Miracle-dz/UniFAR-FTUs huggingface dataset:
Comprehensive Genomic Analysis Identifies Novel Subtypes and Targets of Triple-Negative Breast Cancer

Purpose: Genomic profiling studies suggest that triple-negative breast cancer (TNBC) is a heterogeneous disease. In this study, we sought to define TNBC subtypes and identify subtype-specific markers and targets. Experimental Design: RNA and DNA profiling analyses were conducted on 198 TNBC tumors [estrogen receptor (ER) negativity defined as Allred scale value ≤ 2] with >50% cellularity (discovery set: n = 84; validation set: n = 114) collected at Baylor College of Medicine (Houston, TX). An external dataset of seven publically accessible TNBC studies was used to confirm results. DNA copy number, disease-free survival (DFS), and disease-specific survival (DSS) were analyzed independently using these datasets. Results: We identified and confirmed four distinct TNBC subtypes: (i) luminal androgen receptor (AR; LAR), (ii) mesenchymal (MES), (iii) basal-like immunosuppressed (BLIS), and (iv) basal-like immune-activated (BLIA). Of these, prognosis is worst for BLIS tumors and best for BLIA tumors for both DFS (log-rank test: P = 0.042 and 0.041, respectively) and DSS (log-rank test: P = 0.039 and 0.029, respectively). DNA copy number analysis produced two major groups (LAR and MES/BLIS/BLIA) and suggested that gene amplification drives gene expression in some cases [FGFR2 (BLIS)]. Putative subtype-specific targets were identified: (i) LAR: androgen receptor and the cell surface mucin MUC1, (ii) MES: growth factor receptors [platelet-derived growth factor (PDGF) receptor A; c-Kit], (iii) BLIS: an immunosuppressing molecule (VTCN1), and (iv) BLIA: Stat signal transduction molecules and cytokines. Conclusion: There are four stable TNBC subtypes characterized by the expression of distinct molecular profiles that have distinct prognoses. These studies identify novel subtype-specific targets that can be targeted in the future for the effective treatment of TNBCs. Clin Cancer Res; 21(7); 1688–98. ©2014 AACR. See related commentary by Vidula and Rugo, p. 1511
Dealing with overdispersed count data in applied ecology

Summary 1. The ability to identify key ecological processes is important when solving applied problems. Increasingly, ecologists are adopting Akaike's information criterion (AIC) as a metric to help them assess and select among multiple process-based ecological models. Surprisingly, however, it is still unclear how best to incorporate AIC into the selection process in order to address the trade-off between maximizing the probability of retaining the most parsimonious model while minimizing the number of models retained. 2. Ecological count data are often observed to be overdispersed with respect to best-fitting models. Overdispersion is problematic when performing an AIC analysis, as it can result in selection of overly complex models which can lead to poor ecological inference. This paper describes and illustrates two approaches that deal effectively with overdispersion. The first approach involves modelling the causes of overdispersion implicitly using compound probability distributions. The second approach ignores the causes of overdispersion and uses quasi-AIC (QAIC) as a metric for model parsimony. 3. Simulations and a novel method that identifies the most parsimonious model are used to demonstrate the utility of the two overdispersion approaches within the context of two ecological examples. The first example addresses binomial data obtained from a study of fish survival (as related to habitat structure) and the second example addresses Poisson data obtained from a study of flower visitation by nectarivores. 4. Applying either overdispersion approach reduces the chance of selecting overly complex models, and both approaches result in very similar ecological inference. In addition, inference can be made more reliable by incorporating model nesting into the selection process (i.e. identifying which models are special cases of others), as it reduces the number of models selected without significantly reducing the probability of retaining the most parsimonious models. 5. Synthesis and applications. When data are overdispersed, inference can be improved by either modelling the causes of overdispersion or applying QAIC as a metric for model parsimony. Inference can also be improved by adopting a model filtering procedure based on how models are nested. The general simulation approach presented in this paper for identifying the most parsimonious model, as defined by information theory, should help to improve our understanding of the reliability of model selection when using AIC, and help the development of better selection rules.
Superior-olivary response patterns to monaural and binaural clicks.

