Frailty in patients on dialysis.

Frailty is a condition that is frequently observed among patients undergoing dialysis. Frailty is characterized by a decline in both physiological state and cognitive state, leading to a combination of symptoms, such as weight loss, exhaustion, low physical activity level, weakness, and slow walking speed. Frail patients not only experience a poor quality of life, but also are at higher risk of hospitalization, infection, cardiovascular events, dialysis-associated complications, and death. Frailty occurs as a result of a combination and interaction of various medical issues in patients who are on dialysis. Unfortunately, frailty has no cure. To address frailty, a multifaceted approach is necessary, involving coordinated efforts from nephrologists, geriatricians, nurses, allied health practitioners, and family members. Strategies such as optimizing nutrition and chronic kidney disease-related complications, reducing polypharmacy by deprescription, personalizing dialysis prescription, and considering home-based or assisted dialysis may help slow the decline of physical function over time in subjects with frailty. This review discusses the underlying causes of frailty in patients on dialysis and examines the methods and difficulties involved in managing frailty among this group.

Urinary podocyte stress marker as a prognostic indicator for diabetic kidney disease.

BACKGROUND: Diabetic kidney diseases (DKD) is a the most common cause of end-stage kidney disease (ESKD) around the world. Previous studies suggest that urinary podocyte stress biomarker, e.g. podocin:nephrin mRNA ratio, is a surrogate marker of podocyte injury in non-diabetic kidney diseases. METHOD: We studied 118 patients with biopsy-proved DKD and 13 non-diabetic controls. Their urinary mRNA levels of nephrin, podocin, and aquaporin-2 (AQP2) were quantified. Renal events, defined as death, dialysis, or 40% reduction in glomerular filtration rate, were determined at 12 months. RESULTS: Urinary podocin:nephrin mRNA ratio of DKD was significantly higher than the control group (p = 0.0019), while urinary nephrin:AQP2 or podocin:AQP2 ratios were not different between groups. In DKD, urinary podocin:nephrin mRNA ratio correlated with the severity of tubulointerstitial fibrosis (r = 0.254, p = 0.006). and was associated with the renal event-free survival in 12 months (unadjusted hazard ratio [HR], 1.523; 95% confidence interval [CI] 1.157-2.006; p = 0.003). After adjusting for clinical and pathological factors, urinary podocin:nephrin mRNA ratio have a trend to predict renal event-free survival (adjusted HR, 1.327; 95%CI 0.980-1.797; p = 0.067), but the result did not reach statistical significance. CONCLUSION: Urinary podocin:nephrin mRNA ratio has a marginal prognostic value in biopsy-proven DKD. Further validation is required for DKD patients without kidney biopsy.

Safety Profile and Clinical and Virological Outcomes of Nirmatrelvir-Ritonavir Treatment in Patients With Advanced Chronic Kidney Disease and Coronavirus Disease 2019.

BACKGROUND: Nirmatrelvir-ritonavir is currently not recommended in patients with an estimated glomerular filtration rate (eGFR) <30 mL/minute/1.73 m2. METHODS: To determine the safety profile and clinical and virological outcomes of nirmatrelvir-ritonavir use at a modified dosage in adults with chronic kidney disease (CKD), a prospective, single-arm, interventional trial recruited patients with eGFR <30 mL/minute/1.73 m2 and on dialysis. Primary outcomes included safety profile, adverse/serious adverse events, and events leading to drug discontinuation. Disease symptoms, virological outcomes by serial severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral polymerase chain reaction (PCR) tests, rapid antigen tests, and virological and symptomatic rebound were also recorded. RESULTS: Fifty-nine (69.4%) of the 85 participants had stage 5 CKD and were on dialysis. Eighty (94.1%) completed the full treatment course; 9.4% and 5.9% had adverse and serious adverse events, and these were comparable between those with eGFR < or >30 mL/minute/1.73 m2. The viral load significantly decreased on days 5, 15, and 30 (P < .001 for all), and the reduction was consistent in the subgroup with eGFR <30 mL/minute/1.73 m2. Ten patients had virological rebound, which was transient and asymptomatic. CONCLUSIONS: Among patients with CKD, a modified dose of nirmatrelvir-ritonavir is a well-tolerated therapy in mild COVID-19 as it can effectively suppress the SARS-CoV-2 viral load with a favorable safety profile. Virological and symptomatic rebound, although transient with low infectivity, may occur after treatment. Nirmatrelvir-ritonavir should be considered for use in patients with CKD, including stage 5 CKD on dialysis. Clinical Trials Registration. Clinical Trials.gov; identifier: NCT05624840.

