Miracle-dz/UniFAR-FTUs huggingface dataset:
Safety, Tolerability, and Pharmacokinetics of a Capsule Formulation of DRF‐1042, a Novel Camptothecin Analog, in Refractory Cancer Patients in a Bridging Phase I Study

The purpose of this bridging phase I study was to characterize the toxicity, pharmacokinetics, and antitumor effects of a capsule formulation of DRF‐1042, a novel camptothecin analog, in refractory solid tumor patients. DRF‐1042 was given daily for 5 consecutive days for 2 weeks, repeated every 3 weeks at 81 mg/m2. Adverse events were monitored following NCI‐CTC. Blood samples were processed for bioanalysis using a validated high‐performance liquid chromatography method. The pharmacokinetics of lactone and total (lactone + carboxylate) forms was determined on days 1 and 12 using a noncompartmental pharmacokinetic method. Pharmacokinetic data with the capsule formulation were compared with previously reported pharmacokinetic parameters with a suspension formulation. Efficacy was evaluated by applying World Health Organization criteria. Six patients received 10 courses of therapy. Thrombocytopenia and diarrhea were dose‐limiting toxicities. The upper limit of the area under the curve of DRF‐1042 (lactone and total) with the capsule formulation was higher than a suspension formulation at a similar dose on day 1 (lactone: capsule = 8.53 μM•h, suspension = 5.33 μM•h; total: capsule = 393 μM•h, suspension = 176 μM•h) and day 12 (lactone: capsule= 22.1 μM•h, suspension = 6.1 μM•h; total: capsule = 1302 μM•h, suspension = 309 μM•h). The upper limit of the area under the curve of DRF‐1042 (lactone and total) was higher under fed conditions (lactone = 15.9 μM•h, total = 605 μM•h) relative to fasted conditions (lactone = 8.53 μM•h, total = 393 μM•h) on day 1. One patient experienced stable disease. The toxicity and pharmacokinetics of the capsule correlated well with the suspension. The recommended phase II dose is 81 mg/m2.
Is parenteral nutrition really that risky in the intensive care unit?

Purpose of reviewAlthough enteral nutrition is now the mainstay of nutrition delivery within intensive care, there is a blind faith in its benefits and a disregard of its risks. This has led to the belief that parenteral nutrition is no longer required as it is fraught with risks to the patient. This review attempts to dispel these myths and compares and contrasts the risks of enteral nutrition with those of parenteral nutrition in the critically ill. Recent findingsA greater appreciation of the failings and risks associated with the delivery of enteral nutrition combined with improvements in the formulation and use of parenteral nutrition help explain why parenteral nutrition is not as risky as some have believed. Recent evidence has suggested that enteral nutrition in a few selected circumstances may even carry a higher mortality risk. Real outcome benefits have been described with the new glutamine-containing parenteral nutrition formulations. SummaryParenteral nutrition remains a valuable yet challenging weapon in our therapeutic armoury in the presence of gastrointestinal feed intolerance or failure. However, it should be used wisely and not indiscriminately because the majority of intensive care unit patients with a fully functional gastrointestinal tract may be fed safely with enteral nutrition.
Exercise perceptions among people with stroke: Barriers and facilitators to participation.

BACKGROUND/AIMS: People with stroke continue to lead sedentary lives despite the multiple benefits of exercise. Knowledge regarding stroke survivors' conception of exercise, which is essential for a thorough understanding of the barriers and facilitators to exercise, is lacking. This study aims to explore the perceptions of exercise among stroke survivors, including their concepts and definitions of exercise, as well as their perceptions of barriers and facilitators to exercise. METHODS: This study utilized a qualitative exploratory design. Focus groups were conducted with 11 community dwelling participants with stroke (mean 8 ± 3 years post stroke). Data was analysed using content analysis methods. FINDINGS: Six themes that provided information regarding participants' perceptions of exercise were identified: mobility, balance, self-efficacy, outcomes, support, and exercise as part of an active or healthy lifestyle. Although participants internalized specific benefits of exercise, they did not demonstrate an internalized link between exercise and stroke risk. Low self-efficacy was identified as a barrier to participating in exercise, whereas, support to exercise (e.g., external encouragement, qualified personnel) was identified as a facilitator. CONCLUSION: These findings may provide insight when developing exercise interventions which optimize adherence for people with stroke.
Efectos de un programa de rehabilitación de la musculatura inspiratoria en el postoperatorio de cirugía cardiaca

