Human cytomegalovirus: taking the strain.

In celebrating the 60th anniversary of the first isolation of human cytomegalovirus (HCMV), we reflect on the merits and limitations of the viral strains currently being used to develop urgently needed treatments. HCMV research has been dependent for decades on the high-passage strains AD169 and Towne, heavily exploiting their capacity to replicate efficiently in fibroblasts. However, the genetic integrity of these strains is so severely compromised that great caution needs to be exercised when considering their past and future use. It is now evident that wild-type HCMV strains are not readily propagated in vitro. HCMV mutants are rapidly selected during isolation in fibroblasts, reproducibly affecting gene RL13, the UL128 locus (which includes genes UL128, UL130 and UL131A) and often the U(L)/b' region. As a result, the virus becomes less cell associated, altered in tropism and less pathogenic. This problem is not restricted to high-passage strains, as even low-passage strains can harbour biologically significant mutations. Cloning and manipulation of the HCMV genome as a bacterial artificial chromosome (BAC) offers a means of working with stable, genetically defined strains. To this end, the low-passage strain Merlin genome was cloned as a BAC and sequentially repaired to match the viral sequence in the original clinical sample from which Merlin was derived. Restoration of UL128L to wild type was detrimental to growth in fibroblasts, whereas restoration of RL13 impaired growth in all cell types tested. Stable propagation of phenotypically wild-type virus could be achieved only by placing both regions under conditional expression. In addition to the development of these tools, the Merlin transcriptome and proteome have been characterized in unparalleled detail. Although Merlin may be representative of the clinical agent, high-throughput whole-genome deep sequencing studies have highlighted the remarkable high level of interstrain variation present in circulating virus. There is a need to develop systems capable of addressing the significance of this diversity, free from the confounding effects of genetic changes associated with in vitro adaptation. The generation of a set of BAC clones, each containing the genome of a different HCMV strain repaired to match the sequence in the clinical sample, would provide a pathway to address the biological and clinical effects of natural variation in wild-type HCMV.

Improvement in vision-related function with intravitreal aflibercept: data from phase 3 studies in wet age-related macular degeneration.

PURPOSE: To evaluate the effect of intravitreal aflibercept injection on visual function in wet age-related macular degeneration (AMD). DESIGN: Prospective, multicenter, double-masked, active-controlled, parallel-group, randomized phase 3 clinical studies (VEGF Trap-Eye: Investigation of Efficacy and Safety in Wet AMD [VIEW] 1 and 2 [clinicaltrials.gov identifiers, NCT00509795 and NCT00637377, respectively]). PARTICIPANTS: Patients (n=2419) with active, treatment-naïve, exudative AMD. This analysis included patients who received intravitreal aflibercept 2.0 mg every 8 weeks (2q8; n=607) or ranibizumab 0.5 mg every 4 weeks (0.5q4; n=595). INTERVENTION: Patients were randomized 1:1:1:1 to receive intravitreal aflibercept 2q8 (after 3 initial monthly doses), intravitreal aflibercept 2q4, intravitreal aflibercept 0.5q4, or ranibizumab 0.5q4 in the study eye. Patients in the intravitreal aflibercept 2q8 group received a sham injection alternating with active treatment. MAIN OUTCOME MEASURES: The 25-item National Eye Institute Visual Function Questionnaire (NEI VFQ-25) was administered at baseline and at weeks 12, 24, 36, and 52. The NEI VFQ-25 subscale scores were compared between intravitreal aflibercept 2q8 and ranibizumab 0.5q4 treatment arms, the approved dosing for each agent worldwide. Change in composite NEI VFQ-25 score was evaluated based on categorical change in visual acuity (worsened, unchanged, improved). RESULTS: Baseline NEI VFQ-25 scores were similar for both treatments in both studies. Mean change from baseline to 52 weeks was similar for ranibizumab 0.5q4 and intravitreal aflibercept 2q8 across all 12 subscales, with the greatest improvements noted for mental health and general vision (9.0-11.6 points, both treatments, both studies). Improvement of 4 points or more (both treatments, both studies) also was observed for subscales near vision, distance vision, role difficulties, and dependency. Mean change from baseline to 52 weeks in NEI VFQ-25 composite score (pooled data) stratified by clinical response showed meaningful improvement only in patients who gained 5 Early Treatment Diabetic Retinopathy letters or more (7.3 and 7.8 points for intravitreal aflibercept 2q8 and ranibizumab 0.5q4, respectively). CONCLUSIONS: Visual function outcomes were similar across all NEI VFQ-25 subscales over 52 weeks for intravitreal aflibercept 2q8 and ranibizumab 0.5q4, with clinically meaningful improvement recorded in 6 of 12 subscales.

