Health care services utilization in patients with ovarian cancer receiving PARP inhibitor maintenance treatment in a US community oncology setting.

OBJECTIVES: The objective of this study was to describe healthcare resource use (HCRU) in addition to treatment patterns and discontinuations, in patients with ovarian cancer (OC) initiating PARP inhibitor (PARPi) maintenance treatment in a US community oncology setting. METHODS: This was a retrospective study of patients with OC initiating PARPi monotherapy maintenance during 01/01/2017 to 06/30/2019 (followed until 12/31/2019). Patients aged ≥18 years at first diagnosis of OC with ≥2 visits within The US Oncology Network were included. Structured and chart review data as well as claims data were used to describe treatment patterns and HCRU. RESULTS: Of the 162 charts reviewed, the median age of patients was 66 years and 80% had stage III or IV disease at diagnosis. In the niraparib, rucaparib and olaparib groups, proportions of patients experiencing dose interruptions were 51%, 50%, and 28%, and discontinuations due to toxicity were 37%, 17% and 15%, respectively. Within the first 6 months, mean numbers of total claims were 43.5, 56.4, and 36.0 in the niraparib, rucaparib, and olaparib groups, and laboratory claims were 13.9, 19.4, and 15.6, respectively. Proportions of patients with hospitalizations (niraparib 40%, rucaparib 32%, olaparib 19%; p = 0.03), also differed as did emergency department visits (niraparib 37%, rucaparib 23%, olaparib 16%; p = 0.02). CONCLUSION: Despite patients initiating niraparib having higher rates of dose management events and toxicity-related discontinuations, outpatient and laboratory utilization were similar across all three PARPi. Adequate monitoring of these medications, with differing toxicities, should be emphasized to potentially decrease dose reductions and toxicities.

Recurrence rates in patients with HER2+ breast cancer who achieved a pathological complete response after neoadjuvant pertuzumab plus trastuzumab followed by adjuvant trastuzumab: a real-world evidence study.

PURPOSE: This study assessed real-world risk of invasive disease recurrence (IDR) and associated factors in patients with human epidermal growth factor receptor-2 positive (HER2+) early breast cancer (BC) with pathological complete responses (pCR) after neoadjuvant pertuzumab plus trastuzumab (nPT) plus chemotherapy, followed by adjuvant trastuzumab (aT). METHODS: Patients with HER2+ BC with pCR after nPT from 2013 to 2015 who received aT were identified in the US Oncology Network and followed until IDR or censoring. Kaplan-Meier and Cox regression methods were used to assess invasive disease-free survival (iDFS) and correlation between iDFS and patient characteristics. RESULTS: A total of 217 pCR patients' charts were reviewed; median age was 52 years. Most had stage IIA or IIB disease (62%), Eastern Cooperative Oncology Group performance status (ECOG PS) ≤ 1 (84%), tumor size > 2 cm (75%), positive nodes (N+, 62%) and negative estrogen and progesterone receptor (ER- and PR-) expression (52%). Four-year iDFS rates were 90.0% overall (95% CI 84.6%, 93.6%), 86.2% for the N+ cohort and 96.0% for the N- cohort. Cox regression suggested that age, body mass index, ECOG PS, N+ status, stage T3 or T4, and ER+ or PR+ status were risk factors for IDR but were not statistically significant. CONCLUSIONS: Consistent with previous studies, this real-world study observed that patients with HER2+ BC showing pCR with nPT remain at risk for IDR, especially with node-positive disease at diagnosis. Alternatives to adjuvant trastuzumab alone, including combined trastuzumab and pertuzumab, should be considered to improve outcomes for initially N+ patients showing pCR with nPT.

Interpretable multimodal deep learning for real-time pan-tissue pan-disease pathology search on social media.

