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Background: Conventional home blood glucose measurements require a sample of blood that is obtained by puncturing the skin at the fingertip. To avoid the pain associated with this procedure, there is high demand for medical products that allow glucose monitoring without blood sampling. In this review article, all such products are presented. Methods: In order to identify such products, four different sources were used: (1) PubMed, (2) Google Patents, (3) Diabetes Technology Meeting Startup Showcase participants, and (4) experts in the field of glucose monitoring. The information obtained were filtered by using two inclusion criteria: (1) regulatory clearance, and/or (2) significant coverage in Google News starting in the year 2016, unless the article indicated that the product had been discontinued. The identified bloodless monitoring products were classified into three categories: (1) noninvasive optical, (2) noninvasive fluid sampling, and (3) minimally invasive devices. Results: In total, 28 noninvasive optical, 6 noninvasive fluid sampling, and 31 minimally invasive glucose monitoring products were identified. Subsequently, these products were characterized according to their regulatory, technological, and consumer features. Products with regulatory clearance are described in greater detail according to their advantages and disadvantages, and with design images. Conclusions: Based on favorable technological features, consumer features, and other advantages, several bloodless products are commercially available and promise to enhance diabetes management. Paths for future products are discussed with an emphasis on understanding existing barriers related to both technical and non-technical issues.

Objective Assess the quality of a new disposable nasopharyngolaryngoscope (NPL) through resident feedback at multiple academic institutions and provide a cost analysis of reusable and disposable NPLs at a single academic center. Study Design An online survey was distributed to residents at institutions throughout the United States that have implemented use of a disposable NPL (Ambu aScope 4 Rhinolaryngo). Setting Cost analysis performed at a single academic center. Resident survey distributed to multiple residency programs throughout the United States. Subjects and Methods The survey collected demographic information and asked residents to rate the new disposable NPL and other reusable NPLs using a 5‐point Likert scale. A cost analysis was performed of both reusable and disposable NPLs using information obtained at a single academic center. Results The survey was distributed to 109 residents throughout the country and 37 were completed for a response rate of 33.9%. The disposable NPL was comparable to reusable NPLs based on ergonomics and maneuverability, inferior in imaging quality (P, Nasopharyngolaryngoscopes are universally used by otolaryngologists in the diagnosis and treatment of various conditions of the upper aerodigestive tract. This study sought to compare a novel disposable version of the endoscope to the widely used reusable nasopharyngolaryngoscope through cost analysis and survey of residents at institutions who have employed the novel device.

To compare the Kadish and the modified Dulguerov staging of individual participants to determine the impact of stage and other prognostic factors on disease-free (DFS) and overall survival (OS).Systematic review of EMBASE, MEDLINE, Cochrane Library, and CINAHL databases.The Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) was followed for this study. Articles including patients with olfactory neuroblastoma (ONB) staged with both Kadish and Dulguerov staging systems were reviewed. The raw data from eligible studies were requested to perform an individual participant data (IPD) meta-analysis.Pooled data from 21 studies representing 399 patients with ONB undergoing treatment with curative intent showed that increasing age, treatment with chemotherapy, and positive or unreported margin status portended worse DFS (This study represents the first IPD meta-analysis of ONB directly comparing the outcomes of Kadish and Dulguerov staging systems in patients treated with primary surgery. Both systems correlated with DFS and OS, with superior performance in the Dulguerov system. Furthermore, the Kadish C group represented a heterogeneous group with regard to outcomes after stratification by the Dulguerov system. Dulguerov T4 patients had the worst outcome, with most being approached with open resection.

Terahertz (THz) time-domain spectroscopy provides a direct and nondestructive method for measuring the dielectric properties of materials directly from the phase delay of coherent electromagnetic radiation propagating through the sample. In cases when crystals are embedded within an inert polymeric pellet, the Landau, Lifshitz, and Looyenga (LLL) effective medium model can be used to extract the intrinsic dielectric constant of the crystalline sample. Subsequently, polarizability can be obtained from the Clausius–Mossotti (CM) relationship. Knowledge of the crystal structure density is required for an analytical solution to the LLL and CM relationships. A novel crystal structure-free graphical method is presented as a way to estimate both dielectric constants and polarizability values for the situation when the crystal structure density is unknown, and the crystals are embedded within a pellet composed of a non-porous polymer. The utility of this crystal structure-free method is demonstrated by analyzing THz time-domain spectra collected for a set of amino acids (L-alanine, L-threonine, and L-glutamine) embedded within pellets composed of polytetrafluoroethylene. Crystal structures are known for each amino acid, thereby enabling a direct comparison of results using the analytical solution and the proposed crystal structure-free graphical method. For each amino acid, the intrinsic dielectric constant is extracted through the LLL effective medium model without using information of their crystal structure densities. THz polarizabilities are then calculated with the CM relationship by using the determined intrinsic dielectric constant for each amino acid coupled with its crystal density as determined graphically. Comparison between the analytical and graphical solutions reveal relative differences between dielectric constants of 3.7, 5.1, and 13.6% for threonine, alanine, and glutamine, respectively, and relative differences between polarizability of 0.6, 0.9, and 5.4%, respectively. These values were determined over the 10–20 cm−1 THz frequency range. The proposed method requires no prior knowledge of crystal structure information.

Purpose of review Evidence-based medicine underpins clinical practice. Ideally, our clinical decision-making stems from systematic reviews of randomized controlled trials. However, in practice, this is not often the case, and we must instead rely on the best available evidence. Recent findings We review the history of evidence-based research, the development of the levels of evidence, and the relationship of evidence and bias present in craniomaxillofacial surgery. We also discuss the recent trends in CMF publications and identify areas for improvement. Summary Because of inherent challenges, the quality of evidence in craniomaxillofacial surgery lags behind other surgical and medical specialties. However, over recent years this has improved significantly, with better reporting of data and a higher rate of randomized controlled trials.

