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Objective To investigate whether indicators of patient need (comorbidity burden, fall risk) predict acute care rehabilitation utilization, and whether this relation varies across patient characteristics (ie, demographic characteristics, insurance type). Design Secondary analysis of electronic health records data. Setting Five acute care hospitals. Participants Adults (N=110,209) admitted to 5 regional hospitals between 2014 and 2018. Interventions Not applicable. Main Outcome Measures Occupational therapy (OT) and physical therapy (PT) utilization. Logistic regression models determined whether indicators of patient need predicted OT and PT utilization. Interactions between indicators of need and both demographic factors (eg, minority status, presence of significant other) and insurance type were included to investigate whether the relation between patient need and therapy access varied across patient characteristics. Results Greater comorbidity burden was associated with a higher likelihood of receiving OT and PT. Relative to those with low fall risk, those with moderate and high fall risk were more likely to receive OT and PT. The relation between fall risk and therapy utilization differed across patient characteristics. Among patients with higher levels of fall risk, those with a significant other were less likely to receive OT and PT; significant other status did not explain therapy utilization among patients with low fall risk. Among those with high fall risk, patients with VA insurance and minority patients were more likely to receive PT than those with private insurance and nonminority patients, respectively. Insurance type and minority status did not appear to explain PT utilization among those with lower fall risk. Conclusions Patients with greater comorbidity burden and fall risk were more likely to receive acute care rehabilitation. However, the relation between fall risk and utilization was moderated by insurance type, having a significant other, and race/ethnicity. Understanding the implications of these utilization patterns requires further research.

Objectives To determine the factors associated with acute hospital discharge to the 3 most common postacute settings following total knee arthroplasty (TKA): inpatient rehabilitation facilities (IRFs), skilled nursing facilities (SNFs), and directly back to the community. Design Retrospective cohort study. Setting Acute care hospitals submitting claims to Medicare. Participants National cohort (N=1,189,286) of 100% Medicare Part A data files from 2009-2011. Interventions Not applicable. Main Outcome Measures Observed rates and adjusted odds of discharge to the 3 main postacute settings based on the clinical and facility level variables: amount of comorbidity, bilateral procedures, and facility TKA volume. Results Using IRF discharge as the reference, patients who received a bilateral procedure had lower odds of both SNF and community discharge, patients with more comorbidity had lower odds for community discharge and higher odds for SNF discharge, and patients who received their TKA from hospitals with lower TKA volumes had lower odds of SNF and community discharge. Conclusions Clinical populations within Medicare beneficiaries may systematically vary across the 3 most common discharge settings following TKA. This information may be helpful for a better understanding on which patient or clinical factors influence postacute care settings following TKA. Additional research including functional status, living situation, and social support systems would be beneficial.

The biomedical scientific community is in the midst of a significant expansion in how data are used to accomplish the important goals of reducing disability and improving health care. Data science is the academic discipline emerging from this expansion. Data science reflects a new approach to the acquisition, storage, analysis, and interpretation of scientific knowledge. The potential benefits of data science are transforming biomedical research and will lead physical medicine and rehabilitation in exciting new directions. Understanding this transformation will require modifying and expanding the education, training, and research infrastructure that support rehabilitation science and practice.

From a high throughput screening of commercially available libraries against nontuberculous mycobacteria and Mycobacterium tuberculosis, numerous hits were identified with moderate activity. Extensive medicinal chemistry optimization has led to a series of potent benzothiazole amide antimycobacterial agents. Replacement of the adamantyl group with cyclohexyl derivatives and further development of this series resulted in an advanced lead compound, CRS400393, which demonstrated excellent potency and a mycobacteria-specific spectrum of activity. MIC values ranged from 0.03 to 0.12 μg/mL against Mycobacterium abscessus and other rapid-grower NTM, and 1–2 μg/mL against Mycobacterium avium complex. The preliminary mechanism of action studies suggested these agents may target MmpL3, a mycobacterial mycolic acid transporter. The series has demonstrated in vivo efficacy in a proof of concept mouse model of M. abscessus infection.