Pathologists are responsible for rapidly providing a diagnosis on critical health issues. Challenging cases benefit from additional opinions of pathologist colleagues. In addition to on-site colleagues, there is an active worldwide community of pathologists on social media for complementary opinions. Such access to pathologists worldwide has the capacity to improve diagnostic accuracy and generate broader consensus on next steps in patient care. From Twitter we curate 13,626 images from 6,351 tweets from 25 pathologists from 13 countries. We supplement the Twitter data with 113,161 images from 1,074,484 PubMed articles. We develop machine learning and deep learning models to (i) accurately identify histopathology stains, (ii) discriminate between tissues, and (iii) differentiate disease states. Area Under Receiver Operating Characteristic (AUROC) is 0.805-0.996 for these tasks. We repurpose the disease classifier to search for similar disease states given an image and clinical covariates. We report precision@k = 1 = 0.7618 ± 0.0018 (chance 0.397 ± 0.004, mean ±stdev ). The classifiers find that texture and tissue are important clinico-visual features of disease. Deep features trained only on natural images (e.g., cats and dogs) substantially improved search performance, while pathology-specific deep features and cell nuclei features further improved search to a lesser extent. We implement a social media bot (@pathobot on Twitter) to use the trained classifiers to aid pathologists in obtaining real-time feedback on challenging cases. If a social media post containing pathology text and images mentions the bot, the bot generates quantitative predictions of disease state (normal/artifact/infection/injury/nontumor, preneoplastic/benign/low-grade-malignant-potential, or malignant) and lists similar cases across social media and PubMed. Our project has become a globally distributed expert system that facilitates pathological diagnosis and brings expertise to underserved regions or hospitals with less expertise in a particular disease. This is the first pan-tissue pan-disease (i.e., from infection to malignancy) method for prediction and search on social media, and the first pathology study prospectively tested in public on social media. We will share data through http://pathobotology.org . We expect our project to cultivate a more connected world of physicians and improve patient care worldwide.

Isolation and next generation sequencing of archival formalin-fixed DNA.

DNA from archived organs is presumed unsuitable for genomic studies because of excessive formalin-fixation. As next generation sequencing (NGS) requires short DNA fragments, and Uracil-N-glycosylase (UNG) can be used to overcome deamination, there has been renewed interest in the possibility of genomic studies using these collections. We describe a novel method of DNA extraction capable of providing PCR amplicons of at least 400 bp length from such excessively formalin-fixed human tissues. When compared with a leading commercial formalin-fixed DNA extraction kit, our method produced greater yields of DNA and reduced sequence variations. Analysis of PCR products using bacterial sub-cloning and Sanger sequencing from UNG-treated DNA unexpectedly revealed increased sequence variations, compared with untreated samples. Finally, whole exome NGS was performed on a myocardial sample fixed in formalin for 2 years and compared with lymphocyte-derived DNA (as a gold standard) from the same patient. Despite the reduction in the number and quality of reads in the formalin-fixed DNA, we were able to show that bioinformatic processing by joint calling and variant quality score recalibration (VQSR) increased the sensitivity four-fold to 56% and doubled specificity to 68% when compared with a standard hard-filtering approach. Thus, high-quality DNA can be extracted from excessively formalin-fixed tissues and bioinformatic processing can optimise sensitivity and specificity of results. Sequencing of several sub-cloned amplicons is an important methodological step in assessing DNA quality.

Healthcare utilization and costs for patients initiating Dabigatran or Warfarin.

