Predictability of Fall Risk Assessments in Community-Dwelling Older Adults: A Scoping Review.

Fall risk increases with age, and one-third of adults over 65 years old experience a fall annually. Due to the aging population, the number of falls and related medical costs will progressively increase. Correct prediction of who will fall in the future is necessary to timely intervene in order to prevent falls. Therefore, the aim of this scoping review is to determine the predictive value of fall risk assessments in community-dwelling older adults using prospective studies. A total of 37 studies were included that evaluated clinical assessments (questionnaires, physical assessments, or a combination), sensor-based clinical assessments, or sensor- based daily life assessments using prospective study designs. The posttest probability of falling or not falling was calculated. In general, fallers were better classified than non-fallers. Questionnaires had a lower predictive capability compared to the other assessment types. Contrary to conclusions drawn in reviews that include retrospective studies, the predictive value of physical tests evaluated in prospective studies varies largely, with only smaller-sampled studies showing good predictive capabilities. Sensor-based fall risk assessments are promising and improve with task complexity, although they have only been evaluated in relatively small samples. In conclusion, fall risk prediction using sensor data seems to outperform conventional tests, but the method's validity needs to be confirmed by large prospective studies.

Benchtop NMR for Online Reaction Monitoring of the Biocatalytic Synthesis of Aromatic Amino Alcohols.

Online analytics provides insights into the progress of an ongoing reaction without the need for extensive sampling and offline analysis. In this study, we investigated benchtop NMR as an online reaction monitoring tool for complex enzyme cascade reactions. Online NMR was used to monitor a two-step cascade beginning with an aromatic aldehyde and leading to an aromatic amino alcohol as the final product, applying two different enzymes and a variety of co-substrates and intermediates. Benchtop NMR enabled the concentration of the reaction components to be detected in buffered systems in the single-digit mM range without using deuterated solvent. The concentrations determined via NMR were correlated with offline samples analyzed via uHPLC and displayed a good correlation between the two methods. In summary, benchtop NMR proved to be a sensitive, selective and reliable method for online reaction monitoring in (multi-step) biosynthesis. In future, online analytic systems such as the benchtop NMR devices described might not only enable direct monitoring of the reaction, but may also form the basis for self-regulation in biocatalytic reactions.

Insulin Resistance is Associated with Higher Plasma Viral Load Among HIV-Positive Adults Receiving Longer-Term (1 Year) Combination Antiretroviral Therapy (ART).

Background: As HIV-positive persons survive longer due to the success of combination antiretroviral therapy (ART) in decreasing mortality, the burden of non-communicable diseases including diabetes mellitus (DM) is anticipated to rise. HIV is characterized by systemic inflammations, markers of which decrease quickly following ART initiation, but typically do not completely normalize. Inflammation may be accompanied by insulin resistance (IR), and both are implicated in the pathogenesis of DM in HIV-positive individuals. Sub-Saharan Africa accounts for almost two-thirds of the global HIV burden but there are few reports of IR, DM and HIV in this region. We assessed the relationship between IR and viral suppression among HIV-positive adults in the Zambian national ART program. Methods: We conducted a cross-sectional survey evaluating HIV-positive adults that had received first line ART (usually TDF/FTC/EFV) for 12 months (± 3 months). Twenty clinics were sampled systematically based on the random starting-point, sampling interval and cumulative population size. Eligible patients had plasma viral load (VL), fasting insulin, and glucose performed. Insulin resistance was determined using Homeostatic model assessment (HOMA). We determined proportions for each outcome using linearized standard error 95% confidence intervals and summary estimates. Viral suppression was defined according to the detection threshold of<20 copies/mL and treatment failure was defined as VL>1,000 copies/mL. Results: Of 473 patients enrolled, 46.8% were male and 53.2% were female. 142 (30%) [95% CI: 0.26-0.34] had IR. Among those with IR, 55 (38.7%) were male whereas 87 (61.3%) were female (p value=0.104). 19% of individuals with IR had treatment failure compared to 5.7% without IR (p value<0.0001). 427 (90.3%) participants had treatment success (VL<1,000 copies/mL), and this was associated with a lower likelihood of IR (odds ratio (OR)=0.26 [0.14, 0.48], p value<0.0001). In addition, a significantly lower proportion of patients with IR were virologically suppressed at one-year compared to individuals without IR, 58% [0.54-0.70] versus 70% [0.65-0.75], respectively (p value=0.042). Conclusion: In Zambian adults on ART for a year, the development of insulin resistance was strongly associated with suboptimal HIV outcomes, specifically non-viral suppression and treatment failure. Further investigations are warranted to determine if this positive association between IR and VL is causally related, and if so in which direction.

