Relapsing malignant phyllodes tumour presenting as isolated acrometastases.

Malignant phyllodes tumours (PTs) are aggressive neoplasms with high rates of local recurrence and distant metastasis. With no known effective chemotherapy and no approved targeted therapy in the setting of metastatic disease, prognosis is limited with an often-relapsing course of disease. We report a case of a woman in her late 30s with a diagnosis of recurrent metastatic malignant PT who was found to have acrometastases of the malignant PT to the right distal index and small digits. We emphasise the potential for atypical patterns of metastases in patients with malignant PT and the need to recognise acrometastasis as an unusual but morbid manifestation of disease. Given the high growth rate of malignant PTs, the lack of systemic treatment options, and the ensuing distress for patients, prompt diagnosis and early intervention is crucial.

Examining effects of a novel estrogenic perfluoro-alcohol, 1H,1H,8H,8H-Perfluorooctane-1,8-diol (FC8-diol), using the fathead minnow EcoToxChip.

In a previous in vivo study, adult male fathead minnows (Pimephales promelas) were exposed via water for 4 days to 1H,1H,8H,8H-perfluorooctane-1,8-diol (FC8-diol). The present study expands on the evaluation of molecular responses to this perfluoro-alcohol by analyzing 26 male fathead minnow liver RNA samples from that study (five from each test concentration: 0, 0.018, 0.051, 0.171, and 0.463 mg FC8-diol/L) using fathead minnow EcoToxChips Ver. 1.0. EcoToxChips are a quantitative polymerase chain reaction array that allows for simultaneous measurement of >375 species-specific genes of toxicological interest. Data were analyzed with the online tool EcoToxXplorer. Among the genes analyzed, 62 and 96 were significantly up- and downregulated, respectively, by one or more FC8-diol treatments. Gene expression results from the previous study were validated, showing an upregulation of vitellogenin mRNA (vtg) and downregulation of insulin-like growth factor 1 mRNA (igf1). Additional genes related to estrogen receptor activation including esr2a (estrogen receptor 2a) and esrrb (estrogen related receptor beta) were also affected, providing further confirmation of the estrogenic nature of FC8-diol. Furthermore, genes involved in biological pathways related to lipid and carbohydrate metabolism, innate immune response, endocrine reproduction, and endocrine thyroid were significantly affected. These results both add confidence in the use of the EcoToxChip tool for inferring chemical mode(s) of action and provide further insights into the possible biological effects of FC8-diol. Environ Toxicol Chem 2024;00:1-9. © 2024 SETAC. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

Financial Incentives for Smoking Cessation Among Socioeconomically Disadvantaged Adults: A Randomized Clinical Trial.

