MELLODDY: Cross-pharma Federated Learning at Unprecedented Scale Unlocks Benefits in QSAR without Compromising Proprietary Information.

Federated multipartner machine learning has been touted as an appealing and efficient method to increase the effective training data volume and thereby the predictivity of models, particularly when the generation of training data is resource-intensive. In the landmark MELLODDY project, indeed, each of ten pharmaceutical companies realized aggregated improvements on its own classification or regression models through federated learning. To this end, they leveraged a novel implementation extending multitask learning across partners, on a platform audited for privacy and security. The experiments involved an unprecedented cross-pharma data set of 2.6+ billion confidential experimental activity data points, documenting 21+ million physical small molecules and 40+ thousand assays in on-target and secondary pharmacodynamics and pharmacokinetics. Appropriate complementary metrics were developed to evaluate the predictive performance in the federated setting. In addition to predictive performance increases in labeled space, the results point toward an extended applicability domain in federated learning. Increases in collective training data volume, including by means of auxiliary data resulting from single concentration high-throughput and imaging assays, continued to boost predictive performance, albeit with a saturating return. Markedly higher improvements were observed for the pharmacokinetics and safety panel assay-based task subsets.

Internal Medicine Residents' Perceptions of Virtual Morning Report: a Multicenter Survey.

IMPORTANCE: The COVID-19 pandemic disrupted graduate medical education, compelling training programs to abruptly transition to virtual educational formats despite minimal experience or proficiency. We surveyed residents from a national sample of internal medicine (IM) residency programs to describe their experiences with the transition to virtual morning report (MR), a highly valued core educational conference. OBJECTIVE: Assess resident views about virtual MR content and teaching strategies during the COVID-19 pandemic. DESIGN: Anonymous, web-based survey. PARTICIPANTS: Residents from 14 academically affiliated IM residency programs. MAIN MEASURES: The 25-item survey on virtual MR included questions on demographics; frequency and reason for attending; opinions on who should attend and teach; how the virtual format affects the learning environment; how virtual MR compares to in-person MR with regard to participation, engagement, and overall education; and whether virtual MR should continue after in-person conferences can safely resume. The survey included a combination of Likert-style, multiple option, and open-ended questions. RESULTS: Six hundred fifteen residents (35%) completed the survey, with a balanced sample of interns (39%), second-year (31%), and third-year (30%) residents. When comparing their overall assessment of in-person and virtual MR formats, 42% of residents preferred in-person, 18% preferred virtual, and 40% felt they were equivalent. Most respondents endorsed better peer-engagement, camaraderie, and group participation with in-person MR. Chat boxes, video participation, audience response systems, and smart boards/tablets enhanced respondents' educational experience during virtual MR. Most respondents (72%) felt that the option of virtual MR should continue when it is safe to resume in-person conferences. CONCLUSIONS: Virtual MR was a valued alternative to traditional in-person MR during the COVID-19 pandemic. Residents feel that the virtual platform offers unique educational benefits independent of and in conjunction with in-person conferences. Residents support the integration of a virtual platform into the delivery of MR in the future.

Internal Medicine Residents' Perceptions of Morning Report: a Multicenter Survey.

BACKGROUND: Residents rate morning report (MR) as an essential educational activity. Little contemporary evidence exists to guide medical educators on the optimal content or most effective delivery strategies, particularly in the era of resident duty-hour limitations and shifts towards learner-centric pedagogy in graduate medical education. OBJECTIVE: Assess resident views about MR content and teaching strategies. DESIGN: Anonymous, online survey. PARTICIPANTS: Internal medicine residents from 10 VA-affiliated residency programs. MAIN MEASURES: The 20-item survey included questions on demographics; frequency and reason for attending; opinions on who should attend, who should teach, and how to prioritize the teaching; and respondents' comfort level with participating in MR. The survey included a combination of Likert-style and multiple-choice questions with the option for multiple responses. KEY RESULTS: A total of 497 residents (46%) completed the survey, with a balanced sample of R1s (33%), R2s (35%), and R3s (31%). Self-reported MR attendance was high (31% always attend; 39% attend > 50% of the time), with clinical duties being the primary barrier to attendance (85%). Most respondents felt that medical students (89%), R1 (96%), and R2/R3s (96%) should attend MR; there was less consensus regarding including attendings (61%) or fellows (34%). Top-rated educational topics included demonstration of clinical reasoning (82%), evidence-based medicine (77%), and disease pathophysiology (53%). Respondents valued time spent on diagnostic work-up (94%), management (93%), and differential building (90%). Overall, 82% endorsed feeling comfortable speaking; fewer R1s reported comfort (76%) compared with R2s (87%) or R3s (83%, p = 0.018). Most (81%) endorsed that MR was an inclusive learning environment (81%), with no differences by level of training. CONCLUSIONS: MR remains a highly regarded, well-attended educational conference. Residents value high-quality cases that emphasize clinical reasoning, diagnosis, and management. A supportive, engaging learning environment with expert input and concise, evidence-based teaching is desired.

