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Use of Wolbachia to drive nuclear transgenes through insect populations.

Wolbachia is an inherited intracellular bacterium found in many insects of medical and economic importance. The ability of many strains to spread through populations using cytoplasmic incompatibility, involving sperm modification and rescue, provides a powerful mechanism for driving beneficial transgenes through insect populations, if such transgenes could be inserted into and expressed by Wolbachia. However, manipulating Wolbachia in this way has not yet been achieved. Here, we demonstrate theoretically an alternative mechanism whereby nuclear rather than cytoplasmic transgenes could be driven through populations, by linkage to a nuclear gene able to rescue modified sperm. The spread of a 'nuclear rescue construct' occurs as long as the Wolbachia show imperfect maternal transmission under natural conditions and/or imperfect rescue of modified sperm. The mechanism is most efficient when the target population is already infected with Wolbachia at high frequency, whether naturally or by the sequential release of Wolbachia-infected individuals and subsequently the nuclear rescue construct. The results provide a potentially powerful addition to the few insect transgene drive mechanisms that are available.

Animals↗

Noninvasive imaging for the diagnosis of coronary artery disease: focusing the development of new diagnostic technology.

BACKGROUND: New tests, such as magnetic resonance imaging (MRI) and electron-beam computed tomography (CT), are being developed for the diagnosis of coronary artery disease. OBJECTIVE: To determine the conditions that a new test must meet to be a cost-effective alternative to established imaging tests. DESIGN: Decision model and cost-effectiveness analysis. DATA SOURCES: Literature review and meta-analysis. TARGET POPULATION: 55-year-old men and 65-year-old women presenting with chest pain. TIME HORIZON: Lifetime of the patient. PERSPECTIVE: Health care policy. INTERVENTIONS: MRI, electron-beam CT, exercise echocardiography, exercise single-photon emission CT, and coronary angiography. OUTCOME MEASURES: Target sensitivity and specificity values for a new noninvasive test. RESULTS OF BASE-CASE ANALYSIS: Assuming that society is willing to pay $75000 per quality-adjusted life-year (QALY) gained, a new test that costs $1000 would need a sensitivity of 94% and a specificity of 90% to be cost-effective. RESULTS OF SENSITIVITY ANALYSIS: Assuming that society is willing to pay $50000 per QALY gained, a new test that costs $1000 or more would never be cost-effective. For a test that costs $500, the sensitivity and specificity must each be 95%. CONCLUSIONS: New imaging techniques, such as MRI and electron-beam CT, must be relatively inexpensive and have excellent sensitivity and specificity to be cost-effective compared with other techniques for the diagnosis of coronary artery disease. Similar analyses in other areas of health care may help to focus the development of new diagnostic technology.

Aged↗

Hospital-acquired complications in a randomized controlled clinical trial of a geriatric consultation team.

As part of a controlled clinical trial of a geriatric consultation team (GCT), we investigated whether a GCT could affect the incidence of hospital-acquired complications in elderly patients. One hundred eighty-five patients, aged 75 years and older, were randomized into an intervention (N = 92) and a control (N = 93) group. Members of the intervention group received a GCT consultation and were routinely followed up throughout their hospitalization. The incidence of hospital-acquired complications for the entire study population was 38%. The type and rate of hospital-acquired complications in the intervention and control groups were not significantly different. Functional status on admission and admission to the psychiatry service were predictive for the occurrence of a hospital-acquired complication. In a broadly selected population such as this, the intensity of care available through a GCT was unable to reduce the occurrence of hospital-acquired complications. However, since this is only one aspect of a GCT function, and others may be of great importance, such aspects, and more targeted populations, must be evaluated before final conclusions can be reached about GCT efficiency.

Aged↗

The cost of conducting face-to-face household interviews in a rural, Native American population. The North Carolina Native American Cervical Cancer Prevention Project.

BACKGROUND: This article focuses on planning, developing, implementing, and evaluating the data collection method used for evaluating a community health education program in a rural setting, the North Carolina Native American Cervical Cancer Prevention Program. METHODS: Evaluation of program effectiveness used face-to-face interviews with a randomly selected sample of women from the target population. Selection of a data collection method was based on thorough community and program analysis. Each element of the community's analysis revealed key cultural, environmental, and procedural factors that affected the selection of an appropriate data collection method. RESULTS: Costs per completed interview varied over time, ranging from a low of $48 during the height of survey activity to $243. The average cost per completed interview overall was $113. CONCLUSIONS: Several factors contributed to the overall costs of interviews, including the economy of the community, the number of call-backs made to contact women, and local environmental conditions.

