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Objective: Non-dissolvable nasal packs (Rapid Rhino and Merocel) are widely used in secondary healthcare centres for the control of epistaxis, with some side effects., Methods: A prospective, observational cohort study was conducted of adults who required Rapid Rhino or Merocel packing for acute epistaxis management in a large healthcare centre between March 2020 and 2021. A validated modified version of the 22-item Sino-Nasal Outcome Test was used., Results: A total of 80 adults requiring non-dissolvable packs were recruited. Seventy per cent of patients had Rapid Rhino packs inserted. Embarrassment was greater in patients who used Rapid Rhino than Merocel. Merocel packs had a significantly higher mean pain score on removal compared to Rapid Rhino. There was no correlation between rebleed rate and type of nasal pack used., Conclusion: Non-dissolvable Rapid Rhino and Merocel nasal packs have similar efficacy in controlling epistaxis. Rapid Rhino packs are more embarrassing for patients in comparison to Merocel packs, but are less painful to remove.

Background and Purpose: Endomorphins have shown great promise as pharmaceutics for the treatment of pain. We have previously confirmed that novel endomorphin analogues CEMR-1 and CEMR-2 behaved as potent μ agonists and displayed potent antinociceptive activities at the supraspinal and peripheral levels. The present study was undertaken to evaluate the antinociceptive properties of CEMR-1 and CEMR-2 following intrathecal (i.t.) administration. Furthermore, their antinociceptive tolerance and opioid-like side effects were also determined., Experimental Approach: The spinal antinociceptive effects of CEMR-1 and CEMR-2 were determined in a series of pain models, including acute radiant heat paw withdrawal test, spared nerve injury-induced neuropathic pain, complete Freund's adjuvant-induced inflammatory pain, visceral pain and formalin pain. Antinociceptive tolerance was evaluated in radiant heat paw withdrawal test., Key Results: Spinal administration of CEMR-1 and CEMR-2 produced potent and prolonged antinociceptive effects in acute pain. CEMR-1 and CEMR-2 may produce their antinociception through distinct μ receptor subtypes. These two analogues also exhibited significant analgesic activities in neuropathic, inflammatory, visceral and formalin pain at the spinal level. It is noteworthy that CEMR-1 showed non-tolerance-forming analgesic properties, while CEMR-2 exhibited substantially reduced antinociceptive tolerance. Furthermore, both analogues displayed no or reduced side effects on conditioned place preference response, physical dependence, locomotor activity and gastrointestinal transit., Conclusions and Implications: The present investigation demonstrated that CEMR-1 and CEMR-2 displayed potent and long-lasting antinociception with a favourable side effect profile at the spinal level. Therefore, CEMR-1 and CEMR-2 might serve as promising analgesic compounds with minimal opioid-like side effects., (© 2023 British Pharmacological Society.)

Triple-negative breast cancer (TNBC) remains a clinical challenge due to molecular, metabolic, and genetic heterogeneity as well as the lack of validated drug targets. Thus, therapies or delivery paradigms are needed. Gold-derived compounds including the FDA-approved drug, auranofin have shown promise as effective anticancer agents against several tumors. To improve the solubility and bioavailability of auranofin, we hypothesized that the nanodelivery of auranofin using biodegradable chitosan modified polyethylene glycol (PEG) nanoparticles (NPs) will enhance anticancer activity against TNBC by comparing the best nanoformulation with the free drug. The selection of the nanoformulation was based on synthesis of various chitosan PEG copolymers via formaldehyde-mediated engraftment of PEG onto chitosan to form [chitosan- g -PEG] copolymer. Furthermore, altered physiochemical properties of the copolymer was based on the formaldehyde ratio towards nanoparticles (CP 1-4 NPs). Following the recruitment of PEG onto the chitosan polymer surface, we explored how this process influenced the stiffness of the nanoparticle using atomic force microscopy (AFM), a factor crucial for in vitro and in vivo studies. Our objective was to ensure the full functionality and inherent properties of chitosan as the parent polymer was maintained without allowing PEG to overshadow chitosan's unique cationic properties while improving solubility in neutral pH. Hence, CP 2 NP was chosen. To demonstrate the efficacy of CP 2 NP as a good delivery carrier for auranofin, we administered a dose of 3 mg/kg of auranofin, in contrast to free auranofin, which was given at 5 mg/kg. In vivo studies revealed the potency of encapsulated auranofin against TNBC cells with a severe necrotic effect following treatment superior to that of free auranofin. In conclusion, chitosan- g -PEG nanoparticles have the potential to be an excellent delivery system for auranofin, increasing its effectiveness and potentially reducing its clinical limitations.

Uropathogenic Escherichia coli (UPEC) is the primary causative agent of lower urinary tract infection (UTI). UTI presents a serious health risk and has considerable secondary implications including economic burden, recurring episodes, and overuse of antibiotics. A safe and effective vaccine would address this widespread health problem and emerging antibiotic resistance. Killed, whole-cell vaccines have shown limited efficacy to prevent recurrent UTI in human trials. We explored photochemical inactivation with psoralen drugs and UVA light (PUVA), which crosslinks nucleic acid, as an alternative to protein-damaging methods of inactivation to improve whole-cell UTI vaccines. Exposure of UPEC to the psoralen drug AMT and UVA light resulted in a killed but metabolically active (KBMA) state, as reported previously for other PUVA-inactivated bacteria. The immunogenicity of PUVA-UPEC as compared to formalin-inactivated UPEC was compared in mice. Both generated high UPEC-specific serum IgG titers after intramuscular delivery. However, using functional adherence as a measure of surface protein integrity, we found differences in the properties of PUVA- and formalin-inactivated UPEC. Adhesion mediated by Type-1 and P-fimbriae was severely compromised by formalin but was unaffected by PUVA, indicating that PUVA preserved the functional conformation of fimbrial proteins, which are targets of protective immune responses. In vitro assays indicated that although they retained metabolic activity, PUVA-UPEC lost virulence properties that could negatively impact vaccine safety. Our results imply the potential for PUVA to improve killed, whole-cell UTI vaccines by generating bacteria that more closely resemble their live, infectious counterparts relative to vaccines generated with protein-damaging methods., Importance: Lower urinary tract infection (UTI), caused primarily by uropathogenic Escherichia coli , represents a significant health burden, accounting for 7 million primary care and 1 million emergency room visits annually in the United States. Women and the elderly are especially susceptible and recurrent infection (rUTI) is common in those populations. Lower UTI can lead to life-threatening systemic infection. UTI burden is manifested by healthcare dollars spent (1.5 billion annually), quality of life impact, and resistant strains emerging from antibiotic overuse. A safe and effective vaccine to prevent rUTI would address a substantial healthcare issue. Vaccines comprised of inactivated uropathogenic bacteria have yielded encouraging results in clinical trials but improvements that enhance vaccine performance are needed. To that end, we focused on inactivation methodology and provided data to support photochemical inactivation, which targets nucleic acid, as a promising alternative to conventional protein-damaging inactivation methods to improve whole-cell UTI vaccines., Competing Interests: The authors declare no conflict of interest.

