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Wages have always been one of the most important concerns for employees and unemployment is one of the most important statistics for society. After studying the unemployment rate and wage growth data in the United States in recent years, it is evident that a low unemployment rate does not lead to meaningful wage growth. This paper explains that the main causes of this are domestic and foreign factors in the United States. This paper divides the influencing factors into two broad categories (domestic factors and foreign factors) and summarizes the foreign factors into the composition of employment, the productivity of labor and companies, inflation and labor unions, and the foreign factors are attributed to the effects brought about by globalization.

The accumulation of nutrients in rivers is a major cause of eutrophication, and the change in nutrient content is affected by a variety of factors. Taking the River Yi as an example, this study used wavelet analysis tools to examine the periodic changes in nutrients and environmental factors, as well as the relationship between nutrients and environmental factors. The results revealed that total phosphorus (TP), total nitrogen (TN), and ammonia nitrogen (NH4+–N) exhibit multiscale oscillation features, with the dominating periods of 16–17, 26, and 57–60 months. The continuous wavelet transform revealed periodic fluctuation laws on multiple scales between nutrients and several environmental factors. Wavelet transform coherence (WTC) was performed on nutrients and environmental factors, and the results showed that temperature and dissolved oxygen (DO) have a strong influence on nutrient concentration fluctuation. The WTC revealed a weak correlation between pH and TP. On a longer period, however, pH was positively correlated with TN. The flow was found to be positively correct with N and P, while N and P were found to be negatively correct with DO and electrical conductance (EC) at different scales. In most cases, TP was negatively correlated with 5-day biochemical oxygen demand (BOD5) and permanganate index (CODMn). The correlation between TN and CODMn and BOD5 was limited, and no clear dominant phase emerged. In a nutshell, wavelet analysis revealed that water temperature, pH, DO, flow, EC, CODMn, and BOD5 had a pronounced influence on nutrient concentration in the River Yi at different time scales. In the case of the combination of environmental factors, pH and DO play the largest role in determining nutrient concentration.

The distribution characteristics of soil organic carbon (SOC) and soil nutrients under different land-use types in Linyi City, East China, were studied. The spatial distribution of SOC under different land-use types and the relationship between SOC and soil nutrients were analyzed using remote sensing interpretation and soil sample analyses. The results showed that SOC in Linyi was mainly stored in drylands and paddy fields. SOC and total nitrogen (TN) levels were positively correlated for most land use types. There was a positive linear correlation between SOC and total K in the paddy fields. The coefficients of variation for SOC and TN differed greatly among the land use types studied. Total SOC storage was 8772.73 × 103 kg in the surface 0.2 m soil layer. The order of total SOC storage was drylands (6771.45 × 103 ton) > paddy field (764.67 × 103 ton) > nurseries (510.79 × 103 ton) > forest land (413.49 × 103 ton) > low-cover grasslands (238 × 103 ton) > bare land (74.35 × 103 ton). With the largest SOC storage, and C density, respectively, drylands and paddy fields are conducive to enhancing soil C sequestration, achieving low-carbon goals, and mitigating climate change.

Suaeda salsa (L.) Pall., a typical halophyte plant in the Yellow River estuary, has high enrichment capacity for heavy metals. However, few studies have investigated the Cd absorption characteristics of S. salsa under different sediment burial and exogenous Cd input conditions, especially following the water-sediment regulation scheme (WSRS), which brought sediment burial and exogenous substances to the estuary. So, we established a greenhouse pot culture experiment with four sediment burial depths (0 cm, 3 cm, 6 cm, and 12 cm) and exogenous Cd input levels (0 mg·kg−1, 0.5 mg·kg−1, 1.0 mg·kg−1, and 1.5 mg·kg−1) and analyzed the leaf, stem, root, and total biomass; leaf, stem, and root Cd content; and storage, sediment Cd content, accumulation factor, root/leaf (R/L), root/stem (R/S), and stem/leaf (S/L) ratios to study the Cd absorption characteristics of S. salsa under the different sediment burial and exogenous Cd input. Results showed that high Cd content in roots, stems, and leaves was harmful to S. salsa growth, and then led to a decrease in biomass (characterized by stem, leaf, and total biomass). Suaeda salsa exhibited a survival strategy to deal with Cd toxicity, which involved the roots absorbing Cd from the sediment and storing it in stems and leaves (stem and leaf Cd content peaked at 0.5 mg·kg−1 Cd input) at low Cd input, whereas roots stored more Cd and reduced Cd transport to stems and leaves at high Cd input. Therefore, we observed the maximum value of leaf (500.63 ± 19.15 g·m−2), stem (648.22 ± 50.08 g·m−2), and total biomass (1246.92 ± 55.49 g·m−2) in the treatment with 1.5 mg·kg−1 Cd input and 3-cm sediment depth due to the Cd content in leaves and stems being relatively low. The accumulation factors of leaves, stems, and roots varied (0.39–0.99, 0.19–2.58, and 0.80–20.45, respectively), and most of the accumulation factors for roots and leaves and the R/L and R/S ratios were >1, which indicated that S. salsa had high enrichment levels of Cd, which mostly accumulated in the roots. Shallow or moderate burial depth was beneficial to S. salsa growth, but sediment burial was not beneficial to Cd absorption because the sum of leaf, stem, and root Cd storage was higher at 0-cm depth compared with the other depths. Variance analysis showed that the influence of Cd input on leaf, stem, root, and sediment Cd content and stem and root Cd storage was significant (P 0.05). Therefore, we concluded that more attention should be paid to the control of sediment burial and heavy metal input, especially during the WSRS, in the Yellow River estuary.