Background Relying solely on null hypothesis significance testing to investigate rehabilitation interventions may result in researchers erroneously concluding the presence of a treatment effect. Objective We sought to quantify the strength of evidence in favour of rehabilitation treatment effects by calculating Bayes factors (BF10s) for significant findings. Additionally, we sought to examine associations between BF10s, P-values, and Cohen's d effect sizes. Methods We searched the Cochrane Database of Systematic Reviews for meta-analyses with “rehabilitation” as a keyword that evaluated a rehabilitation intervention. We extracted means, standard deviations, and sample sizes for treatment and comparison groups from individual findings within 175 meta-analyses. Investigators independently classified the interventions according to the Rehabilitation Treatment Specification System. We calculated t-statistics, P-values, effect sizes, and BF10s for each finding. We isolated statistically significant findings (P ≤ 0.05); applied evidential categories to BF10s, P-values, and effect sizes; and examined relationships descriptively. Results We analysed 1935 rehabilitation findings. Across intervention types, 25% of significant findings offered only anecdotal evidence in favour of a treatment effect; only 48% indicated strong evidence. This pattern persisted within intervention types and when conducting robustness analyses. Smaller P-values and larger effect sizes were associated with stronger evidence in favour of a treatment effect. However, a notable portion of findings with P-value 0.01 to 0.05 (63%) or a large effect size (18%) offered anecdotal evidence in favour of an effect. Conclusions For a substantial portion of statistically significant rehabilitation findings, the data neither support nor refute the presence of a treatment effect. This was the case among a notable portion of large treatment effects and for most findings with P-value > 0.01. Rehabilitation evidence would be improved by researchers adopting more conservative levels of significance, complementing the use of null hypothesis significance testing with Bayesian techniques and reporting effect sizes.

Background As defined by Medicare (United States), post-acute rehabilitation services include care provided in inpatient rehabilitation units and facilities, skilled nursing facilities, long-term acute hospitals, and by home health services. Methods We retrospectively evaluated the use of rehabilitation-based post-acute services among Medicare beneficiaries who were hospitalized for lumbar spinal fusion (ICD-9-CM procedure codes 81.04–81.08) in 2012–2014, examined the case-mix for those discharged to rehabilitation- and non-rehabilitation based services, and determined the association between these categories of discharge disposition and 30-day rehospitalization. The independent effect of rehabilitation-based discharge destination on 30-day readmissions was examined with a generalized linear mixed model, first adjusting for patient characteristics and then stratified by clusters that delineated more homogenous clinical profiles. Results Among 261,558 Medicare beneficiaries with lumbar spinal fusion surgery, 50.8% were discharged to a rehabilitation-based post-acute services. Patients discharged to rehabilitation-based services were older and had more comorbidities, and had longer hospital lengths of stays. After adjusting for patient and hospital characteristics, patients discharged to rehabilitation-based post-acute care had increased odds of 30-day rehospitalization than those without discharge to other destinations (OR 1.36; 95%CI = 1.31, 1.40). Analysis of patients by clinical profile clusters found similar results. Conclusions Clinical profiles of Medicare beneficiaries who had lumbar spinal fusion surgery and were discharged to rehabilitation-based post-acute services included more comorbidities than those discharged to non-rehabilitation based settings. Controlling for these differences did not mediate the negative association between use of rehabilitation-based post-acute services and 30-day readmission.

Background Relying solely on null hypothesis significance testing (NHST) to investigate rehabilitation interventions may result in researchers erroneously concluding the absence of a treatment effect. Objective We aimed to distinguish between truly null treatment effects and data that are insensitive to detecting treatment effects by calculating Bayes factors (BF01s) for non-significant findings in the rehabilitation literature. Additionally, to examine associations between BF01, sample size, and observed P-values. Method We searched the Cochrane Database of Systematic Reviews for meta-analyses with “rehabilitation” as a keyword that clearly evaluated a rehabilitation intervention. We extracted means, standard deviations, and sample sizes for treatment and comparison groups for individual findings within 175 meta-analyses. Two independent investigators classified the interventions into 4 categories using the Rehabilitation Treatment Specification System. We calculated t-statistics and associated P-values for each finding in order to extract non-significant results (P > 0.05). We calculated BF01s for 5790 non-significant results and classified BF01s based on the strength of evidence in favour of the null hypothesis (i.e., anecdotal, moderate, and strong) across and within intervention types. We examined correlations between BF01, sample size, and P-values across and within intervention types. Results Across all intervention types, most (71.9%) findings were deemed anecdotal, and this pattern remained within distinct intervention types (58.4–76.0%). Larger sample sizes tended to be associated with greater strength in favour of the null hypothesis, both across and within intervention types. Larger P-values were not associated with greater strength in favour of the null hypothesis; this finding was present both across and within intervention types. Conclusion Our findings indicate that most non-significant rehabilitation findings are unable to distinguish between the true absence of a treatment effect and data that are merely insensitive to detecting a treatment effect. Findings also suggest that rehabilitation researchers may improve the strength of their statistical conclusions by increasing sample size and that Bayes factors may offer unique benefits relative to P-values.

