Citations

AbstractUtility of adjuvant chemotherapy for stage II cancer remains a matter of debate. Clinical guidelines suggest adjuvant chemotherapy for stage II tumors with high‐risk features, in particular T4 tumors. However, limited consensus exists regarding the importance of other high‐risk features (lymphovascular or perineural invasion, microsatellite instability). Our study aimed to investigate the impact of adjuvant chemotherapy for stage IIA (T3N0) colon cancer patients. Patients who underwent colectomy for stage IIA colon adenocarcinoma (2010‐2015) were identified in the National Cancer Database (NCDB) and divided in two groups based on receipt of adjuvant chemotherapy vs observation. Inverse probability of treatment weighting (IPTW)‐adjusted Kaplan‐Meier and Cox proportional hazards regression analyses were performed to compare overall survival between the two groups. Subgroup analysis of patients with specific high‐risk features LVI, PNI and MSI was performed. Among 46 688 surgical patients with stage IIA colon adenocarcinoma 5937 (12.7%) received adjuvant chemotherapy, while 40 751 (87.3%) were observed. Five‐year IPTW‐adjusted survival was higher in the adjuvant chemotherapy group (79.7% [95% CI 79.1, 80.2]) compared to the observation group (70.3% [95% CI 69.7, 70.9]). Patients with high‐risk pathological features showed an estimated 5‐year survival benefit of 11.3% (78.2% [95% CI 77.4, 79.1] vs 66.9% [95% CI 65.9, 67.8]) when treated with adjuvant chemotherapy. This NCDB analysis revealed a survival benefit for patients with stage IIA colon adenocarcinoma and high‐risk features that were treated with adjuvant chemotherapy.

BACKGROUND: Hospital readmission rate is an important quality metric and has been recognized as a key measure of hospital value-based purchasing programs. OBJECTIVE: This study aimed to assess the risk factors for hospital readmission with a focus on potentially preventable early readmissions within 48 hours of discharge. DESIGN: This is a retrospective cohort study. SETTINGS: This study was conducted at a tertiary academic facility with a standardized enhanced recovery pathway. PATIENTS: Consecutive patients undergoing elective major colorectal resections between 2011 and 2016 were included. MAIN OUTCOME MEASURES: Univariable and multivariable risk factors for overall and early (<48 hours) readmissions were identified. Specific surgical and medical reasons for readmission were compared between early and late readmissions. RESULTS: In total, 526 of 4204 patients (12.5%) were readmitted within 30 days of discharge. Independent risk factors were ASA score (≥3; OR, 1.5; 95% CI, 1.1–2), excess perioperative weight gain (OR, 1.7; 95% CI, 1.3–2.3), ileostomy (OR, 1.4; 95% CI, 1–2), and transfusion (OR, 2; 95% CI, 1.4–3), or reoperation (OR, 11.4; 95% CI, 7.4–17.5) during the index stay. No potentially preventable risk factor for early readmission (128 patients, 24.3% of all readmissions, 3% of total cohort) was identified, and index hospital stay of ≤3 days was not associated with increased readmission (OR, 0.9; 95% CI, 0.7–1.2). Although ileus and small-bowel obstruction (early: 43.8% vs late: 15.5%, p < 0.001) were leading causes for early readmissions, deep infections (3.9% vs 16.3%, p < 0.001) and acute kidney injury (0% vs 5%, p = 0.006) were mainly observed during readmissions after 48 hours. LIMITATIONS: Risk of underreporting due to loss of follow-up and the potential co-occurrence of complications were limitations of this study. CONCLUSIONS: Early hospital readmission was mainly due to ileus or bowel obstruction, whereas late readmissions were related to deep infections and acute kidney injury. A suspicious attitude toward potential ileus-related symptoms before discharge and dedicated education for ostomy patients are important. A short index hospital stay was not associated with increased readmission rates. See Video Abstract at http://links.lww.com/DCR/B237. REINGRESOS DENTRO DE LAS 48 HORAS POSTERIORES AL ALTA: RAZONES, FACTORES DE RIESGO Y POSIBLES MEJORAS ANTECEDENTES: La tasa de reingreso hospitalario es una métrica de calidad importante y ha sido reconocida como una medida clave de los programas hospitalarios de compras basadas en el valor. OBJETIVO: Evaluar los factores de riesgo para el reingreso hospitalario con énfasis en reingresos tempranos potencialmente prevenibles dentro de las 48 horas posteriores al alta. DISEÑO: Estudio de cohorte retrospectivo. ESCENARIO: Institución académica terciaria