Stratified Treatments Research Articles

Deciphering the molecular landscape of rheumatoid arthritis offers new insights into the stratified treatment for the condition.

For Rheumatoid Arthritis (RA), a long-term chronic illness, it is essential to identify and describe patient subtypes with comparable goal status and molecular biomarkers. This study aims to develop and validate a new subtyping scheme that integrates genome-scale transcriptomic profiles of RA peripheral blood genes, providing a fresh perspective for stratified treatments. We utilized independent microarray datasets of RA peripheral blood mononuclear cells (PBMCs). Up-regulated differentially expressed genes (DEGs) were subjected to functional enrichment analysis. Unsupervised cluster analysis was then employed to identify RA peripheral blood gene expression-driven subtypes. We defined three distinct clustering subtypes based on the identified 404 up-regulated DEGs. Subtype A, named NE-driving, was enriched in pathways related to neutrophil activation and responses to bacteria. Subtype B, termed interferon-driving (IFN-driving), exhibited abundant B cells and showed increased expression of transcripts involved in IFN signaling and defense responses to viruses. In Subtype C, an enrichment of CD8+ T-cells was found, ultimately defining it as CD8+ T-cells-driving. The RA subtyping scheme was validated using the XGBoost machine learning algorithm. We also evaluated the therapeutic outcomes of biological disease-modifying anti-rheumatic drugs. The findings provide valuable insights for deep stratification, enabling the design of molecular diagnosis and serving as a reference for stratified therapy in RA patients in the future.

A predictive model for HIV-related lymphoma.

To address the paucity of HIV-related lymphoma (HRL)-specific prognostic scores for the Japanese population by analyzing domestic cases of HRL and constructing a predictive model. A single-center retrospective study coupled with a review of case reports of HRL. We reviewed all patients with HRL treated at our hospital between 2007 and 2023 and conducted a comprehensive search for case reports of HRL from Japan using public databases. A multivariate analysis for overall survival (OS) was performed using clinical parameters, leading to the formulation of the HIV-Japanese Prognostic Index (HIV-JPI). A total of 19 patients with HRL were identified in our institution, whereas the literature review yielded 44 cases. In the HIV-JPI, a weighted score of 1 was assigned to the following factors: age at least 45 years, HIV-RNA at least 8.0×10 4 copies/ml, Epstein-Barr virus-encoded small RNA positivity, and Ann Arbor classification stage IV. The overall score ranged from 0 to 4. We defined the low-risk group as scores ranging from 0 to 2 and the high-risk group as scores ranging from 3 to 4. The 3-year OS probability of the high-risk group [30.8%; 95% confidence interval (CI): 9.5-55.4%) was significantly poorer than that of the low-risk group (76.8%; 95% CI: 52.8-89.7%; P < 0.01). This retrospective analysis established pivotal prognostic factors for HRL in Japanese patients. The HIV-JPI, derived exclusively from Japanese patients, highlights the potential for stratified treatments and emphasizes the need for broader studies to further refine this clinical prediction model.

Sex effects on DNA methylation affect discovery in epigenome-wide association study of schizophrenia

Sex differences in the epidemiology and clinical characteristics of schizophrenia are well-known; however, the molecular mechanisms underlying these differences remain unclear. Further, the potential advantages of sex-stratified meta-analyses of epigenome-wide association studies (EWAS) of schizophrenia have not been investigated. Here, we performed sex-stratified EWAS meta-analyses to investigate whether sex stratification improves discovery, and to identify differentially methylated regions (DMRs) in schizophrenia. Peripheral blood-derived DNA methylation data from 1519 cases of schizophrenia (male n = 989, female n = 530) and 1723 controls (male n = 997, female n = 726) from three publicly available datasets, and the TOP cohort were meta-analyzed to compare sex-specific, sex-stratified, and sex-adjusted EWAS. The predictive power of each model was assessed by polymethylation score (PMS). The number of schizophrenia-associated differentially methylated positions identified was higher for the sex-stratified model than for the sex-adjusted one. We identified 20 schizophrenia-associated DMRs in the sex-stratified analysis. PMS from sex-stratified analysis outperformed that from sex-adjusted analysis in predicting schizophrenia. Notably, PMSs from the sex-stratified and female-only analyses, but not those from sex-adjusted or the male-only analyses, significantly predicted schizophrenia in males. The findings suggest that sex-stratified EWAS meta-analyses improve the identification of schizophrenia-associated epigenetic changes and highlight an interaction between sex and schizophrenia status on DNA methylation. Sex-specific DNA methylation may have potential implications for precision psychiatry and the development of stratified treatments for schizophrenia.

Economic evaluation of four treatment strategies for postmenopausal patients with osteoporosis and a recent fracture in mainland China: a cost-effectiveness analysis.

