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OBJECTIVE: To determine if surgery and anesthesia in the elderly may promote Alzheimer’s Disease and Related Dementias (ADRD). BACKGROUND: There is a substantial conflicting literature concerning the hypothesis that surgery and anesthesia promotes ADRD. Much of the literature is confounded by indications for surgery or has small sample size. This study examines elderly patients with appendicitis, a common condition that strikes mostly at random after controlling for some known associations. METHODS: A matched natural experiment of patients undergoing appendectomy for appendicitis versus control patients without appendicitis using Medicare data from 2002 to 2017, examining 54,996 patients without previous diagnoses of ADRD, cognitive impairment, or neurological degeneration, who developed appendicitis between ages 68 through 77 years and underwent an appendectomy (the “Appendectomy” treated group), matching them 5:1 to 274,980 controls, examining the subsequent hazard for developing ADRD. RESULTS: The hazard ratio (HR) for developing ADRD or death was lower in the Appendectomy group than controls: HR = 0.96 (95% CI 0.94, 0.98), P < 0.0001, (28.2% in Appendectomy versus 29.1% in controls, at 7.5 years). The HR for death was 0.97 (0.95, 0.99), P = 0.002, (22.7% versus 23.1% at 7.5 years). The HR for developing ADRD alone was 0.89 (0.86, 0.92), P < 0.0001, (7.6% in Appendectomy versus 8.6% in controls, at 7.5 years). No subgroup analyses found significantly elevated rates of ADRD in the Appendectomy group. CONCLUSIONS: In this natural experiment involving 329,976 elderly patients, exposure to appendectomy surgery and anesthesia did not increase the subsequent rate of ADRD.

The term "multimorbidity" identifies high-risk, complex patients and is conventionally defined as ≥2 comorbidities. However, this labels almost all older patients as multimorbid, making this definition less useful for physicians, hospitals, and policymakers.Develop new medical condition-specific multimorbidity definitions for patients admitted with acute myocardial infarction (AMI), heart failure (HF), and pneumonia patients. We developed three medical condition-specific multimorbidity definitions as the presence of single, double, or triple combinations of comorbidities - called Qualifying Comorbidity Sets (QCSs) - associated with at least doubling the risk of 30-day mortality for AMI and pneumonia, or one-and-a-half times for HF patients, compared to typical patients with these conditions.Cohort-based matching study PARTICIPANTS: One hundred percent Medicare Fee-for-Service beneficiaries with inpatient admissions between 2016 and 2019 for AMI, HF, and pneumonia.Thirty-day all-location mortality KEY RESULTS: We defined multimorbidity as the presence of ≥1 QCS. The new definitions labeled fewer patients as multimorbid with a much higher risk of death compared to the conventional definition (≥2 comorbidities). The proportions of patients labeled as multimorbid using the new definition versus the conventional definition were: for AMI 47% versus 87% (p value0.0001), HF 53% versus 98% (p value0.0001), and pneumonia 57% versus 91% (p value0.0001). Thirty-day mortality was higher among patients with ≥1 QCS compared to ≥2 comorbidities: for AMI 15.0% versus 9.5% (p0.0001), HF 9.9% versus 7.0% (p0.0001), and pneumonia 18.4% versus 13.2% (p0.0001).The presence of ≥2 comorbidities identified almost all patients as multimorbid. In contrast, our new QCS-based definitions selected more specific combinations of comorbidities associated with substantial excess risk in older patients admitted for AMI, HF, and pneumonia. Thus, our new definitions offer a better approach to identifying multimorbid patients, allowing physicians, hospitals, and policymakers to more effectively use such information to consider focused interventions for these vulnerable patients.

OBJECTIVE The aim of the study was to address the controversy surrounding the effects of duty hour reform on new surgeon performance, we analyzed patients treated by new surgeons following the transition to independent practice. SUMMARY BACKGROUND DATA In 2003, duty hour reform affected all US surgical training programs. Its impact on the performance of new surgeons remains unstudied. METHODS We studied 30-day mortality among 1,483,074 Medicare beneficiaries undergoing general and orthopedic operations between 1999 and 2003 ("traditional" era) and 2009 and 2013 ("modern" era). The operations were performed by 2762 new surgeons trained before the reform, 2119 new surgeons trained following reform and 15,041 experienced surgeons. We used a difference-in-differences analysis comparing outcomes in matched patients treated by new versus experienced surgeons within each era, controlling for the hospital, operation, and patient risk factors. RESULTS Traditional era odds of 30-day mortality among matched patients treated by new versus experienced surgeons were significantly elevated [odds ratio (OR) 1.13; 95% confidence interval (CI) (1.05, 1.22), P < 0.001). The modern era elevated odds of mortality were not significant [OR 1.06; 95% CI (0.97-1.16), P = 0.239]. Relative performance of new and experienced surgeons with respect to 30-day mortality did not appear to change from the traditional era to the modern era [OR 0.93; 95% CI (0.83-1.05), P = 0.233]. There were statistically significant adverse changes over time in relative performance to experienced surgeons in prolonged length of stay [OR 1.08; 95% CI (1.02-1.15), P = 0.015], anesthesia time [9 min; 95% CI (8-10), P < 0.001], and costs [255USD; 95% CI (2-508), P = 0.049]. CONCLUSIONS Duty hour reform showed no significant effect on 30-day mortality achieved by new surgeons compared to their more experienced colleagues. Patients of new surgeons, however, trained after duty hour reform displayed some increases in the resources needed for their care.

