Molecular Mechanism of Different Rooting Capacity between Two Clones of Taxodium hybrid 'Zhongshanshan'.

The conifer Taxodium hybrid 'Zhongshanshan' (T. hybrid 'Zhongshanshan') is characterized by rapid growth, strong stress resistance, and high ornamental value and has significant potential for use in afforestation, landscaping, and wood production. The main method of propagating T. hybrid 'Zhongshanshan' is tender branch cutting, but the cutting rooting abilities of different T. hybrid 'Zhongshanshan' clones differ significantly. To explore the causes of rooting ability differences at a molecular level, we analyzed the transcriptome data of cutting base and root tissues of T. hybrid 'Zhongshanshan 149' with a rooting rate of less than 5% and T. hybrid 'Zhongshanshan 118' with rooting rate greater than 60%, at the developmental time points in this study. The results indicated that differentially expressed genes between the two clones were mainly associated with copper ion binding, peroxidase, and oxidoreductase activity, response to oxidative stress, phenylpropanoid and flavonoid biosynthesis, and plant hormone signal transduction, among others. The expression pattern of ThAP2 was different throughout the development of the adventitive roots of the two clone cuttings. Therefore, this gene was selected for further study. It was shown that ThAP2 was a nuclear-localized transcription factor and demonstrated a positive feedback effect on rooting in transgenic Nicotiana benthamiana cuttings. Thus, the results of this study explain the molecular mechanism of cutting rooting and provide candidate gene resources for developing genetic breeding strategies for optimizing superior clones of T. hybrid 'Zhongshanshan'.

A Ten-Year Comparative Study on Ethical Cognition of Experimental Animals among Medical Students in a University / 中国医学伦理学

The study was carried out to understand the changes in the ethical cognition status of laboratory animals and the effectiveness of laboratory animal ethics education among medical students in Xiangya School of Medicine of Central South University (CSU), and provide new enlightenment for further strengthening the ethical education of laboratory animals. In the study, the same self-compiled questionnaire was used to investigate the ethical cognition of experimental animals among medical students in Xiangya School of Medicine of CSU in 2011 and 2021, and 359 and 363 questionnaires were collected respectively. Through comparative analysis of the questionnaire results before and after ten years, it was found that medical students’ animal experiment operation and attitudes towards laboratory animals, cognition of experimental animal ethics knowledge and their attitude to animal experiment ethics education were significantly improved. It showed that the state of experimental animal ethics cognition among medical students in Xiangya School of Medicine of CSU had improved significantly in recent 10 years, but the cognition of experimental animal ethics knowledge was higher than the actual behavior of caring for experimental animals, and there was the phenomenon of "separation of knowledge and action". The ethics education of experimental animals needs to pay more attention to the development of students’ behavior of caring for experimental animals.

Novel molecular markers for Taxodium breeding from the chloroplast genomes of four artificial Taxodium hybrids.

Taxodium "Zhongshanshan" are a group of intraspecific Taxodium hybrids with superparental dominance and high ecological and economic value in southern China. Identifying the parentage of hybrids, especially the male parent, is critically important for genetic studies. However, the large nuclear genomes of members of the genus Taxodium pose a major challenge for the development of molecular markers. Here, we developed novel molecular markers by conducting a comparative analysis of the chloroplast genomes of four artificial Taxodium hybrids and their parents. The lengths of the whole chloroplast genome ranged from 131,942 to 132,128 bp, and the total guanine (GC) content of the chloroplast genomes ranged from 34.6% to 35.81%. A total of 120 unique genes were identified, including 83 protein-coding genes, 33 transfer RNAs, and four ribosomal RNAs. There were 69-71 simple sequence repeats were detected in the four hybrids. Phylogenetic analysis revealed that these hybrids clustered with their paternal parents. Similar findings were obtained by analysis of the GC content of protein-coding genes. Molecular markers were developed using the highly variable regions of the chloroplast genomes, and polymerase chain reaction (PCR) assays revealed that these markers were effective for identifying the male parents of these hybrids. Our findings indicate for the first time that the chloroplast genomes of Taxodium are paternally inherited. Generally, these molecular markers could facilitate breeding and genetic studies of Taxodium.

