A population-based study on trajectories of HER2 status during neoadjuvant chemotherapy for early breast cancer and metastatic progression.

BACKGROUND: This study aimed to investigate the distribution and changes of HER2 status in untreated tumours, in residual disease and in metastasis, and their long-term prognostic implications. METHODS: This is a population-based cohort study of patients treated with neoadjuvant chemotherapy for breast cancer during 2007-2020 in the Stockholm-Gotland region which comprises 25% of the entire Swedish population. Information was extracted from the National Breast Cancer Registry and electronic patient charts to minimize data missingness and misclassification. RESULTS: In total, 2494 patients received neoadjuvant chemotherapy, of which 2309 had available pretreatment HER2 status. Discordance rates were 29.9% between primary and residual disease (kappa = 0.534), 31.2% between primary tumour and metastasis (kappa = 0.512) and 33.3% between residual disease to metastasis (kappa = 0.483). Adjusted survival curves differed between primary HER2 0 and HER2-low disease (p < 0.001), with the former exhibiting an early peak in risk for death which eventually declined below the risk of HER2-low. Across all disease settings, increasing the number of biopsies increased the likelihood of detecting HER2-low status. CONCLUSION: HER2 status changes during neoadjuvant chemotherapy and metastatic progression, and the long-term behaviours of HER2 0 and HER2-low disease differ, underscoring the need for obtaining tissue biopsies and for extended follow-up in breast cancer studies.

Duration of the active first stage of labour and severe perineal lacerations and maternal postpartum complications: a population-based cohort study.

OBJECTIVE: The impact of first stage labour duration on maternal outcomes is sparsely investigated. We aimed to study the association between a longer active first stage and maternal complications in the early postpartum period. DESIGN: A population-based cohort study. SETTING: Regions of Stockholm and Gotland, Sweden, 2008-2020. POPULATION: A cohort of 159 459 term, singleton, vertex pregnancies, stratified by parity groups. METHODS: The exposure was active first stage duration, categorised in percentiles. Poisson regression analysis was performed to estimate the adjusted relative risk (aRR) and the 95% confidence interval (95% CI). To investigate the effect of second stage duration on the outcome, mediation analysis was performed. MAIN OUTCOME MEASURES: Severe perineal lacerations (third or fourth degree), postpartum infection, urinary retention and haematoma in the birth canal or ruptured sutures. RESULTS: The risks of severe perineal laceration, postpartum infection and urinary retention increased with a longer active first stage, both overall and stratified by parity group. The aRR increased with a longer active first stage, using duration of <50th percentile as the reference. In the ≥90th percentile category, the aRR for postpartum infection was 1.64 (95% CI 1.46-1.84) in primiparous women, 2.43 (95% CI 1.98-2.98) in parous women with no previous caesarean delivery (CD) and 2.33 (95% CI 1.65-3.28) in parous women with a previous CD. The proportion mediated by second stage duration was 33.4% to 36.9% for the different outcomes in primiparous women. The risk of haematoma or ruptured sutures did not increased with a longer active first stage. CONCLUSIONS: Increasing active first stage duration is associated with maternal complications in the early postpartum period.

Heavy metal contamination impacts the structure and co-occurrence patterns of bacterial communities in agricultural soils.

Heavy metal (HM) contamination caused by mining and smelting activities can be harmful to soil microbiota, which are highly sensitive to HM stress. Here, we explore the effects of HM contamination on the taxonomic composition, predicted function, and co-occurrence patterns of soil bacterial communities in two agricultural fields with contrasting levels of soil HMs (i.e., contaminated and uncontaminated natural areas). Our results indicate that HM contamination does not significantly influence soil bacterial α diversity but changes the bacterial community composition by enriching the phyla Gemmatimonadetes, Planctomycetes, and Parcubacteria and reducing the relative abundance of Actinobacteria. Our results further demonstrate that HM contamination can strengthen the complexity and modularity of the bacterial co-occurrence network but weaken positive interactions between keystone taxa, leading to the gradual disappearance of some taxa that originally played an important role in healthy soil, thereby possibly reducing the resistance of bacterial communities to HM toxicity. The predicted functions of bacterial communities are related to membrane transport, amino acid metabolism, energy metabolism, and carbohydrate metabolism. Among these, functions related to HM detoxification and antioxidation are enriched in uncontaminated soils, while HM contamination enriches functions related to metal resistance. This study demonstrated that microorganisms adapt to the stress of HM pollution by adjusting their composition and enhancing their network complexity and potential ecological functions.