A multilocus phylogeny of the non-photosynthetic parasitic plant Cistanche (Orobanchaceae) refutes current taxonomy and identifies four major morphologically distinct clades.

Phylogenetic relationships of and within non-photosynthetic parasitic lineages are notoriously poorly known, which negatively affects our understanding of parasitic plants. This is also the case for Cistanche (Orobanchaceae), an Old World genus with about two dozen species, whose relationships have not yet been addressed using molecular phylogenetic approaches. Here we infer phylogenetic relationships within the genus, employing a taxonomically and geographically broad sampling covering all previously distinguished infrageneric groups and most of the currently recognized species. A combined matrix of three plastid markers (trnL-trnF, including the trnL intron and the intergenic spacer (IGS), trnS-trnfM IGS and psbA-trnH IGS) and one nuclear marker (ITS) was analyzed using maximum parsimony, maximum likelihood and Bayesian inference. Cistanche falls into four well-supported and geographically differentiated clades: East Asian Clade, Northwest African Clade, Southwest Asian Clade and Widespread Clade. Of those, only the East Asian Clade corresponds to a previously recognized taxonomic section, whereas the others either contain members of two or three sections (Widespread Clade and Southwest Asian Clade, respectively) or have not been taxonomically recognized so far (Northwest African Clade). Whereas the Southwest Asian Clade exhibits strong phylogenetic structure among and partly within species (the East Asian Clade and the Northwest African Clade are monospecific), phylogenetic resolution within the Widespread Clade is often low and hampered by discrepancies between nuclear and plastid markers. Both molecular and morphological data indicate that species diversity in Cistanche is currently underestimated.

Morphology, geographic distribution, and host preferences are poor predictors of phylogenetic relatedness in the mistletoe genus Viscum L.

Besides their alleged therapeutic effects, mistletoes of the genus Viscum L. (Viscaceae) are keystone species in many ecosystems across Europe, Africa, Asia and Australia because of their complex faunal interactions. We here reconstructed the evolutionary history of Viscum based on plastid and nuclear DNA sequence data. We obtained a highly resolved phylogenetic tree with ten well-supported clades, which we used to understand the spatio-temporal evolution of these aerial parasites and evaluate the contribution of reproductive switches and shifts in host ranges to their distribution and diversification. The genus Viscum originated in the early Eocene in Africa and appeared to have diversified mainly through geographic isolation, in several cases apparently coinciding with shifts in host preferences. During its evolution, switches in the reproductive mode from ancestral dioecy to monoecy imply an important role in the long-distance dispersal of the parasites from Africa to continental Asia and Australia. We also observed multiple cases of photosynthetic surface reduction (evolution of scale leaves) within the genus, probably indicative of increasing specialization associated with the parasitic lifestyle. Even compared with other parasitic angiosperms, where more host generalists than specialists exist, Viscum species are characterized by extraordinarily broad host ranges. Specialization on only a few hosts from a single family or order occurs rarely and is restricted mostly to very recently evolved lineages. The latter mostly derive from or are closely related to generalist parasites, implying that niche shifting to a new host represents an at least temporary evolutionary advantage in Viscum.

The Impact of Changing From a 6+2 to a 3+1 Residency Block Schedule on Patient Access and Other Outcomes.

