Invasion and Amplification of Endogenous Retroviruses in Dasyuridae Marsupial Genomes.

Retroviruses are an ancient viral family that have globally coevolved with vertebrates and impacted their evolution. In Australia, a continent that has been geographically isolated for millions of years, little is known about retroviruses in wildlife, despite the devastating impacts of a retrovirus on endangered koala populations. We therefore sought to identify and characterize Australian retroviruses through reconstruction of endogenous retroviruses from marsupial genomes, in particular the Tasmanian devil due to its high cancer incidence. We screened 19 marsupial genomes and identified over 80,000 endogenous retrovirus fragments which we classified into eight retrovirus clades. The retroviruses were similar to either Betaretrovirus (5/8) or Gammaretrovirus (3/8) retroviruses, but formed distinct phylogenetic clades compared to extant retroviruses. One of the clades (MEBrv 3) lost an envelope but retained retrotranspositional activity, subsequently amplifying throughout all Dasyuridae genomes. Overall, we provide insights into Australian retrovirus evolution and identify a highly active endogenous retrovirus within Dasyuridae genomes.

Participating in Complementary and Integrative Health Approaches Is Associated With Veterans' Patient-reported Outcomes Over Time.

BACKGROUND: Veterans Affairs is dedicated to providing a Whole Health approach to care, including offering complementary and integrative health (CIH) approaches to Veterans. OBJECTIVE: The objective of this study was to examine the association of CIH participation with Veterans' patient-reported outcomes over time. RESEARCH DESIGN: A survey of patient-reported outcomes at 5 timepoints: baseline, 2, 4, 6, and 12 months. SUBJECTS: Veterans participating in any type of CIH approach at 2 Veterans Affairs medical centers. MEASURES: Mixed hierarchical models with repeated variables were used to test the hypothesis that participating in any CIH approach would be associated with Veterans' overall physical/mental health [Patient-Reported Outcomes Measurement Information System 28 (PROMIS 28)], pain intensity, perceived stress (Perceived Stress Scale-4), and engagement in their care (Patient Activation Measure-13), controlling for age, male sex, site, participation in other CIH approaches, and surveys completed. RESULTS: We received 401 surveys from 119 Veterans (72% male, age range: 29-85 y) across all timepoints. Yoga participation was related to decreases in perceived stress (P<0.001), while tai chi participation was associated with improvements in overall PROMIS 28 physical and mental health functioning (P<0.02). Specific types of CIH were associated with significant improvements in PROMIS 28 subscales: meditation participation with physical functioning at 2, 6, and 12 months; tai chi participation with anxiety at 2 and 6 months, and ability to participate in social role activities at 2 months. No CIH approach was associated with Veterans' pain or engagement in their care. CONCLUSION: As specific CIH approaches are associated with improvements in patient-reported outcomes, clinicians, Veterans, and family members may use this information in discussions of nonpharmacological options to address health and well-being.

Acculturative stress as a moderator for international student drinking behaviors and alcohol use consequences.

Drinking behaviors and alcohol use consequences can have a major effect on well-being in college student populations. Little research has addressed how the unique acculturative stress experiences of international students may affect their alcohol use and consequences. This study examined acculturative stress as a moderator of the relationship between international student drinking behaviors and alcohol use consequences. Data were collected from 175 international students and analyzed using hierarchal regression analysis to assess the moderating effect of acculturative stress. Acculturative stress moderated the relationship between alcohol use and related consequences such that the relationship was stronger among those with higher levels of acculturative stress. Efforts to alleviate acculturative stress experiences of this population may help decrease alcohol use consequences.

Five opportunities for healthcare leaders to better support person- and family-centred care in long-term care settings.

