Inspired by nature’s wide range of oxidation-induced modifications to install cross-links and cycles at tyrosine (Tyr) and other phenol-containing residue side chains, we report a Tyr-selective ...strategy for the preparation of Tyr-linked cyclic peptides. This approach leverages N4-substituted 1,2,4-triazoline-3,5-diones (TADs) as azo electrophiles that react chemoselectively with the phenolic side chain of Tyr residues to form stable C–N1-linked cyclic peptides. In the developed method, a precursor 1,2,4-triazolidine-3,5-dione moiety, also known as urazole, is readily constructed at any free amine revealed on a solid-supported peptide. Once prepared, the N4-substituted urazole peptide is selectively oxidized using mild, peptide-compatible conditions to generate an electrophilic N4-substituted TAD peptide intermediate that reacts selectively under aqueous conditions with internal and terminal Tyr residues to furnish Tyr-linked cyclic peptides. The approach demonstrates good tolerance of native residue side chains and enables access to cyclic peptides ranging from 3- to 11-residues in size (16- to 38-atom-containing cycles). The identity of the installed Tyr-linkage, a stable covalent C–N1 bond, was characterized using NMR spectroscopy. Finally, we applied the developed method to prepare biologically active Tyr-linked cyclic peptides bearing the integrin-binding RGDf epitope.
Objectives
To examine the variability of statin use among nursing home residents and prescribing physicians, and to assess statin use by resident frailty.
Design
Population‐based, cross‐sectional ...analysis.
Setting
All nursing home facilities (N = 631) in Ontario, Canada between April 1, 2013 and March 31, 2014.
Participants
All adults aged 66 years and older who received a full clinical assessment while residing in a nursing home facility and their assigned, most responsible, physician.
Measurements
Statin use on date of clinical assessment. Resident‐ and physician‐level characteristics ascertained through clinical assessment and health administrative data. Resident frailty was derived using a previously validated index.
Results
Among 76,226 nursing home residents assigned to 1,919 physicians, 25,648 (33.6%) were statin users. There were 13,331 (30.1%) statin users among the 44,290 residents categorized as frail. In an adjusted mixed‐effects logistic regression model, frail residents (adjusted odds ratio = 0.62, 95% confidence interval 0.58–0.65) were significantly less likely to be statin users compared with non‐frail residents. After adjustment for resident characteristics, the intraclass correlation coefficient indicated that between‐physician variability accounted for 9.1% of the residual unexplained variation in statin use (P < .001). Among the 894 physicians assigned 20 or more residents, funnel plots confirmed there were more low‐outlying (17.4%) and high‐outlying (12.0%) prescribers of statins than expected by chance. Physicians who were high‐outlying prescribers had higher historical rates of statin prescribing.
Conclusions and Relevance
Statin prescribing was substantial within nursing homes, even among frail residents. After controlling for resident characteristics, the likelihood of statin prescribing varied significantly across physicians. Further studies are required to evaluate the risks and benefits of statin use, and discontinuation, among nursing home residents to better inform clinical practice in this setting.
Objective: Given overlapping pathophysiology, this study sought to assess the association between osteoarthritis (OA), functional impairment, and cognitive impairment in the aging population. ...Methods: The National Health and Nutrition Examination Survey was used to identify participants >60 years of age. We analyzed multivariable associations of grouped participants that underwent cognitive function testing using linear and logistic regression, adjusting for sex, age, race, and ethnicity. Results: Of 2776 identified participants representing a population of 50,242,917, 40% did not report OA or functional limitations; 21% had OA but not functional limitations; 15% did not have OA but had functional limitations; 17% had OA and related functional limitations; and 7% had OA and non-arthritic functional limitations. OA was not independently associated with cognitive impairment. Contrarily, functional limitations were associated with cognitive impairment regardless of OA diagnosis. Discussion: Cognitive impairment is not associated with OA, but rather functional limitations, potentially guiding future intervention.
Vinyl chloride (VC) is a prevalent environmental toxicant that is rapidly metabolized within the liver. Its metabolites have been shown to directly cause hepatic injury at high exposure levels. We ...have previously reported that VC metabolite, chloroethanol (CE), potentiates liver injury caused by lipopolysaccharide (LPS). Importantly, that study showed that CE alone, while not causing damage per se, was sufficient to alter hepatic metabolism and increase mTOR phosphorylation in mice, suggesting a possible role for the mTOR pathway. Here, we explored the effect of an mTOR inhibitor, rapamycin, in this model. C57BL/6 J mice were administered CE, followed by rapamycin 1 h and LPS 24 h later. As observed previously, the combination of CE and LPS significantly enhanced liver injury, inflammation, oxidative stress, and metabolic dysregulation. Rapamycin attenuated not only inflammation, but also restored the metabolic phenotype and protected against CE + LPS-induced oxidative stress. Importantly, rapamycin protected against mitochondrial damage and subsequent production of reactive oxygen species (ROS). The protective effect on mitochondrial function by rapamycin was mediated, by restoring the integrity of the electron transport chain at least in part, by blunting the deactivation of mitochondrial c-src, which is involved mitochondrial ROS production by electron transport chain leakage. Taken together, these results further demonstrate a significant role of mTOR-mediated pathways in VC-metabolite induced liver injury and provide further insight into VC-associated hepatic damage. As mTOR mediated pathways are very complex and rapamycin is a more global inhibitor, more specific mTOR (i.e. mTORC1) inhibitors should be considered in future studies.
