Miracle-dz/UniFAR-FTUs huggingface dataset:
Physicians’ attitudes toward end-of-life decisions in amyotrophic lateral sclerosis

Abstract Objective: This study aims (1) to assess physicians’ attitudes toward different palliative end-of-life (EOL) practices in amyotrophic lateral sclerosis (ALS) care, including forgoing artificial nutrition and hydration (FANH), continuous sedation until death (CSD), and withdrawing invasive ventilation (WIV), and toward physician-assisted dying (PAD) including physician-assisted suicide and euthanasia and (2) to explore variables influencing these attitudes. Methods: We used two clinical vignettes depicting ALS patients in different stages of their disease progression to assess the influence of suffering (physical/psycho-existential) on attitudes toward WIV and the influence of suffering and prognosis (short-term/long-term) on attitudes toward FANH, CSD, and PAD. Results: 50 physicians from European ALS centers and neurological departments completed our survey. Short-term prognosis had a positive impact on attitudes toward offering FANH (p = 0.014) and CSD (p = 0.048) as well as on attitudes toward performing CSD (p = 0.036) and euthanasia (p = 0.023). Predominantly psycho-existential suffering was associated with a more favorable attitude toward WIV but influenced attitudes toward performing CSD negatively. Regression analysis showed that religiosity was associated with more reluctant attitudes toward palliative EOL practices and PAD, whereas training in palliative care was associated with more favorable attitudes toward palliative EOL practices only. Conclusion: ALS physicians seem to acknowledge psycho-existential suffering as a highly acceptable motive for WIV but not CSD. Physicians appear to be comfortable with responding to the patient’s requests, but more reluctant to assume a proactive role in the decision-making process. Palliative care training may support ALS physicians in these challenging situations.
Esc2 promotes telomere stability in response to DNA replication stress

Abstract Telomeric regions of the genome are inherently difficult-to-replicate due to their propensity to generate DNA secondary structures and form nucleoprotein complexes that can impede DNA replication fork progression. Precisely how cells respond to DNA replication stalling within a telomere remains poorly characterized, largely due to the methodological difficulties in analysing defined stalling events in molecular detail. Here, we utilized a site-specific DNA replication barrier mediated by the ‘Tus/Ter’ system to define the consequences of DNA replication perturbation within a single telomeric locus. Through molecular genetic analysis of this defined fork-stalling event, coupled with the use of a genome-wide genetic screen, we identified an important role for the SUMO-like domain protein, Esc2, in limiting genome rearrangements at a telomere. Moreover, we showed that these rearrangements are driven by the combined action of the Mph1 helicase and the homologous recombination machinery. Our findings demonstrate that chromosomal context influences cellular responses to a stalled replication fork and reveal protective factors that are required at telomeric loci to limit DNA replication stress-induced chromosomal instability.
Acute Effects of Air Pollution and Noise from Road Traffic in a Panel of Young Healthy Adults

Panel studies are an efficient means to assess short-term effects of air pollution and other time-varying environmental exposures. Repeated examinations of volunteers allow for an in-depth analysis of physiological responses supporting the biological interpretation of environmental impacts. Twenty-four healthy students walked for 1 h at a minimum of four separate occasions under each of the following four settings: along a busy road, along a busy road wearing ear plugs, in a park, and in a park but exposed to traffic noise (65 dB) through headphones. Particle mass (PM2.5, PM1), particle number, and noise levels were measured throughout each walk. Lung function and exhaled nitrogen oxide (NO) were measured before, immediately after, 1 h after, and approximately 24 h after each walk. Blood pressure and heart rate variability were measured every 15 min during each walk. Recorded air pollution levels were found to correlate with reduced lung function. The effects were clearly significant for end-expiratory flows and remained visible up to 24 h after exposure. While immediate increases in airway resistance could be interpreted as protective (muscular) responses to particulate air pollution, the persisting effects indicate an induced inflammatory reaction. Noise levels reduced systolic blood pressure and heart rate variability. Maybe due to the small sample size, no effects were visible per specific setting (road vs. park).
High-Pressure Response of Amyloid Folds