Costs and Cost Analysis↗

Marginal topography of neurons expressing the substance P receptor in the rat suprachiasmatic nucleus.

Neurons expressing the substance P (SP) receptor (NK1 receptor) in the suprachiasmatic nucleus of the hypothalamus (SCN) have been topographically identified using radioactive in situ hybridization histochemistry. In the anterior hypothalamic area, clustered labeled neurons of small size and exhibiting low levels of gene expression are observed exclusively at the dorsolateral margin of the SCN, straddling cytoarchitectural boundaries of the nucleus. The marginal topography of neurons putative target of a SP-containing retinal input to the ventral SCN indicates that their dendrites bearing the receptor extend towards the retinorecipient part of the nucleus, where they can be modulated by overlapping inputs from the intergeniculate leaflet and the raphe. Eventual interactions between glutamatergic and putative tachykininergic retinal pathways for a coherent photic control of circadian rhythms may therefore occur mainly via intrinsic neuronal connections between their distinct target populations. In addition, since glutamate and SP induce electrophysiological responses in ventrolateral neurons with no interactive effect, neurons integrating both chemical signals, subsequently to their modulation by several influences, may be not located within the ventrolateral SCN. Alternatively but not exclusively, marginal neurons could be a target of SP-containing neurons within the SCN or nearby the nucleus, or from ascending projections from the raphé where serotonin and SP colocalize. The marginal topography of neurons expressing the SP receptor supports the view of the involvement of neurons located in the vicinity of the nucleus in the regulation of circadian rhythms.

Animals↗

Biochemical modulation of 5-fluorouacil through dihydropyrimidine dehydrogenase inhibition: a Southwest Oncology Group phase II trial of eniluracil and 5-fluorouracil in advanced resistant colorectal cancer.

PURPOSE: To investigate the hypothesis that a systemic agent designed to inhibit dihydropyrimidine dehydrogenase (DPD), the first enzyme in the fluoropyrimidine degradative pathway, could improve the effective amount of 5-fluorouracil (5-FU) delivered to a tumor resulting in enhanced response. PATIENTS AND METHODS: Eligibility included cytologically or pathologically verified diagnosis of colorectal cancer that recurred during or within 12 months of completion of adjuvant therapy, representing patients generally considered resistant to fluorinated pyrimidine therapy. Stratification was into two cohorts: recurrence while receiving adjuvant therapy, and relapse within 12 months of completing adjuvant therapy. Treatment consisted of 28 days of oral therapy every five weeks with eniluracil and 5-FU administered in a 10:1 ratio. The daily dose of eniluracil was 10 mg/m2 with 5-FU 1 mg/m2, divided into two doses. RESULTS: Twenty-five patients are evaluable for response: 9 relapsed during therapy and 16 relapsed within one year of adjuvant therapy. In the first group, there was one partial response (9%; 95% CI 0-41%); in the second cohort there was one confirmed complete response (5%; 95% CI 0-23%) and one unconfirmed partial response, for an overall response rate of 10%. CONCLUSIONS: This regimen lacks significant activity in this target population. Pre-treatment intratumoral DPD expression was not assessed, therefore the mechanism of fluorinated pyrimidine resistance cannot be specifically attributed to elevated DPD levels. Attempting restoration of chemotherapy sensitivity through blockade of enzymes or signal transduction molecules responsible for resistance is rational, provided that tumor target expression is the basis for trial entry.

Adult↗

Geographical difference in the prevalence of isolated systolic hypertension in middle-aged men and women in Korea: the Korean Health and Genome Study.