FUNDAMENTO: Los musculos respiratorios se ven afectados tras operaciones cardiacas. OBJETIVO: Verificar si el condicionamiento preoperatorio de los musculos inspiratorios podria ayudar a disminuir la disfuncion respiratoria postoperatoria. METODOS: Se dividieron en dos grupos, y de forma randomica, a 30 voluntarios -de ambos sexos, con edad minima de 50 ano- que aguardaban cirugia de revascularizacion del miocardio y/o cirugia de valvula cardiaca. Se incluyo a un total de 15 pacientes en un programa domiciliar, de por lo menos 2 semanas de entrenamiento preoperatorio de los musculos inspiratorios, utilizandose un dispositivo con una carga correspondiente al 40% de la presion inspiratoria maxima. Los otros 15 individuos recibieron orientaciones generales y no entrenaron los musculos inspiratorios. Tanto la espirometria, antes y luego del programa de entrenamiento, asi como la evolucion de los gases sanguineos arteriales y de las presiones inspiratoria y espiratoria maximas, se las evaluaron en ambos grupos antes y tras la cirugia. Se compararon tambien los desenlaces clinicos de los dos grupos. RESULTADOS: Observamos que el entrenamiento de los musculos inspiratorios aumento la capacidad vital forzada, la ventilacion voluntaria maxima y la relacion entre el volumen espirado forzado en el primer segundo y la capacidad vital forzada. La evolucion de los gases sanguineos y de las presiones espiratoria e inspiratoria maximas antes y tras la cirugia se mostro similar en ambos grupos, con desenlaces tambien similares. CONCLUSION: Concluimos que nuestro programa domiciliar de entrenamiento de los musculos inspiratorios fue seguro y produjo la mejora de la capacidad vital forzada y la ventilacion voluntaria maxima, aunque los beneficios clinicos de ese programa no han sido claramente demostrados en el presente estudio.
Flexible Regression Models for Rate Differences, Risk Differences and Relative Risks

Abstract Generalized additive models (GAMs) based on the binomial and Poisson distributions can be used to provide flexible semi-parametric modelling of binary and count outcomes. When used with the canonical link function, these GAMs provide semi-parametrically adjusted odds ratios and rate ratios. For adjustment of other effect measures, including rate differences, risk differences and relative risks, non-canonical link functions must be used together with a constrained parameter space. However, the algorithms used to fit these models typically rely on a form of the iteratively reweighted least squares algorithm, which can be numerically unstable when a constrained non-canonical model is used. We describe an application of a combinatorial EM algorithm to fit identity link Poisson, identity link binomial and log link binomial GAMs in order to estimate semi-parametrically adjusted rate differences, risk differences and relative risks. Using smooth regression functions based on B-splines, the method provides stable convergence to the maximum likelihood estimates, and it ensures that the estimates always remain within the parameter space. It is also straightforward to apply a monotonicity constraint to the smooth regression functions. We illustrate the method using data from a clinical trial in heart attack patients.
Calcium dependence of presynaptic calcium current and post‐synaptic response at the squid giant synapse.

1. Neurotransmitter release has a non‐linear dependence upon the external Ca concentration, [Ca]o. This may be due to a 'co‐operative' action of Ca in triggering release. The dependence of presynaptic Ca currents and post‐synaptic currents (p.s.c.s) upon [Ca]o was examined at voltage‐clamped 'giant' synapses of squid to determine whether this 'co‐operativity' occurs during or after influx of Ca into the presynaptic terminal. 2. Presynaptic Ca current was proportional to [( Ca]o/(1 + [Ca]o/KD]n, where n, the order of the function, was roughly 1 and KD, the apparent dissociation constant for Ca, was approximately 80 mM. 3. P.s. c.s also could be described by the same function, but had an n of 3‐4 and a lower KD. 4. These results suggest that the 'co‐operative' action of Ca occurs at a step or steps beyond entry of Ca into the presynaptic terminal. 5. Synaptic transfer curves relating presynaptic Ca currents, elicited by depolarizations to different potentials, to resultant p.s. c.s were power functions whose exponent depended upon [Ca]o. Maximum exponents were as high as 4 at [Ca]o of 3 mM. The dependence of these curves upon [Ca]o helps to explain why previous determinations, which were performed at a variety of [Ca]o levels, yielded a variety of transfer curve exponent values. 6. Transfer curves generated from responses to constant presynaptic depolarizations, with Ca current varied by [Ca]o changes, also were power functions with exponents of approximately 4. Thus p.s. c.s were high‐exponent power functions of Ca current regardless of whether Ca current was modified by changes in membrane potential or in [Ca]o.
Survey: Did the TFP Growth Rate in Japan Decline in the 1990s?(in Japanese)