To evaluate the cost-effectiveness of four anti-osteoporosis medications (denosumab, zoledronate, teriparatide, and alendronate) for postmenopausal osteoporotic women in mainland China, using a stratified treatment strategy recommended by the American Association of Clinical Endocrinologists and the American College of Endocrinology (AACE/ACE). A microsimulation Markov model was used to compare the cost-effectiveness of the four treatments in postmenopausal osteoporotic patients of different ages (65, 70, 75, and 80 years), with a recent fracture from the Chinese healthcare perspective. The primary outcome was the incremental cost-effectiveness ratio (ICER), which represent the incremental cost per quality-adjusted life-year (QALY) obtained. One-way deterministic sensitivity analysis (DSA) and probabilistic sensitivity analysis (PSA) were performed to assess the robustness of model findings. Alendronate was dominated by denosumab-to-alendronate and zoledronate at all ages examined, indicating that the costs of the two drugs were lower, but QALYs was greater. However, teriparatide-to-alendronate yielded an ICER of $76,432.07/ QALY, compared with alendronate at age 65, which exceeded the pre-determined willingness-to-pay threshold of $37,653/ QALY. The results were similar at other ages. The DSA showed that the most sensitive parameters were drug efficacy for vertebral and wrist fractures, the relative risk of vertebral fractures, and the persistence of the drugs. The PSA showed that zoledronate had a 100% probability of being the most cost-effective treatment, with a willingness-to-pay threshold of $37,653/ QALY. Stratified treatment based on very high fracture risk is more cost-effective than conventional pills in mainland China. Among the stratified treatments, zoledronate is the optimal option.

Effect of Substrate Stratification Without Fine Pine Bark Particles on Growth of Common Nursery Weed Species and Container-grown Ornamental Species

Substrate stratification is a new research area in which multiple substrates, or the same substrate with differing physical properties, are layered within a container to accomplish a production goal, such as decreasing water use, nutrient leaching, or potentially reducing weed growth. Previous research using stratification with pine (Pinus sp.) bark screened to ≤1/2 or 3/4 inch reduced the growth of bittercress (Cardamine flexuosa) by 80% to 97%, whereas liverwort (Marchantia polymorpha) coverage was reduced by 95% to 99%. The objective of this study was to evaluate substrate stratification with pine bark screened to remove all fine particles as the top strata of the substrate and determine its effect on common nursery weeds and ornamental plants. Stratified treatments consisted of pine bark screened to either 1/8 to 1/4 inch, 1/4 to 1/2 inch, or 3/8 to 3/4 inch, applied at depths of either 1 or 2 inches on top of a standard ≤1/2-inch pine bark substrate. An industry-standard treatment was also included in which the substrate was not stratified but consisted of only ≤1/2-inch pine bark throughout the container. A controlled-release fertilizer was incorporated at the bottom strata in all stratified treatments (no fertilizer in the top 1 or 2 inches of the container media), whereas the industry standard treatment had fertilizer incorporated throughout. Compared with the nonstratified industry standard, substrate stratification decreased spotted spurge (Euphorbia maculata) counts by 30% to 84% and bittercress counts by 57% to 94% after seeding containers. The shoot dry weight of spotted spurge was reduced by 14% to 55%, and bittercress shoot dry weight was reduced by 71% to 93% in stratified treatments. Liverwort coverage was reduced by nearly 100% in all the stratified substrate treatments. Compared with the industry standard substrate, stratified treatments reduced shoot dry weight of ligustrum (Ligustrum japonicum) by up to 20%, but no differences were observed in growth index, nor were any growth differences observed in blue plumbago (Plumbago auriculata).

Mutation Spectrum, Characteristics and Impact of Mutation Profiling on Prognosis, Outcome and Treatment Responses in Patients (pts) with Mantle Cell Lymphoma