Fermentation, functional analysis, and biological activities of turmeric kombucha.

BACKGROUND: Kombucha is a popular fermented drink with therapeutic benefits. The present study aimed to examine the fermentation of turmeric-infused kombucha and evaluate its biological activities and functional properties. RESULTS: The study of pH dynamics during fermentation found that turmeric kombucha has a lower pH decrease than standard kombucha, with the lowest pH of 3.1 being observed in 0.1% turmeric kombucha and the maximum pH of 3.8 found in 1% turmeric kombucha. The research shows that the symbiotic consortia of bacteria and yeast alters during the fermentation process with turmeric. Gas chromatogrphy-mass spectrometry analysis revealed that turmeric kombucha is abundant in terpenes, ketones, alcohols, aldehydes, phenols and fatty acids, with higher levels of active ingredients than regular kombucha. The kombucha with 0.6% turmeric had the highest overall acceptance score (9.0) in sensory evaluation. The total phenolic content after fermentation was in the range 0.2-0.8 mg gallic acid equivalents mL-1 . Increasing turmeric concentrations increased the antioxidant, cytotoxic and antibacterial activity of kombucha analogs, with the highest antioxidant activity (89%) observed at 0.8% turmeric, and the maximum cytotoxicity (74%) and antibacterial activity (zones of inhibition of 17.7 and 15.9 mm against Staphylococcus aureus and Escherichia coli, respectively) observed at 1% turmeric. CONCLUSION: The fermentation of kombucha infused with turmeric enhanced its biological activities, making it a healthier alternative to traditional kombucha and presenting new opportunities in the field of functional foods. Further investigations into the mechanisms underlying these effects and in vivo studies are warranted to fully comprehend the impact of turmeric kombucha consumption on human health. © 2023 Society of Chemical Industry.

Latent phase duration and associated outcomes: a contemporary, population-based observational study.

BACKGROUND: Little is known about the latent phase of labor, including whether its duration influences subsequent labor processes or birth outcomes. OBJECTIVE: This study aimed to describe the duration of the latent phase of labor from self-report of the onset of painful contractions to a cervical dilation of 5 cm in a large, Swedish population and evaluate the association between the duration of the latent phase of labor and perinatal processes and outcomes that occurred during the active phase of labor, second stage of labor, birth and immediately after delivery, stratified by parity. STUDY DESIGN: This was a population-based cohort study of 67,267 pregnancies with deliveries between 2008 and 2020 in the Stockholm-Gotland Regions, Sweden. Nulliparous and parous women without a history of cesarean delivery in spontaneous labor with a term (≥37 weeks of gestation), singleton, live, and vertex fetus without major malformations were included. Imputation was used if the notation of the end of the latent phase of labor (ie, cervical dilation of 5 cm) was missing in the partograph. Multivariable logistic regression was used to estimate the association with adjusted odds ratios and 95% confidence intervals, controlling for potential covariates. RESULTS: Including the time from painful contraction onset to a cervical dilation of 5 cm, the median durations of the latent phase of labor were 16.0 (interquartile range, 10.0-26.6) hours for nulliparous women and 9.4 (interquartile range, 5.9-15.3) hours for multiparous women. The durations of the latent phase of labor beyond the median were associated with increased odds of labor dystocia diagnosis during the first stage active phase or second stage of labor and interventions commonly associated with dystocia (amniotomy, oxytocin augmentation, epidural, and cesarean delivery). The duration of the latent phase of labor of ≥90th percentile vs less than the median in nulliparous women demonstrated an increased risk of adverse neonatal outcomes (Apgar score of <7 at 5 minutes and neonatal intensive care unit admission), chorioamnionitis, and fetal occiput posterior. In multiparous women, longer duration of the latent phase of labor was associated with an increased risk of neonatal intensive care unit admission and chorioamnionitis but was not associated with an Apgar score of <7 at 5 minutes. The duration of the latent phase of labor was not associated with additional markers of maternal risk. CONCLUSION: The duration of the latent phase of labor in nulliparous women was longer than that of multiparous women at each point of distribution. A longer duration of the latent phase of labor was associated with more frequent dystocia diagnoses and related interventions during the first stage active phase or second stage of labor, including cesarean delivery, nulliparous fetal occiput posterior position, chorioamnionitis, and markers of neonatal morbidity. More research is needed to identify potential mediating paths between the duration of the latent phase of labor and neonatal morbidity.