This paper surveys the body of research grounded on a basic question "Did the total factor productivity (TFP) growth rate in Japan decline in the 1990s? " In addition, using industry-level data of the Japan Industrial Productivity Database (JIP database) we estimate the mark-ups and the degree of returns to scale and then re-estimate TFP growth rates. Most of studies reviewed in this paper show a decline in TFP growth in the 1990s at the macro-level and the industry-level. There are some studies that show only a small decline in the TFP growth rate during the 1990s. Our estimation results show that mark-ups are positive and statistically significant in almost all industries. The estimated scale effects are also strong and significant in almost all industries. We examine how mark-up and returns to scale estimates affect the estimated TFP growth rates using the Japan Industry Productivity database. We find that the rate of technical progress is faster in the 1990s than in the 1980s if we take economies of scale into account.
Economics, Risk-Cost-Benefit Analysis, and the Linearity Assumption

An offshoot of decision analysis, risk-cost-benefit analysis (RCBA) dominates US policymaking regarding science and technology. In this paper a central normative presupposition of RCBA, called "the linearity assumption" is argued against. This is that there is a linear relationship between the actual probability of fatality and the value of avoiding a social risk or the cost of a social risk. The main object of this essay is to show that the presuppositions underlying the linearity assumption are highly questionable. It is maintained that assessors ought to give more consideration to broadening their interpretations of "unit cost" and "societal risk" and to abandoning their claims about linearity.
3D haptic shape perception using a 2D device

Is a 2-dimensional (2D) force feedback device capable of presenting 3-dimensional (3D) shapes? The answer is a qualified "yes. " "Force shading", a haptic counterpart of bump mapping in computer graphics, presents a non-flat shape on a nominally flat surface by varying the force vector direction in haptic rendering [Morgenbesser and Srinivasan 1996][Robles-De-La-Torre and Hayward 2001]. To our knowledge, such phenomena have been qualitatively measured only by 3D devices, and a quantitative comparison to 2D devices has not been made. We compare thresholds of human shape perception of the plane experimentally, using 2D and 3D force feedback devices.
Measurement of urine total sialic acid: comparison of an automated ultraviolet enzymatic method with a colorimetric assay

Abstract An automated ultraviolet (UV) enzymatic assay for urine total sialic acid (SA), performed on a Cobas Fara analyser, is described and compared with the colorimetric Warren method, which is used widely to determine urine SA. Intra-assay coefficient of variation (CV) for urine total SA determination was 0.83% for the UV assay and 3.5% for the Warren method. Inter-assay CVs were 1.8% and 5.6%, respectively. Recovery of urine total SA ranged from 89% for the UV assay to 61% for the Warren method. Both were linear over a range of urine SA from 20 to 240 mg/L The UV assay was automated, took approximately 20 min to produce a result and avoided the need for solvent extraction; however, the reagents were expensive in comparison to those required for the Warren method. Urine samples with a creatinine concentration >14 mmol/L were diluted with distilled water to optimise SA recovery by the UV method. Urine SA:creatinine ratios for normals were 4.7 (±1.7) g/mol with the Warren method and 4.5 (±1.0) g/mol for the UV method. Similarly, in type-2 diabetic patients, urine SA:creatinine ratios were 7.6 (±2.3) g/mol (P<0.001) and 8.5 (±2.9) g/mol (P<0.001), respectively.
Nucleo-cytoplasmic Shuttling of Id2, a Negative Regulator of Basic Helix-Loop-Helix Transcription Factors*

