Evaluation of the Homogenous Mobility Shift Assay for Infliximab and Adalimumab Anti-drug Antibody Detection in the Clinical Laboratory.

BACKGROUND: Detecting antidrug antibodies (ADAs) against infliximab or adalimumab is useful for therapeutic drug monitoring. Various ADA detection methods exist, and antibody titer is an output in some algorithms. Homogenous mobility shift assay (HMSA) measures relative ADA concentration and determines drug-ADA complex size in vitro. However, the relevance of complex size determination in drug monitoring remains unclear. Hence, the association between complex size, ADA concentration, and sample detectable neutralizing activity was evaluated. METHODS: Sera from infliximab-treated and adalimumab-treated patients who tested positive for ADA in the National Screening Service were analyzed using 3 ADA assays. HMSA determined the relative ADA concentrations and complex sizes, competitive ligand-binding assay evaluated the sample neutralizing capacity, and enzyme-linked immunosorbent assay detected immunoglobulin (Ig)G4 ADA. RESULTS: Most ADA-positive samples (>80%) formed drug-ADA dimer complexes, whereas 17% had dimer and multimer complexes, and 3% had multimeric complexes. Multimer presence had 100% positive predictive value for detectable neutralizing activity. ADA concentration and detectable neutralizing activity were moderately correlated (r = 0.65) in adalimumab-treated patients and strongly correlated (r = 0.81) in infliximab-treated patients. In adalimumab-treated patients, multimer presence was a stronger predictor of neutralizing activity than ADA concentration was, but not in infliximab-treated patients. However, in infliximab-treated patient samples, multimer presence revealed a distinct subset with high ADA concentrations, neutralizing activity, and IgG4 ADA. CONCLUSIONS: Multimers detected using HMSA had a strong positive predictive value for competitive ligand-binding assay detectable neutralizing activity. Multimeric IgG4-containing ADA-drug complexes revealed a distinct subset of infliximab-treated patient samples, whose clinical relevance merits further investigation.

Optimising interruptive clinical decision support alerts for antithrombotic duplicate prescribing in hospital.

INTRODUCTION: Duplicate prescribing clinical decision support alerts can prevent important prescribing errors but are frequently the cause of much alert fatigue. Stat dose prescriptions are a known reason for overriding these alerts. This study aimed to evaluate the effect of excluding stat dose prescriptions from duplicate prescribing alerts for antithrombotic medicines on alert burden, prescriber adherence, and prescribing. MATERIALS AND METHODS: A before (January 1st, 2017 to August 31st, 2022) and after (October 5th, 2022 to September 30th, 2023) study was undertaken of antithrombotic duplicate prescribing alerts and prescribing following a change in alert settings. Alert and prescribing data for antithrombotic medicines were joined, processed, and analysed to compare alert rates, adherence, and prescribing. Alert burden was assessed as alerts per 100 prescriptions. Adherence was measured at the point of the alert as whether the prescriber accepted the alert and following the alert as whether a relevant prescription was ceased within an hour. Co-prescribing of antithrombotic stat dose prescriptions was assessed pre- and post-alert reconfiguration. RESULTS: Reconfiguration of the alerts reduced the alert rate by 29 % (p < 0.001). The proportion of alerts associated with cessation of antithrombotic duplication significantly increased (32.8 % to 44.5 %, p < 0.001). Adherence at the point of the alert increased 1.2 % (4.8 % to 6.0 %, p = 0.012) and 11.5 % (29.4 % to 40.9 %, p < 0.001) within one hour of the alert. When ceased after the alert over 80 % of duplicate prescriptions were ceased within 2 min of overriding. Antithrombotic stat dose co-prescribing was unchanged for 4 out of 5 antithrombotic duplication alert rules. CONCLUSION: By reconfiguring our antithrombotic duplicate prescribing alerts, we reduced alert burden and increased alert adherence. Many prescribers ceased duplicate prescribing within 2 min of alert override highlighting the importance of incorporating post-alert measures in accurately determining prescriber alert adherence.

Four-year review of New Zealand laboratory infliximab and adalimumab concentration results indicating potential for improved dosing.

