Infections in temporal proximity to HPV vaccination and adverse effects following vaccination in Denmark: A nationwide register-based cohort study and case-crossover analysis

BACKGROUND: Public trust in the human papilloma virus (HPV) vaccination programme has been challenged by reports of potential severe adverse effects. The reported adverse symptoms were heterogeneous and overlapping with those characterised as chronic fatigue syndrome (CFS) and have been described as CFS-like symptoms. Evidence suggests that CFS is often precipitated by an infection. The aim of the study was to examine if an infection in temporal proximity to HPV vaccination is a risk factor for suspected adverse effects following HPV vaccination. METHODS AND FINDINGS: The study was a nationwide register-based cohort study and case-crossover analysis. The study population consisted of all HPV vaccinated females living in Denmark, born between 1974 and 2006, and vaccinated between January 1, 2006 and December 31, 2017. The exposure was any infection in the period ± 1 month around time of first HPV vaccination and was defined as (1) hospital-treated infection; (2) redemption of anti-infective medication; or (3) having a rapid streptococcal test done at the general practitioner. The outcome was referral to a specialised hospital setting (5 national HPV centres opened June 1, 2015) due to suspected adverse effects following HPV vaccination. Multivariable logistic regression was used to estimate the association between infection and later HPV centre referral. The participants were 600,400 HPV-vaccinated females aged 11 to 44 years. Of these, 48,361 (9.7%) females had a hospital-treated infection, redeemed anti-infective medication, or had a rapid streptococcal test ± 1 month around time of first HPV vaccination. A total of 1,755 (0.3%) females were referred to an HPV centre. Having a hospital-treated infection in temporal proximity to vaccination was associated with significantly elevated risk of later referral to an HPV centre (odds ratio (OR) 2.75, 95% confidence interval (CI) 1.72 to 4.40; P < 0.001). Increased risk was also observed among females who redeemed anti-infective medication (OR 1.56, 95% CI 1.33 to 1.83; P < 0.001) or had a rapid streptococcal test (OR 1.45, 95% CI 1.10 to 1.93; P = 0.010). Results from a case-crossover analysis, which was performed to adjust for potential unmeasured confounding, supported the findings. A key limitation of the study is that the HPV centres did not open until June 1, 2015, which may have led to an underestimation of the risk of suspected adverse effects, but stratified analyses by year of vaccination yielded similar results. CONCLUSIONS: Treated infection in temporal proximity to HPV vaccination is associated with increased risk for later referral with suspected adverse vaccine effects. Thus, the infection could potentially be a trigger of the CFS-like symptoms in a subset of the referred females. To our knowledge, the study is the first to investigate the role of infection in the development of suspected adverse effects after HPV vaccination and replication of these findings are needed in other studies

Exposure to Advertisement Calls of Reproductive Competitors Activates Vocal-Acoustic and Catecholaminergic Neurons in the Plainfin Midshipman Fish, Porichthys notatus

While the neural circuitry and physiology of the auditory system is well studied among vertebrates, far less is known about how the auditory system interacts with other neural substrates to mediate behavioral responses to social acoustic signals. One species that has been the subject of intensive neuroethological investigation with regard to the production and perception of social acoustic signals is the plainfin midshipman fish, Porichthys notatus, in part because acoustic communication is essential to their reproductive behavior. Nesting male midshipman vocally court females by producing a long duration advertisement call. Females localize males by their advertisement call, spawn and deposit all their eggs in their mate’s nest. As multiple courting males establish nests in close proximity to one another, the perception of another male’s call may modulate individual calling behavior in competition for females. We tested the hypothesis that nesting males exposed to advertisement calls of other males would show elevated neural activity in auditory and vocal-acoustic brain centers as well as differential activation of catecholaminergic neurons compared to males exposed only to ambient noise. Experimental brains were then double labeled by immunofluorescence (-ir) for tyrosine hydroxylase (TH), an enzyme necessary for catecholamine synthesis, and cFos, an immediate-early gene product used as a marker for neural activation. Males exposed to other advertisement calls showed a significantly greater percentage of TH-ir cells colocalized with cFos-ir in the noradrenergic locus coeruleus and the dopaminergic periventricular posterior tuberculum, as well as increased numbers of cFos-ir neurons in several levels of the auditory and vocal-acoustic pathway. Increased activation of catecholaminergic neurons may serve to coordinate appropriate behavioral responses to male competitors. Additionally, these results implicate a role for specific catecholaminergic neuronal groups in auditory-driven social behavior in fishes, consistent with a conserved function in social acoustic behavior across vertebrates

How local is local? Evidence from bank competition and corporate innovation in U.S.

