Hybrid measurement of respiratory aerosol reveals a dominant coarse fraction resulting from speech that remains airborne for minutes

Accurate measurements of the size and quantity of aerosols generated by various human activities in different environments are required for efficacious mitigation strategies and accurate modeling of respiratory disease transmission. Previous studies of speech droplets, using standard aerosol instrumentation, reported very few particles larger than 5 μm. This starkly contrasts with the abundance of such particles seen in both historical slide deposition measurements and more recent light scattering observations. We have reconciled this discrepancy by developing an alternative experimental approach that addresses complications arising from nucleated condensation. Measurements reveal that a large volume fraction of speech-generated aerosol has diameters in the 5- to 20-μm range, making them sufficiently small to remain airborne for minutes, not hours. This coarse aerosol is too large to penetrate the lower respiratory tract directly, and its relevance to disease transmission is consistent with the vast majority of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections initiating in the upper respiratory tract. Our measurements suggest that in the absence of symptoms such as coughing or sneezing, the importance of speech-generated aerosol in the transmission of respiratory diseases is far greater than generally recognized.

Respiratory tract infections are caused by a wide range of pathogenic organisms (1), including a large array of respiratory viruses, such as influenza virus, rhinovirus, measles virus, respiratory syncytial virus, adenovirus, and most recently, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In all these diseases, person-to-person spread involves respiratory droplets, which originate from the mucus layer that covers the epithelium of the respiratory tract or from oral fluid present in the mouth, mostly as saliva. Thus, characterizing respiratory droplets is essential to understanding respiratory pathogen transmission and will inform effective public health policies to curb infections. Four mechanisms for droplet generation are generally considered: breathing, speaking (singing, laughing, etc.), coughing, and sneezing (2). Considering the well-recognized importance of asymptomatic transmission of SARS-CoV-2 (3), our study focuses on the first two of these mechanisms.As highlighted by Wells (4) and Duguid (2) nearly a century ago, the vast majority of respiratory droplets are smaller than ca. 100-μm diameter and fully dehydrate once entering the atmosphere. These desiccated droplets can remain airborne for minutes to hours before landing on solid surfaces. If generated by a person infected by a respiratory virus, they will contain virions that can remain viable and infectious for many hours (5, 6). Upon inhalation, airborne particles can reach different parts of the respiratory tract depending on their size: coarse aerosols with diameter D ≳ 5 μm (7) deposit in the upper respiratory tract (URT), and fine aerosols with D < 5 μm can penetrate deep into the lower respiratory tract (LRT). Many viral pathogens, including SARS-CoV-2, influenza, rhinovirus, and measles virus, can infect both URT and LRT epithelia (1, 8, 9), with URT infections typically associated with mild initial symptoms and LRT infections possibly resulting in life-threatening pneumonia (1, 10–13). Direct infection of the LRT, before the adaptive immune system has been triggered by vaccination or a preceding URT infection, presents a greater risk.An URT infection also can expand into the LRT through microaspiration of oropharyngeal fluids (14, 15). The extent to which inhalation of self-generated URT cough, speech, or sneeze aerosols may contribute to this migration remains unknown. However, it has been argued that this pathway could be significant because an infected carrier is invariably at the center of their own speech aerosol cloud, which results in strongly elevated exposure (16). The risk of migration from the URT to the LRT rises with the viral load and the viability of the virus, which peak around and just prior to the onset of symptoms, respectively (17, 18). For the original Wuhan strain of the SARS-CoV-2 virus, the onset of symptoms occurs about 5 days after the initial infection (17, 19), but it occurs somewhat earlier for the more infectious delta and omicron variants (20).To evaluate the risk of LRT infection, it is important to know the size distribution of particles generated by various respiratory activities. For talking, coughing, and sneezing, studies historically relied on slide sampling techniques of increasing sophistication, followed by microscope observation (2, 21, 22). Droplets generated by breathing or vowel sounds are numerous but very small (≲2 μm) and thus more difficult to evaluate with those classical methods. Instead, such small droplets are now commonly quantified by aerosol detection equipment, such as optical particle sizers (OPSs), based on light scattering (22, 23); aerodynamic particle sizers (APSs), based on the time-of-flight measurement in an accelerating flow field (24); and scanning mobility particle sizers that derive a particle’s size from its mobility in an electric field and are best suited for very small sizes (≲1 μm) (25, 26). APS instruments are less efficient at detecting medium-sized liquid particles, and undercounts as high as 75% for 10-μm droplets have been reported (27).There is some confusion in the literature about the hydration state of reported sizes of respiratory aerosol particles, which shrink by a factor of γ upon evaporation of their aqueous content, thus by a factor of γ³ in volume. After full dehydration, a particle’s radius is determined by its amount of nonvolatile matter. Estimates for γ vary substantially: Nicas et al. (28) proposed γ = 2 for breath particles, based on data extracted from breath condensate by Effros et al. (29) that indicated a high fraction (ca. 8% wt/vol) of glycoproteins, presumably mucins. Holmgren et al. (30) reported γ = 2.4 for breath particles when the relative humidity (RH) is reduced from 99.5% in the small airways to 75%. Bagheri et al. (26) observed γ = 4.5 for singing particles in a diffusion dryer or γ = 4 for large saliva droplets observed directly by microscope imaging. Some of those measurements were conducted directly at the mouth opening, observing the hydrated state using light scattering or holographic imaging techniques (26, 31). Clearly, the concentration of pathogens in dehydrated particles scales with γ³ relative to the originating airway lining fluid (ALF) or saliva. However, the high uncertainty in the applicable γ value, which is frequently not even reported, prevents accurate estimates of airborne virus concentrations.Recently, we and others demonstrated that speech particles can be readily observed by simple video recordings of light scattering by these particles (32–35). Such recordings not only present a visually compelling warning to the public but also provide opportunities to monitor particles before, during, and after dehydration. Those light scattering measurements focused on particles larger than a few microns due to technical sensitivity issues. The intensity of scattered light scales with the square of a particle’s diameter, causing a dynamic range problem and rendering it more challenging to observe the smallest particles, especially in the presence of larger particles. Inexpensive, fast consumer cameras typically use 10- to 12-bit analog-to-digital converters (ADCs), thereby limiting dynamic range; while detectors with an increased ADC range are available, their speed is often insufficient for high-speed recording.Here, we aim to evaluate the entire range of speech droplet sizes produced during different breathing and speaking protocols. To do so, we combined video-recorded light scattering and an OPS to evaluate droplets from 0.3 to 100 μm. Our data show a continuous spectrum that lacks previously reported gaps in the size distribution (36). Our measurements confirm that the gravitational settling rate for dehydrated particles larger than 5 μm steeply increases with size, but considering the high numbers, volumes, and airborne lifetimes of those particles, they are likely to be a dominant factor in transmission of disease.     

