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The U.S. Food and Drug Administration and European Commission have developed successful orphan drug legislation to promote the research, development, and marketing approval of drugs to treat rare diseases. Central to these regulations are the concepts of structural similarity and clinical superiority/significant benefit to achieve orphan drug exclusivity. However, differences in health authority expectations remain regarding the qualification for an orphan drug designation, defining structural similarity, and demonstrating clinical superiority/significant benefit. These differences can create sponsor company uncertainty regarding the approvability of products (e.g., blocking risk by an existing orphan product) and divergent orphan drug decisions among health authorities. A comprehensive assessment of current regulations, case studies in exclusivities, and recommendations for improvement are presented., (© 2022. The Author(s), under exclusive licence to The Drug Information Association, Inc.)

The US Food and Drug Administration in 2008 required new type 2 diabetes (T2D) medications to be subject to cardiovascular outcomes safety requirements. Accordingly, the global LEADER trial investigated cardiovascular outcomes of T2D treatment with liraglutide, a glucagon-like peptide-1 receptor agonist. LEADER (NCT01179048) was a multiregional clinical trial (MRCT) conducted from 2010 to 2016, thus completed before publication of the International Council for Harmonization (ICH) E17 guideline on MRCTs in 2017. Novo Nordisk pre-specified analysis of regional cardiovascular outcomes of LEADER participants. This paper assesses the pre-specified regional outcomes based on the ICH E17 guidelines on consistency evaluation. Regional LEADER participant numbers were broadly aligned with ICH E17 guidance and equally balanced across Europe, Asia, North America, and rest of the world. Overall primary major adverse cardiovascular events (MACE) composite outcome for the trial: hazard ratio (HR) (95% CI) 0.87 (0.78; 0.97); regional results varied, ranging from HR (95% CI) 0.62 (0.37; 1.04) (Asia) to 1.01 (0.84; 1.22) (North America). However, pre-specified Cox proportional-hazard regression analyses did not show clear evidence of interaction between regions and primary outcome ( p = 0.20). Furthermore, post hoc analysis of the US population in the North American region found that adjusting for extrinsic or intrinsic factors did not account for this difference [HR (95% CI) 1.03 (0.84; 1.25)]. LEADER data evaluation demonstrated general consistency in cardiovascular safety across regions, except for US participants. Discrepancies in the North American region may relate to drug exposure or chance, but, as these were post hoc findings, the overall primary result is valid, aligned with ICH E17 guidelines., Competing Interests: HKN and BG are employees and shareholders of Novo Nordisk A/S. SD is an employee of Novo Nordisk, Inc. and a shareholder of Novo Nordisk A/S. Sponsorship for this analysis and article processing charges were funded by Novo Nordisk A/S, which also had a role in the design, analysis and reporting of the trial., (Copyright © 2021 Nielsen, DeChiaro and Goldman.)

The incidence of treatment-related neuroendocrine prostate cancer (t-NEPC) is rising as more potent drugs targeting the androgen signaling axis are clinically implemented. Neuroendocrine transdifferentiation (NEtD), an putative initial step in t-NEPC development, is induced by androgen-deprivation therapy (ADT) or anti-androgens, and by activation of the β 2 -adrenergic receptor (ADRB2) in prostate cancer cell lines. Thus, understanding whether ADRB2 is involved in ADT-initiated NEtD may assist in developing treatment strategies that can prevent or reverse t-NEPC emergence, thereby prolonging therapeutic responses. Here we found that in primary, treatment-naïve prostate cancers, ADRB2 mRNA was positively correlated with expression of luminal differentiation markers, and ADRB2 protein levels were inversely correlated with Gleason grade. ADRB2 mRNA was upregulated in metastatic prostate cancer, and progressively downregulated during ADT and t-NEPC emergence. In androgen-deprivated medium, high ADRB2 was required for LNCaP cells to undergo NEtD, measured as increased neurite outgrowth and expression of neuron differentiation and neuroendocrine genes. ADRB2 overexpression induced a neuroendocrine-like morphology in both androgen receptor (AR)-positive and -negative prostate cancer cell lines. ADRB2 downregulation in LNCaP cells increased canonical Wnt signaling, and GSK3α/β inhibition reduced the expression of neuron differentiation and neuroendocrine genes. In LNCaP xenografts, more pronounced castration-induced NEtD was observed in tumors derived from high than low ADRB2 cells. In conclusion, high ADRB2 expression is required for ADT-induced NEtD, characterized by ADRB2 downregulation and t-NEPC emergence. IMPLICATIONS: This data suggest a potential application of β-blockers to prevent cancer cells committed to a neuroendocrine lineage from evolving into t-NEPC., (©2019 American Association for Cancer Research.)

