Miracle-dz/UniFAR-FTUs huggingface dataset:
Barriers and Solutions to the Inclusion of Broader Benefits in Biopharmaceutical Value Assessments.

OBJECTIVES Evaluate how institutional barriers prevent the inclusion of broader individual and societal benefits associated with new health care innovations from being considered when assessing the value of medical treatments and making health care coverage determinations. METHODS A survey of health insurance providers, pharmacy benefit managers, employee benefit consultancies, and employer group representatives in the US queried respondents' opinions regarding the feasibility of evaluating indirect treatment benefits in four domains: absenteeism, presenteeism, caregiver burden, and quality of life. RESULTS Inclusion of indirect benefits (including absenteeism and presenteeism) in the assessment of a treatment's value was of low importance to payers, but higher importance to employer stakeholders. CONCLUSIONS Therapies that improve physical or mental function accrue benefits both directly and indirectly and can only be adequately assessed if measurement standards for indirect benefits and quantifiable measures are established.
Anterior Cervical Debridement and Fusion for Cervical Pyogenic Spondylodiscitis: Use of Anterior Cervical Plating or Not?

STUDY DESIGN Retrospective multicenter case series. OBJECTIVE We sought to evaluate the safety and efficacy of anterior cervical plating in anterior cervical debridement and fusion (ACDF) for patients with cervical pyogenic spondylodiscitis (CPS). SUMMARY OF BACKGROUND DATA Due to concerns about bacterial seeding on the foreign material after instrumentations in pyogenic infections, the safety and efficacy of anterior cervical plating for CPS are still undetermined and controversial. Little information is available about the safety and efficacy of anterior cervical plating to manage CPS. METHODS Twenty-three patients who underwent ACDF with (n = 12) or without (n = 11) plating for CPS were included. The mean age was 62.6 years. Medical records were reviewed and radiological parameters including segmental height, segmental angle, C2-C7 angle, and fusion status were analyzed. The mean follow-up period after surgery was 21.3 months. RESULTS After ACDF with plating, segmental height, segmental angle, and C2-C7 angle were significantly improved compared with preoperative conditions and remained well-maintained at the last follow-up. After ACDF without plating, three radiological parameters were also initially improved compared with preoperative condition, but significantly deteriorated to preoperative levels at the time of the last follow-up. The fusion rate was higher in the ACDF with plating group compared with the ACDF without plating group (90.9% vs. 63.6%; P < 0.01). One patient who received ACDF with plating and four patients who received ACDF without plating underwent revision surgery due to nonunion or bone graft dislodgement. No recurrence of pyogenic spondylodiscitis occurred in either group. CONCLUSION ACDF with plating showed better surgical outcomes compared with ACDF without plating for CPS. We recommend the use of anterior cervical plating, which can provide biomechanical stability, for better healing of CPS. To our knowledge, this is the largest surgical case series of CPS. LEVEL OF EVIDENCE 4.
The hepatic stellate cell in sight: targeting antiproliferative drugs to the fibrotic liver

