tbuckley/cabot-search huggingface dataset:
Immunotherapies in Clinical Trials: Do They Demand Different Evaluation Tools?
Authors: R. S. Tuma
Journal: JNCI Journal of the National Cancer Institute (2011)

M elanoma patients and immunotherapy researchers alike had cause to celebrate in late March when the U.S. Food and Drug Administration approved ipilimumab (Yervoy) to treat metastatic melanoma. For patients, the drug is a much-needed alternative to the commonly used dacarbazine (DTIC-Dome), the first agent shown to prolong overall survival. For immunotherapy researchers, the drug, which works by binding to a receptor on the surface of T lymphocytes and releasing the brakes on the immune system, represents one more piece of evidence that they can recruit a patient’s immune system to fight cancer. Despite ipilimumab’s success, a key question in the fi eld remains how best to measure disease re sponse in patients treated with immunotherapies. No one will argue with the statistically signifi cant increase in overall survival that occurred in the pivotal ipilimumab trial (10 months in patients treated with ipilimumab with or without an experimental vaccine vs. 6.5 months for patients treated with the experimental vaccine alone). However, many researchers are concerned that response and progressionfree survival criteria developed in the era of cytotoxic therapies are inappropriate measures for immunotherapeutic agents and may lead to premature closures of trials and, perhaps, loss of active therapies. Last fall, an international group of academic and industry researchers, the Cancer Immunotherapy Consortium (CIC), proposed modifi ed criteria for measuring response to drugs that work through the immune system. Many cancer researchers see value in amended criteria and are currently testing them prospectively, but not everyone is convinced they are necessary. “The unique kinetics we see with immunotherapies really challenge the endpoints that we usually use for cancer clinical trials,” said Jedd Wolchok, M.D., Ph.D. , a medical oncologist at Memorial Sloan – Kettering Cancer Center in New York and an associate director of the CIC. “The surrogate endpoints that we’ve become so dependent on—response rate and progressionfree survival—just don’t tell the whole story.”
Disrupted Reinforcement Learning and Maladaptive Behavior in Women With a History of Childhood Sexual Abuse
Authors: Pia Pechtel, Diego A. Pizzagalli
Journal: JAMA Psychiatry (2013)

Childhood sexual abuse (CSA) has been associated with psychopathology, particularly major depressive disorder (MDD), and high-risk behaviors. Despite the epidemiological data available, the mechanisms underlying these maladaptive outcomes remain poorly understood.We examined whether a history of CSA, particularly in conjunction with a past episode of MDD, is associated with behavioral and neural dysfunction in reinforcement learning, and whether such dysfunction is linked to maladaptive behavior.Participants completed a clinical evaluation and a probabilistic reinforcement task while 128-channel event-related potentials were recorded.Academic setting; participants recruited from the community.Fifteen women with a history of CSA and remitted MDD (CSA + rMDD), 16 women with remitted MDD with no history of CSA (rMDD), and 18 healthy women (controls).Three or more episodes of coerced sexual contact (mean [SD] duration, 3.00 [2.20] years) between the ages of 7 and 12 years by at least 1 male perpetrator.Participants' preference for choosing the most rewarded stimulus and avoiding the most punished stimulus was evaluated. The feedback-related negativity and error-related negativity-hypothesized to reflect activation in the anterior cingulate cortex-were used as electrophysiological indices of reinforcement learning.No group differences emerged in the acquisition of reinforcement contingencies. In trials requiring participants to rely partially or exclusively on previously rewarded information, the CSA + rMDD group showed (1) lower accuracy (relative to both controls and the rMDD group), (2) blunted electrophysiological differentiation between correct and incorrect responses (relative to controls), and (3) increased activation in the subgenual anterior cingulate cortex (relative to the rMDD group). A history of CSA was not associated with impairments in avoiding the most punished stimulus. Self-harm and suicidal behaviors correlated with poorer performance of previously rewarded, but not previously punished, trials.Irrespective of past MDD episodes, women with a history of CSA showed neural and behavioral deficits in utilizing previous reinforcement to optimize decision making in the absence of feedback (blunted "Go learning"). Although our study provides initial evidence for reward-specific deficits associated with CSA, future research is warranted to determine if disrupted positive reinforcement learning predicts high-risk behavior following CSA.
Prognostic Model for Predicting Survival in Men With Hormone-Refractory Metastatic Prostate Cancer
Authors: Susan Halabi, Eric J. Small, Philip W. Kantoff, Michael W. Kattan, Ellen B. Kaplan, Nancy A. Dawson, Ellis G. Levine, Brent A. Blumenstein, Nicholas J. Vogelzang
Journal: Journal of Clinical Oncology (2003)