Objectives: Dyschromia is an understudied aspect of hypertrophic scar (HTS). The use of topical tacrolimus has successfully shown repigmentation in vitiligo patients through promotion of melanogenesis and melanocyte proliferation. It was hypothesized that HTSs treated with topical tacrolimus would have increased repigmentation compared to controls., Methodology: Full-thickness burns in red Duroc pigs were either treated with excision and meshed split-thickness skin grafting or excision and no grafting, and these wounds formed hypopigmented HTSs (n = 8). Half of the scars had 0.1% tacrolimus ointment applied to the scar twice a day for 21 days, while controls had no treatment. Further, each scar was bisected with half incurring fractional ablative CO 2 laser treatment before topical tacrolimus application to induce laser-assisted drug delivery (LADD). Pigmentation was evaluated using a noninvasive probe to measure melanin index (MI) at Days 0 (pretreatment), 7, 14, and 21. At each timepoint, punch biopsies were obtained and fixed in formalin or were incubated in dispase. The formalin-fixed biopsies were used to evaluate melanin levels by H&E staining. The biopsies incubated in dispase were used to obtain epidermal sheets. The ESs were then flash frozen and RNA was isolated from them and used in quantitative reverse transcription polymerase chain reaction for melanogenesis-related genes: Tyrosinase (TYR), TYR-related protein-1 (TYRP1), and dopachrome tautomerase (DCT). Analysis of variance test with Šídák's multiple comparisons test was used to compare groups., Results: Over time, within the grafted HTS and the NS group, there were no significant changes in MI, except for Week 3 in the -Tacro group. (+Tacro HTS= pre = 685.1 ± 42.0, w1 = 741.0 ± 54.16, w2 = 750.8 ± 59.0, w3 = 760.9 ± 49.8) (-Tacro HTS= pre = 700.4 ± 54.3, w1 = 722.3 ± 50.7, w2 = 739.6 ± 53.2, w3 = 722.7 ± 50.5). Over time, within the ungrafted HTS and the NS group, there were no significant changes in MI. (+Tacro HTS= pre = 644.9 ± 6.9, w1 = 661.6 ± 3.3, w2 = 650.3 ± 6.2, w3 = 636.3 ± 7.4) (-Tacro HTS= pre = 696.8 ± 8.0, w1 = 695.8 ± 12.3, w2 = 678.9 ± 14.0, w3 = 731.2 ± 50.3). LADD did not lead to any differential change in pigmentation compared to the non-LADD group. There was no evidence of increased melanogenesis within the tissue punch biopsies at any timepoint. There were no changes in TYR, TYRP1, or DCT gene expression after treatment., Conclusion: Hypopigmented HTSs treated with 0.1% tacrolimus ointment with or without LADD did not show significantly increased repigmentation. This study was limited by a shorter treatment interval than what is known to be required in vitiligo patients for repigmentation. The use of noninvasive, topical treatments to promote repigmentation are an appealing strategy to relieve morbidity associated with dyschromic burn scars and requires further investigation., (© 2024 Wiley Periodicals LLC.)

Background: Inflammatory pain is caused by damaged tissue or noxious stimuli, accompanied by the release of inflammatory mediators that often leads to severe hyperalgesia and allodynia with limited therapy options. Recently, a novel mitochondrial-derived peptide (named MOTS-c) was reported to regulate obesity, metabolic homeostasis and inflammatory response. The aim of this study was to investigate the effects of MOTS-c and its related regulatory mechanisms involved in inflammatory pain., Methods: Male Kunming mice (8-10 weeks-old) were intraplantar injected with formalin, capsaicin, λ-Carrageenan and complete Freund adjuvant (CFA) to establish acute and chronic inflammatory pain. The effects of MOTS-c on the above inflammatory pain mice and its underlying mechanisms were examined by behavioral tests, quantitative polymerase chain reaction (qPCR), western blotting, enzyme linked immunosorbent assay (ELISA), immunohistochemistry (IHC) and immunofluorescence (IF)., Results: Behavioral experiments investigated the potential beneficial effects of MOTS-c on multiple acute and chronic inflammatory pain in mice. The results showed that MOTS-c treatment produced potent anti-allodynic effects in formalin-induced acute inflammatory pain, capsaicin-induced nocifensive behaviors and λ-Carrageenan/CFA-induced chronic inflammatory pain model. Further mechanistic studies revealed that central MOTS-c treatment significantly ameliorated CFA-evoked the release of inflammatory factors and activation of glial cells and neurons in the spinal dorsal horn. Moreover, peripheral MOTS-c treatment reduced CFA-evoked inflammatory responses in the surface structure of hindpaw skin, accompanied by inhibiting excitation of peripheral calcitonin gene-related peptide (CGRP) and P2X3 nociceptive neurons., Conclusions: The present study indicates that MOTS-c may serve as a promising therapeutic target for inflammatory pain.

Background: Merocel is a commonly used material for nasal packing; nevertheless, the majority of patients experience pain when the nasal packing is removed. Aims/Objectives:  This study aims to introduce a novel technique for nasal packing using Surgicel-wrapped Merocel., Material and Methods: Patients who underwent septoplasty received either Merocel or Surgicel-wrapped Merocel as nasal packing. Clinical complications related to bleeding and subjective symptoms associated with the packing materials were assessed., Results: Between 2018 and 2021, a total of thirty-three patients with a deviated nasal septum underwent septoplasty. Among them, eight patients received Merocel nasal packing, while twenty-five patients were treated with the new nasal packing technique involving Surgicel-wrapped Merocel. We observed a significant reduction in pain during removal in the Surgicel-wrapped Merocel group compared to the Merocel group ( p  = .008). However, no significant differences were noted in other discomforts related to packing or bleeding after removal between these two groups. Conclusions and Significance: Using Surgicel-wrapped Merocel as nasal packing following septoplasty is an effective method to alleviate pain during removal.

Accurate evaluation of human epidermal growth factor receptor type 2 (HER2) expression is crucial for determining chemotherapy regimens in gastric cancer. However, formalin fixation status has been identified as an important factor affecting HER2 assessment reliability. This retrospective cohort study aimed to investigate the correlation between sample collection day (weekday vs. weekend) and source (biopsy vs. surgical specimens) in assessing HER2 expression in patients with unresectable advanced/recurrent gastric cancer. Data were collected from gastric cancer patients who received chemotherapy at a single public hospital in Japan from 2008 to 2021. The analysis included 177 patients (109 men, 68 women) with a median age of 68.0 (21-88) years, and the primary outcome was the HER2 positivity rate. The overall HER2 positivity rate was 18.1%, with higher rates on weekdays (20.0%) compared to weekends (12.8%). Biopsies had higher positivity rates on weekdays (23.9%) but lower rates on weekends (11.1%) than surgical specimens. Significant differences were observed in formalin fixation times between weekdays and weekends for both biopsies and surgical samples. The study findings suggest that longer formalin fixation times on weekends may lead to underestimating HER2 expression, particularly in biopsies. Therefore, it is crucial to be cautious of excessive formalin fixation when collecting samples, especially during weekend biopsies., (© 2023 The Authors. Pathology International published by Japanese Society of Pathology and John Wiley & Sons Australia, Ltd.)

The current study aimed to evaluate the anti-inflammatory activity of Dicliptera bupleuroides Nees aerial parts methanol extract and its different fractions namely hexane, chloroform, ethyl acetate and butanol in vitro using cyclooxygenase inhibitory assay (COX-2). In vivo anti-inflammatory evaluation was performed using carrageenan and formalin induced inflammation in rat models followed by molecular docking. High performance liquid chromatography (HPLC) and gas chromatography coupled with mass chromatography (GC/MS) analyses were used for chemical analyses of the tested samples. The tested samples showed significant inhibition in COX-2 inhibitory assay where methanol extract (DBM) showed the highest inhibitory potential at 100 μg/mL estimated by 67.86 %. At a dose of 400 mg/kg, all of the examined samples showed pronounced results in carrageenan induced acute inflammation in rat model at 4 th h interval with DBM showed the highest efficiency displaying 65.32 % inhibition as compared to the untreated rats. Formalin model was employed for seven days and DBM exhibited 65.33 % and 69.39 % inhibition at 200 and 400 mg/kg, respectively approaching that of the standard on the 7 th day. HPLC revealed the presence of caffeic acid, gallic acid and sinapic acid, quercetin and myricetin in DBM. GC/MS analysis of its hexane fraction revealed the presence of 16 compounds belonging mainly to fatty acids and sterols that account for 85.26 % of the total detected compounds. Molecular docking showed that hexadecanoic acid followed by decanedioic acid and isopropyl myristate showed the best fitting within cyclooxygenase-II (COX-II) while nonacosane followed by hexatriacontane and isopropyl myristate revealed the most pronounced fitting within the 5-lipoxygenase (5-LOX) active sites. Absorption, metabolism, distribution and excretion and toxicity prediction (ADMET/ TOPKAT) concluded that most of the detected compounds showed reasonable pharmacokinetic, pharmacodynamic and toxicity properties that could be further modified to be more suitable for incorporation in pharmaceutical dosage forms combating inflammation and its undesirable consequences., (© 2023 Wiley-VHCA AG, Zurich, Switzerland.)

