Preparation and characterization of protein-nanotube conjugates

This chapter describes methods of immobilizing proteins on carbon nanotubes, using two different routes—physical adsorption and covalent attachment. We also provide an overview on how such conjugates can be characterized with the help of various techniques, such as Raman, Fourier transform infrared (FT-IR), circular dichroism (CD), and fluorescence spectroscopies, in addition to the standard enzyme kinetic analyses of activity and stability. Both the attachment routes—covalent and noncovalent—could be used to prepare protein conjugates that retained a significant fraction of their native structure and function; furthermore, the protein conjugates were operationally stable, reusable, and functional even under harsh denaturing conditions. These studies therefore corroborate the use of these immobilization methods to engineer functional carbon nanotube-protein hybrids that are highly active and stable

Learning to Prescribe Interventions for Tuberculosis Patients Using Digital Adherence Data

Digital Adherence Technologies (DATs) are an increasingly popular method for verifying patient adherence to many medications. We analyze data from one city served by 99DOTS, a phone-call-based DAT deployed for Tuberculosis (TB) treatment in India where nearly 3 million people are afflicted with the disease each year. The data contains nearly 17,000 patients and 2.1M dose records. We lay the groundwork for learning from this real-world data, including a method for avoiding the effects of unobserved interventions in training data used for machine learning. We then construct a deep learning model, demonstrate its interpretability, and show how it can be adapted and trained in different clinical scenarios to better target and improve patient care. In the real-time risk prediction setting our model could be used to proactively intervene with 21% more patients and before 76% more missed doses than current heuristic baselines. For outcome prediction, our model performs 40% better than baseline methods, allowing cities to target more resources to clinics with a heavier burden of patients at risk of failure. Finally, we present a case study demonstrating how our model can be trained in an end-to-end decision focused learning setting to achieve 15% better solution quality in an example decision problem faced by health workers.Comment: 10 pages, 6 figure

上野老台宛状（貴子退身の事は追々聞？云々）

BACKGROUND: Electronic health records (EHRs), when linked across primary and secondary care and curated for research use, have the potential to improve our understanding of care quality and outcomes. OBJECTIVE: To evaluate new opportunities arising from linked EHRs for improving quality of care and outcomes for patients at risk of or with coronary disease across the patient journey. DESIGN: Epidemiological cohort, health informatics, health economics and ethnographic approaches were used. SETTING: 230 NHS hospitals and 226 general practices in England and Wales. PARTICIPANTS: Up to 2 million initially healthy adults, 100,000 people with stable coronary artery disease (SCAD) and up to 300,000 patients with acute coronary syndrome. MAIN OUTCOME MEASURES: Quality of care, fatal and non-fatal cardiovascular disease (CVD) events. DATA PLATFORM AND METHODS: We created a novel research platform [ClinicAl disease research using LInked Bespoke studies and Electronic health Records (CALIBER)] based on linkage of four major sources of EHR data in primary care and national registries. We carried out 33 complementary studies within the CALIBER framework. We developed a web-based clinical decision support system (CDSS) in hospital chest pain clinics. We established a novel consented prognostic clinical cohort of SCAD patients. RESULTS: CALIBER was successfully established as a valid research platform based on linked EHR data in nearly 2 million adults with > 600 EHR phenotypes implemented on the web portal (see https://caliberresearch.org/ portal). Despite national guidance, key opportunities for investigation and treatment were missed across the patient journey, resulting in a worse prognosis for patients in the UK compared with patients in health systems in other countries. Our novel, contemporary, high-resolution studies showed heterogeneous associations for CVD risk factors across CVDs. The CDSS did not alter the decision-making behaviour of clinicians in chest pain clinics. Prognostic models using real-world data validly discriminated risk of death and events, and were used in cost-effectiveness decision models. CONCLUSIONS: Emerging ‘big data’ opportunities arising from the linkage of records at different stages of a patient’s journey are vital to the generation of actionable insights into the diagnosis, risk stratification and cost-effective treatment of people at risk of, or with, CVD. FUTURE WORK: The vast majority of NHS data remain inaccessible to research and this hampers efforts to improve efficiency and quality of care and to drive innovation. We propose three priority directions for further research. First, there is an urgent need to ‘unlock’ more detailed data within hospitals for the scale of the UK’s 65 million population. Second, there is a need for scaled approaches to using EHRs to design and carry out trials, and interpret the implementation of trial results. Third, large-scale, disease agnostic genetic and biological collections linked to such EHRs are required in order to deliver precision medicine and to innovate discovery. STUDY REGISTRATION: CALIBER studies are registered as follows: study 2 – NCT01569139, study 4 – NCT02176174 and NCT01164371, study 5 – NCT01163513, studies 6 and 7 – NCT01804439, study 8 – NCT02285322, and studies 26–29 – NCT01162187. Optimising the Management of Angina is registered as Current Controlled Trials ISRCTN54381840. FUNDING: The National Institute for Health Research (NIHR) Programme Grants for Applied Research programme (RP-PG-0407-10314) (all 33 studies) and additional funding from the Wellcome Trust (study 1), Medical Research Council Partnership grant (study 3), Servier (study 16), NIHR Research Methods Fellowship funding (study 19) and NIHR Research for Patient Benefit (study 33)

