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Background: Current treatment paradigms recommend surgical intervention when conventional medical management proves ineffective in resolving chronic rhinosinusitis with nasal polyposis., Objectives: To assess and compare the efficacy of dupilumab and functional endoscopic sinus surgery (FESS) for the treatment of chronic rhinosinusitis with nasal polyp (CRSwNP) over time., Methods: Studies comparing CRSwNP patients who received dupilumab with those who underwent FESS were included. Outcome measures included the nasal congestion score (NCS), Sino-nasal Outcome Test-22 (SNOT-22), University of Pennsylvania Smell Identification Test-40 (UPSIT-40), and nasal polyp score (NPS). The risk of bias was evaluated using the Newcastle-Ottawa Scale., Results: A total of 4 studies with 724 participants were included. The dupilumab group had a superior NCS, but an inferior NPS, compared to the FESS group during the follow-up period. The SNOT-22 score of the dupilumab group was inferior to that of the FESS group until 6 months posttreatment, but the scores were similar at around 1 year. A similar trend was observed for the UPSIT-40 score, but the score of the dupilumab group was higher at around 1 year., Conclusion: Functional endoscopic sinus surgery was more effective than dupilumab for several months after treatment. However, at 1 year after treatment, the effects of the 2 treatments became similar, with greater olfactory improvement seen in the dupilumab group., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objective: To evaluate the clinical efficacy of vidian neurectomy (VN) or posterior nasal neurectomy (PNN) combined with endoscopic sinus surgery (ESS) in patients with chronic rhinosinusitis with nasal polyps (CRSwNP)., Data Sources: A systematic search of six databases (PubMed, SCOPUS, Embase, Web of Science, Google Scholar, and Cochrane) was conducted to identify relevant studies up to May 2024., Review Methods: The effects of combining VN or PNN with ESS were evaluated in comparison to ESS alone. Outcomes were assessed by evaluating changes in Lund-Kennedy score, patient-reported symptom scores (VAS), quality of life, as well as adverse effects and recurrence rate of CRSwNP., Results: A total of 6 studies, comprising 407 patients, were included in the analysis. The neurectomy group showed significant improvements in Lund-Kennedy score (SMD = 0.7276 [0.5695; 0.8857]), with statistically significant improvements maintained at 6, 12, and 24 months postoperatively. The treatment group maintained better improvements in sinusitis-related quality of life (SMD = 0.4540 [0.1784; 0.7297]) and VAS (SMD = 0.7096 [0.4356; 0.9837]) until 12 months postoperatively, but not at 24 months. Regarding adverse effects, additional neurectomy did not significantly induce epistaxis (odds ratio [OR] = 0.9806 [0.2348; 4.0960]) or dry eye (OR = 2.4194 [0.1114; 52.5255]) compared to the control group. On the other hand, there was no difference in the recurrence rate of CRSwNP between the 2 groups during the follow-up periods., Conclusion: Additional neurectomy shows better efficacy in improving endoscopic findings and symptoms in patients with CRSwNP and appears to be a safe and effective treatment., (© 2024 American Academy of Otolaryngology–Head and Neck Surgery Foundation.)

Maintaining the differentiated phenotype and function of primary hepatocytes in vitro and in vivo represents a distinct challenge. Our paper describes microcapsules comprised of a bioactive polymer and overcoated with an ultrathin film as a means of maintaining the function of entrapped hepatocytes for at least two weeks. We previously demonstrated that heparin (Hep)-based microcapsules improved the function of entrapped primary hepatocytes by capturing and releasing cell-secreted inductive signals, including hepatocyte growth factor (HGF). Further enhancement of hepatic function could be gained by loading exogenous HGF into microcapsules. In this study, we demonstrate that an ultrathin coating of tannic acid (TA) further enhances endogenous HGF signaling for entrapped hepatocytes and increases by 2-fold the rate of uptake of exogenous HGF by Hep microcapsules. Hepatocytes in overcoated microcapsules exhibited better function and hepatic gene expression than in capsules without a TA coating. Our study showcases the potential application of ultrathin coatings to modulate the bioactivity of microcapsules and may enable the use of encapsulated hepatocytes for modeling drug toxicity or treating liver diseases.

Human pluripotent stem cells (hPSCs) represent an excellent cell source for regenerative medicine and tissue engineering applications. However, there remains a need for robust and scalable differentiation of stem cells into functional adult tissues. In this paper, we sought to address this challenge by developing magnetic microcapsules carrying hPSC spheroids. A co-axial flow-focusing microfluidic device was employed to encapsulate stem cells in core-shell microcapsules that also contained iron oxide magnetic nanoparticles (MNPs). These microcapsules exhibited excellent response to an external magnetic field and could be held at a specific location. As a demonstration of utility, magnetic microcapsules were used for differentiating hPSC spheroids as suspension cultures in a stirred bioreactor. Compared to standard suspension cultures, magnetic microcapsules allowed for more efficient media change and produced improved differentiation outcomes. In the future, magnetic microcapsules may enable better and more scalable differentiation of hPSCs into adult cell types and may offer benefits for cell transplantation., (© 2024. The Author(s).)

Objectives: To assess the safety and effectiveness of perioperative ibuprofen in pediatric tonsillectomy through a meta-analysis of relevant randomized controlled trials., Methods: We conducted a comprehensive review of studies available in PubMed, SCOPUS, Embase, Web of Science, and Cochrane databases up to June 2024. This analysis compared perioperative ibuprofen administration to control groups (saline, acetaminophen, or opioids). Outcomes assessed were postoperative pain management, as indicated by the frequency of analgesic use, and morbidity rates, which included the incidence of postoperative nausea and vomiting and post-tonsillectomy hemorrhage (PTH). PTH was further categorized as primary (occurring on the day of operation) or secondary (occurring after the day of operation), and classified as type 1 (observed at home or evaluated in the emergency department without further intervention), type 2 (requiring readmission for observation), or type 3 (necessitating a return to the operating room for hemorrhage control)., Results: This analysis included nine studies involving a total of 1545 patients. Incidences of primary PTH (OR = 1.0949, 95 % CI [0.4169; 2.8755], I 2  = 0.0 %), secondary PTH (OR = 1.6433 95 % CI [0.7783; 3.4695], I 2  = 0.1 %), and overall PTH (OR = 1.4296 95 % CI [0.8383; 2.4378], I 2  = 0.0 %) were not significantly higher in the ibuprofen group than the control groups. Administration of ibuprofen led to a significant decrease in postoperative nausea and vomiting (OR = 0.4228 95 % CI [0.2500; 0.7150], I 2  = 40.0 %) and frequency of postoperative analgesic uptake (OR = 0.4734 95 % CI [0.2840; 0.7893]; I 2  = 19.8 %). There was no difference in bleeding by type between the ibuprofen and control groups., Conclusions: Our meta-analysis demonstrated that administration of ibuprofen for pediatric tonsillectomy did not significantly increase the incidence of postoperative bleeding but did decrease postoperative emesis and improve pain control., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background and Objectives : We investigated the effects of using a BiZact™ device for tonsillectomy on operating time, intraoperative blood loss, postoperative bleeding rate, and pain through a meta-analysis of the relevant literature. Materials and Methods : We reviewed studies retrieved from the databases of PubMed, SCOPUS, Google Scholar, Embase, Web of Science, and Cochrane up to March 2024. The results were analyzed following PRISMA guidelines. Six studies that compared the outcomes of patients receiving perioperative BiZact™ tonsillectomy with those in control groups (cold steel dissection or bipolar tonsillectomy) were included for this analysis of the outcomes, which included intraoperative bleeding and time, postoperative pain, and frequency of postoperative bleeding. Results : The operative time (SMD -11.5985, 95%CI [-20.3326; -2.8644], I 2 = 99.5%) in the treatment group was significantly reduced compared to the control group. However, BiZact™ showed no significant efficacy in reducing intraoperative bleeding when compared with the control group (SMD -0.0480, 95%CI [-1.8200; 1.7240], I 2 = 98.6%). Postoperative pain on day 1 (SMD -0.0885, 95%CI [-0.4368; 0.2598], I 2 = 98.9%), day 3 (SMD -0.2118, 95%CI [-0.6110; 0.1873], I 2 = 99.5%), and later than day 7 (SMD 0.0924, 95%CI [-0.2491; 0.4338], I 2 = 98.6%) in the treatment group was not significantly reduced relative to the control group. When compared to the control group, BiZact™ did not reduce the incidence of secondary postoperative bleeding control in the operation room (OR 0.5711, 95%CI [0.2476; 1.3173], I 2 = 32.1%), primary bleeding (OR 0.4514, 95%CI [0.0568; 3.5894], I 2 = 0.0%), or all postoperative bleeding events (OR 0.8117, 95%CI [0.5796; 1.1368], I 2 = 26.3%). Conclusions : This study demonstrated that using the BiZact™ device for tonsillectomy significantly decreased the operative time but could not effectively reduce intraoperative bleeding or postoperative pain and bleeding., Competing Interests: The authors declare no conflicts of interest.