The benefits of Person- and Family-Centred Care (PFCC) are well documented, and many healthcare organizations have expressed their commitment to take this approach. Yet, it can be a difficult endeavour, with common barriers identified at the point-of-care, organizational and system levels. We implemented a PFCC education program with healthcare leaders, providers, and support staff working in home, community, and long-term care organizations across Canada. Focus groups were then conducted with almost 200 workshop participants and 20 long-term care home residents and family members. Five key opportunities for healthcare leaders to better support the provision of PFCC were revealed. In this article, specific recommendations from focus group participants for addressing each of these five opportunities are provided. These findings can assist healthcare leaders to proactively ensure the supports and processes are in place to enable staff to provide care in a more person- and family-centred way.

Rare presentation of small bowel intussusception in childhood.

Small bowel intussusception complicated simultaneously by volvulus in an older child is rare but clinically significant, necessitating urgent operative management. We report a local case of jejuno-jejunal intussusception complicated by volvulus and bowel infarction in a 9-year-old Chinese girl, with diagnosis made on preoperative computed tomography and confirmed at laparotomy. An intestinal polyp as the lead point for intussusception was identified operatively.

Liver X receptor (LXR) partial agonists: biaryl pyrazoles and imidazoles displaying a preference for LXRß.

A series of biaryl pyrazole and imidazole Liver X Receptor (LXR) partial agonists has been synthesized displaying LXRß selectivity. The LXRß selective partial agonist 18 was identified with potent induction of ATP binding transporters ABCA1 and ABCG1 in human whole blood (EC50=1.2µM, 55% efficacy). In mice 18 displayed peripheral induction of ABCA1 at 3 and 10mpk doses with no significant elevation of plasma or hepatic triglycerides at these doses, showing an improved profile compared to a full pan-agonist.

Can pre-operative axial CT imaging predict syndesmosis instability in patients sustaining ankle fractures? Seven years' experience in a tertiary trauma center.

OBJECTIVE: The purpose of this study is to explore the diagnostic accuracy of CT measurements in predicting syndesmosis instability of injured ankle, with correlation to operative findings. METHODS: From July 2006 to June 2013, 123 patients presented to a single tertiary hospital who received pre-operative CT for ankle fractures were retrospectively reviewed. All patients underwent open reduction and internal fixation for fractures and intra-operative syndesmosis integrity tests. The morphology of incisura fibularis was categorized as deep or shallow. The tibiofibular distance (TFD) between the medial border of the fibula and the nearest point of the lateral border of tibia were measured at anterior (aTFD), middle (mTFD), posterior (pTFD), and maximal (maxTFD) portions across the syndesmosis on axial CT images at 10 mm proximal to the tibial plafond. Statistical analysis was performed with independent samples t test and ROC curve analysis. Intraobserver reproducibility and inter-observers agreement were also evaluated. RESULTS: Of the 123 patients, 39 (31.7%) were operatively diagnosed with syndesmosis instability. No significant difference of incisura fibularis morphology (deep or shallow) and TFDs was demonstrated respective to genders. The axial CT measurements were significantly higher in ankles diagnosed with syndesmosis instability than the group without (maxTFD means 7.2 ± 2.96 mm vs. 4.6 ± 1.4 mm, aTFD mean 4.9 ± 3.7 mm vs. 1.8 ± 1.4 mm, mTFD mean 5.3 ± 2.4 mm vs. 3.2 ± 1.6 mm, pTFD mean 5.3 ± 1.8 mm vs. 4.1 ± 1.3 mm, p < 0.05). Their respective cutoff values with best sensitivity and specificity were calculated; the aTFD (AUC 0.798) and maxTFD (AUC 0.794) achieved the highest diagnostic accuracy. The optimal cutoff levels were aTFD = mm (sensitivity, 56.4%; specificity, 91.7%) and maxTFD = 5.65 mm (sensitivity, 74.4%; specificity, 79.8%). The inter-observer agreement was good for all aTFD, mTFD, pTFD, and maxTFD measurements (ICC 0.959, 0.799, 0.783, and 0.865). The ICC for intraobserver agreement was also very good, ranging from 0.826 to 0.923. CONCLUSIONS: Axial CT measurements of tibiofibular distance were useful predictors for syndesmosis instability in fractured ankles. The aTFD and maxTFD are the most powerful parameters to predict positive operative instability.