Introduction: The Danish Adult Diabetes Database (DADD) annually reports a quality indicator for lipid-lowering treatment of type 2 diabetes mellitus (T2DM) patients. This retrospective cohort study aims to A) investigate the reasons for inadequate or lacking lipid-lowering treatment and to B) assess the validity of the DADD indicator as a measure of quality of care., Methods: A) A pop-up questionnaire enquiring about reasons for lack of treatment was added to the clinicians' data entry tool in the Central Denmark Region. B) The DADD indicator was compared on a per-clinic basis with the achieved median low-density lipoprotein (LDL) cholesterol level and with an internationally widely used indicator of lipid-lowering treatment quality., Results: A) A total of 3,491 patients were registered from 1 January 2013 to 28 February 2015. For 170 (62%) of 309 patients with an LDL level > 2.5 mmol/l who were not receiving lipid-lowering treatment, there was no "good" explanation for lacking treatment. Among 518 patients with an LDL level > 2.5 mmol/l despite lipid-lowering treatment, 259 (50%) did not receive high-intensity treatment. B) The DADD quality indicator was neither associated with the international quality indicator nor with the median per-clinic LDL level for T2DM patients., Conclusions: A) We found substantial potential for improvement of lipid management among T2DM patients in Denmark by initiating and/or intensifying lipid-lowering treatment. B) The current DADD indicator is not a valid measure of lipid-lowering quality of care., Funding: supported by the Rosa and Asta Jensen Foundation., Trial Registration: not relevant., (Articles published in the DMJ are “open access”. This means that the articles are distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits any non-commercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.)

Photoactivated disinfection has a strong local antimicrobial effect. In the field of dentistry it is an emerging adjunct to mechanical debridement during endodontic and periodontal treatment. In the present study, we investigate the effect of photoactivated disinfection using riboflavin as a photosensitizer and blue LED light for activation, and compare it to photoactivated disinfection with the widely used combination of toluidine blue O and red light. Riboflavin is highly biocompatible and can be activated with LED lamps at hand in the dental office. To date, no reports are available on the antimicrobial effect of photoactivated disinfection using riboflavin/blue light on oral microorganisms. Planktonic cultures of eight organisms frequently isolated from periodontal and/or endodontic lesions (Aggregatibacter actinomycetemcomitans, Candida albicans, Enterococcus faecalis, Escherischia coli, Lactobacillus paracasei, Porphyromonas gingivalis, Prevotella intermedia and Propionibacterium acnes) were subjected to photoactivated disinfection with riboflavin/blue light and toluidine blue O/red light, and survival rates were determined by CFU counts. Within the limited irradiation time of one minute, photoactivated disinfection with riboflavin/blue light only resulted in minor reductions in CFU counts, whereas full kills were achieved for all organisms when using toluidine blue O/red light. The black pigmented anaerobes P. gingivalis and P. intermedia were eradicated completely by riboflavin/blue light, but also by blue light treatment alone, suggesting that endogenous chromophores acted as photosensitizers in these bacteria. On the basis of our results, riboflavin cannot be recommended as a photosensitizer used for photoactivated disinfection of periodontal or endodontic infections.

