Miracle-dz/UniFAR-FTUs huggingface dataset:
Limitations in Activities of Daily Living in Community-Dwelling People Aged 75 and Over: A Systematic Literature Review of Risk and Protective Factors

Background Most older people wish to age in place, for which functional status or being able to perform activities of daily living (ADLs) is an important precondition. However, along with the substantial growth of the (oldest) old, the number of people who develop limitations in ADLs or have functional decline dramatically increases in this part of the population. Therefore, it is important to gain insight into factors that can contribute to developing intervention strategies at older ages. As a first step, this systematic review was conducted to identify risk and protective factors as predictors for developing limitations in ADLs in community-dwelling people aged 75 and over. Methods Four electronic databases (CINAHL (EBSCO), EMBASE, PsycINFO and PubMed) were searched systematically for potentially relevant studies published between January 1998 and March 2016. Results After a careful selection process, 6,910 studies were identified and 25 were included. By far most factors were examined in one study only, and most were considered risk factors. Several factors do not seem to be able to predict the development of limitations in ADLs in people aged 75 years and over, and for some factors ambiguous associations were found. The following risk factors were found in at least two studies: higher age, female gender, diabetes, hypertension, and stroke. A high level of physical activity and being married were protective in multiple studies. Notwithstanding the fact that research in people aged 65 years and over is more extensive, risk and protective factors seem to differ between the ‘younger’ and ‘older’ olds. Conclusion Only a few risk and protective factors in community-dwelling people aged 75 years and over have been analysed in multiple studies. However, the identified factors could serve both detection and prevention purposes, and implications for future research are given as well.
Acute effects of zinc and insulin on arcuate anorexigenic proopiomelanocortin neurons

Acute insulin administration hyperpolarized, with concomitant decrease of firing rate, a subpopulation of arcuate proopiomelanocortin (POMC) and neuropeptide Y/agouti‐related peptide cells. This rapid effect on cellular activity has been proposed as a cellular correlate of insulin effects on energy balance and glucose homoeostasis. Recent evidence suggests that zinc in mammalian insulin formulations is required for the insulin‐induced inhibition of arcuate POMC neurons, while guinea pig insulin, which fails to bind zinc, activates POMC neurons in mice. Here, we tested the effects of zinc and insulin formations on arcuate POMC neurons.
Hepatic Autophagy Deficiency Compromises Farnesoid X Receptor Functionality and Causes Cholestatic Injury

Autophagy is important for hepatic homeostasis, nutrient regeneration, and organelle quality control. We investigated the mechanisms by which liver injury occurred in the absence of autophagy function. We found that mice deficient in autophagy because of the lack of autophagy‐related gene 7 or autophagy‐related gene 5, key autophagy‐related genes, manifested intracellular cholestasis with increased levels of serum bile acids, a higher ratio of tauromuricholic acid/taurocholic acid in the bile, increased hepatic bile acid load, abnormal bile canaliculi, and altered expression of hepatic transporters. In determining the underlying mechanism, we found that autophagy sustained and promoted the basal and up‐regulated expression of farnesoid X receptor (Fxr) in the fed and starved conditions, respectively. Consequently, expression of Fxr and its downstream genes, particularly bile salt export pump, and the binding of FXR to the promoter regions of these genes, were suppressed in autophagy‐deficient livers. In addition, codeletion of nuclear factor erythroid 2‐related factor 2 (Nrf2) in autophagy deficiency status reversed the FXR suppression. Furthermore, the cholestatic injury of autophagy‐deficient livers was reversed by enhancement of FXR activity or expression, or by Nrf2 deletion. Conclusion: Together with earlier reports that FXR can suppress autophagy, our findings indicate that autophagy and FXR form a regulatory loop and deficiency of autophagy causes abnormal FXR functionality, leading to the development of intracellular cholestasis and liver injury.
Making Sense of Residues on Flaked Stone Artefacts: Learning from Blind Tests