Intrarenal and Urinary Glycogen Synthase Kinase-3 Beta Levels in Diabetic and Nondiabetic Chronic Kidney Disease.

BACKGROUND: Renal glycogen synthase kinase-3 beta (GSK3ß) overactivity has been associated with a diverse range of kidney diseases. GSK3ß activity in urinary exfoliated cells was reported to predict the progression of diabetic kidney disease (DKD). We compared the prognostic value of urinary and intrarenal GSK3ß levels in DKD and nondiabetic chronic kidney disease (CKD). METHODS: We recruited 118 consecutive biopsy-proved DKD patients and 115 nondiabetic CKD patients. Their urinary and intrarenal GSK3ß levels were measured. They were then followed for dialysis-free survival and rate of renal function decline. RESULTS: DKD group had higher intrarenal and urinary GSK3ß levels than nondiabetic CKD (p < 0.0001 for both), but their urinary GSK3ß mRNA levels were similar. Urinary p-GSK3ß level is statistically significantly correlated with the baseline estimated glomerular filtration rate (eGFR), but urinary GSK3ß level by ELISA, its mRNA level, the p-GSK3ß level, or the p-GSK3ß/GSK3ß ratio had no association with dialysis-free survival or the slope of eGFR decline. In contrast, the intrarenal pY216-GSK3ß/total GSK3ß ratio significantly correlated with the slope of eGFR decline (r = -0.335, p = 0.006) and remained an independent predictor after adjusting for other clinical factors. CONCLUSION: Intrarenal and urinary GSK3ß levels were increased in DKD. The intrarenal pY216-GSK3ß/total GSK3ß ratio was associated with the rate of progression of DKD. The pathophysiological roles of GSK3ß in kidney diseases deserve further studies.

Relationship between Serial Serum Neutrophil-Lymphocyte Ratio, Cardiovascular Mortality, and All-Cause Mortality in Chinese Peritoneal Dialysis Patients.

INTRODUCTION: It is believed that the excessive cardiovascular (CV) burden of patients on peritoneal dialysis (PD) is closely associated with chronic inflammation. Neutrophil-lymphocyte ratio (NLR) is an inflammatory marker that was shown to correlate with CV outcomes. However, little is known about the significance of serial monitoring of serum NLR. We aimed to determine the prognostic value of serial NLR on all-cause mortality and CV mortality in PD patients. METHODS: Serial measurement of NLR was obtained from 225 incident PD patients in a single center, with each measurement 1 year apart. Patients were divided into two groups ("high" vs. "low") by the median value of NLR. The primary and secondary outcome measure was all-cause and CV mortality, respectively. RESULTS: After a median of follow-up for 43.9 months, patients with lower baseline NLR demonstrated a higher survival rate (p = 0.01). Patients with persistently high NLR values on serial measurement had the lowest survival rate (p = 0.03). Multivariate Cox regression showed that this group of patients had significantly higher all-cause mortality (HR: 1.74, 95% CI: 1.09-2.79, p = 0.02). However, the NLR failed to demonstrate a statistically significant relationship with CV mortality. CONCLUSIONS: While baseline NLR was an independent predictor of all-cause mortality in PD patients, persistent elevation in NLR appeared to further amplify the risk. Regular monitoring of serial serum NLR may enable early identification of patients who are at risk of adverse outcome.

From MIA to FIFA: The vicious matrix of frailty, inflammation, fluid overload and atherosclerosis in peritoneal dialysis.

