Miracle-dz/UniFAR-FTUs huggingface dataset:
Longitudinal Trends in the Direct Costs and Health Care Utilization Ascribable to Inflammatory Bowel Disease in the Biologic Era: Results From a Canadian Population-Based Analysis.

OBJECTIVES The prevalence of inflammatory bowel disease (IBD) is increasing. The total direct costs of IBD have not been assessed on a population-wide level in the era of biologic therapy. DESIGN We identified all persons with IBD in Manitoba between 2005 and 2015, with each matched to 10 controls on age, sex, and area of residence. We enumerated all hospitalizations, outpatient visits and prescription medications including biologics, and their associated direct costs. Total and per capita annual IBD-attributable costs and health care utilization (HCU) were determined by taking the difference between the costs/HCU accrued by an IBD case and their controls. Generalized linear modeling was used to evaluate trends in direct costs and Poisson regression for trends in HCU. RESULTS The number of people with IBD in Manitoba increased from 6,323 to 7,603 between 2005 and 2015. The total per capita annual costs attributable to IBD rose from $3,354 in 2005 to $7,801 in 2015, primarily driven by an increase in per capita annual anti-tumor necrosis factor costs, which rose from $181 in 2005 to $5,270 in 2015. There was a significant decline in inpatient costs for CD ($99 ± 25/yr. P < 0.0001), but not for ulcerative colitis ($8 increase ±$18/yr, P = 0.63). DISCUSSION The direct health care costs attributable to IBD have more than doubled over the 10 years between 2005 and 2015, driven mostly by increasing expenditures on biological medications. IBD-attributable hospitalization costs have declined modestly over time for persons with CD, although no change was seen for patients with ulcerative colitis.
Efficacy of Preoperative Chemotherapy in High-Risk Upper Tract Urothelial Carcinoma (UTUC).

PURPOSE The impact of preoperative chemotherapy (PC) in patients with upper urinary tract urothelial carcinoma (UTUC) remains poorly investigated. We assessed the rates of pathologic complete response (pCR; pT0N0/X) and downstaging (pDS; ≤pT1N0/X) at radical nephroureterectomy (RNU) after PC and evaluated their impact on survival. MATERIAL AND METHODS This was an international observational study of patients who underwent PC and RNU for high-risk UTUC between 2005 and 2017. Multiple imputation of chained equations was applied to account for missing values. Logistic regression analyses were performed to identify predictors of pathologic response. Cox proportional hazard regression models were used to estimate recurrence-free survival (RFS), cancer-specific survival (CSS) and overall survival (OS). RESULTS A total of 267 patients met our inclusion criteria. Among included patients, 82 (31%) received methotrexate, vinblastine, doxorubicin and cisplatin (MVAC), 123 (46%) gemcitabine and cisplatin (GC), 25 (9%) gemcitabine and carboplatin (GCb), and 32 (12%) other regimens. The overall rates of pCR and pDS were 10.1% and 44.9%, respectively. On multivariable analysis, the use of GC and GCb was not statistically different from MVAC in achieving pCR and pDS, respectively. The number of administered cycles did not appear to have an effect on pathologic responses. Pathologic downstaging was the strongest prognostic factor for RFS (HR 0.2, p<0.001), CSS (HR 0.19, p<0.001) and OS (HR 0.40, p<0.001). CONCLUSIONS Pathologic downstaging after PC is a robust prognostic factor at RNU, and is associated with improved survival outcomes. Although PC appears to be effective, well-designed prospective studies are still needed.
Molecular mechanisms of vancomycin resistance

