#### The Statistical Analysis of Failure Time Data

Preface.1. Introduction.1.1 Failure Time Data.1.2 Failure Time Distributions.1.3 Time Origins, Censoring, and Truncation.1.4 Estimation of the Survivor Function.1.5 Comparison of Survival Curves.1.6 Generalizations to Accommodate Delayed Entry.1.7 Counting Process Notation.Bibliographic Notes.Exercises and Complements.2. Failure Time Models.2.1 Introduction.2.2 Some Continuous Parametric Failure Time Models.2.3 Regression Models.2.4 Discrete Failure Time Models.Bibliographic Notes.Exercises and Complements.3. Inference in Parametric Models and Related Topics.3.1 Introduction.3.2 Censoring Mechanisms.3.3 Censored Samples from an Exponential Distribution.3.4 Large-Sample Likelihood Theory.3.5 Exponential Regression.3.6 Estimation in Log-Linear Regression Models.3.7 Illustrations in More Complex Data Sets.3.8 Discrimination Among Parametric Models.3.9 Inference with Interval Censoring.3.10 Discussion.Bibliographic Notes.Exercises and Complements.4. Relative Risk (Cox) Regression Models.4.1 Introduction.4.2 Estimation of beta.4.3 Estimation of the Baseline Hazard or Survivor Function.4.4 Inclusion of Strata.4.5 Illustrations.4.6 Counting Process Formulas. 4.7 Related Topics on the Cox Model.4.8 Sampling from Discrete Models.Bibliographic Notes.Exercises and Complements.5. Counting Processes and Asymptotic Theory.5.1 Introduction.5.2 Counting Processes and Intensity Functions.5.3 Martingales.5.4 Vector-Valued Martingales.5.5 Martingale Central Limit Theorem.5.6 Asymptotics Associated with Chapter 1.5.7 Asymptotic Results for the Cox Model.5.8 Asymptotic Results for Parametric Models.5.9 Efficiency of the Cox Model Estimator.5.10 Partial Likelihood Filtration.Bibliographic Notes.Exercises and Complements.6. Likelihood Construction and Further Results.6.1 Introduction.6.2 Likelihood Construction in Parametric Models.6.3 Time-Dependent Covariates and Further Remarks on Likelihood Construction.6.4 Time Dependence in the Relative Risk Model.6.5 Nonnested Conditioning Events.6.6 Residuals and Model Checking for the Cox Model.Bibliographic Notes.Exercises and Complements.7. Rank Regression and the Accelerated Failure Time Model.7.1 Introduction.7.2 Linear Rank Tests.7.3 Development and Properties of Linear Rank Tests.7.4 Estimation in the Accelerated Failure Time Model.7.5 Some Related Regression Models.Bibliographic Notes.Exercises and Complements.8. Competing Risks and Multistate Models.8.1 Introduction.8.2 Competing Risks.8.3 Life-History Processes.Bibliographic Notes.Exercises and Complements.9. Modeling and Analysis of Recurrent Event Data.9.1 Introduction.9.2 Intensity Processes for Recurrent Events.9.3 Overall Intensity Process Modeling and Estimation.9.4 Mean Process Modeling and Estimation.9.5 Conditioning on Aspects of the Counting Process History.Bibliographic Notes.Exercises and Complements.10. Analysis of Correlated Failure Time Data.10.1 Introduction.10.2 Regression Models for Correlated Failure Time Data.10.3 Representation and Estimation of the Bivariate Survivor Function.10.4 Pairwise Dependency Estimation.10.5 Illustration: Australian Twin Data.10.6 Approaches to Nonparametric Estimation of the Bivariate Survivor Function.10.7 Survivor Function Estimation in Higher Dimensions.Bibliographic Notes.Exercises and Complements.11. Additional Failure Time Data Topics.11.1 Introduction.11.2 Stratified Bivariate Failure Time Analysis.11.3 Fixed Study Period Survival Studies.11.4 Cohort Sampling and Case-Control Studies.11.5 Missing Covariate Data.11.6 Mismeasured Covariate Data.11.7 Sequential Testing with Failure Time Endpoints.11.8 Bayesian Analysis of the Proportional Hazards Model.11.9 Some Analyses of a Particular Data Set.Bibliographic Notes.Exercises and Complements.Glossary of Notation.Appendix A: Some Sets of Data.Appendix B: Supporting Technical Material.Bibliography.Author Index.Subject Index.