The Stockholm-Gotland perinatal cohort-A population-based cohort including longitudinal data throughout pregnancy and the postpartum period.

BACKGROUND: Register-based reproductive and perinatal databases rarely contain detailed information from medical records or repeated measurements throughout pregnancy and delivery. This lack of enriched pregnancy and birth data led to the initiation of the Swedish Stockholm-Gotland Perinatal Cohort (SGPC). OBJECTIVES: To describe the strengths of the SGPC, as well as the unique research questions that can be addressed using this cohort. POPULATION: The SGPC is a prospectively collected, population-based cohort that includes all births (from 22 completed gestational weeks onwards) between 1 January 2008 and 15 June 2020 in the Stockholm and Gotland regions of Sweden (335,153 singleton and 11,025 multiple pregnancies). DESIGN: Descriptive study. METHODS: The SGPC is based on the electronic medical records of women and their infants. The medical record system is used for all antenatal clinic visits and admissions, delivery and neonatal admissions, as well as postpartum clinical visits. SGPC has been further enriched with data linkages to 10 Swedish National Health Care and Quality Registers. PRELIMINARY RESULTS: In contrast to other reproductive and perinatal databases available in Sweden, including the Medical Birth Register and the Pregnancy Register, SGPC contains highly detailed medical record data, including time-varying serial measurements for physiological parameters throughout pregnancy, delivery, and postpartum, for both mother and infant. These strengths have enabled studies that were previously inconceivable; the effects of serial measurements of pregnancy weight gain, changes in haemoglobin counts and blood pressure during pregnancy, fetal weight estimations by ultrasound, duration of stages and phases of labour, cervical dilatation and oxytocin use during delivery, and constructing reference curves for umbilical cord pH. CONCLUSIONS: The SGPC-with its rich content, repeated measurements and linkages to numerous health care and quality registers-is a unique cohort that enables high-quality perinatal studies that would otherwise not be possible.

Optimizing transcardial perfusion of small molecules and biologics for brain penetration and biodistribution studies in rodents.

Efficiently removing blood from the brain vasculature is critical to evaluate accurately the brain penetration and biodistribution of drug candidates, especially for biologics as their blood concentrations are substantially higher than the brain concentrations. Transcardial perfusion has been used widely to remove residual blood in the brain; however, the perfusion conditions (such as the perfusion rate and time) reported in the literature are quite varied, and the performance of these methods on blood removal has not been investigated thoroughly. In this study, the effectiveness of the perfusion conditions was assessed by measuring brain hemoglobin levels. Sodium nitrite (NaNO2 ) as an additive in the perfusate was evaluated at different concentrations. Blood removal was significantly improved with 2% NaNO2 over a 20 min perfusion in mouse without disrupting the integrity of the blood-brain barrier (BBB). In mice, the optimized perfusion method significantly lowered the measured brain-to-plasma ratio (Kp,brain ) for monoclonal antibodies due to the removal of blood contamination and small molecules with a moderate-to-high BBB permeability and with a high brain-unbound-fraction (fu,brain ) presumably due to flux out of the brain during perfusion. Perfusion with or without NaNO2 clearly removed the residual blood in rat brain but with no difference observed in Kp,brain between the perfusion groups with or without 2% NaNO2 . In conclusion, a perfusion method was successfully developed to evaluate the brain penetration of small molecules and biologics in rodents for the first time. The transcardial perfusion with 2% NaNO2 effectively removed the residual blood in the brain and significantly improved the assessment of brain penetration of biologics. For small molecules, however, transcardial perfusion may not be performed, as small molecule compounds could be washed away from the brain by the perfusion procedure.

18O-Enabled High-Throughput Acyl Glucuronide Stability Assay.