ADH Gene Cloning and Identification of Flooding-Responsive Genes in Taxodium distichum (L.) Rich.

As a flooding-tolerant tree species, Taxodium distichum has been utilized in afforestation projects and proven to have important value in flooding areas. Alcohol dehydrogenase (ADH), which participates in ethanol fermentation, is essential for tolerance to the anaerobic conditions caused by flooding. In a comprehensive analysis of the ADH gene family in T. distichum, TdADHs were cloned on the basis of whole-genome sequencing, and then bioinformatic analysis, subcellular localization, and gene expression level analysis under flooding were conducted. The results show that the putative protein sequences of 15 cloned genes contained seven TdADHs and eight TdADH-like genes (one Class III ADH included) that were divided into five clades. All the sequences had an ADH_N domain, and except for TdADH-likeE2, all the other genes had an ADH_zinc_N domain. Moreover, the TdADHs in clades A, B, C, and D had a similar motif composition. Additionally, the number of TdADH amino acids ranged from 277 to 403, with an average of 370.13. Subcellular localization showed that, except for TdADH-likeD3, which was not expressed in the nucleus, the other genes were predominantly expressed in both the nucleus and cytosol. TdADH-likeC2 was significantly upregulated in all three organs (roots, stems, and leaves), and TdADHA3 was also highly upregulated under 24 h flooding treatment; the two genes might play key roles in ethanol fermentation and flooding tolerance. These findings offer a comprehensive understanding of TdADHs and could provide a foundation for the molecular breeding of T. distichum and current research on the molecular mechanisms driving flooding tolerance.

Medicinal plants and natural compounds against acyclovir-resistant HSV infections.

Herpes simplex virus (HSV), an alphaherpesvirus, is highly prevalent in the human population and is known to cause oral and genital herpes and various complications. Represented by acyclovir (ACV), nucleoside analogs have been the main clinical treatment against HSV infection thus far. However, due to prolonged and excessive use, HSV has developed ACV-resistant strains. Therefore, effective treatment against ACV-resistant HSV strains is urgently needed. In this review, we summarized the plant extracts and natural compounds that inhibited ACV-resistant HSV infection and their mechanism of action.

Andrographolide Inhibits Proliferation and Promotes Apoptosis in Bladder Cancer Cells by Interfering with NF- κ B and PI3K/AKT Signaling In Vitro and In Vivo.

OBJECTIVE: To explore the influences of andrographolide (Andro) on bladder cancer cell lines and a tumor xenograft mouse model bearing 5637 cells. METHODS: For in vitro experiments, T24 cells were stimulated with Andro (0-40 µmol/L) and 5637 cells were stimulated with Andro (0 to 80 µmol/L). Cell growth, migration, and infiltration were assessed using cell counting kit-8, colony formation, wound healing, and transwell assays. Apoptosis rate was examined using flow cytometry. In in vivo study, the antitumor effect of Andro (10 mg/kg) was evaluated by 5637 tumor-bearing mice, and levels of nuclear factor κ B (NF- κ B) and phosphoinositide 3-kinase/AKT related-proteins were determined by immunoblotting. RESULTS: Andro suppressed growth, migration, and infiltraion of bladder cancer cells (P⩽0.05 or P⩽0.01). Additionally, Andro induced intrinsic mitochondria-dependent apoptosis in bladder cancer cell lines. Furthermore, Andro inhibited bladder cancer growth in mice (P⩽0.01). The expression of p65, p-AKT were suppressed by Andro treatment in vitro and in vivo (P⩽0.05 or P⩽0.01). CONCLUSIONS: Andrographolide inhibits proliferation and promotes apoptosis in bladder cancer cells by interfering with NF- κ B and PI3K/AKT signaling in vitro and in vivo.

Molecular Cloning, Transcriptional Profiling, Subcellular Localization, and miRNA-Binding Site Analysis of Six SCL9 Genes in Poplar.

