An Extremely Indolent T-cell Leukemia: An 18-year Follow-Up.

T-cell prolymphocytic leukemia (T-PLL) is a rare malignancy that comprises about 2% of all mature lymphoid neoplasms. Patients usually present with prominent peripheral blood lymphocytosis, splenomegaly, hepatomegaly, lymphadenopathy, B symptoms, and occasionally with skin lesions.¹ The disease follows an aggressive clinical course with rapid progression and typically has a median survival of less than 1 year. In some cases, the disease is indolent for a period of time before becoming aggressive.² In 2002, 7 years after initial diagnosis in 1995, the case discussed herein was reported as a rare, indolent form of T-PLL.³ We now present 11 additional years of follow-up of this case, during which time the patient remained asymptomatic with respect to his lymphoid neoplasm

The transient receptor potential vanilloid 4 channel modulates uterine tone during pregnancy

The importance of gaining insight into the mechanisms underlying uterine quiescence and contractility is highlighted by the absence of an effective strategy to prevent or treat preterm labor, the greatest cause of perinatal mortality and morbidity worldwide. Although current evidence suggests that in myometrial smooth muscle cells (mSMCs) calcium homeostasis is modulated near term to promote uterine contractility, the efficacy of blocking voltage-operated calcium channels is limited by dose-related cardiovascular side effects. Thus, we considered whether uterine contractility might be modulated by calcium entry via transient receptor potential vanilloid 4 (TRPV4) channels. In mSMC, TRPV4 gene and protein expression increased with gestation, and TRPV4-mediated Ca2+ entry and contractility were increased in mSMC from pregnant compared to nonpregnant rats. Cell membrane TRPV4 expression was specifically increased, whereas the expression of β-arrestin-1 and β-arrestin-2, molecules that can sequester TRPV4 in the cytoplasm, decreased. Physical interaction of β-arrestin-2 and TRPV4 was apparent in nonpregnant, but absent in pregnant, mouse uterus. Moreover, direct pharmacologic activation of TRPV4 increased uterine contraction, but oxytocin-induced myometrial contraction was blocked by pharmacologic inhibition of TRPV4 and decreased in mice with global deletion of TRPV4. Finally, TRPV4 channel blockade prolonged pregnancy in two distinct in vivomurinemodels of preterm labor, whereas the absence of either β-arrestin-1 or β-arrestin-2 increased susceptibility to preterm labor. These data suggest that TRPV4 channel activity modulates uterine contractility and might represent a therapeutic target to address preterm labor

Evidence-Based Interventions and Strategies for the Grand Challenges Approach: The Need for Judgement

What is the value of evidence-based interventions in addressing “Grand Challenges”? Building upon the EPOS Grand Challenges work (Sakhrani et al., 2017), this paper explores whether evidence-based approaches developed for management and policy are relevant to addressing Grand Challenges. It discusses the criticisms of the Evidence-based Management approach and argues that evidence is a necessary, but not sufficient input in the decisionmaking process of addressing Grand Challenges

Nuclear receptor REVERBα is a state-dependent regulator of liver energy metabolism

The nuclear receptor REVERBα is a core component of the circadian clock and proposed to be a dominant regulator of hepatic lipid metabolism. Using antibody-independent ChIP-sequencing of REVERBα in mouse liver, we reveal a high-confidence cistrome and define direct target genes. REVERBα-binding sites are highly enriched for consensus RORE or RevDR2 motifs and overlap with corepressor complex binding. We find no evidence for transcription factor tethering and DNA-binding domain-independent action. Moreover, hepatocyte-specific deletion of Reverbα drives only modest physiological and transcriptional dysregulation, with derepressed target gene enrichment limited to circadian processes. Thus, contrary to previous reports, hepatic REVERBα does not repress lipogenesis under basal conditions. REVERBα control of a more extensive transcriptional program is only revealed under conditions of metabolic perturbation (including mistimed feeding, which is a feature of the global Reverbα -/- mouse). Repressive action of REVERBα in the liver therefore serves to buffer against metabolic challenge, rather than drive basal rhythmicity in metabolic activity

A frequentist framework of inductive reasoning

Reacting against the limitation of statistics to decision procedures, R. A. Fisher proposed for inductive reasoning the use of the fiducial distribution, a parameter-space distribution of epistemological probability transferred directly from limiting relative frequencies rather than computed according to the Bayes update rule. The proposal is developed as follows using the confidence measure of a scalar parameter of interest. (With the restriction to one-dimensional parameter space, a confidence measure is essentially a fiducial probability distribution free of complications involving ancillary statistics.) A betting game establishes a sense in which confidence measures are the only reliable inferential probability distributions. The equality between the probabilities encoded in a confidence measure and the coverage rates of the corresponding confidence intervals ensures that the measure's rule for assigning confidence levels to hypotheses is uniquely minimax in the game. Although a confidence measure can be computed without any prior distribution, previous knowledge can be incorporated into confidence-based reasoning. To adjust a p-value or confidence interval for prior information, the confidence measure from the observed data can be combined with one or more independent confidence measures representing previous agent opinion. (The former confidence measure may correspond to a posterior distribution with frequentist matching of coverage probabilities.) The representation of subjective knowledge in terms of confidence measures rather than prior probability distributions preserves approximate frequentist validity.Comment: major revisio

