Smallpox vaccination campaigns resulted in age-associated population cross-immunity against monkeypox virus.

Increased human-to-human transmission of monkeypox virus (MPXV) is cause for concern, and antibodies directed against vaccinia virus (VACV) are known to confer cross-protection against Mpox. We used 430 serum samples derived from the Scottish patient population to investigate antibody-mediated cross-neutralization against MPXV. By combining electrochemiluminescence immunoassays with live-virus neutralization assays, we show that people born when smallpox vaccination was routinely offered in the United Kingdom have increased levels of antibodies that cross-neutralize MPXV. Our results suggest that age is a risk factor of Mpox infection, and people born after 1971 are at higher risk of infection upon exposure.

Impact of Japanese L1 Rhythm on English L2 Speech.

The study aimed to examine whether L1 speech rhythm affects L2 speech by assessing how the speech rhythm of Japanese L2 English speakers differed from native speakers. We chose Japanese and English because they differ markedly in the phonological properties that likely contribute to speech rhythm. Speech rhythm was measured by the variability of vowel and consonant intervals using rate-normalized rhythm metrics (VarcoV and VarcoC; nPVI-V and nPVI-C) and %V. The study utilized recordings of spoken sentences in English by 10 native Australian English speakers; and in English and also in Japanese by 10 native Japanese speakers (who had limited experience in speaking English). Experiment 1 compared the rhythm of L1 English (by measuring 1,750 vowels and 3,093 consonants from 20 sentences) and L1 Japanese (1,923 vowels and 2,097 consonants from 10 sentences). The results showed that for all measures, Japanese had reduced durational variability in both consonant and vowel intervals compared with English. In Experiment 2, we examined the rhythm characteristics of L1 and L2 English using 40 sentences (including the 20 in Experiment 1). The results showed that vowel and consonant intervals were less variable in L2 (Japanese English) than in L1 (Australian English) speech, mirroring the results of Experiment 1. Overall, the results are consistent with the proposal that L1 (Japanese) speech rhythm influenced L2 (English) speech.

Partner-directed gaze and co-speech hand gestures: effects of age, hearing loss and noise.

Research on the adaptations talkers make to different communication conditions during interactive conversations has primarily focused on speech signals. We extended this type of investigation to two other important communicative signals, i.e., partner-directed gaze and iconic co-speech hand gestures with the aim of determining if the adaptations made by older adults differ from younger adults across communication conditions. We recruited 57 pairs of participants, comprising 57 primary talkers and 57 secondary ones. Primary talkers consisted of three groups: 19 older adults with mild Hearing Loss (older adult-HL); 17 older adults with Normal Hearing (older adult-NH); and 21 younger adults. The DiapixUK "spot the difference" conversation-based task was used to elicit conversions in participant pairs. One easy (No Barrier: NB) and three difficult communication conditions were tested. The three conditions consisted of two in which the primary talker could hear clearly, but the secondary talkers could not, due to multi-talker babble noise (BAB1) or a less familiar hearing loss simulation (HLS), and a condition in which both the primary and secondary talkers heard each other in babble noise (BAB2). For primary talkers, we measured mean number of partner-directed gazes; mean total gaze duration; and the mean number of co-speech hand gestures. We found a robust effects of communication condition that interacted with participant group. Effects of age were found for both gaze and gesture in BAB1, i.e., older adult-NH looked and gestured less than younger adults did when the secondary talker experienced babble noise. For hearing status, a difference in gaze between older adult-NH and older adult-HL was found for the BAB1 condition; for gesture this difference was significant in all three difficult communication conditions (older adult-HL gazed and gestured more). We propose the age effect may be due to a decline in older adult's attention to cues signaling how well a conversation is progressing. To explain the hearing status effect, we suggest that older adult's attentional decline is offset by hearing loss because these participants have learned to pay greater attention to visual cues for understanding speech.

The gut microbiome modulates the impact of Anaerobutyricum soehngenii supplementation on glucose homeostasis in mice.

Background: There is growing interest in the development of next-generation probiotics to prevent or treat metabolic syndrome. Previous studies suggested that Anaerobutyricum soehngenii may represent a promising probiotic candidate. A recent human study showed that while A. soehngenii supplementation is well tolerated and safe, it resulted in variable responses among individuals with a subset of the subjects significantly benefiting from the treatment. We hypothesized that gut microbiome variation is linked to the heterogeneous responses to A. soehngenii treatment observed in humans. Results: We colonized germ-free mice with fecal microbiota from human subjects that responded to A. soehngenii treatment (R65 and R55) and non-responder subjects (N96 and N40). Colonized mice were fed a high-fat diet (45% kcal from fat) to induce insulin resistance, and orally treated with either live A. soehngenii culture or heat-killed culture. We found that R65-colonized mice received a benefit in glycemic control with live A. soehngenii treatment while mice colonized with microbiota from the other donors did not. The glucose homeostasis improvements observed in R65-colonized mice were positively correlated with levels of cecal propionate, an association that was reversed in N40-colonized mice. To test whether the microbiome modulates the effects of propionate, R65- or N40-colonized mice were treated with tripropionin (TP, glycerol tripropionate), a pro-drug of propionate, or glycerol (control). TP supplementation showed a similar response pattern as that observed in live A. soehngenii treatment, suggesting that propionate may mediate the effects of A. soehngenii. We also found that TP supplementation to conventional mice reduces adiposity, improves glycemic control, and reduces plasma insulin compared to control animals supplemented with glycerol. Conclusions: These findings highlight the importance of the microbiome on glycemic control and underscore the need to better understand personal microbiome-by-therapeutic interactions to develop more effective treatment strategies.