A review of laboratory results across New Zealand for therapeutic drug monitoring (TDM) of infliximab and adalimumab concentrations and antidrug antibodies (ADAs) over 4 years was completed. Of 6591 results, the median serum concentration for infliximab was 5.7 mg/L and for adalimumab was 5.5 mg/L. Subtherapeutic drug concentrations (<7 mg/L) were measured in 54% of samples. Drug concentrations <2 mg/L were measured in 23% of samples, with ADAs detected in 51% of these. The high number of samples with subtherapeutic drug concentrations and common ADA detection is consistent with failing therapy but could also suggest that standard dosing is frequently too low for patients. These results reinforce the value of antitumour necrosis factor drug TDM in making decisions to adjust dosing or switch agents in patients taking infliximab and adalimumab.

Evaluation of the Prescribing Skills Assessment implementation, performance and medical student experience in Australia and New Zealand.

AIMS: The UK Prescribing Safety Assessment was modified for use in Australia and New Zealand (ANZ) as the Prescribing Skills Assessment (PSA). We investigated the implementation, student performance and acceptability of the ANZ PSA for final-year medical students. METHODS: This study used a mixed-method approach involving student data (n = 6440) for 2017-2019 (PSA overall score and 8 domain subscores). Data were also aggregated by medical school and included student evaluation survey results. Quantitative data were analysed using descriptive and multivariate analyses. The pass rate was established by a modified Angoff method. Thematic analyses of open-ended survey comments were conducted. RESULTS: The average pass rate was slightly higher in 2017 (89%) which used a different examination to 2018 (85%) and 2019 (86%). Little difference was identified between schools for the PSA overall performance or domain subscores. There was low intercorrelation between subscores. Most students provided positive feedback about the PSA regarding the interface and clarity of questions, but an average of 35% reported insufficient time for completion. Further, 70% on average felt unprepared by their school curricula for the PSA, which is in part explained by the low prescribing experience; 69% reported completing ≤10 prescriptions during training. CONCLUSION: The ANZ PSA was associated with high pass rates and acceptability, although student preparedness was highlighted as a concern for further investigation. We demonstrate how a collaboration of medical schools can adapt a medical education assessment resource (UK PSA) as a means for fulfilling an unmet need.

High thermo-optic tunability in PECVD silicon-rich amorphous silicon carbide.

In this work, the thermo-optic coefficient (TOC) of the silicon-rich amorphous silicon carbide (a-SiC) thin film deposited by plasma-enhanced chemical vapor deposition (PECVD) was characterized. We found that the TOC of the film increases as its silicon content increases. A more than threefold improvement in the TOC was measured, reaching a TOC as high as 1.88×10-4 ∘C-1, which is comparable to that of crystalline silicon. An efficient thermo-optic phase shifter has also been demonstrated by integrating the silicon-rich a-SiC micro-ring structure with a NiCr heater. Tunability of 0.117 nm/mW was demonstrated, and a corresponding tuning efficiency P π as low as 4.2 mW has been measured at an optical wavelength of 1550 nm. These findings make silicon-rich a-SiC a good candidate material for thermo-optic applications in photonic integrated circuits.

The pharmacogenetics of CYP2D6 and CYP2C19 in a case series of antidepressant responses.

Pharmacogenetics has potential for optimizing use of psychotropics. CYP2D6 and CYP2C19 are two clinically relevant pharmacogenes in the prescribing of antidepressants. Using cases recruited from the Understanding Drug Reactions Using Genomic Sequencing (UDRUGS) study, we aimed to evaluate the clinical utility of genotyping CYP2D6 and CYP2C19 in antidepressant response. Genomic and clinical data for patients who were prescribed antidepressants for mental health disorders, and experienced adverse reactions (ADRs) or ineffectiveness, were extracted for analysis. Genotype-inferred phenotyping of CYP2D6 and CYP2C19 was carried out as per Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines. A total of 52 patients, predominantly New Zealand Europeans (85%) with a median age (range) of 36 years (15-73), were eligible for analysis. Thirty-one (60%) reported ADRs, 11 (21%) ineffectiveness, and 10 (19%) reported both. There were 19 CYP2C19 NMs, 15 IMs, 16 RMs, one PM and one UM. For CYP2D6, there were 22 NMs, 22 IMs, four PMs, three UMs, and one indeterminate. CPIC assigned a level to each gene-drug pair based on curated genotype-to-phenotype evidence. We analyzed a subgroup of 45 cases, inclusive of response type (ADRs/ineffectiveness). Seventy-nine (N = 37 for CYP2D6, N = 42 for CYP2C19) gene-drug/antidepressant-response pairs with CPIC evidence levels of A, A/B, or B were identified. Pairs were assigned as 'actionable' if the CYP phenotypes potentially contributed to the observed response. We observed actionability in 41% (15/37) of CYP2D6-antidepressant-response pairs and 36% (15/42) of CYP2C19-antidepressant-response pairs. In this cohort, CYP2D6 and CYP2C19 genotypes were actionable for a total of 38% pairs, consisting of 48% in relation to ADRs and 21% in relation to drug ineffectiveness.