Background: Driver molecular aberrations, such as epidermal growth factor receptor (EGFR) mutation and anaplastic lymphoma kinase (ALK) gene rearrangement, play an important role in the oncogenesis and progression of non-squamous non-small-cell lung cancers (NSCLC). Therefore, this study aimed to detect the incidence of driver mutations among non-squamous NSCLC., Patients and Methods: This was a retrospective-prospective cohort study on 131 patients with non-squamous NSCLC. Data on age, smoking status, chest symptoms, method of lung cancer diagnosis, molecular testing, including EGFR mutations in formalin-fixed paraffin-embedded (FFPE) tumor tissue and serum circulating tumor DNA using next-generation sequencing and ALK gene rearrangement by FFPE tumor tissue, and follow-up data regarding treatment modalities and outcomes were collected., Results: The median age of the patients was 57 years (range: 32-79 years). Out of 131 patients, 97 were males (74%), and 90 (68.7%) were smokers. Among 128 patients tested, 16 (12.5%) had EGFR mutations detected with either technique by formalin-fixed paraffin-embedded (FFPE) tumor tissue or/and serum circulating tumor DNA using next-generation sequencing, and 6 (4.7%) had ALK rearrangement by FFPE tumor tissue. The majority (62.6%) presented with metastatic disease. Among the 102 patients who received first-line systemic therapy, the objective response rate was 50.0% in mutated NSCLC versus 14.6% in non-mutated (p < 0.001). Among the eight mutated patients who received first-line tyrosine kinase inhibitors (TKIs), 7 patients achieved either complete response or partial response. Among the 22 mutated patients, the median overall survival was 3 months in those who did not receive targeted therapy versus not reached in those who received any type of targeted therapy (p < 0.001)., Conclusion: Screening patients with newly diagnosed non-squamous NSCLC for driver mutations is essential for major prognostic and therapeutic implications. Early administration of TKIs in mutated patients significantly improves disease outcomes., (© 2023. The Author(s).)

Inflammatory pain is the most important clinical symptom of inflammatory diseases. Despite intensive research into inflammatory pain mechanisms, the majority of analgesics available are based on mechanistic classes of compounds that have been known for many years, as a result, inflammatory pain control remains a challenge for drug design in the context of clinically unmet needs in terms of safety and efficacy. A growing literature supports that pro-inflammatory cytokine signaling plays a crucial role in the development of inflammatory pain. Modulation of the pro-inflammatory cytokine may hold the key to improved pain management. Previous studies have reported that dorsomorphin played key roles in inflammation. But the role of dorsomorphin in the formalin-induced inflammatory nociception in mice has never been reported. Here, we report a new function of dorsomorphin which can inhibit formalin-induced inflammatory nociception in mice. The antinociceptive effect of dorsomorphin mainly depended on inhibiting the p38 MAPK/c-fos signaling and regulating inflammatory mediators., 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 © 2022 Elsevier B.V. All rights reserved.)

Objectives: Locoregional recurrence of non-small cell lung cancer (NSCLC) occurs even among patients with stage I disease, as a result of tumor proliferative activity. The aim of this study was to evaluate the clinical reliability of a new rapid immunohistochemistry (IHC) technique for assessing malignant potential through detection of tumoral Ki-67 expression., Materials and Methods: The rapid IHC method uses non-contact alternating current (AC) mixing to achieve more rapid/stable staining within 20 min during surgery. First, to investigate the association between clinical outcomes and tumoral Ki-67 labeling with rapid IHC, 21 pairs of surgical patients treated between 2012 and 2020 for pStage IA1-3 NSCLC with/without recurrence were retrospectively reviewed. Second, 40 frozen section (FS) samples in patients with NSCLC for whom radical surgery was planned between April 2021 and February 2022 were deemed eligible for comparison of the clinical performance of conventional IHC and intraoperative rapid Ki-67 IHC with FS., Results: Detection of tumoral Ki-67 expression using rapid IHC with formalin-fixed, paraffin-embedded (FFPE) blocks was significantly associated with clinical outcomes in R0 pStage IA NSCLC surgical patients, including overall and recurrence-free survival (P = 0.0043 and P &lt; 0.0001, respectively). Levels of Ki-67 expression among resectable NSCLC patients detected using rapid IHC with FS significantly correlated with those detected using conventional FFPE-IHC (p &lt; 0.001). An intraoperative cut-off of &gt; 7.5 % tumor cell Ki-67 positivity accurately predicted pathological stage more advanced than IA3 [P = 0.0185, Odds ratio = 20.477, 95 % confidence interval (CI): 1.660-252.55]., Conclusion: Rapid Ki-67 IHC with AC mixing could potentially serve as a clinical tool for intraoperative determination of tumor malignancy status. The present study suggests that segmentectomy for early small NSCLCs is oncologically safe and a reasonable alternative to lobectomy, but only when there is adequate intraoperative selection for primary tumors with low-grade malignancy, which could be verified using intraoperative rapid Ki-67 IHC with FS., 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 © 2022 Elsevier B.V. All rights reserved.)

Background: Advanced cholangiocarcinoma has a poor prognosis. Molecular targeted approaches have been proposed for patients after progression under first-line chemotherapy treatment. Here, molecular profiling of intrahepatic cholangiocarcinoma in combination with a comprehensive umbrella concept was applied in a real-world setting., Methods: In total, 101 patients received molecular profiling and matched treatment based on interdisciplinary tumour board decisions in a tertiary care setting. Parallel DNA and RNA sequencing of formalin-fixed paraffin-embedded tumour tissue was performed using large panels., Results: Genetic alterations were detected in 77% of patients and included gene fusions in 21 patients. The latter recurrently involved the FGFR2 and the NRG1 gene loci. The most commonly altered genes were BAP1, ARID1A, FGFR2, IDH1, CDKN2A, CDKN2B, PIK3CA, TP53, ATM, IDH2, BRAF, SMARCA4 and FGFR3. Molecular targets were detected in 59% of patients. Of these, 32% received targeted therapy. The most relevant reason for not initiating therapy was the deterioration of performance status. Patients receiving a molecular-matched therapy showed a significantly higher survival probability compared to patients receiving conventional chemotherapy only (HR: 2.059, 95% CI: 0.9817-4.320, P < 0.01)., Conclusions: Molecular profiling can be successfully translated into clinical treatment of intrahepatic cholangiocarcinoma patients and is associated with prolonged survival of patients receiving a molecular-matched treatment., (© 2022. The Author(s).)

