Predictive and Experimental Motif Interaction Analysis Identifies Functions of the WNK-OSR1/SPAK Pathway.

The WNK-OSR1/SPAK protein kinase signaling pathway regulates ion homeostasis and cell volume, but its other functions are poorly understood. To uncover undefined signaling functions of the pathway we analyzed the binding specificity of the conserved C-terminal (CCT) domains of OSR1 and SPAK to find all possible interaction motifs in human proteins. These kinases bind the core consensus sequences R-F-x-V/I and R-x-F-x-V/I. Motifs were ranked based on sequence, conservation, cellular localization, and solvent accessibility. Out of nearly 3,700 motifs identified, 90% of previously published motifs were within the top 2% of those predicted. Selected candidates (TSC22D1, CAVIN1, ATG9A, NOS3, ARHGEF5) were tested. Upstream kinases WNKs 1-4 and their close relatives, the pseudokinases NRBP1/2, contain CCT-like domains as well. We identified additional distinct motif variants lacking the conserved arginine previously thought to be required, and found that the NRBP1 CCT-like domain binds TSC22D1 via the same motif as OSR1 and SPAK. Our results further highlight the rich and diverse functionality of CCT and CCT-like domains in connecting WNK signaling to cellular processes.

Predicting the stereoselectivity of chemical reactions by composite machine learning method.

Stereoselective reactions have played a vital role in the emergence of life, evolution, human biology, and medicine. However, for a long time, most industrial and academic efforts followed a trial-and-error approach for asymmetric synthesis in stereoselective reactions. In addition, most previous studies have been qualitatively focused on the influence of steric and electronic effects on stereoselective reactions. Therefore, quantitatively understanding the stereoselectivity of a given chemical reaction is extremely difficult. As proof of principle, this paper develops a novel composite machine learning method for quantitatively predicting the enantioselectivity representing the degree to which one enantiomer is preferentially produced from the reactions. Specifically, machine learning methods that are widely used in data analytics, including Random Forest, Support Vector Regression, and LASSO, are utilized. In addition, the Bayesian optimization and permutation importance tests are provided for an in-depth understanding of reactions and accurate prediction. Finally, the proposed composite method approximates the key features of the available reactions by using Gaussian mixture models, which provide suitable machine learning methods for new reactions. The case studies using the real stereoselective reactions show that the proposed method is effective and provides a solid foundation for further application to other chemical reactions.

Permanent fluidic magnets for liquid bioelectronics.

Brownian motion allows microscopically dispersed nanoparticles to be stable in ferrofluids, as well as causes magnetization relaxation and prohibits permanent magnetism. Here we decoupled the particle Brownian motion from colloidal stability to achieve a permanent fluidic magnet with high magnetization, flowability and reconfigurability. The key to create such permanent fluidic magnets is to maintain a stable magnetic colloidal fluid by using non-Brownian magnetic particles to self-assemble a three-dimensional oriented and ramified magnetic network structure in the carrier fluid. This structure has high coercivity and permanent magnetization, with long-term magnetization stability. We establish a scaling theory model to decipher the permanent fluid magnet formation criteria and formulate a general assembly guideline. Further, we develop injectable and retrievable permanent-fluidic-magnet-based liquid bioelectronics for highly sensitive, self-powered wireless cardiovascular monitoring. Overall, our findings highlight the potential of permanent fluidic magnets as an ultrasoft material for liquid devices and systems, from bioelectronics to robotics.

A multimodal magnetoelastic artificial skin for underwater haptic sensing.

Future exploitation of marine resources in a sustainable and eco-friendly way requires autonomous underwater robotics with human-like perception. However, the development of such intelligent robots is now impeded by the lack of adequate underwater haptic sensing technology. Inspired by the populational coding strategy of the human tactile system, we harness the giant magnetoelasticity in soft polymer systems as an innovative platform technology to construct a multimodal underwater robotic skin for marine object recognition with intrinsic waterproofness and a simple configuration. The bioinspired magnetoelastic artificial skin enables multiplexed tactile modality in each single taxel and obtains an impressive classification rate of 95% in identifying seven types of marine creatures and marine litter. By introducing another degree of freedom in underwater haptic sensing, this work represents a milestone toward sustainable marine resource exploitation.

First-trimester and early-second-trimester transvaginal cervical length before 16 weeks among women with preterm and term birth: a systematic review and meta-analysis.