Solving ethical problems in medical settings during psychological assessment: a decisional model.

The unique culture of medical settings impacts the style, pace, and quality of psychological consultation provided in that setting. Matters of life and death and other health emergencies, relationships with the courts, and contact with severely impaired patients are typical events. Medical psychologists (MPs) share many, but not all, of the ethical values that guide provision of services by other medical professionals under such circumstances. This generates the need to develop an interdependent but independent ethical orientation on the part of MPs in all professional activities, including psychological assessment. In this article, background information is presented on values that frequently drive medical treatment that may conflict with the MPs' ethical standards. A model appropriate for use in situations requiring complex decisional processes is reviewed, and vignettes are presented as examples of bioethical problem solving under this systematic decisional framework.

Immunohistochemical study of the BCAR1/p130Cas protein in non-malignant and malignant human breast tissue.

BCAR1/p130Cas is a docking protein involved in intracellular signaling pathways and in vitro resistance of estrogen-dependent breast cancer cells to antiestrogens. The BCAR1/p130Cas protein level in primary breast cancer cytosols was found to correlate with rapid recurrence of disease. A high BCAR1/p130Cas level was also associated with a higher likelihood of resistance to first-line tamoxifen treatment in patients with advanced breast cancer. Using antibodies raised against the rat p130Cas protein, we determined by immunohistochemical methods the BCAR1/p130Cas localization in primary breast carcinomas, in tumors of stromal origin, and in non-neoplastic breast tissues. The BCAR1/p130Cas protein was detected in the cytoplasm of non-malignant and neoplastic epithelial cells and in the vascular compartment of all tissue sections analyzed. Immunohistochemistry demonstrated variable intensity of BCAR1/p130Cas staining and variation in the proportion of BCAR1/p130Cas-positive epithelial tumor cells for the different breast carcinomas. Double immunohistochemical staining for BCAR1/p130Cas and estrogen receptor confirmed coexpression in non-malignant luminal epithelial cells and malignant breast tumor cells. The stromal cells in non-malignant tissues and tumor tissues as well as breast tumors of mesodermal origin did not stain for BCAR1/p130Cas. This immunohistochemical study demonstrates a variable expression of BCAR1/p130Cas in malignant and non-malignant breast epithelial cells, which may be of benefit for diagnostic purposes.

Association of alcohol use and other high-risk behaviors among trauma patients.

BACKGROUND: Risk behaviors and psychological problems may limit recovery after trauma, may be related to injury recidivism, and may limit the effectiveness of alcohol interventions in trauma patients. The aim of the current study was to evaluate the prevalence of behaviors associated with injury and their relationship with alcohol use in adult trauma patients. METHODS: A prospective cohort of 301 adult patients admitted to a single Level I trauma center were interviewed regarding risk behaviors and alcohol use. RESULTS: There was evidence of acute and/or chronic alcohol use in 48.2% of cases. Over three fourths of patients (77%) engaged in one or more high-risk driving practices, 40% engaged in one or more violence-related behaviors, and 19% reported suicidal ideation in the last year. These risk behaviors were more common in patients who evidenced acute and/or chronic alcohol use. CONCLUSION: Behaviors that place an individual at greater risk for traumatic injury are common among seriously injured adult patients admitted to an urban Level I trauma center and frequently coexist with alcohol use. Their importance to injury, injury recidivism, and recovery after trauma requires further investigation.