Determination of intracellular unbound concentrations and subcellular localization of drugs in rat sandwich-cultured hepatocytes compared with liver tissue.

Prediction of clinical efficacy, toxicity, and drug-drug interactions may be improved by accounting for the intracellular unbound drug concentration (C(unbound)) in vitro and in vivo. Furthermore, subcellular drug distribution may aid in predicting efficacy, toxicity, and risk assessment. The present study was designed to quantify the intracellular C(unbound) and subcellular localization of drugs in rat sandwich-cultured hepatocytes (SCH) compared with rat isolated perfused liver (IPL) tissue. Probe drugs with distinct mechanisms of hepatocellular uptake and accumulation were selected for investigation. Following drug treatment, SCH and IPL tissues were homogenized and fractionated by differential centrifugation to enrich for subcellular compartments. Binding in crude lysate and cytosol was determined by equilibrium dialysis; the C(unbound) and intracellular-to-extracellular C(unbound) ratio (K(pu,u)) were used to describe accumulation of unbound drug. Total accumulation (K(pobserved)) in whole tissue was well predicted by the SCH model (within 2- to 3-fold) for the selected drugs. Ritonavir (K(pu,u) ∼1) was evenly distributed among cellular compartments, but highly bound, which explained the observed accumulation within liver tissue. Rosuvastatin was recovered primarily in the cytosolic fraction, but did not exhibit extensive binding, resulting in a K(pu,u) >1 in liver tissue and SCH, consistent with efficient hepatic uptake. Despite extensive binding and sequestration of furamidine within liver tissue, a significant portion of cellular accumulation was attributed to unbound drug (K(pu,u) >16), as expected for a charged, hepatically derived metabolite. Data demonstrate the utility of SCH to predict quantitatively total tissue accumulation and elucidate mechanisms of hepatocellular drug accumulation such as active uptake versus binding/sequestration.

Self-reported stressors of National Guard women veterans before and after deployment: the relevance of interpersonal relationships.

BACKGROUND: With their rapidly expanding roles in the military, women service members experience significant stressors throughout their deployment experience. However, there are few studies that examine changes in women Veterans' stressors before and after deployment. OBJECTIVE: This study examines the types of stressors women Veterans report before deployment, immediately after deployment, 3 months after deployment, and 1 year post-deployment. DESIGN: Descriptive data on reported stressors was collected at four time points of a longitudinal study (HEROES Project). Open-ended responses from the Coping Response Inventory (CRI) were coded into six possible major stressor categories for analysis. PARTICIPANTS: Seventy-nine Army National Guard and Reserve female personnel deploying to Operation Enduring Freedom (OFF)/Operation Iraqi Freedom (OIF) were surveyed prior to deployment. Of these participants, 35 women completed Phase 2, 41 completed Phase 3, and 48 completed Phase 4 of the study. KEY RESULTS: We identified six major stressor categories: (1) interpersonal (i.e., issues with family and/or friends), (2) deployment-related and military-related, (3) health concerns, (4) death of a loved one, (5) daily needs (i.e., financial/housing/transportation concerns), and (6) employment or school-related concerns. At all time points, interpersonal issues were one of the most common type of stressor for this sample. Daily needs concerns increased from 3 months post-deployment to 1 year post-deployment. CONCLUSIONS: Interpersonal concerns are commonly reported by women Veterans both before and after their combat experience, suggesting that this is a time during which interpersonal support is especially critical. We discuss implications, which include the need for a more coordinated approach to women Veterans' health care (e.g., greater community-based outreach), and the need for more and more accessible Veterans Affairs (VA) services to address the needs of female Veterans.

What pre-deployment and early post-deployment factors predict health function after combat deployment?: a prospective longitudinal study of Operation Enduring Freedom (OEF)/Operation Iraqi Freedom (OIF) soldiers.