The Logarithmic Number System (LNS) is useful in applications that tolerate approximate computation, such as classification using multi-layer neural networks that compute nonlinear functions of weighted sums of inputs from previous layers. Supervised learning has two phases: training (find appropriate weights for the desired classification), and inference (use the weights with approximate sum of products). Several researchers have observed that LNS ALUs in inference may minimize area and power by being both low-precision and approximate (allowing low-cost, tableless implementations). However, the few works that have also trained with LNS report at least part of the system needs accurate LNS. This paper describes a novel approximate LNS ALU implemented simply as logic (without tables) that enables the entire back-propagation training to occur in LNS, at one-third the cost of fixed-point implementation.

Terahertz (THz) imaging has attracted much attention within the past decade as an emerging nondestructive evaluation technique. In this paper, we present a novel Laser-based Metamaterial Fabrication (LMF) process for high-throughput fabrication of transparent conducting surfaces on dielectric substrates such as glass, quartz and polymers to achieve tunable THz bandpass characteristics. The LMF process comprises two steps: (1) applying ultrathin-film metal deposition, with a typical thickness of 10 nm, on the dielectric substrate; (2) creating a ~100-micron feature pattern on the metal film using nanosecond pulsed laser ablation. Our results demonstrate the use of laser-textured ultra-thin film with newly integrated functional capabilities: (a) highly conductive with ~20 Ω/sq sheet resistance, (b) optically transparent with ~70% transmittance within visible spectrum, and (c) tunable bandpass filtering effect in the THz frequency range. A numerical analysis is performed to help determine the fundamental mechanism of THz bandpass filtering for the LMF-built samples. The scientific findings from this work render an economical and scalable manufacturing technique capable of treating large surface area for multi-functional metamaterials.

Partial intracapsular tonsillectomy (PIT) is a well-established technique for reducing post-operative morbidity in pediatric patients with sleep disordered breathing (SDB). Although tonsillar re-growth rates are reported as low, risks of symptom recurrence or need for completion tonsillectomy are clear disadvantages when compared to traditional tonsillectomy (TT). We aim to identify cohort differences to better guide clinical decision making and identify patient-specific factors that may influence this decision. A secondary aim was to evaluate potential risk factors for tonsillar regrowth.Retrospective chart review of pediatric patients who underwent TT or PIT for SDB between 2015 and 2019 at a tertiary care academic medical center. Records were reviewed for age, gender, race, body mass index, comorbidities, diagnosis, apnea-hypopnea index, pre-operative Brodsky tonsil size, length of stay, post-operative hemorrhage, tonsillar regrowth, symptom recurrence, and need for completion tonsillectomy.315 patients were included: 174 underwent TT and 141 underwent PIT. Patients undergoing TT were more likely to have a sleep study showing OSA (OR 3.01, p 0.0001), asthma (OR 4.28, p = 0.000124), and other comorbidities (OR 4.06, p = 0.0258). The overall complication rate was 4.44% (14/315). Tonsillar regrowth was exclusive to the PIT group, occurring in 7/141 patients (4.96%). Age ≤4 years was significantly associated with increased risk of tonsillar regrowth (≤4 years: 7.69%,4 years: 0%; p = 0.049). Race and pre-operative tonsil size were not associated with regrowth.Our study supports the low incidence of tonsillar regrowth in PIT and suggests an association with younger age. Moreover, we found that patients undergoing TT are more likely to be older, have OSA, asthma, and other comorbidities.

Terahertz (THz) optoelectronics have great potentials in communication, imaging, sensing and security applications. However, the state-of-the-art fabrication processes for THz devices are costly and time-consuming. In this work, we present a novel laser-based metamaterial fabrication (LMF) process for high-throughput fabrication of transparent conducting surfaces on dielectric substrates such as quartz and transparent polymers to achieve tunable THz bandpass filtering characteristics. The LMF process comprises two steps: (1) applying ultrathin-film metal deposition, with a typical thickness of 10 nm, on the dielectric substrate; (2) creating periodic surface pattern with a feature size of ~100 microns on the metal film using nanosecond pulsed laser ablation. Our results demonstrate the LMF-fabricated ultra-thin metal film exhibits newly integrated functionalities: (a) highly conductive with sheet resistance of ~20 Ω/sq; (b) optically transparent with visible transmittance of ~70%; (c) tunable bandpass filtering effect in the THz frequency range; and (d) extraordinary mechanical durability during repeated fatigue bending cycles. The scientific findings from this work will render an economical and scalable manufacturing technique capable of treating large surface area for multi-functional THz metamaterials.

Objectives/hypothesis To determine outcomes of patients with displaced nasal bone fractures after closed nasal reduction (CNR). Study design Retrospective patient review. Methods Review of all patients presenting to the emergency department of a tertiary-care, level 1 trauma hospital with a nasal bone fracture over a 2-year period, followed by telephone survey after CNR. Results Six hundred seven patients presented to the emergency department in 2015 and 2016 with a diagnosis of nasal bone fracture. Of these, 134 patients met inclusion criteria and underwent CNR without septal reduction. Those with sports-related injuries and those with a septal fracture identified on computed tomography imaging were significantly more likely to undergo CNR. Ninety-one patients completed the post-CNR telephone survey. Over 90% of patients were satisfied with the procedure. However, patients with septal fractures reported worse outcomes, as 53.6% versus 24.1% (P = .0025) disagreed that CNR improved nasal breathing. Of all patients, 11 (2%) eventually underwent septorhinoplasty, with the presence of septal fracture on imaging a significant risk factor. Conclusions Nasal bone fractures are a common injury, often managed initially with CNR. Patients with septal fractures should be counseled on the high risk of posttraumatic nasal deformity and obstruction despite CNR. In addition, addressing a septal fracture found on imaging may be warranted with either closed septal reduction or early aggressive management given the poorer outcomes seen in the present study. Although these patients are more likely to have definitive treatment, many forego later intervention despite persistent symptoms, emphasizing the need for early intervention or close follow-up. Level of evidence 3 Laryngoscope, 129:1784-1790, 2019.