Second Allogeneic Hematopoietic Cell Transplantation for Relapsed Adult Acute Myeloid Leukemia: Outcomes and Prognostic Factors.

Second allogeneic hematopoietic cell transplantation (HCT2) is potentially curative for adults with acute myeloid leukemia (AML) or myelodysplastic neoplasm (MDS)/AML experiencing relapse after a first allograft (HCT1), but prognostic factors for outcomes are poorly characterized. To provide a detailed analysis of HCT2 outcomes and associated prognostic factors in a large single-center cohort, with a focus on identifying predictors of relapse and nonrelapse mortality (NRM). We studied adults ≥18 years who underwent HCT2 at a single institution between April 2006 and June 2022 for relapsed AML (n = 73) or MDS/AML (n = 8). With a median follow-up among survivors of 74.0 (range: 10.4 to 187.3) months, there were 30 relapses and 57 deaths, of which 29 were NRM events, contributing to the estimates for relapse, overall survival (OS), relapse-free survival (RFS), and NRM. Three-year estimates for relapse, RFS, and OS were 37% (95% confidence interval: 27% to 48%), 32% (23% to 44%), and 35% (26% to 47%). The rate of NRM at 100 days and 18 months was 20% (12% to 29%) and 28% (19% to 39%). Outcomes differed markedly across patient subsets and were substantially worse for patients who underwent HCT2 with active disease (ie, morphologic evidence of bone marrow and/or extramedullary disease), for patients who relapsed ≤6 months after HCT1, and for patients with higher HCT-specific Comorbidity Index (HCT-CI) or treatment-related mortality (TRM) scores. After multivariable adjustment, active disease was associated with a higher risk of relapse (hazard ratio [HR] = 3.19, P = .006) and shorter RFS (HR = 2.41, P = .008) as well as OS (HR = 2.17, P = .027) compared to transplant in morphologic remission without multiparameter flow cytometric evidence of measurable residual disease. Similarly, a relapse-free interval ≤6 months after the first allograft was associated with higher risk of relapse (HR = 5.86, P < .001) and shorter RFS (HR = 2.86; P = .001) and OS (HR = 2.45, P = .003). Additionally, a high HCT-CI score was associated with increased NRM (HR = 4.30, P = .035), and shorter RFS (HR = 3.87, P = .003) and OS (HR = 3.74, P = .006). Likewise, higher TRM scores were associated with increased risk of relapse (HR = 2.27; P = .024) and NRM (HR = 2.01, P = .001), and inferior RFS (HR = 1.90 P = .001) and OS (HR = 1.88, P = .001). A significant subset of patients with AML or MDS/AML relapse after HCT1 are alive and leukemia-free 3 years after undergoing HCT2. Our study identifies active leukemia at the time of HCT2 and early relapse after HCT1 as major adverse prognostic factors, highlighting patient subsets in particular need of novel therapeutic approaches, and supports the use of the HCT-CI and TRM scores for outcome prognostication.

Impact of socioeconomic disparities on outcomes in adults undergoing allogeneic hematopoietic cell transplantation for acute myeloid leukemia.

Racial and socioeconomic disparities impact outcomes after chemotherapy and limit access to allogeneic hematopoietic cell transplantation (HCT) in acute myeloid leukemia (AML), yet studies have yielded mixed results on the influence of disparities on post-HCT outcomes. Therefore, we studied 1024 adults with AML who underwent allogeneic HCT between 5/2006 and 10/2021 at a single large university-affiliated cancer center. Collected data included non-biologic and demographic characteristics (including race/ethnicity, marital status, distance traveled, and household size), transplant- and disease-related characteristics, and area-level and individual-level socioeconomic factors (i.e., area deprivation index and occupational status). After multivariable adjustment, no socioeconomic- or non-biologic factors were associated with non-relapse mortality (NRM), overall survival (OS), relapse-free survival (RFS), or relapse except being married (associated with improved NRM: hazard ratio [HR] = 0.7 [0.50-0.97]) and having no insurance (associated with worse OS: HR = 1.49 [1.05-2.12] and RFS: HR = 1.41 [1.00-1.98]). Despite a relatively racially homogenous cohort, Asian race was associated with improved NRM (HR = 0.47 [0.23-0.93]) and American Indian/Alaskan Native race was associated with higher relapse risk (HR = 2.45 [1.08-5.53]). In conclusion, in our retrospective analysis, socioeconomic-, demographic-, and non-biologic factors had limited impact on post-HCT outcomes in AML patients allografted in morphologic remission. Further research is needed to investigate disparities among HCT-eligible patients.

Hepatitis C virus diversity and treatment outcomes in Benin: a prospective cohort study.