Purpose: To assess the short-term effects of topical platelet-rich plasma (PRP) injection on persistent refractory olfactory dysfunction., Methods: A comprehensive literature search of the PubMed, SCOPUS, EMBASE, Web of Science, Google Scholar, and Cochrane databases was conducted for articles up to November 2023. The search focused on studies that compared the amelioration of olfactory dysfunction between a topical PRP treatment cohort and a control group (receiving either placebo or no treatment), along with pre- and post-treatment comparisons. Subgroup analysis of the evaluation of olfactory function was also performed., Results: The improvement in olfactory scores 1-3 months post-treatment (standardized mean difference = 1.5354 [95% confidence interval: 0.7992; 2.2716], I 2  = 83.8%) was greater in the treatment group than in the control group. In the treatment group, PRP increased the threshold, discrimination, and identification (TDI) score for Sniffin' Sticks by > 5.5 (minimum clinically significant difference; mean difference = 6.1789 [3.9788; 8.3789], I 2  = 0.0%), indicating clinically significant improvement based on verified examinations. The rate of significant improvement among patients was 0.6683 [0.5833; 0.7436] after treatment. All TDI subdomains were significantly and similarly improved after treatment., Conclusion: This meta-analysis suggests that injection of PRP into the olfactory fissure or surrounding mucosal areas is an effective treatment for persistent refractory olfactory dysfunction in the short term., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objectives: This study aimed to evaluate the safety and efficacy of perioperative ibuprofen administration by conducting a meta-analysis of pertinent literature., Methods: We conducted a comprehensive review of studies sourced from PubMed, SCOPUS, Embase, Web of Science, and Cochrane databases. The studies covered the period from database inception to June 2024. A perioperative ibuprofen administration group was compared to a control group administered either saline, acetaminophen, paracetamol, or opioids. The primary outcome was post-tonsillectomy bleeding that was categorized into overall bleeding and further classified as type 1 (observed at home or evaluated in the emergency department without additional intervention), type 2 (necessitating readmission for observation), and type 3 (requiring a return to the operating room for hemorrhage control). Morbidity incidence rates for postoperative nausea and vomiting were also assessed. The secondary outcomes assessed were postoperative pain management and the frequency of analgesic drug usage. Postoperative pain management was assessed from the incidence of emergency department visits or nurses' calls for pain independent of the presence or absence of dehydration., Results: Twenty-two studies with 27,149 patients were included and reviewed for this meta-analysis. Post-tonsillectomy bleeding (OR = 0.9954, 95 % CI [0.8800; 1.1260], I 2  = 0.0 %) was not significantly higher in the ibuprofen administration group compared to the control group. In subgroup analysis of post-tonsillectomy bleeding severity, ibuprofen caused clinically insignificant type 1 post-tonsillectomy bleeding that did not require intervention (OR = 1.1310 [0.7398; 1.7289]). Clinically significant bleeding requiring hospital admission (type 2) or surgical control (type 3) was not observed. Administration of ibuprofen has demonstrated efficacy in reducing the need for analgesic drugs (OR = 0.4734, 95 % CI [0.2840; 0.7893]; I 2  = 19.8 %) and is associated with a significant decrease in the incidence of postoperative nausea and vomiting (OR = 0.4886, 95 % CI [0.3156; 0.7562], I 2  = 34.3 %)., Conclusion: This study demonstrated that administration of ibuprofen for pediatric tonsillectomy did not increase the incidence of clinically significant postoperative bleeding. Ibuprofen administration decreased the incidence and severity of postoperative pain, nausea, and vomiting., Competing Interests: Declaration of competing interest None., (Copyright © 2024. Published by Elsevier Inc.)

Purpose: To compare the effects of doxycycline (DOX) and conventional management in patients with refractory chronic rhinosinusitis and nasal polyps (CRSwNP)., Methods: Six databases were searched to September 2023. We retrieved studies that compared improvements in refractory chronic sinusitis-related symptoms between DOX-treated and control groups., Results: DOX significantly reduced the Lund-Kennedy (LK) score [- 0.3670 (range - 0.6173; - 0.1166); I 2  = 92.8%], the nasal polyposis score [- 0.9484 (- 1.2287; - 0.6680); I 2  = 92.5%], the patient-reported Sinonasal Outcome Test (SNOT) score [- 0.3141 (- 0.4622; - 0.1660); I 2  = 91.2%], and the nasal obstruction score [- 0.1813 (- 0.3382; - 0.0243); I 2  = 86.2%]. On subgroup analyses by the measurement timepoints, the extent of nasal polyposis was significantly lower in the DOX group during treatment, at the end of treatment, and 4 and 8 weeks later. The LK scores also indicated improvements during treatment and at the end of treatment. The SNOT score tended to decrease with time in the treatment group. Nasal obstruction symptoms improved during treatment and 4 weeks later., Conclusion: DOX enhances the postoperative endoscopic outcomes of refractory CRSwNP patients by reducing recurrent polyposis and inflammation., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objectives: The primary aim of this study was to assess disparities in nasal nitric oxide (NO) levels between individuals diagnosed with eosinophilic chronic rhinosinusitis (ECRS) and those without ECRS. The second aim was to ascertain the comparative predictive efficacy of these nasal NO levels for the presence of ECRS., Methods: A systematic analysis was conducted on relevant studies that compared nasal NO levels in individuals with ECRS and those without. Furthermore, the discriminatory capacity of nasal NO in distinguishing ECRS from non-ECRS cohorts was quantified. The risk of bias across studies was evaluated utilizing the Newcastle-Ottawa scale., Results: The comprehensive review encompassed a total of 5 studies involving 470 participants. Findings revealed that patients diagnosed with ECRS exhibited significantly higher levels of nasal NO, as measured in parts per billion (ppb), compared to their non-ECRS patients. The mean difference was 130.03 ppb (95% confidence interval: [66.30, 193.75], I2 = 58.7%). The diagnostic odds ratio for nasal NO in identifying ECRS was 9.29 ([5.85, 14.75], I2 = 26.4%). The area under the summary receiver operating characteristic curve was 0.82. The correlation between sensitivity and false positive rate was 0.53, suggesting a lack of heterogeneity. Sensitivity, specificity, negative predictive value, and positive predictive value were 69% ([0.55, 0.79], I2   = 77.0%), 83% ([0.73, 0.90], I 2 = 68.5%), 77% ([0.69, 0.83], I 2   = 50.1%), and 75% ([0.67, 0.82], I 2   = 41.5%), respectively., Conclusion: Nasal NO has the potential as a noninvasive diagnostic measure and endotype tool for ECRS., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: We investigated the role of perioperative intraoral glossopharyngeal nerve block to minimize postoperative pain in patients undergoing tonsillectomy through a meta-analysis of the relevant literature., Methods: We retrieved eight studies from PubMed, Scopus, Embase, Web of Science, and Cochrane databases up to August 2023. We compared perioperative glossopharyngeal nerve block with a control group, in order to examine postoperative pain, analgesic use, and other postoperative morbidities., Results: Postoperative pain was significantly reduced at 1-4 h (SMD -1.26, 95% CI [-2.35; -0.17], I 2  = 94.7%, P = 0.02) and 5-8 hours (SMD -1.40, 95% CI [-2.47; -0.34], I 2  = 96.1%, p = 0.01) in the treatment groups compared to the control group. However, glossopharyngeal nerve block showed no efficacy in reducing pain or use of analgesic drugs after 12 h compared to the control group. The incidences of postoperative bleeding (OR 0.95, 95% CI [0.35; 2.52], I 2  = 0.0%), local agent toxicity (OR 4.14, 95% CI [0.44; 38.63], I 2  = 0.0%), nasal problems (OR 1.25, 95% CI [0.60; 2.61], I 2  = 0.0%), postoperative nausea and vomiting (OR 1.35, 95% CI [0.78; 2.33], I 2  = 0.0%), swallowing difficulty (OR 1.61, 95% CI [0.76; 3.42], I 2  = 56.0%), and voice change (OR 3.11, 95% CI [0.31; 30.80], I 2  = 0.0%) were not significantly different between the treatment and control groups. The treatment group showed higher prevalence of respiratory problems and dry mouth compared to control without statistical significance, but a significant increase in throat discomfort (p = 0.02)., Conclusion: Intraoral glossopharyngeal nerve block for tonsillectomy did not significantly impact postoperative pain management and was associated with some adverse effects with increases in respiratory problems, dry mouth, and throat discomfort compared to controls., (© 2024 Royal Australasian College of Surgeons.)