A novel application of terahertz time-domain spectroscopy (THz-TDS) is described for the determination of permittivity and polarizability of organic crystals, as exemplified by measurements with the polymorph I form of crystalline aspirin (acetylsalicylic acid). The coherent nature of the THz pulse experiment, coupled with gated-detection, permits direct measure of differences in the phase angle of the electric field vector after passing through a pellet composed of the aspirin crystals embedded within an inert polymer matrix. An effective media model is used to extract dielectric information for the crystals from the measured time-domain signal that is representative of the entire pellet composition. Polarizability is then obtained for these organic crystals by using the Clausius–Mossotti relationship. Dielectric spectra and polarizability spectra are presented over the 0.3–3 THz frequency range (10–100 cm−1). The average polarizability values measured over the low frequency range (10–20 cm−1) are 22.4 ± 0.3 and 22.4 ± 0.5 Å3 for aspirin crystals embedded within matrixes of polytetrafluoroethylene (PTFE) and polyethylene (PE), respectively.

This case report describes the novel use of transoral robotic surgery (TORS) with delayed transoral laser microsurgery (TLM) for residual disease in the resection of a pediatric neurofibroma with supraglottic and parapharyngeal space extension. Postoperatively, the patient had excellent functional outcomes. This case demonstrates that pediatric TORS is feasible, safe, and complementary to TLM. Neurofibroma is just one of the diverse pathologic processes of the pediatric airway that can be managed via transoral surgery, and applications of TORS with TLM will continue to broaden as our experience develops. Laryngoscope, 2525-2528, 2018.

YHWH’s statement to Moses, אהיה אשר אהיה , has been much discussed by biblical scholars and theologians. For much of the last century this discussion related to matters of etymology or history of religion, or the precise grammar of the text. However, recently there has been renewed interest in understanding the statement in its present context as part of the book of Exodus, and in particular its role in the call of Moses. My thesis seeks to deepen understanding of the implications of this statement through a close reading of the dialogues between Moses and YHWH. My close reading of individual dialogues involves three steps: first investigation of the way in which the narrator portrays the actions of the characters, then the manner in which the narrator portrays individual speech of the characters and finally the way in which an analysis of the dialogues utilising principles from the socio-linguistic field of Conversation Analysis adds to an understanding of the characters. Through this close reading I show that the phrase אהיה אשר אהיה is best understood as linking the meaning of the name YHWH to the verb “to be” and in particular God’s promise to “be with” Moses in 3:12. The phrase affirms both YHWH’s presence with Moses and his freedom to be present in the manner he chooses and the implications of this affirmation of presence and freedom are worked out more fully in the narrative of Exodus. In the thesis my reading of the dialogues in Exodus 3-4 shows that YHWH transforms Moses into the means by which YHWH delivers his people from Egypt and also by which YHWH is present with his people. My examination of the dialogues in Exodus 5-7 demonstrates that YHWH’s plans are accomplished by his speech which re-designates and reshapes those with and about whom he is speaking. My analysis of Exodus 19-24 finds that the dialogues demonstrate YHWH’s freedom to be present as he chooses to different people at different points. Exodus 32:7-33:11 gives further meaning and significance to the divine name in terms of YHWH’s withdrawal in response to the idolatry of the people. From the final section of dialogue, Exodus 33:12-34:35, I show that the intercession of Moses is critical to the demonstration of YHWH’s mercy and compassion. My analysis of each of these dialogues demonstrates that a key means by which YHWH is present to his people is in and through Moses.

Importance Venous thromboembolism (VTE) is associated with substantial morbidity and is the most common factor associated with preventable death among hospitalized patients. Data from otolaryngologic studies suggest that the risk of VTE may be underestimated among high-risk patients, particularly among those undergoing oncologic procedures. The incorporation of prolonged-duration chemoprophylaxis (PDC) into preventive therapy has been associated with substantial decreases in VTE incidence among patients undergoing oncologic surgery. However, bleeding remains a major concern among otolaryngologists, and substantial variation exists in the use of thromboprophylaxis. Objective To assess the association between PDC and VTE in high-risk patients with head and neck cancer undergoing oncologic procedures. Design, setting, and participants This retrospective cohort study identified 750 patients with biopsy-confirmed head and neck cancer and a Caprini risk score of 8 or higher who underwent inpatient oncologic surgery at a tertiary care referral center between January 1, 2014, and February 1, 2020. After exclusions, 247 patients were included in the study; patients were divided into 2 cohorts, traditional and PDC, based on the duration of prophylaxis. Univariate and multivariate analyses were performed to examine the development of VTE and bleeding-associated complications during the 30-day postoperative period. Data were analyzed from April 1 to April 30, 2020. Exposures PDC, defined as 7 or more postoperative days of chemoprophylaxis. Main outcomes and measures VTE and bleeding events during the 30-day postoperative period. Results Among 247 patients (mean [SD] age, 63.1 [11.1] years; 180 men [72.9%]) included in the study, 106 patients (42.9%) received traditional prophylaxis, and 141 patients (57.1%) received PDC. The incidence of VTE was 5 of 106 patients (4.7%) in the traditional cohort and 1 of 141 patients (0.7%) in the PDC cohort (odds ratio [OR], 0.15; 95% CI, 0.003-1.33). In the multivariate logistic regression analysis, PDC was independently associated with reductions in the risk of VTE (OR, 0.04; 95% CI, 0.001-0.46). The incidence of bleeding events was 1 of 106 patients (0.9%) in the traditional cohort and 6 of 141 patients (4.3%) in the PDC cohort (OR, 4.64; 95% CI, 0.55-217.00). Conclusions and relevance The use of chemoprophylaxis for high-risk patients with head and neck cancer remains a high-priority topic. The results of this study suggest that PDC may be associated with reductions in VTE among this patient population. However, the associated increase in nonfatal bleeding events warrants careful consideration and further highlights the need to determine an optimal duration for chemoprophylaxis among this distinct cohort.

