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Background To date, there are no studies that have analyzed the possible influence of exposure to prenatal sex hormones on the risk of laryngeal cancer (LC) and premalignant laryngeal lesion—vocal fold leukoplakia (VFL). Digit ratio (2D:4D) is suggested to be a proxy of prenatal sex hormone exposure. Objective To examine 2D:4D in patients with LC and clarify if it could add to the verified risk factors in estimating the overall risk of LC. Methods 511 subjects participated in the study. The study group included 269 patients: with LC (N = 114, 64 men) and VFL (N = 155, 116 men). Controls included 242 healthy individuals (66.40 ± 4.50 years (106 men)). Results Predictive models estimating the risk of VFL and LC in women, based solely on predictors like smoking and alcohol consumption had a lower area under the ROC curve (AUC) than the model with left 2D:4D. AUC for the model estimating the likelihood of VFL increased from 0.83 to 0.85, and for LC from 0.76 to 0.79. Conclusions Low left 2D:4D may be associated with an increased risk of developing leukoplakia and laryngeal cancer in women. In the case of laryngeal cancer, left 2D:4D may serve as additional variable (to other known risk factors, such as smoking and/or alcohol consumption), which can improve cancer risk prediction.

SARS-CoV-2 virus has recently given rise to the current COVID-19 pandemic where infected individuals can range from being asymptomatic, yet highly contagious, to dying from acute respiratory distress syndrome. Although the world has mobilized to create antiviral vaccines and therapeutics to combat the scourge, their long-term efficacy remains in question especially with the emergence of new variants. In this work, we exploit a class of compounds that has previously shown success against various viruses. A salicylanilide library was first screened in a SARS-CoV-2 activity assay in Vero cells. The most efficacious derivative was further evaluated in a prophylactic mouse model of SARS-CoV-2 infection unveiling a salicylanilide that can reduce viral loads, modulate key cytokines, and mitigate severe weight loss involved in COVID-19 infections. The combination of anti-SARS-CoV-2 activity, cytokine inhibitory activity, and a previously established favorable pharmacokinetic profile for the lead salicylanilide renders salicylanilides in general as promising therapeutics for COVID-19.

Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) with unusual features, including some that can overlap morphologically with classic Hodgkin lymphoma (CHL), have been described. Herein, we describe 12 cases of NLPHL with fibrous bands and capsular fibrosis resembling, in part, nodular sclerosis (NS) CHL. Seven of 12 cases harbored Reed-Sternberg-like cells, further suggestive of CHL, but all cases lacked associated eosinophils and/or plasma cells in the background. In this cohort, all cases had areas of so-called pattern D (nodular T-cell rich) as a sole component in 7 (58%) cases or as a hybrid pattern along with pattern E (diffuse T-cell/histiocyte-rich) in 5 (42%) cases. The immunophenotype of the large neoplastic cells in these cases supported their being lymphocyte predominant cells of NLPHL, positive for CD20, CD79a, and OCT2, and negative for CD15 and CD30. However, PAX5 was weak in 9 of 11 cases similar to Hodgkin/Reed-Sternberg cells in CHL. We conclude that some cases of NLPHL are associated with fibrous bands and capsular fibrosis and resemble, in part, NS CHL. In our experience, NLPHL with NS-like features occurs in 10% to 15% of cases of NLPHL and is associated with a variant pattern (D and/or E). In addition, all patients in this cohort were not treated before biopsy, suggesting that the prominent sclerosis in these cases is inherent to disease biology. Recognition of NLPHL with NS-like features further expands the morphologic spectrum of NLPHL and helps avoid potential misdiagnosis as CHL.

Several highly pathogenic mammarenaviruses cause severe hemorrhagic and neurologic disease in humans for which vaccines and antivirals are limited or unavailable. New World (NW) mammarenavirus Machupo virus (MACV) infection causes Bolivian hemorrhagic fever in humans. We previously reported that the disruption of specific N-linked glycan sites on the glycoprotein (GPC) partially attenuates MACV in an interferon alpha/beta and gamma (IFN-α/β and -γ) receptor knockout (R(−/−)) mouse model. However, some capability to induce neurological pathology still remained. The highly pathogenic Junin virus (JUNV) is another NW arenavirus closely related to MACV. An F427I substitution in the GPC transmembrane domain (TMD) rendered JUNV attenuated in a lethal mouse model after intracranial inoculation. In this study, we rationally designed and rescued a MACV containing mutations at two glycosylation sites and the corresponding F438I substitution in the GPC TMD. The MACV mutant is fully attenuated in IFN-α/β and -γ R(−/−) mice and outbred guinea pigs. Furthermore, inoculation with this mutant MACV completely protected guinea pigs from wild-type MACV lethal challenge. Last, we found the GPC TMD F438I substitution greatly impaired MACV growth in neuronal cell lines of mouse and human origins. Our results highlight the critical roles of the glycans and the TMD on the GPC in arenavirus virulence, which provide insight into the rational design of potential vaccine candidates for highly pathogenic arenaviruses. IMPORTANCE For arenaviruses, the only vaccine available is the live attenuated Candid#1 vaccine, a JUNV vaccine approved in Argentina. We and others have found that the glycans on GPC and the F427 residue in the GPC TMD are important for virulence of JUNV. Nevertheless, mutating either of them is not sufficient for full and stable attenuation of JUNV. Using reverse genetics, we disrupted specific glycosylation sites on MACV GPC and also introduced the corresponding F438I substitution in the GPC TMD. This MACV mutant is fully attenuated in two animal models and protects animals from lethal infection. Thus, our studies highlight the feasibility of rational attenuation of highly pathogenic arenaviruses for vaccine development. Another important finding from this study is that the F438I substitution in GPC TMD could substantially affect MACV replication in neurons. Future studies are warranted to elucidate the underlying mechanism and the implication of this mutation in arenavirus neural tropism.