Vancomycin and related glycopeptides are drugs of last resort for the treatment of severe infections caused by Gram‐positive bacteria such as Enterococcus species, Staphylococcus aureus, and Clostridium difficile. Vancomycin was long considered immune to resistance due to its bactericidal activity based on binding to the bacterial cell envelope rather than to a protein target as is the case for most antibiotics. However, two types of complex resistance mechanisms, each comprised of a multi‐enzyme pathway, emerged and are now widely disseminated in pathogenic species, thus threatening the clinical efficiency of vancomycin. Vancomycin forms an intricate network of hydrogen bonds with the d‐Ala‐d‐Ala region of Lipid II, interfering with the peptidoglycan layer maturation process. Resistance to vancomycin involves degradation of this natural precursor and its replacement with d‐Ala‐d‐lac or d‐Ala‐d‐Ser alternatives to which vancomycin has low affinity. Through extensive research over 30 years after the initial discovery of vancomycin resistance, remarkable progress has been made in molecular understanding of the enzymatic cascades responsible. Progress has been driven by structural studies of the key components of the resistance mechanisms which provided important molecular understanding such as, for example, the ability of this cascade to discriminate between vancomycin sensitive and resistant peptidoglycan precursors. Important structural insights have been also made into the molecular evolution of vancomycin resistance enzymes. Altogether this molecular data can accelerate inhibitor discovery and optimization efforts to reverse vancomycin resistance. Here, we overview our current understanding of this complex resistance mechanism with a focus on the structural and molecular aspects.
Increased Drp1 Acetylation by Lipid Overload Induces Cardiomyocyte Death and Heart Dysfunction

Supplemental Digital Content is available in the text. Rationale: Lipid overload-induced heart dysfunction is characterized by cardiomyocyte death, myocardial remodeling, and compromised contractility, but the impact of excessive lipid supply on cardiac function remains poorly understood. Objective: To investigate the regulation and function of the mitochondrial fission protein Drp1 (dynamin-related protein 1) in lipid overload-induced cardiomyocyte death and heart dysfunction. Methods and Results: Mice fed a high-fat diet (HFD) developed signs of obesity and type II diabetes mellitus, including hyperlipidemia, hyperglycemia, hyperinsulinemia, and hypertension. HFD for 18 weeks also induced heart hypertrophy, fibrosis, myocardial insulin resistance, and cardiomyocyte death. HFD stimulated mitochondrial fission in mouse hearts. Furthermore, HFD increased the protein level, phosphorylation (at the activating serine 616 sites), oligomerization, mitochondrial translocation, and GTPase activity of Drp1 in mouse hearts, indicating that Drp1 was activated. Monkeys fed a diet high in fat and cholesterol for 2.5 years also exhibited myocardial damage and Drp1 activation in the heart. Interestingly, HFD decreased nicotinamide adenine dinucleotide (oxidized) levels and increased Drp1 acetylation in the heart. In adult cardiomyocytes, palmitate increased Drp1 acetylation, phosphorylation, and protein levels, and these increases were abolished by restoration of the decreased nicotinamide adenine dinucleotide (oxidized) level. Proteomics analysis and in vitro screening revealed that Drp1 acetylation at lysine 642 (K642) was increased by HFD in mouse hearts and by palmitate incubation in cardiomyocytes. The nonacetylated Drp1 mutation (K642R) attenuated palmitate-induced Drp1 activation, its interaction with voltage-dependent anion channel 1, mitochondrial fission, contractile dysfunction, and cardiomyocyte death. Conclusions: These findings uncover a novel mechanism that contributes to lipid overload-induced heart hypertrophy and dysfunction. Excessive lipid supply created an intracellular environment that facilitated Drp1 acetylation, which, in turn, increased its activity and mitochondrial translocation, resulting in cardiomyocyte dysfunction and death. Thus, Drp1 may be a critical mediator of lipid overload-induced heart dysfunction as well as a potential target for therapy.
Bortezomib, cyclophosphamide, dexamethasone versus lenalidomide, cyclophosphamide, dexamethasone in multiple myeloma patients at first relapse

Bortezomib‐ and lenalidomide‐containing regimens are well‐established therapies in multiple myeloma (MM). However, despite their extensive use, head‐to‐head comparisons have never been performed. Therefore, we compared bortezomib and lenalidomide in fixed‐duration therapies. In this open‐label, phase III study, we randomized MM patients at first relapse to receive either nine cycles of bortezomib plus cyclophosphamide plus dexamethasone (VCD) or lenalidomide plus cyclophosphamide plus dexamethasone (RCD). The primary endpoint was achievement of a very good partial response (VGPR) or better at six weeks after nine treatment cycles. From March 2011 to February 2015, 155 patients were randomized. VGPR or better was achieved by 12 patients (15%) in the VCD arm and 14 patients (18%) in the RCD arm (P = 0·70). Median progression‐free survival (PFS) was 16·3 (95% CI: 12·1–22·4) with VCD and 18·6 months (95% CI: 14·7–25·5) with RCD, and the two‐year overall survival (OS) was 75% (95% CI: 66–86%) and 74% (95% CI: 64–85%) respectively. In subgroup analyses, no differences in PFS were observed in bortezomib‐ and lenalidomide‐naïve patients, nor in patients who received a bortezomib‐based regimen in first line. Adverse events were consistent with the well‐established safety profiles of both drugs. Bortezomib and lenalidomide treatments were equally effective in terms of depth of response, PFS, and OS in MM patients at first relapse.
In Vitro Evaluation of a Novel Osteo-Inductive Scaffold for Osteogenic Differentiation of Bone-Marrow Mesenchymal Stem Cells.

