Miracle-dz/UniFAR-FTUs huggingface dataset:
Diagnosis of Idiopathic Pulmonary Fibrosis. An Official ATS/ERS/JRS/ALAT Clinical Practice Guideline

Background: This document provides clinical recommendations for the diagnosis of idiopathic pulmonary fibrosis (IPF). It represents a collaborative effort between the American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, and Latin American Thoracic Society. Methods: The evidence syntheses were discussed and recommendations formulated by a multidisciplinary committee of IPF experts. The evidence was appraised and recommendations were formulated, written, and graded using the Grading of Recommendations, Assessment, Development, and Evaluation approach. Results: The guideline panel updated the diagnostic criteria for IPF. Previously defined patterns of usual interstitial pneumonia (UIP) were refined to patterns of UIP, probable UIP, indeterminate, and alternate diagnosis. For patients with newly detected interstitial lung disease (ILD) who have a high‐resolution computed tomography scan pattern of probable UIP, indeterminate, or an alternative diagnosis, conditional recommendations were made for performing BAL and surgical lung biopsy; because of lack of evidence, no recommendation was made for or against performing transbronchial lung biopsy or lung cryobiopsy. In contrast, for patients with newly detected ILD who have a high‐resolution computed tomography scan pattern of UIP, strong recommendations were made against performing surgical lung biopsy, transbronchial lung biopsy, and lung cryobiopsy, and a conditional recommendation was made against performing BAL. Additional recommendations included a conditional recommendation for multidisciplinary discussion and a strong recommendation against measurement of serum biomarkers for the sole purpose of distinguishing IPF from other ILDs. Conclusions: The guideline panel provided recommendations related to the diagnosis of IPF.
A blast from the past: online time-travel debugging with BITE

Conventional back-in-time debuggers fashion a record and replay approach to facilitate inspecting all events in the past execution. This usually implies a significant performance overhead for tracing and storing information. Furthermore the recording only becomes available after the monitored code has terminated. In other words, conventional back-in-time-debuggers operate offline. In this paper we present a novel approach of online back-in-time debugging, called Back-in-Time Evaluation (BITE). It offers the capabilities to evaluate code-snippets in the context of previous execution states. Thus, we can focus the trace recording on execution contexts accessible in online debugging, to meet the higher requirements for responsiveness of the debugger. For this purpose, BITE only collects the results of operations that potentially yield different results when they are reevaluated. These are initially stored in the call frame of the executing method, which has a performance overhead of at most 5%. The downside is that once a frame is popped from the stack, the contained trace is disposed of as well. Therefore, BITE also allows to persist the trace collected in a frame before it is popped, at the cost of potentially increasing the overhead. The performance impact of this depends on the amount of trace information that needs to be persisted, as well as the strategy for storing this information. When storing the information in-memory, the overhead induced ranges from having no additional impact at all, up to a factor of 50x. Since memory capabilities are not unlimited, our approach allows for optionally serializing these objects. However, this induces a higher performance overhead.
Anti-anginal drugs–beliefs and evidence: systematic review covering 50 years of medical treatment

Chronic stable angina is the most prevalent symptom of ischaemic heart disease and its management is a priority. Current guidelines recommend pharmacological therapy with drugs classified as being first line (beta blockers, calcium channel blockers, short acting nitrates) or second line (long-acting nitrates, ivabradine, nicorandil, ranolazine, and trimetazidine). Second line drugs are indicated for patients who have contraindications to first line agents, do not tolerate them or remain symptomatic. Evidence that one drug is superior to another has been questioned. Between January and March 2018, we performed a systematic review of articles written in English over the past 50 years English-written articles in Medline and Embase following preferred reporting items and the Cochrane collaboration approach. We included double blind randomized studies comparing parallel groups on treatment of angina in patients with stable coronary artery disease, with a sample size of, at least, 100 patients (50 patients per group), with a minimum follow-up of 1 week and an outcome measured on exercise testing, duration of exercise being the preferred outcome. Thirteen studies fulfilled our criteria. Nine studies involved between 100 and 300 patients, (2818 in total) and a further four enrolled greater than 300 patients. Evidence of equivalence was demonstrated for the use of beta-blockers (atenolol), calcium antagonists (amlodipine, nifedipine), and channel inhibitor (ivabradine) in three of these studies. Taken all together, in none of the studies was there evidence that one drug was superior to another in the treatment of angina or to prolong total exercise duration. There is a paucity of data comparing the efficacy of anti-anginal agents. The little available evidence shows that no anti-anginal drug is superior to another and equivalence has been shown only for three classes of drugs. Guidelines draw conclusions not from evidence but from clinical beliefs.
AggScore: Prediction of aggregation‐prone regions in proteins based on the distribution of surface patches