Transgendered belief—the conviction that one is the opposite gender to one’s natal gender—may be influenced by prenatal sex steroids. We consider this possibility by examining the relationship between digit ratio (2D:4D—a suggested correlate of fetal testosterone and estrogen), natal gender, felt gender, and transsexual drug therapy in a large online survey (the BBC Internet Study). There were 209,317 participants who reported their gender, their felt gender, and whether they were taking/had taken transsexual drug therapy (male-to-female (MtF) or female-to-male (FtM)). Participants included natal males who felt male (M→M, n = 104,939) and those who felt female (M→F, n = 4760) and natal females who felt female (F→F, n = 84,904) and those who felt male (F→M, n = 4705). Transsexual drug therapy (MtF and FtM) was reported by 830 and 223 participants, respectively. Digit length was determined by direct self-measurement. Mean 2D:4D of M→F and MtF individuals was higher (more “feminized”) than for M→M and natal males, respectively. These effects were found in the total sample, the most numerous ethnic group (Whites) and the two largest national White samples (the UK and the USA). The mean 2D:4D of F→M and FtM participants did not differ from that of F→F and natal females, respectively. We conclude that M→F and MtF individuals may have experienced lower prenatal testosterone and higher estrogen than M→M and natal males, respectively. There was no evidence for an effect of prenatal sex steroids on transgendered belief or transsexualism in F→M and FtM individuals.

Several highly pathogenic mammarenaviruses cause severe hemorrhagic and neurologic disease in humans, for which vaccines and antivirals are limited or unavailable. New World (NW) mammarenavirus Machupo virus (MACV) infection causes Bolivian hemorrhagic fever in humans. We previously reported that the disruption of specific N-linked glycan sites on the glycoprotein (GPC) partially attenuate MACV in an IFN-αβ/γ receptor knockout mouse model. However, some capability to induce neurological pathology still remained. Highly pathogenic Junin virus (JUNV) is another NW arenavirus closely related to MACV. A F427I substitution in the GPC transmembrane domain (TMD) rendered JUNV attenuated in a lethal mouse model after intracranial inoculation. In this study, we rationally designed and rescued a MACV containing mutations at two glycosylation sites and the corresponding F438I substitution in GPC TMD. The MACV mutant is fully attenuated in IFN-αβ/γ receptor knockout mice and outbred guinea pigs. Furthermore, inoculation with this mutant MACV fully protected guinea pigs from wild-type MACV lethal challenge. Lastly, we found the GPC TMD F438I substitution greatly impaired MACV growth in neuronal cell lines of mouse and human origins. Our results highlight the critical roles of the glycans and the TMD on the GPC in arenavirus virulence, which informs the rational design of potential vaccine candidates for highly pathogenic arenaviruses.ImportanceFor arenaviruses, the only vaccine available is the live-attenuated Candid#1 vaccine, a JUNV vaccine approved in Argentina. We and others have found that the glycans on GPC and the F427 residue in the GPC TMD are important for virulence of JUNV. Nevertheless, mutating either of them is not sufficient for full and stable attenuation of JUNV. Using reverse genetics, we disrupted specific glycosylation sites on MACV GPC, and also introduced the corresponding F438I substitution in the GPC TMD. This MACV mutant is fully attenuated in two animal models and protects animals from lethal infection. Thus, our studies highlight the feasibility of rational attenuation of highly pathogenic arenaviruses for vaccine development. Another important finding from this study is that the F438I substitution in GPC TMD could substantially affect MACV replication in neurons. Future studies are warranted to elucidate the underlying mechanism and the implication of this mutation in arenavirus neural tropism.

Digit ratio – a putative measure of prenatal sex steroids – may be related to body mass index (BMI). However, reports of correlations between 2D:4D and BMI have yielded mixed results with some studies showing no relationship while others have reported positive associations in men or women only. This study considers associations between self-reported 2D:4D and BMI in a large online survey (i.e. the BBC Internet Study). At the individual level, there was a weak positive association between 2D:4D and BMI in both sexes with greater effect sizes in women. Body mass index was positively related to age and negatively related to parental income; however, the relationship between 2D:4D and BMI was independent of both variables. At the national level, mean 2D:4D per country showed positive associations with mean national BMI but those correlations were restricted to females. It is concluded that BMI is positively related to low prenatal testosterone and high prenatal oestrogen. Parental income inequality may influence both prenatal sex steroids (through a ‘Trivers–Willard’ effect) and BMI such that increases in inequality result in reductions in prenatal testosterone and increases in BMI at the individual and national level.