Importance: Socioeconomically disadvantaged individuals (ie, those with low socioeconomic status [SES]) have difficulty quitting smoking and may benefit from incentive-based cessation interventions. Objectives: To evaluate the impact of incentivizing smoking abstinence on smoking cessation among adults with low SES. Design, Setting, and Participants: This study used a 2-group randomized clinical trial design. Data collection occurred between January 30, 2017, and February 7, 2022. Participants included adults with low SES who were willing to undergo smoking cessation treatment. Data were analyzed from April 18, 2023, to April 19, 2024. Interventions: Participants were randomized to usual care (UC) for smoking cessation (counseling plus pharmacotherapy) or UC plus abstinence-contingent financial incentives (UC plus FI). Main Outcomes and Measures: The primary outcome was biochemically verified 7-day point prevalence smoking abstinence (PPA) at 26 weeks after the quit date. Secondary outcomes included biochemically verified 7-day PPA at earlier follow-ups, 30-day PPA at 12 and 26 weeks, repeated 7-day PPA, and continuous abstinence. Multiple approaches were employed to handle missing outcomes at follow-up, including categorizing missing data as smoking (primary), complete case analysis, and multiple imputation. Results: The 320 participants had a mean (SD) age of 48.9 (11.6) and were predominantly female (202 [63.1%]); 82 (25.6%) were Black, 15 (4.7%) were Hispanic, and 200 (62.5%) were White; and 146 (45.6%) participated during the COVID-19 pandemic. Overall, 161 were randomized to UC and 159 were randomized to UC plus FI. After covariate adjustment with missing data treated as smoking, assignment to UC plus FI was associated with a greater likelihood of 7-day PPA at the 4-week (adjusted odds ratio [AOR], 3.11 [95% CI, 1.81-5.34]), 8-week (AOR, 2.93 [95% CI, 1.62-5.31]), and 12-week (AOR, 3.18 [95% CI, 1.70-5.95]) follow-ups, but not at the 26-week follow-up (22 [13.8%] vs 14 [8.7%] abstinent; AOR, 1.79 [95% CI, 0.85-3.80]). However, the association of group assignment with smoking cessation reached statistical significance at all follow-ups, including 26 weeks, with multiple imputation (37.37 [23.5%] in the UC plus FI group vs 19.48 [12.1%] in the UC group were abstinent; AOR, 2.29 [95% CI, 1.14-4.63]). Repeated-measures analyses indicated that participants in the UC plus FI group were significantly more likely to achieve PPA across assessments through 26 weeks with all missing data estimation methods. Other secondary cessation outcomes also showed comparable patterns across estimation methods. Participants earned a mean (SD) of $72 ($90) (of $250 possible) in abstinence-contingent incentives. Participation during the COVID-19 pandemic reduced the likelihood of cessation across assessments. Conclusions and Relevance: In this randomized clinical trial, incentivizing smoking cessation did not increase cessation at 26 weeks when missing data were treated as smoking; however, the UC plus FI group had greater odds of quitting at follow-ups through 12 weeks. Cessation rates were higher for the UC plus FI group at all follow-ups through 26 weeks when multiple imputation was used to estimate missing outcomes. Trial Registration: ClinicalTrials.gov Identifier: NCT02737566.

Bacteroides expand the functional versatility of a universal transcription factor and transcribed DNA to program capsule diversity.

Human gut Bacteroides species encode numerous (eight or more) tightly regulated capsular polysaccharides (CPS). Specialized paralogs of the universal transcription elongation factor NusG, called UpxY (Y), and an anti-Y UpxZ (Z) are encoded by the first two genes of each CPS operon. The Y-Z regulators combine with promoter inversions to limit CPS transcription to a single operon in most cells. Y enhances transcript elongation whereas Z inhibits noncognate Ys. How Y distinguishes among cognate CPS operons and how Z inhibits only noncognate Ys are unknown. Using in-vivo nascent-RNA sequencing and p romoter-less in v itr o transcription (PIVoT), we establish that Y recognizes a paused RNA polymerase via sequences in both the exposed non-template DNA and the upstream duplex DNA. Y association is aided by novel 'pause-then-escape' nascent RNA hairpins. Z binds non-cognate Ys to directly inhibit Y association. This Y-Z hierarchical regulatory program allows Bacteroides to create CPS subpopulations for optimal fitness.

Adolescent Alcohol Exposure Promotes Mechanical Allodynia and Alters Synaptic Function at Inputs from the Basolateral Amgydala to the Prelimbic Cortex.

Binge drinking is common among adolescents despite mounting evidence linking it to various adverse health outcomes that includes heightened pain perception. The prelimbic (PrL) cortex is vulnerable to insults from adolescent alcohol exposure and receives input from the basolateral amygdala (BLA) while sending projections to the ventrolateral periaqueductal gray (vlPAG) - two brain regions implicated in nociception. In this study, adolescent intermittent ethanol (AIE) exposure was carried out in male and female rats using a vapor inhalation procedure. Mechanical and thermal sensitivity, assessed throughout adolescence and into adulthood, revealed that AIE exposure induced protracted mechanical allodynia in both male and female rats. However, a carrageenan inflammatory paw pain challenge in adult rats revealed that AIE did not further augment carrageenan-induced hyperalgesia. To investigate synaptic function at BLA inputs onto defined populations of PrL neurons, retrobeads and viral labelling were combined with optogenetics and slice electrophysiology. Recordings from retrobead labelled cells in the PrL revealed AIE reduced BLA driven feedforward inhibition of neurons projecting from the PrL to the vlPAG (PrL PAG neurons), resulting in augmented excitation/inhibition (E/I) balance and increased intrinsic excitability. Consistent with this finding, recordings from virally tagged PrL parvalbumin interneurons (PVINs) demonstrated that AIE exposure reduced both E/I balance at BLA inputs onto PVINs and PVIN intrinsic excitability when assessed in adulthood. These findings provide compelling evidence that AIE and acute pain alter synaptic function and intrinsic excitability within a prefrontal nociceptive circuit.