Residue analysis has become a frequently applied method for identifying prehistoric stone tool use. Residues adhering to the stone tool with varying frequencies are interpreted as being the result of an intentional contact with the worked material during use. Yet, other processes during the life cycle of a stone tool or after deposition may leave residues and these residues may potentially lead to misinterpretations. We present a blind test that was designed to examine this issue. Results confirm that production, retouch, prehension, hafting, various incidental contacts during use and deposition may lead to residue depositions that significantly affect the accurateness of identifications of tool-use. All currently applied residue approaches are concerned. We therefore argue for a closer interaction with independent wear studies and a step-wise procedure in which a low magnification of wear traces is used as a first step for selecting potentially used flakes in archaeological contexts. In addition, residue concentrations on a tool’s edge should be sufficiently dense before linking them with use.
The Evolution and the Advantages of MicroED

MicroED is a method which combines cryo-EM sample preparation and instrumentation, with electron and X-ray crystallography data analysis, and it has been employed to solve many protein crystal structures at high resolution. Initially, the main doubts of this method for structure determination were the dynamic scattering of electrons, which would cause severe inaccuracies in the measured intensities. In this paper, we will review the evolution of MicroED data collection and processing, the major differences of multiple scattering effects in protein crystals and inorganic material, and the advantages of continuous rotation data collection. Additionally, because of the periodic nature of the crystalline sample, radiation doses can be kept significantly lower than those used in single particle data collection. We review the work where this was used to assess the radiation damage of a high-energy electron beam on the protein molecules at much lower dose ranges compared to imaging.
Guidelines for the prevention of intravascular catheter-related infections.

BACKGROUND Although many catheter-related bloodstream infections (CRBSIs) are preventable, measures to reduce these infections are not uniformly implemented. OBJECTIVE To update an existing evidenced-based guideline that promotes strategies to prevent CRBSIs. DATA SOURCES The MEDLINE database, conference proceedings, and bibliographies of review articles and book chapters were searched for relevant articles. STUDIES INCLUDED Laboratory-based studies, controlled clinical trials, prospective interventional trials, and epidemiologic investigations. OUTCOME MEASURES Reduction in CRBSI, catheter colonization, or catheter-related infection. SYNTHESIS The recommended preventive strategies with the strongest supportive evidence are education and training of healthcare providers who insert and maintain catheters; maximal sterile barrier precautions during central venous catheter insertion; use of a 2% chlorhexidine preparation for skin antisepsis; no routine replacement of central venous catheters for prevention of infection; and use of antiseptic/antibiotic-impregnated short-term central venous catheters if the rate of infection is high despite adherence to other strategies (ie, education and training, maximal sterile barrier precautions, and 2% chlorhexidine for skin antisepsis). CONCLUSION Successful implementation of these evidence-based interventions can reduce the risk for serious catheter-related infection.
Surgical resection vs radiofrequency ablation in older adults with early stage hepatocellular carcinoma: Where do we stand?

The prevalence of hepatocellular carcinoma (HCC) has increased significantly over the last few decades and it is the third cause of cancer‐related mortality worldwide. [1,2] Several published guidelines on the management of HCC have indicated that liver transplantation, surgical resection (SR), and local regional therapy such as radiofrequency ablation (RFA) are the treatment options for early stage HCC. [2,3]Although liver transplantation is the best curative option for HCC patients, it may not be feasible due to organ shortages, unacceptable surgical risk due to advanced patient’s age or comorbidities, and high cost; RFA has therefore been widely used in clinical practice for the management of HCC. RFA has the advantage of being minimal invasive with low peri‐ and post‐procedural risk especially among elderly patients. [2,3] However, SR may provide a greater long‐term survival benefit compared to RFA among HCC patients. [4]
Functional analysis of a biosynthetic cluster essential for production of 4-formylaminooxyvinylglycine , a germination-arrest factor from Pseudomonas fluorescens WH 6