Liver fibrosis is characterized by the accumulation of excessive amounts of scar tissue in response to chronic liver injury. Important causes of chronic liver injury are viral hepatitis, metabolic disorders such as Wilson’s disease, autoimmune diseases and chronic exposure to certain chemicals, alcohol or drugs. It is also becoming increasingly clear that obesity is a risk factor for steatohepatitis, finally leading to fibrosis. Although initially the synthesis of scar tissue in the injured liver serves as a repair mechanism to allow proper healing of the damaged tissue, liver fibrosis can be viewed upon as a derailed healing response, in which the deposition of scar tissue is disproportionate to the extent of tissue damage. In its advanced stages the disease is characterized by its self-perpetuating nature, reflected by the fact that fibrosis progresses even after withdrawal of the inciting stimulus. Eventually, fibrosis may develop into an irreversible condition referred to as liver cirrhosis, in which regenerative nodules of still functional liver parenchyma are encapsulated in fibrotic septa, resulting in complete liver failure and, ultimately, death. As outlined in chapter 2, for many patients no effective pharmacological treatment is available and to date a liver transplantation is the only curative option. Extensive research on the pathophysiology of liver fibrosis has identified the hepatic stellate cell (HSC) as the key fibrogenic cell of the liver. HSC proliferation appears to be a crucial step in fibrogenesis, and attenuating the proliferation of this cell type therefore seems a relevant strategy to inhibit liver fibrosis pharmacologically. However, a serious problem of systemic treatment with antiproliferative drugs would be the unacceptable toxicity in organs other than the liver. Yet, even within the liver systemic treatment with antiproliferative drugs will undesirably affect other cell types. Inhibition of hepatocyte proliferation, for example, may result in an impaired regenerative capacity of the liver, while particularly this process is of great importance for the renewal of the liver parenchyma after massive hepatocyte injury. Because of these serious adverse effects, the use of cytostatics and other potent antiproliferative drugs has not been examined. One possible approach to reduce the adverse effects is to increase the specificity of antiproliferative agents for activated HSC by cell-selective targeting. With the recent development of the first generation of HSC-selective drug carriers, this has now become an option. The work described in this thesis focuses on the use of the HSC-selective drug carrier mannose-6-phosphate-modified human serum albumin (M6PHSA). This carrier has been designed to specifically bind to mannose-6-phosphate/insulin-like growth factor-II (M6P/IGF-II) receptors, which are upregulated on the cell surface of activated HSC.
DSA Are Associated With More Graft Injury, More Fibrosis, and Upregulation of Rejection-associated Transcripts in Subclinical Rejection

Supplemental Digital Content is available in the text. Background. Subclinical T cell-mediated rejection (subTCMR) is commonly found after liver transplantation and has a good short-term prognosis, even when it is left untreated. Donor-specific antibodies (DSA) are putatively associated with a worse prognosis for recipient and graft after liver transplantation. Methods. To assess the immune regulation in subTCMR grafts, gene expression of 93 transcripts for graft injury, tolerance, and immune regulation was analyzed in 77 biopsies with “no histologic rejection” (NHR; n = 25), “clinical TCMR” (cTMCR; n = 16), and subTCMR (n = 36). In addition, all available subTCMR biopsies (n = 71) were tested for DSA with bead assays. Results. SubTCMR showed heterogeneous and intermediate expression profiles of transcripts that were upregulated in cTCMR. Graft gene expression suggested a lower activation of effector lymphocytes and a higher activation of regulatory T cells in grafts with subTCMR compared to cTCMR. DSA positivity in subTCMR was associated with histological evidence of more severe graft inflammation and fibrosis. This more severe DSA+ associated graft injury in subTCMR was converged with an upregulation of cTCMR-associated transcripts. In nonsupervised analysis, DSA positive subTCMR mostly clustered together with cTCMR, while DSA negative subTCMR clustered together with NHR. Conclusions. T cell-mediated rejection seems to form a continuum of alloimmune activation. Although subTCMR exhibited less expression of TCMR-associated transcript, DSA positivity in subTCMR was associated with an upregulation of rejection-associated transcripts. The identification of DSA positive subclinical rejection might help to define patients with more inflammation in the graft and development of fibrosis.
A potential barrier to adherence? Memory for future intentions is impaired in hemodialysis patients

End‐stage renal disease (ESRD) has been associated with a range of cognitive deficits, including impaired retrospective memory and attention. Prospective memory (PM) is memory for future intentions, such as remembering to take medication on time. Prospective memory has not been examined in any ESRD patients; yet, the implications upon diet and medication management could potentially have detrimental effects on patient welfare. This is the first study to examine PM in ESRD patients being treated with hemodialysis (HD).
Comparative and quantitative assessment on statin efficacy and safety: insights into inter-statin and inter-individual variability via dose- and exposure-response relationships