To compare outcomes and costs between major teaching and nonteaching hospitals on a national scale by closely matching on patient procedures and characteristics.Teaching hospitals have been shown to often have better quality than nonteaching hospitals, but cost and value associated with teaching hospitals remains unclear.A study of Medicare patients at 340 teaching hospitals (resident-to-bed ratios ≥ 0.25) and matched patient controls from 2444 nonteaching hospitals (resident-to-bed ratios0.05).We studied 86,751 pairs admitted for general surgery (GS), 214,302 pairs of patients admitted for orthopedic surgery, and 52,025 pairs of patients admitted for vascular surgery.In GS, mortality was 4.62% in teaching hospitals versus 5.57%, (a difference of -0.95%,0.0001), and overall paired cost difference = $915 (P0.0001). For the GS quintile of pairs with highest risk on admission, mortality differences were larger (15.94% versus 18.18%, difference = -2.24%, P0.0001), and paired cost difference = $3773 (P0.0001), yielding $1682 per 1% mortality improvement at 30 days. Patterns for vascular surgery outcomes resembled general surgery; however, orthopedics outcomes did not show significant differences in mortality across teaching and nonteaching environments, though costs were higher at teaching hospitals.Among Medicare patients, as admission risk of mortality increased, the absolute mortality benefit of treatment at teaching hospitals also increased, though accompanied by marginally higher cost. Major teaching hospitals appear to return good value for the extra resources used in general surgery, and to some extent vascular surgery, but this was not apparent in orthopedic surgery.

BACKGROUND: Concern persists that extended shifts in medical residency programs may adversely affect patient safety. METHODS: We conducted a cluster-randomized noninferiority trial in 63 internal-medicine residency programs during the 2015–2016 academic year. Programs underwent randomization to a group with standard duty hours, as adopted by the Accreditation Council for Graduate Medical Education (ACGME) in July 2011, or to a group with more flexible duty-hour rules that did not specify limits on shift length or mandatory time off between shifts. The primary outcome for each program was the change in unadjusted 30-day mortality from the pretrial year to the trial year, as ascertained from Medicare claims. We hypothesized that the change in 30-day mortality in the flexible programs would not be worse than the change in the standard programs (difference-in-difference analysis) by more than 1 percentage point (noninferiority margin). Secondary outcomes were changes in five other patient safety measures and risk-adjusted outcomes for all measures. RESULTS: The change in 30-day mortality (primary outcome) among the patients in the flexible programs (12.5% in the trial year vs. 12.6% in the pretrial year) was noninferior to that in the standard programs (12.2% in the trial year vs. 12.7% in the pretrial year). The test for noninferiority was significant (P = 0.03), with an estimate of the upper limit of the one-sided 95% confidence interval (0.93%) for a between-group difference in the change in mortality that was less than the prespecified noninferiority margin of 1 percentage point. Differences in changes between the flexible programs and the standard programs in the unadjusted rate of readmission at 7 days, patient safety indicators, and Medicare payments were also below 1 percentage point; the noninferiority criterion was not met for 30-day readmissions or prolonged length of hospital stay. Risk-adjusted measures generally showed similar findings. CONCLUSIONS: Allowing program directors flexibility in adjusting duty-hour schedules for trainees did not adversely affect 30-day mortality or several other measured outcomes of patient safety. (Funded by the National Heart, Lung, and Blood Institute and Accreditation Council for Graduate Medical Education; iCOMPARE ClinicalTrials.gov number, NCT02274818.)