Lesions Causing Alice in Wonderland Syndrome Map to a Common Brain Network Linking Body and Size Perception.

OBJECTIVE: Alice in Wonderland syndrome (AIWS) profoundly affects human perception of size and scale, particularly regarding one's own body and the environment. Its neuroanatomical basis has remained elusive, partly because brain lesions causing AIWS can occur in different brain regions. Here, we aimed to determine if brain lesions causing AIWS map to a distributed brain network. METHODS: A retrospective case-control study analyzing 37 cases of lesion-induced AIWS identified through systematic literature review was conducted. Using resting-state functional connectome data from 1,000 healthy individuals, the whole-brain connections of each lesion were estimated and contrasted with those from a control dataset comprising 1,073 lesions associated with 25 other neuropsychiatric syndromes. Additionally, connectivity findings from lesion-induced AIWS cases were compared with functional neuroimaging results from 5 non-lesional AIWS cases. RESULTS: AIWS-associated lesions were located in various brain regions with minimal overlap (≤33%). However, the majority of lesions (≥85%) demonstrated shared connectivity to the right extrastriate body area, known to be selectively activated by viewing body part images, and the inferior parietal cortex, involved in size and scale judgements. This pattern was uniquely characteristic of AIWS when compared with other neuropsychiatric disorders (family-wise error-corrected p < 0.05) and consistent with functional neuroimaging observations in AIWS due to nonlesional causes (median correlation r = 0.56, interquartile range 0.24). INTERPRETATION: AIWS-related perceptual distortions map to one common brain network, encompassing regions critical for body representation and size-scale processing. These findings lend insight into the neuroanatomical localization of higher-order perceptual functions, and may inform future therapeutic strategies for perceptual disorders. ANN NEUROL 2024.

Clinical pathway development to standardize pharmacological medication management of agitation in pediatric inpatient settings.

Objective: Acute agitation in pediatrics is commonly encountered in hospital settings, can contribute to significant physical and psychological distress, and management is highly varied in practice. As such, the development of a standardized pharmacologic guideline is paramount. We aimed to develop a novel clinical pathway (CP) for management of acute agitation for all hospitalized pediatric patients in Canada. Methods: Healthcare professionals in Canada with expertise in treating and managing pediatric agitation formed a working group and developed a CP through conducting a literature review, engaging key partners, and obtaining interdisciplinary consensus (iterative real-time discussions with content experts). Once developed, the preliminary CP was presented to additional internal and external partners via multiple grand rounds and a webinar; feedback from participants guided final CP revisions. Results: The working group created a pediatric inpatient CP to guide pharmacologic management of agitation and serve as an easy-to-use clinical and educational resource with three complementary sections including: 1) a treatment algorithm, 2) a quick reference medication chart, and 3) two supporting documents, which provide a general overview of non-pharmacologic strategies prior to CP implementation and an illustrative scenario to accompany the medication chart to ensure effective utilization. Conclusions: This is the first CP to standardize pharmacological treatment and management of acute agitation in children in inpatient settings in Canada. Although further research is warranted to assess implementation and support process improvement, the CP can be adapted by individual institutions to assist in prompt pharmacological management of pediatric agitation to potentially improve outcomes for patients, families, and healthcare professionals.

