Social frailty and the incidence of motoric cognitive risk syndrome in older adults.

INTRODUCTION: Various associations between social factors and motoric cognitive risk syndrome (MCR) have been reported. However, whether social frailty (integrated from multiple social factors) is associated with MCR is still unclear. METHODS: We included 4657 individuals without MCR at Round 1 of the NHATS as the discovery sample, and 3075 newly recruited individuals from Round 5 of the NHATS as the independent validation sample. Social frailty was assessed by five social items. MCR was defined as the presence of both subjective cognitive complaints and slow gait speed in individuals without dementia or mobility disability. RESULTS: Compared with normal individuals, those with social frailty had higher risk of incident MCR (hazard ratio [HR]: 1.57, 95% confidence interval [CI]: 1.34-1.84). Each additional unfavorable social item was associated with an increased risk of MCR (HR: 1.32, 95% CI: 1.22-1.43). DISCUSSION: Social frailty was associated with an increased risk of incident MCR in older adults. HIGHLIGHTS: Various associations between social factors and motoric cognitive risk syndrome (MCR) have been reported. Social frailty that integrated from multiple social factors was associated with an increased risk of incident MCR. Social frailty should be included in the early screening of individuals to identify those at higher risk of MCR.

Effect of the L74I Polymorphism on Fitness of Cabotegravir-Resistant Variants of Human Immunodeficiency Virus 1 Subtype A6.

The presence of human immunodeficiency virus (HIV) 1 subtype A6, characterized by the L74I integrase (IN) polymorphism, is associated with confirmed virologic failure in clinical trials of long-acting cabotegravir and rilpivirine. We investigated the effect of L74I on replication capacity (RC) of recombinant viruses carrying this polymorphism in combination with various IN stand-transfer inhibitor resistance mutations. The presence of L74I conferred greater RC to recombinant viruses expressing HIV-1 A6 IN when present together with G118R, G140R, Q148H, and R263K; no significant difference in RC was observed for the Q148K or R mutants. These findings may explain, in part, the association of HIV-1 subtype A6 with virologic failure.

Association of immunity markers with the risk of incident frailty: the Rugao longitudinal aging study.

BACKGROUND: The neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and systemic immune-inflammation index (SII) are readily available circulatory immunity markers that are associated with components of frailty. However, few studies have investigated the relationship between these immunity markers and frailty, and it remains unknown whether they are predictive of incident frailty in older adults in general. Hence, we aimed to examine the association of these immunity markers with the risk of incident frailty. RESULTS: Overall, 1822 older adults (mean age was 78.03 ± 4.46 years) were included in the Rugao Longitudinal Aging Study. NLR, PLR and SII were calculated from blood cell counts. The frailty definition was based on the Fried phenotype. At baseline, 200 (10.98%) individuals were defined as frailty, and no significant associations of NLR, PLR and SII with frailty were found. During the 2-year follow-up, 180 (15.67%) individuals were new-onset frailty. After adjustment, an increased logNLR (odds ratio [OR] 2.92, 95% confidence interval [CI] 1.20-7.18), logPLR (OR 2.54, 95% CI: 1.01-6.53) and logSII (OR 2.34, 95% CI: 1.16-4.78) were significantly associated with a higher risk of incident frailty in all individuals. Additionally, the associations of logNLR (OR 4.21, 95% CI 1.54-11.62 logPLR (OR 3.38, 95% CI: 1.17-9.91) and logSII (OR 2.56, 95% CI: 1.15-5.72) with incident frailty were remained after excluding individuals with comorbidities. In further analyzed, individuals with higher levels of NLR and SII had higher risk of incident frailty when we stratified individuals by quartiles of these immunity markers. CONCLUSION: NLR and SII are easily obtained immunity markers that could be used to predict incident frailty in clinical practice.

Three Kinetic Patterns for the Oxidation of Emerging Organic Contaminants by Fe(VI): The Critical Roles of Fe(V) and Fe(IV).

