Substrate Insolubility Dictates Hsp104-Dependent Endoplasmic-Reticulum-Associated Degradation.

Misfolded proteins in the endoplasmic reticulum (ER) are destroyed by ER-associated degradation (ERAD). Although the retrotranslocation of misfolded proteins from the ER has been reconstituted, how a polypeptide is initially selected for ERAD remains poorly defined. To address this question while controlling for the diverse nature of ERAD substrates, we constructed a series of truncations in a single ER-tethered domain. We observed that the truncated proteins exhibited variable degradation rates and discovered a positive correlation between ERAD substrate instability and detergent insolubility, which demonstrates that aggregation-prone species can be selected for ERAD. Further, Hsp104 facilitated degradation of an insoluble species, consistent with the chaperone's disaggregase activity. We also show that retrotranslocation of the ubiquitinated substrate from the ER was inhibited in the absence of Hsp104. Therefore, chaperone-mediated selection frees the ER membrane of potentially toxic, aggregation-prone species.

Who Transmits Tuberculosis to Whom: A Cross-Sectional Analysis of a Cohort Study in Lima, Peru.

RATIONALE: The persistent burden of TB disease emphasizes the need to identify individuals with TB for treatment and those at a high risk of incident TB for prevention. Targeting interventions towards those at high risk of developing and transmitting tuberculosis is a public health priority. OBJECTIVES: We aimed to identify characteristics of individuals involved in tuberculosis transmission in a community setting, which may guide the prioritization of targeted interventions. METHODS: We collected clinical and socio-demographic data from a cohort of tuberculosis patients in Lima, Peru. We used whole-genome sequencing data to assess the genetic distance between all possible pairs of patients; we considered pairs to be the result of a direct transmission event if they differed by three or fewer SNPs and we assumed that the first diagnosed patient in a pair was the transmitter and the second to be the recipient. We used logistic regression to examine the association between host factors and the likelihood of direct tuberculosis transmission. MAIN RESULTS: Analyzing data from 2,518 tuberculosis index patients, we identified 1,447 direct transmission pairs. Regardless of recipient attributes, individuals less than 34 years old, males, and those with a history of incarceration had a higher likelihood of being transmitters in direct transmission pairs. Direct transmission was more likely when both patients were drinkers or smokers. CONCLUSIONS: This study identifies men, young adults, former prisoners, alcohol consumers, and smokers as priority groups for targeted interventions. Innovative strategies are needed to extend tuberculosis screening to social groups like young adults and prisoners with limited access to routine preventive care. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Differential sensitivity of the yeast Lon protease Pim1p to impaired mitochondrial respiration.

Mitochondria are essential organelles whose proteome is well protected by regulated protein degradation and quality control. While the ubiquitin-proteasome system can monitor mitochondrial proteins that reside at the mitochondrial outer membrane or are not successfully imported, resident proteases generally act on proteins within mitochondria. Herein, we assess the degradative pathways for mutant forms of three mitochondrial matrix proteins (mas1-1HA, mas2-11HA, and tim44-8HA) in Saccharomyces cerevisiae. The degradation of these proteins is strongly impaired by loss of either the matrix AAA-ATPase (m-AAA) (Afg3p/Yta12p) or Lon (Pim1p) protease. We determine that these mutant proteins are all bona fide Pim1p substrates whose degradation is also blocked in respiratory-deficient "petite" yeast cells, such as in cells lacking m-AAA protease subunits. In contrast, matrix proteins that are substrates of the m-AAA protease are not affected by loss of respiration. The failure to efficiently remove Pim1p substrates in petite cells has no evident relationship to Pim1p maturation, localization, or assembly. However, Pim1p's autoproteolysis is intact, and its overexpression restores substrate degradation, indicating that Pim1p retains some functionality in petite cells. Interestingly, chemical perturbation of mitochondria with oligomycin similarly prevents degradation of Pim1p substrates. Our results demonstrate that Pim1p activity is highly sensitive to mitochondrial perturbations such as loss of respiration or drug treatment in a manner that we do not observe with other proteases.

Microbial metabolism of caffeine and potential applications in bioremediation.

