Miracle-dz/UniFAR-FTUs huggingface dataset:
Mini‐Exome Coupled to Read‐Depth Based Copy Number Variation Analysis in Patients with Inherited Ataxias

Next‐generation sequencing (NGS) has an established diagnostic value for inherited ataxia. However, the need of a rigorous process of analysis and validation remains challenging. Moreover, copy number variations (CNV) or dynamic expansions of repeated sequence are classically considered not adequately detected by exome sequencing technique. We applied a strategy of mini‐exome coupled to read‐depth based CNV analysis to a series of 33 patients with probable inherited ataxia and onset <50 years. The mini‐exome consisted of the capture of 4,813 genes having associated clinical phenotypes. Pathogenic variants were found in 42% and variants of uncertain significance in 24% of the patients. These results are comparable to those from whole exome sequencing and better than previous targeted NGS studies. CNV and dynamic expansions of repeated CAG sequence were identified in three patients. We identified both atypical presentation of known ataxia genes (ATM, NPC1) and mutations in genes very rarely associated with ataxia (ERCC4, HSD17B4). We show that mini‐exome bioinformatics data analysis allows the identification of CNV and dynamic expansions of repeated sequence. Our study confirms the diagnostic value of the proposed genetic analysis strategy. We also provide an algorithm for the multidisciplinary process of analysis, interpretation, and validation of NGS data.
Seizure as an initial presentation of human immunodeficiency virus: acute toxoplasmosis mimicking glioblastoma multiforme

We present a case of a 46-year-old man with a history significant only for hypertension and depression that presented with a new onset seizure resulting from a right parietal lobe mass. Further evaluation determined the parietal mass to be central nervous system toxoplasmosis, which was the initial presentation of his underlying HIV/AIDS. This case provided a diagnostic challenge and demonstrates the importance of a thorough evaluation as it pertains to a newly diagnosed brain lesion.
The Zero-Free Intervals for Characteristic Polynomials of Matroids

Let M be a loopless matroid with rank r and c components. Let P(M, t) be the characteristic polynomial of M. We shall show that (−1)rP(M, t)[ges ](1−t)r for t∈(−∞, 1), that the multiplicity of the zeros of P(M, t) at t=1 is equal to c, and that (−1)r+cP(M, t)[ges ](t−1)r for t∈(1, 32/27]. Using a result of C. Thomassen we deduce that the maximal zero-free intervals for characteristic polynomials of loopless matroids are precisely (−∞, 1) and (1, 32/27].
The vaginal flora of women in Zimbabwe.

High vaginal and cervical swabs were taken from 199 pregnant women and 156 nonpregnant patients attending an STD clinic in Zimbabwe. Trichomonas vaginalis was isolated from 31% of pregnant women and 37% of STD patients. The bacterial flora in both groups was similar to that found in women from developed countries except that fecal organisms were more and lactobacilli less commonly isolated. N. gonorrheae was not isolated from any of the pregnant women, but was isolated from 13 of the STD patients, in 2 cases from the rectal swab only. Lactobacilli were cultured from 41% of pregnant women and 40% of STD patients, while fecal organisms and Bacteroides sp. were common. Group B B-hemolytic streptococci were isolated from 8% of pregnant women and 29% of STD patients. There was no evidence that T. Vaginalis was associated with the presence or absence of other micro-organisms in the genital tract in either patient group. N. gonorrheae was recovered from the genital tract of 11 women and lactobacilli were absent from 10 of these. This agrees with other studies which have shown that lactobacilli are often absent in gonococcal infection. 9 patients with N. gonorrheae also harbored T. vaginalis, an association probably related to the sexual transmission of both organisms. Yeasts, mainly C. albicans, were isolated from 39% of pregnant women and 26% of STD patients.
A review of the evidence for pathogenic mechanisms that may link periodontitis and diabetes.

