Different emerging viral infections may emerge in different regions of the world and pose a global pandemic threat with high fatality. Clarification of the immunopathogenesis of different emerging ...viral infections can provide a plan for the crisis management and prevention of emerging infections. This perspective article describes how an emerging viral infection evolves from microbial mutation, zoonotic and/or vector-borne transmission that progresses to a fatal infection due to overt viremia, tissue-specific cytotropic damage or/and immunopathology. We classified immunopathogenesis of common emerging viral infections into 4 categories: 1) deficient immunity with disseminated viremia (e.g., Ebola); 2) pneumocytotropism with/without later hyperinflammation (e.g., COVID-19); 3) augmented immunopathology (e.g., Hanta); and 4) antibody-dependent enhancement of infection with altered immunity (e.g., Dengue). A practical guide to early blocking of viral evasion, limiting viral load and identifying the fatal mechanism of an emerging viral infection is provided to prevent and reduce the transmission, and to do rapid diagnoses followed by the early treatment of virus neutralization for reduction of morbidity and mortality of an emerging viral infection such as COVID-19.
Many viruses recognize specific sugar residues, particularly sulfated or sialylated glycans, as the infection receptors. A change of sialic acid (2-6)-linked galactose (SA-alpha2,6Gal) to ...SA-alpha2,3Gal determines the receptor for avian flu infection. The receptor for enterovirus 71 (EV71) infection that frequently causes fatal encephalitis in Asian children remains unclear. Currently, there is no effective vaccine or anti-virus agent for EV71 infection. Using DLD-1 intestinal cells, this study investigated whether SA-linked glycan on DLD-1 intestinal cells was a receptor for EV71, and whether natural SA-linked sugars from human milk could block EV71 infection.
EV71 specifically infected DLD-1 intestinal cells but not K562 myeloid cells. Depletion of O-linked glycans or glycolipids, but not N-linked glycans, significantly decreased EV71 infection of DLD-1 cells. Pretreatment of DLD-1 cells with sialidase (10 mU, 2 hours) significantly reduced 20-fold EV71 replication (p < 0.01). Taken together, these results suggest that SA-linked O-glycans and glycolipids, but not N-glycans, on DLD-1 cells were responsible for EV71 infection. Purified SA-alpha2,3Gal and SA-alpha2,6Gal from human milk significantly inhibited EV71 infection of DLD-1 cells, indicating terminal SA-linked glycans could be receptors and inhibitors of EV71 infection.
This is the first in the literature to demonstrate that EV71 uses SA-linked glycans as receptors for infection, and natural SA-linked glycans from human milk can protect intestinal cells from EV71 infection. Further studies will test how a SA-containing glycan can prevent EV71 in the future.
INTRODUCTION: The importance of bisphosphonate drugs (BP) in preventing fractures is well known. Initial guidelines focused on early primary prevention of fracture for postmenopausal women using a ...BMD T-score -2.0 or lower, regardless of age (T-score < -1.5 with risk factors). In 2008, national guidelines focused treatment on osteoporosis (T-score < -2.5) or osteopenia (-1 > T-score > -2.5) with high fracture risk based on FRAX. This study examines whether there has been a shift in the characteristics of women initiating BP therapy for primary prevention (no previous fracture) over time from 2002 to 2013. METHOD: We included female members age within an integrated healthcare delivery system who were age 50-79y, initiated oral BP in 2002-2013, and had BMD measured within the 2 previous years. Women with fracture history (except head, fingers, toes), metastatic cancer, and advanced kidney disease were excluded. Age at BP initiation, race/ethnicity, and the proportions with normal BMD (T-score > -1), osteopenia, and osteoporosis each year and within earlier (2002-2007) and later (2008-2013) treatment eras were examined. Analyses were also stratified by race/ethnicity. RESULTS: 28,495 women age 50-79y (mean age 66y; 56% non-Hispanic White, 27% Asian, and 17% all others) met inclusion criteria. For each year from 2002-2013, the proportions of women <65y declined as the proportions >65y increased among those initiating BP. By age decade, the proportion 50-59y declined from 31% to 12%, while the proportion 60-69y and 70-79y increased from 39% to 54% and 29% to 34%, respectively, from 2002-2013. In 2013, the predominant age group initiating BP was 60-69y (54% overall; 51% in whites, 63% in Asians). During this same period, the percentage of women initiating BP who had osteoporosis progressively increased from 62% in 2002 to 79% in 2013. For whites, the overall percentage with osteoporosis was 65%, increasing from 58% in 2002 to 71% in 2013; for Asians, the percentage with osteoporosis was higher at 82%, increasing from 74% to 95% in these same years. Only among older women (70-79y) there appeared to be no temporal change (71% in 2002-2007 vs 69% in 2008-2013, p=0.1). DISCUSSION: Over time, there has been a remarkable shift in the type of woman initiating BP for primary prevention, from younger to older and from those with osteopenia to osteoporosis. By 2013, over half of the women initiating BP were 60-69y, and compared to 2002, there was a 27% higher prevalence of osteoporosis among women starting BP. Within the health plan, 13-15% of older women are Asian compared to 27% of our study population, indicating that Asians appear to be more likely to begin BP for primary prevention. Future studies should assess the impact of the observed shift in BP prescribing on fracture outcomes, focusing on the possible impact of age, race/ethnicity, and cost-effectiveness.