Rhizosphere-associated Pseudomonas fluorescens WH6 produces the germination-arrest factor 4-formylaminooxyvinylglycine (FVG). FVG has previously been shown to both arrest the germination of weedy grasses and inhibit the growth of the bacterial plant pathogen Erwinia amylovora. Very little is known about the mechanism by which FVG is produced. Although a previous study identified a region of the genome that may be involved in FVG biosynthesis, it has not yet been determined which genes within that region are sufficient and necessary for FVG production. In the current study, we explored the role of each of the putative genes encoded in that region by constructing deletion mutations. Mutant strains were assayed for their ability to produce FVG with a combination of biological assays and TLC analyses. This work defined the core FVG biosynthetic gene cluster and revealed several interesting characteristics of FVG production. We determined that FVG biosynthesis requires two small ORFs of less than 150 nucleotides and that multiple transporters have overlapping but distinct functionality. In addition, two genes in the centre of the biosynthetic gene cluster are not required for FVG production, suggesting that additional products may be produced from the cluster. Transcriptional analysis indicated that at least three active promoters play a role in the expression of genes within this cluster. The results of this study enrich our knowledge regarding the diversity of mechanisms by which bacteria produce non-proteinogenic amino acids like vinylglycines.
Mechanistic insight into spontaneous transition from cellular alternans to arrhythmia—A simulation study

Cardiac electrical alternans (CEA), manifested as T-wave alternans in ECG, is a clinical biomarker for predicting cardiac arrhythmias and sudden death. However, the mechanism underlying the spontaneous transition from CEA to arrhythmias remains incompletely elucidated. In this study, multiscale rabbit ventricular models were used to study the transition and a potential role of INa in perpetuating such a transition. It was shown CEA evolved into either concordant or discordant action potential (AP) conduction alternans in a homogeneous one-dimensional tissue model, depending on tissue AP duration and conduction velocity (CV) restitution properties. Discordant alternans was able to cause conduction failure in the model, which was promoted by impaired sodium channel with either a reduced or increased channel current. In a two-dimensional homogeneous tissue model, a combined effect of rate- and curvature-dependent CV broke-up alternating wavefronts at localised points, facilitating a spontaneous transition from CEA to re-entry. Tissue inhomogeneity or anisotropy further promoted break-up of re-entry, leading to multiple wavelets. Similar observations have also been seen in human atrial cellular and tissue models. In conclusion, our results identify a mechanism by which CEA spontaneously evolves into re-entry without a requirement for premature ventricular complexes or pre-existing tissue heterogeneities, and demonstrated the important pro-arrhythmic role of impaired sodium channel activity. These findings are model-independent and have potential human relevance.
Stress hormone signaling through β‐adrenergic receptors regulates macrophage mechanotype and function

Critical functions of immune cells require them to rapidly change their shape and generate forces in response to cues from their surrounding environment. However, little is known about how soluble factors that may be present in the microenvironment modulate key aspects of cellular mechanobiology—such as immune cell deformability and force generation—to impact functions such as phagocytosis and migration. Here we show that signaling by soluble stress hormones through β‐adrenoceptors (β‐AR) reduces the deformability of macrophages; this is dependent on changes in the organization of the actin cytoskeleton and is associated with functional changes in phagocytosis and migration. Pharmacologic interventions reveal that the impact of β‐AR signaling on macrophage deformability is dependent on actin‐related proteins 2/3, indicating that stress hormone signaling through β‐AR shifts actin organization to favor branched structures rather than linear unbranched actin filaments. These findings show that through remodeling of the actin cytoskeleton, β‐AR‐mediated stress hormone signaling modulates macrophage mechanotype to impact functions that play a critical role in immune response. —Kim, T. ‐H. , Ly, C. , Christodoulides, A. , Nowell, C. J., Gunning, P. W. , Sloan, E. K. , Rowat, A. C. Stress hormone signaling through β‐adrenergic receptors regulates macrophage mechanotype and function. FASEB J. 33, 3997–4006 (2019). www.fasebj. org
Statistical issues and methods in designing and analyzing survival studies.