Toward a redefinition of psychiatric emergency.

OBJECTIVE: To compare three methods for rating legitimate use of psychiatric emergency services (PES) in order to develop criteria that can differentiate appropriate from inappropriate PES service requests. METHOD: Ratings of PES visits by treating physicians and ratings of the same visits made during review of medical records. STUDY DESIGN: Two previously used methods of identifying justified PES service use were compared with the treating physician's rating of the same: (1) hospitalization as visit outcome and (2) retrospective chart ratings of visit characteristics using traditional medico-surgical criteria for "emergent" illness episodes. DATA EXTRACTION METHODS: Data were extracted through use of a physician questionnaire, and medical and administrative record review. PRINCIPAL FINDINGS: Agreement between the methods ranged from 47.1 percent to 74.1 percent. A total of 21.7 percent of visits were rated as true health "emergencies" by the traditional definition, while 70.4 percent of visits were rated as "necessary" by treating physicians, and 21.0 percent resulted in hospitalization. Acuteness of behavioral dyscontrol and imminent dangerousness at the time of the visit were common characteristics of appropriate use by most combinations of the three methods of rating visits. CONCLUSIONS: The rating systems employed in similar recent studies produce widely varying percentages of visits so classified. However, it does appear likely that a minimum of 25-30 percent of visits are nonemergent and could be triaged to other, less costly treatment providers. Proposed criteria by which to identify "legitimate" psychiatric emergency room treatment requests includes only patient presentations with (a) acute behavioral dyscontrol or (b) imminent dangerousness to self or others.

The nature of help-seeking during psychiatric emergency service visits by a patient and an accompanying adult.

Utilization rates for urban psychiatric emergency services remain high, and the decision to seek care in this setting is poorly understood. Three hundred individuals accompanying patients to a psychiatric emergency service were interviewed about their help seeking and choice of treatment setting. Twenty-three of the interviewees (7.7 percent) were caregivers accompanying patients with severe and persistent mental illness. They were significantly more likely than other interviewees to know the difference between psychiatric emergency services and services offered by other outpatient providers. More than half reported that the patient they accompanied was intermittently noncompliant, which required visiting either a walk-in service during a moment when the patient was cooperative or a facility equipped to provide involuntary treatment.

Complete sequencing of TP53 predicts poor response to systemic therapy of advanced breast cancer.

TP53 has been implicated in regulation of the cell cycle, DNA repair, and apoptosis. We studied, in primary breast tumors through direct cDNA sequencing of exons 2-11, whether TP53 gene mutations can predict response in patients with advanced disease to either first-line tamoxifen therapy (202 patients, of whom 55% responded) or up-front (poly)chemotherapy (41 patients, of whom 46% responded). TP53 mutations were detected in 90 of 243 (37%) tumors, and one-fourth of these mutations resulted in a premature termination of the protein. The mutations were observed in 32% (65 of 202) of the primary tumors of tamoxifen-treated patients and in 61% (25 of 41) of the primary tumors of the chemotherapy patients. TP53 mutation was significantly associated with a poor response to tamoxifen [31% versus 66%; odds ratio (OR), 0.22; 95% confidence interval (CI), 0.12-0.42; P < 0.0001]. Patients with TP53 gene mutations in codons that directly contact DNA or with mutations in the zinc-binding domain loop L3 showed the lowest response to tamoxifen (18% and 15% response rates, respectively). TP53 mutations were related, although not significantly, to a poor response to up-front chemotherapy (36% versus 63%; OR, 0.34; 95% CI, 0.09-1.24). In multivariate analysis for response including the classical parameters age and menopausal status, disease-free interval, dominant site of relapse, and levels of estrogen receptor and progesterone receptor, TP53 mutation was a significant predictor of poor response in the tamoxifen-treated group (OR, 0.29; 95% CI, 0.13-0.63; P = 0.0014). TP53-mutated and estrogen receptor-negative (<10 fmol/mg protein) tumors appeared to be the most resistant phenotype. Interestingly, the response of patients with TP53 mutations to chemotherapy after tamoxifen was not worse than that of patients without these mutations (50% versus 42%; OR, 1.35, nonsignificant). The median progression-free survival after systemic treatment was shorter for patients with a TP53 mutation than for patients with wild-type TP53 (6.6 and 0.6 months less for tamoxifen and up-front chemotherapy, respectively). In conclusion, TP53 gene mutation of the primary tumor is helpful in predicting the response of patients with metastatic breast disease to tamoxifen therapy. The type of mutation and its biological function should be considered in the analyses of the predictive value of TP53.