The SCL9 subfamily is a key member of the GRAS family that regulates plant development and stress responses. Nevertheless, the functional role of these genes in the growth and development of poplar still unclear. Here, we reported the six SCL9 genes, which were found to be differentially expressed during poplar adventitious root formation. The full-length sequences of PeSCL9 genes of 'Nanlin895' poplar (Populus deltoids × Populus euramericana) were cloned by the RACE technique All PeSCL9 genes lacked introns. RT-qPCR revealed that PeSCL9 genes displayed a dynamic expression pattern in the adventitious root of poplar, according to RT-qPCR data. A series of comprehensive genes characteristics analysis were carried out for six genes by bioinformation. Meanwhile, transient expression analysis of the Populus protoplasts showed that all the PeSCL9 proteins were localized in the nucleus. In addition, the degradome and sRNA of 'Nanlin895' poplar in combination were used to predict miRNAs that regulate PeSCL9. It was found that miR396a and miR396c may affect PeSCL9 expression via cleavage, which was further verified by a transient expression experiment in Populus protoplasts. Overall, the development of poplar adventitious root and other tissues was closely related to these six SCL9 genes, and they serve as a starting point for further research into the mechanisms regulating poplar growth and development.

The complete chloroplast genome sequence of Taxodium ascendens × T. mucronatum hybrid (Cupressaceae).

Taxodium 'Zhongshanshan 401' is an important economic plant with ornamental and ecological values, and has been widely planted in southeastern China. In this study, the complete chloroplast (cp) genome of T. 'Zhongshanshan 401' was sequenced and illustrated to add the more genetic information. The entire cp genome of T. 'Zhongshanshan 401' was 132,037 bp in length with 35.3% overall GC content. The cp genome contained 120 genes, including 83 protein-coding genes, 33 tRNA genes, and four rRNA genes. Fifteen genes contain two exons and two contains three exons. Phylogenetic analysis based on whole cp genome sequences showed that T. 'Zhongshanshan 401' was more closely related to T. mucronatum.

Identification and Functional Analysis of ThADH1 and ThADH4 Genes Involved in Tolerance to Waterlogging Stress in Taxodium hybrid 'Zhongshanshan 406'.

The Taxodium hybrid 'Zhongshanshan 406' (T. hybrid 'Zhongshanshan 406') [Taxodium mucronatum Tenore × Taxodium distichum (L.). Rich] has an outstanding advantage in flooding tolerance and thus has been widely used in wetland afforestation in China. Alcohol dehydrogenase genes (ADHs) played key roles in ethanol metabolism to maintain energy supply for plants in low-oxygen conditions. Two ADH genes were isolated and characterized-ThADH1 and ThADH4 (GenBank ID: AWL83216 and AWL83217-basing on the transcriptome data of T. hybrid 'Zhongshanshan 406' grown under waterlogging stress. Then the functions of these two genes were investigated through transient expression and overexpression. The results showed that the ThADH1 and ThADH4 proteins both fall under ADH III subfamily. ThADH1 was localized in the cytoplasm and nucleus, whereas ThADH4 was only localized in the cytoplasm. The expression of the two genes was stimulated by waterlogging and the expression level in roots was significantly higher than those in stems and leaves. The respective overexpression of ThADH1 and ThADH4 in Populus caused the opposite phenotype, while waterlogging tolerance of the two transgenic Populus significantly improved. Collectively, these results indicated that genes ThADH1 and ThADH4 were involved in the tolerance and adaptation to anaerobic conditions in T. hybrid 'Zhongshanshan 406'.

Andrographolide sensitizes human renal carcinoma cells to TRAIL­induced apoptosis through upregulation of death receptor 4.