#### The Statistical Analysis of Failure Time Data

Chapter 5, “Inference Procedures for Log-Location-Scale Distributions,” is concerned with likelihood-based inference under various censoring schemes for the important case where the logarithm of the lifetime is modeled with a location-scale distribution. The Weibull, extreme value, lognormal, and loglogistic distributions are discussed. In addition, two distributions with an additional parameter, the generalized log-Burr and the generalized log-gamma, are discussed. Chapter 6, “Parametric Regression Models,” presents models where one or more distribution parameters are modeled as a linear function of some regression parameters. The most popular of such models, the accelerated failure time model, where the location parameter in a location-scale distribution is modeled as a linear function of regression parameters, is discussed in detail. Extensions of this model in which the distribution is allowed to be the generalized log-Burr or the generalized log-gamma and the scale parameter is modeled with regression parameters are discussed. Also discussed in detail are graphical modelchecking techniques for assessing regression model t. Chapter 7, “Semiparametric Multiplicative Hazards Regression Models,” focuses on the proportional hazards model. Chapter 8, “Rank-Type and Other Semiparametric Procedures for Log-Location-Scale Models,” presents the accelerated failure time analog to the models of Chapter 7. The regression model has a location-scale form, but no speci c distribution is assumed. Chapter 9, “Multiple Modes of Failure,” gives a careful treatment of the analysis of data when failures can occur due to multiple failure modes. Chapter 10, “Goodness-of-Fit Tests,” begins with a general discussion of methods for testing goodness of t. Some speci c tests of t for the exponential, Weibull, extreme value, normal, and lognormal are then presented for the case of type 2 censoring or complete data. Tests of t in regression models are brie y discussed. Simulation methods for overcoming restrictions on the testing procedures are discussed in each case. Finally, Chapter 11, “Beyond Univariate Survival Analysis,” introduces multivariate lifetime data, discussing clustered lifetimes, event history data, and data where an internal process is related to the lifetime of interest. For those working with reliability data, the books by Meeker and Escobar (1998) or Nelson (1982) may be more useful as primary references because of their emphasis on engineering methodology and applications. However, this book complements the other references well, and merits a place on the bookshelf of anyone concerned with the analysis of lifetime data from any eld.

#### Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy.

BACKGROUND Diabetic nephropathy is the leading cause of end-stage renal disease. Interruption of the renin-angiotensin system slows the progression of renal disease in patients with type 1 diabetes, but similar data are not available for patients with type 2, the most common form of diabetes. We assessed the role of the angiotensin-II-receptor antagonist losartan in patients with type 2 diabetes and nephropathy. METHODS A total of 1513 patients were enrolled in this randomized, double-blind study comparing losartan (50 to 100 mg once daily) with placebo, both taken in addition to conventional antihypertensive treatment (calcium-channel antagonists, diuretics, alpha-blockers, beta-blockers, and centrally acting agents), for a mean of 3.4 years. The primary outcome was the composite of a doubling of the base-line serum creatinine concentration, end-stage renal disease, or death. Secondary end points included a composite of morbidity and mortality from cardiovascular causes, proteinuria, and the rate of progression of renal disease. RESULTS A total of 327 patients in the losartan group reached the primary end point, as compared with 359 in the placebo group (risk reduction, 16 percent; P=0.02). Losartan reduced the incidence of a doubling of the serum creatinine concentration (risk reduction, 25 percent; P=0.006) and end-stage renal disease (risk reduction, 28 percent; P=0.002) but had no effect on the rate of death. The benefit exceeded that attributable to changes in blood pressure. The composite of morbidity and mortality from cardiovascular causes was similar in the two groups, although the rate of first hospitalization for heart failure was significantly lower with losartan (risk reduction, 32 percent; P=0.005). The level of proteinuria declined by 35 percent with losartan (P<0.001 for the comparison with placebo). CONCLUSIONS Losartan conferred significant renal benefits in patients with type 2 diabetes and nephropathy, and it was generally well tolerated.

#### A Limited Memory Algorithm for Bound Constrained Optimization

An algorithm for solving large nonlinear optimization problems with simple bounds is described. It is based on the gradient projection method and uses a limited memory BFGS matrix to approximate the Hessian of the objective function. It is shown how to take advantage of the form of the limited memory approximation to implement the algorithm efficiently. The results of numerical tests on a set of large problems are reported.