BACKGROUND: Physical and mental function are strong indicators of disability and mortality. OEF/OIF Veterans returning from deployment have been found to have poorer function than soldiers who have not deployed; however the reasons for this are unknown. METHODS: A prospective cohort of 790 soldiers was assessed both pre- and immediately after deployment to determine predictors of physical and mental function after war. RESULTS: On average, OEF/OIF Veterans showed significant declines in both physical (t=6.65, p<.0001) and mental function (t=7.11, p<.0001). After controlling for pre-deployment function, poorer physical function after deployment was associated with older age, more physical symptoms, blunted systolic blood pressure reactivity and being injured. After controlling for pre-deployment function, poorer mental function after deployment was associated with younger age, lower social desirability, lower social support, greater physical symptoms and greater PTSD symptoms. CONCLUSIONS: Combat deployment was associated with an immediate decline in both mental and physical function. The relationship of combat deployment to function is complex and influenced by demographic, psychosocial, physiological and experiential factors. Social support and physical symptoms emerged as potentially modifiable factors.

ChillsDB: A Gold Standard for Aesthetic Chills Stimuli.

We introduce ChillsDB the first validated database of audiovisual stimuli eliciting aesthetic chills (goosebumps, psychogenic shivers) in a US population. To discover chills stimuli "in the wild", we devised a bottom-up, ecologically-valid method consisting in searching for mentions of the emotion' somatic markers in user comments throughout social media platforms (YouTube and Reddit). We successfully captured 204 chills-eliciting videos of three categories: music, film, and speech. We then tested the top 50 videos in the database on 600+ participants and validated a gold standard of 10 stimuli with a 0.9 probability of generating chills. All ChillsDB tools and data are fully available on GitHub for researchers to be able to contribute and perform further analysis.

A semiphysiologically based pharmacokinetic modeling approach to predict the dose-exposure relationship of an antiparasitic prodrug/active metabolite pair.

Dose selection during antiparasitic drug development in animal models and humans traditionally has relied on correlations between plasma concentrations obtained at or below maximally tolerated doses that are efficacious. The objective of this study was to improve the understanding of the relationship between dose and plasma/tissue exposure of the model antiparasitic agent, pafuramidine, using a semiphysiologically based pharmacokinetic (semi-PBPK) modeling approach. Preclinical and clinical data generated during the development of pafuramidine, a prodrug of the active metabolite, furamidine, were used. A whole-body semi-PBPK model for rats was developed based on a whole-liver PBPK model using rat isolated perfused liver data. A whole-body semi-PBPK model for humans was developed on the basis of the whole-body rat model. Scaling factors were calculated using metabolic and transport clearance data generated from rat and human sandwich-cultured hepatocytes. Both whole-body models described pafuramidine and furamidine disposition in plasma and predicted furamidine tissue (liver and kidney) exposure and excretion profiles (biliary and renal). The whole-body models predicted that the intestine contributes significantly (30-40%) to presystemic furamidine formation in both rats and humans. The predicted terminal elimination half-life of furamidine in plasma was 3- to 4-fold longer than that of pafuramidine in rats (170 versus 47 h) and humans (64 versus 19 h). The dose-plasma/tissue exposure relationship for the prodrug/active metabolite pair was determined using the whole-body models. The human model proposed a dose regimen of pafuramidine (40 mg once daily) based on a predefined efficacy-safety index. A similar approach could be used to guide dose-ranging studies in humans for next-in-class compounds.

Revealing the uncharacterised diversity of amphibian and reptile viruses.

