Current Status of Companion and Complementary Diagnostics: Strategic Considerations for Development and Launch.

US Food and Drug Administration (FDA)-approved diagnostic assays play an increasingly common role in managing patients to prolong lifespan while also enhancing quality of life. Diagnostic assays can be essential for the safe and effective use of therapeutics (companion diagnostic), or may inform on improving the benefit/risk ratio without restricting drug access (complementary diagnostic). This tutorial reviews strategic considerations for drug and assay development resulting in FDA-approved companion or complementary diagnostic status.

Blindness prevalence and cataract surgical coverage in Lumbini Zone and Chetwan District of Nepal.

AIM: To determine the prevalence of blindness, visual impairment and the cataract surgical coverage for people aged 50 years and older in the Lumbini Zone and the Chitwan District (Narayani Zone) of Nepal. METHODS: A population-based cross-sectional study in 2006 selected subjects aged 50 years and older through a random multistage cluster sampling and door-to-door enumeration. Ophthalmic examination included visual-acuity assessment and refraction, and anterior and posterior segment examination of the eyes carried out by a trained ophthalmologist and two ophthalmic assistants at centralised locations. RESULTS: The survey examined 5138 of 5196 persons enumerated (response rate of 86.8%). The mean age of the subjects was 61 (SD 9.2) years, and 2701 (52.6%) subjects were women. The age-sex-adjusted prevalence of blindness (best presenting vision <6/60) and visual impairment (better-eye presenting visual acuity of <6/18 to > or = 6/60) were 4.6% (95% CI 3.4 to 5.8) and 18.9% (95% CI 16.4 to 21.4), respectively. Blindness was significantly lower in the hill (3.3%) compared with the plain (5.8%) regions (OR 0.6; 95% CI 0.4 to 0.9). The primary causes for blind eyes were cataract (n = 228, 48.1%), refractive error (n = 149, 31.4%), retinal disorders (n = 19, 4.0%) and corneal opacity (n = 18, 3.8%). The overall cataract surgical coverage was 66.6%. Cataract surgical coverage was not significantly associated with age, sex, literacy or District. CONCLUSION: Although the prevalence of blindness and visual impairment is lower than 10 years ago, particularly among women, correctable blindness due to cataract and refractive error (79.5% of blind people) remains a significant population health problem in Lumbini Zone and Chitwan District.

Blood pressure lowering efficacy of renin inhibitors for primary hypertension: a Cochrane systematic review.

We conducted a systematic review and meta-analysis of double-blind randomized controlled trials to quantify the dose-related systolic (SBP) and diastolic blood pressure (DBP) lowering efficacy of renin inhibitors vs placebo in the treatment of adults with primary hypertension. Databases searched were Medline (1966-March 2008), EMBASE (1988-March 2008) and Cochrane Central Register of Controlled Trials (CENTRAL). Six trials in 3694 patients met the inclusion criteria. All examined aliskiren, the only renin inhibitor licensed for marketing in Canada and the United States. Aliskiren caused a dose-related SBP/DBP lowering effect compared to placebo: weighted mean difference with 95% CI: aliskiren 75 mg, -2.9 (-4.6, -1.3)/-2.3 (-3.3, -1.3) mm Hg; aliskiren 150 mg, -5.5 (-6.5, -4.4)/-3.0 (-3.7, -2.3) mm Hg; aliskiren 300 mg, -8.7 (-9.7,-7.6)/-5.0 (-5.6, -4.3) and aliskiren 600 mg, -11.4 (-13.5, -9.2)/-6.6 (-7.9, -5.2) mm Hg. Aliskiren 300 mg significantly lowered both SBP -3.0 (-4.0, -2.0) and DBP -1.7 (-2.3, -1.0) as compared to aliskiren 150 mg. Aliskiren has no effect on blood pressure variability. No data were available to assess the effect of aliskiren on heart rate or pulse pressure. This review found weak evidence that during 4- to 8-week use, aliskiren did not increase withdrawals due to adverse effects as compared to placebo. We concluded that aliskiren has a dose-related blood pressure lowering effect better than placebo and magnitude of effect is similar to that determined for angiotensin-converting enzyme inhibitors and angiotensin receptor blockers.

