Miracle-dz/UniFAR-FTUs huggingface dataset:
Clinical experience with insulin detemir, biphasic insulin aspart and insulin aspart in people with type 2 diabetes: Results from the South India cohort of the A1chieve study

Background: The A1chieve, a multicentric (28 countries), 24-week, non-interventional study evaluated the safety and effectiveness of insulin detemir, biphasic insulin aspart and insulin aspart in people with T2DM (n = 66,726) in routine clinical care across four continents. Materials and Methods: Data was collected at baseline, at 12 weeks and at 24 weeks. This short communication presents the results for patients enrolled from South India. Results: A total of 9273 patients were enrolled in the study. Four different insulin analogue regimens were used in the study. Patients had started on or were switched to biphasic insulin aspart (n = 7217), insulin detemir (n = 1001), insulin aspart (n = 734), basal insulin plus insulin aspart (n = 117) and other insulin combinations (n = 189). At baseline glycaemic control was poor for both insulin naïve (mean HbA1c: 9.2%) and insulin user (mean HbA1c: 9.1%) groups. After 24 weeks of treatment both the groups showed improvement in HbA1c (insulin naïve: −1.6%, insulin users: −1.3%). SADRs including major hypoglycaemic events or episodes did not occur in any of the study patients. Conclusion: Starting or switching to insulin analogues was associated with improvement in glycaemic control with a low rate of hypoglycaemia.
A Scoring System for Pneumocystis Pneumonia Based on Clinical Symptoms and Laboratory Findings in a Rat Model

Background and Objective: Effective clinical prediction of Pneumocystis carinii pneumonia (PCP) is quite critical, especially in high risk groups. Different scoring systems have been reported to help the physicians before patients entering the acute stage. This research study was conducted to evaluate the possibility of grading the disease based on clinical symptoms and laboratory findings of pneumocystosis in a rat model. Materials and Methods: Twenty female rats (two-month age, a weight of 150-200 g, SpragueDawley strain) were stimulated artificially by methyl prednizolone acetate to infect them. Changes of clinical signs and symptoms were followed up for two months. All changes were registered and graded according to defined criteria. Oral swab, broncho-alveolar lavage, and lung homogenate were collected before injection and at weeks 2, 3, 4, 5, 6 and 7 from test and control groups. All specimens were tested by Giemsa and Gomori’s metenamin silver staining and PCR methods. Results: Three stages were determined for infection of PCP on the basis of clinical symptoms and laboratory findings. Conclusion: With regard to the correlation between staining and PCR results and clinical symptoms in the studied groups, those animal models under suppressed immune system are in a healthy condition up to 10 days after injection, but those from days 11-20, 21-30, and over 30 are in phases 1, 2 and 3 respectively.
Clinical experience with insulin detemir, biphasic insulin aspart and insulin aspart in people with type 2 diabetes: Results from the Hyderabad cohort of the A1chieve study

Background: The A1chieve, a multicentric (28 countries), 24-week, non-interventional study evaluated the safety and effectiveness of insulin detemir, biphasic insulin aspart and insulin aspart in people with T2DM (n = 66,726) in routine clinical care across four continents. Materials and Methods: Data was collected at baseline, at 12 weeks and at 24 weeks. This short communication presents the results for patients enrolled from Hyderabad, India. Results: A total of 1249 patients were enrolled in the study. Four different insulin analogue regimens were used in the study. Patients had started on or were switched to biphasic insulin aspart (n = 893), insulin detemir (n = 158), insulin aspart (n = 124), basal insulin plus insulin aspart (n = 19) and other insulin combinations (n = 54). At baseline glycaemic control was poor for both insulin naïve (mean HbA1c: 9.0%) and insulin user (mean HbA1c: 9.5%) groups. After 24 weeks of treatment, both the groups showed improvement in HbA1c (insulin naïve: −0.9%, insulin users: −1.1%). SADRs including major hypoglycaemic events or episodes did not occur in any of the study patients. Conclusion: Starting or switching to insulin analogues was associated with improvement in glycaemic control with a low rate of hypoglycaemia.
Opioid receptor targeting ligands for pain management: a review and update