Cardiovascular disease (CVD) is a major cause of mortality and morbidity in peritoneal dialysis (PD) patients. Two decades ago, the common co-existence of malnutrition and systemic inflammation PD patients with atherosclerosis and CVD led to the proposed terminology of 'malnutrition-inflammation-atherosclerosis (MIA) syndrome'. Although the importance of malnutrition is well accepted, frailty represents a more comprehensive assessment of the physical and functional capability of the patient and encompasses the contributions of sarcopenia (a key component of malnutrition), obesity, cardiopulmonary as well as neuropsychiatric impairment. In recent years, it is also increasingly recognized that fluid overload is not only the consequence but also play an important role in the pathogenesis of CVD. Moreover, fluid overload is closely linked with the systemic inflammatory status, presumably by gut oedema, gastrointestinal epithelial barrier dysfunction and leakage of bacterial fragments to the systemic circulation. There are now a wealth of published evidence to show intricate relations between frailty, inflammation, fluid overload and atherosclerotic disease in patients with chronic kidney disease (CKD) and those on PD, a phenomenon that we propose the term 'FIFA complex'. In this system, frailty and atherosclerotic disease may be regarded as two patient-oriented outcomes, while inflammation and fluid overload are two inter-connected pathogenic processes. However, there remain limited data on how the treatment of one component affect the others. It is also important to define how treatment of fluid overload affect the systemic inflammatory status and to develop effective anti-inflammatory strategies that could alleviate atherosclerotic disease and frailty.

Plasma vaspin levels and clinical outcome in incident peritoneal dialysis patients.

BACKGROUND: Vaspin is an adipokine that regulates glucose and lipid metabolism. Plasma vaspin level is increased in chronic kidney disease but decreased in hemodialysis patients. However, plasma vaspin level in peritoneal dialysis (PD) patients, as well as its prognostic role, has not been studied. METHODS: We recruited 146 incident PD patients. Their baseline plasma vaspin levels, body anthropometry, the profile of insulin resistance, bioimpedance spectroscopy parameters, dialysis adequacy, and nutritional indices were measured. They were followed for up to 5 years for survival analysis. RESULTS: The average age was 58.4 ± 11.8 years; 96 patients (65.8%) were men, and 90 (61.6%) had diabetes. The median vaspin level was 0.18 ng/dL (interquartile range [IQR] 0.11 to 0.30 ng/dL). Plasma vaspin level did not have a significant correlation with adipose tissue mass or baseline insulin level. However, plasma vaspin level had a modest correlation with the change in insulin resistance, as represented by the HOMA-IR index, in non-diabetic patients (r = -0.358, p = 0.048). Although the plasma vaspin level quartile did not have a significant association with patient survival in the entire cohort, it had a significant interaction with diabetic status (p < 0.001). In nondiabetic patients, plasma vaspin level quartile was an independent predictor of patient survival after adjusting for confounding clinical factors (adjusted hazard ratio 2.038, 95% confidence interval 1.191-3.487, p = 0.009), while the result for diabetic patients was not significant. CONCLUSIONS: Plasma vaspin level quartile had a significant association with patient survival in non-diabetic PD patients. Baseline plasma vaspin level also had a modest inverse correlation with the subsequent change in the severity of insulin resistance, but the exact biological role of vaspin deserves further studies.

Urinary Long Non-Coding RNA Levels as Biomarkers of Lupus Nephritis.

BACKGROUND: Emerging evidence suggests that long non-coding RNA (lncRNA) plays important roles in the regulation of gene expression. We determine the role of using urinary lncRNA as a non-invasive biomarker for lupus nephritis. METHOD: We studied three cohorts of lupus nephritis patients (31, 78, and 12 patients, respectively) and controls (6, 7, and 24 subjects, respectively). The urinary sediment levels of specific lncRNA targets were studied using real-time quantitative polymerase chain reactions. RESULTS: The severity of proteinuria inversely correlated with urinary maternally expressed gene 3 (MEG3) (r = -0.423, p = 0.018) and ANRIL levels (r = -0.483, p = 0.008). Urinary MEG3 level also inversely correlated with the SLEDAI score (r = -0.383, p = 0.034). Urinary cancer susceptibility candidate 2 (CASC2) levels were significantly different between histological classes of nephritis (p = 0.026) and patients with pure class V nephritis probably had the highest levels, while urinary metastasis-associated lung carcinoma transcript 1 (MALAT1) level significantly correlated with the histological activity index (r = -0.321, p = 0.004). Urinary taurine-upregulated gene 1 (TUG1) level was significantly lower in pure class V lupus nephritis than primary membranous nephropathy (p = 0.003) and minimal change nephropathy (p = 0.04), and urinary TUG1 level correlated with eGFR in class V lupus nephritis (r = 0.706, p = 0.01). CONCLUSIONS: We identified certain urinary lncRNA targets that may help the identification of lupus nephritis and predict the histological class of nephritis. Our findings indicate that urinary lncRNA levels may be developed as biomarkers for lupus nephritis.