For the first time, this study showed that the apparent second-order rate constants (kapp) of six selected emerging organic contaminants (EOCs) oxidation by Fe(VI) increased, remained constant, or declined with time, depending on [EOC]0/[Fe(VI)]0, pH, and EOCs species. Employing excess caffeine as the quenching reagent for Fe(V) and Fe(IV), it was found that Fe(V)/Fe(IV) contributed to 20-30% of phenol and bisphenol F degradation by Fe(VI), and the contributions of Fe(V)/Fe(IV) remained nearly constant with time under all the tested conditions. However, the contributions of Fe(V)/Fe(IV) accounted for over 50% during the oxidation of sulfamethoxazole, bisphenol S, and iohexol by Fe(VI), and the variation trends of kapp of their degradation by Fe(VI) with time displayed three different patterns, which coincided with those of the contributions of Fe(V)/Fe(IV) to their decomposition with time. Results of the quenching experiments were validated by simulating the oxidation kinetic data of methyl phenyl sulfoxide by Fe(VI), which revealed that the variation trends of kapp with time were significantly determined by the change in the molar ratio of Fe(V) to Fe(VI) with time, highlighting the key role of Fe(V) in the oxidative process. This study provides comprehensive and insightful information on the roles of Fe(V)/Fe(IV) during EOC oxidation by Fe(VI).

Altered viral fitness and drug susceptibility in HIV-1 carrying mutations that confer resistance to nonnucleoside reverse transcriptase and integrase strand transfer inhibitors.

UNLABELLED: Nonnucleoside reverse transcriptase (RT) inhibitors (NNRTI) and integrase (IN) strand transfer inhibitors (INSTI) are key components of antiretroviral regimens. To explore potential interactions between NNRTI and INSTI resistance mutations, we investigated the combined effects of these mutations on drug susceptibility and fitness of human immunodeficiency virus type 1 (HIV-1). In the absence of drug, single-mutant viruses were less fit than the wild type; viruses carrying multiple mutations were less fit than single-mutant viruses. These findings were explained in part by the observation that mutant viruses carrying NNRTI plus INSTI resistance mutations had reduced amounts of virion-associated RT and/or IN protein. In the presence of efavirenz (EFV), a virus carrying RT-K103N together with IN-G140S and IN-Q148H (here termed IN-G140S/Q148H) mutations was fitter than a virus with a RT-K103N mutation alone. Similarly, in the presence of EFV, the RT-E138K plus IN-G140S/Q148H mutant virus was fitter than one with the RT-E138K mutation alone. No effect of INSTI resistance mutations on the fitness of RT-Y181C mutant viruses was observed. Conversely, RT-E138K and -Y181C mutations improved the fitness of the IN-G140S/Q148H mutant virus in the presence of raltegravir (RAL); the RT-K103N mutation had no effect. The NNRTI resistance mutations had no effect on RAL susceptibility. Likewise, the IN-G140S/Q148H mutations had no effect on EFV or RPV susceptibility. However, both the RT-K103N plus IN-G140S/Q148H and the RT-E138K plus IN-G140S/Q148H mutant viruses had significantly greater fold increases in 50% inhibitory concentration (IC50) of EFV than viruses carrying a single NNRTI mutation. Likewise, the RT-E138K plus IN-G140S/Q148H mutant virus had significantly greater fold increases in RAL IC50 than that of the IN-G140S/Q148H mutant virus. These results suggest that interactions between RT and IN mutations are important for NNRTI and INSTI resistance and viral fitness. IMPORTANCE: Nonnucleoside reverse transcriptase inhibitors and integrase inhibitors are used to treat infection with HIV-1. Mutations that confer resistance to these drugs reduce the ability of HIV-1 to reproduce (that is, they decrease viral fitness). It is known that reverse transcriptase and integrase interact and that some mutations can disrupt their interaction, which is necessary for proper functioning of these two enzymes. To determine whether resistance mutations in these enzymes interact, we investigated their effects on drug sensitivity and viral fitness. Although individual drug resistance mutations usually reduced viral fitness, certain combinations of mutations increased fitness. When present in certain combinations, some integrase inhibitor resistance mutations increased resistance to nonnucleoside reverse transcriptase inhibitors and vice versa. Because these drugs are sometimes used together in the treatment of HIV-1 infection, these interactions could make viruses more resistant to both drugs, further limiting their clinical benefit.

Long-term reduction in peripheral blood HIV type 1 reservoirs following reduced-intensity conditioning allogeneic stem cell transplantation.

