Rare MED12L variants is associated with susceptibility to guttate psoriasis in the Han Chinese Population.

INTRODUCTION: According to the common disease/rare variant (CDRV) hypothesis, it is important to study the role of rare variants in complex diseases. The association of rare variants with psoriasis has been demonstrated, but the association between rare variants and specific clinical subtypes of psoriasis has not been investigated. METHODS: Gene-based and gene-level meta-analyses were performed on data extracted from our previous study data sets(2,483 patients with guttate psoriasis and 8,292 patients with non-guttate psoriasis) for genotyping. Then, haplotype analysis was performed for rare loss-of-function variants located in MED12L, and protein function prediction was performed for MED12L. Gene-based analysis at each stage had a moderate significance threshold (P < 0.05). A chi-square test was then conducted on the three potential genes, and the merged gene-based analysis was used to confirm the results. We also conducted association analysis and meta-analysis for functional variants located on the identified gene. RESULTS: Through these gene-level analyses, we determined that MED12L is a guttate psoriasis susceptibility gene (P=9.99x10-5), and the single-nucleotide polymorphism (SNP) with the strongest association was rs199780529 (P_combine=1x10-3, P_meta=2x10-3). CONCLUSIONS: In our study, a guttate psoriasis-specific subtype-associated susceptibility gene was confirmed in a Chinese Han population. These findings contribute to a better genetic understanding of different subtypes of psoriasis.

Correlated Allele Frequency Changes Reveal Clonal Structure and Selection in Temporal Genetic Data.

In evolving populations where the rate of beneficial mutations is large, subpopulations of individuals with competing beneficial mutations can be maintained over long times. Evolution with this kind of clonal structure is commonly observed in a wide range of microbial and viral populations. However, it can be difficult to completely resolve clonal dynamics in data. This is due to limited read lengths in high-throughput sequencing methods, which are often insufficient to directly measure linkage disequilibrium or determine clonal structure. Here, we develop a method to infer clonal structure using correlated allele frequency changes in time-series sequence data. Simulations show that our method recovers true, underlying clonal structures when they are known and accurately estimate linkage disequilibrium. This information can then be combined with other inference methods to improve estimates of the fitness effects of individual mutations. Applications to data suggest novel clonal structures in an E. coli long-term evolution experiment, and yield improved predictions of the effects of mutations on bacterial fitness and antibiotic resistance. Moreover, our method is computationally efficient, requiring orders of magnitude less run time for large data sets than existing methods. Overall, our method provides a powerful tool to infer clonal structures from data sets where only allele frequencies are available, which can also improve downstream analyses.

Laparoscopic vs open surgery for gastric cancer: Assessing time, recovery, complications, and markers.

BACKGROUND: Gastric cancer (GC) is one of the most common cancers worldwide. Morbidity and mortality have increased in recent years, making it an urgent issue to address. Laparoscopic radical surgery (LRS) is a crucial method for treating patients with GC; However, its influence on tumor markers is still under investigation. AIM: To determine the effects of LRS on patients with GC and their serum tumor markers. METHODS: The data of 194 patients treated at Chongqing University Cancer Hospital between January 2018 and January 2019 were retrospectively analyzed. Patients who underwent traditional open surgery and LRS were assigned to the control (n = 90) and observation groups (n = 104), respectively. Independent sample t-tests and χ2 tests were used to compare the two groups based on clinical efficacy, changes in tumor marker levels after treatment, clinical data, and the incidence of postoperative complications. To investigate the association between tumor marker levels and clinical efficacy in patients with GC, three-year recurrence rates in the two groups were compared. RESULTS: Patients in the observation group had a shorter duration of operation, less intraoperative blood loss, an earlier postoperative eating time, and a shorter hospital stay than those in the control group (P < 0.05). No significant difference was observed between the two groups regarding the number of lymph node dissections (P > 0.05). After treatment, the overall response rate in the control group was significantly lower than that in the observation group (P = 0.001). Furthermore, after treatment, the levels of carbohydrate antigen 19-9, cancer antigen 72-4, carcinoembryonic antigen, and cancer antigen 125 decreased significantly. The observation group also exhibited a significantly lower incidence rate of postoperative complications compared to the control group (P < 0.001). Additionally, the two groups did not significantly differ in terms of three-year survival and recurrence rates (P > 0.05). CONCLUSION: LRS effectively treats early gastric cancer by reducing intraoperative bleeding, length of hospital stays, and postoperative complications. It also significantly lowers tumor marker levels, thus improving the short-term prognosis of the disease.