Background The "X+Y" residency scheduling model includes "X" weeks of uninterrupted inpatient or subspecialty rotations, followed by "Y" week(s) of uninterrupted outpatient rotations. The optimal ratio of X to Y is unclear. Objective Determine the impact of moving from a 6+2 to a 3+1 schedule on patient access to care, perceived quality of care, and resident/faculty satisfaction. Methods Our residency program switched from a 6+2 to a 3+1 scheduling model in July 2018. We measured access to care before and after the change using the "third next available" (TNA) metric. In June 2019, we administered a voluntary, anonymous, 20-item survey to residents, staff, and faculty who worked in resident clinic in both the 6+2 and 3+1 years. Results Patient access to appointments with their resident physician, as measured by TNA, improved significantly after the schedule change (mean 34.1 days in 6+2, mean 26.5 days in 3+1, P<.0001). Fifteen of 17 (88%) eligible residents and 13 of 24 (54%) faculty/staff filled out the voluntary anonymous survey. Surveyed residents and faculty/staff had concordant perception that the schedule change led to improvement in patient continuity, quality of care, and ability of residents to follow up on diagnostic tests and have regular interaction with clinic attendings. However, residents did not report a change in satisfaction with continuity clinic. Conclusions Changing from a 6+2 to a 3+1 schedule was associated with improvement in patient access to care. Residents and faculty/staff perceived that this schedule change improved several aspects of patient care.

Medications for alcohol-use disorder and follow-up after hospitalization for alcohol withdrawal: A multicenter study.

BACKGROUND: Alcohol withdrawal is a common reason for admission to acute care hospitals. Prescription of medications for alcohol-use disorder (AUD) and close outpatient follow-up are commonly recommended, but few studies report their effects on postdischarge outcomes. OBJECTIVES: The objective of this study is to evaluate the effects of medications for AUD and follow-up appointments on readmission and abstinence. METHODS: This retrospective cohort study evaluated veterans admitted for alcohol withdrawal to medical services at 19 Veteran Health Administration hospitals between October 1, 2018 and September 30, 2019. Factors associated with all-cause 30-day readmission and 6-month abstinence were examined using logistic regression. RESULTS: Of the 594 patients included in this study, 296 (50.7%) were prescribed medications for AUD at discharge and 459 (78.5%) were discharged with follow-up appointments, including 251 (42.8%) with a substance-use clinic appointment, 191 (32.9%) with a substance-use program appointment, and 73 (12.5%) discharged to a residential program. All-cause 30-day readmission occurred for 150 patients (25.5%) and 103 (17.8%) remained abstinent at 6 months. Medications for AUD and outpatient discharge appointments were not associated with readmission or abstinence. Discharge to residential treatment program was associated with reduced 30-day readmission (adjusted odds ratio [AOR]: 0.39, 95% confidence interval [95% CI]: 0.18-0.82) and improved abstinence (AOR: 2.50, 95% CI: 1.33-4.73). CONCLUSIONS: Readmission and return to heavy drinking are common for patients discharged for alcohol withdrawal. Medications for AUD were not associated with improved outcomes. The only intervention at the time of discharge that improved outcomes was discharge to residential treatment program, which was associated with decreased readmission and improved abstinence.

Contemporary Management and Outcomes of Veterans Hospitalized With Alcohol Withdrawal: A Multicenter Retrospective Cohort Study.

OBJECTIVES: Few studies describe contemporary alcohol withdrawal management in hospitalized settings or review current practices considering the guidelines by the American Society of Addiction Medicine (ASAM). METHODS: We conducted a retrospective cohort study of patients hospitalized with alcohol withdrawal on medical or surgical wards in 19 Veteran Health Administration (VHA) hospitals between October 1, 2018, and September 30, 2019. Demographic and comorbidity data were obtained from the Veteran Health Administration Corporate Data Warehouse. Inpatient management and hospital outcomes were obtained by chart review. Factors associated with treatment duration and complicated withdrawal were examined. RESULTS: Of the 594 patients included in this study, 51% were managed with symptom-triggered therapy alone, 26% with fixed dose plus symptom-triggered therapy, 10% with front loading regimens plus symptom-triggered therapy, and 3% with fixed dose alone. The most common medication given was lorazepam (87%) followed by chlordiazepoxide (33%), diazepam (14%), and phenobarbital (6%). Symptom-triggered therapy alone (relative risk [RR], 0.68; 95% confidence interval [CI], 0.57-0.80) and front loading with symptom-triggered therapy (RR, 0.75; 95% CI, 0.62-0.92) were associated with reduced treatment duration. Lorazepam (RR, 1.20; 95% CI, 1.02-1.41) and phenobarbital (RR, 1.28; 95% CI, 1.06-1.54) were associated with increased treatment duration. Lorazepam (adjusted odds ratio, 4.30; 95% CI, 1.05-17.63) and phenobarbital (adjusted odds ratio, 6.51; 95% CI, 2.08-20.40) were also associated with complicated withdrawal. CONCLUSIONS: Overall, our results support guidelines by the ASAM to manage patients with long-acting benzodiazepines using symptom-triggered therapy. Health care systems that are using shorter acting benzodiazepines and fixed-dose regimens should consider updating alcohol withdrawal management pathways to follow ASAM recommendations.