BACKGROUND: Novel oral anticoagulants (NOAC) such as dabigatran, when compared to warfarin, have been shown to potentially reduce the risk of stroke in patients with non-valvular atrial fibrillation (NVAF) together with lower healthcare resource utilization (HCRU) and similar total costs. This study expands on previous work by comparing HCRU and costs for patients newly diagnosed with NVAF and newly initiated on dabigatran or warfarin, and is the first study specifically in a Medicare population. METHODS: A retrospective matched-cohort study was conducted using data from administrative health care claims during the study period 01/01/2010-12/31/2012. Cox regression analyses were used to compare all-cause risk of first hospitalizations and emergency room (ER) visits. Medical, pharmacy, and total costs per-patient-per-month (PPPM) were compared between dabigatran and warfarin users. RESULTS: A total of 1110 patients initiated on dabigatran were propensity score-matched with corresponding patients initiated on warfarin. The mean number of hospitalizations (0.92 vs. 1.13, P = 0.012), ER visits (1.32 vs. 1.56, P < 0.01), office visits (21.43 vs. 29.41; P < 0.01), and outpatient visits (10.86 vs. 22.02; P < 0.01) were lower among dabigatran compared to warfarin users. Patients initiated on dabigatran had significantly lower risk of first all-cause ER visits [hazard ratio (HR): 0.84, 95% confidence interval (CI): 0.73-0.98] compared to those initiated on warfarin. Adjusted mean pharmacy costs PPPM were significantly greater for dabigatran users ($510 vs. $250, P < 0.001); however, mean medical costs PPPM ($1912 vs. $1956, P = 0.55) and mean total costs PPPM ($2381 vs. $2183, P = 0.10) were not significantly different compared to warfarin users. CONCLUSIONS: Dabigatran users had significantly lower HCRU compared to warfarin users. In addition, dabigatran users had lower risk of all-cause ER visits. Despite higher pharmacy costs, the two cohorts did not differ significantly in medical or total all-cause costs.

Outcomes for pembrolizumab stratified by pemetrexed maintenance post pembrolizumab-platinum-pemetrexed induction in metastatic non-small-cell lung cancer.

Aim: We assessed treatment patterns and outcomes in patients with metastatic nonsquamous non-small-cell lung cancer (mNSCLC) who initiated first-line pembrolizumab-platinum-pemetrexed (induction) in US community oncology settings. Methods: Patients initiating induction were retrospectively identified. Patients continuing pembrolizumab afterward underwent chart review. Clinical outcomes were described by maintenance pemetrexed exposure after inverse probability of treatment weighting (IPTW). Results: Median induction pembrolizumab and pemetrexed durations were 5.1 and 4.2 months. Among patients continuing pembrolizumab after induction, 64% received maintenance pemetrexed. Common discontinuation reasons for induction pemetrexed were completion of planned therapy (79%) and partial response (68%) and progressive disease (38%) and toxicity (29%) for maintenance pemetrexed. After IPTW, median overall survival and real-world progression-free survival were longer in patients continuing pembrolizumab with versus without maintenance pemetrexed (20.3 vs 12.0 months and 10.3 vs 5.8 months, respectively). Conclusion: Patient characteristics and planned treatment decisions affect maintenance pemetrexed utilization in the community oncology setting.

What is this summary about? Pembrolizumab is a drug that helps the lung cancer patient's immune system fight the cancer, even after the cancer has spread, or metastasized. After the patient gets better, the patient is treated with chemotherapy so the cancer will not come back. This is called 'maintenance treatment'. In KEYNOTE-189, a clinical trial, patients lived longer if they had pembrolizumab added to pemetrexed and platinum, which are chemotherapy drugs. If patients had maintenance treatment with pembrolizumab and pemetrexed, they also lived longer. However, do patients in community practices get those treatments? What were the results? We found that at cancer practices in the community instead of clinical trials, not all patients received pemetrexed in maintenance treatment. Many had finished their planned therapy and their tumors had shrunk. Also, some physicians chose not to give their patients pemetrexed. In addition, some women and some older and sicker patients did not get pemetrexed. Some patients had pemetrexed in maintenance but stopped because their cancer grew worse or because they had side effects. Those patients did not live as long as patients who did have maintenance pemetrexed. What do the results mean? Patients with metastatic non-small-cell lung cancer in the community practice do better on the treatments tested in clinical trials. However, certain patients do not get those treatments. The reasons need to be understood, to make sure that those patients get better treatments.

Frontline pembrolizumab monotherapy for metastatic non-small cell lung cancer with PD-L1 expression ≥50%: real-world outcomes in a US community oncology setting.