Quarter-Wave Plate Metasurfaces for Generating Multi-Channel Vortex Beams.

Metasurfaces of quarter-wave plate (QWP) meta-atoms have exhibited high flexibility and versatile functionalities in the manipulation of light fields. However, the generation of multi-channel vortex beams with the QWP meta-atom metasurfaces presents a significant challenge. In this study, we propose dielectric metasurfaces composed of QWP meta-atoms to manipulate multi-channel vortex beams. QWP meta-atoms, systematically arranged in concentric circular rings, are designed to introduce the modulations via the propagation phase and geometric phase, leading to the generation of co- and cross-polarized vortex beams in distinct channels. Theoretical investigations and simulations are employed to analyze the modulation process, confirming the capability of QWP meta-atom metasurfaces for generating the multi-channel vortex beams. This study presents prospective advancements for the compact, integrated, and multifunctional nanophotonic platforms, which have potential applications in classical physics and quantum domains.

Apigenin delays postovulatory oocyte aging by reducing oxidative stress through SIRT1 upregulation.

After ovulation, senescent oocytes inevitably experience reduced quality and defects in embryonic development. Apigenin (API) is a flavonoid with a wide range of pharmacological effects. Therefore, this study examined the protective effects of API on the quality of porcine oocytes during in-vitro ageing and the underlying mechanisms. The results showed that API treatment could reduce the activation rate after aging for 48 h. In addition, API significantly reduced reactive oxygen species, abnormal distribution of mitochondria, early apoptosis in ageing oocytes, increased glutathione, and mitochondrial adenosine triphosphate levels in ageing oocytes. Importantly, API increased the embryonic development rate in aged oocytes. We also examined molecular changes, finding decreased sirtuin 1 expression in in-vitro postovulatory oocytes, but API reversed this effect. Our results suggest that API attenuates the deterioration of oocyte quality during in-vitro ageing, possibly by reducing oxidative stress through the upregulation of sirtuin 1.

MERIT: Controlling Monte-Carlo error rate in large-scale Monte-Carlo hypothesis testing.

The use of Monte-Carlo (MC) p $$ p $$ -values when testing the significance of a large number of hypotheses is now commonplace. In large-scale hypothesis testing, we will typically encounter at least some p $$ p $$ -values near the threshold of significance, which require a larger number of MC replicates than p $$ p $$ -values that are far from the threshold. As a result, some incorrect conclusions can be reached due to MC error alone; for hypotheses near the threshold, even a very large number (eg, 1 0 6 $$ 1{0}^6 $$ ) of MC replicates may not be enough to guarantee conclusions reached using MC p $$ p $$ -values. Gandy and Hahn (GH)6-8 have developed the only method that directly addresses this problem. They defined a Monte-Carlo error rate (MCER) to be the probability that any decisions on accepting or rejecting a hypothesis based on MC p $$ p $$ -values are different from decisions based on ideal p $$ p $$ -values; their method then makes decisions by controlling the MCER. Unfortunately, the GH method is frequently very conservative, often making no rejections at all and leaving a large number of hypotheses "undecided". In this article, we propose MERIT, a method for large-scale MC hypothesis testing that also controls the MCER but is more statistically efficient than the GH method. Through extensive simulation studies, we demonstrate that MERIT controls the MCER while making more decisions that agree with the ideal p $$ p $$ -values than GH does. We also illustrate our method by an analysis of gene expression data from a prostate cancer study.