Background Nursing resources, such as staffing ratios and skill mix, vary across hospitals. Better nursing resources have been linked to better patient outcomes but are assumed to increase costs. The value of investments in nursing resources, in terms of clinical benefits relative to costs, is unclear. Objective To determine whether there are differential clinical outcomes, costs, and value among medical patients at hospitals characterized by better or worse nursing resources. Design Matched cohort study of patients in 306 acute care hospitals. Patients A total of 74,045 matched pairs of fee-for-service Medicare beneficiaries admitted for common medical conditions (25,446 sepsis pairs; 16,332 congestive heart failure pairs; 12,811 pneumonia pairs; 10,598 stroke pairs; 8858 acute myocardial infarction pairs). Patients were also matched on hospital size, technology, and teaching status. Main Measures Better (n = 76) and worse (n = 230) nursing resourced hospitals were defined by patient-to-nurse ratios, skill mix, proportions of bachelors-degree nurses, and nurse work environments. Outcomes included 30-day mortality, readmission, and resource utilization-based costs. Key Results Patients in hospitals with better nursing resources had significantly lower 30-day mortality (16.1% vs 17.1%, p

BackgroundThere are known clinical benefits associated with investments in nursing. Less is known about their value.AimsTo compare surgical patient outcomes and costs in hospitals with better versus worse nursing resources and to determine if value differs across these hospitals for patients with different mortality risks.MethodsRetrospective matched-cohort design of patient outcomes at hospitals with better versus worse nursing resources, defined by patient-to-nurse ratios, skill mix, proportions of bachelors-degree nurses and nurse work environments. The sample included 62 715 pairs of surgical patients in 76 better nursing resourced hospitals and 230 worse nursing resourced hospitals from 2013 to 2015. Patients were exactly matched on principal procedures and their hospital’s size category, teaching and technology status, and were closely matched on comorbidities and other risk factors.ResultsPatients in hospitals with better nursing resources had lower 30-day mortality: 2.7% vs 3.1% (pConclusionHospitals with better nursing resources provided better clinical outcomes for surgical patients at a small additional cost. Generally, the sicker the patient, the greater the value at better nursing resourced hospitals.

INTRODUCTION: This study develops a measure of Alzheimer’s disease and Related Dementias (ADRD) using Medicare claims. METHODS: Validation resembles the approach of the American Psychological Association, including (i) content validity, (ii) construct validity, and (iii) predictive validity. RESULTS: We found that four items -- a Medicare claim recording ADRD 1-year ago, 2-years ago, 3-years ago, and a total stay of 6-months in a nursing home -- exhibit a pattern of association consistent with a single underlying ADRD construct, and presence of any two of these four items predict a direct measure of cognitive function and also future claims for ADRD. DISCUSSION: Our four items are internally consistent with the measurement of a single quantity. The presence of any two items do a better job than a single claim when predicting both a direct measure of cognitive function and future ADRD claims.

BACKGROUND: There are numerous definitions of multimorbidity. None systematically examines specific comorbidity combinations accounting for multiple testing when exploring large datasets. OBJECTIVES: Develop and validate a list of all single, double, and triple comorbidity combinations, with each individual Qualifying Comorbidity Set (QCS) at least doubling the odds of mortality versus its reference population. Patients with at least one QCS were defined as having multimorbidity. RESEARCH DESIGN: Cohort-based study with a matching validation study. SUBJECTS: All fee-for-service Medicare patients between age 65 and 85 without dementia or metastatic solid tumors undergoing general surgery in 2009–2010, and an additional 2011–2013 dataset. MEASURES: 30-day all-location mortality RESULTS: There were 576 qualifying comorbidity sets (2 singles, 63 doubles and 511 triples), each set at least doubling the odds of dying. In 2011, 36% of eligible patients had multimorbidity. As a group, multimorbid patients (mortality rate = 7.0%) had a mortality Mantel-Haenszel OR = 1.90 (1.77, 2.04) versus a reference that included both multimorbid and non-multimorbid patients (mortality rate = 3.3%), and Mantel-Haenszel OR = 3.72 (3.51, 3.94) versus only non-multimorbid patients (mortality rate = 1.6%). When matching 3,151 pairs of multimorbid patients from low-volume hospitals to similar patients in high-volume hospitals, the mortality rates were 6.7% versus 5.2%, respectively (P = 0.006). CONCLUSIONS: A list of QCSs identified a third of older patients undergoing general surgery that had greatly elevated mortality. These sets can be used to identify vulnerable patients and the specific combinations of comorbidities that make them susceptible to poor outcomes.