BACKGROUND: The long-term impact of allogeneic hematopoietic stem cell transplantation (HSCT) on human immunodeficiency virus type 1 (HIV-1) reservoirs in patients receiving combination antiretroviral therapy (cART) is largely unknown. METHODS: We studied the effects of a reduced-intensity conditioning allogeneic HSCT from donors with wild-type-CCR5(+) cells on HIV-1 peripheral blood reservoirs in 2 patients heterozygous for the ccr5Δ32 mutation. In-depth analyses of the HIV-1 reservoir size in peripheral blood, coreceptor use, and specific antibody responses were performed on samples obtained before and up to 3.5 years after HSCT receipt. RESULTS: Although HIV-1 DNA was readily detected in peripheral blood mononuclear cells (PBMCs) before and 2-3 months after HSCT receipt, HIV-1 DNA and RNA were undetectable in PBMCs, CD4(+) T cells, or plasma up to 21 and 42 months after HSCT. The loss of detectable HIV-1 correlated temporally with full donor chimerism, development of graft-versus-host disease, and decreases in HIV-specific antibody levels. CONCLUSIONS: The ability of donor cells to engraft without evidence of ongoing HIV-1 infection suggests that HIV-1 replication may be fully suppressed during cART and does not contribute to maintenance of viral reservoirs in peripheral blood in our patients. HSCTs with wild-type-CCR5(+) donor cells can lead to a sustained reduction in the size of the peripheral reservoir of HIV-1.

Refined Bonded Terms in Coarse-Grained Models for Intrinsically Disordered Proteins Improve Backbone Conformations.

Coarse-grained models designed for intrinsically disordered proteins and regions (IDP/Rs) usually omit some bonded potentials (e.g., angular and dihedral potentials) as a conventional strategy to enhance backbone flexibility. However, a notable drawback of this approach is the generation of inaccurate backbone conformations. Here, we addressed this problem by introducing residue-specific angular, refined dihedral, and correction map (CMAP) potentials, derived based on the statistics from a customized coil database. These bonded potentials were integrated into the existing Mpipi model, resulting in a new model, denoted as the "Mpipi+" model. Results show that the Mpipi+ model can improve backbone conformations. More importantly, it can markedly improve the secondary structure propensity (SSP) based on the experimental chemical shift and, consequently, succeed in capturing transient secondary structures. Moreover, the Mpipi+ model preserves the liquid-liquid phase separation (LLPS) propensities of IDPs.

Effect of body mass index and cholesterol-rich apolipoprotein-B-containing lipoproteins on clinical outcome in NSCLC patients treated with immune checkpoint inhibitors-based therapy: A retrospective analysis.

OBJECTIVES: Obesity and hypercholesterolemia are linked to unfavor clinical outcomes. Recent studies declared the paradox that high body mass index (BMI) and serum cholesterol were independently connected to better clinical outcome of immune checkpoint inhibitors (ICIs) monotherapy in non-small cell lung cancer (NSCLC). The aim of the study is to investigate the prognosis of BMI and serum cholesterol in ICIs-based therapy. METHODS: This is a retrospective study of 95 NSCLC patients treated with ICIs-based therapy at the Department of Oncology and Lung Cancer Center of China-Japan Friendship Hospital. Treatment efficacy was assessed using durable clinical benefit (DCB) versus nondurable benefit (NDB), best response (active vs. nonactive), and progression-free survival (PFS). The prognostic value of BMI, LDL-C, and RC was determined by multivariate regression analyses, while controlling for confounding factors including age, gender, diabetes status, smoking history, and statin usage. BMI was considered a confounding factor in the analysis when examining the impact of lipoproteins. RESULTS: In our study, we found that in the whole group, BMI ≥25 kg/m2 was linked to a higher risk of poor therapeutic response (OR = 5.92, 95% CI 1.99-19.51, p.val = 0.002) and shorter progression-free survival (HR = 3.00, 95% CI 1.59-5.68, p.val = 0.001). In addition, low levels of RC were associated with better therapeutic response (OR = 0.12, 95% CI 0.02-0.64, p.val = 0.019), while low levels of serum LDL-C were found to predict longer PFS (HR = 0.40, 95% CI 0.19-0.82, p.val = 0.012). These associations were consistent in advanced NSCLC patients receiving ICIs and chemotherapy. CONCLUSIONS: Our study suggest that BMI ≥25 kg/m2 and elevated levels of apoB-containing lipoproteins, including LDL-C and RC, could potentially serve as useful prognostic markers for predicting poor treatment outcomes in advanced NSCLC patients treated with the combination of chemotherapy and ICIs.