The Lunch Conference Diet: Fostering Resident Engagement in Culinary Medicine Through a Curriculum Centered on Changes to Provided Conference Food.

BACKGROUND: Despite the burden of chronic disease attributable to lifestyle, most internal medicine residents do not receive adequate training in nutrition and nutrition counseling. METHODS: We held a culinary medicine workshop in September 2018, followed by didactic sessions throughout the academic year. Changes were made to lunch conference food to more closely follow the Mediterranean diet and to encourage healthy eating. With a modified NUTCOMP (Nutrition Competence Questionnaire) instrument, we assesses residents' perceived competence with nutrition counseling before and after the curriculum. RESULTS: Twenty-six of 30 residents completed the pre-curriculum and post-curriculum surveys (not the same 26). The mean NUTCOMP score increased from 3.5 to 4.0 (P < .0001), indicating an increased perceived competence with nutritional counseling. Residents felt that nutritional counseling was important before and after the curriculum (4.2 to 4.3, P = .48). Conference food was more nutritious at the end of the intervention (Mediterranean diet score range 1-4 to 4-7) and residents enjoyed the food more. CONCLUSIONS: An innovative, multimodal nutrition curriculum centered on changes to catered lunch conference food improved resident's confidence with nutritional counseling. This could feasibly be integrated into other residency programs with supportive leadership and adequate training.

The ABC of binding-protein-dependent transport in Archaea.

The recent solution of the crystal structure of an entire binding-protein-dependent ABC transporter complex from the archaeon Archaeoglobus fulgidus by Locher and his colleagues marks a milestone in the understanding of the ABC transport mechanism. The structure elegantly demonstrates how the motor ATPase alternately opens and closes the inside and outside pores of the transporter and how the substrate-binding protein delivers its substrate. Binding-protein-dependent sugar ABC transporters in the archaea and in bacteria have an additional feature that could connect ABC transporters to gene regulation and to the control of transport activity by cellular processes.

Contemporaneous radiations of fungi and plants linked to symbiosis.

Interactions between fungi and plants, including parasitism, mutualism, and saprotrophy, have been invoked as key to their respective macroevolutionary success. Here we evaluate the origins of plant-fungal symbioses and saprotrophy using a time-calibrated phylogenetic framework that reveals linked and drastic shifts in diversification rates of each kingdom. Fungal colonization of land was associated with at least two origins of terrestrial green algae and preceded embryophytes (as evidenced by losses of fungal flagellum, ca. 720 Ma), likely facilitating terrestriality through endomycorrhizal and possibly endophytic symbioses. The largest radiation of fungi (Leotiomyceta), the origin of arbuscular mycorrhizae, and the diversification of extant embryophytes occurred ca. 480 Ma. This was followed by the origin of extant lichens. Saprotrophic mushrooms diversified in the Late Paleozoic as forests of seed plants started to dominate the landscape. The subsequent diversification and explosive radiation of Agaricomycetes, and eventually of ectomycorrhizal mushrooms, were associated with the evolution of Pinaceae in the Mesozoic, and establishment of angiosperm-dominated biomes in the Cretaceous.

Changes in Resident Well-Being at One Institution Across a Decade of Progressive Work Hours Limitations.

