Progressively increasing fracture risk with advancing age after initial incident fragility fracture: The Tromsø Study

The risk of subsequent fracture is increased after initial fractures; however, proper understanding of its magnitude is lacking. This population‐based study examines the subsequent fracture risk in women and men by age and type of initial incident fracture. All incident nonvertebral fractures between 1994 and 2009 were registered in 27,158 participants in the Tromsø Study, Norway. The analysis included 3108 subjects with an initial incident fracture after the age of 49 years. Subsequent fracture (n = 664) risk was expressed as rate ratios (RR) and absolute proportions irrespective of death. The rates of both initial and subsequent fractures increased with age, the latter with the steepest curve. Compared with initial incident fracture rate of 30.8 per 1000 in women and 12.9 per 1000 in men, the overall age‐adjusted RR of subsequent fracture was 1.3 (95% CI, 1.2–1.5) in women, and 2.0 (95% CI, 1.6–2.4) in men. Although the RRs decreased with age, the absolute proportions of those with initial fracture who suffered a subsequent fracture increased with age; from 9% to 30% in women and from 10% to 26% in men, between the age groups 50–59 to 80+ years. The type of subsequent fracture varied by age from mostly minor fractures in the youngest to hip or other major fractures in the oldest age groups, irrespective of type and severity of initial fracture. In women and men, 45% and 38% of the subsequent hip or other major fractures, respectively, were preceded by initial minor fractures. The risk of subsequent fracture is high in all age groups. At older age, severe subsequent fracture types follow both clinically severe and minor initial incident fractures. Any fragility fracture in the elderly reflects the need for specific osteoporosis management to reduce further fracture risk. © 2013 American Society for Bone and Mineral Research.     

The heavy users of a psychiatric hospital: A description of patient characteristics,admission patterns,and need for care

Characteristics, diagnosis, need for care, GAF score, and admission patterns were obtained for a group of patients (n 48) who were heavy users of a psychiatric hospital. The need for care was measured with the Camberwell assessment of need. More than half of the patients had a diagnosis of schizophrenia. The second most common diagnosis was personality disorder. Mean age was 37.5 years. Median number of need for care was 11 according to the patients and 12 according to the staff. Overall, the results showed very heterogeneous patterns with regard to age, disability, need for care, and admission patterns. This could indicate that the mental health services should become more differentiated and flexible owing to the presence of a heterogeneous, long-term patient population. Individual needs assessment and treatment programs tailored the single long-term patient are necessary.     

Mathematical Modelling of Glucose‐Dependent Insulinotropic Polypeptide and Glucagon‐like Peptide‐1 following Ingestion of Glucose

The incretin hormones, glucose‐dependent insulinotropic polypeptide (GIP) and glucagon‐like peptide‐1 (GLP‐1), play an important role in glucose homeostasis by potentiating glucose‐induced insulin secretion. Furthermore, GLP‐1 has been reported to play a role in glucose homeostasis by inhibiting glucagon secretion and delaying gastric emptying. As the insulinotropic effect of GLP‐1 is preserved in patients with type 2 diabetes (T2D), therapies based on GLP‐1 have been developed in recent years, and these have proven to be efficient in the treatment of T2D. The endogenous secretion of both GIP and GLP‐1 is stimulated by glucose in the small intestine, and the release is dependent on the amount. In this work, we developed a semimechanistic model describing the release of GIP and GLP‐1 after ingestion of various glucose doses in healthy volunteers and patients with T2D. In the model, the release of both hormones is stimulated by glucose in the proximal small intestine, and no differences in the secretion dynamics between healthy individuals and patients with T2D were identified after taking differences in glucose profiles into account.     

Comparison of Spinal Cord Stimulation Outcomes Between Preoperative Opioid Users and Nonusers: A Cohort Study of 467 Patients