BACKGROUND Failure-to-rescue (FTR), originally developed to study quality of care in surgery, measures an institution's ability to prevent death after a patient becomes complicated. OBJECTIVES Develop an FTR metric modified to analyze acute myocardial infarction (AMI) outcomes. RESEARCH DESIGN Split-sample design: a random 20% of hospitals to develop FTR definitions, a second 20% to validate test characteristics, and an out-of-sample 60% to validate results. SUBJECTS Older Medicare beneficiaries admitted to short-term acute-care hospitals for AMI between 2009 and 2011. MEASURES Thirty-day mortality and FTR rates, and in-hospital complication rates. RESULTS The 60% out-of-sample validation included 234,277 patients across 1142 hospitals that admitted at least 50 patients over 2.5 years. In total, 72.1% of patients were defined as Medically Complicated (complex on admission or subsequently developed a complication or died without a recorded complication) of whom 19.3% died. Spearman r between hospital risk-adjusted 30-day mortality and FTR was 0.89 (P

ObjectiveTo determine whether outcomes achieved by new surgeons are attributable to inexperience or to differences in the context in which care is delivered and patient complexity.BackgroundAlthough prior studies suggest that new surgeon outcomes are worse than those of experienced surgeons, factors that underlie these phenomena are poorly understood.MethodsA nationwide observational tapered matching study of outcomes of Medicare patients treated by new and experienced surgeons in 1221 US hospitals (2009-2013). The primary outcome studied is 30-day mortality. Secondary outcomes were examined.ResultsIn total, 694,165 patients treated by 8503 experienced surgeons were matched to 68,036 patients treated by 2119 new surgeons working in the same hospitals. New surgeons' patients were older (25.8% aged ≥85 vs 16.3%,P

BACKGROUND: Teaching hospitals typically pioneer investment in new technology and cultivate workforce characteristics generally associated with better quality, but the value of this extra investment is unclear. OBJECTIVE: Compare outcomes and costs between major teaching and non-teaching hospitals by closely matching on patient characteristics. DESIGN: Medicare patients at 339 major teaching hospitals (resident-to-bed (RTB) ratios ≥ 0.25); matched patient controls from 2439 non-teaching hospitals (RTB ratios

POLICY POINTS: Patients with low socioeconomic status (SES) experience poorer survival rates after diagnosis of breast cancer, even when enrolled in Medicare and Medicaid. Most of the difference in survival is due to more advanced cancer on presentation and the general poor health of lower SES patients, while only a very small fraction of the SES disparity is due to differences in cancer treatment. Even when comparing only low‐ versus not‐low‐SES whites (without confounding by race) the survival disparity between disparate white SES populations is very large and is associated with lower use of preventive care, despite having insurance. CONTEXT: Disparities in breast cancer survival by socioeconomic status (SES) exist despite the “safety net” programs Medicare and Medicaid. What is less clear is the extent to which SES disparities affect various racial and ethnic groups and whether causes differ across populations. METHODS: We conducted a tapered matching study comparing 1,890 low‐SES (LSES) non‐Hispanic white, 1,824 black, and 723 Hispanic white women to 60,307 not‐low‐SES (NLSES) non‐Hispanic white women, all in Medicare and diagnosed with invasive breast cancer between 1992 and 2010 in 17 US Surveillance, Epidemiology, and End Results (SEER) regions. LSES Medicare patients were Medicaid dual‐eligible and resided in neighborhoods with both high poverty and low education. NLSES Medicare patients had none of these factors. Measurements: 5‐year and median survival. FINDINGS: LSES non‐Hispanic white patients were diagnosed with more stage IV disease (6.6% vs 3.6%; p < 0.0001), larger tumors (24.6 mm vs 20.2 mm; p < 0.0001), and more chronic diseases such as diabetes (37.8% vs 19.0%; p < 0.0001) than NLSES non‐Hispanic white patients. Disparity in 5‐year survival (NLSES − LSES) was 13.7% (p < 0.0001) when matched for age, year, and SEER site (a 42‐month difference in median survival). Additionally, matching 55 presentation factors, including stage, reduced the disparity to 4.9% (p = 0.0012), but further matching on treatments yielded little further change in disparity: 4.6% (p = 0.0014). Survival disparities among LSES blacks and Hispanics, also versus NLSES whites, were significantly associated with presentation factors, though black patients also displayed disparities related to initial treatment. Before being diagnosed, all LSES populations used significantly less preventive care services than matched NLSES controls. CONCLUSIONS: In Medicare, SES disparities in breast cancer survival were large (even among non‐Hispanic whites) and predominantly related to differences of presentation characteristics at diagnosis rather than differences in treatment. Preventive care was less frequent in LSES patients, which may help explain disparities at presentation.