Harvesting is an important method used to control the overproduction of Potamogeton crispus in lakes. A three-year comparative field study was performed in a eutrophic lake (harvested area) and its connected lake (non-harvested area) to determine the effects of harvesting on the phosphorus (P) composition and environmental factors in the water and sediment. Results revealed that harvesting significantly reduced the dissolved total P (DTP) and dissolved organic P (DOP) and increased the alkaline phosphatase activity (APA) and particulate P (PP) in the water. No significant differences were detected in the water total P (TP), soluble reactive P (SRP), chlorophyll-a (Chl-a), pH, and dissolved oxygen (DO) between the harvested and non-harvested areas. Sediment TP and organic P (OP) were significantly reduced in the harvested area. Harvesting changed the P composition in the water. In the non-harvested area, P was mainly formed by DOP (40%) in the water body, while in the harvested area, PP was the main water component (47%). Harvesting increased the proportion of inorganic P (IP) in the sediment and decreased the proportion of OP. In the water, the IP to TP ratio in the non-harvested and harvested areas were 58.26% and 63.51%, respectively. Our results showed that harvesting changed the P composition in the water and sediment. In the harvesting of submerged vegetation, our results can serve as a reference for the management of vegetation-rich lakes.

BackgroundShingrix (recombinant zoster vaccine) was licensed to prevent herpes zoster, dispensed as 2 doses given 2–6 months apart among adults aged ≥50 years. Clinical trials yielded efficacy of >90% for confirmed herpes zoster, but post-market performance has not been evaluated. Efficacy of a single dose and a delayed second dose and efficacy among persons with autoimmune or immunosuppressive conditions have not been studied. We aimed to assess post-market vaccine effectiveness of Shingrix.MethodsWe conducted a cohort study among Medicare Part D community-dwelling beneficiaries aged >65 years. Herpes zoster was identified using a medical office visit diagnosis with treatment, and postherpetic neuralgia was identified using a validated algorithm. We used inverse probability of treatment weighting to improve cohort balance and marginal structural models to estimate hazard ratios.ResultsWe found a vaccine effectiveness of 70.1% (95% confidence interval [CI], 68.6–71.5) and 56.9% (95% CI, 55.0–58.8) for 2 and 1 doses, respectively. The 2-dose vaccine effectiveness was not significantly lower for beneficiaries aged >80 years, for second doses received at ≥180 days, or for individuals with autoimmune conditions. The vaccine was also effective among individuals with immunosuppressive conditions. Two-dose vaccine effectiveness against postherpetic neuralgia was 76.0% (95% CI, 68.4–81.8).ConclusionsThis large real-world observational study of the effectiveness of Shingrix demonstrates the benefit of completing the 2-dose regimen. Second doses administered beyond the recommended 6 months did not impair effectiveness. Our effectiveness estimates were lower than the clinical trials estimates, likely due to differences in outcome specificity.

To assess potential phosphorus removal, we utilized Potamogeton crispus to determine the effects of calcium addition on phosphorus removal. Plastic film was used to block material exchange between the overlying water and the sediment, and we compared the experimental results with long-term monitoring results of Yimeng Lake, which contained a dense population of P. crispus. The results revealed that the first 10-40 days constituted a period of rapid P decrease, as P. crispus could effectively remove the phosphorus in the water through coprecipitation of CaCO

Surface roughening of hollow glass microspheres (HGMs) is a necessary step determining their adhesion ability with the following electroless plated metallization coating. In this paper, a new KF roughening and alkali washing strategy was proposed to replace HF roughening as a surface pretreatment for the following electroless plating metallization. In order to remove the byproduct of K2SiF6 from the roughening reaction of KF with HGMs, NaOH washing and KOH washing were conducted, the former of which was found to dissolve K2SiF6 effectively. The effects of KF roughening temperature, alkali concentration and HGMs loading on the recovery ratio, phase composition, surface morphology and performance of HGMs were investigated, through which such a pretreating strategy was found to not only decrease the damage ratio of HGMs compared to that by HF roughening, but also render the metallized HGMs a competitive absorbing ability for the electromagnetic wave in X-band and Ku-band. Finally, the related surface treatment and electroless plating mechanism were discussed. This paper illustrates successfully a new pretreatment strategy for development of lightweight HGMs-supported functional materials.