con programa de recuperación mejorada estandarizado. PACIENTES: Pacientes consecutivos sometidos a resecciones colorrectales mayores electivas entre 2011 y 2016. PRINCIPALES MEDIDAS DE RESULTADO: Se identificaron factores de riesgo uni y multivariables para reingresos totales y tempranos (<48 horas). Se compararon razones médicas y quirúrgicas específicas para el reingreso entre reingresos tempranos y tardíos. RESULTADOS: En total, 526/4204 pacientes (12,5%) fueron readmitidos dentro de los 30 días posteriores al alta. Los factores de riesgo independientes fueron puntuación ASA (≥3, OR 1.5; IC 95% 1.1–2), aumento de peso perioperatorio excesivo (OR 1.7; IC 95% 1.3–2.3), ileostomía (OR 1.4, IC 95%: 1–2) y transfusión (OR 2, IC 95% 1.4–3) o reoperación (OR 11.4; IC 95% 7.4–17.5) durante la estadía índice. No se identificó ningún factor de riesgo potencialmente prevenible para el reingreso temprano (128 pacientes, 24.3% de todos los reingresos, 3% de la cohorte total), y la estadía hospitalaria índice de ≤ 3 días no se asoció con un aumento en el reingreso (OR 0.9; IC 95% 0.7–1.2) Mientras que el íleo / obstrucción del intestino delgado (temprano: 43.8% vs. tardío: 15.5%, p < 0.001) fueron las principales causas de reingresos tempranos, infecciones profundas (3.9% vs 16.3%, p < 0.001) y lesión renal aguda (0 vs 5%, p = 0.006) se observaron principalmente durante los reingresos después de 48 horas. LIMITACIONES: Riesgo de subregistro debido a la pérdida en el seguimiento, posible co-ocurrencia de complicaciones. CONCLUSIONES: El reingreso hospitalario temprano se debió principalmente a íleo u obstrucción intestinal, mientras que los reingresos tardíos se relacionaron con infecciones profundas y lesión renal aguda. Es importante tener una actitud suspicaz hacia los posibles síntomas relacionados con el íleo antes del alta y una educación específica para los pacientes con ostomía. La estadía hospitalaria índice corta no se asoció con mayores tasas de reingreso. Consulte Video Resumen en http://links.lww.com/DCR/B237.

8020 Background: Patients with R/R DLBCL ineligible for autologous stem cell transplant (ASCT) have a poor prognosis. In these patients, tafasitamab (anti-CD19 antibody) plus lenalidomide (LEN) has shown encouraging results in the open-label, single-arm, phase II L-MIND study (n = 81; NCT02399085). To evaluate the contribution of tafasitamab to the activity of this doublet, we conducted a global, real-world study of patients treated with LEN monotherapy (RE-MIND; NCT04150328). Here we present the primary analysis of a 1:1 patient-level matched comparison between the L-MIND and RE-MIND cohorts. Methods: Patients treated with LEN monotherapy for R/R DLBCL were enrolled in the observational, retrospective RE-MIND cohort. As in L-MIND, patients had 1–3 prior systemic therapies, including ≥1 CD20-targeting regimen; were aged ≥18 years; and were not eligible for ASCT. A 1:1 estimated propensity score (ePS) matching methodology ensured balancing of nine pre-specified baseline covariates. The primary analysis set, Matched Analysis Set 25 (MAS25), included patients who received a LEN starting dose of 25 mg/day. The primary endpoint was investigator-assessed best objective response rate (ORR). Key secondary endpoints included overall survival (OS) and complete response (CR) rate. Results: 490 patients were enrolled in RE-MIND across 58 centers in the US and Europe, of which 140 fulfilled the ePS matching criteria. The MAS25 included 76 patients each from the two cohorts. Baseline characteristics between cohorts were comparable. The primary endpoint was met with a significantly better ORR of 67.1% (95% CI: 55.4–77.5) for the L-MIND cohort versus 34.2% (95% CI: 23.7–46.0) for the RE-MIND cohort (odds ratio 3.89; 95% CI: 1.90–8.14; p < 0.0001). The CR rate was 39.5% (95% CI: 28.4–51.4) in the L-MIND cohort and 13.2% (95% CI: 6.5–22.9) in the RE-MIND cohort. A significant difference in OS favored the L-MIND cohort (HR = 0.499; 95% CI: 0.317–0.785). ORR and CR outcomes in the RE-MIND cohort were similar to the published literature for LEN monotherapy in R/R DLBCL. Conclusions: Significantly better ORR, CR and OS indicate potential synergistic effects of the tafasitamab + LEN combination in ASCT-ineligible R/R DLBCL. ePS-based 1:1 matching allows robust estimation of the treatment effect of tafasitamab when added to LEN. RE-MIND demonstrates the utility of real-world data in interpreting non-randomized trials. Clinical trial information: NCT04150328 .