Objectif: L'agitation aiguë en pédiatrie survient couramment en milieu hospitalier, elle peut contribuer à une détresse physique et psychologique significative, et la prise en charge en est très variée dans la pratique. Ainsi, l'élaboration de lignes directrices pharmacologiques standardisées est essentielle. Nous cherchions à développer un nouveau parcours clinique (PC) de la prise en charge de l'agitation aiguë pour tous les patients pédiatriques hospitalisés au Canada. Méthodes: Les professionnels de la santé au Canada qui ont l'expertise du traitement et de la prise en charge de l'agitation pédiatrique ont formé un groupe de travail et développé un PC en menant une revue littéraire, en embauchant des partenaires cibles, et en obtenant un consensus interdisciplinaire (discussions itératives en temps réel avec des experts en contenu). Une fois développé, le PC préliminaire a été présenté à des partenaires internes et externes additionnels lors de multiples grandes rondes et à un webinaire; les commentaires des participants ont guidé les révisions finales du PC. Résultats: Le groupe de travail a créé un PC pour patient psychiatrique hospitalisé afin de guider la prise en charge pharmacologique de l'agitation et de servir de ressource clinique et éducative facile à utiliser munie de trois sections complémentaires notamment : 1) un algorithme de traitement, 2) un tableau des médicaments de référence, et 3) deux documents de soutien, qui offrent un aperçu général de stratégies non-pharmacologiques avant la mise en œuvre du PC et un scénario illustré pour accompagner le tableau des médicaments afin d'assurer une utilisation efficace. Conclusions: C'est le premier PC qui normalise le traitement pharmacologique et la prise en charge de l'agitation aiguë chez les enfants en milieu hospitalier au Canada. Bien que plus de recherche soit justifiée afin d'évaluer la mise en œuvre et de soutenir l'amélioration du processus, le PC peut être adapté par les institutions individuelles afin d'aider à une gestion pharmacologique rapide de l'agitation pédiatrique et de potentiellement aider à la gestion pharmacologique de l'agitation pédiatrique pour les patients, les familles et les professionnels de la santé.

Thiourea-functionalized aminoglutethimide derivatives as anti-leishmanial agents.

Aim: We aim to develop new anti-leishmanial agents against Leishmania major and Leishmania tropica. Materials & methods: A total of 23 thiourea derivatives of (±)-aminoglutethimide were synthesized and evaluated for in vitro activity against promastigotes of L. major and L. tropica. Results & conclusion: The N-benzoyl analogue 7p was found potent (IC50 = 12.7 µM) against L. major and non toxic to normal cells. The docking studies, indicates that these inhibitors may target folate and glycolytic pathways of the parasite. The N-hexyl compound 7v was found strongly active against both species, and lacked cytotoxicity against normal cells, whereas compound 7r, with a 3,5-bis-(tri-fluoro-methyl)phenyl unit, was active against Leishmania, but was cytotoxic in nature. Compound 7v was thus identified as a hit for further studies.

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Effects of ondansetron on symptoms during a gastric emptying study and enteral lipid challenge and on daily symptoms in diabetic gastroenteropathy.

BACKGROUND: This study compared the effects of ondansetron and placebo in patients with diabetes mellitus and symptoms of dyspepsia (diabetic gastroenteropathy [DGE]). METHODS: We performed a randomized, double-blinded, placebo-controlled study of ondansetron tablets (8 mg) three times daily for 4 weeks in DGE patients. Symptoms were assessed with the Gastroparesis Cardinal Symptom Index daily diaries. Gastric emptying (GE) of solids (scintigraphy) and duodenal lipid infusions (300 kcal over 2 h) were each assessed twice, with placebo and ondansetron. Drug effects on GE, symptoms during the GE study and during lipid infusion, and daily symptoms were analyzed. KEY RESULTS: Of 41 patients, 37 completed both GE studies and one completed 1; 31 completed both lipid infusions and four only placebo; and all 35 randomized patients completed 4 weeks of treatment. Compared to placebo, ondansetron reduced the severity of fullness (p = 0.02) and belching (p = 0.049) during lipid infusion but did not affect GE T1/2. Both ondansetron and placebo improved daily symptoms versus the baseline period (p < 0.05), but the differences were not significant. In the analysis of covariance of daily symptoms during the treatment period, the interaction term between treatment and the acute effect of ondansetron on symptoms during lipid challenge was significant (p = .024). CONCLUSIONS & INFERENCES: Ondansetron significantly reduced fullness during enteral lipid infusion in patients with DGE. Overall, ondansetron did not improve daily symptoms versus placebo. But patients in whom ondansetron improved symptoms during enteral lipid challenge were perhaps more likely to experience symptom relief during daily treatment.

