An examination of the potential core symptoms of posttraumatic stress disorder: What is integral after removing general psychopathology & distress?

Many confirmatory factor analyses (CFA) have examined the structure of posttraumatic stress disorder (PTSD) with some suggesting increased complexity (i.e., 6+ factors), while others suggesting a more refined structure (i.e., 2-factors). These competing PTSD structures may be due to conflation of non-trauma specific symptoms that have been added overtime. However, none of these studies examined if all symptoms being examined are specific to PTSD or potentially more related to general distress and psychopathology. The current study re-evaluated the structure of PTSD using bifactor exploratory factor analysis (EFA) to identify the construct's core symptoms. Data for EFA models were taken from a sample of Veterans (N = 694) attending outpatient therapy for PTSD and were cross-validated using CFA in a sample of 297 Veterans attending residential treatment. Clinician Administered PTSD Scale for DSM-5 (CAPS-5) at pre-treatment was used across sample. Factor analyses resulted in a 2-factor, bifactor model comprised of eight total items. Model fit was robust, RMSEA = 0 [0.000, 0.036]; robust CFI = 1; robust TLI = 1.017. The bifactor analytic approach captured what might be the core structure of PTSD, which were pathognomonic symptoms of PTSD (Factor one). A distinct second factor related to depression was also found. In identifying this structure, the model eliminates redundancies and lesser performing items and differentiates depressive reactions as potentially distinct and separate. Overall, these findings may assist in future research of PTSD by determining the unique elements of the construct within a veteran sample versus associated features, general psychological distress, and comorbid psychopathology.

Prevalence and nature of prior developmental and medical concerns in toddlers who screen positive for autism in primary care.

LAY ABSTRACT: The American Academy of Pediatrics recommends that all children be screened for autism at their 18- and 24-month well-child visit. For children who screen positive for autism, it is unknown whether this usually represents the first time a developmental concern has been raised or if other developmental concerns typically precede a positive autism screen. Such knowledge could help guide providers in how to appropriately convey feedback regarding autism screening. This study found that, for close to 80% of children with a positive autism screen, caregivers or providers had a prior autism, language, motor, or other developmental concern documented in the electronic health record. Many also had other prior concerns frequently linked to autism, such as sleep and gastrointestinal problems, and received physical or speech therapy. On average, prior to screening children who received a positive Modified-Checklist for Autism in Toddlers had two documented concerns by at 1 year of age and three concerns by 2 years of age. These findings imply that screening for autism as a part of routine pediatric care likely takes place in the context of larger conversations regarding existing developmental concerns, allowing for a less stigmatizing discussion of autism. Framing the presence of prior concerns in the setting of a positive screen in this context may create a reaffirming space for existing caregiver concerns and a lessened emotional burden on caregivers.

Are DEA-waivered buprenorphine prescribers colocated with behavioral health clinicians?

BACKGROUND AND OBJECTIVES: Medication for opioid use disorder (MOUD) in primary care includes a combination of medication, behavioral therapy, and/or other psychosocial services. This study assessed rates of colocation between waivered prescribers and behavioral health clinicians across the United States to understand if rates varied by provider type and geographic indicators. METHODS: Data from the DEA-Drug Addiction Treatment Act of 2000 provider list as of March 2022 and the National Plan and Provider Enumeration System's National Provider Identifier database were gathered, cleaned, and formatted in Stata. Data were geocoded with ESRI StreetMap® database and ArcGIS software. Covariates at individual, county, and state levels were examined and compared. Chi-square statistics and a mixed-effects logistic regression were analyzed. RESULTS: The sample (N = 71, 292 prescribers) included physicians (64%), nurse practitioners (29%), and physician assistants (7%). About 48% of prescribers were colocated with a behavioral health clinician. Physicians were the least likely to be colocated (47%), but differences between provider types were modest. We observed significant geographic differences in provider colocation by provider type. Mixed effects logistic regression identified significant predictors of colocation at individual, county, and state levels. DISCUSSION AND CONCLUSIONS: Optimally distributing the workforce providing MOUD is necessary to broadly ensure the provision of comprehensive MOUD care based on practice guidelines. SCIENTIFIC SIGNIFICANCE: Less than half of all waivered prescribers, outside of hospitals, are colocated with behavioral health clinicians. Findings offer greater clarity on where integrated MOUD is occurring, among which types of providers, and where it needs to be expanded to increase MOUD uptake.

