The neurophysiology of closed-loop auditory stimulation in sleep: A magnetoencephalography study.

Closed-loop auditory stimulation (CLAS) is a brain modulation technique in which sounds are timed to enhance or disrupt endogenous neurophysiological events. CLAS of slow oscillation up-states in sleep is becoming a popular tool to study and enhance sleep's functions, as it increases slow oscillations, evokes sleep spindles and enhances memory consolidation of certain tasks. However, few studies have examined the specific neurophysiological mechanisms involved in CLAS, in part because of practical limitations to available tools. To evaluate evidence for possible models of how sound stimulation during brain up-states alters brain activity, we simultaneously recorded electro- and magnetoencephalography in human participants who received auditory stimulation across sleep stages. We conducted a series of analyses that test different models of pathways through which CLAS of slow oscillations may affect widespread neural activity that have been suggested in literature, using spatial information, timing and phase relationships in the source-localized magnetoencephalography data. The results suggest that auditory information reaches ventral frontal lobe areas via non-lemniscal pathways. From there, a slow oscillation is created and propagated. We demonstrate that while the state of excitability of tissue in auditory cortex and frontal ventral regions shows some synchrony with the electroencephalography (EEG)-recorded up-states that are commonly used for CLAS, it is the state of ventral frontal regions that is most critical for slow oscillation generation. Our findings advance models of how CLAS leads to enhancement of slow oscillations, sleep spindles and associated cognitive benefits and offer insight into how the effectiveness of brain stimulation techniques can be improved.

Resident Assessment of Clinician Educators According to Core ACGME Competencies.

BACKGROUND: The Accreditation Council for Graduate Medical Education (ACGME) requires faculty to pursue annual development to enhance their teaching skills. Few studies exist on how to identify and improve the quality of teaching provided by faculty educators. Understanding the correlation between numeric scores assigned to faculty educators and their tangible, practical teaching skills would be beneficial. OBJECTIVE: This study aimed to identify and describe qualities that differentiate numerically highly rated and low-rated physician educators. DESIGN: This observational mixed-methods study evaluated attending physician educators between July 1, 2015, and June 30, 2021. Quantitative analysis involved descriptive statistics, normalization of scores, and stratification of faculty into tertiles based on a summary score. We compared the highest and lowest tertiles during qualitative analyses of residents' comments. PARTICIPANTS: Twenty-five attending physicians and 111 residents in an internal medicine residency program. MAIN MEASURES: Resident evaluations of faculty educators, including 724 individual assessments of faculty educators on 15 variables related to the ACGME core competencies. KEY RESULTS: Quantitative analyses revealed variation in attending physician educators' performance across the ACGME core competencies. The highest-rated teaching qualities were interpersonal and communication skills, medical knowledge, and professionalism, while the lowest-rated teaching quality was systems-based practice. Qualitative analyses identified themes distinguishing high-quality from low-quality attending physician educators, such as balancing autonomy and supervision, role modeling, engagement, availability, compassion, and excellent teaching. CONCLUSIONS: This study provides insights into areas where attending physicians' educational strategies can be improved, emphasizing the importance of role modeling and effective communication. Ongoing efforts are needed to enhance the quality of faculty educators and resident education in internal medicine residency programs.

A Quality Improvement Initiative to Increase Documentation of Preferences for Life-Sustaining Treatment in Hospitalized Adults.

BACKGROUND: Portable Orders for Life-Sustaining Treatment (POLST) forms allow patients to codify their preferences for life-sustaining treatments across inpatient and outpatient settings. In 2019 only 29.5% of our hospitalized internal medicine patients with an inpatient do-not-resuscitate (DNR) order and no DNR POLST at admission discharged with a DNR POLST. This presented an opportunity to improve POLST completion and avoid undesired or inappropriate care after discharge. METHODS: Using electronic health record (EHR) data, the authors identified hospitalized adults (age ≥ 50 years) admitted to an internal medicine service with a DNR order and discharged alive. Patient records were cross-referenced with the state's POLST registry for an active POLST form. Among patients with a missing or full-code POLST form at admission, the authors calculated the proportion with a DNR POLST form completed by discharge. These data were tracked over time with control charts to detect performance shifts following three Plan-Do-Study-Act (PDSA) cycles over 34 months, which included a single educational training on electronic POLST navigation, an EHR discharge navigator notification, and quarterly e-mailed individualized performance reports. RESULTS: The study population (N = 387) was 55.0% male and predominately non-Hispanic white (80.9%). Patients discharging to a skilled nursing facility or hospice were three times more likely to discharge with a DNR POLST compared to patients discharging home. Overall, the proportion of DNR POLST forms completed by discharge increased from 0.36 to 0.60 after three PDSA cycles (p < 0.001). CONCLUSION: This quality improvement initiative demonstrated improved POLST form completion rates in a target population of adults at elevated risk for readmission and death.