The Fusarium fungi is found in cereals and feedstuffs and may produce mycotoxins, which are secondary metabolites, such as the T-2 toxin (T-2). In this work, we explored the hepatotoxicity of T-2 using microfluidic 3D hepatic cultures. The objectives were: (i) exploring the benefits of microfluidic 3D cultures compared to conventional 3D cultures available commercially (Aggrewell plates), (ii) establishing 3D co-cultures of hepatic cells (HepG2) and stellate cells (LX2) and assessing T-2 exposure in this model, (iii) characterizing the induction of metabolizing enzymes, and (iv) evaluating inflammatory markers upon T-2 exposure in microfluidic hepatic cultures. Our results demonstrated that, in comparison to commercial (large-volume) 3D cultures, spheroids formed faster and were more functional in microfluidic devices. The viability and hepatic function decreased with increasing T-2 concentrations in both monoculture and co-cultures. The RT-PCR analysis revealed that exposure to T-2 upregulates the expression of multiple Phase I and Phase II hepatic enzymes. In addition, several pro- and anti-inflammatory proteins were increased in co-cultures after exposure to T-2.

Purpose: To investigate the molecular characteristics of and potential for precision medicine in KRAS wildtype pancreatic ductal adenocarcinoma (PDAC)., Patients and Methods: We investigated 27 patients with KRAS WT PDAC at our institution. Clinical data were obtained via chart review. Tumor specimens for each subject were interrogated for somatic single nucleotide variants, insertion and deletions, and copy number variants by DNA sequencing. Gene fusions were detected from RNA-seq. A patient-derived organoid (PDO) was developed from a patient with a MET translocation and expanded ex vivo to predict therapeutic sensitivity prior to enrollment in a phase 2 clinical trial., Results: Transcriptomic analysis showed our cohort may be stratified by the relative gene expression of the KRAS signaling cascade. The PDO derived from our patient harboring a TFG-MET rearrangement was found to have in vitro sensitivity to the multi-tyrosine kinase inhibitor crizotinib. The patient was enrolled in the phase 2 SPARTA clinical trial and received monotherapy with vebrelitinib, a c-MET inhibitor, and achieved a partial and durable response., Conclusions: KRAS WT PDAC is molecularly distinct from KRAS MUT and enriched with potentially actionable genetic variants. In our study, transcriptomic profiling revealed that the KRAS signaling cascade may play a key role in KRAS WT PDAC. Our report of a KRAS WT PDAC patient with TFG-MET rearrangement who responded to a cMET inhibitor further supports the pursuit of precision oncology in this sub-population. Identification of targetable mutations, perhaps through approaches like RNA-seq, can help enable precision-driven approaches to select optimal treatment based on tumor characteristics.

Objectives: In this study, we evaluated the associations between birth-related exposures, postnatal factors, and the risk of allergic rhinitis and asthma in children and adolescents., Methods: We performed a comprehensive search of five literature databases up to May 2023. To quantify the associations of birth-related exposures (birth weight, delivery mode, prematurity, sex, maternal age, and parental allergy history) and postnatal factors (birth order, number of siblings, breastfeeding exclusivity, and breastfeeding duration) with allergic disease, we calculated pooled odds ratios and 95% confidence intervals. We conducted subgroup analyses for allergic disease type, birth order, number of siblings, and parental allergy history. The methodological quality of the identified studies was evaluated using the Newcastle-Ottawa Scale., Results: This meta-analysis included 31 studies, encompassing 218,899 patients in total. The birth-related exposures of low birth weight, maternal age, and prematurity (less than 37 weeks gestation) were not significantly associated with the risk of asthma or allergic rhinitis during childhood or adolescence. Male sex, family history of allergy, and cesarean delivery were linked to an elevated risk of asthma or allergic rhinitis. Among postnatal factors, exclusive breastfeeding, breastfeeding for longer than 6 months, second or later birth order, and having siblings exhibited protective effects against allergic diseases in offspring., Conclusion: The risks of allergic rhinitis and asthma were elevated in male patients, those delivered by cesarean section, and those with a family history of allergy. Conversely, exclusive breastfeeding, breastfeeding for longer than 6 months, and having siblings corresponded to a reduced risk of respiratory allergic diseases.

A common challenge in microfluidic cell cultures has to do with analysis of cell function without replacing a significant fraction of the culture volume and disturbing local concentration gradients of signals. To address this challenge, we developed a microfluidic cell culture device with an integrated bioanalysis unit to enable on-chip analysis of picoliter volumes of cell-conditioned media. The culture module consisted of an array of 140 microwells with a diameter of 300 m which were made low-binding to promote organization of cells into 3D spheroids. The bioanalysis module contained a droplet generator unit, 15 micromechanical valves and reservoirs loaded with reagents. Each 0.8 nL droplet contained an aliquot of conditioned media mixed with assay reagents. The use of microvalves allowed us to load enzymatic assay and immunoassay into sequentially generated droplets for detection of glucose and albumin, respectively. As a biological application of the microfluidic device, we evaluated hormonal stimulation and glucose consumption of hepatic spheroids. To mimic physiological processes occurring during feeding and fasting, hepatic spheroids were exposed to pancreatic hormones, insulin or glucagon. The droplet-based bioanalysis module was used to measure uptake or release of glucose upon hormonal stimulation. In the future, we intend to use this microfluidic device to mimic and measure pathophysiological processes associated with hepatic insulin resistance and diabetes in the context of metabolic syndrome., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Objectives: This systematic review and meta-analysis evaluates and compares the effects of two treatments that ablate the posterior nasal nerves for rhinitis-related symptoms: cryotherapy and radiofrequency neurolysis., Methods: We reviewed studies retrieved from PubMed, SCOPUS, Embase, the Web of Science and the Cochrane database up to June 2023. Papers reporting quality-of-life and rhinitis-related symptom scores before and after cryotherapy, and sham-controlled studies, were analyzed., Results: In total, 738 patients enrolled in 10 studies were evaluated. Both cryotherapy and radiofrequency neurolysis significantly improved rhinitis-related symptoms including congestion, itching, rhinorrhea, and sneezing, and quality of life during 12 months of follow-up. Radiofrequency neurolysis was significantly more effective than cryotherapy in terms of reducing total nasal symptom scores at up to 12 months postoperatively. In terms of individual symptoms, itching, rhinorrhea, and congestion were significantly alleviated or tended to be reduced more by radiofrequency neurolysis than by cryotherapy. The improvements in the minimal clinically important difference in total nasal symptom scores (1.0 point) after 3 months of cryotherapy and radiofrequency therapy were 81.8 % and 92.7 %, respectively., Conclusions: Cryotherapy and radiofrequency neurolysis both improved rhinitis-symptom and quality-of-life scores. Especially, radiofrequency neurolysis showed the better effectiveness for improving the nasal symptoms related to the rhinitis than cryotherapy., Competing Interests: Declaration of competing interest The authors declare that there are no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objectives: To assess the safety and effectiveness of bilateral axillo-breast approach robotic thyroidectomy in thyroid tumor., Methods: Bilateral axillo-breast approach robotic thyroidectomy and other approaches (open thyroidectomy, transoral robotic thyroidectomy, and bilateral axillo-breast approach endoscopic thyroidectomy) were compared in studies from 6 databases., Results: Twenty-two studies (8830 individuals) were included. Bilateral axillo-breast approach robotic thyroidectomy had longer operation time, greater cosmetic satisfaction, and reduced transient hypoparathyroidism than conventional open thyroidectomy. Compared to bilateral axillo-breast approach endoscopic thyroidectomy, bilateral axillo-breast approach robotic thyroidectomy had greater amount of drainage, lower chances of transient vocal cord palsy and permanent hypothyroidism, and better surgical completeness (postopertive thyroblobulin level and lymph node removal). Bilateral axillo-breast approach robotic thyroidectomy induced greater postoperative drainage and greater patient dissatisfaction than transoral robotic thyroidectomy., Conclusion: Bilateral axillo-breast approach robotic thyroidectomy is inferior to transoral robotic thyroidectomy in drainage and cosmetic satisfaction but superior to bilateral axillo-breast approach endoscopic thyroidectomy in surgical performance. Its operation time is longer, but its cosmetic satisfaction is higher than open thyroidectomy., (Copyright © 2023 Associação Brasileira de Otorrinolaringologia e Cirurgia Cérvico-Facial. Published by Elsevier España S.L.U. All rights reserved.)