To compare geographical difference in the prevalence of isolated systolic hypertension (ISH) in between urban (Ansan) and rural (Ansung) Korean adults aged 40-69 years, 4351 men and 4604 women enrolled in the Korean Health and Genome Study were analysed. Information was collected regarding gender, alcohol intake, smoking status, household income, occupation, and years of education by trained interviewers. Eligible subjects included untreated hypertensive and normotensive subjects. ISH was defined as a systolic blood pressure (SBP) > or = 140 mmHg and diastolic BP <90 mmHg. The overall age-adjusted prevalence of ISH was 4.1%. The prevalence of ISH in Ansung (5.7%) was higher than in Ansan (2.5%, P < 0.05). Also it increased with increments of age, from 1.0 to 12.8% in Ansung (P < 0.05) and from 0.3 to 13.0% in Ansan (P < 0.05). In those with body mass index (BMI) > or = 30.0 kg/m2 in Ansung, the prevalence of ISH in women was twice as much as in men. The prevalence of ISH in obese men and women with a waist-hip ratio > or =1.0 and > or = 0.85, respectively, was more than that of nonobese men and women in both areas. In Korea, because of industrialization, the age distribution was skewed and the Korean population in rural areas is more aged. ISH will become a truly major health problem in rural area, because ISH is related to age, BMI and waist-hip ratio. Therefore, the Korean government will be required to institute different policies in the hypertension management to target populations in rural and urban areas.

Female↗

An assessment of the effectiveness of the Mottep model for increasing donation rates and preventing the need for transplantation--adult findings: program years 1998 and 1999.

The National Minority Organ Tissue Transplant Education Program (MOTTEP) evaluated the effects of a community-implemented health education program for adult members of minority population groups to affect attitude, knowledge, and intent to change behavior. In addition, this study represents 1 of the first major initiatives to formally address prevention as a strategy to contribute to reducing the need for organ/tissue transplantation among minorities in the United States. The study targeted students (youth) and adults representing different ethnic groups (African-Americans, Alaskan Natives, Filipinos, Latinos, and Native Americans) who attended health education presentations addressing organ tissue donation, transplantation, and illness prevention in 15 different cities in churches, schools, and other sites. A cross-sectional study that used questionnaires was designed for collecting data from all participants. This article presents data on the adult sample only. Preintervention and postintervention data were collected from 914 adult participants to determine any immediate effects of the intervention. By using data from matched sets of the preintervention and postintervention questionnaires for all adult participants, there were significant increases in (P < or =.000) trust in doctors, future plans to become organ donors, and in participants' spiritual/religious beliefs about organ/tissue donation. There was also a significant increase (P <.05) in participants' awareness of the perceived need for organ/tissue donation. African-American participants were significantly more likely (P < or =.000) to report trust in doctors, future plans to donate organs/tissue, and perceive the need for donation as a result of MOTTEP presentation. Caucasian participants showed a significant increase (P < or =.007) in trust in doctors, perceived need for organ donation (P < or =.05), and in shifting spiritual/religious beliefs about organ/tissue donation (P < or =.02). Attitudes, knowledge, beliefs, and behavioral intentions about organ/tissue donation and illness prevention can be affected by culturally appropriate health education programs designed for targeted population groups. Sustained changes in behavioral intentions toward organ donation and illness prevention may require multiple educational interventions in different community settings to increase donation rates and improve behavioral health practices to prevent illness.

Adult↗

Cost effectiveness of cardiovascular disease prevention strategies: a perspective on EU food based dietary guidelines.

For policymakers considering strategy options for the prevention of cardiovascular disease (CVD) the distinction between effectiveness and cost effectiveness is critical. When cost limitations apply, an evaluation of cost effectiveness is essential if a rational decision is to be made. Policy changes and resource reallocation have opportunity costs, and therefore it is necessary to compare the cost of health gains achievable by means of different policies. Here the broad question is: How cost effective are diet change strategies compared to other measures aimed at reducing cardiovascular disease in EU member states? An overview of published studies of cost-effectiveness in the primary and secondary prevention of cardiovascular disease was conducted. Few comprehensive studies were available. Estimated costs per life year gained were as follows: population-based healthy eating Pound Sterling 14-560; smoking cessation Pound Sterling 300-790; nurse screening and life style advice Pound Sterling 900 (minimum); simvastatin (HMGCoA reductase inhibitor) Pound Sterling 6200-11,300. Cost effectiveness is dependent on the underlying level of CVD risk in the target population, and the duration of the achieved alterations in behaviours and risk factors. The limited evidence from these studies tends to support the view that health protection strategies which promote healthy eating are likely to be more cost-effective than strategies involving modern cholesterol-lowering drugs, screening and advice in primary care, and are comparable to or less expensive per year of life saved than anti-smoking strategies. Given the considerable diversity in food habits, health care and public health systems among current and prospective EU member states, careful appraisal of the policy options within each member state is desirable to ensure that health gain is maximised. EU wide food based dietary guidelines are potentially the basis of large health gains in Europe, and cost-effectiveness studies tend to support their adoption.