Improving the Standard of Care for All-A Practical Guide to Developing a Center of Excellence.

Pancreatic surgery is one of the more challenging procedures performed by surgeons. The operations are technically complex and have historically been accompanied by a substantial risk for mortality and postoperative complications. Other pancreatic pathologies require advanced therapeutic procedures that are highly endoscopist-dependent, requiring specific, knowledge-based training for optimal outcomes. An increase in diagnosed pancreatic pathologies every year reinforces a critical need for experienced surgeons, gastroenterologists/endoscopists, hospitals, and support personnel in the management of complex pancreatic cases and thus, well-designed Centers of Excellence (CoE). In this paper, we outline the framework for a Pancreas CoE across three developmental domains: (1) establishing the foundation; (2) formalizing the program; (3) solidifying the CoE status. This framework can likely be translated to any disease or procedure-specific service-line and facilitate the development of a successful CoE.

Nox2 Inhibition Regulates Stress Response and Mitigates Skeletal Muscle Fiber Atrophy during Simulated Microgravity.

Insufficient stress response and elevated oxidative stress can contribute to skeletal muscle atrophy during mechanical unloading (e.g., spaceflight and bedrest). Perturbations in heat shock proteins (e.g., HSP70), antioxidant enzymes, and sarcolemmal neuronal nitric oxidase synthase (nNOS) have been linked to unloading-induced atrophy. We recently discovered that the sarcolemmal NADPH oxidase-2 complex (Nox2) is elevated during unloading, downstream of angiotensin II receptor 1, and concomitant with atrophy. Here, we hypothesized that peptidyl inhibition of Nox2 would attenuate disruption of HSP70, MnSOD, and sarcolemmal nNOS during unloading, and thus muscle fiber atrophy. F344 rats were divided into control (CON), hindlimb unloaded (HU), and hindlimb unloaded +7.5 mg/kg/day gp91ds-tat (HUG) groups. Unloading-induced elevation of the Nox2 subunit p67phox-positive staining was mitigated by gp91ds-tat. HSP70 protein abundance was significantly lower in HU muscles, but not HUG. MnSOD decreased with unloading; however, MnSOD was not rescued by gp91ds-tat. In contrast, Nox2 inhibition protected against unloading suppression of the antioxidant transcription factor Nrf2. nNOS bioactivity was reduced by HU, an effect abrogated by Nox2 inhibition. Unloading-induced soleus fiber atrophy was significantly attenuated by gp91ds-tat. These data establish a causal role for Nox2 in unloading-induced muscle atrophy, linked to preservation of HSP70, Nrf2, and sarcolemmal nNOS.

Fasciculoventricular and atrioventricular accessory pathways in patients with Danon disease and preexcitation: A multicenter experience.