ImportanceThe association of 13-valent pneumococcal conjugate vaccine (PCV13) use with pneumonia hospitalization in older adults, especially those with underlying medical conditions, is not well described.ObjectiveTo evaluate the association of PCV13 use with pneumonia, non–health care–associated (non-HA) pneumonia, and lobar pneumonia (LP) hospitalization among US Medicare beneficiaries 65 years or older.Design, Setting, and ParticipantsThis cohort study with time-varying exposure assignment analyzed claims data from US Medicare beneficiaries 65 years or older enrolled in Parts A/B with a residence in the 50 US states or the District of Columbia by September 1, 2014. New Medicare Parts A/B beneficiaries within 6 months after their 65th birthday were continuously included in the cohort after September 1, 2014, and followed through December 31, 2017. Participants were censored if they died, changed enrollment status, or developed a study outcome. Most of the analyses were conducted from 2018 to 2019, and additional analyses were performed from 2021 to 2022.ExposuresUse of PCV13 vaccination 14 days or more before pneumonia hospitalization.Main Outcomes and MeasuresDiscrete-time survival models were used to estimate the incidence rate ratio (IRR) and number of pneumonia hospitalizations averted through PCV13 use. The adjusted IRR for the association of PCV13 vaccination with pneumonia hospitalization was used to estimate vaccine effectiveness (VE).ResultsAt the end of follow-up (December 2017), 24 121 625 beneficiaries (13 593 975 women [56.4%]; 418 005 [1.7%] Asian, 1 750 807 [4.8%] Black, 338 044 [1.4%] Hispanic, 111 508 [0.5%] Native American, and 20 700 948 [85.8%] White individuals) were in the cohort; 4 936 185 (20.5%) had received PCV13 only, and 10 646 220 (79.5%) had not received any pneumococcal vaccines. More than half of the beneficiaries in the cohort were younger than 75 years, White, and had either immunocompromising or chronic medical conditions. Coverage with PCV13 increased from 0.8% (September 2014) to 41.5% (December 2017). The VE for PCV13 was estimated at 6.7% (95% CI, 5.9%-7.5%) for pneumonia, 4.7% (95% CI, 3.9%-5.6%) for non-HA pneumonia, and 5.8% (95% CI, 2.6%-8.9%) for LP. From September 2014 through December 2017, an estimated 35 127 pneumonia (95% CI, 33 011-37 270), 24 643 non-HA pneumonia (95% CI, 22 761-26 552), and 1294 LP (95% CI, 797–1819) hospitalizations were averted through PCV13 use.Conclusions and RelevanceThe study results suggest that PCV13 use was associated with reduced pneumonia hospitalization among Medicare beneficiaries 65 years or older, many of whom had underlying medical conditions. Increased PCV13 coverage and use of recently approved higher-valent pneumococcal conjugate vaccines may avert additional pneumonia hospitalizations in adults.

Purpose Medicare claims can provide real-world evidence (RWE) to support the Food and Drug Administration's ability to conduct postapproval studies to validate products' safety and effectiveness. However, Medicare claims do not contain comprehensive information on some important sources of bias. Thus, we piloted an approach using the Medicare Current Beneficiary Survey (MCBS), a nationally representative survey of the Medicare population, to (a) assess cohort balance with respect to unmeasured confounders in a herpes zoster vaccine (HZV) effectiveness claims-based study and (b) augment Medicare claims with MCBS data to include unmeasured covariates. Methods We reanalyzed data from our published HZV effectiveness Medicare analysis, using linkages to MCBS to obtain information on impaired mobility, education, and health-seeking behavior. We assessed survey variable balance between the matched cohorts and selected imbalanced variables for model adjustment, applying multiple imputation by chained equations (MICE) to impute these potential unmeasured confounders. Results The original HZV effectiveness study cohorts appeared well balanced with respect to variables we selected from the MCBS. Our imputed results showed slight shifts in HZV effectiveness point estimates with wider confidence intervals, but indicated no statistically significant differences from the original study estimates. Conclusions Our innovative use of linked survey data to assess cohort balance and our imputation approach to augment Medicare claims with MCBS data to include unmeasured covariates provide potential solutions for addressing bias related to unmeasured confounding in large database studies, thus adding new tools for RWE studies.

Roughening of non-conductive substrate ceramic materials with hydrofluoric acid (HF) is usually an essential step to enhance adhesion of the coating by electroless chemical plating. However, the violent reaction between HF and the hollow glass microspheres (HGMs) usually causes breakage and damage of the thin shells of HGMs. This paper proposes a modified roughening strategy for Ni electroless plating, i.e., eroding HGMS slowly with a mixture of sodium fluoride (NaF) and hydrochloric acid (HCl). The Na2SiF6 by-products from the reaction of NaF with SiO2 were erased by the following NaOH washing to expose the surface of HGMs without any obvious pores or breakage. Such a modified roughening and followed alkali washing strategy can thus not only reduce the surface corrosion, but also hinder the further damage of HGMs by covering Na2SiF6 sediments. The successive plating of uniform Ni nanoparticles on HGMs was conducted, and the related mechanism was discussed in detail.

Sphingosine-1-phosphate (S1P) is a highly potent sphingolipid metabolite, which controls numerous physiological and pathological process via its extracellular and intracellular functions. The breast is mainly composed of epithelial cells (mammary gland) and adipocytes (stroma). Adipocytes play an important role in regulating the normal functions of the breast. Compared to the vast amount studies on breast epithelial cells, the functions of S1P in breast adipocytes are much less known. Thus, in the current study, we used human preadipocyte cell lines SGBS and mouse preadipocyte cell line 3T3-L1 as in vitro models to evaluate the effects of S1P on cell viability, differentiation, and gene expression in adipocytes. Our results showed that S1P increased cell viability in SGBS and 3T3-L1 preadipocytes but moderately reduced cell viability in differentiated SGBS and 3T3-L1 adipocytes. S1P was also shown to inhibit adipogenic differentiation of SGBS and 3T3-L1 at concentration higher than 1000 nM. Transcriptome analyses showed that S1P was more influential on gene expression in differentiated adipocytes. Furthermore, our network analysis in mature adipocytes showed that the upregulated DEGs (differentially expressed genes) were related to regulation of lipolysis, PPAR (peroxisome proliferator-activated receptor) signaling, alcoholism, and toll-like receptor signaling, whereas the downregulated DEGs were overrepresented in cytokine-cytokine receptor interaction, focal adhesion, starch and sucrose metabolism, and nuclear receptors pathways. Together previous studies on the functions of S1P in breast epithelial cells, the current study implicated that S1P may play a critical role in modulating the bidirectional regulation of adipocyte-extracellular matrix-epithelial cell axis and maintaining the normal physiological functions of the breast., publishedVersion