Tumor necrosis factor­related apoptosis­inducing ligand (TRAIL) selectively induces apoptosis in cancer cells, with minimal toxicity to normal tissues. However, accumulating evidence suggests that certain cancer types are insensitive to TRAIL signaling. The aim of this study was to identify an effective combination regimen, which can overcome TRAIL resistance in renal cancer cell. Herein, we found that human renal carcinoma cells (RCCs) are widely resistant to TRAIL­mediated growth inhibition and subsequently identified that andrographolide (Andro), a major constituent of Andrographis paniculate, an annual herbaceous plant in the family Acanthaceae, counteracts TRAIL resistance in RCCs. Combined treatment with TRAIL and Andro suppressed cell viability as determined by MTS and proliferation as determined by EdU in a dose­dependent manner and inactivated the clonogenic and migration ability of RCCs. Andro significantly enhances TRAIL­mediated cell cycle arrest at the G2/M phase as determined by flow cytometry and senescence. Moreover, Andro restored TRAIL signaling, which in turns activated pro­apoptosis caspases as determined by immunoblot assay. The TRAIL receptor, death receptor (DR)4, but not DR5, was found to be significantly upregulated in Andro­treated RCC cells, which contributed to the role of Andro as a TRAIL sensitizer. The present study demonstrated that the combined treatment of Andro and TRAIL has potential therapeutic value against renal cancer.

Comparative chloroplast genomics of the genus Taxodium.

BACKGROUND: Chloroplast (cp) genome information would facilitate the development and utilization of Taxodium resources. However, cp genome characteristics of Taxodium were poorly understood. RESULTS: We determined the complete cp genome sequences of T. distichum, T. mucronatum, and T. ascendens. The cp genomes are 131,947 bp to 132,613 bp in length, encode 120 genes with the same order, and lack typical inverted repeat (IR) regions. The longest small IR, a 282 bp trnQ-containing IR, were involved in the formation of isomers. Comparative analysis of the 3 cp genomes showed that 91.57% of the indels resulted in the periodic variation of tandem repeat (TR) motifs and 72.46% single nucleotide polymorphisms (SNPs) located closely to TRs, suggesting a relationship between TRs and mutational dynamics. Eleven hypervariable regions were identified as candidates for DNA barcode development. Hypothetical cp open reading frame 1(Ycf1) was the only one gene that has an indel in coding DNA sequence, and the indel is composed of a long TR. When extended to cupressophytes, ycf1 genes have undergone a universal insertion of TRs accompanied by extreme length expansion. Meanwhile, ycf1 also located in rearrangement endpoints of cupressophyte cp genomes. All these characteristics highlight the important role of repeats in the evolution of cp genomes. CONCLUSIONS: This study added new evidence for the role of repeats in the dynamics mechanism of cp genome mutation and rearrangement. Moreover, the information of TRs and hypervariable regions would provide reliable molecular resources for future research focusing on the infrageneric taxa identification, phylogenetic resolution, population structure and biodiversity for the genus Taxodium and Cupressophytes.

The Clinical Course after Long-Term Acute Care Hospital Admission among Older Medicare Beneficiaries.

OBJECTIVES: Long-term acute care (LTAC) hospitals provide extended complex post-acute care to more than 120 000 Medicare beneficiaries annually, with the goal of helping patients to regain independence and recover. Because little is known about patients' long-term outcomes, we sought to examine the clinical course after LTAC admission. DESIGN: Nationally representative 5-year cohort study using 5% Medicare data from 2009 to 2013. SETTING: LTAC hospitals. PARTICIPANTS: Hospitalized Medicare fee-for-service beneficiaries 65 years of age or older who were transferred to an LTAC hospital. MEASUREMENTS: Mortality, recovery (defined as achieving 60 consecutive days alive without inpatient care), time spent in an inpatient facility following LTAC hospital admission, receipt of an artificial life-prolonging procedure (feeding tube, tracheostomy, hemodialysis), and palliative care physician consultation. RESULTS: Of 14 072 hospitalized older adults transferred to an LTAC hospital, median survival was 8.3 months, and 1- and 5-year survival rates were 45% and 18%, respectively. Following LTAC admission, 53% never achieved a 60-day recovery. The median time of their remaining life a patient spent as an inpatient after LTAC admission was 65.6% (interquartile range = 21.4%-100%). More than one-third (36.9%) died in an inpatient setting, never returning home after the LTAC admission. During the preceding hospitalization and index LTAC admission, 30.9% received an artificial life-prolonging procedure, and 1% had a palliative care physician consultation. CONCLUSION: Hospitalized older adults transferred to LTAC hospitals have poor survival, spend most of their remaining life as an inpatient, and frequently undergo life-prolonging procedures. This prognostic understanding is essential to inform goals of care discussions and prioritize healthcare needs for hospitalized older adults admitted to LTAC hospitals. Given the exceedingly low rates of palliative care consultations, future research is needed to examine unmet palliative care needs in this population. J Am Geriatr Soc 67:2282-2288, 2019.

