Miracle-dz/UniFAR-FTUs huggingface dataset:
Periprocedural myocardial and renal injury in patients undergoing elective percutaneous coronary interventions – is there an association?

Abstract Periprocedural myocardial injury (PMI) and contrast-induced nephropathy (CIN) are frequent complications of percutaneous coronary intervention (PCI) associated with early and late major adverse cardiovascular events. Both conditions are associated with similar risk factors, which could imply their possible association. The aim of our study was to assess the correlation of PMI and early postprocedural creatinine shift (ECS) as a marker of renal injury. A total of 209 hospitalized patients with stable coronary artery disease (CAD) were enrolled, who underwent an elective PCI in a period of 12 months. All patients had their serum high-sensitivity troponin I (hsTnI) measured at baseline and 16 hours after the PCI. PMI was defined according to the elevation of postprocedural hsTnI using criteria provided by both the most recent consensus documents as well as evidence-based data. Renal injury was evaluated using the ECS concept. Serum creatinine (SCr) was also measured at baseline and at 16 hours. ECS was defined as SCr >5% at 16 hours compared to baseline. Although incidence of both PMI (77.5%) and ECS (44.5%) were high, no association of these 2 conditions could be found. Further analyses of our data showed that diabetes is associated with a higher incidence of ECS, while patients on beta-blocker therapy had a lower incidence of ECS. In our study, no association between PMI and ECS was found. Additional studies with a larger number of patients and longer patient observation are needed to assess the correlation between PMI and CIN as well as to validate the attractive, but controversial, concept of ECS as an early marker of CIN.
The senotherapeutic nicotinamide riboside raises platelet nicotinamide adenine dinucleotide levels but cannot prevent storage lesion

Supplementation of the nicotinamide adenine dinucleotide (NAD) precursor nicotinamide riboside (NR) has recently been shown to increase life‐span of cells, tissues, and entire organisms. [Correction added on 13 December 2019, after first online publication: In the preceding sentence, “adenine nicotinamide” was revised to “nicotinamide adenine. ”] The impact of NR on platelet longevity has not been tested.
Generation of a MOR‐CreER knock‐in mouse line to study cells and neural circuits involved in mu opioid receptor signaling

Mu opioid receptor (MOR) is involved in various brain functions, such as pain modulation, reward processing, and addictive behaviors, and mediates the main pharmacologic effects of morphine and other opioid compounds. To gain genetic access to MOR‐expressing cells, and to study physiological and pathological roles of MOR signaling, we generated a MOR‐CreER knock‐in mouse line, in which the stop codon of the Oprm1 gene was replaced by a DNA fragment encoding a T2A peptide and tamoxifen (Tm)‐inducible Cre recombinase. We show that the MOR‐CreER allele undergoes Tm‐dependent recombination in a discrete subtype of neurons that express MOR in the adult nervous system, including the olfactory bulb, cerebral cortex, striosome compartments in the striatum, hippocampus, amygdala, thalamus, hypothalamus, interpeduncular nucleus, superior and inferior colliculi, periaqueductal gray, parabrachial nuclei, cochlear nucleus, raphe nuclei, pontine and medullary reticular formation, ambiguus nucleus, solitary nucleus, spinal cord, and dorsal root ganglia. The MOR‐CreER mouse line combined with a Cre‐dependent adeno‐associated virus vector enables robust gene manipulation in the MOR‐enriched striosomes. Furthermore, Tm treatment during prenatal development effectively induces Cre‐mediated recombination. Thus, the MOR‐CreER mouse is a powerful tool to study MOR‐expressing cells with conditional gene manipulation in developing and mature neural tissues.
Targeting the Somatostatin Receptor 2 with the Miniaturized Drug Conjugate, PEN-221: A Potent and Novel Therapeutic for the Treatment of Small Cell Lung Cancer

