Miracle-dz/UniFAR-FTUs huggingface dataset:
Increasing access to renal transplantation in India through our single‐center kidney paired donation program: a model for the developing world to prevent commercial transplantation

Because access to transplantation with HLA‐desensitization protocols and ABO incompatible transplantation is very limited due to high costs and increased risk of infections from more intense immunosuppression, kidney paired donation (KPD) promises hope to a growing number of end‐stage renal disease (ESRD) patient in India. We present a government and institutional ethical review board approved study of 56 ESRD patients [25 two‐way and 2 three‐way pairs] who consented to participate in KPD transplantation at our center in 2013, performed to avoid blood group incompatibility (n = 52) or positive cross‐match (n = 4). All patients had anatomic, functional, and immunologically comparable donors. The waiting time in KPD was short as compared to deceased donor transplantation. Laparoscopic donor nephrectomy was performed in 54 donors. Donor relationships were spousal (n = 40), parental (n = 13), others (n = 3), with median HLA match of 1. Graft survival was 97.5%. Three patients died with functioning graft. 16% had biopsy‐proven acute rejection. Mean serum creatinine was 1.2 mg/dl at 0.73 ± 0.32 months follow‐up. KPD is a viable, legal, and rapidly growing modality for facilitating LDRT for patients who are incompatible with their healthy, willing living donor. To our knowledge, this is the largest single‐center report from India.
A randomised controlled trial of written information: the effect on parental non-concordance with occlusion therapy

Background/aims: It is well documented that non-concordance with occlusion therapy is both substantial and a major factor leading to treatment failure. Parental understanding in previous work has been found to be poor in key areas such as the critical period and effect of age on prognosis. Research in other areas of medicine has shown that the level of understanding can have a direct effect on the level of concordance. The aims of this study were to assess the ability of educational material in the form of a leaflet, to improve parental understanding of amblyopia and occlusion, and subsequently increase concordance. Methods: Parents of children aged between 1 and 7 years receiving a minimum of 1 hour of occlusion for amblyopia were recruited. A randomised controlled trial was undertaken where, on inclusion, the patients were randomised into a leaflet group, whose parents were issued with written educational material, and a control group whose parents did not receive the written information. Patients were paired and matched for age (<2 years difference) and amount of prescribed occlusion (no more than 1 hour difference). Concordance was monitored by a parental diary and knowledge and parental reasons for non-concordance were assessed by a questionnaire. Concordance was analysed by means of a concordance index and by calculating the proportion of non-concordant parents by setting a threshold of concordance at 80%. Results: Parental knowledge was significantly greater in the leaflet group (88% had complete knowledge) compared to the control group (49% had complete knowledge) (p <0.001). There were also differences between the groups in the area of the treatment regimen, with errors only occurring in the control group (three patients occluded the incorrect eye), but this did not reach statistical significance. Concordance was significantly greater in the leaflet group (mean concordance index 0.85) compared to the non-leaflet group (mean concordance index (0.71) (p <0.001). Comparison of the proportion of non-concordant parents was also statistically different (p <0.005) at 0.23 (95% CI 0.13 to 0.35) for the leaflet group compared to 0.54 (95% CI 0.41 to 0.67) for the control group. Conclusion: A large proportion of patients would benefit by increasing parental knowledge in key areas such as the critical period, importance of occlusion, and potential negative consequences of not treating amblyopia. Written information is a simple, inexpensive, easy to implement, yet effective method of improving parental understanding and subsequent concordance.
In Vitro Interaction of Flucytosine Combined with Amphotericin B or Fluconazole against Thirty-Five Yeast Isolates Determined by both the Fractional Inhibitory Concentration Index and the Response Surface Approach