RTOG 0518: Randomized Phase III Trial to Evaluate Zoledronic Acid for Prevention of Osteoporosis and Associated Fractures in Prostate Cancer Patients

Background: RTOG 0518 evaluated the potential benefit of zoledronic acid therapy in preventing bone fractures for patients with high grade and/or locally advanced, non-metastatic prostate adenocarcinoma receiving luteinizing hormone-releasing hormone (LHRH) agonist and radiotherapy (RT). Methods: Eligible patients with T-scores of the hip ( −2.5 vs. > −1.0) and negative bone scans were prospectively randomized to either zoledronic acid, 4 mg, concurrently with the start of RT and then every six months for a total of 6 infusions (Arm 1) or observation (Arm 2). Vitamin D and calcium supplements were given to all patients. Secondary objectives included quality of life (QOL) and bone mineral density (BMD) changes over a period of three years. Results: Of 109 patients accrued before early closure, 96 were eligible. Median follow-up was 36.3 months for Arm I and 34.8 months for Arm 2. Only two patients experienced a bone fracture (1 in each arm) resulting in no difference in freedom from any bone fracture (p=0.95), nor in QOL. BMD percent changes from baseline to 36 months were statistically improved with the use of zoledronic acid compared to observation for the lumbar spine (6% vs. −5%, p<0.0001), left total hip (1% vs. −8%, p=0.0002), and left femoral neck (3% vs. −8%, p=0.0007). Conclusions: For patients with advanced, non-metastatic prostate cancer receiving LHRH agonist and RT, the use of zoledronic acid was associated with statistically improved BMD percent changes. The small number of accrued patients resulted in decreased statistical power to detect any differences in the incidence of bone fractures or QOL

Pharmacokinetic and exposure-response analysis of pertuzumab in patients with HER2-positive metastatic gastric or gastroesophageal junction cancer

Purpose: To characterize the pharmacokinetics (PK) of pertuzumab and trastuzumab in patients with HER2-positive metastatic gastric or gastroesophageal junction cancer in the randomized, double-blind, phase III JACOB study (NCT01774786), and to evaluate the appropriateness of the pertuzumab regimen in these patients. Methods: Patients received 840 mg intravenous pertuzumab or placebo plus trastuzumab q3w and chemotherapy. Pertuzumab and trastuzumab were administered until disease progression or unacceptable toxicity. Chemotherapy was administered for up to six cycles or disease progression or unacceptable toxicity. Serum concentrations of pertuzumab and trastuzumab were measured. Pertuzumab PK was characterized across treatment cycles. The impact of anti-drug antibodies (ADAs) on pertuzumab PK and the impact of pertuzumab on trastuzumab PK were assessed. An exploratory exposure-efficacy analysis was also conducted. Results: In total, 374 patients in the pertuzumab arm had evaluable PK data. The mean observed pertuzumab steady-state serum trough (minimum) concentration (C) ± standard deviation was 114 ± 51.8 μg/mL. The target pertuzumab C of ≥ 20 μg/mL was reached in 99.3% of patients at Cycle 5 (steady state) and beyond. Greater than 90% of patients were above the PK target right after the first pertuzumab dose. There was no apparent impact of ADAs on pertuzumab PK nor of pertuzumab on trastuzumab PK. There were no differences in overall survival across Cycle 1 pertuzumab (C) or Cycle 5 pertuzumab (C) exposure quartiles. Conclusions: Pertuzumab exposure in JACOB was consistent with prior studies in advanced gastric cancer and breast cancer. The 840 mg q3w dose allowed the majority of patients in JACOB to achieve target pertuzumab concentrations and appears to be an appropriate dose selectio

Carotid Artery Stenting and Its Impact on Cognitive Function: A Prospective Observational Study

Purpose Carotid artery stenting (CAS) has evolved as a first-line therapeutic option for carotid revascularization in indicated patients for stroke prevention, but there is still a lack of data on its effect on cognitive function (CF), especially among Indian patients. To determine the effect of CAS on CF and to study the immediate and delayed complications of CAS in Indian patients. Materials and Methods This was a prospective, observational, single-center study. CF was assessed using Addenbrooke’s cognitive examination version III (ACE) before and 3 months after stenting. The demographic and clinical parameters were also assessed. A follow-up evaluation after 3 months was done to compare CF and to observe the occurrence of any complications. Results Out of 31 patients, 3 were lost to follow up. There were no immediate or delayed procedure-related complications. There was a statistically significant improvement in overall ACE score and memory before and after stenting. On subgroup analysis of those with and without strokes, there was a significant improvement in visuospatial function and mean ACE score. Those with left CAS had significant improvement in memory, visuospatial, language, and ACE scores than right CAS. Conclusion CAS was associated with significant improvement in CF in patients