To describe impairment-specific patterns in shorter- and longer-than-expected lengths of stay in inpatient rehabilitation, and examine the independent effects of social support on deviations from expected lengths of stay.Retrospective cohort study.Inpatient rehabilitation facilities.Medicare fee-for-service beneficiaries (N=119,437) who were discharged from inpatient rehabilitation facilities in 2012 after stroke, lower extremity fracture, or lower extremity joint replacement.Not applicable.Relative length of stay (actual minus expected). The Centers for MedicareMedicaid Services posts annual expected lengths of stay based on patients' clinical profiles at admission. We created a 3-category outcome variable: short, expected, long. Our primary independent variable (social support) also included 3 categories: family/friends, paid/other, none.Mean ± SD actual lengths of stay for joint replacement, fracture, and stroke were 9.8±3.6, 13.8±4.5, and 15.8±7.3 days, respectively; relative lengths of stay were -1.2±3.1, -1.6±3.7, and -1.7±5.2 days. Nearly half of patients (47%-48%) were discharged more than 1 day earlier than expected in all 3 groups, whereas 14% of joint replacement, 15% of fracture, and 20% of stroke patients were discharged more than 1 day later than expected. In multinomial regression analysis, using family/friends as the reference group, paid/other support was associated (P.05) with higher odds of long stays in joint replacement. No social support was associated with lower odds of short stays in all 3 impairment groups and higher odds of long stays in fracture and joint replacement.Inpatient rehabilitation experiences and outcomes can be substantially affected by a patient's level of social support. More research is needed to better understand these relationships and possible unintended consequences in terms of patient access issues and provider-level quality measures.

To link, classify and describe the content of the Multicenter Benchmarking Study Burn Outcomes Questionnaires (BOQ) using the International Classification of Functioning, Disability and Health (ICF) to determine if the information garnered provides researchers with the data necessary to develop a comprehensive understanding of life after burns.Two ICF linking experts used a standardized linking technique endorsed by the World Health Organization to link all BOQ concepts to the ICF. Linking results were analyzed to determine the comprehensiveness of each of the five measures.The activities and participation component was most frequently addressed followed by the body functions component. Environmental factors are not extensively covered and body structures are not addressed. ICF chapter and category distribution were skewed and varied between assessments. The majority of BOQ items are of the health status perspective.BOQ item composition could be improved with a more even distribution of pertinent ICF topics. Assessment authors may consider addressing the impact of environmental factors on participation. Including body structure concepts would allow investigators to track structural deformation and/or developmental delay. Generally speaking, this data should not be used to examine quality of life outcomes.

To examine and describe regional variation in outcomes for persons with stroke receiving inpatient medical rehabilitation.Retrospective cohort design.Inpatient rehabilitation units and facilities contributing to the Uniform Data System for Medical Rehabilitation from the United States.Patients (N=143,036) with stroke discharged from inpatient rehabilitation during 2006 and 2007.Not applicable.Community discharge, length of stay (LOS), and discharge functional status ratings (motor, cognitive) across 10 geographic service regions defined by the Centers for Medicare and Medicaid Services (CMS).Approximately 71% of the sample was discharged to the community. After adjusting for covariates, the percentage discharged to the community varied from 79.1% in the Southwest (CMS region 9) to 59.4% in the Northeast (CMS region 2). Adjusted LOS varied by 2.1 days, with CMS region 1 having the longest LOS at 18.3 days and CMS regions 5 and 9 having the shortest at 16.2 days.Rehabilitation outcomes for persons with stroke varied across CMS regions. Substantial variation in discharge destination and LOS remained after adjusting for demographic and clinical characteristics.