Background: This study investigated real-world time on treatment (rwToT) and overall survival (OS) for patients with metastatic non-small cell lung cancer (mNSCLC) who initiated first-line (1L) pembrolizumab monotherapy. We also explored discontinuation reasons and subsequent treatments, stratified by number of cycles among those who completed ≥17 cycles of 1L pembrolizumab. Methods: Patients with mNSCLC without actionable genetic aberrations, Eastern Cooperative Oncology Group performance status (ECOG PS) 0-2 and unknown, and PD-L1 TPS ≥ 50% starting 1L pembrolizumab monotherapy between 24-Oct-2016 and 31-Dec-2018 within The US Oncology Network were identified retrospectively and evaluated using structured data, with a data cutoff of 30-Sep-2021. Patient characteristics and disposition were summarized using descriptive statistics. OS and rwToT were evaluated using Kaplan-Meier method for all ECOG PS and PS 0-1. A subgroup of patients who completed ≥17 cycles were evaluated using supplemental chart review data to discern reasons for discontinuation. Results: Of the 505 patients with mNSCLC with PD-L1 TPS ≥50%, 61% had ECOG PS 0-1, 23% had ECOG PS 2, and 65% had nonsquamous histology. Median rwToT and OS of pembrolizumab were 7.0 (95% CI, 6.0-8.4) months and 24.5 (95% CI, 20.1-29.3) months, respectively. In the subgroup with ECOG PS 0-1, they were 7.6 months (95% CI, 6.2-9.2) and 28.8 months (95% CI, 22.4-37.5), respectively. Of the 103 patients who completed ≥17 cycles, 57 (55.3%) patients received 17 - 34 cycles and 46 (44.7%) patients received ≥35 cycles. Approximately 7.7% of the study population received pembrolizumab beyond 35 cycles. Most common reasons for discontinuation were disease progression (38.6%) and toxicity (19.3%) among patients who received 17-34 cycles of pembrolizumab, and disease progression (13.0%) and completion of therapy (10.9%) among patients who received ≥35 cycles. Conclusion: Consistent with findings from KEYNOTE-024 and other real-world studies, this study demonstrates the long-term effectiveness of pembrolizumab monotherapy as 1L treatment for mNSCLC with PD-L1 TPS ≥50%. Among patients who completed ≥17 cycles, nearly half completed ≥35 cycles. Disease progression and toxicity were the most common reasons for discontinuation among patients who received 17-34 cycles of pembrolizumab. Reasons for discontinuation beyond 35 cycles need further exploration.

Characterization of Wnt/ß-catenin signaling in rhabdomyosarcoma.

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children and accounts for about 5% of all malignant paediatric tumours. ß-Catenin, a multifunctional nuclear transcription factor in the canonical Wnt signaling pathway, is active in myogenesis and embryonal somite patterning. Dysregulation of Wnt signaling facilitates tumour invasion and metastasis. This study characterizes Wnt/ß-catenin signaling and functional activity in paediatric embryonal and alveolar RMS. Immunohistochemical assessment of paraffin-embedded tissues from 44 RMS showed ß-catenin expression in 26 cases with cytoplasmic/membranous expression in 9/14 cases of alveolar RMS, and 15/30 cases of embryonal RMS, whereas nuclear expression was only seen in 2 cases of embryonal RMS. The potential functional significance of ß-catenin expression was tested in four RMS cell lines, two derived from embryonal (RD and RD18) RMS and two from alveolar (Rh4 and Rh30) RMS. Western blot analysis demonstrated the expression of Wnt-associated proteins including ß-catenin, glycogen synthase kinase-3ß, disheveled, axin-1, naked, LRP-6 and cadherins in all cell lines. Cell fractionation and immunofluorescence studies of the cell lines (after stimulation by human recombinant Wnt3a) showed reduced phosphorylation of ß-catenin, stabilization of the active cytosolic form and nuclear translocation of ß-catenin. Reporter gene assay demonstrated a T-cell factor/lymphoid-enhancing factor-mediated transactivation in these cells. In response to human recombinant Wnt3a, the alveolar RMS cells showed a significant decrease in proliferation rate and induction of myogenic differentiation (myogenin, MyoD1 and myf5). These data indicate that the central regulatory components of canonical Wnt/ß-catenin signaling are expressed and that this pathway is functionally active in a significant subset of RMS tumours and might represent a novel therapeutic target.