109 Background: RET gene fusions are targetable oncogenic drivers in multiple tumor types, including up to 20% of papillary thyroid cancers (PTC). Pralsetinib is an investigational, highly potent, selective inhibitor of oncogenic RET alterations. In the registration-enabling Phase 1/2 ARROW study (NCT03037385), pralsetinib demonstrated an overall response rate (ORR; response-evaluable patients [REP], central review) of 73% (19/26) in treatment-naïve patients and 61% (49/80; 2 pending confirmation) in platinum-exposed patients with RET fusion+ non-small cell lung cancer (NSCLC) and was well tolerated (data cut-off November 18, 2019). We provide an update on the clinical activity of pralsetinib in other RET fusion+ solid tumor types. Methods: ARROW consists of a phase 1 dose escalation (30–600 mg once [QD] or twice daily) followed by a phase 2 expansion (400 mg QD) in patients with advanced RET-altered solid tumors. Primary objectives were ORR and safety. Results: As of November 18, 2019, 29 patients with metastatic solid tumor types other than NSCLC (16 PTC, 1 undifferentiated thyroid, 3 pancreatic, 3 colon, 6 other) bearing a RET fusion have received pralsetinib. Efficacy data are presented for REP enrolled by July 11, 2019. In patients with thyroid cancer that is RET fusion+, ORR (investigator assessment) was 75% (9/12; all confirmed). Median (range) duration of response (DOR) was 14.5 (3.7+, 16.8) months (mo), with 67% of responding patients continuing treatment. Two patients with stable disease were continuing treatment at 11.5+ and 19.3+ mo. In other RET fusion+ cancers, ORR was 60% (3/5; all confirmed) with partial responses in 2/2 patients with pancreatic cancer (DOR 5.5, 7.4+ mo) and 1 patient with intrahepatic bile duct carcinoma (DOR 7.5 mo). Two patients with colon cancer had stable disease for 7.3 and 9.3 mo. Responses were observed across multiple fusion genotypes. In the entire safety population (all patients treated with 400 mg QD pralsetinib, regardless of diagnosis; n = 354), most treatment-related adverse events (TRAEs) were grade 1-2, and included increased aspartate aminotransferase (31%), anemia (22%), increased alanine aminotransferase (21%), constipation (21%) and hypertension (20%). Only 4% of patients in the safety population discontinued due to TRAEs. Conclusions: Pralsetinib demonstrated broad and durable antitumor activity across multiple advanced solid tumor types, regardless of RET fusion genotype, and was well tolerated. The study is ongoing and still enrolling patients in this cohort. Clinical trial information: NCT03037385.

Abstract The severe acute respiratory syndrome coronavirus 2 pandemic of 2019 to 2020 has resulted in multiple hospitalizations, deaths, and economic hardships worldwide. Although respiratory involvement in patients with coronavirus disease 2019 ( COVID ‐19) is well known, the potential cardiovascular and cerebrovascular manifestations are less understood. We performed a PubMed and Google Scholar search and reviewed relevant literature on COVID ‐19 and cardiovascular system involvement. Severe acute respiratory syndrome coronavirus 2 possesses high affinity for angiotensin‐converting enzyme 2 receptor, which is highly concentrated in the lungs and cardiovascular tissue, thereby provoking concern for cardiovascular involvement in COVID ‐19 cases. Preexisting cardiovascular and cerebrovascular disease has been shown in previous reports to be a risk factor for severe infection. On the basis of our review of published studies, COVID ‐19 patients may be more likely to experience acute cardiac injury, arrhythmia, coagulation defects, and acute stroke and are likely to have poorer outcomes as a result. As the COVID ‐19 pandemic continues, more data about potential cardiovascular and cerebrovascular manifestations of the disease are required.