#### Epidemiology of sarcopenia among the elderly in New Mexico.

Muscle mass decreases with age, leading to "sarcopenia," or low relative muscle mass, in elderly people. Sarcopenia is believed to be associated with metabolic, physiologic, and functional impairments and disability. Methods of estimating the prevalence of sarcopenia and its associated risks in elderly populations are lacking. Data from a population-based survey of 883 elderly Hispanic and non-Hispanic white men and women living in New Mexico (the New Mexico Elder Health Survey, 1993-1995) were analyzed to develop a method for estimating the prevalence of sarcopenia. An anthropometric equation for predicting appendicular skeletal muscle mass was developed from a random subsample (n = 199) of participants and was extended to the total sample. Sarcopenia was defined as appendicular skeletal muscle mass (kg)/height2 (m2) being less than two standard deviations below the mean of a young reference group. Prevalences increased from 13-24% in persons under 70 years of age to >50% in persons over 80 years of age, and were slightly greater in Hispanics than in non-Hispanic whites. Sarcopenia was significantly associated with self-reported physical disability in both men and women, independent of ethnicity, age, morbidity, obesity, income, and health behaviors. This study provides some of the first estimates of the extent of the public health problem posed by sarcopenia.

#### What Is Agency?1

This article aims (1) to analytically disaggregate agency into its several component elements (though these are interrelated empirically), (2) to demonstrate the ways in which these agentic dimensions interpenetrate with forms of structure, and (3) to point out the implications of such a conception of agency for empirical research. The authors conceptualize agency as a temporally embedded process of social engagement, informed by the past (in its “iterational” or habitual aspect) but also oriented toward the future (as a “projective” capacity to imagine alternative possibilities) and toward the present (as a “practical‐evaluative” capacity to contextualize past habits and future projects within the contingencies of the moment).

#### SNOPT: An SQP Algorithm for Large-Scale Constrained Optimization

Sequential quadratic programming (SQP) methods have proved highly effective for solving constrained optimization problems with smooth nonlinear functions in the objective and constraints. Here we consider problems with general inequality constraints (linear and nonlinear). We assume that first derivatives are available and that the constraint gradients are sparse. We discuss an SQP algorithm that uses a smooth augmented Lagrangian merit function and makes explicit provision for infeasibility in the original problem and the QP subproblems. SNOPT is a particular implementation that makes use of a semidefinite QP solver. It is based on a limited-memory quasi-Newton approximation to the Hessian of the Lagrangian and uses a reduced-Hessian algorithm (SQOPT) for solving the QP subproblems. It is designed for problems with many thousands of constraints and variables but a moderate number of degrees of freedom (say, up to 2000). An important application is to trajectory optimization in the aerospace industry. Numerical results are given for most problems in the CUTE and COPS test collections (about 900 examples).

#### The Agency for Healthcare Research and Quality

The mission of the Agency for Healthcare Research and Quality is “to improve the quality, safety, efficiency, and effectiveness of health care for all Americans”. The organization and selected major activities of the Agency are briefly described.

#### Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial

BACKGROUND Everolimus (RAD001) is an orally administered inhibitor of the mammalian target of rapamycin (mTOR), a therapeutic target for metastatic renal cell carcinoma. We did a phase III, randomised, double-blind, placebo-controlled trial of everolimus in patients with metastatic renal cell carcinoma whose disease had progressed on vascular endothelial growth factor-targeted therapy. METHODS Patients with metastatic renal cell carcinoma which had progressed on sunitinib, sorafenib, or both, were randomly assigned in a two to one ratio to receive everolimus 10 mg once daily (n=272) or placebo (n=138), in conjunction with best supportive care. Randomisation was done centrally via an interactive voice response system using a validated computer system, and was stratified by Memorial Sloan-Kettering Cancer Center prognostic score and previous anticancer therapy, with a permuted block size of six. The primary endpoint was progression-free survival, assessed via a blinded, independent central review. The study was designed to be terminated after 290 events of progression. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00410124. FINDINGS All randomised patients were included in efficacy analyses. The results of the second interim analysis indicated a significant difference in efficacy between arms and the trial was thus halted early after 191 progression events had been observed (101 [37%] events in the everolimus group, 90 [65%] in the placebo group; hazard ratio 0.30, 95% CI 0.22-0.40, p<0.0001; median progression-free survival 4.0 [95% CI 3.7-5.5] vs 1.9 [1.8-1.9] months). Stomatitis (107 [40%] patients in the everolimus group vs 11 [8%] in the placebo group), rash (66 [25%] vs six [4%]), and fatigue (53 [20%] vs 22 [16%]) were the most commonly reported adverse events, but were mostly mild or moderate in severity. Pneumonitis (any grade) was detected in 22 (8%) patients in the everolimus group, of whom eight had pneumonitis of grade 3 severity. INTERPRETATION Treatment with everolimus prolongs progression-free survival relative to placebo in patients with metastatic renal cell carcinoma that had progressed on other targeted therapies.