Adipose expression of miR-130b and miR-17-5p with wasting, cardiovascular event and mortality in advanced chronic kidney disease patients.

BACKGROUND: There are limited data on the association of adipose microRNA expression with body composition and adverse clinical outcomes in patients with advanced chronic kidney disease (CKD). We aimed to evaluate the association of adipose miR-130b and miR-17-5p expressions with body composition, functional state, cardiovascular outcome and mortality in incident dialysis patients. METHODS: We performed a single-center prospective cohort study. Patients who were planned for peritoneal dialysis were recruited. miR-130b and miR-17-5p expressions were measured from subcutaneous and pre-peritoneal fat tissue obtained during peritoneal dialysis catheter insertion. Body composition and physical function were assessed by bioimpedance spectroscopy and Clinical Frailty Scale. Primary outcome was 2-year survival. Secondary outcomes were 2-year technique survival and major adverse cardiovascular event (MACE) rate. RESULTS: Adipose expression of miR-130b and miR-17-5p correlated with parameters of muscle mass including intracellular water (miR-130b: r = 0.191, P = 0.02; miR-17-5p: r = 0.211, P = 0.013) and lean tissue mass (miR-17-5p: r = 0.176, P = 0.04; miR-17-5p: r = 0.176, P = 0.004). miR-130b expression predicted frailty significantly (P = 0.017). Adipose miR-17-5p expression predicted 2-year all-cause survival (P = 0.020) and technique survival (P = 0.036), while miR-130b expression predicted incidence of MACE (P = 0.015). CONCLUSIONS: Adipose miR-130b and miR-17-5p expressions correlated with body composition parameters, frailty, and predicted cardiovascular events and mortality in advanced CKD patients.

Chemoenzymatic synthesis, computational investigation, and antitumor activity of monocyclic lankacidin derivatives.

We investigated the importance of the δ-lactone ring (C1-C5) in lankacidin C using chemoenzymatic synthesis and computational prediction and assessing biological activity, including antitumor activity. Pyrroloquinoline quinone-dependent dehydrogenase (Orf23) in Streptomyces rochei was used in the chemoenzymatic synthesis of lankacyclinone C, a novel lankacidin C congener lacking the δ-lactone moiety. Orf23 could convert the monocyclic lankacidinol derivatives, lankacyclinol and 2-epi-lankacyclinol, to the C-24 keto compounds, lankacyclinone C and 2-epi-lankacyclinone C, respectively, elucidating the relaxed substrate specificity of Orf23. Computational prediction using molecular dynamics simulations and the molecular mechanics/generalized Born-surface area protocol indicated that binding energy values of all the monocyclic derivatives are very close to those of lankacidin C, which may reflect a comparable affinity to tubulin. Monocyclic lankacidin derivatives showed moderate antitumor activity when compared with bicyclic lankacidins, suggesting that the δ-lactone moiety is less important for antitumor activity in lankacidin-group antibiotics.

Automated classification of mitotic catastrophe by use of the centromere fragmentation morphology.

Mitotic catastrophe is a common mode of tumor cell death. Cancer cells with a defective cell-cycle checkpoint often enter mitosis with damaged or under replicated chromosomes following genotoxic treatment. Premature condensation of the under-replicated (or damaged) chromosomes results in double-stranded DNA breaks at the centromere (centromere fragmentation). Centromere fragmentation is a morphological marker of mitotic catastrophe and is distinguished by the clustering of centromeres away from the chromosomes. We present an automated 2-step system for segmentation of cells exhibiting centromere fragmentation. The first step segments individual cells from clumps. We added two new terms, weighted local repelling term (WLRt) and weighted gradient term (WGt), in the energy functional of the traditional Chan-Vese based level set method. WLRt was used to generate a repelling force when contours of adjacent cells merged and then penalized the overlap. WGt enhances gradients between overlapping cells. The second step consists of a new algorithm, SBaN (shape-based analysis of each nucleus), which extracts features like circularity, major-axis length, minor-axis length, area, and eccentricity from each chromosome to identify cells with centromere fragmentation. The performance of SBaN algorithm for centromere fragmentation detection was statistically evaluated and the results were robust.