BACKGROUND: Studies have suggested that a fasciculoventricular pathway (FVP) may be the cause of preexcitation in patients with Danon disease, a rare X-linked dominant genetic disorder of hypertrophic cardiomyopathy. OBJECTIVE: The purpose of this study was to describe the prevalence of ventricular preexcitation on resting 12-lead electrocardiogram (ECG) in patients with Danon disease and the electrophysiological study (EPS) results of those with preexcitation. METHODS: Patients with confirmed Danon disease diagnosed with preexcitation (PR ≤120 ms, delta wave, QRS >110 ms) on ECG were included from a multicenter registry. The incidence of arrhythmias, implantable cardioverter-defibrillator (ICD) procedures, ICD shocks, and EPS results were collected. RESULTS: Thirteen of 40 patients (32.5%) with Danon disease were found to have preexcitation (mean age 17.3 years; 38% women). EPS performed in 9 of 13 patients (69%) demonstrated FVP only in 2 (22.2%), extranodal pathway without exclusion of FVP in 2 (22.2%), and both FVP and extranodal pathway in 5 (55.6%). Two patients had malignant accessory pathway (AP) properties. Over median follow-up of 842 days (interquartile range 138-1678), 11 patients (85%) had ICD placement, and 6 (46.1%) underwent heart transplantation. No patients required therapy for ventricular tachycardia, and 2 patients (15%) had paroxysmal atrial fibrillation. CONCLUSION: In a large multicenter cohort of patients with Danon disease, there was a high prevalence of FVP and extranodal pathways diagnosed on EPS in those with preexcitation. These findings suggest patients with preexcitation and Danon disease should undergo EPS to assess for FVP and potentially malignant extranodal AP.

An Evaluation of Diagnostic Yield From Bronchoscopy: The Impact of Clinical/Radiographic Factors, Procedure Type, and Degree of Suspicion for Cancer.

BACKGROUND: Bronchoscopy is commonly used to evaluate suspicious lung lesions. The yield is likely dependent on patient, radiographic, and bronchoscopic factors. Few studies have assessed these factors simultaneously while also including the preprocedure physician-assessed probability of cancer (pCA) when assessing yield. METHODS: This study is a secondary data analysis from a prospective multicenter trial. Diagnostic yield of standard bronchoscopy with biopsy ± fluoroscopy, endobronchial ultrasound with transbronchial needle aspiration (EBUS-TBNA), electromagnetic navigation, and combination bronchoscopies was assessed. Definitions for diagnostic and nondiagnostic bronchoscopies were rigorously predefined. The association of diagnostic yield with individual variables was examined by using univariate and multivariate logistic regression analyses where appropriate. RESULTS: A total of 687 patients were included from 28 sites. Overall diagnostic yield was 69%; 80% for EBUS, 55% for bronchoscopy with biopsy ± fluoroscopy, 57% for electromagnetic navigation, and 74% for combination procedures (P < .001). Patients with larger, central lesions with adenopathy were significantly more likely to undergo a diagnostic bronchoscopy. Patients with pCA < 10% and 10% to 60% had lower yields (44% and 42%, respectively), whereas pCA > 60% yielded a positive result in 77% (P < .001). In multivariate logistic regression, the use of EBUS-TBNA, larger sized lesions, and central location were significantly associated with a diagnostic bronchoscopy. Seventeen percent of those with a malignant diagnosis and 28% of those with a benign diagnosis required secondary procedures to establish a diagnosis. CONCLUSIONS: This study is the first to assess the yield of bronchoscopy according to physician-assessed pCA in a large, prospective multicenter trial. The yield of bronchoscopy varied greatly according to physician suspicion that cancer is present, the patients' clinical/radiographic features, and the type of procedure performed. Of the procedures performed, EBUS-TBNA was the most likely to provide a diagnosis.

Acute Pancreatitis Task Force on Quality: Development of Quality Indicators for Acute Pancreatitis Management.

INTRODUCTION: Detailed recommendations and guidelines for acute pancreatitis (AP) management currently exist. However, quality indicators (QIs) are required to measure performance in health care. The goal of the Acute Pancreatitis Task Force on Quality was to formally develop QIs for the management of patients with known or suspected AP using a modified version of the RAND/UCLA Appropriateness Methodology. METHODS: A multidisciplinary expert panel composed of physicians (gastroenterologists, hospitalists, and surgeons) who are acknowledged leaders in their specialties and who represent geographic and practice setting diversity was convened. A literature review was conducted, and a list of proposed QIs was developed. In 3 rounds, panelists reviewed literature, modified QIs, and rated them on the basis of scientific evidence, bias, interpretability, validity, necessity, and proposed performance targets. RESULTS: Supporting literature and a list of 71 proposed QIs across 10 AP domains (Diagnosis, Etiology, Initial Assessment and Risk Stratification, etc.) were sent to the expert panel to review and independently rate in round 1 (95% of panelists participated). Based on a round 2 face-to-face discussion of QIs (75% participation), 41 QIs were classified as valid. During round 3 (90% participation), panelists rated the 41 valid QIs for necessity and proposed performance thresholds. The final classification determined that 40 QIs were both valid and necessary. DISCUSSION: Hospitals and providers managing patients with known or suspected AP should ensure that patients receive high-quality care and desired outcomes according to current evidence-based best practices. This physician-led initiative formally developed 40 QIs and performance threshold targets for AP management. Validated QIs provide a dependable quantitative framework for health systems to monitor the quality of care provided to patients with known or suspected AP.