OBJECTIVE: To examine how similar summary scores of physical functioning using the FIM can represent very different patient clinical profiles. DESIGN: Retrospective cohort study. SETTING: Inpatient rehabilitation facilities submitting claims and assessment data to the Centers for Medicare and Medicaid Services in 2012 and 2013. PARTICIPANTS: Medicare fee-for-service beneficiaries discharged from inpatient rehabilitation (N=765,441). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: We used patients’ scores on items from the Functional Independence Measure (FIM) to quantify their level of independence in both self-care and mobility domains. We then identified patients as requiring “No Physical Assistance” at discharge from inpatient rehabilitation using a rule and score-based approach. RESULTS: Among those patients with FIM self-care and mobility summary scores suggesting no physical assistance needed, we found physical assistance was in fact needed frequently in bathroom related activities (e.g., continence, toilet and tub transfers, hygiene, clothes management) and with stairs. In other words, it was not uncommon for actual performance to be lower than what may be suggested by a summary score in those domains. CONCLUSIONS: Further research is needed into creating clinically meaningful descriptions of summary scores from combined performances on individual items of physical functioning.

Objectives The objectives of this study were to determine the association between patients’ functional status at discharge from skilled nursing facility (SNF) care and 30-day potentially preventable hospital readmissions, and to examine common reasons for potentially preventable readmissions. Design Retrospective cohort study. Setting SNFs and acute care hospitals submitting claims to Medicare. Participants National cohort of Medicare fee-for-service beneficiaries discharged from SNF care between July 15, 2013, and July 15, 2014 (n = 693,808). Average age was 81.4 (SD 8.1) years, 67.1% were women, and 86.3% were non-Hispanic white. Measurements Functional items from the Minimum Data Set 3.0 were categorized into self-care, mobility, and cognition domains. We used specifications for the SNF potentially preventable 30-day postdischarge readmission quality metric to identify potentially preventable readmissions. Results The overall observed rate of 30-day potentially preventable readmissions following SNF discharge was 5.7% (n = 39,318). All 3 functional domains were independently associated with potentially preventable readmissions in the multivariable models. Odds ratios for the most dependent category versus the least dependent category from multilevel models adjusted for patients’ sociodemographic and clinical characteristics were as follows: mobility, 1.54 (95% confidence interval [CI] 1.49–1.59); self-care, 1.50 (95% CI 1.44–1.55); and cognition, 1.12 (95% CI 1.04–1.20). The 5 most common conditions were congestive heart failure (n = 7654, 19.5%), septicemia (n = 7412, 18.9%), urinary tract infection/kidney infection (n = 4297, 10.9%), bacterial pneumonia (n = 3663, 9.3%), and renal failure (n = 3587, 9.1%). Across all 3 functional domains, septicemia was the most common condition among the most dependent patients and congestive heart failure among the least dependent. Conclusions Patients with functional limitations at SNF discharge are at increased risk of hospital readmissions considered potentially preventable. Future research is needed to determine whether improving functional status reduces risk of potentially preventable readmissions among this vulnerable population.

To investigate the effects of facility-level factors on 30-day unplanned risk-adjusted hospital readmission after discharge from inpatient rehabilitation facilities (IRFs).Study using 100% Medicare claims data, covering 269,306 discharges from 1094 IRFs between October 2010 and September 2011.IRFs with at least 30 discharges.A total number of 1094 IRFs (N=269,306) serving Medicare fee-for-service beneficiaries.Not applicable.Risk-standardized readmission rate (RSRR) for 30-day hospital readmission.Profit status was the only provider-level IRF characteristic significantly associated with unplanned readmissions. For-profit IRFs had a significantly higher RSRR (13.26±0.51) than did nonprofit IRFs (13.15±0.47) (P.001). After controlling for all other facility characteristics (except for accreditation status because of its collinearity with facility type), for-profit IRFs had a 0.1% point higher RSRR than did nonprofit IRFs, and census region was the only significant region-level characteristic, with the South showing the highest RSRR of all regions (type III test, P=.005 for both).Our findings support the inclusion of profit status on the IRF Compare website (a platform including IRF comparators to indicate quality of services). For-profit IRFs had a higher RSRR than did nonprofit IRFs for Medicare beneficiaries. The South had a higher RSRR than did other regions. The RSRR difference between for-profit and nonprofit IRFs could be due to the combined effects of organizational and regional factors.

