Patient Outcomes After Unsuccessful Endoscopic Sialolith Extraction.

OBJECTIVE/HYPOTHESIS: To evaluate clinical outcomes following failed endoscopic extraction of salivary calculi and to assess any relation between clinical outcome and calculi location, number, size, and mobility. If sialendoscopy fails to extract the calculus, subsequent spontaneous passage of the calculus out of the ductoglandular system or secondary effects of sialendoscopy could mitigate the clinical impact of a residual sialolithiasis. STUDY DESIGN: Prospective observational study. METHODS: Prospective comparative study of endoscopic procedures for sialolithiasis performed in the Manukau Surgery Center, in Auckland, New Zealand, from 2010 to 2020. The recurrent symptoms and the variables related to the need for additional surgical intervention for salivary calculi were analyzed. RESULTS: Among the 465 sialendoscopy procedures, 154 (33.1%) were for obstructive sialolithiasis. Among these, there were 30 (19.4%) with unsuccessful stone extraction with re-operation for these failures performed in 14 of the 27 failed submandibular cases (52%) and 2 of the 3 parotids (66.7%). Location of calculi was a significant factor in predicting the need of further surgery. Patients with perihilar stones were 5 times more likely to have a failed procedure (P = .001). If the stone was intraglandular, the likelihood increased to 8.5 times (P = .005). The likelihood for a revision procedure increased almost 11 times if the stone was intraglandular (P = .004). Calculi size, mobility, multiple calculi, and presence of concurrent stenosis did not correlate with need for further surgery. CONCLUSIONS: A significant proportion of "failed" sialendoscopy did not require further intervention. Stone location was a significant factor in predicting a failed procedure and the need for re-intervention. Laryngoscope, 132:1029-1033, 2022.

Biophysical matter in a marine estuary identified by the Sentinel-3B OLCI satellite and the presence of terrestrial iron (Fe) nanoparticles.

The analysis of marine matter using the Sentinel-3B OLCI (Ocean Land Color Instrument) satellite is the most advanced technique for evaluating: the absorption of colored detrital and dissolved material (ADG_443_NN), total suspended matter concentration (TSM_NN) and of chlorophyll-a (CHL_NN) on a global scale. The objective is to analyze ADG_443_NN, TSM_NN and CHL_NN using the Sentinel-3B OLCI satellite and the presence of Fe-nanoparticles (NPs) + hazardous elements (HEs) in suspended sediments (SSs) in the maritime estuary of the Colombian city of Barranquilla. The study used the unpublished image of the Sentinel-3B OLCI satellite in the evaluation of ADG_443_NN, TSM_NN and CHL_NN in 72 sampled points. Subsequently, 36 samples of SSs were carried out in the Magdalena River, in the identification of Fe-NPs by advanced electron microscopies. The Sentinel-3B satellite revealed particulate accumulations in OCE1 through the intensity of OLCI in ocean. There was also a high Fe-NPs intensity of SSs in the Magdalena channel, spreading contamination to large regions.

Dupilumab suppresses type 2 inflammatory biomarkers across multiple atopic, allergic diseases.