Abstract Objective. Several smaller studies on adrenal incidentalomas (AI) suggested an association between autonomous cortisol secretion (ACS) and mortality (Di Dalmazi Lancet Diabetes Endocrinol 2014, Debono J Clin Endocrinol Metab 2014, Patrova Endocrine 2017). However, a recent meta-analysis (9 studies, 1356 patients) could not confirm these findings (Elhassan Ann Intern Med 2019). Aim. To investigate the effects of ACS on mortality, prevalence of cardiovascular (CV) risk factors, and (CV) morbidity, in a representative cohort of AI. Design. Retrospective observational study conducted at 27 ENS@T centers from 15 countries. Methods. Inclusion criteria: AI diagnosed 1996-2015, 1 mg dexamethasone suppression test, follow-up (FU) of ≥36 months, known survival status. Exclusion criteria: clinically relevant adrenal hormone excess (i.e. Cushing’s syndrome, pheochromocytoma, primary hyperaldosteronism), known malignancy. Patient stratification: serum cortisol after dexamethasone (&gt;5 µg/dl, ACS; 1.9-5 µg/dl, possible ACS (PACS); ≤1.8 µg/dl, non-functioning adenoma (NFA)). Definition of CV events (CVE): hospitalization due to myocardial infarction and related interventions (PTCA, surgical bypass), stroke, deep vein thrombosis, pulmonary embolism. Results. 3640 patients (57% NFA, 36% PACS, 7% ACS) were considered eligible: 64% females; median age 61 years (range 18-91); median FU 84 months (36-277) (distribution between subgroups n.s.). 352 patients died during FU. Age- and sex adjusted overall survival was significantly reduced in patients with PACS (HR 1.55; 95%CI 1.24-1.94) and ACS (1.84; 1.29-2.61). Prevalence of CV risk factors were significantly higher in PACS and ACS than in NFA (hypertension: 72, 73, 57%, p&lt;0.0001; dyslipidemia: 42, 49, 35%, p&lt;0.0001; diabetes: 22, 25, 17%, p&lt;0.0001) When adjusted to relevant confounders (i.e. age, sex, CV risk factors), time to first CVE was shorter in PACS (HR 1.36; 1.07-1.73) and ACS (HR 1.62; 1.10-2.40) compared to NFA. Conclusion. PACS and ACS are associated with increased overall mortality and CV morbidity. However, to prove causality a large randomized intervention trial is required.

AbstractMiglustat has been indicated for the treatment of Niemann‐Pick disease type C (NP‐C) since 2009. The aim of this observational study was to assess the effect of miglustat on long‐term survival of patients with NP‐C. Data for 789 patients from five large national cohorts and from the NPC Registry were collected and combined. Miglustat‐treated and untreated patients overall and within sub‐groups according to age‐at‐neurological‐onset, that is, early infantile‐onset (<2 years), late infantile‐onset (2 to <6 years), juvenile‐onset (6 to <15 years), and adolescent/adult‐onset (≥15 years) were analysed and compared. Survival was analysed from the time of first neurological manifestation (Neurological onset group, comprising 669 patients) and from diagnosis (Diagnosis group, comprising 590 patients) using a Cox proportional hazard model adjusted for various covariates. Overall, 384 (57.4%) patients in the Neurological onset group and 329 (55.8%) in the Diagnosis group were treated with miglustat. Miglustat treatment was associated with a significant reduction in risk of mortality in both groups (entire Neurological onset group, Hazard ratio [HR] = 0.51; entire Diagnosis group, HR = 0.44; both P < .001). The effect was observed consistently in all age‐at‐neurological‐onset sub‐groups (HRs = 0.3 to 0.7) and was statistically significant for late infantile‐onset patients in both groups (Neurological onset group, HR = 0.36, P < .05; Diagnosis group, HR = 0.32, P < .01), and juvenile‐onset patients in the Diagnosis group only (HR = 0.30, P < .05). Despite the limitations of the data that urge cautious interpretation, the findings are consistent with a beneficial effect of miglustat on survival in patients with NP‐C.