Burden of menstrual symptoms in Japanese women: results from a survey-based study.

UNLABELLED: . OBJECTIVE: Menstrual symptoms are associated with various health problems in women and may also significantly impact their lives. This study aims to assess the current burden of menstrual symptoms in Japanese women. METHODS: Two online surveys were conducted among women aged 15-49 years, where sampling was designed to approximate the age and geographic distribution in Japan. The first survey collected data on menstrual symptom severity based on a modified, 35-item, Japanese version of the Menstrual Distress Questionnaire (mMDQ), current treatments, and impact on work productivity. The second survey collected costs of outpatient treatment within the previous 3 months. Additional outcomes of the second survey will be presented in a separate paper. RESULTS: In this study, 19,254 women had menses, with 74% suffering from menstrual symptoms. A total of 50% reported pain and 19% reported heavy bleeding. Increasing severity of menstrual symptoms and self-reported heavy bleeding were related to more outpatient visits and greater work productivity loss. Among subjects with heavy bleeding, increasing severity of symptoms was related to greater interference with daily life. The estimated annual economic burden extrapolated to the Japanese female population was 683 billion Japanese Yen (JPY) or ~8.6 billion United States Dollars (USD). LIMITATIONS: The study population may be biased due to the online survey method. CONCLUSIONS: To the authors' knowledge, this is the first large-scale research assessing outcomes by severity categories for all menstrual symptoms and women's perception of bleeding. A large proportion of women suffer from menstrual symptoms, and symptom severity impacts women's lives. Menstrual symptoms lead to significant economic burden, mainly due to work productivity loss. However, the majority of women do not visit a gynecologist, even when their menstrual symptoms are severe. Thus, increasing public awareness on the recently available medical treatments has the potential to improve the overall burden of menstrual problems.

Assessing quality of life in the treatment of patients with age-related macular degeneration: clinical research findings and recommendations for clinical practice.

BACKGROUND: The importance of incorporating quality-of-life (QoL) assessments into medical practice is growing as health care practice shifts from a "disease-based" to a "patient-centered" model. The prevalence of age-related macular degeneration (AMD) is increasing in today's aging population. The purpose of this paper is: (1) to discuss, by reviewing the current literature, the impact of AMD on patients' QoL and the utility of QoL assessments in evaluating the impact of AMD and its treatment; and (2) to make a recommendation for incorporating QoL into clinical practice. METHODS: We conducted a PubMed and an open Internet search to identify publications on the measurement of QoL in AMD, as well as the impact of AMD and the effect of treatment on QoL. A total of 28 articles were selected. RESULTS: AMD has been found to cause a severity-dependent decrement in QoL that is comparable to systemic diseases such as cancer, ischemic heart disease, and stroke. QoL impairment manifests as greater social dependence, difficulty with daily living, higher rates of clinical depression, increased risk of falls, premature admission to nursing homes, and suicide. The National Eye Institute Visual Functioning Questionnaire (NEI VFQ-25) is the most widely used eye disease-specific QoL instrument in AMD. It has been shown to correlate significantly with visual acuity (VA). QoL reflects aspects of AMD including psychological well-being, functional capacity, and the ability to perform patients' valued activities, which are not captured by a single, numerical VA score. CONCLUSION: The literature shows that the adverse impact of AMD on QoL is comparable to serious systemic disease. Eye disease-specific instruments for measuring QoL, such as the NEI VFQ-25, have shown a significant correlation of QoL decrement with measures of disease severity, as well as significant QoL improvement with treatment. The NEI VFQ-25 and other validated instruments provide a wide-ranging assessment of vision-related functioning that is important to patients and complementary to VA measurement. We strongly recommend the incorporation of QoL assessment into routine clinical practice.

Burden of comorbidities among Japanese patients with atrial fibrillation: a case study of dyspepsia.

BACKGROUND: The aim of this study was to investigate the link between atrial fibrillation (AF) and dyspepsia, as well as the contribution of dyspepsia to the overall burden of AF. METHODS: The 2008, 2009, and 2010 Japan National Health and Wellness Survey (NHWS) datasets were used in this study. The NHWS is an Internet-based survey administered to the adult population in Japan using a random stratified sampling framework to ensure demographic representativeness. The presence of dyspepsia was compared between those with and without AF. Among those with AF, the effect of dyspepsia on health status, work productivity, and activity impairment was examined, along with health care resource use using multivariable regression modeling and controlling for baseline differences. RESULTS: Among patients with AF (n = 565), the three most commonly reported comorbidities were hypertension (38.76%), dyspepsia (37.35%), and overactive bladder (28.72%). Patients with AF had 48.59% greater odds of reporting dyspepsia than those without AF (P < 0.05). Patients with dyspepsia used more AF medications (2.05 versus 1.54) and had been diagnosed more recently (9.97 versus 10.58 years). Dyspepsia was associated with significantly worse physical health status (P < 0.05) and significantly more absenteeism, overall work impairment, activity impairment, physician visits, and emergency room visits (all P < 0.05). CONCLUSION: Patients with AF in Japan experience a number of comorbidities, with dyspepsia being the most common noncardiovascular comorbidity. Given the prevalence and additional burden of this comorbidity across both humanistic and economic outcomes, the management of dyspepsia among patients with AF should be an area of greater focus.