Computer Vision Analysis of Caregiver-Child Interactions in Children with Neurodevelopmental Disorders: A Preliminary Report.

We report preliminary results of computer vision analysis of caregiver-child interactions during free play with children diagnosed with autism (N = 29, 41-91 months), attention-deficit/hyperactivity disorder (ADHD, N = 22, 48-100 months), or combined autism + ADHD (N = 20, 56-98 months), and neurotypical children (NT, N = 7, 55-95 months). We conducted micro-analytic analysis of 'reaching to a toy,' as a proxy for initiating or responding to a toy play bout. Dyadic analysis revealed two clusters of interaction patterns, which differed in frequency of 'reaching to a toy' and caregivers' contingent responding to the child's reach for a toy by also reaching for a toy. Children in dyads with higher caregiver responsiveness had less developed language, communication, and socialization skills. Clusters were not associated with diagnostic groups. These results hold promise for automated methods of characterizing caregiver responsiveness in dyadic interactions for assessment and outcome monitoring in clinical trials.

Predictive Value of Early Autism Detection Models Based on Electronic Health Record Data Collected Before Age 1 Year.

Importance: Autism detection early in childhood is critical to ensure that autistic children and their families have access to early behavioral support. Early correlates of autism documented in electronic health records (EHRs) during routine care could allow passive, predictive model-based monitoring to improve the accuracy of early detection. Objective: To quantify the predictive value of early autism detection models based on EHR data collected before age 1 year. Design, Setting, and Participants: This retrospective diagnostic study used EHR data from children seen within the Duke University Health System before age 30 days between January 2006 and December 2020. These data were used to train and evaluate L2-regularized Cox proportional hazards models predicting later autism diagnosis based on data collected from birth up to the time of prediction (ages 30-360 days). Statistical analyses were performed between August 1, 2020, and April 1, 2022. Main Outcomes and Measures: Prediction performance was quantified in terms of sensitivity, specificity, and positive predictive value (PPV) at clinically relevant model operating thresholds. Results: Data from 45 080 children, including 924 (1.5%) meeting autism criteria, were included in this study. Model-based autism detection at age 30 days achieved 45.5% sensitivity and 23.0% PPV at 90.0% specificity. Detection by age 360 days achieved 59.8% sensitivity and 17.6% PPV at 81.5% specificity and 38.8% sensitivity and 31.0% PPV at 94.3% specificity. Conclusions and Relevance: In this diagnostic study of an autism screening test, EHR-based autism detection achieved clinically meaningful accuracy by age 30 days, improving by age 1 year. This automated approach could be integrated with caregiver surveys to improve the accuracy of early autism screening.

A tablet-based game for the assessment of visual motor skills in autistic children.

Increasing evidence suggests that early motor impairments are a common feature of autism. Thus, scalable, quantitative methods for measuring motor behavior in young autistic children are needed. This work presents an engaging and scalable assessment of visual-motor abilities based on a bubble-popping game administered on a tablet. Participants are 233 children ranging from 1.5 to 10 years of age (147 neurotypical children and 86 children diagnosed with autism spectrum disorder [autistic], of which 32 are also diagnosed with co-occurring attention-deficit/hyperactivity disorder [autistic+ADHD]). Computer vision analyses are used to extract several game-based touch features, which are compared across autistic, autistic+ADHD, and neurotypical participants. Results show that younger (1.5-3 years) autistic children pop the bubbles at a lower rate, and their ability to touch the bubble's center is less accurate compared to neurotypical children. When they pop a bubble, their finger lingers for a longer period, and they show more variability in their performance. In older children (3-10-years), consistent with previous research, the presence of co-occurring ADHD is associated with greater motor impairment, reflected in lower accuracy and more variable performance. Several motor features are correlated with standardized assessments of fine motor and cognitive abilities, as evaluated by an independent clinical assessment. These results highlight the potential of touch-based games as an efficient and scalable approach for assessing children's visual-motor skills, which can be part of a broader screening tool for identifying early signs associated with autism.