Importance of the field: Discovery and synthesis of analgesic ligands can potentially improve analgesia, reduce side effects, minimize psychologic dependence and delay analgesic tolerance. Areas covered in this review: This review covers opioid peptides and analogs and bifunctional opioid ligands, and bifunctional opioid/non-opioid ligands as new, potentially useful analgesics. Several lines of investigation have resulted in potentially useful agents. What the reader will gain: Modifications of peptide structures have improved opioid receptor affinity, efficacy, stability, half-life and CNS penetrations. Opioid μ receptor agonists have been used to form multi-targeted directed ligands (MDL), which in animal models improve the therapeutic index of the analgesic relative to monovalent potent μ receptor agents. These new opioid ligands are reviewed in detail. Take home message: Modified opioid peptides and MDL ligands are potentially better analgesics than morphine.
Health economics in India: The case of diabetes mellitus

As we work to tackle the growing burden of endocrinopathy, including diabetes and associated noncommunicable disease, we often find the distinctions between clinical endocrinology, and other medical and nonmedical specialties, blurring. Examples of clinical disciplines which interface endocrinology include nephrology, cardiology, geriatrics, and gynecology; many of these issues have been covered earlier in the IJEM. [1‐4] The para clinical subjects also contribute to the growth of endocrinology as a science: Public health, pharmacology, and psychology are but a few examples. [5‐7]
Training health researchers: Challenges, systemic changes, and a model solution

Improving a nation’s health through evidencebased practice requires basic and applied health research and translating the resulting knowledge into clinical practice and policy (Sung et al., 2003). These endeavors require highly trained researchers, but concerns about the declining numbers of all researchers, and clinical researchers (traditionally physician-scientists) in particular, have permeated the health literature for decades (Wyngaarden, 1979; Canadian Institutes of Health Research CIHR, 2002). The objectives of this commentary are: (1) to highlight challenges in the health research pipeline (i.e. recruiting, training, and retaining researchers); (2) to describe an innovative training program addressing the problem in pediatric pain (Pain in Child Health; PICH); and (3) to encourage researchers to build training networks in their own area of expertise. Since some of the challenges faced by clinical researchers are also experienced by scientists in general, both difficulties unique to health researchers as well as more general issues will be discussed.
Dietary habits and exposure to pesticides in Dutch infants

Background: Children are known to have higher dietary exposure levels to pesticide residues than adults due to higher consumption levels per kilogram bodyweight. Also social concern exists on the effects of these residues in young children, who are growing rapidly. To assess whether a certain compound may pose a risk for young children, it is important to have consumption levels of the foods that may contain the compound of interest in this age group. In the Netherlands food consumption data are available of children from 1 year onwards. However, the majority of children (if not all) already consume solid foods before age 1. Aims: Performance of a food consumption survey among Dutch infants aged 8 12 months gathering data on food consumption levels, and measuring and estimating the dietary exposure to selected pesticide residues Approach: Food consumption data were collected using a 1-daydietary record method. Weighing scales were provided, so that the amount consumed could be quantified accurately. During the study also duplicate portions of all the foods consumed by the Grey Literature European Journal of Nutrition & Food Safety, 4(1): 4-5, 2014 5 children during the study day were collected. These duplicate portions were analysed for 19pesticides at the RIKILT Institute of Food Safety to estimate the real intake of pesticides. Results: In total 373 infants (186 girls and 187 boys) were included. The fruit most eaten by this age group was banana (58%), followed by apple (34%), pear (28%) and kiwi (20%). Carrot (18%) was the most favorite vegetable, followed by broccoli (9%) and green beans (8%). Potato was also consumed frequently (49%). Of all the fruits and vegetables consumed by the children large portion sizes (LPs) were calculated at the level of the raw agricultural commodity. These LPs can be used in the point estimate approach to assess the acute dietary intake of toxic pesticide residues in the field of pesticide regulation. The infant food consumption database can also be used for probabilistic modelling of acute dietary exposure. Of 250 infants the duplicate portions were analysed for 19 pesticides. Of these samples a significant percentage (11%) had a low exposure to one or more pesticides. None of the exposures exceeded the toxicological reference level (acceptable daily intake (ADI) or acute reference dose (ARfD)). Conclusion: This study among infants resulted in a first impression of actual intake levels of pesticide residues by this age group in the Netherlands via the diet, an estimate of the LPs of fruits and vegetables consumed by young children for use in the point estimate approach and a database with consumption levels useful for probabilistic exposure assessments. Furthermore the duplicate portions collected can be used for the analysis of other compounds that may affect the development of young growing children (e.g. deoxynivalenol (DON), acrylamide, heavy metals). The complete report can be downloaded for free from http://edepot.wur. nl/44408. Full report is also available as ‘Supplementary File’.
Regulatory T cells and immune tolerance after allogeneic hematopoietic stem cell transplantation