ABSTRACT Combination therapy could be of benefit for the treatment of invasive yeast infections. However, in vitro interaction studies are relatively scarce and the interpretation of the fractional inhibitory concentration (FIC) index can be contradictory due to various definitions used; not all information on the interaction study is used in the index, and different MIC end points exist for different classes of drugs. Fitting an interaction model to the whole response surface and estimation of an interaction coefficient alpha (ICα) would overcome these objections and has the additional advantage that confidence intervals of the interaction are obtained. The efficacy of flucytosine (5FC) in combination with amphotericin B (AB) and fluconazole (FCZ) was studied against 35 yeast isolates in triplicate (Candida albicans [n = 9], Candida glabrata [n = 9], Candida krusei [n = 9], and Cryptococcus neoformans [n = 8]) using a broth microdilution checkerboard method and measuring growth after 48 h by a spectrophotometer. The FIC index and ICα were determined, the latter by estimation from the response surface approach described by Greco et al. (W. R. Greco, G. Bravo, and J. C. Parsons, Pharmacol. Rev. 47:331-385, 1995) by using a computer program developed for that purpose. For the 5FC-FCZ combination, the interactions determined by the ICα generally were in concordance with the interactions determined by the FIC index, but large discrepancies were found between both methods for the 5FC-AB combination. These could mainly be explained by shortcomings in the FIC approach. The in vitro interaction of 5FC-AB demonstrated variable results depending on the tested Candida isolate. In general, the 5FC-FCZ combination was antagonistic against Candida species, but for some Candida isolates synergism was found. For C. neoformans the interaction for both combinations was highly dependent on the tested isolate and the method used. Response surface approach is an alternative method for determining the interaction between antifungal agents. By using this approach, some of the problems encountered with the FIC were overcome.
Nanosizing of valsartan by high pressure homogenization to produce dissolution enhanced nanosuspension: pharmacokinetics and pharmacodyanamic study

Abstract Purpose: The purpose of the present study was to formulate and evaluate nanosuspension of Valsartan (VAL), a poorly water soluble and low bioavailable drug (solubility of 0.18 mg mL−1; 23% of oral bioavailability) with the aim of improving the aqueous solubility thus the bioavailability and consequently better anti-hypertensive activity. Methods: Valsartan nanosuspension (VAL-NS) was prepared using high-pressure homogenization followed by lyophilisation. The screening of homogenization factors influencing nanosuspension was done by 3-factorial, 3-level Box-Behnken statistical design. Model suggested the influential role of homogenization pressure and cycles on drug nanosizing. The optimized formulation containing Poloxamer−188 (PXM 188) was homogenized for 2 cycles at 500 and 1000 bar, followed by 5 cycles at 1500 bars. Results: The size analysis and transmission electron microscopy showed nanometric size range and uniform shape of the nanosuspension. The in vitro dissolution showed an enhanced release of VAL from nanosuspension (VAL-NS) compared to physical mixture with PXM 188. Pharmacodynamic results showed that, oral administration of VAL-NS significantly lowered (p ≤ 0.001) blood pressure in comparison to non-homogenized VAL (VAL-Susp) in Wistar rat. The level of VAL in rat plasma treated with VAL-NS showed significant difference (p ≤ 0.005) in Cmax (1627.47 ± 112.05 ng mL−1), Tmax (2.00 h) and AUC0→24 (13279.2 ± 589.426 ng h mL−1) compared to VAL-Susp that was found to be 1384.73 ± 98.76 ng mL−1, 3.00 h and 9416.24 ± 218.48 ng h mL−1 respectively. The lower Tmax value, proved the enhanced dissolution rate of VAL. Conclusion: The overall results proved that newly developed VAL-NS increased the plasma bioavailability and pharmacodyanamic potential over the reference formulation containing crude VAL.
Transcription factor Oct‐2A contains functionally redundant activating domains and works selectively from a promoter but not from a remote enhancer position in non‐lymphoid (HeLa) cells.