Cataract surgical coverage remains lower in women.

BACKGROUND: Cataract remains the leading cause of global blindness. Evidence from population-based surveys, carried out up to 2000, and the launch of the VISION 2020 initiative to address avoidable blindness showed that women in low- and middle-income countries had a lower cataract surgical coverage (CSC) than men. METHODS: A systematic review identified population-based surveys reporting CSC in low- and middle-income countries published since 2000. Researchers extracted data on sex-specific CSC rates and estimated the overall CSC differences using meta-analyses. RESULTS: Among the 23 surveys selected for this review, 21 showed higher CSC among men. The Peto odds ratio revealed that men were 1.71 times (95% CI 1.48 to 1.97) more likely to have cataract surgery than women. The risk difference in the rates of surgery varied from -0.025 to 0.276, and the combined average was 0.116 (95% CI 0.082 to 0.149). DISCUSSION: Gender inequity in use of cataract surgical services persists in the low- and middle-income countries. It is estimated in this study that blindness and severe visual impairment from cataract could be reduced by around 11% in the low- and middle-income countries if women were to receive cataract surgery at the same rate as men. Additional effort globally is needed to ensure that women receive the benefits of cataract surgery at the same rate as men.

Contrast sensitivity and visual hallucinations in patients referred to a low vision rehabilitation clinic.

AIM: To examine the association of reported visual hallucinations and measured visual parameters in adult patients referred for low vision rehabilitation. METHODS: All patients (N = 225) referred to a low vision rehabilitation clinic for a calendar year were asked a standardised question about symptoms of formed visual hallucinations. Best corrected visual acuity and contrast sensitivity using the Pelli-Robson chart were measured. We conducted multiple logistic regression analysis of the association between visual hallucinations and visual parameters. RESULTS: Of the total cohort, 78 (35%) reported visual hallucinations. Visual acuity and contrast sensitivity were considered in four quartiles. In multiple logistic regression controlling for contrast sensitivity, age, gender, report of depression and independence, measured acuity in each of the poorer three categories (compared to the best) was not associated with reported hallucinations. Contrast sensitivity in the three poorer quartiles (compared to the best) was strongly associated with the report of hallucinations (OR 4.1, CI 1.1, 15.9; OR 10.5, CI 2.6, 42.1; OR 28.1, CI 5.6, 140.9) after controlling for acuity, age, sex, depression and independence. CONCLUSIONS: Lowest contrast sensitivity was the strongest predictor of reported hallucinations after adjusting for visual acuity.

The prevalence of low vision and blindness in Canada.

PURPOSE: The purpose of this study was to ascertain the prevalence and primary causes of visual impairment in a representative Canadian population. METHODS: We reviewed a representative sample of patients who attended ophthalmologists' offices in a medium-sized Canadian city between 1996 and 2001 in order to estimate the prevalence of visual impairment. Demographic data, visual diagnoses, best-corrected visual acuities (BCVA), and visual field information were recorded. Visual status was categorized based on accepted World Health Organization (WHO) and North American criteria. Population data were obtained from the Canadian census. RESULTS: The prevalence of low vision and blindness in our population was 35.6 and 3.8 per 10 000 individuals, according to the WHO classification, and 71.2 and 23.6 per 10 000 individuals, using the North American definition. Among individuals with some vision loss (vision worse than 20/40), cataract and visual pathway disease were the most common causes, together accounting for 40% of visual impairment. Age-related macular degeneration and other retinal diseases were the next most common causes of vision loss. Diabetic retinopathy and glaucoma were less frequently encountered as causes of visual impairment. CONCLUSION: The overall prevalence of low vision and blindness in Canada are in keeping with data from large population-based studies from other developed nations. Cataract, visual pathway disease, and macular degeneration are the leading causes of visual impairment. These results are important for enhancing our understanding of the scope of vision health in Canada and may direct future health planning and cost-utilization research.

