Mortality Risk of Hypnotics: Strengths and Limits of Evidence

Sleeping pills, more formally defined as hypnotics, are sedatives used to induce and maintain sleep. In a review of publications for the past 30 years, descriptive epidemiologic studies were identified that examined the mortality risk of hypnotics and related sedative-anxiolytics. Of the 34 studies estimating risk ratios, odds ratios, or hazard ratios, excess mortality associated with hypnotics was significant (p < 0.05) in 24 studies including all 14 of the largest, contrasted with no studies at all suggesting that hypnotics ever prolong life. The studies had many limitations: possibly tending to overestimate risk, such as possible confounding by indication with other risk factors; confusing hypnotics with drugs having other indications; possible genetic confounders; and too much heterogeneity of studies for meta-analyses. There were balancing limitations possibly tending towards underestimates of risk such as limited power, excessive follow-up intervals with possible follow-up mixing of participants taking hypnotics with controls, missing dosage data for most studies, and over-adjustment of confounders. Epidemiologic association in itself is not adequate proof of causality, but there is proof that hypnotics cause death in overdoses; there is thorough understanding of how hypnotics euthanize animals and execute humans; and there is proof that hypnotics cause potentially lethal morbidities such as depression, infection, poor driving, suppressed respiration, and possibly cancer. Combining these proofs with consistent evidence of association, the great weight of evidence is that hypnotics cause huge risks of decreasing a patient's duration of survival

Pain and analgesic use associated with skeletal-related events in patients with advanced cancer and bone metastases

PURPOSE: Bone metastases secondary to solid tumors increase the risk of skeletal-related events (SREs), including the occurrence of pathological fracture (PF), radiation to bone (RB), surgery to bone (SB), and spinal cord compression (SCC). The aim of this study was to evaluate the impact of SREs on patients' pain, analgesic use, and pain interference with daily functioning. METHODS: Data were combined from patients with solid tumors and bone metastases who received denosumab or zoledronic acid across three identically designed phase 3 trials (N = 5543). Pain severity (worst pain) and pain interference were assessed using the Brief Pain Inventory at baseline and each monthly visit. Analgesic use was quantified using the Analgesic Quantification Algorithm. RESULTS: The proportion of patients with moderate/severe pain and strong opioid use generally increased in the 6 months preceding an SRE and remained elevated, while they remained relatively consistent over time in patients without an SRE. Regression analysis indicated that all SRE types were significantly associated with an increased risk of progression to moderate/severe pain and strong opioid use. PF, RB, and SCC were associated with significantly greater risk of pain interference overall. Results were similar for pain interference with emotional well-being. All SRE types were associated with significantly greater risk of pain interference with physical function. CONCLUSIONS: SREs are associated with increased pain and analgesic use in patients with bone metastases. Treatments that prevent SREs may decrease pain and the need for opioid analgesics and reduce the impact of pain on daily functioning

Pain and analgesic use associated with skeletal-related events in patients with advanced cancer and bone metastases

PURPOSE: Bone metastases secondary to solid tumors increase the risk of skeletal-related events (SREs), including the occurrence of pathological fracture (PF), radiation to bone (RB), surgery to bone (SB), and spinal cord compression (SCC). The aim of this study was to evaluate the impact of SREs on patients' pain, analgesic use, and pain interference with daily functioning. METHODS: Data were combined from patients with solid tumors and bone metastases who received denosumab or zoledronic acid across three identically designed phase 3 trials (N = 5543). Pain severity (worst pain) and pain interference were assessed using the Brief Pain Inventory at baseline and each monthly visit. Analgesic use was quantified using the Analgesic Quantification Algorithm. RESULTS: The proportion of patients with moderate/severe pain and strong opioid use generally increased in the 6 months preceding an SRE and remained elevated, while they remained relatively consistent over time in patients without an SRE. Regression analysis indicated that all SRE types were significantly associated with an increased risk of progression to moderate/severe pain and strong opioid use. PF, RB, and SCC were associated with significantly greater risk of pain interference overall. Results were similar for pain interference with emotional well-being. All SRE types were associated with significantly greater risk of pain interference with physical function. CONCLUSIONS: SREs are associated with increased pain and analgesic use in patients with bone metastases. Treatments that prevent SREs may decrease pain and the need for opioid analgesics and reduce the impact of pain on daily functioning

The use of insecticide treated nets by age: implications for universal coverage in Africa