BACKGROUND Racial disparities in general surgical outcomes are known to exist but not well understood. OBJECTIVES To determine if black-white disparities in general surgery mortality for Medicare patients are attributable to poorer health status among blacks on admission or differences in the quality of care provided by the admitting hospitals. RESEARCH DESIGN Matched cohort study using Tapered Multivariate Matching. SUBJECTS All black elderly Medicare general surgical patients (N=18,861) and white-matched controls within the same 6 states or within the same 838 hospitals. MEASURES Thirty-day mortality (primary); others include in-hospital mortality, failure-to-rescue, complications, length of stay, and readmissions. RESULTS Matching on age, sex, year, state, and the exact same procedure, blacks had higher 30-day mortality (4.0% vs. 3.5%, P

Kidney transplant recipients often receive antibody induction. Previous studies of induction therapy were often limited by short follow-up and/or absence of information about complications. After linking Organ Procurement and Transplantation Network data with Medicare claims, we compared outcomes between three induction therapies for kidney recipients. Using novel matching techniques developed on the basis of 15 clinical and demographic characteristics, we generated 1:1 pairs of alemtuzumab-rabbit antithymocyte globulin (rATG) (5330 pairs) and basiliximab-rATG (9378 pairs) recipients. We used paired Cox regression to analyze the primary outcomes of death and death or allograft failure. Secondary outcomes included death or sepsis, death or lymphoma, death or melanoma, and healthcare resource utilization within 1 year. Compared with rATG recipients, alemtuzumab recipients had higher risk of death (hazard ratio [HR], 1.14; 95% confidence interval [95% CI], 1.03 to 1.26; P

With increasing Medicaid coverage, it has become especially important to determine whether racial differences exist within the Medicaid system. We asked whether disparities exist in hospital practice and patient outcomes between matched black and white Medicaid children with chronic conditions undergoing surgery.We conducted a matched cohort study, matching 6,398 pairs within states on detailed patient characteristics using data from 25 states contributing adequate Medicaid Analytic eXtract claims for admissions of children with chronic conditions undergoing the same surgical procedures between January 1, 2009 and November 30, 2010 for ages 1 to 18 years.The black patient 30-day revisit rate was 19.3% vs 19.8% in matched white patients (p = 0.61), 30-day readmission rates were 7.0% vs 6.9% (p = 0.43), and 30-day mortality rates were 0.38% vs 0.19% (p = 0.06), respectively. A higher percentage of black patients exceeded their own state's individual median length of stay (44.0% vs 39.6%; p0.001) and median ICU length of stay (25.9% vs 23.8%; p0.001). Intensive care unit use was higher in black patients (25.9% vs 23.8%; p0.001). After adjusting for multiple testing, only 2 states were found to differ significantly by race (New York for length of stay and New Jersey for ICU use).We did not observe disparities in 30-day revisits and readmissions for chronically ill children in Medicaid undergoing surgery, and only slight differences in length of stay, ICU length of stay, and use of the ICU, where blacks displayed somewhat elevated rates compared with white controls.

BACKGROUND AND OBJECTIVES: Black children with asthma comprise one-third of all asthma patients in Medicaid. With increasing Medicaid coverage, it has become especially important to monitor Medicaid for differences in hospital practice and patient outcomes by race. METHODS: A multivariate matched cohort design, studying 11 079 matched pairs of children in Medicaid (black versus white matched pairs from inside the same state) admitted for asthma between January 1, 2009 and November 30, 2010 in 33 states contributing adequate Medicaid Analytic eXtract claims. RESULTS: Ten-day revisit rates were 3.8% in black patients versus 4.2% in white patients (P = .12); 30-day revisit and readmission rates were also not significantly different by race (10.5% in black patients versus 10.8% in white patients; P = .49). Length of stay (LOS) was also similar; both groups had a median stay of 2.0 days, with a slightly lower percentage of black patients exceeding their own state’s median LOS (30.2% in black patients versus 31.8% in white patients; P = .01). The mean paired difference in LOS was 0.00 days (95% confidence interval, –0.08 to 0.08). However, ICU use was higher in black patients than white patients (22.2% versus 17.5%; P < .001). After adjusting for multiple testing, only 4 states were found to differ significantly, but only in ICU use, where blacks had higher rates of use. CONCLUSIONS: For closely matched black and white patients, racial disparities concerning asthma admission outcomes and style of practice are small and generally nonsignificant, except for ICU use, where we observed higher rates in black patients.