The systemic response to surgery triggers the outgrowth of distant immune-controlled tumors in mouse models of dormancy.

Patients undergoing surgical resection of primary breast tumors confront a risk for metastatic recurrence that peaks sharply 12 to 18 months after surgery. The cause of early metastatic relapse in breast cancer has long been debated, with many ascribing these relapses to the natural progression of the disease. Others have proposed that some aspect of surgical tumor resection triggers the outgrowth of otherwise-dormant metastases, leading to the synchronous pattern of relapse. Clinical data cannot distinguish between these hypotheses, and previous experimental approaches have not provided clear answers. Such uncertainty hinders the development and application of therapeutic approaches that could potentially reduce early metastatic relapse. We describe an experimental model system that definitively links surgery and the subsequent wound-healing response to the outgrowth of tumor cells at distant anatomical sites. Specifically, we find that the systemic inflammatory response induced after surgery promotes the emergence of tumors whose growth was otherwise restricted by a tumor-specific T cell response. Furthermore, we demonstrate that perioperative anti-inflammatory treatment markedly reduces tumor outgrowth in this model, suggesting that similar approaches might substantially reduce early metastatic recurrence in breast cancer patients.

Assessing the Correlation Between Physical Activity and Quality of Life in Advanced Lung Cancer.

BACKGROUND AND OBJECTIVE: Increasing physical activity (PA) is safe and beneficial in lung cancer (LC) patients. Advanced-stage LC patients are under-studied and have worse symptoms and quality of life (QoL). We evaluated the feasibility of monitoring step count in advanced LC as well as potential correlations between PA and QoL. METHODS: This is a prospective, observational study of 39 consecutive patients with advanced-stage LC. Daily step count over 1 week (via Fitbit Zip), QoL, dyspnea, and depression scores were collected. Spearman rank testing was used to assess correlations. Correlation coefficients (ρ) >0.3 or <-0.3 (more and less correlated, respectively) were considered potentially clinically significant. RESULTS: Most (83%) of the patients were interested in participating, and 67% of those enrolled were adherent with the device. Of those using the device (n = 30), the average daily step count was 4877 (range = 504-12 118) steps/d. Higher average daily step count correlated with higher QoL (ρ = 0.46), physical (ρ = 0.61), role (ρ = 0.48), and emotional functioning (ρ = 0.40) scores as well as lower depression (ρ = -0.40), dyspnea (ρ = -0.54), and pain (ρ = -0.37) scores. CONCLUSION: Remote PA monitoring (Fitbit Zip) is feasible in advanced-stage LC patients. Interest in participating in this PA study was high with comparable adherence to other PA studies. In those utilizing the device, higher step count correlates with higher QoL as well as lower dyspnea, pain, and depression scores. PA monitoring with wearable devices in advanced-stage LC deserves further study.

Feasibility of developing a pediatric telehealth network in Honduras with international consultation support.

INTRODUCTION: Honduras is the second poorest country in Central America, and roughly 50% of the population lives in rural areas. A telehealth network linking these areas to larger health centers may improve patient access to care, and physician access to educational opportunities. This pilot study assessed the feasibility of establishing a pediatric telehealth network between underserved clinics in Honduras and the Medical University of South Carolina (MUSC). METHODS: Two underserved Honduran clinics were identified and invited to participate in the telehealth network. Providers from these clinics connected remotely to educational conferences at MUSC, and received teleconsults from MUSC physicians and physicians from the other Honduran site. Honduran providers completed five-point Likert scale satisfaction surveys following participation in the conferences and teleconsults. RESULTS: Survey feedback was positive, with 100% of respondents stating they would utilize telemedicine in the future. Dissatisfaction was expressed subjectively in the survey comments with regards to poor Internet connectivity and unreliable electrical power. CONCLUSIONS: The establishment of a telehealth network between Honduras and MUSC is feasible, and rural providers were receptive to the clinical and educational opportunities this network provides. Future projects will expand telehealth capabilities to other Honduran sites and focus on intra-country collaboration to ensure sustainability.