The abnormal protein aggregates in progressive neurodegenerative disorders, such as Alzheimer’s, Parkinson’s and prion diseases, adopt a generic structural form called amyloid fibrils. The precise amyloid fold can differ between patients and these differences are related to distinct neuropathological phenotypes of the diseases. A key focus in current research is the molecular mechanism governing such structural diversity, known as amyloid polymorphism. In this review, we focus on our recent work on recombinant prion protein (recPrP) and the use of pressure as a variable for perturbing protein structure. We suggest that the amyloid polymorphism is based on volumetric features. Accordingly, pressure is the thermodynamic parameter that fits best to exploit volume differences within the states of a chemical reaction, since it shifts the equilibrium constant to the state that has the smaller volume. In this context, there are analogies with the process of correct protein folding, the high pressure-induced effects of which have been studied for more than a century and which provides a valuable source of inspiration. We present a short overview of this background and review our recent results regarding the folding, misfolding, and aggregation-disaggregation of recPrP under pressure. We present preliminary experiments aimed at identifying how prion protein fibril diversity is related to the quaternary structure by using pressure and varying protein sequences. Finally, we consider outstanding questions and testable mechanistic hypotheses regarding the multiplicity of states in the amyloid fold.
Rapid Induction of Liver Regeneration for Major Hepatectomy (REBIRTH): A Randomized Controlled Trial of Portal Vein Embolisation versus ALPPS Assisted with Radiofrequency

To avoid liver insufficiency following major hepatic resection, portal vein embolisation (PVE) is used to induce liver hypertrophy pre-operatively. Associating liver partition with portal vein ligation for staged hepatectomy assisted with radiofrequency (RALPPS) was introduced as an alternative method. A randomized controlled trial comparing PVE with RALPPS for the pre-operative manipulation of liver volume in patients with a future liver remnant volume (FLRV) ≤25% (or ≤35% if receiving preoperative chemotherapy) was conducted. The primary endpoint was increase in size of the FLRV. The secondary endpoints were length of time taken for the volume gain, morbidity, operation length and post-operative liver function. Between July 2015 and October 2017, 57 patients were randomised to RALPPS (n = 29) and PVE (n = 28). The mean percentage of increase in the FLRV was 80.7 ± 13.7% after a median 20 days following RALPPS compared to 18.4 ± 9.8% after 35 days (p < 0.001) following PVE. Twenty-four patients after RALPPS and 21 after PVE underwent stage-2 operation. Final resection was achieved in 92.3% and 66.6% patients in RALPPS and PVE, respectively (p = 0.007). There was no difference in morbidity, and one 30-day mortality after RALPPS (p = 0.991) was reported. RALPPS is more effective than PVE in increasing FLRV and the number of patients for surgical resection.
Unity Makes Strength: A Review on Mutualistic Symbiosis in Representative Insect Clades

Settled on the foundations laid by zoologists and embryologists more than a century ago, the study of symbiosis between prokaryotes and eukaryotes is an expanding field. In this review, we present several models of insect–bacteria symbioses that allow for the detangling of most known features of this distinctive way of living, using a combination of very diverse screening approaches, including molecular, microscopic, and genomic techniques. With the increasing the amount of endosymbiotic bacteria genomes available, it has been possible to develop evolutionary models explaining the changes undergone by these bacteria in their adaptation to the intracellular host environment. The establishment of a given symbiotic system can be a root cause of substantial changes in the partners’ way of life. Furthermore, symbiont replacement and/or the establishment of bacterial consortia are two ways in which the host can exploit its interaction with environmental bacteria for endosymbiotic reinvigoration. The detailed study of diverse and complex symbiotic systems has revealed a great variety of possible final genomic products, frequently below the limit considered compatible with cellular life, and sometimes with unanticipated genomic and population characteristics, raising new questions that need to be addressed in the near future through a wider exploration of new models and empirical observations.
Thymoquinone Selectively Kills Hypoxic Renal Cancer Cells by Suppressing HIF-1α-Mediated Glycolysis