#### Stewardship Theory or Agency Theory: CEO Governance and Shareholder Returns

Agency theory argues that shareholder interests require protection by separation of incumbency of rôles of board chair and CEO. Stewardship theory argues shareholder interests are maximised by shared incumbency of these rôles. Results of an empirical test fail to support agency theory and provide some support for stewardship theory.

#### Coronary-artery calcification in young adults with end-stage renal disease who are undergoing dialysis.

BACKGROUND Cardiovascular disease is common in older adults with end-stage renal disease who are undergoing regular dialysis, but little is known about the prevalence and extent of cardiovascular disease in children and young adults with end-stage renal disease. METHODS We used electron-beam computed tomography (CT) to screen for coronary-artery calcification in 39 young patients with end-stage renal disease who were undergoing dialysis (mean [+/-SD] age, 19+/-7 years; range, 7 to 30) and 60 normal subjects 20 to 30 years of age. In those with evidence of calcification on CT scanning, we determined its extent. The results were correlated with the patients' clinical characteristics, serum calcium and phosphorus concentrations, and other biochemical variables. RESULTS None of the 23 patients who were younger than 20 years of age had evidence of coronary-artery calcification, but it was present in 14 of the 16 patients who were 20 to 30 years old. Among those with calcification, the mean calcification score was 1157+/-1996, and the median score was 297. By contrast, only 3 of the 60 normal subjects had calcification. As compared with the patients without coronary-artery calcification, those with calcification were older (26+/-3 vs. 15+/-5 years, P<0.001) and had been undergoing dialysis for a longer period (14+/-5 vs. 4+/-4 years, P< 0.001). The mean serum phosphorus concentration, the mean calcium-phosphorus ion product in serum, and the daily intake of calcium were higher among the patients with coronary-artery calcification. Among 10 patients with calcification who underwent follow-up CT scanning, the calcification score nearly doubled (from 125+/-104 to 249+/-216, P=0.02) over a mean period of 20+/-3 months. CONCLUSIONS Coronary-artery calcification is common and progressive in young adults with end-stage renal disease who are undergoing dialysis.