Acyl glucuronides (AGs) are common metabolites of carboxylic acid-containing compounds. In some circumstances, AGs are suspected to be involved in drug toxicity due to formation of acyl migration products that bind covalently to cellular components. The risk of this adverse effect has been found to be correlated with the chemical stability of the AG, and assays have been described that monitor acyl migration by liquid chromatography coupled with mass spectrometry (LC-MS). This analysis can be challenging as it requires baseline chromatographic separation of the unmigrated 1-ß-acyl glucuronide from the migrated isomers and thus needs to be individually optimized for each aglycone. Therefore, a high-throughput assay that eliminates LC method development is desirable. Herein, we report an improved acyl glucuronide stability assay based on the rate of 18O-incorporation from [18O] water, which is compatible with high-throughput bioanalytical LC-MS workflows. Synthetic AGs with shorter migration half-lives showed faster incorporation of 18O. The level of differential incorporation of 18O following a 24 h incubation correlates well with the migration tendency of AGs. This assay was developed further, exploring in situ generation of AGs by human hepatic microsomal fraction. The results from 18 in situ-formed acyl glucuronides were similar to those obtained using authentic reference standards. In this format, this new 18O-labeling method offers a simplified workflow, requires no LC method development or AG reference standard, and thus facilitates AG liability assessment in early drug discovery.

Association between first and second stage of labour duration and mode of delivery: A population-based cohort study.

BACKGROUND: Active first stage of labour duration can widely vary between women. However, the nature of the relationship between the active first stage and second stage of labour duration is sparsely studied. OBJECTIVES: To determine whether active first stage of labour duration (i) influences second stage of labour duration; and (ii) is associated with mode of delivery. METHODS: A population-based cohort study of 13,379 women primiparous women, with spontaneous start in Stockholm-Gotland Region, Sweden, between 2008 and 2014. Duration of the active first stage of labour was examined in relation to second-stage duration using univariate and multivariable quantile regressions, with the first quartile (first stage duration) as the reference. Nonlinearity of associations was tested by restricted cubic splines. Association between active first-stage duration with mode of delivery was estimated using a multinomial logistic regression based on adjusted odds ratios. RESULTS: Longer active first stage of labour duration was linearly associated with longer second stage of labour duration until approximately 12 h of active first stage of labour duration. After 12 h, a non-linear trend is seen, demonstrated by a plateau in the second-stage duration. In addition, longer active first stage of labour duration was associated with increased occurrence of operative vaginal delivery (adjusted odds ratio 3.36, 95% confidence interval [CI] 2.89, 3.89) and caesarean delivery (adjusted odds ratio 4.75, 95% CI 3.85, 5.80). CONCLUSIONS: Among primiparous women with spontaneous onset of labour, longer active first stage of labour duration was associated with both longer second stage of labour duration and higher odds of operative delivery. This study contributes with findings, which may inform future discussions regarding how to properly account for second-stage duration, with applications in obstetric and perinatal epidemiology.

Risk of gestational diabetes mellitus in relation to early pregnancy and gestational weight gain before diagnosis: A population-based cohort study.

INTRODUCTION: Gestational diabetes mellitus (GDM) is a common pregnancy complication associated with adverse consequences for the mother and offspring in both short and long term. The aim of this study was to investigate associations between risk of GDM and gestational weight gain in early pregnancy and before diagnosis. MATERIAL AND METHODS: Our population-based cohort study included 131 164 singleton pregnancies in the Stockholm-Gotland region in Sweden from 2008 through 2013. The exposures were weight gain in early pregnancy (<22 weeks) and weight gain before diagnosis, standardized into gestational age-specific z scores. The outcome was GDM. We used logistic regression models with a generalized estimating equations method to estimate odds ratios with 95% confidence intervals for GDM, stratified by early-pregnancy body mass index (BMI) category. RESULTS: Above average weight gain before diagnosis (z score >0) was associated with increased risk of GDM among all BMI groups except for obese III. Early gestational weight gain above average was associated with increased risk for GDM in overweight women. Below average weight gain before diagnosis (z score <0) was only associated with decreased risk of GDM in obese III. Early gestational weight gain below average was associated with reduced risks of GDM in obese class I, II, and III women. CONCLUSIONS: The risk of GDM increased with higher weight gain before diagnosis in all BMI groups except obese class III, whereas the risk was reduced with lower weight gain before diagnosis in obese III women only. The risk of GDM increased with higher early gestational weight gain in overweight women, while the risk was reduced with lower early gestational weight gain among obese women. Obese women may benefit from lower weight gain, especially in early pregnancy.