Background: Genomic profiles of mantle cell lymphoma (MCL) are associated with clinical outcomes. BTKi Resistance in MCL can be predicted with mutation profile. Identifying these patients (pts) early can help guide therapy decisions and predict outcomes. We describe results from a clinical NGS based assay with a customized 162-gene panel in routine work-ups of MCL pts. Materials and Methods: We reviewed data from MCL patients who underwent CLIA approved lymphoma gene panel testing at MDACC from October 2020 until the end of June 2022. Data on treatment response, outcomes, and patient characteristics were collected. Mutation panel testing was conducted on various patient samples. Genomic DNA was isolated from fresh bone marrow (BM) aspirate, formalin-fixed paraffin-embedded (FFPE) tissues, fine needle aspirate (FNA) and peripheral blood (PB) specimens. Sequencing was performed using the Illumina NextSeq platform (Illumina, San Diego, CA). Variant calling was performed using Agilent SureCall software v4.1 and post-variant call analysis and annotation were performed using an in-house bioinformatics pipeline (OncoSeek v 1.1). Analytical sensitivity of the assay was established at 2% using a per base coverage cut-off of 200x. The assay was performed in cases with >10% lymphoma cells in the sample. Results: We included 227 MCL pts in this study: 129 treatment naïve and 97 with prior therapies. The distribution of patients according to the sample type included: BM (n=107), FFPE (n=50; 24 lymph node, 20 GI tract, and 6 miscellaneous tissues), FNA from involved nodal and non-nodal tissues (n=50) and PB (n=20). Baseline pt features included a median age of 67 years (range, 38-88 years). There were 164 men and 63 women. Histomorphology was classic in 165 pts, blastoid in 31, pleomorphic in 19 and blastoid/pleomorphic in 2. Ten pts had unclear histomorphology. Ki-67% in involved tissues was evaluable in 180 pts (in 47 pts Ki-67% was not available). Ki-67% was high (>=30%) in 98 and low in 82 biopsy specimens. Among the 97 previously treated pts, 47 had BTKi refractory disease. Twenty-three pts were treated with standard of care brexucabtagene autoleucel (CART). The spectrum of gene mutations is depicted by both previously untreated and pts with prior therapy in figure-1A. The most common mutated genes were: ATM (51.5%), TP53 (29.5%), KMT2D (21.1%), CCND1 (19.3%), BIRC3 (16.2%), NSD2 (11.4%), SMARCA4 (10.1%), UBR5 (9%), NOTCH1 (8.3%), CARD11 (7%), SAMHD1 (7%), NFKB1E (6.6%), SP140 (6.6%), S1PR1 (6.6%), DNMT3A (6%), NOTCH2 (6%), IGLL5 (6%), TRAF2 (5%), TET2 (5%). Unlike chronic lymphocytic leukemia, mutations of BTK (n=5; 2%) and PLCg (n=4; 2%) were rare. BTK mutations included missense mutations: C481Y, C481R, T474I and 2 with L528W. All patients with BTK mutations were resistant to prior BTKi and 4/5 died with refractory disease. Additional mutations of prognostic interest in other lymphomas were detected at very low frequency (<3%) and included CDKN2A, CD79b, MYD88, MEF2B, MAP3K14, Rb1, PAX5, SPEN, SF3B1, DIS3. We also evaluated pt survival from the date of gene panel testing and noted that TP53 mutant MCL pts had significantly inferior survival. We further divided the pts based on >=3 mutations (n=77) vs < 3 mutations (n=150) and identified that pts with a higher number of mutations had inferior survival, P <0.0001 (Figure 1C). Pts with SMARCA4 and TRAF2 mutations also demonstrated shorter survival compared to those which were wild type (not shown). Twenty-three pts received CART therapy and 7 had progressed and 16 have not. The distribution of mutations before CART in the two groups was not significantly different. Among the 47 BTKi refractory MCL, the frequency of certain mutations was higher: TP53 (49%), ATM (55%), KMT2D (31%), CCND1 (23%), 10% each for SMARCA4, NSD2 and SP140. Currently, we are utilizing this test to evaluate and include pts with high risk MCL on our clinical trials in MCL and treat with risk stratified treatments. Conclusion: The clinical NGS-based assay for MCL pts at our institution has proven to have prognostic significance. Resistant MCL pts exhibit a preponderance of mutations involving TP53, epigenetic modifier and chromatin regulator genes. Comprehensive risk stratification of pts early on and during therapy is very useful and improves patient care, helps design next generation clinical trials and improves our understanding of the biology of resistant MCL in the BTKi and CART era. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Single-screen Bark Particle Separation Can be Used to Engineer Stratified Substrate Systems

Substrate stratification is an emerging substrate management strategy involving layering multiple substrate materials within a single container to modify physiochemical characteristics of the substrate system. Specifically, stratifying allows growers and researchers to rearrange the air–water balance within a container to modify hydraulic characteristics. Moreover, fertilizer can be incorporated into just the upper strata to reduce leaching. Research to date has shown benefits associated with resource efficiency, production timing, and weed control. With the associated benefits for substrate stratification, interested growers will need pragmatic solutions for onsite trials. Therefore, the objective of this study was to identify a cost-effective solution for growers interested in exploring stratification options. As such, this research was designed to identify a single-screen bark separation to generate fine and coarse bark textures suitable for use as the top and bottom substrate strata. Loblolly pine bark (Pinus taeda) was screened with either a 4.0-mm, 1/4-inch, or 3/8-inch screen, with the particles passing through the screen (unders) separated from retained particles (overs). Stratified substrate systems were engineered with an individual screen wherein the fines were layered atop the coarse particles from the same screen. ‘Natchez’ crepe myrtle (Lagerstroemia indica) liners were planted in either of the three stratified substrate treatments or a nonstratified control. Substrate physical characteristics were assessed for each strata by pre- and postproduction properties to identify changes of substrate. The final growth index of the crop was unaffected by the substrate treatment (P = 0.90); however, stratified substrates did increase dry root weight (P = 0.02), with the smallest screen (4.0 mm) resulting in the greatest root weight. Separation of roots between the two strata indicated the presence of more roots in the upper strata in all substrates. However, the stratified substrates resulted in a greater shift in root location, encouraging increased rooting in the upper strata with fine particles, with the largest screen (3/8 inch) resulting in the greatest differentiation between upper and lower rooting. Each stratified treatment had increase in water-holding capacity in the lower (coarser) strata without changes in the upper strata. Thus, we conclude that single screens can be used to build stratified substrate systems. Moreover, screen aperture size may be used to achieve different outcomes with regard to root growth and development as well as water–air balance. Further research may indicate that screen selection may be used to target specific crop needs.