Higher doses of subcutaneous IgG reduce resource utilization in patients with primary immunodeficiency.

The recommended dose of IgG in primary immunodeficiency (PID) has been increasing since its first use. This study aimed to determine if higher subcutaneous IgG doses resulted in improved patient outcomes by comparing results from two parallel clinical studies with similar design. One patient cohort received subcutaneous IgG doses that were 1.5 times higher than their previous intravenous doses (mean 213 mg/kg/week), whereas the other cohort received doses identical to previous subcutaneous or intravenous doses (mean 120 mg/kg/week). While neither cohort had any serious infections, the cohort maintained on higher mean IgG dose had significantly lower rates of non-serious infections (2.76 vs. 5.18 episodes/year, P < 0.0001), hospitalization (0.20 vs. 3.48 days/year, P < 0.0001), antibiotic use (48.50 vs. 72.75 days/year, P < 0.001), and missed work/school activity (2.10 vs. 8.00 days/year, P < 0.001). The higher-dose cohort had lower health care utilization and improved indices of well being compared to the cohort treated with traditional IgG doses.

Community-based evaluation of etanercept in patients with rheumatoid arthritis.

OBJECTIVES: Etanercept is one of a new subgroup of biological disease modifying antirheumatic drugs (DMARD) to treat patients with rheumatoid arthritis (RA) who are non-responsive or intolerant to conventional DMARD. We evaluated the effects of etanercept (Enbrel) therapy in patients with RA in community-based clinical practice in Canada. METHODS: Using a cohort design, patients requesting etanercept therapy were stratified into treatment and control arms based upon their individual accessibility to obtain the drug. Patients were interviewed serially during a 12-month period of monitoring. The study measured painful or tender joint count, morning stiffness, pain severity, quality of life measures, medication utilization, health services utilization, and presence of adverse events. RESULTS: The baseline demographic and clinical variables for the treatment group (n = 223) and the control group (n = 208) were similar, except for education, income, and drug plan coverage. In followup, there was greater improvement in most clinical variables in the treatment arm compared to the control arm during the first 6 months, but the magnitude of difference between the 2 groups for some clinical variables decreased or became non-significant during the second 6 months. During the 12 month followup period there were 40 (18%) patient dropouts in the treatment group. CONCLUSION: In a community based setting for the treatment of RA, etanercept can effectively improve the disease state, functional class, work disability, and quality of life during the first 6 months of use. To determine the longterm sustainability of these effects studies with more than 12 months' duration will be required.

ATP and purinergic receptor-dependent membrane traffic in bladder umbrella cells.

The umbrella cells that line the bladder are mechanosensitive, and bladder filling increases the apical surface area of these cells; however, the upstream signals that regulate this process are unknown. Increased pressure stimulated ATP release from the isolated uroepithelium of rabbit bladders, which was blocked by inhibitors of vesicular transport, connexin hemichannels, ABC protein family members, and nucleoside transporters. Pressure-induced increases in membrane capacitance (a measure of apical plasma membrane surface area where 1 microF approximately equals 1 cm2) were inhibited by the serosal, but not mucosal, addition of apyrase or the purinergic receptor antagonist PPADS. Upon addition of purinergic receptor agonists, increased capacitance was observed even in the absence of pressure. Moreover, knockout mice lacking expression of P2X2 and/or P2X3 receptors failed to show increases in apical surface area when exposed to hydrostatic pressure. Treatments that prevented release of Ca2+ from intracellular stores or activation of PKA blocked ATPgammaS-stimulated changes in capacitance. These results indicate that increased hydrostatic pressure stimulates release of ATP from the uroepithelium and that upon binding to P2X and possibly P2Y receptors on the umbrella cell, downstream Ca2+ and PKA second messenger cascades may act to stimulate membrane insertion at the apical pole of these cells.

The value of medicines in Canada.

