Anticholinergics, Antipsychotics and Associated Risks in Dementia Seeking to improve the Safety of Prescribing

To date, there is no cure for dementia and no treatments exist that have been unequivocally shown to interrupt or reverse the disease progression. Therapeutic interventions are therefore targeted at specific symptoms or to improve or slow the decline in cognitive function for a limited period. In view of the limited treatment options available for Alzheimer’s disease, it is imperative to try to prevent dementia where possible as well as trying to improve outcomes and preserve cognitive function for as long as possible. This thesis focusses on exploring ways to improve the safety of prescribing in people with dementia. Over the last 15 years, growing evidence of serious effects associated with anticholinergic agents in older people has emerged. Long-term use of anticholinergic drugs in older people is associated with an increased risk of cognitive decline, dementia and early death. I investigated the effect of anticholinergic burden of drugs on dementia outcomes and found that drugs with a high Anticholinergic Effect on Cognition (AEC) score were associated with increased mortality and hospitalisation compared to those with low scores. This highlights the importance of keeping the central anticholinergic burden to a minimum. When looking at antidepressants and antipsychotic drugs specifically, this association was not seen, suggesting that other properties are considered when prescribing these psychotropic agents, and that there may be other confounding factors not considered. In contrast, when I compared bladder anticholinergic drugs in people with dementia, those with high AEC scores were associated with significantly increased mortality, by 55% compared to those with low AEC scores. Additionally, I led on the development of Medichec, a desktop and phone app that helps to identify drugs that have a high central anticholinergic burden in addition to drugs that are reported to cause QTc prolongation, hyponatraemia, bleeding risk, dizziness, drowsiness and constipation. Medichec can facilitate access to side-effects information for multiple medications at once, aid clinical decision-making and optimise treatment. Finally, because antipsychotic drugs have been associated with increased cerebrovascular accidents and mortality in dementia for nearly 20 years, I led a project in South London and Maudsley (SLaM) NHS Foundation Trust that enhanced the prescribing and monitoring of antipsychotic drugs in people with dementia.<br/

Is Toxoplasma gondii IgG seropositivity a predisposing factor for infertility?

Toxoplasmosis is a disease caused by an obligate intracellular protozoan parasite Toxoplasma gondii. Approximately one-third of the world population is infected with this parasite. Several studies have examined the causes of human infertility in the Middle East. A high proportion of secondary infertility and a great contribution of the female factor was the major finding in most of these studies. In this study, we aim to explore the relationship between Toxoplasma gondii seropositivity and female infertile patients. Serum samples from 83 female patients visiting the infertility clinic and 57 normal prim gravid females attending the ANC clinic were collected during the year 2014. Serum samples were analyzed for anti-Toxoplasma IgG by chemiluminescent microparticle immunoassay (CMIA) technology. Patients visiting the infertility clinic, aged from 18-40 years (x=29.7) while normal prim gravid females attending the ANC clinic aged from 18-38 (x=26.1). Of the 83 samples collected from patients visiting the infertility clinic, 15 samples were positive for anti-Toxoplasma IgG while only 2 samples (out of 57) collected from normal prim gravid females attending the ANC clinic were positive. There was a statistically significant correlation between positive anti-Toxoplasma IgG and infertility (p<0.01). We suggest considering the presence of anti-Toxoplasma antibodies in serum of young females as an indicator for possible future infertility

Biocompatibility and immunogenicity of decellularised allogeneic aorta in the orthotopic rat model

Background and aim of the study: Peripheral arterial disease causes blood vessel dysfunction that requires surgical intervention. Current surgical interventions employ synthetic or allogeneic vascular grafts, which offer biocompatible materials solutions that are not able to regenerate or grow with the patient. Decellularised scaffolds have gained significant momentum in the past few years, since they have the potential to regenerate in the patient. The aim of this study was to investigate the effects of modified decellularisation protocol on the biocompatibility and immunogenicity of allogeneic rat abdominal aorta in an orthotopic rat model. Methods: Native syngeneic Wistar (W) and allogeneic Dark Agouti (DA) aortas, together with decellularised allogeneic DA aortas, were assessed histologically, immunohistochemically and biomechanically. The immunogenicity of the untreated and decellularized syngeneic and allogeneic grafts was assessed in W rats, implanted orthotopically. Following implantation for 6 weeks, the grafts were explanted and assessed for the presence of T cells and macrophages by immunohistochemistry, and for their biomechanical integrity and histoarchitecture. Results: No obvious histoarchitectural differences were observed between the native W and DA aortas, with both presenting similar three-layered structures. Histological analysis of decellularized DA aortas did not reveal any remaining cells. Explanted native DA allografts showed media necrosis, partial elastic fibre degradation and adventitia thickening, as well as infiltration by lymphocytes (CD3+, CD4+) and macrophages (CD68+) in the adventitia. The explanted decellularized DA allografts indicated reduced immune injury compared to the explanted native DA allografts. The explanted native W syngeneic grafts showed a mild immune response, with an intact media and no lymphocyte infiltration. The explanted native DA allografts showed significantly lower collagen phase slope than the decellularized DA allografts prior implantation, and significantly higher thickness than the explanted decellularized DA allografts. Conclusions: The results indicated that the modified decellularization protocol did not affect significantly the mechanical and histological properties of the native DA rat aorta. Overall, the immune response was improved by decellularization. Native DA allografts induced an adverse immune response in W rats, whereas syngeneic W grafts showed good tissue integration