Abstract 6238: Profiling of the circulating cell-free DNA methylome for detection and subtyping of small cell lung cancers

Abstract Introduction: Small-cell lung cancer (SCLC) is a high-grade neuroendocrine carcinoma characterised by high proliferation rate and early, rapid metastatic spread. Although SCLC is treated as a homogenous disease, recent studies revealed morphologic and transcriptomic heterogeneity with several molecular subtypes described based on predominant transcription factor expression (ASCL1, NEUROD1, ATOH1, POU2F3, YAP1) (Rudin et al., 2019; Simpson et al., 2020) which in preclinical studies exhibit differing vulnerabilities raising the potential of stratified therapy. DNA methylation is also thought be an important regulator of SCLC biology (Gazdar et al., 2017) and epigenetically distinct subtypes derived from SCLC primary tumour samples reported (Poirier et al., 2015). Here, we developed a robust workflow for genome-wide DNA methylation profiling to examine the potential use of cfDNA methylation profiling for detection and subtyping of SCLC. Results: To evaluate SCLC genome-wide DNA methylation patterns we employed a bisulfite-free enrichment-based approach (T7-MBD-seq). We tested this approach on tissue samples from preclinical models and from normal lung (n=110) and on cfDNA samples from both patients with SCLC and from non-cancer controls (n=157). Methylation profiles from preclinical models (patient-derived xenografts (PDX) and CTC derived explant (CDX) models) were comparable to previously described methylation patterns from SCLC primary tumours and were recapitulated in patients’ cfDNA samples. A tumour/normal classifier, based on 4,061 genomic regions detected as being hypermethylated in SCLC preclinical models, correctly assigned 93% and 100% cfDNA samples from patients with limited and extensive stage SCLC respectively, with a statistically significant correlation of prediction scores with disease stage (P=0.0076). Finally, to determine whether cfDNA methylation profiling could subtype SCLC patients, we built a subtype classifier, based on methylation signatures derived from 59 established SCLC cell lines. We applied the classifier to cfDNA samples from 56 patients and 10/11 with known subtypes (identified from a donor matched CDX model) were correctly classified. Overall, 73% of cfDNA samples were classified as ASCL1, 13% were classified as NEUROD1 and 14% were classified as being double negative with the distribution of the subtypes correlating closely to previously published IHC data from SCLC tissue samples (Baine et al., 2020). Conclusions: Our data reveal two potential clinical utilities of cfDNA methylation profiling; a universally applicable liquid biopsy approach for more sensitive detection and monitoring of SCLC and molecular subtyping to ease the path to future clinical trials of subtype stratified treatments for patients with SCLC. Citation Format: Dominic G. Rothwell, Francesca Chemi, Simon Pearce, Alex Clipson, Steven Hill, Alicia Marie Conway, Sophie Richardson, Katarzyna Murat, Rebecca Caeser, Jacklynn Egger, John T. Poirier, Alastair Kerr, Fiona Blackhall, Charles M. Rudin, Caroline Dive. Profiling of the circulating cell-free DNA methylome for detection and subtyping of small cell lung cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6238.

Neurobiologically Based Stratification of Recent-Onset Depression and Psychosis: Identification of Two Distinct Transdiagnostic Phenotypes