Different steam explosion conditions were applied to Salix chips and the effect of this pretreatment was evaluated by running both enzymatic hydrolysis and biogas tests. Total enzymatic release of glucose and xylose increased with pretreatment harshness, with maximum values being obtained after pretreatment for 10 min at 210°C. Harsher pretreatment conditions did not increase glucose release, led to degradation of xylose and to formation of furfurals. Samples pretreated at 220 and 230°C initially showed low production of biogas, probably because of inhibitors produced during the pretreatment, but the microbial community was able to adapt and showed high final biogas production. Interestingly, final biogas yields correlated well with sugar yields after enzymatic hydrolysis, suggesting that at least in some cases a 24h enzymatic assay may be developed as a quick method to predict the effects of pretreatment of lignocellulosic biomass on biogas yields., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

In aspirin-treated patients with acute coronary syndromes without ST-segment elevation unfractionated heparin (UFH) or low molecular weight heparin (LMWH) treatment < 7 days significantly reduce the risk of acute myocardial infarction (AMI), and LMWH furthermore reduces revascularisation. There is a non-significant effect on mortality compared with placebo and an insignificantly increased risk of haemorrhagic complications. No net clinical benefit of LMWH was found compared to UHF, but LMWH has pharmacokinetic advantages. The optimal duration of heparin treatment remains controversial.

Superficial thrombophlebitis is a common disease. Recently, a relatively high incidence of concomitant venous thromboembolism has been found. Graduated compressing stockings and low-molecular heparin subcutaneously in weight-based therapeutic doses for 10-30 days are considered the best treatment. Non-steroidal-anti-inflammatory drugs or local treatment with heparinoid may reduce the pain. A new Cochrane analysis concludes that the existing studies do not demonstrate strong recommendations for any treatment. Ongoing trials will add to our knowledge about optimal treatment of ST.

High mobility group (HMG) proteins are usually considered ubiquitous components of the eukaryotic chromatin. Using HMG gene promoter-GUS reporter gene fusions we have examined the expression of the reporter gene in transgenic Arabidopsis plants. These experiments have revealed that the different HMGA and HMGB promoters display overlapping patterns of activity, but they also show tissue- and developmental stage-specific differences. Moreover, leader introns that are present in some of the HMGB genes can modulate reporter gene expression. The differential HMG gene expression supports the view that the various HMG proteins serve partially different architectural functions in plant chromatin.

The pathogenesis of deep vein thrombosis (DVT) involves vascular changes or injury, stasis and alterations in the blood composition. The risk increases with age; however, important risk factors are cancer, surgery, immobilisation and hormone therapy. DVT most often appears in the crural veins. The diagnosis is based on ultrasound, d-dimer and clinical examination. Correct treatment requires gradient compression hosiery, low-molecular heparins and anticoagulant therapy. Duration of treatment depends on the individual risk of recurrence.

It has been an accepted fact for more than 40 years that the E center in Si (the group-V impurity--vacancy pair)--one of the most studied defects in semiconductors--has only one energy level in the band gap: namely, the acceptor level at about 0.45 eV below the conduction band. We now demonstrate that it has a second level, situated in the lower half of the band gap at 0.27 eV above the valence band. The existence of this level, having a donor character, is disclosed by a combination of different transient-capacitance techniques and electronic-structure calculations. The finding seriously questions some diffusion-modeling approaches performed in the past.

The high-mobility group (HMG) proteins of the HMGB family are chromatin-associated proteins that act as architectural factors in various nucleoprotein structures, which regulate DNA-dependent processes such as transcription and recombination. Database analyses revealed that in addition to the previously identified HMGB1-HMGB5 proteins, the Arabidopsis genome encodes at least three other family members having the typical overall structure of a central HMG-box DNA binding domain, which is flanked by basic and acidic regions. These novel HMGB proteins display some structural differences, when compared to HMGB1-HMGB5. Therefore, a representative of the identified proteins, now termed HMGB6, was further analyzed. The HMGB6 protein of approximately 27 kDa is the largest plant HMGB protein identified so far. This is essentially due to its unusually extended N-terminal domain of 109 amino acid residues. Subcellular localization experiments demonstrate that it is a nuclear protein. According to CD measurements, HMGB6 has an alpha-helical HMG-box domain. HMGB6 can bind DNA structure-specifically, and it is a substrate for the protein kinase CK2alpha. Because of these features, HMGB6, and presumably its relatives, can be considered members of the plant HMGB protein family. Hence, eight different chromosomal HMGB proteins are expressed in Arabidopsis, and they may serve specialized architectural functions assisting various DNA-dependent processes.