Several arenaviruses cause hemorrhagic fevers in humans with high case fatality rates. A vaccine named Candid#1 is available only against Junin virus (JUNV) in Argentina. Specific N-linked glycans on the arenavirus surface glycoprotein (GP) mask important epitopes and help the virus evade antibody responses. However the role of GPC glycans in arenavirus pathogenicity is largely unclear. In a lethal animal model of hemorrhagic fever-causing Machupo virus (MACV) infection, we found that a chimeric MACV with the ectodomain of GPC from Candid#1 vaccine was partially attenuated. Interestingly, mutations resulting in acquisition of N-linked glycans at GPC N83 and N166 frequently occurred in late stages of the infection. These glycosylation sites are conserved in the GPC of wild-type MACV, indicating that this is a phenotypic reversion for the chimeric MACV to gain those glycans crucial for infection in vivo. Further studies indicated that the GPC mutant viruses with additional glycans became more resistant to neutralizing antibodies and more virulent in animals. On the other hand, disruption of these glycosylation sites on wild-type MACV GPC rendered the virus substantially attenuated in vivo and also more susceptible to antibody neutralization, while loss of these glycans did not affect virus growth in cultured cells. We also found that MACV lacking specific GPC glycans elicited higher levels of neutralizing antibodies against wild-type MACV. Our findings revealed the critical role of specific glycans on GPC in arenavirus pathogenicity and have important implications for rational design of vaccines against this group of hemorrhagic fever-causing viruses., Author summary Several arenaviruses cause severe hemorrhagic fevers in humans. The only vaccine against arenavirus infections is Candid#1, a live attenuated vaccine against Argentine hemorrhagic fever. So far, we have successfully attenuated additional one of the arenaviruses, Machupo virus, the causative agent of Bolivian hemorrhagic fever. Unraveling this attenuation mechanism might help the development of live-attenuated vaccines for other arenaviruses. In this study, we revealed that the specific glycans of the viral glycoproteins play an important role in pathogenicity in vivo. The glycans facilitate the virus to evade neutralizing antibodies. This study would contribute to the development of arenavirus vaccine candidates.

Lassa virus (LASV) is the causative agent of Lassa fever (LF), which presents as a lethal hemorrhagic disease in severe cases. LASV-induced hearing loss in survivors is a huge socioeconomic burden, however, the mechanism(s) leading to hearing loss is unknown. In this study, we evaluate in a mouse LF model the auditory function using auditory brainstem response (ABR) and distortion product otoacoustic emissions (DPOAE) to determine the mechanisms underlying LASV-induced hearing loss. In the process, we pioneered measures of ABR and DPOAE tests in rodents in biosafety level 4 (BSL-4) facilities. Our T cell depletion studies demonstrated that CD4 T-cells play an important role in LASV-induced hearing loss, while CD8 T-cells are critical for the pathogenicity in the acute phase of LASV infection. Results presented in this study may help to develop future countermeasures against acute disease and LASV-induced hearing loss.

We have previously reported that the SARS-CoV-2 neutralizing antibody, STI-2020, potently inhibits cytopathic effects of infection by genetically diverse clinical SARS-CoV-2 pandemic isolates in vitro, and has demonstrated efficacy in a hamster model of COVID-19 when administered by the intravenous route immediately following infection. We now have extended our in vivo studies of STI-2020 to include disease treatment efficacy, profiling of biodistribution of STI-2020 in mice when antibody is delivered intranasally (IN) or intravenously (IV), as well as pharmacokinetics in mice following IN antibody administration. Importantly, SARS-CoV-2-infected hamsters were treated with STI-2020 using these routes, and treatment effects on severity and duration of COVID-19-like disease in this model were evaluated. In SARS-CoV-2 infected hamsters, treatment with STI-2020 12 hours post-infection using the IN route led to a decrease in severity of clinical disease signs and a more robust recovery during 9 days of infection as compared to animals treated with an isotype control antibody. Treatment via the IV route using the same dose and timing regimen resulted in a decrease in the average number of consecutive days that infected animals experienced weight loss, shortening the duration of disease and allowing recovery to begin more rapidly in STI-2020 treated animals. Following IN administration in mice, STI-2020 was detected within 10 minutes in both lung tissue and lung lavage. The half-life of STI-2020 in lung tissue is approximately 25 hours. We are currently investigating the minimum effective dose of IN-delivered STI-2020 in the hamster model as well as establishing the relative benefit of delivering neutralizing antibodies by both IV and IN routes.

SARS-CoV-2 neutralizing antibodies represent an important component of the ongoing search for effective treatment of and protection against COVID-19. We report here on the use of a naïve phage display antibody library to identify a panel of fully human SARS-CoV-2 neutralizing antibodies. Following functional profiling in vitro against an early pandemic isolate as well as a recently emerged isolate bearing the D614G Spike mutation, the clinical candidate antibody, STI-1499, and the affinity-engineered variant, STI-2020, were evaluated for in vivo efficacy in the Syrian golden hamster model of COVID-19. Both antibodies demonstrated potent protection against the pathogenic effects of the disease and a dose-dependent reduction of virus load in the lungs, reaching undetectable levels following a single dose of 500 micrograms of STI-2020. These data support continued development of these antibodies as therapeutics against COVID-19 and future use of this approach to address novel emerging pandemic disease threats.