Outcomes of surgical treatment for active infective endocarditis under COVID-19 pandemic.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has been and will continue to be a challenge to the healthcare system worldwide. In this context, we aimed to discuss the impact of the COVID-19 pandemic on the diagnosis, timing, and prognosis of surgical treatment for active infective endocarditis (IE) during the pandemic and share our coping strategy. METHODS: A total of 39 patients were admitted for active IE in the year 2020. The number of the same period last year was 50. Medical information of these two groups was extracted from our surgical database. Data were compared between the two groups and differences with or without statistical significance were discussed. RESULTS: In the pandemic year, we admitted fewer transferred patients (64.1% vs. 80%, p = .094). Timespan for diagnosis were prolonged (60 vs. 34.5 days, p = .081). More patients were admitted in emergency (41% vs. 20%, p = .030) More patients had heart failure (74.4% vs. 40%, p = .001), sepsis (69.2% vs. 42.0%, p = .018), or cardiogenic shock (25.6% vs. 8.0%, p = .038). Overall surgical risk (EuroSCORE II) was higher (4.15% vs. 3.24%, p = .019) and more commando surgery was performed (7.7% vs. 2.0%, p = .441). However, we did not see more postoperative complications, and early mortality was not worse either (0 vs. 4%, p = .502). CONCLUSIONS: The negative impact of the COVID-19 pandemic on the clinical practice of surgical treatment for active IE was multifaceted. However, with the preservation of the effectiveness of multidisciplinary IE surgical team, the early outcomes were comparable with those in the normal years.

Repair versus replacement for active endocarditis of the mitral valve: 9 years of experience.

BACKGROUND AND AIM: To determine the factors contributing to successful mitral valve repair (MVP) and to discuss the effect of complex techniques on the durability of MVP for active infective endocarditis (IE) affecting the mitral valve. METHODS: One hundred and eighty-seven patients were enrolled; 39.6% underwent mitral valve replacement (MVR) and 60.4% underwent MVP. We used logistic regression to identify influencing factors of the choice of surgical technique. The results were compared between groups and subgroups after propensity score matching (PSM). RESULTS: Risk factors for MVR included poor valve quality (odds ratio [OR] 23.3, p = .001), a large defect after debridement (OR 16.4, p < .001), and heavy valve infection (OR 3.7, p = .027). After PSM, we did not find a significant difference in the frequency of major postoperative complications or the in-hospital or postdischarge death rate. The reintervention rate for MVP was significantly higher than that for MVR (p = .047). Subgroup analysis found a significant relationship between the use of a complex repair technique and the need for reoperation (p = .020). CONCLUSIONS: The choice of valve repair or replacement for patients with active IE affecting the mitral valve was influenced by the intraoperative characteristics of the infected valve rather than the severity of systemic infection or overall health status. The choice of surgical treatment strategy had no effect on major postoperative complications, in-hospital mortality, or medium-term survival. However, the medium-term durability of MVP was poorer than that of MVR. The use of the patch technique for free margins or extensive leaflet defects was associated with a need for reintervention.

Comparison of Sternal Fixation Strategies After Open-Heart Surgery Via a Median Sternal Incision.

OBJECTIVES: To explore the personalized treatment strategy of sternal fixation and closure of sternal median incision in open cardiac surgery. METHODS: A total of 293 patients who underwent open-heart surgery with a median sternal incision at Peking Union Medical College Hospital from January 2019 to March 2021 were divided into two groups, according to the timing and type of treatment. The first 169 patients received single-wire fixation and closure (control group), while the subsequent 124 patients received double-wire fixation and closure (study group). The patients were followed up for three months to observe the duration of pain, sternal instability, and occurrence of chest wound infection. RESULTS: The average age was 53±30 years in the control group and 55±34 years in the study group (P = 0.594). There were no significant differences in baseline data between the two groups (P > 0.05). Compared with the control group, the study group had a shorter duration of pain (P < 0.05), smaller drainage volume within three days postoperatively (650 ml vs. 770 ml, P < 0.05), lower incidence of superficial sternal wound infection (2.4% vs. 8.9%, P = 0.042), and lower incidence of sternal instability (1.6% vs. 8.3%, P = 0.026). Deep sternal wound infection occurred in two patients in the control group and none in the study group; however, this difference was not significant. No surgery-related deaths occurred. CONCLUSIONS: Selecting the appropriate sternal fixation and closure method, according to the characteristics of patients, can reduce the incidence of sternal incision complications. We proposed a personalized selection strategy for sternal fixation and closure, which requires verification in clinical studies.