Does the Addition of Oral Sampling Improve Waveform Capnography When Compared to Traditional Nasal Sampling in Open-Airway Patients?

BACKGROUND: End-tidal carbon dioxide (EtCO2) is an invaluable anesthesia measure due to minimal delay in monitoring ventilation. Oral and Maxillofacial Surgery (OMS) presents special challenges because oral exhalations are not sampled effectively via nasal cannula normally used to avoid interfering with procedures. PURPOSE: The purpose of the study was to compare EtCO2 waveforms obtained in subjects using nasal monitoring and combined nasal and oral monitoring under simulated ventilatory conditions. STUDY DESIGN, SETTING, SAMPLE: A single-blinded, randomized crossover controlled study was conducted at the University of Illinois Chicago with healthy volunteers, who were blinded to the monitoring system used. Inclusion criteria required subjects be ≥ 18 years of age, be consentable, and English-speaking. Exclusion criteria required no airway abnormalities, no edentulism, and no conditions that preclude undergoing an OMS procedure under sedation. PREDICTOR VARIABLE: The primary predictor variable was the EtCO2 monitoring system: nasal with a standard nasal cannula, and combined with a nasal cannula and oral device. The secondary predictor variable evaluated 3 ventilatory states (nasal breathing, oral breathing, and apnea) in each arm, standardizing by maintaining consistent breath counts across observation periods. MAIN OUTCOME VARIABLE: The main outcome variable was the number of waveforms recorded over 30 seconds for nasal and combined monitoring. Each recording was standardized by dividing it by the baseline waveforms and multiplying by 20. Higher values, closer to baseline, were considered more accurate depictions of ventilation. COVARIATES: Covariates were body mass index (BMI), age, sex, Mallampati score, and breathing method. ANALYSES: Analysis of variance, analysis of covariance, and multivariate analysis of variance were performed. P value < .05 was considered statistically significant. RESULTS: The sample included 25 subjects (18 male and 7 female) with mean age 29.9 ± 7.98 years and BMI 23.9 ± 3.51 kg/m2. Combined sampling detected more waveforms during nasal and oral breathing (P < .001). Higher BMI correlated with reduced waveform capture during nasal sampling in oral breathing (P = .013). Combined sampling detected more waveforms during nasal breathing (P = .005) in subjects with BMI < 23.5 kg/m2. Mallampati score correlated with increased waveforms during nasal breathing. CONCLUSION AND RELEVANCE: Oral EtCO2 sampling may improve accuracy of capnography waveform capture. Further clinical studies in sedated subjects undergoing OMS procedures are needed.

Human plasma cells engineered to secrete bispecifics drive effective in vivo leukemia killing.

Bispecific antibodies are an important tool for the management and treatment of acute leukemias. As a next step toward clinical translation of engineered plasma cells, we describe approaches for secretion of bispecific antibodies by human plasma cells. We show that human plasma cells expressing either fragment crystallizable domain-deficient anti-CD19 × anti-CD3 (blinatumomab) or anti-CD33 × anti-CD3 bispecific antibodies mediate T cell activation and direct T cell killing of B acute lymphoblastic leukemia or acute myeloid leukemia cell lines in vitro. We demonstrate that knockout of the self-expressed antigen, CD19, boosts anti-CD19-bispecific secretion by plasma cells and prevents self-targeting. Plasma cells secreting anti-CD19-bispecific antibodies elicited in vivo control of acute lymphoblastic leukemia patient-derived xenografts in immunodeficient mice co-engrafted with autologous T cells. In these studies, we found that leukemic control elicited by engineered plasma cells was similar to CD19-targeted chimeric antigen receptor-expressing T cells. Finally, the steady-state concentration of anti-CD19 bispecifics in serum 1 month after cell delivery and tumor eradication was comparable with that observed in patients treated with a steady-state infusion of blinatumomab. These findings support further development of ePCs for use as a durable delivery system for the treatment of acute leukemias, and potentially other cancers.