Reistetter TA, Graham JE, Deutsch A, Granger CV, Markello S, Ottenbacher KJ . Utility of functional status for classifying community versus institutional discharges after inpatient rehabilitation for stroke. Objective To evaluate the ability of patient functional status to differentiate between community and institutional discharges after rehabilitation for stroke. Design Retrospective cross-sectional design. Setting Inpatient rehabilitation facilities contributing to the Uniform Data System for Medical Rehabilitation. Participants Patients (N=157,066) receiving inpatient rehabilitation for stroke from 2006 and 2007. Interventions Not applicable. Main Outcome Measure Discharge FIM rating and discharge setting (community vs institutional). Results Approximately 71% of the sample was discharged to the community. Receiver operating characteristic curve analyses revealed that FIM total performed as well as or better than FIM motor and FIM cognition subscales in differentiating discharge settings. Area under the curve for FIM total was .85, indicating very good ability to identify persons discharged to the community. A FIM total rating of 78 was identified as the optimal cut point for distinguishing between positive (community) and negative (institution) tests. This cut point yielded balanced sensitivity and specificity (both=.77). Conclusions Discharge planning is complex, involving many factors. Identifying a functional threshold for classifying discharge settings can provide important information to assist in this process. Additional research is needed to determine if the risks and benefits of classification errors justify shifting the cut point to weight either sensitivity or specificity of FIM ratings.

Graham JE, Radice-Neumann DM, Reistetter TA, Hammond FM, Dijkers M, Granger CV. Influence of sex and age on inpatient rehabilitation outcomes among older adults with traumatic brain injury.To assess the influence of sex and age on inpatient rehabilitation outcomes in a large national sample of older adults with traumatic brain injury (TBI).Prospective case series.Eight hundred forty-eight inpatient rehabilitation facilities that subscribe to the Uniform Data System for Medical Rehabilitation.Patients (n=18,413) age 65 years and older admitted for inpatient rehabilitation after TBI from 2005 through 2007.None.Rehabilitation length of stay, discharge FIM motor and cognitive ratings, discharge setting, and scheduled home health services at discharge.Mean age +/- SD of the sample was 79+/-7 years, and 47% were women. In multivariable models, higher age was associated with shorter lengths of stay (P.001), lower discharge FIM motor and cognitive ratings (P.001), and greater odds of home health services at discharge (P.001). Women demonstrated shorter lengths of stay (P=.006) and greater odds of being scheduled for home health services at discharge (P.001) than men. The sex-by-age interaction term was not significant in any outcome model. Sex differences and trends were consistent across the entire age range of the sample.Sex and age patterns in rehabilitation outcomes among older adults with TBI varied by outcome. The current findings related to rehabilitation length of stay may be helpful for facility-level resource planning. Additional studies are warranted to identify the factors associated with returning to home and to assess the long-term benefits of combined inpatient rehabilitation and home health services for older adults with TBI.

Ottenbacher KJ, Graham JE. The state-of-the-science: access to postacute care rehabilitation services. A review. Objective To identify and summarize potential factors that influence access to postacute care (PAC) rehabilitation services. Data Sources Ovid Medline and agency-specific (eg, RAND Corp, Research Triangle Institute, U.S. Department of Health and Human Services) searches, using combinations of the terms health services accessibility , delivery of healthcare , access to care , post-acute , postacute , and access . Names of prominent authors were also searched to retrieve their relevant articles. Study Selection The initial search resulted in 823 articles published between 1980 and 2006. After we reviewed titles and abstracts, we obtained and examined 49 potential sources. Our final sample of 35 studies had descriptions and/or analyses of measures that might serve as indictors of access to PAC settings. Data Extraction Key information abstracted from each article and document included author(s), year of publication, patient groups, sample size, health care setting, and a brief summary of the access-related issues in PAC. Data Synthesis Studies varied by patient group, care setting, and access categories. Indicators of access to PAC rehabilitation services were classified into 4 categories: financial (46%), personal (31%), structural (26%), and attitudinal (23%). Many studies assessed more than 1 category. Conclusions We identified categories of information that can be used to develop a monitoring system for PAC services. The inclusion of access indicators in existing health report cards and quality indicator systems should be further explored.