This study presents responses to dichotic clicks obtained from neurons of the medial superior‐olivary nucleus of anesthetized cats. The neurons described in this study evidenced interactive patterns to both time and intensity differences by changes in their probabilities of response and by shifts in their latency. These findings suggest a complex synaptic organization of neurons, some of which are responsive to large and some to small interaural time differences. The former neurons that show interactions to large time differences (ca. 10.0 msec) respond consistently to both monaural left and right clicks. Binaural clicks, however, significantly decrease the probability of firing in response to stimulation of the lagging ear. Some of the latter neurons that show interactions to small time differences (ca. 0–2.0 msec) fire only once, while others discharge twice to a monaural click; these single and double responders exhibit changes in latency and probability of their firings upon binaural stimulation and, .
Impact of improved glycaemic control on rates of hypoglycaemia in insulin dependent diabetes mellitus

Increased emphasis on strict glycaemic control of insulin dependent diabetes mellitus (IDDM) in young patients may be expected to cause increases in rates of significant hypoglycaemia. To evaluate whether this is the case for a large population based sample of IDDM children and adolescents rates of severe (coma, convulsion) and moderate (requiring assistance for treatment) hypoglycaemia were studied prospectively over a four year period. A total of 709 patients were studied yielding 2027 patient years of data (mean (SD) age: 12.3 (4.4); range 0–18 years, duration IDDM: 4.9 (3.8) years). Details of hypoglycaemia were recorded at clinic visits every three months when glycated haemoglobin (HbA1c) was also measured. Overall the incidence of severe hypoglycaemia was 7.8 and moderate was 15.4 episodes/100 patient years. Over the four years mean (SD) clinic HbA1c steadily fell from 10.2 (1.6)% in 1992 to 8.8 (1.5)% in 1995. In parallel with this there was a dramatic increase in the rate of hypoglycaemia, especially in the fourth year of the study, when severe hypoglycaemia increased from 4.8 to 15.6 episodes/100 patient years. This increase was particularly marked in younger children (<6 years) in whom severe hypoglycaemia increased from 14.9 to 42.1 episodes/100 patient years in 1995. It is concluded that attempts to achieve improved metabolic control must be accompanied by efforts to minimise the effects of significant hypoglycaemia, particularly in the younger age group.
Laparoscopic and Transvaginal Ultrasound Guided Aspiration Cytology of Ovarian Cysts

Objective: To compare and evaluate the effectiveness of laparoscopy and transvaginal ultrasound guided aspiration of ovarian cysts. Materials and Methods: One hundred and twenty-five patients diagnosed to have an ovarian cyst ‡5 cm in diameter which persisted for more than three months between 01.01. 1999 and 01.01. 2001 were included in the analysis. Ninety cases with simple cysts having Ca-125 level <35 U/ml underwent laparoscopy guided cyst aspiration followed by excision (Group I) while thirty-five cases with simple cysts with Ca-125 level <35 U/ml underwent transvaginal ultrasound guided cyst aspiration (Group II). All patients were followed up via transvaginal ultrasound every three months for twelve months. Recurrences were treated via laparoscopic excision. Results: The mean age of the patients were 33.2‐9.2. All patients in Group I had benign cytology and postoperative pathological examination revealed serous cyst in 60 cases (66%), mucinous cyst in 12 cases (13%) and follicular cyst in 18 cases (20%). One (1%) recurrence occured in Group I and was benign in nature. All patients in Group II had benign cytology. In Group II three recurrences (8%) were identified and postoperative pathology revealed borderline serous carcinoma in one case (3%) while the other two (5%) were benign in nature. Recurrences were significantly more frequent in Group II (p=0.04). C o n c l u s i o n : Laparoscopy guided and transvaginal ultrasound guided aspiration of ovarian cysts do not differ in effectiveness in terms of getting sufficient material for cytology. Transvaginal ultrasound guided aspiration and cytological evaluation is a valuable and precise tool for patients who have operative risks, however its efficiency in diagnosing borderline malignant tumors should be evaluated with further studies.
T regulatory lymphocytes in type 1 diabetes: Impaired CD25 expression and IL-2 induced STAT5 phosphorylation in pediatric patients