Protein aggregation is a phenomenon that has attracted considerable attention within the pharmaceutical industry from both a developability standpoint (to ensure stability of protein formulations) and from a research perspective for neurodegenerative diseases. Experimental identification of aggregation behavior in proteins can be expensive; and hence, the development of accurate computational approaches is crucial. The existing methods for predicting protein aggregation rely mostly on the primary sequence and are typically trained on amyloid‐like proteins. However, the training bias toward beta amyloid peptides may worsen prediction accuracy of such models when applied to larger protein systems. Here, we present a novel algorithm to identify aggregation‐prone regions in proteins termed “AggScore” that is based entirely on three‐dimensional structure input. The method uses the distribution of hydrophobic and electrostatic patches on the surface of the protein, factoring in the intensity and relative orientation of the respective surface patches into an aggregation propensity function that has been trained on a benchmark set of 31 adnectin proteins. AggScore can accurately identify aggregation‐prone regions in several well‐studied proteins and also reliably predict changes in aggregation behavior upon residue mutation. The method is agnostic to an amyloid‐specific aggregation context and thus may be applied to globular proteins, small peptides and antibodies.
Replication-dependent histone isoforms: a new source of complexity in chromatin structure and function

Abstract Replication-dependent histones are expressed in a cell cycle regulated manner and supply the histones necessary to support DNA replication. In mammals, the replication-dependent histones are encoded by a family of genes that are located in several clusters. In humans, these include 16 genes for histone H2A, 22 genes for histone H2B, 14 genes for histone H3, 14 genes for histone H4 and 6 genes for histone H1. While the proteins encoded by these genes are highly similar, they are not identical. For many years, these genes were thought to encode functionally equivalent histone proteins. However, several lines of evidence have emerged that suggest that the replication-dependent histone genes can have specific functions and may constitute a novel layer of chromatin regulation. This Survey and Summary reviews the literature on replication-dependent histone isoforms and discusses potential mechanisms by which the small variations in primary sequence between the isoforms can alter chromatin function. In addition, we summarize the wealth of data implicating altered regulation of histone isoform expression in cancer.
MyD88 Regulates the Expression of SMAD4 and the Iron Regulatory Hormone Hepcidin

The myeloid differentiation primary response gene 88 (MyD88) is an adaptive protein that is essential for the induction of inflammatory cytokines through almost all the Toll-like receptors (TLRs). TLRs recognize molecular patterns present in microorganisms called pathogen-associated molecular patterns. Therefore, MyD88 plays an important role in innate immunity since its activation triggers the first line of defense against microorganisms. Herein, we describe the first reported role of MyD88 in an interconnection between innate immunity and the iron-sensing pathway (BMP/SMAD4). We found that direct interaction of MyD88 with SMAD4 protein activated hepcidin expression. The iron regulatory hormone hepcidin is indispensable for the intestinal regulation of iron absorption and iron recycling by macrophages. We show that MyD88 induces hepcidin expression in a manner dependent on the proximal BMP responsive element on the hepcidin gene (HAMP) promoter. We identified the Toll/interleukin-1 receptor (TIR) domain of MyD88 as the domain of interaction with SMAD4. Furthermore, we show that BMP6 stimulation, which activates SMAD6 expression, also induces MyD88 proteosomal degradation as a negative feedback mechanism to limit hepcidin induction. Finally, we report that the MyD88 gain-of-function L265P mutation, frequently encountered in B-cell lymphomas such as Waldenström’s macroglobulinemia, enhances hepcidin expression and iron accumulation in B cell lines. Our results reveal a new potential role for MyD88 in the SMAD signaling pathway and iron homeostasis regulation.
Circling the undefined—A grounded theory study of intercultural consultations in Swedish primary care