Although recent technological advances in DNA sequencing and computational biology now allow scientists to compare entire microbial genomes, comparisons of closely related bacterial species and individual isolates by whole-genome sequencing approaches remains prohibitively expensive for most laboratories. Here we report the development and testing of a biochemical approach for targeted sequencing of only those chromosomal regions that differ between two DNA preparations. The method, designated GFE (genome fragment enrichment) uses competitive solution hybridization and positive selection to obtain genomic DNA fragments that are present in one pool of fragments but not another. Repeated comparisons of the genomes of Enterococcus faecalis and E. faecium led to the identification of 225 putative genome-specific DNA fragments. Species and strain variations within these fragments were confirmed by both experimental and bioinformatic analyses. The E. faecalis genome-specific sequences identified included both a preponderance of those predicted to encode surface-exposed proteins, as well as several previously described unique marker regions embedded within highly conserved rrn operons. The GFE strategy we describe efficiently identified genomic differences between two enterococcal genomes, and will be widely applicable for studying genetic variation among closely related bacterial species.

Arylamine N-acetyltransferases (NAT; EC 2.3.1.5) catalyse the transfer of acetyl groups from acetylCoA to xenobiotics, including drugs and carcinogens. The enzyme is found extensively in both eukaryotes and prokaryotes, yet the endogenous roles of NATs are still unclear. In order to study the properties of eukaryotic NATs, high-throughput substrate and inhibitor screens have been developed using pure soluble recombinant Syrian hamster NAT2 (shNAT2) protein. The assay can be used with a wide range of compounds and was used to determine substrate specificity of shNAT2. We describe the expression and characterisation of shNAT2 and also purified recombinant human NAT1 and NAT2, including the use of the assay to explore the substrate specificities of each of the enzymes. Hamster NAT2 has similar substrate specificity to human NAT1, acetylating para-aminobenzoate but not arylhydrazine and hydralazine compounds. The overlapping but distinct substrate-specific activity profiles of human NAT1 and NAT2 were clearly observed from the screen. Naturally occurring compounds were tested as substrates or inhibitors of shNAT2 and succinylCoA was found to be a potent inhibitor of shNAT2.

Background & Aims: Helicobacter pylori inhabits a highly restricted ecological niche in the human gastric mucosa. Microbial gene expression in the context of persistent infection remains largely uncharacterized. Methods: An RNA analysis method, selective capture of transcribed sequences, was used in conjunction with genomic array hybridization to characterize H. pylori complementary DNAs (cDNAs) obtained from both human and experimentally infected gerbil gastric tissue specimens. Results: Bacterial cDNAs obtained by selective capture of transcribed sequences from tissues hybridized to arrayed DNA fragments representing approximately 70% of open reading frames in the H. pylori genome. RNAs for most of these open reading frames were also detected by array hybridization analyses of total RNA prepared from the isolated H. pylori strains cultured in vitro. However, a subset of H. pylori RNAs detected in gastric tissue specimens was consistently undetectable in bacteria grown in vitro. The majority of these RNAs encode factors unique to H. pylori that are potentially produced in response to interactions with mammalian gastric mucosa. Conclusions: The combination of selective capture of transcribed sequences with array hybridization has allowed a global analysis of bacterial gene expression occurring in human tissues during a natural infection. GASTROENTEROLOGY 2002;123:1637-1648

Background In an effort to improve quality and reduce costs, payments are being increasingly tied to value through alternative payment models, such as episode-based payments. The objective of this study was to better understand the pattern and variation in outcomes among Medicare beneficiaries receiving lower extremity joint arthroplasty over 90-day episodes of care. Methods Observed rates of mortality, complications, and readmissions were calculated over 90-day episodes of care among Medicare fee-for-service beneficiaries who received elective knee arthroplasty and elective or nonelective hip arthroplasty procedures in 2013-2014 (N = 640,021). Post–acute care utilization of skilled nursing and inpatient rehabilitation facilities was collected from Medicare files. Results Mortality rates over 90 days were 0.4% (knee arthroplasty), 0.5% (elective hip arthroplasty), and 13.4% (nonelective hip arthroplasty). Complication rates were 2.1% (knee arthroplasty), 3.0% (elective hip arthroplasty), and 8.5% (nonelective hip arthroplasty). Inpatient rehabilitation facility utilization rates were 6.0% (knee arthroplasty), 6.7% (elective hip arthroplasty), and 23.5% (nonelective hip arthroplasty). Skilled nursing facility utilization rates were 33.9% (knee arthroplasty), 33.4% (elective hip arthroplasty), and 72.1% (nonelective hip arthroplasty). Readmission rates were 6.3% (knee arthroplasty), 7.0% (elective hip arthroplasty), and 19.2% (nonelective hip arthroplasty). Patients' age and clinical characteristics yielded consistent patterns across all outcomes. Conclusion Outcomes in our national cohort of Medicare beneficiaries receiving lower extremity joint arthroplasties varied across procedure types and patient characteristics. Future research examining trends in access to care, resource use, and care quality over bundled episodes will be important for addressing the challenges of value-based payment reform.