Cataract surgical coverage and outcome in the Tibet Autonomous Region of China.

BACKGROUND: A recently published, population based survey of the Tibet Autonomous Region (TAR) of China reported on low vision, blindness, and blinding conditions. This paper presents detailed findings from that survey regarding cataract, including prevalence, cataract surgical coverage, surgical outcome, and barriers to use of services. METHODS: The Tibet Eye Care Assessment (TECA) was a prevalence survey of people from randomly selected households from three of the seven provinces of the TAR (Lhoka, Nakchu, and Lingzhr), representing its three main environmental regions. The survey, conducted in 1999 and 2000, assessed visual acuity, cause of vision loss, and eye care services. RESULTS: Among the 15,900 people enumerated, 12,644 were examined (79.6%). Cataract prevalence was 5.2% and 13.8%, for the total population, and those over age 50, respectively. Cataract surgical coverage (vision <6/60) for people age 50 and older (85-90% of cataract blind) was 56% overall, 70% for men and 47% for women. The most common barriers to use of cataract surgical services were distance and cost. In the 216 eyes with cataract surgery, 60% were aphakic and 40% were pseudophakic. Pseudophakic surgery left 19% of eyes blind (<6/60) and an additional 20% of eyes with poor vision (6/24-6/60). Aphakic surgery left 24% of eyes blind and an additional 21% of eyes with poor vision. Even though more women remained blind than men, 28% versus 18% respectively, the different was not statistically significant (p = 0.25). CONCLUSIONS: Cataract surgical coverage was remarkably high despite the difficulty of providing services to such an isolated and sparse population. Cataract surgical outcome was poor for both aphakic and pseudophakic surgery. Two main priorities are improving cataract surgical quality and cataract surgical coverage, particularly for women.

Blindness and eye diseases in Tibet: findings from a randomised, population based survey.

BACKGROUND: Public health officials of the Tibet Autonomous Region (TAR) of China requested a survey of blindness, eye diseases, and eye care service utilisation to assist the development of a 10 year blindness prevention and treatment plan. The objective of the survey was to determine the prevalence of blindness and visual impairment, as well as cataract surgical coverage and surgical outcome in the TAR. METHODS: The Tibet Eye Care Assessment was a cross sectional prevalence study of three of the seven prefectures (provinces) of the TAR (Lhoka, Nakchu, and Lingzhr) selected to represent its three main environmental regions. The survey sample was selected using a random multistage cluster method. Two teams conducted the survey in a standardised fashion in each prefecture, Lhoka during May and Nakchu during June 1999, and Lingzhr during May 2000. Visual acuity, cause of vision loss, trachoma, and vitamin A deficiency were included in the clinical examination. RESULTS: Among the 15,900 people enumerated, 12,644 were examined for an overall response rate of 79.6%. The crude prevalence of blindness (presenting better eye visual acuity of less than 6/60) was 2.3%; age and sex adjusted blindness prevalence was 1.4% (95% CI 1.3 to 1.5). Visual impairment (better eye presenting visual acuity of 6/24 to 6/60) was found in 10.9% (95% CI 10.5 to 11.2) of the population (age and sex adjusted). Cataract was the primary cause of blindness (50.7%), followed by macular degeneration (12.7%) and corneal opacity (9.7%). CONCLUSION: Blindness is a serious public health problem in Tibet, with prevalence higher than in similar studies in eastern China. As elsewhere in the world, women have an excess burden of blindness compared to men. About 75% of blindness in Tibet can be either prevented or treated. Eye care planning for Tibet must focus on cataract, particularly among women.

Gender and blindness: a meta-analysis of population-based prevalence surveys.