Well-functioning physician-patient communication is central to primary care consultations. An increasing demand on primary care in many countries to manage a culturally diverse population has highlighted the need for improved communication skills in intercultural consultations. In previous studies, intercultural consultations in primary care have often been described as complex for various reasons, but studies exploring physician-patient interactions contributing to the understanding of why they are complex are lacking. Therefore, the aim of this study was to explore intercultural physician-patient communication in primary care consultations, generating a conceptual model of the interpersonal interactions as described by both the patients and the physicians. Using grounded theory methodology, 15 residents in family medicine and 30 foreign-born patients, the latter with Arabic and Somali as native languages, were interviewed. The analysis generated a conceptual model named circling the undefined, where a silent agreement on issues fundamental to the core of the consultation was inadequately presumed and the communicative behaviors used did not contribute to clarity. This could be a possible contributory cause of the perceived complexity of intercultural consultations. Identifying what takes place on an interpersonal level in intercultural consultations might be a first step towards building a common ground for increased mutual understanding, thereby bringing us one step closer to sharing, rather than circling the undefined.
An overview of tenofovir and renal disease for the HIV-treating clinician

Tenofovir disoproxil fumarate (TDF, commonly termed ‘tenofovir’) is the antiretroviral most commonly implicated in antiretroviral-induced nephrotoxicity. As patients on successful antiretroviral therapy (ART) age, their risk for developing renal disease may increase in part because of ART itself, but more importantly, because of HIV-associated and non-HIV-associated comorbidity. Therefore, clinicians need an approach to managing renal disease in people on TDF. TDF as a cause of acute kidney injury (AKI) or chronic kidney disease (CKD) is uncommon, and clinicians should actively exclude other causes (Box 1). In TDF-associated AKI, TDF should be interrupted in all cases, and replaced, or ART interrupted altogether. Tenofovir disoproxil fumarate toxicity can present as AKI or CKD, and as a full or partial Fanconi’s syndrome. TDF has a small but definite negative impact on kidney function (up to a 10% decrease in glomerular filtration rate [GFR]). This occurs because of altered tubular function in those exposed to TDF for treatment and as pre-exposure prophylaxis. Renal function should be assessed using creatinine-based estimated GFR at the time of initiation of TDF, if ART is changed, at 1–3 months, and then ideally every 6–12 months if stable. Specific tests of tubular function are not routinely recommended; in the case of clinical concern, a spot protein or albumin: creatinine ratio is preferable, but in resource-limited settings, urine dipstick can be used. More frequent monitoring may be required in those with established CKD (estimated glomerular filtration rate [eGFR] < 50 mL/min/1.73 m2) or risk factors for kidney disease. The most common risk factors are comorbid hypertension, diabetes, HIV-associated kidney disease, hepatitis B or C co-infection, and TDF in combination with a ritonavir-boosted protease inhibitor. Management of these comorbid conditions must be prioritised in this group. If baseline screening eGFR is < 50 mL/min/1.73 m2, abacavir (the preferred option), and dose-adjusted TDF (useful if concomitant hepatitis B), zidovudine or stavudine (d4T) remain alternatives to full-dose TDF. If there is a rapid decline in kidney function (eGFR drops by more than 25% and decreases to < 50 mL/min/1.73 m2 from of baseline function), or there is new onset or worsening of proteinuria or albuminuria, clinicians should review ART and other potentially nephrotoxic medications and comorbidity and conduct further testing if indicated. If kidney function does not improve after addressing reversible causes of renal failure, then referral to a nephrologist is appropriate. In the case of severe CKD, timeous referral for planning for renal replacement therapy is recommended. Tenofovir alafenamide, a prodrug of tenofovir, appears to have less renal toxicity and is likely to replace TDF in future.
Bayesian detection of potential risk using inference on blinded safety data