BACKGROUND: 10 million people are chronically infected with the hepatitis C virus (HCV) in sub-Saharan Africa. The assessment of viral genotypes and treatment response in this region is necessary to achieve the WHO target of worldwide elimination of viral hepatitis by 2030. We aimed to investigate the prevalence of HCV genotypes and outcomes of treatment with direct-acting antiviral agents in Benin, a country with a national HCV seroprevalence of 4%. METHODS: This prospective cohort study was conducted at two referral hospitals in Benin. Individuals were eligible for inclusion if they were seropositive for HCV and willing to consent to participation in the study; exclusion criteria were an inability to give consent or incarceration. Viraemia was confirmed by PCR. The primary outcomes were to identify HCV genotypes and measure sustained virological response rates 12 weeks after completion of treatment (SVR12) with a 12-week course of sofosbuvir-velpatasvir or sofosbuvir-ledipasvir, with or without ribavirin. We conducted phylogenetic and resistance analyses after the next-generation sequencing of samples with a cycle threshold (Ct) value of 30 or fewer cycles. The in-vitro efficacy of NS5A inhibitors was tested using a subgenomic replicon assay. FINDINGS: Between June 2, 2019, and Dec 30, 2020, 148 individuals were screened for eligibility, of whom 100 were recruited prospectively to the study. Plasma samples from 79 (79%) of the 100 participants were positive for HCV by PCR. At the time of the study, 52 (66%) of 79 patients had completed treatment, with an SVR12 rate of 94% (49 of 52). 57 (72%) of 79 samples had a Ct value of 30 or fewer cycles and were suitable for whole-genome sequencing, from which we characterised 29 (51%) samples as genotype 1 and 28 (49%) as genotype 2. Three new genotype 1 subtypes (1q, 1r, and 1s) and one new genotype 2 subtype (2xa) were identified. The most commonly detected subtype was 2d (12 [21%] of 57 samples), followed by 1s (eight [14%]), 1r (five [9%]), 1b (four [7%]), 1q (three [5%]), 2xa (three [5%]), and 2b (two [3%]). 20 samples (11 genotype 2 and nine genotype 1) were unassigned new singleton lineages. 53 (93%) of 57 sequenced samples had at least two resistance-associated substitutions within the NS5A gene. Subtype 2d was associated with a lower-than-expected SVR12 rate (eight [80%] of ten patients). For one patient, with subtype 2b, treatment was not successful. INTERPRETATION: This study revealed a high SVR rate in Benin among individuals treated for HCV with sofosbuvir-velpatasvir, including those with highly diverse viral genotypes. Further studies of treatment effectiveness in genotypes 2d and 2b are indicated. FUNDING: Medical Research Council, Wellcome, Global Challenges Research Fund, Academy of Medical Sciences, and PHARMBIOTRAC.

Viruses associated with measles-like illnesses in Uganda.

OBJECTIVES: In this study, we investigated the causes of measles-like illnesses (MLI) in the Uganda national surveillance program in order to inform diagnostic assay selection and vaccination strategies. METHODS: We used metagenomic next-generation sequencing (M-NGS) on the Illumina platform to identify viruses associated with MLI (defined as fever and rash in the presence of either cough, coryza or conjunctivitis) in patient samples that had tested IgM negative for measles between 2010 and 2019. RESULTS: Viral genomes were identified in 87/271 (32%) of samples, of which 44/271 (16%) contained 12 known viral pathogens. Expected viruses included rubella, human parvovirus B19, Epstein Barr virus, human herpesvirus 6B, human cytomegalovirus, varicella zoster virus and measles virus (detected within the seronegative window-period of infection) and the blood-borne hepatitis B virus. We also detected Saffold virus, human parvovirus type 4, the human adenovirus C2 and vaccine-associated poliovirus type 1. CONCLUSIONS: The study highlights the presence of undiagnosed viruses causing MLI in Uganda, including vaccine-preventable illnesses. NGS can be used to monitor common viral infections at a population level, especially in regions where such infections are prevalent, including low and middle income countries to guide vaccination policy and optimize diagnostic assays.

Widespread human exposure to ledanteviruses in Uganda: A population study.

Le Dantec virus (LDV), assigned to the species Ledantevirus ledantec, genus Ledantevirus, family Rhabdoviridae has been associated with human disease but has gone undetected since the 1970s. We describe the detection of LDV in a human case of undifferentiated fever in Uganda by metagenomic sequencing and demonstrate a serological response using ELISA and pseudotype neutralisation. By screening 997 individuals sampled in 2016, we show frequent exposure to ledanteviruses with 76% of individuals seropositive in Western Uganda, but lower seroprevalence in other areas. Serological cross-reactivity as measured by pseudotype-based neutralisation was confined to ledanteviruses, indicating population seropositivity may represent either exposure to LDV or related ledanteviruses. We also describe the discovery of a closely related ledantevirus in blood from the synanthropic rodent Mastomys erythroleucus. Ledantevirus infection is common in Uganda but is geographically heterogenous. Further surveys of patients presenting with acute fever are required to determine the contribution of these emerging viruses to febrile illness in Uganda.