ObjectivesSpinal cord stimulation (SCS) is a surgical treatment modality reserved for a subset of patients with neuropathic pain in which conventional pharmacologic treatment has proven insufficient. Previous studies have suggested a possible negative relationship between opioid use at referral and subsequent success of SCS therapy. The aim of this cohort study was to investigate whether preoperative opioid use was associated with inferior SCS outcomes.Materials and MethodsData were obtained from the Danish Neurizon Neuromodulation Database and comprised preoperative registrations of analgesic use, postoperative Patients’ Global Impression of Change (PGIC) ratings, pre- and postoperative pain intensity scores (Numeric Rating Scale), and detailed surgical data. Patients were dichotomized according to preoperative opioid use (users vs nonusers) with subsequent assessment of the latest PGIC rating, reduction in pain intensity, and current treatment status (implanted/explanted). In addition, daily preoperative opioid dosages were quantified in oral morphine equivalents (OME) and correlated to the treatment outcomes.ResultsA total of 467 patients were included; 296 consumed opioids before SCS implantation (median 80 OME/d). Preoperative opioid use was not associated with the latest PGIC rating, reduction in pain intensity (30% or 50%), or risk of undergoing explantation (median follow-up = 3.0 years). Likewise, preoperative median OME per day of opioid users was not correlated with any of the defined outcomes.ConclusionsPreoperative opioid usage did not predict the outcome of SCS therapy in a large cohort of patients permanently implanted with an SCS system. The results do not support withholding otherwise well-indicated SCS therapy in patients with chronic neuropathic pain conditions based merely on preoperative opioid usage.     

Predicting alcohol dependence from multi-site brain structural measures

To identify neuroimaging biomarkers of alcohol dependence (AD) from structural magnetic resonance imaging, it may be useful to develop classification models that are explicitly generalizable to unseen sites and populations. This problem was explored in a mega-analysis of previously published datasets from 2,034 AD and comparison participants spanning 27 sites curated by the ENIGMA Addiction Working Group. Data were grouped into a training set used for internal validation including 1,652 participants (692 AD, 24 sites), and a test set used for external validation with 382 participants (146 AD, 3 sites). An exploratory data analysis was first conducted, followed by an evolutionary search based feature selection to site generalizable and high performing subsets of brain measurements. Exploratory data analysis revealed that inclusion of case- and control-only sites led to the inadvertent learning of site-effects. Cross validation methods that do not properly account for site can drastically overestimate results. Evolutionary-based feature selection leveraging leave-one-site-out cross-validation, to combat unintentional learning, identified cortical thickness in the left superior frontal gyrus and right lateral orbitofrontal cortex, cortical surface area in the right transverse temporal gyrus, and left putamen volume as final features. Ridge regression restricted to these features yielded a test-set area under the receiver operating characteristic curve of 0.768. These findings evaluate strategies for handling multi-site data with varied underlying class distributions and identify potential biomarkers for individuals with current AD.     

The Th1 immune response against HIV-1 Gag p24-derived peptides in mice expressing HLA-A02.01 and HLA-DR1

Using HLA-DR1-transgenic H-2 class II knockout mice, we identified two new HLA-DR1-restricted HIV-1 Gag p24-derived epitopes (Gag(321-340 )and Gag(331-350)) and confirmed the immunogenicity of seven that have been previously described. The human relevance was confirmed for the two new ones (Gag(321-340 )and Gag(331-350)) assaying peripheral blood mononuclear cells from HLA-DR1(+) HIV-1-infected long-term asymptomatic subjects and showing that Gag(331-350) could prime CD4(+) T cells from two HLA-DR1(+) HIV-1 seronegative donors in vitro. Seven of these epitopes, structurally conserved among HIV-1 clade B isolates, were selected for a comparative evaluation of their Th1 helper potential by immunizing HLA-A02.01/HLA-DR1-transgenic, H-2 class I/class II knockout mice with recombinant mouse invariant chain constructs in which each helper epitope was inserted in association with two reporter HIV-1-derived HLA-A02.01-restricted CD8(+) T cell epitopes. A T helper effect was demonstrated in all cases, and was particularly strong with epitopes Gag(301-320),Gag(321-340 )and Gag(271-290), which should, therefore, be considered in the design of new vaccines.     

Reversal of resistance in microorganisms by help of non-antibiotics

Intracellular efflux pumps have been largely the research focus in multidrug-resistant (MDR) Gram-positive and Gram-negative microorganisms and parasites including cancers. However, drug efflux mechanisms other than pumps per se have been observed, supported by the effects of isomeric, non-antibiotic depressant (DPR), phenothiazines and thixenes, and antidepressant (ADPR) phenylpiperidine neurotropic drugs, alone or in combination with classical antimicrobials on MDR Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus faecalis, Streptococcus pyogenes and Streptococcus pneumoniae. Of the non-antibiotics we investigated, the DPR l-thioridazine, trans-clopenthixol and isomers of phenylpiperidines NNC 20-4962 (isomer of femoxetine) and NNC 20-7052 (isomer of paroxetine) were potent antimicrobials with the least neurotropic activity, pointing to a possible general isomeric structure-activity relationship. These compounds may be regarded as new efflux inhibitors. Moreover, these isomers have considerably reduced, in some cases absent, neurotropism and reduced mammalian toxicity. This may alleviate concerns about adverse effects and therapeutic safety for infected patients in life-threatening situations where the non-antibiotic dosage would be in the lower, non-chronic dosage ranges generally prescribed for individuals with mild mental health problems. The results point to the prokaryotic and eukaryotic microorganisms' phospholipid/protein domain involvement of the cationic, amphiphilic, non-antibiotic DPR and ADPR, with the phospholipids being the initial sites attracting and concentrating the neurotropes to induce a form of suspended animation, followed by gross changes of cell wall and membrane structure, and thereby potentiating their destructive or immobilizing effects on various as yet only hinted at resistance and efflux mechanisms. Combination of appropriate isomeric non-antibiotic DPR and ADPR of low neurotropism and toxicity with conventional and classical antimicrobials promises early, new therapeutic strategies salutary against microbial resistance, resistance development, pathogenicity and virulence.     