Soluble epoxide hydrolase deficiency attenuates airway inflammation in COPD via IRE1α/JNK/AP-1 signaling pathway.

BACKGROUND: Soluble Epoxide Hydrolase (sEH) metabolizes anti-inflammatory epoxyeicosatrienoic acids and critically affects airway inflammation in chronic obstructive pulmonary disease (COPD). Considering the excessive endoplasmic reticulum stress is associated with the earlier onset of COPD. The role of sEH and endoplasmic reticulum stress in the pathogenesis of COPD remains unknown. METHOD: 16 weeks of cigarette-exposed mice were used to detect the relationship between sEH and endoplasmic reticulum stress in COPD. Human epithelial cells were used in vitro to determine the regulation mechanism of sEH in endoplasmic reticulum stress induced by cigarette smoke. RESULTS: sEH deficiency helps reduce emphysema formation after smoke exposure by alleviating endoplasmic reticulum stress response. sEH deficiency effectively reverses the upregulation of phosphorylation IRE1α and JNK and the nuclear expression of AP-1, alleviating the secretion of inflammatory factors induced by cigarette smoke extract. Furthermore, the treatment with endoplasmic reticulum stress and IRE1α inhibitor downregulated cigarette smoke extract-induced sEH expression and the secretion of inflammatory factors. CONCLUSION: sEH probably alleviates airway inflammatory response and endoplasmic reticulum stress via the IRE1α/JNK/AP-1 pathway, which might attenuate lung injury caused by long-term smoking and provide a new pharmacological target for preventing and treating COPD.

Dual-Cross-Linked PEI/PVA Hydrogel for pH-Responsive Drug Delivery.

Herein, a pH-responsive dual cross-linked hydrogel for controlled drug release is presented. The hydrogel was constructed with reversible borate ester bonds and crystalline poly(vinyl alcohol). By changing the environmental pH, its physicochemical characteristics, including rheological properties, mechanical properties, microstructural features, and the biocompatibility of the gels, were evaluated. The gels at tumor acidic conditions exhibited swelling and lower compressive strength and modulus than those in a physiological environment, which was attributed to the pH-responsive borate ester bonds and the protonation of amine groups on the PEI polyelectrolyte. Importantly, the drug-encapsulated biocompatible hydrogel showed sustained and increased release under an acidic environment, and it followed the Fickian diffusion mechanism. Therefore, it exemplifies that borate ester bond-based pH-responsive biomaterials have high promise in biomedical research, especially for drug delivery.

Dual Signal-Enhanced Electrochemiluminescence Strategy Based on Functionalized Biochar for Detecting Aflatoxin B1.

Metal-organic frameworks (MOFs) are often used as carriers in the preparation of electrochemiluminescent (ECL) materials, and ECL materials stabilized in the aqueous phase can be prepared by encapsulating chromophores inside MOFs by an in situ growth method. In this study, nanocomposites MIL-88B(Fe)-NH2@Ru(py)32+ with excellent ECL response were prepared by encapsulating Tris(2,2'-bipyridine)ruthenium dichloride (Ru(py)32+) inside MIL-88B(Fe)-NH2 using the one-step hydrothermal method. MIL-88B(Fe)-NH2 possesses abundant amino groups, which can accelerate the catalytic activation process of K2S2O8, and its abundant pores are also conducive to the enhancement of the transmission rate of co-reactant agents, ions, and electrons, which effectively improves the ECL efficiency. In order to obtain more excellent ECL signals, we prepared aminated biochar (NH2-biochar) using Pu-erh tea dregs as precursor and loaded gold nanoparticles (Au NPs) on its surface as substrate material for modified electrodes. Both NH2-biochar and Au NPs can also be used as a co-reactant promoter to catalyze the activation process of co-reactant K2S2O8. Therefore, a sandwich-type ECL immunosensor was prepared based on a dual signal-enhanced strategy for the highly sensitive and selective detection of aflatoxin B1 (AFB1). Under the optimal experimental conditions, the sensitive detection of AFB1 was achieved in the range of 1 pg·mL-1~100 ng·mL-1 with a detection limit of 209 fg·mL-1. The proposed dual signal-enhanced ECL immunosensor can provide a simple, convenient, and efficient method for the sensitive detection of AFB1 in food and agricultural products.