Aim The aim of this is to identify the gene expression profiles indicative of reversible versus irreversible injury in experimental (murine) renal artery stenosis (RAS). Method Two‐kidney‐one‐cuff hypertension was established by placement of a polytetrafluoroethylene cuff on the right renal artery (N=18). Sham surgery was performed by manipulating the right renal artery without cuff placement (N=6). To determine potential reversibility, the cuff was removed at 7 days (7D cuff‐off, N=6) and 14 days (14D cuff‐off, N=6) after initial RAS surgery. In a control RAS group, the cuff was left in place for 28 days (28D RAS, N=6). Kidneys were harvested at 28 days for assessment of atrophy and fibrosis. Renal blood perfusion and oxygenation were measured using 16.4T MRI. RNASeq analysis was performed on all the groups at 28 days following initial surgery. Results Following cuff placement, intra‐renal perfusion was reduced by 65% (p<0.0001 vs. baseline). In the 7D cuff‐off group intra‐renal perfusion was restored to baseline values after cuff removal, whereas in the 14D cuff‐off group perfusion was not significantly improved following cuff removal. In the 28D RAS group the reduction in perfusion was maintained throughout the study period. The 7D cuff‐off group had a significantly lower % atrophy (7 ± 2.2%, p=0.0042) and % area of interstitial fibrosis (0.57 ± 0.08 %, p<0.0001) compared to 28D RAS group (atrophy 66 ± 13%, area of fibrosis 7.79 ± 0.89 %). The 14D cuff‐off group had severe atrophy (56 ± 16.6%) and interstitial fibrosis (5.05 ± 1.22%) similar to that seen in 28D RAS group. RNASeq analysis data were normalized to appropriate sham controls in all the groups and was performed at 28 days following initial surgery. Induction of greater than Log2 ratio >2 and p values < 0.00001 were considered significant (following adjustment for multiple comparisons). Fibrosis associated genes were differentially regulated in the 7D cuff‐off compared to the 14D cuff‐off and 28D RAS group (table ). Conclusion We conclude that cuff removal at 7 days is associated with relative preservation of renal structure, indicating that renal injury at this point is reversible. We have identified a number of fibrosis associated genes that are differentially regulated in the 7D cuff‐off group versus 14D cuff‐off group. Further analysis will determine the functional relevance of these differentially regulated genes. Support or Funding Information This project was funded by National Institutes of Health, NIAID R01 AI100911. Values of Log 2 Ratio Genes 7D Cuff‐off vs Sham 14D Cuff‐off vs Sham 28D RAS vs Sham COL1A1 0.96 2.62 2.23 COL1A2 0.79 2.07 1.91 COL3A1 1.26 2.60 2.35 MMP12 1.24 2.85 2.95 MMP14 1.34 2.70 2.55 MMP19 2.89 3.86 4.05 MMP2 1.55 3.49 3.22 MMP7 6.96 9.22 9.59 MTOR −0.46 −1.67 −2.06 SERPINE1 1.25 3.37 2.35 TGFB1i1 0.44 1.46 1.53 TGFB2 0.82 1.83 1.97 TGFB3 0.59 1.91 1.99 TGFBi 0.98 1.88 2.02 KLF15 −0.90 −1.76 −2.60 UBD 4.49 6.23 6.18 TIMP1 2.94 5.30 5.16 TIMP2 0.50 1.46 1.52 TIMP3 −0.35 −1.26 −1.36 HSPB1 0.16 2.00 2.13 HSPB8 1.51 2.26 2.30 CCL2 3.44 4.89 4.31 CCL12 2.88 3.71 4.12 SERPINE1 1.25 3.37 2.35 SERPINE2 1.17 2.39 2.35 SERPINF1 2.02 2.76 3.11 SERPINF2 −0.51 −2.03 −2.71 SERPING1 1.15 1.81 2.09 CLU 1.45 2.54 3.07 STC1 0.45 1.99 2.12 SPP1 1.75 3.06 3.37

Abstract Background Xeroderma pigmentosum (XP) patients present a high risk of developing skin cancer and other complications at an early age. This disease is characterized by mutations in the genes related to the DNA repair system. Objectives To describe the clinical and molecular findings in a cohort of 32 Brazilian individuals who received a clinical diagnosis of XP. Methods Twenty‐seven families were screened for germline variants in eight XP‐related genes. Results All patients ( N = 32) were diagnosed with bi‐allelic germline pathogenic or potentially pathogenic variants, including nine variants previously undescribed. The c.2251‐1G>C XPC pathogenic variant, reported as the founder mutation in Comorian and Pakistani patients, was observed in 15 cases in homozygous or compound heterozygous. Seven homozygous patients for POLH/XPV variants developed their symptoms by an average age of 7.7 years. ERCC2 / XPD , DDB2 / XPE and ERCC5 / XPG variants were found in a few patients. Aside from melanoma and non‐melanoma skin tumours, a set of patients developed skin sebaceous carcinoma, leiomyosarcoma, angiosarcoma, mucoepidermoid carcinoma, gastric adenocarcinoma and serous ovarian carcinoma. Conclusions We reported a high frequency of XPC variants in 32 XP Brazilian patients. Nine new variants in XP‐related genes, unexpected non‐skin cancer lesions and an anticipation of the clinical manifestation in POLH/XPV cases were also described.