AIMS To review the evidence for the molecular and cellular processes that may potentially link periodontal disease and diabetes. The pathogenic roles of cytokines and metabolic molecules (e.g. glucose, lipids) are explored and the role of periodontal bacteria is also addressed. Paradigms for bidirectional relationships between periodontitis and diabetes are discussed and opportunities for elaborating these models are considered. METHODS Database searches were performed using MeSH terms, keywords, and title words. Studies were evaluated and summarized in a narrative review. RESULTS Periodontal microbiota appears unaltered by diabetes and there is little evidence that it may influence glycaemic control. Small-scale clinical studies and experiments in animal models suggest that IL-1β, TNF-α, IL-6, OPG and RANKL may mediate periodontitis in diabetes. The AGE-RAGE axis is likely an important pathway of tissue destruction and impaired repair in diabetes-associated periodontitis. A role for locally activated pro-inflammatory factors in the periodontium, which subsequently impact on diabetes, remains speculative. CONCLUSION There is substantial information on potential mechanistic pathways which support a close association between diabetes and periodontitis, but there is a real need for longitudinal clinical studies using larger patient groups, integrated with studies of animal models and cells/tissues in vitro.
Cadmium accumulation and loss in the Pacific oyster Crassostrea gigas along the west coast of the USA

Oysters can accumulate cadmium (Cd) in very high concentrations in their tissues and there is now increasing concern for the seafood safety of farmed oysters worldwide. Bioaccumulation and biokinetics of Cd (dietary assimilation, uptake from the dissolved phase, and efflux) were mea- sured in different populations of Pacific oyster Crassostrea gigas collected along the west coast of the USA in 2 different seasons. Triploid juvenile oysters were first transplanted to 5 Washington sites and 1 Oregon site for 3 mo, then transported back to the laboratory for tissue Cd measurements and bio- kinetic experiments. A second group of seed oysters was collected from California and Washington for additional analysis. Oysters from all sites had Cd concentrations lower than the food standard limit and there was spatial difference in tissue Cd concentrations. A significant fraction of Cd was associ- ated with metallothionein-like proteins, implying that the oysters can detoxify Cd by induction of metallothionein. The difference in Cd dietary assimilation (using diatoms as a food source) and efflux in oysters transplanted to different locations was not significant. The uptake rate constants for Cd from the dissolved phase, however, differed markedly among the transplanted populations, and appeared to be affected by the oysters' clearance rate, depending on the population. This uptake rate was also negatively affected by the size of oysters. Dietary assimilation of Cd was comparable at diatom food concentrations below 2 to 5 mg l -1 , and was lower with ingested sediments than with diatoms. Measurements of Cd kinetics in different populations of Pacific oysters under a variety of environmental conditions provide an insight into the Cd accumulation in this commercially important species.
Serum AFP and AFP-L3 in clinically distinguished hepatocellular carcinoma from patients with liver masses.

OBJECTIVE To determine the ability of alpha fetoprotein (AFP) and AFP-L3% serum level in discriminating hepatocellular carcinoma (HCC) from other types of liver mass. MATERIAL AND METHOD This study was performed according to a prospective-specimen-collection, retrospective-blinded-evaluation (PRoBE) design. A total of 109 HCC patients and 51 patients with other types of liver mass were consecutively selected. The levels of AFP and AFP-L3% in their sera were measured. RESULTS AFP levels in serum significantly elevated while AFP-L3% levels significantly decreased in HCC patients (AFP: p < 0.001, AFP-L3%: p < 0.001). The area under the curve (AUC) of a receiver operating characteristic (ROC) curve analysis for the diagnosis of HCC of AFP and AFP-L3% was 0.71 and 0.67, respectively. In addition, the serum level of AFP-L3% was significantly different between the small (mass occupying lesser than 50% of liver volume) and large (mass occupying more than 50% of liver volume) HCC (p = 0.040). CONCLUSION The diagnostic accuracy of serum AFP and AFP-L3% could provide them as candidate biomarkers to discriminate patients with HCC from patients with other types of liver mass. Serum AFP-L3% as a prognostic factor for HCC should be further evaluated in more details.
Activation of P1‐ and P2Y‐purinoceptors by ADP‐ribose in the guinea‐pig taenia coli, but not of P2X‐purinoceptors in the vas deferens