Junin virus (JUNV) is a New World arenavirus that is the causative agent of Argentine hemorrhagic fever (AHF). Candid#1 (Can) is a live-attenuated vaccine strain of JUNV that since its introduction has resulted in a marked decrease in AHF incidence within the endemic regions of the Pampas in Argentina. Originally, the viral determinants and mechanisms of Can attenuation were not well understood. Recent work has identified the glycoprotein as the major attenuating factor for Can. The establishment of attenuating strategies based on any of the other viral proteins, however, has not been pursued. Here, we document the role of Can Z resulting in incompatibilities with wild type JUNV that results in decreased growth in vitro. In addition, this incompatibility results in attenuation of the virus in the guinea pig model. Further, we identify a single mutation (V64G) in the Z protein that is able to confer this demonstrated attenuation. By establishing and characterizing a novel attenuation strategy for New World mammarenaviruses, we hope to aid future vaccine development for related emerging pathogens including Machupo virus (MACV), Guanarito virus (GTOV), and Sabia virus (SABV)., Author summary The continual development of safe, effective vaccines against emerging diseases is one of the greatest challenges facing the scientific community. The New World group of mammarenaviruses contains multiple human pathogens, each capable of causing severe hemorrhagic disease. Among these, only Junin virus has a distributed vaccine. By utilizing this vaccine, we are able to determine vaccine development strategies for related New World viruses that represent an emerging threat. Here we demonstrate that manipulation of the viral Z protein is able to produce an incompatibility that ultimately attenuates the virus. This provides yet another tool for future vaccine development to further global public health.

A prenatal sex steroid environment of high prenatal testosterone and low prenatal oestrogen inhibits lung development and may predispose individuals to be vulnerable to lung disease in later life. Therefore, the aim of this report was to investigate whether there is an association between right and left 2D:4D (biomarker of prenatal sex steroids exposure) and primary lung cancer in women and men. Also, we considered the relationship between right–left 2D:4D (Δ2D:4D, a negative correlate of high prenatal testosterone and low prenatal oestrogen) and the age of lung cancer diagnosis. The study included 109 patients (61 men) with lung cancer and 197 controls (78 men). In the study we found that: (i) women with lung cancer have lower 2D:4D compared to controls (the effect was independent of smoking), (ii) among women with cancer, age at diagnosis was positively related to 2D:4D, i.e. women with masculinized 2D:4D present earlier with the cancer than women with feminized 2D:4D, (iii) among men with lung cancer, those with the most aggressive form (small-cell lung cancer) had masculinized (low) Δ2D:4D compared to those with the less aggressive form (non-small cell lung cancer). The data suggests that masculinized right 2D:4D and Δ2D:4D are associated with a predisposition to lung cancer and/or the more aggressive forms of lung cancer.

Graphical abstract Image 1, Prevalence of Kaposi sarcoma-associated herpesvirus (KSHV/HHV-8) varies greatly in different populations. We hypothesized that the actual prevalence of KSHV/HHV8 infection in humans is underestimated by the currently available serological tests. We analyzed four independent patient cohorts with post-surgical or post-chemotherapy sepsis, chronic lymphocytic leukemia and post-surgical patients with abdominal surgical interventions. Levels of specific KSHV-encoded miRNAs were measured by reverse transcription-quantitative polymerase chain reaction (RT-qPCR), and KSHV/HHV-8 IgG were measured by immunoassay. We also measured specific miRNAs from Epstein Barr Virus (EBV), a virus closely related to KSHV/HHV-8, and determined the EBV serological status by ELISA for Epstein-Barr nuclear antigen 1 (EBNA-1) IgG. Finally, we identified the viral miRNAs by in situ hybridization (ISH) in bone marrow cells. In training/validation settings using independent multi-institutional cohorts of 300 plasma samples, we identified in 78.50% of the samples detectable expression of at least one of the three tested KSHV-miRNAs by RT-qPCR, while only 27.57% of samples were found to be seropositive for KSHV/HHV-8 IgG (P, Highlights • There is no agreement on a standard assay to detect the true prevalence of Kaposi sarcoma-associated herpesvirus (KSHV) infection. • Measurement of the viral miRNAs in plasma by RT-qPCR allows a direct and accurate assessment of viral infection. • Measurement of the viral miRNAs in plasma by RT-qPCR shows prevalence of KSHV infection in immuno-depressed patients. • Measurement of plasma viral miRNAs for viral infection assessment has the potential to become a “gold” standard method in the clinical practice. Chronic viral infections represent risk factors for diseases and development of infection-related complications. There is no agreement on a standard assay to detect the true prevalence of Kaposi sarcoma-associated herpesvirus (KSHV) infection. The current method used in the clinical practice (ELISA-test) identifies a great geographic variation in KSHV seroprevalence and may underestimate the true-prevalence of KSHV infection. Here we showed that detection of plasma viral miRNAs levels for the identification of viral infection (e.g., KSHV, Epstein-Bar virus or EBV) is more accurate than the current method for detection of virus-derived antigen, especially in patients with low number of immune cells.