In non‐lymphoid cells such as HeLa cells, ectopic expression of the lymphocyte‐specific transcription factor Oct‐2A can activate reporter genes whose promoters consist of a single octamer sequence (ATTTGCAT) upstream of a TATA box. While the factor is strongly active in a promoter position, it tails as an enhancer factor: an enhancer consisting of multiple copies of the octamer sequence placed downstream of the reporter gene is not active in HeLa cells, even at high concentration of Oct‐2A. In B lymphoid cells, however, the same enhancer is highly active. This could mean that an additional factor is required for enhancer activation in B cells. Furthermore, we have tested the transcriptional activation potential of Oct‐2A with a series of N‐terminal and C‐terminal deletions. We show that a glutamine‐rich domain near the N‐terminus is required for full activity. Otherwise, large segments of the N‐terminal half or the entire C‐terminal region are dispensable in our assay, as long as the deletions do not impinge on the conserved POU domain which is sufficient for DNA binding. While N‐terminal and C‐terminal regions can functionally compensate for each other, a combined deletion that only retains the POU domain is a strong down mutation. We also find that activity depends on the promoter structure of the reporter gene: the POU domain by itself shows some activity with a promoter where the octamer sequence is located very close to the TATA box, but no activity with another promoter construction where the octamer sequence is located further upstream. The two promoters also respond differently to the deletion of the glutamine‐rich stretch important for transcriptional activation. From these experiments we consider it likely that the natural octamer factor variants can selectively activate the different naturally occurring octamer‐containing promoters.
Evolution in Fast Forward: a Potential Role for Mutators in Accelerating Staphylococcus aureus Pathoadaptation

ABSTRACT Pathogen evolution and subsequent phenotypic heterogeneity during chronic infection are proposed to enhance Staphylococcus aureus survival during human infection. We tested this theory by genetically and phenotypically characterizing strains with mutations constructed in the mismatch repair (MMR) and oxidized guanine (GO) system, termed mutators, which exhibit increased spontaneous-mutation frequencies. Analysis of these mutators revealed not only strain-dependent increases in the spontaneous-mutation frequency but also shifts in mutational type and hot spots consistent with loss of GO or MMR functions. Although the GO and MMR systems are relied upon in some bacterial species to prevent reactive oxygen species-induced DNA damage, no deficit in hydrogen peroxide sensitivity was found when either of these DNA repair pathways was lost in S. aureus. To gain insight into the contribution of increased mutation supply to S. aureus pathoadaptation, we measured the rate of α-hemolysin and staphyloxanthin inactivation during serial passage. Detection of increased rates of α-hemolysin and staphyloxanthin inactivation in GO and MMR mutants suggests that these strains are capable of modifying virulence phenotypes implicated in mediating infection. Accelerated derivation of altered virulence phenotypes, combined with the absence of increased ROS sensitivity, highlights the potential of mutators to drive pathoadaptation in the host and serve as catalysts for persistent infections.
White matter connectivity and Internet gaming disorder

Internet use and on‐line game play stimulate corticostriatal‐limbic circuitry in both healthy subjects and subjects with Internet gaming disorder (IGD). We hypothesized that increased fractional anisotropy (FA) with decreased radial diffusivity (RD) would be observed in IGD subjects, compared with healthy control subjects, and that these white matter indices would be associated with clinical variables including duration of illness and executive function. We screened 181 male patients in order to recruit a large number (n = 58) of IGD subjects without psychiatric co‐morbidity as well as 26 male healthy comparison subjects. Multiple diffusion‐weighted images were acquired using a 3.0 Tesla magnetic resonance imaging scanner. Tract‐based spatial statistics was applied to compare group differences in diffusion tensor imaging (DTI) metrics between IGD and healthy comparison subjects. IGD subjects had increased FA values within forceps minor, right anterior thalamic radiation, right corticospinal tract, right inferior longitudinal fasciculus, right cingulum to hippocampus and right inferior fronto‐occipital fasciculus (IFOF) as well as parallel decreases in RD value within forceps minor, right anterior thalamic radiation and IFOF relative to healthy control subjects. In addition, the duration of illness in IGD subjects was positively correlated with the FA values (integrity of white matter fibers) and negatively correlated with RD scores (diffusivity of axonal density) of whole brain white matter. In IGD subjects without psychiatric co‐morbidity, our DTI results suggest that increased myelination (increased FA and decreased RD values) in right‐sided frontal fiber tracts may be the result of extended game play.
ROBUST MONETARY POLICY UNDER MODEL UNCERTAINTY IN A SMALL MODEL OF THE U.S. ECONOMY