1 The activity of adenosine 5′‐diphosphoribose (ADP‐ribose), a ribosylated purine nucleotide, was investigated on the carbachol‐contracted taenia coli, a tissue possessing P1‐ (A2) and P2Y‐purinoceptors and on the guinea‐pig vas deferens which possesses P2X‐purinoceptors. 2 In the vas deferens, where ATP (1 μm‐1 mm) produced concentration‐dependent contractions, ADP‐ribose was without effect at concentrations up to 1 mm. 3 In the taenia coli, ADP‐ribose (0.1 μm‐1 mm) produced concentration‐dependent relaxations with a potency similar to that of adenosine, but less than that of ATP. The pD2 values for ADP‐ribose, adenosine and ATP were 4.5 ± 0.07 (27), 4.4 ± 0.10 (9) and 5.5 ± 0.14 (21), respectively. The time‐course of the relaxations elicited by ADP‐ribose was found to be significantly longer than that for ATP and significantly shorter than that for adenosine. 4 The P1‐purinoceptor antagonist, 8‐phenyltheophylline (5 μm), produced parallel rightward shifts in the concentration‐response curves of the relaxations of the taenia coli elicited by ADP‐ribose and adenosine but not ATP. 5 Dipyridamole (0.3 μm), a purine nucleoside uptake inhibitor, potentiated the responses to adenosine and ADP‐ribose in the taenia coli. These potentiations were sensitive to 8‐phenyltheophylline (5 μm). 6 Reactive blue 2, a P2Y‐purinoceptor antagonist, antagonized the inhibitory responses of ADP‐ribose and ATP in the taenia coli, without significantly altering the inhibitory responses of either adenosine or noradrenaline. 7 In the presence of the potassium channel blocker, apamin (0.3 μm), the inhibitory responses of ADP‐ribose were severely attenuated, and the inhibitory responses of ATP in the taenia coli were converted to transient contractions. Further addition of 8‐PT blocked the residual responses of ADP‐ribose. 8 The P2‐purinoceptor antagonist, suramin (500 μm), antagonized responses to ATP and ADP‐ribose, but not adenosine. Further addition of 8‐PT antagonized the residual responses to ADP‐ribose, but not to ATP. 9 It is concluded that ADP‐ribose has a mixed pharmacological profile, evoking both P1 (A2)‐purinoceptor‐mediated responses and P2Y‐purinoceptor‐mediated responses, while being inert at P2X‐purinoceptors. It is suggested that ADP‐ribose may provide a useful starting point for the generation of structural analogues which have specific activity at the P2Y‐purinoceptor.
Intensive Care at Home: An Opportunity or Threat

Although efficient hospital and intensive care unit (ICU) throughput depends upon the expeditious admission and discharge of ICU patients (1), health care systems are facing ethical challenges of caring for complex patients that are known as multimorbidity (2-8). A vast majority of patients need ICU admission; furthermore, when hospital occupancy is near its full capacity, prompt discharge of ICU patients to ward beds may not be feasible.
Ambrisentan therapy in patients with pulmonary arterial hypertension who discontinued bosentan or sitaxsentan due to liver function test abnormalities.

BACKGROUND Some endothelin receptor antagonists (ERAs) are associated with liver function test (LFT) result abnormalities. However, ambrisentan has an incidence of serum aminotransferase levels more than three times the upper limit of normal (ULN), similar to that observed in PAH patients who are not receiving ERAs. Because ambrisentan may provide benefits in PAH patients who have discontinued ERA therapy due to LFT abnormalities, we evaluated the safety and efficacy of ambrisentan in this patient population. METHODS Patients who previously discontinued bosentan and/or sitaxsentan due to LFT abnormalities received ambrisentan, 2.5 mg qd, for 4 weeks followed by 5 mg/d for 8 weeks. The primary end point was the incidence of aminotransferase levels more than three times ULN considered by the investigator to be related to ambrisentan and resulting in drug discontinuation. Secondary end points included aminotransferase levels more than five times ULN requiring drug discontinuation and more than three times ULN requiring dose reduction, as well as changes in 6-min walk distance (6MWD), Borg dyspnea index, World Health Organization functional class, and Short Form-36 health survey score. Patients continued treatment beyond the 12-week end point with monthly monitoring of LFTs. RESULTS Thirty-six patients who previously discontinued bosentan (n = 31), sitaxsentan (n = 2), or both (n = 3) were enrolled. At baseline, 69.4% of patients were receiving prostanoid and/or sildenafil therapy. No patient had an aminotransferase level more than three times ULN that required ambrisentan discontinuation. One patient had a transient aminotransferase level more than three times ULN that resolved following a temporary dose reduction. No additional aminotransferase levels more than three times ULN were observed with long-term treatment (median exposure, 102 weeks), despite dose increases to 10 mg qd in more than half of the patients. Significant improvements in 6MWD and other efficacy assessments were observed. CONCLUSIONS Ambrisentan treatment may be an option for patients who have discontinued bosentan and/or sitaxsentan therapy due to LFT result abnormalities. TRIAL REGISTRATION Clinicaltrials.gov Identifier NCT00423592.
Phase 1 Study Assessing the Pharmacokinetic Profile and Safety of Avibactam in Patients With Renal Impairment