Progression in Physical Frailty in Peritoneal Dialysis Patients.

BACKGROUND: Physical frailty contributes to adverse clinical outcomes in peritoneal dialysis (PD) patients. Little has been reported about frailty transitions in this population. We aimed to describe the transitions of frailty in PD patients and identify factors that predicted changes in frailty state. METHODS: In a prospective observational study, we recruited 267 PD patients. Frailty was assessed by a validated frailty score. Depression was graded by PHQ-9 score, and nutritional status was evaluated by serum albumin, Subjective Global Assessment (SGA), and comprehensive Malnutrition Inflammation Score (MIS). The primary outcome was the change in frailty score at follow-up compared to baseline. RESULTS: At baseline, 194 (72.7%) patients were classified as frail. With time, their frailty scores significantly increased (p < 0.001), and 93 of the surviving subjects (78.2%) were classified as frail. There was a modest significant correlation between change in MIS (p < 0.001), change in SGA score (p < 0.001), and change in PHQ-9 score (p < 0.001) with change in frailty score. An increase in PHQ-9 score (p < 0.001) and MIS (p = 0.001), as well as longer duration of hospitalization (p = 0.001), was independently associated with a greater change in frailty score after adjustment for confounding factors. Frailty score was also improved in patients who were converted to hemodialysis (p = 0.048) and received renal transplantation (p = 0.005). CONCLUSION: Our findings suggested that frailty transitions were common in PD patients. Worsening in nutrition and depression, together with a longer duration of hospitalization, were associated with worsening in frailty.

Survey of patient-specific quality assurance practice for IMRT and VMAT.

A first-time survey across 15 cancer centers in Ontario, Canada, on the current practice of patient-specific quality assurance (PSQA) for intensity modulated radiation therapy (IMRT) and volumetric modulated arc therapy (VMAT) delivery was conducted. The objectives were to assess the current state of PSQA practice, identify areas for potential improvement, and facilitate the continued improvement in standardization, consistency, efficacy, and efficiency of PSQA regionally. The survey asked 40 questions related to PSQA practice for IMRT/VMAT delivery. The questions addressed PSQA policy and procedure, delivery log evaluation, instrumentation, measurement setup and methodology, data analysis and interpretation, documentation, process, failure modes, and feedback. The focus of this survey was on PSQA activities related to routine IMRT/VMAT treatments on conventional linacs, including stereotactic body radiation therapy but excluding stereotactic radiosurgery. The participating centers were instructed to submit answers that reflected the collective view or opinion of their department and represented the most typical process practiced. The results of the survey provided a snapshot of the current state of PSQA practice in Ontario and demonstrated considerable variations in the practice. A large majority (80%) of centers performed PSQA measurements on all VMAT plans. Most employed pseudo-3D array detectors with a true composite (TC) geometry. No standard approach was found for stopping or reducing frequency of measurements. The sole use of delivery log evaluation was not widely implemented, though most centers expressed interest in adopting this technology. All used the Gamma evaluation method for analyzing PSQA measurements; however, no universal approach was reported on how Gamma evaluation and pass determination criteria were determined. All or some PSQA results were reviewed regularly in two-thirds of the centers. Planning related issues were considered the most frequent source for PSQA failures (40%), whereas the most frequent course of action for a failed PSQA was to review the result and decide whether to proceed to treatment.

Automated radiosynthesis of [68 Ga]Ga-PSMA-11 and [177 Lu]Lu-PSMA-617 on the iPHASE MultiSyn module for clinical applications.

Prostate-specific membrane antigen (PSMA)-targeted imaging and therapy of prostate cancer using theranostic pairs is rapidly changing clinical practice. To facilitate clinical trials, fully automated procedures for the radiosyntheses of [68 Ga]Ga-PSMA-11 and [177 Lu]Lu-PSMA-617 were developed from commercially available precursors using the cassette based iPHASE MultiSyn module. Formulated and sterile radiopharmaceuticals were obtained in 76 ± 3% (n = 20) and 91 ± 4% (n = 15) radiochemical yields after 17 and 20 min, respectively. Radiochemical purity was always >95% and molar activities exceeded 792 ± 100 and 88 ± 6 GBq/µmol, respectively. Quality control showed conformity with all relevant release criteria and radiopharmaceuticals were used in the clinic.