Host cell infection with HIV-1 requires fusion of viral and cell membranes. Sifuvirtide (SFT) is a peptide-based HIV-1 fusion inhibitor approved for phase III clinical trials in China. Here, we focused on characterizing HIV-1 variants highly resistant to SFT to gain insight into the molecular resistance mechanism. Three primary substitutions (V38A, A47I, and Q52R) located at the inhibitor-binding site of HIV-1's envelope protein (Env) and one secondary substitution (N126K) located at the C-terminal heptad repeat region of the viral protein gp41, which is part of the envelope, conferred high SFT resistance and cross-resistance to the anti-HIV-1 drug T20 and the template peptide C34. Interestingly, SFT's resistance profile could be dramatically improved with an M-T hook structure-modified SFT (MTSFT) and with short-peptide inhibitors that mainly target the gp41 pocket (2P23 and its lipid derivative LP-19). We found that the V38A and Q52R substitutions reduce the binding stabilities of SFT, C34, and MTSFT, but they had no effect on the binding of 2P23 and LP-19; in sharp contrast, the A47I substitution enhanced fusion inhibitor binding. Furthermore, the primary resistance substitutions impaired Env-mediated membrane fusion and cell entry and changed the conformation of the gp41 core structure. Importantly, whereas the V38A and Q52R substitutions disrupted the N-terminal helix of gp41, a single A47I substitution greatly enhanced its thermostability. Taken together, our results provide crucial structural insights into the mechanism of HIV-1 resistance to gp41-dependent fusion inhibitors, which may inform the development of additional anti-HIV drugs.

Detachment and transport of particles by raindrop impact and runoff determine the characteristics of soil aggregate loss, which are largely related to surface hydrologic conditions. The water ponding and sediment deposition in furrow areas within contour ridge systems complicate the effects of raindrop impact and runoff on soil aggregate loss responding to surface hydrologic conditions. The objective of this study was to determine the effect of raindrop impact and runoff to macro-aggregate and micro-aggregate losses under surface hydrologic conditions within contour ridge systems. The losses of 16 size aggregates were measured under three surface hydrologic conditions (free drainage, soil saturation, and seepage) and two soil surface conditions (with and without raindrop impact) through simulated rainfalls. Results showed that raindrop impact was the dominant factor controlling soil aggregate loss under free drainage condition, while soil aggregate loss was mostly affected by runoff under soil saturation and seepage conditions. Under free drainage condition, raindrop impact accounted for 44.6 %–100 % of the loss of each size aggregate, with maximum losses from 0.5 to 1 mm and 20–50 μm aggregates. Raindrop impact mainly caused the breakdown of >0.5 mm and 50–250 μm aggregates, and enhanced the transport of 20–50 μm aggregates by saltation. Under soil saturation and seepage conditions, runoff contributed 25.5 %–247.6 % to the loss of each size aggregate, and most dramatically to the losses of 2–5 mm and 10–50 μm aggregates. The role of runoff was mainly characterized by the breakdown of 0.25–1 mm and 50–250 μm aggregates, exhibiting a propensity toward transporting 2–5 mm aggregates by rolling, following 10–50 μm aggregates by suspension/saltation. This study highlights the need to understand the effects of raindrop impact and runoff on erosion processes associated with surface hydrologic conditions for better erosion modeling, and provides guidance for soil erosion control within contour ridge systems.

Importance Previous studies have found that the risk of severe hypoglycemia does not differ between long-acting insulin analogs and neutral protamine Hagedorn (NPH) insulin in patients with type 2 diabetes. However, these studies did not focus on patients 65 years or older, who are at an increased risk for hypoglycemia, or did not include patients with concomitant prandial insulin use. Objective To examine the risk of emergency department (ED) visits or hospitalizations for hypoglycemia among older community-residing patients with type 2 diabetes who initiated long-acting insulin or NPH insulin in real-world settings. Design, Setting, and Participants This retrospective, new-user cohort study assessed Medicare beneficiaries 65 years or older who initiated insulin glargine (n = 407 018), insulin detemir (n = 141 588), or NPH insulin (n = 26 402) from January 1, 2007, to July 31, 2019. Exposures Insulin glargine, insulin detemir, and NPH insulin. Main Outcomes and Measures The primary outcome was time to first ED visit or hospitalization for hypoglycemia, defined using a modified validated algorithm. Propensity score–weighted Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% CIs. The risk of recurring hypoglycemia events was estimated using the Andersen-Gill model. Post hoc analyses were conducted investigating possible effect modification by age. Results Of the 575 008 patients initiating use of insulin (mean [SD] age 74.9 [6.7] years; 53% female), 407 018 used glargine, 141 588 used detemir, and 26 402 used NPH insulin. The study included 7347 ED visits or hospitalizations for hypoglycemia (5194 for glargine, 1693 for detemir, and 460 for NPH insulin, with a median follow-up across the 3 cohorts of 0.37 years (interquartile range, 0.20-0.76 years). Initiation of glargine and detemir use was associated with a reduced risk of hypoglycemia compared with NPH insulin use (HR for glargine vs NPH insulin, 0.71; 95% CI, 0.63-0.80; HR, detemir vs NPH insulin, 0.72; 95% CI, 0.63-0.82). The HRs were similar for the recurrent event analysis. The protective association of long-acting insulin analogs varied by age and was not seen with concomitant prandial insulin use. Conclusions and Relevance In this cohort study, initiation of long-acting analogs was associated with a lower risk of ED visits or hospitalizations for hypoglycemia compared with NPH insulin in older patients with type 2 diabetes in Medicare. However, this association was not seen with concomitant prandial insulin use.