BACKGROUND: Many individual surveys of blindness have reported slightly higher rates of blindness for women. In order to gain a continent-by-continent and global sense of the burden of blindness by sex we conducted a meta-analysis of published, population-based surveys of blindness. METHOD: Published reports were collected using a predetermined search protocol involving commercial electronic databases, hand-searching of references and direct contact with researchers. Studies were included that were population-based, included clinical examination and had a minimum sample size of 1000. The studies were critically appraised to determine methodological rigour. Data were analysed using the Cochrane Collaboration Review Manager. RESULTS: The overall odds ratio (age-adjusted) of blind women to men is 1.43 (95% CI 1.33-1.53), ranging from 1.39 (95% CI 1.20-1.61) in Africa, 1.41 (95% CI 1.29-1.54) in Asia, and 1.63 (95% CI 1.30-2.05) in industrialised countries. There was good homogeneity of findings from Africa, Asia, and the industrialised countries. Globally, women bear excess blindness compared to men. In these surveys, overall, women account for 64.5% of all blind people. The excess of blindness in women was marked among the elderly and not due only to differential life expectancy. CONCLUSION: The excess burden of blindness among women is likely due to a number of factors, which are different in industrialised countries compared to developing countries. Particular attention to gender differences in blindness is needed in the creation of targets for blindness reduction and in the development of interventions.

Metal lawn and garden edging: the hidden knife?

OBJECTIVE: Lacerations account for many visits to the pediatric emergency department. We observed children presenting to local emergency departments in a large metropolitan area with lacerations incurred from metal lawn and garden edging, a landscaping tool. We sought to describe the severity of lacerations caused by metal edging, the characteristics of wound repair, and the need for subspecialty consultation. DESIGN: A retrospective chart review including all pediatric patients (< 18 years) presenting with lacerations caused by metal lawn and garden edging from January 1995 to October 1997 was performed. Patients were seen at one of three emergency departments in Colorado. RESULTS: One hundred twenty-six patients were enrolled (76% male, 24% female), with a median age of 9 years. The most frequent location of laceration was the foot (40%), followed by the knee (26%). The median length of laceration was 3 cm (range 1-22 cm). Sixteen patients (13%) received either intravenous or oral antibiotics, and six patients (5%) received orthopedic evaluation. CONCLUSIONS: Metal lawn and garden edging in landscaped neighborhoods presents a previously undescribed laceration danger to children. Some lacerations sustained from the metal lawn edging are extensive, receiving either multiple layer closure and/or the need for subspecialty consultation.

Use of propofol sedation in a pediatric emergency department: a prospective study.

The purpose of this study was to determine the efficacy and safety of propofol sedation for pediatric procedures in the emergency department. For patients needing painful procedures, propofol was administered intravenously. Vital signs, complications, and time to recovery were recorded. Patient amnesia and parent, patient, and operator satisfaction with sedation were assessed. The mean age was 7.4 years; 65% were male. Most underwent fracture reduction. Mean total dose was 3.3 mg/kg. Thirty percent experienced desaturation. One required assisted ventilation. Most had decreases in blood pressure. Mean recovery time was 18 minutes. Satisfaction with sedation was rated "excellent." Propofol was an effective sedation with minimal complications in the emergency department setting.

Do clinical practice guidelines reflect research evidence?

OBJECTIVES: To examine whether existing clinical practice guidelines (CPGs) for cholesterol testing reflect research evidence and hence may control or reduce costs while maintaining or improving the quality of care. METHODS: A systematic search for published and unpublished cholesterol testing CPGs and independent critical appraisal of the CPGs by two researchers using a standard checklist. RESULTS: In four of the five CPGs analysed, the link between the research evidence and the recommendations was not maintained. The appraisal, local experience and the literature all suggest that panel composition is an important explanation, in that the greater the involvement of clinical experts in the development process of the CPGs, the less the recommendations reflected the research evidence. Even though their participation is important for CPG uptake, clinical expert panels appear to have difficulty limiting CPGs to research-based recommendations. CONCLUSIONS: Existing cholesterol testing CPGs are unlikely to improve the quality of care while controlling or reducing costs. The problem lies not with guideline implementation but with the guidelines themselves. It is unclear how best to ensure that recommendations reflect research evidence but this is likely to require significant and progressive changes to the current guideline development process, including a redefinition of the clinical experts' role.