Unraveling the motion and deformation characteristics of red blood cells in a deterministic lateral displacement device.

Deterministic Lateral Displacement (DLD) device has gained widespread recognition and trusted for filtering blood cells. However, there remains a crucial need to explore the complex interplay between deformable cells and flow within the DLD device to improve its design. This paper presents an approach utilizing a mesoscopic cell-level numerical model based on dissipative particle dynamics to effectively capture this complex phenomenon. To establish the model's credibility, a series of numerical simulations were conducted and the numerical results were validated with nominal experimental data from the literature. These include single cell stretching experiment, comparisons of the morphological characteristics of cells in DLD, and comparison the specific row-shift fraction of DLD required to initiate the zigzag mode. Additionally, we investigate the effect of cell rigidity, which serves as an indicator of cell health, on average flow velocity, trajectory, and asphericity. Moreover, we extend the existing theory of predicting zigzag mode for solid spherical particles to encompass the behavior of red blood cells. To achieve this, we introduce a new concept of effective diameter and demonstrate its applicability in providing highly accurate predictions across a wide range of conditions.

A machine learning model that outperforms conventional global subseasonal forecast models.

Skillful subseasonal forecasts are crucial for various sectors of society but pose a grand scientific challenge. Recently, machine learning-based weather forecasting models outperform the most successful numerical weather predictions generated by the European Centre for Medium-Range Weather Forecasts (ECMWF), but have not yet surpassed conventional models at subseasonal timescales. This paper introduces FuXi Subseasonal-to-Seasonal (FuXi-S2S), a machine learning model that provides global daily mean forecasts up to 42 days, encompassing five upper-air atmospheric variables at 13 pressure levels and 11 surface variables. FuXi-S2S, trained on 72 years of daily statistics from ECMWF ERA5 reanalysis data, outperforms the ECMWF's state-of-the-art Subseasonal-to-Seasonal model in ensemble mean and ensemble forecasts for total precipitation and outgoing longwave radiation, notably enhancing global precipitation forecast. The improved performance of FuXi-S2S can be primarily attributed to its superior capability to capture forecast uncertainty and accurately predict the Madden-Julian Oscillation (MJO), extending the skillful MJO prediction from 30 days to 36 days. Moreover, FuXi-S2S not only captures realistic teleconnections associated with the MJO but also emerges as a valuable tool for discovering precursor signals, offering researchers insights and potentially establishing a new paradigm in Earth system science research.

Ratio of Red Blood Cell Distribution Width to Albumin Level and Risk of Mortality.