Customer engagement marketing—defined as a firm’s deliberate effort to motivate, empower, and measure customer contributions to marketing functions—marks a shift in marketing research and business practice. After defining and differentiating engagement marketing, the authors present a typology of its two primary forms and offer tenets that link specific strategic elements to customer outcomes and thereby firm performance, theorizing that the effectiveness of engagement marketing arises from the establishment of psychological ownership and self-transformation. The authors provide evidence in support of the derived tenets through case illustrations, as well as a quasi-experimental field test of the central tenet of engagement marketing.

With the growing focus on translational research and the use of biomarkers to drive drug development and approvals, biomarkers have become a significant area of research within the pharmaceutical industry. However, until the US Food and Drug Administration’s (FDA) 2013 draft guidance on bioanalytical method validation included consideration of biomarker assays using LC-MS and LBA, those assays were created, validated, and used without standards of performance. This lack of expectations resulted in the FDA receiving data from assays of varying quality in support of efficacy and safety claims. The AAPS Crystal City VI (CC VI) Workshop in 2015 was held as the first forum for industry-FDA discussion around the general issues of biomarker measurements (e.g., endogenous levels) and specific technology strengths and weaknesses. The 2-day workshop served to develop a common understanding among the industrial scientific community of the issues around biomarkers, informed the FDA of the current state of the science, and will serve as a basis for further dialogue as experience with biomarkers expands with both groups.

Frontal sinus fractures are an uncommon injury of the maxillofacial skeleton, and account for 5–15% of all maxillofacial fractures. As the force of impact increases, fractures may extend beyond the anterior table to involve adjacent skull, posterior table and frontal sinus outflow tract (FSOT). Fractures at these subsites should be evaluated independently to assess the need for and type of operative intervention. Historically, these fractures were managed aggressively with open techniques resulting in obliteration or cranialization. With significant injuries, these approaches are still indispensable. However, the treatment of frontal sinus fractures has changed dramatically over the past half-century, and recent case series have demonstrated favorable outcomes with conservative management. Concurrently, there has been an increasing role of minimally invasive endoscopic techniques, both for primary and expectant management, with a focus on sinus preservation. Here, we review the diagnosis and management of frontal sinus fractures, with an emphasis on subsite evaluation. Following a detailed assessment, an appropriate treatment strategy is selected from a variety of open and minimally invasive approaches available in the surgeon's armamentarium.

Purpose – The purpose of this study is to explore consumers’ overall attitude toward relationship marketing and to determine the influence of consumers’ overall attitude on consumers’ intentions and behaviors. Many services companies practice relationship marketing and customer relationship management. Although the benefits and drawbacks of relationship marketing for consumers have been established, little is known about whether consumers have a relatively positive or negative attitude toward relationship marketing practices. Design/methodology/approach – This research investigates consumers’ attitudes toward relationship marketing using a national survey of 245 consumers and a survey of 417 consumers living in the southern region of the USA. Findings – Although approximately 70 per cent of our national consumer sample had a somewhat positive attitude toward relationship marketing, about 30 per cent had a somewhat negative or neutral attitude. Furthermore, approximately 39 per cent of consumers in the study would choose a company that does not engage in relationship marketing over a company that does. The results also indicate that consumers’ overall attitude toward relationship marketing impacts their likelihood to respond favorably to specific relationship marketing tactics. Research limitations/implications – Some limitations should be noted. First and not uncommon to most survey research in marketing, the relationships between constructs in this study may be inflated because of common methods bias. Second, this research reports the results from two studies. Although one of the studies represents a national sample, additional research using the scales developed in this research is needed. Practical implications – This research indicates that consumers’ attitudes toward relationship marketing impacts their willingness to engage in relationships with service companies and their response to specific relationship marketing tactics. Because consumer attitudes toward relationship marketing vary, companies should consider segmenting their customer base using this information. Originality/value – This study extends previous research by using quantitative techniques to measure consumers’ overall attitudes toward relationship marketing and assessing the influence of those attitudes on intentions and behaviors.

Aims: A cross-laboratory experiment has been performed on a novel dried blood sampler in order to investigate whether it overcomes issues associated with blood volume and hematocrit (HCT) that are observed when taking a subpunch from dried blood spot samples. Materials & methods: An average blood volume of 10.6 μl was absorbed by the samplers across the different HCTs investigated (20–65%). Results: No notable change of volume absorbed was noted across the HCT range. Furthermore, the variation in blood sample volumes across six different laboratories was within acceptable limits. Conclusion: The novel volumetric absorptive microsampling device has the potential to deliver the advantages of dried blood spot sampling while overcoming some of the issues associated with the technology.