BackgroundIdentifying neurobiologically based transdiagnostic categories of depression and psychosis may elucidate heterogeneity and provide better candidates for predictive modeling. We aimed to identify clusters across patients with recent-onset depression (ROD) and recent-onset psychosis (ROP) based on structural neuroimaging data. We hypothesized that these transdiagnostic clusters would identify patients with poor outcome and allow more accurate prediction of symptomatic remission than traditional diagnostic structures. MethodsHYDRA (Heterogeneity through Discriminant Analysis) was trained on whole-brain volumetric measures from 577 participants from the discovery sample of the multisite PRONIA study to identify neurobiologically driven clusters, which were then externally validated in the PRONIA replication sample (n = 404) and three datasets of chronic samples (Centre for Biomedical Research Excellence, n = 146; Mind Clinical Imaging Consortium, n = 202; Munich, n = 470). ResultsThe optimal clustering solution was two transdiagnostic clusters (cluster 1: n = 153, 67 ROP, 86 ROD; cluster 2: n = 149, 88 ROP, 61 ROD; adjusted Rand index = 0.618). The two clusters contained both patients with ROP and patients with ROD. One cluster had widespread gray matter volume deficits and more positive, negative, and functional deficits (impaired cluster), and one cluster revealed a more preserved neuroanatomical signature and more core depressive symptomatology (preserved cluster). The clustering solution was internally and externally validated and assessed for clinical utility in predicting 9-month symptomatic remission, outperforming traditional diagnostic structures. ConclusionsWe identified two transdiagnostic neuroanatomically informed clusters that are clinically and biologically distinct, challenging current diagnostic boundaries in recent-onset mental health disorders. These results may aid understanding of the etiology of poor outcome patients transdiagnostically and improve development of stratified treatments.

Evaluating Stratified Substrates Effect on Containerized Crop Growth under Varied Irrigation Strategies

Growers rely on soilless substrates to provide sufficient water and nutrients to containerized crops. Traditional bark-based substrates are engineered to have relatively low water-holding capabilities, which can lead to nonuniform rewetting patterns and inefficient usage of water resources. Engineering substrates to redistribute water dynamics and maximize aeration within the container may improve water resource efficiencies. The goal of this study was to evaluate whether more efficient irrigation schedules can be used when stratifying unique substrates within a container for added crop water and nutrient efficiency. Loropetalum chinense ‘Ruby’ liners were planted and grown in a conventional pine bark substrate or one of three stratified substrate treatments, including a bark:peat, bark:coir, or fine bark layered on top of a coarse bark. The crops were grown under four different irrigation schedules, including single daily application, single application at deficit levels, cyclic application, or cyclic at deficit schedules. Stratified substrates improved crop growth, quality, and yield when compared with plants grown in conventional bark in the single application irrigation treatment. Measured at final harvest, substrates positively influenced plant growth index (P &lt; 0.0001), whereas irrigation scheduling alone had no effect (P = 0.6321). There was a strong interaction between substrate and irrigation schedules on Δ growth index (P = 0.0141). There were strong substrate effects on shoot dry weight (P = 0.0060), root dry weight (P = 0.0342), and growth index (P = 0.0040). The stratified bark:coir treatment outgrew all other substrate treatments. In addition, within all irrigation treatments, plants grown with the stratified bark:coir substrate had the highest survival ratings among the other substrate treatments, whereas the conventional bark had the lowest survival rates. Substrate and irrigation had an effect on nitrogen and potassium leachate concentrations levels (P = 0.0107 and P = 0.0004, respectively). Evaluation of microbial communities showed that substrate (P = 0.0010) and the stratified layer (P = 0.0010) had strong influences on the type of community present and the relative abundance in the treatments used herein this study. Specifically, within cyclic scheduling, bark:peat actinomycete populations were significantly greater than other substrate treatments. Furthermore, under deficit irrigation, stratified substrate systems were able to mitigate crop water stress. The results indicate that when crops such as the Loropetalum are grown in the stratified system, crop growth can be sustained when drought conditions are present. This is possible by providing adequate water availability even under low water inputs until subsequent irrigations during the fragile establishment period, when compared with using traditional bark-based substrates.

A retrospective cohort study in Chinese patients with adult polymyositis and dermatomyositis: risk of comorbidities and subclassification using machine learning.

To identify the risk factors in Chinese patients with adult polymyositis and dermatomyositis for their comorbidities and explore a subclassification system. Clinical records of 397 patients with idiopathic inflammatory myopathies were retrospectively reviewed. Logistic regression was used to identify potential risk factors for interstitial lung disease (ILD), other rheumatic diseases, and malignancy after bivariate analysis. Hierarchical clustering and decisional tree were utilised to identify subgroups and explore a subclassification system. A total of 119 polymyositis and 191 dermatomyositis patients were included. Anti-PM/Scl, anti-Ro52, anti-aminoacyl-tRNA synthetase and anti-MDA5 (adjusted odds ratios (AOR)=4.779, 1.917, 5.092 and 7.714 respectively) antibodies were risks (p<0.05), whereas overlapping malignancy was protective (AOR=0.107; p=0.002) for ILD across polymyositis, dermatomyositis and the total group. In subgroup models, Raynaud's phenomenon, arthralgia and semi-quantitative anti-nuclear antibody (AOR=51.233, 4.261, 3.047 respectively) were risks for other overlapping rheumatic diseases (p<0.05). For overlapping malignancy, male and anti-TIF1γ antibodies (AOR=2.533, 16.949) were risks (p<0.05), whereas disease duration and combination of ILD (AOR=0.954, 0.106) were protective in the total group (p<0.05); while anti-NXP2 antibodies were identified as risk factors (AOR=73.152; p=0.038) in polymyositis. Hierarchical clustering suggested a subclassification with 6 subgroups: malignancy overlapping dermatomyositis, classical dermatomyositis, polymyositis with severe muscle involvement, dermatomyositis with ILD, polymyositis with ILD, and overlapping of myositis with other rheumatic diseases. Accompanying ILD, other rheumatic diseases and malignancy are strongly associated with clinical manifestation and myositis-specific or myositis-associated autoantibodies among Chinese polymyositis and dermatomyositis patients. The subclassification system proposed a more precise phenotype defining toward stratified treatments.