Pharmacokinetic-pharmacodynamic modelling and simulation of methotrexate dosing in patients with rheumatoid arthritis.

AIMS: To develop a non-linear mixed-effects population pharmacokinetic and pharmacodynamic (PK-PD) model describing the change in the concentration of methotrexate polyglutamates in erythrocytes (ery-MTX-PGn with "n" number of glutamate, representing PK component) and how this relates to modified 28-joint Disease Activity Score incorporating erythrocyte sedimentation rate (DAS-28-3) for rheumatoid arthritis (RA), representing PD component. METHODS: An existing PK model was fitted to data from a study consisting of 117 RA patients. The estimation of population PK-PD parameters was performed using stochastic approximation expectation maximisation algorithm in Monolix 2021R2. The model was used to perform Monte Carlo simulations of a loading dose regimen (50mg subcutaneous methotrexate as loading doses, then 20mg weekly oral methotrexate) compared to a standard dosing regimen (10mg weekly oral methotrexate for 2 weeks, then 20mg weekly oral methotrexate). RESULTS: Every 40 nmol/L increase in ery-MTX-PG3-5 total concentration correlated with 1-unit reduction in DAS-28-3. Significant covariate effects on the therapeutic response of methotrexate included the use of prednisolone in the first 4 weeks (positive use correlated with 25% reduction in DAS-28-3 when other variables were constant) and patient age (every 10-year increase in age correlated with 3.4% increase in DAS-28-3 when other variables were constant). 4 methotrexate loading doses led to a higher percentage of patients achieving a good/moderate response compared to the standard regimen (Week 4: 87.6% vs. 39.8%; Week 10: 64.7% vs. 57.0%). CONCLUSIONS: A loading dose regimen was more likely to achieve higher ery-MTX-PG concentration and better therapeutic response after 4 weeks of methotrexate treatment.

Curating an online checklist for Erica L. (Ericaceae): contributing to and supporting global conservation through the World Flora Online.

To support the work of the Global Conservation Consortium for Erica and update the Erica checklist in the World Flora Online (WFO), we have curated the taxonomic backbone in the WFO by expanding it to include updated nomenclatural information from the International Plant Name Index, missing names present in the World Checklist of Vascular Plants (WCVP), the Botanical Database of Southern Africa (BODATSA), and from the "International register of heather names" database, a data source not readily available online. The result is the most robust database of Erica names to date, including 851 species, 111 subspecies, 244 varieties, and 2787 synonyms, which is a reliable reference for initiatives such as the Erica identification aid, conservation prioritisation, and gap analyses. We disambiguate common orthographic variants within the database and present an overview of these. We also comment on the correct orthography of E.heleophila Guthrie & Bolus and E.michellensis Dulfer and the validity of E.tegetiformis E.G.H.Oliv. are discussed, and the use of E.adunca Benth. for a South African species rather than E.triceps Link, which is here regarded as insufficiently known and of uncertain application, is clarified.

Human Factors Validation of a Wearable, On-Body Infusor for Subcutaneous Administration of Furosemide.

Purpose: Furoscix® (subcutaneous furosemide) is administered using a wearable On-Body Infusor (OBI) and is approved for the treatment of congestion associated with heart failure (HF). The purpose of this study was to assess the safe and effective use of the OBI and Instructions for Use (IFU) by patients with HF, caregivers, and healthcare practitioners (HCPs). Methods: Sixty participants (patients, n=30; caregivers, n=15; HCPs, n=15) were evaluated on completion of OBI use tasks and IFU knowledge tasks in a simulated use environment. Fifteen of the patients received OBI/IFU training before evaluation. Results: Overall, 893/900 (99.2%) use tasks and 2211/2220 (99.6%) knowledge tasks were completed successfully, without differences due to training. The most common (n=6) use error was failure to wipe skin or cartridge tip with an alcohol wipe. Errors were due to forgetfulness/misinterpretation rather than IFU clarity. Conclusion: The subcutaneous furosemide OBI can be safely and effectively used by patients, caregivers, and HCPs, regardless of training.