textabstractThe story of allogeneic hematopoietic stem cell transplantation (allo-SCT) begins after the atomic bombings of Hiroshima and Nagasaki in 1945. It was observed that fallout radiation caused dose-dependent depression of hematopoiesis 1. Research first focused on how to protect the hematopoietic system from irradiation injury and it was discovered that infusion of spleen or marrow cells from a healthy donor restored hematopoiesis through the establishment of hematopoietic donor chimerism in an irradiated recipient 2. This finding led to the realization that it might also be applied to treat hematological malignancies. In 1957, a new approach to human cancer treatment was reported: radiation and chemotherapy followed by the intravenous infusion of healthy donor bone marrow 3,4. However, all the early clinical transplantation attempts in the late 50’s and early 60’s failed due to, what was later discovered, inappropriate donor selection. Eventually, in 1968, the first successful allogeneic bone marrow transplantations using human leukocyte antigen (HLA)-identical siblings was reported 5,6. More than four decades later, allogeneic hematopoietic stem cell transplantation (allo-SCT) is an established treatment modality for patients with hematological malignancies, aplastic anemia, and inborn errors of hematopoietic progenitor cells 7. The preferred donor for an allogeneic transplant is still an HLA-identical sibling. However, as only 25-30% of patients have an HLA-matched sibling donor available, hematopoietic stem cells (HSC) from HLA-matched-unrelated-donors are increasingly used. Matched-unrelated-donors can be identified from the bone marrow donor worldwide registry, in which more than 10 million HLA-typed volunteer donors are registered 8. Currently, granulocyte-colony stimulating factor-mobilized peripheral blood stem cells are the most common source of stem cells, as transplantation of these cells results in more rapid reconstitution compared to transplantation of bone marrow (BM) cells 9. However, for high-risk patients the time to obtain a transplant from a suitable donor may be too long as the median time span between the start of the search and actual SCT is 4 months 10. In this case, more readily available alternative stem cells sources including haplo-identical donors 11 or cord blood (CB) 12 can be considered.
Gender incongruence/gender dysphoria and its classification history

Abstract In this article we discuss the changes in the Diagnostic and Statistical Manual of Mental Disorders (DSM) classification of gender identity-related conditions over time, and indicate how these changes were associated with the changes in conceptualization. A diagnosis of ‘transsexualism’ appeared first in DSM-III in 1980. This version also included a childhood diagnosis: gender identity disorder of childhood. As research about gender incongruence/gender dysphoria increased, the terminology, placement and criteria were reviewed in successive versions of the DSM. Changes in various aspects of the diagnosis, however, were not only based on research. Social and political factors contributed to the conceptualization of gender incongruence/gender dysphoria as well.
Mental health and gender dysphoria: A review of the literature