Cardiovascular Diseases↗

Trends in incidence, case-fatality rate, and severity of stroke in northern Sweden, 1985-1991.

UNLABELLED: BACKGROUND AND PURPOSE--Incidence, case-fatality rate at 28 days, and severity of acute stroke were recorded for 7 years in a large population-based stroke register to understand the reasons for the decline in stroke mortality in northern Sweden. METHODS: Within the framework of the World Health Organization MONICA Project, acute stroke was monitored in people aged 35 to 74 years in northern Sweden from 1985 through 1991 (target population in 1985, 238,948). RESULTS: The annual incidence of stroke decreased by an average of 2.3%/y in men aged 35 to 64 years (P = .074) and increased significantly by 1.1%/y in men aged 65 to 74 years (P = .041). No significant changes in incidence occurred in either age group in women. The 28-day case-fatality rate in first-ever strokes (both sexes together) declined from 21.9% to 15.4% in patients aged 65 to 74 years (P = .02). Among survivors, the proportion with extensive motor deficits (at any time during the first 28 days) declined in patients younger than 65 years as well as in those older than 65 years (P = .007 and P = .019, respectively). In patients aged 35 to 64 years, the proportion with aphasia/dysphasia also decreased significantly (P = .032), but no such trend was seen in those aged 65 to 74 years. CONCLUSIONS: A shift toward higher ages has been noted in the occurrence of first-ever strokes in men, while incidence has remained unchanged in women. During the 7 years of observation, stroke has become a less severe disease.

Adult↗

Defining and counting the chronically mentally ill.

The shifts in the pattern and locus of mental health care arising from the deinstitutionalization movement have resulted in a lack of definitive information on the scope of the problem of chronic mental illness. In addition, there is a lack of consensus on the boundaries that define the chronically mentally ill population, boundaries that can guide national policy-makers in a more scientific assessment of needs. In a national study following up the recommendations of the President's Commission on Mental Health, the authors developed a detailed definition of the chronically mentally ill population based on diagnosis, disability, duration of illness, and the institutional and community settings in which chronic mental patients may be found. They used prevalence data from a number of sources to arrive at a national estimate of between 1.7 million and 2.4 million in the target population, including 900,000 in institutions.

Chronic Disease↗

Street outreach with no streets.

A street nurse position in the rural and small-town interior of British Columbia has been addressing the needs of street-involved or otherwise marginalized client populations by bringing healthcare services to wherever those clients are, rather than waiting for the clients to seek care. The primary reason for a street outreach approach is that marginalized populations face a variety of barriers to accessing traditional healthcare services--barriers such as homelessness, mental health problems, criminal involvement, lack of transportation, lack of ability to pay for prescriptions, lack of specialized or knowledgeable providers and provider discrimination. In the rural street nurse program, the target population includes the usual street nurse populations of illegal drug users and sex trade workers, which are more hidden in small communities than in larger urban centres, creating the community denial that is a barrier to healthcare access. Yet another barrier is the co-locaton of services common in small communities, where public health clinics might share a building with police services, making marginalized clients reluctant to attend clinics. The rural street nurse collaborates with public health nurses and other care providers (mental health workers, social workers, etc) with collegial advice and support, making and receiving referrals, and generally assisting one another--the street nurse through his rapport with the marginalized individuals and the others with their specialized knowledge. Rural street services are delivered whereverthe clientsfeel comfortable: a school, a drop-in centre, a mall, a youth centre or simplythe street. Services provided include sexually transmitted infection testing, chlamydia treatments, pregnancy testing emergency contraception pills and assistance with filling out forms for financial support. Accordingly, the street nurse's truck is equipped as a mobile treatment centre and office, with a cellphone and a stock of testing and treatment supplies.

Canada↗

Antigen-specific CD8+ T cells switch the immune response induced by antigen from an IgG to a cell-mediated mode.