In September 2013, the FDA released a draft revision of the Bioanalytical Method Validation (BMV) Guidance, which included a number of changes to the expectations for bioanalysis, most notably the inclusion of biomarker assays and data. To provide a forum for an open, inclusive discussion of the revised draft BMV Guidance, the AAPS and FDA once again collaborated to convene a two-and-a-half day workshop during early December 2013 in Baltimore, MD, USA. The resulting format embodied extensive open discussion and each thematic session included only brief, concise descriptions by Agency and industry representatives prior to opening the floor discussion. The Workshop was built around four thematic sessions (Common Topics, Chromatographic, Ligand-Binding Assays, and Biomarkers) and a final session with international regulators, concluding with a review of the outcomes and recommendations from the thematic sessions. This Workshop report summarizes the outcomes and includes topics of agreement, those where the FDA will consider the Industry's perspective, and those where the workshop provided a first open dialogue. This article will be available to the bioanalytical community at http://www.aaps.org/BMV13 .

The 2014 8th Workshop on Recent Issues in Bioanalysis (8th WRIB), a 5-day full immersion in the evolving field of bioanalysis, took place in Universal City, California, USA. Close to 500 professionals from pharmaceutical and biopharmaceutical companies, contract research organizations and regulatory agencies worldwide convened to share, review, discuss and agree on approaches to address current issues of interest in bioanalysis. The topics covered included both small and large molecules, and involved LCMS, hybrid LBA/LCMS, LBA approaches and immunogenicity. From the prolific discussions held during the workshop, specific recommendations are presented in this 2014 White Paper. As with the previous years’ editions, this paper acts as a practical tool to help the bioanalytical community continue advances in scientific excellence, improved quality and better regulatory compliance. Due to its length, the 2014 edition of this comprehensive White Paper has been divided into three parts for editorial reasons. This publication (Part 2) covers the recommendations for Hybrid LBA/LCMS, Electronic Laboratory Notebook and Regulatory Agencies’ Input. Part 1 (Small molecules bioanalysis using LCMS) was published in the Bioanalysis issue 6(22) and Part 3 (Large molecules bioanalysis using LBA and Immunogenicity) will be published in the Bioanalysis issue 6(24).

The 2014 8th Workshop on Recent Issues in Bioanalysis (8th WRIB), a 5-day full immersion in the evolving field of bioanalysis, took place in Universal City, California, USA. Close to 500 professionals from pharmaceutical and biopharmaceutical companies, contract research organizations and regulatory agencies worldwide convened to share, review, discuss and agree on approaches to address current issues of interest in bioanalysis. The topics covered included both small and large molecules, and involved LCMS, hybrid LBA/LCMS, LBA approaches and immunogenicity. From the prolific discussions held during the workshop, specific recommendations are presented in this 2014 White Paper. As with the previous years’ editions, this paper acts as a practical tool to help the bioanalytical community continue advances in scientific excellence, improved quality and better regulatory compliance. Due to its length, the 2014 edition of this comprehensive White Paper has been divided into three parts for editorial reasons. This publication (Part 1) covers the recommendations for small molecule bioanalysis using LCMS. Part 2 (Hybrid LBA/LCMS, Electronic Laboratory Notebook and Regulatory Agencies’ input) and Part 3 (Large molecules bioanalysis using LBA and Immunogenicity) will be published in the upcoming issues of Bioanalysis.

Near-infrared spectroscopy is considered to be one of the most promising spectroscopic techniques for upstream bioprocess monitoring and control. Traditionally the nature of near-infrared spectroscopy has demanded multivariate calibration models to relate spectral variance to analyte concentrations. The resulting analytical measurements have proven unreliable for the measurement of metabolic substrates for bioprocess batches performed outside the calibration process. This paper presents results of an innovative near-infrared spectroscopic monitor designed to follow the concentrations of glycerol and methanol, as well as biomass, in real time and continuously during the production of a monoclonal antibody by a Pichia pastoris high cell density process. A solid state instrumental design overcomes the ruggedness limitations of conventional interferometer-based spectrometers. Accurate monitoring of glycerol, methanol, and biomass is demonstrated over 274 days postcalibration. In addition, the first example of feedback control to maintain constant methanol concentrations, as low as 1 g/L, is presented. Postcalibration measurements over a 9-month period illustrate a level of reliability and robustness that promises its adoption for online bioprocess monitoring throughout product development, from early laboratory research and development to pilot and manufacturing scale operation. © 2014 American Institute of Chemical Engineers Biotechnol. Prog., 30:749–759, 2014

Bioanalytical data submitted to global health authorities in support of drug approval applications is expected to meet certain regulatory standards and requirements. Bioanalytical assay validation and the conduct of study sample analysis is addressed with a multitude of regulatory guidance documents. This chapter provides an overview of the regulations from a historical perspective to current day developments. Originally written around bioanalysis to support pharmacokinetic studies, bioanalysis regulatory language is now being applied to endogenous biomarker assays and evaluating immunogenicity of large molecule therapeutics. Quality management and documentation are also discussed in this chapter along with the process of how modern bioanalysis regulations are continuing to develop.

The 2016 10th Workshop on Recent Issues in Bioanalysis (10th WRIB) took place in Orlando, Florida with participation of close to 700 professionals from pharmaceutical/biopharmaceutical companies, biotechnology companies, contract research organizations, and regulatory agencies worldwide. WRIB was once again a 5-day, weeklong event – A Full Immersion Week of Bioanalysis including Biomarkers and Immunogenicity. As usual, it was specifically designed to facilitate sharing, reviewing, discussing and agreeing on approaches to address the most current issues of interest including both small and large molecule analysis involving LCMS, hybrid LBA/LCMS, and LBA approaches, with the focus on biomarkers and immunogenicity. This 2016 White Paper encompasses recommendations emerging from the extensive discussions held during the workshop, and is aimed to provide the bioanalytical community with key information and practical solutions on topics and issues addressed, in an effort to enable advances in scientific excellence, improved quality and better regulatory compliance. This white paper is published in 3 parts due to length. This part (Part 1) discusses the recommendations for small molecules, peptides and small molecule biomarkers by LCMS. Part 2 (Hybrid LBA/LCMS and regulatory inputs from major global health authorities) and Part 3 (large molecule bioanalysis using LBA, biomarkers and immunogenicity) will be published in the Bioanalysis journal, issue 23.