Abstract T regulatory cells (Tregs) are essential for maintaining tolerance and preventing autoimmune diseases, such as type 1 diabetes (T1D). In our study, we investigated CD25 + FoxP3 + Tregs and thymic FoxP3 + Helios + Tregs in large cohorts of children with T1D at onset and with long-term T1D, and further in their relatives and healthy controls. We observed significantly decreased numbers of CD25 + FoxP3 + Tregs, but not FoxP3 + Helios + Tregs, in long-term patients compared with the control group and T1D onset. Furthermore, long-term T1D patients exhibited highly significant decrease of CD25 expression on both CD25 + FoxP3 + Tregs and FoxP3 + Helios + Tregs, independently on age or the duration of diabetes. A similar reduction of CD25 expression was also found in T1D relatives, more significant in those with positive autoantibodies. Low CD25 expression was associated with impaired signal transducer and activator of transcription 5 (STAT5) phosphorylation after IL-2 exposure. Our results show that the frequency of Tregs is altered in a large cohort of long-term T1D patients, a profound decrease in CD25 expression and altered IL-2 signaling are typical features of Tregs populations in long-term diabetic patients and their relatives.
Prescription and dispensing practices in public sector health facilities in Pakistan: survey report.

OBJECTIVES To gather information on existing prescription practices, dispensing practices and patient satisfaction in government health services of the NWFP, Baluchistan and Punjab province. METHODS A cross sectional study design was used for this purpose. Ten health care facilities were selected from each province keeping appropriate representation from first level health facilities, district health facilities and tertiary care hospital. Analysis of selected indicators was carried out on the basis of provinces, health facilities, gender and different age groups. RESULTS Documentation of 914 responses was completed from three provinces. Almost equal distribution of encounters was maintained representing different health facilities. Forty seven percent of encounters involved children under 15 years of age. Female patients comprised of 56% and the mean age of the entire sample was 26 years. The mean dispensing time was only 38 seconds, the mean consultation time was 1.79 minutes and the average number of drugs per prescription turned out to be 2.7 out of which only 1.6 drugs were being dispensed from the facility. More than half of the prescriptions contained antibiotics and 15% of patients were prescribed with injectables. Only half of the patients expressed satisfaction with their visit to health facility. CONCLUSIONS Like many other developing countries, prescription and dispensing practices are not satisfactory in public sector health facilities of Pakistan. Appropriate and workable solutions need to be developed and implemented in the country to improve systems. Regular audits and qualitative studies should become part of the effort.
FOREBRAIN OSMOTIC REGULATION OF THE SYMPATHETIC NERVOUS SYSTEM

1 Accumulating evidence in both humans and animals indicates that acute increases in plasma osmolality elevate sympathetic nerve activity (SNA). In addition, plasma hyperosmolality (or hypernatraemia) can produce sustained increases in SNA and arterial blood pressure (ABP) through stimulation of forebrain osmoreceptors. 2 Although an abundance of information exists regarding the osmoregulatory circuits for thirst and secretion of antidiuretic hormone, much less is known about those pathways and synaptic mechanisms linking osmotic perturbations and SNA. To date, the available evidence suggests that osmosensitive sites within the forebrain lamina terminalis, such as the organum vasculosum of the lamina terminalis, are key elements that link plasma hypertonicity to elevated SNA. 3 The major efferent target of osmosensitive regions in the forebrain lamina terminalis is the hypothalamic paraventricular nucleus (PVH). Evidence from a number of studies indicates that the PVH contributes to both acute and chronic osmotically driven increases in SNA. In turn, PVH neurons increase SNA through a direct vasopressinergic spinal pathway and/or a glutamatergic pathway to bulbospinal sympathetic neurons of the rostral ventrolateral medulla. 4 Future studies are needed to: (i) define the contribution of various osmosensitive regions of the forebrain lamina terminalis to acute and chronic osmotically driven increases in SNA; (ii) identify the cellular mechanisms and neural circuitry linking plasma osmolality and SNA; and (iii) define whether such mechanisms contribute to elevated SNA in salt‐sensitive hypertension.
The tragedy of the commons revisite.