With increasing global consumption of caffeine-rich products, such as coffee, tea, and energy drinks, there is also an increase in urban and processing waste full of residual caffeine with limited disposal options. This waste caffeine has been found to leach into the surrounding environment where it poses a threat to microorganisms, insects, small animals, and entire ecosystems. Growing interest in harnessing this environmental contaminant has led to the discovery of 79 bacterial strains, eight yeast strains, and 32 fungal strains capable of metabolizing caffeine by N-demethylation and/or C-8 oxidation. Recently observed promiscuity of caffeine-degrading enzymes in vivo has opened up the possibility of engineering bacterial strains capable of producing a wide variety of caffeine derivatives from a renewable resource. These engineered strains can be used to reduce the negative environmental impact of leached caffeine-rich waste through bioremediation efforts supplemented by our increasing understanding of new techniques such as cell immobilization. Here, we compile all of the known caffeine-degrading microbial strains, discuss their metabolism and related enzymology, and investigate their potential application in bioremediation.

Prioritizing Quality Measures in Acute Stroke Care : A Cost-Effectiveness Analysis.

BACKGROUND: The American Heart Association and American Stroke Association (AHA/ASA) endorsed 15 process measures for acute ischemic stroke (AIS) to improve the quality of care. Identifying the highest-value measures could reduce the administrative burden of quality measure adoption while retaining much of the value of quality improvement. OBJECTIVE: To prioritize AHA/ASA-endorsed quality measures for AIS on the basis of health impact and cost-effectiveness. DESIGN: Individual-based stroke simulation model. DATA SOURCES: Published literature. TARGET POPULATION: U.S. patients with incident AIS. TIME HORIZON: Lifetime. PERSPECTIVE: Health care sector. INTERVENTION: Current versus complete (100%) implementation at the population level of quality measures endorsed by the AHA/ASA with sufficient clinical evidence (10 of 15). OUTCOME MEASURES: Life-years, quality-adjusted life-years (QALYs), incremental cost-effectiveness ratios, and incremental net health benefits. RESULTS OF BASE-CASE ANALYSIS: Discounted life-years gained from complete implementation would range from 472 (tobacco use counseling) to 34 688 (early carotid imaging) for an annual AIS patient cohort. All AIS quality measures were cost-saving or highly cost-effective by AHA standards (<$50 000 per QALY for high-value care). Early carotid imaging and intravenous tissue plasminogen activator contributed the largest fraction of the total potential value of quality improvement (measured as incremental net health benefit), accounting for 72% of the total value. The top 5 quality measures accounted for 92% of the total potential value. RESULTS OF SENSITIVITY ANALYSIS: A web-based user interface allows for context-specific sensitivity and scenario analyses. LIMITATION: Correlations between quality measures were not incorporated. CONCLUSION: Substantial variation exists in the potential net benefit of quality improvement across AIS quality measures. Benefits were highly concentrated among 5 of 10 measures assessed. Our results can help providers and payers set priorities for quality improvement efforts and value-based payments in AIS care. PRIMARY FUNDING SOURCE: National Institute of Neurological Disorders and Stroke.

I spy: Factors influencing the observation of oxytetracycline in calcified structures of fishes viewed using standard light and fluorescence microscopy.

The antibiotic oxytetracycline (OTC) is a fluorochrome marker, and fluorescence microscopy is used to view OTC marks in fishes' calcified structures. However, OTC marks have been observed in calcified structures using standard light microscopy for multiple species. Therefore, we conducted an experiment to investigate potential factors (i.e., season, total length of fish, growth rate, and sex) influencing the observation of OTC in calcified structures (otoliths and fin rays or spines) from channel catfish Ictalurus punctatus, gray redhorse Moxostoma congestum, Guadalupe bass Mircopterus treculii, and redbreast sunfish Lepomis auritus viewed using standard light and fluorescence microscopy. OTC stains were not observed in any otoliths under standard light; however, OTC marks were commonly observed in I. punctatus spines using standard light microscopy (56.2%). Ninety-nine percent of otoliths and 88.9% of spines and fin rays had a visible fluorescent OTC mark when viewed using fluorescence microscopy. There was a negative relationship between the observed OTC mark and total length of fish for each season, but fish injected in the summer had the most structures with an observed OTC mark under either light condition. Understanding how OTC marking is affected by biological processes and environmental conditions will assist in future studies that rely on chemical marking of calcified structures by increasing efficacy of OTC marking and interpretation of marks.