Wastewater inputs reduce the CO2 uptake by coastal oceans.

Every year a large quantity of wastewater is generated worldwide, but its influence on the carbon dioxide (CO2) uptake by coastal oceans is not well understood. Here, sea surface CO2 partial pressure (pCO2) and air-sea CO2 flux were examined in the Jiaozhou Bay (JZB), a temperate coastal bay strongly disturbed by wastewater inputs. Monthly surveys from April 2014 through March 2015 showed that surface pCO2 in the JZB substantially varied both temporally and spatially between 163 µatm and 1222 µatm, with an annual average of 573 µatm. During April-December, surface pCO2 was oversaturated with respect to the atmosphere, with high values exceeding 1000 µatm in the northeastern part of the bay, where seawater salinity was low mainly due to the inputs of wastewater with salinity close to zero. During January-March, surface pCO2 was undersaturated, with the lowest value of <200 µatm also mainly in the northeastern part because of low water temperature and strong biological production. Over an annual cycle, apparently sea surface temperature dominated the monthly variation of surface pCO2 in this shallow bay, while wastewater inputs and related biological production/respiration dominated its spatial variability. Overall, the JZB was a net CO2 source to the atmosphere, emitting 9.6 ± 10.8 mmol C m-2 d-1, unlike its adjacent western part of the Yellow Sea and most of the temperate coastal oceans which are a net CO2 sink. This was possibly associated with wastewater inputs that cause high sea surface pCO2 via direct inputs of CO2 and degradation of organic matter. Thus, from this viewpoint reducing wastewater discharge or lowering CO2 levels in discharged wastewater may be important paths to enhancing the CO2 uptake by coastal oceans in the future.

Restoration of PITPNA in Type 2 diabetic human islets reverses pancreatic beta-cell dysfunction.

Defects in insulin processing and granule maturation are linked to pancreatic beta-cell failure during type 2 diabetes (T2D). Phosphatidylinositol transfer protein alpha (PITPNA) stimulates activity of phosphatidylinositol (PtdIns) 4-OH kinase to produce sufficient PtdIns-4-phosphate (PtdIns-4-P) in the trans-Golgi network to promote insulin granule maturation. PITPNA in beta-cells of T2D human subjects is markedly reduced suggesting its depletion accompanies beta-cell dysfunction. Conditional deletion of Pitpna in the beta-cells of Ins-Cre, Pitpnaflox/flox mice leads to hyperglycemia resulting from decreasing glucose-stimulated insulin secretion (GSIS) and reducing pancreatic beta-cell mass. Furthermore, PITPNA silencing in human islets confirms its role in PtdIns-4-P synthesis and leads to impaired insulin granule maturation and docking, GSIS, and proinsulin processing with evidence of ER stress. Restoration of PITPNA in islets of T2D human subjects reverses these beta-cell defects and identify PITPNA as a critical target linked to beta-cell failure in T2D.

An ultrasensitive split-type electrochemical immunosensor based on controlled-release strategy for detection of CA19-9.

