RAD51 foci as a functional biomarker of homologous recombination repair and PARP inhibitor resistance in germline BRCA-mutated breast cancer.

Background: BRCA1 and BRCA2 (BRCA1/2)-deficient tumors display impaired homologous recombination repair (HRR) and enhanced sensitivity to DNA damaging agents or to poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi). Their efficacy in germline BRCA1/2 (gBRCA1/2)-mutated metastatic breast cancers has been recently confirmed in clinical trials. Numerous mechanisms of PARPi resistance have been described, whose clinical relevance in gBRCA-mutated breast cancer is unknown. This highlights the need to identify functional biomarkers to better predict PARPi sensitivity. Patients and methods: We investigated the in vivo mechanisms of PARPi resistance in gBRCA1 patient-derived tumor xenografts (PDXs) exhibiting differential response to PARPi. Analysis included exome sequencing and immunostaining of DNA damage response proteins to functionally evaluate HRR. Findings were validated in a retrospective sample set from gBRCA1/2-cancer patients treated with PARPi. Results: RAD51 nuclear foci, a surrogate marker of HRR functionality, were the only common feature in PDX and patient samples with primary or acquired PARPi resistance. Consistently, low RAD51 was associated with objective response to PARPi. Evaluation of the RAD51 biomarker in untreated tumors was feasible due to endogenous DNA damage. In PARPi-resistant gBRCA1 PDXs, genetic analysis found no in-frame secondary mutations, but BRCA1 hypomorphic proteins in 60% of the models, TP53BP1-loss in 20% and RAD51-amplification in one sample, none mutually exclusive. Conversely, one of three PARPi-resistant gBRCA2 tumors displayed BRCA2 restoration by exome sequencing. In PDXs, PARPi resistance could be reverted upon combination of a PARPi with an ataxia-telangiectasia mutated (ATM) inhibitor. Conclusion: Detection of RAD51 foci in gBRCA tumors correlates with PARPi resistance regardless of the underlying mechanism restoring HRR function. This is a promising biomarker to be used in the clinic to better select patients for PARPi therapy. Our study also supports the clinical development of PARPi combinations such as those with ATM inhibitors.

Efficacy of behavioral management and patient education on vascular access cleansing compliance in hemodialysis patients.

Compared four treatment conditions to test their ability to enhance compliance with vascular access cleansing (VAC) procedures in a group of 56 hemodialysis patients. The conditions were patient education, behavioral management with monetary incentive, patient education/behavioral management, and attention control. Behavioral observers rated VAC behavior at pretreatment, posttreatment 1-month follow-up, and 1-year follow-up. Knowledge of VAC procedures was also assessed via a questionnaire at pretreatment and posttreatment. Data were analyzed using repeated-measures multivariate analyses of variance. Results indicated that the patients in the education/behavioral, behavioral, and education groups gave significantly more correct answers on our VAC knowledge questionnaires at posttreatment than did patients in the attention control group. Further, patients in the education/behavioral and behavioral groups completed significantly more VAC steps at posttreatment and 1-month follow-up than did patients in the education group and in the attention control group. Differences were not maintained at 1-year follow-up, although more than 50% of the patients were lost to follow-up. Implications of the present findings for behavioral and educational interventions are discussed.

Factors associated with depression in a heterogeneous HIV-infected sample.

The present study examined factors contributing to depressive symptomatology in a low SES, heterogeneous HIV seropositive sample. The sample was comprised of 120 HIV-infected patients who completed psychosocial measures upon their initial visit to an outpatient HIV clinic. Length of time since HIV seropositive notification and HIV-related symptomatology were also assessed. Social support, major life stress, and HIV-related symptomatology were significantly associated with depression. Perceived availability of social support accounted for the greatest variance in depression scores. Length of time since seropositive notification was not significantly associated with depression. These findings extend previous research with middle-class, homosexual, white males to the rapidly growing minority, heterosexual, and low SES populations and point to the need for the inclusion of social support interventions in the provision of services of these individuals.

The relation of stress and depression to interdialytic weight gain in hemodialysis patients.

Nonadherence to fluid restrictions is a common problem with serious health consequences for patients with end-stage renal disease (ESRD). For the present study, the authors evaluated psychological variables of stress, as measured by major and minor life events, and depression. They sought to determine the role of these events in patients' failure to adhere to fluid restrictions as measured by increased interdialytic weight gain. Forty-two hemodialysis patients completed inventories assessing major life events, daily stressful events, and depression on three consecutive dialysis sessions. Fluid adherence was measured by interdialytic weight gain. A path analysis model found daily minor stress to have a direct effect on nonadherence, whereas there was a direct inverse effect of depression on nonadherence. Possible mechanisms and implications for future studies are discussed.