Several reports have shown that thymoquinone (TQ) effectively attenuates angiogenesis in cancer cells, resulting in suppression of tumor growth. However, it is not yet clear whether TQ reduces hypoxia-inducible factor-1α (HIF-1α) expression in hypoxic cancer cells. Here, we found that TQ was a novel HIF-1α inhibitor through hypoxia response element (HRE)-luciferase assay-based large screening by using 502 natural compounds containing chemical library. TQ reduced HIF-1α protein levels in renal cancer cells; however, it did not affect the HIF-1α protein levels in the presence of proteasome inhibitor, MG132, indicating that the reduction effects of TQ on HIF-1α protein are mediated via the ubiquitination-proteasome dependent pathway. TQ boosted HIF-1α protein degradation, and the mechanism was revealed by inhibiting interaction between HSP90 and HIF-1α. TQ suppressed downstream genes of HIF-1α, indicating negative impact of TQ on HIF-1α transcriptional activities. In addition, TQ altered glucose, lactate, and ATP levels, leading to anaerobic metabolic disturbance. TQ induced apoptosis in hypoxic cancer cells as determined by crystal violet staining and flow cytometry for annexin V-stained cells. Taken together, we suggested that TQ is a potential anticancer agent targeting HIF-1α.
Mouse and human urothelial cancer organoids: A tool for bladder cancer research

Significance Bladder cancer poses a big clinical challenge, particularly in advanced cases. Here we present a culture system for bladder cancer based on organoid culture technology. We have created a living biobank containing organoids grown from over 50 patient samples, which reflects many aspects of bladder cancer pathogenesis. Organoids of human bladder cancer cells can be maintained for prolonged periods of time, and closely resemble the tumor histology. Bladder organoids can be used for drug screening, and therefore provide a platform for development of new drugs for the treatment of bladder cancer and personalized medicine. Bladder cancer is a common malignancy that has a relatively poor outcome. Lack of culture models for the bladder epithelium (urothelium) hampers the development of new therapeutics. Here we present a long-term culture system of the normal mouse urothelium and an efficient culture system of human bladder cancer cells. These so-called bladder (cancer) organoids consist of 3D structures of epithelial cells that recapitulate many aspects of the urothelium. Mouse bladder organoids can be cultured efficiently and genetically manipulated with ease, which was exemplified by creating genetic knockouts in the tumor suppressors Trp53 and Stag2. Human bladder cancer organoids can be derived efficiently from both resected tumors and biopsies and cultured and passaged for prolonged periods. We used this feature of human bladder organoids to create a living biobank consisting of bladder cancer organoids derived from 53 patients. Resulting organoids were characterized histologically and functionally. Organoid lines contained both basal and luminal bladder cancer subtypes based on immunohistochemistry and gene expression analysis. Common bladder cancer mutations like TP53 and FGFR3 were found in organoids in the biobank. Finally, we performed limited drug testing on organoids in the bladder cancer biobank.
Sex comparisons of agonist and antagonist muscle electromyographic parameters during two different submaximal isometric fatiguing tasks