This paper aims to fill in a research gap in the effects of bank competition on corporate innovation. In addition to the evidence on the favorable effects of bank competition on corporate innovation, we show novel evidence on the substitution effects of bank competition in a wider region and neighbor-state to local bank competition in financing corporate innovation activities. In banking market, we show ‘how local is local’ depends on the operating scope and information transparency of firms. Local banks have an information advantage over distant banks in financing local businesses and informationally opaque corporate innovation activities

Sarcopenia Exacerbates Obesity-Associated Insulin Resistance and Dysglycemia: Findings from the National Health and Nutrition Examination Survey III

Sarcopenia often co-exists with obesity, and may have additive effects on insulin resistance. Sarcopenic obese individuals could be at increased risk for type 2 diabetes. We performed a study to determine whether sarcopenia is associated with impairment in insulin sensitivity and glucose homeostasis in obese and non-obese individuals.We performed a cross-sectional analysis of National Health and Nutrition Examination Survey III data utilizing subjects of 20 years or older, non-pregnant (N = 14,528). Sarcopenia was identified from bioelectrical impedance measurement of muscle mass. Obesity was identified from body mass index. Outcomes were homeostasis model assessment of insulin resistance (HOMA IR), glycosylated hemoglobin level (HbA1C), and prevalence of pre-diabetes (6.0≤ HbA1C<6.5 and not on medication) and type 2 diabetes. Covariates in multiple regression were age, educational level, ethnicity and sex.Sarcopenia was associated with insulin resistance in non-obese (HOMA IR ratio 1.39, 95% confidence interval (CI) 1.26 to 1.52) and obese individuals (HOMA-IR ratio 1.16, 95% CI 1.12 to 1.18). Sarcopenia was associated with dysglycemia in obese individuals (HbA1C ratio 1.021, 95% CI 1.011 to 1.043) but not in non-obese individuals. Associations were stronger in those under 60 years of age. We acknowledge that the cross-sectional study design limits our ability to draw causal inferences.Sarcopenia, independent of obesity, is associated with adverse glucose metabolism, and the association is strongest in individuals under 60 years of age, which suggests that low muscle mass may be an early predictor of diabetes susceptibility. Given the increasing prevalence of obesity, further research is urgently needed to develop interventions to prevent sarcopenic obesity and its metabolic consequences

Remodeling Lipid Metabolism and Improving Insulin Responsiveness in Human Primary Myotubes

OBJECTIVE: Disturbances in lipid metabolism are strongly associated with insulin resistance and type 2 diabetes (T2D). We hypothesized that activation of cAMP/PKA and calcium signaling pathways in cultured human myotubes would provide further insight into regulation of lipid storage, lipolysis, lipid oxidation and insulin responsiveness. METHODS: Human myoblasts were isolated from vastus lateralis, purified, cultured and differentiated into myotubes. All cells were incubated with palmitate during differentiation. Treatment cells were pulsed 1 hour each day with forskolin and ionomycin (PFI) during the final 3 days of differentiation to activate the cAMP/PKA and calcium signaling pathways. Control cells were not pulsed (control). Mitochondrial content, (14)C lipid oxidation and storage were measured, as well as lipolysis and insulin-stimulated glycogen storage. Myotubes were stained for lipids and gene expression measured. RESULTS: PFI increased oxidation of oleate and palmitate to CO(2) (p<0.001), isoproterenol-stimulated lipolysis (p = 0.01), triacylglycerol (TAG) storage (p<0.05) and mitochondrial DNA copy number (p = 0.01) and related enzyme activities. Candidate gene and microarray analysis revealed increased expression of genes involved in lipolysis, TAG synthesis and mitochondrial biogenesis. PFI increased the organization of lipid droplets along the myofibrillar apparatus. These changes in lipid metabolism were associated with an increase in insulin-mediated glycogen storage (p<0.001). CONCLUSIONS: Activation of cAMP/PKA and calcium signaling pathways in myotubes induces a remodeling of lipid droplets and functional changes in lipid metabolism. These results provide a novel pharmacological approach to promote lipid metabolism and improve insulin responsiveness in myotubes, which may be of therapeutic importance for obesity and type 2 diabetes

Neuromuscular Electrical Stimulation as a Method to Maximize the Beneficial Effects of Muscle Stem Cells Transplanted into Dystrophic Skeletal Muscle