Research on association between digit ratio (2D:4D; a putative correlate of prenatal sex steroids) and mental masculinity/femininity (Masc/Fem) has reported mixed findings. This may be due to differences in protocols for assessing 2D:4D and Masc/Fem across studies. Here, we consider the relationship between direct self-measured 2D:4D and occupational preference, and self-rated Masc/Fem from participants in a large internet survey (i.e., the BBC internet study). Men and women provided information about interest in occupations and rated themselves on Masc/Fem. There were significant sex differences in 2D:4D and occupational preference. Men reported lower 2D:4Ds and higher interest in “male-type” occupations, while women reported a stronger preference for “female-type” occupations and a higher 2D:4D. Correlations between 2D:4D and a composite score for “male-type” occupations were significantly negative for heterosexual men and women and for bisexual women. A composite score of “female-type” occupations showed only one positive correlation for 2D:4D (female right 2D:4D). Digit ratio was also negatively related to a composite measure of the difference between “male-type” and “female-type” occupations, and for individual occupations, the pattern of negative correlations was confirmed for “male-type” occupations. Self-rated Masc/Fem showed a significant sex difference (women < men). These relationships were independent of sexual orientation, age, and height. There were significant negative correlations between 2D:4D and self-rated Masc/Fem. These were stronger for women than for men and were independent of sexual orientation, age, and height. Thus, prenatal sex steroids may have an effect on the development of occupational preferences and self-rated Masc/Fem, especially for “male-type” occupations, with higher levels of androgenization (lower 2D:4D) leading to “male-type” occupational preference and higher self-rated Masc.

Argentine hemorrhagic fever is a potentially lethal disease that is caused by Junin virus (JUNV). There are currently around 5 million individuals at risk of infection within regions of endemicity in Argentina. The live attenuated vaccine strain Candid #1 (Can) is approved for use in regions of endemicity and has substantially decreased the number of annual Argentine hemorrhagic fever (AHF) cases. The glycoprotein (GPC) gene is primarily responsible for attenuation of the Can strain, and we have shown that the absence of an N-linked glycosylation motif in the subunit G1 of the glycoprotein complex of Can, which is otherwise present in the wild-type pathogenic JUNV, causes GPC retention in the endoplasmic reticulum (ER). Here, we show that Can GPC aggregates in the ER of infected cells, forming incorrect cross-chain disulfide bonds, which results in impaired GPC processing into G1 and G2. The GPC fails to cleave into its G1 and G2 subunits and is targeted for degradation within lysosomes. Cells infected with the wild-type Romero (Rom) strain do not produce aggregates that are observed in Can infection, and the stress on the ER remains minimal. While the mutation of the N-linked glycosylation motif (T168A) is primarily responsible for the formation of aggregates, other mutations within G1 that occurred earlier in the passage history of the Can strain also contribute to aggregation of the GPC within the ER. IMPORTANCE The development of vaccines and therapeutics to combat viral hemorrhagic fevers remains a top priority within the Implementation Plan of the U.S. Department of Health and Human Services Public Health Emergency Medical Countermeasures Enterprise. The Can strain, derived from the pathogenic XJ strain of JUNV, has been demonstrated to be both safe and protective against AHF. While the vaccine strain is approved for use in regions of endemicity within Argentina, the mechanisms of Can attenuation have not been elucidated. A better understanding of the viral genetic determinants of attenuation will improve our understanding of the mechanisms contributing to disease pathogenesis and provide critical information for the rational design of live attenuated vaccine candidates for other viral hemorrhagic fevers.

Lassa virus, the causative agent of Lassa fever, is a zoonotic pathogen causing annual outbreaks in West African countries. Human patients can develop lethal hemorrhagic fever in severe cases. Although Lassa virus is one of the most alarming pathogens from a public health perspective, there are few available countermeasures, such as antiviral drugs or vaccines. Moreover, the fact that animal models are not readily accessible and the fact that mostly laboratory viruses, which have been passaged many times after isolation, are used for studies further limits the successful development of countermeasures. In this study, we demonstrate that a human isolate of Lassa virus causes lethal infection uniformly in Hartley guinea pigs. This novel animal model of Lassa fever may contribute to Lassa fever research and the development of vaccines and therapeutics., Lassa virus (LASV), a member of the family Arenaviridae, is the causative agent of Lassa fever. Lassa virus is endemic in West African countries, such as Nigeria, Guinea, Liberia, and Sierra Leone, and causes outbreaks annually. Lassa fever onset begins with “flu-like” symptoms and may develop into lethal hemorrhagic disease in severe cases. Although Lassa virus is one of the most alarming pathogens from a public health perspective, there are few licensed vaccines or therapeutics against Lassa fever. The fact that animal models are limited and the fact that mostly laboratory-derived viruses are used for studies limit the successful development of countermeasures. In this study, we demonstrated that the LASV isolate LF2384-NS-DIA-1 (LF2384), which was directly isolated from a serum sample from a fatal human Lassa fever case in the 2012 Sierra Leone outbreak, causes uniformly lethal infection in outbred Hartley guinea pigs without virus-host adaptation. This is the first report of a clinically isolated strain of LASV causing lethal infection in outbred guinea pigs. This novel guinea pig model of Lassa fever may contribute to Lassa fever research and the development of vaccines and therapeutics. IMPORTANCE Lassa virus, the causative agent of Lassa fever, is a zoonotic pathogen causing annual outbreaks in West African countries. Human patients can develop lethal hemorrhagic fever in severe cases. Although Lassa virus is one of the most alarming pathogens from a public health perspective, there are few available countermeasures, such as antiviral drugs or vaccines. Moreover, the fact that animal models are not readily accessible and the fact that mostly laboratory viruses, which have been passaged many times after isolation, are used for studies further limits the successful development of countermeasures. In this study, we demonstrate that a human isolate of Lassa virus causes lethal infection uniformly in Hartley guinea pigs. This novel animal model of Lassa fever may contribute to Lassa fever research and the development of vaccines and therapeutics.