We have developed an in vivo/in vitro immunization procedure with xenogeneic RBC as Ag that results in the generation of a lymphoid population that expresses potent delayed-type hypersensitivity (DTH) and produces little, if any, antibody. This lymphoid population contains Ag-specific CD8+ T cells that can inhibit the induction of a strong IgG response. These CD8+ T cells are shown to not only inhibit the antibody response in an Ag-specific manner but allow the Ag to induce cells of the target population to express DTH. Furthermore, the Ag-specific inhibition of the antibody response and the Ag-specific enhancement of the induction of DTH appear to be coordinately regulated, as the same number of CD8+ T cells cells is required to achieve both effects. Thus these CD8+ T cells are shown to switch the response induced by Ag from a humoral to a cell-mediated mode. These regulatory characteristics are consistent with a physiologic role for these cells of ensuring the absence of antibody production during a strong, cell-mediated response.

Animals↗

Forecasting need and demand for home health care: a selective review.

THREE MODELS FOR FORECASTING HOME HEALTH CARE (HHC) NEEDS ARE ANALYZED: HSA/SP model (Health Systems Agency of Southwestern Pennsylvania); Florida model (Florida State Department of Health and Rehabilitative Services); and Rhode Island model (Rhode Island Department of Community Affairs). A utilization approach to forecasting is also presented.In the HSA/SP and Florida models, need for HHC is based on a certain proportion of (a) hospital admissions and (b) patients entering HHC from other sources. The major advantage of these models is that they are relatively easy to use and explain; their major weaknesses are an imprecise definition of need and an incomplete model specification.The Rhode Island approach defines need for HHC in terms of the health status of the population as measured by chronic activity limitations. The major strengths of this approach are its explicit assumptions and its emphasis on consumer needs. The major drawback is that it requires considerable local area data.The utilization approach is based on extrapolation from observed utilization experience of the target population. Its main limitation is that it is based on current market imperfections; its major advantage is that it exposes existing deficiencies in HHC.The author concludes that each approach should be tested empirically in order to refine it, and that need and demand approaches be used jointly in the planning process.

Aged↗

Evaluation of the accuracy of serum MMP-9 as a test for colorectal cancer in a primary care population.

BACKGROUND: Bowel cancer is common and is a major cause of death. Meta-analysis of randomised controlled trials estimates that screening for colorectal cancer using faecal occult blood (FOB) test reduces mortality from colorectal cancer by 16%. However, FOB testing has a low positive predictive value, with associated unnecessary cost, risk and anxiety from subsequent investigation, and is unacceptable to a proportion of the target population. Increased levels of an enzyme called matrix metalloproteinase 9 (MMP-9) have been found to be associated with colorectal cancer, and this can be measured from a blood sample. Serum MMP-9 is potentially an accurate, low risk and cost-effective population screening tool. This study aims to evaluate the accuracy of serum MMP-9 as a test for colorectal cancer in a primary care population. METHODS/DESIGN: People aged 50 to 69 years, who registered in participating general practices in the West Midlands Region, will be asked to complete a questionnaire that asks about symptoms. Respondents who describe any colorectal symptoms (except only abdominal bloating and/or anal symptoms) and are prepared to provide a blood sample for MMP9 estimation and undergo a colonoscopy (current gold standard investigation) will be recruited at GP based clinics by a research nurse. Those unfit for colonoscopy will be excluded. Colonoscopies will be undertaken in dedicated research clinics. The accuracy of MMP-9 will be assessed by comparing the MMP-9 level with the colonoscopy findings, and the combination of factors (e.g. symptoms and MMP-9 level) that best predict a diagnosis of malignancy (invasive disease or polyps) will be determined. DISCUSSION: Colorectal cancer is a major cause of morbidity and mortality. Most colorectal cancers arise from adenomas and there is a period for early detection by screening, but available tests have risks, are unacceptable to many, have high false positive rates or are expensive. This study will establish the potential of serum MMP-9 as a screening test for colorectal cancer. If it is confirmed as accurate and acceptable, this serum marker has the potential to assist with reducing the morbidity and mortality from colorectal cancer.

Aged↗

Population-based study of the incidence of Shigella diarrhea and causative serotypes in Santiago, Chile.

