Site-specific acetylation of polynucleotide kinase 3'-phosphatase regulates its distinct role in DNA repair pathways.

Mammalian polynucleotide kinase 3'-phosphatase (PNKP), a DNA end-processing enzyme with 3'-phosphatase and 5'-kinase activities, is involved in multiple DNA repair pathways, including base excision (BER), single-strand break (SSBR), and double-strand break repair (DSBR). However, little is known as to how PNKP functions in such diverse repair processes. Here we report that PNKP is acetylated at K142 (AcK142) by p300 constitutively but at K226 (AcK226) by CBP, only after DSB induction. Co-immunoprecipitation analysis using AcK142 or AcK226 PNKP-specific antibodies showed that AcK142-PNKP associates only with BER/SSBR, and AcK226 PNKP with DSBR proteins. Despite the modest effect of acetylation on PNKP's enzymatic activity in vitro, cells expressing non-acetylable PNKP (K142R or K226R) accumulated DNA damage in transcribed genes. Intriguingly, in striatal neuronal cells of a Huntington's Disease (HD)-based mouse model, K142, but not K226, was acetylated. This is consistent with the reported degradation of CBP, but not p300, in HD cells. Moreover, transcribed genomes of HD cells progressively accumulated DSBs. Chromatin-immunoprecipitation analysis demonstrated the association of Ac-PNKP with the transcribed genes, consistent with PNKP's role in transcription-coupled repair. Thus, our findings demonstrate that acetylation at two lysine residues, located in different domains of PNKP, regulates its distinct role in BER/SSBR versus DSBR.

Implementation of a High-Value, Evidence-Based Care Program: Impact and Opportunities for Learning Organizations.

GOAL: Value-based care is not simply a matter of cost, but also one of outcomes and harms per dollar spent. This definition encompasses three key components: healthcare delivery that is organized around patients' medical conditions, costs and outcomes that are actively and consistently measured, and information technology that enables the other two components. Our objective in this project was to implement and measure a systemwide high-value, evidence-based care initiative with five pillars of high-value practices. METHODS: We performed a quasi-experimental study from September 1, 2019, to August 31, 2022, of a new care program at the University of Texas Medical Branch. Drawing from the ABIM Foundation's Choosing Wisely Campaign, the program was based on five pillars-blood management and antimicrobial, laboratory, imaging, and opioid stewardship-with interdisciplinary teams led by institutional subject matter experts (i.e., administrative leaders) accompanied by nursing, information technology, pharmacy, and clinical and nonclinical personnel including faculty and trainees. Each pillar addressed two goals with targeted interventions to assess improvements during the first three fiscal years (FYs) of implementation. The targets were set at 10% improvement by the end of each FY. Monthly measurements were recorded for each FY. PRINCIPAL FINDINGS: We tracked performance toward 30 pillar goals and determined that the teams were successful in 50%, 50%, and 70% of their goals for FY 2020, 2021, and 2022, respectively. For example, in the antimicrobial stewardship FY 2021 pillar, one goal was to decrease meropenem days of therapy (DOT) by 10% (baseline was 45 DOT/1,000 patient days; the target was 40.5 DOT/1,000 patient days). We measured quarterly DOT/1,000 patient day rates of 32.02, 30.57, and 26.9, respectively, for a cumulative rate of 26.9. Critical interventions included engaging and empowering providers and service lines (including outliers whose performance was outside norms), educational conferences, and transparent data analyses. PRACTICAL APPLICATIONS: We showed that a multidisciplinary approach to the implementation of an evidence-based, high-value care program through a partnership of engaged administrative leaders, providers, and trainees can result in sustainable and measurable high-value healthcare delivery. Specifically, structuring the program with pillars to address defined metrics resulted in progressive improvement in meeting value-based goals at the University of Texas Medical Branch. Also, challenges can be embraced as learning opportunities to inform value-based interventions that range from technological to educational tactics. The results at the University of Texas Medical Branch provide a benchmark for the implementation of a program that engages, empowers, and aligns innovative value-based care initiatives.

Co-prescribing of Central Nervous System-Active Medications for COPD Patients: Impact on Emergency Room Visits and Hospitalization.