Residual confounding after adjustment for age: a minor issue in breast cancer screening effectiveness

Residual confounding, after adjustment for age, is the major criticism of observational studies on breast cancer screening effectiveness. We developed realistic scenarios for the prevalence and strength of risk factors on screened and not screened groups, and explored the impact of residual confounding bias. Our results demonstrate that residual confounding bias is a minor issue in screening programme evaluations

Estimating Design Effect and Calculating Sample Size for Respondent-Driven Sampling Studies of Injection Drug Users in the United States

Respondent-driven sampling (RDS) has become increasingly popular for sampling hidden populations, including injecting drug users (IDU). However, RDS data are unique and require specialized analysis techniques, many of which remain underdeveloped. RDS sample size estimation requires knowing design effect (DE), which can only be calculated post hoc. Few studies have analyzed RDS DE using real world empirical data. We analyze estimated DE from 43 samples of IDU collected using a standardized protocol. We find the previous recommendation that sample size be at least doubled, consistent with DE = 2, underestimates true DE and recommend researchers use DE = 4 as an alternate estimate when calculating sample size. A formula for calculating sample size for RDS studies among IDU is presented. Researchers faced with limited resources may wish to accept slightly higher standard errors to keep sample size requirements low. Our results highlight dangers of ignoring sampling design in analysis

What Do Computer Scientists Tweet? Analyzing the Link-Sharing Practice on Twitter

Twitter communication has permeated every sphere of society. To highlight and share small pieces of information with possibly vast audiences or small circles of the interested has some value in almost any aspect of social life. But what is the value exactly for a scientific field? We perform a comprehensive study of computer scientists using Twitter and their tweeting behavior concerning the sharing of web links. Discerning the domains, hosts and individual web pages being tweeted and the differences between computer scientists and a Twitter sample enables us to look in depth at the Twitter-based information sharing practices of a scientific community. Additionally, we aim at providing a deeper understanding of the role and impact of altmetrics in computer science and give a glance at the publications mentioned on Twitter that are most relevant for the computer science community. Our results show a link sharing culture that concentrates more heavily on public and professional quality information than the Twitter sample does. The results also show a broad variety in linked sources and especially in linked publications with some publications clearly related to community-specific interests of computer scientists, while others with a strong relation to attention mechanisms in social media. This refers to the observation that Twitter is a hybrid form of social media between an information service and a social network service. Overall the computer scientists’ style of usage seems to be more on the information-oriented side and to some degree also on professional usage. Therefore, altmetrics are of considerable use in analyzing computer science

The significance of the Van Nuys prognostic index in the management of ductal carcinoma in situ

<p>Abstract</p> <p>Background</p> <p>Debate regarding the benefit of radiotherapy after local excision of ductal carcinoma <it>in situ </it>(DCIS) continues. The Van Nuys Prognostic Index (VNPI) is thought to be a useful aid in deciding which patients are at increased risk of local recurrence and who may benefit from adjuvant radiotherapy (RT). Recently published interim data from the Sloane project has showed that the VNPI score did significantly affect the chances of getting planned radiotherapy in the UK, suggesting that British clinicians may already be using this scoring system to assist in decision making. This paper independently assesses the prognostic validity of the VNPI in a British population.</p> <p>Patients and methods</p> <p>A retrospective review was conducted of all patients (n = 215) who underwent breast conserving surgery for DCIS at a single institution between 1997 – 2006. No patients included in the study received additional radiotherapy or hormonal treatment. Kaplan Meier survival curves were calculated, to determine disease free survival, for the total sample and a series of univariate analyses were performed to examine the value of various prognostic factors including the VNPI. The log-rank test was used to determine statistical significance of differential survival rates. Multivariate Cox regression analysis was performed to analyze the significance of the individual components of the VNPI. All analyses were conducted using SPSS software, version 14.5.</p> <p>Results</p> <p>The mean follow-up period was 53 months (range 12–97, SD19.9). Ninety five tumours were high grade (44%) and 84 tumours exhibited comedo necrosis (39%). The closest mean initial excision margin was 2.4 mm (range 0–22 mm, standard deviation 2.8) and a total of 72 tumours (33%) underwent further re-excision. The observed and the actuarial 8 year disease-free survival rates in this study were 91% and 83% respectively. The VNPI score and the presence of comedo necrosis were the only statistically significant prognostic indicators (P < 0.05).</p> <p>Conclusion</p> <p>This follow-up study of 215 patients with DCIS treated with local excision and observation alone is one of the largest series in which rates of recurrence are unaffected by radiation therapy, hormone manipulation or chemotherapy. It has afforded us the opportunity to assess the prognostic impact of patient and tumour characteristics free of any potentially confounding treatment related influences. The results suggest that the VNPI can be used to identify a subset of patients who are at risk of local recurrence and who may potentially benefit from RT.</p