Avibactam is a non‐β‐lactam β‐lactamase inhibitor intended for use as a fixed‐dose combination with ceftazidime for the treatment of certain serious Gram‐negative infections. As avibactam is primarily excreted unchanged in the urine, renal impairment may affect its pharmacokinetics. This phase 1 study investigated the effect of renal impairment and hemodialysis on avibactam pharmacokinetics and safety. Healthy controls and subjects with increasing degrees of renal impairment received a single 30‐minute intravenous (IV) infusion of avibactam (100 mg). Anuric subjects requiring hemodialysis received the same infusion pre‐ and posthemodialysis, separated by a 7‐ to 14‐day washout. Blood and urine samples were collected, and pharmacokinetics were analyzed using noncompartmental methods. The relationships between avibactam total plasma clearance (CL) or renal clearance (CLR) and creatinine clearance (CrCL) were evaluated by linear correlation analysis. Safety was also monitored. Increasing severity of renal impairment was associated with decreasing CL and CLR and increasing exposure and terminal half‐life (t1/2). Avibactam CL and CLR demonstrated an approximately linear relationship with CrCL comparable to that previously observed for ceftazidime. In patients requiring hemodialysis, >50% of the administered avibactam was removed during a 4‐hour hemodialysis session, demonstrating that avibactam should be administered after hemodialysis. No new safety findings were reported. To conclude, avibactam dose adjustment is warranted in patients with renal impairment based on the severity of impairment. Because the slope of the linear relationship between avibactam total plasma CL and CrCL is similar to that of ceftazidime, renal impairment dose adjustments should maintain the currently advised 4:1 ratio of ceftazidime:avibactam.
Genetic basis for a rare floral mutant in an Andean species of Solanaceae.

PREMISE OF THE STUDY White forms of typically pigmented flowers are one of the most common polymorphisms in flowering plants. Although the range of genetic changes that give rise to white phenotypes is well known from model systems, few studies have identified causative mutations in natural populations. METHODS Here we combine genetic studies, in vitro enzyme assays, and biochemical analyses to identify the mechanism underlying the loss of anthocyanin pigment production in the naturally occurring white-flowered morph of Iochroma calycinum (Solanaceae). KEY RESULTS Comparison of anthocyanin gene sequences revealed a putative loss-of-function mutation, an 11 amino-acid deletion in dihydroflavonol 4-reductase (DFR), in the white morph. Functional assays of Dfr alleles from blue and white morphs demonstrated that this deletion results in a loss of enzymatic activity, indicating that the deletion could be solely responsible for the lack of pigment production. Consistent with this hypothesis, quantitative PCR showed no significant differences in expression of anthocyanin genes between the morphs. Also, thin layer chromatography confirmed that the white morph continues to accumulate compounds upstream of the DFR enzyme. CONCLUSIONS Collectively, these experiments indicate that the structural mutation at Dfr underlies the rare white flower morph of I. calycinum. This study is one of only a few examples where a flower color polymorphism is due to a loss-of-function mutation in the coding region of an anthocyanin enzyme. The rarity of such mutations in nature suggests that negative consequences prevent fixation across populations.
Association between use of bleeding avoidance strategies and risk of periprocedural bleeding among patients undergoing percutaneous coronary intervention.