利培酮口服液合并氯硝西泮治疗精神分裂症急性兴奋的临床研究

目的研究利培酮口服液合并氯硝西泮治疗精神分裂症患者急性兴奋的疗效和安全性。方法将精神分裂症急性兴奋患者87例随机分为两组,治疗组44例予利培酮口服液合并氯硝西泮肌内注射;对照组43例予氟哌啶醇肌内注射,疗程均为7天。采用阳性症状和阴性症状量表（PANSS）评定临床疗效,副作用量表（TESS）评定不良反应。结果治疗7天的疗效相当（P〉0．05）,治疗组不良反应的发生率明显低于对照组（P〈0．05）。结论利培酮口服液合并氯硝西泮治疗精神分裂症急性兴奋疗效肯定,安全性优于氟哌啶醇。     

The homeostatic malfunction of a novel feedback pathway formed by lncRNA021545, miR-330-3p and epiregulin contributes in hepatocarcinoma progression via mediating epithelial-mesenchymal transition

A better understanding of tumor metastasis is urgently required for the treatment and prognosis of hepatocarcinoma patients. Current work contributes a novel ceRNA feedback regulation pathway composed of epiregulin (EREG), microRNA-330-3p (miR-330-3p) and long non-coding RNA 021545 (lncRNA021545) in regulating hepatocarcinoma malignancy via epithelial-mesenchymal transition (EMT) process. Closely correlated, the deficiencies of EREG and lncRNA021545 and the overexpression of miR-330-3p were involved in the clinical progression of hepatocarcinoma. In vitro results showed that 1) lncRNA021545 downregulation promoted, 2) miR-330-3p dysexpression positively correlated, and 3) EREG dysexpression reversely correlated with the migratory and invasive properties of hepatocarcinoma HCCLM3 and Huh7 cell lines. By directly binding to EREG and lncRNA021545, miR-330-3p expression change reversely correlated with their expressions in HCCLM3 and Huh7 cells, which was also confirmed in primary tumors from HCCLM3-xenograft mice in responding to miR-330-3p change. LncRNA021545 and EREG positively regulated each other, and lncRNA021545 negatively regulated miR-330-3p, while, EREG dysregulation unchanged miR-330-3p expression in hepatocarcinoma cells. Furthermore, systemic in vitro cellular characterizations showed that the malfunctions of the three molecules mediated the invasiveness of hepatocarcinoma cells via EMT process through affecting the expressions of E-cadherin, N-cadherin, vimentin, snail and slug, which was further confirmed by in vivo miR-330-3p promotion on the tumorigenicity and metastasis of HCCLM3 bearing nude mice and by in vitro miR-330-3p promotion on the migration and invasion of hepatocarcinoma cells to be antagonized by EREG overexpression through acting on EMT process. Our work indicates, that by forming a circuit signaling feedback pathway, the homeostatic expressions of lncRNA021545, miR-330-3p and EREG are important in liver health. Its collapse resulted from the downregulations of lncRNA021545 and EREG together with miR-330-3p overexpression promote hepatocarcinoma progression by enhancing the invasiveness of tumor cells through EMT activation. These discoveries suggest that miR-330-3p/lncRNA021545/EREG axis plays a critical role in hepatocarcinoma progression and as a candidate for its treatment.     