Changes in inpatient medicine prescribing during COVID-19 lockdown.

BACKGROUND: New Zealand went into lockdown March 2020 successfully eliminating the circulation of the coronavirus disease 2019 (COVID-19) virus. During lockdown there were reduced rates of respiratory infections and hospital admission numbers were low. At the time, rumours of benefit and harm of medicines for COVID-19 were widespread in the lay and medical media. AIM: To describe changes in inpatient prescribing in an acute general medicine service during the New Zealand COVID-19 lockdown in 2020. METHODS: Rates of prescribing of medicines during the 33 days of lockdown were compared with a 33-day control period before lockdown. Prescriptions, patients and bed days were calculated from the hospital patient administration and electronic prescribing and administration systems. RESULTS: In the general medicine service, acute admissions were 20% lower during lockdown (from 1216 pre-lockdown to 974). There was a small decrease in the rate of prescriptions per patient (10.1 vs 10.4, P = 0.01) during lockdown, and the average length of stay was shorter (3.2 vs 3.6 days). Nebulised administration decreased by 75% (1.3% vs 5.3% of admissions) but unexpectedly there was no change in the prescribing rates of antibacterial medicines, e.g. amoxicillin (26% vs 26%). There were no changes in rates of prescribing of medicines being rumoured to potentially improve (e.g. hydroxychloroquine) or worsen (e.g. angiotensin-converting enzyme inhibitors) COVID-19 outcomes. CONCLUSIONS: Acute medical admissions decreased 20% during lockdown for COVID-19, with a proportional decrease in prescriptions. Reduced rates of respiratory tract infections did not lead to decreased prescribing of antibacterial medicines. Rumour-based prescribing did not eventuate.

Frequency of pharmacological target attainment with flucloxacillin and cefazolin in invasive methicillin-susceptible Staphylococcus aureus infection: a prospective cohort study in hospitalized patients.

BACKGROUND: The proportion of patients with invasive methicillin-susceptible Staphylococcus aureus (MSSA) infection who achieve target concentrations of flucloxacillin or cefazolin with standard dosing regimens is uncertain. This study measured drug concentrations in a prospective cohort of patients with invasive S. aureus infections to determine the frequency of target concentration attainment, and risk factors for failure to achieve target concentrations. PATIENTS AND METHODS: Unbound flucloxacillin and cefazolin plasma concentrations were measured at the midpoint between intravenous doses. Adequate and optimal targets were defined as an unbound plasma concentration of ≥1 and ≥2 times the minimum inhibitory concentration (MIC) (flucloxacillin 0.5 mg/L, cefazolin 2 mg/L), respectively (50%fT≥1MIC, 50%fT≥2MIC). RESULTS: There were 50 patients in each of the flucloxacillin and cefazolin groups. Eighty-five (85%) patients met the target of 50%fT≥2MIC and 95 (95%) patients met the target of 50%fT≥1MIC. The median unbound flucloxacillin concentration was 2.6 mg/L [interquartile range (IQR) 1.0-8.1]. The median unbound cefazolin concentration was 15.4 mg/L (IQR 8.8-28.2). A higher proportion of patients in the flucloxacillin group failed to achieve the optimal target compared with the cefazolin group [13 (26%) vs 2 (4%); P=0.002]. Younger age and higher creatinine clearance were associated with lower plasma concentrations. CONCLUSIONS: Standard dosing of flucloxacillin and cefazolin in the treatment of invasive MSSA infections may not achieve target plasma concentrations for a subgroup of patients. Measuring drug concentrations identifies this subgroup and facilitates dose individualization.

Silicon-organic hybrid thermo-optic switch based on a slot waveguide directional coupler.