BACKGROUND: The scaling of malaria control to achieve universal coverage requires a better understanding of the population sub-groups that are least protected and provide barriers to interrupted transmission. Here we examine the age pattern of use of insecticide treated nets (ITNs) in Africa in relation to biological vulnerabilities and the implications for future prospects for universal coverage. METHODS: Recent national household survey data for 18 malaria endemic countries in Africa were assembled to identify information on use of ITNs by age and sex. Age-structured medium variant projected population estimates for the mid-point year of the earliest and most recent national surveys were derived to compute the population by age protected by ITNs. RESULTS: All surveys were undertaken between 2005 and 2009, either as demographic health surveys (n = 12) or malaria indicator surveys (n = 6). Countries were categorized into three ITN use groups: or =20% and projected population estimates for the mid-point year of 2007 were computed. In general, the pattern of overall ITNs use with age was similar by country and across the three country groups with ITNs use initially high among children <5 years of age, sharply declining among the population aged 5-19 years, before rising again across the ages 20-44 years and finally decreasing gradually in older ages. For all groups of countries, the highest proportion of the population not protected by ITNs (38% - 42%) was among those aged 5-19 years. CONCLUSION: In malaria-endemic Africa, school-aged children are the least protected with ITNs but represent the greatest reservoir of infections. With increasing school enrollment rates, school-delivery of ITNs should be considered as an approach to reach universal ITNs coverage and improve the likelihood of impacting upon parasite transmission

Dental management considerations for the patient with an acquired coagulopathy. Part 1: Coagulopathies from systemic disease

Current teaching suggests that many patients are at risk for prolonged bleeding during and following invasive dental procedures, due to an acquired coagulopathy from systemic disease and/or from medications. However, treatment standards for these patients often are the result of long-standing dogma with little or no scientific basis. The medical history is critical for the identification of patients potentially at risk for prolonged bleeding from dental treatment. Some time-honoured laboratory tests have little or no use in community dental practice. Loss of functioning hepatic, renal, or bone marrow tissue predisposes to acquired coagulopathies through different mechanisms, but the relationship to oral haemostasis is poorly understood. Given the lack of established, science-based standards, proper dental management requires an understanding of certain principles of pathophysiology for these medical conditions and a few standard laboratory tests. Making changes in anticoagulant drug regimens are often unwarranted and/or expensive, and can put patients at far greater risk for morbidity and mortality than the unlikely outcome of postoperative bleeding. It should be recognised that prolonged bleeding is a rare event following invasive dental procedures, and therefore the vast majority of patients with suspected acquired coagulopathies are best managed in the community practice setting

Unraveling the molecular interactions between α7 nicotinic receptor and a RIC3 variant associated with backward speech

Recent work putatively linked a rare genetic variant of the chaperone Resistant to Inhibitors of acetylcholinesterase (RIC3) (NM_024557.4:c.262G>A, NP_078833.3:p.G88R) to a unique ability to speak backwards, a language skill that is associated with exceptional working memory capacity. RIC3 is important for the folding, maturation, and functional expression of α7 nicotinic acetylcholine receptors (nAChR). We compared and contrasted the effects of RIC3G88R on assembly, cell surface expression, and function of human α7 receptors using fluorescent protein tagged α7 nAChR and Förster resonance energy transfer (FRET) microscopy imaging in combination with functional assays and 125I-α-bungarotoxin binding. As expected, the wild-type RIC3 protein was found to increase both cell surface and functional expression of α7 receptors. In contrast, the variant form of RIC3 decreased both. FRET analysis showed that RICG88R increased the interactions between RIC3 and α7 protein in the endoplasmic reticulum. These results provide interesting and novel data to show that a RIC3 variant alters the interaction of RIC3 and α7, which translates to decreased cell surface and functional expression of α7 nAChR

Pleosporales

One hundred and five generic types of Pleosporales are described and illustrated. A brief introduction and detailed history with short notes on morphology, molecular phylogeny as well as a general conclusion of each genus are provided. For those genera where the type or a representative specimen is unavailable, a brief note is given. Altogether 174 genera of Pleosporales are treated. Phaeotrichaceae as well as Kriegeriella, Zeuctomorpha and Muroia are excluded from Pleosporales. Based on the multigene phylogenetic analysis, the suborder Massarineae is emended to accommodate five families, viz. Lentitheciaceae, Massarinaceae, Montagnulaceae, Morosphaeriaceae and Trematosphaeriaceae

Baseline characteristics influencing quality of life in women undergoing gynecologic oncology surgery