Background: To compare conventional smears (CSs) and liquid-based preparations (LBPs) for diagnosing thyroid malignant or suspicious lesions., Methods: Studies in the PubMed, SCOPUS, Embase, Web of Science, and Cochrane database published up to December 2023. We reviewed 17 studies, including 15,861 samples., Results: The diagnostic odds ratio (DOR) for CS was 23.6674. The area under the summary receiver operating characteristic curve (AUC) was 0.879, with sensitivity, specificity, negative predictive value, and positive predictive value of 0.8266, 0.8668, 0.8969, and 0.7841, respectively. The rate of inadequate specimens was 0.1280. For LBP, the DOR was 25.3587, with an AUC of 0.865. The sensitivity, specificity, negative predictive value, and positive predictive value were 0.8190, 0.8833, 0.8515, and 0.8562. The rate of inadequate specimens was 0.1729. For CS plus LBP, the AUC was 0.813, with a lower DOR of 9.4557 compared to individual methods. Diagnostic accuracy did not significantly differ among CS, LBP, and CS plus LBP. Subgroup analysis was used to compare ThinPrep and SurePath. The DORs were 29.1494 and 19.7734. SurePath had a significantly higher AUC., Conclusions: There was no significant difference in diagnostic accuracy or proportion of inadequate smears between CS and LBP. SurePath demonstrated higher diagnostic accuracy than ThinPrep. Recommendations for fine-needle aspiration cytology should consider cost, feasibility, and accuracy.

Patient-derived cancer organoids (PDOs) hold considerable promise for personalizing therapy selection and improving patient outcomes. However, it is challenging to generate PDOs in sufficient numbers to test therapies in standard culture platforms. This challenge is particularly acute for pancreatic ductal adenocarcinoma (PDAC) where most patients are diagnosed at an advanced stage with non-resectable tumors and where patient tissue is in the form of needle biopsies. Here the development and characterization of microfluidic devices for testing therapies using a limited amount of tissue or PDOs available from PDAC biopsies is described. It is demonstrated that microfluidic PDOs are phenotypically and genotypically similar to the gold-standard Matrigel organoids with the advantages of 1) spheroid uniformity, 2) minimal cell number requirement, and 3) not relying on Matrigel. The utility of microfluidic PDOs is proven by testing PDO responses to several chemotherapies, including an inhibitor of glycogen synthase kinase (GSKI). In addition, microfluidic organoid cultures are used to test effectiveness of immunotherapy comprised of NK cells in combination with a novel biologic. In summary, our microfluidic device offers considerable benefits for personalizing oncology based on cancer biopsies and may, in the future, be developed into a companion diagnostic for chemotherapy or immunotherapy treatments., (© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Purpose: This systematic review and meta-analysis evaluates the effect of TRNP on rhinitis-related symptoms., Methods: We reviewed studies retrieved from PubMed, SCOPUS, Embase, the Web of Science, and the Cochrane database to June 2023. Studies that evaluated quality-of-life and rhinitis-related symptom scores before and after treatment were analyzed, as was one sham-treatment-controlled study., Results: In total, 406 patients evaluated in five studies were analyzed. TRNP significantly improved rhinitis-related symptoms-congestion, itching, rhinorrhea, and sneezing-for up to 12 months after treatment, compared to before treatment. The most significant symptom decreases were those of rhinorrhea and nasal congestion. Rhinitis-related symptoms had improved significantly at 3 months after TRNP, compared to sham surgery. TRNP improved disease-specific quality-of-life scores on the Rhinoconjunctivitis Quality of Life Questionnaire at 6 months after treatment, compared to before treatment. The rates of clinical improvement in terms of all nasal symptoms (reduction > 30% from baseline) and in quality of life (minimal clinically important difference > 0.4) after TRNP were 79% and 84% respectively. There was no severe adverse event associated with either device use or the overall procedure., Conclusions: TRNP treatment improved subjective symptoms related to rhinitis, especially rhinorrhea and nasal congestion, and also improved disease-specific quality-of-life scores., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: Internal nasal valve dysfunction is a prevalent cause of nasal obstruction. This systematic review, along with a Meta-analysis, evaluated the efficacy of temperature-controlled radiofrequency device (RFD) treatment in alleviating nasal obstruction by rectifying nasal valve collapse., Data Sources: A comprehensive review of studies retrieved from PubMed, SCOPUS, Embase, Web of Science, and Cochrane databases (up to December 2022) was conducted., Review Methods: We included studies that evaluated the quality of life and nasal obstruction scores before and after RFD treatment. In addition, sham-controlled studies were analyzed., Results: In total, 451 patients across 8 studies were included in the analysis. Patients who underwent RFD treatment reported a significantly enhanced quality of life 24 months after treatment compared to pretreatment scores. The rates of clinically improved states and positive responses regarding quality of life after treatment were 82% and 91%, respectively. Moreover, the disease-specific quality of life, as assessed by the Nasal Obstruction Symptom Evaluation score, significantly improved., Conclusion: RFD may help improve nasal obstruction symptoms. Further randomized clinical studies on larger cohorts are essential to substantiate its efficacy in enhancing nasal valve function., (© 2023 American Academy of Otolaryngology-Head and Neck Surgery Foundation.)

Objectives: Multiple minimally invasive techniques for chronic rhinitis treatment focus on posterior nasal nerve ablation. We conducted a systematic review and meta-analysis to evaluate the efficacy of cryotherapy and radiofrequency ablation for alleviating symptoms in patients with allergic and nonallergic rhinitis., Methods: We retrieved studies from PubMed, Scopus, Embase, Web of Science, and Cochrane Database up to July 2023. Data on the impact of cryotherapy and radiofrequency ablation on quality of life and symptom ratings of rhinitis were extracted and evaluated., Results: An analysis of 12 studies involving 788 patients demonstrated significant improvements in quality of life and rhinitis-related symptoms (nasal obstruction, itching, rhinorrhea, and sneezing) in patients treated with cryotherapy or radiofrequency ablation (symptom score at 24 months and quality of life score at 3 months). However, radiofrequency ablation had a more positive effect on nasal symptoms after 3 months than cryotherapy. Nonallergic rhinitis patients responded more favorably to posterior nerve ablation than patients with allergic rhinitis. Both techniques enhanced disease-specific quality of life during the initial 3 months of treatment (cryotherapy, 84.6%; radiofrequency, 81.6%; P=0.564). After 3 months of treatment, a clinical improvement in all nasal symptoms (minimal clinically important difference in the total nasal symptom score: >1.0 points) was seen in 81.8% and 91.9% of patients who underwent cryotherapy and radiofrequency ablation, respectively (P=0.005), suggesting that radiofrequency is more likely to lead to clinical improvement., Conclusion: Rhinitis-associated subjective symptom scores and quality of life may be improved by both cryotherapy and radiofrequency ablation. Ablation was more efficacious than cryotherapy for nasal symptoms in patients with nonallergic rhinitis. To corroborate these findings, further randomized controlled studies directly comparing these two techniques are warranted.