Demarginalization through initiation of resettlement program since 1978 is an inevitable progress faced by the indigenous Orang Asli (OA) population in Peninsular Malaysia. As Malaysian huntergatherers, the Negrito has been exposed to various environmental-cultural variations. These changes may influence the pattern of soil-transmitted helminth (STH) infections, the common malady amongst OA. This study evaluated the deworming effects of single-dosage albendazole (400 mg) and STH-reinfection rate between Negritos who are still living in the inland jungle versus those living in resettlements at town peripheries (RPS). Stool samples from the consented participants were first examined using the direct faecal smear, formalin-ether sedimentation and Kato Katz techniques. Subsequently, stool collections were carried out in three time points following treatment (i.e., 21 days, 3 months and 6 months). In brief, a total number of 54 Negritos (inland: 24; RPS: 30) with a complete set of stool collection was included in this longitudinal study. This study revealed 72.2% cure rate against T. trichiura in the inland but only 15.0% in the RPS. Although the efficacy of albendazole against T. trichiura was ultimately low in the RPS, 62.6% egg reduction rate (ERR) (arithmetic mean) was noted (p = 0.001). For A. lumbricoides and hookworm, high cure rates were found in both communities (85.7-100.0%). Reinfection for T. trichiura was seen in less than 1 month with higher rate in the RPS (90.0%) as opposed to the inland (44.4%) at 21 days following treatment. This study found that the inland OA had better tolerability to single-dosage albendazole and experienced slower STH reinfection rates versus the RPS. Hence, the selection of albendazole dosage should be targeted and the use of single- dosage albendazole (biannually) would be more suitable for the inland OA. Conversely, we propose the use of 3-days albendazole regimens in the resettled RPS population.

Objective: Neoadjuvant chemotherapy with 5-fluorouracil (5FU) is one of the most effective treatment options for gastric cancer patients.  However, treatment response varies significantly between patients based on their genetic profile. The purpose of this study was to determine the association between thymidylate synthase (TS) and enolase superfamily member 1 (ENOSF1) polymorphisms, treatment response, and overall survival in patients with gastric cancer., Methods: The TS and ENOSF1 variants were analyzed in formalin-fixed paraffin-embedded (FFPE) tissue from 100 gastric cancer patients receiving neoadjuvant 5FU-based chemotherapy. Polymerase chain reaction (PCR) amplification and restriction fragment length polymorphism (RFLP) were used to determine TS polymorphisms' genotypes, and the Tetra Arms PCR method was used to identify ENOSF1 polymorphisms. Patients were followed for up to five years, and the association between variants, treatment response, and overall survival (OS) was examined., Results: There was a significant association between the TS 5' UTR polymorphism and response to treatment in patients with gastric cancer who received neoadjuvant 5FU therapy (P=0.032). Patients with the 2R3R genotype responded better to treatment, whereas those with the 3R3R genotype did not respond to treatment. Patients with the 2R2R and 3R3R genotypes had the longest and shortest median survival times, respectively, and the observed differences were significant (p=0.003). There was a statistically significant relationship between rs2612091 and chemotherapy response (P=0.017). Patients with genotype AG did not respond to treatment., Conclusion: This study established that the TS 5' UTR and ENOSF1 rs2612091 polymorphisms could be used to predict treatment response and overall survival in patients with gastric cancer who received neoadjuvant chemotherapy based on 5FU.

Oncogenic fusions represent compelling druggable targets in solid tumours highlighted by the recent site agnostic FDA approval of larotrectinib for NTRK rearrangements. However screening for fusions in routinely processed tissue samples is constrained due to degradation of nucleic acid as a result of formalin fixation., To investigate the clinical utility of semiconductor sequencing optimised for detection of actionable fusion transcripts in formalin fixed samples, we have undertaken an analysis of test trending data generated by a clinically validated next generation sequencing platform designed to capture 867 of the most clinically relevant druggable driver-partner oncogenic fusions. Here we show across a real-life cohort of 1112 patients with solid tumours that actionable fusions occur at high frequency (7.4%) with linkage to a wide range of targeted therapy protocols including seven fusion-drug matches with FDA/EMA approval and/or NCCN/ESMO recommendations and 80 clinical trials. The more prevalent actionable fusions identified were independent of tumour type in keeping with signalling via evolutionary conserved RAS/RAF/MEK/ERK, PI3K/AKT/MTOR, PLCy/PKC and JAK/STAT pathways. Taken together our data indicates that semiconductor sequencing for detection of actionable fusions can be integrated into routine diagnostic pathology workflows enabling the identification of personalised treatment options that have potential to improve clinical cancer management across many tumour types., Competing Interests: The authors have read the journal’s policy and the authors of this manuscript have the following competing interests: Authors ML, KH, AL, RT, and GW are currently salaried employees at Oncologica UK Ltd. TH was a salaried employee at the time of data generation for this manuscript. There are no patents, products in development, or marketed products associated with this research to declare. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: Pentazocine produces a wide variety of actions in the treatment of perioperative analgesia. Neostigmine is a cholinesterase inhibitor used to antagonize the residual effects of muscle relaxants and also produces an analgesic effect., Objectives: To investigate the analgesic effects of intrathecally injected pentazocine and neostigmine and their interaction., Methods: Sprague-Dawley rats were used to test the analgesic effect of pentazocine and neostigmine using the paw formalin pain model and the incision mechanical allodynia model. Pentazocine (3, 10, 30, and 100  μ g), neostigmine (0.3, 1, 3, and 10  μ g) or a pentazocine-neostigmine mixture were separately injected to evaluate their antinociceptive effects alone on the treatment groups. The corresponding control group received an intrathecal injection containing the same volume of saline. The formalin pain test, or the plantar incision pain behavior test were performed 30 minutes later. Isobolographic analysis was used to evaluate the interaction between pentazocine and neostigmine. Intrathecally administered selective mu-opioid receptor antagonist CTAP, selective kappa-opioid receptor antagonist nor-Binaltorphimine (nor-BNI), nonselective opioid receptor antagonist naloxone, and muscarinic acetylcholine receptor antagonist atropine were also used to test the possible interaction mechanism. These antagonists were used 30 minutes before the pentazocine and neostigmine mixtures which were intrathecally injected., Results: Intrathecally administered pentazocine (3, 10, 30, and 100  μ g) and neostigmine (0.3, 1, 3, and 10  μ g) alone had a marked dose-related impact on suppressing the biphasic responses in the formalin test. Pentazocine (3, 10, 30, and 100  μ g) and neostigmine (0.3, 1, 3, and 10  μ g) alone attenuated the mechanical allodynia in a plantar incision model in a dose-dependent manner. Isobolographic analysis revealed that the mixture of intrathecal pentazocine and neostigmine synergistically decreased both phase I and II activity in the formalin test and mechanical allodynia in the plantar incision model. Pretreatment of intrathecally administered nor-BNI, naloxone, atropine, but not CTAP, antagonized the analgesic effect of the pentazocine-neostigmine mixture., Conclusions: All of these results suggest that the combined application of pentazocine and neostigmine is an effective way to relieve pain from formalin and acute incision mechanical allodynia. The synergistic effect between pentazocine and neostigmine is mostly attributed to the kappa-opioid receptor and the cholinergic receptor in the spinal cord., Competing Interests: The authors declare that they have no competing interests., (Copyright © 2022 Huiying Huang et al.)

Botulinum neurotoxin type A1 (BoNT-A) reduces the peripheral peptide and cytokine upregulation in rats with antigen-evoked persistent immunogenic hypersensitivity (PIH) of the temporomandibular joint (TMJ). Herein, we examined the effects of two preparations of BoNT-A, abobotulinumtoxinA (aboBoNT-A; Dysport) and onabotulinumtoxinA (onaBoNT-A; Botox), on spontaneous and evoked nociceptive behaviors, as well as on central neuronal and astroglial activation. The antigen-evoked PIH was induced in rats via repeated systemic and unilateral intra-articular (i.a.) injections of methylated bovine serum albumin (mBSA). Rats were subsequently injected with unilateral i.a. aboBoNT-A (14 U/kg), onaBoNT-A (7 U/kg), or the vehicle (saline). After i.a. treatments, spontaneous and mechanically evoked nocifensive behaviors were assessed before and after the low-dose i.a. formalin (0.5%) challenge. The central effects of BoNT-A were assessed by an immunohistochemical analysis of cleaved synaptosomal-associated protein 25 (cSNAP-25) presence, c-Fos, GFAP, and CGRP expression in the trigeminal nucleus caudalis (TNC). Both BoNT-A preparations similarly reduced the formalin-induced spontaneous pain-related behaviors and mechanical allodynia of the hypernociceptive rats. Likewise, their effects were associated with the central occurrence of cSNAP-25 and reduction of c-Fos and GFAP upregulation in the TNC. BoNT-A antinociceptive activity on the PIH is associated with the toxin axonal transport to trigeminal sensory areas and reduction of neuronal and glial activation in central nociceptive regions.