Using D-Amino Acids to Delineate the Mechanism of Protein Folding: Application to Trp-cage.

Using the miniprotein Trp-cage as a model, we show that D-amino acids can be used to facilitate the delineation of protein folding mechanism. Specifically, we study the folding-unfolding kinetics of three Trp-cage mutants where the native glycine residue near the C-terminus of the α-helix is replaced by a D-amino acid. A previous study showed that these mutations increase the Trp-cage stability, due to a terminal capping effect. Our results show that the stabilizing effect of D-asparagine and D-glutamine originates almost exclusively from a decrease in the unfolding rate, while the D-alanine mutation results in a similar decrease in the unfolding rate, but it also increases the folding rate. Together, these results support a folding mechanism wherein the α-helix formation in the transition state is nucleated at the N-terminus, whereas those long-range native interactions stabilizing this helix are developed at the downhill side of the folding free energy barrier.

Temporal changes in treatment patterns by age group and functional status before and after PD-1/L1 inhibitor approvals in advanced urothelial carcinoma.

Introduction: Metastatic urothelial carcinoma (mUC) has poor prognosis. A high unmet need exists for novel treatment for those who are unfit for platinum-based chemotherapy. Methods: We aimed to describe real-world temporal changes in patient characteristics and 1L treatment selection for mUC patients in the United States following the approval of anti-PD-1/L1 treatments. This study was a retrospective, observational study using anonymized and structured oncology electronic medical record (EMR) data from IQVIA and the US Oncology Network iKnowMed (USON). Results: After approval of 1L anti-PD-1/L1 treatment for mUC, there is a marked increase in the use of 1L anti-PD-1/L1 monotherapies, accompanied by a proportional decrease in 1L platinum-based treatments and non-guideline-based therapy; particularly among the elderly (> 75 years) and those with poor ECOG performance status (ECOG PS 2+). Discussion: Anti-PD-1/L1 monotherapies fulfill the prior unmet need of frail mUC patients who are ineligible for platinum-based therapies.

Mosaicism in Hartsfield syndrome.

Hartsfield syndrome is a rare condition characterised by the co-occurrence of ectrodactyly and holoprosencephaly spectrum disorders; cleft lip and palate is a common associated feature. This is due to either monoallelic, or less commonly, biallelic variants in FGFR1 with a loss of function or dominant negative effect. To date 37 individuals have been reported, including two instances of germline mosaicism. We report a further family with Hartsfield syndrome due to a novel variant in FGFR1, with two affected fetuses, and somatic and germline mosaicism in the father detected on Sanger sequencing. The father had not come to medical attention prior to this finding. In light of our findings and those in the published literature, we suggest that mosaicism, either germline or germline and somatic, may be a relatively frequent finding, affecting 3 of 35 (9%) reported families, which has important implications for genetic counselling.

The Left Ventricular Myocardium in Hypoplastic Left Heart Syndrome.

Hypoplastic left heart syndrome (HLHS) is a collective term applied to severe congenital cardiac malformations, characterised by a combination of abnormalities mainly affecting the left ventricle, associated valves, and ascending aorta. Although in clinical practice HLHS is usually sub-categorised based on the patency of the mitral and aortic (left-sided) valves, it is also possible to comprehensively categorise HLHS into defined sub-groups based on the left ventricular morphology. Here, we discuss the published human-based studies of the ventricular myocardium in HLHS, evaluating whether the available evidence is in keeping with this ventricular morphology concept. Specifically, we highlight results from histological studies, indicating that the appearance of cardiomyocytes can be different based on the sub-group of HLHS. In addition, we discuss the histological appearances of endocardial fibroelastosis (EFE), which is a common feature of one specific sub-group of HLHS. Lastly, we suggest investigations that should ideally be undertaken using HLHS myocardial tissues at early stages of HLHS development to identify biological pathways and aid the understanding of HLHS aetiology.