BACKGROUND Demineralized bone matrices (DBMs) were demonstrated to be a promising candidate for bone regeneration by previous studies. However, the limited osteoinductivity of DBMs was insufficient for a better repairing of bone defect. Osteoblasts (OBs), the major cellular component of bone tissues, play an important role in the formation of new bone. The extracellular matrix (ECM) of OB is one of the main components of bone formation niche. OBJECTIVE To combine the DBMs with the ECM of OBs to construct a novel scaffold that could be used for bone reconstruction. METHODS In this study, OBs were cultured on the surface of DBMs for 10 days and removed by Triton X-100 and ammonium hydroxide to prepare the OBs-ECM-DBMs (OEDBMs). A series of material features such as residues of OBs and ECM, cytotoxity, and osteoinductive capability of OEDBMs were evaluated. RESULTS Low cell residues and low content of DNA were observed in OEDBMs. Compared with DBMs, OEDBMs possessed more bone tissues organic matrix proteins, such as osteocalcin, osteopontin, and collagen I. Rat bone marrow mesenchymal stem cells (rBMSCs) presented a good viability when cultured on both 2 materials. The significant upregulations of osteogenic genes and proteins of rBMSCs were observed in OEDBMs group compared with DBMs group. CONCLUSION Taken together, these findings suggested that the OB-secreted ECM may be qualified as an ideal modification method for enhancing the performance of engineered bone scaffold.
Poverty and Health in Tennessee

The impact of poverty on health at both the US and international levels has been well documented. This study sought to identify the effects of poverty on health among the 95 counties of Tennessee. Using 5-year median household income, richest and poorest quartiles were compared for a variety of key measures, as were the 5 wealthiest and poorest counties. Supplemental digital content is available in the text. Objectives Understanding the impact of poverty on health can inform efforts to target social programs and regional economic development. This study examined the effects of poverty on health among the 95 counties of Tennessee. Methods All of the counties of Tennessee were ranked by 5-year median household income, from the wealthiest to the poorest. The counties were divided into quintiles, from wealthiest to poorest, to reflect the general impact of wealth on health. Next, the five wealthiest counties and the five poorest counties were identified, allowing for examination of the extremes of poverty and wealth within Tennessee. Comparisons of quintiles and five wealthiest and poorest counties on key measures were performed using the independent t test. Results People living in the wealthiest quintile lived on average 2.5 to 4 years longer and had lower rates of all health behaviors and health outcomes investigated compared with those in the poorest quintile. This disparity was even more pronounced when comparing the wealthiest five counties to the poorest five. The five poorest counties, for example, had twice the years of potential life lost and were overwhelmingly rural in character, with similar accompanying disparities such as median income, high unemployment, and a more aged population. Conclusions This study highlights the fact that lower income is associated with significantly worse health outcomes in Tennessee and reinforces the importance of economic development, specifically, and addresses the social determinants, more generally, in helping to improve Tennessee’s overall health statistics.
ATRX affects the repair of telomeric DSBs by promoting cohesion and a DAXX-dependent activity

Alpha thalassemia/mental retardation syndrome X-linked chromatin remodeler (ATRX), a DAXX (death domain-associated protein) interacting protein, is often lost in cells using the alternative lengthening of telomeres (ALT) pathway, but it is not known how ATRX loss leads to ALT. We report that ATRX deletion from mouse cells altered the repair of telomeric double-strand breaks (DSBs) and induced ALT-like phenotypes, including ALT-associated promyelocytic leukemia (PML) bodies (APBs), telomere sister chromatid exchanges (T-SCEs), and extrachromosomal telomeric signals (ECTSs). Mechanistically, we show that ATRX affects telomeric DSB repair by promoting cohesion of sister telomeres and that loss of ATRX in ALT cells results in diminished telomere cohesion. In addition, we document a role for DAXX in the repair of telomeric DSBs. Removal of telomeric cohesion in combination with DAXX deficiency recapitulates all telomeric DSB repair phenotypes associated with ATRX loss. The data reveal that ATRX has an effect on telomeric DSB repair and that this role involves both telomere cohesion and a DAXX-dependent pathway.
Electrical Coupling of Heterotypic Ganglion Cells in the Mammalian Retina