Identification and functional analysis of LecRLK genes in Taxodium 'Zhongshanshan'.

BACKGROUND: Lectin receptor-like protein kinases (LecRLKs) can transform external stimuli into intracellular signals and play important regulatory roles in plant development and response to environmental stressors. However, research on the LecRLK gene family of conifers has seldom been reported. METHODS: Putative LecRLK genes were identified in the transcriptome of Taxodium 'Zhongshanshan'. The classification, domain structures, subcellular localization prediction, and expression patterns of LecRLK genes, as well as co-expressed genes, were analyzed using bioinformatics methods. Fifteen representative genes were further selected for qRT-PCR analysis in six tissues and under five different environmental stressor conditions. RESULTS: In total, 297 LecRLK genes were identified, including 155 G-type, 140 L-type, and 2 C-type. According to the classification, G-type and L-type LecRLK genes both can be organized into seven groups. The domain architecture of G-type proteins were more complex compared with that of L- and C-type proteins. Conservative motifs were found in G-type and L-type diverse lectin domains. Prediction and transient expression experiments to determine subcellular localization showed that LecRLKs were mainly concentrated in the cell membrane system, and some members were located at multiple sites at the same time. RNA-seq-based transcriptomics analysis suggested functional redundancy and divergence within each group. Unigenes co-expressed with LecRLKs in the transcriptome were found to be enriched in pathways related to signal transduction and environmental adaptation. Furthermore, qRT-PCR analysis of representative genes showed evidence of functional divergence between different groups. CONCLUSIONS: This is the first study to conduct an identification and expression analysis of the LecRLK gene family in Taxodium. These results provide a basis for future studies on the evolution and function of this important gene family in Taxodium.

Regional and racial variations in the utilization of endoscopic retrograde cholangiopancreatography among pancreatic cancer patients in the United States.

BACKGROUND: Pancreatic cancer is projected to become the second leading cause of cancer-related deaths by 2030. Endoscopic retrograde cholangiopancreatography (ERCP) is recommended as first-line therapy for biliary decompression in pancreatic cancer. The aim of our study was to characterize geographic and racial/ethnic disparities in ERCP utilization among patients with pancreatic cancer. METHODS: Retrospective cohort study using the US Surveillance, Epidemiology, and End Results (SEER)-Medicare database to identify patients diagnosed with pancreatic cancer from 2003-2013. The primary outcome was receipt of ERCP, with or without stent placement, vs any non-ERCP biliary intervention. RESULTS: Of the 36 619 patients with pancreatic cancer, 37.5% (n = 13 719) underwent an ERCP, percutaneous drainage, or surgical biliary bypass. The most common biliary intervention (82.6%) was ERCP. After adjusting for tumor location and stage, Blacks were significantly less likely to receive ERCP than Whites (aOR 0.84, 95% CI 0.72, 0.97) and more likely to receive percutaneous transhepatic biliary drainage (PTBD) (aOR 1.38, 95% CI 1.14, 1.66). Patients in the Southeast and the West were more likely to receive ERCP than those in the Northeast (Southeast aOR 1.21, 95% CI 1.04, 1.40; West aOR 1.16, 95% CI 1.01, 1.32). CONCLUSION: Racial/ethnic and geographic disparities in access to biliary interventions including ERCP exist for patients with pancreatic cancer in the United States. Our results highlight the need for further research and policies to improve access to appropriate biliary intervention for all patients.

An Integrated Transcriptome and Proteome Analysis Reveals Putative Regulators of Adventitious Root Formation in Taxodium 'Zhongshanshan'.