Stress and social support as predictors of dietary compliance in hemodialysis patients.

This study examined the effects of minor stress on variations in biochemical indices of dietary compliance in hemodialysis patients. Subjects completed the Schedule of Recent Events, the Weekly Stress Inventory, and the Social Support Questionnaire. In addition, two biochemical measures of dietary compliance were obtained from the patients' medical charts. Multiple regression analysis, with baseline levels of compliance and the relatively stable influence of major life events and social support controlled for, revealed that minor stress was significantly predictive of changes in dietary compliance. The results suggest that minor stress may affect health status in the chronically ill by reducing compliance behaviors.

Patient care and daily stress among emergency medical technicians.

INTRODUCTION: There is conflicting research regarding the extent to which patient care is a source of stress for emergency medical technicians (EMTs). Some research indicates that it is important, whereas other studies suggest that it takes a "back seat" to administrative and organizational problems. This study sought to explore this issue further by investigating the relationship between caring for patients, daily workday stress, and daily non-workday stress among EMTs. METHODS: All EMTs employed by East Baton Rouge Parish Emergency Medical Services were eligible for participation. After the study was described, subjects completed a demographic information sheet and informed consent was obtained. Participants then completed 30 days of monitoring with a standardized measure of daily stress (the Daily Stress Inventory) and a measure of patient care stress designed for use in this study (Emergency Call Questionnaire). RESULTS: A very large portion of the variance in the EMTs' overall daily workday stress was associated with patient care (r = 0.677, p < 0.001). Additionally, patient care stress on workdays significantly predicted overall daily stress on the following nonworkday (i.e., postworkday) (r = 0.633, p < 0.001). Finally, EMTs who had stressful pre-workdays rated their patient care as more stressful on the following workday (r = 0.512, p < 0.01). CONCLUSIONS: Results suggest that patient care is a critical factor in daily stress among EMTs, both on workdays and post-workdays, providing preliminary evidence for a carryover effect. Evidence also suggests that stress on the day before work may influence EMTs' perceptions of their patients on workdays.

Will patients use a computer to give a medical history?

BACKGROUND: A patient-entered computerized history, can be used as a means of medical data collection in a large inner city population. We evaluated whether a patient presenting to the Charity Hospital campus of the Medical Center of Louisiana in New Orleans would use a computer to provide medical information. OBJECTIVE: To determine whether patients would self-administer a computerized medical history and find this an acceptable experience DESIGN: A survey questionnaire was given to 100 patients selected from the emergency department walk-in clinic waiting area. SETTING: Charity Hospital emergency room walk-in clinic METHODS: One hundred patients older than 18 years were selected to give a random sample of the population using the Charity Hospital emergency room walk-in clinic for care. The patients received a questionnaire for rating their experience with the computer. Demographics were collected for all patients, including the 13 who declined participation. The main outcome was the patient's perception of the acceptability of using the computerized medical history. A second important outcome measure was patient refusal to participate in the study. RESULTS: Our analysis of the acceptability ratings revealed adequate internal validity (Cronbach alpha=0.75). A single total score was created for these ratings. The participants' scores ranged from 2.0 to 4.0, with a mean of 3.3 (standard error of the mean=0.04). We observed an 83% positive experience in the participating population. CONCLUSIONS: The patients were able to use the computer to enter their medical information. They responded favorably to the experience and appeared to be capable and willing to provide medical information through use of this technology.

Lafayette's family practice residency program: practice patterns of graduates.

The Lafayette Family Practice Residency Program graduated 25 physicians prior to 1995. This project was undertaken to support our assumption that graduates establish their practices in communities near their residency programs. Further we surveyed the graduates to determine graduate satisfaction and practice characteristics. The vast majority (88%) of these physicians were practicing in Louisiana at the time of this survey. Over half the graduates were practicing in Acadiana. The results suggest that these physicians are indeed satisfied in their careers as family physicians.

The Family Practice Residency in Baton Rouge: practice patterns of graduates.

One hundred twenty-four physicians have completed the Baton Rouge Family Practice Residency since 1973. Eighty-two percent of the graduates who are currently active physicians are practicing medicine in Louisiana. Most are practicing family medicine. The graduates were sent questionnaires asking about practice characteristics, office procedures performed, hospital privileges held, and career satisfaction. Responses were received from 74 family physicians serving small, medium, and large communities. Most reported they are satisfied with their career choices. The respondents perform a variety of procedures in their offices. This finding was not affected by community size. Hospital privileges were affected by community size. The residency is meeting its principal mission: (1) training family practitioners for Louisiana, and (2) training doctors to practice in any sized community.