Small cell lung cancer (SCLC) is an aggressive neuroendocrine carcinoma with a 95% mortality rate with no improvement to treatment in decades, and new therapies are desperately needed. PEN-221 is a miniaturized peptide–drug conjugate (∼2 kDa) designed to target SCLC via a Somatostatin Receptor 2 (SSTR2)–targeting ligand and to overcome the high proliferation rate characteristic of this disease by using the potent cytotoxic payload, DM1. SSTR2 is an ideal target for a drug conjugate, as it is overexpressed in SCLC with limited normal tissue expression. In vitro, PEN-221 treatment of SSTR2-positive cells resulted in PEN-221 internalization and receptor-dependent inhibition of cellular proliferation. In vivo, PEN-221 exhibited rapid accumulation in SSTR2-positive SCLC xenograft tumors with quick clearance from plasma. Tumor accumulation was sustained, resulting in durable pharmacodynamic changes throughout the tumor, as evidenced by increases in the mitotic marker of G2–M arrest, phosphohistone H3, and increases in the apoptotic marker, cleaved caspase-3. PEN-221 treatment resulted in significant antitumor activity, including complete regressions in SSTR2-positive SCLC xenograft mouse models. Treatment was effective using a variety of dosing schedules and at doses below the MTD, suggesting flexibility of dosing schedule and potential for a large therapeutic window in the clinic. The unique attributes of the miniaturized drug conjugate allowed for deep tumor penetration and limited plasma exposure that may enable long-term dosing, resulting in durable tumor control. Collectively, these data suggest potential for antitumor activity of PEN-221 in patients with SSTR2-positive SCLC.
Role of phytochemicals as nutraceuticals for cognitive functions affected in ageing

Cognitive decline can occur with normal ageing and in age‐related brain disorders, such as mild cognitive impairment and dementia, including Alzheimer's disease, with limited pharmacological therapies available. Other approaches to reduce cognitive decline are urgently needed, and so, the role of dietary interventions or nutraceuticals has received much attention in this respect. In this review, we examine the evidence for dietary plants and their chemical constituents as nutraceuticals, relevant to both cognitive decline in normal ageing and in dementia. Pharmacological (in vitro and in vivo), clinical and epidemiological evidence is assessed for both frequently consumed plants and their dietary forms, including tea, coffee, cocoa (chocolate), red wine, grapes, citrus and other fruits; in addition to plants used less frequently in certain diets and those that cross the blurred boundaries between foods, nutraceuticals and medicinal plants. For the latter, turmeric, saffron, sage, rosemary and lemon balm are examples of those discussed.
Effect of variation in miRNA-binding site (rs8176318) of the BRCA1 gene in breast cancer patients

Background/aim A variation in the 3 prime untranslated regions (3′-UTRs) affects the binding of microRNA (miRNA) to the breast cancer (BC) susceptibility gene 1 (BRCA1) gene, and thus regulate its expression. In this study, the consequences of a variation in the miRNA-binding site (rs8176318G>T) in the 3′-UTRs of BRCA1 and its association with the risk of BC were investigated. Materials and methods The selected variation (rs8176318G>T) was genotyped in BC patients (n = 300) and healthy controls (n = 300) using allele-specific polymerase chain reaction (PCR) [tetra-primer amplification refractory mutation system-PCR (T-ARMS-PCR)]. The results of the T-ARMS-PCR were further confirmed by Sanger sequencing through a random selection of 10% previously analyzed samples by T-ARMS-PCR. Association of this variation with BC was tested by calculating the odds ratio (OR) (at 95% CI) and χ2-value using 4 different genetic models (codominant, dominant, recessive, and additive models). Results Using Fisher’s exact test, a significant association between variant rs8176318 (G>T) and BC was found in codominant [χ2-value = 15.68, df: 2 P < 0.0004], dominant [OR = 1.557 (1.082–2.241), P <0.0213], recessive [OR = 0.474 (0.3204–0.7017), P = 0.0002] and additive models [OR = 1.609 (1.282–2.018), P < 0.0001]. Conclusion It was therefore concluded that there is a significant association between rs8176318 and BC risk in a case-control study in a Pakistani population. Furthermore, an association study using a large sample size is required to further verify these findings.
Survival Outcomes After Adding Stereotactic Body Radiotherapy to Metastatic Renal Cell Carcinoma Patients Treated With Tyrosine Kinase Inhibitors