OBJECTIVE: This study aimed to evaluate the differences in first-trimester and early-second-trimester transvaginal cervical length between patients with spontaneous preterm birth and those with term birth. DATA SOURCES: PubMed, MEDLINE, Embase, and the Cochrane Library were systematically searched through August 2023. STUDY ELIGIBILITY CRITERIA: Studies had to include (1) transvaginal cervical length measurement before 16+0 weeks of gestation and (2) transvaginal cervical length measurement in a population of patients who delivered preterm and at term. Abstracts, studies with duplicated data, and those with cervical length measured by transabdominal ultrasound scan were excluded. METHODS: K.W.C. and J.L. searched for, screened, and reviewed the articles independently. The quality of the studies was assessed using the Newcastle-Ottawa scale. Mean differences were calculated using a random-effects model and pooled through a meta-analysis. RESULTS: A total of 5727 published articles were identified. Only 10 studies (which analyzed 22,151 pregnancies) met the inclusion criteria. All studies excluded iatrogenic preterm birth. Transvaginal cervical length was significantly shorter in women with spontaneous preterm birth than in those who delivered at term (mean difference, -0.97; 95% confidence interval, -1.65 to -0.29; P=.005; I2=69%). When a linear technique was used to measure transvaginal cervical length, a significantly shorter transvaginal cervical length was associated with spontaneous preterm birth as opposed to term birth (mean difference, -1.09; 95% confidence interval, -1.96 to -0.21; P=.02; I2=77%). A shorter transvaginal cervical length measured by other techniques was also associated with spontaneous preterm birth before 34 to 35 weeks (mean difference, -1.87; 95% confidence interval, -3.04 to -0.70; P=.002; I2=0%). When studies where interventions were given for a "short" cervix or studies with a mean transvaginal cervical length ≥40 mm were excluded, a significantly shorter transvaginal cervical length was observed among those with spontaneous preterm birth (mean difference, -1.13; 95% confidence interval, -1.89 to -0.37; P=.004; mean difference, -0.86; 95% confidence interval, -1.67 to -0.04; P=.04; respectively). The optimal transvaginal cervical length cutoff was 38 to 39 mm, yielding pooled sensitivity of 0.80, specificity of 0.45, positive likelihood ratio of 1.16, negative likelihood ratio of 0.33, diagnostic odds ratio of 5.12, and an area under the curve of 0.75. CONCLUSION: Women with spontaneous preterm birth had significantly shorter transvaginal cervical length before 16 weeks of gestation compared with those who delivered at term. The linear method and the 2-line method are acceptable techniques for measuring transvaginal cervical length.

A rational analysis and computational modeling perspective on IAM and déjà vu.

The proposed memory architecture by Barzykowski and Moulin is compelling, and could be improved by incorporating a rational analysis of the functional roles of involuntary autobiographical memory and déjà vu. Additionally, modeling these phenomena computationally would remove ambiguities from the proposal. We provide examples of past work that illustrate how the phenomena may be described more precisely.

Economic and Health Care Resource Use Burden of Systemic Sclerosis.

OBJECTIVE: To describe the health care resource use (HCRU) and costs of patients with systemic sclerosis (SSc) prior to and after diagnosis. METHODS: This retrospective study used a claims data set (Merative MarketScan; 2015-2019). Eligible patients with SSc were identified by diagnosis codes and required at least 24 months of enrollment without an SSc diagnosis before their first SSc claim and at least 12 months of enrollment thereafter. Total HCRU and costs were reported for three intervals: 2 years and 1 year before and 1 year after index diagnosis. A general population cohort without SSc was matched 1:1 to the SSC cohort on age and sex for comparison. RESULTS: Eligibility criteria identified 902 patients with SSc (mean age: 54 years old; 85% female). Mean per-member per year costs increased each year from $22,383 to $29,708 to $47,095, 2 years before, 1 year before, and 1 year after index diagnosis versus $10,232 to $9656 to $9714 in the general population cohort. Outpatient settings represented the largest proportion of cost 1 year after SSc diagnosis ($16,392), followed by prescription drugs ($10,692), physician office ($10,523), and inpatient ($9448) settings. CONCLUSION: Patients with SSC accrued greater costs and required more services than a general population cohort. These elevated expenditures and HCRU were observed at least 2 years before an SSc diagnosis and increased over time, reflecting both the progressive, multisystem nature of SSc and potential challenges in diagnosis. These findings suggest that SSc poses a substantial burden on the US health care system and highlights the need for early diagnosis and effective therapies.