Importance: The ratio of red blood cell distribution width (RDW) to albumin concentration (RAR) has emerged as a reliable prognostic marker for mortality in patients with various diseases. However, whether RAR is associated with mortality in the general population remains unknown. Objectives: To explore whether RAR is associated with all-cause and cause-specific mortality and to elucidate their dose-response association. Design, Setting, and Participants: This population-based prospective cohort study used data from participants in the 1998-2018 US National Health and Nutrition Examination Survey (NHANES) and from the UK Biobank with baseline information provided from 2006 to 2010. Included participants had complete data on serum albumin concentration, RDW, and cause of death. The NHANES data were linked to the National Death Index records through December 31, 2019. For the UK Biobank, dates and causes of death were obtained from the National Health Service Information Centre (England and Wales) and the National Health Service Central Register Scotland (Scotland) to November 30, 2022. Main Outcomes and Measures: Potential associations between RAR and the risk of all-cause and cause-specific mortality were evaluated using Cox proportional hazards regression models. Restricted cubic spline regressions were applied to estimate possible nonlinear associations. Results: In NHANES, 50 622 participants 18 years of age or older years were included (mean [SD] age, 48.6 [18.7] years; 26 136 [51.6%] female), and their mean (SD) RAR was 3.15 (0.51). In the UK Biobank, 418 950 participants 37 years of age or older (mean [SD], 56.6 [8.1] years; 225 038 [53.7%] female) were included, and their mean RAR (SD) was 2.99 (0.31). The NHANES documented 7590 deaths over a median (IQR) follow-up of 9.4 (5.1-14.2) years, and the UK Biobank documented 36 793 deaths over a median (IQR) follow-up of 13.8 (13.0-14.5) years. According to the multivariate analysis, elevated RAR was significantly associated with greater risk of all-cause mortality (NHANES: hazard ratio [HR], 1.83 [95% CI, 1.76-1.90]; UK Biobank: HR, 2.08 [95% CI, 2.03-2.13]), as well as mortality due to malignant neoplasm (NHANES: HR, 1.89 [95% CI, 1.73-2.07]; UK Biobank: HR, 1.93 [95% CI, 1.86-2.00]), heart disease (NHANES: HR, 1.88 [95% CI, 1.74-2.03]; UK Biobank: HR, 2.42 [95% CI, 2.29-2.57]), cerebrovascular disease (NHANES: HR, 1.35 [95% CI, 1.07-1.69]; UK Biobank: HR, 2.15 [95% CI, 1.91-2.42]), respiratory disease (NHANES: HR, 1.99 [95% CI, 1.68-2.35]; UK Biobank: HR, 2.96 [95% CI, 2.78-3.15]), diabetes (NHANES: HR, 1.55 [95% CI, 1.27-1.90]; UK Biobank: HR, 2.83 [95% CI, 2.35-3.40]), and other causes of mortality (NHANES: HR, 1.97 [95% CI, 1.86-2.08]; UK Biobank: HR, 2.40 [95% CI, 2.30-2.50]) in both cohorts. Additionally, a nonlinear association was observed between RAR levels and all-cause mortality in both cohorts. Conclusions and Relevance: In this cohort study, a higher baseline RAR was associated with an increased risk of all-cause and cause-specific mortality in the general population. These findings suggest that RAR may be a simple, reliable, and inexpensive indicator for identifying individuals at high risk of mortality in clinical practice.

Equilibrium points and their stability of COVID-19 in US.

This study aims to develop an advanced mathematic model and investigate when and how will the COVID-19 in the US be evolved to endemic. We employed a nonlinear ordinary differential equations-based model to simulate COVID-19 transmission dynamics, factoring in vaccination efforts. Multi-stability analysis was performed on daily new infection data from January 12, 2021 to December 12, 2022 across 50 states in the US. Key indices such as eigenvalues and the basic reproduction number were utilized to evaluate stability and investigate how the pandemic COVD-19 will evolve to endemic in the US. The transmissional, recovery, vaccination rates, vaccination effectiveness, eigenvalues and reproduction numbers ([Formula: see text] and [Formula: see text]) in the endemic equilibrium point were estimated. The stability attractor regions for these parameters were identified and ranked. Our multi-stability analysis revealed that while the endemic equilibrium points in the 50 states remain unstable, there is a significant trend towards stable endemicity in the US. The study's stability analysis, coupled with observed epidemiological waves in the US, suggested that the COVID-19 pandemic may not conclude with the virus's eradication. Nevertheless, the virus is gradually becoming endemic. Effectively strategizing vaccine distribution is pivotal for this transition.

Extracellular Matrix-Trapped Bioinspired Lipoprotein Prolongs Tumor Retention to Potentiate Antitumor Immunity.

The immunomodulatory effects of many therapeutic agents are significantly challenged by their insufficient delivery efficiency and short retention time in tumors. Regarding the distinctively upregulated fibronectin (FN1) and tenascin C (TNC) in tumor stroma, herein a protease-activated FN1 and/or TNC binding peptide (FTF) is designed and an extracellular matrix (ECM)-trapped bioinspired lipoprotein (BL) (FTF-BL-CP) is proposed that can be preferentially captured by the TNC and/or FN1 for tumor retention, and then be responsively dissociated from the matrix to potentiate the antitumor immunity. The FTF-BL-CP treatment produces a 6.96-, 9.24-, 6.72-, 7.32-, and 6.73-fold increase of CD3+CD8+ T cells and their interferon-γ-, granzyme B-, perforin-, and Ki67-expressing subtypes versus the negative control, thereby profoundly eliciting the antitumor immunity. In orthotopic and lung metastatic breast cancer models, FTF-BL-CP produces notable therapeutic benefits of retarding tumor growth, extending survivals, and inhibiting lung metastasis. Therefore, this ECM-trapping strategy provides an encouraging possibility of prolonging tumor retention to potentiate the antitumor immunity for anticancer immunotherapy.