PURPOSE: To measure changes in markers of resident well-being over time as progressive work hours limitations (WHLs) were enforced, and to investigate resident perceptions of the 2011 WHLs. METHOD: A survey study of internal medicine residents was conducted at the University of Washington's multihospital residency program in 2012. The survey included validated well-being questions: the Maslach Burnout Inventory, the two-question PRIME-MD depression screen, and career satisfaction questions. Chi-square tests were used to compare 2012 well-being questionnaire responses against nearly identical surveys conducted in 2001 and 2004 at the same institution. In addition, residents were asked to rate the impact of WHLs on resident well-being and education as well as patient care, and to state preferences for future WHLs. RESULTS: Significantly different proportions of residents met burnout criteria across time, with fewer meeting criteria in 2012 than in 2001 (2001: 76% [87/115]; 2004: 64% [75/118]; 2012: 61% [68/112]; P = .039). Depression screening results also differed across time, with fewer screening positive in 2012 than in 2004 (2001: 45% [52/115]; 2004: 55% [65/118]; 2012 [35/112]: 31%; P = .001). Residents, especially seniors, reported perceived negative impacts of WHLs on their well-being, education, and patient care. Most senior residents favored reverting to the pre-July 2011 system of WHLs. Interns were more divided. CONCLUSIONS: Validated measures of resident well-being changed across the three time points measured. Residents had the lowest rates of burnout and depression in 2012. Resident perceptions of the 2011 WHLs, however, were generally negative.

Synthesis of thieno[2,3-b]pyridinones acting as cytoprotectants and as inhibitors of [3H]glycine binding to the N-methyl-D-aspartate (NMDA) receptor.

The standard glycine site antagonist of the N-methyl-D-aspartate (NMDA) receptor, 3-phenyl-4-hydroxyquinolin-2(1H)-one (21), was used as a template for bioisostere benzene/thiophene exchange. Phenylacetylation of aminothiophene carboxylic acid methyl esters and subsequent cyclization delivered the three possible thienopyridinone isomers. 4-Hydroxy-5-phenylthieno[2,3-b]pyridin-6(7H)-one (3a), with the shortest distance between the sulfur and the nitrogen atom, was the most potent isomer (K(i) against the binding of [(3)H]glycine to rat membranes 16 microM), comparable in potency to the model quinolinone (21, 12 microM). Replacement of the phenyl substituent of 21 by a 2-thienyl residue resulted in a 2-5-fold loss in potency and was abandoned. In the thieno part of the thienopyridinone nucleus, the most successful substituents were halogen (Cl or Br) close to the sulfur atom and short alkyl chains at the other position, resulting in 7h, 8h, 8i, and 8m, with K(i) values between 5.8 and 10.5 nM. Introduction of a 3'-phenoxy moiety yielded several compounds with still higher potencies (18h, 18i, 18l, and 18m; K(i) between 1.1 and 2.0 nM). Quantitative structure-activity relationship (QSAR) calculations resulted in a consistent interpretation of the potencies of most compounds. Several of these 3'-phenoxy derivatives protected mouse fibroblast cell lines with transfected NMDA receptors from glutamate-induced toxicity. In addition, we report in vivo results for four of these compounds.

Phosphorylation of the RNA-binding protein Dazl by MAPKAP kinase 2 regulates spermatogenesis.

Developing male germ cells are exquisitely sensitive to environmental insults such as heat and oxidative stress. An additional characteristic of these cells is their unique dependence on RNA-binding proteins for regulating posttranscriptional gene expression and translational control. Here we provide a mechanistic link unifying these two features. We show that the germ cell-specific RNA-binding protein deleted in azoospermia-like (Dazl) is phosphorylated by MAPKAP kinase 2 (MK2), a stress-induced protein kinase activated downstream of p38 MAPK. We demonstrate that phosphorylation of Dazl by MK2 on an evolutionarily conserved serine residue inhibits its interaction with poly(A)-binding protein, resulting in reduced translation of Dazl-regulated target RNAs. We further show that transgenic expression of wild-type human Dazl but not a phosphomimetic form in the Drosophila male germline can restore fertility to flies deficient in boule, the Drosophila orthologue of human Dazl. These results illuminate a novel role for MK2 in spermatogenesis, expand the repertoire of RNA-binding proteins phosphorylated by this kinase, and suggest that signaling by the p38-MK2 pathway is a negative regulator of spermatogenesis via phosphorylation of Dazl.

High-Throughput Crystallography: Reliable and Efficient Identification of Fragment Hits.