Prognostic value of CD44 variant expression in primary breast cancer.

CD44 is a family of cell surface transmembrane glycoproteins members which differ in the extracellular part by sequences derived by alternative splicing of 10 variant exons (v1-v10). CD44 proteins containing such variant sequences have been implicated in tumor metastasis formation. Here, we have evaluated the expression of CD44 variants by immuno-histochemistry in primary breast cancer samples of 237 node-negative and 230 node-positive patients. For the analysis of samples derived from node-negative patients, the exon-specific antibodies used were DIII, vff7 and vff18 (v6), vff17 (v7/v8), fw11.24 (v9) and vff16 (v10). With the different antibodies which recognize v6 epitopes, the majority of tumors were positively stained (> or = 65% of the tumors) with varying intensities. Thirty-nine percent of the tumors were positively stained with the antibody vff16, and approximately half of the tumors with the antibodies vff17 and fw11.24. The expression of CD44 v6 epitopes in tumors from node-negative patients was associated with a favorable prognosis, both upon univariate and multivariate analysis. The expression of CD44 v7/8, v9 or v10 epitopes was not significantly related with relapse-free survival. Samples from node-positive patients were only examined with the antibodies vff7, vff17 and vff18. The staining with none of these antibodies was correlated with the length of relapse-free survival of the patients. Our data suggest that, generally, the usefulness of knowledge of CD44 variant expression is of limited value for assessing the risk of relapse in patients with primary breast cancer. However, the expression of exon v6 of CD44 may be a marker to identify patients with a relatively favorable prognosis in node-negative patients.

Loss of imprinting of IGF2 and not H19 in breast cancer, adjacent normal tissue and derived fibroblast cultures.

Insulin-like growth factors are involved in the paracrine growth regulation of human breast tumor cells. IGF2 is imprinted in most tissues, and shows expression of the paternal allele only. To investigate whether disruption of this monoallelic IGF2 expression is involved in breast cancer development, a series of primary tumors and adjacent, histologically normal, breast tissue samples, as well as matched primary in vitro fibroblast cultures were studied. Biallelic expression (partial) of IGF2 was found in the majority of in vivo samples, and corresponding fibroblast cultures, while monoallelic expression was found in a normal breast sample. In contrast, H19, a closely apposed, but reciprocally imprinted gene, assumed to be regulated by a common control element, showed retention of monoallelic H19 expression in all in vivo and in the majority of in vitro samples. These data indicate that IGF2, but not H19, is prone to loss of imprinting in breast cancer.

A comparison of psychotic and nonpsychotic substance users in the psychiatric emergency room.

Current illicit drug and alcohol users were identified by laboratory evaluation of urine samples from nonpsychotic patients without a primary clinical diagnosis of a substance use disorder seen in a psychiatric emergency room. Urine screens revealed that 32 of 93 nonpsychotic patients (34 percent) had used a substance just before visiting the emergency room. Compared with nonusers, users were more often Caucasian females with adjustment disorders who admitted their previous substance use. The prevalence of concurrent use among nonpsychotic patients was higher than among psychotic patients. Nonpsychotic and psychotic users differed in gender, marital status, level of suicidality, self-report of use, the clinician's suspicion of use, use of seclusion during the visit, admitting status, level of care, and disposition.