Sensitivity of Various Case Detection Algorithms for Community-based Tuberculosis Screening.

Using data from 388 people diagnosed with tuberculosis through a community-based screening program in Lima, Peru, we estimated that cough screening followed by sputum smear microscopy would have detected only 23% of cases found using an algorithm of radiographic screening followed by rapid nucleic acid amplification testing and clinical evaluation.

Modulating the immune system as a therapeutic target for myelodysplastic syndromes and acute myeloid leukemia.

Modulating the immune system to treat diseases, including myeloid malignancies, has resulted in the development of a multitude of novel therapeutics in recent years. Myelodysplastic syndromes or neoplasms (MDS) and acute myeloid leukemia (AML) are hematologic malignancies that arise from defects in hematopoietic stem and progenitor cells (HSPCs). Dysregulated immune responses, especially in innate immune and inflammatory pathways, are highly associated with the acquisition of HSPC defects in MDS and AML pathogenesis. In addition to utilizing the immune system in immunotherapeutic interventions such as chimeric antigen receptor T cell therapy, vaccines, and immune checkpoint inhibitors, mitigating dysregulation of innate immune and inflammatory responses in MDS and AML remains a priority in slowing the initiation and progression of these myeloid malignancies. This review provides a comprehensive summary of the current progress of diverse strategies to utilize or modulate the immune system in the treatment of MDS and AML.

Physician Work Hours and the Gender Pay Gap - Evidence from Primary Care.

BACKGROUND: The gender gap in physician pay is often attributed in part to women working fewer hours than men, but evidence to date is limited by self-report and a lack of detail regarding clinical revenue and gender differences in practice style. METHODS: Using national all-payer claims and data from electronic health records, we conducted a cross-sectional analysis of 24.4 million primary care office visits in 2017 and performed comparisons between female and male physicians in the same practices. Our primary independent variable was physician gender; outcomes included visit revenue, visit counts, days worked, and observed visit time (interval between the initiation and the termination of a visit). We created multivariable regression models at the year, day, and visit level after adjustment for characteristics of the primary care physicians (PCPs), patients, and types of visit and for practice fixed effects. RESULTS: In 2017, female PCPs generated 10.9% less revenue from office visits than their male counterparts (-$39,143.2; 95% confidence interval [CI], -53,523.0 to -24,763.4) and conducted 10.8% fewer visits (-330.5 visits; 95% CI, -406.6 to -254.3) over 2.6% fewer clinical days (-5.3 days; 95% CI, -7.7 to -3.0), after adjustment for age, academic degree, specialty, and number of sessions worked per week, yet spent 2.6% more observed time in visits that year than their male counterparts (1201.3 minutes; 95% CI, 184.7 to 2218.0). Per visit, after adjustment for PCP, patient, and visit characteristics, female PCPs generated equal revenue but spent 15.7% more time with a patient (2.4 minutes; 95% CI, 2.1 to 2.6). These results were consistent in subgroup analyses according to the gender and health status of the patients and the type and complexity of the visits. CONCLUSIONS: Female PCPs generated less visit revenue than male colleagues in the same practices owing to a lower volume of visits, yet spent more time in direct patient care per visit, per day, and per year. (Funded in part by the Robert Wood Johnson Foundation.).

Remote patient monitoring for management of diabetes mellitus in pregnancy is associated with improved maternal and neonatal outcomes.