We propose and demonstrate a passively biased 2 × 2 thermo-optic switch with high power efficiency and fast response time. The device benefits from the highly concentrated optical field of a slot waveguide mode and the strong thermo-optic effect of a nematic liquid crystal (NLC) cladding. The NLC fills the nano-slot region and is aligned by the subwavelength grating inside. The measured power consumption and thermal time constant are 0.58 mW and 11.8 µs, respectively, corresponding to a figure-of-merit of 6.8 mW µs. The proposed silicon-organic hybrid device provides a new solution to design thermo-optic actuators having low power consumption and fast operation speed.

Omeprazole Treatment Failure in Gastroesophageal Reflux Disease and Genetic Variation at the CYP2C Locus.

Omeprazole is extensively used to manage gastroesophageal reflux disease (GERD). It is primarily metabolized by CYP2C19. The CYP2C19*17 (rs12248560) allele and the recently described CYP2C:TG haplotype (rs11188059 and rs2860840) are associated with increased enzymatic activity, and may reduce omeprazole exposure. This observational study aimed to investigate the association between these genetic variants and omeprazole treatment failure in GERD. We recruited predominantly New Zealand European GERD patients who either did not respond to omeprazole or experienced breakthrough heartburn symptoms despite at least 8 weeks of omeprazole (≥40 mg/day). The GerdQ score was used to gauge symptomatic severity. A total of 55 cases were recruited with a median age (range) of 56 years (19-82) and GerdQ score of 11 (5-17). Of these, 19 (34.5%) were CYP2C19*17 heterozygotes and two (3.6%) were CYP2C19*17 homozygotes. A total of 30 (27.3%) CYP2C:TG haplotypes was identified in our cohort, with seven (12.7%) CYP2C:TG homozygotes, and 16 (29%) CYP2C:TG heterozygotes. No significant differences were observed for overall CYP2C19*17 alleles, CYP2C19*17/*17, overall CYP2C:TG haplotypes, and CYP2C:TG heterozygotes (p > 0.05 for all comparisons). Gastroscopy and 24-h esophageal pH/impedance tests demonstrated objective evidence of GERD in a subgroup of 39 (71%) cases, in which the CYP2C:TG/TG was significantly enriched (p = 0.03) when compared with the haplotype frequencies in a predominantly (91%) New Zealand European reference population, but not the CYP2C19*17/*17 (p > 0.99), when compared with the allele frequencies for the non-Finnish European subset of gnomAD. We conclude that omeprazole treatment failure in GERD is associated with CYP2C:TG/TG, but not CYP2C19*17.

A meta-analysis of protein binding of flucloxacillin in healthy volunteers and hospitalized patients.

OBJECTIVES: The aim of this study was to develop a mechanistic protein-binding model to predict the unbound flucloxacillin concentrations in different patient populations. METHODS: A mechanistic protein-binding model was fitted to the data using non-linear mixed-effects modelling. Data were obtained from four datasets, containing 710 paired total and unbound flucloxacillin concentrations from healthy volunteers, non-critically ill and critically ill patients. A fifth dataset with data from hospitalized patients was used for evaluation of our model. The predictive performance of the mechanistic model was evaluated and compared with the calculation of the unbound concentration with a fixed unbound fraction of 5%. Finally, we performed a fit-for-use evaluation, verifying whether the model-predicted unbound flucloxacillin concentrations would lead to clinically incorrect dose adjustments. RESULTS: The mechanistic protein-binding model predicted the unbound flucloxacillin concentrations more accurately than assuming an unbound fraction of 5%. The mean prediction error varied between -26.2% to 27.8% for the mechanistic model and between -30.8% to 83% for calculation with a fixed factor of 5%. The normalized root mean squared error varied between 36.8% and 69% respectively between 57.1% and 134%. Predicting the unbound concentration with the use of the mechanistic model resulted in 6.1% incorrect dose adjustments versus 19.4% if calculated with a fixed unbound fraction of 5%. CONCLUSIONS: Estimating the unbound concentration with a mechanistic protein-binding model outperforms the calculation with the use of a fixed protein binding factor of 5%, but neither demonstrates acceptable performance. When performing dose individualization of flucloxacillin, this should be done based on measured unbound concentrations rather than on estimated unbound concentrations from the measured total concentrations. In the absence of an assay for unbound concentrations, the mechanistic binding model should be preferred over assuming a fixed unbound fraction of 5%.