Use of Intravenous Infusion Study Design to Simultaneously Determine Brain Penetration and Systemic Pharmacokinetic Parameters in Rats.

In drug discovery, the extent of brain penetration as measured by free brain/plasma concentration ratio (Kp,uu) is normally determined from one experiment after constant intravenous infusion, and pharmacokinetics (PK) parameters, including clearance (CL), volume of distribution at steady state (Vss), and effective half-life (t 1/2 ,eff) are determined from another experiment after a single intravenous bolus injection. The objective of the present study was to develop and verify a method to simultaneously determine Kp,uu and PK parameters from a single intravenous infusion experiment. In this study, nine compounds (atenolol, loperamide, minoxidil, N-[3-(4'-fluorophenyl)-3-(4'-phenylphenoxy)propyl]sarcosine, sulpiride, and four proprietary compounds) were intravenously infused for 4 hours at 1 mg/kg or 24 hours at 1 or 6 mg/kg or bolus injected at 1 mg/kg. Plasma samples were serially collected, and brain and cerebrospinal fluid samples were collected at the end of infusion. The PK parameters were obtained using noncompartmental analysis (NCA) and compartmental analysis. The Kp,uu,brain values of those compounds increased up to 2.86-fold from 4 to 24 hours. The CL calculated from infusion rate over steady-state concentration from the 24-hour infusion studies was more consistent with the CL from the intravenous bolus studies than that from 4-hour infusion studies (CL avg. fold of difference 1.19-1.44 vs. 2.10). The compartmental analysis using one- and two-compartment models demonstrated better performance than NCA regardless of study design. In addition, volume of distribution at steady state and t 1/2,eff could be accurately obtained by one-compartment analysis within 2-fold difference. In conclusion, both unbound brain-to-plasma ratio and PK parameters can be successfully estimated from a 24-hour intravenous infusion study design. SIGNIFICANCE STATEMENT: We demonstrated that the extent of brain penetration and pharmacokinetic parameters (such as clearance, Vss, and effective t 1/2) can be determined from a single constant intravenous infusion study in rats.

Preparation and mechanism research of bio-inspired dopamine decorated expanded graphite/silicone rubber composite with high thermal conductivity and excellent insulation.

This study looked at the process of designing and synthesized expanded graphite (EG) and modifying it with bio-inspired dopamine (DOPA). This is a process used to improve the thermal conductivity and dielectric properties of methyl vinyl silicone rubber (VMQ). The results demonstrated that the EG-DOPA-VMQ composites acquired an exceptional thermal conductivity of 1.015 W mK-1at the loading of 10 wt%, approximately 480% higher than that of pure silicone rubber (0.175 W mK-1). This enhancement is mainly attributed to the improved dispersion capability of EG-DOPA and the robust interfacial interaction between EG-DOPA-VMQ interfaces; specifically, this is the result when compared with pristine EG. Moreover, throughout this process, the composites maintained an excellent insulating property with a resistance of ≈1012Ω · cm; this particular result was due to the DOPA deposited on EG surfaces because they acted as an insulating layer, inhibiting the electron transfer in composites. Overall, this work demonstrated that it could present a promising strategy for synchronized manufacturing of polymer composites with high thermal conductivity and insulating capability.

Relationship between antidepressive agents and incidence risk of breast cancer: systematic review and meta-analysis.