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•Rapamycin protects against liver injury caused by chloroethanol (CE) and LPS.•Rapamycin reverses metabolic dyshomeostasis and oxidative stress in that model.•CE + LPS disrupts the integrity of the electron transport chain.•Rapamycin protects against mitochondrial damage.
Progress toward the design and synthesis of ambiphilic aryl thiol–iminium-based small molecules for organocatalyzed thioacyl aminolysis is reported. Here we describe the synthesis of a novel ...tetrahydroisoquinoline-derived scaffold, bearing both thiol and iminium functionalities, capable of promoting the transthioesterification and subsequent amine capture reactions necessary to achieve organocatalyzed thioacyl aminolysis. Model studies demonstrate the ability of this designed organocatalyst to deliver critical intermediates capable of undergoing these individual reactions necessary for the proposed process. Future design improvements and directions toward cysteine-independent organocatalyzed native chemical ligation are discussed.
Particle-induced osteolysis resulting from polyethylene wear remains a source of implant failure in anatomic total shoulder designs. Modern polyethylene components are irradiated in an oxygen-free ...environment to induce cross-linking, but reducing the resulting free radicals with melting or heat annealing can compromise the component’s mechanical properties. Vitamin E has been introduced as an adjuvant to thermal treatments. Anatomic shoulder arthroplasty models with a ceramic head component have demonstrated that vitamin E–enhanced polyethylene show improved wear compared with highly cross-linked polyethylene (HXLPE). This study aimed to assess the biomechanical wear properties and particle size characteristics of a novel vitamin E–enhanced highly cross-linked polyethylene (VEXPE) glenoid compared to a conventional ultrahigh-molecular-weight polyethylene (UHMWPE) glenoid against a cobalt chromium molybdenum (CoCrMo) head component.
Biomechanical wear testing was performed to compare the VEXPE glenoid to UHMWPE glenoid with regard to pristine polyethylene wear and abrasive endurance against a polished CoCrMo alloy humeral head in an anatomic shoulder wear-simulation model. Cumulative mass loss (milligrams) was recorded, and wear rate calculated (milligrams per megacycle Mc). Under pristine wear conditions, particle analysis was performed, and functional biologic activity (FBA) was calculated to estimate particle debris osteolytic potential. In addition, 95% confidence intervals for all testing conditions were calculated.
The average pristine wear rate was statistically significantly lower for the VEXPE glenoid compared with the HXLPE glenoid (0.81 ± 0.64 mg/Mc vs. 7.00 ± 0.45 mg/Mc) (P < .05). Under abrasive wear conditions, the VEXPE glenoid had a statistically significant lower average wear rate compared with the UHMWPE glenoid comparator device (18.93 ± 5.80 mg/Mc vs. 40.47 ± 2.63 mg/Mc) (P < .05). The VEXPE glenoid demonstrated a statistically significant improvement in FBA compared with the HXLPE glenoid (0.21 ± 0.21 vs. 1.54 ± 0.49 (P < .05).
A new anatomic glenoid component with VEXPE demonstrated significantly improved pristine and abrasive wear properties with lower osteolytic particle debris potential compared with a conventional UHMWPE glenoid component. Vitamin E–enhanced polyethylene shows early promise in shoulder arthroplasty components. Long-term clinical and radiographic investigation needs to be performed to verify if these biomechanical wear properties translate to diminished long-term wear, osteolysis, and loosening.
Objective. The aim of this study was to determine the outcomes of Stage I endometrial carcinoma patients who are managed without adjuvant radiation after comprehensive surgical staging.
Methods. A ...computerized hospital database identified women diagnosed with adenocarcinoma of the endometrium from 1993 to 1998. A chart review identified 864 women as having primary surgery for adenocarcinoma of the endometrium. A total of 670 of 864 patients (78%) underwent comprehensive surgical staging with total hysterectomy, bilateral salpingo-oophorectomy, pelvic/para-aortic lymphadenectomy, and peritoneal cytology. After 57 patients with high-risk histologic subtypes were excluded, 613 patients remained for analysis.
