Data and safety monitoring in social behavioral intervention trials: the REACH II experience

Background Psychosocial and behavioral interventions trials targeting a broad range of complex social and behavioral problems such as smoking, obesity and family caregiving have proliferated in the past 30 years. At the same time the use of Data and Safety Monitoring Boards (DSMBs) to monitor the progress and quality of intervention trials and the safety of study participants has increased substantially. Most of the existing literature and guidelines for safety monitoring and reporting of adverse events focuses on medical interventions. Consequently, there is little guidance for investigators conducting social and behavior trials. Purpose This paper summarizes how issues associated with safety monitoring and adverse event reporting were handled in the Resources for Enhancing Alzheimer\u27s Caregiver Health (REACH II) program, a multi-site randomized clinical trial, funded by the National Institutes on Aging (NIA) and the National Institutes of Nursing Research (NINR), that tested the efficacy of a multicomponent social/behavioral intervention for caregivers of persons with Alzheimer\u27s disease. Methods A task force was formed to define adverse events for the trial and protocols for reporting and resolving events that occurred. The task force conducted a review of existing polices and protocols for data and safety monitoring and adverse event reporting and identified potential risks particular to the study population. An informal survey regarding data and safety monitoring procedures with investigators on psychosocial intervention trials was also conducted. Results Two categories of events were defined for both caregivers and patients; adverse events and safety alerts. A distinction was also made between events detected at baseline assessment and those detected post-randomization. Standardized protocols were also developed for the reporting and resolution of events that occurred and training of study personnel. Results from the informal survey indicated wide variability in practices for data safety and monitoring across psychosocial intervention trials. Conclusions Overall, the REACH II experience demonstrates that existing guidelines regarding safety monitoring and adverse event reporting pose unique challenges for social/behavioral intervention trials. Challenges encountered in the REACH II program included defining and classifying adverse events, defining resolution of adverse events and attributing causes for events that occurred. These challenges are highlighted and recommendations for addressing them in future studies are discussed

Evolutionary genetics of immunological supertypes reveals two faces of the Red Queen

Red Queen host-parasite co-evolution can drive adaptations of immune-genes by positive selection that erodes genetic variation (Red Queen Arms Race), or result in a balanced polymorphism (Red Queen Dynamics) and the long-term preservation of genetic variation (trans-species polymorphism). These two Red Queen processes are opposite extremes of the co-evolutionary spectrum. Here we show that both Red Queen processes can operate simultaneously, analyzing the Major Histocompatibility Complex (MHC) in guppies (Poecilia reticulata and P. obscura), and swamp guppies (Micropoecilia picta). Sub-functionalization of MHC alleles into “supertypes” explains how polymorphisms persist during rapid host-parasite co-evolution. Simulations show the maintenance of supertypes as balanced polymorphisms, consistent with Red Queen Dynamics, whereas alleles within supertypes are subject to positive selection in a Red Queen Arms Race. Building on the Divergent Allele Advantage hypothesis, we show that functional aspects of allelic diversity help to elucidate the evolution of polymorphic genes involved in Red Queen co-evolution

A CI-Independent Form of Replicative Inhibition: Turn Off of Early Replication of Bacteriophage Lambda

Several earlier studies have described an unusual exclusion phenotype exhibited by cells with plasmids carrying a portion of the replication region of phage lambda. Cells exhibiting this inhibition phenotype (IP) prevent the plating of homo-immune and hybrid hetero-immune lambdoid phages. We have attempted to define aspects of IP, and show that it is directed to repλ phages. IP was observed in cells with plasmids containing a λ DNA fragment including oop, encoding a short OOP micro RNA, and part of the lambda origin of replication, oriλ, defined by iteron sequences ITN1-4 and an adjacent high AT-rich sequence. Transcription of the intact oop sequence from its promoter, pO is required for IP, as are iterons ITN3–4, but not the high AT-rich portion of oriλ. The results suggest that IP silencing is directed to theta mode replication initiation from an infecting repλ genome, or an induced repλ prophage. Phage mutations suppressing IP, i.e., Sip, map within, or adjacent to cro or in O, or both. Our results for plasmid based IP suggest the hypothesis that there is a natural mechanism for silencing early theta-mode replication initiation, i.e. the buildup of λ genomes with oop+ oriλ+ sequence