To examine the task failure time of the force‐ and position‐based submaximal elbow flexion fatiguing tasks for both sexes, twelve men and eight women visited the laboratory for two separate experimental occasions. During the experiment, they pulled against a rigid restraint for the force task and maintained a constant elbow joint angle to support an equivalent inertial load for the position task. For both fatiguing tasks (50% of the isometric strength at the elbow joint angle of 135 degree), the task failure time, along with the surface electromyographic (EMG) amplitude and mean frequency (MNF) were measured. The average failure time was longer for the force task than that for the position task (sexes combined: 39.6 ± 16.6 sec vs. 33.9 ± 14.9 sec, P = 0.033). In addition, men were overall less fatigable than women (tasks combined: 42.0 ± 14.7 sec vs. 28.7 ± 10.3 sec, P = 0.020). The multiple regression analyses showed that the task failure time in women was solely predicted by the rate of change of the triceps EMG MNF. Thus, more fatigability of women in this study was likely due to the quicker fatiguing rate of the antagonist triceps brachii muscle. Different from most previous studies that have used 90‐degree elbow joint angle, the current 135‐degree joint angle setup might have created a situation where greater muscle activity from the related muscles (e.g., the antagonist) were required for women than for men to stabilize the joint, thereby resulting in a shorter task failure time.
Mammary Gland Transcriptome and Proteome Modifications by Nutrient Restriction in Early Lactation Holstein Cows Challenged with Intra-Mammary Lipopolysaccharide

The objective is to study the effects of nutrient restrictions, which induce a metabolic imbalance on the inflammatory response of the mammary gland in early lactation cows. The aim is to decipher the molecular mechanisms involved, by comparing a control, with a restriction group, a transcriptome and proteome, after an intra-mammary lipopolysaccharide challenge. Multi-parous cows were either allowed ad libitum intake of a lactation diet (n = 8), or a ration containing low nutrient density (n = 8; 48% barley straw and dry matter basis) for four days starting at 24 ± 3 days in milk. Three days after the initiation of their treatments, one healthy rear mammary quarter of 12 lactating cows was challenged with 50 µg of lipopolysaccharide (LPS). Transcriptomic and proteomic analyses were performed on mammary biopsies obtained 24 h after the LPS challenge, using bovine 44K microarrays, and nano-LC-MS/MS, respectively. Restriction-induced deficits in energy, led to a marked negative energy balance (41 versus 97 ± 15% of Net Energy for Lactation (NEL) requirements) and metabolic imbalance. A microarray analyses identified 25 differentially expressed genes in response to restriction, suggesting that restriction had modified mammary metabolism, specifically β-oxidation process. Proteomic analyses identified 53 differentially expressed proteins, which suggests that the modification of protein synthesis from mRNA splicing to folding. Under-nutrition influenced mammary gland expression of the genes involved in metabolism, thereby increasing β-oxidation and altering protein synthesis, which may affect the response to inflammation.
THE EVALUATION OF INCIDENTALLY DISCOVERED ADRENAL MASSES.

OBJECTIVE The objective of this Disease State Clinical Review is to provide clinicians with a practical approach to the evaluation of incidentally discovered adrenal masses. METHODS A case-based clinical approach to the evaluation of adrenal masses is presented. Recommendations were developed using available prospective and randomized studies, cohort studies, cross-sectional studies, anecdotal observations, and expert opinions. RESULTS Incidentally discovered adrenal masses are common. The approach to the patient with an adrenal mass should involve assessment of malignant potential via imaging characteristics and adrenal hormone excess via clinical and biochemical features. The roles of biopsy, surgical or medical therapy, and longitudinal surveillance are also important to consider and are influenced by case-specific factors. Inappropriate or inadequate evaluations may put patients at increased risk for developing preventable adverse cardiometabolic outcomes or cancer. CONCLUSION Incidentally discovered adrenal masses require a multimodal assessment that involves interpretation of multiple imaging characteristics, dynamic and static hormonal measurements, and a nuanced approach to considering interventional diagnostics, treatments, and longitudinal surveillance. Herein, we review these evaluations and provide a practical approach for clinicians. ABBREVIATIONS ACTH = adrenocorticotropic hormone; CS = Cushing syndrome; CT = computed tomography; DHEAS = dehydroepiandrosterone sulfate; HU = Hounsfield units; MRI = magnetic resonance imaging; UFC = urinary free cortisol.
A qualitative study investigating perceived barriers to medication adherence in chronic illness patients of Karachi, Pakistan.