Abstract Studies investigating the prevalence of psychiatric disorders among trans individuals have identified elevated rates of psychopathology. Research has also provided conflicting psychiatric outcomes following gender-confirming medical interventions. This review identifies 38 cross-sectional and longitudinal studies describing prevalence rates of psychiatric disorders and psychiatric outcomes, pre- and post-gender-confirming medical interventions, for people with gender dysphoria. It indicates that, although the levels of psychopathology and psychiatric disorders in trans people attending services at the time of assessment are higher than in the cis population, they do improve following gender-confirming medical intervention, in many cases reaching normative values. The main Axis I psychiatric disorders were found to be depression and anxiety disorder. Other major psychiatric disorders, such as schizophrenia and bipolar disorder, were rare and were no more prevalent than in the general population. There was conflicting evidence regarding gender differences: some studies found higher psychopathology in trans women, while others found no differences between gender groups. Although many studies were methodologically weak, and included people at different stages of transition within the same cohort of patients, overall this review indicates that trans people attending transgender health-care services appear to have a higher risk of psychiatric morbidity (that improves following treatment), and thus confirms the vulnerability of this population.
Therapeutic Plasmapheresis in Kidney Transplantation

In 1960’s, with succesfully renal transplantations, acute rejection became to be a serious problem for graft survival. From 1965 to 2010, with the introduction of new immunosuppressant agents such as cyclosporine, mycophenolate mofetile and tacrolimus, the acute rejection rates declined from 80% to 10% . There is an ongoing gradual improvement in allograft survival. Use of Therapeutic plasma exchange (TPE) is not evidence based treatment, but TPE is necessary for pre- and also post transplantation in patients with DSA. TPE is also a main treatment for antibody mediated rejection (AMR) , but in clinical practice the duration and frequency of TPE and individual difference of antibody production is unclear. There is a requirement for more specific antibody elimination. Further randomised controlled studies are needed to elucidate TPE use before and after kidney transplantation.
The application of Chinese medicine to novel drug discovery

Introduction: The apparent productivity crisis in the pharmaceutical industry and the economic and political rise of China have contributed to renewed interest in the application of Chinese medicine for drug discovery. Areas covered: The author presents an overview of the historical development and basic principles of theory and practice of Chinese herbal medicine, its materia medica and prescription formulas, and discusses the motivation for and rationale of its application to drug discovery. Furthermore, the author distinguishes the five main approaches to drug discovery from Chinese herbal medicine, based on the decreasing amount and detail of historical and clinical Chinese medicine knowledge that informed the research effort. Expert opinion: Many compounds that have been isolated from the Chinese materia medica exhibit pharmacological activities comparable to pharmaceutical drugs. With the exception of the antimalarial drug artemisinin, however, this knowledge has not led to the successful development of new drugs outside of China. The chance of success in a Chinese medicine–based drug discovery effort will be increased by consideration of the empirical knowledge that has been documented over many centuries in the historical materia medica and prescription literature. Most Chinese medicine–derived compounds affect more than one target and do not correspond to the one compound/one-target drug discovery paradigm. A new frontier is opening up with the development of drugs consisting of combinations of multiple compounds acting on multiple targets under the paradigm of network pharmacology. The ancient practice of combining multiple drugs in prescription formulas can serve as inspirational analogy and a practical guide.
The value of monitoring ciclosporin concentration 2 hours post-dose (C2) in dermatology: A prospective cohort study