Computational design of thermostabilizing D-amino acid substitutions.

Judicious incorporation of D-amino acids in engineered proteins confers many advantages such as preventing degradation by endogenous proteases and promoting novel structures and functions not accessible to homochiral polypeptides. Glycine to D-alanine substitutions at the carboxy termini can stabilize α-helices by reducing conformational entropy. Beyond alanine, we propose additional side chain effects on the degree of stabilization conferred by D-amino acid substitutions. A detailed, molecular understanding of backbone and side chain interactions is important for developing rational, broadly applicable strategies in using D-amino acids to increase protein thermostability. Insight from structural bioinformatics combined with computational protein design can successfully guide the selection of stabilizing D-amino acid mutations. Substituting a key glycine in the Trp-cage miniprotein with D-Gln dramatically stabilizes the fold without altering the protein backbone. Stabilities of individual substitutions can be understood in terms of the balance of intramolecular forces both at the α-helix C-terminus and throughout the protein.

Treatment patterns and outcomes for patients with newly diagnosed glioblastoma multiforme: a retrospective cohort study.

Aim: Investigate real-world outcomes and healthcare utilization of patients with glioblastoma multiforme (GBM) related to O6-methylguanine DNA methyltransferase (MGMT) promoter testing and methylation. Patients & methods: US Oncology Network data were analyzed for patients receiving first-line (1L) treatment for GBM. Results: Most patients received 1L radiation with temozolomide. Unadjusted median overall survival (OS) was higher in tested versus untested (median:18.1 vs 11.8 months) and in methylated versus unmethylated (median: 25.5 vs 12.4 months). Untested status, unmethylated MGMT and older age were associated with reduced OS and longer 1L treatment with increased OS. Similar findings were observed for progression-free survival. Utilization was similar between cohorts. Conclusion: In community oncology practices, MGMT methylation and testing were predictive of better survival in GBM.

Lay abstract We studied the characteristics and survival of patients with newly diagnosed glioblastoma multiforme (GBM) in community-based oncology practices. These patients had received temozolomide and radiotherapy with surgery, which is the standard of care for GBM. We were interested in how patient survival was related to methylation of the O⁶-methylguanine DNA methyltransferase (MGMT) promoter. The study showed that patients with methylated versus unmethylated MGMT GBM survived longer. However, patients who were tested for methylation, whether MGMT was methylated or not, also survived longer. This may be because patients who get tested also get better care in general.

Health care resource utilization among patients with T2D and cardiovascular-, heart failure-, or renal-related hospitalizations.

OBJECTIVES: In patients with type 2 diabetes (T2D), comorbidity-related hospitalizations can have significant impact on longitudinal care. This study aimed to estimate incremental all-cause health care resource utilization (HCRU) and costs between patients with T2D who experienced cardiovascular (CV)-, heart failure (HF)-, or renal-related hospitalizations vs those who did not. STUDY DESIGN: This was a retrospective cohort study using data from a large national health plan. METHODS: Patients with T2D aged 18 to 90 years with CV, HF, or renal hospitalizations were identified from the Humana claims database from October 1, 2009, to September 30, 2015, and separated into CV, HF, and renal cohorts. Patients had 12 months of continuous enrollment prior to the date of first hospitalization (index) and were followed for up to 12 months. Per-patient per-month (PPPM) all-cause HCRU and costs for hospitalized patients were compared with those of no-CV, no-HF, and no-renal cohorts. Differences in baseline characteristics between cohorts were controlled for using generalized linear models. RESULTS: A total of 221,229, 68,126, and 120,105 patients were included in the CV, HF, and renal cohorts, respectively; these patients were older and had higher Deyo-Charlson Comorbidity Index scores than patients in the no-CV, no-HF, and no-renal cohorts. Adjusted for baseline covariates, they had higher mean PPPM inpatient stays, outpatient visits, emergency department visits, and total health care costs. CONCLUSIONS: Among patients with T2D, concurrent CV, HF, or renal events present significant disease burden leading to poor quality of life. This information can be used to guide disease management strategies and interventions aimed at reducing comorbidity-related hospitalizations and health care costs, thus providing improved quality of life for these patients.