Current landscape of research ethics consultation services: National survey results.

Introduction: The goal of a research ethics consultation service (RECS) is to assist relevant parties in navigating the ethical issues they encounter in conduct of research. The goal of this survey was to describe the current landscape of research ethics consultation and document if and how it has changed over the last decade. Methods: The survey instrument was based on the survey previously circulated. We included a number of survey domains from the previous survey with the goal of direct comparison of outcomes. The survey was sent to 57 RECS in the USA and Canada. Results: Forty-nine surveys were completed for an overall response rate of 86%. With the passing of 10 years, the volume of consults received by RECS surveyed has increased. The number of consults received by a subset of RECS remains low. RECS continues to receive requests for consults from a wide range of stakeholders. About a quarter of RECS surveyed actively evaluate their services, primarily through satisfaction surveys routinely shared with requestors. The number of RECS evaluating their services has increased. We identified a group of eight key competencies respondents find as key to providing RECS. Conclusions: The findings from our survey demonstrate that there have been growth and development of RECS since 2010. Further developing evaluation and competency guidelines will help existing RECS continue to grow and facilitate newly established RECS maturation. Both will allow RECS personnel to better serve their institutions and add value to the research conducted.

Noble-Nanoparticle-Decorated Ti3C2T x MXenes for Highly Sensitive Volatile Organic Compound Detection.

Two-dimensional transition-metal carbides and nitrides (MXenes) have been regarded as promising sensing materials because of their high surface-to-volume ratios and outstanding electronic, optical, and mechanical properties with versatile transition-metal and surface chemistries. However, weak gas-molecule adsorption of MXenes poses a serious limitation to their sensitivity and selectivity, particularly for trace amounts of volatile organic compounds (VOCs) at room temperature. To deal with these issues, Au-decorated MXenes are synthesized by a facile solution mixing method for room-temperature sensing of a wide variety of oxygen-based and hydrocarbon-based VOCs. Dynamic sensing experiments reveal that optimal decoration of Au nanoparticles (NPs) on Ti3C2T x MXene significantly elevates the response and selectivity of the flexible sensors, especially in detecting formaldehyde. Au-Ti3C2T x gas sensors exhibited an extremely low limit of detection of 92 ppb for formaldehyde at room temperature. Au-Ti3C2T x provides reliable gas response, low noise level, ultrahigh signal-to-noise ratio, high selectivity, as well as parts per billion level of formaldehyde detection. The prominent mechanism for Au-Ti3C2T x in sensing formaldehyde is elucidated theoretically from density functional theory simulations. The results presented here strongly suggest that decorating noble-metal NPs on MXenes is a feasible strategy for the development of next-generation ultrasensitive sensors for Internet of Things.

Four profiles of symptom change in residential Cognitive Processing Therapy.

A significant portion of veterans do not respond to evidence-based treatments for PTSD. Therefore, researchers have sought to predict who will respond well to trauma-focused treatment. The present study examined pre- and posttreatment symptom profiles, session-by-session change, as well as demographic and additional diagnostic information to better understand PTSD treatment response. Participants included 332 veterans undergoing residential Cognitive Processing Therapy. Latent profile analyses were computed, and four meaningful profiles emerged: Fast Responders, Steady Responders, Partial Responders, and Minimal Responders. Each profile demonstrated symptom reduction at approximately the same rate in the first half of treatment. Two specific profiles, Steady Responders and Minimal Responders, showed key clinically important differences. Both profiles demonstrated severe pretreatment PTSD symptom severity; however, in the second half of treatment, Steady Responders saw the steepest decrease in symptoms of any of the profiles while Minimal Responders saw less symptom reduction compared to all other profiles. Via a thorough examination, membership in Steady Responders compared to Minimal Responders was not associated with demographic or health variables. Results suggest that pretreatment symptom severity does not necessarily determine a client's posttreatment symptom severity. Pretreatment symptom severity did not determine outcome, though some veterans (Minimal Responders) did not experience the same symptom change and treatment effectiveness. Further identifying the factors that lead to the separation of these groups will add important information for determining treatment selection and potential obstacles to effectiveness.