The interstitial insertion of genetic material from one chromosome into another can achieve the type of gene-gene fusions more usually associated with chromosome translocations. An example of such an interstitial insertion, which has created an MLL-AF10 fusion in an acute myeloid leukaemia, has been analysed at the genomic level. The genomic fusion, which resulted in the juxtaposition of 3' AF10 sequence to 5' MLL sequence, was identified within MLL and AF10 intronic sequences. It was further established that the remaining 3' MLL sequence, from exon 6 onwards, was fused to novel sequence of unknown origin (named FM3 for fused to MLL 3'). The points of fusion of these 5' and 3' portions of MLL matched to adjacent nucleotides and lay between exons 5 and 6. The FM3 sequence was shown to be from chromosome arm 10p and located close to AF10 in a proximal position. It was subsequently demonstrated that in the leukaemia a third fusion existed between 5' AF10 and the FM3 sequence at a point immediately downstream from its fusion to MLL. It was therefore concluded that the MLL-AF10 gene fusion is the result of a simultaneous transposition of genetic material into the MLL gene and the joining of the remaining free ends on chromosome 10. This kind of event, characterised completely here for the first time, is a means to achieve a fusion when the genes involved lie in opposite orientations and results in three genomic junctions.

MUC3 is a large mucin glycoprotein expressed by the human intestine and gall bladder. In this manuscript, we present details of the deduced protein structure of MUC3. The MUC3 carboxyl-terminal domain is 617 residues in length, including 511 residues of a non-repetitive mucin-like domain (27% Thr, 22% Ser, and 11% Pro) and a 106-residue Cys-rich domain with homology to the epidermal growth factor (EGF) -like structural motifs found in many proteins. The region of MUC3 located upstream of the previously described 51-base pair (bp) tandem repeats, which encode a major Ser and Thr-rich domain, consists of a second type of repetitive structure with an imperfect periodicity of approximately 1125 bp. This domain is also mucin-like and appears to be considerably larger than 2000 residues (6000 bp). The MUC3 gene itself is large and complex. Using pulse field gel electrophoresis and blot analysis, the smallest fragment found that contained all human genomic DNA hybridizing to the 51-bp tandem repeat probe was 200 kilobases with restriction enzyme SwaI. Both PvuII and PstI produced two sets of hybridizing fragments that were hypervariable within the human population with a pattern suggestive of both a variation in the number of tandem repeats (VNTR) and sequence polymorphism. These fragments varied independently of each other, but no genetic recombination was detected in a study of 40 human families. Thus, the MUC3 gene encodes a very large glycoprotein with a structure very different from that of any mucin currently described.

HT-29 cells resistant to 10−6M methotrexate (HT29-MTX) secrete mucins with gastric immunoreactivity (Lesuffleur, T., Barbat, A., Dussaulx, E., and Zweibaum, A.(1990) Cancer Res. 50, 6334-6343). A 3310-base pair mucin cDNA clone (L31) was isolated from an HT29-MTX expression library using a polyclonal serum specific for normal gastric mucosa. It shows a high level of identity (98.6%) to clone NP3a isolated from a nasal polyp cDNA library (Meerzaman, D., Charles, P., Daskal, E., Polymeropoulos, M. H., Martin, B. M., and Rose, M. C.(1994) J. Biol. Chem. 269, 12932-12939). However, as a result of changes in reading frame, the 1042-amino acid deduced peptide contains four regions of a low similarity to the NP3a peptide. The amino acid sequence shows 36.3% similarity to part of the carboxyl-terminal sequence of MUC2 including the so-called D4 domain and 21.3% to the pro von Willebrand factor. A short amino acid sequence is similar to cysteine-rich sequences repeated in tracheobronchial, gastric, and colonic mucin cDNAs. The gene corresponding to L31 is located in the mucin gene cluster on chromosome 11p15.5. The patterns of mRNA expression were indistinguishable from those revealed with the JER58 probe (MUC5AC). Southern blot analysis indicates that the L31 and JER 58 sequences are within 20 kilobase pairs of each other. Together, these results suggest that L31 clone is the 3′ end of MUC5AC.

Background Early rehospitalization (1 pre-KT hospitalizations (aOR 1.32, 95% CI 1.17–1.49) were more likely to be rehospitalized. All three health status metrics and early rehospitalization were independently associated with post-KT mortality in a multivariable Cox model (adjusted hazard ratio for rehospitalization: 1.41, 95% CI 1.28–1.56) Conclusions Pre-transplant metrics of health status, measured by dialysis providers or administrative data, are independently associated with early rehospitalization and mortality risk after KT. Transplant providers may consider utilizing metrics of pre-KT global health status as early signals of vulnerability when transitioning care after KT.