OBJECTIVE To assess whether initiation of insulin glargine (glargine), compared with initiation of NPH or insulin detemir (detemir), was associated with an increased risk of breast cancer in women with diabetes. RESEARCH DESIGN AND METHODS This was a retrospective new-user cohort study of female Medicare beneficiaries aged ≥65 years initiating glargine (203,159), detemir (67,012), or NPH (47,388) from September 2006 to September 2015, with follow-up through May 2017. Weighted Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% CIs for incidence of breast cancer according to ever use, cumulative duration of use, cumulative dose of insulin, length of follow-up time, and a combination of dose and length of follow-up time. RESULTS Ever use of glargine was not associated with an increased risk of breast cancer compared with NPH (HR 0.97; 95% CI 0.88–1.06) or detemir (HR 0.98; 95% CI 0.92–1.05). No increased risk was seen with glargine use compared with either NPH or detemir by duration of insulin use, length of follow-up, or cumulative dose of insulin. No increased risk of breast cancer was observed in medium- or high-dose glargine users compared with low-dose users. CONCLUSIONS Overall, glargine use was not associated with an increased risk of breast cancer compared with NPH or detemir in female Medicare beneficiaries.

How to quickly detect the characteristics of water quality flora, such as bacterial flora number, is a key problem of water quality safety, the traditional manual counting method has some serious defects such as low efficiency, low accuracy, easy to cause visual fatigue and hard to deal with large samples. This paper designs an automated method for bacterial flora counting based on image analysis, including such modules as pretreatment of bacterial image classification and colony counting of culture medium images by filter method (using Hough circle detection algorithm and a circle deduplication algorithm). The accuracy of experimental results is above 90%, which is in line with international standards, and the time complexity of the algorithms is up to the order of square. This method can solve the problems of heavy workload and low efficiency in traditional manual counting method.

Concentrated flow in furrows may lead to serious rill erosion in production systems where ridges are mulched with plastic film in contouring ridges. Studying the effect of influential factors on soil erosion in such systems could improve our understanding on erosion process and take appropriate control treatments. Considering a furrow with mulched ridges on both sides as a width-limited eroding rill, an in situ field experiment was conducted to analyze the effect of row grades and row lengths on soil erosion. Soil erosion indices, including runoff, runoff modulus, sediment concentration, soil loss, and soil loss modulus were monitored. Row grade and length exerted significant effect on all indices at p 2 > 0.950, p 2 > 0.830, p

Background T20 (enfuvirtide) is the first approved HIV entry inhibitor and currently the only viral fusion inhibitor, but its low efficacy and genetic barrier to resistance significantly limit its application, calling for a next-generation drug. Design On the basis of the M-T hook structure, we recently developed a short-peptide named HP23, which mainly targets the deep pocket site of gp41 and possesses highly potent antiviral activity. To improve the pharmaceutical properties of a peptide-based inhibitor, we modified HP23 by different classes of lipids including fatty acid, cholesterol, and sphingolipids. To avoid the potential problem of oxidation, the methionine residue in the M-T hook sequence of HP23 was replaced with leucine. Methods Peptides were synthesized and their anti-HIV activity and biophysical properties were determined. Results A group of lipopeptides were generated with greatly improved anti-HIV activity. Promisingly, a fatty acid-conjugated lipopeptide named LP-11 showed potent and broad inhibitory activity against diverse primary HIV-1 isolates and clinically drug-resistant mutants, and it had dramatically increased ex-vivo antiviral activity and extended half-life. Also, LP-11 displayed highly enhanced α-helicity and thermal stability, and it was physically stable under high temperature and humidity. Conclusion LP-11 has high potentials for clinical development and it can serve as an ideal tool for exploring the mechanisms of HIV-1 fusion and inhibition.