Objectives: To assume the ideal cut-off values and diagnostic performance of two thyroid imaging reporting and data systems published by the Korean Thyroid Association/Korean Society of Thyroid Radiology (Korean TI-RADS) and the American Thyroid Association (ATA TI-RADS)., Methods: Eighteen studies with 25,422 patients from PubMed, SCOPUS, Embase, Web of Science, and Cochrane Library databases up to August 2022. True and false positive and negative values with characteristics were extracted., Results: The highest area under the receiver operating characteristic curve (AUC) was 0.893 and 0.887 for Korean and ATA TI-RADS. High suspicion was judged as the best cut-off value with the highest AUC based on optimal sensitivity and specificity. In determining the risk of malignant thyroid nodules, high suspicion in Korean and ATA TI-RADS showed sensitivity as 71.3% and 73.5%, specificity as 7.9% and 86.4%, diagnostic odds ratios as 20.0289 and 20.9076, AUC as 0.893 and 0.887. There was no significant difference when directly comparing the diagnostic accuracy of both TI-RADS., Conclusion: The two risk stratification systems had good diagnostic performance with high AUC and no significant differences. The ideal cut-off can depend on the medical condition or thyroid nodules, because the changes of cut-off point may reciprocally alter sensitivity and specificity., (© 2023. Italian Society of Medical Radiology.)

Background and Objectives : Through a comprehensive meta-analysis of the pertinent literature, this study evaluated the utility and efficacy of perioperative infraorbital and/or infratrochlear nerve blocks in reducing postoperative pain and related morbidities in patients undergoing septorhinoplasty. Materials and Methods : We reviewed studies retrieved from the PubMed, SCOPUS, Embase, Web of Science, and Cochrane databases up to August 2023. The analysis included a selection of seven articles that compared a treatment group receiving perioperative infraorbital and/or infratrochlear nerve blocks with a control group that either received a placebo or no treatment. The evaluated outcomes covered parameters such as postoperative pain, the amount and frequency of analgesic medication administration, the incidence of postoperative nausea and vomiting, as well as the manifestation of emergence agitation. Results : The treatment group displayed a significant reduction in postoperative pain (mean difference = -1.7236 [-2.6825; -0.7646], I 2 = 98.8%), as well as a significant decrease in both the amount (standardized mean difference = -2.4629 [-3.8042; -1.1216], I 2 = 93.0%) and frequency (odds ratio = 0.3584 [0.1383; 0.9287], I 2 = 59.7%) of analgesic medication use compared to the control. The incidence of emergence agitation (odds ratio = 0.2040 [0.0907; 0.4590], I 2 = 0.0%) was notably lower in the treatment group. The incidence of postoperative nausea and vomiting (odds ratio = 0.5393 [0.1309; 2.2218], I 2 = 60.4%) showed a trend towards reduction, although it was not statistically significant. While no adverse effects reaching statistical significance were reported in the analyzed studies, hematoma (proportional rate = 0.2133 [0.0905; 0.4250], I 2 = 76.9%) and edema (proportional rate = 0.1935 [0.1048; 0.3296], I 2 = 57.2%) after blocks appeared at rates of approximately 20%. Conclusions : Infraorbital and/or infratrochlear nerve blocks for septorhinoplasty effectively reduce postoperative pain and emergence agitation without notable adverse outcomes.

Human pluripotent stem cells (hPSCs) are capable of unlimited proliferation and can undergo differentiation to give rise to cells and tissues of the three primary germ layers. While directing lineage selection of hPSCs has been an active area of research, improving the efficiency of differentiation remains an important objective. In this study, we describe a two-compartment microfluidic device for co-cultivation of adult human hepatocytes and stem cells. Both cell types were cultured in a 3D or spheroid format. Adult hepatocytes remained highly functional in the microfluidic device over the course of 4 weeks and served as a source of instructive paracrine cues to drive hepatic differentiation of stem cells cultured in the neighboring compartment. The differentiation of stem cells was more pronounced in microfluidic co-cultures compared to a standard hepatic differentiation protocol. In addition to improving stem cell differentiation outcomes, the microfluidic co-culture system described here may be used for parsing signals and mechanisms controlling hepatic cell fate.

Background: To assess the surgical outcomes of various minimally invasive and remote-access surgical approaches for thyroid cancer patients., Methods: We collected studies from January 2020 to July 2022 in 6 databases. Pairwise and network meta-analyses were performed for outcomes and complications of 9 minimally invasive interventions (minimally invasive video-assisted, endoscopic or robotic bilateral axillo-breast approach, endoscopic or robotic postauricular, endoscopic or robot transaxillary approach, transoral endoscopic thyroidectomy vestibular approach or robotic thyroidectomy) and conventional thyroidectomy (control)., Results: Multiplicity and bilaterality of cancer, lymph node metastasis, and coincidence of thyroiditis showed no significant difference between minimally invasive interventions and control. However, larger tumor size (robotic bilateral axillo-breast approach standardized mean difference -1.3989, 95% confidence interval [-2.1717 to -0.6262]), higher body mass index (robot transaxillary approach standardized mean difference -0.5350, 95% confidence interval [-0.9557 to -0.1144], robotic bilateral axillo-breast approach standardized mean difference -0.2301, 95% confidence interval [-0.4389 to -0.0214]), and frequent extrathyroidal extension (robotic bilateral axillo-breast approach standardized mean difference 0.7435, 95% confidence interval [0.5602-0.9869]) were observed in control. In surgical outcomes and adverse effects, there was no significant difference in hospitalization or retrieved lymph node number between minimally invasive interventions and control. However, longer operative time was observed in the robotic bilateral axillo-breast approach(standardized mean difference 6.5393, 95% confidence interval [5.0476-8.0309]) and transoral robotic thyroidectomy (standardized mean difference 5.4946, 95% confidence interval [2.9984-7.9907]) groups than in control. In surgical completion, the rate of low postoperative serum thyroglobulin, postoperative thyroglobulin level, and postoperative radioactive iodine ablation dose showed no significant difference between minimally invasive interventions and control., Conclusion: Minimally invasive thyroidectomy did not show inferior results compared to conventional thyroidectomy despite the longer operative time. Surgeons need to prudently consider all aspects of patients to determine the proper surgical approach for thyroid cancer., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The ability to maintain functional hepatocytes has important implications for bioartificial liver development, cell-based therapies, drug screening, and tissue engineering. Several approaches can be used to restore hepatocyte function in vitro, including coating a culture substrate with extracellular matrix (ECM), encapsulating cells within biomimetic gels (Collagen- or Matrigel-based), or co-cultivation with other cells. This paper describes the use of bioactive heparin-based core-shell microcapsules to form and cultivate hepatocyte spheroids. These microcapsules are comprised of an aqueous core that facilitates hepatocyte aggregation into spheroids and a heparin hydrogel shell that binds and releases growth factors. We demonstrate that bioactive microcapsules retain and release endogenous signals thus enhancing the function of encapsulated hepatocytes. We also demonstrate that hepatic function may be further enhanced by loading exogenous hepatocyte growth factor (HGF) into microcapsules and inhibiting transforming growth factor (TGF)-β1 signaling. Overall, bioactive microcapsules described here represent a promising new strategy for the encapsulation and maintenance of primary hepatocytes and will be beneficial for liver tissue engineering, regenerative medicine, and drug testing applications., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors.)

Extracellular vesicles (EVs) are lipid bilayer nanovesicles secreted by cells. EVs contain biological information related to parental cells and provide biomarkers for disease diagnosis. We have previously shown that the levels of podocin and nephrin expression on urinary EVs may be used to diagnose renal injury associated with preeclampsia. This paper describes a nanoparticle-enabled immunoassay integrated with an electrochemical plate for quantifying podocin and nephrin expression in urinary EVs. The strategy entailed capturing EVs on an electrode surface and then labeling EVs with gold nanoparticles that are both functionalized with antibodies for target specificity and impregnated with redox-active metal ions for electrochemical detection. These immunoprobes produced an electrochemical redox signal proportional to the expression level of EV surface markers. Electrochemical immunoassays were carried out in a novel microtiter plate that contained 16 wells with working electrodes connected to onboard counter/reference electrodes via capillary valves. Upon validation with recombinant proteins, a microtiter plate was used for analysis of urinary EVs from healthy and preeclamptic pregnant women. This analysis revealed a higher podocin to nephrin ratio for preeclamptic women compared to healthy controls (4.31 vs 1.69) suggesting that this ratio may be used for disease diagnosis.