Neutrophils Suppress Intraluminal NK Cell-Mediated Tumor Cell Clearance and Enhance Extravasation of Disseminated Carcinoma Cells.

UNLABELLED: Immune cells promote the initial metastatic dissemination of carcinoma cells from primary tumors. In contrast to their well-studied functions in the initial stages of metastasis, the specific roles of immunocytes in facilitating progression through the critical later steps of the invasion-metastasis cascade remain poorly understood. Here, we define novel functions of neutrophils in promoting intraluminal survival and extravasation at sites of metastatic dissemination. We show that CD11b(+)/Ly6G(+) neutrophils enhance metastasis formation via two distinct mechanisms. First, neutrophils inhibit natural killer cell function, which leads to a significant increase in the intraluminal survival time of tumor cells. Thereafter, neutrophils operate to facilitate extravasation of tumor cells through the secretion of IL1ß and matrix metalloproteinases. These results identify neutrophils as key regulators of intraluminal survival and extravasation through their cross-talk with host cells and disseminating carcinoma cells. SIGNIFICANCE: This study provides important insights into the systemic contributions of neutrophils to cancer metastasis by identifying how neutrophils facilitate intermediate steps of the invasion-metastasis cascade. We demonstrate that neutrophils suppress natural killer cell activity and increase extravasation of tumor cells. Cancer Discov; 6(6); 630-49. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 561.

Impact of urinary tract infection definitions on colorectal outcomes.

BACKGROUND: Hospital-acquired urinary tract infections (UTIs) significantly impact hospital outcomes. Colorectal surgery is inherently high risk for postoperative infections including UTI, and these patients may have unique outcomes as compared to other medical and surgical hospitalizations. We aim to assess the impact of the differing definitions of UTI captured by our hospital quality measures on hospital charges, length of stay (LOS), and mortality after colorectal resections at our institution. MATERIALS AND METHODS: Existing hospital quality surveillance was used to retrospectively identify postcolorectal resection UTI, as defined by the National Surgical Quality Improvement Program (NSQIP), and the Centers for Disease Control and Prevention's National Healthcare Safety Network (NHSN)-defined catheter-associated UTIs (CAUTI), from 2006-2012. Both groups were compared to colorectal resections performed during the same period that did not develop a UTI. Groups were compared for differences in 30-d surgical outcomes with multivariate analysis of total hospital charges and LOS. RESULTS: During our study period, we identified 18 CAUTIs and 42 NSQIP-UTI, and 1064 other colorectal resections (UTI rate, 5.3%). Our overall mortality rate was 4.4% and was not associated with CAUTI or NSQIP-UTI on univariate analysis. CAUTI, but not NSQIP-UTI, was associated with a 73% increase in LOS and 70% increase in total hospital charges on multivariate analysis. CONCLUSIONS: By reviewing quality outcomes surveillance modalities at our hospital, we identified postcolorectal resection CAUTI, but not NSQIP-UTI, to be associated with increased total hospital charges and LOS. Neither was associated with mortality.

An integrin-linked machinery of cytoskeletal regulation that enables experimental tumor initiation and metastatic colonization.

Recently extravasated metastatic cancer cells use the Rif/mDia2 actin-nucleating/polymerizing machinery in order to extend integrin ß1-containing, filopodium-like protrusions (FLPs), which enable them to interact productively with the surrounding extracellular matrix; this process governs the initial proliferation of these cancer cells. Here, we identify the signaling pathway governing FLP lifetime, which involves integrin-linked kinase (ILK) and ß-parvin, two integrin:actin-bridging proteins that block cofilin-mediated actin-filament severing. Notably, the combined actions of Rif/mDia2 and ILK/ß-parvin/cofilin pathways on FLPs are required not only for metastatic outgrowth but also for primary tumor formation following experimental implantation. This provides one mechanistic explanation for how the epithelial-mesenchymal transition (EMT) program imparts tumor-initiating powers to carcinoma cells, since it enhances FLP formation through the activation of ILK/ß-parvin/cofilin pathway.