Setting Risk Limits and Ensuring Fairness in Learning Health Care.

Historical abuses resulted in the segregation of clinical research and clinical care. While this approach has protected participants, it is extremely inefficient, leading commentators to propose (re)integrating research and care into learning health care systems. Previous commentators have argued that, in these systems, it could be appropriate to condition care on patients' consent to participation in research, but only when the added research risks are minimal. In the article "Compulsory Research in Learning Health Care: Against a Minimal Risk Limit," Robert Steel agrees about making research participation a condition for receiving care in these systems, but he argues that the limit to minimal risks is unfounded, and he offers compelling reasons to think that, in principle, permitting greater research risks could be fair and consistent with individual rights. Unfortunately, the nature of current institutions suggests that this approach is unlikely to be implemented fairly. We conclude that, to ensure fair learning health care systems, research and care may need to be reformed in more fundamental ways.

Cytoplasmic switch of ARS2 isoforms promotes nonsense-mediated mRNA decay and arsenic sensitivity.

The life of RNA polymerase II (RNAPII) transcripts is shaped by the dynamic formation of mutually exclusive ribonucleoprotein complexes (RNPs) that direct transcript biogenesis and turnover. A key regulator of RNA metabolism in the nucleus is the scaffold protein ARS2 (arsenic resistance protein 2), bound to the cap binding complex (CBC). We report here that alternative splicing of ARS2's intron 5, generates cytoplasmic isoforms that lack 270 amino acids from the N-terminal of the protein and are functionally distinct from nuclear ARS2. Switching of ARS2 isoforms within the CBC in the cytoplasm has dramatic functional consequences, changing ARS2 from a NMD inhibitor to a NMD promoter that enhances the binding of UPF1 to NCBP1 and ERF1, favouring SURF complex formation, SMG7 recruitment and transcript degradation. ARS2 isoform exchange is also relevant during arsenic stress, where cytoplasmic ARS2 promotes a global response to arsenic in a CBC-independent manner. We propose that ARS2 isoform switching promotes the proper recruitment of RNP complexes during NMD and the cellular response to arsenic stress. The existence of non-redundant ARS2 isoforms is relevant for cell homeostasis, and stress response.

Effectiveness of cognitive behavioral conjoint therapy for posttraumatic stress disorder (PTSD) in a U.S. Veterans Affairs PTSD clinic.

Cognitive behavioral conjoint therapy (CBCT) for posttraumatic stress disorder (PTSD) is a 15-session conjoint treatment for PTSD designed to improve PTSD symptoms and enhance intimate relationship functioning. Numerous studies of CBCT for PTSD document improvements in patient PTSD and comorbid symptoms, partner mental health, and relationship adjustment. However, little is known about its effectiveness in real-world clinical settings. Using an intention-to-treat sample of couples who participated in CBCT for PTSD in an outpatient U.S. Veterans Affairs (VA) PTSD clinic (N = 113), trajectories of session-by-session reports of veterans' PTSD symptoms and both partners' relationship happiness were examined. Across sessions, there were significant reductions in veteran-rated PTSD symptoms, d = -0.69, and significant increases in veteran- and partner-rated relationship happiness, ds = 0.36 and 0.35, respectively. Partner ratings of veterans' PTSD symptoms increased before significantly decreasing, d = -0.24. Secondary outcomes of veteran and partner relationship satisfaction, ds = 0.30 and 0.42, respectively; veteran and partner depressive symptoms, ds = -0.75 and -0.29, respectively; and partner accommodation of PTSD symptoms, d = -0.44, also significantly improved from pre- to posttreatment. The findings suggest that CBCT for PTSD was effective for decreasing PTSD and comorbid symptoms in veterans, as well as for improving relationship functioning and partners' mental health, among a sample of real-world couples seeking treatment in a VA PTSD specialty clinic.