Safety surveillance is a critical issue for ongoing clinical trials to actively identify and evaluate important safety information. With the new regulatory emphasis on aggregate review of safety, sponsors are faced with the challenge to develop systematic and sound quantitative methods to assess risk from blinded safety data during the pre‐approval period of a new therapy. To address this challenge, a novel statistical method is proposed to monitor and detect safety signals with data from blinded ongoing clinical trials, specifically for adverse events of special interest (AESI) when historical data are available to provide background rates. This new method is a two‐step Bayesian evaluation of safety signals composed of a screening analysis followed by a sensitivity analysis. This Bayesian modeling framework allows making inference on the relative risk in blinded ongoing clinical trials to detect any safety signal for AESI. The blinded safety teams can use this method to assess the signal and decide if any safety signals should be escalated for unblinded review.
Targeted Gene Sequencing in Children with Crohn’s Disease and Their Parents: Implications for Missing Heritability

Crohn’s disease is a complex genetic trait characterized by chronic relapsing intestinal inflammation. Genome wide association studies (GWAS) have identified more than 170 loci associated with the disease, accounting for ∼14% of the disease variance. We hypothesized that rare genetic variation in GWAS positional candidates also contribute to disease pathogenesis. We performed targeted, massively-parallel sequencing of 101 genes in 205 children with Crohn’s disease, including 179 parent-child trios and 200 controls, both of European ancestry. We used the gene burden test implemented in VAAST and estimated effect sizes using logistic regression and meta-analyses. We identified three genes with nominally significant p-values: NOD2, RTKN2, and MGAT3. Only NOD2 was significant after correcting for multiple comparisons. We identified eight novel rare variants in NOD2 that are likely disease-associated. Incorporation of rare variation and compound heterozygosity nominally increased the proportion of variance explained from 0.074 to 0.089. We estimated the population attributable risk and total heritability of variation in NOD2 to be 32.9% and 3.4%, respectively, with 3.7% and 0.25% accounted for by rare putatively functional variants. Sequencing probands (as opposed to genotyping) to identify rare variants and incorporating phase by sequencing parents can recover a portion of the missing heritability of Crohn’s disease.
Comment on “Unexpected reversal of C3 versus C4 grass response to elevated CO2 during a 20-year field experiment”

Reich et al. (Reports, 20 April 2018, p. 317) reported that elevated carbon dioxide (eCO2) switched its effect from promoting C3 grasses to favoring C4 grasses in a long-term experiment. We argue that the authors did not appropriately elucidate the interannual climate variation as a potential mechanism for the reversal of C4-C3 biomass in response to eCO2.
Potential Metabolic Drug–Drug Interaction of Citrus aurantium L. (Rutaceae) Evaluating by Its Effect on 3 CYP450

Aim: Fructus aurantii (FA) is widely used in clinic as an expectorant and digestant herb in traditional Chinese medicine and proven to have a variety of pharmacological functions. FA is close to grapefruit either by botanical taxonomy or by their same components (flavonoids, etc.) and grapefruit has been proven to cause drug–drug interaction when co-administrated with CYP3A4 substrates. Besides, FA contains many compounds, such as flavonoids, which have been reported to impact the expressions of CYP450. However, the effect of FA on CYP450, whose change may affect drug safety and clinical efficacy attributed to drug–drug interaction, still remains unknown. Methods: The protein, mRNA expression and enzyme activity of CYP1A2, CYP3A4, and CYP2E1 in rat were determined by Western Blotting, RT-PCR method, the cocktail method, respectively, after orally administration of FA in succession for 7 days. CYP1A2, CYP3A4, and CYP2E1 mRNA expression were investigated in HepG2 cells following FA-medicated serum incubation for 24 h. Results: In rat, compared to the control group, CYP1A2, CYP3A4 protein, and mRNA expression were significantly induced consistent with the corresponding CYP activities; the protein expression of CYP2E1 was significantly upregulated, while the corresponding mRNA expression and enzyme activity showed no significant change. In HepG2 cells, compared to the control group, the mRNA expression of CYP1A2 and CYP3A4 was up-regulated statistically while CYP2E1 mRNA expression was not significantly induced or inhibited. Conclusion: FA may be a potential slight inducer of CYP1A2 and CYP3A4 and is unlikely to impact CYP2E1 until clinical researches are conducted.
Remini-Sing: A Feasibility Study of Therapeutic Group Singing to Support Relationship Quality and Wellbeing for Community-Dwelling People Living With Dementia and Their Family Caregivers