#### The Statistical Analysis of Failure Time Data

Preface.1. Introduction.1.1 Failure Time Data.1.2 Failure Time Distributions.1.3 Time Origins, Censoring, and Truncation.1.4 Estimation of the Survivor Function.1.5 Comparison of Survival Curves.1.6 Generalizations to Accommodate Delayed Entry.1.7 Counting Process Notation.Bibliographic Notes.Exercises and Complements.2. Failure Time Models.2.1 Introduction.2.2 Some Continuous Parametric Failure Time Models.2.3 Regression Models.2.4 Discrete Failure Time Models.Bibliographic Notes.Exercises and Complements.3. Inference in Parametric Models and Related Topics.3.1 Introduction.3.2 Censoring Mechanisms.3.3 Censored Samples from an Exponential Distribution.3.4 Large-Sample Likelihood Theory.3.5 Exponential Regression.3.6 Estimation in Log-Linear Regression Models.3.7 Illustrations in More Complex Data Sets.3.8 Discrimination Among Parametric Models.3.9 Inference with Interval Censoring.3.10 Discussion.Bibliographic Notes.Exercises and Complements.4. Relative Risk (Cox) Regression Models.4.1 Introduction.4.2 Estimation of beta.4.3 Estimation of the Baseline Hazard or Survivor Function.4.4 Inclusion of Strata.4.5 Illustrations.4.6 Counting Process Formulas. 4.7 Related Topics on the Cox Model.4.8 Sampling from Discrete Models.Bibliographic Notes.Exercises and Complements.5. Counting Processes and Asymptotic Theory.5.1 Introduction.5.2 Counting Processes and Intensity Functions.5.3 Martingales.5.4 Vector-Valued Martingales.5.5 Martingale Central Limit Theorem.5.6 Asymptotics Associated with Chapter 1.5.7 Asymptotic Results for the Cox Model.5.8 Asymptotic Results for Parametric Models.5.9 Efficiency of the Cox Model Estimator.5.10 Partial Likelihood Filtration.Bibliographic Notes.Exercises and Complements.6. Likelihood Construction and Further Results.6.1 Introduction.6.2 Likelihood Construction in Parametric Models.6.3 Time-Dependent Covariates and Further Remarks on Likelihood Construction.6.4 Time Dependence in the Relative Risk Model.6.5 Nonnested Conditioning Events.6.6 Residuals and Model Checking for the Cox Model.Bibliographic Notes.Exercises and Complements.7. Rank Regression and the Accelerated Failure Time Model.7.1 Introduction.7.2 Linear Rank Tests.7.3 Development and Properties of Linear Rank Tests.7.4 Estimation in the Accelerated Failure Time Model.7.5 Some Related Regression Models.Bibliographic Notes.Exercises and Complements.8. Competing Risks and Multistate Models.8.1 Introduction.8.2 Competing Risks.8.3 Life-History Processes.Bibliographic Notes.Exercises and Complements.9. Modeling and Analysis of Recurrent Event Data.9.1 Introduction.9.2 Intensity Processes for Recurrent Events.9.3 Overall Intensity Process Modeling and Estimation.9.4 Mean Process Modeling and Estimation.9.5 Conditioning on Aspects of the Counting Process History.Bibliographic Notes.Exercises and Complements.10. Analysis of Correlated Failure Time Data.10.1 Introduction.10.2 Regression Models for Correlated Failure Time Data.10.3 Representation and Estimation of the Bivariate Survivor Function.10.4 Pairwise Dependency Estimation.10.5 Illustration: Australian Twin Data.10.6 Approaches to Nonparametric Estimation of the Bivariate Survivor Function.10.7 Survivor Function Estimation in Higher Dimensions.Bibliographic Notes.Exercises and Complements.11. Additional Failure Time Data Topics.11.1 Introduction.11.2 Stratified Bivariate Failure Time Analysis.11.3 Fixed Study Period Survival Studies.11.4 Cohort Sampling and Case-Control Studies.11.5 Missing Covariate Data.11.6 Mismeasured Covariate Data.11.7 Sequential Testing with Failure Time Endpoints.11.8 Bayesian Analysis of the Proportional Hazards Model.11.9 Some Analyses of a Particular Data Set.Bibliographic Notes.Exercises and Complements.Glossary of Notation.Appendix A: Some Sets of Data.Appendix B: Supporting Technical Material.Bibliography.Author Index.Subject Index.

#### Direct conversion of fibroblasts to functional neurons by defined factors

Cellular differentiation and lineage commitment are considered to be robust and irreversible processes during development. Recent work has shown that mouse and human fibroblasts can be reprogrammed to a pluripotent state with a combination of four transcription factors. This raised the question of whether transcription factors could directly induce other defined somatic cell fates, and not only an undifferentiated state. We hypothesized that combinatorial expression of neural-lineage-specific transcription factors could directly convert fibroblasts into neurons. Starting from a pool of nineteen candidate genes, we identified a combination of only three factors, Ascl1, Brn2 (also called Pou3f2) and Myt1l, that suffice to rapidly and efficiently convert mouse embryonic and postnatal fibroblasts into functional neurons in vitro. These induced neuronal (iN) cells express multiple neuron-specific proteins, generate action potentials and form functional synapses. Generation of iN cells from non-neural lineages could have important implications for studies of neural development, neurological disease modelling and regenerative medicine.

#### Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy.

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium-glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to <90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], >300 to 5000) and were treated with renin-angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P = 0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P = 0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P = 0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years. (Funded by Janssen Research and Development; CREDENCE ClinicalTrials.gov number, NCT02065791.).

#### Exercise of Human Agency Through Collective Efficacy

Social cognitive theory adopts an agentic perspective in which individuals are producers of experiences and shapers of events. Among the mechanisms of human agency, none is more focal or pervading than the belief of personal efficacy. This core belief is the foundation of human agency. Unless people believe that they can produce desired effects and forestall undesired ones by their actions, they have little incentive to act. The growing interdependence of human functioning is placing a premium on the exercise of collective agency through shared beliefs in the power to produce effects by collective action. The present article analyzes the nature of perceived collective efficacy and its centrality in how people live their lives. Perceived collective efficacy fosters groups' motivational commitment to their missions, resilience to adversity, and performance accomplishments.