SC29EK is an electronically constrained α-helical peptide HIV-1 fusion inhibitor that is highly effective against both wild-type and enfuvirtide (T20)-resistant viruses. In this study, we focused on investigating the mechanism of HIV-1 resistance to SC29EK by two approaches. First, SC29EK-escaping HIV-1 variants were selected and characterized. Three mutant viruses, which possessed two (N43K/E49A) or three (Q39R/N43K/N126K and N43K/E49A/N126K) amino acid substitutions in the N- and C-terminal repeat regions of gp41 were identified as conferring high resistance to SC29EK and cross-resistance to the first-generation (T20 and C34) and newly designed (sifuvirtide, MT-SC29EK, and 2P23) fusion inhibitors. The resistance mutations could reduce the binding stability of SC29EK, impair viral Env-mediated cell fusion and entry, and change the conformation of the gp41 core structure. Further, we determined the crystal structure of SC29EK in complex with a target mimic peptide, which revealed the critical intra- and interhelical interactions underlying the mode of action of SC29EK and the genetic pathway to HIV-1 resistance. Taken together, the present data provide new insights into the structure and function of gp41 and the structure-activity relationship (SAR) of viral fusion inhibitors. IMPORTANCE T20 is the only membrane fusion inhibitor available for treatment of viral infection, but it has relatively low anti-HIV activity and genetic barriers for resistance, thus calling for new drugs blocking the viral fusion process. As an electronically constrained α-helical peptide, SC29EK is highly potent against both wild-type and T20-resistant HIV-1 strains. Here, we report the characterization of HIV-1 variants resistant to SC29EK and the crystal structure of SC29EK. The key mutations mediating high resistance to SC29EK and cross-resistance to the first and new generations of fusion inhibitors as well as the underlying mechanisms were identified. The crystal structure of SC29EK bound to a target mimic peptide further revealed its action mode and genetic pathway to inducing resistance. Hence, our data have shed new lights on the mechanisms of HIV-1 fusion and its inhibition.

Background Efficacy of 13-valent pneumococcal conjugate vaccine (PCV13) against pneumococcal pneumonia in adults aged >65 years was shown in a 2014 clinical trial. However, its benefits in countries with a mature PCV infant program remain unclear. In August 2014, PCV13 was recommended for all US adults aged >65 years. We evaluated the direct effect of this recommendation on pneumonia hospitalizations among the elderly. Methods We analyzed claims data from US Medicare beneficiaries aged >65 years enrolled in part A/B during September 1, 2014 through December 31, 2017. Participants were followed until they died, left part A/B, or developed a study outcome: community-acquired pneumonia (CAP), non-healthcare-associated CAP (non-HA CAP) or lobar pneumonia (LP). We identified outcomes using inpatient diagnosis codes, and vaccination status using procedure codes. We used discrete-time survival models, stratified by influenza season (October–April) and influenza vaccination status, to estimate incidence rate ratios (IRR) by pneumococcal vaccination status (PCV13-only vs. no pneumococcal vaccination). We adjusted for demographic factors, healthcare utilization, month/year of hospital discharge, and underlying conditions. We derived vaccine effectiveness (VE) and number of hospitalizations averted by PCV13 from the IRRs. Results Of 26.6 million beneficiaries in September 2014, 43.4% were male, 54.2% were aged 65–74 years, and 28.9% had a Charlson comorbidity score >3. PCV13 coverage increased from 0.8% in September 2014 to 41.5% in December 2017. Annual incidence of CAP, non-HA CAP, and LP are shown in the figure. PCV13-vaccinated persons were more likely to be older, sicker, and have received flu vaccine than unvaccinated persons. VE estimates for CAP, non-HA CAP, and LP ranged from 6.0–11.4%, 5.0–11.0%, and 1.3–11.0%, respectively. From September 2014 to December 2017, an estimated 28,600 (95% CI: 21,000–36,000) CAP, 18,700 (12,000–25,800) non-HA CAP and 1,100 (190–1,900) LP hospitalizations were averted. Conclusion Within 40 months after implementation of the adult PCV13 program, 2.0% (28,600) of US CAP hospitalizations were averted. Despite PCV13 effectiveness against adult CAP, only a small fraction of CAP hospitalizations was prevented. Disclosures All authors: No reported disclosures.

Background Pneumococcal conjugate vaccine (PCV13) was recommended in series with PPSV23 for all US adults ≥65 years in late 2014. We evaluated effectiveness of PCV13 against invasive pneumococcal disease (IPD) among Medicare beneficiaries ≥65 years old to assess this new policy. Methods We linked records for IPD cases (pneumococcus isolated from sterile sites) in persons ≥65 years old identified through Active Bacterial Core surveillance with those of Medicare beneficiaries. Isolates were serotyped and classified as PCV13 (with or without cross-reacting type 6C), and nonvaccine types. We selected Medicare beneficiaries with no record of IPD or pneumonia as controls, and matched to cases on age, residence census tract, and length of Medicare enrollment; we included all eligible controls. Vaccination and medical histories were obtained through Medicare. We estimated vaccine effectiveness (VE) as 1 minus the IPD odds ratio for vaccinated (PCV13) vs. unvaccinated (no PCV13 or PPSV23) persons using conditional logistic regression, adjusted for sex and underlying conditions. Results From 2,246 IPD cases identified in 2015–2016, 1,017 (45%) were matched to Medicare beneficiaries. After excluding cases in persons residing in long-term care facilities or with 75 years of age (VE 61%, 95% CI 14, 82). VE was 26% (95% CI −58, 65%) against serotype 3 and 67% (95% CI 11, 88%) against other PCV13-types (+6C). PCV13 was not effective against nonvaccine types. Conclusion PCV13 was effective in preventing IPD caused by PCV13 types when excluding type 3; no effectiveness was demonstrated against serotype 3. Disclosures W. Schaffner, Merck: Member, Data Safety Monitoring Board, Consulting fee. Pfizer: Member, Data Safety Monitoring Board, Consulting fee. Dynavax: Consultant, Consulting fee. Seqirus: Consultant, Consulting fee. SutroVax: Consultant, Consulting fee. Shionogi: Consultant, Consulting fee.