Amphibians and non-avian reptiles represent a significant proportion of terrestrial vertebrates, however knowledge of their viruses is not proportional to their abundance. Many amphibians and reptiles have strict habitual environments and localised populations and are vulnerable to viral outbreaks and potential elimination as a result. We sought to identify viruses that were hidden in amphibian and reptile metatranscriptomic data by screening 235 RNA-sequencing datasets from a 122 species covering 25 countries. We identified 26 novel viruses and eight previously characterised viruses from fifteen different viral families. Twenty-five viruses had RNA genomes with identity to Arteriviridae, Tobaniviridae, Hantaviridae, Rhabdoviridae, Astroviridae, Arenaviridae, Hepeviridae, Picornaviridae, Orthomyxoviridae, Reoviridae, Flaviviridae and Caliciviridae. In addition to RNA viruses, we also screened datasets for DNA viral transcripts, which are commonly excluded from transcriptomic analysis. We identified ten DNA viruses with identity to Papillomaviridae, Parvoviridae, Circoviridae and Adomaviridae. With the addition of these viruses, we expand the global amphibian and reptile virome and identify new potentially pathogenic viruses that could challenge populations. We speculate that amphibian viruses often have simpler genomes than those in amniotes, as in the case of the Secondpapillomavirinae and Orthomyxoviridae viruses identified in this study. In addition, we find evidence of inter-family recombination in RNA viruses, and we also identify new members of the recombinant Adomaviridae family. Overall, we provide insights into the uncharacterised diversity of amphibian and reptile viruses with the aim of improving population management, treatment and conservation into the future.

Aesthetic chills cause an emotional drift in valence and arousal.

Aesthetic chills are an embodied peak emotional experience induced by stimuli such as music, films, and speeches and characterized by dopaminergic release. The emotional consequences of chills in terms of valence and arousal are still debated and the existing empirical data is conflicting. In this study, we tested the effects of ChillsDB, an open-source repository of chills-inducing stimuli, on the emotional ratings of 600+ participants. We found that participants experiencing chills reported significantly more positive valence and greater arousal during the experience, compared to participants who did not experience chills. This suggests that the embodied experience of chills may influence one's perception and affective evaluation of the context, in favor of theoretical models emphasizing the role of interoceptive signals such as chills in the process of perception and decision-making. We also found an interesting pattern in the valence ratings of participants, which tended to harmonize toward a similar mean after the experiment, though initially disparately distributed. We discuss the significance of these results for the diagnosis and treatment of dopaminergic disorders such as Parkinson's, schizophrenia, and depression.

Multi-center prospective population pharmacokinetic study and the performance of web-based individual dose optimization application of intravenous vancomycin for adults in Hong Kong: A study protocol.

A recent consensus guideline recommends migrating the therapeutic drug monitoring practice for intravenous vancomycin for the treatment of methicillin-resistant Staphylococcus aureus infection from the traditional trough-based approach to the Bayesian approach based on area under curve to improve clinical outcomes. To support the implementation of the new strategy for hospitals under Hospital Authority, Hong Kong, this study is being proposed to (1) estimate and validate a population pharmacokinetic model of intravenous vancomycin for local adults, (2) develop a web-based individual dose optimization application for clinical use, and (3) evaluate the performance of the application by comparing the treatment outcomes and clinical satisfaction against the traditional approach. 300 adult subjects prescribed with intravenous vancomycin and not on renal replacement therapy will be recruited for population pharmacokinetic model development and validation. Sex, age, body weight, serum creatinine level, intravenous vancomycin dosing records, serum vancomycin concentrations etc. will be collected from several electronic health record systems maintained by Hospital Authority. Parameter estimation will be performed using non-linear mixed-effect modeling techniques. The web-based individual dose optimization application is based on a previously reported application and is built using R and the package shiny. Data from another 50 subjects will be collected during the last three months of the study period and treated as informed by the developed application and compared against historical control for clinical outcomes. Since the study will incur extra blood-taking procedures from patients, informed consent is required. Other than that, recruited subjects should receive medical treatments as usual. Identifiable patient data will be available only to site investigators and clinicians in each hospital. The study protocol and informed consent forms have been approved by the Joint Chinese University of Hong Kong-New Territories East Cluster Clinical Research Ethics Committee (reference number: NTEC-2021-0215) and registered at the Chinese Clinical Trial Registry (registration number: ChiCTR2100048714).