Dasatinib and interferon alpha synergistically induce pyroptosis-like cell death in philadelphia chromosome positive acute lymphoblastic leukemia

Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) is a high-risk disease subtype with a dismal prognosis. Inhibiting BCR-ABL kinase alone is insufficient to eradicate Ph+ALL clones, and alternative BCR-ABL-dependent and -independent pathways need to be targeted as an effective strategy. Our study revealed that the combination of dasatinib and interferon-α showed synergistic activity against Ph+ALL, inducing mitochondrial dysfunction and causing necrosis-like cell lysis. Mechanistic studies showed that the induced cell death was caspase-3-independent. Canonical necroptosis signals, such as RIP1 and MLKL, were not activated; instead, the pyroptosis executor Gasdermin D was upregulated expression and activated. The expression levels of extracellular ATP and IL-1β were also upregulated, both of which are markers of pyroptotic cell death. In a murine Ph+ALL model, the dual drug treatment prolonged the survival of tumor-bearing mice. More importantly, we incorporated the dual drugs to maintenance therapy in 39 patients who were unfit for allogeneic stem cell transplantation (allo-HSCT). The median follow-up was 28.5 months, the 4-year disease-free survival and overall survival rates were 52.2% and 65.2%, respectively. Our data suggest that the combination of dasatinib and interferon-α has potential synergistic activity against Ph+ALL and shows promise as a maintenance therapy for Ph+ALL patients who are unfit for allo-HSCT.     

非酒精性脂肪性肝炎患者肝脏受控衰减参数的变化

目的 探讨瞬时弹性记录仪(FibroScan)检测肝脏受控衰减参数(CAP)诊断非酒精性脂肪性肝炎(NASH)的效能.方法 2016年1月～2020年1月我院收治的NASH患者142例和同期健康体检者130例,使用FibroScan检测肝脏CAP值.采用受试者工作特征曲线(ROC)并计算曲线下面积(AUC)评价CAP值...     

Association between clustering of cardiovascular risk factors and resting heart rate in Chinese population: a cross-sectional study

BACKGROUNDEpidemiologic studies have explored the association between a single cardiovascular risk factor (CVRF) and resting heart rate (RHR), but the research on the relation of multiple risk factors with RHR remains scarce. This study aimed to explore the associations between CVRFs clustering and the risk of elevated RHR.METHODSIn this cross-sectional study, adults aged 35–75 years from 31 provinces were recruited by the China PEACE Million Persons Projects from September 2015 to August 2020. We focused on seven risk factors: hypertension, diabetes mellitus, dyslipidemia, obesity, smoking, alcohol use, and low physical activity. Multivariate logistic regression was used to calculate odds ratios (OR) for elevated RHR (> 80 beats/min).RESULTSAmong 1,045,405 participants, the mean age was 55.67 ± 9.86 years, and 60.4% of participants were women. The OR (95% CI) for elevated RHR for the groups with 1, 2, 3, 4 and ≥ 5 risk factor were 1.11 (1.08–1.13), 1.36 (1.33–1.39), 1.68 (1.64–1.72), 2.01 (1.96–2.07) and 2.58 (2.50–2.67), respectively (P_trend < 0.001). The association between the CVRFs clustering number and elevated RHR was much more pronounced in young males than in other age-sex subgroups. Clusters comprising more metabolic risk factors were associated with a higher risk of elevated RHR than those comprising more behavioral risk factors. CONCLUSIONSThere was a significant positive association between the CVRFs clustering number and the risk of elevated RHR, particularly in young males. Compared clusters comprising more behavioral risk factors, clusters comprising more metabolic risk factors were associated with a higher risk of elevated RHR. RHR may serve as an indicator of the cumulative effect of multiple risk factors.