Distinct mechanisms govern the phosphorylation of different SR protein splicing factors.

Serine-arginine (SR) proteins are essential splicing factors containing a canonical RNA recognition motif (RRM), sometimes followed by a pseudo-RRM, and a C-terminal arginine/serine-rich (RS) domain that undergoes multisite phosphorylation. Phosphorylation regulates the localization and activity of SR proteins, and thus may provide insight into their differential biological roles. The phosphorylation mechanism of the prototypic SRSF1 by serine-arginine protein kinase 1 (SRPK1) has been well-studied, but little is known about the phosphorylation of other SR protein members. In the present study, interaction and kinetic assays unveiled how SRSF1 and the single RRM-containing SRSF3 are phosphorylated by SRPK2, another member of the SRPK family. We showed that a conserved SRPK-specific substrate-docking groove in SRPK2 impacts the binding and phosphorylation of both SR proteins, and the localization of SRSF3. We identified a nonconserved residue within the groove that affects the kinase processivity. We demonstrated that, in contrast to SRSF1, for which SRPK-mediated phosphorylation is confined to the N-terminal region of the RS domain, SRSF3 phosphorylation sites are spread throughout its entire RS domain in vitro Despite this, SRSF3 appears to be hypophosphorylated in cells at steady state. Our results suggest that the absence of a pseudo-RRM renders the single RRM-containing SRSF3 more susceptible to dephosphorylation by phosphatase. These findings suggest that the single RRM- and two RRM-containing SR proteins represent two subclasses of phosphoproteins in which phosphorylation statuses are maintained by unique mechanisms, and pose new directions to explore the distinct roles of SR proteins in vivo.

Should we use kidneys from donors with acute kidney injury for renal transplantation?

The scarcity of donor organs for transplant results in long waiting times for kidney transplantation and low transplant rate worldwide. Utilization of kidneys from donors with acute kidney injury (AKI) is one of the strategies that has attracted attention recently. This article reviewed the outcomes of transplanted renal allografts from donors with acute kidney injury. Key findings about the transplant outcomes included a higher incidence of delayed graft function and primary non function, but respectable outcomes in the context of similar acute rejection rates, and graft function and graft survival. Against this background and with evidence of high mortality for patients remaining on waiting list of transplant, we advocate consideration of AKI donors for kidney transplantation.

Depression does not predict clinical outcome of Chinese peritoneal Dialysis patients after adjusting for the degree of frailty.

BACKGROUND: Depression and frailty contribute to the adverse clinical outcome of peritoneal dialysis (PD) patients. However, the interaction between depression and frailty in PD patients remains uncertain. We determined the prevalence of depression and frailty in prevalent Chinese PD patients, dissected the internal relationship between depression and frailty, and determined their relative contribution to the adverse clinical outcome in PD patients. METHODS: In a prospective observational study, we recruited 267 prevalent PD patients. Depression was identified by Patient Health Questionnaire (PHQ-9). Frailty was identified by a validated Frailty Score. All cases were followed for one year. Outcome measures included number and duration of hospitalization, peritonitis rate, and all-cause mortality. RESULTS: Of the 267 patients, 197 patients (73.8%) were depressed, and 157 (58.8%) were frail. There was a substantial overlap between depression and frailty. Although depression and frailty were associated the number and duration of hospitalization by univariate analysis, the association became insignificant after adjusting for confounding factors by multivariate analysis. Both depression and frailty were associated with one-year mortality by univariate analysis. One-year patient survival was 95.9, 86.5, 82.4 and 71.0% for patients with nil, mild, moderate and severe frailty, respectively (p = 0.001). Frailty was an independent predictor of patient survival by multivariate analysis (adjusted hazard ratio 1.424, 95% confidence interval 1.011-2.005. p = 0.043), while the prognostic effect of depression disappears after adjusting for frailty score. CONCLUSION: Depression and frailty were common among Chinese PD patients. Frailty, but not depression, was an independent predictor of one-year mortality.

Quantified VMAT plan complexity in relation to measurement-based quality assurance results.