Computational Methods to Measure Patterns of Gaze in Toddlers With Autism Spectrum Disorder.

Importance: Atypical eye gaze is an early-emerging symptom of autism spectrum disorder (ASD) and holds promise for autism screening. Current eye-tracking methods are expensive and require special equipment and calibration. There is a need for scalable, feasible methods for measuring eye gaze. Objective: Using computational methods based on computer vision analysis, we evaluated whether an app deployed on an iPhone or iPad that displayed strategically designed brief movies could elicit and quantify differences in eye-gaze patterns of toddlers with ASD vs typical development. Design, Setting, and Participants: A prospective study in pediatric primary care clinics was conducted from December 2018 to March 2020, comparing toddlers with and without ASD. Caregivers of 1564 toddlers were invited to participate during a well-child visit. A total of 993 toddlers (63%) completed study measures. Enrollment criteria were aged 16 to 38 months, healthy, English- or Spanish-speaking caregiver, and toddler able to sit and view the app. Participants were screened with the Modified Checklist for Autism in Toddlers-Revised With Follow-up during routine care. Children were referred by their pediatrician for diagnostic evaluation based on results of the checklist or if the caregiver or pediatrician was concerned. Forty toddlers subsequently were diagnosed with ASD. Exposures: A mobile app displayed on a smartphone or tablet. Main Outcomes and Measures: Computer vision analysis quantified eye-gaze patterns elicited by the app, which were compared between toddlers with ASD vs typical development. Results: Mean age of the sample was 21.1 months (range, 17.1-36.9 months), and 50.6% were boys, 59.8% White individuals, 16.5% Black individuals, 23.7% other race, and 16.9% Hispanic/Latino individuals. Distinctive eye-gaze patterns were detected in toddlers with ASD, characterized by reduced gaze to social stimuli and to salient social moments during the movies, and previously unknown deficits in coordination of gaze with speech sounds. The area under the receiver operating characteristic curve discriminating ASD vs non-ASD using multiple gaze features was 0.90 (95% CI, 0.82-0.97). Conclusions and Relevance: The app reliably measured both known and new gaze biomarkers that distinguished toddlers with ASD vs typical development. These novel results may have potential for developing scalable autism screening tools, exportable to natural settings, and enabling data sets amenable to machine learning.

Voltammetric detection of arsenic (III) using gold nanoparticles modified carbon screen printed electrodes: Application for facile and rapid analysis in commercial apple juice.

This paper describes a voltammetric method and data analysis program developed for the detection of arsenic(III) in commercial apple juice. Arsenic(III) was detected using square wave stripping voltammetry with gold nanoparticle modified screen printed electrodes. The only sample pretreatment performed was the addition of a 100 mM phosphate buffer with a pH of 7. To compensate for interference from high ascorbic acid concentrations, a data analysis program was developed in MATLAB to fit a non-linear baseline, allowing for accurate peak height measurement. With this data analysis program, the developed methodology had a sensitivity of 0.1007 µA (µg L-1)-1 and a limit of detection of 16.73 µg L-1. A comparison between the voltammetric method and graphite furnace atomic absorption spectroscopy showed no bias in the voltammetric results and a good correlation between the two sets of predicted concentrations, with an R2 of 0.939.

Inpatient Opioid Consumption Variability following Total Knee Arthroplasty: Analysis of 4,038 Procedures.

