twenty-four out of 237 samples (52.3%) were positive for one or more viruses. Picornaviruses were the most prevalent viruses (n = 61, 43.6%), followed by respiratory syncytial virus (n = 34, 24.3%) and Adenovirus (n = 25, 17.9%); hMPV (n = 9, 6.4%) was the fourth most common virus detected. HBoV and HCoV showed a low prevalence (respectively 2.9% and 2.1%). RSV was the prevalent agent of LRTI (38%). Viruses were identified in more than 50% of the studied ARTI, providing useful information on clinical features and epidemiology of specific agents affecting children in cold months. Although routine surveillance of respiratory viruses does not seem cost-effective, continuous monitoring of ARTI etiology could be a useful tool for planning resources for the development of new vaccines and antiviral agents.