#### CAMDEX: A Standardised Instrument for the Diagnosis of Mental Disorder in the Elderly with Special Reference to the Early Detection of Dementia

A new interview schedule for the diagnosis and measurement of dementia in the elderly is described. The schedule named the Cambridge Mental Disorders of the Elderly Examination (CAMDEX), consists of three main sections: (1) A structured clinical Interview with the patient to obtain systematic information about the present state, past history and family history; (2) a range of objective cognitive tests which constitute a minineuropsychological battery; (3) a structured Interview with a relative or other Informant to obtain Independent Information about the respondent's present state, past history and family history. The CAMDEX Is acceptable to patients, has a high inter-rater reliability and the cognitive section has been shown to have high sensitivity and specificity.

#### Agency Relationships in Family Firms: Theory and Evidence

Does owner management necessarily eliminate the agency costs of ownership? Drawing on agency literature and on the economic theory of the household, we argue that private ownership and owner management expose privately held, owner-managed firms to agency threats ignored by Jensen's and Meckling's (1976) agency model. Private ownership and owner management not only reduce the effectiveness of external control mechanisms, they also expose firms to a "self-control" problem created by incentives that cause owners to take actions which "harm themselves as well as those around them" (Jensen 1994, p. 43). Thus, shareholders have incentive to invest resources in curbing both managerialand owner opportunism. We extend this thesis to the domain of the family firm. After developing hypotheses which describe how family dynamics and, specifically, altruism, exacerbate agency problems experienced by these privately held, owner-managed firms, we use data obtained from a large-scale survey of family businesses to field test our hypotheses and find evidence which suggests support for our proposed theory. Finally, we discuss the implications of our theory for research on family and other types of privately held, owner-managed firms.

#### STUDIES ON EXPERIMENTAL HYPERTENSION I. THE PRODUCTION OF PERSISTENT ELEVATION OF SYSTOLIC BLOOD PRESSURE BY MEANS OF RENAL ISCHEMIA

These experiments indicate that, in dogs at least, ischemia localized to the kidneys is a sufficient condition for the production of persistently elevated systolic blood pressure. When the constriction of both main renal arteries is made only moderately severe in the beginning, the elevation of systolic blood pressure is unaccompanied by signs of materially decreased renal function. In this respect the hypertension in these animals resembles the hypertension which is associated with so called benign nephrosclerosis in man. Subsequent increase of the constriction of the main renal arteries does not materially damage renal function, probably because of adequate development of accessory circulation. More delicate methods for detecting a change may yet prove that some damage does occur. Almost complete constriction of both main renal arteries, from the beginning, results in great elevation of systolic blood pressure which is accompanied by severe disturbance of renal function and uremia. This resembles the type of hypertension which is associated with so called malignant nephrosclerosis, in the sense of Fahr (17). In several of the animals with persistent elevation of systolic blood pressure, anatomical changes were observed in the glomeruli, vessels and parenchyma of the kidneys which are most probably directly referable to the ischemia. It is hoped that these investigations will afford a means of studying the pathogenesis of hypertension that is associated with renal vascular disease.

#### The Effects of Dietary Protein Restriction and Blood-Pressure Control on the Progression of Chronic Renal Disease

Background Restricting protein intake and controlling hypertension delay the progression of renal disease in animals. We tested these interventions in 840 patients with various chronic renal diseases. Methods In study 1, 585 patients with glomerular filtration rates of 25 to 55 ml per minute per 1.73 m2 of body-surface area were randomly assigned to a usual-protein diet or a low-protein diet (1.3 or 0.58 g of protein per kilogram of body weight per day) and to a usual- or a low-blood-pressure group (mean arterial pressure, 107 or 92 mm Hg). In study 2, 255 patients with glomerular filtration rates of 13 to 24 ml per minute per 1.73 m2 were randomly assigned to the low-protein diet (0.58 g per kilogram per day) or a very-low-protein diet (0.28 g per kilogram per day) with a keto acid-amino acid supplement, and a usual- or a low-blood-pressure group (same values as those in study 1). An 18-to-45-month follow-up was planned, with monthly evaluations of the patients. Results The mean follow-up was 2.2 years. ...

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