BACKGROUND: Shigella is an important cause of diarrheal disease in children in developing countries. The increasing prevalence of antibiotic-resistant strains has stimulated interest in the use of multivalent Shigella vaccines. Because Shigella vaccines under development are based on eliciting immunity to O antigens, monitoring the distribution of serotypes in defined target populations is critical. We initiated health center-based surveillance in a poor semirural community in Colina, Santiago (7489 children <60 months of age) to determine the age-specific incidence of Shigella disease and the responsible serotypes. FINDINGS: Surveillance was maintained at the 2 health centers during warm seasons (November 1 through April 30) for 4 successive years (1994 to 1998). Shigella was recovered from 54 of 243 cases of dysentery (22%) and from 215 of 3966 cases of nondysenteric diarrhea (5.4%) (P < 0.001). The peak mean annual incidence of shigellosis occurred among children 12 to 47 months of age (9.0 to 12.6 cases/10(3) children), although the incidence in infants (5.2/10(3)) and children 48 to 59 months of age (6.2/10(3)) was also substantial. During the 1995 through 1996 season, an age-matched healthy control was cultured for every child <60 months of age with diarrhea. Shigella isolation from cases (34 of 576, 5.9%) was >8-fold higher than controls (4 of 576, 0.7%) (P < 0.01). Four serotypes, Shigella sonnei (45%), Shigella flexneri 2b (19%), S. flexneri 2a (14%) and S. flexneri 6 (11%), accounted for 89% of all cases. INTERPRETATION: Shigella remains an important pediatric pathogen in Santiago. The serotype distribution from Colina, which closely resembles data from a population-based surveillance study in Santiago in the mid-1980s, demonstrates a remarkable degree of serotype stability in Santiago during a 15-year period.

Case-Control Studies↗

Blood rheology associated with cardiovascular risk factors and chronic cardiovascular diseases: results of an epidemiologic cross-sectional study.

As part of an epidemiologic cross-sectional study to determine cardiovascular (CV) risk factors in the population (total serum cholesterol, smoking, blood pressure, and body weight) hemoglobin (Hb) and plasma viscosity (PV) were measured. A two-stage cluster sample of 5,312 persons, aged twenty-five to sixty-four (available 5,069) was selected from a mixed urban-rural target population of 282,279 inhabitants, from which 4,022 (79.3%) participated in the study. Patients with chronic myocardial infarction (MI), cerebral infarction (CI), angina pectoris (AP), and peripheral arterial disease (PAD) were identified by questionnaire. The results show that there is no age or sex dependency of PV in healthy participants, while hemoglobin shows the well-known sex difference. In contrast, PV increases continuously with age in the total population. In men, increased PV is found in untreated hypertension, in hypercholesterolemia, and in smokers. In women, it is raised in hypercholesterolemia and in gross obesity. Male MI patients and patients of both sexes after CI in particular show statistically significantly elevated PV. Finally, in male patients with chronic AP or patients of both sexes with PAD, PV is elevated and a tendency to higher Hb values is seen. These results confirm smaller clinical trials suggesting that blood fluidity is pathologically altered in patients with CV risk factors or diseases. Since impaired blood fluidity may worsen the hemodynamic situation, in particular in patients with limited vasomotor reserve, hemorheologic parameters may be of prognostic relevance. Therapeutic implications of these findings should be considered.

Adult↗

Association of IGF-I levels with muscle strength and mobility in older women.

The functional consequences of the age-associated decline in IGF-I are unknown. We hypothesized that low IGF-I levels in older women would be associated with poor muscle strength and mobility. We assessed this question in a population representative of the full spectrum of health in the community, obtaining serum IGF-I levels from women aged 70-79 yr, enrolled in the Women's Health and Aging Study I or II. Cross-sectional analyses were performed using 617 women with IGF-I levels drawn within 90 d of measurement of outcomes. After adjustment for age, there was an association between IGF-I and knee extensor strength (P = 0.004), but not anthropometry or other strength measures. We found a positive relationship between IGF-I levels and walking speed for IGF-I levels below 50 microg/liter (P < 0.001), but no relationship above this threshold. A decline in IGF-I level was associated with self-reported difficulty in mobility tasks. All findings were attenuated after multivariate adjustment. In summary, in a study population including frail and healthy older women, low IGF-I levels were associated with poor knee extensor muscle strength, slow walking speed, and self-reported difficulty with mobility tasks. These findings suggest a role for IGF-I in disability as well as a potential target population for interventions to raise IGF-I levels.

Activities of Daily Living↗