Defensive medicine during hospital obstetrical care: a byproduct of the technological age.

This paper presents an alternative perspective on defensive medicine. Defensive medicine is usually understood as arising from the effect of law on medicine through fear of litigation. Of equal significance, however, is the complementary influence of medicine on law through technological innovation, and, more importantly, the way that medicine and law develop dialectically. Each shapes the other in establishing the standards of care central to both clinical medicine and to actual or potential legal action. Excessive testing owing to fear of litigation indicates that defensive medicine is being practised in a particular setting, but it does not explain why this is so. To understand why defensive medicine occurs and why it is so troubling to clinicians requires an understanding, not only of medical and legal developments, but of a political-economic system and the beliefs and values of a society. Defensive medicine is discussed in relation to hospital obstetrical scenarios commonly associated with fear of litigation: fetal oxygen deprivation ("distress"), which is detected using an electronic fetal monitor, and prolonged labor, known as "dystocia". The material presented is taken from a medical anthropological study of obstetrical care in rural British Columbia, Canada. Litigation fears are shown to result less from rare, albeit often devastating, allegations of malpractice than from doctors adopting a role as "fetal champions", together with the introduction of electronic monitoring technology. The paper concludes by asserting that, rather than being in an adversarial relationship, medical practice and associated litigation primarily work together to reinforce each other, and the social conditions in which defensive medicine occurs.

Are signs and symptoms associated with persistent corneal abrasions in children?

BACKGROUND: Corneal abrasions are common eye injuries in children. Most are treated with antibiotic drops or ointment, patching of the affected eye, and follow-up within 24 hours to confirm resolution by fluorescein examination. OBJECTIVE: To determine if signs and symptoms at follow-up were associated with the presence of a persistent corneal abrasion or abnormal visual acuity. DESIGN: Retrospective case series. SETTING: A children's hospital. PATIENTS: Children who were aged 4 years or older with the diagnosis of corneal abrasion between May 1992 and December 1996 and who had a follow-up examination. RESULTS: Seventy-seven patients (57% male) were enrolled (median age, 7 years). The respective sensitivities, specificities, positive predictive values, and negative predictive values of selective signs and symptoms for persistent abrasions were as follows: for pain, 53%, 93%, 80%, and 80%; for photophobia, 57%, 100%, 100%, and 80%; for redness, 100%, 46%, 44%, and 100%; for pain and redness, 40%, 96%, 80%, and 80%; and for at least 1 sign or symptom, 95%, 48%, 47%, and 95%. Twenty-six patients had persistent corneal abrasions at follow-up. Six of these 26 patients were symptom free at follow-up, and 15 patients had only redness as a persistent sign. Five patients had abnormal visual acuity, one of whom was asymptomatic. All 3 patients with complications were symptomatic. CONCLUSIONS: Signs and symptoms are inconsistently associated with persistent corneal abrasions. Asymptomatic patients may have persistent corneal abrasions, suggesting the need for selective follow-ups.

Localizing ingested coins with a metal detector.

This study was conducted to determine the utility of metal detection in coin localization by inexperienced operators, and determine the rate of spontaneous passage of asymptomatic esophageal coins. All children who presented to the emergency department of an urban children's hospital with a suspected coin ingestion were eligible. Coin location was predicted from metal detector results, while radiographs confirmed location. Asymptomatic patients with esophageal coins were observed for spontaneous passage. Ninety-one children (ages 9 months to 17 years) were prospectively enrolled. The metal detector had a sensitivity of 98% (53/54) in coin detection and 98% (81/83) in determining coin location as esophageal. Symptoms were poor predictors of coin location. Six of eight asymptomatic patients with esophageal coins spontaneously passed their coins. These results show that metal detection is a good screening test for coin presence and to determine coin location as esophageal. Spontaneous passage of asymptomatic esophageal coins warrants further study.