Spending on drugs has become a target for cost-containment measures because of its continual growth, both in absolute terms and as a proportion of overall healthcare expenditures. However, considering drug spending in isolation from other healthcare components neglects the benefit of drugs to Canada's healthcare system, society and economy. Drugs, when used appropriately as part of overall disease management, have increased life expectancy and quality of life, have avoided more costly alternatives such as hospitalisation and surgery, and have decreased worker absenteeism and increased their productivity. Current evidence suggests that drugs represent good value for money and are an integral part of a cost-effective and sustainable healthcare system. Cost-containment measures should focus on appropriate use of medications and improving adherence to therapeutic regimens for optimal patient outcomes.

Remission from depression : a review of venlafaxine clinical and economic evidence.

Worldwide, major depression is the leading cause of years lived with a disability, and the fourth cause of disability-adjusted life years. Depression is second only to hypertension as the most common chronic condition encountered in general medical practice. Unfortunately, despite the high prevalence of depression, under-recognition and under-treatment are common.Historically, clinicians have assessed the short-term effectiveness of antidepressants by response rates, often defined as a 50% reduction in depressive symptoms. However, this usually does not reflect true clinical remission, and residual symptoms are common. Persistence of residual symptoms appears to be a common link to relapse, chronic disability and suicide. The burden of not treating depression effectively to remission is significant, as the disease is an important contributor to the disability levels of the general population. Disability, in turn, has a profound impact on lost productivity and medical expenses. In 2000, depression cost the US more than US 83 billion dollars annually in lost productivity, medical expenses and premature death.Venlafaxine, a dual-acting serotonin norepinephrine (noradrenaline) reuptake inhibitor, may improve a patient's response to treatment and their chances of achieving complete remission compared with conventional antidepressant therapies, with the evidence for this being the strongest for comparisons with the selective serotonin receptor inhibitors (SSRIs). To date, there are only a small number of economic studies of venlafaxine, and most are cost or resource utilisation analyses with significant limitations. Nevertheless, two cost-effectiveness analyses of venlafaxine are available. They found venlafaxine had a lower average cost per patient achieving remission or per symptom-free day compared with SSRIs; one reported an incremental cost-effectiveness ratio for venlafaxine of US 586 dollars (year 2002 values) per additional patient achieving remission over 8 weeks, and the other found venlafaxine to be a dominant treatment choice over SSRIs over 6 months (year 2001 values). Although requiring further confirmation, these initial data suggest that venlafaxine is a cost-effective strategy for the treatment of depression. The availability of an effective armamentarium of antidepressant strategies, including venlafaxine, to achieve and sustain remission offers both clinical and economic value to all those touched by the burden of depression.

Hydrostatic pressure-regulated ion transport in bladder uroepithelium.

The effect of hydrostatic pressure on ion transport in the bladder uroepithelium was investigated. Isolated rabbit uroepithelium was mounted in modified Ussing chambers and mechanically stimulated by applying hydrostatic pressure across the mucosa. Increased hydrostatic pressure led to increased mucosal-to-serosal Na+ absorption across the uroepithelium via the amiloride-sensitive epithelial Na+ channel. In addition to this previously characterized pathway for Na+ absorption, hydrostatic pressure also induced the secretion of Cl- and K+ into the mucosal bathing solution under short-circuit conditions, which was confirmed by a net serosal-to-mucosal flux of 36Cl- and 86Rb+. K+ secretion was likely via a stretch-activated nonselective cation channel sensitive to 100 microM amiloride, 10 mM tetraethylammonium, 3 mM Ba2+, and 1 mM Gd3+. Hydrostatic pressure-induced ion transport in the uroepithelium may play important roles in electrolyte homeostasis, volume regulation, and mechanosensory transduction.

A pharmacoeconomic evaluation of 7-valent pneumococcal conjugate vaccine in Canada.

The objective of this study was to evaluate the projected health benefits, costs, and cost-effectiveness of pneumococcal conjugate vaccination for infants and children aged <5 years in Canada. A health state model incorporating incidence, vaccine efficacy, costs, and transitional probabilities for the health states (well, meningitis, bacteremia, otitis media, pneumonia, and death) was constructed for a 10-year time horizon. Implementation of a pneumococcal conjugate vaccine program in Canada for each annual birth cohort of 340,000 persons observed over 10 years would be expected to save approximately 12 lives and 100,000 cases of pneumococcal disease over 10 years, resulting in total savings of $67 million (Canadian dollars [Can$]). Vaccination of healthy infants would result in net savings for society if the vaccine costs less than Can$50 per dose. Moreover, for a vaccine purchase price of Can$67.50, infant vaccination would cost society Can$79,000 per life-year gained. Pneumococcal conjugate vaccination is a potentially cost-effective means of pneumococcal disease prevention.