BACKGROUND: Diabetes mellitus is a common medical complication of pregnancy, and its treatment is complex. Recent years have seen an increase in the application of mobile health tools and advanced technologies, such as remote patient monitoring, with the aim of improving care for diabetes mellitus in pregnancy. Previous studies of these technologies for the treatment of diabetes in pregnancy have been small and have not clearly shown clinical benefit with implementation. OBJECTIVE: Remote patient monitoring allows clinicians to monitor patients' health data (such as glucose values) in near real-time, between office visits, to make timely adjustments to care. Our objective was to determine if using remote patient monitoring for the management of diabetes in pregnancy leads to an improvement in maternal and neonatal outcomes. STUDY DESIGN: This was a retrospective cohort study of pregnant patients with diabetes mellitus managed by the maternal-fetal medicine practice at one academic institution between October 2019 and April 2021. This practice transitioned from paper-based blood glucose logs to remote patient monitoring in February 2020. Remote patient monitoring options included (1) device integration with Bluetooth glucometers that automatically uploaded measured glucose values to the patient's Epic MyChart application or (2) manual entry in which patients manually logged their glucose readings into their MyChart application. Values in the MyChart application directly transferred to the patient's electronic health record for review and management by clinicians. In total, 533 patients were studied. We compared 173 patients managed with paper logs to 360 patients managed with remote patient monitoring (176 device integration and 184 manual entry). Our primary outcomes were composite maternal morbidity (which included third- and fourth-degree lacerations, chorioamnionitis, postpartum hemorrhage requiring transfusion, postpartum hysterectomy, wound infection or separation, venous thromboembolism, and maternal admission to the intensive care unit) and composite neonatal morbidity (which included umbilical cord pH <7.00, 5 minute Apgar score <7, respiratory morbidity, hyperbilirubinemia, meconium aspiration, intraventricular hemorrhage, necrotizing enterocolitis, sepsis, pneumonia, seizures, hypoxic ischemic encephalopathy, shoulder dystocia, trauma, brain or body cooling, and neonatal intensive care unit admission). Secondary outcomes were measures of glycemic control and the individual components of the primary composite outcomes. We also performed a secondary analysis in which the patients who used the two different remote patient monitoring options (device integration vs manual entry) were compared. Chi-square, Fisher's exact, 2-sample t, and Mann-Whitney tests were used to compare the groups. A result was considered statistically significant at P<.05. RESULTS: Maternal baseline characteristics were not significantly different between the remote patient monitoring and paper groups aside from a slightly higher baseline rate of chronic hypertension in the remote patient monitoring group (6.1% vs 1.2%; P=.011). The primary outcomes of composite maternal and composite neonatal morbidity were not significantly different between the groups. However, remote patient monitoring patients submitted more glucose values (177 vs 146; P=.008), were more likely to achieve glycemic control in target range (79.2% vs 52.0%; P<.0001), and achieved the target range sooner (median, 3.3 vs 4.1 weeks; P=.025) than patients managed with paper logs. This was achieved without increasing in-person visits. Remote patient monitoring patients had lower rates of preeclampsia (5.8% vs 15.0%; P=.0006) and their infants had lower rates of neonatal hypoglycemia in the first 24 hours of life (29.8% vs 51.7%; P<.0001). CONCLUSION: Remote patient monitoring for the management of diabetes mellitus in pregnancy is superior to a traditional paper-based approach in achieving glycemic control and is associated with improved maternal and neonatal outcomes.

The impact of clinical placement site, community clinic versus tertiary hospital, on midwifery students' clinical learning experience in Sierra Leone: a cohort study.

BACKGROUND: In midwifery education, the clinical learning experience (CLE) is a critical component to gaining competency and should comprise greater than 50% of a student's education. Many studies have identified positive and negative factors affecting students' CLE. However, few studies have directly compared the difference in CLE based on placement at a community clinic versus a tertiary hospital. METHODS: The aim of this study was to examine how clinical placement site, clinic or hospital, impacts students' CLE in Sierra Leone. A once 34-question survey was given to midwifery students attending one of four public midwifery schools in Sierra Leone. Median scores were compared for survey items by placement site using Wilcoxon tests. The relationship between clinical placement and student's experience were assessed using multilevel logistic regression. RESULTS: Two-hundred students (hospitals students = 145 (72.5%); clinic students = 55 (27.5%) across Sierra Leone completed surveys. Most students (76%, n = 151) reported satisfaction with their clinical placement. Students placed at clinics were more satisfied with opportunities to practice/develop skills (p = 0.007) and more strongly agreed preceptors treated them with respect (p = 0.001), helped improve their skills (p = 0.001), provided a safe environment to ask questions (p = 0.002), and had stronger teaching/mentorship skills (p = 0.009) than hospital students. Students placed at hospitals had greater satisfaction in exposure to certain clinical opportunities including completing partographs (p < 0.001); perineal suturing (p < 0.001); drug calculations/administration (p < 0.001) and estimation of blood loss (p = 0.004) compared to clinic students. The odds of students spending more than 4 h per day in direct clinical care were 5.841 (95% CI: 2.187-15.602) times higher for clinic students versus hospital students. There was no difference between clinical placement sites in regards to number of births students attended (OR 0.903; 95% CI: 0.399, 2.047) or number of births students managed without a preceptor/clinician present (OR 0.729; 95% CI: 0.285, 1.867). CONCLUSION: The clinical placement site, hospital or clinic, impacts midwifery students' CLE. Clinics offered students significantly greater attributes of a supportive learning environment and access to direct, hands-on opportunities for patient care. These findings may be helpful for schools when using limited resources to improve the quality of midwifery education.