ABSTRACT Introduction: Statins are prescribed widely for cholesterol-lowering therapy, but it is known that their efficacy and safety profiles vary, despite the shared pharmacophore and pharmacological target. The immense body of related clinical and preclinical data offers a unique opportunity to explore the possible factors underlying inter-statin and inter-individual variabilities. Area covered: Clinical and preclinical data from various statins were compiled with regard to the efficacy (cholesterol-lowering effect) and safety (muscle toxicity). Based on the compiled data, dose- and exposure-response relationships were explored to obtain mechanistic and quantitative insights into the variations in the efficacy and safety profiles of statins. Expert opinion: Our analyses indicated that the inter-statin variability in the cholesterol-lowering effect may be mainly attributable to variations in potency of inhibition of the pharmacological target, rather than variations in drug exposure at the site of drug action. However, the drug exposure at the sites of drug action (i.e., the liver for efficacy and the muscle for safety) may contribute to the differences in the efficacy and safety observed in individual patients.
MiR145-5p inhibits proliferation of PMVECs via PAI-1 in experimental hepatopulmonary syndrome rat pulmonary microvascular hyperplasia

ABSTRACT Hepatopulmonary syndrome (HPS) is a triad of advanced liver disease, intrapulmonary vasodilatation and arterial hypoxemia. Increasing evidence shows that HPS is associated with pulmonary microvascular hyperplasia. The aim of this work was to investigate the underlying mechanism of miR-145 in regulating the proliferation of pulmonary microvascular endothelial cells (PMVECs) and angiogenesis in HPS via plasminogen activator inhibitor-1 (PAI-1). To test this, morphology score and number of pulmonary microvascular were assessed in lung tissues from rats with HPS by Hematoxylin and Eosin (H&E) staining. Expression levels of PAI-1 were assessed in lung tissues from HPS rats, as well as in PMVECs treated with HPS rat serum. We also selected the putative microRNA binding site on PAI-1 by bioinformatics analysis. Then, miR145-3p and miR145-5p expression levels in the lungs and PMVECs of rats were detected by qRT-PCR because miR145-5p is a microRNA binding site on PAI-1. In addition, the effects of miR-145-5p regulation on PAI-1 were examined by upregulation and downregulation of miR-145-5p and specific lentivirus transfection was used to overexpress and knockdown PAI-1 to assess PAI-1 function on PMVECs proliferation. Our data showed that levels of PAI-1 expression in lung tissue of rats increased significantly when rats were treated with common bile duct ligation. We found that levels of miR-145-5p were frequently downregulated in HPS tissues and cell lines, and overexpression of miR-145-5p dramatically inhibited PMVECs proliferation. We further verified PAI-1 as a novel and direct target of miR-145-5p in HPS. MiR-145-5p inhibits PAI-1 synthesis and the expression changes of PAI-1 directly affect the proliferation of PMVECs. We concluded that miR-145-5p negatively regulates PMVEC proliferation through PAI-1 expression. In addition, overexpression of miR-145-5p may prove beneficial as a therapeutic strategy for HPS treatment. Summary: Our findings provide proof of principle that microRNAs may be useful for the future development of novel therapeutic strategies in HPS.
Draft Genome Sequence of a Granaticin-Producing Strain of Streptomyces parvus Isolated from a Roman Tomb in the Necropolis of Carmona, Spain

Streptomyces parvus strain C05 was isolated from the walls of a Roman tomb located in Carmona, Seville, Spain. Subsequent studies determined the capability of this strain for producing granaticins. Here, we report the 8.7-Mbp draft genome sequence for this bacterium. ABSTRACT Streptomyces parvus strain C05 was isolated from the walls of a Roman tomb located in Carmona, Seville, Spain. Subsequent studies determined the capability of this strain for producing granaticins. Here, we report the 8.7-Mbp draft genome sequence for this bacterium.
The subgenomes show asymmetric expression of alleles in hybrid lineages of Megalobrama amblycephala × Culter alburnus

Hybridization drives rapid speciation by shaping novel genotypic and phenotypic profiles. Genomic incompatibility and transcriptome shock have been observed in hybrids, although this is rarer in animals than in plants. Using the newly sequenced genomes of the blunt snout bream (Megalobrama amblycephala [BSB]) and the topmouth culter (Culter alburnus [TC]), we focused on the sequence variation and gene expression changes in the reciprocal intergeneric hybrid lineages (F1–F3) of BSB × TC. A genome-wide transcriptional analysis identified 145–974 expressed recombinant genes in the successive generations of hybrid fish, suggesting the rapid emergence of allelic variation following hybridization. Some gradual changes of gene expression with additive and dominance effects and various cis and trans regulations were observed from F1 to F3 in the two hybrid lineages. These asymmetric patterns of gene expression represent the alternative strategies for counteracting deleterious effects of the subgenomes and improving adaptability of novel hybrids. Furthermore, we identified positive selection and additive expression patterns in transforming growth factor, beta 1b (tgfb1b), which may account for the morphological variations of the pharyngeal jaw in the two hybrid lineages. Our current findings provide insights into the evolution of vertebrate genomes immediately following hybridization.
What is the importance of canal-to-diaphysis ratio on osteoporosis-related hip fractures?