INTRODUCTION: Older women with proximal femur (hip) fractures have high morbidity and mortality; over 10% are re-hospitalized within 30 days of discharge and the overall mortality at 1 year is ...20-25%. Outcomes differ for women with atypical femur fractures (AFF), although published findings have shown conflicting results. One study found a greater risk of death in patients with AFF (median survival 9 months) compared to non-AFF diaphyseal femur fractures, although AFF cases also had greater comorbidity burden (JCD 19:359-67, 2016). A second study found that mortality was much lower for patients with AFF compared to non-AFF diaphyseal fractures, with no deaths in the first year following fracture (JBMR 31:491-497, 2015). This study further examines morbidity and mortality in women who experienced an AFF, focusing on rehospitalization and all-cause mortality outcome in comparison to proximal femur fractures. METHODS: This retrospective cohort study used post-fracture outcome data from 112 women (age 67.1 ± 8.4, 63% Asian, 26% white, 11% all others) who experienced an AFF after initiating oral bisphosphonate therapy in 2002-2014. Exclusion criteria included use of intravenous bisphosphonates, teriparatide, denosumab, skeletal disorders, or advanced chronic kidney disease. Women were followed up to 1 year after the initial AFF event to determine rehospitalization outcome within 30 and 90 days of discharge. Mortality was examined at 6 months and 1 year after AFF, and results were compared to published findings for typical femur fractures occurring in the same healthcare setting. RESULTS: Among 112 women who had an AFF during 2002-2015, 38% were age 65-74 years and 22% age 75-84 years; none were age 85 and older. This contrasts with previous findings in older women with hip fracture where more than one-third were age 85 and older, the age subgroup with highest mortality (over 30%). Six women with AFF were re-hospitalized within 30 days (5.4%) and 10 within 90 days (8.9%), with principal indications for rehospitalization within 30 days relating to infection (3/6) and cardiac arrhythmia (2/6). Six-month and one-year mortality were extremely low at 0.9% overall, and by age group: 2% among age <65 years, 0% among women age 65-74 years and 0% among women age 75-84 years. These results contrast with much higher one-year mortality previously reported for women age 65-74 years (14%) and 75-84 years (18%) who experienced a proximal femur fracture within the same health plan setting. DISCUSSION: Women with AFF appear to have substantially different survival outcomes compared to women with typical femur (hip) fracture, consistent with findings reported in other studies. Whether these differences are primarily related to health status and physical function, or the relationship of chronic disease and (typical) fracture risk, should be further examined.
Pain is a complex process that involves both detection in the peripheral nervous system and perception in the CNS. Individual-to-individual differences in pain are well documented, but not well ...understood. Here we capitalized on inherited erythromelalgia (IEM), a well characterized human genetic model of chronic pain, and studied a unique family containing related IEM subjects with the same disease-causing Na
1.7 mutation, which is known to make dorsal root ganglion (DRG) neurons hyperexcitable, but different pain profiles (affected son with severe pain, affected mother with moderate pain, and an unaffected father). We show, first, that, at least in some cases, relative sensitivity to pain can be modeled in subject-specific induced pluripotent stem cell (iPSC)-derived sensory neurons
; second, that, in some cases, mechanisms operating in peripheral sensory neurons contribute to interindividual differences in pain; and third, using whole exome sequencing (WES) and dynamic clamp, we show that it is possible to pinpoint a specific variant of another gene,
in this particular kindred, that modulates the excitability of iPSC-derived sensory neurons in this family. While different gene variants may modulate DRG neuron excitability and thereby contribute to interindividual differences in pain in other families, this study shows that subject-specific iPSCs can be used to model interindividual differences in pain. We further provide proof-of-principle that iPSCs, WES, and dynamic clamp can be used to investigate peripheral mechanisms and pinpoint specific gene variants that modulate pain signaling and contribute to interindividual differences in pain.
Individual-to-individual differences in pain are well documented, but not well understood. In this study, we show, first, that, at least in some cases, relative sensitivity to pain can be modeled in subject-specific induced pluripotent stem cell-derived sensory neurons
; second, that, in some cases, mechanisms operating in peripheral sensory neurons contribute to interindividual differences in pain; and third, using whole exome sequencing and dynamic clamp, we show that it is possible to pinpoint a specific gene variant that modulates pain signaling and contributes to interindividual differences in pain.
Abstract
Background
Previous studies suggest that the nose/throat microbiome may play an important role in shaping host immunity and modifying the risk of respiratory infection. Our aim is to ...quantify the association between the nose/throat microbiome and susceptibility to influenza virus infection.