Purpose: This study aimed to review the association between antidepressive agent (AD) use and the incidence risk of breast cancer. Methods: CBM, WOS, Embase, PubMed and Cochrane Library were systematically searched in July 2019. The methodological quality of the studies was assessed through the Newcastle-Ottawa Scale. Results: We included 19 studies from six countries or regions with relationships between breast cancer and ADs. Subgroup analysis showed no significant association in nested case-control or case-control studies; however, cohort studies revealed a significant association (odds ratio = 1.11; 95% CI: 1.04-1.17). Conclusions: This meta-analysis indicates that breast cancer was not associated with the use of ADs when considering all types of studies, but an association was observed if we considered cohort studies.

Hybridization Liquid Chromatography-Tandem Mass Spectrometry: An Alternative Bioanalytical Method for Antisense Oligonucleotide Quantitation in Plasma and Tissue Samples.

Quantitative bioanalysis in plasma and tissues samples is required to study the pharmacokinetic and pharmacodynamic properties of antisense oligonucleotides (ASOs). To overcome intrinsic drawbacks in specificity, sensitivity, and throughput of traditional ligand-binding assay (LBA) and liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods, an alternative bioanalytical method was developed by combining oligonucleotide hybridization and LC-MS/MS technologies. Target ASOs were extracted from biological samples by hybridization with biotinylated sense-strand oligonucleotides coupled to streptavidin magnetic beads. Using ion-pairing chromatography and tandem mass spectrometry, this method demonstrated high sensitivity (0.5 ng/mL using 100 µL of plasma), high specificity, wide linear range, complete automation, and generic applications in tests with multiple ASOs. The typical challenge of sensitivity drop in traditional ion-pairing LC-MS/MS was for the first time overcome by the introduction of a ternary pump system. Due to the high specificity, quantitation in various biological matrixes was achieved using calibration standards in plasma, largely improving efficiency and consistency. Another major advantage was the capability of simultaneous quantitation of ASO metabolites. The hybridization LC-MS/MS was considered an improved alternative for quantitation of ASOs and metabolites in plasma and tissue samples, showing a great potential to replace traditional LBA and LC-MS/MS methods.

Characterization of Antineovascularization Activity and Ocular Pharmacokinetics of Phosphoinositide 3-Kinase/Mammalian Target of Rapamycin Inhibitor GNE-947.

The objectives of the present study were to characterize GNE-947 for its phosphoinositide 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) inhibitory activities, in vitro anti-cell migration activity in human umbilical vein endothelial cells (HUVECs), in vivo antineovascularization activity in laser-induced rat choroidal neovascular (CNV) eyes, pharmacokinetics in rabbit plasma and eyes, and ocular distribution using matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI-IMS) and autoradioluminography. Its PI3K and mTOR K i were 0.0005 and 0.045 µM, respectively, and its HUVEC IC50 was 0.093 µM. GNE-947 prevented neovascularization in the rat CNV model at 50 or 100 µg per eye with repeat dosing. After a single intravenous injection at 2.5 and 500 µg/kg in rabbits, its plasma terminal half-lives (t 1/2) were 9.11 and 9.59 hours, respectively. After a single intravitreal injection of a solution at 2.5 µg per eye in rabbits, its apparent t 1/2 values were 14.4, 16.3, and 23.2 hours in the plasma, vitreous humor, and aqueous humor, respectively. After a single intravitreal injection of a suspension at 33.5, 100, 200 µg per eye in rabbits, the t 1/2 were 29, 74, and 219 days in the plasma and 46, 143, and 191 days in the eyes, respectively. MALDI-IMS and autoradioluminography images show that GNE-947 did not homogenously distribute in the vitreous humor and aggregated at the injection sites after injection of the suspension, which was responsible for the long t 1/2 of the suspension because of the slow dissolution process. This hypothesis was supported by pharmacokinetic modeling analyses. In conclusion, the PI3K/mTOR inhibitor GNE-947 prevented neovascularization in a rat CNV model, with t 1/2 up to approximately 6 months after a single intravitreal injection of the suspension in rabbit eyes. SIGNIFICANCE STATEMENT: GNE-947 is a potent phosphoinositide 3-kinase/mammalian target of rapamycin inhibitor and exhibits anti-choroidal neovascular activity in rat eyes. The duration of GNE-947 in the rabbit eyes after intravitreal injection in a solution is short, with a half-life (t 1/2) of less than a day. However, the duration after intravitreal dose of a suspension is long, with t 1/2 up to 6 months due to low solubility and slow dissolution. These results indicate that intravitreal injection of a suspension for low-solubility drugs can be used to achieve long-term drug exposure.