SOCIOLOGICAL FACTORS IN HIGH BLOOD PRESSURE

High blood pressure is a silent killer and is therefore one of the most significant of the medically related problems that afflicts modern man. Approximately 25 million people living in the United States have the disease. In reality, it is not a disease in the classic meaning of that term; instead its sequelae, or subsequent effects, are diseases that are all too familiar and deadly: stroke, kidney disease and myocardial infarction (heart attack), to name just a few. In fact, there are more deaths in the United States each year attributable to the sequelae of high blood pressure than to cancer. High blood pressure is a direct consequence of the heart having to force blood through excessively constricted blood vessels. Therefore, the heart is overtaxed and can fail; furthermore, blood vessels are exposed to high pressure and therefore have the potential for sttoke, or the bursting of a blood vessel in the brain. In addition, the presence of high blood pressure accelerates the process of atherosclerosis or hardening of the arteries. Despite these clear dangers and their growing prevalence, it was not until 1967 and 1970 when it was conclusively demonstrated that the treatment of both severe and even mildly elevated blood pressure had any effect on the reduction of the various morbidities mentioned above.1.2 Now that the benefits of treatment have been documented, other problems have become apparent and demand answers from the various scientific disciplines involved in research in this field. One of these problems is the fact that the disease generally has no symptoms until end organ damage has resulted some ten or more years after the onset of even a mild form of the disease. The only way that a person knows that he/she has high blood pressure is to have the blood pressure read by use of a sphygmomanometer (a blood pressure cuff). The procedure takes approximately 30 seconds, is simple to do and painless; but in only 66 percent of physician visits was this procedure performed. 3 Once high blood pressure is documented through a series of three or four blood pressure readings, the treatment of the vast majority of cases of high blood pressure is rather simple. The patient is put on an appropriate medication which he/she will probably have to take for the rest of his/her life. While that may sound simple enough, one of the most significance problems in blood pressure control is helping the patient toward self motivation to maintain him/herself on therapy. The maintenance of such therapy is problematic because the patient is asymptomatic and occasional undesirable side effects may accompany therapy thus militating against pill taking. Some of the research to be reported on here involves this issue of patient facilitation in maintaining clinical regimens

Reading and understanding applied statistics : A Self-learning approach

xvii, 374 p.; 23 cm

Medical comorbidity in complicated grief: Results from the HEAL collaborative trial

ObjectiveTo describe medical comorbidity in persons with Complicated Grief (CG) and to test whether medical comorbidity in individuals with CG is associated with the severity and duration of CG, after adjusting for age, sex, race, and current depressive symptoms.MethodsIn exploratory analyses, we compared data from participants in an NIMH-sponsored multisite clinical trial of CG ("HEAL": "Healing Emotions After Loss") to archival data from participants matched on age, gender, and race/ethnicity, stratified by the presence or absence of current major depression. We used the Cumulative Illness Rating Scale for Geriatrics (CIRS-G) as a measure of medical polymorbidity. We investigated the association between CG and medical comorbidity via multiple linear regression, adjusting for sociodemographic and clinical variables, including severity of depressive symptoms.ResultsChronological age and severity of co-occurring symptoms of major depression correlated with cumulative medical polymorbidity in persons with Complicated Grief. The severity of CG and the time since loss did not correlate with global medical polymorbidity (CIRS-G score). Nor was there an interaction between severity of depressive symptoms and severity of CG symptoms in predicting global CIRS-G score. Cumulative medical comorbidity, as measured by CIRS-G scores, was greater in subjects with current major depression ("DEPRESSED") than in CG subjects, and both DEPRESSED and CG subjects had greater medical morbidity than CONTROLS.ConclusionMedical comorbidity is prevalent in Complicated Grief, associated with increasing age and co-occurring depressive symptoms but apparently not with chronicity and severity of Complicated Grief per se. This observation suggests that treating depression in the context of CG may be important to managing medical conditions in individuals with Complicated Grief to attenuate or prevent the long-term medical sequelae of CG