BACKGROUND: Type 2 inflammation is common in numerous atopic/allergic diseases and can be identified by elevated biomarker levels. Dupilumab, a fully human monoclonal antibody, blocks the shared receptor component for interleukin-4 and interleukin-13, key and central drivers of type 2 inflammation. OBJECTIVE: Assessment of dupilumab effect on type 2 inflammatory biomarkers in atopic dermatitis (AD), asthma, chronic rhinosinusitis with nasal polyps (CRSwNP) and eosinophilic esophagitis (EoE). METHODS: Data were extracted from three randomized placebo-controlled trials of dupilumab in AD (NCT02277743, N = 671; NCT02277769, N = 708; NCT02260986, N = 740); and one each in asthma (NCT02414854, N = 1902); CRSwNP (NCT02898454, N = 448); and EoE (NCT02379052, N = 47). Biomarkers assessed were serum thymus and activation-regulated chemokine (TARC), plasma eotaxin-3, serum total immunoglobulin E (IgE), serum periostin and blood eosinophil count. RESULTS: Dupilumab versus placebo significantly suppressed most type 2 inflammatory biomarker levels across all studies/indications where data were assessed. Reductions in serum TARC, plasma eotaxin-3 and serum periostin occurred rapidly, whereas reductions in serum total IgE were more gradual. Across diseases, at the end of treatment, median percentage change from baseline in TARC levels ranged from -24.8% to -88.6% (placebo +2.6% to -53.6%); -38.2% to -51.5% (placebo +8.3% to -0.16%) in eotaxin-3; -24.8% to -76.7% (placebo +8.3% to -4.4%) in total IgE; and -13.6% to -41.1% (placebo +10.1% to -6.94%) in periostin levels. Blood eosinophil responses to dupilumab varied by disease, with minimal changes in AD in the SOLO studies (median percentage change from baseline to end of treatment: 0% [95% CI: -15.8, 0]); transient increases followed by decreases to below-baseline levels in asthma (-14.6% [-20.0, -7.7]) and CRSwNP (-29.4% [-40.0, -16.3]); and significant decreases in EoE (-50.0% [-50.0, -33.3]). CONCLUSION AND CLINICAL RELEVANCE: Dupilumab reduced levels of type 2 biomarkers across clinical studies in patients with AD, asthma, CRSwNP and EoE.

Organic Anion Transporter Polypeptide 1B1 Polymorphism Modulates the Extent of Drug-Drug Interaction and Associated Biomarker Levels in Healthy Volunteers.

Understanding transporter-mediated drug-drug interactions is an integral part of risk assessment in drug development. Recent studies support the use of hexadecanedioate (HDA), tetradecanedioate (TDA), coproporphyrin (CP)-I, and CP-III as clinical biomarkers for evaluating organic anion-transporting polypeptide (OATP)1B1 (SLCO1B1) inhibition. The current study investigated the effect of OATP1B1 genotype c.521T>C (OATP1B1-Val174Ala) on the extent of interaction between cyclosporin A (CsA) and pravastatin, and associated endogenous biomarkers of the transporter (HDA, TDA, CP-I, and CP-III), in 20 healthy volunteers. The results show that the levels of each clinical biomarker and pravastatin were significantly increased in plasma samples of the volunteers following administration of pravastatin plus CsA compared with pravastatin plus placebo. The overall fold change in the area under the concentration-time curve (AUC) and maximum plasma concentration (Cmax ) was similar among the four biomarkers (1.8-2.5-fold, paired t-test P value < 0.05) in individuals who were homozygotes or heterozygotes of the major allele, c.521T. However, the fold change in AUC and Cmax for HDA and TDA was significantly abolished in the subjects who were c.521-CC, whereas the respective fold change in AUC and Cmax for pravastatin and CP-I and CP-III were slightly weaker in individuals who were c.521-CC compared with c.521-TT/TC genotypes. In addition, this study provides the first evidence that SLCO1B1 c.521T>C genotype is significantly associated with CP-I but not CP-III levels. Overall, these results suggest that OATP1B1 genotype can modulate the effects of CsA on biomarker levels; the extent of modulation differs among the biomarkers.

Hearing Loss in Pediatric Septo-Optic Dysplasia.

OBJECTIVE: To identify and characterize hearing loss (HL) in children with septo-optic dysplasia (SOD). METHODS: Otologic and audiometric data for patients less than 18 years of age identified as having SOD who were seen in the Children's Healthcare of Atlanta-Scottish Rite Hospital clinic between 2013 and 2017 were collected and reviewed through a HIPAA-compliant medical record search. Relevant literature was also reviewed with the assistance of Medline. RESULTS: Sixty-four patients with SOD were identified, and 7 of those patients (10.9%) were diagnosed with hearing loss. Type of hearing loss was sensorineural (SNHL) in 5 patients (63%), mixed (MHL) in 1(14%), and conductive (CHL) in 1(14%). Bilateral loss presented in 60% (3/5) of SNHL patients, while the rest demonstrated unilateral loss. Unilateral findings included cochlear nerve deficiency (1) and atresia/microtia (1). Tympanostomy tubes were required in 57% (4/7) of SOD children with hearing loss. Amplification was successfully implemented in 86% (6/7). CONCLUSIONS: Hearing loss was found in nearly 11% of SOD children, and SNHL was identified as (63%) the predominant form of loss. To our knowledge, this is the first retrospective review of hearing loss in a pediatric SOD cohort and the first to report of cochlear nerve deficiency and atresia/microtia in this population. Based on these findings, early identification of hearing loss with imaging when appropriate and treatment of otitis in this population is recommended.