To develop and validate a model that can be used to predict the overall survival probability among metastatic hormone-refractory prostate cancer patients (HRPC).Data from six Cancer and Leukemia Group B protocols that enrolled 1,101 patients with metastatic hormone-refractory adenocarcinoma of the prostate during the study period from 1991 to 2001 were pooled. The proportional hazards model was used to develop a multivariable model on the basis of pretreatment factors and to construct a prognostic model. The area under the receiver operating characteristic curve (ROC) was calculated as a measure of predictive discrimination. Calibration of the model predictions was assessed by comparing the predicted probability with the actual survival probability. An independent data set was used to validate the fitted model.The final model included the following factors: lactate dehydrogenase, prostate-specific antigen, alkaline phosphatase, Gleason sum, Eastern Cooperative Oncology Group performance status, hemoglobin, and the presence of visceral disease. The area under the ROC curve was 0.68. Patients were classified into one of four risk groups. We observed a good agreement between the observed and predicted survival probabilities for the four risk groups. The observed median survival durations were 7.5 (95% confidence interval [CI], 6.2 to 10.9), 13.4 (95% CI, 9.7 to 26.3), 18.9 (95% CI, 16.2 to 26.3), and 27.2 (95% CI, 21.9 to 42.8) months for the first, second, third, and fourth risk groups, respectively. The corresponding median predicted survival times were 8.8, 13.4, 17.4, and 22.80 for the four risk groups.This model could be used to predict individual survival probabilities and to stratify metastatic HRPC patients in randomized phase III trials.
Study of modifiable risk factors for asthma exacerbations: virus infection and allergen exposure increase the risk of asthma hospital admissions in children
Authors: C S Murray
Journal: Thorax (2005)

<b>Background:</b> Asthma exacerbation is the most common cause of hospital admission in children. A study was undertaken to investigate the importance of allergen exposure in sensitised individuals in combination with viral infections and other potentially modifiable risk factors precipitating asthma hospital admission in children. <b>Methods:</b> Eighty four children aged 3–17 years admitted to hospital over a 1 year period with an acute asthma exacerbation (AA) were matched for age and sex with two control groups: stable asthmatics (SA) and children admitted to hospital with non-respiratory conditions (IC). Risk factors were assessed by questionnaires and determination of allergen sensitisation, home allergen exposure, pollen exposure, and respiratory virus infection. <b>Results:</b> Several non-modifiable factors (atopy, duration of asthma) were associated with increased risk. Among the modifiable factors, pet ownership, housing characteristics, and parental smoking did not differ between the groups. Regular inhaled corticosteroid treatment was significantly less common in the AA group than in the SA group (OR 0.2, 95% CI 0.1 to 0.6; p = 0.002). A significantly higher proportion of the AA group were virus infected (44%) and sensitised and highly exposed to sensitising allergen (76%) compared with the SA (18% and 48%) and IC groups (17% and 28%; both p&lt;0.001). In a multiple conditional logistic regression (AA <i>v</i> SA), allergen sensitisation and exposure or virus detection alone were no longer independently associated with hospital admission. However, the combination of virus detection and sensitisation with high allergen exposure substantially increased the risk of admission to hospital (OR 19.4, 95% CI 3.7 to 101.5, p&lt;0.001). <b>Conclusions:</b> Natural virus infection and real life allergen exposure in allergic asthmatic children increase the risk of hospital admission. Strategies for preventing exacerbations will need to address these factors.
A Phase II Trial of Flavopiridol (NSC #649890) in Patients with Previously Untreated Metastatic Androgen-Independent Prostate Cancer
Authors: Glenn Liu, David R. Gandara, Primo N. Lara, Derek Raghavan, James H. Doroshow, Przemyslaw Twardowski, Philip Kantoff, William Oh, KyungMann Kim, George Wilding
Journal: Clinical Cancer Research (2004)