Adventitious root (AR) formation from cuttings is the primary manner for the commercial vegetative propagation of trees. Cuttings is also the main method for the vegetative reproduction of Taxodium 'Zhongshanshan', while knowledge of the molecular mechanisms regulating the processes is limited. Here, we used mRNA sequencing and an isobaric tag for relative and absolute quantitation-based quantitative proteomic (iTRAQ) analysis to measure changes in gene and protein expression levels during AR formation in Taxodium 'Zhongshanshan'. Three comparison groups were established to represent the three developmental stages in the AR formation process. At the transcript level, 4743 genes showed an expression difference in the comparison groups as detected by RNA sequencing. At the protein level, 4005 proteins differed in their relative abundance levels, as indicated by the quantitative proteomic analysis. A comparison of the transcriptome and proteome data revealed regulatory aspects of metabolism during AR formation and development. In summary, hormonal signal transduction is different at different developmental stages during AR formation. Other factors related to carbohydrate and energy metabolism and protein degradation and some transcription factor activity levels, were also correlated with AR formation. Studying the identified genes and proteins will provide further insights into the molecular mechanisms controlling AR formation.

Examining the Association between Healthcare Utilization and Clinical Characteristics among Cancer Patients in a Safety Net Health System.

OBJECTIVE: The goal of this study was to examine the association between available patient and clinical characteristics and healthcare utilization in a cohort of breast, lung, and colorectal cancer patients within a safety-net hospital system. METHODS: Data for 979 breast, lung, and colorectal cancer patients admitted to a large, urban hospital for the year 2010 were extracted from the electronic medical record (EMR). Univariate and multivariate logistic regression analyses were performed to examine the association between relevant independent variables that were able to be captured from the EMR in discrete fields, emergency room (ER) utilization, and hospitalizations among members of the cohort. Spearman correlation coefficients to test the correlations between nonsteroidal anti-inflammatory drug and opioid prescriptions and healthcare utilization were also calculated. RESULTS: Of the 979 patients, 22% were 65 years and older, 43% were non-Hispanic black, 42% had Medicare, and 56% had colorectal cancer. Patient and clinical characteristics that were associated with increased ER utilization, included Hispanic ethnicity (adjusted odds ratio; AOR: 2.21, 95% confidence interval; CI: 1.52-3.21), non-Hispanic black race (AOR: 2.01, 95% CI: 1.43-2.82), and referral to palliative care (AOR: 2.15, 95% CI: 1.36-3.41). Referral to palliative care (AOR: 3.84, 95% CI: 1.47-10.0), low albumin (AOR: 2.42, 95% CI: 1.20-4.89), and presence of metastases (AOR: 1.98, 95% CI: 1.29-3.06) were associated with greater odds of hospitalization. Number of opioids prescribed strongly correlated with number of hospitalizations (ρ correlation = 0.74). Only 10.6% of patients had been referred to outpatient palliative care during the study period. CONCLUSIONS: Some patient and clinical characteristics associated with increased ER visits and hospitalizations in this cohort include race/ethnicity, palliative care referral, markers of advanced disease, and number opioids prescribed. Increasing knowledge of palliative care and access to palliative care among the underserved should be a focus of future research.

High-density genetic map construction and quantitative trait loci identification for growth traits in (Taxodium distichum var. distichum × T. mucronatum) × T. mucronatum.

BACKGROUND: 'Zhongshanshan' is the general designation for the superior interspecific hybrid clones of Taxodium species, which is widely grown for economic and ecological purposes in southern China. Growth is the priority objective in 'Zhongshanshan' tree improvement. A high-density linkage map is vital to efficiently identify key quantitative trait loci (QTLs) that affect growth. RESULTS: In total, 403.16 Gb of data, containing 2016,336 paired-end reads, was obtained after preprocessing. The average sequencing depth was 28.49 in T. distichum var. distichum, 25.18 in T. mucronatum, and 11.12 in each progeny. In total, 524,662 high-quality SLAFs were detected, of which 249,619 were polymorphic, and 6166 of the polymorphic markers met the requirements for use in constructing a genetic map. The final map harbored 6156 SLAF markers on 11 linkage groups, and was 1137.86 cM in length, with an average distance of 0.18 cM between adjacent markers. Separate QTL analyses of traits in different years by CIM detected 7 QTLs. While combining multiple-year data, 13 QTLs were detected by ICIM. 5 QTLs were repeatedly detected by the two methods, and among them, 3 significant QTLs (q6-2, q4-2 and q2-1) were detected in at least two traits. Bioinformatic analysis discoveried a gene annotated as a leucine-rich repeat receptor-like kinase gene within q4-2. CONCLUSIONS: This map is the most saturated one constructed in a Taxodiaceae species to date, and would provide useful information for future comparative mapping, genome assembly, and marker-assisted selection.