Enhanced neutralization of SARS-CoV-2 variant BA.2.86 and XBB sub-lineages by a tetravalent COVID-19 vaccine booster.

Emerging SARS-CoV-2 sub-lineages like XBB.1.5, XBB.1.16, EG.5, HK.3 (FLip), and XBB.2.3 and the variant BA.2.86 have recently been identified. Understanding the efficacy of current vaccines on these emerging variants is critical. We evaluate the serum neutralization activities of participants who received COVID-19 inactivated vaccine (CoronaVac), those who received the recently approved tetravalent protein vaccine (SCTV01E), or those who had contracted a breakthrough infection with BA.5/BF.7/XBB virus. Neutralization profiles against a broad panel of 30 sub-lineages reveal that BQ.1.1, CH.1.1, and all the XBB sub-lineages exhibit heightened resistance to neutralization compared to previous variants. However, despite their extra mutations, BA.2.86 and the emerging XBB sub-lineages do not demonstrate significantly increased resistance to neutralization over XBB.1.5. Encouragingly, the SCTV01E booster consistently induces higher neutralizing titers against all these variants than breakthrough infection does. Cellular immunity assays also show that the SCTV01E booster elicits a higher frequency of virus-specific memory B cells. Our findings support the development of multivalent vaccines to combat future variants.

Potent and broadly neutralizing antibodies against sarbecoviruses induced by sequential COVID-19 vaccination.

The current SARS-CoV-2 variants strikingly evade all authorized monoclonal antibodies and threaten the efficacy of serum-neutralizing activity elicited by vaccination or prior infection, urging the need to develop antivirals against SARS-CoV-2 and related sarbecoviruses. Here, we identified both potent and broadly neutralizing antibodies from a five-dose vaccinated donor who exhibited cross-reactive serum-neutralizing activity against diverse coronaviruses. Through single B-cell sorting and sequencing followed by a tailor-made computational pipeline, we successfully selected 86 antibodies with potential cross-neutralizing ability from 684 antibody sequences. Among them, PW5-570 potently neutralized all SARS-CoV-2 variants that arose prior to Omicron BA.5, and the other three could broadly neutralize all current SARS-CoV-2 variants of concern, SARS-CoV and their related sarbecoviruses (Pangolin-GD, RaTG13, WIV-1, and SHC014). Cryo-EM analysis demonstrates that these antibodies have diverse neutralization mechanisms, such as disassembling spike trimers, or binding to RBM or SD1 to affect ACE2 binding. In addition, prophylactic administration of these antibodies significantly protects nasal turbinate and lung infections against BA.1, XBB.1, and SARS-CoV viral challenge in golden Syrian hamsters, respectively. Importantly, post-exposure treatment with PW5-5 and PW5-535 also markedly protects against XBB.1 challenge in these models. This study reveals the potential utility of computational process to assist screening cross-reactive antibodies, as well as the potency of vaccine-induced broadly neutralizing antibodies against current SARS-CoV-2 variants and related sarbecoviruses, offering promising avenues for the development of broad therapeutic antibody drugs.

Vicriviroc resistance decay and relative replicative fitness in HIV-1 clinical isolates under sequential drug selection pressures.