Fatal tumour pulmonary embolism.

A 30-year-old female with no significant past medical history was referred to our facility with sudden onset of shortness of breath. She had a low clinical probability for pulmonary thromboembolism and a computed tomography angiogram showed enlarged pulmonary arteries but no in situ thrombi. She developed recurrent episodes of hypotension and hypoxia, and was transferred to the intensive care unit where she died despite active resuscitation. An autopsy revealed extensive lymphatic and pulmonary vascular tumour emboli as the immediate cause of death. Pulmonary tumour embolism is a very rare cause of death, but can occur in patients who have an occult neoplasm.

Hydrocarbon stapled B chain analogues of relaxin-3 retain biological activity.

Relaxin-3 or insulin-like peptide 7 (INSL7) is the most recently discovered relaxin/insulin-like family peptide. Mature relaxin-3 consists of an A chain and a B chain held by disulphide bonds. According to structure activity relationship studies, the relaxin-3 B chain is more important in binding and activating the receptor. RXFP3 (also known as Relaxin-3 receptor 1, GPCR 135, somatostatin- and angiotensin- like peptide receptor or SALPR) was identified as the cognate receptor for relaxin-3 by expression profiles and binding studies. Recent studies imply roles of this system in mediating stress and anxiety, feeding, metabolism and cognition. Stapling of peptides is a technique used to develop peptide drugs for otherwise undruggable targets. The main advantages of stapling include, increased activity due to reduced proteolysis, increased affinity to receptors and increased cell permeability. Stable agonists and antagonists of RXFP3 are crucial for understanding the physiological significance of this system. So far, agonists and antagonists of RXFP3 are peptides. In this study, for the first time, we have introduced stapling of the relaxin-3 B chain at 14th and 18th positions (14s18) and 18th and 22nd position (18s22). These stapled peptides showed greater helicity than the unstapled relaxin-3 B chain in circular dichroism analysis. Both stapled peptides bound RXFP3 and activated RXFP3 as observed in an inhibition of forskolin-induced cAMP assay and a ERK1/2 activation assay, although with different potencies. Therefore, we conclude that stapling of the relaxin3 B chain does not compromise its ability to activate RXFP3 and is a promising method for developing stable peptide agonists and antagonists of RXFP3 to aid relaxin-3/RXFP3 research.

Sphenopalatine Artery Ligation for Epistaxis: Factors Influencing Outcome and Impact of Timing of Surgery.

OBJECTIVE: Sphenopalatine artery ligation is a commonly employed surgical intervention for control of posterior epistaxis unresponsive to nasal packing. The objective of the present study was to evaluate the outcome of sphenopalatine artery ligation for control of epistaxis at our institution and the impact of timing and other factors on outcome. STUDY DESIGN: Case series with chart review. SETTING: Academic tertiary referral center. SUBJECTS AND METHODS: Case notes were reviewed for 45 consecutive patients undergoing sphenopalatine artery ligation for control of epistaxis between October 2008 and October 2014. RESULTS: Forty-one patients had nasal packing prior to sphenopalatine artery ligation, with 33 undergoing ≥2 packings. Postoperatively, 6 patients had rebleeding, which was treated with repacking (n = 4) and return to the operating room (n = 2). The overall success rate of sphenopalatine artery ligation was 87% (39 of 45). Rebleeding rate was not affected by concomitant septoplasty, anterior ethmoidal artery ligation, or postoperative nasal packing. Patients undergoing SPA ligation within the first 24 hours of admission had a significantly shorter hospital length of stay (3 vs 6 days, P = .02) and treatment cost (€5905 vs €10,001, P = .03). Length of stay was not influenced by sphenopalatine artery ligation after ≤1 nasal pack versus ≥2 packs. Timing of sphenopalatine artery ligation did not affect blood transfusion requirement (P = .84). CONCLUSION: Sphenopalatine artery ligation is an effective management strategy for surgical control of refractory epistaxis. Early timing of sphenopalatine artery ligation may lead to reductions in length of stay.