Objectives: Nasal septal surgery is one of the most common surgical procedure performed by otolaryngologists. Nasal packs are used for bleeding control, prevention of septal hematoma, replacement of mucoperichondrial flaps, and stabilization of the septum after nasal septal surgery. The aim of this study was to investigate the effects of albumin-glutaraldehyde-based tissue adhesive (Bioglue), which can be used as an alternative to nasal pack on the nasal septum after experimental nasal septum surgery., Methods: A total of 16 female Wistar albino rats were randomly separated into the study group (n = 10) and the control group (n = 6). After raising the mucoperichondrial flap on one side of the septum, Bioglue was used to fix the mucoperichondrial flap over the septal cartilage ın the study group and nasal packs (Merocel) were used for fixation in the control group. The rats were sacrificed at 2 and 4 weeks after septoplasty. All the tissue samples were evaluated under light microscope by the same pathologist in respect of foreign-body reaction, degree of inflammation, granulation tissue, fibrosis, cartilage damage, and cilia and goblet cell damage. In the control group, the Merocel packs were removed after 2 days and the groups were compared in terms of hematoma., Results: No hematoma was observed in any group. Septal perforation was determined in all the study group participants and loss of cilia and goblet cells and foreign-body reaction were found in 8 samples of the study group participants and in none of the control group., Conclusions: The results of this study show that Bioglue caused segmental cartilage injury; therefore, it may not suitable for use following septal surgery.

Background: Various methods have been used for treatment of hemorrhagic radiation proctitis (HRP) with variable results. Currently, the preferred treatment is formalin application or endoscopic therapy with argon plasma coagulation. Recently, a novel therapy with colonic water irrigation and oral antibiotics showed promising results and more effective compared to 4% formalin application for HRP. The study objective is to compare the effect of water irrigation and oral antibiotics versus 4% formalin application in improving per rectal bleeding due to HRP and related symptoms such as diarrhoea, tenesmus, stool frequency, stool urgency and endoscopic findings., Methods: We conducted a study on 34 patients with HRP and randomly assigned the patients to two treatment arm groups (n=17). The formalin group underwent 4% formalin dab and another session 4 weeks later. The irrigation group self-administered daily rectal irrigation at home for 8 weeks and consumed oral metronidazole and ciprofloxacin during the first one week. We measured the patients' symptoms and endoscopic findings before and after total of 8 weeks of treatment in both groups., Results: Our study showed that HRP patients had reduced per rectal bleeding (p = 0.003) in formalin group, whereas irrigation group showed reduced diarrhoea (p=0.018) and tenesmus (p=0.024) symptoms. The comparison between the two treatment arms showed that irrigation technique was better than formalin technique for tenesmus (p=0.043) symptom only., Conclusion: This novel treatment showed benefit in treating HRP. It could be a new treatment option which is safe and conveniently self-administered at home or used as a combination with other therapies to improve the treatment outcome for HRP., .

The aim of this study was to evaluate an ethanolic extract of propolis and clove essential oil as a substitute for paraformaldehyde for the sanitation of fertile eggs. In total, 1,800 hatching eggs (from 40-week-old CPK [Pesadão Vermelho] breeder hens) were randomly distributed among the treatments (grain alcohol, clove essential oil, ethanolic extract of propolis, and paraformaldehyde). Spraying was the application method for all treatments except for paraformaldehyde, for which fumigation was used. The experimental design was a randomized block design with 4 treatments. Analysis of the incubation parameters was based on 6 replications per treatment. The egg weight loss was lower in the eggs treated with ethanolic extract of propolis (8.59 ± 3.34%) than in the eggs treated with grain alcohol (13.40 ± 2.87%), clove essential oil (12.96 ± 3.33%), and paraformaldehyde (13.05 ± 3.24%). The hatchability of the fertile eggs (51.39 ± 5.81%) and the hatchability of the set eggs (44.74 ± 6.79%) were negatively affected by the application of ethanolic extract of propolis. Late mortality of eggs treated was higher than early mortality in the grain alcohol (12.14 ± 4.72%; 2.86 ± 3.30%), clove essential oil (4.60 ± 5.95%; 3.03 ± 3.50%), and ethanolic extract of propolis (36.63 ± 6.60%, 11.98 ± 4.30%) treatments. The eggs treated with clove essential oil (67.90 ± 1.87%), paraformaldehyde (67.80 ± 1.85%), or grain alcohol (67.50 ± 1.92%) presented chick yields as expected. However, despite the ideal yield of eggs treated with ethanolic extract of propolis (69.25 ± 1.68%), its application at the concentration used in the present research is not recommended. Clove essential oil, when sprayed on fertile eggs as a sanitizing agent, did not differ from paraformaldehyde in relation to hatchery performance parameters., (Copyright © 2019. Published by Elsevier Inc.)

Background: In this study, we evaluated how the Merocel and nasal splint packing placed in the nose after septoplasty surgery affects the olfactory and mucociliary functions of the nose in the early period, and compared the 2 packing with each other., Material and Method: The study included 60 patients with isolated septal deviation and 30 patients in the control group. The patients were randomly divided into 2 groups. Nasal splint was inserted after septoplasty in group A (n = 30). Merocel was inserted in group B (n = 30). The Sniffin sticks test and saccharin test were applied to the patients before surgery and 15 days after the surgery. The same tests were applied to the control group consisting of 30 patients and the results were compared., Results: No complications, such as postoperative bleeding, submucoperichondrial hematoma, or abscess formation, were found in both groups. Mucociliary function was improved after septoplasty, and it was statistically significant, but there was no statistically significant difference between both packing groups. A statistically significant difference was found for the odor test in patients who used nasal splint packing in comparison with patients who used Merocel in the early period., Conclusion: The odor test showed significant differences between the 2 groups and this was statistically significant in the early period. Mucociliary function was better after surgery, but there was no statistical difference in the different nasal packing groups.