BACKGROUND: Anxiety and chronic pain are common comorbidities in patients with chronic obstructive pulmonary disease (COPD), which are frequently managed with benzodiazepines (BZDs) and opioids, respectively. OBJECTIVE: The purpose of this study was to determine whether different combinations of opioids, BZD, and their substitutes-gabapentinoids (GABA) and selective serotonin reuptake inhibitors/serotonin-norepinephrine reuptake inhibitors (SSRIs/SNRIs)-are associated with lower risk of acute respiratory events in COPD patients with co-occurring chronic pain and anxiety. METHODS: This retrospective cohort study used a nationally representative sample of Medicare beneficiaries with COPD, chronic pain, and anxiety. Patients were grouped based on drug combination (opioid + BZD/Z-hypnotics, opioid + GABA, opioid + SSRI/SNRI, BZD/Z-hypnotics + GABA, BZD/Z-hypnotics + SSRI/SNRI, GABA + SSRI/SNRI, or ≥3 drugs). The primary outcome was emergency room (ER) visit or hospitalization due to acute respiratory events assessed up to 180 days following initiation of drug combination. Overdose secondary to central nervous system (CNS)-related drugs was also assessed up to 180 days following initiation of drug combination. RESULTS: The drug combination opioid + GABA was associated with decreased risk for ER visit (hazard ratio [HR] = 0.73; 95% CI = 0.61-0.87) and hospitalization (HR = 0.69; 95% CI = 0.55-0.85). Opioid + SSRI/SNRI also showed decreased risk for ER visit (HR = 0.84; 95% CI = 0.71-0.99). There was no significant difference in risk for CNS-related drug overdose among different drug combinations compared with opioid + BZD/Z-hypnotics. CONCLUSION AND RELEVANCE: Opioids in combination with GABA and SSRI/SNRI demonstrate relatively lower risk for acute respiratory events among patients with COPD and comorbid chronic pain and anxiety. The findings emphasize the need for multimodal management in this vulnerable population.

Intrapulmonary administration of purified NEIL2 abrogates NF-κB-mediated inflammation.

Aberrant or constitutive activation of nuclear factor kappa B (NF-κB) contributes to various human inflammatory diseases and malignancies via the upregulation of genes involved in cell proliferation, survival, angiogenesis, inflammation, and metastasis. Thus, inhibition of NF-κB signaling has potential for therapeutic applications in cancer and inflammatory diseases. We reported previously that Nei-like DNA glycosylase 2 (NEIL2), a mammalian DNA glycosylase, is involved in the preferential repair of oxidized DNA bases from the transcriptionally active sequences via the transcription-coupled base excision repair pathway. We have further shown that Neil2-null mice are highly sensitive to tumor necrosis factor α (TNFα)- and lipopolysaccharide-induced inflammation. Both TNFα and lipopolysaccharide are potent activators of NF-κB. However, the underlying mechanism of NEIL2's role in the NF-κB-mediated inflammation remains elusive. Here, we have documented a noncanonical function of NEIL2 and demonstrated that the expression of genes, such as Cxcl1, Cxcl2, Cxcl10, Il6, and Tnfα, involved in inflammation and immune cell migration was significantly higher in both mock- and TNFα-treated Neil2-null mice compared with that in the WT mice. NEIL2 blocks NF-κB's binding to target gene promoters by directly interacting with the Rel homology region of RelA and represses proinflammatory gene expression as determined by co-immunoprecipitation, chromatin immunoprecipitation, and electrophoretic mobility-shift assays. Remarkably, intrapulmonary administration of purified NEIL2 via a noninvasive nasal route significantly abrogated binding of NF-κB to cognate DNA, leading to decreased expression of proinflammatory genes and neutrophil recruitment in Neil2-null as well as WT mouse lungs. Our findings thus highlight the potential of NEIL2 as a biologic for inflammation-associated human diseases.

Readmissions Reduction Program: Mortality and Readmissions for Chronic Obstructive Pulmonary Disease.