Clinical study on the correlation between psychogenic dental prosthesis incompatibility, oral stereognosis, and the psychologic diagnostic tools SCL-90-R and CES-D

PURPOSE: The objective of this study was to use an oral stereognosis test to evaluate possible intraoral/sensorimotor causes in patients with a psychologic diagnosis of psychogenic prosthesis incompatibility, and to evaluate possible correlations between oral stereognosis and the psychologic diagnostic tools Symptom Checklist-90-R (SCL-90-R) and Center of Epidemiological Studies Depression Scale (CES-D). MATERIALS AND METHODS: The study cohort comprised 83 patients with complete dentures fabricated according to a standardized protocol. Twelve patients diagnosed with psychogenic prosthesis incompatibility (11 women, 1 man) using the SCL-90-R and CES-D scales in a previous study and a group of 24 randomly selected control subjects (14 women, 10 men) underwent an oral stereognosis test with 10 neutral-tasting plastic test specimens with a maximum edge length of 8 mm in 2 test cycles. RESULTS: The results revealed no significant differences in oral stereognostic ability between patients with diagnosed psychogenic dental prosthesis incompatibility and the control patients. The patients in the test group expressed clear dissatisfaction with their dentures. No correlation was found between oral stereognostic ability and the SCL-90-R or CES-D values. CONCLUSIONS: This study is the first to use oral stereognosis tests for patients with psychologically diagnosed psychogenic dental prosthesis incompatibility. The diagnosis of psychogenic prosthesis incompatibility by the SCL-90-R and CES-D scales is affirmed by the lack of correlations between the functional/anatomic aspects of oral stereognostic ability, psychologic diagnostic tools, and the clinical picture of psychogenic prosthesis incompatibility. Thus, psychogenic prosthesis incompatibility can be classified more explicitly as a psychosomatic disorder.     

Relationship between Optimum Mini‐doses of Glucagon and Insulin Levels when Treating Mild Hypoglycaemia in Patients with Type 1 Diabetes – A Simulation Study

Hypoglycaemia remains the main limiting factor in type 1 diabetes management. We developed an insulin‐dependent glucagon dosing regimen for treatment of mild hypoglycaemia based on simulations. A validated glucose–insulin–glucagon model was used to describe seven virtual patients with insulin pump‐treated type 1 diabetes. In each simulation, one of ten different and individualized subcutaneous insulin boluses was administered to decrease plasma glucose (PG) from 7.0 to ≤3.9 mmol/l. Insulin levels were estimated as ratio of actual to baseline serum insulin concentration (se/ba‐insulin), insulin on board (IOB) or percentage of IOB to total daily insulin dose (IOB/TDD). Insulin bolus sizes were chosen to provide pre‐defined insulin levels when PG reached 3.9 mmol/l, where one of 17 subcutaneous glucagon boluses was administered. Optimum glucagon bolus to treat mild hypoglycaemia at varying insulin levels was the lowest dose that in most patients caused PG peak between 5.0 and 10.0 mmol/l and sustained PG ≥ 3.9 mmol/l for 2 hr after the bolus. PG response to glucagon declined with increasing insulin levels. The glucagon dose to optimally treat mild hypoglycaemia depended exponentially on insulin levels, regardless of how insulin was estimated. A 125‐μg glucagon dose was needed to optimally treat mild hypoglycaemia when insulin levels were equal to baseline levels. In contrast, glucagon doses >500 μg were needed when se/ba‐insulin >2.5, IOB >2.0 U or IOB/TDD >6%. Although the proposed model‐based glucagon regimen needs confirmation in clinical trials, this is the first attempt to develop an insulin‐dependent glucagon dosing regimen for treatment of insulin‐induced mild hypoglycaemia in patients with type 1 diabetes.