We previously described an HIV-1-infected individual who developed resistance to vicriviroc (VCV), an investigational CCR5 antagonist, during 28 weeks of therapy (Tsibris AM et al., J. Virol. 82:8210-8214, 2008). To investigate the decay of VCV resistance mutations, a standard clonal analysis of full-length env (gp160) was performed on plasma HIV-1 samples obtained at week 28 (the time of VCV discontinuation) and at three subsequent time points (weeks 30, 42, and 48). During 132 days, VCV-resistant HIV-1 was replaced by VCV-sensitive viruses whose V3 loop sequences differed from the dominant pretreatment forms. A deep-sequencing analysis showed that the week 48 VCV-sensitive V3 loop form emerged from a preexisting viral variant. Enfuvirtide was added to the antiretroviral regimen at week 30; by week 48, enfuvirtide treatment selected for either the G36D or N43D HR-1 mutation. Growth competition experiments demonstrated that viruses incorporating the dominant week 28 VCV-resistant env were less fit than week 0 viruses in the absence of VCV but more fit than week 48 viruses. This week 48 fitness deficit persisted when G36D was corrected by either site-directed mutagenesis or week 48 gp41 domain swapping. The correction of N43D, in contrast, restored fitness relative to that of week 28, but not week 0, viruses. Virus entry kinetics correlated with observed fitness differences; the slower entry of enfuvirtide-resistant viruses corrected to wild-type rates in the presence of enfuvirtide. These findings suggest that while VCV and enfuvirtide select for resistance mutations in only one env subunit, gp120 and gp41 coevolve to maximize viral fitness under sequential drug selection pressures.

HIV-1 clinical isolates resistant to CCR5 antagonists exhibit delayed entry kinetics that are corrected in the presence of drug.

HIV CCR5 antagonists select for env gene mutations that enable virus entry via drug-bound coreceptor. To investigate the mechanisms responsible for viral adaptation to drug-bound coreceptor-mediated entry, we studied viral isolates from three participants who developed CCR5 antagonist resistance during treatment with vicriviroc (VCV), an investigational small-molecule CCR5 antagonist. VCV-sensitive and -resistant viruses were isolated from one HIV subtype C- and two subtype B-infected participants; VCV-resistant isolates had mutations in the V3 loop of gp120 and were cross-resistant to TAK-779, an investigational antagonist, and maraviroc (MVC). All three resistant isolates contained a 306P mutation but had variable mutations elsewhere in the V3 stem. We used a virus-cell ß-lactamase (BlaM) fusion assay to determine the entry kinetics of recombinant viruses that incorporated full-length VCV-sensitive and -resistant envelopes. VCV-resistant isolates exhibited delayed entry rates in the absence of drug, relative to pretherapy VCV-sensitive isolates. The addition of drug corrected these delays. These findings were generalizable across target cell types with a range of CD4 and CCR5 surface densities and were observed when either population-derived or clonal envelopes were used to construct recombinant viruses. V3 loop mutations alone were sufficient to restore virus entry in the presence of drug, and the accumulation of V3 mutations during VCV therapy led to progressively higher rates of viral entry. We propose that the restoration of pre-CCR5 antagonist therapy HIV entry kinetics drives the selection of V3 loop mutations and may represent a common mechanism that underlies the emergence of CCR5 antagonist resistance.

Assessment of Physical Resilience Using Residual Methods and Its Association With Adverse Outcomes in Older Adults.

Background and Objectives: Physical resilience (PR) is recognized as the ability to recover from the adverse effects of a stressor. However, there is a lack of consensus on how to optimally measure PR in older adults in general. We aimed to measure PR using residuals from regression analyses and investigated its association with adverse outcomes in older adults. Research Design and Methods: A total of 6 508 older adults were included from the National Health and Aging Trends Study, which was a population-based prospective cohort study. PR was assessed using residual methods from a linear model regressing the short physical performance battery on clinical diseases, age, sex, race/ethnicity, and health condition. Adverse outcomes included all-cause mortality, falls, and overnight hospitalization. Results: The mean age was 77.48 (7.84) years. Increased PR was associated with a lower risk of all-cause mortality (hazard ratio [HR] = 0.85, 95% confidence interval [CI]: 0.83-0.87). Compared to participants with reduced PR, those with normal PR had a lower risk for mortality (HR = 0.51, 95% CI: 0.46-0.56). Specifically, restricted cubic spline regression revealed a dose-response relationship between PR and all-cause mortality (p-overall < .0001, p-nonlinear = .011). Additionally, we also found significant associations of increased PR with lower risks of falls (HR = 0.98, 95% CI: 0.96-0.99) and overnight hospitalization (HR = 0.98, 95% CI: 0.97-1.00). Discussion and Implications: PR, measured by residual methods, was robustly and independently associated with all-cause mortality, falls, and overnight hospitalization. Our findings provide evidence that this approach may be a simple and feasible strategy to assess PR.