Biocatalytic production of 7-methylxanthine by a caffeine-degrading Escherichia coli strain.

7-Methylxanthine, a derivative of caffeine (1,3,7-trimethylxanthine), is a high-value compound that has multiple medical applications, particularly with respect to eye health. Here, we demonstrate the biocatalytic production of 7-methylxanthine from caffeine using Escherichia coli strain MBM019, which was constructed for production of paraxanthine (1,7-dimethylxanthine). The mutant N-demethylase NdmA4, which was previously shown to catalyze N3 -demethylation of caffeine to produce paraxanthine, also retains N1 -demethylation activity toward paraxanthine. This study demonstrates that whole cell biocatalysts containing NdmA4 are more active toward paraxanthine than caffeine. We used four serial resting cell assays, with spent cells exchanged for fresh cells between each round, to produce 2,120 µM 7-methylxanthine and 552 µM paraxanthine from 4,331 µM caffeine. The purified 7-methylxanthine and paraxanthine were then isolated via preparatory-scale HPLC, resulting in 177.3 mg 7-methylxanthine and 48.1 mg paraxanthine at high purity. This is the first reported strain genetically optimized for the biosynthetic production of 7-methylxanthine from caffeine.

Concordance of Drug-resistance Profiles Between Persons With Drug-resistant Tuberculosis and Their Household Contacts: A Systematic Review and Meta-analysis.

BACKGROUND: Household contacts of patients with drug-resistant tuberculosis (TB) are at high risk for being infected with Mycobacterium tuberculosis and for developing TB disease. To guide regimen composition for the empirical treatment of TB infection and disease in these household contacts, we estimated drug-resistance profile concordance between index patients with drug-resistant TB and their household contacts. METHODS: We performed a systematic review and meta-analysis of studies published through 24 July 2018 that reported resistance profiles of drug-resistant TB index cases and secondary cases within their households. Using a random-effects meta-analysis, we estimated resistance profile concordance, defined as the percentage of secondary cases whose M. tuberculosis strains were resistant to the same drugs as strains from their index cases. We also estimated isoniazid/rifampin concordance, defined as whether index and secondary cases had identical susceptibilities for isoniazid and rifampin only. RESULTS: We identified 33 eligible studies that evaluated resistance profile concordance between 484 secondary cases and their household index cases. Pooled resistance profile concordance was 54.3% (95% confidence interval [CI], 40.7-67.6%; I2 = 85%). Pooled isoniazid/rifampin concordance was 82.6% (95% CI, 72.3-90.9%; I2 = 73%). Concordance estimates were similar in a subanalysis of 16 studies from high-TB-burden countries. There were insufficient data to perform a subanalysis among pediatric secondary cases. CONCLUSIONS: Household contacts of patients with drug-resistant TB should receive treatment for TB infection and disease that assumes that they, too, are infected with a drug-resistant M. tuberculosis strain. Whenever possible, drug susceptibility testing should be performed for secondary cases to optimize regimen composition.

Nephron-deficient HSRA rats exhibit renal injury with age but have limited renal damage from streptozotocin-induced hyperglycemia.