Maximizing medication adherence in low-income hypertensives: a pilot study.

A pilot study was conducted to examine the association between free medication and comprehensive care on blood pressure control for 60 adults with uncontrolled essential hypertension (mean blood pressure = 157/96 mm Hg) referred from a variety of primary care clinics at a public teaching hospital. Subjects received comprehensive care, free antihypertensive medication dispensed in the clinic, and patient education regarding hypertension and medication compliance. Matched-pair t-tests revealed average drops in blood pressure of 22 mm Hg systolic and 13 mm Hg diastolic for the entire sample from baseline to 6 months post-enrollment (both P's < .001). The comprehensive hypertension management program with education and free medication was significantly related to reduced blood pressure across the 6 months of the study period.

Rac1 is required for Prkar1a-mediated Nf2 suppression in Schwann cell tumors.

Schwannomas are peripheral nerve sheath tumors that often occur in the setting of an inherited tumor predisposition syndrome, including neurofibromatosis types 1 (NF1) and 2 (NF2), familial schwannomatosis and Carney complex. Loss of the NF2 tumor suppressor (encoding NF2, or Merlin) is associated with upregulation of the Rac1 small GTPase, which is thought to have a key role in mediating tumor formation. In prior studies, we generated a mouse model of schwannomas by performing tissue-specific knockout (KO) of the Carney complex gene Prkar1a, which encodes the type 1A regulatory subunit of protein kinase A. These tumors exhibited down-regulation of Nf2 protein and an increase in activated Rac1. To assess the requirement for Rac1 in schwannoma formation, we generated a double KO (DKO) of Prkar1a and Rac1 in Schwann cells and monitored tumor formation. Loss of Rac1 reduced tumor formation by reducing proliferation and enhancing apoptosis. Surprisingly, the reduction of tumor formation was accompanied by re-expression of the Nf2 protein. Furthermore, activated Rac1 was able to downregulate Nf2 in vitro in a Pak-dependent manner. These in vivo data indicate that activation of Rac1 is responsible for suppression of Nf2 protein production; deficiency of Nf2 in Schwann cells leads to loss of cellular growth control and tumor formation. Further, PKA activation through mutation in Prkar1a is sufficient to initiate Rac1 signaling, with subsequent reduction of Nf2 and schwannomagenesis. Although in vitro evidence has shown that loss of Nf2 activates Rac1, our data indicate that signaling between Nf2 and Rac1 occurs in a bidirectional fashion, and these interactions are modulated by PKA.

Systemic mastocytosis presenting as profound cardiovascular collapse during anaesthesia.

Mastocytosis is a rare disorder with serious anaesthetic implications. Anaesthetic management is hazardous since trauma, stress, extremes of temperature and drugs may precipitate intra-operative mast cell degranulation. Release of histamine and other mast cell mediators can lead to profound cardiovascular collapse and even death. We present a case report of a patient with mastocytosis who suffered cardiac arrest during anaesthesia. Anaphylactoid/anaphylactic shock may be delayed and lack supporting signs of histamine release such as cutaneous flushing and bronchospasm.

The relation between daily stress and Crohn's disease.

This study examined the effect of minor daily stressors on the primary indices of Crohn's disease in 10 adult volunteers from a support group for individuals with inflammatory bowel disease. All subjects monitored the occurrence of daily stress concurrently with the signs and symptoms of their disease for 28 days. The results of the regression and between-subject analyses indicate a relation between daily stress and self-rated disease severity in Crohn's disease. The effects of daily stress on signs and symptoms of Crohn's disease were significant even after controlling for the effects of major life events. Individual within-subject correlations, however, indicated that stress and indicators of disease were highly related for only three subjects. The results of the current study therefore suggest that at least for some individuals with Crohn's disease, daily stress is related to self-reported indicators of the illness.

A Daily Stress Inventory: development, reliability, and validity.

This article describes the development of the Daily Stress Inventory, a measure introduced to provide researchers and clinicians with a psychometrically sound self-report instrument for the daily assessment of the sources and individualized impact of relatively minor stressful events. It was designed to assess sources of stress not typically assessed by major life-event scales. Generalizability coefficients indicate that the scale has significant homogeneity and a useful degree of stability. Several studies investigating the concurrent and construct validities suggest that the scale measures the construct commonly referred to as "stress." Implications for uses in theoretical and basic research as well as clinical assessment are discussed.

Modifiable high-risk behaviors for cardiovascular disease among family physicians in the United States. A national Survey.