Substance use among patients with a psychotic disorder in a psychiatric emergency room.

OBJECTIVE: This study used laboratory tests to identify current drug and alcohol users among psychotic patients seeking treatment in an urban psychiatric emergency room. Rates of clinician-suspected use and self-reported use were compared, as were treatment and disposition of users and nonusers. METHODS: Logistic regression modeling was used to identify factors that differentiated current substance users from nonusers in a sample of 112 psychotic patients. RESULTS: Laboratory analyses revealed that 24 of the 112 psychotic patients (21 percent) had used alcohol or an illegal substance before visiting the emergency room. Younger age, male gender, African-American ethnicity, clinician-suspected substance use, and presentation in the emergency room between 7 p.m. and 7 a.m. were associated with a higher likelihood of positive results on the urine test. Only five of the patients who had positive results (21 percent) self-reported substance use. Clinicians suspected that 59 patients (53 percent) were under the influence; however, only 17 of those suspected (29 percent) had positive laboratory results. Patients with positive laboratory results required more intense care in the psychiatric emergency room and were more often hospitalized. CONCLUSIONS: Some demographic and clinical factors were associated with concurrent substance use among psychotic patients in the emergency room. Clinicians' suspicions of use in this sample of psychotic patients lacked specificity due to the fact that potential use was suspected in a large number of cases for which laboratory results were negative. In contrast, self-reported use was uncommon among patients with positive results. Because neither clinician judgment nor patient self-report meaningfully predicts current substance use, routine urine drug screens may be appropriate.

The clinical significance of androgen receptors in breast cancer and their relation to histological and cell biological parameters.

To analyse the clinical significance of the presence of androgen receptors (AR) in breast carcinomas, clinical and histological parameters of 153 primary breast carcinomas (median follow-up 46 months) were examined. Oestrogen (ER) and progesterone receptor (PR) levels were determined in cytosol preparations using enzyme immunoassay assays and in cryostat sections by immunohistochemistry. AR and Ki-67 levels were only determined immunohistochemically. Data were analysed by uni- and multivariate models. 94/153 (61%) breast carcinomas were ER+ PR+ AR+, while 14 cases were only positive for AR. All grade III tumours (n = 17) were steroid receptor negative and 14 (76%) of these cases demonstrated high Ki-67 values suggestive of more aggressive behaviour. Strikingly, 14 ductal carcinomas negative for ER and PR were positive for AR. In univariate analysis, AR as well as ER, tumour size, lymph node status, grade and Ki-67 proved to be significant prognostic factors for disease-free survival (DFS). Multivariate analysis, however, showed lymph node status, tumour size and ER status to be the only independent prognostic factors for DFS within this model. We conclude that simple histological and cell biological parameters, including AR, can be used to select high- and low-risk patients at the time of primary surgery and can provide valuable information on treatment options.

Differential regulation of breast tumor cell proliferation by stromal fibroblasts of various breast tissue sources.

A stromal fibroblast-mediated paracrine regulation of epithelial tumor cell proliferation and differentiation plays an important role in the development and progression of breast tumors. We have studied the paracrine growth regulation of various phenotypically different breast cancer cell lines using conditioned serum-free media (C-SFM) from primary breast fibroblasts. Fibroblast cultures were established from malignant primary tumors and adjacent normal breast tissue, benign fibroadenomas, cosmetic reduction mammoplasties and breast skin tissues. All fibroblast-conditioned media were shown to stimulate the proliferation of breast cancer cell lines. However, the C-SFM-induced MCF-7 proliferative response was shown to be significantly higher than the proliferative response observed with any of the other cell lines tested. More importantly, the MCF-7 proliferative response obtained with malignant tumor tissue fibroblast C-SFM was shown to be significantly higher than the response to C-SFM from paired (and unpaired) normal adjacent breast tissue fibroblasts. The MCF-7 proliferative response to fibroblast C-SFM from normal tissue (adjacent to the tumor) was further shown to be comparable to the MCF-7 response using benign or reduction mammoplastic tissue fibroblast C-SFM. In addition, we show that IGFs are only partly responsible for the observed proliferative effect of the C-SFMs, while EGF, TGF alpha and basic-FGF are shown not to be involved. We conclude that stromal fibroblasts can differentially regulate breast cancer cell proliferation. Both the fibroblast's tissue source as well as the target tumor cell's phenotype will determine the extent of the proliferative response.