Hypertension and diabetes are the greatest factors influencing the progression of chronic kidney disease (CKD). Investigation into the role of nephron number in CKD alone or with hypertension has revealed a strong inverse relationship between the two; however, not much is known about the connection between nephron number and diabetic kidney disease. The heterogeneous stock-derived model of unilateral renal agenesis (HSRA) rat, a novel model of nephron deficiency, provides a unique opportunity to study the association between nephron number and hypertension and diabetes on CKD. HSRA rats exhibit failure of one kidney to develop in 50-75% of offspring, whereas the remaining offspring are born with two kidneys. Rats born with one kidney (HSRA-S) develop significant renal injury with age compared with two-kidney littermates (HSRA-C). The induction of hypertension as a secondary stressor leads to significantly more renal injury in HSRA-S compared with HSRA-C rats and nephrectomized HSRA-C (HSRA-UNX) rats. The present study sought to address the hypothesis that nephron deficiency in the HSRA rat would hasten renal injury in the presence of a secondary stressor of hyperglycemia. HSRA animals did not exhibit diabetes-related traits at any age; thus, streptozotocin (STZ) was used to induce hyperglycemia in HSRA-S, HSRA-C, and HSRA-UNX rats. STZ- and vehicle-treated animals were followed for 15 wk. STZ-treated animals developed robust hyperglycemia, but in contrast to the response to hypertension, neither HSRA-S nor HSRA-UNX animals developed proteinuria compared with vehicle treatment. In total, our data indicate that hyperglycemia from STZ alone does not have a significant impact on the onset or progression of injury in young one-kidney HSRA animals.NEW & NOTEWORTHY The HSRA rat, a novel model of nephron deficiency, provides a unique opportunity to study the association between nephron number and confounding cardiovascular complications that impact kidney health. Although hypertension was previously shown to exacerbate renal injury in young HSRA animals, diabetic hyperglycemia did not lead to worse renal injury, suggesting that nephron number has limited impact on kidney injury, at least in this model.

Validation of a Community-Acquired Pneumonia Score To Improve Empiric Antibiotic Selection at an Academic Medical Center.

The 2019 American Thoracic Society and the Infectious Diseases Society of America community-acquired pneumonia (CAP) guidelines recommend that drug-resistant pathogens (DRP) be empirically covered if locally validated risk factors are present. This retrospective case-control validation study evaluated the performance of the drug resistance in pneumonia (DRIP) clinical prediction score. Two hundred seventeen adult patients with ICD-10 (https://www.who.int/classifications/classification-of-diseases) pneumonia diagnosis, positive confirmed microbiologic data, and clinical signs and symptoms were included. A DRIP score of ≥4 was used to assess model performance. Logistic regression was used to select for significant predictors and create a modified DRIP score, which was evaluated to define clinical application. The DRIP score predicted pneumonia due to a DRP with a sensitivity of 67% and specificity of 73%. The area under the receiver operating characteristic (AUROC) curve was 0.76 (95% confidence interval [CI], 0.69 to 0.82). From regression analysis, prior infection with a DRP and antibiotics in the last 60 days, yielding scores of 2 points and 1 point, respectively, remained local risk factors in predicting drug-resistant pneumonia. Sensitivity (47%) and specificity (94%) were maximized at a threshold of ≥2 in the modified DRIP model. Therefore, prior infection with a DRP remained the only clinically relevant predictor for drug-resistant pneumonia. The original DRIP score demonstrated a decreased performance in our patient population and behaved similarly to other clinical prediction models. Empiric CAP therapy without anti-methicillin-resistant Staphylococcus aureus and antipseudomonal coverage should be considered for noncritically ill patients without a drug resistant pathogen infection in the past year. Our data support the necessity of local validation to authenticate clinical risk predictors for drug-resistant pneumonia.

A structurally unique E2-binding domain activates ubiquitination by the ERAD E2, Ubc7p, through multiple mechanisms.

Cue1p is an integral component of yeast endoplasmic reticulum (ER)-associated degradation (ERAD) ubiquitin ligase (E3) complexes. It tethers the ERAD ubiquitin-conjugating enzyme (E2), Ubc7p, to the ER and prevents its degradation, and also activates Ubc7p via unknown mechanisms. We have now determined the crystal structure of the Ubc7p-binding region (U7BR) of Cue1p with Ubc7p. The U7BR is a unique E2-binding domain that includes three α-helices that interact extensively with the "backside" of Ubc7p. Residues essential for E2 binding are also required for activation of Ubc7p and for ERAD. We establish that the U7BR stimulates both RING-independent and RING-dependent ubiquitin transfer from Ubc7p. Moreover, the U7BR enhances ubiquitin-activating enzyme (E1)-mediated charging of Ubc7p with ubiquitin. This demonstrates that an essential component of E3 complexes can simultaneously bind to E2 and enhance its loading with ubiquitin. These findings provide mechanistic insights into how ubiquitination can be stimulated.

Daily Walking and the Risk of Knee Replacement Over 5 Years Among Adults With Advanced Knee Osteoarthritis in the United States.