A nationwide survey on therapeutic drug monitoring of anti-tumour necrosis factor agents for inflammatory bowel disease.

BACKGROUND: Routine therapeutic drug monitoring (TDM) during treatment with anti-tumour necrosis factor (anti-TNF) agents in inflammatory bowel disease may increase treatment efficacy and cost-effectiveness, and reduce the risk of loss of response. AIMS: To assess the current use of anti-TNF agent TDM, including trough concentration and anti-drug antibodies, among gastroenterology practitioners in New Zealand. METHODS: A web-based survey was delivered to gastroenterologists and advanced trainees in New Zealand, identified by the New Zealand Society of Gastroenterology. RESULTS: The response rate was 36% (48/134). Adalimumab was the most common initial anti-TNF agent used (78%, infliximab 22%). Ninety-three percent of those who completed the survey used TDM, mainly in cases of non-response or loss or response. Most respondents (93% and 83% for adalimumab and infliximab, respectively) measured trough concentrations within 24 h prior to the next administration. In patients in clinical remission but with endoscopic inflammation on anti-TNF agents, 72% would measure drug concentrations. In the presence of anti-drug antibodies, 45% would add an immunomodulator in patients with active disease and 47% would add an immunomodulator in patients in remission. With low trough concentrations, 77% would make no changes if the patient was in remission, and 75% would increase the dose in case of active disease. CONCLUSION: TDM was routinely used among inflammatory bowel disease gastroenterology clinicians who responded to this survey. However, interpretation of results and decision-making is variable, suggesting more guidance is required.

Determinants of vancomycin nephrotoxicity when administered to outpatients as a continuous 24-hour infusion.

Vancomycin continuous infusion (VCI) is used to treat serious Gram-positive infections in outpatients. This study was conducted to retrospectively investigate the rate of nephrotoxicity and associated risk factors in out-patients on VCI between May 2013 and November 2018. Vancomycin concentration was monitored twice-weekly to ensure adequate concentrations while avoiding high concentrations linked to nephrotoxicity (a rise in serum creatinine of ≥50% or 44 µmol/L from baseline). The likelihood of developing nephrotoxicity was evaluated using multivariable logistic regression. The 223 patients treated had a mean (standard deviation) age of 61 (16.7) years, baseline serum creatinine of 83.9 (21.2) µmol/L and estimated glomerular filtration rate (eGFR) of 80.6 (20.1) mL/min/1.73m2. Most patients (66%) were treated for bone and joint infections. Eight patients (3.6%) developed nephrotoxicity. In the most parsimonious model, nephrotoxicity was independently associated with an increased median (interquartile range) weighted-average serum vancomycin concentration (28.0 [24.3-32.6] vs. 22.4 [20.2-24.5] mg/L; odds ratio [OR] 1.25; 95% confidence interval [95% CI] 1.09-1.46; P<0.002) and Charlson co-morbidity index (OR 1.62; 95% CI 1.07-2.47; P=0.02). Post-hoc analysis identified 26 patients with a lower nephrotoxicity threshold (rise in serum creatinine of ≥30% or 27 µmol/L). Independent predictors of nephrotoxicity in this group were an increased weighted-average vancomycin concentration, diabetes, con-gestive heart failure and exposure to non-loop diuretics. The nephrotoxicity rate during VCI in this study was lower than previously reported (3.6% vs 15.0-17.0%).  Reducing the weighted-average serum vancomycin concentration may reduce nephrotoxicity while maintaining efficacy.

Simultaneous Determination of Dabigatran, Rivaroxaban, and Apixaban in Human Plasma by Liquid Chromatography/Tandem Mass Spectrometry.