Acute manifestations of atherosclerosis, e.g. myocardial infarction and ischaemic stroke, are among the most common causes of death in the western part of the world. Rupture of an atherosclerotic plaque results in activation, adhesion and aggregation of platelets. Antithrombotic treatment has shown to reduce mortality and morbidity and is used in both primary and secondary prevention. The thienopyridine Clopidogrel specifically and irreversibly inhibits the binding of ADP to platelet surface ADP-receptors, thereby inhibiting platelet activation and aggregation. In this publication the pharmacological background and clinical documentation for the use of Clopidogrel both as monotherapy and in combination with Acetylicsalisylic acid are reviewed.

An array of 12 new saphenamycin analogues modified at the benzoate moiety was synthesized on solid support. Synthesis commenced with a chemoselective anchoring of saphenic acid through the carboxyl group to a 2-chlorotrityl functionalized polystyrene resin. The secondary alcohol was acylated in parallel with a series of differently substituted benzoic acid derivatives. Treatment with TFA-CH(2)Cl(2) (5:995) released the expected saphenamycin analogues into solution. These new analogues were purified, characterized and screened for antimicrobial activity against Bacillus subtilis and Proteus mirabilis. Eight analogues exhibited MIC values against B. subtilis ranging from 0.07 to 3.93 microg/mL, comparable to the activities of previously reported saphenamycin analogues.

To study the association between smoking and thyroid disease (Graves' disease [E05.0], nodular toxic goiter [E05.2], and autoimmune hypothyroidism [E03.9]) in a low-iodine intake area a case-control study was undertaken. A self-administered questionnaire was issued to 864 consecutive patients with hyperthyroidism and 628 patients with autoimmune hypothyroidism treated at five university or regional endocrinologic clinics in Denmark between January 1, 1990 and December 31, 1998. Each respondent was compared to an age- (+/- 5 years) and gender-matched normal control person randomly drawn from the background population. A total of 621 patients with hyperthyroidism (72%) and 411 patients with autoimmune hypothyroidism (66%) responded. Of these, 617 (542 females) and 408 (364 females) could be analyzed, respectively. There was an increased risk of both Graves' disease (odds ratio [OR] = 2.5, 95% confidence interval [CI]: 1.8-3.5), toxic nodular goiter (OR = 1.7, 95% CI: 1.1-2.5), and autoimmune hypothyroidism (OR = 1.5, 95% CI: 1.1-2.1) with ever smoking compared to never smoking in women, but not in men. With the high proportion of ever-smokers among women (56%), the attributable risk of smoking in women was 45% in Graves' disease, 28% in toxic nodular goiter, and 23% in autoimmune hypothyroidism. Ever use of oral contraceptives was associated with a slightly lower risk of Graves' disease in women, but not of toxic nodular goiter or autoimmune hypothyroidism. In conclusion, smoking is a powerful risk factor for thyroid disease, especially in populations with a high smoking frequency. Oral contraceptive use is associated with a slightly lower frequency of Graves' disease.

Background: Acetylsalicylic acid (ASA) is now a standard treatment of acute myocardial infarction (AMI). ASA inhibits thromboxane A(2) (TXA(2)) production by blocking the constitutive cyclooxygenase (COX)-1 enzyme, but only to a small degree the inducible COX-2. COX-2 is induced by increased concentrations of cytokines, which is related to an enhanced inflammatory response. Previously, we have found a complete inhibition of TXA(2) synthesis in healthy volunteers after intravenous administration of 50 mg of ASA. We measured in a randomized, placebo-controlled pilot trial the effect of 100 mg of ASA injected intravenously on TXA(2) synthesis in AMI patients treated with streptokinase., Methods and Results: Nineteen patients with AMI treated with streptokinase were randomized to 100 mg of ASA or placebo injected intravenously. Se-TXB(2) and bleeding time were measured before and after drug administration. One hundred and eighty minutes after intravenous ASA administration, treatment with oral ASA was initiated. We found a significant decrease in serum concentrations of TXB(2) after 30, 60 and 180 min following ASA injection compared to placebo, but in none of the patients was complete inhibition of TXA(2) production achieved. No significant change in bleeding time could be demonstrated., Conclusion: Intravenous ASA in a dosage of 100 mg did not completely prevent TXA(2) production in AMI patients treated with streptokinase. This may be due to synthesis of TXA(2) by the inducible COX-2 enzyme and/or to a transcellular metabolism in platelets of prostanoids generated by endothelial cells.