Lassa virus (LASV), the causative agent of Lassa fever (LF), was first identified in 1969. Since then, outbreaks in the endemic countries of Nigeria, Liberia, and Sierra Leone occur on an annual basis resulting in a case-fatality rate of 15-70% in hospitalized patients. There is currently no licensed vaccine and there are limited animal models to test vaccine efficacy. An estimated 37.7 million people are at risk of contracting LASV; therefore, there is an urgent need for the development of a safe, effective vaccine against LASV infection. The LF endemic countries are also inflicted with HIV, Ebola, and malaria infections. The safety in immunocompromised populations must be considered in LASV vaccine development. The novel adenovirus vector-based platform, Ad5 (E1-,E2b-) has been used in clinical trial protocols for treatment of immunocompromised individuals, has been shown to exhibit high stability, low safety risk in humans, and induces a strong cell-mediated and pro-inflammatory immune response even in the presence of pre-existing adenovirus immunity. To this nature, our lab has developed an Ad5 (E1-,E2b-) vector-based vaccine expressing the LASV-NP or LASV-GPC. We found that guinea pigs vaccinated with two doses of Ad5 (E1-,E2b-) LASV-NP and Ad5 (E1-,E2b-) LASV-GPC were protected against lethal LASV challenge. The Ad5 (E1-,E2b-) LASV-NP and LASV-GPC vaccine represents a potential vaccine candidate against LF.

Objective Male digit ratio (2D:4D) correlates positively with the national case fatality rate (CFR) for COVID-19. The severity of COVID-19 may be influenced by a counterbalance between the angiotensin-converting enzyme (ACE) and angiotensin-converting enzyme 2 (ACE2). SARS-CoV2 cleaves with ACE2 and enters cells leaving an unopposed effect of ACE in the lungs. Both 2D:4D and the ACE I/D polymorphism are covariates of oxygen metabolism. COVID-19 leads to lung damage and a reduction in oxygen saturation of the blood. Here, we examine the interrelationships between 2D:4D, ACE polymorphism, and COVID-19 CFR. Methods National frequencies/rates were obtained for 2D:4D from the BBC Internet study (n = 41), published values of ACE I/II (n = 39), and COVID-19 CFR from three World Health Organization situation reports (n = 41). Results 2D:4D was negatively associated with national ACE I/II frequencies. However, there was a positive relationship between male 2D:4D and CFR (right and left 2D:4D, two, and three situation reports respectively). The relationships between ACE I/II and CFR were non-significant. Relationships between male 2D:4D and CFR's were independent of female 2D:4D and ACE I/II. Conclusions The ACE I/D polymorphism may influence 2D:4D such that ACE II individuals have lower 2D:4D than ACE DD individuals. Low 2D:4D and ACE II individuals show efficient oxygen metabolism. Therefore, low 2D:4D and ACE II together may protect against COVID-19 severity. The sex-dependent positive correlation between male 2D:4D and CFR is independent of ACE I/II, suggesting that the sex-dependent variation in the ACE2 gene may also influence the 2D:4D phenotype., Highlights • Digit ratio (2D:4D) and the ACE I/D polymorphism are covariates of oxygen metabolism. • 2D:4D was negatively associated with national ACE I/II frequencies. • Male 2D:4D correlates positive with the national case fatality rate for COVID-19. • ACE II individuals have lower 2D:4D than ACE DD individuals. • Low 2D:4D and ACE II together may protect against COVID-19 severity.

Background Digit ratio (2D:4D) is a putative marker for prenatal testosterone and is correlated with performance in many sports. Low 2D:4D has been linked to strength but the evidence is mixed and strength is also influenced by mass, testosterone, and behavioural factors. It has been hypothesised that the 2D:4D-strength correlation may be strongest in challenge conditions when short-term changes occur in steroid hormones. Aims We tested this suggestion in men. Study design We used a cross-over study design with a challenge (an aggressive video of rugby tackles) and control (a blank screen) condition. Subjects 89 healthy men. Outcome measures Finger lengths (2nd and 4th for both hands), hand-grip strength (HGS), testosterone (T), cortisol (C), aggression (Buss-Perry Aggression Questionnaire) and personality type (Ten Item Personality Measure). In both conditions participants provided saliva samples (for hormone assays). Results In the challenge condition there was a highly significant increase in HGS, and modest changes in T, physical aggression and emotional stability. HGS correlated negatively with left hand 2D:4D. In a multiple regression, left hand 2D:4D was negatively related to HGS and emotional stability was positively related to HGS. In the control condition HGS was not correlated with 2D:4D. In a multiple regression, BMI, physical aggression, and emotional stability were significantly related to HGS. Conclusions 2D:4D is a negative correlate of strength in challenge situations. This finding may in part explain associations between 2D:4D and sports performance.