BACKGROUND: Pharmacokinetic studies and therapeutic drug monitoring of anticoagulants require a simple, rapid, and reliable analytical method for monitoring plasma concentrations. The aims of the current work were to develop and validate a liquid chromatography/tandem mass spectrometry method for the simultaneous determination of 3 direct oral anticoagulants (dabigatran, rivaroxaban, and apixaban) in human plasma that is suitable for pharmacokinetic studies and routine therapeutic drug monitoring in busy hospital laboratories. METHODS: This method included a hydrolysis step to account for the active acylglucuronide metabolites of dabigatran that demonstrate an equivalent anticoagulant effect as dabigatran. After hydrolysis, a simple one-step protein precipitation was used for sample preparation. Total dabigatran (the sum of free dabigatran and the contribution from dabigatran acylglucuronides), rivaroxaban, and apixaban, and their corresponding isotopically labeled internal standards were resolved on a C18(2) column. All compounds were detected using electrospray ionization liquid chromatography/tandem mass spectrometry in the positive mode. RESULTS: For all 3 anticoagulants, standard curves were linear over the concentration range of 1.0-1000 mcg/L (r > 0.99), bias was < ±10%, and intraday and interday coefficients of variation (imprecision) were <10%. The limit of quantification was 1.0 mcg/L. For all 3 anticoagulants and corresponding isotopically labeled internal standards, the absolute recoveries were similar and consistent, with mean values of 93%-102%. No significant matrix effects were observed. CONCLUSIONS: This method is simple, rapid, robust, and reliable and can be used to analyze the plasma concentrations of the drugs in patients on dabigatran or rivaroxaban therapy.

Clinical decision support in a hospital electronic prescribing system informed by local data: experience at a tertiary New Zealand centre.

BACKGROUND: An electronic prescribing and administration (ePA) system has been progressively rolled out to Canterbury District Health Board (CDHB, Christchurch, New Zealand) public hospitals since 2014, and is currently used for around 1300 tertiary beds. ePA data can be used to monitor user behaviour, and to evaluate and inform the local customisation of clinical decision support (CDS) tools within the ePA system. AIMS: To describe retrospectively illustrative vignettes of CDHB ePA analyses that have been used for CDS. METHODS: Alerts were developed according to a set of common principles agreed upon by the CDHB CDS Working Group. Alerts were informed and evaluated by extracting and parsing data for various time periods during 2016 to 2018 from the CDHB ePA database. RESULTS: There was a median of 74 000 prescriptions a month. After examining 525 spironolactone prescriptions, the high dose alert threshold was set at 100 mg with an expected alert burden of 3%. The presence of a ceftriaxone shortage prescribing alert for 1 week was associated with a prescribing rate that was lower than 95% of the preceding 52 weeks. Following review of 367 fentanyl patch alerts, revision of the alert led to false positives falling from 43% to 3% (P < 0.0001). At the point of firing, 6% of antithrombotic drug interactions alerts led to immediate changes in prescriptions (94% overridden), and a further 22% were changed within 30 min after the alert. CONCLUSIONS: Local data extracts from ePA systems can inform iterative configuration of the software and monitor user behaviour.

Simultaneous Determination of Cefalexin, Cefazolin, Flucloxacillin, and Probenecid by Liquid Chromatography-Tandem Mass Spectrometry for Total and Unbound Concentrations in Human Plasma.

BACKGROUND: Pharmacokinetic studies and therapeutic drug monitoring of antibiotics require a simple, rapid, and reliable analytical method for monitoring the concentrations in plasma, including unbound concentrations for highly protein-bound drugs. The aim of the current work was to develop and validate a liquid chromatography-tandem mass spectrometry method for the simultaneous determination of total and unbound concentrations of 3 widely used ß-lactam antibiotics (cefalexin, cefazolin, and flucloxacillin) and the often coadministered drug probenecid in human plasma, suitable for pharmacokinetic studies and for routine use in ordinary, busy hospital laboratories. METHODS: Unbound drug was separated from bound drug by ultrafiltration. A simple 1-step protein precipitation was used for sample preparation. Cefalexin, cefazolin, flucloxacillin, probenecid, and their corresponding isotopically labeled internal standards were then resolved on a C18 (2) column. All the compounds were detected using electrospray ionization in the positive mode. RESULTS: Standard curves were linear for all compounds over the concentration range of 0.2-100 mg/L (r > 0.99) for total drug in plasma and 0.01-10 mg/L (r > 0.99) for unbound drug in plasma ultrafiltrate. For both total and unbound drugs, bias was <±10%, and intra- and interday coefficients of variation (imprecision) were <10%. The limit of quantification was 0.2 mg/L for total plasma concentrations and 0.01 mg/L for plasma ultrafiltrate concentrations of all drugs. CONCLUSIONS: The method has proven to be simple, rapid, robust, and reliable and is currently being used in clinical pharmacokinetic studies and in the routine clinical service to enhance the effective use of the ß-lactam antibiotics.