Double knockout of carbonic anhydrase II (CAII) and Na(+)-Cl(-) cotransporter (NCC) causes salt wasting and volume depletion.

BACKGROUND AND AIMS: The thiazide-sensitive Na(+)-Cl(-) cotransporter NCC and the Cl(-)/HCO3(-)exchanger pendrin are expressed on apical membranes of distal cortical nephron segments and mediate salt absorption, with pendrin working in tandem with the epithelial Na(+) channel (ENaC) and the Na(+)-dependent chloride/bicarbonate exchanger (NDCBE), whereas NCC is working by itself. A recent study showed that NCC and pendrin compensate for loss of each other under basal conditions, therefore masking the role that each plays in salt reabsorption. Carbonic anhydrase II (CAII, CA2 or CAR2) plays an important role in acid-base transport and salt reabsorption in the proximal convoluted tubule and acid-base transport in the collecting duct. Animals with CAII deletion show remodeling of intercalated cells along with the downregulation of pendrin. NCC KO mice on the other hand show significant upregulation of pendrin and ENaC. Neither model shows any significant salt wasting under baseline conditions. We hypothesized that the up-regulation of pendrin is essential for the prevention of salt wasting in NCC KO mice. METHODS AND RESULTS: To test this hypothesis, we generated NCC/CAII double KO (dKO) mice by crossing mice with single deletion of NCC and CAII. The NCC/CAII dKO mice displayed significant downregulation of pendrin, along with polyuria and salt wasting. As a result, the dKO mice developed volume depletion, which was associated with the inability to concentrate urine. CONCLUSIONS: We conclude that the upregulation of pendrin is essential for the prevention of salt and water wasting in NCC deficient animals and its downregulation or inactivation will result in salt wasting, impaired water conservation and volume depletion in the setting of NCC inactivation or inhibition.

The outgrowth of micrometastases is enabled by the formation of filopodium-like protrusions.

UNLABELLED: Disseminated cancer cells that have extravasated into the tissue parenchyma must interact productively with its extracellular matrix components to survive, proliferate, and form macroscopic metastases. The biochemical and cell biologic mechanisms enabling this interaction remain poorly understood. We find that the formation of elongated integrin ß(1)-containing adhesion plaques by cancer cells that have extravasated into the lung parenchyma enables the proliferation of these cells via activation of focal adhesion kinase. These plaques originate in and appear only after the formation of filopodium-like protrusions (FLP) that harbor integrin ß(1) along their shafts. The cytoskeleton-regulating proteins Rif and mDia2 contribute critically to the formation of these protrusions and thereby enable the proliferation of extravasated cancer cells. Hence, the formation of FLPs represents a critical rate-limiting step for the subsequent development of macroscopic metastases. SIGNIFICANCE: Although the mechanisms of metastatic dissemination have begun to be uncovered, those involved in the establishment of extravasated cancer cells in foreign tissue microenvironments remained largely obscure. We have studied the behavior of recently extravasated cancer cells in the lungs and identified a series of cell biologic processes involving the formation of filopodium-like protrusions and the subsequent development of elongated, mature adhesion plaques, which contribute critically to the rapid proliferation of the micrometastatic cells and thus are prerequisites to the eventual lung colonization by these cells.

Hospice eligibility in patients who died in a tertiary care center.

BACKGROUND: Hospice is a service that patients, families, and physicians find beneficial, yet a majority of patients die without receiving hospice care. Little is known about how many hospitalized patients are hospice eligible at the time of hospitalization. METHODS: Retrospective chart review was used to examine all adult deaths (n = 688) at a tertiary care center during 2009. Charts were selected for full review if the death was nontraumatic and the patient had a hospital admission within 12 months of the terminal admission. The charts were examined for hospice eligibility based on medical criteria, evidence of a hospice discussion, and hospice enrollment. RESULTS: Two hundred nine patients had an admission in the year preceding the terminal admission and a nontraumatic death. Sixty percent were hospice eligible during the penultimate admission. Hospice discussions were documented in 14% of the hospice-eligible patients. Patients who were hospice eligible had more subspecialty consults on the penultimate admission compared to those not hospice eligible (P = 0.016), as well as more overall hospitalizations in the 12 months preceding their terminal admission (P = 0.0003), and fewer days between their penultimate admission and death (P = 0.001). CONCLUSION: The majority of terminally ill inpatients did not have a documented discussion of hospice with their care provider. Educating physicians to recognize the stepwise decline of most illnesses and hospice admission criteria will facilitate a more informed decision-making process for patients and their families. A consistent commitment to offer hospice earlier than the terminal admission would increase access to community or home-based care, potentially increasing quality of life.