Granulomas and shelly hoof (SH), are lesions of sheep feet. Our objective was to use data from four questionnaires on lameness sent to English sheep farmers in 2004, 2013, 2014 and 2015 to further understanding of the risks and aetiologies of both lesions. Granulomas were more likely in flocks where routine foot trimming (odds ratio [OR]=3.17; 95% confidence intervals [CI] 1.11-11.47) and routine footbathing (OR=2.38; 95% CI 1.19-4.83) were practised than where these management protocols were not. SH was more likely in flocks that were footbathed in formalin compared with not footbathing (OR=1.65; 95% CI 1.19-2.30), and was less common in flocks that stocked ewes at more than eight vs. four per acre (OR=0.34; 95% CI 0.17-0.68). There were weak associations between SH and foot trimming. In 2004 only, SH was more likely in flocks where therapeutic foot trimming was practised than not practised (OR=2.24; 95% CI 1.12-4.68). In 2014 only, SH was marginally less likely in flocks where no feet bled during trimming, compared with flocks not routinely trimmed (OR=0.55; CI 0.30-1.00); SH was not related to foot trimming once severe footrot was included. We propose that flocks with granulomas and SH would decrease if farmers stopped footbathing in general, in particular with formalin, and avoided foot trimming whether as a therapeutic or routine practice. Further work is needed to understand the role of stocking density., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Purpose: Nasal packing is frequently used after septoplasty and some complications caused by nasal packing are unavoidable. A nasal septal retainer has recently been developed. We evaluated the safety and clinical efficacy of the retainer in septoplasty, and the subjective symptoms of patients with the retainer were compared with Merocel nasal packing., Methods: A prospective, randomized, controlled study was performed in patients who had undergone septoplasty. In total, 39 patients were randomized to receive Merocel (n = 17) or the retainer (n = 22) after septoplasty. The deviation of nasal septum and nasal mucosa was evaluated by endoscopy. The clinical efficacy and subjective symptoms were compared using the visual analog scale., Results: During the packing/retaining period, the mean scores of headache, nasal obstruction, epiphora, and facial pressure in the retainer group were significantly lower than in the Merocel group (P < 0.05); the mean scores of nasal pain, nasal itching, rhinorrhea, dysphagia, and sleep disturbance in the retainer group were lower than in the Merocel group, but the difference did not reach statistical significance. On the removal of Merocel/retainer, nasal pain was significantly lower in patients with the retainer (P < 0.05). In the retainer group, the incidence of grade 1 bleeding was 45.5%, and grade 0 bleeding was 54.5%. In the Merocel group, the incidence of grade 2 bleeding was 23.5%, grade 1 was 47.1%, and grade 0 was 29.4%., Conclusions: The nasal septal retainer is suitable for use after septoplasty with more beneficial effects than nasal packing.

Axolotls ( Ambystoma mexicanum ) from a research colony presented with multifocal, white chalky to gray skin lesions, a diffuse whitish to blue hue to the integument, and friable gill filaments. Skin scrapings and wet mounts revealed Chilodonella , Ichthyobodo , and a trichodinid species. The average overall burden (that is, all 3 species) per axolotl ranged from 0 to 25 parasites per 40 × field (p40f; mean ± 1 SD, 2.6 ± 5.5), with a prevalence of 12%, 60%, and 48%, respectively. Concurrent with husbandry modifications, axolotls were treated with an 8-h static immersion bath that contained 0.025 mL/L 37% formaldehyde. Chilodonella organisms were no longer observed after the initial treatment, and Ichthyobodo decreased from 2.4 ± 5.6 to 0.6 ± 1.8 organisms p40f. However, the average overall burden increased 4-fold to 10.5 ± 9.8 parasites p40f, and the trichodinid organisms increased 13-fold from 0.8 ± 2.3 to 10.4 ± 9.2 organisms p40f. A second treatment consisted of an 8-h immersion bath that contained 0.05 mL/L 37% formaldehyde on 2 consecutive days. A significant change was noted in the average overall burden of 0.5 ± 1.1 parasites p40f, a greater than 5- and 21-fold decrease from pretreatment and after the initial treatment, respectively. No significant change between the first and second treatment was observed for Ichthyobodo , with 0.6 ± 1.2 organisms p40f, but this number represented a significant decrease from pretreatment. After the second treatment, the trichodinid organism was detected in only one axolotl, with a low overall burden of 0.2 ± 0.4 organisms p40f and resulting in a significant decrease in the trichodinid count to 0.01 ± 0.04 organisms p40f. Treatment with formalin (37% formaldehyde), in conjunction with husbandry improvements, was effective in significantly reducing ectoparasite burden and eliminating clinical symptoms in axolotls but did not fully eliminate all protozoa.

Study Objective: The primary objective of this study is to compare the effectiveness of 3 treatment protocols to stop anterior epistaxis: classic compression, nasal packing, and local application of tranexamic acid. It also aims to determine the frequency of rebleeding after each of these protocols., Methods: This single-center, prospective, randomized controlled study was conducted with patients who had spontaneous anterior epistaxis. The study compared the effect of 3 treatment options, tranexamic acid with compression but without nasal packing, nasal packing (Merocel), and simple nasal external compression, on the primary outcome of stopping anterior epistaxis bleeding within 15 minutes., Results: Among the 135 patients enrolled, the median age was 60 years (interquartile range 25% to 75%: 48 to 72 years) and 70 patients (51.9%) were women. The success rate in the compression with tranexamic acid group was 91.1% (41 of 45 patients); in the nasal packing group, 93.3% (42 of 45 patients); and in the compression with saline solution group, 71.1% (32 of 45 patients). There was an overall statistically significant difference among the 3 treatment groups but no significant difference in pairwise comparison between the compression with tranexamic acid and nasal packing groups. In regard to no rebleeding within 24 hours, the study found rates of 86.7% in the tranexamic acid group, 74% in the nasal packing group, and 60% in the compression with saline solution group., Conclusion: Applying external compression after administering tranexamic acid through the nostrils by atomizer stops bleeding as effectively as anterior nasal packing using Merocel. In addition, the tranexamic acid approach is superior to Merocel in terms of decreasing rebleeding rates., (Copyright © 2019 American College of Emergency Physicians. Published by Elsevier Inc. All rights reserved.)

Different sanitization methods were evaluated as alternatives to formaldehyde fumigation for the reduction of eggshell and yolk sac microbiological counts, improvement of eggshell quality, incubation parameters, and day-old chick quality. A total of 10,080 hatching eggs were collected from a 70-wk-old commercial broiler breeder flock and distributed in a completely randomized block design with seven treatments: fumigation with paraformaldehyde (5.03 g/m3/30 min), fumigation with ozone (5-15 ppm/30 min), ultraviolet light-C irradiation (8.09 mW/cm2; 120 s; UV-C), hydrogen peroxide spraying (3%; 0.69 mL/egg), peracetic acid spraying (0.3%; 0.69 mL/egg; PAA), water spraying (0.69 mL/egg; water control), and without disinfection (dry control-DC). Spraying eggs with PAA and UV-C significantly reduced aerobic bacteria plate counts compared to the DC group. In addition, eggs disinfected with PAA had lower Enterobacteriaceae counts than the DC and water control groups. Eggshell quality, incubation parameters, and microbiological counts for yolk sac did not differ (P > 0.05) among treatments. This study demonstrated the potential for the application of PAA and UV-C for eggshell disinfection instead of formaldehyde; however, an electronic microscopic evaluation of the eggshell is necessary to determine if these methods cause any damage to the cuticle., (© 2019 Poultry Science Association Inc.)

Formalin is commonly used as a component of antiparasitic baths in fisheries. In this study the impact of this bath on the immune profile and oxidative stress parameters was evaluated. A formalin bath was prepared in the concentration of 185.3 mg L -1 (0.17 mL L -1 ) at a temperature of 20 °C. A total of 96 common carp Cyprinus carpio (Linnaeus, 1758) individuals were immersed in this bath for 60 min. The effects were monitored immediately, and then after 24, 48 h and 10 days following the treatment. The study revealed the most effects 10 days after the treatment, when we observed the decrease of lysozyme in skin mucus, the decrease of anti-inflammatory cytokine transforming growth factor beta in gill tissue and increase of interleukin 10 in cranial kidney tissue. The pro-inflammatory cytokine interleukin 1b showed an increase in gill tissue immediately after the bath and the increase in glutathione peroxidase in gill tissue was also observed 24 h and 10 days after bath treatment. The other investigated parameters did not show any significant changes. In conclusion, even though the formalin bath elevated some parameters as mentioned above, formalin used in the bath is probably safe as an antiparasitic treatment of fish., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Continued developments in immuno-oncology require an increased understanding of the mechanisms of cancer immunology. The immunoprofiling analysis of tissue samples from formalin-fixed, paraffin-embedded (FFPE) biopsies has become a key tool for understanding the complexity of tumor immunology and discovering novel predictive biomarkers for cancer immunotherapy. Immunoprofiling analysis of tissues requires the evaluation of combined markers, including inflammatory cell subpopulations and immune checkpoints, in the tumor microenvironment. The advent of novel multiplex immunohistochemical methods allows for a more efficient multiparametric analysis of single tissue sections than does standard monoplex immunohistochemistry (IHC). One commercially available multiplex immunofluorescence (IF) method is based on tyramide-signal amplification and, combined with multispectral microscopic analysis, allows for a better signal separation of diverse markers in tissue. This methodology is compatible with the use of unconjugated primary antibodies that have been optimized for standard IHC on FFPE tissue samples. Herein we describe in detail an automated protocol that allows multiplex IF labeling of carcinoma tissue samples with a six-marker multiplex antibody panel comprising PD-L1, PD-1, CD68, CD8, Ki-67, and AE1/AE3 cytokeratins with 4',6-diamidino-2-phenylindole as a nuclear cell counterstain. The multiplex panel protocol is optimized in an automated IHC stainer for a staining time that is shorter than that of the manual protocol and can be directly applied and adapted by any laboratory investigator for immuno-oncology studies on human FFPE tissue samples. Also described are several controls and tools, including a drop-control method for fine quality control of a new multiplex IF panel, that are useful for the optimization and validation of the technique.