Inflammatory Activity of Epithelial Stem Cell Variants from Cystic Fibrosis Lungs Is Not Resolved by CFTR Modulators.

Rationale: CFTR (cystic fibrosis transmembrane conductance regulator) modulator drugs restore function to mutant channels in patients with cystic fibrosis (CF) and lead to improvements in body mass index and lung function. Although it is anticipated that early childhood treatment with CFTR modulators will significantly delay or even prevent the onset of advanced lung disease, lung neutrophils and inflammatory cytokines remain high in patients with CF with established lung disease despite modulator therapy, underscoring the need to identify and ultimately target the sources of this inflammation in CF lungs. Objectives: To determine whether CF lungs, like chronic obstructive pulmonary disease (COPD) lungs, harbor potentially pathogenic stem cell "variants" distinct from the normal p63/Krt5 lung stem cells devoted to alveolar fates, to identify specific variants that might contribute to the inflammatory state of CF lungs, and to assess the impact of CFTR genetic complementation or CFTR modulators on the inflammatory variants identified herein. Methods: Stem cell cloning technology developed to resolve pathogenic stem cell heterogeneity in COPD and idiopathic pulmonary fibrosis lungs was applied to end-stage lungs of patients with CF (three homozygous CFTR:F508D, one CFTR F508D/L1254X; FEV1, 14-30%) undergoing therapeutic lung transplantation. Single-cell-derived clones corresponding to the six stem cell clusters resolved by single-cell RNA sequencing of these libraries were assessed by RNA sequencing and xenografting to monitor inflammation, fibrosis, and mucin secretion. The impact of CFTR activity on these variants after CFTR gene complementation or exposure to CFTR modulators was assessed by molecular and functional studies. Measurements and Main Results: End-stage CF lungs display a stem cell heterogeneity marked by five predominant variants in addition to the normal lung stem cell, of which three are proinflammatory both at the level of gene expression and their ability to drive neutrophilic inflammation in xenografts in immunodeficient mice. The proinflammatory functions of these three variants were unallayed by genetic or pharmacological restoration of CFTR activity. Conclusions: The emergence of three proinflammatory stem cell variants in CF lungs may contribute to the persistence of lung inflammation in patients with CF with advanced disease undergoing CFTR modulator therapy.

Cloning a profibrotic stem cell variant in idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive, irreversible, and rapidly fatal interstitial lung disease marked by the replacement of lung alveoli with dense fibrotic matrices. Although the mechanisms initiating IPF remain unclear, rare and common alleles of genes expressed in lung epithelia, combined with aging, contribute to the risk for this condition. Consistently, single-cell RNA sequencing (scRNA-seq) studies have identified lung basal cell heterogeneity in IPF that might be pathogenic. We used single-cell cloning technologies to generate "libraries" of basal stem cells from the distal lungs of 16 patients with IPF and 10 controls. We identified a major stem cell variant that was distinguished from normal stem cells by its ability to transform normal lung fibroblasts into pathogenic myofibroblasts in vitro and to activate and recruit myofibroblasts in clonal xenografts. This profibrotic stem cell variant, which was shown to preexist in low quantities in normal and even fetal lungs, expressed a broad network of genes implicated in organ fibrosis and showed overlap in gene expression with abnormal epithelial signatures identified in previously published scRNA-seq studies of IPF. Drug screens highlighted specific vulnerabilities of this profibrotic variant to inhibitors of epidermal growth factor and mammalian target of rapamycin signaling as prospective therapeutic targets. This profibrotic stem cell variant in IPF was distinct from recently identified profibrotic stem cell variants in chronic obstructive pulmonary disease and may extend the notion that inappropriate accrual of minor and preexisting stem cell variants contributes to chronic lung conditions.

Human Papillomavirus Self-Sampling for Primary Cervical Cancer Screening in Under-Screened Women in Hong Kong during the COVID-19 Pandemic.