CONTEXT Bleeding complications with percutaneous coronary intervention (PCI) are associated with adverse patient outcomes. The association between the use of bleeding avoidance strategies and post-PCI bleeding as a function of a patient's preprocedural risk of bleeding is unknown. OBJECTIVE To describe the use of 2 bleeding avoidance strategies, vascular closure devices and bivalirudin, and associated post-PCI bleeding rates in a nationally representative PCI population. DESIGN, SETTING, AND PATIENTS Analysis of data from 1,522,935 patients undergoing PCI procedures performed at 955 US hospitals participating in the National Cardiovascular Data Registry (NCDR) CathPCI Registry from January 1, 2004, through September 30, 2008. MAIN OUTCOME MEASURE Periprocedural bleeding. RESULTS Bleeding occurred in 30,654 patients (2%). Manual compression, vascular closure devices, bivalirudin, or vascular closure devices plus bivalirudin were used in 35%, 24%, 23%, and 18% of patients, respectively. Bleeding events were reported in 2.8% of patients who received manual compression, compared with 2.1%, 1.6%, and 0.9% of patients receiving vascular closure devices, bivalirudin, and both strategies, respectively (P < .001). Bleeding rates differed by preprocedural risk assessed with the NCDR bleeding risk model (low risk, 0.72%; intermediate risk, 1.73%; high risk, 4.69%). In high-risk patients, use of both strategies was associated with lower bleeding rates (manual compression, 6.1%; vascular closure devices, 4.6%; bivalirudin, 3.8%; vascular closure devices plus bivalirudin, 2.3%; P < .001). This association persisted following adjustment using a propensity-matched and site-controlled model. Use of both strategies was used least often in high-risk patients (14.4% vs 21.0% in low-risk patients, P < .001). CONCLUSIONS In a large national PCI registry, vascular closure devices and bivalirudin were associated with significantly lower bleeding rates, particularly among patients at greatest risk for bleeding. However, these strategies were less often used among higher-risk patients.
Enhanced protection against Clonorchis sinensis induced by co‐infection with Trichinella spiralis in rats

Although co‐infection with multiple parasites is a frequent occurrence, changes in the humoral immune response against a pre‐existing parasite induced as a result of a subsequent parasitic infection remain undetermined. Here, we utilized enzyme‐linked immunosorbent assay (ELISA) to investigate antibody responses, cytokine production and enhanced resistance in Clonorchis sinensis‐infected rats (Sprague–Dawley) upon Trichinella spiralis infection. Higher levels of C. sinensis‐specific IgG and IgA were elicited upon T. spiralis infection, and these levels remained higher than in rats infected with C. sinensis alone. Upon subsequent infection with T. spiralis, IgG antibodies against C. sinensis appeared to be rapidly boosted at day 3, and IgA antibodies were boosted at day 7. Challenge infection of C. sinensis‐infected rats with T. spiralis induced substantial mucosal IgG and IgA responses in the liver and intestine and increases in antibody‐secreting plasma cells in the spleen and bone marrow. Subsequent infection also appeared to confer effective control of liver C. sinensis loads, resulting in enhanced resistance. Memory B cells generated in response to C. sinensis infection were rapidly amplified into antibody‐secreting cells upon T. spiralis infection. These results indicate that enhanced C. sinensis clearance induced by co‐infection is associated with systemic and mucosal IgG and IgA responses.
Socio-economic disadvantage at the area level poses few direct barriers to smoking cessation for Australian smokers: findings from the International Tobacco Control Australian cohort survey.

INTRODUCTION Area-level indicators of socio-economic variation are frequently included in models of individual health outcomes. Area disadvantage is linearly related to smoking prevalence, but its relation to cessation outcomes is less well understood. AIMS To explore the relationship between area-level disadvantage and prospective data on smoking cessation. DESIGN AND METHODS The Australian cohort of the International Tobacco Control Four-Country Survey (N = 3503) was used to prospectively examine the contribution of area-level socio-economic disadvantage to predicting three important smoking-cessation outcomes: making a quit attempt, achieving 1 month abstinence and achieving 6 month abstinence from smoking, while controlling for individual-level socio-economic indicators and other individual-level covariates related to smoking cessation. RESULTS Only two independent associations were observed between socio-economic disadvantage and cessation outcomes. Area-level disadvantage was related to 1 month abstinence in a non-linear fashion, and the individual experience of smoking-induced deprivation was associated with a lower likelihood of making quit attempts. DISCUSSION Despite the documented higher prevalence of smoking among the more disadvantaged and in more disadvantaged areas, socio-economic disadvantage was not consistently related to making quit attempts, nor to medium-term success. Nevertheless, indirect effects of disadvantage, like its impact on psychological distress, cannot be ruled out, and considering smokers' individual psychosocial circumstances is likely to aid cessation efforts. CONCLUSION Socio-economic disadvantage, particularly at the area level, poses few direct barriers to smoking cessation.