The peptide drug enfuvirtide (T20) is the only viral fusion inhibitor used in combination therapy for HIV-1 infection, but it has relatively low antiviral activity and easily induces drug resistance. Emerging studies demonstrate that lipopeptide-based fusion inhibitors, such as LP-11 and LP-19, which mainly target the gp41 pocket site, have greatly improved antiviral potency and in vivo stability. In this study, we focused on developing a T20-based lipopeptide inhibitor that lacks pocket-binding sequence and targets a different site. First, the C-terminal tryptophan-rich motif (TRM) of T20 was verified to be essential for its target binding and inhibition; then, a novel lipopeptide, termed LP-40, was created by replacing the TRM with a fatty acid group. LP-40 showed markedly enhanced binding affinity for the target site and dramatically increased inhibitory activity on HIV-1 membrane fusion, entry, and infection. Unlike LP-11 and LP-19, which required a flexible linker between the peptide sequence and the lipid moiety, addition of a linker to LP-40 sharply reduced its potency, implying different binding modes with the extended N-terminal helices of gp41. Also, interestingly, LP-40 showed more potent activity than LP-11 in inhibiting HIV-1 Env-mediated cell-cell fusion while it was less active than LP-11 in inhibiting pseudovirus entry, and the two inhibitors displayed synergistic antiviral effects. The crystal structure of LP-40 in complex with a target peptide revealed their key binding residues and motifs. Combined, our studies have not only provided a potent HIV-1 fusion inhibitor, but also revealed new insights into the mechanisms of viral inhibition. IMPORTANCE T20 is the only membrane fusion inhibitor available for treatment of viral infection; however, T20 requires high doses and has a low genetic barrier for resistance, and its inhibitory mechanism and structural basis remain unclear. Here, we report the design of LP-40, a T20-based lipopeptide inhibitor that has greatly improved anti-HIV activity and is a more potent inhibitor of cell-cell fusion than of cell-free virus infection. The binding modes of two classes of membrane-anchoring lipopeptides (LP-40 and LP-11) verify the current fusion model in which an extended prehairpin structure bridges the viral and cellular membranes, and their complementary effects suggest a vital strategy for combination therapy of HIV-1 infection. Moreover, our understanding of the mechanism of action of T20 and its derivatives benefits from the crystal structure of LP-40.

In nonregular problems where the conventional $$n$$n out of $$n$$n bootstrap is inconsistent, the $$m$$m out of $$n$$n bootstrap provides a useful remedy to restore consistency. Conventionally, optimal choice of the bootstrap sample size $$m$$m is taken to be the minimiser of a frequentist error measure, estimation of which has posed a major difficulty hindering practical application of the $$m$$m out of $$n$$n bootstrap method. Relatively little attention has been paid to a stronger, stochastic, version of the optimal bootstrap sample size, defined as the minimiser of an error measure calculated directly from the observed sample. Motivated by this stronger notion of optimality, we develop procedures for calculating the stochastically optimal value of $$m$$m. Our procedures are shown to work under special forms of Edgeworth-type expansions which are typically satisfied by statistics of the shrinkage type. Theoretical and empirical properties of our methods are illustrated with three examples, namely the James---Stein estimator, the ridge regression estimator and the post-model-selection regression estimator.

Background Pertussis in adults may be underdiagnosed and underreported; there is limited information on the incidence and severity of pertussis in older adults. We compared pertussis diagnoses identified using medical claims data with national surveillance data to examine the use of claims data as a source for disease burden estimates. Methods We examined claims data in persons aged ≥65 years in the United States enrolled in Medicare A and B from January 1, 2008 to December 31, 2017. We identified provider-diagnosed pertussis through pertussis-related ICD9/ICD10 diagnostic codes (033.XX, 484.3, A37.XX). We examined whether any were categorized as inpatient claims and if there were claims for laboratory tests within 30 days of the initial pertussis claim. We estimated claims-based pertussis incidence using person-time for all Medicare A/B enrollees and compared incidence estimates to those reported by the Nationally Notifiable Diseases Surveillance System (NNDSS) for the same period and age group. Results Among 27,269,361 Medicare beneficiaries, 24,355 (0.09%) had claims with pertussis diagnostic codes. Of these, 1,875 (7.7%) had claims associated with inpatient hospitalizations; 7,964 (33%) had laboratory testing performed. The mean annual incidence of claims-based pertussis was 11.5/100,000 person-years (range: 9.37 to 14.3/100,000 person-years) (figure). In contrast, 6,722 pertussis cases in persons aged ≥65 years were reported to NNDSS. Among the 5,101 cases whose hospitalization status was known, 783 (15%) were hospitalized. Mean annual reported pertussis incidence was 1.5/100,000 person-years (0.67 cases to 2.63 cases/100,000 person-years) in this age group. Conclusion Many more Medicare beneficiaries with pertussis-related claims were identified than pertussis cases in persons ≥65 years reported to public health authorities, suggesting pertussis is likely diagnosed more frequently in older adults than national incidence estimates indicate. A smaller proportion of Medicare beneficiaries with pertussis-related claims were hospitalized compared with reported cases and a majority did not have laboratory testing performed. It is unknown what proportion of pertussis-associated claims represent true pertussis disease. Disclosures All authors: No reported disclosures.