Introduction: Septoplasty or septal reconstruction is a corrective surgical procedure performed to straighten the nasal septum. It may be associated with numerous complications. To minimize these complications, both nasal cavities are frequently packed with different types of nasal packing., Materials and Methods: This prospective, observational, and comparative study was undertaken in the Department of ENT, Rajindra Hospital, Patiala, Punjab, India. A total of sixty patients fulfilling the inclusion criteria participated in the study. They were divided into two groups, Groups A and B. After septoplasty, the nasal cavity was packed with gloved Merocel ® in Group A and ungloved Merocel ® in control group (Group B). The efficacy and patient tolerance for both nasal packings were compared and assessed. The data collected were compiled and analyzed statistically., Results: In our study, it was demonstrated that gloved Merocel ® produces less pain during pack insertion (P = 0.001) and produces less pain while insertion of pack in situ (P = 0.001) and during pack removal (P = 0.001). Saccharin transit time (STT) returned back to normal in gloved Merocel ® group (P = 0.001) in most of patients (27) by the 2 nd week, whereas STT in ungloved Merocel ® group returned back to normal by the 4 th week postoperatively. The differences in impairment in STT between the two groups were found to be statistically significant. There was no statistical significance between both groups for other parameters., Conclusion: Gloved Merocel ® may be preferred over ungloved Merocel ® as nasal packing following septoplasty since both types of packs had similar hemostatic, adhesion prevention properties and similar incidence in postoperative complications and gloved Merocel ® produces less pain during its insertion, while it is in situ, during its removal with early recovery of nasal mucociliary clearance mechanism of nose., Competing Interests: There are no conflicts of interest.

Background: Storage and temperature significantly impact bronchoalveolar lavage fluid (BALF) analysis, and shipment of samples to diagnostic laboratories is often necessary. Alternative sample preparation methods could limit storage and temperature effects., Objectives: This study aimed to determine if airway wash samples that were fixed in formalin after being embedded in Histogel or Gelfoam gave comparable results to fresh cytocentrifuged or sediment smear preparations for the evaluation of cell morphology., Methods: Eleven bronchoalveolar lavage and 3 transtracheal wash fluids were available, including 8 canine, 1 feline, and 5 equine samples. Cytocentrifuged and sediment smear preparations were prepared for routine analysis. Airway fluids were reserved for further evaluation. Total nucleated cell counts (TNCCs) were determined using a hemocytometer. The remaining fluid was used for Histogel and Gelfoam preparations. Each preparation was analyzed by a single board-certified clinical pathologist and assigned cellularity (1-3) and morphology scores (1-4)., Results: Cellularity and morphology were significantly worse for the sediment smear, Histogel, and Gelfoam preparations compared with the cytocentrifuged preparations. The Gelfoam preparations had significantly worse cellularity scores than all other methods. Cellularity scores for sediment smears and Histogel preparations were significantly correlated with TNCCs., Conclusions: TNCCs impacted the cellularity of the sediment smears and Histogel preparations. Cytocentrifuged preparations resulted in the best cellularity and morphology and are, therefore, recommended whenever possible. Neither the Histogel nor the Gelfoam methods demonstrated any advantage over sediment smear preparations, and both performed poorly when compared with cytocentrifuged preparations. Therefore, we do not recommend the use of these methods., (© 2018 American Society for Veterinary Clinical Pathology.)

Purpose of Review: There are various specific therapeutic intervention available to treat hemorrhagic cystitis, once emergency treatment has been carried out. The lack of prospective studies, because of the relative rarity of this condition, makes it difficult to hierarchize the therapeutic sequence. The present review presents and summarizes the literature published on radiation-induced hemorrhagic cystitis from April 2015, date of a precedent exhaustive review, to March 2018., Recent Findings: During our period of interest, 13 clinical studies and two new clinical trials protocols were published. Most of the clinical studies were retrospective and presented data about hyperbaric oxygen (HBO) therapy, comforting its place as a well tolerated and effective first-line treatment. Other studies reported the outcomes of treatments with alum, formalin, silver nitrate, fulguration with laser or definitive surgery., Summary: Although authors seem to agree that formalin and surgery have their role as effective but potentially morbid last-line treatments, there is no consensus on primary approach to management of radiation-induced hemorrhagic cystitis beyond symptomatic measures. Several treatments have proven excellent response rates and few side effects. The results of on-going prospective studies on mesenchymal stromal cells or tacrolimus instillations are awaited, but the main discriminating factor to choose between treatments remains local availability.

Cannabinoids have shown promise for the treatment of intractable pain states and may represent an alternative pharmacotherapy for pain management. A growing body of clinical evidence suggests a role for sex in pain perception and in cannabinoid response. We examined cannabinoid sensitivity and tolerance in male and female mice expressing a desensitization-resistant form (S426A/S430A) of the cannabinoid type 1 receptor (CB1R). Mice were assessed for acute and inflammatory nociceptive behaviors in the formalin test following pretreatment with either vehicle or mixed CB1R/CB2R agonists, Δ-9-tetrahydrocannabinol ([INCREMENT]-THC) (1-6 mg/kg) or CP 55,940 (0.06-0.2 mg/kg). Tolerance to the effects of 6 mg/kg [INCREMENT]-THC or 0.1 mg/kg CP 55,940 was examined by the formalin test following chronic daily dosing. Female mice showed decreased sensitivity to the effects of [INCREMENT]-THC and CP 55,940 compared with male mice. The S426A/S430A mutation increased the attenuation of nociceptive behaviors for both agonists in both sexes. Female mice displayed delayed tolerance to [INCREMENT]-THC compared with male mice, whereas the S426A/S430A mutation conferred a delay in tolerance to [INCREMENT]-THC in both sexes. Male S426A/S430A mutant mice also display resistance to tolerance to CP 55,940 compared with wild-type controls. This study demonstrates sex and genotype differences in response for two different cannabinoid agonists. The results underscore the importance of including both male and female mice in preclinical studies of pain and cannabinoid pharmacology.