Supplemental Digital Content is available in the text. Objective: Long-lasting control is rarely achieved with tyrosine kinase inhibitors (TKI) alone in metastatic renal cell carcinoma (mRCC). Our study aimed to investigate the survival outcomes of adding stereotactic body radiotherapy (SBRT) to TKI in mRCC. Materials and Methods: From September 2015 to September 2018, 56 patients treated with TKI received SBRT for 103 unresectable lesions. A total of 24 and 32 patients were irradiated before and after TKI failure, respectively. Overall survival (OS) was calculated from metastases. Progression-free survival (PFS) was calculated from SBRT. Results: Overall, 10, 32, and 12 patients had International Metastatic Renal Cell Carcinoma Database Consortium favorable, intermediate, and poor risk. Median follow-up was 21.7 months (range, 5.1 to 110.6 mo). Median OS was 61.2 months. The median PFS was 11.5 months, while the 2-year LC rate was 94%. Sixteen (34%) lesions achieved complete response (CR) in patients irradiated before TKI failure, whereas only 4 (7%) lesions yielded CR in those irradiated after TKI failure (P=0.001). The median PFS in CR group was significantly longer than that of non-CR group (18.9 vs. 7.1 mo; P=0.003). The 5-year OS in CR group was 86%, compared with 48% in non-CR group (P=0.010). Four (7%) patients experienced Grade 3 toxicity. Conclusions: Adding SBRT to TKI is safe and seems to improve survival in mRCC. Patients irradiated before TKI failure have higher CR rate, and the favorable local response might turn into survival benefit.
Factors associated with depressive symptoms in patients with ankylosing spondylitis in Northern Taiwan

Patients with ankylosing spondylitis (AS) experience impaired physical function and reduced quality of life, which puts this group at high risk for depression. Identifying factors associated with depressive symptoms could improve outcomes for this at-risk group. However, few studies have examined the relationship between demographic and clinical variables and depressive symptoms in patients with AS. This cross-sectional correlation study recruited patients with AS by convenience sampling from the division of immunology and rheumatology of a medical center in Northern Taiwan. Participants (N = 120) included 91 males and 29 females, age ≥ 20 years. Data were collected from chart reviews, and structural questionnaires, which included demographic information regarding employment status, history of falls, impact of AS on work; clinical information relative to AS was obtained from structural questionnaires: the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and functional index (BASFI), Numerical Rating Scale (NRS), Body Image Scale (BIS), and Beck Depression Inventory-II (BDI-II). Multiple regression analysis identified predictors of depression. The mean BDI-II score was 9.50 ± 8.30; 25% had scores indicating mild to severe depressive symptoms. Mean score on the BIS was 68.17 ± 16.14; 14.2% had fallen within the previous year; and 57.5% reported AS affected their work. Variables associated with depressive symptoms were work affected by AS (β = 0.14, p = .049), occurrence of a fall within the previous year (β = 0.14, p = .032), higher scores on the BASDAI (β = 0.21, p = .032), and lower body image (β = −0.38, p < .001). Clinical professionals should regularly assess patients with AS for depressive symptoms. Health care planning should provide instruction in fall prevention and control of disease activity, and strategies to improve body image, which could improve patients’ self-management capabilities and body image as well as mitigate depressive symptoms.
Mother’s curse and indirect genetic effects: Do males matter to mitochondrial genome evolution?

Maternal inheritance of mitochondrial DNA (mtDNA) was originally thought to prevent any response to selection on male phenotypic variation attributable to mtDNA, resulting in a male‐biased mtDNA mutation load (“mother's curse”). However, the theory underpinning this claim implicitly assumes that a male's mtDNA has no effect on the fitness of females he comes into contact with. If such “mitochondrially encoded indirect genetics effects” (mtIGEs) do in fact exist, and there is relatedness between the mitochondrial genomes of interacting males and females, male mtDNA‐encoded traits can undergo adaptation after all. We tested this possibility using strains of Drosophila melanogaster that differ in their mtDNA. Our experiments indicate that female fitness is influenced by the mtDNA carried by males that the females encounter, which could plausibly allow the mitochondrial genome to evolve via kin selection. We argue that mtIGEs are probably common, and that this might ameliorate or exacerbate mother's curse.
DA-EPOCH-R combined with high-dose methotrexate in patients with newly diagnosed stage II-IV CD5-positive diffuse large B-cell lymphoma: a single-arm, open-label, phase 2 study.