Over the past several years, the rapid development of smart wrist-worn devices has resulted in a convenient approach to monitoring resting heart rate (RHR) in daily life. RHR is becoming a promising indicator of cardiovascular health. Observational studies have shown that elevated RHR is associated with increased all-cause and cardiovascular mortality in populations with or without cardiovascular disease (CVD).^[1,2] Elevated RHR has also been found to be associated with cardiovascular risk factors (CVRFs), such as hypertension, diabetes mellitus, dyslipidemia, low physical activity and smoking, indicating its potential to reflect total cardiac risk.^[3–7] There is abundant epidemiologic evidence supporting the association between a single CVRF and RHR, but studies exploring associations between multiple CVRFs and RHR are limited. CVRFs tend to cluster within individuals, and several weak risk factors combined may result in a much higher risk than that due to a single strong risk factor. According to a cross-sectional survey in China, more than 45% of Chinese adults have two or more coexisting CVRFs.^[8] Thus, it is important to consider the situation of multiple CVRFs clustering. However, very few studies have analyzed the association between CVRFs clustering and RHR, and several aspects remain unknown. Firstly, prior studies mainly focused on the relation between metabolic risk factors and RHR.^[9–11] Behavioral risk factors such as smoking, physical activity and alcohol use have rarely been considered, even though these risk factors also have a significant effect on heart rate.^[3,5,7] Secondly, most studies merely dealt with the relation of CVRFs clustering number with RHR, while regarding each number of risk factors, different combinations of risk factors have not yet been considered before.^[9,12] It is important to consider different CVRF clustering patterns since some risk factors combined may lead to a higher risk of elevated RHR than others, even if the number of CVRFs is the same. Thirdly, prior studies did not assess associations stratified by sex and age. It has been well documented that RHR levels differ by sex and age. The RHR in women was on average 2–7 beats/min higher than that in men, and there was a decrease in the RHR with age.^[13,14] As such, whether the associations of CVRFs clustering with RHR varied between sex and age remains unclear. Taking advantage of the large sample size in our study, we are able to include a wider range of CVRFs (metabolic and behavioral risk factors), comprehensively evaluate the association between these CVRFs clustering and RHR, and further explore sex and age differences. This finding may inform us whether RHR can be used as a simple and efficient metric for the identification of high-risk individuals who require more intensive risk factor evaluation and earlier cardiovascular health monitoring in resource-constrained countries with substantial CVD burdens, such as China. To bridge this knowledge gap, we used data from the China PEACE Million Persons Projects, a nationwide screening project, to explore (1) the association between the number of CVRFs clustering and elevated RHR in the overall population and populations stratified by age and sex; and (2) the associations between different CVRFs clusters and the risk of elevated RHR in the overall population and populations stratified by sex.     

Association of body mass index with risk of prediabetes in Chinese adults: A population‐based cohort study

Aims/IntroductionOverweight and obesity in adults are strongly associated with an increased risk of prediabetes, and this study set out to gain a better understanding of the optimal body mass index (BMI) range for assessing the risk of prediabetes in the Chinese population.Materials and MethodsThe cohort study included 100,309 Chinese adults who underwent health screening. Participants were divided into six groups based on the cut‐off point for BMI recommended by the World Health Organization (underweight: <18.5 kg/m², normal‐weight: 18.5–24.9 kg/m², pre‐obese: 25.0–29.9 kg/m², obese class I: 30.0–34.9 kg/m², obese class II: 35.0–39.9 kg/m², and obese class III ≥40 kg/m²). The association of BMI with prediabetes and the shape of the correlation were modeled using multivariate Cox regression and restricted cubic spline regression, respectively.ResultsIn the multivariate Cox regression model, with normal weight as the control group, underweight people had a lower risk of developing prediabetes, whereas obese and pre‐obese people had a higher risk of prediabetes. Additionally, in the restricted cubic spline model, we found that the association of BMI with prediabetes follows a positive dose–response relationship, but does not conform to the pattern of obesity paradox. Among the general population in China, a BMI of 23.03 kg/m² might be a potential intervention threshold for prediabetes.ConclusionsThe national cohort study found that the association of BMI with prediabetes follows a positive dose–response relationship, rather than a pattern of obesity paradox. For Chinese people with normal weight, more attention should be paid to glucose metabolism when BMI exceeds 23.03 kg/m².