In this study, a novel split-type electrochemical immunosensor based on controlled release strategy was proposed for sensitive analysis and detection of tumor marker carbohydrate antigen 199 (CA19-9). Specifically, glucose (Glu) was encapsulated in carrier mesoporous silica (MSN) with encapsulation technology, and surface functionalized Zinc sulfide (ZnS) caps were used as "gatekeepers". The complex is formed by encapsulating Glu within MSN with ZnS (ZnS@MSN-Glu) as a signal amplifier labeled on the signal antibody (Ab2). And the Ab2 can detect the presence of antibodies. To reduce the interference of biological analysis, the immune recognition process of ZnS@MSN-Glu-Ab2 bioconjugate and antigen was carried out in 96-well microplate, which did not interfere with the electrochemical analysis process. Therefore, the low sensitivity detection caused by biofouling of nanomaterials and immunoreaction on the testing platform is eliminated. Subsequently, the opening and timed release of mesopores were controlled by external stimuli, the disulfide bond cleavage by dithiothreitol (DTT), and glucose was effectively released. Then nickel cobalt layered double hydroxide (NiCo-LDH) were directly hydrothermally grown on carbon cloth (CC) electrodeposited with copper selenide (CuSe) nanosheets to construct three-dimensional (3D) cactus-like NiCo-LDH/CuSe/CC sensing platform. It can realize the catalytic oxidation of released glucose, triggering glucose-mediated signal amplification. The synergistic effect of the 3D cactus structure and active nanomaterials promotes electron conduction. Taking the detection of carbohydrate antigen CA19-9 as an example, the immunosensor shows a wide linear concentration range (0.001-100 U/mL) with the limit of detection of 0.0005 U/mL, realizing highly sensitive detection of CA19-9. This biosensing technique has considerable advantages and provides an innovative approach for trace detection of other biomarkers.

Candy-like heterojunction nanocomposite of WO3/Fe2O3-based semiconductor gas sensor for the detection of triethylamine.

A highly efficient gas sensor for the detection of triethylamine based on candy-like WO3/Fe2O3 nanocomposite was prepared. The control of morphology and sensing performance of n-n heterojunction WO3/Fe2O3 nanocomposites were successfully achieved by the modulation of Fe element content. When the ratio of Fe to W is 0.4, the candy-like nanocomposite of WO3/Fe2O3 with great performance is obtained. It is interesting that the candy-like nanocomposite of WO3/Fe2O3 with a large specific surface area exhibits better selectivity and sensitivity for sensing TEA gases at a lower operating temperature (260 °C) compared with the gas sensor prepared by using WO3 alone. To verify the feasibility, the sensing mechanism was investigated and real sample tests were conducted and discussed. Finally, a TEA gas sensor with low limit of detection, short response/recovery time (15/162 s), and high sensitivity was developed. In addition, the prepared gas sensor has satisfactory stability and selectivity and has practical application value.

Estimating linkage disequilibrium and selection from allele frequency trajectories.

Genetic sequences collected over time provide an exciting opportunity to study natural selection. In such studies, it is important to account for linkage disequilibrium to accurately measure selection and to distinguish between selection and other effects that can cause changes in allele frequencies, such as genetic hitchhiking or clonal interference. However, most high-throughput sequencing methods cannot directly measure linkage due to short-read lengths. Here we develop a simple method to estimate linkage disequilibrium from time-series allele frequencies. This reconstructed linkage information can then be combined with other inference methods to infer the fitness effects of individual mutations. Simulations show that our approach reliably outperforms inference that ignores linkage disequilibrium and, with sufficient sampling, performs similarly to inference using the true linkage information. We also introduce two regularization methods derived from random matrix theory that help to preserve its performance under limited sampling effects. Overall, our method enables the use of linkage-aware inference methods even for data sets where only allele frequency time series are available.

Superconductivity and density-wave fluctuations in an extended triangular Hubbard model: an application to SnSe2.

We employ the fluctuation-exchange approximation to study the relation of superconducting pairing symmetries and density-wave fluctuations based on the extended triangular Hubbard model upon electron doping and interactions, with an possible application to the layered metal dichalcogenide SnSe2. For the case where the interactions between electrons contain only the on-site Hubbard term, the superconducting pairings are mainly mediated by spin fluctuations, and the spin-singlet pairing with thed-wave symmetry robustly dominates in the low and moderate doping levels, and ad-wave to extendeds-wave transition is observed as the electron doping reachesn = 1. When the near-neighbor site Coulomb interactions are also included, the charge fluctuations are enhanced, and the spin-triplet pairings with thep-wave andf-wave symmetries can be realized in the high and low doping levels, respectively.