Rationale: Implementation of the Hospital Readmissions Reduction Program (HRRP) following discharge of patients with chronic obstructive pulmonary disease (COPD) has led to a reduction in 30-day readmissions with unknown effects on postdischarge mortality.Objectives: To examine the association of HRRP with 30-day hospital readmission and 30-day postdischarge mortality rate in patients after discharge from COPD hospitalization.Methods: Retrospective cohort study of readmission and mortality rates in a national cohort (N = 4,587,542) of admissions of Medicare fee-for-service beneficiaries 65 years or older with COPD from 2006 to 2017.Measurements and Main Results: Data were analyzed for three nonoverlapping periods based on implementation of the HRRP specific to COPD: 1) preannouncement (December 2006 to March 2010), 2) announcement (April 2010 to August 2014), and 3) implementation (October 2014 to November 2017). The 30-day readmission rate decreased from 20.54% in the preannouncement period (December 2006 to July 2008) to 18.74% in the implementation period (May 2016 to November 2017). The 30-day risk-standardized postdischarge mortality rates were 6.91%, 6.59%, and 7.30% for the preannouncement, announcement, and implementation periods, respectively. Generalized estimating equations analyses estimated an additional 1,196 deaths (October 2014 to April 2016) and 3,858 deaths (May 2016 to November 2017) during the HRRP implementation period.Conclusions: We found a reduction in 30-day all-cause readmission rate during the implementation period compared with the preannouncement phase. HRRP implementation was also associated with a significant increase in 30-day mortality after discharge from COPD hospitalization. Additional research is necessary to confirm our findings and understand the factors contributing to increased mortality in patients with COPD in the HRRP implementation period.

Osteoarthritis of the hip: are degenerative tears of the acetabular labrum predictable from features on hip radiographs?

BACKGROUND: A common feature of hip arthritis is the presence of labra tears. Recent literature suggests against the use of magnetic resonance imaging (MRI) in patients aged >45 years for the assessment of hip pain related to arthritis. PURPOSE: To determine if radiographic features of osteoarthritis detectable on routine hip radiographs are accurate and reliable surrogate markers of degenerative acetabular labral tears identified on MR arthrography (MRA) and corroborated during arthroscopy. MATERIAL AND METHODS: A retrospective study involving 86 symptomatic patients (hip pain) with radiologic work-up included MRA and pelvic or hip radiographs that underwent hip arthroscopy within three months. Imaging characteristics assessed on hip radiographs include measurements of superior acetabular, femoral head osteophyte, cortical thickness of the femoral shaft, and minimum joint space as well as presence of subchondral sclerosis of the femoral head and acetabulum, femoral shaft buttressing, and grade of arthritis. Presence of a labral tear was determined by consensus between three readers as well as by surgical correlation. The Pearson's chi-squared and Fisher's exact tests were used to compare presence of labral tears with each radiographic feature. RESULTS: Seventy-one patients (82.6%) had labral tears: 49 (69%) women and 22 (31%) men. Receiver operating characteristic analysis showed statistical significance (P<0.05) between presence of a labral tear and acetabular and femoral head osteophyte sizes but failed to demonstrate any significance regarding acetabular subchondral sclerosis, cortical thickness, buttressing, or minimum joint space. CONCLUSIONS: Radiographic markers such as the acetabular and femoral head osteophyte sizes demonstrated statistical significance with the presence of labral tears.

Circular economy fertilization: Phycoremediated algal biomass as biofertilizers for sustainable crop production.

There is an urgent need to meet the demand of water and nutrients by their reuse and recycling to gratify sustainable food production system and resource conservation. Chlorella minutissima was found to be very effective in the removal of electrical conductivity (EC), total dissolved solids, phosphorous (P), potassium (K), ammonium, nitrate, biological oxygen demand (BOD5) and chemical oxygen demand (COD) of sewage wastewater. We tested the effects of phycoremediated algal biomass addition to soil in field plots of baby corn and spinach, on plant growth, yield and soil chemical properties. The application of 100% nitrogen (N) fertilizer by algal biomass lead to higher economic yield of spinach and baby corn than recommended dose of mineral fertilizers. The available N and P content in experimental plots applied with algae biomass as biofertilizers were significantly higher than other treatments. The soil enzymes, such as urease, nitrate reductase, and dehydrogenase were analysed during the cropping season of baby corn and spinach. The soil supplied with 100% N by algae biomass (C. minutissima) significantly (P < 0.05) increased the dehydrogenase activity in spinach grown soil. While the nitrate reductase activity in soil supplied with algal manure was maximum (0.13 mg NO2-N produced g-1 soil 24 h-1) and significantly higher than other treatments in baby corn grown soil. This study revealed that phycoremediation coupled with biofertilizers production from algae biomass is a recycling and resource conservation exercise to reduce eutrophication, recycling of wastewater, recycling of plant nutrients and improvement of the soil quality in circular economy fertilization.

Reliability of a functional magnetic resonance imaging task of emotional conflict in healthy participants.