Purpose: To assess the role of chemoradiation as a primary treatment for vulvar carcinoma. Methods and Materials: Between December 1989 and August 1997, there were 14 patients with the diagnosis of squamous cell carcinoma of the vulva. Two patients were excluded from this study because of advanced stage at presentation. Key information about the remaining 12 patients was extracted from their charts. All patients had biopsy prior to treatment, and were treated with chemoradiation. Radiation was administered to the vulva only. Surgical biopsies from the vulva and inguinal nodal dissection were done 4–6 weeks after radiation treatment. All patients were followed for evaluation of response and clinical detection of recurrence. The period of follow-up ranged from 8 to 125 months. Mean follow-up period was 41 months. Results: All 12 patients showed complete response to the treatment. Only 1 patient (8.3%) developed local recurrence at 3 months posttreatment. Another patient (8.3%) developed nodal recurrence at 30 months posttreatment. Both patients were salvaged by surgical treatment and remained disease free. The actuarial 5-year disease-free survival was 43%. The actuarial 3-year disease-free survival was 84%. The majority of patients developed mild-to-moderate complications due to chemoradiation. These were well tolerated and responded to medical treatment. None of the patients developed late complications to chemoradiation treatment. Conclusions: Chemoradiation is an effective primary treatment for vulvar carcinoma as shown by these successfully managed cases.

The in vitro function of the coliphage lambda tR1 Rho-dependent terminator is governed primarily by a tripartite upstream sequence element designated rut. To determine the contribution of the different components of the rut site to terminator function in the normal context of coupled translation of the nascent cro message, tR1 variants lacking different rut site sequences were tested for terminator function in vivo. Intact rutA and rutB sequences were both necessary for efficient termination. However, deletion of the upstream rutA was far more detrimental than deletion of rutB. The intervening boxB, which encodes a short RNA stem and loop, could be deleted without reducing termination or detectably altering Rho's interaction with the corresponding cro transcript. The relative importance of these sequence elements was also the same in a minimal in vitro termination assay system. Rut sequences are therefore essential for terminator function in vivo and rutA contributes substantially more to tR1 function than does rutB. The relative contribution of these elements can be ascribed to differences in Rho's binding affinity for the encoded transcripts. If other cellular factors also bind the rut element RNA, they do not alter the relative contribution of its two regions to Rho-dependent transcription termination in vivo.

Single-molecule biophysics and enzymology has become a vast field of investigation of biomolecules in the last decade. Application of these techniques enabled the characterization of molecular phenomena in a previously unprecedented resolution and highlighted previously hidden mechanisms of actions of enzymes. Lambda phage DNA is widely used for studying DNA biophysics and protein-DNA interactions because of its optimal size for single-molecule manipulations. However, single-molecule analysis of reactions that require specific DNA sequences or specialized DNA structures, including positioned nucleosomes to study chromatin remodeling, have been an unresolved problem. Here we demonstrate the development of a versatile lambda phage system (λKytos) modified to receive any types of DNA in the middle of lambda DNA. We integrated an array of nucleosome positioning sequences into λKytos and reconstituted fluorescently labeled nucleosomes on this substrate. Our results show that there is a strong bias for the nucleosomes to bind to the positioning sequences along the lambda DNA (30% of the nucleosomes bound to the positioning region which is 3% of the total length). The reconstituted chromatin can be visualized by optical trapping and TIRF microscopy that enables us to study sequence specific chromatin remodeling with a previously inaccessible resolution. We also demonstrate applications of the λKytos system where we introduced a replication origin, a single-stranded (ss) DNA gap, and a DNA bubble consisting of two non-pairing ssDNA region in the middle of λKytos. These substrates - and similar derivatives - will greatly facilitate single-molecule studies of DNA replication, recombination and repair in the presence and absence of reconstituted chromatin.