Chemical imaging is demonstrated by using an innovative near infrared spectrometer that uses a digital micro-mirror array device (DMD) to provide both spatial and spectral resolution. Hadamard transform spectroscopy is used to enhance the signal-to-noise ratio of the measurement compared to single point raster scanning. The concept is demonstrated by collecting a spectral image of a polymer sample composed of separate regions of polystyrene and polypropylene. The resulting image is composed of 63 spectral resolution elements across the first overtone region of the near infrared spectrum (1538–1818 nm), as well as 65 spatial resolution elements across the longitudinal direction of the DMD (11.3 mm).

Biological sample dilution is a rate-limiting step in bioanalytical sample preparation when the concentrations of samples are beyond standard curve ranges, especially when multiple dilution factors are needed in an analytical run. We have developed and validated a Microsoft Excel-based robotic sample preparation program (RSPP) that automatically transforms Watson worklist sample information (identification, sequence and dilution factor) to comma-separated value (CSV) files. The Freedom EVO liquid handler software imports and transforms the CSV files to executable worklists (.gwl files), allowing the robot to perform sample dilutions at variable dilution factors. The dynamic dilution range is 1- to 1000-fold and divided into three dilution steps: 1- to 10-, 11- to 100-, and 101- to 1000-fold. The whole process, including pipetting samples, diluting samples, and adding internal standard(s), is accomplished within 1 h for two racks of samples (96 samples/rack). This platform also supports online sample extraction (liquid-liquid extraction, solid-phase extraction, protein precipitation, etc.) using 96 multichannel arms. This fully automated and validated sample dilution and preparation process has been applied to several drug development programs. The results demonstrate that application of the RSPP for fully automated sample processing is efficient and rugged. The RSPP not only saved more than 50% of the time in sample pipetting and dilution but also reduced human errors. The generated bioanalytical data are accurate and precise; therefore, this application can be used in regulated bioanalysis.

Advances in ultrafast lasers and semiconductor technologies have facilitated access to the terahertz (THz) frequency range for spectroscopic and imaging purposes. THz time-domain spectroscopy (TDS) is commonly used to acquire spectral data having high signal-to-noise ratios (SNRs) over a broad range of THz frequencies. THz-TDS instrumentation is commercially available, thereby enabling novel applications of THz time-domain (TD) imaging and spectroscopy in a myriad of applications. This review gives a general description of the instrumentation available for collecting THz-TD data and focuses on measurements of solid samples. Measurement geometries useful for collecting THz-TD data from solid samples are reviewed and a summary is presented of the major applications to the analysis of solid samples related to security issues, as well as samples originating from the pharmaceutical industry, dental sciences, biological samples, and polymer materials. Emphasis is also given to analytical applications i...

This University of Wisconsin School of Pharmacy bioanalytical conference is presented each year by the Extension Services in Pharmacy, the professional development department within the school. The purpose of this 4-day conference is to provide an educational forum to discuss issues and applications associated with the analysis of xenobiotics, metabolites, biologics and biomarkers in biological matrices. The conference is designed to include and encourage an open exchange of scientific and methodological applications for bioanalysis. To increase the interactive nature of the conference, the program was a mixture of lectures, poster sessions, round table discussions and workshops. This article summarizes the presentations at the 12th Annual Conference.

BACKGROUND Multiple laboratory tests are used to diagnose and manage patients with diabetes mellitus. The quality of the scientific evidence supporting the use of these tests varies substantially. APPROACH An expert committee compiled evidence-based recommendations for the use of laboratory testing for patients with diabetes. A new system was developed to grade the overall quality of the evidence and the strength of the recommendations. Draft guidelines were posted on the Internet and presented at the 2007 Arnold O. Beckman Conference. The document was modified in response to oral and written comments, and a revised draft was posted in 2010 and again modified in response to written comments. The National Academy of Clinical Biochemistry and the Evidence-Based Laboratory Medicine Committee of the American Association for Clinical Chemistry jointly reviewed the guidelines, which were accepted after revisions by the Professional Practice Committee and subsequently approved by the Executive Committee of the American Diabetes Association. CONTENT In addition to long-standing criteria based on measurement of plasma glucose, diabetes can be diagnosed by demonstrating increased blood hemoglobin A1c (HbA1c) concentrations. Monitoring of glycemic control is performed by self-monitoring of plasma or blood glucose with meters and by laboratory analysis of HbA1c. The potential roles of noninvasive glucose monitoring, genetic testing, and measurement of autoantibodies, urine albumin, insulin, proinsulin, C-peptide, and other analytes are addressed. SUMMARY The guidelines provide specific recommendations that are based on published data or derived from expert consensus. Several analytes have minimal clinical value at present, and their measurement is not recommended.

To compete globally, pharmaceutical companies desire to use bioanalytical data and reports as a single version for all filings; not revising for specific countries or regions. Historically, this meant following the US FDA and International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use guidance/guidelines; finding them sufficient to achieve global acceptance. However, a growing challenge of the past decade has been additional country-specific and regional regulations that have been released. The differences between the bioanalytical regulations among countries have been recognized as a challenge to the pharmaceutical industry and its CRO partners. Harmonization of the regulations at a global level has been the subject of a number of recent articles and editorials, and the topic has been vigorously discussed at several conferences over the past year. Since all have been in agreement about the need to harmonize regulations, this article will not focus on harmonization but rather it will provide a comparison of the USA/Canadian regulations versus those of South America, in particular Brazil, noting the additional work needed to achieve compliance with country-specific regulations. All countries discussed have specific guidance or regulations on clinical bioequivalence studies, and due to the higher standards for these studies, the regulations for bioequivalence studies will be used as the basis for comparison in the article.