<p>Abstract</p> <p>Background</p> <p>Quality of life (QoL) measurements are important in evaluating cancer treatment outcomes. Factors other than cancer and its treatment may have significant effects on QoL and affect assessment of treatments. Baseline data from longitudinal studies of women with endometrial or ovarian cancer or adnexal mass determined at surgery to be benign were analyzed to determine the degree to which QoL is affected by baseline differences in demographic variables and health.</p> <p>Methods</p> <p>This study examined the effect of independent variables on domains of the Functional Assessment of Cancer Therapy (FACT-G) pre-operatively in gynecologic oncology patients undergoing surgery for pelvic mass suspected to be malignant or endometrial cancer. Patients also completed the Short Form Medical Outcomes Survey (SF-36) questionnaire (a generic health questionnaire that measures physical and mental health). Independent variables were surgical diagnosis (ovarian or endometrial cancer, benign mass), age, body mass index (BMI), educational level, marital status, smoking status, physical (PCS) and mental (MCS) summary scores of the SF-36. Multiple regression analysis was used to determine the influence of these variables on FACT-G domain scores (physical, functional, social and emotional well-being).</p> <p>Results</p> <p>Data were collected on 157 women at their pre-operative visit (33 ovarian cancer, 45 endometrial cancer, 79 determined at surgery to be benign). Mean scores on the FACT-G subscales and SF-36 summary scores did not differ as a function of surgical diagnosis. PCS, MCS, age, and educational level were positively correlated with physical well-being, while increasing BMI was negatively correlated. Functional well-being was positively correlated with PCS and MCS and negatively correlated with BMI. Social well-being was positively correlated with MCS and negatively correlated with BMI and educational level. PCS, MCS and age were positively correlated with emotional well-being. Models that included PCS and MCS accounted for 30 to 44% of the variability in baseline physical, emotional, and functional well-being on the FACT-G.</p> <p>Conclusion</p> <p>At the time of diagnosis and treatment, patients' QoL is affected by inherent characteristics. Assessment of treatment outcome should take into account the effect of these independent variables. As treatment options become more complex, these variables are likely to be of increasing importance in evaluating treatment effects on QoL.</p

Pharmacotherapeutic intervention in impulsive preschool children: The need for a comprehensive therapeutic approach

Impulsive and aggressive behaviour symptoms often are serious problems in children, even already at preschool age. Thus, effective treatment approaches are requested. In this comment pharmacotherapeutic treatment approaches, first of all risperidone, their limitations and alternative psychotherapeutic approaches are outlined

Effect of Neuraminidase Inhibitor–Resistant Mutations on Pathogenicity of Clade 2.2 A/Turkey/15/06 (H5N1) Influenza Virus in Ferrets

The acquisition of neuraminidase (NA) inhibitor resistance by H5N1 influenza viruses has serious clinical implications, as this class of drugs can be an essential component of pandemic control measures. The continuous evolution of the highly pathogenic H5N1 influenza viruses results in the emergence of natural NA gene variations whose impact on viral fitness and NA inhibitor susceptibility are poorly defined. We generated seven genetically stable recombinant clade 2.2 A/Turkey/15/06-like (H5N1) influenza viruses carrying NA mutations located either in the framework residues (E119A, H274Y, N294S) or in close proximity to the NA enzyme active site (V116A, I117V, K150N, Y252H). NA enzyme inhibition assays showed that NA mutations at positions 116, 117, 274, and 294 reduced susceptibility to oseltamivir carboxylate (IC50s increased 5- to 940-fold). Importantly, the E119A NA mutation (previously reported to confer resistance in the N2 NA subtype) was stable in the clade 2.2 H5N1 virus background and induced cross-resistance to oseltamivir carboxylate and zanamivir. We demonstrated that Y252H NA mutation contributed for decreased susceptibility of clade 2.2 H5N1 viruses to oseltamivir carboxylate as compared to clade 1 viruses. The enzyme kinetic parameters (Vmax, Km and Ki) of the avian-like N1 NA glycoproteins were highly consistent with their IC50 values. None of the recombinant H5N1 viruses had attenuated virulence in ferrets inoculated with 106 EID50 dose. Most infected ferrets showed mild clinical disease signs that differed in duration. However, H5N1 viruses carrying the E119A or the N294S NA mutation were lethal to 1 of 3 inoculated animals and were associated with significantly higher virus titers (P<0.01) and inflammation in the lungs compared to the wild-type virus. Our results suggest that highly pathogenic H5N1 variants carrying mutations within the NA active site that decrease susceptibility to NA inhibitors may possess increased virulence in mammalian hosts compared to drug-sensitive viruses. There is a need for novel anti-influenza drugs that target different virus/host factors and can limit the emergence of resistance