Substrate Stratification: Layering Unique Substrates within a Container Increases Resource Efficiency without Impacting Growth of Shrub Rose

Nurseries rely on soilless substrates to provide suitable growing media for container grown crops. These soilless substrates have been developed to readily drain water to prevent issues with waterlogging and associated soil-borne disease. A negative consequence of high porosity and subsequent drainage throughout the container profile is the required high or frequent irrigation rates with poor retention of applied nutrients. Substrates with relatively high levels of moisture and nutrient retention placed on top of a coarse and freely draining substrate could further optimize water and nutrient retention, while allowing for needed gas exchange for plant establishment and growth. Containerized Red Drift® rose (Rosa ‘Meigalpio’ PP17877) plants were grown under 16 mm or 12 mm daily irrigation, utilizing a traditional pine bark substrate or stratified substrates with either a conventional bark, bark fines, or a bark–peat mixture on top of a coarse bark within a container. The stratified substrates received 20% less controlled-release fertilizer; however, the fertilizer in the stratified treatments was concentrated in the upper strata only. During the first growing phase or season, plants grown in stratified substrates outperformed those grown in conventional, non-stratified bark substrates under normal irrigation. The stratified substrates did not reduce growth under reduced irrigation regimes. Overall, crop growth was equal or superior for stratified substrates when compared to the non-stratified controls, even with a 20% reduction of fertilizer. This research suggests that stratified substrate systems can be used to reduce fertilizer and irrigation rates while producing crops of similar or superior quality to conventionally grown containerized crops.

Clinical characteristics and outcomes of bullous pemphigoid patients with versus without oral prednisolone treatment.

Bullous pemphigoid (BP) varies in severity and stratified treatments are needed. However, there are no definitive standards for choosing appropriate treatments. To elucidate the factors involved in choosing treatments and the clinical outcomes of BP, we retrospectively reviewed the clinical records of 78 BP patients at a single center. Of the 78 patients, 49 (62.8%) were treated with oral prednisolone (PSL) and 29 (37.2%) were treated without PSL. The patients with older age, lower Bullous Pemphigoid Disease Area Index (BPDAI), and/or lower anti-BP180NC16a antibody titer at onset tended to be treated without oral PSL. Notably, only 9.1% patients without PSL experienced relapse, whereas 36.7% patients with oral PSL experienced relapse when the PSL was around 0.1mg/kg. It suggests that the patients with mild disease severity could be well controlled without oral PSL. Receiver-operator curve analysis demonstrated that the cut-off value for the use of oral PSL was 31 for total BPDAI and was 7 for BPDAI skin urticaria/erythema, with a high (>0.9) area under the curve. Notably, none of the patients who were negative for the anti-BP180NC16a antibody at onset experienced relapse even though they were treated without PSL. In conclusion, in BP patients who were negative for anti-BP180NC16a antibody at onset, with a total BPDAI score of less than 31 or with an urticaria/erythema score of less than 7 can be treated without PSL. When the PSL is tapered to around 0.1mg/kg, we should carefully monitor the patients to detect relapse.

Stratified treatment of fit and unfit acute myeloid leukemia

The etiology and pathogenesis of acute myeloid leukemia (AML) have been elucidated at chromosomal and genetic levels. The classification and prognosis for its treatment has clearly involved specific chromosomal aberrations and genetic mutations. The recent comprehensive genomic analysis represented by next-generation sequencers has led to discovering new genetic mutations in AML. These findings have not only been applied clinically as prognostic factors and MRD markers but also contributed to the development of new molecular-targeting drugs. Many new drugs have already been approved in the USA and Europe, and new stratified treatments have tried to incorporate them. With the advent of venetoclax, treatment strategies, especially for patients with poor prognosis and who are unfit, have been substantially revised, and the maintenance therapy for AML is also being reevaluated in accordance to the National Comprehensive Cancer Network guidelines. This article will review the current status of AML treatment in Japan and according to Western guidelines.