New insights into risk factors for transplant-associated thrombotic microangiopathy in pediatric HSCT.

This study aimed to identify a risk profile for development of transplant-associated thrombotic microangiopathy (TA-TMA) in children undergoing hematopoietic stem cell transplantation (HSCT). Between 2013 and 2016, 439 children underwent 474 HSCTs at 2 supraregional United Kingdom centers. At a median of 153 days post-HSCT, TA-TMA occurred among 25 of 441 evaluable cases (5.6%) with no evidence of center variation. Sex, underlying disease, intensity of the conditioning, total body irradiation-based conditioning, the use of calcineurin inhibitors, venoocclusive disease, and viral reactivation did not influence the development of TA-TMA. Donor type: matched sibling donor/matched family donor vs matched unrelated donor vs mismatched unrelated donor/haplo-HSCT, showed a trend toward the development of TA-TMA in 1.8% vs 6.1% vs 8.3%, respectively. Presence of active comorbidity was associated with an increased risk for TA-TMA; 13% vs 3.7% in the absence of comorbidity. The risk of TA-TMA was threefold higher among patients who received >1 transplant. TA-TMA rates were significantly higher among patients with acute graft-versus-host disease (aGVHD) grades III to IV vs aGVHD grade 0 to II. On multivariate analysis, the presence of active comorbidity, >1 transplant, aGVHD grade III to IV were risk factors for TA-TMA (odds ratio [OR]: 5.1, 5.2, and 26.9; respectively), whereas the use of cyclosporine A/tacrolimus-based GVHD prophylaxis was not a risk factor for TA-TMA (OR: 0.3). Active comorbidity, subsequent transplant, and aGVHD grades III to IV were significant risk factors for TA-TMA. TA-TMA might represent a form of a vascular GVHD, and therefore, continuing control of aGVHD is important to prevent worsening of TA-TMA associated with GVHD.

Mirrors in the PDB: left-handed alpha-turns guide design with D-amino acids.

BACKGROUND: Incorporating variable amino acid stereochemistry in molecular design has the potential to improve existing protein stability and create new topologies inaccessible to homochiral molecules. The Protein Data Bank has been a reliable, rich source of information on molecular interactions and their role in protein stability and structure. D-amino acids rarely occur naturally, making it difficult to infer general rules for how they would be tolerated in proteins through an analysis of existing protein structures. However, protein elements containing short left-handed turns and helices turn out to contain useful information. Molecular mechanisms used in proteins to stabilize left-handed elements by L-amino acids are structurally enantiomeric to potential synthetic strategies for stabilizing right-handed elements with D-amino acids. RESULTS: Propensities for amino acids to occur in contiguous alpha(L) helices correlate with published thermodynamic scales for incorporation of D-amino acids into alpha(R) helices. Two backbone rules for terminating a left-handed helix are found: an alpha(R) conformation is disfavored at the amino terminus, and a beta(R) conformation is disfavored at the carboxy terminus. Helix capping sidechain-backbone interactions are found which are unique to alpha(L) helices including an elevated propensity for L-Asn, and L-Thr at the amino terminus and L-Gln, L-Thr and L-Ser at the carboxy terminus. CONCLUSION: By examining left-handed alpha-turns containing L-amino acids, new interaction motifs for incorporating D-amino acids into right-handed alpha-helices are identified. These will provide a basis for de novo design of novel heterochiral protein folds.

Spirometry evaluation to assess performance of a claims-based predictive model identifying patients with undiagnosed COPD.