Microsatellite instability-related prognostic risk score (MSI-pRS) defines a subset of lung squamous cell carcinoma (LUSC) patients with genomic instability and poor clinical outcome.

Background: Lung squamous cell carcinoma (LUSC) shares less typical onco-drivers and target resistance, but a high overall mutation rate and marked genomic complexity. Mismatch repair (MMR) deficiency leads to microsatellite instability (MSI) and genomic instability. MSI is not an ideal option for prognosis of LUSC, whereas its function deserves exploration. Method: MSI status was classified by MMR proteins using unsupervised clustering in the TCGA-LUSC dataset. The MSI score of each sample was determined by gene set variation analysis. Intersections of the differential expression genes and differential methylation probes were classified into functional modules by weighted gene co-expression network analysis. Least absolute shrinkage and selection operator regression and stepwise gene selection were performed for model downscaling. Results: Compared with the MSI-low (MSI-L) phenotype, MSI-high (MSI-H) displayed higher genomic instability. The MSI score was decreased from MSI-H to normal samples (MSI-H > MSI-L > normal). A total of 843 genes activated by hypomethylation and 430 genes silenced by hypermethylation in MSI-H tumors were classified into six functional modules. CCDC68, LYSMD1, RPS7, and CDK20 were used to construct MSI-related prognostic risk score (MSI-pRS). Low MSI-pRS was a protective prognostic factor in all cohorts (HR = 0.46, 0.47, 0.37; p-value = 7.57e-06, 0.009, 0.021). The model contains tumor stage, age, and MSI-pRS that showed good discrimination and calibration. Decision curve analyses indicated that microsatellite instability-related prognostic risk score added extra value to the prognosis. A low MSI-pRS was negatively correlated with genomic instability. LUSC with low MSI-pRS was associated with increased genomic instability and cold immunophenotype. Conclusion: MSI-pRS is a promising prognostic biomarker in LUSC as the substitute of MSI. Moreover, we first declared that LYSMD1 contributed to genomic instability of LUSC. Our findings provided new insights in the biomarker finder of LUSC.

Treatment-related adverse events of immune checkpoint inhibitors combined with angiogenesis inhibitors in advanced lung cancer: A systematic review and meta-analysis.

BACKGROUND: Immune checkpoint inhibitors (ICIs) with angiogenesis inhibitors have been used to treat advanced lung cancer. Their associated treatment-related adverse events (trAEs) are currently considered acceptable; however, no conclusion has been reached. We aimed to summarize the trAEs caused by ICIs combined with angiogenesis inhibitors in patients with advanced lung cancer. METHODS: Pulled studies met the following criteria: patients with advanced lung cancer who received treatment involving ICIs combined with angiogenesis inhibitors (with or without chemotherapy) in interventional or observational studies. Results included the type and number of trAEs or immune-related adverse events (irAEs), treatment-associated discontinuation and mortality, overall survival (OS), and progression-free survival (PFS). PROSPERO: CRD42022337656. RESULTS: The study enrolled 32 trials involving 2313 patients who had 7768 any-grade trAEs and 1078 grade ≥3 trAEs. The pooled incidences were 87.33% (95% confidence interval [CI]: 79.49-93.65; I2 = 94.04%) for any-grade trAEs, and 38.63% (95% CI: 28.28-49.50; I2 = 95.61%) for grade ≥3 trAEs. There were 132 kinds of any-grade trAEs involving 18 systems, and 99 kinds of grade ≥3 trAEs involving 16 systems. For all trAEs, we observed significant differences in the line of therapy, trial design, therapy combination, and types of angiogenesis inhibitors (all P < 0.05). The rate of trAEs increased with dosage and frequency of medication. Pooled incidences of discontinuation and mortality were 10.64% and 0.81%, respectively. Nearly 647 patients experienced irAEs, including 636 any-grade irAEs and 154 grade ≥3 irAEs. CONCLUSIONS: Overall, the incidence of trAEs caused by ICIs combined with angiogenesis inhibitors is generally acceptable. These trAEs have a wide spectrum nearly covering the full range of adverse events. Grade ≥3 trAEs are more closely associated with angiogenesis inhibitors than any grade. However, treatment-associated mortality remains concerning.