Abstract Background: Ciclosporin (CsA) is an effective treatment for several inflammatory dermatoses, including psoriasis and eczema. In contrast to transplantation medicine, dermatologists do not routinely use CsA blood concentrations to guide therapy. Objective: To determine the range of CsA levels at 2 hours after dosing (C2 levels) and whether these C2 levels had any relationship to clinically relevant parameters, such as CsA dose, serum creatinine, blood pressure, PASI (psoriasis area and severity index) or DLQI (dermatology life quality index). Methods: A total of 18 patients on CsA maintenance therapy (cohort 1) and eight patients commencing on CsA (cohort 2) were included in the study. In cohort 1, CsA blood concentrations were measured at 2 hours post-dose on one occasion only, while in cohort 2, C2 levels were performed at baseline and at 4, 8 and 12 weeks after commencing CsA treatment. Results: In cohort 1, a significant relationship between C2 levels and PASI was found. However, no relationship was found between C2 levels and CsA dose, blood pressure, or serum creatinine. In cohort 2, higher C2 levels were associated with lower PASI scores (p < 0.05) and DLQI scores at 4 weeks (p = 0.014). Conclusion: We suggest that C2 levels may be beneficial in patients who are not responding well to CsA treatment in the loading phase.
Severity of Nicotine Withdrawal Symptoms after Smoking Cessation

Background: Smoking is among the most common preventable causes of early death in the world. Implementation of smoking cessation programs is among the effective strategies of tobacco control. More than half the smokers experience nicotine withdrawal syndrome after quitting and this could be one of the main reasons of unsuccessful smoking cessation. This study evaluated the severity of nicotine withdrawal symptoms 14 days after quitting (the last visit of smokers to the smoking cessation clinic).
Targeting protein palmitoylation: selective inhibitors and implications in disease

Introduction: Palmitoylation describes the enzymatic attachment of the 16-carbon fatty acid, palmitate, to specific cysteines of proteins via a labile thioester bond. This post-translational modification increases the lipophilicity of the modified protein, thus regulating its subcellular distribution and function. The transfer of palmitate to a substrate is mediated by palmitoyl acyltransferases (PATs), while depalmitoylation is catalyzed by acyl protein thioesterases (APTs). Nearly one-third of the 23 genes that encode PATs are linked to human diseases, representing important targets for drug development. Areas covered: In this review, the authors summarize the recent technical advances in the field of palmitoylation and how they will affect our ability to understand palmitoylation and its relevance to human disease. They also review the current literature describing existing palmitoylation inhibitors. The aim of this article is to increase the awareness of the importance of palmitoylation in disease by reviewing the recent progress made in identifying pharmacological modulators of PATs/APTs. It also aims to provide suggestions for general considerations in the development of selective and potent PAT inhibitors. Expert opinion: Developing therapeutically useful pharmacological modulators of palmitoylation will require that they be developed within the context of well-characterized PAT/APT-related signaling systems. The successful development of potent, specific drugs in similarly complex systems suggests that development of useful drugs targeting PATs is feasible.
Targeting unimolecular G-quadruplex nucleic acids: a new paradigm for the drug discovery?

Introduction: G-quadruplexes (G4s) are targets of great interest because of their roles in crucial biological processes, such as aging and cancer. G4s are based on the formation of G-quartets, stabilised by Hoogsteen-type hydrogen bonds and by interaction with cations between the tetrads. These biologically relevant conformations were first discovered in eukaryotic chromosomal telomeric DNA, but have also been found in the proximal location of promoters in a number of human genes. Therefore, the extensive analysis of an intriguing target could move towards the rational drug design of new selective anticancer agents. Areas covered: The authors review G4 structural characterisation, with detailed insight related to the polymorphism issue. The authors describe the topologically distinct G4 structural forms and the factors involved in their interconversion mechanisms, such as the sequence of the oligonucleotides, the strand stoichiometry and orientation, the syn–anti conformation of the guanine glycosidic bonds and the G4 loop types and the environmental factors. Furthermore, the authors report several studies related to folding and unfolding kinetic profiles in order to understand the conformational view of monomolecular G4 formations. Expert opinion: G4 unimolecular nucleic acids can be considered as valid targets for the rational drug development of novel anticancer agents. Structural biology represents an essential link between the biology and medicinal chemistry knowledge in this field. In silico methods have already been demonstrated to be useful, especially if well integrated with biophysical tests. If this proves successful, the G4-targeting paradigm could also be extended to drug discovery beyond neoplastic pathologies.