DNA Hierarchical Superstructures from Micellar Units: Stiff Hydrogels and Anisotropic Nanofibers.

Supramolecular materials have been assembled using a wide range of interactions, including the hydrophobic effect, DNA base-pairing, and hydrogen bonding. Specifically, DNA amphiphiles with a hydrophobic building block self-assemble into diverse morphologies depending on the length and composition of both blocks. Herein, we take advantage of the orthogonality of different supramolecular interactions - the hydrophobic effect, Watson-Crick-Franklin base pairing and RNA kissing loops - to create hierarchical self-assemblies with controlled morphologies on both the nanometer and the micrometer scales. Assembly through base-pairing leads to the formation of hybrid, multi-phasic hydrogels with high stiffness and self-healing properties. Assembly via hydrophobic core interactions gives anisotropic, discrete assemblies, where DNA fibers with one sequence are terminated with DNA spheres bearing different sequences. This work opens new avenues for the bottom-up construction of DNA-based materials, with promising applications in drug delivery, tissue engineering, and the creation of complex DNA structures from a minimum array of components.

Postsurgical Pain Risk Stratification to Enhance Pain Management Workflow in Adult Patients: Design, Implementation, and Pilot Evaluation.

BACKGROUND: Exposure to opioids after surgery is the initial contact for some people who develop chronic opioid use disorder. Hence, effective postoperative pain management, with less reliance on opioids, is critical. The Perioperative Opioid Quality Improvement (POQI) program developed (1) a digital health platform leveraging patient-survey-reported risk factors and (2) a postsurgical pain risk stratification algorithm to personalize perioperative care by integrating several commercially available digital health solutions into a combined platform. Development was reduced in scope by the COVID-19 pandemic. OBJECTIVE: This pilot study aims to assess the screening performance of the risk algorithm, quantify the use of the POQI platform, and evaluate clinicians' and patients' perceptions of its utility and benefit. METHODS: A POQI platform prototype was implemented in a quality improvement initiative at a Canadian tertiary care center and evaluated from January to September 2022. After surgical booking, a preliminary risk stratification algorithm was applied to health history questionnaire responses. The estimated risk guided the patient assignment to a care pathway based on low or high risk for persistent pain and opioid use. Demographic, procedural, and medication administration data were extracted retrospectively from the electronic medical record. Postoperative inpatient opioid use of >90 morphine milligram equivalents per day was the outcome used to assess algorithm performance. Data were summarized and compared between the low- and high-risk groups. POQI use was assessed by completed surveys on postoperative days 7, 14, 30, 60, 90, and 120. Semistructured patient and clinician interviews provided qualitative feedback on the platform. RESULTS: Overall, 276 eligible patients were admitted for colorectal procedures. The risk algorithm stratified 203 (73.6%) as the low-risk group and 73 (26.4%) as the high-risk group. Among the 214 (77.5%) patients with available data, high-risk patients were younger than low-risk patients (age: median 53, IQR 40-65 years, vs median 59, IQR 49-69 years, median difference five years, 95% CI 1-9; P=.02) and were more often female patients (45/73, 62% vs 80/203, 39.4%; odds ratio 2.5, 95% CI 1.4-4.5; P=.002). The risk stratification was reasonably specific (true negative rate=144/200, 72%) but not sensitive (true positive rate=10/31, 32%). Only 39.7% (85/214) patients completed any postoperative quality of recovery questionnaires (only 14, 6.5% patients beyond 60 days after surgery), and 22.9% (49/214) completed a postdischarge medication survey. Interviewed participants welcomed the initiative but noted usability issues and poor platform education. CONCLUSIONS: An initial POQI platform prototype was deployed operationally; the risk algorithm had reasonable specificity but poor sensitivity. There was a significant loss to follow-up in postdischarge survey completion. Clinicians and patients appreciated the potential impact of preemptively addressing opioid exposure but expressed shortcomings in the platform's design and implementation. Iterative platform redesign with additional features and reevaluation are required before broader implementation.