Airborne particulate matter, population mobility and COVID-19: a multi-city study in China.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is an emerging infectious disease, which has caused numerous deaths and health problems worldwide. This study aims to examine the effects of airborne particulate matter (PM) pollution and population mobility on COVID-19 across China. METHODS: We obtained daily confirmed cases of COVID-19, air particulate matter (PM2.5, PM10), weather parameters such as ambient temperature (AT) and absolute humidity (AH), and population mobility scale index (MSI) in 63 cities of China on a daily basis (excluding Wuhan) from January 01 to March 02, 2020. Then, the Generalized additive models (GAM) with a quasi-Poisson distribution were fitted to estimate the effects of PM10, PM2.5 and MSI on daily confirmed COVID-19 cases. RESULTS: We found each 1 unit increase in daily MSI was significantly positively associated with daily confirmed cases of COVID-19 in all lag days and the strongest estimated RR (1.21, 95% CIs:1.14 ~ 1.28) was observed at lag 014. In PM analysis, we found each 10 µg/m3 increase in the concentration of PM10 and PM2.5 was positively associated with the confirmed cases of COVID-19, and the estimated strongest RRs (both at lag 7) were 1.05 (95% CIs: 1.04, 1.07) and 1.06 (95% CIs: 1.04, 1.07), respectively. A similar trend was also found in all cumulative lag periods (from lag 01 to lag 014). The strongest effects for both PM10 and PM2.5 were at lag 014, and the RRs of each 10 µg/m3 increase were 1.18 (95% CIs:1.14, 1.22) and 1.23 (95% CIs:1.18, 1.29), respectively. CONCLUSIONS: Population mobility and airborne particulate matter may be associated with an increased risk of COVID-19 transmission.

The frailty index is a predictor of cause-specific mortality independent of familial effects from midlife onwards: a large cohort study.

BACKGROUND: Frailty index (FI) is a well-established predictor of all-cause mortality, but less is known for cause-specific mortality and whether familial effects influence the associations. Middle-aged individuals are also understudied for the association between FI and mortality. Furthermore, the population mortality impact of frailty remains understudied. METHODS: We estimated the predictive value of FI for all-cause and cause-specific mortality, taking into account familial factors, and tested whether the associations are time-dependent. We also assessed the proportion of all-cause and cause-specific deaths that are attributable to increased levels of frailty. We analyzed 42,953 participants from the Screening Across the Lifespan Twin Study (aged 41-95 years at baseline) with up to 20 years' mortality follow-up. The FI was constructed using 44 health-related items. Deaths due to cardiovascular disease (CVD), respiratory-related causes, and cancer were considered in the cause-specific analysis. Generalized survival models were used in the analysis. RESULTS: Increased FI was associated with higher risks of all-cause, CVD, and respiratory-related mortality, with the corresponding hazard ratios of 1.28 (1.24, 1.32), 1.31 (1.23, 1.40), and 1.23 (1.11, 1.38) associated with a 10% increase in FI in male single responders, and 1.21 (1.18, 1.25), 1.27 (1.15, 1.34), and 1.26 (1.15, 1.39) in female single responders. No significant associations were observed for cancer mortality. No attenuation of the mortality associations in unrelated individuals was observed when adjusting for familial effects in twin pairs. The associations were time-dependent with relatively greater effects observed in younger ages. Before the age of 80, the proportions of deaths attributable to FI levels > 0.21 were 18.4% of all-cause deaths, 25.4% of CVD deaths, and 20.4% of respiratory-related deaths in men and 19.2% of all-cause deaths, 27.8% of CVD deaths, and 28.5% of respiratory-related deaths in women. After the age of 80, the attributable proportions decreased, most notably for all-cause and CVD mortality. CONCLUSIONS: Increased FI predicts higher risks of all-cause, CVD, and respiratory-related mortality independent of familial effects. Increased FI presents a relatively greater risk factor at midlife than in old age. Increased FI has a significant population mortality impact that is greatest through midlife until the age of 80.