Hydrogen sulfide promotes adipogenesis in 3T3L1 cells.

The effect of hydrogen sulfide (H2S) on differentiation of 3T3L1-derived adipocytes was examined. Endogenous H2S was increased after 3T3L1 differentiation. The expression of the H2S-synthesising enzymes, cystathionine γ-lyase (CSE), cystathionine ß-synthase (CBS) and 3-mercaptopyruvate sulfurtransferase (3-MST), was increased in a time-dependent manner during 3T3L1 differentiation. Expression of genes associated with adipogenesis related genes including fatty acid binding protein 4 (FABP4/aP2), a key regulator of this process, was increased by GYY4137 (a slow-releasing H2S donor compound) and sodium hydrosulfide (NaHS, a classical H2S donor) but not by ZYJ1122 or time-expired NaHS. Furthermore expression of these genes were reduced by aminooxyacetic acid (AOAA, CBS inhibitor), DL-propargylglycine (PAG, CSE inhibitor) as well as by CSE small interference RNA (siCSE) and siCBS. The size and number of lipid droplets in mature adipocytes was significantly increased by both GYY4137 and NaHS, which also impaired the ability of CL316,243 (ß3-agonist) to promote lipolysis in these cells. In contrast, AOAA and PAG had the opposite effect. Taken together, we show that the H2S-synthesising enzymes CBS, CSE and 3-MST are endogenously expressed during adipogenesis and that both endogenous and exogenous H2S modulate adipogenesis and adipocyte maturation.

Management of retinopathy of prematurity.

While current management of retinopathy of prematurity (ROP) is well evidenced, the recent Neonatal Oxygenation Prospective Meta-analysis (NeoPROM) oxygen therapy trials, and the Bevacizumab Eliminates the Angiogenic Threat of Retinopathy of Prematurity (BEAT-ROP) trial of intravitreal injection bevacizumab, have reopened debate on optimal management. Early postnatal manipulation of oxygen therapy, nutrition and serum IGF 1 levels may improve early retinal blood vessel development and prevent later severe ROP. While the use of intravitreal injections of antivascular endothelial growth factor (VEGF) agents may appear to be an attractive alternative to laser ablation of the peripheral retina, caution is needed. The optimal choice of agent and dose remain unknown, and suppression of serum VEGF levels might interfere with normal angiogenesis processes in developing tissues. There is a pressing need for good Phase 1 studies of these agents, and safety trials.

Prospective-retrospective biomarker analysis for regulatory consideration: white paper from the industry pharmacogenomics working group.

One approach to delivering cost-effective healthcare requires the identification of patients as individuals or subpopulations that are more likely to respond to an appropriate dose and/or schedule of a therapeutic agent, or as subpopulations that are less likely to develop an adverse event (i.e., personalized or stratified medicine). Biomarkers that identify therapeutically relevant variations in human biology are often only uncovered in the later stage of drug development. In this article, the Industry Pharmacogenomics Working Group provides, for regulatory consideration, its perspective on the rationale for the conduct of what is commonly referred to as the prospective-retrospective analysis (PRA) of biomarkers. Reflecting on published proposals and materials presented by the US FDA, a decision tree for generating robust scientific data from samples collected from an already conducted trial to allow PRA is presented. The primary utility of the PRA is to define a process that provides robust scientific evidence for decision-making in situations where it is not necessary, nor practical or ethical to conduct a new prospective clinical study.