Results. A total of 321 of 325 Stage IB patients (99%) did not receive adjuvant radiation. Fifteen of 321 patients (5%) recurred; 9 recurred in the pelvis or vagina. All 9 local recurrences were salvaged with whole pelvic radiation (XRT) and brachytherapy (BT). Seventy-seven patients were diagnosed with Stage IC disease; 53 (69%) received no adjuvant therapy. Four patients (8%) recurred, of which 2 recurred in the vagina. Three of 4 patients (75%) were salvaged, 2 with XRT/BT and 1 with surgery and chemotherapy. For all Stage I patients, the 5-year disease-free survival was 93% and the 5-year overall survival was 98%.
Conclusions. Surgically staged patients with endometrial carcinoma confined to the uterine corpus have a small risk of recurrence and the majority of these recurrences can be salvaged with radiation therapy. Conservative management of Stage I endometrial carcinoma patients is an effective treatment strategy.
Potentially inappropriate antipsychotic use has declined in nursing homes over the past decade; however, increases in the documentation of relevant clinical indications (eg, delusions) and the use of ...other psychotropic medications have raised concerns about diagnosis upcoding and medication substitution. Few studies have examined how these trends over time vary across and within nursing homes, information that may help to support antipsychotic reduction efforts.
To jointly model facility-level time trends in potentially inappropriate antipsychotic use, antidepressant use, and the indications used to define appropriate antipsychotic use.
We conducted a repeated cross-sectional study of all nursing homes in Ontario, Canada between April 1, 2010 and December 31, 2019 using linked health administrative data (N=649). Each nursing home's quarterly prevalence of potentially inappropriate antipsychotic use, antidepressant use, and relevant indications were measured as outcome variables. With time as the independent variable, multivariate random effects models jointly estimated time trends for each outcome across nursing homes and the correlations between time trends within nursing homes.
We observed notable variations in the time trends for each outcome across nursing homes, especially for the relevant indications. Within facilities, we found no correlation between time trends for potentially inappropriate antipsychotic and antidepressant use ( r =-0.0160), but a strong negative correlation between time trends for potentially inappropriate antipsychotic use and relevant indications ( r =-0.5036).
Nursing homes with greater reductions in potentially inappropriate antipsychotics tended to show greater increases in the indications used to define appropriate antipsychotic use-possibly leading to unmonitored use of antipsychotics.
Understanding the extent to which current antibiotic prescribing behaviour is influenced by clinicians' historical patterns of practice will help target interventions to optimize antibiotic use in ...long-term care. Our objective was to evaluate whether clinicians' historical prescribing behaviours influence the start, prolongation and class selection for treatment with antibiotics in residents of long-term care facilities.
We conducted a retrospective cohort study of all physicians who prescribed to residents in long-term care facilities in Ontario between Jan. 1 and Dec. 31, 2014. We examined variability in antibiotic prescribing among physicians for 3 measures: start of treatment with antibiotics, use of prolonged durations exceeding 7 days and selection of fluoroquinolones. Funnel plots with control limits were used to determine the extent of variation and characterize physicians as extreme low, low, average, high and extreme high prescribers for each tendency. Multivariable logistic regression was used to assess whether a clinician's prescribing tendency in the previous year predicted current prescribing patterns, after accounting for residents' demographics, comorbidity, functional status and indwelling devices.
Among 1695 long-term care physicians, who prescribed for 93 132 residents, there was wide variability in the start of antibiotic treatment (median 45% of patients, interquartile range IQR 32%-55%), use of prolonged treatment durations (median 30% of antibiotic prescriptions, IQR 19%-46%) and selection of fluoroquinolones (median 27% of antibiotic prescriptions, IQR 18%-37%). Prescribing tendencies for antibiotics by physicians in 2014 correlated strongly with tendencies in the previous year. After controlling for individual resident characteristics, prior prescribing tendency was a significant predictor of current practice.
Physicians prescribing antibiotics exhibited individual, measurable and historical tendencies toward start of antibiotic treatment, use of prolonged treatment duration and class selection. Prescriber audit and feedback may be a promising tool to optimize antibiotic use in long-term care facilities.
To investigate whether trazodone is being initiated in lieu of antipsychotics following antipsychotic reduction efforts, this study described changes in medication initiation over time.
We conducted ...a retrospective cohort study of new admissions to nursing homes in Ontario, Canada between April 2010 and December 2019 using health administrative data (N = 61,068). The initiation of antipsychotic and trazodone use was compared by year of admission using discrete time survival analysis and stratified by history of dementia.
Relative to residents admitted in 2014, antipsychotic initiation significantly decreased in later years (e.g., 2017 admission year hazard odds ratio HOR
=0.72 95% confidence interval (95%CI)=0.62-0.82) while trazodone initiation modestly increased (e.g., HOR
=1.09 95%CI=0.98-1.21). The relative increase in trazodone initiation was larger among residents with dementia (e.g., HOR
=1.22 95%CI=1.07-1.39).
Differences in which medications were started following nursing home admission were observed and suggest trazodone may be initiated in lieu of antipsychotics.
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