Bioanalysis in Pharmaceutical Research & Development has been at the crossroad of science, technology, and regulations from its onset [1]. The first American Association of Pharmaceutical Scientists (AAPS)/Food and Drug Administration (FDA) Bioanalytical Workshop in 1990 in Crystal City, USA (CCI) was a major landmark for the industry to agree on execution and documentation of bioanalytical experiments. And although the resulting conference report was not a regulatory guidance, it was a roadmap for bioanalysts around the world for a decade on how to validate and apply bioanalytical methods [2]. In early 1999, the FDA promoted bioanalysis in support of pharmacokinetic evaluation in clinical and preclinical studies more formally into the regulated space by issuing a draft guidance. After broad industry consultation during an AAPS/FDA meeting again in Crystal City (CC-II) in early 2000 [3], FDA issued a guidance for Industry on Bioanalytical Method Validation in May 2001 [4]. This guidance provided the bioanalytical community the regulatory framework for bioanalytical method validation and the application of these methods. Although the guidance set clear expectations in many areas, the lack of detail on expectations in some paragraphs resulted in different interpretations in industry or by the inspectors. This, in combination with the rapid technological advancements in separation sciences, mass spectrometry, and ligand binding assay (LBA) or cell-based assay formats, resulted in individual views on how to validate bioanalytical methods and apply them to routine sample analysis. In trying to provide assistance in the interpretation of this guidance, the FDA continued to reach out to industry at conferences. In addition, some inspection findings documented in Form 483s provided a way forward. The 2001 guidance only referred to LBAs that enabled small molecule analysis and did not address the bioanalysis of macromolecules. In support of the rapidly growing ligand binding assay scientific community, two additional white papers were published to cover LBA aspects of macromolecule bioanalysis [5, 6]. To further discuss and clarify the 2001 FDA Guidance, FDA/AAPS organized a next meeting in Crystal City (CC-III), from which a comprehensive conference report was issued [7]. Crystal City III also put Incurred Sample Reanalysis (ISR) back on the foreground, a controversial topic which was further discussed during Crystal City IV [8]. Next, as mentioned in the Kudoh paper [1], multiple other guidelines or best practices on GLPs, GCPs, computer/software, or analytical instrument validation increasingly impacted the bioanalytical laboratory. Last but not least, other regions/countries besides the USA issued their own guidelines on regulated bioanalysis [9–11]. Building the Global Bioanalytical Consortium At the initiative of four regional professional organizations from Europe (European Bioanalysis Forum (EBF)) and North America (AAPS, Applied Pharmaceutical Analysis (APA) APA and Calibration & validation group (CVG—currently represented in GBC by Canadian Forum for Analytical and Bioanalytical Sciences CFABS), a letter was sent to the FDA and the European Medicine Agency (EMA)), formally requesting the health authorities and bioanalytical community to join hands and harmonize global bioanalysis scientific best practices. The need for global harmonization of the bioanalytical guidance was also supported by publishing this letter as an open letter [12], an initiative which was supported by many [13–15]. At the same time, the authors from aforementioned open letter together with additional representatives from these organizations (currently referred to as founding members), proposed to form an organization which brings together experts from the global bioanalytical community to discuss, share, and finally propose a harmonized view on bioanalytical best practices that could lead to a guidance: the Global Bioanalysis Consortium (GBC). A consensus was reached among around 280 delegates, including five Regulatory Agencies, during the 5th Workshop on Recent Issues in Bioanalysis (5th WRIB) in April 2010 on the main characteristic of what a “harmonization and Global Bioanalytical Guidance” should be based upon the following: science driven with inclusion of a rationale behind each requirement to prevent “box checking”. In addition, it should have a global perspective (not local issues), should not be prescriptive, and finally must get buy-in from all the countries [16]. From there, the GBC founding members proposed the mission of the organization [17] and reached out into the global bioanalytical community to build the GBC ensuring balanced representation from North America, Latin America, Europe/Middle East/Africa and Asia-Pacific.

This University of Wisconsin School of Pharmacy Bioanalytical Conference is arranged by the Extension Services in Pharmacy, the professional development department within the School. The purpose of this 4 day conference is to provide an educational forum to discuss issues and applications associated with the analysis of xenobiotics, metabolites, biologics and biomarkers in biological matrices. The conference is designed to include and encourage an open exchange of scientific and methodological applications for bioanalysis. To increase the interactive nature of the conference, the program was a mixture of lectures, poster sessions, round-table discussions and workshops. This paper summarizes the presentations at the Eleventh Annual Conference.

This study, using a sample of Korean multinational corporations, focuses on testing the relationships between the constructs of experiential knowledge, creativity, and performance in the context of international marketing projects. Relying on a multi-level conceptualization of experiential knowledge and creativity, our findings suggest that process-based creativity is enhanced when the team members have a higher level of experiential knowledge, but outcome-based creativity is not significantly influenced by either team- or firm-level experiential knowledge. It is concluded that, in the context of international marketing projects, the domain-relevant knowledge of the actors (i.e., the team-level experiential knowledge in the foreign markets) largely governs the level of their process-based creativity. The findings also suggest that project performance is directly influenced by firm-level experiential knowledge and process-based creativity, and is indirectly influenced by team-level experiential knowledge through the mediation of process-based creativity.