Digit ratio (2D:4D) from soft-tissue measurements of fingers from children and adults from Black and White ethnic groups show sex differences (malesfemales) and group differences (BlackWhite). However, less is known about such differences in radiographic 2D:4D.To consider sex and ethnic differences in radiographic 2D:4D of children of Afro-Caribbean descent and to compare these means with "standards" from White children.A cross-sectional design with samples from Afro-Caribbean children aged 6 to 11 years compared to published radiographic measurements for White children in the Fels Longitudinal Study.Radiographic 2D:4D showed ethnic differences such that Afro-CaribbeansWhites. There was an age-stable right-side sex difference (boysgirls) in the 2D:4D of the distal phalanx and the distal soft-tissue tip in the Afro-Caribbean children but not in the proximal- and middle-phalanges or the composite length of the phalanges. Sex differences in 2D:4D (boysgirls) were present in the White children in the middle and proximal phalanges and composite phalange length but not in the distal phalanx.In Afro-Caribbean children, mean radiographic 2D:4D was lower than that of White children and sexual dimorphism of 2D:4D (boysgirls) was confined to the distal phalanx and fingertip soft-tissue. In contrast in White children, there were no sex differences in the distal phalanx but there were in the middle-, proximal and composite phalanges (boysgirls). We discuss whether these differences in 2D:4D are widespread among Blacks and Whites and the implications for the interpretation of radiographic 2D:4D and morphological soft-tissue 2D:4D across macro-ethnic groups.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the novel coronavirus responsible for the ongoing COVID-19 pandemic, which has resulted in over 2.5 million confirmed cases and 170,000 deaths worldwide as of late April 2020. The pandemic currently presents major public health and economic burdens worldwide. No vaccines or therapeutics have been approved for use to treat COVID-19 cases in the United States despite the growing disease burden, thus creating an urgent need for effective treatments. The adenosine analogue remdesivir (REM) has recently been investigated as a potential treatment option, and has shown some activity in limiting SARS-CoV-2 replication. We previously reported that the IMPDH inhibitor merimepodib (MMPD) provides a dose-dependent suppression of SARS-CoV-2 replication in vitro. Here, we report that a 4-hour pre-treatment of Vero cells with 2.5µM MMPD reduces the infectious titer of SARS-CoV-2 more effectively than REM at the same concentration. Additionally, pre-treatment of Vero cells with both REM and MMPD in combination reduces the infectious titer of SARS-CoV-2 to values below the detectable limit of our TCID50 assay. This result was achieved with concentrations as small as 1.25 µM MMPD and 2.5 µM REM. At concentrations of each agent as low as 0.31 µM, significant reduction of viral production occurred. This study provides evidence that REM and MMPD administered in combination might be an effective treatment for COVID-19 cases.

Background Testosterone (T) is taken or prescribed to enhance appearance, increase athletic performance and libido and to treat hypogonadism. Digit ratio (2D:4D) is thought to be a negative correlate of prenatal T. Here we consider the relationship between 2D:4D and T supplementation. Aims Our sample was taken from the BBC internet study. Respondents were asked (y/n) if they were taking; (i) T, (ii) hormone replacement therapy with T (HRTwT). We removed extreme 2D:4D values and age and considered the most numerous ethnic group (i.e. “Whites”). Analyses were performed with a two-factor (sex*T) analysis of variance with covariate age and dependent variables 2D:4D or right-left 2D:4D (Dr-l). Results Out of 197,589 respondents, 793 (598 males) reported taking T. There was a significant main effect for right 2D:4D such that T supplementing males had higher 2D:4D than those who did not. The sex*T interaction was significant, but the effect reversed in females. There were 22,576 (661 males) participants who reported taking HRTwT. We found a significant main effect for right 2D:4D, males taking HRTwT had higher 2D:4D than those who did not. This was reversed in females. The sex*HRTwT interaction was significant, a high Dr-l was also found in males reporting HRTwT. Conclusion Males who reported taking T or HRTwT had high right 2D:4D and/or Dr-l. The situation with females may be the reverse of that found in males but effect sizes are less. The health implications of an association between high (feminized) 2D:4D and T supplementation in males are discussed.

Purpose The authors examined the prevalence of a histologic change of ocular adnexal lymphoma (OAL) grade in patients with a history of lymphoma in nonocular sites. Methods In this retrospective study, the authors reviewed the clinical and pathological data of 209 patients with OAL treated by the senior author during 2000 to 2017. Results Of 209 patients with OAL, 65 (31%) had a history of lymphoma. In 54 of the 65 patients (83%), the original lymphoma and OAL were of the same histologic type. In 8 of the 65 patients (12.3%), the OAL was more indolent than the original lymphoma: 6 patients with a history of diffuse large B-cell lymphoma, one of mantle cell lymphoma, and one of grade 3 follicular lymphoma had biopsy-proven extranodal marginal-zone lymphoma in the orbital area. Two additional patients (3%) with a history of chronic lymphocytic leukemia developed OAL: diffuse large B-cell lymphoma in one patient and extranodal marginal-zone lymphoma in the other. One patient (1.5%) with a history of a low-grade follicular lymphoma relapsed as a different low-grade histology of extranodal marginal-zone lymphoma. Lower-grade OAL than the original lymphoma was more common than higher-grade OAL than the original lymphoma (p = 0.048). Conclusions In this cohort of 209 patients with OAL, the authors found that nearly one third had a history of lymphoma, 17% of whom had a different histologic type of lymphoma in the orbit, more commonly a more indolent type. This underscores the importance of biopsy of OAL even in patients with a known history of lymphoma to determine the histologic subtype of orbital lymphoma and to help guide appropriate treatment.