Universal aspects of vacancy-mediated disordering dynamics: the effect of external fields

We investigate the disordering of an initially phase-segregated binary alloy, due to a highly mobile defect which couples to an electric or gravitational field. Using both mean-field and Monte Carlo methods, we show that the late stages of this process exhibit dynamic scaling, characterized by a set of exponents and scaling functions. A new scaling variable emerges, associated with the field. While the scaling functions carry information about the field and the boundary conditions, the exponents are universal. They can be computed analytically, in excellent agreement with simulation results.Comment: 15 pages, 6 figure

Prognostic significance of troponin in patients with malignancy ( NIHR Health Informatics Collaborative TROP-MALIGNANCY study )

Background: Cardiac troponin is commonly raised in patients presenting with malignancy. The prognostic significance of raised troponin in these patients is unclear. Objectives: We sought to investigate the relation between troponin and mortality in a large, well characterised cohort of patients with a routinely measured troponin and a primary diagnosis of malignancy. Methods: We used the National Institute for Health Research (NIHR) Health Informatics Collaborative data of 5571 patients, who had troponin levels measured at 5 UK cardiac centres between 2010 and 2017 and had a primary diagnosis of malignancy. Patients were classified into solid tumour or haematological malignancy subgroups. Peak troponin levels were standardised as a multiple of each laboratory’s 99th -percentile upper limit of normal (xULN). Results: 4649 patients were diagnosed with solid tumours and 922 patients with haematological malignancies. Raised troponin was an independent predictor of mortality in all patients (Troponin > 10 vs. <1 adjusted HR 2.01, 95% CI 1.73 to 2.34), in solid tumours (HR 1.84, 95% CI 1.55 to 2.19), and in haematological malignancy (HR 2.72, 95% CI 1.99 to 3.72). There was a significant trend in increasing mortality risk across troponin categories in all three subgroups (p < 0.001). Conclusion: Raised troponin level is associated with increased mortality in patients with a primary diagnosis of malignancy regardless of cancer subtype. Mortality risk is stable for patients with a troponin level below the ULN but increases as troponin level increases above the ULN in the absence of acute coronary syndrome

Sleep Apnea Is Associated with Hearing Impairment: The Hispanic Community Health Study/Study of Latinos

Sleep apnea (SA) may promote hearing impairment (HI) through ischemia and inflammation of the cochlea. Our objective was to assess an independent association between SA and HI in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) participants

Synergistic effects of activated carbon and nano-zerovalent copper on the performance of hydroxyapatite-alginate beads for the removal of As\u3csup\u3e3+\u3c/sup\u3e from aqueous solution

© 2019 Elsevier Ltd In this study, activated carbon (AC) and nano-zerovalent copper (nZVCu) functionalized hydroxyapatite (HA) and alginate beads were synthesized and used for the removal of As3+ from aqueous solution. The characterization by X-ray diffraction, scanning electron microscopy, X-ray energy dispersive spectroscopy, X-ray photoelectron spectroscopy, transmission electron microscopy, high resolution transmission electron microscopy, BET surface area analysis, thermogravimetric analysis, and Fourier transform infrared spectroscopy revealed successful formation of the AC/nZVCu/HA-alginate, nZVCu/HA-alginate, AC/HA-alginate, and HA-alginate beads. The scanning electron microscopy and surface analysis revealed the prepared beads to be highly mesoporous which led to the maximum adsorption of As3+, i.e., 13.97, 29.33, 30.96, and 39.06 mg/g by HA-alginate, AC/HA-alginate, nZVCu/HA-alginate, and AC/nZVCu/HA-alginate beads, respectively. The thermogravimteric analysis showed the nZVCu/HA-alginate beads to be highly stable while the AC composite beads as the least stable to heat treatment. The HA-alginate beads achieved 39% removal of As3+, however, removal efficiency was promoted to 95% by coupling AC and nZVCu with HA-alginate beads at a reaction time of 120 min. The removal of As3+ by the prepared AC & nZVCu coupled HA-alginate beads was promoted with increasing [As3+]0 and [AC/nZVCu/HA-alginate]0. The pH of aqueous solution significantly influenced the removal of As3+ by AC/nZVCu/HA-alginate beads and maximum removal was achieved at pH 5.8. Freundlich adsorption isotherm and pseudo-second-order kinetic models were found to best fit the removal of As3+ by the synthesized beads. The high performance of AC/nZVCu/HA-alginate beads in the removal of As3+ even after seven cyclic treatment as well as least leaching of Cu ions into aqueous solution suggest enhanced reusability and stability of HA-alginate beads by coupling with AC and nZVCu. The results suggest that the synthesized beads have good potential for the removal of As3+ from aqueous solutions