There has developed in the contemporary natural sciences a recognition that there is a subset of problems such as population atomic war and environmental corruption for which there are no technical solutions (1 2). There is also an increasing recognition among contemporary social scientists that there is a subset of problems such as population atomic war environmental corruption and the recovery of a livable urban environment for which there are no current political solutions [(3)]. The thesis of this article is that the common area shared by these two subsets contains most of the critical problems that threaten the very existence of contemporary man. (excerpt)
Admission levels and early changes in serum interleukin‐10 are predictive of poor outcome in acute liver failure and decompensated cirrhosis

Backround & Aim: Immunoparesis contributes to prognosis in acute liver failure (ALF) and decompensated cirrhosis, a phenomenon thought to be mediated by the anti‐inflammatory cytokine interleukin (IL)‐10. We investigated the prognostic value of admission IL‐10 levels and their evolution during the early phase of treatment in intensive care, in comparison to the pro‐inflammatory cytokines IL‐6 and tumour necrosis factor (TNF)‐α.
Children with specific language impairment and resolved late talkers: working memory profiles at 5 years.

PURPOSE The evidence of a deficit in working memory in specific language impairment (SLI) is of sufficient magnitude to suggest a primary role in developmental language disorder. However, little research has investigated memory in late talkers who recover from their early delay. Drawing on a longitudinal, community sample, this study compared the memory profiles of 3 groups of 5-year-olds: children with SLI who had been identified as late talkers, resolved late talkers (RLTs), and children with typical language development (TLD). METHOD Participants were 25 children with SLI, 45 RLTs, and 32 children with TLD. Subtests from the Working Memory Test Battery for Children and the Children's Memory Scale plus recalling sentences and nonword repetition tasks were administered to test the components of Baddeley's working memory model. RESULTS The SLI group showed significantly poorer performance than the RLT and TLD groups on measures of the phonological loop and episodic buffer. The RLT and TLD groups scored similarly on all memory measures. CONCLUSIONS The results support previous findings that sentence recall and nonword repetition are markers of SLI. Although residual effects of late-talking status may emerge over time, RLTs do not necessarily show memory deficits at 5 years of age despite delayed early vocabulary development.
Effect of extracorporeal shock wave therapy on the biochemical composition and metabolic activity of tenocytes in normal tendinous structures in ponies.

REASONS FOR PERFORMING STUDY Extracorporeal shockwave therapy (ESWT) has recently been introduced as a new therapy for tendon injuries in horses, but little is known about the basic mechanism of action of this therapy. OBJECTIVES To study the effect of ESWT on biochemical parameters and tenocyte metabolism of normal tendinous structures in ponies. METHODS Six Shetland ponies, free of lameness and with ultrasonographically normal flexor and extensor tendons and suspensory ligaments (SL), were used. ESWT was applied at the origin of the suspensory ligament and the mid-metacarpal region of the superficial digital flexor tendon (SDFT) 6 weeks prior to sample taking, and at the mid-metacarpal region (ET) and the insertion on the extensor process of the distal phalanx (EP) of the common digital extensor tendon 3 h prior to tendon sampling. In all animals one front leg was treated and the other front leg was used as control. After euthanasia, tendon explants were harvested aseptically for in vitro cell culture experiments and additional samples were taken for biochemical analyses. RESULTS In the explants harvested 3 h after treatment, glycosaminoglycan (GAG) and protein syntheses were increased (P<0.05). The synthesis of all measured parameters was decreased 6 weeks after ESWT treatment. Biochemically, the level of degraded collagen was increased 3 h after treatment (P<0.05). Six weeks after treatment, there was a decrease of degraded collagen and GAG contents. DNA content had not changed in either tendon samples or explants after culturing. CONCLUSIONS ESWT causes a transient stimulation of metabolism in tendinous structures of ponies shortly after treatment. After 6 weeks metabolism has decreased significantly and GAG levels are lower than in untreated control limbs. POTENTIAL RELEVANCE The stimulating short-term effect of ESWT might accelerate the initiation of the healing process in injured tendons. The long-term effect seems less beneficial. Further research should aim at determining the duration of this effect and at assessing its relevance for end-stage tendon quality.
A prospective randomized study of a collar versus a collarless femoral prosthesis.