The aim of this study was to assess the effectiveness of HPV self-sampling for cervical cancer screening and the best means of service delivery, with a specific focus on under-screened women, particularly during the COVID-19 pandemic. Using three arms of service delivery (social media, school outreach and underserved outreach), we recruited under-screened women aged 30-65 years from two population groups: the general public and specific underserved communities, from whom self-sampled specimens and optional clinician-sampled cervical specimens were obtained for HPV testing. A total of 521 self-sampling kits were distributed, of which 321 were returned, giving an overall uptake rate of 61.6%. The response rate was higher in the face-to-face underserved outreach (65.5%) compared to social media (22.8%) and school outreach (18.2%). The concordance for HPV detection between self-sampled and clinician-sampled specimens was 90.2% [95% confidence interval (CI) 85.1-93.8%; Cohen's kappa 0.59 (95% CI 0.42-0.75)]. Overall, 89.2% of women were willing to have self-sampling again. In conclusion, HPV self-sampling is an effective method for cervical cancer screening and can be considered as an option, particularly in women who are reluctant or unable to attend regular screening. Various service deliveries could be considered to increase participation in cervical cancer screening.

Diagnostic Performance of Risk of Malignancy Algorithm (ROMA), Risk of Malignancy Index (RMI) and Expert Ultrasound Assessment in a Pelvic Mass Classified as Inconclusive by International Ovarian Tumour Analysis (IOTA) Simple Rules.

The accurate prediction of malignancy for a pelvic mass detected on ultrasound allows for appropriate referral to specialised care. IOTA simple rules are one of the best methods but are inconclusive in 25% of cases, where subjective assessment by an expert sonographer is recommended but may not always be available. In the present paper, we evaluate the methods for assessing the nature of a pelvic mass, including IOTA with subjective assessment by expert ultrasound, RMI and ROMA. In particular, we investigate whether ROMA can replace expert ultrasound when IOTA is inconclusive. This prospective study involves one cancer centre and three general units. Women scheduled for an operation for a pelvic mass underwent a pelvic ultrasound pre-operatively. The final histology was obtained from the operative sample. The sensitivity, specificity and accuracy for each method were compared with the McNemar test. Of the 690 women included in the study, 171 (25%) had an inconclusive IOTA. In this group, expert ultrasound was more sensitive in diagnosing a malignant mass compared to ROMA (81% vs. 63%, p = 0.009) with no significant difference in the specificity or accuracy. All assessment methods involving IOTA had similar accuracies and were more accurate than RMI or ROMA alone. In conclusion, when IOTA was inconclusive, assessment by expert ultrasound was more sensitive than ROMA, with similar specificity.

Association Between Treatment Progression, Disease Refractoriness, and Burden of Illness Among Hospitalized Patients With Status Epilepticus.

Importance: Status epilepticus (SE) is associated with poor clinical outcomes and high cost. Increased levels of refractory SE require treatment with additional medications and carry increased morbidity and mortality, but the associations between SE refractoriness, clinical outcomes, and cost remain poorly characterized. Objective: To examine differences in clinical outcomes and costs associated with hospitalization for SE of varying refractoriness. Design, Setting, and Participants: A cross-sectional study of 43 988 US hospitalizations from January 1, 2016 to December 31, 2018, was conducted, including patients with primary or secondary International Statistical Classification of Diseases, Tenth Revision, diagnosis specifying "with status epilepticus." Exposure: Patients were categorized by administration of antiseizure drugs given during hospitalization. Low refractoriness denoted treatment with none or 1 intravenous antiseizure drug. Moderate refractoriness denoted treatment with more than 1 intravenous antiseizure drug. High refractoriness denoted treatment with 1 or more intravenous antiseizure drug, more than 1 intravenous anesthetic, and intensive care unit admission. Main Outcomes and Measures: Outcomes included discharge disposition, hospital length of stay, intensive care unit length of stay, hospital-acquired conditions, and cost (total and per diem). Results: Among 43 988 hospitalizations for SE, 22 851 patients (51.9%) were male; mean age was 49.9 years (95% CI, 49.7-50.1 years). There were 14 694 admissions (33.4%) for low refractory, 10 140 (23.1%) for moderate refractory, and 19 154 (43.5%) for highly refractory SE. In-hospital mortality was 11.2% overall, with the highest rates among patients with highly (18.9%) compared with moderate (6.3%) and low (4.6%) refractory SE (P < .001 for all comparisons). Median hospital length of stay was 5 days (interquartile range [IQR], 2-10 days) with greater length of stay in highly (8 days; IQR, 4-15 days) compared with moderate (4 days; IQR, 2-8 days) and low (3 days; IQR, 2-5 days) refractory SE (P < .001 for all comparisons). Patients with highly refractory SE also had greater hospital costs, with median costs of $25 105 (mean [SD], $41 858 [$59 063]) in the high, $10 592 (mean [SD], $18 328 [$30 776]) in the moderate, and $6812 (mean [SD], $11 532 [$17 228]) in the low refractory cohorts (P < .001 for all comparisons). Conclusions and Relevance: Status epilepticus apparently continues to be associated with a large burden on patients and the US health system, with high mortality and costs that increase with disease refractoriness. Interventions that prevent SE from progressing to a more refractory state may have the potential to improve outcomes and lower costs associated with this neurologic condition.