Abstract Purpose: Flavopiridol is a cyclin-dependent kinase inhibitor with preclinical activity against prostate cancer cell lines. A Phase II trial was conducted to determine the activity of flavopiridol in patients with metastatic hormone-refractory prostate cancer. Experimental Design: A total of 36 patients was enrolled from several institutions and treated with a 72-h continuous infusion of flavopiridol every 14 days at the eventual starting dose of 40 mg/m2/day. Dose escalation up to 60 mg/m2/day was permitted if no significant toxicity was observed. Responses were assessed every 12 weeks. Only those patients completing four courses of the 72-h infusion were considered evaluable for response because the primary objective was to determine progression-free survival at 6 months given the cytostatic nature of the agent. Results: This study was conducted in a two-stage fashion. During the first stage, at least 20 evaluable patients needed to be enrolled to assess response. There were 22 of 36 patients evaluable for response. No objective responses were observed. Only 4 patients had stable disease for 16, 26, 29, and 48 weeks, respectively, stopping the trial by design as only 3 of 22 (14%) of the patients met the 6-month progression-free survival end point. The most common toxicities were diarrhea (grade 1 and 2) and nausea, although some grade 3 and 4 diarrhea (11 and 6%, respectively) were evident. Conclusions: Flavopiridol has disappointing single-agent activity in hormone-refractory prostate cancer when administered at this dose and schedule. Its use in prostate cancer should be reserved for evaluation in combination therapies or alternative schedules.
Translocation of the inhibitor of apoptosis protein c-IAP1 from the nucleus to the Golgi in hematopoietic cells undergoing differentiation: a nuclear export signal-mediated event
Authors: Stéphanie Plenchette, Séverine Cathelin, Cédric Rébé, Sophie Launay, Sylvain Ladoire, Olivier Sordet, Tibor Ponnelle, Najet Debili, Thi-Hai Phan, Rose-Ann Padua, Laurence Dubrez-Daloz, Eric Solary
Journal: Blood (2004)
Molecular Analysis of Bacterial Pathogens in Otitis Media With Effusion
Authors: J. Christopher Post
Journal: JAMA (1995)

<h3>Objective.</h3> —To determine if the polymerase chain reaction (PCR) can detect bacterial DNA in pediatric middle ear effusions that are sterile by standard cultural methods. <h3>Design.</h3> —Single-center, blinded, comparative study of diagnostic assays. The PCR-based detection systems for<i>Moraxella catarrhalis, Haemophilus influenzae</i>, and<i>Streptococcus pneumoniae</i>were designed and validated using a battery of DNAs obtained from cultured bacteria. Chronic middle ear effusion specimens were collected and comparatively analyzed by culture and the PCR. <h3>Setting.</h3> —Tertiary care pediatric hospital. <h3>Patients.</h3> —A total of 97 middle ear effusions were collected from pediatric outpatients at Children's Hospital of Pittsburgh (Pa) during myringotomy and tube placement for chronic otitis media with effusion (duration &gt;3 months). All patients had failed multiple courses of antimicrobial therapy and were diagnosed by a combination of validated otoscopy and tympanograms. <h3>Main Outcome Measure.</h3> —Differences in the percentage of positive test results between PCR-based assays and culture for<i>M catarrhalis, H influenzae</i>, and<i>S pneumoniae</i>. <h3>Results.</h3> —Of the 97 specimens of otitis media with effusion, 28 (28.9%) tested positive by both culture and PCR for<i>M catarrhalis, H influenzae</i>, or<i>S pneumoniae</i>. An additional 47 specimens (48%) were PCR positive/culture negative for these three bacterial species. Thus, 75 (77.3%) of the 97 specimens tested PCR positive for one or more of the three test organisms. The minimum number of bacterial genomic equivalents present in the average culture-negative ear was estimated to be greater than 10<sup>4</sup>based on dilutional experiments. <h3>Conclusions.</h3> —The PCR-based assay systems can detect the presence of bacterial DNA in a significant percentage of culturally sterile middle ear effusions. While this finding is not proof of an active bacterial infectious process, the large number of bacterial genomic equivalents present in the ears is suggestive of an active process. (<i>JAMA</i>. 1995;273:1598-1604)
A1C and Diabetes Diagnosis Among Filipino Americans, Japanese Americans, and Native Hawaiians
Authors: Maria Rosario G. Araneta, Andrew Grandinetti, Healani K. Chang
Journal: Diabetes Care (2010)

OBJECTIVE To examine the sensitivity and specificity of A1C ≥6.5% to diagnose diabetes among Filipino Americans, Japanese Americans, and Native Hawaiians. RESEARCH DESIGN AND METHODS This was a cross-sectional study among middle-aged adults without prior diagnosis of type 2 diabetes who completed a 2-h 75-g oral glucose tolerance test (OGTT) and A1C measures. RESULTS The 933 participants had a mean age of 54.2 years, and 73% were women. A total of 425 (45.5%) subjects had impaired fasting glucose or impaired glucose tolerance, 145 (15.5%) had type 2 diabetes (by OGTT), and 83 (8.9%) had A1C ≥6.5%. The sensitivity and specificity of A1C ≥6.5% to define diabetes (by OGTT) was 40.0 and 96.8% and 68.9 and 95.3%, respectively (by fasting plasma glucose only). However, (64.8%) of Filipino and Japanese subjects with diabetes had isolated postchallenge hyperglycemia; AIC ≥6.5% sensitivity and specificity was 19.1 and 92.1%, respectively, to define isolated postchallenge hyperglycemia in the total sample. CONCLUSIONS A1C ≥6.5% had low sensitivity and may delay diagnosis of type 2 diabetes without OGTT. This limitation is exacerbated by isolated postchallenge hyperglycemia in Asian Americans.
Mechanism of decreased baroreceptor activity in chronic hypertensive rabbits. Role of endogenous prostanoids.
Authors: P L Xie, M W Chapleau, T S McDowell, G Hajduczok, F M Abboud
Journal: Journal of Clinical Investigation (1990)