Deep phenotyping of synovial molecular signatures by integrative systems analysis in rheumatoid arthritis.

RA encompasses a complex, heterogeneous and dynamic group of diseases arising from molecular and cellular perturbations of synovial tissues. The aim of this study was to decipher this complexity using an integrative systems approach and provide novel insights for designing stratified treatments. An RNA sequencing dataset of synovial tissues from 152 RA patients and 28 normal controls was imported and subjected to filtration of differentially expressed genes, functional enrichment and network analysis, non-negative matrix factorization, and key driver analysis. A naïve Bayes classifier was applied to the independent datasets to investigate the factors associated with treatment outcome. A matrix of 1241 upregulated differentially expressed genes from RA samples was classified into three subtypes (C1-C3) with distinct molecular and cellular signatures. C3 with prominent immune cells and proinflammatory signatures had a stronger association with the presence of ACPA and showed a better therapeutic response than C1 and C2, which were enriched with neutrophil and fibroblast signatures, respectively. C2 was more occupied by synovial fibroblasts of destructive phenotype and carried highly expressed key effector molecules of invasion and osteoclastogenesis. CXCR2, JAK3, FYN and LYN were identified as key driver genes in C1 and C3. HDAC, JUN, NFKB1, TNF and TP53 were key regulators modulating fibroblast aggressiveness in C2. Deep phenotyping of synovial heterogeneity captured comprehensive and discrete pathophysiological attributes of RA regarding clinical features and treatment response. This result could serve as a template for future studies to design stratified approaches for RA patients.

Feasibility study of using high-throughput drug sensitivity testing to target recurrent glioblastoma stem cells for individualized treatment

BackgroundDespite the well described heterogeneity in glioblastoma (GBM), treatment is standardized, and clinical trials investigate treatment effects at population level. Genomics-driven oncology for stratified treatments allow clinical decision making in only a small minority of screened patients. Addressing tumor heterogeneity, we aimed to establish a clinical translational protocol in recurrent GBM (recGBM) utilizing autologous glioblastoma stem cell (GSC) cultures and automated high-throughput drug sensitivity and resistance testing (DSRT) for individualized treatment within the time available for clinical application.ResultsFrom ten patients undergoing surgery for recGBM, we established individual cell cultures and characterized the GSCs by functional assays. 7/10 GSC cultures could be serially expanded. The individual GSCs displayed intertumoral differences in their proliferative capacity, expression of stem cell markers and variation in their in vitro and in vivo morphology. We defined a time frame of 10 weeks from surgery to complete the entire pre-clinical work-up; establish individualized GSC cultures, evaluate drug sensitivity patterns of 525 anticancer drugs, and identify options for individualized treatment. Within the time frame for clinical translation 5/7 cultures reached sufficient cell yield for complete drug screening. The DSRT revealed significant intertumoral heterogeneity to anticancer drugs (p < 0.0001). Using curated reference databases of drug sensitivity in GBM and healthy bone marrow cells, we identified individualized treatment options in all patients. Individualized treatment options could be selected from FDA-approved drugs from a variety of different drug classes in all cases.ConclusionsIn recGBM, GSC cultures could successfully be established in the majority of patients. The individual cultures displayed intertumoral heterogeneity in their in vitro and in vivo behavior. Within a time frame for clinical application, we could perform DSRT in 50% of recGBM patients. The DSRT revealed a remarkable intertumoral heterogeneity in sensitivity to anticancer drugs in recGBM that could allow tailored therapeutic options for functional precision medicine.

SLAP TEARS IN THE PEDIATRIC PATIENT: WHO IS TREATING THEM AND WHERE?