A family of four highly polymorphic genes encoding secreted gel forming mucins is located in the middle of a recombination rich region of the short arm of chromosome 11 (11p15.5; tel MUC6-MUC2-MUC5AC-MUC5B cen; approx. 400 kb). These genes are of interest as risk factors for inflammatory diseases of the epithelia, and we have for example reported association of a VNTR polymorphism of the major mucin domain of MUC2 with asthma, despite the fact that MUC2 is not a major respiratory mucin. To understand the significance of this and other mucin gene associations it is important to describe the patterns of linkage disequilibrium (LD) across this chromosomal region, which is still incomplete on HapMap and the UCSC Golden Path sequence. Our previous studies on the 40 core CEPH families provided direct evidence for several recombination events within the immediate region of the gene complex. This study examines these recombination events in more detail, and also the patterns of LD across the gene complex. We refine the location of the breakpoints, and the combined data suggest two probable recombination hotspots. Three breakpoints are located between MUC6 and MUC2: there is no association between MUC6 and MUC2, and the data collected here, combined with that publicly available, maps a hotspot to a region of 4 kb. The other recombinants map between MUC2 and intron 8 of MUC5B. Relatively strong LD is detected between MUC2 and MUC5AC, and although 10/70 of the chromosomes tested shared a common haplotype, which extends from MUC2 to MUC5B, statistically significant association was not detected between MUC2 and the markers tested in MUC5B. We discuss the possibility that the previously reported association between MUC2 and asthma is most likely attributable to association with functional variation in MUC5AC, which encodes one of the two major mucins expressed in both healthy and diseased airways.

Importance Patient outcomes associated with the 2011 Accreditation Council for Graduate Medical Education (ACGME) duty hour reforms have not been evaluated at a national level. Objective To evaluate the association of the 2011 ACGME duty hour reforms with mortality and readmissions. Design, Setting, and Participants Observational study of Medicare patient admissions (6 384 273 admissions from 2 790 356 patients) to short-term, acute care, nonfederal hospitals (n = 3104) with principal medical diagnoses of acute myocardial infarction, stroke, gastrointestinal bleeding, or congestive heart failure or a Diagnosis Related Group classification of general, orthopedic, or vascular surgery. Of the hospitals, 96 (3.1%) were very major teaching, 138 (4.4%) major teaching, 442 (14.2%) minor teaching, 443 (14.3%) very minor teaching, and 1985 (64.0%) nonteaching. Exposure Resident-to-bed ratio as a continuous measure of hospital teaching intensity. Main Outcomes and Measures Change in 30-day all-location mortality and 30-day all-cause readmission, comparing patients in more intensive relative to less intensive teaching hospitals before (July 1, 2009–June 30, 2011) and after (July 1, 2011–June 30, 2012) duty hour reforms, adjusting for patient comorbidities, time trends, and hospital site. Results In the 2 years before duty hour reforms, there were 4 325 854 admissions with 288 422 deaths and 602 380 readmissions. In the first year after the reforms, accounting for teaching hospital intensity, there were 2 058 419 admissions with 133 547 deaths and 272 938 readmissions. There were no significant postreform differences in mortality accounting for teaching hospital intensity for combined medical conditions (odds ratio [OR], 1.00; 95% CI, 0.96-1.03), combined surgical categories (OR, 0.99; 95% CI, 0.94-1.04), or any of the individual medical conditions or surgical categories. There were no significant postreform differences in readmissions for combined medical conditions (OR, 1.00; 95% CI, 0.97-1.02) or combined surgical categories (OR, 1.00; 95% CI, 0.98-1.03). For the medical condition of stroke, there were higher odds of readmissions in the postreform period (OR, 1.06; 95% CI, 1.001-1.13). However, this finding was not supported by sensitivity analyses and there were no significant postreform differences for readmissions for any other individual medical condition or surgical category. Conclusions and Relevance Among Medicare beneficiaries, there were no significant differences in the change in 30-day mortality rates or 30-day all-cause readmission rates for those hospitalized in more intensive relative to less intensive teaching hospitals in the year after implementation of the 2011 ACGME duty hour reforms compared with those hospitalized in the 2 years before implementation.

We have prospectively analysed and correlated the gene expression profiles of children presenting with acute leukaemia to the Royal London and Great Ormond Street Hospitals with morphological diagnosis, immunophenotype and karyotype. Total RNA extracted from freshly sorted blast cells was obtained from 84 lymphoblastic [acute lymphoblastic leukaemia (ALL)], 20 myeloid [acute myeloid leukaemia (AML)] and three unclassified acute leukaemias and hybridised to the high density Affymetrix U133A oligonucleotide array. Analysis of variance and significance analysis of microarrays was used to identify discriminatory genes. A novel 50-gene set accurately identified all patients with ALL and AML and predicted for a diagnosis of AML in three patients with unclassified acute leukaemia. A unique gene set was derived for each of eight subtypes of acute leukaemia within our data set. A common profile for children with ALL with an ETV6-RUNX1 fusion, amplification or deletion of ETV6, amplification of RUNX1 or hyperdiploidy with an additional chromosome 21 was identified. This suggests that these rearrangements share a commonality in biological pathways that maintains the leukaemic state. The gene TERF2 was most highly expressed in this group of patients. Our analyses demonstrate that not only is microarray analysis the single most effective tool for the diagnosis of acute leukaemias of childhood but it has the ability to identify unique biological pathways. To further evaluate its prognostic value it needs to be incorporated into the routine diagnostic analysis for large-scale clinical trials in childhood acute leukaemias.