We examined the contribution of endogenous prostanoids to baroreceptor activation in chronic renal hypertension. Baroreceptor activity was recorded from the vascularly isolated carotid sinus during slow ramp increases in pressure in rabbits anesthetized with pentothal and chloralose. Mean arterial pressure averaged 133 +/- 4 mmHg in hypertensive rabbits (one kidney, one wrap, n = 12) and 85 +/- 3 mmHg in normotensive rabbits (one kidney, no wrap, n = 13). Baroreceptor activity was decreased significantly (P less than 0.05) in the hypertensive compared with the normotensive rabbits. The decreased baroreceptor activity could not be explained by decreased distensibility of the carotid sinus (sonomicrometers). Inhibition of the endogenous formation of prostanoids with intrasinus administration of indomethacin (50 microM) decreased baroreceptor activity in normotensive (P less than 0.05) but not in hypertensive rabbits over a wide range of pressures. At a pressure of 120 mmHg, activity declined from 61 +/- 14 spikes/s before indomethacin to 47 +/- 12 spikes/s with indomethacin, i.e., a drop of 24 +/- 4%. In contrast, corresponding values in hypertensive rabbits averaged 41 +/- 13 and 40 +/- 12 spikes/s (-1 +/- 2%). Intrasinus prostacyclin, on the other hand, increased activity in both groups: at 120 mmHg activity increased from 62 +/- 9 to 92 +/- 15 spikes/s (51 +/- 17%) in normotensive rabbits and from 29+/- 7 to 47 +/- 14 spikes/s (68 +/- 23%) in hypertensive rabbits. Neither indomethacin nor prostacyclin (n = 5) influenced the pressure-diameter relation of the carotid sinus. The increase in prostacyclin (6-keto-PGF 1 alpha) formation by the sinus in response to its exposure to arachidonic acid (10 microM) was significant (P less than 0.05) in the normotensives (1,627 +/- 344%; n = 5) but not in the hypertensives (583 +/- 353%; n = 5). We conclude that the decreased baroreceptor activity in chronic hypertension may not be caused by decreased distensibility of the vascular wall of the sinus and that endogenous prostanoids that contribute to baroreceptor activation in normotensive rabbits fail to do so in hypertensive rabbits. This appears to be due to decreased formation of prostacyclin rather than decreased sensitivity of the baroreceptors to prostacyclin. The results suggest a new mechanism that contributes to chronic baroreceptor resetting in hypertension.
NHS staff numbers begin to fall as fears rise over effect of efficiency savings
Authors: A. O'Dowd
Journal: BMJ (2010)

The number of NHS staff in England has started to fall for the first time in several years, prompting concerns that this may be the start of a trend of a shrinking NHS workforce.

New figures on hospital and community health services from the NHS Information Centre show that the NHS’s workforce headcount fell by 3351 from March this year to April, from 1 219 500 to 1 216 149 (a 0.3% drop).

The number in April was, however, 1% higher than in September last year, when it stood at 1 204 590, indicating that the downward trend may have just begun.

The NHS employed 1151 fewer managers and senior managers in March this year than in April (a …
“Tree in bud” attributable to organising pneumonia
Authors: E M T Bots, M A den Bakker, M S Wijsenbeek, L M van den Toorn, B van den Blink
Journal: Thorax (2012)

A 19-year-old man presented with dyspnoea, a non-productive cough and subfebrile temperature. Chest radiography showed a diffuse nodular pattern and a pneumomediastinum. HR-CT revealed a diffuse ‘tree in bud’ pattern (figure 1). An infectious bronchiolitis was suspected. Despite treatment with moxifloxacin he developed hypercapnic respiratory failure requiring mechanical ventilation. Extensive microbiological investigations did not reveal a pathogenic microorganism. Continued treatment with antibiotics, low-dose steroids and neomacrolides was not effective, and an open lung biopsy was performed. Histology showed an organising pneumonia (OP) with extensive endobronchiolar granulation tissue (figure 2). The treatment was converted …
Evolutionarily Conserved Signaling Pathways: Acting in the Shadows of Acute Myelogenous Leukemia's Genetic Diversity
Authors: Florian H. Heidel, Patricia Arreba-Tutusaus, Scott A. Armstrong, Thomas Fischer
Journal: Clinical Cancer Research (2015)