This paper examines monetary policy in a two-equation macroeconomic model when the policymaker recognizes that the model is an approximation and is uncertain about the quality of that approximation. It is argued that the minimax approach of robust control provides a general and tractable alternative to the conventional Bayesian decision theoretic approach. Robust control techniques are used to construct robust monetary policies. In most (but not all) cases, these robust policies are more aggressive than the optimal policies absent model uncertainty. The specific robust policies depend strongly on the formulation of model uncertainty used, and we make some suggestions about which formulation is most relevant for monetary policy applications.
Science of Composite Tissue Allotransplantation

The science of composite tissue allotransplantation (CTA) is rooted in progressive thinking by surgeons, fueled by innovative solutions, and aided by understanding the immunology of tolerance and rejection. These three factors have allowed CTA to progress from science fiction to science fact. Research using preclinical animal models has allowed an understanding of the antigenicity of complex tissue transplants and mechanisms to promote graft acceptance. As a result, translation to the clinic has shown that CTA is a viable treatment option well on the way of becoming a standard of care for those who have lost extremities and suffered large tissue defects. The field of CTA has been progressing exponentially over the past decade. Transplantation of hands, larynx, vascularized knee, trachea, face, and abdominal wall has been performed. Several important observations have emerged from translation to the clinic. Although it was predicted that rejection would pose a major limitation, this has not proven true. In fact, steroid-sparing protocols for immunosuppression that have been successfully used in renal transplantation are sufficient to prevent rejection of limbs. Although skin is highly antigenic when transplanted alone in animal models, when part of a CTA, it has not proven to be. Chronic rejection has not been conclusively demonstrated in hand transplant recipients and is difficult to induce in rodent models of CTA. This review focuses on the science of CTA, provides a snapshot of where we are in the clinic, and discusses prospects for the future to make the procedures even more widely available.
Tools for Trans-Splicing Drug Interference Evaluation in Kinetoplastid

It should be noted that the biochemical cell repertoire is conserved in all living organisms on the planet. Since 1990, the scientists observed that eukaryotes have excessively large genomes with hundreds of thousands of introns which were inserted into genes. Most protein-coding genes in human genome are composed of multiple exons interrupted by introns. Advances in the knowledge of genomics and proteomics of mammals confirmed the need for reprogramming of mRNA used to obtain the products of genes and production of proteins and the significance of pre-mRNA splicing, which is an essential step of gene expression by removing noncoding sequences (introns) to ligate together coding sequences (exons). The exons are usually relatively short about 50–250 base pairs, whereas introns are much larger and can be up to several thousands of base pairs. Splicing is a complex nuclear RNA processing event, where different exons from pre-mRNA molecules are joined together. The intron sequences are removed from the pre-mRNA and the exons fused together resulting in the formation of the mature messenger RNA (mRNA), which is subsequently capped at its 5’ end and polyadenylated at its 3’ end, and transported out of the nucleus to be translated into protein in the cytoplasm.
Atto-Joule gates for the whole voltage range

Reducing the supply voltage is by far the most widely used low-power technique, as reducing dynamic power quadratically and leakage power linearly, while sacrificing on performances. A similar but less explored route is to reduce and/or limit currents (instead of reducing voltages), e.g., through transistor sizing. This paper details a comparison of a reverse-sized CMOS scheme (which reduces currents), with both a classical CMOS implementation and an ultra low power (ULP) sub-threshold CMOS scheme. Simulation results show that the reverse-sized CMOS inverter performs well over the whole range of supply voltages: (i) it dissipates significantly less than a classical CMOS inverter (20–60×), while it does degrade performances (5–20×) but less than power gaining, i.e., not proportionally; (ii) it is much faster (100–200×) than a ULP inverter, at moderately larger power consumptions (10–40×), but again less than proportional; and (iii) its power-delay-product (PDP) is constantly 5–8× lower than that of the other two inverters considered over the whole range of supply voltages. In particular, a reverse-sized CMOS inverter in 16nm at 300mV has a delay of 9.16ns while breaking the atto-Joule barrier (0.906aJ).
Auditory nerve representation of vowels in background noise.