Aim: To study fracture risk and risk factors for fractures in patients with primary idiopathic hypothyroidism (ICD 10: E03.9)., Design: Historical follow-up., Material and Methods: A self-administered questionnaire was issued to 628 patients with primary idiopathic levothyroxine-substituted hypothyroidism. A total of 412 (65.6%) responded and of these, 408 could be analyzed. The 408 respondents were age- (+/- 5 years) and gender-matched with 408 normal controls randomly selected from the background population who responded to the same questionnaire., Results: Overall fracture risk was increased in patients compared to controls (relative risk: RR = 1.6, 95% CI: 1.0-2.5). However, the increase was temporary and limited to the period within the first 2 years after the diagnosis of hypothyroidism (RR = 3.1, 95% CI: 1.4-7.0). Before the diagnosis and more than 2 years after the diagnosis, the fracture risk in patients did not deviate from that of the controls. The increase in fracture risk was only significant in the age group above 50 years (RR = 1.8, 95% CI: 1-3.2), and was limited to the forearms (RR = 3.0, 95% CI: 1.4-6.3 for the entire patient population)., Conclusions: There was a temporary increase in fracture risk within the first 2 years after diagnosis of primary idiopathic hypothyroidism. The fracture risk was mainly increased in the age group above 50 years, and the increased risk was limited to the forearms.

In 1998, the sale of vitamin K antagonists (VKA) in Denmark corresponded to the amount used for treatment of more than 20,000 patients for one year. This is more than three times more than ten years earlier. The reasons for the increasing use of VKA are new indications for permanent anticoagulant treatment, especially chronic atrial fibrillation and venous thromboembolism associated with permanent thromboembolic risk factors. The risk of bleeding is higher in the introductory phase of anticoagulant treatment than later on. It is now recommended to commence anticoagulant therapy without a loading dose. This seems to hasten a good estimate of the maintenance dose. The metabolism of VKA depends on a number of genetic and acquired factors. Knowledge of these factors is crucial for optimal regulation of the treatment, and it is important that patients at start of treatment are thoroughly informed about these factors in order to minimize the risk of complications.

A combination of different methods was applied to investigate the occurrence of anaerobic processes in aerated activated sludge. Microsensor measurements (O(2), NO(2)(-), NO(3)(-), and H(2)S) were performed on single sludge flocs to detect anoxic niches, nitrate reduction, or sulfate reduction on a microscale. Incubations of activated sludge with (15)NO(3)(-) and (35)SO(4)(2-) were used to determine denitrification and sulfate reduction rates on a batch scale. In four of six investigated sludges, no anoxic zones developed during aeration, and consequently denitrification rates were very low. However, in two sludges anoxia in flocs coincided with significant denitrification rates. Sulfate reduction could not be detected in any sludge in either the microsensor or the batch investigation, not even under short-term anoxic conditions. In contrast, the presence of sulfate-reducing bacteria was shown by fluorescence in situ hybridization with 16S rRNA-targeted oligonucleotide probes and by PCR-based detection of genes coding for the dissimilatory sulfite reductase. A possible explanation for the absence of anoxia even in most of the larger flocs might be that oxygen transport is not only diffusional but enhanced by advection, i.e., facilitated by flow through pores and channels. This possibility is suggested by the irregularity of some oxygen profiles and by confocal laser scanning microscopy of the three-dimensional floc structures, which showed that flocs from the two sludges in which anoxic zones were found were apparently denser than flocs from the other sludges.