Task-based functional neuroimaging methods are increasingly being used to identify biomarkers of treatment response in psychiatric disorders. To facilitate meaningful interpretation of neural correlates of tasks and their potential changes with treatment over time, understanding the reliability of the blood-oxygen-level dependent (BOLD) signal of such tasks is essential. We assessed test-retest reliability of an emotional conflict task in healthy participants collected as part of the Canadian Biomarker Integration Network in Depression. Data for 36 participants, scanned at three time points (weeks 0, 2, and 8) were analyzed, and intra-class correlation coefficients (ICC) were used to quantify reliability. We observed moderate reliability (median ICC values between 0.5 and 0.6), within occipital, parietal, and temporal regions, specifically for conditions of lower cognitive complexity, that is, face, congruent or incongruent trials. For these conditions, activation was also observed within frontal and sub-cortical regions, however, their reliability was poor (median ICC < 0.2). Clinically relevant prognostic markers based on task-based fMRI require high predictive accuracy at an individual level. For this to be achieved, reliability of BOLD responses needs to be high. We have shown that reliability of the BOLD response to an emotional conflict task in healthy individuals is moderate. Implications of these findings to further inform studies of treatment effects and biomarker discovery are discussed.

Timing and Outcomes of Tracheostomy Performed by Pulmonary and/or Critical Care Physicians.

BACKGROUND: Although pulmonary and/or critical care (P/CC) physicians perform percutaneous tracheostomy in mechanically ventilated patients, the trends, timing, and outcomes of this procedure have not been well described. This study aims to describe the trends, timing, and outcomes of this procedure. METHODS: Using 5% medicare data, we retrospectively examined a cohort who had tracheostomy performed after initiation of mechanical ventilation during acute hospitalization to describe the timing of tracheostomy placement by pulmonary and/or critical care (P/CC) physicians and associated outcomes. RESULTS: There were 4864 participants in the study cohort from 2007 to 2014. We examined the timing of tracheostomy (in days from initiation of mechanical ventilation), length of hospital stay, in-hospital death, and death within 30 days after hospital discharge. The percentage of tracheostomies performed by P/CC physicians increased significantly, from 7.2% in 2007 to 14.1% in 2014 (Cochran-Armitage test for trend, P = .001). Tracheostomies performed by P/CC physicians were more common in larger hospitals and major academic medical centers. After adjustment for baseline characteristics, the following parameters did not differ by provider: time to tracheostomy, length of hospital stay (days), in-hospital death, and death within 30 days after discharge. A tracheostomy was more likely to be performed by a P/CC physician at a larger (≥500 beds) hospital (adjusted odds ratio: 1.85, 95% confidence interval: 1.47-2.34). CONCLUSIONS: Tracheostomies are increasingly performed by P/CC physicians with similar outcomes, likely related to patient selection.

Performance of a rapid two-sequence screening protocol for osteomyelitis of the foot.

OBJECTIVE: Compare a two sequence protocol to a standard protocol in the detection of pedal osteomyelitis (OM) and abscesses and to identify patients that benefit from a full protocol. MATERIALS AND METHODS: One hundred thirty-two foot MRIs ordered to assess for OM were enrolled, and the following items were extracted from the clinical reports: use of IV contrast, the presence of OM, reactive osteitis, and a soft tissue abscess. Using only one T1 nonfat-suppressed and one fluid sensitive fat-suppressed sequences, two experienced musculoskeletal radiologists reviewed each case for the presence of OM, reactive osteitis, or an abscess. A Kappa test was calculated to assess for interobserver agreement, and diagnostic performance was determined. The McNemar test was used to assess for the effect of contrast. RESULTS: Agreement between both observers and the clinical report on the presence of osteomyelitis was substantial ( k = 0.63 and 0.72, p < 0.001), while the agreement for abscess was fair (k = 0.29 and 0.38, p < 0.001). For osteomyelitis, both observers showed good accuracy (0.85 and 0.86). When screening bone for a normal versus abnormal case, this method was highly sensitive (0.97-0.98), but was less sensitive for abscess (0.63-0.75). Fifty-one percent of exams used contrast, and it did impact the diagnosis of abscess for one observer. CONCLUSION: This rapid protocol is accurate in making the diagnosis of OM, and its high sensitivity makes it useful to screen for patients that would benefit from a full protocol.