Corrigendum: The incidence risk of breast and gynecological cancer by antidepressant use: A systematic review and dose-response meta-analysis of epidemiological studies involving 160,727 patients.

[This corrects the article DOI: 10.3389/fonc.2022.939636.].

The incidence risk of breast and gynecological cancer by antidepressant use: A systematic review and dose-response meta-analysis of epidemiological studies involving 160,727 patients.

Background and objective: Antidepressants are widely prescribed to treat depression and anxiety disorders that may become chronic conditions among women. Epidemiological studies have yielded inconsistent results on the correlation between antidepressant use and the incidence risk of female breast and gynecological cancer, along with uncertain dose-response relationship. Therefore, we performed a systematic review and dose-response meta-analysis to investigate the association. Methods: Web of Science, Embase, PubMed, The Cochrane Library, and PsycINFO were systematically searched in January 2022, with no language limits. Random-effect models were used to calculate pooled effect sizes and 95% confidence intervals between studies. Linear and non-linear dose-response analyses were performed to evaluate the dose or duration of antidepressant use affecting the incidence risk of female breast and gynecological cancer. Further subgroup analyses were systematically performed by stratifying almost all study characteristics and important potential confounders, in order to further clarify and validate the important potential hypotheses regarding the biological mechanism underlying this association. Results: Based on a systematic literature search, 34 eligible studies (27 case-control studies and 7 cohort studies) involving 160,727 female breast and gynecological cancer patients found that antidepressant use did not increase the incidence risk of female breast and gynecological cancer (pooled OR: 1.01; 95% CI: 0.97, 1.04, I² = 71.5%, p < 0.001), and even decreased the incidence risk of ovarian cancer (pooled OR: 0.91; 95% CI: 0.83, 1, I² = 17.4%, p = 0.293). There were a non-linear dose-response relationship (p non-linearity < 0.05) between the duration of antidepressant use and incidence risk of female breast cancer, and an inverse linear dose-response relationship between antidepressant use and the incidence risk of gynecological cancer, specifically with an increase of cumulative defined daily dose or duration to a high level, like 25,550 doses (OR: 0.91, 95% CI: 0.85-0.98, p linearity < 0.05) or 4,380 days (OR: 0.82; 95% CI: 0.7, 0.96, p linearity < 0.05), compared to never antidepressant users. Conclusion: This systematic review and dose-response meta-analysis found that antidepressant use did not increase the incidence risk of female breast and gynecological cancer and even decreased the incidence risk of ovarian cancer, along with a non-linear or linear dose-response relationship. Systematic Review Registration: PROSPERO https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=313364, identifier CRD42022313364.

A robust molecularly imprinted electrochemiluminescence sensor based on a Ni-Co nanoarray for the sensitive detection of spiramycin.

To prepare portable and robust sensors for the sensitive and selective detection of small molecules is still a challenge for the study of electroanalytical sensors. Here, we developed a molecularly imprinted electrochemiluminescence sensor (MIECL) for the detection of spiramycin (SPI), a type of multi-component macrolide antibiotic. First, Ni-Co LDH nanoarrays were synthesized by a one-step hydrothermal method and then directly used as a sensing platform. Then, as-synthesized N-Ti3C2 was modified on the nanoarrays. Due to the functional nanomaterial N-Ti3C2 not only serving as a substrate material to enable loading a large amount of perylene tetracarboxylic acid (PTCA) but also acting as a co-reaction promoter to accelerate the decomposition of S2O82- to generate more SO4˙-, the modified nanoarrays displayed a significantly enhanced electrochemiluminescence (ECL) signal. Finally, the molecularly imprinted polymer (MIP) and ECL techniques were combined to greatly improve the selectivity and sensitivity of the sensor. Under the optimal conditions, the easily constructed MIECL sensor showed good selectivity, reproducibility, and stability, and a detection limit of up to 3.14 × 10-13 M. The as-fabricated sensor was further evaluated by applying it to detect SPI in milk samples.