DesJardin and Schlesinger correctly acknowledge the potential, and the possible pitfalls, of new technologies for the identification of Mycobacterium tuberculosis virulence factors, and we appreciate the positive statements in the commentary. However, we would like to comment specifically on aspects of the PCR-based strategies discussed, as methods based on nucleic acid amplification will be crucial to the study of mycobacterial virulence in human disease, firstly using cultured primary human macrophages and, subsequently, by analysis of infected animal and human tissues.The method described by Plum and Clark-Curtiss1xInduction of Mycobacterium avium gene expression following phagocytosis by human macrophages. Plum, G. and Clark-Curtiss, J.E. Infect. Immun. 1994; 62: 476–483PubMedSee all References is a subtractive hybridization approach, in which complementary cDNAs prepared from Mycobacterium avium grown in human macrophages and broth cultures are hybridized and removed, leaving behind cDNAs unique to phagocytosed bacilli. We described an alternative approach2xIdentification of Mycobacterium tuberculosis RNAs synthesized in response to phagocytosis by human macrophages by selective capture of transcribed sequences (SCOTS). Graham, J.E. and Clark-Curtiss, J.E. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 11554–11559Crossref | PubMed | Scopus (342)See all References, selective capture of transcribed sequences (SCOTS), in which bacterial cDNAs unique to M. tuberculosis growing in human macrophages are selected by differential hybridization to bacterial genomic DNA that has been pre-hybridized (blocked) with both total cDNA from broth-grown bacilli and rDNA fragments.The instability of RNA presents a serious challenge. With SCOTS, we attempted to obtain reproducible RNA expression patterns by directly isolating bacterial RNA from infected macrophages, thereby avoiding changes associated with separating host cells and microorganisms. To reduce the biases inherent in amplifying complex cDNA mixtures, SCOTS uses random priming of both cDNA strands to generate a library of short fragments (200–400 bp) that have been shown to be amplified without significant bias within a limited number of cycles3xUnbiased amplification of a highly complex mixture of DNA fragments by ‘lone linker’-tagged PCR. Ko, M.S. et al. Nucleic Acids Res. 1990; 18: 4293–4294Crossref | PubMed | Scopus (44)See all References, 4xPCR amplification of megabase DNA with tagged random primers (T-PCR). Grothues, D. et al. Nucleic Acids Res. 1993; 21: 1321–1322Crossref | PubMed | Scopus (63)See all References. This also provides a variety of different sequence contexts in which any particular sequence can be amplified, providing redundancy in representation of the original RNAs. Additionally, we used between three and ten parallel PCR reactions for each amplification. We acknowledge that the composition of the RNA pool might have an effect on reverse transcription, but consider it unlikely that increasing the level of potential target mRNA orders of magnitude (by PCR) while decreasing the complexity of the pool to a similar extent (via several rounds of SCOTS) would lead to the inability to obtain a specific cDNA. Nevertheless, we agree that repeated sampling of RNA and further analysis of additional cDNAs is important. So far, in an analysis of shorter duration macrophage infections (J.E. Graham and J.E. Clark-Curtiss, unpublished), we have obtained comparable complex hybridization patterns and cDNAs for previously described M. tuberculosis genes2xIdentification of Mycobacterium tuberculosis RNAs synthesized in response to phagocytosis by human macrophages by selective capture of transcribed sequences (SCOTS). Graham, J.E. and Clark-Curtiss, J.E. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 11554–11559Crossref | PubMed | Scopus (342)See all References.The same obstacles to determining the role of differentially expressed genes exist for other, more resource-intensive, genome-wide analysis methods, including microarray hybridization. It seems likely to us, given the variation in abundance of individual microbial RNAs within an ‘ocean’ of rRNA, that amplification methods which also equalize representation of mRNAs as cDNA, a fundamental aspect of SCOTS, will be necessary before microarray methods can be fully applied to the analysis of in vivo prokaryotic gene expression. Having identified, for the first time, M. tuberculosis genes expressed in response to interaction with human cells, we also look forward to the application of other recently described techniques to this difficult problem, and hope that the timely release of our initial findings will facilitate further analyses and selection of candidate targets for new treatment strategies.

Every attempt should be made to differentiate tumor simulating hypertrophic gastritis from carcinoma of the stomach clinically or, if necessary, by exploratory laparotomy with biopsy. On the basis of available statistical evidence tumor simulating hypertrophic gastritis is not a proven premalignant lesion. The majority of symptoms in this disease entity will respond to medical management. Therefore, there are only a very few patients in whom gastrectomy is indicated.