BACKGROUND Cancer studies that are designed for early detection and screening, or used for identifying prognostic factors, or assessing treatment efficacy and health outcome are frequently assessed with survival or time-to-event outcomes. These studies typically require specific methods of data analysis. Appropriate statistical methods in the context of study design and objectives are required for obtaining reliable results and valid inference. Unfortunately, variable methods for the same study objectives and dubious reporting have been noticed in the survival analysis of oncology research. Applied researchers often face difficulties in selecting appropriate statistical methods due to the complex nature of cancer studies. RECENT FINDINGS In this report, we describe briefly major statistical issues along with related challenges in planning, designing, and analyzing of survival studies. For applied researchers, we provided flow charts for selecting appropriate statistical methods. Various available statistical procedures in common statistical packages for applying survival analysis were classified according to different objectives of the study. In addition, an illustration of the statistical analysis of some common types of time-to-event outcomes was shown with STATA codes. CONCLUSIONS We anticipate that this review article assists oncology researchers in understanding important statistical concepts involved in survival analysis and appropriately select the statistical approaches for survival analysis studies. Overall, the review may help in improving designing, conducting, analyzing, and reporting of data in survival studies.
Baroreflex function, haemodynamic responses to an orthostatic challenge, and falls in haemodialysis patients

Background Stage 5 chronic kidney disease patients on haemodialysis (HD) often present with dizziness and pre-syncopal events as a result of the combined effect of HD therapy and cardiovascular disease. The dysregulation of blood pressure (BP) during orthostasis may be implicated in the aetiology of falls in these patients. Therefore, we explored the relationship between baroreflex function, the haemodynamic responses to a passive orthostatic challenge, and falls in HD patients. Methods Seventy-six HD patients were enrolled in this cross-sectional study. Participants were classified as “fallers” and “non-fallers” and completed a passive head up tilting to 60o (HUT-60°) test on an automated tilt table. ECG signals, continuous and oscillometric BP measurements and impedance cardiography were recorded. The following variables were derived from these measurements: heart rate (HR) stroke volume (SV), cardiac output (CO), total peripheral resistance (TPR), number of baroreceptor events, and baroreceptor effectiveness index (BEI). Results The forty-four participants who were classified as fallers (57.9%) had a lower number of baroreceptor events (6.5±8.5 vs 14±16.7, p = .027) and BEI (20.8±24.2% vs 33.4±23.3%, p = .025). In addition, fallers experienced a significantly larger drop in systolic (-6.4±10.9 vs -0.4±7.7 mmHg, p = .011) and diastolic (-2.7±7.3 vs 1.8±6 mmHg, p = .027) oscillometric BP from supine to HUT-60° compared with non-fallers. None of the variables taken for the analysis were significantly associated with falls in multivariate logistic regression analysis. Conclusions This cross-sectional comparison indicates that, at rest, HD patients with a positive history of falls present with a lower count of baroreceptor sequences and BEI. Short-term BP regulation warrants further investigation as BP drops during a passive orthostatic challenge may be implicated in the aetiology of falls in HD.
Snap shot view on anaemia in chronic kidney disease of uncertain aetiology

Anaemia is a well‐known complication of chronic kidney disease but there are no published studies on the pattern of anaemia in chronic kidney disease of uncertain aetiology (CKDu). This study aims to find out the prevalence, causes and associations of anaemia in CKDu to identify any unique features which are different from already described anaemia in chronic kidney disease.
Undifferentiated carcinoma with osteoclast-like giant cells of pancreas