The Canadian Biomarker Integration Network in Depression (CAN-BIND): magnetic resonance imaging protocols

Studies of clinical populations that combine MRI data generated at multiple sites are increasingly common. The Canadian Biomarker Integration Network in Depression (CAN-BIND; www.canbind.ca) is a national depression research program that includes multimodal neuroimaging collected at several sites across Canada. The purpose of the current paper is to provide detailed information on the imaging protocols used in a number of CAN-BIND studies. The CAN-BIND program implemented a series of platform-specific MRI protocols, including a suite of prescribed structural and functional MRI sequences supported by real-time monitoring for adherence and quality control. The imaging data are retained in an established informatics and databasing platform. Approximately 1300 participants are being recruited, including almost 1000 with depression. These include participants treated with antidepressant medications, transcranial magnetic stimulation, cognitive behavioural therapy and cognitive remediation therapy. Our ability to analyze the large number of imaging variables available may be limited by the sample size of the substudies. The CAN-BIND program includes a multimodal imaging database supported by extensive clinical, demographic, neuropsychological and biological data from people with major depression. It is a resource for Canadian investigators who are interested in understanding whether aspects of neuroimaging ­ alone or in combination with other variables ­ can predict the outcomes of various treatment modalities.

Impact of PAP therapy on hospitalization rates in Medicare beneficiaries with COPD and coexisting OSA.

OBJECTIVE: Growing evidence supports that patients with chronic obstructive pulmonary disease (COPD) and coexisting obstructive sleep apnea (OSA) have poor prognosis. This association is described as overlap syndrome. Positive airway pressure (PAP) therapy is now the preferred treatment for OSA. We hypothesized that use of PAP therapy in elderly patients with overlap syndrome would be associated with lower healthcare utilization. METHODS: In this retrospective cohort study, we analyzed data from 5% national sample of fee-for-service Medicare beneficiaries with a diagnosis of COPD who were newly started on PAP therapy in 2011. We examined the effect of PAP therapy on emergency room (ER) visits and hospitalizations for all-cause and COPD-related conditions in the 1 year pre- and 1 year post-initiation of PAP therapy. RESULTS: In year 2011, we identified 319 patients with overlap syndrome who were new users of PAP therapy. In this cohort of patients, hospitalization rates for COPD-related conditions were significantly lower in the 1 year post-initiation of PAP therapy compared to the 1-year pre-initiation period (19.4 vs 25.4%, P value = 0.03). However, ER visits (for any cause or COPD-related conditions) and hospitalization rates for any cause did not differ significantly in the pre- and post-initiation periods. PAP therapy was more beneficial in older adults, those with higher COPD complexity, and those with three or more comorbidities. CONCLUSION: Initiation of PAP therapy in elderly patients with overlap syndrome is associated with a reduction in hospitalization for COPD-related conditions, but not for all-cause hospitalizations and ER visits.

Trends in tobacco use and tobacco cessation counselling codes among Medicare beneficiaries, 2001-2014.

BACKGROUND: Analysis of Medicare data is often used to determine epidemiology, healthcare utilization and effectiveness of disease treatments. We were interested in whether Medicare data could be used to estimate prevalence of tobacco use. Currently, data regarding tobacco use is derived from Behavioral Risk Factor Surveillance System (BRFSS) survey data. We compare administrative claims data for tobacco diagnosis among Medicare beneficiaries to survey (BRFSS) estimates of tobacco use from 2001 to 2014. METHODS: Retrospective cross-sectional study comparing tobacco diagnoses using International Classification of Disease, Ninth Revision (ICD-9) codes for tobacco use in Medicare data to BRFSS data from 2001 to 2014 in adults age ≥ 65 years. Beneficiary data included age, gender, race, socioeconomic status, and comorbidities. Tobacco cessation counselling was also examined using Healthcare Common Procedure Coding System codes. RESULTS: The prevalence of Medicare enrollees aged ≥65 years who had a diagnosis of current tobacco use increased from 2.01% in 2001 to 4.8% in 2014, while the estimates of current tobacco use from BRFSS decreased somewhat (10.03% in 2001 vs. 8.77% in 2014). However, current tobacco use based on Medicare data remained well below the estimates from BRFSS. Use of tobacco cessation counselling increased over the study period with largest increases after 2010. CONCLUSIONS: The use of tobacco-related diagnosis codes increased from 2001 to 2014 in Medicare but still substantially underestimated the prevalence of tobacco use compared to BRFSS data.