TLR7/8 agonist treatment induces an increase in bone marrow resident dendritic cells and hematopoietic progenitor expansion and mobilization.

There is accumulating evidence suggesting that toll-like receptor (TLR) signals play an important role in the regulation of hematopoietic stem/progenitor cells (HSPCs). TLR7/8 stimulation induces the myeloid differentiation of normal HSPCs and acute myeloid leukemia cells. However, the in vivo effect of TLR7/8 agonists on hematopoiesis is largely unknown. Here, we show that, similar to TLR4 and TLR2, treatment with the TLR7/8 agonist R848 induces an expansion of phenotypic hematopoietic stem cells (HSCs) with reduced repopulating potential and HSPC mobilization. In contrast to chronic TLR4 stimulation, treatment with R848 for 5 days did not induce a significant increase in myeloid-biased HSCs. Treatment with R848 results in a significant increase in classic dendritic cells (DCs) in the bone marrow, but a decrease in common dendritic cell progenitors and pre-DCs. Phenotypic analysis of DCs revealed that R848 treatment is associated with altered expression of certain chemokines, activation markers, and migratory receptors. Together, these data indicate that systemic administration of a TLR7/8 agonist has unique effects on hematopoiesis, including the expansion of DCs in the bone marrow, that might have clinical relevance to augment responses to certain immunotherapies, such as cancer vaccines and immune checkpoint blockade.

New-Onset Gout as an Independent Risk Factor for Returning to Dialysis After Kidney Transplantation.

BACKGROUND: The causal relationship between gout and renal transplant outcomes is difficult to assess due to multiple interacting covariates. This study sought to estimate the independent effect of new-onset gout on renal transplant outcomes using a methodology that accounted for these interactions. METHODS: This study analyzed data on patients in the US Renal Data System (USRDS) who received a primary kidney transplant between 2008 and 2015. The exposure was new-onset gout, and the primary endpoint was returning to dialysis >12 months postindex date (transplant date). A marginal structural model (MSM) was fitted to determine the relative risk of new-onset gout on return to dialysis. RESULTS: 18 525 kidney transplant recipients in the USRDS met study eligibility. One thousand three hundred ninety-nine (7.6%) patients developed new-onset gout, and 1420 (7.7%) returned to dialysis >12 months postindex. Adjusting for baseline and time-varying confounders via the MSM showed new-onset gout was associated with a 51% increased risk of return to (RR, 1.51; 95% CI, 1.03-2.20). CONCLUSIONS: This finding suggests that new onset gout after kidney transplantation could be a harbinger for poor renal outcomes, and to our knowledge is the first study of kidney transplant outcomes using a technique that accounted for the dynamic relationship between renal dysfunction and gout.

Nurse-led follow-up in survivorship care of gynaecological malignancies-A randomised controlled trial.

OBJECTIVE: To assess clinical and psychosocial outcomes of nurse-led follow-up in survivorship care of gynaecological malignancies. METHODS: Women with endometrial or ovarian cancer who were attending regular post-treatment follow-up at a tertiary referral centre were randomised into two groups-group-1: telephone follow-up by nurses and group-2: gynaecologists-led clinic follow-up. Women in group-1 were asked about their symptoms and quality of life (QoL) by nurses. Women in group-2 were followed up by gynaecologists and underwent symptom reviews and physical examinations. All ovarian cancer patients in both groups also had CA125 measured. All recruited women completed a QoL questionnaire (EORTC QLQ-C30), HADS-anxiety questionnaire and symptom checklist. RESULTS: 385 women (215 with endometrial and 170 with ovarian cancer) were randomised. There was no significant difference in the detection of recurrence according to the two follow-up protocols. However, women in the nurse-led arm scored higher on emotional (p = 0.023) and cognitive functioning (p = 0.012). Those in the gynaecologist-led arm scored higher on the HADS-anxiety scale (p = 0.001) and were more likely to report symptoms. CONCLUSIONS: Our results demonstrate a preliminary non-inferiority of nurse-led follow-up, with improved psychological morbidity and QoL. Thus, nurse-led follow-up can be considered an effective substitute for hospital-based care.