Liver cultures may be used for disease modeling, testing therapies and predicting drug-induced injury. The complexity of the liver cultures has evolved from hepatocyte monocultures to co-cultures with non-parenchymal cells and finally to precision-cut liver slices. The latter culture format retains liver's native biomolecular and cellular complexity and therefore holds considerable promise for in vitro testing. However, liver slices remain functional for ~72 h in vitro and display limited utility for some disease modeling and therapy testing applications that require longer culture times. This paper describes a microfluidic device for longer-term maintenance of functional organotypic liver cultures. Our microfluidic culture system was designed to enable direct injection of liver tissue into a culture chamber through a valve-enabled side port. Liver tissue was embedded in collagen and remained functional for up to 31 days, highlighted by continued production of albumin and urea. These organotypic cultures also expressed several enzymes involved in xenobiotic metabolism. Conversely, matched liver tissue embedded in collagen in a 96-well plate lost its phenotype and function within 3-5 days. The microfluidic organotypic liver cultures described here represent a significant advance in liver cultivation and may be used for future modeling of liver diseases or for individualized liver-directed therapies., Competing Interests: Conflict of Interest The authors have no conflicts to disclose.

Background: To evaluate the diagnostic performance of ultrasound risk-stratification systems for the discrimination of benign and malignant thyroid nodules and to determine the optimal cutoff values of individual risk-stratification systems., Methods: PubMed, Embase, SCOPUS, Web of Science, and Cochrane library databases were searched up to August 2022. Sensitivity and specificity data were collected along with the characteristics of each study related to ultrasound risk stratification systems., Results: Sixty-seven studies involving 76,512 thyroid nodules were included in this research. The sensitivity, specificity, diagnostic odds ratios, and area under the curves by K-TIRADS (4), ACR-TIRADS (TR5), ATA (high suspicion), EU-TIRADS (5), and Kwak-TIRADS (4b) for malignancy risk stratification of thyroid nodules were 92.5%, 63.5%, 69.8%, 70.6%, and 95.8%, respectively; 62.8%, 89.6%, 87.2%, 83.9%, and 63.8%, respectively; 20.7111, 16.8442, 15.7398, 12.2986, and 38.0578, respectively; and 0.792, 0.882, 0.859, 0.843, and 0.929, respectively., Conclusion: All ultrasound-based risk-stratification systems had good diagnostic performance. Although this study determined the best cutoff values in individual risk-stratification systems based on statistical assessment, clinicians could adjust or alter cutoff values based on the clinical purpose of the ultrasound and the reciprocal changes in sensitivity and specificity.

The field of oncology increasingly focuses on strategies to predict effectiveness of a given therapy on a patient-by-patient basis. Such precision or personalized oncology has the potential of significantly extending patient survival time. Patient-derived organoids are seen as the main source of patient tumor tissue that may be used for therapy testing in personalized oncology. The gold standard approach for culturing cancer organoids is in standard multi-well plates coated with Matrigel. Despite their effectiveness, these standard organoid cultures have drawbacks, namely, requirement of a large starting cell population and polydispersity of cancer organoid sizes. The latter drawback makes it challenging to monitor and quantify changes in organoid size in response to therapy. Microfluidic devices with integrated arrays of microwells may be used to both decrease the amount of starting cellular material required to form organoids and to standardize organoid size to make therapy assessment easier. Herein, we describe methodology for making microfluidic device as well as for seeding patient-derived cancer cells, culturing organoids, and testing therapies using these devices., (© 2023. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: To assess the safety and effectiveness of transoral robotic thyroidectomy (TORT) in thyroid tumor., Methods: PubMed, Embase, Web of Science, SCOPUS, Cochrane database, and Google Scholar up to June 2022. Studies comparing outcomes and complications between TORT and control groups (robotic bilateral axillo-breast, trans-axillary, postauricular approach, conventional open thyroidectomy (OT), and transoral endoscopic approach) were analyzed., Results: Ten studies of 1420 individuals. The operative time (SMD 1.15, 95%CI [0.48; 1.89]) was significantly longer and the number of retrieved lymph nodes (LNs) (SMD -0.27, 95%CI [-0.39; -0.16]) was fewer in TORT than in the control group. The postoperative cosmetic satisfaction score (SMD 0.60, 95%CI [0.28; 0.92]) was statistically higher in TORT than in the control group. In subgroup analysis, there was no significant difference between robotic surgeries. However, TORT had significantly longer operative times (SMD 2.08, 95%CI [0.95; 3.20]) and fewer retrieved LNs (SMD -0.32, 95%CI [-0.46; -0.17]) than OT. TORT satisfied significantly more patients in cosmetic view. However, it increased hospitalization days and postoperative pain on the operation day and first day compared to OT., Conclusions: TORT is not inferior to other robotic-assisted approaches. Its operation time and hospitalization days are longer and postoperative pain is greater than OT, although its cosmetic satisfaction is high.

We developed a microfluidic device for the rapid analysis of biomarkers in small volumes of whole blood. This device includes an onboard plasma separation module connected to a downstream bioanalysis module in which plasma mixes with reagents and the results of a colorimetric assay are recorded. Actuation of onboard microvalves within a bioanalysis module creates active mixing conditions that allowed us to achieve solution homogeneity within 5 min. To demonstrate utility, we carried out glucose detection in our device. With 5 μL of whole blood as an input, our microfluidic device enabled a time-to-answer of 10 min with a limit of detection of 0.21 ± 0.04 mM for glucose. This device has immediate applications for rapid and sensitive monitoring of hypoglycemia at the point of care (POC). Furthermore, our automated microfluidic device represents a platform technology that may be used to detect other biomarkers in whole blood.

Human pluripotent stem cells (hPSCs) may be differentiated into any adult cell type and therefore hold incredible promise for cell therapeutics and disease modeling. There is increasing interest in three-dimensional (3D) hPSC culture because of improved differentiation outcomes and potential for scale up. Our team has recently described bioactive heparin (Hep)-containing core-shell microcapsules that promote rapid aggregation of stem cells into spheroids and may also be loaded with growth factors for the local and sustained delivery to the encapsulated cells. In this study, we explored the possibility of further modulating bioactivity of microcapsules through the use of an ultrathin coating composed of tannic acid (TA). Deposition of the TA film onto model substrates functionalized with Hep and poly(ethylene glycol) was characterized by ellipsometry and atomic force microscopy. Furthermore, the presence of the TA coating was observed to increase the amount of basic fibroblast growth factor (bFGF) incorporation by up to twofold and to extend its release from 5 to 7 days. Most significantly, TA-microcapsules loaded with bFGF induced higher levels of pluripotency expression compared to uncoated microcapsules containing bFGF. Engineered microcapsules described here represent a new stem cell culture approach that enables 3D cultivation and relies on local delivery of inductive cues.

Human pluripotent stem cells (hPSC) hold considerable promise as a source of adult cells for treatment of diseases ranging from diabetes to liver failure. Some of the challenges that limit the clinical/translational impact of hPSCs are high cost and difficulty in scaling-up of existing differentiation protocols. In this paper, we sought to address these challenges through the development of bioactive microcapsules. A co-axial flow focusing microfluidic device was used to encapsulate hPSCs in microcapsules comprised of an aqueous core and a hydrogel shell. Importantly, the shell contained heparin moieties for growth factor (GF) binding and release. The aqueous core enabled rapid aggregation of hPSCs into 3D spheroids while the bioactive hydrogel shell was used to load inductive cues driving pluripotency maintenance and endodermal differentiation. Specifically, we demonstrated that one-time, 1 h long loading of pluripotency signals, fibroblast growth factor (FGF)-2 and transforming growth factor (TGF)-β1, into bioactive microcapsules was sufficient to induce and maintain pluripotency of hPSCs over the course of 5 days at levels similar to or better than a standard protocol with soluble GFs. Furthermore, stem cell-carrying microcapsules that previously contained pluripotency signals could be reloaded with an endodermal cue, Nodal, resulting in higher levels of endodermal markers compared to stem cells differentiated in a standard protocol. Overall, bioactive heparin-containing core-shell microcapsules decreased GF usage five-fold while improving stem cell phenotype and are well suited for 3D cultivation of hPSCs., Competing Interests: The authors declare no competing financial interest., (© 2021 The Authors.)