Nanostructuring Multilayer Hyperbolic Metamaterials for Ultrafast and Bright Green InGaN Quantum Wells.

Semiconductor quantum well (QW) light-emitting diodes (LEDs) have limited temporal modulation bandwidth of a few hundred MHz due to the long carrier recombination lifetime. Material doping and structure engineering typically leads to incremental change in the carrier recombination rate, whereas the plasmonic-based Purcell effect enables dramatic improvement for modulation frequency beyond the GHz limit. By stacking Ag-Si multilayers, the resulting hyperbolic metamaterials (HMMs) have shown tunability in the plasmonic density of states for enhancing light emission at various wavelengths. Here, nanopatterned Ag-Si multilayer HMMs are utilized for enhancing spontaneous carrier recombination rates in InGaN/GaN QWs. An enhancement of close to 160-fold is achieved in the spontaneous recombination rate across a broadband of working wavelengths accompanied by over tenfold enhancement in the QW peak emission intensity, thanks to the outcoupling of dominating HMM modes. The integration of nanopatterned HMMs with InGaN QWs will lead to ultrafast and bright QW LEDs with a 3 dB modulation bandwidth beyond 100 GHz for applications in high-speed optoelectronic devices, optical wireless communications, and light-fidelity networks.

Anticoagulation Use and Clinical Outcomes After Major Bleeding on Dabigatran or Warfarin in Atrial Fibrillation.

BACKGROUND AND PURPOSE: Little is known about the clinical outcomes associated with posthemorrhage anticoagulation resumption for atrial fibrillation. This study had 2 objectives: first, to evaluate anticoagulation use after a first major bleed on warfarin or dabigatran and, second, to compare effectiveness and safety outcomes between patients discontinuing anticoagulation after a major bleed and patients restarting warfarin or dabigatran. METHODS: Using 2010 to 2012 Medicare Part D data, we identified atrial fibrillation patients who experienced a major bleeding event while using warfarin (n=1135) or dabigatran (n=404) and categorized them by their posthemorrhage use of anticoagulation. We followed them until an ischemic stroke, recurrent hemorrhage, or death through December 31, 2012. We constructed logistic regression models to evaluate factors affecting anticoagulation resumption and Cox proportional hazard models to compare the combined risk of ischemic stroke and all-cause mortality and the risk of recurrent bleeding between treatment groups. RESULTS: Resumption of anticoagulation with warfarin (hazard ratio [HR] 0.76; 95% confidence interval [CI] 0.59-0.97) or dabigatran (HR 0.66; 95% CI 0.44-0.99) was associated with lower combined risk of ischemic stroke and all-cause mortality than anticoagulation discontinuation. The incidence of recurrent major bleeding was higher for patients prescribed warfarin after the event than for those prescribed dabigatran (HR 2.31; 95% CI 1.19-4.76) or whose anticoagulation ceased (HR 1.56; 95% CI 1.10-2.22), but did not differ between patients restarting dabigatran and those discontinuing anticoagulation (HR 0.65; 95% CI 0.32-1.33). CONCLUSIONS: Dabigatran was associated with a superior benefit/risk ratio than warfarin and anticoagulation discontinuation in the treatment of atrial fibrillation patients who have survived a major bleed.

Which patients may benefit from dose adjustment of non-vitamin K antagonist oral anticoagulants?

The commercially available non-vitamin K antagonist oral anticoagulants (NOAC) are an emerging therapeutic class, which includes dabigatran, rivaroxaban, apixaban, and edoxaban. Dose adjustment of the NOAC currently takes into account the presence of particular patient characteristics that may alter NOAC concentrations. These characteristics include the presence of renal impairment and concomitant drugs affecting proteins involved with the transport and metabolism of the NOAC. NOAC concentrations reflect anticoagulant activity; some studies have shown some correlation with the risks of adverse events, while others have not, and the association is debated by workers in the field. However, dose adjustment based on characteristics before dosing assumes that the patient has drug oral availability and clearance at the mean of patients with these characteristics. Direct quantification of NOAC concentrations, for example, through the use of calibrated coagulation assays, is likely to add further to individualization of dosing to the particular patient.