Normal and neoplastic nonstem cells can spontaneously convert to a stem-like state.

Current models of stem cell biology assume that normal and neoplastic stem cells reside at the apices of hierarchies and differentiate into nonstem progeny in a unidirectional manner. Here we identify a subpopulation of basal-like human mammary epithelial cells that departs from that assumption, spontaneously dedifferentiating into stem-like cells. Moreover, oncogenic transformation enhances the spontaneous conversion, so that nonstem cancer cells give rise to cancer stem cell (CSC)-like cells in vitro and in vivo. We further show that the differentiation state of normal cells-of-origin is a strong determinant of posttransformation behavior. These findings demonstrate that normal and CSC-like cells can arise de novo from more differentiated cell types and that hierarchical models of mammary stem cell biology should encompass bidirectional interconversions between stem and nonstem compartments. The observed plasticity may allow derivation of patient-specific adult stem cells without genetic manipulation and holds important implications for therapeutic strategies to eradicate cancer.

Proarrhythmic risk with antipsychotic and antidepressant drugs: implications in the elderly.

The quinidine-like effects of some antidepressant drugs (particularly tricyclic antidepressants) and many antipsychotic drugs (particularly the phenothiazines) confound treatment of psychosis and depression in patients with major mental illness. This is especially true among elderly patients with existing risk factors for corrected QT (QTc) interval prolongation. We used PubMed, previously reported review articles and the extensive personal files of the authors to identify cases of subjects aged>or=60 years who developed QTc interval prolongation, polymorphic ventricular tachycardia (PVT)/torsade de pointes (TdP) and/or sudden cardiac death while taking antipsychotic or antidepressant drugs or a combination of these medications. We identified 37 patients who had taken, in total, 46 antipsychotic or antidepressant drugs. Our most striking finding was that almost four-fifths of our cases involved women. When the 14 critically ill subjects receiving haloperidol intravenously were excluded, 91.3% of our subjects were women. Almost three-quarters of our study subjects had cardiovascular disease. Intravenous administration of haloperidol in the critically ill and profoundly agitated elderly warrants particular comment. Of the 14 subjects in this category identified, six were men and eight were women. In 13 cases, the drug dose far exceeded the 2 mg necessary to produce an antipsychotic effect. These clinicians were using an agent to achieve sedation that usually requires very high doses in the critically ill and profoundly agitated elderly to achieve this effect. Inclusion criteria for our literature review required antipsychotic and/or antidepressant drug-induced QTc interval prolongation. Even so, our finding that 31 of our 37 subjects developed PVT is sobering. However, the reader should not conclude that drug-induced QTc interval prolongation is highly predictive of PVT or its TdP subtype. All of our study subjects had at least two risk factors for TdP, with age and sex being the most common. We included the rare case of a patient with congenital long QT syndrome who developed further lengthening of the QTc interval and TdP when prescribed an antidepressant drug well known to produce QTc interval prolongation. We conclude with recommendations for clinicians not expert in the specialty of cardiology to deal with the many questions raised in this review. Specifically, such clinicians treating elderly patients with antipsychotic and antidepressant drugs that may prolong the QTc interval should aggressively obtain a baseline ECG for elderly female patients with additional risk factors such as personal or family history of pre-syncope or syncope, electrolyte disturbances or cardiovascular disease. Elderly male patients are also subject to QTc interval prolongation when such risk factors are present. It is important that the clinicians themselves inspect ECGs. If the QT interval is more than half the RR interval, QTc interval prolongation is likely to be present. In such cases, a cardiology colleague interested in QTc interval issues and TdP should be asked to review the ECG. Finally, nothing in our recommendations replaces meticulous attention to US FDA guidelines in the package insert of each drug.