Extracellular vesicles (EVs) are lipid bilayer particles secreted from various cells. EVs carry molecular information of parent cells and hold considerable promise for early disease diagnostics. This paper describes a general strategy for multiplexed immunosensing of EV surface proteins, focusing on surface markers CD63, CD81, nephrin, and podocin to prove the concept. This sensing strategy entailed functionalizing gold nanoparticles (AuNPs) with two types of antibodies and then tagging with metal ions, either Pb 2+ or Cu 2+ . The metal ions served as redox reporters, generating unique redox peaks at -0.23 and 0.28 V (vs Ag/AgCl) during electrochemical oxidation of Pb 2+ and Cu 2+ , respectively. Capture of EVs on the working electrode, followed by labeling with immunoprobes and square wave voltammetry, produced redox currents proportional to concentrations of EVs and levels of expression of EV surface markers. Importantly, metal-ion tagging of immunoprobes enabled detection of two EV surface markers simultaneously from the same electrode. We demonstrated dual detection of either CD63/CD81 or podocin/nephrin surface markers from urinary EVs. The NP-enabled immunoassay had a sensitivity of 2.46 × 10 5 particles/mL (or 40.3 pg/mL) for CD63- and 5.80 × 10 5 particles/mL (or 47.7 pg/mL) for CD81-expressing EVs and a linear range of four orders of magnitude. The limit of detection for podocin and nephrin was 3.1 and 3.8 pg/mL, respectively. In the future, the capacity for multiplexing may be increased by extending the repertoire of metal ions used for redox tagging of AuNPs.

Hepatocytes are parenchymal cells of the liver responsible for drug detoxification, urea and bile production, serum protein synthesis, and glucose homeostasis. Hepatocytes are widely used for drug toxicity studies in bioartificial liver devices and for cell-based liver therapies. Because hepatocytes are highly differentiated cells residing in a complex microenvironment in vivo , they tend to lose hepatic phenotype and function in vitro . This paper first reviews traditional culture approaches used to rescue hepatic function in vitro and then discusses the benefits of emerging microfluidic-based culture approaches. We conclude by reviewing integration of hepatocyte cultures with bioanalytical or sensing approaches., (© 2021 Author(s).)

Three-dimensional (3D) or spheroid cultures of human pluripotent stem cells (hPSCs) offer the benefits of improved differentiation outcomes and scalability. In this paper, we describe a strategy for the robust and reproducible formation of hPSC spheroids where a co-axial flow focusing device is utilized to entrap hPSCs inside core-shell microcapsules. The core solution contained single cell suspension of hPSCs and was made viscous by the incorporation of high molecular weight poly(ethylene glycol) (PEG) and density gradient media. The shell stream comprised of PEG-4 arm-maleimide or PEG-4-Mal and flowed alongside the core stream toward two consecutive oil junctions. Droplet formation occurred at the first oil junction with shell solution wrapping itself around the core. Chemical crosslinking of the shell occurred at the second oil junction by introducing a di-thiol crosslinker (1,4-dithiothreitol or DTT) to these droplets. The crosslinker reacts with maleimide functional groups via click chemistry, resulting in the formation of a hydrogel shell around the microcapsules. Our encapsulation technology produced 400 µm diameter capsules at a rate of 10 capsules per second. The resultant capsules had a hydrogel shell and an aqueous core that allowed single cells to rapidly assemble into aggregates and form spheroids. The process of encapsulation did not adversely affect the viability of hPSCs, with >95% viability observed 3 days post-encapsulation. For comparison, hPSCs encapsulated in solid gel microparticles (without an aqueous core) did not form spheroids and had <50% viability 3 days after encapsulation. Spheroid formation of hPSCs inside core-shell microcapsules occurred within 48 h after encapsulation, with the spheroid diameter being a function of cell inoculation density. Overall, the microfluidic encapsulation technology described in this protocol was well-suited for hPSCs encapsulation and spheroid formation.

Objectives: This study evaluated the diagnostic value of various symptoms of coronavirus disease 2019 (COVID-19) in screening for this disease., Methods: Two authors (working independently) comprehensively reviewed six databases (PubMed, Cochrane Database, Embase, Web of Science, Scopus, and Google Scholar) from their dates of inception until November 2020. The predictive value of patient-reported symptoms, including otolaryngologic and general symptoms, was evaluated in adults who underwent testing for COVID-19. True-positive, true-negative, false-positive, and false-negative data were extracted from each study. The methodological quality of the included studies was evaluated using the quality assessment of diagnostic accuracy studies tool (ver. 2)., Results: Twenty-eight prospective and retrospective studies were included in the meta-analysis. The diagnostic odds ratio (DOR) of a change in olfaction and/or taste was 10.20 (95% confidence interval [CI], 8.43-12.34). The area under the summary receiver operating characteristic curve was 0.8. Olfactory and/or taste changes had a low sensitivity (0.57; 95% CI, 0.47-0.66) but moderate negative (0.78; 95% CI, 0.69-0.85] and positive (0.78; 95% CI, 0.66-0.87) predictive values and a high specificity (0.91; 95% CI, 0.83-0.96). Olfactory and/or taste changes had a higher diagnostic value than the other otolaryngologic symptoms, a higher DOR and specificity, and a similar or higher diagnostic value than the other general symptoms., Conclusion: Among otolaryngologic symptoms, olfactory and/or taste dysfunction was the most closely associated with COVID-19 and its general symptoms, and should therefore be considered when screening for the disease.

Cellular therapies based on human pluripotent stem cells (hPSCs) offer considerable promise for treating numerous diseases including diabetes and end stage liver failure. Stem cell spheroids may be cultured in stirred bioreactors to scale up cell production to cell numbers relevant for use in humans. Despite significant progress in bioreactor culture of stem cells, areas for improvement remain. In this study, we demonstrate that microfluidic encapsulation of hPSCs and formation of spheroids. A co-axial droplet microfluidic device was used to fabricate 400 μm diameter capsules with a poly(ethylene glycol) hydrogel shell and an aqueous core. Spheroid formation was demonstrated for three hPSC lines to highlight broad utility of this encapsulation technology. In-capsule differentiation of stem cell spheroids into pancreatic β-cells in suspension culture was also demonstrated.

Microfluidic systems can be used to control picoliter to microliter volumes in ways not possible with other methods of fluid handling. In recent years, the field of microfluidics has grown rapidly, with microfluidic devices offering possibilities to impact biology and medicine. Microfluidic devices populated with human cells have the potential to mimic the physiological functions of tissues and organs in a three-dimensional microenvironment and enable the study of mechanisms of human diseases, drug discovery and the practice of personalized medicine. In the field of otorhinolaryngology, various types of microfluidic systems have already been introduced to study organ physiology, diagnose diseases, and evaluate therapeutic efficacy. Therefore, microfluidic technologies can be implemented at all levels of otorhinolaryngology. This review is intended to promote understanding of microfluidic properties and introduce the recent literature on application of microfluidic-related devices in the field of otorhinolaryngology.

There is increasing interest in utilizing in vitro cultures as patient avatars to develop personalized treatment for cancer. Typical cultures utilize Matrigel-coated plates and media to promote the proliferation of cancer cells as spheroids or tumor explants. However, standard culture conditions operate in large volumes and require a high concentration of cancer cells to initiate this process. Other limitations include variability in the ability to successfully establish a stable line and inconsistency in the dimensions of these microcancers for in vivo drug response measurements. This paper explored the utility of microfluidics in the cultivation of cancer cell spheroids. Six patient-derived xenograft (PDX) tumors of high-grade serous ovarian cancer were used as the source material to demonstrate that viability and epithelial marker expression in the microfluidic cultures was superior to that of Matrigel or large volume 3D cultures. To further demonstrate the potential for miniaturization and multiplexing, we fabricated multichamber microfluidic devices with integrated microvalves to enable serial seeding of several chambers followed by parallel testing of several drug concentrations. These valve-enabled microfluidic devices permitted the formation of spheroids and testing of seven drug concentrations with as few as 100,000 cancer cells per device. Overall, we demonstrate the feasibility of maintaining difficul-to-culture primary cancer cells and testing drugs in a microfluidic device. This microfluidic platform may be ideal for drug testing and personalized therapy when tumor material is limited, such as following the acquisition of biopsy specimens obtained by fine-needle aspiration., Competing Interests: Conflict of interestThe authors declare that they have no conflict of interest., (© The Author(s) 2020.)