Methods
In this household transmission study, index cases with confirmed influenza virus infection and their household contacts were followed for 9–12 days to identify secondary influenza infections. Respiratory swabs were collected at enrollment to identify and quantify bacterial species via high-performance sequencing. Data were analyzed by an individual hazard-based transmission model that was adjusted for age, vaccination, and household size.
Results
We recruited 115 index cases with influenza A(H3N2) or B infection and 436 household contacts. We estimated that a 10-fold increase in the abundance in Streptococcus spp. and Prevotella salivae was associated with 48% (95% credible interval CrI, 9–69%) and 25% (95% CrI, 0.5–42%) lower susceptibility to influenza A(H3N2) infection, respectively. In contrast, for influenza B infection, a 10-fold increase in the abundance in Streptococcus vestibularis and Prevotella spp. was associated with 63% (95% CrI, 17–83%) lower and 83% (95% CrI, 15–210%) higher susceptibility, respectively.
Conclusions
Susceptibility to influenza infection is associated with the nose/throat microbiome at the time of exposure. The effects of oligotypes on susceptibility differ between influenza A(H3N2) and B viruses. Our results suggest that microbiome may be a useful predictor of susceptibility, with the implication that microbiome could be modulated to reduce influenza infection risk, should these associations be causal.
The upper respiratory microbiome may play a role in susceptibility to influenza virus. This study examines the role of the nose/throat microbiome on influenza infection using a household influenza transmission study.
Patients with chronic hepatitis B virus (HBV) infection who develop antiviral resistance lose benefits of therapy and may be predisposed to further resistance. Entecavir (ETV) resistance (ETVr) ...results from HBV reverse transcriptase substitutions at positions T184, S202, or M250, which emerge in the presence of lamivudine (LVD) resistance substitutions M204I/V ± L180M. Here, we summarize results from comprehensive resistance monitoring of patients with HBV who were continuously treated with ETV for up to 5 years. Monitoring included genotypic analysis of isolates from all patients at baseline and when HBV DNA was detectable by polymerase chain reaction (≥300 copies/mL) from Years 1 through 5. In addition, genotyping was performed on isolates from patients experiencing virologic breakthrough (≥1 log10 rise in HBV DNA). In vitro phenotypic ETV susceptibility was determined for virologic breakthrough isolates, and for HBV containing novel substitutions emerging during treatment. The results over 5 years of therapy showed that in nucleoside‐naïve patients, the cumulative probability of genotypic ETVr and genotypic ETVr associated with virologic breakthrough was 1.2% and 0.8%, respectively. In contrast, a reduced barrier to resistance was observed in LVD‐refractory patients, as the LVD resistance substitutions, a partial requirement for ETVr, preexist, resulting in a 5‐year cumulative probability of genotypic ETVr and genotypic ETVr associated with breakthrough of 51% and 43%, respectively. Importantly, only four patients who achieved <300 copies/mL HBV DNA subsequently developed ETVr. Conclusion: Long‐term monitoring showed low rates of resistance in nucleoside‐naïve patients during 5 years of ETV therapy, corresponding with potent viral suppression and a high genetic barrier to resistance. These findings support ETV as a primary therapy that enables prolonged treatment with potent viral suppression and minimal resistance. (HEPATOLOGY 2009.)
The burden of pneumococcal disease in China is high, and a 13-valent pneumococcal conjugate vaccine (PCV13) recently received regulatory approval and is available to Chinese infants. PCV13 protects ...against the most prevalent serotypes causing invasive pneumococcal disease (IPD) in China, but will not provide full societal benefits until made broadly available through a national immunization program (NIP).
To estimate clinical and economic benefits of introducing PCV13 into a NIP in China using local cost estimates and accounting for variability in vaccine uptake and indirect (herd protection) effects.
We developed a population model to estimate the effect of PCV13 introduction in China. Modeled health states included meningitis, bacteremia, pneumonia (PNE), acute otitis media, death and sequelae, and no disease. Direct healthcare costs and disease incidence data for IPD and PNE were derived from the China Health Insurance and Research Association database; all other parameters were derived from published literature. We estimated total disease cases and associated costs, quality-adjusted life years (QALYs), and deaths for three scenarios from a Chinese Payer Perspective: (1) direct effects only, (2) direct+indirect effects for IPD only, and (3) direct+indirect effects for IPD and inpatient PNE.
Scenario (1) resulted in 370.3 thousand QALYs gained and 12.8 thousand deaths avoided versus no vaccination. In scenarios (2) and (3), the PCV13 NIP gained 383.2 thousand and 3,580 thousand QALYs, and avoided 13.1 thousand and 147.5 thousand deaths versus no vaccination, respectively. In all three scenarios, the vaccination cost was offset by cost reductions from prevented disease yielding net costs of ¥29,362.32 million, ¥29,334.29 million, and ¥13,524.72 million, respectively. All resulting incremental cost-effectiveness ratios fell below a 2x China GDP cost-effectiveness threshold across a range of potential vaccine prices.
Initiation of a PCV13 NIP in China incurs large upfront costs but is good value for money, and is likely to prevent substantial cases of disease among children and non-vaccinated individuals.
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