This study examined an early iteration of an inpatient opioid administration-reporting tool, which standardized patient opioid consumption as an average daily morphine milligram equivalence per surgical encounter (MME/day/encounter) among total knee arthroplasty (TKA) recipients. The objective was to assess the variability of inpatient opioid administration rates among surgeons after implementation of a multimodal opioid sparing pain protocol. We queried the electronic medical record at our institution for patients undergoing elective primary TKA between January 1, 2016 and June 30, 2018. Patient demographics, inpatient and surgical factors, and inpatient opioid administration were retrieved. Opioid consumption was converted into average MME for each postoperative day. These MME/day/encounter values were used to determine mean and variance of opioids prescribed by individual surgeons. A secondary analysis of regional inpatient opioid consumption was determined by patient zip codes. In total, 23 surgeons performed 4,038 primary TKA. The institutional average opioid dose was 46.24 ± 0.75 MME/day/encounter. Average intersurgeon (IS) opioid prescribing ranged from 17.67 to 59.15 MME/day/encounter. Intrasurgeon variability ranged between ± 1.01 and ± 7.51 MME/day/encounter. After adjusting for patient factors, the average institutional MME/day/encounter was 38.43 ± 0.42, with average IS variability ranging from 18.29 to 42.84 MME/day/encounter, and intrasurgeon variability ranging between ± 1.05 and ± 2.82 MME/day/encounter. Our results suggest that there is intrainstitutional variability in opioid administration following primary TKA even after controlling for potential patient risk factors. TKA candidates may benefit from the implementation of a more rigid standardization of multimodal pain management protocols that can control pain while minimizing the opioid burden. This is a level of evidence III, retrospective observational analysis.

Deciphering the Enigma of the Histone H2A.Z-1/H2A.Z-2 Isoforms: Novel Insights and Remaining Questions.

The replication independent (RI) histone H2A.Z is one of the more extensively studied variant members of the core histone H2A family, which consists of many replication dependent (RD) members. The protein has been shown to be indispensable for survival, and involved in multiple roles from DNA damage to chromosome segregation, replication, and transcription. However, its functional involvement in gene expression is controversial. Moreover, the variant in several groups of metazoan organisms consists of two main isoforms (H2A.Z-1 and H2A.Z-2) that differ in a few (3-6) amino acids. They comprise the main topic of this review, starting from the events that led to their identification, what is currently known about them, followed by further experimental, structural, and functional insight into their roles. Despite their structural differences, a direct correlation to their functional variability remains enigmatic. As all of this is being elucidated, it appears that a strong functional involvement of isoform variability may be connected to development.

Simultaneous voltammetric detection of cadmium(II), arsenic(III), and selenium(IV) using gold nanostar-modified screen-printed carbon electrodes and modified Britton-Robinson buffer.

The present work reports a newly developed square wave anodic stripping voltammetry (SWASV) methodology using novel gold nanostar-modified screen-printed carbon electrodes (AuNS/SPCE) and modified Britton-Robinson buffer (mBRB) for simultaneous detection of trace cadmium(II), arsenic(III), and selenium(IV). During individual and simultaneous detection, Cd2+, As3+, and Se4+ exhibited well-separated SWASV peaks at approximately - 0.48, - 0.09, and 0.65 V, respectively (versus Ag/AgCl reference electrode), which enabled a highly selective detection of the three analytes. Electrochemical impedance spectrum tests showed a significant decrease in charge transfer resistance with the AuNS/SPCE (0.8 kΩ) compared with bare SPCE (2.4 kΩ). Cyclic voltammetry experiments showed a significant increase in electroactive surface area with electrode modification. The low charge transfer resistance and high electroactive surface area contributed to the high sensitivity for Cd2+ (0.0767 µA (0.225 µg L-1)-1), As3+ (0.2213 µA (µg L-1)-1), and Se4+ (µA (µg L-1)-1). The three analytes had linear stripping responses over the concentration range of 0 to 100 µg L-1, with the obtained LoD for Cd2+, As3+, and Se4+ of 1.6, 0.8, and 1.6 µg L-1, respectively. In comparison with individual detection, the simultaneous detection of As3+ and Se4+ showed peak height reductions of 40.8% and 42.7%, respectively. This result was associated with the possible formation of electrochemically inactive arsenic triselenide (As2Se3) during the preconcentration step. Surface water analysis resulted in average percent recoveries of 109% for Cd2+, 93% for As3+, and 92% for Se4+, indicating the proposed method is accurate and reliable for the simultaneous detection of Cd2+, As3+, and Se4+ in real water samples. Graphical abstract.

Voltammetric codetection of arsenic(III) and copper(II) in alkaline buffering system with gold nanostar modified electrodes.