Acute myelogenous leukemia stem cells (AML-LSC) give rise to the leukemic bulk population and maintain disease. Relapse can arise from residual LSCs that have distinct sensitivity and dependencies when compared with the AML bulk. AML-LSCs are driven by genetic and epigenomic changes, and these alterations influence prognosis and clonal selection. Therapies targeting these molecular aberrations have been developed and show promising responses in advanced clinical trials; however, so far success with LSCs has been limited. Besides the genetic diversity, AML-LSCs are critically influenced by the microenvironment, and a third crucial aspect has recently come to the fore: A group of evolutionarily conserved signaling pathways such as canonical Wnt signaling, Notch signaling, or the Hedgehog pathway can be essential for maintenance of AML-LSC but may be redundant for normal hematopoietic stem cells. In addition, early reports suggest also regulators of cell polarity may also influence hematopoietic stem cells and AML biology. Interactions between these pathways have been investigated recently and suggest a network of signaling pathways involved in regulation of self-renewal and response to oncogenic stress. Here, we review how recent discoveries on regulation of AML-LSC-relevant evolutionarily conserved pathways may open opportunities for novel treatment approaches eradicating residual disease.
Weekend Hospital Admission, Acute Kidney Injury, and Mortality
Authors: Matthew T. James, Ron Wald, Chaim M. Bell, Marcello Tonelli, Brenda R. Hemmelgarn, Sushrut S. Waikar, Glenn M. Chertow
Journal: Journal of the American Society of Nephrology (2010)

Admission to the hospital on weekends is associated with increased mortality for several acute illnesses. We investigated whether patients admitted on a weekend with acute kidney injury (AKI) were more likely to die than those admitted on a weekday. Using the Nationwide Inpatient Sample, a large database of admissions to acute care, nonfederal hospitals in the United States, we identified 963,730 admissions with a diagnosis of AKI between 2003 and 2006. Of these, 214,962 admissions (22%) designated AKI as the primary reason for admission (45,203 on a weekend and 169,759 on a weekday). We used logistic regression models to examine the adjusted odds of in-hospital mortality associated with weekend versus weekday admission. Compared with admission on a weekday, patients admitted with a primary diagnosis of AKI on a weekend had a higher odds of death [adjusted odds ratio (OR) 1.07, 95% confidence interval (CI) 1.02 to 1.12]. The risk for death with admission on a weekend for AKI was more pronounced in smaller hospitals (adjusted OR 1.17, 95% CI 1.03 to 1.33) compared with larger hospitals (adjusted OR 1.07, 95% CI 1.01 to 1.13). Increased mortality was also associated with weekend admission among patients with AKI as a secondary diagnosis across a spectrum of co-existing medical diagnoses. In conclusion, among patients hospitalized with AKI, weekend admission is associated with a higher risk for death compared with admission on a weekday.
The 3-Night Hospital Stay and Medicare Coverage for Skilled Nursing Care
Authors: Lewis A. Lipsitz
Journal: JAMA (2013)

According to current Medicare coverage policies, Medicare requires a patient to have been a hospital inpatient for at least 3 consecutive days to receive coverage for rehabilitation in a skilled nursing facility (SNF) after hospital discharge.

Consider the following 2 clinical scenarios. In the first, an 80-year-old man who falls at home and can no longer walk independently is evaluated in the emergency department but does not meet criteria for hospitalization. He needs rehabilitation in an SNF to regain his ability to walk but must be admitted to a hospital for 3 nights to qualify for Medicare payment for this rehabilitation. Without a 3-night stay, the patient or his family must either pay the cost of SNF care (about $430 per day), admit him to a nursing home (about $300 per day), or hire caregivers to support him at home ($20-$30 per hour). In the second scenario, a 90-year-old nursing home resident develops pneumonia and dehydration. The licensed practical nurse responsible for her care is overwhelmed by many sick residents and moreover cannot administer intravenous fluids. She asks the covering physician for a hospital transfer. If the resident is transferred to the hospital for 3 nights, costing Medicare about $12?300,1 she can return to the same nursing home under the SNF benefit for an additional $430 per day.