Subchondral insufficiency fracture of the knee: grading, risk factors, and outcome.

OBJECTIVE: To propose an magnetic resonance imaging (MRI) grading system for subchondral insufficiency fracture of the knee (SIFK) to predict outcome and assess risk factors. MATERIALS AND METHODS: A total of 50 SIFK patients were retrospectively reviewed utilizing two MRI examinations approximately a year apart and compared them with 51 control subjects. A grading system was introduced that classifies lesions as low- vs high-grade. Lesion location 3D dimensions, extent of bone marrow edema (BME), location of meniscal tears and associated extrusion, degree of chondrosis and among other parameters were stratified according to lesion grade and compared with follow-up examinations. Statistical analyses were performed (Pearson's correlation, binary logistic regression, and Chi-squared analysis). RESULTS: The majority of SIFK lesions were low-grade (LG; 78%) and most of them (70%) were observed in the medial femoral condyle. Predictor variables comparing low-grade and high-grade SIFK lesions included meniscal tear (p = 0.01), degree of extrusion (p < 0.003), chondrosis (p = 0.01), medial chondrosis grade (p = 0.001), medial femoral condyle (p = 0.01), surface collapse (p < 0.0001), marrow edema improvement (p < 0.0001), first MRI anteroposterior dimension (p = 0.001), transverse dimension (p < 0.001), and ellipsoid volume (p = 0.02). Predictor variables found to be significantly different between controls and patients were meniscal tear (p = 0.024), location of the medial meniscal tear (p < 0.0001), degree of extrusion (p < 0.0001), chondrosis (p < 0.0001), joint effusion (p < 0.0001), Baker's cyst (p < 0.0001), knee lock (p = 0.03) and buckle (p = 0.01), and history of trauma (p = 0.01). CONCLUSION: A SIFK grading system for MRI is introduced. Surrogate markers of high-grade lesions include medial meniscus posterior root tears with associated moderate to severe extrusion, high-grade chondrosis, larger lesion sizes (anteroposterior/transverse), and articular surface collapse. Improvement of BME on follow-up was highly predictive of low-grade disease.

CT can stratify patients as low risk for tibial neuropathy following a talus fracture.

OBJECTIVE: Determine the incidence of tibial neuropathy following talus fractures and CT's ability to stratify patients at risk for developing post-traumatic neuropathy. MATERIALS AND METHODS: In this IRB-approved retrospective analysis, 71 talus fractures and 8 contralateral control ankle CTs were reviewed by one observer blinded to clinical information. CT evidence suggestive of tibial neurovascular bundle injury included nerve displacement, perineural fat effacement/edema, and bone touching nerve. The association between these CT findings and clinically evident tibial neuropathy was analyzed. A semi-quantitative likelihood score was assigned based on the degree of the CT findings around the nerve. Interobserver agreement was calculated between 2 other readers. RESULTS: Twenty-five percent of patients in this cohort had clinical evidence of tibial neuropathy. There was a high specificity (0.87-0.93) and negative predictive value (0.83-0.87), a moderate accuracy (0.80-0.82), but a lower sensitivity (0.33-0.56) associated with the CT findings. Among the CT findings, nerve displacement (p < 0.0001) and bone touching nerve (p = 0.01) were associated with tibial neuropathy. A likelihood score of 2-5 was associated (p = 0.007-0.015) with tibial neuropathy. The presence of tibial neuropathy and nerve recovery were not associated with hospital length of stay, while CT findings were. There was substantial agreement between the three readers: likelihood scores 2+ (k = 0.78) and 3+ (k = 0.72). CONCLUSIONS: Tibial neuropathy occurs following talus fractures, and CT findings may help surgeons narrow down the number of patients requiring close neurological follow-up.

Testosterone replacement therapy and hospitalization rates in men with COPD.