One of the challenges preventing rapid, onsite voltammetric detection of arsenic(III) is the overlapping oxidation peak of copper(II). This paper describes a novel methodology for the voltammetric detection of trace levels of arsenic(III) in the presence of high copper(II) concentrations (up to the action level of 1.3 mg L-1 set by the US EPA for drinking water). Square wave stripping voltammetry tests were performed using disposable carbon screen printed electrodes modified with gold nanostars on samples buffered with Britton-Robinson buffer. The optimized parameters for accurate codetection of arsenic(III) and copper(II) were a buffer pH of 9.5, a loading of gold nanostars of 2.39*10-5 nmol per electrode, a deposition voltage of -0.8 V, and a deposition time of 180 s. Based on calibration testing, the limits of detection for arsenic(III) and copper(II) were determined to be 2.9 µg L-1 and 42.5 µg L-1, respectively. Furthermore, the linear ranges for arsenic and copper were 0-100 µg L-1 and 0-250 µg L-1 with sensitivities of 0.101 µA (µg L-1)-1 and 0.121 µA (µg L-1)-1, respectively. Interference testing was performed with several common ionic species, sodium bicarbonate, sodium chloride, tannic acid, iron(iii) chloride, magnesium chloride, calcium nitrate, and sodium sulfate, with only sodium bicarbonate significantly affecting the response. Validation testing in real-world samples was performed by comparison with graphite furnace atomic absorption spectroscopy. The validation testing demonstrated good accuracy and precision, expressed as percent recovery and relative standard deviation (RSD), respectively, in river water and tap water, with mean percent recoveries of 87.7% (RSD = 4.20%) and 83.2% (RSD = 10.02%), respectively.

A Microfluidic Perfusion Platform for In Vitro Analysis of Drug Pharmacokinetic-Pharmacodynamic (PK-PD) Relationships.

Static in vitro cell culture studies cannot capture the dynamic concentration profiles of drugs, nutrients, and other factors that cells experience in physiological systems. This limits the confidence in the translational relevance of in vitro experiments and increases the reliance on empirical testing of exposure-response relationships and dose optimization in animal models during preclinical drug development, introducing additional challenges owing to species-specific differences in drug pharmacokinetics (PK) and pharmacodynamics (PD). Here, we describe the development of a microfluidic cell culture device that enables perfusion of cells under 2D or 3D culture conditions with temporally programmable concentration profiles. Proof-of-concept studies using doxorubicin and gemcitabine demonstrated the ability of the microfluidic PK-PD device to examine dose- and time-dependent effects of doxorubicin as well as schedule-dependent effects of doxorubicin and gemcitabine combination therapy on cell viability using both step-wise drug concentration profiles and species-specific (i.e., mouse, human) drug PK profiles. The results demonstrate the importance of including physiologically relevant dynamic drug exposure profiles during in vitro drug testing to more accurately mimic in vivo drug effects, thereby improving translatability across nonclinical studies and reducing the reliance on animal models during drug development.

Team Approach: Evaluation and Management of Low-Grade Cartilaginous Lesions.

¼ Assessment of chondral lesions begins with a clinical evaluation and radiographs. ¼ Longitudinal follow-up with serial radiographs is appropriate in cases without evidence of aggressive radiographic features. ¼ Concerning radiographic features include periosteal reaction, soft-tissue extension, cortical destruction, endosteal scalloping of greater than two-thirds of the native cortex, larger lesion size (≥5 cm), and location in the axial skeleton. ¼ Biomarkers such as IMP3, SOX4, microRNA, and periostin may be used as an adjunct in histologic assessment to help differentiate benign enchondroma from a low-grade chondrosarcoma. ¼ Advanced-imaging studies, such as computed tomography (CT), bone scans, magnetic resonance imaging (MRI), dynamic contrast-enhanced MRI, and fluorodeoxyglucose positron emission tomography (FDG-PET), may be considered for borderline cases. ¼ Aggressive or concerning radiographic features should prompt evaluation with advanced imaging or referral to an orthopaedic oncologist.