A number of cell culture approaches have been described for maintenance of primary hepatocytes. Forming hepatocytes into three-dimensional (3-D) spheroids is one well-accepted method for extending epithelial phenotype of these cells. Our laboratory has previously observed enhanced function of two-dimensional (2-D, monolayer) hepatocyte cultures in microfluidic devices due to increased production of several hepato-inductive growth factors, including hepatocyte growth factor (HGF). In the present study, we wanted to test a hypothesis that culturing hepatocyte spheroids (3-D) in microfluidic devices will also result in enhanced phenotype and function. To test this hypothesis, we fabricated devices with small and large volumes. Both types of devices included a microstructured floor containing arrays of pyramidal wells to promote assembly of hepatocytes into spheroids with individual diameters of ~100 µm. The hepatocyte spheroids were found to be more functional, as evidenced by higher level of albumin synthesis, bile acid production, and hepatic enzyme expression, in low-volume compared with large-volume devices. Importantly, high functionality of spheroid cultures correlated with elevated levels of HGF secretion. Although decay of hepatic function (albumin secretion) was observed over the course 3 wk, this behavior could be abrogated by inhibiting TGF-β1 signaling. With TGF-β1 inhibitor, microfluidic hepatocyte spheroid cultures maintained high and stable levels of albumin synthesis over the course of 4 wk. To further highlight utility of this culture platform for liver disease modeling, we carried out alcohol injury experiments in microfluidic devices and tested protective effects of interleukin-22: a potential therapy for alcoholic hepatitis.

Oxygen tension is a central component of the cellular microenvironment and can serve as a trigger for changes in cell phenotype and function. There is a strong need to precisely control and modulate oxygen tension in cell culture systems in order to more accurately model the physiology and pathophysiology observed in vivo. The objective of this paper was to develop a simple, yet effective strategy for local control of oxygen tension in microfluidic cell cultures. Our strategy relied on fabrication of microfluidic devices using oxygen-permeable and impermeable materials. This composite device was designed so as to incorporate regions of gas permeability into the roof of the cell culture chamber and was outfitted with a reservoir for the oxygen-consuming chemical pyrogallol. When assembled and filled with pyrogallol, this device allowed oxygen depletion to occur within a specific region of the microfluidic culture chamber. The geometry and dimensions of the hypoxic region inside a microfluidic chamber were controlled by features fabricated into the oxygen-impermeable layer. Oxygen tension as low as 0.5% could be achieved using this strategy. To prove the utility of this device, we demonstrated that hypoxia induced anaerobic metabolism in a group of liver cancer cells, and that neighboring cancer cells residing under normoxic conditions upregulated the expression of transporters for taking up lactate - a product of anaerobic respiration. The microfluidic devices described here may be broadly applicable for mimicking multiple physiological scenarios where oxygen tension varies on the length scale of tens of micrometers including the cancer microenvironment, liver zonation, and luminal microenvironment of the gut.

Cytokines are small proteins secreted by immune cells in response to pathogens/infections; therefore, these proteins can be used in diagnosing infectious diseases. For example, release of a cytokine interferon (IFN)-γ from T-cells is used for blood-based diagnosis of tuberculosis (TB). Our lab has previously developed an atpamer-based electrochemical biosensor for rapid and sensitive detection of IFN-γ. In this study, we explored the use of silicon nanowires (NWs) as a way to create nanostructured electrodes with enhanced sensitivity for IFN-γ. Si NWs were covered with gold and were further functionalized with thiolated aptamers specific for IFN-γ. Aptamer molecules were designed to form a hairpin and in addition to terminal thiol groups contained redox reporter molecules methylene blue. Binding of analyte to aptamer-modified NWs (termed here nanowire aptasensors) inhibited electron transfer from redox reporters to the electrode and caused electrochemical redox signal to decrease. In a series of experiments we demonstrate that NW aptasensors responded 3× faster and were 2× more sensitive to IFN-γ compared to standard flat electrodes. Most significantly, NW aptasensors allowed detection of IFN-γ from as few as 150 T-cells/mL while ELISA did not pick up signal from the same number of cells. One of the challenges faced by ELISA-based TB diagnostics is poor performance in patients whose T-cell numbers are low, typically HIV patients. Therefore, NW aptasensors developed here may be used in the future for more sensitive monitoring of IFN-γ responses in patients coinfected with HIV/TB.

Hepatocytes are highly differentiated epithelial cells that lose their phenotype and function when removed from the in vivo environment. Given the importance of hepatic cultures for drug toxicity, bioartificial liver assist devices and basic biology studies, considerable efforts have been focused on the maintenance of hepatic function in vitro. The methods used to date include co-cultivation of hepatocytes with stromal cells, organizing these cells into spheroids and imbedding them into bioactive gels. Our team has recently demonstrated that primary rat hepatocytes confined to microfluidic channels in the absence of convection maintained the epithelial phenotype through upregulation of endogenous signals including hepatocyte growth factor (HGF). The objective of the present study was to transition from microfluidic devices, which are somewhat specialized and challenging to use, towards low volume multiwell plates ubiquitous in biology laboratories. Using a combination of 3D printing and micromolding we have constructed inserts that can be placed into standard 12-well plates and can be used to create low volume culture conditions under which primary hepatocytes maintained a differentiated phenotype. This phenotype enhancement was confirmed by hepatic function assays including albumin synthesis and expression. Importantly we confirmed upregulation of HGF inside the low volume culture plates and demonstrated that inhibition of HGF signaling degraded the hepatic phenotype in our cell culture platform. Overall, this study outlines a new cell culture system that leverages the low volume effects of microfluidic channels in a multiwell plate format. Beyond hepatocytes, such a system may be of use in the maintenance of other difficult-to-culture cells including stem cells and primary cancer cells.

3D hepatic microtissues can serve as valuable liver analogues for cell-based therapies and for hepatotoxicity screening during preclinical drug development. However, hepatocytes rapidly dedifferentiate in vitro, and typically require 3D culture systems or co-cultures for phenotype rescue. In this work we present a novel microencapsulation strategy, utilizing coaxial flow-focusing droplet microfluidics to fabricate microcapsules with liquid core and poly(ethylene glycol) (PEG) gel shell. When entrapped inside these capsules, primary hepatocytes rapidly formed cell-cell contacts and assembled into compact spheroids. High levels of hepatic function were maintained inside the capsules for over ten days. The microencapsulation approach described here is compatible with difficult-to-culture primary epithelial cells, allows for tuning gel mechanical properties and diffusivity, and may be used in the future for high density suspension cell cultures., Statement of Significance: Our paper combines an interesting new way for making capsules with cultivation of difficult-to-maintain primary epithelial cells (hepatocytes). The microcapsules described here will enable high density suspension culture of hepatocytes or other cells and may be used as building blocks for engineering tissues., (Copyright © 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Microfluidic systems provide an interesting alternative to standard macroscale cell cultures due to the decrease in the number of cells and reagents as well as the improved physiology of cells confined to small volumes. However, the tools available for cell-secreted molecules inside microfluidic devices remain limited. In this paper, we describe an integrated microsystem composed of a microfluidic device and a fluorescent microbead-based assay for the detection of the hepatocyte growth factor (HGF) and the transforming growth factor (TGF)-β1 secreted by primary hepatocytes. This microfluidic system is designed to separate a cell culture chamber from sensing chambers using a permeable hydrogel barrier. Cell-secreted HGF and TGF-β1 diffuse through the hydrogel barrier into adjacent sensing channels and are detected using fluorescent microbead-based sensors. The specificity of sensing microbeads is defined by the choice of antibodies; therefore, our microfluidic culture system and sensing microbeads may be applied to a variety of cells and cell-secreted factors., Competing Interests: COMPETING INTERESTS The authors declare no conflict of interest.