This conference was arranged by the Extension Services in Pharmacy at the University of Wisconsin School of Pharmacy. The purpose of this annual 4-day conference is to provide an educational forum to discuss issues and applications associated with the analysis of xenobiotics and metabolites in biological matrices. The conference is designed to include and encourage an open exchange of scientific and methodological applications for bioanalysis. To increase the interactive nature of the conference, the program will be a mixture of lectures, poster sessions, round table discussions and workshops. This paper summarizes the presentations at the Tenth Annual Conference.

An overview of our research results on the implementation of model predictive control (MPC) on-chip is presented, with central focus the development of small-size, energy efficient controllers suitable for drug delivery systems and devices. Profiling simulations coupled with codesign techniques are used in order to reveal algorithmic bottlenecks and to effectively customize implementation designs. Hardware in-the-loop simulations using a general purpose processor and a field programmable gate array, and emulations of an application specific processor are provided. The performance measurements and estimates illustrate that MPC is suitable for on-chip real-time optimal control of complex systems with fast dynamics.

The 2015 9th Workshop on Recent Issues in Bioanalysis (9th WRIB) took place in Miami, Florida with participation of over 600 professionals from pharmaceutical and biopharmaceutical companies, biotechnology companies, contract research organizations and regulatory agencies worldwide. It is once again a 5-day week long event – a full immersion bioanalytical week – specifically designed to facilitate sharing, reviewing, discussing and agreeing on approaches to address the most current issues of interest in bioanalysis. The topics covered included both small and large molecules, and involved LCMS, hybrid LBA/LCMS, LBA approaches including the focus on biomarkers and immunogenicity. This 2015 White Paper encompasses recommendations that emerged from the extensive discussions held during the workshop, and is aimed to provide the bioanalytical community with key information and practical solutions on topics and issues addressed, in an effort to advance scientific excellence, improve quality and deliver better regulatory compliance. Due to its length, the 2015 edition of this comprehensive White Paper has been divided into three parts. Part 1 covers the recommendations for small molecule bioanalysis using LCMS. Part 2 (hybrid LBA/LCMS and regulatory agencies’ inputs) and Part 3 (large molecule bioanalysis using LBA, biomarkers and immunogenicity) will also be published in volume 7 of Bioanalysis, issues 23 and 24, respectively.

The objective of this study was to assess the pharmacokinetics of a newly identified active metabolite of buspirone, 6-hydroxybuspirone (6OHB), over the therapeutic dose range of buspirone. A 26-day, open-label, nonrandomized, single-sequence, dose-escalation study in normal healthy volunteers was conducted (N = 13). Subjects received escalating doses of buspirone with each dose administered for 5 days starting at a dose of 5 mg twice daily and increasing up to 30 mg twice daily. Plasma concentrations of 6OHB were approximately 40-fold greater than those of buspirone. 6OHB was rapidly formed following buspirone administration, and exposure increased proportionally with buspirone dose. Further research regarding the safety and efficacy of 6OHB itself is warranted.

We study the problem of hydrodynamic regulation of a flow stream in a microfluidic geometry using model predictive control (MPC). Via bit-accurate emulations we mimic, on a 32-bit microcontroller, the optimization operations associated with MPC. Additionally, we use finite element method simulations to solve the coupled partial differential equation problem that describes the flow and diffusive transport in the examined microfluidic geometry. This combination of simulations and hardware emulations allows us to examine the feasibility of a real-time embedded MPC chip in closed loop with a microsystem, and provide estimates of the performance.

Tight control of blood glucose levels has been shown to dramatically reduce the long-term complications of diabetes. Current invasive technology for monitoring glucose levels is effective but underutilized by people with diabetes because of the pain of repeated finger-sticks and the cost of reagent strips. Optical sensing of glucose could potentially allow more frequent monitoring and tighter glucose control for people with diabetes. The key to a successful optical non-invasive measurement of glucose is the collection of an optical spectrum with a very high signal-to-noise-ratio in a spectral region with significant glucose absorption. Unfortunately, the optical throughput of skin is very small due to absorption and scattering. To overcome these difficulties, we have developed a high-brightness tunable laser system for measurements in the 2.0-2.5 μm wavelength range. The system is based on a 2.3 micron wavelength, strained quantum-well laser diode incorporating GaInAsSb wells and AlGaAsSb barrier and cladding layers. Wavelength control is provided by coupling the laser diode to an external cavity that includes an acousto-optic tunable filter. Tuning ranges of greater than 110 nm have been obtained. Because the tunable filter has no moving parts, scans can be completed very quickly, typically in less than 10 ms. We describe the performance of the laser system and its potential for use in a non-invasive glucose sensor.

The ability to measure glucose noninvasively in human subjects is a major objective for many research groups. Success will revolutionize the treatment of diabetes by providing a means to improve glycemic control, thereby delaying the onset of the medical complications associated with this disease. This article focuses on the current state of the art and attempts to identify the principal areas of research necessary to advance the field. Two fundamentally different approaches are identified for the development of noninvasive glucose sensing technology. The indirect approach attempts to measure glucose on the basis of its effect on a secondary process. The direct approach is based on the unique chemical structure of the glucose molecule. Advances for each approach are limited by issues of selectivity. Several critical parameters are discussed for the direct approach, including issues related to the optical path length, wavelength range, dimensionality of the multivariate calibration model, net analyte signal, spectral variance, and assessment of the chemical basis of measurement selectivity. A set of publication standards is recommended as a means to enhance progress toward a successful noninvasive monitor.

We propose a framework for embedding model predictive control for Systems-on-a-Chip applications. In order to allow the implementation of such a computationally expensive controller on chip, we propose reducing the precision of the operations coupled with using logarithmic number system arithmetic. Two particular control problems are examined. We provide the methodology for choosing the design parameters; we emulate the performance of the embedded controller for the examined cases and we give the microprocessor architecture details.