Testosterone deficiency is common in men with chronic obstructive pulmonary disease (COPD) and may exacerbate their condition. Research suggests that testosterone replacement therapy (TRT) may have a beneficial effect on respiratory outcomes in men with COPD. To date, however, no large-scale nationally representative studies have examined this association. The objective of the study was to assess whether TRT reduced the risk of respiratory hospitalizations in middle-aged and older men with COPD. We conducted two retrospective cohort studies. First, using the Clinformatics Data Mart-a database of one of the largest commercially insured populations in the United States-we examined 450 men, aged 40-63 years, with COPD who initiated TRT between 2005 and 2014. Second, using the national 5% Medicare database, we examined 253 men, aged ≥66 years, with COPD who initiated TRT between 2008 and 2013. We used difference-in-differences (DID) statistical modeling to compare pre- versus post-respiratory hospitalization rates in TRT users versus matched TRT nonusers over a parallel time period. DID analyses showed that TRT users had a greater relative decrease in respiratory hospitalizations compared with nonusers. Specifically, middle-aged TRT users had a 4.2% greater decrease in respiratory hospitalizations compared with nonusers (-2.4 decrease vs. 1.8 increase; p = 0.03); and older TRT users had a 9.1% greater decrease in respiratory hospitalizations compared with nonusers (-0.8 decrease vs. 8.3 increase; p = 0.04). These findings suggest that TRT may slow disease progression in patients with COPD. Future studies should examine this association in larger cohorts of patients, with particular attention to specific biological pathways.

Neil2-null Mice Accumulate Oxidized DNA Bases in the Transcriptionally Active Sequences of the Genome and Are Susceptible to Innate Inflammation.

Why mammalian cells possess multiple DNA glycosylases (DGs) with overlapping substrate ranges for repairing oxidatively damaged bases via the base excision repair (BER) pathway is a long-standing question. To determine the biological role of these DGs, null animal models have been generated. Here, we report the generation and characterization of mice lacking Neil2 (Nei-like 2). As in mice deficient in each of the other four oxidized base-specific DGs (OGG1, NTH1, NEIL1, and NEIL3), Neil2-null mice show no overt phenotype. However, middle-aged to old Neil2-null mice show the accumulation of oxidative genomic damage, mostly in the transcribed regions. Immuno-pulldown analysis from wild-type (WT) mouse tissue showed the association of NEIL2 with RNA polymerase II, along with Cockayne syndrome group B protein, TFIIH, and other BER proteins. Chromatin immunoprecipitation analysis from mouse tissue showed co-occupancy of NEIL2 and RNA polymerase II only on the transcribed genes, consistent with our earlier in vitro findings on NEIL2's role in transcription-coupled BER. This study provides the first in vivo evidence of genomic region-specific repair in mammals. Furthermore, telomere loss and genomic instability were observed at a higher frequency in embryonic fibroblasts from Neil2-null mice than from the WT. Moreover, Neil2-null mice are much more responsive to inflammatory agents than WT mice. Taken together, our results underscore the importance of NEIL2 in protecting mammals from the development of various pathologies that are linked to genomic instability and/or inflammation. NEIL2 is thus likely to play an important role in long term genomic maintenance, particularly in long-lived mammals such as humans.

Validation of the Readmission Risk Score in Heart Failure Patients at a Tertiary Hospital.

BACKGROUND: The Readmission Risk score (RR score) is a software application developed to identify patients at increased risk for readmission. This score was developed to improve on the methodology for 30-day risk-standardized all-cause readmission rates (RSRRs) used by the Centers for Medicare and Medicaid Services for its quality reporting system. However, the utility of the RR score in clinical practice has not been independently validated. METHODS AND RESULTS: We included patients admitted with the primary discharge diagnosis of congestive heart failure (CHF) from September 2011 to August 2013. Data on individual components of the RR score were obtained by means of detailed chart review. We calculated the RR score of all admissions and examined its ability to predict 30-day all-cause readmission. We repeated the analysis by randomly selecting 1 admission per patient and also by including only those ≥ 65 years old. A total of 1,046 admissions met the inclusion criteria. Of these, 369 (35.28%) were readmitted within 30 days of discharge. The performance of the RR score was poor, with an area under the receiver operating characteristic curve (AUC) of 0.61 (95% confidence interval [CI] 0.57-0.64) for all age groups and 0.59 (95% CI 0.53-0.64) for patients aged ≥ 65 years. The AUC for the RR score was 0.58 (95% CI 0.50-0.65) in a randomly selected patient-level model. However, patients in the highest quartile of RR score were twice as likely to be readmitted as those in the lowest quartile (47.24% vs 24.69%; P < .001). The sensitivity and specificity of the RR score in predicting all cause readmissions were poor. CONCLUSION: Based on our single-institution data, patients with CHF readmitted within 30 days had a higher RR score than those not readmitted. The ability of the RR score to predict future all-cause readmission was modest at best.