Long-Term Acute Care Hospital Use of Non-Mechanically Ventilated Hospitalized Older Adults.

OBJECTIVES: To determine why non-mechanically ventilated hospitalized older adults are transferred to long-term acute care (LTAC) hospitals rather than remaining in the hospital. DESIGN: Observational cohort. SETTING: National Medicare data. PARTICIPANTS: Non-mechanically ventilated hospitalized adults aged 65 and older with fee-for-service Medicare in 2012 who were transferred to an LTAC hospital (n=1,831) or had a prolonged hospitalization without transfer (average hospital length of stay or longer of those transferred to an LTAC hospital) and had one of the 50 most common hospital diagnoses leading to LTAC transfer (N=12,875). MEASUREMENTS: We assessed predictors of transfer using a multilevel model, adjusting for patient-, hospital-, and hospital referral region (HRR)-level factors. We estimated proportions of variance at each level and adjusted hospital- and HRR-specific LTAC transfer rates using sequential models. RESULTS: The strongest predictor of transfer was being hospitalized near an LTAC hospital (<1.4 vs > 33.6 miles, adjusted odds ratio=6.2, 95% confidence interval (CI)=4.2-9.1). After adjusting for case mix, differences between hospitals explained 15.4% of the variation in LTAC use and differences between regions explained 27.8%. Case mix-adjusted LTAC use was high in the South, where many HRRs had rates between 20.3% and 53.1%, whereas many HRRs were less than 5.4% in the Pacific Northwest, North, and New England. From our fully adjusted model, the median adjusted hospital LTAC transfer rate was 7.2% (interquartile range 2.8-17.5%), with substantial within-region variation (intraclass coefficient=0.25, 95% CI=0.21-0.30). CONCLUSIONS: Nearly half of the variation in LTAC use is independent of illness severity and is explained by which hospital and what region the individual was hospitalized in. Because of the greater fragmentation of care and Medicare spending with LTAC transfers (because LTAC hospitals generate a separate bundled payment from the hospital), greater attention is needed to define the optimal role of LTAC hospitals in caring for older adults. J Am Geriatr Soc 66:2112-2119, 2018.

Effect of Site-Neutral Payment Policy on Long-Term Acute Care Hospital Use.

OBJECTIVE: To assess the projected effect of the Centers for Medicare and Medicaid Services new site-neutral payment policy, which aims to decrease unnecessary long-term acute care hospital (LTACH) admissions by reducing reimbursements for less-ill individuals by 2020. DESIGN: Observational. SETTING: National 5% Medicare data (2011-12). MEASUREMENTS: We examined the proportion of site-neutral LTACH admissions. Regional LTACH market supply was defined as LTACH beds per 100,000 residents, categorized according to tertile. We conducted a hospital-level analysis to compare the projected effect of site-neutral payment on "propensity score" matched high- and low-LTACH-use hospitals. RESULTS: Forty-one percent of LTACH admissions would be subjected to site-neutral payment. The proportion of site-neutral admissions was large, varied considerably according to LTACH (median 40%, interquartile range 22-60%), and was only modestly greater with greater market supply (Pearson correlation coefficient=0.23, p<.001; coefficient of determination=0.10). The site-neutral payment policy would affect 47% of admissions from the highest-supply regions, versus 30% from the lowest-supply regions (p<.001); and 43% from high-use hospitals versus 36% from propensity score-matched low-use hospitals (p<.001). CONCLUSION: A considerable proportion of LTACH admissions will be subjected to lower site-neutral payments. Although the policy will disproportionately affect high-use regions and hospitals, it will also affect nearly one-third of the current LTACH population from low-use hospitals and regions. As such, the site-neutral payment policy may limit LTACH access in existing LTAC-scarce markets, with potential adverse implications for recovery of hospitalized older adults. J Am Geriatr Soc 66:2104-2111, 2018.