This study was designed to survey the reservoir sediment properties, assess the phosphorus (P) sorption isotherm, and analyze the relationship between sediment properties and sorption parameters. Physicochemical analysis indicated that sediment from the FUSHI reservoir in Zhejiang Province, China, has similar physical and chemical properties and has been contaminated by P. Sorption isotherm experiments showed that the sorption process could be described by Langmuir and Freundlich models. The parameters of Q max (Phosphorus sorption maximum) and K (Freundlich adsorption isotherm constant) ranged from 618.98 to 825.70 mg kg−1 and 114.18 to 170.74 l kg−1, respectively. EPC0 (zero P equilibrium concentration) ranged from 0.14 to 0.24 mg l−1, more than the total P concentration in the water of the reservoir. Thus, the reservoir sediment releases P into the water and acts as a “P resource”. The clay, Feo, Alt, and Fet + Alt content were the main active components in P sorption. Q max had a highly significant positive relationship with some properties and could be estimated by a combination of these.

One of the challenges in personalized e-learning research is how to find the unique learning strategies according to a learner’s personality characteristic. A learner’s personality characteristic may have many attributes, and all of them may not have equal values. Correlation analysis, regression analysis, discriminator function, and educational psychology have been used to find solutions, but these methods have their shortcomings. This article proposes an improved approach based on rough set theory to find the key personality attributes and evaluates the importance of these attributes. The approach has been successfully used in the actual e-learning environment for a major research university in China.

In the post WWW era, the research of e-learning focuses on facilitating intelligent and proactive services for learners. The quality of user experience determines whether e-learning services would be accepted by learners. However, many researchers traditionally focus on the effectiveness of computer systems or the accuracy of algorithms themselves rather than on user-centric psychological experience. How to model and evaluate user experience taking into account user psychological and cognitive properties are challenging research topics. There are some traditional methods typically proposed to evaluate users’ psychological experience, such as interview, questionnaire etc. They are qualitative and easy to conduct but need more time and resource. And they are liable to subjective views. Based on user web log data, the current paper presents a quantitative approach of modeling user psychological experience in the context of intelligent e-learning. The properties and elements, which affect user experience, are analyzed and quantified. The holistic user experience is quantified through the fusion of analytic hierarchy process (AHP) and Delphi methods. A case study, at a university in China, is conducted for diagnosing whether the result of the proposed approach can be uniform with user subjective experience, and indicates that the proposed approach is effective and complements existing user experience research in intelligent e-learning.

Studying on human personality is an important part of personalized service in e-Learning system. By understanding the personality characteristics of learners, we can provide better services to help learners improve learning efficiency. Grouping learners can help interaction and discussion among learners in e-Learning system. But how to compose groups is a problem. The paper proposes a method based on data mining technology to group e-learners automatically according to their personality characteristics. Five groups, which have distinctive features, are obtained. At last, an empirical study is presented to evaluate the result.

Learner modeling is the key aspect in personalized e-learning. The quality of the personalization largely depends on the accuracy of the learner model. The core data of a learner model include generally learner’s personality characteristics, interesting etc. While personality characteristics can describe a learner’s stable traces internally, interest can describe something that a learner wants externally. But, a learner’s personality characteristic may have many attributes, and all of them may not have equal values, while learner interests exist implicitly in the information of learner network behavior. The work discusses and evaluates how to find the key personality attributes and their weight, and how to mine learner interest from learner behavior. The method has been successfully used in China e-learning for a major research university. The experimental evaluation shows the modeling method is effective in personalized e-learning.

Dimension reduction has been widely employed to deal with the curse of dimensionality before training supervised learning such as neural network and this framework combining dimension reduction and supervised learning algorithms is called as two-stage approach. However during the process of this approach, the system has to store original data and pre-process data simultaneously which will increase the complexity and re-compute the SVD when the new data arrive. To address the above problems, this paper proposes a novel learning algorithm for high-dimension large-scale data, by combining a new incremental dimension reduction with feed-forward neural network training simultaneously, called Incremental Projection Vector Machine (IPVM). With new samples arriving, instead of re-computing the full rank SVD of the whole dataset, an incremental method is applied to update the original SVD. It is suitable for high-dimension large-sample data for the singular vectors are updated incrementally. Experimental results showed that the proposed one-stage algorithm IPVM was faster than two-stage learning approach such as SVD+BP and SVD+ELM, and performed better than conventional supervised algorithms.

One of the challenges in personalized e-learning research is how to find the unique learning strategies according to a learner’s personality characteristic. A learner’s personalitycharacteristic may have many attributes, and all of them may not have equal values. Correlation analysis, regression analysis, discriminator function, and educational psychology have been used to find solutions, but these methods have their shortcomings. This article proposes an improved approach based on rough set theory to find thekey personality attributes and evaluates the importance of these attributes. The approach has been successfully used in the actual e-learning environment for a major research university in China.

One of the challenges in personalized e-learning research field is how to meet the unique learning strategies according to a learner's personality characteristic. But a learner's characteristic may have many attributes, and some of them have not equal value for personalized e-learning. This paper exploits the aspect to evaluate the important attributes, puts forward the concept of key personality characteristic and an improved algorithm basing on rough set theory to find the key attributes. Systematic experiments and their results are reported and shows the dimensions of personality characteristic can be decreased to below one-quarter.