BACKGROUND: Although rare in comparison to adult cohorts, superior labral anterior to posterior (SLAP) tears do occur in children and adolescents. Previous publications have focused on the varied surgical treatments of SLAP tears in pediatric hospitals but have not stratified treatments by surgeon training or hospital setting. The objective of this study is to evaluate the demographics of patients under the age of 18 undergoing SLAP surgery as well as to evaluate the influence of hospital setting (hospital self-designation as pediatric vs. non-pediatric) and the trends of treatment choice (debridement versus repair) over a period of time. METHODS: The California statewide outpatient database (OSHPD) was queried for all patients under 18 years old who underwent a SLAP debridement or repair in the state of California between 2008 and 2016. The effect of age, hospital setting (pediatric versus adult hospital), gender, insurance type, race, and year of service were assessed using logistic regression. RESULTS: A total of 1,349 patients under age 18 years underwent surgery for a SLAP tear between 2008 and 2016. SLAP repair was performed in 83.8% of patients while SLAP debridement was performed in 16.2% of patients. 80.9% of patients were treated at non-children’s hospitals and 19.1% were treated at children’s hospitals. At non-children’s hospitals, 161 (14.7%) had SLAP debridement and 931 (85.3%) had SLAP repair. At children’s hospitals, 57 patients (22.2%) had SLAP debridement and 200 (77.8%) had SLAP repair. The odds of having a SLAP repair over SLAP debridement decreases by a factor of .58 (p &lt; 0.01) when patients have surgery at a children’s hospital versus at a non-children’s hospital. Age, gender, race, and insurance type were not statistically significant in predicting whether patients underwent SLAP repair versus debridement. Analysis of each individual year of service over the study period from 2008 to 2016 revealed the odds of having a SLAP repair over debridement increased each year by a factor of 1.1 (p &lt; 0.001). CONCLUSIONS: The majority of surgeries treating SLAP tears in patients under the age of 18 are performed in non-pediatric hospitals. However, previous literature reporting on outcomes of SLAP surgery on patients under 18 is based in tertiary care pediatric centers,, which is likely not representative of this patient population. We hypothesize that this discrepancy may be due to shoulder surgeries more often being performed by sports medicine trained orthopedic surgeons who are not tied to operating in pediatric hospitals. Further, the yearly increased rate of SLAP repair over debridement is likely due to the prevailing knowledge in the orthopedic sports literature that repair is preferable to debridement in younger patients.

The Syndrome We Agreed to Call Bronchiolitis.

We are ignoring evidence suggesting that the diagnosis of bronchiolitis encompasses several diseases with distinct underlying mechanisms, considerable heterogeneity in treatment responses, and ultimately different therapeutic targets. Understanding this heterogeneity may be the only way to deliver appropriate, stratified treatments.

Childhood Asthma: Advances Using Machine Learning and Mechanistic Studies.

A paradigm shift brought by the recognition that childhood asthma is an aggregated diagnosis that comprises several different endotypes underpinned by different pathophysiology, coupled with advances in understanding potentially important causal mechanisms, offers a real opportunity for a step change to reduce the burden of the disease on individual children, families, and society. Data-driven methodologies facilitate the discovery of "hidden" structures within "big healthcare data" to help generate new hypotheses. These findings can be translated into clinical practice by linking discovered "phenotypes" to specific mechanisms and clinical presentations. Epidemiological studies have provided important clues about mechanistic avenues that should be pursued to identify interventions to prevent the development or alter the natural history of asthma-related diseases. Findings from cohort studies followed by mechanistic studies in humans and in neonatal mouse models provided evidence that environments such as traditional farming may offer protection by modulating innate immune responses and that impaired innate immunity may increase susceptibility. The key question of which component of these exposures can be translated into interventions requires confirmation. Increasing mechanistic evidence is demonstrating that shaping the microbiome in early life may modulate immune function to confer protection. Iterative dialogue and continuous interaction between experts with different but complementary skill sets, including data scientists who generate information about the hidden structures within "big data" assets, and medical professionals, epidemiologists, basic scientists, and geneticists who provide critical clinical and mechanistic insights about the mechanisms underpinning the architecture of the heterogeneity, are keys to delivering mechanism-based stratified treatments and prevention.

Semantic and Phonemic Verbal Fluency Performance in Patients with General Anxiety Disorders and Allostatic Load under Alprazolam Treatment

Purpose: Anxiety disorders are frequently associated with chronic stress with possible cognitive consequences. The aim of this study was to determine the verbal fluency performance in a cohort of patients with anxiety disorders and allostatic load, treated with alprazolam during 12 weeks. Methods: Patients with GAD (general anxiety disorders, DSM IV), with >6 in Hamilton Anxiety Rating Scale (HAM-A), neuroticism > 18 (NEO-FFI inventory), and normal Mini-Mental State Examination were included. Clinical and Psychiatric examination, Allostatic Load Index and cognitive assessment were analyzed before and after 12 weeks of treatment. The phonemic and semantic verbal fluency tests were determined in all patients. The scoring for each fluency task was determined by counting the number of correct words. The total score from each semantic and phonemic verbal task was analyzed comparing the individual score with normal data controlled by age and sex. Patients with scores > ?2 standard deviation (SD) from normative data were considered impaired. Results: Fifty-four patients completed the semantic verbal fluency test before treatment and fifty patients completed after treatment. According to the z-scores before treatment 7 patients of 54 (12.9%) had verbal fluency impairments. After treatment none patients showed semantic verbal fluency deficits but 3 patients of 50 (6%) showed phonemic impairments. Impaired group was significantly associated with an older age before treatment (p = 0.033) and with a similar tendency but not significant (p = 0.09) after treatment (Student t test). Conclusion: In this study older age factor was associated with verbal fluency impairment in GAD patients. Stratified treatments analyzing age and sex factors, including allostatic load measurements and cognitive assessments may be useful tools to determine the effectiveness and the safety of psychopharmacological treatments.