Id proteins function as negative regulators for basic helix-loop-helix transcriptional factors that play important roles in cell fate determination. They preferentially associate with ubiquitously expressed E proteins of the basic helix-loop-helix family and prevent them from binding to DNA and activating transcription. Although their small size suggests that Id proteins enter and exit the nucleus by passive diffusion, several studies have indicated that other pathways may regulate their subcellular localization. In this study, we obtained evidence that Id2 has the ability to shuttle between the nucleus and the cytoplasm. When passive diffusion was prevented by fusion with green fluorescent protein (GFP), Id2 was predominantly localized in the cytoplasm. Using GFP fusion constructs, we demonstrated that the C-terminal region is required for cytoplasmic localization. Nuclear accumulation of GFP-Id2 in cells treated with the nuclear export inhibitor leptomycin B suggests that the nuclear export receptor chromosome region maintenance protein 1 mediates the cytoplasmic localization of Id2. Id2 contains two putative leucine-rich nuclear export signals, and the nuclear export signal in the C-terminal region is essential for nuclear export. On the other hand, the helix-loop-helix domain is important for nuclear localization. Finally, experiments using reporter assays revealed an inverse correlation between nuclear export and transcriptional repression via the E-box sequence. Based on all these findings, we propose that nucleo-cytoplasmic shuttling is a novel mechanism for the regulation of Id2 function.
The pragmatic language abilities of children with ADHD following a play-based intervention involving peer-to-peer interactions

Abstract Children with Attention Deficit Hyperactivity Disorder (ADHD) commonly experience significant pragmatic language deficits which put them at risk of developing emotional and social difficulties. This study aimed to examine the pragmatic language exhibited in a peer-to-peer interaction between the children with ADHD and their playmates following a pilot play-based intervention. Participants were children (aged 5–11 years) diagnosed as having ADHD (n = 14) and their self-selected typically-developing playmate. Pragmatic language was measured using the Pragmatic Protocol (PP) and the Structured Multidimensional Assessment Profiles (S-MAPs). Children's structural language was also screened and compared against their pragmatic language skills pre–post play-based intervention. The pragmatic language of children with ADHD improved significantly from pre–post intervention as measured by both the PP and S-MAPs. Both children with and without structural language difficulties improved significantly from pre- to post-intervention using S-MAPs; only children with structural language difficulties improved significantly using PP. The findings support the notion that pragmatic skills may improve following a play-based intervention that is characterized by didactic social interaction. As pragmatic language is a complex construct, it is proposed that clinicians and researchers reconsider the working definition of pragmatic language and the operationalization thereof in assessments.
Fine needle aspiration cytology of Hashimoto's thyroiditis – A diagnostic pitfall with review of literature

Hashimoto's thyroiditis is the second most common thyroid lesion next to goiter diagnosed on fine needle aspiration cytology (FNAC). It is also an important cause for hypothyroidism. FNAC plays a significant role in the diagnosis of thyroid lesions due to its simplicity and low cost. It can accurately diagnose Hashimoto's thyroidits in most patients. However, a small percentage of cases may be missed due to the inherent limitations of this procedure and the varied cytomorphology of this lesion. Therefore thorough cytological evaluation and an integrated approach are necessary to pick up correct diagnosis and to avoid unnecessary surgery. We present a 56-year-old female with solitary thyroid nodule diagnosed as Hurthle cell neoplasm on FNAC, but subsequent histopathological diagnosis following resection revealed Hashimoto's thyroiditis with marked Hurthle cell change.
La Voz Y La Lealtad Mejoran La Eficiencia De Los Mercados (Voice and Loyalty Improve Market Efficiency)

La voz y la lealtad cumplen un papel importante porque facilitan los ajustes en el mercado y mejoran la eficiencia. La teoria convencional establece una relacion inmediata entre los precios y la salida, y desconoce las complejidades que introduce la interaccion humana en los mercados. La voz y la lealtad posponen la salida, y estos mecanismos le ayudan a las empresas a mejorar sus relaciones con los clientes. La perspectiva de Hirschman ayuda a tender puentes entre la economia y la politica. Como el dijo: “Espero mostrarle a los politologos la utilidad de los conceptos economicos, y a los economistas la utilidad de los conceptos politicos. ”Voice and loyalty play an important role because they facilitate market adjustments and improve efficiency. Conventional theory establishes an immediate relationship between prices and output, and ignores the complexities introduced by human interaction in markets. Voice and loyalty postpone exit, and these mechanisms will help companies to improve their relationships with customers. Hirschman’s perspective builds bridges between economics and politics. As he said: “I hope to show political science academics the value of economic concepts, and economists the value of political ideas. ”
The acute effects of glycemic control on axonal excitability in human diabetics