CD5-positive diffuse large B-cell lymphoma (CD5+ DLBCL) is characterized by poor prognosis and a high frequency of central nervous system relapse after standard immunochemotherapy. We conducted a phase 2 study to investigate the efficacy and safety of dose-adjusted (DA)- EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) combined with high-dose methotrexate (HD-MTX) in newly diagnosed patients with CD5+ DLBCL. Previously untreated patients with stage II to IV CD5+ DLBCL according to the 2008 WHO classification were eligible. Four cycles of DA-EPOCH-R followed by 2 cycles of HD-MTX and 4 additional cycles of DA-EPOCH-R (DA-EPOCH-R/HD-MTX) were planned as the protocol treatment. The primary endpoint was 2-year progression-free survival. Between September 25, 2012 and November 11, 2015, we enrolled 47 evaluable patients. Forty-five (96%) patients completed the protocol treatment. There were no deviations or violations in the DA-EPOCH-R dose levels. The complete response rate was 91%, and the overall response rate was 94%. At a median follow-up of 3.1 years (range, 2.0-4.9), the 2-year progression-free survival was 79% (95% confidence interval, 64-88). The 2-year overall survival was 89% (95% confidence interval, 76-95). Toxicity included grade 4 neutropenia in 46 (98%) patients, grade 4 thrombocytopenia 12 (26%) patients, and febrile neutropenia in 31 (66%) patients. No treatment-related death was noted during the study. DA-EPOCH-R/HD-MTX might be a first-line therapy option for stage II-IV CD5+ DLBCL and warrants further investigation. UMIN-CTR: UMIN000008507.
Glycogen Metabolism Supports Photosynthesis Start through the Oxidative Pentose Phosphate Pathway in Cyanobacteria1[OPEN]

Glycogen metabolism kick-starts photosynthesis during cyanobacterial diurnal growth. Cyanobacteria experience drastic changes in their carbon metabolism under daily light/dark cycles. During the day, the Calvin-Benson cycle fixes CO2 and diverts excess carbon into glycogen storage. At night, glycogen is degraded to support cellular respiration. The dark/light transition represents a universal environmental stress for cyanobacteria and other photosynthetic lifeforms. Recent studies revealed the essential genetic background necessary for the fitness of cyanobacteria during diurnal growth. However, the metabolic processes underlying the dark/light transition are not well understood. In this study, we observed that glycogen metabolism supports photosynthesis in the cyanobacterium Synechococcus elongatus PCC 7942 when photosynthesis reactions start upon light exposure. Compared with the wild type, the glycogen mutant ∆glgC showed a reduced photosynthetic efficiency and a slower P700+ rereduction rate when photosynthesis starts. Proteomic analyses indicated that glycogen is degraded through the oxidative pentose phosphate (OPP) pathway during the dark/light transition. We confirmed that the OPP pathway is essential for the initiation of photosynthesis and further showed that glycogen degradation through the OPP pathway contributes to the activation of key Calvin-Benson cycle enzymes by modulating NADPH levels. This strategy stimulates photosynthesis in cyanobacteria following dark respiration and stabilizes the Calvin-Benson cycle under fluctuating environmental conditions, thereby offering evolutionary advantages for photosynthetic organisms using the Calvin-Benson cycle for carbon fixation.
Acute lower respiratory tract infections: Symptoms, findings and management in Danish general practice

Abstract Background Acute lower respiratory tract infections (LRTIs) are among the most common infections managed in general practice. Objectives To describe differences in reported symptoms, findings and management of patients diagnosed with acute LRTIs, and to explore possible associations between these findings and being diagnosed with pneumonia. Methods During one winter season (2017 or 2018), a prospective registration of patients diagnosed with either acute bronchitis (ICPC-2: R78) or pneumonia (ICPC-2: R81) was conducted in Danish general practice for 20 days. A 42 item registration chart was filled in for each patient. Descriptive statistics, Pearson's chi-square test and multiple logistic regressions were used for data analysis. Results In total, 70 general practices participated with 1384 patients registered. Patients diagnosed with pneumonia were more often reported as having a fever, dyspnoea, increased purulent sputum, abnormal pulmonary auscultation/chest retractions, and were more often assessed as unwell by the healthcare professional, than those diagnosed with acute bronchitis. Very few patients had a chest X-ray. Contrary, most patients had a C-reactive protein (CRP) test performed (pneumonia: 83%; acute bronchitis: 71%). Respectively, 93% and 20% of patients were treated with antibiotics. Having a fever, an abnormal pulmonary auscultation/chest retractions or being assessed as unwell increased the likelihood of the diagnosis pneumonia at least fivefold. Even a slightly elevated CRP (≥11 mg/L) was positively associated with being diagnosed with pneumonia. Conclusion Danish healthcare professionals are highly influenced by symptoms, signs and CRP tests when diagnosing patients with acute LRTIs in general practice.
Delayed Implantation of Pumped Kidneys Decreases Renal Allograft Futility in Combined Liver-Kidney Transplantation.