OBJECTIVES This study aims to investigate whether the ratio of the canal-to-diaphysis in femoral subtrochanteric region is helpful in determining risk before hip fracture. PATIENTS AND METHODS The study group consisted of 116 patients with osteoporotic hip fractures (26 males, 90 females; mean age 77.8 years; range, 61 to 89 years) and the control group consisted of 56 subjects (11 males, 45 females; mean age 75.3 years; range, 60 to 83 years). The canal-to-diaphysis ratio of patients in the study group was measured on plain radiographs. The results of the affected side and intact side were compared. To ensure the interobserver reliability of the measurements and to minimize technical errors, the assessments were performed twice (two weeks apart) by two different orthopedic surgeons. RESULTS The canal-to-diaphysis ratio was significantly increased in patients with hip fracture compared with the intact side of same patient (p<0.001) and control subjects (p<0.001). According to the results of the receiver operating characteristic analysis, canal-to-diaphysis ratio had a diagnostic value in predicting hip fracture in osteoporosis patients, and the limit value was approximately 0.53 (sensitivity: 81%, specificity: 86%). An index of 0.53 represents a risk of intertrochanteric hip fracture of 89%. CONCLUSION This method can be easily applied by all physicians as X-ray device is readily accessible with low cost. The risk of hip fracture should be determined, osteoporosis should be evaluated, and treatment should be started in patients with high risk to take the necessary precautions before the fracture develops.
Hazards assessment of the intake of trace metals by common mallow (Malva parviflora K.) growing in polluted soils

Abstract Human risks increase by consuming plants growing in trace/heavy metals contaminated soil irrigated with polluted water. The present study aims to assess the ability of common mallow to accumulate trace/heavy metals from polluted soils at South Greater Cairo, Egypt; and their hazardous effects on consumer’s health. Five quadrats were used to collect soil and plant samples from three sites of un-polluted and polluted fields for chemical analysis and measurement of growth variables, as well as for assessing the daily intake of metals (DIM) and hazard quotient (HQ). Irrigation water analysis showed elevated concentrations of the investigated metals and mineral salts in the polluted area compared with the un-polluted one. Plant samples showed reduction in their growth parameters; as well as pigments and nutrient content in the metal-contaminated soil. In addition, Pb, Cd, Cu, Ni, Fe, Mn, Zn, and Co concentrations in the shoots and roots of plants grown in polluted fields were higher compared with plants grown in un-polluted site. The bioaccumulation and translocation factors of most investigated metals indicated the great ability of common mallow to accumulate such metals, which would increase the human intake of metals in their daily diets compared to their reference values (RfD). The hazard quotient (HQ) of Pb, Cr, Fe, Mn and Zn for children and Pb, Cd, Fe and Mn for adults was >1, indicating health hazards for the consumers of common mallow cultivated in the polluted area.
The effects of acupuncture on cognitive impairment of vascular dementia patients

Abstract Background: Vascular dementia (VaD) is the second prevalent dementia worldwide attributable to cognitive impairments. Acupuncture has been applied in clinic as a therapeutic modality to treat VaD. This systematic review and meta-analysis aims to evaluate current evidence to explore the effectiveness and safety of acupuncture treatment to cognitive impairment of VaD. Methods: Randomized controlled trials will be searched restricted to their inception from January 1, 2000 to September 15, 2019. The following literature databases will be searched, including 4 English databases: PubMed, Excerpta Medica Database, the Cochrane Library, Medline, and 4 Chinese databases, namely the China National Knowledge Infrastructure Database, the Wanfang Database, the Chinese Scientific Journal Database, and the Chinese BioMedical Literature Database. After the selection and extraction of eligible studies, a meta-analysis will be undertaken to assess the efficacy and safety of acupuncture on VaD. The Review Manager Software V.5. 3.5 will be employed for meta-analysis to assess the risk of bias, data synthesis, and subgroup analysis. Results: The systematic review and meta-analysis will be carried out to evaluate the efficacy and safety of acupuncture in the treatment of VaD, further provide an evidence-based synthesis for clinical and research applications. Conclusions: The summary of our systematic review will determine whether acupuncture intervention to VaD is safe and well-tolerated in global status.
PACAP and Other Neuropeptide Targets Link Chronic Migraine and Opioid-induced Hyperalgesia in Mouse Models*