Rationale: Undifferentiated carcinoma with osteoclast-like giant cells (UC-OGCs) of the pancreas is an extremely rare and aggressive pancreatic malignancy. To our knowledge, the computed tomography (CT) findings of this disease have rarely been analyzed. Patient concerns: A 65-year-old man who experienced weight loss of about 4 kg over 3 months presented to our clinic. The abdominal ultrasound (US) detected a 5.8 × 5.5 cm well-defined, cystic-solid mass in the head of the pancreas, which had been present for 1 month. Diagnosis: A benign pancreatic tumor was initially suspected on the basis of the US findings. The patient then received serum tumor markers and CT examinations for further diagnosis, including carbohydrate antigen 199 (CA199), carcinoembryonic antigen (CEA), carbohydrate antigen 125 (CA125), contrast-enhanced CT (CECT) and CT angiography (CTA). His CA199, CEA, and CA125 marker levels were normal, which supported the diagnosis of a benign tumor. CECT showed a well-defined cystic-solid mass in the head of the pancreas, with a slightly enhanced solid portion and pancreatic ductal dilatation, which led us to consider the possibility of a malignant tumor. CTA revealed that the tumor nourishing arteries emitted from the pancreaticoduodenal superior and inferior arteries into the mass. Then, the patient underwent a pancreaticoduodenectomy. Finally, postoperative pathology and immunohistochemistry confirmed UC-OGC of the pancreas. Interventions: The patient has been treated by a pancreaticoduodenectomy alone. Outcomes: The operation had no complications, and the patient recovered well after surgery. Ten months after surgery, the patient reviewed the CECT, and no recurrence or metastasis was noted. Lessons: Old patients with cystic-solid lesions in the pancreas should be aware of UC-OGC. CT findings usually show a clear boundary and a slightly enhanced mass with pancreatic duct expansion.
Inhibition of VEGFR2 Activation and Its Downstream Signaling to ERK1/2 and Calcium by Thrombospondin-1 (TSP1): In silico Investigation

VEGF signaling through VEGFR2 is a central regulator of the angiogenic response. Inhibition of VEGF signaling by the stress-induced matricellular protein TSP1 plays a role in modulating the angiogenic response to VEGF in both health and disease. TSP1 binding to CD47 inhibits VEGFR2 activation. The full implications of this inhibitory interaction are unknown. We developed a detailed rule-based computational model to inquire if TSP1-CD47 signaling through VEGF had downstream effects upon ERK1/2 and calcium. Our Simulations suggest that enhanced degradation of VEGFR2 initiated by the binding of TSP1 to CD47 is sufficient to explain the inhibition of VEGFR2 phosphorylation, calcium elevation, and ERK1/2 activation downstream of VEGF. A complementary mechanism involving the recruitment of phosphatases to the VEGFR2 complex with consequent increase in the rate of receptor dephosphorylation may augment the inhibition of the VEGF signal. The model was then utilized to simulate the effect of inhibiting external TSP1 or the depletion of CD47 as potential therapeutic strategies in restoring VEGF signaling. Results suggest that depleting CD47 is a more efficient strategy in inhibiting the effects of TSP1/CD47 on VEGF signaling. Our results highlight the utility of in silico investigations in elucidating and clarifying molecular mechanisms at the intersection of TSP1 and VEGF biology and in differentiating between competing pro-angiogenic therapeutic strategies relevant to peripheral arterial disease (PAD) and wound healing.
Kabuki syndrome: international consensus diagnostic criteria

Background Kabuki syndrome (KS) is a clinically recognisable syndrome in which 70% of patients have a pathogenic variant in KMT2D or KDM6A. Understanding the function of these genes opens the door to targeted therapies. The purpose of this report is to propose diagnostic criteria for KS, particularly when molecular genetic testing is equivocal. Methods An international group of experts created consensus diagnostic criteria for KS. Systematic PubMed searches returned 70 peer-reviewed publications in which at least one individual with molecularly confirmed KS was reported. The clinical features of individuals with known mutations were reviewed. Results The authors propose that a definitive diagnosis can be made in an individual of any age with a history of infantile hypotonia, developmental delay and/or intellectual disability, and one or both of the following major criteria: (1) a pathogenic or likely pathogenic variant in KMT2D or KDM6A; and (2) typical dysmorphic features (defined below) at some point of life. Typical dysmorphic features include long palpebral fissures with eversion of the lateral third of the lower eyelid and two or more of the following: (1) arched and broad eyebrows with the lateral third displaying notching or sparseness; (2) short columella with depressed nasal tip; (3) large, prominent or cupped ears; and (4) persistent fingertip pads. Further criteria for a probable and possible diagnosis, including a table of suggestive clinical features, are presented. Conclusion As targeted therapies for KS are being developed, it is important to be able to make the correct diagnosis, either with or without molecular genetic confirmation.