Volumetric-modulated arc therapy (VMAT) treatment plans that are highly modulated or complex may result in disagreements between the planned dose distribution and the measured dose distribution. This study investigated established VMAT complexity metrics as a means of predicting phantom-based measurement results for 93 treatments delivered on a TrueBeam linac, and 91 treatments delivered on two TrueBeam STx linacs. Complexity metrics investigated showed weak correlations to gamma passing rate, with the exception of the Modulation Complexity Score for VMAT, yielding moderate correlations. The Spearman's rho values for this metric were 0.502 (P < 0.001) and 0.528 (P < 0.001) for the TrueBeam and TrueBeam STx, respectively. Receiver operating characteristic analysis was also performed. The aperture irregularity on the TrueBeam achieved a 53% true positive rate and a 9% false-positive rate to correctly identify complex plans. Similarly, the average field width on the TrueBeam STx achieved a 60% true-positive rate and an 8% false-positive rate. If incorporated into clinical workflow, these thresholds can identify highly modulated plans and reduce the number of dose verification measurements required.

Programmable Metal/Semiconductor Nanostructures for mRNA-Modulated Molecular Delivery.

Cytotoxic chemotherapeutics are important tools for the clinical treatment of a variety of solid tumors. However, their use is often complicated by multidrug resistance that can develop in patients, limiting the potencies of these agents. New strategies are needed to provide versatile systems that can respond to and disable resistance mechanisms. We demonstrate the use of a new family of materials, programmable metal/semiconductor nanostructures, for drug delivery and mRNA sensing in drug-resistant cells. These materials are composed of a central core gold nanoparticle surrounded by a layer of DNA-capped quantum dots. The modularity of these "core-satellite" assemblies allows for the construction of superstructures with controlled size and the incorporation of multiple functionalities for drug delivery. The DNA sequence within the nanoparticle specifically binds to an mRNA encoding an important drug resistance factor, MRP1, inside cancer cells, releasing a potent anticancer drug doxorubicin. This event triggers a turn-on fluorescence emission along with a downregulation of the MRP1 drug efflux pump, a main resistance factor for doxorubicin, yielding a remarkable improvement in therapeutic efficacy against drug-resistant cancer cells. This work paves the way for the development of programmable materials with multiple synergistic functionalities for biomedical applications.

Depression and Physical Frailty Have Additive Effect on the Nutritional Status and Clinical Outcome of Chinese Peritoneal Dialysis.

BACKGROUND/AIMS: Frailty and depression both contribute to malnutrition and adverse clinical outcome of peritoneal dialysis (PD) patients. However, their interaction is incompletely defined. METHODS: We studied 178 adult Chinese PD patients. Physical frailty was assessed by a validated in-house questionnaire; depressive symptoms was screened by the Geriatric Depression Scale; nutritional status was determined by subjective global assessment (SGA) and malnutrition inflammation score (MIS). All patients were followed for up to 24 months for survival and hospitalization analysis. RESULTS: There were 111 patients (62.4%) physically frail, amongst those 48 (43.2%) had depressive symptoms. Only 1 patient had depressive symptoms without frailty. There was an additive effect of depressive symptoms and physical frailty on nutritional status. For the groups with no frailty, frail but no depressive symptoms, and frail with depressive symptoms, serum albumin decreased in a stepwise manner (35.8 ± 5.6, 34.9 ± 4.4, and 32.9 ± 5.3 g/L, respectively, p=0.025); overall SGA score was 5.75 ± 0.61, 5.41 ± 0.59, and 5.04 ± 0.77, respectively (p< 0.0001), and MIS was 5.12 ± 2.30, 7.13 ± 3.22, and 9.48 ± 3.97, respectively (p< 0.0001). At 24 months, patient survival was 86.6%, 71.4%, and 62.5% for patients with no frailty, frail but no depressive symptoms, and frail with depressive symptoms, respective (p=0.001). The median number of hospital stay was 8.04 (inter-quartile range [IQR] 0.91 - 19.42), 14.05 (IQR 3.57 - 37.27), and 26.62 (IQR 10.65 - 61.18) days per year of follow up, respectively (p< 0.0001). CONCLUSION: Physical frailty and depressive symptoms are both common in Chinese PD patients, and they have additive adverse effect on the nutritional status and clinical outcome.