Responses of auditory nerve fibers to steady-state vowels presented alone and in the presence of background noise were obtained from anesthetized cats. Representation of vowels based on average discharge rate and representation based primarily on phase-locked properties of responses are considered. Profiles of average discharge rate versus characteristic frequency (CF) ("rate-place" representation) can show peaks of discharge rate in the vicinity of formant frequencies when vowels are presented alone. These profiles change drastically in the presence of background noise, however. At moderate vowel and noise levels and signal/noise ratios of +9 dB, there are not peaks of rate near the second and third formant frequencies. In fact, because of two-tone suppression, rate to vowels plus noise is less than rate to noise alone for fibers with CFs above the first formant. Rate profiles measured over 5-ms intervals near stimulus onset show clear formant-related peaks at higher sound levels than do profiles measured over intervals later in the stimulus (i.e., in the steady state). However, in background noise, rate profiles at onset are similar to those in the steady state. Specifically, for fibers with CFs above the first formant, response rates to the noise are suppressed by the addition of the vowel at both vowel onset and steady state. When rate profiles are plotted for low spontaneous rate fibers, formant-related peaks appear at stimulus levels higher than those at which peaks disappear for high spontaneous fibers. In the presence of background noise, however, the low spontaneous fibers do not preserve formant peaks better than do the high spontaneous fibers. In fact, the suppression of noise-evoked rate mentioned above is greater for the low spontaneous fibers than for high. Representations that reflect phase-locked properties as well as discharge rate ("temporal-place" representations) are much less affected by background noise. We have used synchronized discharge rate averaged over fibers with CFs near (+/- 0.25 octave) a stimulus component as a measure of the population temporal response to that component. Plots of this average localized synchronized rate (ALSR) versus frequency show clear first and second formant peaks at all vowel and noise levels used. Except at the highest level (vowel at 85 dB sound pressure level (SPL), signal/noise = +9 dB), there is also a clear third formant peak. At signal-to-noise ratios where there are no second formant peaks in rate profiles, human observers are able to discriminate second formant shifts of less than 112 Hz. ALSR plots show clear second formant peaks at these signal/noise ratios.
Progesterone for hot flush and night sweat treatment – effectiveness for severe vasomotor symptoms and lack of withdrawal rebound

A controlled trial recently showed that oral micronized progesterone (Progesterone, 300 mg at h.s. daily) was effective for vasomotor symptoms (VMS) in 133 healthy early postmenopausal women. Here, we present subgroup data in women with severe VMS (50 VMS of moderate–severe intensity/wk) and also 1-mo withdrawal study outcomes. Women with severe VMS (n = 46) resembled the full cohort but experienced 10 VMS/d of 3 of 4 intensity. On therapy, the progesterone VMS number (#) decreased significantly more than placebo # to 5.5/day (d) versus 8/d (ANCOVA −2.0 95% CI: −3.5 to −0.4). Just after trial mid-point, a withdrawal substudy (D/C) was added – 56 women were invited and 34 (61%) took part (progesterone 17; placebo 17). Those in the D/C cohort resembled the whole cohort. On stopping, VMS gradually increased – at D/C week 4, on progesterone, VMS daily # reached 78% and significantly less than baseline (−3.0 to −0.8) but placebo VMS # did not differ from run-in. In summary, progesterone is effective for severe VMS and does not cause a rebound increase in VMS when stopped. That progesterone may be used alone for severe VMS and unlike estrogen does not appear to cause a withdrawal rebound increases VMS treatment options.
Application of the mixed venous blood concentration equation in desflurane anesthesia

Background: We have previously proposed an equation derived from Fick's law and Lin's concept of effective blood concentration (EBC) to calculate the mixed venous blood concentration (MVBC) of isoflurane. Desflurane has a lower blood/air partition coefficient than isoflurane and, as such, promotes a faster induction and recovery from anesthesia. In this study, we investigated the application of the MVBC equation to predict the MVBC of desflurane.