Electrical coupling has been reported to occur only between homotypic retinal ganglion cells, in line with the concept of parallel processing in the early visual system. Here, however, we show reciprocal correlated firing between heterotypic ganglion cells in multielectrode array recordings during light stimulation in retinas of adult guinea pigs of either sex. Heterotypic coupling was further confirmed via tracer spread after intracellular injections of single cells with neurobiotin. Electrical coupling has been reported to occur only between homotypic retinal ganglion cells, in line with the concept of parallel processing in the early visual system. Here, however, we show reciprocal correlated firing between heterotypic ganglion cells in multielectrode array recordings during light stimulation in retinas of adult guinea pigs of either sex. Heterotypic coupling was further confirmed via tracer spread after intracellular injections of single cells with neurobiotin. Both electrically coupled cell types were sustained ON center ganglion cells but showed distinct light response properties and receptive field sizes. We identified one of the involved cell types as sustained ON α-ganglion cells. The presence of electrical coupling between heterotypic ganglion cells introduces a network motif in which the signals of distinct ganglion cell types are partially mixed at the output stage of the retina. SIGNIFICANCE STATEMENT The visual information is split into parallel pathways, before it is sent to the brain via the output neurons of the retina, the ganglion cells. Ganglion cells can form electrical synapses between dendrites of neighboring cells in support of lateral information exchange. To date, ganglion-to-ganglion cell coupling is thought to occur only between cells of the same type. Here, however, we show that electrical coupling between different types of ganglion cells exists in the mammalian retina. We provide functional and anatomical evidence that two different types of ganglion cells share information via electrical coupling. This new network motif extends the impact of the heavily studied coding benefits of homotypic coupling to heterotypic coupling across parallel neuronal pathways.
Characteristics of Faecal Microbiota in Korean Patients with Clostridioides difficile-associated Diarrhea

Background The intestinal microbiota plays an important role in the pathogenesis of Clostridioides difficile-associated diarrhea, and regional and racial characteristics influence the microbiome composition and diversity. We investigated the intestinal microbiome characteristics of patients with C. difficile colitis (CD+) compared to those of patients with colitis not due to C. difficile (CD−), patients with vancomycin-resistant enterococci (VRE) colonization, and healthy controls, in Korea. Materials and Methods We collected stool samples from 24, 18, 11 and 13 subjects within CD+, CD−, VRE and healthy control groups, respectively. The microbial communities were evaluated by 454-pyrosequencing of bacterial 16s rRNA. Results The species richness and microbial diversity were significantly lower in the CD+ group compared to those in healthy controls, but not compared to those in CD− and VRE groups. Phylum-level analysis showed that the proportion of Actinobacteria in the CD+ group was significantly lower than in the healthy control, but was unchanged compared to that in CD− and VRE groups. At the genus level, compared to the healthy group, the CD+ group showed significantly lower proportions of Blautia, Bifidobacterium, Faecalibacterium et al. Compared to the VRE group, the CD+ group showed a significantly higher proportion of Anaerostipes. Conclusions We could identify the intestinal microbiome characteristics of Koreans with C. difficile colitis. It might help to develop microbiome based diagnostic and treatment modalities.
Phase Ib/II trial testing combined radiofrequency ablation and ipilimumab in uveal melanoma (SECIRA-UM)