Transforming growth factor beta secretion from primary breast cancer fibroblasts.

Transforming growth factor beta (TGF-beta) is a hormonally regulated growth inhibitor with autocrine and/or paracrine functions in human breast cancer. In vivo, enhanced immunohistochemical staining of extracellular TGF-beta 1 has been detected around stromal fibroblasts in response to the antiestrogen treatment. We have investigated the effects of tamoxifen on the production of TGF-beta by primary human breast fibroblast cultures in serum-free medium. Highly variable levels of mainly latent TGF-beta 1 were detected in conditioned media from both tumor and normal tissue derived fibroblasts. Hydroxy-tamoxifen was shown to increase latent TGF-beta 1 secretion in three of the eight tumor tissue-derived fibroblast cultures. Such effect of hydroxy-tamoxifen was not observed in fibroblast cultures established from normal adjacent breast tissue.

Immunohistochemical determination of androgen receptors in relation to oestrogen and progesterone receptors in female breast cancer.

The expression of oestrogen (ER), progesterone (PR) and androgen (AR) receptors in female breast cancer was investigated by immunohistochemistry on snap-frozen tissue specimens of a series of 100 breast cancers. For detection of the AR we used a recently developed mouse monoclonal antibody specific for the N-terminal domain of the human AR. Expression of AR was compared with that of ER and PR as well as with tumour grade and age. Of the breast cancers investigated, 76% were AR-positive. This high percentage corresponds well with previous data on AR expression in breast cancer determined with ligand-binding assays. In 53% of the tumours AR, ER and PR were present, while 9% of the tumours were positive for AR and negative for ER and PR. In 13% of the tumours no ER, PR or AR expression was seen; these were all grade-III tumours. A positive correlation was found between age and ER expression, but no correlation was seen between age and PR or AR. Future studies should establish the prognostic value of the combination ER, PR and AR determinations on female breast cancer with regard to biological behaviour and response rate to hormonal therapy.

Stromal influences on breast cancer cell growth.

Paracrine influences from fibroblasts derived from different sources of breast tissue on epithelial breast cancer cell growth in vitro were investigated. Medium conditioned (CM) by fibroblasts derived from tumours, adjacent normal breast tissue, and normal breast tissue obtained from reduction mammoplasty or from skin tissue significantly stimulated the growth of the steroid-receptor positive cell lines MCF-7 and ZR 75.1. The proliferation index (PI) on MCF-7 cells with CM from fibroblasts derived from breast tumour tissue was significantly higher than that obtained with fibroblasts derived from adjacent normal breast tissue (2p less than 0.05, n = 8). The PI obtained with CM from normal fibroblast cultures from reduction mammoplasty tissue, like normal tissue adjacent to the tumour, fell in the lower range of values. Skin fibroblast, like tumour tissue derived fibroblast, CM caused a high range PI. MDA-MB-231 and Evsa-T, two steroid-receptor negative cell lines, showed only a minor growth stimulatory responses with some of the fibroblast CM's. Evsa-T was occasionally inhibited by CM's. In conclusion, stromal factors play a role in the growth regulation of human breast cancer cells. The effects on cancer cell growth are, however, varying depending on the source of the stroma and the characteristics of the epithelial tumour cells.