OBJECTIVE: To examine the association of the volume and intensity of daily walking at baseline with the risk of knee replacement (KR) over 5 years in adults with advanced structural knee osteoarthritis. DESIGN: Prospective, longitudinal, and multicenter observational study. SETTING: Osteoarthritis Initiative study with follow-up from 2008-2015. PARTICIPANTS: Community-dwelling adults with or at risk of knee osteoarthritis were recruited from 4 sites in the United States (N=516; mean age, 67.7±8.6y; body mass index, 29.3±4.7 kg/m2; 52% female). We included participants with advanced structural disease, without KR and had valid daily walking data (quantified using Actigraph GT1M), at baseline. INTERVENTIONS: Not applicable. MAIN OUTCOMES: KR. Walking volume was measured as steps/day and intensity as minutes/day spent not walking (0 steps/min) and walking at very light (1-49 steps/min), light (50-100 steps/min), or moderate (>100 steps/min) intensities. To examine the relationship of walking volume and intensity with the risk of KR, we calculated hazard ratios (HRs) and 95% confidence intervals (CIs) adjusting for covariates. RESULTS: Of 516 adults with advanced structural disease, 88 received a KR over 5 years (17%). Walking an additional 1000 steps/d was not associated with the risk of KR (adjusted HR=0.95; 95% CI, 0.84-1.04). Statistically, replacing 10 min/d of very light and light walking with 10 min/d of moderate walking reduced the risk of KR incidence by 35% and 37%, respectively (adjusted HR=0.65, 95% CI, 0.45-0.94, for very light and adjusted HR=0.63; 95% CI, 0.40-1.00, for light). CONCLUSIONS: Daily walking volume and intensity did not increase KR risk over 5 years and may be protective in some cases in adults with advanced structural knee osteoarthritis.

Whole genome sequencing and novel candidate genes for CAKUT and altered nephrogenesis in the HSRA rat.

The HSRA rat is a model of congenital abnormalities of the kidney and urogenital tract (CAKUT). Our laboratory has used this model to investigate the role of nephron number (functional unit of the kidney) in susceptibility to develop kidney disease as 50-75% offspring are born with a single kidney (HSRA-S), while 25-50% are born with two kidneys (HSRA-C). HSRA-S rats develop increased kidney injury and hypertension with age compared with nephrectomized two-kidney animals (HSRA-UNX), suggesting that even slight differences in nephron number can be an important driver in decline in kidney function. The HSRA rat was selected and inbred from a family of outbred heterogeneous stock (NIH-HS) rats that exhibited a high incidence of CAKUT. The HS model was originally developed from eight inbred strains (ACI, BN, BUF, F344, M520, MR, WKY, and WN). The genetic make-up of the HSRA is therefore a mosaic of these eight inbred strains. Interestingly, the ACI progenitor of the HS model exhibits CAKUT in 10-15% of offspring with the genetic cause being attributed to the presence of a long-term repeat (LTR) within exon 1 of the c-Kit gene. Our hypothesis is that the HSRA and ACI share this common genetic cause, but other alleles in the HSRA genome contribute to the increased penetrance of CAKUT (75% HSRA vs. 15% in ACI). To facilitate genetic studies and better characterize the model, we sequenced the whole genome of the HSRA to a depth of ~50×. A genome-wide variant analysis of high-impact variants identified a number of novel genes that could be linked to CAKUT in the HSRA model. In summary, the identification of new genes/modifiers that lead to CAKUT/loss of one kidney in the HSRA model will provide greater insight into association between kidney development and susceptibility to develop cardiovascular disease later in life.

Identification of factors associated with delayed treatment of obstetric hypertensive emergencies.