The t(10;11)(p13;q14-21) is a non-random translocation described in acute lymphoblastic and myeloid leukaemias. It results in the fusion of the gene CALM, which encodes a clathrin assembly protein, on 11q14 to the gene AF10, a putative transcription factor on 10p13. Here we describe for the first time, the occurrence of a CALM-AF10 fusion in a case of acute megakaryoblastic leukaemia. Fluorescence in situ hybridisation and reverse transcriptase polymerase chain reaction were used to confirm the presence of a CALM-AF10 fusion. A novel splice variant of CALM missing nt 1927-2091 was also detected. Though CALM is a cytoplasmic protein, the chimaeric fusion product is able to localise to both the nucleus and cytoplasm. Analysis of the fusion variants suggests, however, that the critical fusion product is likely to be cytoplasmic and contain the interactive leucine zipper of AF10.

A region of 150 kb has been analysed around a previously isolated, lymphoma associated, translocation breakpoint located at chromosome band 11q23. This balanced and reciprocal translocation, t(11;14)(q32;q23), has been shown to result in the fusion between chromosome 11 specific sequence and the switch gamma4 region of the IGH locus. The LPC gene, encoding a novel proprotein convertase belonging to the furin family, has been identified in this region. In order to characterize further the region surrounding the translocation, we have determined the detailed structure of LPC. Here we show that LPC consists of at least 16 exons covering 25 kb, and that there is a partial duplication, involving mobile genetic elements and containing LPC exons 13-17 in a tail-tail configuration at 65 kb downstream. Since the chromosomal breakpoint lay between these two structures, the intervening region was further analysed and shown to contain at least two unrelated genes. The previously known SM22 gene was localized close to the 3' tail of LPC. Furthermore, we identified the gene encoding the alpha2 subunit of platelet-activating factor acetylhydrolase (Pafah1a2) at the chromosomal breakpoint. The position of another previously identified breakpoint was also located to within the first intron of this gene. Altogether, our results give evidence of a genomic instability of this area of 11q23 and show that Pafah1a2 and not LPC is the gene disrupted by the translocation, suggesting that deregulated Pafah1a2 may have a role in lymphomagenesis.

A family of four genes that encode major secreted mucins (MUC6, MUC2, MUC5AC and MUC5B) map to within 400 kb on chromosome 11p15.5. These genes contain long stretches of tandem repeats of sequence that encode serine- and threonine-rich domains but that otherwise show no similarity from gene to gene, and regions of unique sequence domains that do show evidence of sequence homology. We have previously reported the existence of polymorphism in three of these genes but the extent and nature of this allelic variation is now described here in detail. Variable number tandem repeat polymorphisms of MUC6, MUC2 and MUC5AC are predicted to encode mucin polypeptides that differ in length. In the case of MUC2 and MUC6 these length differences are substantial (up to twofold). MUC5B in contrast does not show common allele length variation. Three MUC2 mutations are reported, none of which are associated with the meiotic recombinations previously observed in this region of chromosome 11.

Four distinct genes that encode mucins have previously been mapped to chromosome 11p15.5. Three of these genes (MUC2, MUC5AC, and MUC6) show a high level of genetically determined polymorphism and were analyzed in the CEPH families. Linkage analysis placed all three genes on the genetic map in a cluster between HRAS and INS, and more detailed analysis of recombinant breakpoints revealed that MUC6 is telomeric to MUC2. Using these recombinants D11S150 was mapped close to MUC2. Ten of the 11 recombinant chromosomes studied in detail were paternal, and the recombinant events were distributed throughout the 11p15 region, suggesting that the high level of recombination observed in 11p15.5 is not due to a particular recombinational hot spot. Pulsed-field gel electrophoresis was used to make a detailed physical map of the MUC cluster and to integrate the physical and genetical maps. The gene order was determined to be HRAS-MUC6-MUC2-MUC5AC-MUC5B-IGF2. The MUC genes span a region of some 400 kb and the map extends 770 kb and contains 15 putative CpG islands. The order of the MUC genes on the map corresponds to the relative order of their expression along the anterior-posterior axis of the body, suggesting a possible functional significance to the gene order.