Wheeze in Preschool Age Is Associated with Pulmonary Bacterial Infection and Resolves after Antibiotic Therapy

BACKGROUND: Neonates with airways colonized by Haemophilus influenzae, Streptococcus pneumoniae or Moraxella catarrhalis are at increased risk for recurrent wheeze which may resemble asthma early in life. It is not clear whether chronic colonization by these pathogens is causative for severe persistent wheeze in some preschool children and whether these children might benefit from antibiotic treatment. We assessed the relevance of bacterial colonization and chronic airway infection in preschool children with severe persistent wheezing and evaluated the outcome of long-time antibiotic treatment on the clinical course in such children. METHODOLOGY/PRINCIPAL FINDINGS: Preschool children (n = 42) with severe persistent wheeze but no symptoms of acute pulmonary infection were investigated by bronchoscopy and bronchoalveolar lavage (BAL). Differential cell counts and microbiological and virological analyses were performed on BAL samples. Patients diagnosed with bacterial infection were treated with antibiotics for 2-16 weeks (n = 29). A modified ISAAC questionnaire was used for follow-up assessment of children at least 6 months after bronchoscopy. Of the 42 children with severe wheezing, 34 (81%) showed a neutrophilic inflammation and 20 (59%) of this subgroup had elevated bacterial counts (≥ 10⁴ colony forming units per milliliter) suggesting infection. Haemophilus influenzae, Streptococcus pneumoniae and Moraxella catarrhalis were the most frequently isolated species. After treatment with appropriate antibiotics 92% of patients showed a marked improvement of symptoms upon follow-up examination. CONCLUSIONS/SIGNIFICANCE: Chronic bacterial infections are relevant in a subgroup of preschool children with persistent wheezing and such children benefit significantly from antibiotic therapy

Medical, ethical, and legal considerations in fertility preservation

The past 2 decades have seen a significant rise in cancer survival rates, and an increasing proportion of survivors at reproductive age are interested in childbearing. Although assisted reproduction provides physicians with an array of potential possibilities to help patients whose fertility is compromised by cancer treatment, there is still a dearth of regulation regarding the application of this technology. The present paper reviews the current options for fertility preservation, with a particular focus on the legal and ethical challenges that confront providers of this type of care.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/135176/1/ijgo11.pd

Magnetic Resonance Elastography Shear Wave Velocity Correlates with Liver Fibrosis and Hepatic Venous Pressure Gradient in Adults with Advanced Liver Disease

Background. Portal hypertension, an elevation in the hepatic venous pressure gradient (HVPG), can be used to monitor disease progression and response to therapy in cirrhosis. Since obtaining HVPG measurements is invasive, reliable noninvasive methods of assessing portal hypertension are needed. Methods. Noninvasive markers of fibrosis, including magnetic resonance elastography (MRE) shear wave velocity, were correlated with histologic fibrosis and HVPG measurements in hepatitis C (HCV) and/or HIVinfected patients with advanced liver disease enrolled in a clinical trial of treatment with simtuzumab, an anti-LOXL2 antibody. Results. This exploratory analysis includes 23 subjects: 9 with HCV monoinfection, 9 with HIV and HCV, and 5 with HIV and nonalcoholic steatohepatitis. Median Ishak fibrosis score was 4 (range 1-6); 11 subjects (48%) had cirrhosis. Median HVPG was 6 mmHg (range 3-16). Liver stiffness measured by MRE correlated with HVPG ( = 0.64, = 0.01), histologic fibrosis score ( = 0.71, = 0.004), noninvasive fibrosis indices, including APRI ( = 0.81, &lt; 0.001), and soluble LOXL2 ( = 0.82, = 0.001). On stepwise multivariate regression analysis, MRE was the only variable independently associated with HVPG ( 2 = 0.377, = 0.02). Conclusions. MRE of the liver correlated independently with HVPG. MRE is a valid noninvasive measure of liver disease severity and may prove to be a useful tool for noninvasive portal hypertension assessment. Trial Registration Number. This trial is registered with NCT01707472