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.

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.

The utility of the CES-D as a depression screening measure among low-income women attending primary care clinics. The Center for Epidemiologic Studies-Depression.

OBJECTIVE: Depressive disorders are among the most common medical disorders seen in primary care practice. The Center for Epidemiologic Studies-Depression (CES-D) scale is one of the measures commonly suggested for detecting depression in these clinics. However, to our knowledge, there have been no previous studies examining the validity of the CES-D among low-income women attending primary care clinics. METHOD: Low-income women attending public primary care clinics (n = 179, ages 20-77) completed the CES-D and the Diagnostic Interview Schedule for the DSM-IV (DIS-IV). RESULTS: The results supported the validity of the CES-D. The standard cut-score of 16 and above yielded a sensitivity of .95 and specificity of .70 in predicting Major Depressive Disorder (MDD). However, over two-thirds of those who screened positive did not meet criteria for MDD (positive predictive value = .28). The standard cut-score appears valid, but inefficient for depression screening in this population. An elevated cut-score of 34 yielded a higher specificity (.95) and over 50 percent of the patients who screened positive had a MDD (positive predictive value = .53), but at great cost to sensitivity (.45). CONCLUSION: Results indicated that the CES-D appears to be as valid for low-income, minority women as for any other demographic group examined in the literature. Despite similar validity, the CES-D appears to be inadequate for routine screening in this population. The positive predictive value remains very low no matter which cut-scores are used. The costs of the false positive rates could be prohibitive, especially in similar public primary care settings.

A prospective study of the impact of stress on quality of life: an investigation of low-income individuals with hypertension.

The role that major and minor life events play in the quality of life in low-income hypertensives was examined. Participants were randomly recruited from 2 primary care clinics at a public medical center. The study utilized a prospective design. Participants were determined to have hypertension and were being treated with antihypertensive medication prior to and throughout the duration of the study. Participants were administered the Life Experiences Survey and the Weekly Stress Inventory repeatedly during Year 1 to assess major and minor stress, respectively. Participants were repeatedly administered the RAND 36-Item Health Survey during Year 2 to assess quality of life. Usable data were obtained from 183 patients. Analyses revealed that major and minor stress were significant predictors of all measured domains of quality of life, even after age and number of chronic illnesses were statistically controlled. Minor stress contributed uniquely to the prediction of each dimension of quality of life even when age, number of chronic illnesses, and major life events were accounted for. Findings suggest that stress has a significant, persistent impact on the quality of life of low-income patients with established hypertension. These findings extend prior research that has examined the impact of medications on quality of life and suggest that stress needs to be accounted for as well.

Utilization of medical services and quality of life among low-income patients with generalized anxiety disorder attending primary care clinics.

OBJECTIVE: Anxiety disorders appear to influence morbidity and medical utilization. However, little is known about the relationship between Generalized Anxiety Disorder, quality of life, and medical utilization, especially among low-income patients. The goals of this investigation were to 1) determine if low-income patients with GAD utilize medical services more than patients with other Axis I diagnoses, or no psychopathology, and 2) compare the health-related quality of life of these three groups. METHOD: Participants were randomly recruited from public primary care clinics and administered intake assessments of demographics, stress, and health-related self-report questionnaires. At the end of the first year a structured psychiatric interview was administered (N = 431). Over the second year, patients (n = 360) were administered a health-related quality of life measure every three months for four assessments. Medical charts were abstracted to collect information about chronic illnesses and visits to outpatient clinics and the emergency department during the two years. RESULTS: Patients were predominantly middle-aged, low-income, uninsured African-American females. In this low-income sample, patients with GAD utilized the emergency department more and reported poorer quality of life than patients with other Axis I disorders and patients without any psychopathology. CONCLUSION: Low-income patients with GAD utilize the emergency department more and report poorer quality of life than patients with other Axis I disorders and patients without any psychopathology. Programs to identify and treat patients with GAD may yield improvements in quality of life, as well as reduce emergency department utilization.

Diagnostic value of arterial blood gas measurement in suspected pulmonary embolism.

Pulmonary embolism (PE) is a common and lethal yet treatable condition. Several authors have reported on the diagnostic value of combinations of arterial blood gas (ABG) and other clinical data (i. e., prediction rules), and have claimed that these combinations can be safely used to exclude PE. The purpose of this investigation was to evaluate the diagnostic value of ABG measurement and to attempt to validate the ABG prediction rules published by these various authors for the assessment of patients with suspected PE. Two hundred ninety-three consecutive patients referred for imaging to investigate suspected PE were approached to participate in the investigation. ABG and other clinical data were obtained from consenting and eligible patients before an outcome classification (PE versus non-PE) was performed. None of the ABG data or prediction rules had sufficient negative predictive value, specificity, or likelihood ratios to be useful in the management of patients with suspected PE. We conclude that ABG data alone or in combination with other clinical data are not useful in the assessment of suspected PE.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Ozone level effect on respiratory illness: an investigation of emergency department visits.

This project examined the relationship of daily ozone (O3) levels to the number of respiratory-related emergency department (ED) visits. The confounding effects of temperature, humidity, mold, and pollen counts were examined, as were the effects of day of the week on numbers of ED visits. The design is a time-series relating concurrently measured variables that are repeatedly measured over time. Respiratory-related ED visits at three hospitals in a southern city were examined. Visits were analyzed separately for pediatric, adult, and geriatric patients. A significant association was found between elevated O3 levels and respiratory-related visits for adults. The same association was not found for pediatric or geriatric ED visits. Days with higher ozone were accompanied by higher numbers of adults going to the emergency department because of respiratory complaints. However, the effect was not large and does not appear to hold for pediatric or geriatric ED visits.

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.