Background: Living at home following a diagnosis of dementia can be difficult for both the person living with dementia (PwD) and their family caregivers (FCG). Active group music participation may provide an avenue for emotional release, offer psychosocial support to caregivers and stimulate meaningful interaction between caregivers and loved ones with dementia. Therapeutic music interventions also have the capacity to facilitate reminiscence and social engagement and can help to manage challenging symptoms associated with dementia, such as anxiety, apathy, and agitation. Method: This feasibility study examined the acceptability of a 20-week therapeutic group singing intervention (Remini-Sing) and quantitative research assessments for PwD/FCG dyads living in the community. Quantitative measures for the following outcomes were tested for sensitivity and acceptability: relationship quality (PwD and FCG); life satisfaction, caregiver satisfaction, flourishing, and depression for FCGs; and anxiety, apathy, agitation, and quality of life for PwD. Quantitative assessments were conducted before, during (midway) and after 20 weeks of participation in a therapeutic singing group attended by the PwD and FCG together. The Remini-Sing intervention incorporated vocal warm ups, singing familiar songs, learning new songs, and opportunities for social interaction. Qualitative interviews were conducted with all dyads that completed the intervention. Results: Twelve PWD/FCG dyads were recruited and enrolled in the study. High participation and retention rates indicated that the intervention was received favorably by participants. There were no statistically significant changes on measures from pre to post intervention. However, favorable baseline scores on relationship quality and wellbeing measures were sustained over the 20-week intervention. The testing of these measures for feasibility also revealed that some were too difficult for PwD and thus yielded questionable results, some were potentially less relevant, and there were likely floor and ceiling effects on several of the measures utilized. Conclusions: This study demonstrated good feasibility for a research protocol and therapeutic group singing intervention for community-dwelling PwD and their FCGs. Participant reflections and researcher observations yielded useful information guiding the selection of quantitative outcome measures for future research in this area.
Echocardiographic determination of resting haemodynamics and optimal positioning in term pregnant women

Optimal positioning for anaesthesia in pregnant women involves balancing the need for ideal tracheal intubation conditions (achieved by the head elevated ramped position), with the prevention of reduced cardiac output from aortocaval compression (achieved by left lateral pelvic tilt). No studies have examined the effect on cardiac output of left lateral pelvic tilt in the ramped position. We studied non‐labouring, non‐anaesthetised healthy term pregnant women who underwent baseline (left lateral decubitus) cardiac assessment using transthoracic echocardiography. We then compared cardiac output, maternal physiological variables, fetal heart rate and comfort scores in three positions: left lateral decubitus; ramped position with wedge; and ramped position alone. Thirty women completed the study. Mean (SD) age, gestation and body mass index were 33.5 (3.93) years, 38.5 (0.94) weeks and 29.0 (4.0) kg.m−2, respectively. Mean ejection fraction, left ventricular internal diameter and mitral valve E/e’ were 55.2 (6.8) %, 4.70 (0.43) cm and 7.50 (1.82), respectively. There were no differences in cardiac output between the positions (p = 0.503). There were no differences in systolic (p = 0.955) or diastolic (p = 0.987) blood pressure, maternal heart rate (p = 0.133), oxygen saturation, respiratory rate (p = 0.964) or fetal heart rate (p = 0.361) between ramped with wedge and ramped alone positions. Left lateral decubitus was most comfortable (p = 0.001), however, there were no differences in comfort levels between ramped with wedge and ramped alone positions. The ramped position without left lateral tilt is safe and acceptable in non‐labouring, non‐anaesthetised, healthy term pregnant women. Left lateral pelvic tilt may be unnecessary in the head elevated ramped position in term pregnant women.