Impacts of fast production of afucosylated antibodies and Fc mutants in ExpiCHO-S™ for enhancing FcγRIIIa binding and NK cell activation.

This study has employed mammalian transient expression systems to generate afucosylated antibodies and antibody Fc mutants for rapid candidate screening in discovery and early development. While chemical treatment with the fucose analogue 2-fluoro-peracetyl-fucose during transient expression only partially produced antibodies with afucosylated N-glycans, the genetic inactivation of the FUT8 gene in ExpiCHO-S™ by CRISPR/Cas9 enabled the transient production of fully afucosylated antibodies. Human IgG1 and murine IgG2a generated by the ExpiCHOfut8KO cell line possessed a 8-to-11-fold enhanced FcγRIIIa binding activity in comparison with those produced by ExpiCHO-S™. The Fc mutant S239D/S298A/I332E produced by ExpiCHO-S™ had an approximate 2-fold higher FcγRIIIa affinity than that of the afucosylated wildtype molecule, although it displayed significantly lower thermal-stability. When the Fc mutant was produced in the ExpiCHOfut8KO cell line, the resulting afucosylated Fc mutant antibody had an additional approximate 6-fold increase in FcγRIIIa binding affinity. This synergistic effect between afucosylation and the Fc mutations was further verified by a natural killer (NK) cell activation assay. Together, these results have not only established an efficient large-scale transient CHO system for rapid production of afucosylated antibodies, but also confirmed a cooperative impact between afucosylation and Fc mutations on FcγRIIIa binding and NK cell activation.

Mechanisms underlying differences in systemic exposure of structurally similar active metabolites: comparison of two preclinical hepatic models.

Selection of in vitro models that accurately characterize metabolite systemic and hepatobiliary exposure remains a challenge in drug development. In the present study, mechanisms underlying differences in systemic exposure of two active metabolites, furamidine and 2,5-bis (5-amidino)-2-pyridyl furan (CPD-0801), were examined using two hepatic models from rats: isolated perfused livers (IPLs) and sandwich-cultured hepatocytes (SCH). Pafuramidine, a prodrug of furamidine, and 2,5-bis [5-(N-methoxyamidino)-2-pyridyl] furan (CPD-0868), a prodrug of CPD-0801, were selected for investigation because CPD-0801 exhibits greater systemic exposure than furamidine, despite remarkable structural similarity between these two active metabolites. In both IPLs and SCH, the extent of conversion of CPD-0868 to CPD-0801 was consistently higher than that of pafuramidine to furamidine over time (at most 2.5-fold); area under the curve (AUC) of CPD-0801 in IPL perfusate and SCH medium was at least 7-fold higher than that of furamidine. Pharmacokinetic modeling revealed that the rate constant for basolateral (liver to blood) net efflux (k(A_net efflux)) of total formed CPD-0801 (bound + unbound) was 6-fold higher than that of furamidine. Hepatic accumulation of both active metabolites was extensive (>95% of total formed); the hepatic unbound fraction (f(u,L)) of CPD-0801 was 5-fold higher than that of furamidine (1.6 versus 0.3%). Incorporation of f(u,L) into the pharmacokinetic model resulted in comparable k(A_net efflux,u) between furamidine and CPD-0801. In conclusion, intrahepatic binding markedly influenced the disposition of these active metabolites. A higher f(u,L) explained, in part, the enhanced perfusate AUC of CPD-0801 compared with furamidine in IPLs. SCH predicted the disposition of prodrug/metabolite in IPLs.

Ancient viral integrations in marsupials: a potential antiviral defence.