Cellular therapy is a potential approach to improve the regenerative capacity of damaged or diseased skeletal muscle. However, its clinical use has often been limited by impaired donor cell survival, proliferation and differentiation following transplantation. Additionally, functional improvements after transplantation are all-too-often negligible. Because the host microenvironment plays an important role in the fate of transplanted cells, methods to modulate the microenvironment and guide donor cell behavior are warranted. The purpose of this study was to investigate whether the use of neuromuscular electrical stimulation (NMES) for 1 or 4 weeks following muscle-derived stem cell (MDSC) transplantation into dystrophic skeletal muscle can modulate the fate of donor cells and enhance their contribution to muscle regeneration and functional improvements. Animals submitted to 4 weeks of NMES after transplantation demonstrated a 2-fold increase in the number of dystrophin+ myofibers as compared to control transplanted muscles. These findings were concomitant with an increased vascularity in the MDSC+NMES group when compared to non-stimulated counterparts. Additionally, animals subjected to NMES (with or without MDSC transplantation) presented an increased maximal specific tetanic force when compared to controls. Although cell transplantation and/or the use of NMES resulted in no changes in fatigue resistance, the combination of both MDSC transplantation and NMES resulted in a faster recovery from fatigue, when compared to non-injected and non-stimulated counterparts. We conclude that NMES is a viable method to improve MDSC engraftment, enhance dystrophic muscle strength, and, in combination with MDSC transplantation, improve recovery from fatigue. These findings suggest that NMES may be a clinically-relevant adjunct approach for cell transplantation into skeletal muscle. © 2013 Distefano et al

The fitness for the Ageing Brain Study II (FABS II): protocol for a randomized controlled clinical trial evaluating the effect of physical activity on cognitive function in patients with Alzheimer's disease

Background: Observational studies have documented a potential protective effect of physical exercise in older adults who are at risk for developing Alzheimer's disease. The Fitness for the Ageing Brain II (FABS II) study is a multicentre randomized controlled clinical trial (RCT) aiming to determine whether physical activity reduces the rate of cognitive decline among individuals with Alzheimer's disease. This paper describes the background, objectives of the study, and an overview of the protocol including design, organization and data collection methods

Improving a Natural CaMKII Inhibitor by Random and Rational Design

CaM-KIIN has evolved to inhibit stimulated and autonomous activity of the Ca(2+)/calmodulin (CaM)-dependent protein kinase II (CaMKII) efficiently, selectively, and potently (IC50 ∼100 nM). The CN class of peptides, derived from the inhibitory region of CaM-KIIN, provides powerful new tools to study CaMKII functions. The goal of this study was to identify the residues required for CaMKII inhibition, and to assess if artificial mutations could further improve the potency achieved during evolution.First, the minimal region with full inhibitory potency was identified (CN19) by determining the effect of truncated peptides on CaMKII activity in biochemical assays. Then, individual residues of CN19 were mutated. Most individual Ala substitutions decreased potency of CaMKII inhibition, however, P3A, K13A, and R14A increased potency. Importantly, this initial Ala scan suggested a specific interaction of the region around R11 with the CaMKII substrate binding site, which was exploited for further rational mutagenesis to generate an optimized pseudo-substrate sequence. Indeed, the potency of the optimized peptide CN19o was >250fold improved (IC50 <0.4 nM), and CN19o has characteristics of a tight-binding inhibitor. The selectivity for CaMKII versus CaMKI was similarly improved (to almost 100,000fold for CN19o). A phospho-mimetic S12D mutation decreased potency, indicating potential for regulation by cellular signaling. Consistent with importance of this residue in inhibition, most other S12 mutations also significantly decreased potency, however, mutation to V or Q did not.These results provide improved research tools for studying CaMKII function, and indicate that evolution fine-tuned CaM-KIIN not for maximal potency of CaMKII inhibition, but for lower potency that may be optimal for dynamic regulation of signal transduction

Fluctuations around Bjorken Flow and the onset of turbulent phenomena

We study how fluctuations in fluid dynamic fields can be dissipated or amplified within the characteristic spatio-temporal structure of a heavy ion collision. The initial conditions for a fluid dynamic evolution of heavy ion collisions may contain significant fluctuations in all fluid dynamical fields, including the velocity field and its vorticity components. We formulate and analyze the theory of local fluctuations around average fluid fields described by Bjorken's model. For conditions of laminar flow, when a linearized treatment of the dynamic evolution applies, we discuss explicitly how fluctuations of large wave number get dissipated while modes of sufficiently long wave-length pass almost unattenuated or can even be amplified. In the opposite case of large Reynold's numbers (which is inverse to viscosity), we establish that (after suitable coordinate transformations) the dynamics is governed by an evolution equation of non-relativistic Navier-Stokes type that becomes essentially two-dimensional at late times. One can then use the theory of Kolmogorov and Kraichnan for an explicit characterization of turbulent phenomena in terms of the wave-mode dependence of correlations of fluid dynamic fields. We note in particular that fluid dynamic correlations introduce characteristic power-law dependences in two-particle correlation functions.Comment: 40 pages, 5 figures, published versio