BACKGROUND: A claims-based model to predict patients likely to have undiagnosed COPD was developed by Moretz et al in 2015. This study aims to assess the performance of the aforementioned model using prospectively collected spirometry data. METHODS: A study population aged 40-89 years enrolled in a Medicare Advantage plan with prescription drug coverage or commercial health plan and without a claim for COPD diagnosis was identified from April 1, 2012 to March 31, 2016 in the Humana claims database. This population was stratified into subjects likely or unlikely to have undiagnosed COPD using the claims-based predictive model. Subjects were randomly selected for spirometry evaluation of FEV1 and FVC. The predictive model was validated using airflow limitation ratio (FEV1/FVC <0.70). RESULTS: A total of 218 subjects classified by the predictive model as likely and 331 not likely to have undiagnosed COPD completed spirometry evaluation. Those predicted to have undiagnosed COPD had a higher mean age (70.2 vs 67.9 years, P=0.0012) and a lower mean FEV1/FVC ratio (0.724 vs 0.753, P=0.0002) compared to those predicted not to have undiagnosed COPD. Performance metrics for the predictive model were: area under the curve =0.61, sensitivity =52.5%, specificity =64.6%, positive predictive value =33.5%, and negative predictive value =80.1%. CONCLUSION: The claims-based predictive model identifies those not at risk of having COPD eight out of ten times, and those who are likely to have COPD one out of three times.

Development and validation of a predictive model to identify patients at risk of severe COPD exacerbations using administrative claims data.

Background: Patients with COPD often experience severe exacerbations involving hospitalization, which accelerate lung function decline and reduce quality of life. This study aimed to develop and validate a predictive model to identify patients at risk of developing severe COPD exacerbations using administrative claims data, to facilitate appropriate disease management programs. Methods: A predictive model was developed using a retrospective cohort of COPD patients aged 55-89 years identified between July 1, 2010 and June 30, 2013 using Humana's claims data. The baseline period was 12 months postdiagnosis, and the prediction period covered months 12-24. Patients with and without severe exacerbations in the prediction period were compared to identify characteristics associated with severe COPD exacerbations. Models were developed using stepwise logistic regression, and a final model was chosen to optimize sensitivity, specificity, positive predictive value (PPV), and negative PV (NPV). Results: Of 45,722 patients, 5,317 had severe exacerbations in the prediction period. Patients with severe exacerbations had significantly higher comorbidity burden, use of respiratory medications, and tobacco-cessation counseling compared to those without severe exacerbations in the baseline period. The predictive model included 29 variables that were significantly associated with severe exacerbations. The strongest predictors were prior severe exacerbations and higher Deyo-Charlson comorbidity score (OR 1.50 and 1.47, respectively). The best-performing predictive model had an area under the curve of 0.77. A receiver operating characteristic cutoff of 0.4 was chosen to optimize PPV, and the model had sensitivity of 17%, specificity of 98%, PPV of 48%, and NPV of 90%. Conclusion: This study found that of every two patients identified by the predictive model to be at risk of severe exacerbation, one patient may have a severe exacerbation. Once at-risk patients are identified, appropriate maintenance medication, implementation of disease-management programs, and education may prevent future exacerbations.

Factors influencing dabigatran or warfarin medication persistence in patients with nonvalvular atrial fibrillation.

Factors influencing differences in persistence between dabigatran and warfarin in patients with nonvalvular atrial fibrillation (NVAF) remain unclear. AIM: Compare differences in persistence between new dabigatran and warfarin users in patients newly diagnosed with NVAF, adjusting for sociodemographics, clinical characteristics, patient out-of-pocket cost and other covariates. METHODS: A retrospective matched-cohort study was conducted using a US claims database of Medicare and commercially insured patients with NVAF aged≥ 18 years. Persistence and monthly out-of-pocket costs for dabigatran or warfarin were calculated and adjusted for covariates using Cox proportional hazard models. RESULTS & CONCLUSION: Unadjusted persistence was significantly lower among dabigatran users (n = 1025) compared with matched warfarin users (38 vs 46%). Adjusting for covariates rendered this difference insignificant (hazard ratio = 0.930).