BACKGROUND Combined liver-kidney transplantation (CLKT) improves survival for liver transplant recipients with renal dysfunction; however, the tenuous perioperative hemodynamic and metabolic milieu in high acuity CLKT recipients increases delayed graft function and kidney allograft failure. We sought to analyze whether delayed KT through pumping would improve kidney outcomes following CLKT. METHODS A retrospective analysis (UCLA [n=145], TMH [n=79]) was performed of all adults receiving CLKT at 2 high-volume transplant centers from February 2004 through January 2017, and recipients were analyzed for patient and allograft survival as well as renal outcomes following CLKT. RESULTS 63 patients (28.1%) underwent delayed implantation of pumped kidneys (dCLKT) and 161 patients (71.9%) received early implantation of nonpumped kidneys (eCLKT). Most recipients were high-acuity with median biologic MELD 35 for dCLKT and 34 for eCLKT (p=ns). Pretransplant, dCLKT had longer ICU stay, were more often intubated, and had greater vasopressor use. Despite this, dCLKT exhibited improved 1-, 3-, and 5-yr patient and kidney survival (p=0.02) and decreased length of stay (p=0.001), kidney allograft failure (p=0.012), and dialysis duration (p=0.031). This reduced kidney allograft futility (death or continued need for hemodialysis within 3 months posttransplant) for dCLKT (6.3%) compared with eCLKT (19.9%) (p=0.013). CONCLUSIONS Delayed implantation of pumped kidneys is associated with improved patient and renal allograft survival and decreased hospital length of stay despite longer kidney cold ischemia. These data should inform the ethical debate as to the futility of performing CLKT in high-acuity recipients.
Propranolol is a mechanism‐based inhibitor of CYP2D and CYP2D6 in humanized CYP2D6‐transgenic mice: Effects on activity and drug responses

Genetics and drug interactions contribute to large interindividual variation in human CYP2D6 activity. Here, we have characterized propranolol inhibition of human and mouse CYP2D using transgenic (TG) mice, which express both mouse CYP2D and human CYP2D6, and wild‐type (WT) mice. Our purpose was to develop a method for in vivo manipulation of CYP2D6 enzyme activity which could be used to investigate the role of CYP2D6 in drug‐induced behaviours.
Treatment of adult isolated ulnar diaphyseal fractures: A comparison of new-generation locked intramedullary nail and plate fixation.

OBJECTIVES This study aims to compare the radiological and functional results of adult patients with isolated ulnar diaphyseal fractures treated with plate and new-generation locked intramedullary nail (IMN). PATIENTS AND METHODS The study included 57 patients (38 males, 19 females; mean age 39.1 years; range, 18 to 77 years) with isolated ulnar diaphyseal fractures treated with IMN or plate fixation between January 2008 and December 2017. Thirty patients (Plate group) were treated with plate fixation and 27 patients (IMN group) with IMN. Functional results were evaluated according to the Grace-Eversmann evaluation system and the disabilities of the arm, shoulder and hand (DASH) questionnaire. RESULTS The mean union time was 12.8±1.2 weeks in the IMN group and 13.7±1.4 weeks in the plate group (p=0.092). The mean operation time was significantly shorter in the IMN group (30 minutes) than in the plate group (46 minutes; p<0.001). The mean DASH score was 7.0±4.5 in the IMN group and 7.7±8.6 in the plate group (p=0.766). CONCLUSION With similar union rates, functional results, and shorter operation times, locked IMNs are a suitable alternative to plate osteosynthesis in adult isolated ulnar diaphyseal fractures.
Investigation of dissolution rate kinetics of bulk pharmaceutical feed streams within a stirred tank vessel and a twin screw extruder

Abstract The introduction of continuous manufacturing of pharmaceuticals has highlighted the challenging area of continuous dissolution of solids for work ups to flow chemistry systems. In this study, the use of a 16 mm twin screw extruder (TSE) as a platform technology for solid feeds is investigated using four solid pharmaceutical ingredients (PI) in a mixture of water and IPA. In order for comparison, the same experiments were also carried out in a batch traditional stirred tank vessel (STV). The objectives of this work are to gain further scientific understanding on dissolution kinetics and to compare kinetics in both a batch and continuous system. The concentration of each PI during dissolution is monitored using an in-line UV-ATR probe, allowing the extraction of dissolution kinetics. Faster dissolution rates are achieved in the TSE than in the STV due to higher power dissipation generated by the aggressive shear mixing and thermal energy within the TSE. Complete dissolution of paracetamol is obtained within the residence time of the TSE; complete dissolution of benzoic acid and acetylsalicylic acid are achieved at higher barrel temperatures; however full dissolution of nicotinic acid is not achievable in the TSE under the experimental conditions. Graphical Abstract