Background Digit ratio (2D:4D), has been the subject of many studies. However, the best method of measuring digit length, either directly (d2D:4D) or indirectly (i2D:4D), is controversial. In many reports i2D:4D has been found to show a directional effect such that d2D:4D > i2D:4D. The exception is three studies from one group of researchers in Austria. Thus, it is unclear whether this effect is nation- or lab-specific. Aims To examine evidence for effects of direct versus indirect measurements of mean 2D:4D in Austrians. Study design We compared 2D:4D based on direct and indirect measurements of digit lengths of Austrians. Subjects There were 80 participants, 21 adults and 59 children. Outcome measures 2D:4D of right and left hands, measured directly (from the palm) and indirectly (from hand scans). Results Repeatability was high for both d2D:4D and i2D:4D, with the latter slightly higher than the former. d2D:4D and i2D:4D correlated strongly and the sex difference in 2D:4D (males i2D:4D for both right (d = −0.53) and left hands (d = −0.80). Conclusion There was no evidence of an “Austrian” effect on direct versus indirect measurements of 2D:4D, i.e. mean d2D:4D was greater than i2D:4D. We discuss our findings in the light of issues regarding “clarity of report” from earlier Austrian studies.

Objectives: The primary aim of this study was to examine relationships between digit ratio (2D:4D) and game-related statistics in professional and semi-professional male basketball players. The secondary aim was to quantify differences in mean 2D:4Ds between starting and reserve players. Methods: Using a cross-sectional design, 93 male basketball players from the professional Australian National Basketball League and the semi-professional South Australian Premier League were measured in-season for height, mass, and 2D:4D, with game-related statistics collected end-season. Linear relationships between right and left 2D:4Ds and game-related statistics were quantified using nonparametric partial correlations, and differences in mean 2D:4Ds between starting and reserve players were quantified using analysis of covariance (ANCOVA). All partial correlations and ANCOVAs were adjusted for playing experience, body size, and competitive standard. Results: 2D:4D was a weak to moderate negative correlate of points scored and assists-to-turnovers ratio, indicating that males with lower 2D:4Ds were generally better offensively as they recorded more points and assists relative to turnovers. The difference in mean 2D:4D between starting and reserve players was negligible. Conclusions: 2D:4D was favorably correlated with open-skill sports performance, as evidenced by the better offensive statistics of male basketball players with lower 2D:4Ds. These results probably reflect the organizational benefits of prenatal testosterone and indicate that 2D:4D may be a useful complement to traditional physical, physiological, skill, and behavioral predictors of basketball success Refereed/Peer-reviewed

Background Digit ratio (2D:4D) is a marker for prenatal sex steroids and a correlate of sporting performance. This association may exist because low 2D:4D is linked to high prenatal levels of testosterone (T) and low oestrogens (E). It was recently suggested that low 2D:4D, and particularly low right-left 2D:4D (or Dr-l), is a marker for T changes in response to physical and aggressive challenges. If correct, this link may in part explain the association between 2D:4D and sports performance. Aims We tested this hypothesis in adults. Study design Three experimental treatments were completed using a randomised, cross-over design; (i) cycle sprints plus an aggressive video (S + V), (ii) aggressive video plus cycle sprints (V + S), and (iii) a control session. Subjects 24 healthy adults (12 men and 12 women). Outcome measures Salivary T, oestradiol (E2) and cortisol (C) levels were measured on six occasions across each session and pooled for analysis. Results The S + V treatment was associated with a rise in T and C levels, and Dr-l was significantly and negatively correlated with T and E2 with these effects confined to men. The right 2D:4D and Dr-l were also negatively correlated with the T/C ratio and Dr-l negatively related to the E2/C ratio in men during the S + V treatment. Conclusions We suggest that the hormonal responses to a challenge are programmed by prenatal levels of T and E with possible links to sporting performance in adulthood.

OBJECTIVE Sex differences are often reported in digit lengths and digit ratio (2D:4D). However, the ontogeny of these sex differences and their interrelationships are less well known. METHODS We considered sex differences in the lengths of the 2nd (2D) and 4th (4D) digit and 2D:4D in children aged 2 to 18 years (Sample I, n = 680) and adults aged 18 to 30 years (Sample II, n = 89,246). Digit length was determined by direct experimenter-measurement (Sample I) and direct self-measurement (Sample II). The data were tested with two-factor ANOVA's (sex and year-group). RESULTS In both samples, there were significant main effects of sex and year-group, and a significant interaction effect on digit length. Digit length was positively related to age in both samples. Boys had longer digits than girls but only after 13 years. Men had longer digits than women and the dimorphism increased from 18 to 30 years. There were significant sex differences in 2D:4D (males