Marsupial viruses are understudied compared to their eutherian mammal counterparts, although they may pose severe threats to vulnerable marsupial populations. Genomic viral integrations, termed 'endogenous viral elements' (EVEs), could protect the host from infection. It is widely known past viral infections and EVEs play an active role in antiviral defence in invertebrates and plants. This study aimed to characterise actively transcribed EVEs in Australian marsupial species, because they may play an integral role in cellular defence against viruses. This study screened publicly available RNA sequencing data sets (n = 35) and characterised 200 viral transcripts from thirteen Australian marsupial species. Of the 200 transcripts, 188 originated from either Bornaviridae, Filoviridae, or Parvoviridae EVEs. The other twelve transcripts were from putative active infections from members of the Herpesviridae and Anelloviridae, and Hepadnaviridae. EVE transcripts (n = 188) were mapped to marsupial genomes (where available, n = 5/13) to identify the genomic insertion sites. Of the 188 transcripts, 117 mapped to 39 EVEs within the koala, bare-nosed wombat, tammar wallaby, brushtail possum, and Tasmanian devil genomes. The remaining eight animals had no available genome (transcripts n = 71). Every marsupial has Bornaviridae, Filoviridae, and Parvoviridae EVEs, a trend widely observed in eutherian mammals. Whilst eutherian bornavirus EVEs are predominantly nucleoprotein-derived, marsupial bornavirus EVEs demonstrate a surprising replicase gene bias. We predicted these widely distributed EVEs were conserved within marsupials from ancient germline integrations, as many were over 65 million years old. One bornavirus replicase EVE, present in six marsupial genomes, was estimated to be 160 million years old, predating the American-Australian marsupial split. We considered transcription of these EVEs through small non-coding RNA as an ancient viral defence. Consistent with this, in koala small RNA sequence data sets, we detected Bornaviridae replicase and Filoviridae nucleoprotein produced small RNA. These were enriched in testis tissue, suggesting they could protect marsupials from vertically transmitted viral integrations.

Choices in hemodialysis therapies: variants, personalized therapy and application of evidence-based medicine.

The extent of removal of the uremic toxins in hemodialysis (HD) therapies depends primarily on the dialysis membrane characteristics and the solute transport mechanisms involved. While designation of 'flux' of membranes as well toxicity of compounds that need to be targeted for removal remain unresolved issues, the relative role, efficiency and utilization of solute removal principles to optimize HD treatment are better delineated. Through the combination and intensity of diffusive and convective removal forces, levels of concentrations of a broad spectrum of uremic toxins can be lowered significantly and successfully. Extended clinical experience as well as data from several clinical trials attest to the benefits of convection-based HD treatment modalities. However, the mode of delivery of HD can further enhance the effectiveness of therapies. Other than treatment time, frequency and location that offer clinical benefits and increase patient well-being, treatment- and patient-specific criteria may be tailored for the therapy delivered: electrolytic composition, dialysate buffer and concentration and choice of anticoagulating agent are crucial for dialysis tolerance and efficacy. Evidence-based medicine (EBM) relies on three tenets, i.e. clinical expertise (i.e. doctor), patient-centered values (i.e. patient) and relevant scientific evidence (i.e. science), that have deviated from their initial aim and summarized to scientific evidence, leading to tyranny of randomized controlled trials. One must recognize that practice patterns as shown by Dialysis Outcomes and Practice Patterns Study and personalization of HD care are the main driving force for improving outcomes. Based on a combination of the three pillars of EBM, and particularly on bedside patient-clinician interaction, we summarize what we have learned over the last 6 decades in terms of best practices to improve outcomes in HD patients. Management of initiation of dialysis, vascular access, preservation of kidney function, selection of biocompatible dialysers and use of dialysis fluids of high microbiological purity to restrict inflammation are just some of the approaches where clinical experience is vital in the absence of definitive scientific evidence. Further, HD adequacy needs to be considered as a broad and multitarget approach covering not just the dose of dialysis provided, but meeting individual patient needs (e.g. fluid volume, acid-base, blood pressure, bone disease metabolism control) through regular assessment-and adjustment-of a series of indicators of treatment efficiency. Finally, in whichever way new technologies (i.e. artificial intelligence, connected health) are embraced in the future to improve the delivery of dialysis, the human dimension of the patient-doctor interaction is irreplaceable. Kidney medicine should remain 'an art' and will never be just 'a science'.