Tungsten disulfide nanosheets-based colorimetric assay for glucose sensing.

We have developed a glucose oxidase (GOx)-mediated strategy for glucose detection, which is based on the intrinsic peroxidase-like activity of WS2 as a catalyst for the 3,3',5,5'-tetramethylbenzidine­hydrogen peroxide (TMB-H2O2) reaction. The colorimetric assay involves two parts: generation of H2O2 from the oxidation of glucose catalyzed by GOx, and WS2 nanosheets that catalyze the reaction between TMB and H2O2. In this colorimetric assay, the enhancement of colorimetric signals depends directly on the increased H2O2 concentration, which, in turn, relies on the glucose concentration. The results show that the concentrations of the glucose were directly proportional to absorbance of the TMB solutions over a range of 1 nM-500 µM with a limit of detection of 0.1445 nM. In addition, this new colorimetric assay has been utilized for glucose detection in human serum with a satisfactory result.

Dynamics of HBV surface antigen related end points in chronic hepatitis B infection: a systematic review and meta-analysis.

BACKGROUND: In chronic hepatitis B (CHB) treatment, hepatitis B surface antigen (HBsAg) is regarded as a promising clinical end point associated with long-term clinical outcomes. We performed a meta-analysis to characterize the dynamics and influencing factors of HBsAg. METHODS: Literature search was conducted through PubMed from January 1995 to May 2015 for papers reporting HBsAg in patients receiving various antiviral treatments. We conducted weighted linear regression to select for potential influencing factors on maximum HBsAg loss percentage, and subgroup analysis to calculate the pooled estimates of maximum HBsAg loss and seroconversion percentage following treatment of interferon (IFN), nucleoside analogue (NUC) or combination therapies (NUC+IFN), respectively. Study heterogeneity was assessed through sensitivity test and I-square statistics. RESULTS: We collected data from 24 papers involving 6,674 adult CHB patients. In most studies, average HBsAg level decreased during treatment but relapsed after treatment cessation, while HBsAg loss or seroconversion percentage continued to increase or remained stable after treatment cessation. No strong relationship was observed between maximum HBsAg change and its baseline level. The pooled estimates of maximum HBsAg loss percentage for IFN (5.3%, 2.7-7.9%) and NUC+IFN (5.2%, 3.1-7.4%) were significantly higher than that of NUC (0.93%, 0.29-1.6%). Higher maximum HBsAg loss percentage is associated with longer peak time. Pooled maximum HBsAg seroconversion percentage estimates were 1.6%, 0.56% and 6.2% for IFN, NUC and NUC+IFN. CONCLUSIONS: With respect to HBsAg lowering, this meta-analysis confirmed the importance of longer treatment duration and addition of IFN, which revealed the potential value of immune-based therapies.

A Retrospective Cohort Study of the Effect of Gout on Mortality Among Patients with a History of Kidney Transplantation.

BACKGROUND Kidney transplantation is associated with increased prevalence of gout. However, evidence of the effect of gout on long-term kidney transplantation outcomes is mixed. This study examined mortality risk among patients with a history of kidney transplantation with vs. without gout. MATERIAL AND METHODS A retrospective study was conducted using Medicare Fee-for-Service administrative claims of patients with a history of kidney transplantation. Cox proportional hazards models determined the effect of gout on all-cause mortality, controlling for confounders, including comorbid mortality risk, via the Charlson Comorbidity Index. Because the relationships between gout and components of the Charlson Comorbidity Index are also debated, 3 different model assumptions were used: 1) gout shares a common cause with these comorbidities, 2) gout is upstream of these comorbidities, 3) the effect of gout on mortality is modified by these comorbidities. RESULTS Gout increased the risk of all-cause mortality in the unadjusted model (hazard ratio: 1.44, 95% CI 1.27-1.63) and after adjustment for demographics and transplant vintage (hazard ratio: 1.16, 95% CI 1.02-1.32). Gout was not a significant risk after adjustment for baseline Charlson Comorbidity Index (hazard ratio: 1.03, 95% CI 0.90-1.17). Gout was associated with greater mortality among patients without baseline comorbidities (Charlson Comorbidity Index=0; hazard ratio: 3.48, 95% CI 1.27-9.57) in the stratified model. CONCLUSIONS Among patients with a history of kidney transplantation, gout did not have an independent effect on all-cause mortality. However, gout was a predictor of mortality among patients with no comorbidities, suggesting that gout is an early warning sign of poor health in kidney transplantation patients.