A prospective, randomized study of 44 collared versus 40 collarless cemented HD-2 total hip arthroplasties (THAs) was performed in 84 patients. Seventy patients were examined at an average of 4.6 years after surgery. Five hips have required, or are scheduled to have, revision arthroplasty: two with collared prostheses and three with collarless prostheses. Good collar contact with the proximal medial femur was achieved in 47% of the collared prostheses. No patient with good contact has required or is scheduled to have revision hip surgery. Radiolucent lines were greater in both frequency and width in Gruen Zones 2 and 7 in patients with a collarless prosthesis. Loss of endosteal height of the femoral neck was 3.5 mm in patients with collarless prostheses and 1.7 mm in patients with collared prostheses. Loss in height of the femoral neck was 2.6 mm in patients with collared prostheses with poor bone contact and 0.7 mm in patients with collared prostheses with good bone contact. The mean preoperative and postoperative Harris hip scores for the collarless group and for the collared group were not statistically different. There were no statistically significant differences in acetabular position, the incidence of acetabular radiolucent lines, or femoral subsidence between patients treated with collared or collarless prostheses. This study demonstrates that it is possible to stress the proximal medial portion of the femur with a collared prosthesis. Furthermore, a significant increase is identified in both the frequency and width of radiolucent lines in patients with collarless prostheses in Zones 2 and 7. (ABSTRACT TRUNCATED AT 250 WORDS)
Selenium deficiency occurs in some patients with moderate-to-severe cirrhosis and can be corrected by administration of selenate but not selenomethionine: a randomized controlled trial.

BACKGROUND Selenomethionine, which is the principal dietary form of selenium, is metabolized by the liver to selenide, which is the form of the element required for the synthesis of selenoproteins. The liver synthesizes selenium-rich selenoprotein P (SEPP1) and secretes it into the plasma to supply extrahepatic tissues with selenium. OBJECTIVES We conducted a randomized controlled trial to determine whether cirrhosis is associated with functional selenium deficiency (the lack of selenium for the process of selenoprotein synthesis even though selenium intake is not limited) and, if it is, whether the deficiency is associated with impairment of selenomethionine metabolism. DESIGN Patients with Child-Pugh (C-P) classes A, B, and C (mild, moderate, and severe, respectively) cirrhosis were supplemented with a placebo or supranutritional amounts of selenium as selenate (200 or 400 μg/d) or as selenomethionine (200 μg/d) for 4 wk. Plasma SEPP1 concentration and glutathione peroxidase (GPX) activity, the latter due largely to the selenoprotein GPX3 secreted by the kidneys, were measured before and after supplementation. RESULTS GPX activity was increased more by both doses of selenate than by the placebo in C-P class B patients. The activity was not increased more by selenomethionine supplementation than by the placebo in C-P class B patients. Plasma selenium was increased more by 400 μg Se as selenate than by the placebo in C-P class C patients. Within the groups who responded to selenate, there was a considerable variation in responses. CONCLUSION These results indicate that severe cirrhosis causes mild functional selenium deficiency in some patients that is associated with impaired metabolism of selenomethionine. This trial was registered at clinicaltrials.gov as NCT00271245.
Reflect NHS clinical realities

Beral and Peto argue that the British and Irish cancer registries’ consistent record of inferior survival compared with other European countries is caused by survival estimation biased by incomplete registration.1 However, poor survival from lung cancer in the UK compared with Italy has been confirmed using prospectively acquired data rather than registration records,2 and …
Manual vs. pressure‐controlled facemask ventilation for anaesthetic induction in paralysed children: a randomised controlled trial

During anaesthetic induction with a facemask, the inconsistent inspiratory flow with manual ventilation (MV) raises the peak airway pressure (PAP), which can be significantly higher than PAP during pressure‐controlled ventilation (PCV). In this study, PAP was compared between MV and PCV at the same tidal volume of 8–10 ml/kg during facemask ventilation for anaesthetic induction in children. The occurrence of gastric insufflation (GI) was evaluated with ultrasonography and stethoscopic auscultation.