INTRODUCTION The cerebral cortex underlies our complex cognitive capabilities. Variations in human cortical surface area and thickness are associated with neurological, psychological, and behavioral traits and can be measured in vivo by magnetic resonance imaging (MRI). Studies in model organisms have identified genes that influence cortical structure, but little is known about common genetic variants that affect human cortical structure. RATIONALE To identify genetic variants associated with human cortical structure at both global and regional levels, we conducted a genome-wide association meta-analysis of brain MRI data from 51,665 individuals across 60 cohorts. We analyzed the surface area and average thickness of the whole cortex and 34 cortical regions with known functional specializations. RESULTS We identified 369 nominally genome-wide significant loci ( P < 5 × 10 −8 ) associated with cortical structure in a discovery sample of 33,992 participants of European ancestry. Of the 360 loci for which replication data were available, 241 loci influencing surface area and 66 influencing thickness remained significant after replication, with 237 loci passing multiple testing correction ( P < 8.3 × 10 −10 ; 187 influencing surface area and 50 influencing thickness). Common genetic variants explained 34% (SE = 3%) of the variation in total surface area and 26% (SE = 2%) in average thickness; surface area and thickness showed a negative genetic correlation ( r G = −0.32, SE = 0.05, P = 6.5 × 10 −12 ), which suggests that genetic influences have opposing effects on surface area and thickness. Bioinformatic analyses showed that total surface area is influenced by genetic variants that alter gene regulatory activity in neural progenitor cells during fetal development. By contrast, average thickness is influenced by active regulatory elements in adult brain samples, which may reflect processes that occur after mid-fetal development, such as myelination, branching, or pruning. When considered together, these results support the radial unit hypothesis that different developmental mechanisms promote surface area expansion and increases in thickness. To identify specific genetic influences on individual cortical regions, we controlled for global measures (total surface area or average thickness) in the regional analyses. After multiple testing correction, we identified 175 loci that influence regional surface area and 46 that influence regional thickness. Loci that affect regional surface area cluster near genes involved in the Wnt signaling pathway, which is known to influence areal identity. We observed significant positive genetic correlations and evidence of bidirectional causation of total surface area with both general cognitive functioning and educational attainment. We found additional positive genetic correlations between total surface area and Parkinson’s disease but did not find evidence of causation. Negative genetic correlations were evident between total surface area and insomnia, attention deficit hyperactivity disorder, depressive symptoms, major depressive disorder, and neuroticism. CONCLUSION This large-scale collaborative work enhances our understanding of the genetic architecture of the human cerebral cortex and its regional patterning. The highly polygenic architecture of the cortex suggests that distinct genes are involved in the development of specific cortical areas. Moreover, we find evidence that brain structure is a key phenotype along the causal pathway that leads from genetic variation to differences in general cognitive function. Identifying genetic influences on human cortical structure. ( A ) Measurement of cortical surface area and thickness from MRI. ( B ) Genomic locations of common genetic variants that influence global and regional cortical structure. ( C ) Our results support the radial unit hypothesis that the expansion of cortical surface area is driven by proliferating neural progenitor cells. ( D ) Cortical surface area shows genetic correlation with psychiatric and cognitive traits. Error bars indicate SE. IMAGE CREDITS: (A) K. COURTNEY; (C) M. R. GLASS