Immunosuppressant Use and Gout in the Prevalent Solid Organ Transplantation Population.

INTRODUCTION: Gout is a common comorbidity among solid organ transplantation patients and is usually attributed to the use of cyclosporine. This study aims to evaluate the prevalence of gout among solid organ transplantation patients to determine the prevalence in the tacrolimus era. RESEARCH QUESTIONS: To what degree is cyclosporine still used among prevalent solid organ transplantation patients? How prevalent is gout in the solid organ transplantation population not being treated by cyclosporine? METHODS: Immunosuppressant regimens and gout prevalence among prevalent solid organ transplantation patients were assessed using retrospective claims data for a representative sample of commercially insured patients. For comparison to the prevalent solid organ transplantation population, immunosuppressant use at time of transplantation was compiled from published reports. RESULTS: Between 2012 and 2016, the use of cyclosporine declined while use of tacrolimus increased, with greater cyclosporine use among prevalent versus incident solid organ transplantation patients. The prevalence of gout was 18.3%, 9.3%, and 9.1% for solid organ transplantation patients on cyclosporine, tacrolimus, and neither, respectively. Among all solid organ transplantation patients with gout, 66.6% and 21.5% were on tacrolimus versus cyclosporine. The prevalence of gout among noncyclosporine solid organ transplantation patients was significantly higher than in the general population without solid organ transplantation. DISCUSSION: Despite declining cyclosporine use, gout prevalence remains high, with the majority of patients with gout receiving tacrolimus rather than cyclosporine. In summary, gout remains a frequent comorbidity of solid organ transplantation.

Costs Associated with the Treatment of Low Back Disorders: A Comparison of Surgeons and Physiatrists.

BACKGROUND: Spine care is costly and subject to wide variability. Defining costs and patterns of care for different specialties is critical to improving value. OBJECTIVE: Determine costs, utilization, and differences therein for nonoperative and operative specialists in treating low back disorders. We hypothesized costs associated with nonoperative specialists would be lower. DESIGN: Retrospective cohort. SETTING: Medicare Limited Data Set (5% sample), 2011 to 2014. PARTICIPANTS: A total of 170 011 patients saw a primary care provider for a low back disorder between 1 July 2011, and 1 January 2013. Excluding those seen for a low back disorder in the preceding 6 months, final cohorts totaled 11 829 patients subsequently evaluated by a physiatrist (specialist in physical medicine and rehabilitation; 3183 patients) or surgeon (orthopedic or neurosurgeon; 8646 patients) within the following 6 months. MAIN OUTCOME MEASURES: Total Medicare expenditures, spine-specific costs, spine surgical rates over 24 months. RESULTS: Cohorts had comparable demographics, initial diagnoses, and baseline mean per-member per-month (PMPM) total spending. Mean 2-year spine-specific spending was $3978 for the physiatrist cohort and $7387 for the surgeon cohort. Comparatively, the physiatrist cohort had lower total mean 2-year spine-specific spending (-$3409; 95% confidence interval [CI] -$3824 to -$2994), mean PMPM total spending (-$122/mo; CI -$184 to -$60), and surgical rate (7.8% vs. 18.9%, risk ratio [RR] = 0.41; CI 0.36-0.47). Surgery predominantly drove cost differential. Mean PMPM total spending for both cohorts remained elevated at 24 months compared to baseline mean spending (physiatrist: +$293; CI $447 to $138; surgeon: +$325; CI $425 to $225). CONCLUSIONS: Following a new episode of a low back disorder, substantial costs were seen for those subsequently evaluated by a physiatrist or surgeon. Costs were considerably lower for those first seen by a physiatrist. Patients in both cohorts displayed long-term increases in health care costs. Our data suggest that early engagement in nonoperative care, when appropriate, may improve value.