Difference in bypass for inpatient care and its determinants between rural and urban residents in China.

BACKGROUND: Bypass for inpatient care is an event of excessive demand. Though primary care facilities provide inpatient care in China, local residents may choose more distant higher-level hospital for inpatient care services. Given the differences in accessibility of hospitals and socioeconomic development between urban and rural areas, this study aims to estimate the rate of bypass for inpatient care and explore the factors predictive of bypass among rural and urban residents in China. METHODS: The rates of bypass for inpatient care were estimated using data from 1352 hospitalized patients, obtained from the 2018 Sixth National Health Service Survey of Hubei, China. Bypass for inpatient care was identified if the patient was hospitalized in a hospital for a certain disease that should be treated at primary care facilities in accordance with government requirement. Anderson's Behavioral Model of Health Services Use was used as a theoretical framework for determining the factors of bypass. Logistic regression was used to identify the relationship between bypass for inpatient care and predisposing, enabling, and need characteristics for urban and rural residents. RESULTS: The rate of bypass for inpatient care was 73.8%. This rate for inpatient care (91.3%) in cities is higher than that in rural areas (56.2%). Age were associated with bypass for both rural (OR, 0.982; 95% CI, 0.969-0.995) and urban (OR, 0.947; 95% CI, 0.919-0.976) patients. The patients whose closest healthcare facility was hospitals were more likely to have bypass behavior in rural (OR, 26.091; 95% CI, 7.867-86.537) and urban (OR, 8.323; 95% CI, 2.936-23.591) areas than those living closest to township/community health centers. Signing a family doctor was not helpful for retaining patients at primary care facility. Among rural patients, those with circulatory (OR, 2.378; 95% CI, 1.328-4.258), digestive (OR, 2.317; 95% CI, 1.280-4.192), or skin and bone (OR, 1.758; 95% CI, 1.088-2.840) system diseases were more likely to show bypass behavior than those with respiratory diseases. CONCLUSIONS: Bypass for inpatient care is sizable, and urban residents have a higher bypass rate for inpatient care than rural residents in China. More actionable measures in strengthening and leading patients to primary care are needed. Gradual establishment of a referral system is recommended. Inpatient care for circulatory, digestive, or skin and bone system diseases may be prioritized to be improved at primary care facilities in rural China.

Testing microbiome associations with survival times at both the community and individual taxon levels.

BACKGROUND: Finding microbiome associations with possibly censored survival times is an important problem, especially as specific taxa could serve as biomarkers for disease prognosis or as targets for therapeutic interventions. The two existing methods for survival outcomes, MiRKAT-S and OMiSA, are restricted to testing associations at the community level and do not provide results at the individual taxon level. An ad hoc approach testing each taxon with a survival outcome using the Cox proportional hazard model may not perform well in the microbiome setting with sparse count data and small sample sizes. METHODS: We have previously developed the linear decomposition model (LDM) for testing continuous or discrete outcomes that unifies community-level and taxon-level tests into one framework. Here we extend the LDM to test survival outcomes. We propose to use the Martingale residuals or the deviance residuals obtained from the Cox model as continuous covariates in the LDM. We further construct tests that combine the results of analyzing each set of residuals separately. Finally, we extend PERMANOVA, the most commonly used distance-based method for testing community-level hypotheses, to handle survival outcomes in a similar manner. RESULTS: Using simulated data, we showed that the LDM-based tests preserved the false discovery rate for testing individual taxa and had good sensitivity. The LDM-based community-level tests and PERMANOVA-based tests had comparable or better power than MiRKAT-S and OMiSA. An analysis of data on the association of the gut microbiome and the time to acute graft-versus-host disease revealed several dozen associated taxa that would not have been achievable by any community-level test, as well as improved community-level tests by the LDM and PERMANOVA over those obtained using MiRKAT-S and OMiSA. CONCLUSIONS: Unlike existing methods, our new methods are capable of discovering individual taxa that are associated with survival times, which could be of important use in clinical settings.