Improving assay feasibility and biocompatibility of 3D cyclic olefin copolymer microwells by superhydrophilic modification via ultrasonic spray deposition of polyvinyl alcohol.

Sample partitioning is a crucial step towards digitization of biological assays on polymer microfluidic platforms. However, effective liquid filling into microwells and long-term hydrophilicity remain a challenge in polymeric microfluidic devices, impeding the applicability in diagnostic and cell culture studies. To overcome this, a method to produce permanent superhydrophilic 3-dimensional microwells using cyclic olefin copolymer (COC) microfluidic chips is presented. The COC substrate is oxidized using UV treatment followed by ultrasonic spray coating of polyvinyl alcohol solution, offering uniform and long-term coating of high-aspect ratio microfeatures. The coated COC surfaces are UV-cured before bonding with a hydrophobic pressure-sensitive adhesive to drive selective filling into the wells. The surface hydrophilicity achieved using this method remains unchanged (water contact angle of 9°) for up to 6 months and the modified surface is characterized for physical (contact angle & surface energy, morphology, integrity of microfeatures and roughness), chemical composition (FTIR, Raman spectroscopy) and coating stability (pH, temperature, time). To establish the feasibility of the modified surface in biological applications, PVA-coated COC microfluidic chips are tested for DNA sensing (digital LAMP detection of CMV), and biocompatibility through protein adsorption and cell culture studies (cell adhesion, viability, and metabolic activity). Kidney and breast cells remained viable for the duration of testing (7 days) on this modified surface, and the coating did not affect the protein content, morphology or quality of the cultured cells. The ultrasonic spray coated system, coating with 0.25 % PVA for 15 cycles with 0.12 A current after UV oxidation, increased the surface energy of the COC (naturally hydrophobic) from 22.04 to 112.89 mJ/m2 and improved the filling efficiency from 40 % (native untreated COC) to 94 % in the microwells without interfering with the biocompatibility of the surface, proving to be an efficient, high-throughput and scalable method of microfluidic surface treatment for diagnostic and cell growth applications.

Does a postmortem redistribution affect the concentrations of the 7 azaindole-derived synthetic cannabinoid 5F-MDMB-P7AICA in tissues and body fluids following pulmonary administration to pigs?

Many fatal intoxications have been reported in connection with the consumption of newer, highly potent synthetic cannabinoids. Yet, a possible postmortem redistribution (PMR) might complicate reliable interpretation of analytical results. Thus, it is necessary to investigate the PMR-potential of new synthetic cannabinoids. The pig model has already proven to be suitable for this purpose. Hence, the aim of this study was to study the PMR of the synthetic cannabinoid 5F-MDMB-P7AICA and its main metabolite 5F-MDMB-P7AICA-dimethylbutanoic acid (DBA). 5F-MDMB-P7AICA (200 µg/kg body weight) was administered by inhalation to anesthetized and ventilated pigs. At the end of the experiment, the animals were euthanized and stored at room temperature for 3 days. Tissue and body fluid samples were taken daily. Specimens were analyzed after solid phase extraction using a standard addition method and LC-MS/MS, blood was quantified after protein precipitation using a validated method. In perimortem samples, 5F-MDMB-P7AICA was found mainly in adipose tissue, bile fluid, and duodenum contents. Small amounts of 5F-MDMB-P7AICA were found in blood, muscle, brain, liver, and lung. High concentrations of DBA were found primarily in bile fluid, duodenum contents, urine, and kidney/perirenal fat tissue. In the remaining tissues, rather low amounts could be found. In comparison to older synthetic cannabinoids, PMR of 5F-MDMB-P7AICA was less pronounced. Concentrations in blood also appear to remain relatively stable at a low level postmortem. Muscle, kidney, fat, and duodenum content are suitable alternative matrices for the detection of 5F-MDMB-P7AICA and DBA, if blood specimens are not available. In conclusion, concentrations of 5F-MDMB-P7AICA and its main metabolite DBA are not relevantly affected by PMR.