BACKGROUND: Obstetric hypertensive emergency is defined as having systolic blood pressure ≥160 mm Hg or diastolic blood pressure ≥110 mm Hg, confirmed 15 minutes apart. The American College of Obstetricians and Gynecologists recommends that acute-onset, severe hypertension be treated with first line-therapy (intravenous labetalol, intravenous hydralazine or oral nifedipine) within 60 minutes to reduce risk of maternal morbidity and death. OBJECTIVE: Our objective was to identify barriers that lead to delayed treatment of obstetric hypertensive emergency. STUDY DESIGN: A retrospective cohort study was performed that compared women who were treated appropriately within 60 minutes vs those with delay in first-line therapy. We identified 604 patients with discharge diagnoses of chronic hypertension, gestational hypertension, or preeclampsia using International Classification of Diseases-10 codes and obstetric antihypertensive usage in a pharmacy database at 1 academic institution from January 2017 through June 2018. Of these, 267 women (44.2%) experienced obstetric hypertensive emergency in the intrapartum period or within 2 days of delivery; the results from 213 women were used for analysis. We evaluated maternal characteristics, presenting symptoms and circumstances, timing of hypertensive emergency, gestational age at presentation, and administered medications. Chi square, Fisher's exact, Wilcoxon rank-sum, and sample t-tests were used to compare the 2 groups. Univariable logistic regression was applied to determine predictors of delayed treatment. Multivariable regression model was also performed; C-statistic and Hosmer and Lemeshow goodness-of-fit test were used to assess the model fit. A result was considered statistically significant at P<.05. RESULTS: Of the 213 women, 110 (51.6%) had delayed treatment vs 103 (48.4%) who were treated within 60 minutes. Patients who had delayed treatment were 3.2 times more likely to have an initial blood pressure in the nonsevere range vs those who had timely treatment (odds ratio, 3.24; 95% confidence interval, 1.85-5.68). Timeliness of treatment was associated with presence or absence of preeclampsia symptoms; patients without preeclampsia symptoms were 2.7 times more likely to have delayed treatment (odds ratio, 2.68; 95% confidence interval, 1.50-4.80). Patients with hypertensive emergencies that occurred overnight between 10 pm and 6 am were 2.7 times more likely to have delayed treatment vs those emergencies that occurred between 6 am and 10 pm (odds ratio, 2.72; 95% confidence interval, 1.27-5.83). Delayed treatment also had an association with race, with white patients being 1.8 times more likely to have delayed treatment (odds ratio, 1.79; 95% confidence interval, 1.04-3.08). Patients who were treated at <60 minutes had a lower gestational age at presentation vs those with delayed treatment (34.6±5 vs 36.6±4 weeks, respectively; P<.001). For every 1-week increase in gestational age at presentation, there was a 9% increase in the likelihood of delayed treatment (odds ratio, 1.11; 95% confidence interval, 1.04-1.19). Another factor that was associated with delay of treatment was having a complaint of labor symptoms, which made patients 2.2 times as likely to experience treatment delay (odds ratio, 2.17; 95% confidence interval, 1.07-4.41). CONCLUSION: Initial blood pressure in the nonsevere range, absence of preeclampsia symptoms, presentation overnight, white race, having complaint of labor symptoms, and increasing gestational age at presentation are barriers that lead to a delay in the treatment of obstetric hypertensive emergency. Quality improvement initiatives that target these barriers should be instituted to improve timely treatment.

Routine Chest Radiographs in Children After Image-Guided Central Lines Offer Little Diagnostic Value.

BACKGROUND: The aim of this study was to investigate the utility of postoperative chest radiograph (CXR) after image-guided central venous line (CVL) placement in children. METHODS: A retrospective review was conducted of all tunneled CVLs placed at two pediatric institutions from 2010 to 2017. A subgroup analysis comparing a clinically driven approach to postoperative imaging against routine imaging was performed. RESULTS: During the study period, 1080 lines were placed in 915 patients. There were 892 postoperative CXRs (82.6%). An abnormality was seen on 40 radiographs (4.5%, n = 891), with 16 false-positive (1.3%) and 5 false-negative (0.6%) CXRs. The sensitivity and specificity of CXR to identify complications requiring intervention were 50.0% (95% confidence interval [95% CI], 10.0-90.0) and 95.8% (95% CI, 94.5-97.1), respectively. Positive predictive value of CXR was 7.5% (95% CI, 0-15.7) with a negative predictive value of 99.6% (95% CI, 99.2-100). A clinically driven approach to postoperative imaging was associated with 41% decrease in CXR (P < 0.001) without increased incidence of missed complications. Only three complications requiring intervention (0.3%) were suspected on postoperative CXR alone, and all of those were symptomatic before intervention. CONCLUSIONS: Routine postoperative CXR offers minimal value in identifying technical complications requiring intervention after image-guided CVL placement in asymptomatic children. We recommend abandoning this practice in favor of a clinical symptom-driven approach to postoperative imaging.