OBJECTIVES: To study the prevalence of modifiable high-risk behaviors that contribute to mortality and morbidity from cardiovascular disease among family physicians in the United States, to examine whether these prevalence rates would differ across geographic regions of the United States, and to determine whether a family history of coronary artery disease differentiated physicians who engage in these high-risk behaviors from those who do not. DESIGN: A mailed self-report survey. SETTING: Family physician members of the American Board of Family Practice. PARTICIPANTS: The survey was mailed to 1500 randomly selected members of the American Board of Family Practice. RESULTS: The response was 62%. The results showed that 97% of the physicians were nonsmokers, 54% engaged in exercise regularly, 36% considered themselves overweight, and 91% knew their lipid profile. Of the respondents, 63% reported having a family physician, 78% reported visiting their physician as needed, and 41% reported having had a physician visit in the past year. Forty-one percent of the physicians reported having a family history of coronary artery disease. There were no notable differences regarding the prevalence of these behaviors across the 5 geographic areas or between respondents with a family history of coronary artery disease and those without such a history. CONCLUSION: Our results suggest that the respondents as a group engage in health practices that help to prevent cardiovascular disease. However, the frequency of exercise among these physicians is below the recommended level, and efforts should be made in promoting exercise among this population.

Predictors of outpatient medical appointment attendance among persons with HIV.

Non-adherence to medical regimens is a critical threat to the health of HIV-infected individuals. Patients who do not adhere to routine medical care cannot fully benefit from the increasingly efficacious treatments available to them. Consistent attendance at medical appointments plays a central role in both prolonging life and enhancing quality of life for persons living with HIV/AIDS. By identifying why many patients do not reliably attend medical services, interventions can be undertaken to improve appointment-keeping. The primary purpose of the present study was to identify factors predictive of HIV-related medical appointment attendance. One-hundred-and-forty-four outpatients in a public hospital ambulatory care HIV clinic were followed for seven months. Demographic, medical care and psychosocial factors were measured in order to prospectively predict the percentage of missed clinic appointments by persons with HIV disease. Greater outpatient appointment non-attendance was associated with younger age, minority status, less severe illness and lower perceived social support. Treatment duration, provider consistency, hopelessness and religious coping did not emerge as significant predictors of outpatient appointment-keeping in this sample. Practical and theoretical implications of these findings are discussed in light of recent medical advances in HIV/AIDS care.

Minor stressors and generalized anxiety disorder among low-income patients attending primary care clinics.

The total number of minor life events and subjective ratings of distress associated with these events were assessed for individuals with generalized anxiety disorder (GAD) and for nonanxious controls. Participants consisted of 256 randomly selected, low-income patients from primary care medical clinics. Diagnoses were obtained using the Diagnostic Interview Schedule for the DSM-IV (DIS-IV). An analysis of variance revealed that GAD individuals reported significantly more minor life events than did nonanxious controls (F = 50.97, p < .001). An analysis of covariance indicated that persons with GAD perceived their minor stressors as significantly more stressful than did nonanxious controls, even after the total number of events was controlled (F = 42.07, p < .001). These findings are consistent with cognitive theories of GAD and current revisions to the definition of the disorder in the Diagnostic and Statistical Manual of Mental Disorders (DSM). Implications for theory and research on GAD are discussed.

Practice patterns for peptic ulcer disease: are family physicians testing for H. pylori?

BACKGROUND: Peptic ulcer disease (PUD) is a problem common in family medicine. Recent evidence of Helicobacter pylori as an etiological agent of PUD has led to National Institutes of Health recommendations for treatment to eradicate H. pylori through antibiotic therapy. The purpose of this study is to examine practice patterns of family physicians in treating PUD, their use of H. pylori testing, and knowledge of current recommendations for PUD. MATERIALS AND METHODS: A mail survey was sent to a random sample of 1,500 members of the American Academy of Family Physicians. Six hundred thirty useable surveys (49.1%) were available for analysis. Descriptive statistics were obtained, as were inferential statistics focusing on the relationship of physician background characteristics to practices. RESULTS: Thirty-eight percent of the respondents order diagnostic procedures for the majority (50% or more) of their suspected PUD cases. Of the physicians who reported ordering any diagnostic tests, 52% ordered the combination of upper gastrointestinal series and endoscopic gastroduodenoscopy. For patients with clinical diagnoses of PUD, 77% of doctors reported ordering a diagnostic test for H. pylori. Approximately 68% were aware that some kind of guidelines existed; only 11% reported that they were familiar with the National Institutes of Health recommendations for PUD. CONCLUSIONS: Although some of the practices of family physicians for treatment of PUD deviate from current recommendations, the majority of practices are consistent with current evidence.