Supplemental Digital Content is available in the text. Approximately, 50% of patients with uveal melanoma develop distant metastasis for which no standard therapy is established. In contrast to cutaneous melanoma, the anti-CTLA-4 antibody ipilimumab showed no clinical activity in uveal melanoma. Liver directed therapies improve local control, but fail to show overall survival (OS) benefit. Preclinical experiments demonstrated that radiofrequency ablation (RFA) induced durable responses in combination with anti-CTLA-4. The aim of this phase Ib/II study was to assess safety and efficacy of RFA plus ipilimumab in uveal melanoma. Patients underwent RFA of one liver lesion and subsequently received four courses ipilimumab 0.3, 3 or 10 mg/kg every 3 weeks in a 3 + 3 design. Primary endpoints were safety in terms of dose limiting toxicities per cohort to define the recommended phase II dose (RP2D) in the phase Ib part and confirmed the objective response rate and disease control rate (DCR) of non-RFA lesions in the phase II part. Secondary endpoints were progression-free survival (PFS) and OS. Ipilimumab 10 mg/kg + RFA was initially defined as the RP2D. However, after 19 patients, the study was amended to adjust the RP2D to ipilimumab 3 mg/kg + RFA, because 47% of patients treated with 10 mg/kg had developed grade 3 colitis. In the 3 mg/kg cohort, also 19 patients have been treated. Immunotherapy-related grade ≥3 adverse events were observed in 53% of patients in the 10 mg/kg cohort versus 32% in the 3 mg/kg cohort. No confirmed objective responses were observed; the confirmed DCR was 5% in the 10 mg/kg cohort and 11% in the 3 mg/kg cohort. Median PFS was 3 months and comparable for both cohorts, median OS was 14.2 months for the 10 mg/kg cohort versus 9.7 months for the 3 mg/kg cohort. Combining RFA with ipilimumab 3 mg/kg was well tolerated, but showed very limited clinical activity in uveal melanoma.
Transcranial Random Noise Stimulation for the Acute Treatment of Depression: A Randomized Controlled Trial

Abstract Background Transcranial electrical stimulation has broad potential as a treatment for depression. Transcranial random noise stimulation, which delivers randomly fluctuating current intensities, may have greater cortical excitatory effects compared with other forms of transcranial electrical stimulation. We therefore aimed to investigate the antidepressant efficacy of transcranial random noise stimulation. Methods Depressed participants were randomly assigned by computer number generator to receive 20 sessions of either active or sham transcranial random noise stimulation over 4 weeks in a double-blinded, parallel group randomized-controlled trial. Transcranial random noise stimulation was delivered for 30 minutes with a direct current offset of 2 mA and a random noise range of 2 mA. Primary analyses assessed changes in depression severity using the Montgomery-Asperg Depression Rating Scale. Neuroplasticity, neuropsychological, and safety outcomes were analyzed as secondary measures. Results Sixty-nine participants were randomized, of which 3 discontinued treatment early, leaving 66 (sham n = 34, active n = 32) for per-protocol analysis. Depression severity scores reduced in both groups (Montgomery-Asperg Depression Rating Scale reduction in sham = 7.0 [95% CI = 5.0–8.9]; and active = 5.2 [95% CI = 3.2–7.3]). However, there were no differences between active and sham groups in the reduction of depressive symptoms or the number of participants meeting response (sham = 14.7%; active = 3.1%) and remission criteria (sham = 5.9%; active = 0%). Erythema, paresthesia, fatigue, and dizziness/light-headedness occurred more frequently in the active transcranial random noise stimulation group. Neuroplasticity, neuropsychological, and acute cognitive effects were comparable between groups. Conclusion Our results do not support the use of transcranial random noise stimulation with the current stimulation parameters as a therapeutic intervention for the treatment of depression. Clinical trial registration at clinicaltrials gov/NCT01792414.
Effect of Body Composition and Energy Expenditure on Permethrin Biomarker Concentrations among US Army National Guard Members.

OBJECTIVE To examine relationships between percent body fat (%BF) and total energy expenditure (TEE) on permethrin exposure among Army National Guard (ARNG) Soldiers wearing permethrin-treated uniforms. METHODS ARNG members (n = 47) participated in a nine-day study. Repeated body composition (height, weight, %BF) measurements and daily urine samples, analyzed for permethrin and N,N-diethyl-meta-toluamide (DEET) metabolites, were collected. TEE was determined via doubly labeled water protocol. Linear mixed and regression models were used for analyses. RESULTS Neither %BF nor TEE were significantly associated with permethrin or DEET biomarkers. However, a significant interaction effect (F = 10.76; p = 0.0027) between laundering history and %BF was observed; 10% higher %BF was significantly associated with 25% higher permethrin biomarker concentrations among those wearing uniforms washed ≤ 25 (compared to >25) times. CONCLUSIONS Uniform laundering history significantly affects the association between %BF and permethrin-treated uniform exposure.