In diabetic nerves, the activation of the polyol pathway and a resulting decrease in Na+‐K+ ATPase activity lead to intra‐axonal Na+ accumulation and a smaller Na+ gradient across the axolemma than normal. To investigate whether glycemic control is associated with acutely reversible changes in axonal excitability and Na+ conductance, we measured the multiple excitability indices (strength‐duration time constant, rheobase, refractoriness, and refractory period) of the median motor axons of 21 diabetic patients before and after intensive insulin treatment. Within 4 weeks after treatment was begun, there was a significant improvement in nerve conduction velocities, associated with increased strength‐duration time constant, decreased rheobase, increased refractoriness, and prolonged refractory periods. Assuming that the strength‐duration time constant partly reflects persistent Na+ conductance, and that refractoriness/refractory periods depend on inactivation of transient Na+ channels caused by prior depolarization (the influx of Na+), the patterns of changes in these indices may reflect a reduced trans‐axonal Na+ gradient during hyperglycemia and its restoration by glycemic control in diabetic patients. Measurement of the excitability indices could provide new insights into the pathophysiology of human diabetic neuropathy. Ann Neurol 2004;56:462–467
Mapping out the multistage fibrillation of glucagon

The 29‐residue peptide hormone glucagon forms many different morphological types of amyloid‐like fibrils, depending on solvent conditions. Here, we combine time‐series far‐UV CD with singular value decomposition analysis to reveal six different conformational states populated during fibrillation at 25 °C and pH 2.5. The existence of these states is supported by complementary fluorescence and electron microscopy data. This highlights a multitude of structural transitions of glucagon from unordered structure to β sheets, β turns and further tertiary‐level changes. We attribute the observed unusual far‐UV CD spectra to tertiary‐level structural changes during the formation and maturation of fibrils. The fibrillation model for the whole process involves the formation of three oligomeric species and two different morphologies of fibrils in the same solution. The visualization of annular pore‐like species in the early stages of glucagon fibrillation and the prevalence of such species in the amyloidogenesis of several proteins indicates that they may be a common feature of the fibrillation process. This study gives significant insights into the stepwise conversion of soluble glucagon to its fibrillar state and identifies the importance of fibril twisting for its thermodynamic stabilization.
Prognostic factors for overall survival with sunitinib as first-line therapy in patients with metastatic renal cell carcinoma (mRCC).

5042 Background: Sunitinib demonstrated superior progression-free survival (PFS; the primary endpoint) over interferon-alfa (IFN-α) as first-line mRCC therapy (NEJM 2007;356:115). Median overall survival (OS) with sunitinib compared to IFN-α was: 26.4 vs. 21.8 months (HR=0.821; P=0.051 by unstratified log-rank test; Proc ASCO 2008;26, May 20 suppl; abstr 5024). An analysis of prognostic factors for OS was performed on data from this trial. METHODS 750 treatment-naïve mRCC patients were randomized 1:1 to receive sunitinib or IFN-α. By Cox proportional hazards model, selected pretreatment variables were evaluated univariately and in a multivariate model for each treatment arm. Multivariate models for each treatment arm were based on a stepwise algorithm with a type I error of 0.25 for entry and 0.15 for elimination. Further elimination was applied to identify variables significant at P<0.05. RESULTS In multivariate analysis of sunitinib patients, factors associated with longer OS include: interval from diagnosis to treatment ≥1 yr, ECOG PS of 0, lower corrected calcium, absence of bone metastases, lower lactic dehydrogenase (LDH), and higher hemoglobin (Hgb) ( table ). For the IFN-α treatment arm, male gender, absence of bone or lymph node metastases, lower LDH, higher Hgb, lower corrected calcium, higher neutrophil count, and interval from diagnosis to treatment ≥1 yr were associated with longer OS. CONCLUSIONS For patients in the sunitinib treatment arm, prognostic factors identified were similar to the factors previously identified in the MSKCC risk groups (J Clin Oncol 2002;20:289). Additional prognostic factors were identified for the IFN-α arm. Further studies are warranted to independently validate these findings as well as to identify tumor-specific prognostic factors. [Table: see text] [Table: see text].