OBJECTIVE The study aimed to perceived barriers to medication adherence in patients with chronic illnesses. METHODS A qualitative study was conducted in a tertiary care hospital in Karachi in September 2017, using grounded theory and inductive approach. Interviews were conducted using a checklist in Urdu language from patients of chronic illnesses determined based on medicines dispensed from the out-patient pharmacy in hospital. Interviews were recorded, transcribed verbatim, translated in English and validated. The translated quotations were analysed using a qualitative analysis software, and thematic analysis was conducted. Codes were generated and analysed by semantic linkages and network analysis using ATLAS.ti qualitative research software. RESULTS Of the 16 patients interviewed, 8(50%) were males and 8(50%) were females. Barriers to medication adherence identified were patient behaviour (intentional and un-intentional non-adherence), comorbidity and pill burden, cost-related non-adherence, and low patient knowledge. The last barrier was associated with the rest. CONCLUSIONS Counselling has the potential to increase patient knowledge regarding medication use, and active pharmacist-physician collaboration can improve medication adherence.
Everyday life after a hip fracture: what community-living older adults perceive as most beneficial for their recovery

Abstract Objective to gain insight into what older adults after hip fracture perceive as most beneficial to their recovery to everyday life. Design qualitative research approach. Setting six skilled nursing facilities. Participants 19 older community dwelling older adults (aged 65–94), who had recently received geriatric rehabilitation after hip fracture. Methods semi-structured interviews were conducted with 19 older adults after hip fracture. Coding techniques based on constructivist grounded theory were applied. Results four categories were derived from the data: ‘restrictions for everyday life’, ‘recovery process’, ‘resources for recovery’ and ‘performing everyday activities’. Physical and psychological restrictions are consequences of hip fracture that older adults have struggled to address during recovery. Three different resources were found to be beneficial for recovery; ‘supporting and coaching’, ‘myself’ and ‘technological support’. These resources influenced the recovery process. Having successful experiences during recovery led to doing everyday activities in the same manner as before; unsuccessful experiences led to ceasing certain activities altogether. Conclusion participants highlight their own role (‘myself’) as essential for recovery. Additionally, coaching provides emotional support, which boosts self-confidence in performing everyday activities. Furthermore, technology can encourage older adults to become more active and being engaged in the recovery process. The findings suggest that more attention should be paid to follow-up interventions after discharge from inpatient rehabilitation to support older adults in finding new routines in their everyday activities. A conceptual model is presented and provides an understanding of the participants’ experiences and perspectives concerning their process of recovery after hip fracture to everyday life.
Greater Susceptibility for Metabolic Syndrome in Pediatric Solid Organ and Stem Cell Transplant Recipients.

BACKGROUND Cardiovascular (CV) comorbidity is of increasing importance after transplantation (Tx). Metabolic syndrome (MS) contributes to the risk for CV sequelae. Our aim was to assess the risk for MS in pediatric solid organ and stem cell transplant recipients by comparing them to matched untransplanted peers in a multicenter study. METHODS We prospectively assessed MS in 295 pediatric transplant recipients and compared them to 1.475 age- and sex-matched controls. RESULTS Post transplant metabolic syndrome (PTMS) was most frequent in lung (43%) and kidney (39%), followed by liver (16%) and stem cell (13%) recipients compared to non transplanted peers (4%; p<0.01). The risk of displaying PTMS was almost 22-fold higher after lung (95%CI 8.2-57.4), 16-fold higher after kidney (95%CI 9.1-28.9), 5-fold higher after liver (95%CI 2.1-10.1) and 4-fold higher after stem cell (95%CI 1.4-9.5) Tx. The contribution of individual components leading to MS differed depending on transplant type. In the combined analysis of all transplant groups older age, less physical activity, calcineurin- or mammalian target of rapamycin inhibitor based immunosuppression, and hypovitaminosis D were associated with PTMS. CONCLUSIONS By investigating a large group of patients, our study not only shows a high prevalence of PTMS, but also identifies kidney and lung transplant patients as being at a particularly high risk. Moreover, knowledge on the factors associated with PTMS allows for individualized treatment approaches as well as potential preventive measures.