Today the identification of lead structures for drug development often starts from small fragment-like molecules raising the chances to find compounds that successfully pass clinical trials. At the heart of the screening for fragments binding to a specific target, crystallography delivers structural information essential for subsequent drug design. While it is common to search for bound ligands in electron densities calculated directly after an initial refinement cycle, we raise the important question whether this strategy is viable for fragments characterized by low affinities. Here, we describe and provide a collection of high-quality diffraction data obtained from 364 protein crystals treated with diverse fragments. Subsequent data analysis showed that ∼25% of all hits would have been missed without further refining the resulting structures. To enable fast and reliable hit identification, we have designed an automated refinement pipeline that will inspire the development of optimized tools facilitating the successful application of fragment-based methods.

The three-dimensional structure of TrmB, a transcriptional regulator of dual function in the hyperthermophilic archaeon Pyrococcus furiosus in complex with sucrose.

TrmB is a repressor that binds maltose, maltotriose, and sucrose, as well as other α-glucosides. It recognizes two different operator sequences controlling the TM (Trehalose/Maltose) and the MD (Maltodextrin) operon encoding the respective ABC transporters and sugar-degrading enzymes. Binding of maltose to TrmB abrogates repression of the TM operon but maintains the repression of the MD operon. On the other hand, binding of sucrose abrogates repression of the MD operon but maintains repression of the TM operon. The three-dimensional structure of TrmB in complex with sucrose was solved and refined to a resolution of 3.0 Å. The structure shows the N-terminal DNA binding domain containing a winged-helix-turn-helix (wHTH) domain followed by an amphipathic helix with a coiled-coil motif. The latter promotes dimerization and places the symmetry mates of the putative recognition helix in the wHTH motif about 30 Å apart suggesting a canonical binding to two successive major grooves of duplex palindromic DNA. This suggests that the structure resembles the conformation of TrmB recognizing the pseudopalindromic TM promoter but not the conformation recognizing the nonpalindromic MD promoter.

Heralded entanglement between widely separated atoms.

Entanglement is the essential feature of quantum mechanics. Notably, observers of two or more entangled particles will find correlations in their measurement results that cannot be explained by classical statistics. To make it a useful resource, particularly for scalable long-distance quantum communication, the heralded generation of entanglement between distant massive quantum systems is necessary. We report on the creation and analysis of heralded entanglement between spins of two single rubidium-87 atoms trapped independently 20 meters apart. Our results illustrate the viability of an integral resource for quantum information science, as well as for fundamental tests of quantum mechanics.

Crystal structure of the sugar binding domain of the archaeal transcriptional regulator TrmB.

TrmB is an alpha-glucoside-sensing transcriptional regulator controlling two operons encoding maltose/trehalose and maltodextrin ABC transporters of Pyrococcus furiosus. The crystal structure of an N-terminal truncated derivative of TrmB (amino acids 2-109 deleted; TrmB(delta2-109)) was solved at 1.5 A resolution. This protein has lost its DNA binding domain but has retained its sugar recognition site. The structure represents a novel sugar-binding fold. TrmB(delta2-109) bound maltose, glucose, sucrose, and maltotriose, exhibiting Kd values of 6.8, 25, 34, and 160 microM, respectively. TrmB(delta2-109) behaved as a monomer in dilute buffer solution in contrast to the full-length protein, which is a dimer. Co-crystallization with bound maltose identified a binding site involving seven amino acid residues: Ser229, Asn305, Gly320, Met321, Val324, Ile325, and Glu326. Six of these residues interact with the nonreducing glucosyl residue of maltose. The nonreducing glucosyl residue is shared by all substrates bound to TrmB, suggesting it as a common recognition motif.

Linear and nonlinear functions on modeling of aqueous solubility of organic compounds by two structure representation methods.

Several quantitative models for the prediction of aqueous solubility of organic compounds were developed based on a diverse dataset with 2084 compounds by using multi-linear regression analysis and backpropagation neural networks. The compounds were described by two different structure representation methods: (1) with 18 topological descriptors; and (2) with 32 radial distribution function codes representing the 3D structure of a molecule and eight additional descriptors. The dataset was divided into a training and a test set based on Kohonen's self-organizing neural network. Good prediction results were obtained for backpropagation neural network models: with 18 topological descriptors, for the 936 compounds in the test set, a correlation coefficient of 0.92, and a standard deviation of 0.62 were achieved; with 3D descriptors, for the 866 compounds in the test set, a correlation coefficient of 0.90, and a standard deviation of 0.73 were achieved. The models were also tested by using another dataset, and the relationship of the two datasets was examined by Kohonen's self-organizing neural network.