The neuropeptides within seven nervous system regions involved in relaying pain signals have been identified and quantified in mouse models of chronic migraine and opioid-induced hyperalgesia using label-free peptidomics. Of the >1500 peptides identified, only a few neuropeptides were significantly altered between the two conditions, including the known pro-migraine molecule, calcitonin-gene related peptide. As pituitary adenylate cyclase activating enzyme (PACAP)-related peptides were similarly altered in both groups, we validated PACAP as an overlapping mechanism of chronic migraine-associated pain and opioid-induced hyperalgesia. Graphical Abstract Highlights Characterized the peptides involved in migraine and opioid-induced hyperalgesia (OIH). Identified more than 1500 peptides in seven nervous system regions. Discovered seven peptides significantly changed with migraine and nine with OIH. Validated PACAP involvement in both conditions via pharmacological studies. Chronic use of opioids can produce opioid-induced hyperalgesia (OIH), and when used to treat migraine, these drugs can result in increased pain and headache chronicity. We hypothesized that overlapping mechanisms between OIH and chronic migraine occur through neuropeptide dysregulation. Using label-free, non-biased liquid chromatography-mass spectrometry to identify and measure changes in more than 1500 neuropeptides under these two conditions, we observed only 16 neuropeptides that were altered between the two conditions. The known pro-migraine molecule, calcitonin-gene related peptide, was among seven peptides associated with chronic migraine, with several pain-processing neuropeptides among the nine other peptides affected in OIH. Further, composite peptide complements Pituitary adenylate cyclase-activating polypeptide (PACAP), Vasoactive intestinal peptide (VIP) and Secretogranin (SCG) showed significant changes in both chronic migraine and OIH. In a follow-up pharmacological study, we confirmed the role of PACAP in models of these two disorders, validating the effectiveness of our peptidomic approach, and identifying PACAP as a mechanistic link between chronic migraine and OIH. Data are available via ProteomeXchange with identifier PXD013362.
Are we scientifically ready to adopt tranexamic acid as a routine in arthroplasty?

The orthopedic literature is abundant in studies on use of tranexamic acid (TXA); most showing its effectiveness in reducing blood loss and transfusion requirement leading to better outcome, shorter length of hospital stay and reduced costs. [1,2] History of TXA dates back to 1960s and TXA is a relatively cheap agent. However, being old and cheap have not restrained TXA to revolutionize the perioperative blood management in the last decade of orthopedic practice, particularly in arthroplasty procedures which make up for a big portion of elective surgeries. [3-5] However, despite the great interest in and the enthusiasm surrounding this agent, its pharmacokinetic characteristics, dosing and optimal modality of administration for different clinical scenarios still remain largely unknown. Tranexamic acid is a fibrin clot stabilizer and not actually a pro-coagulant agent, but it is still commonly associated with increased risk of venous thromboembolic events (VTEs) (e.g. stroke, deep venous thromboembolism, pulmonary embolism), myocardial infarction and to a lesser extent, retinal injury, seizures and nausea. Although this increased risk profile has not been demonstrated, neither it has been totally ruled out in arthroplasty procedures. Considering that even the meta-analyses including data from highest quality randomized controlled trials struggle to provide concrete evidence on safety of TXA use and, for prospective studies, there is need for at least 5,000 patients in each group even to detect a 1% difference with an 80% power, TXA’s widespread adoption seems to continue lacking strong scientific background. [6,7] It has also not been approved by the U.S. Food and Drug Administration for uses other than dental bleeding prophylaxis in hemophilic patients and menorrhagia. [8,9]