Objectives: To compare results of surgical treatment and complications of patients with unilateral or bilateral thoracic and combined pulmonary echinococcosis., Methods: This cross-sectional analysis of a prospective study was conducted in the Department of Thoracic and Pediatric Surgery, Scientific Center of Surgery, Almaty, Kazakhstan among 598 patients with pulmonary echinococcosis, who had surgical treatment with various surgical methods, depending on the prevalence of echinococcosis, as follows: right lung in 357 (59.5%) patients, left lung in 243 (40.5%) patients, bilateral in 95 (15.8%) patients, and complicated echinococcosis in 317 (52.8%) patients. Length of stay per hospital stay has been decreased (p less than 0.0001) by video-thoracoscopic echinococcectomy with the high-energy laser (HEL) treatment of cyst, than after echinococcectomy by cyst treatment with povidone-iodine. Treatment with formalin presented the most longest hospital stay (p less than 0.0001)., Results: Comparative analysis of patients with uncomplicated and complicated pulmonary echinococcosis showed a high frequency of postoperative complications associated with complicated echinococcosis (OR = 2.2, p less than 0.0001). Conclusion: Despite the success of surgical treatment of pulmonary echinococcosis, issues of intraoperative dissemination and safety remain, and treatment success rates can be improved. These factors require further prospective multicenter studies.

Background: After resection, specimens are subjected to formalin fixation during histological processing. This procedure can result in tissue shrinkage, with the amount of shrinkage related to tissue composition and tissue type., Aims: To evaluate the shrinkage of nasal mucosa and cartilage tissue and compare differences in shrinkage after resection, after formalin fixation, and during microscopic examination to understand differences in the rate of shrinkage of different tissue types., Study Design: Animal experimentation., Methods: Fresh nasal septa were excised from sheep (10 mm diameter in 40 sheep and 20 mm diameter in 40 sheep). The mucosa was separated from one side of the cartilage, with the contralateral mucosa remaining attached to the cartilage. Specimen diameters were measured in situ, after resection, after fixation for 6 or 24 hours (10% formalin), and during microscopic examination., Results: There were no differences between the in situ and after resection diameters of any tissue components (free mucosa, mucosa attached to cartilage, and cartilage) of all nasal specimens (10- or 20-mm diameter and 6- or 24-hour fixation). However, significant shrinkage occurred between resection and after-fixation. Regarding tissue specimens that were fixed for different durations (6 or 24 hours), we observed a significantly smaller mean tissue diameter in specimens fixed for 24 hours versus those fixed for 6 hours for mucosa attached to cartilage (in the 10-mm diameter after-fixation samples), free mucosa (in the 20-mm diameter after-fixation samples), mucosa attached to cartilage (in the 20-mm diameter after-fixation and microscopic measurement samples), and cartilage (in the 20-mm diameter after-fixation samples). Tissue shrinkage was greatest in free mucosal tissue and least in cartilage., Conclusion: These results should be considered when evaluating patients undergoing surgical procedures for nasal cavity and paranasal sinus malignancies. Surgical margins should be measured before fixation or evaluated if possible before fixation and shrinkage.

Immunofluorescence is a common method used to visualize subcellular compartments and to determine the localization of specific proteins within a tissue sample. A great hindrance to the acquisition of high quality immunofluorescence images is endogenous autofluorescence of the tissue caused by aging pigments such as lipofuscin or by common sample preparation processes such as aldehyde fixation. This protocol describes how background fluorescence can be greatly reduced through photobleaching using white phosphor light emitting diode (LED) arrays prior to treatment with fluorescent probes. The broad-spectrum emission of white phosphor LEDs allow for bleaching of fluorophores across a range of emission peaks. The photobleaching apparatus can be constructed from off-the-shelf components at very low cost and offers an accessible alternative to commercially available chemical quenchers. A photobleaching pre-treatment of the tissue followed by conventional immunofluorescence staining generates images free of background autofluorescence. Compared to established chemical quenchers which reduced probe as well as background signals, photobleaching treatment had no effect on probe fluorescence intensity while it effectively reduced background and lipofuscin fluorescence. Although photobleaching requires more time for pre-treatment, higher intensity LED arrays may be used to reduce photobleaching time. This simple method can potentially be applied to a variety of tissues, particularly postmitotic tissues that accumulate lipofuscin such as the brain and cardiac or skeletal muscles.

The demand for nucleic acid and protein derivatives from formalin-fixed paraffin-embedded (FFPE) tissue has greatly increased due to advances in extraction and purification methods, making these derivatives available for numerous genomic and proteomic platforms. Previously, DNA, RNA, microRNA (miRNA), or protein derived from FFPE tissue blocks were considered "unfit" for such platforms, as the process of tissue immobilization by FFPE resulted in cross-linked, fragmented, and chemically modified macromolecules. We conducted a systematic examination of nucleic acids and proteins co-extracted from 118 FFPE blocks sampled from the AIDS and Cancer Specimen Resource (ACSR) at The George Washington University after stratification by storage duration and the three most common tumor tissue types at the ACSR (adenocarcinoma, squamous cell carcinoma, and papillary carcinoma). DNA, RNA, miRNA, and protein could be co-extracted from 98% of the FFPE blocks sampled, with DNA and miRNA "fit" for diverse genomic purposes including sequencing. While RNA was the most labile of the FFPE derivatives, especially when assessed by RNA integrity number (RIN), it was still "fit" for genomic methods that use smaller sequence lengths, e.g., quantitative PCR. While more than half of the protein derivatives were fit for proteomic purposes, our analyses indicated a significant interaction effect on the absorbance values for proteins derived from FFPE, implying that storage duration may affect protein derivatives differently by tumor tissue type. The mean absorbance value for proteins derived from more recently stored FFPE was greater than protein derived from older FFPE, with the exception of adenocarcinoma tissue. Finally, the fitness of one type of derivative was weakly associated with the fitness of derivatives co-extracted from the same FFPE block. The current study used several novel quality assurance approaches and metrics to show that archival FFPE tissue blocks are a valuable resource for contemporary genomic and proteomic platforms.

Purpose: The aim of this quasi-experimental study is to evaluate a novel technique for an outpatient application of formalin for chronic rectal bleeding after prostate irradiation., Methods: This is a quasi- experimental clinical trial developed between January 2010 and July 2015, including 35 patients with chronic radiation rectitis (CRP) due to a previous prostate radiation course. The study's eligibility was (1) completed external beam radiation therapy for prostate carcinoma >6 months previously, (2) rectal bleeding, defined as a frequency of >1× per week and/or needing of blood transfusions, and (3) diagnosis of chronic proctitis at colonoscopy. The 5% formalin application was performed by a custom applicator, which requires neither anesthesia nor sigmoidoscopy. The endpoint of the study was bleeding cessation and hemoglobin level., Results: The onset of bleeding due to chronic rectitis was 12 months (6-36). During a median follow-up of 24 months, the rate of overall efficacy was 94%. The sustained complete response in 1 and 2 years was 80% and 73%, respectively. The Hb mean pre- and post-treatment differed significantly (12.2 vs 14.4, p = 0.0001). The rates of blood transfusion differed significantly, pre- and post-treatment (17% vs 5.7%, p = 0.031)., Conclusion: The technique is very effective and safe, resulting to a significant improvement of hemoglobin levels and quality of life scores. Further studies are warranted to compare this technique with other treatment options for chronic radiation-induced rectal bleeding.

Aim: The authors aimed to research the effects of autologous platelet-rich plasma, which is known for the positive effects on wound healing, on postoperatif living quality of the patients after using on nasal surgery., Methods: Patients who undergo nasal operation according to randomized patient's choice have been injected with saline merocel pack and platelet-rich plasma (PRP) in their nasal path. Postoperative is followed by 1 month; Nose Obstruction Symptom Evaluation (NOSE) scala score, bleeding, pain, and crust rate have been compared between 2 groups., Results: As a result of the 1 month follow-up, it was seen that the treatment group experienced better results in terms of NOSE scale than the control group patients and this was significant difference in terms of NOSE. Less bleeding and crust was seen on the treatment group patients than the control group patients and statically significant difference was found. In terms of visual analogue scale score no statically significant difference was found between 2 groups., Conclusion: According to the authors' study on PRP, the authors found out that by using PRP wound can be healed faster in early period of postoperative. It was seen with the authors' research that on postoperative early period crusts, bleeding and postoperative complaints are lesser.

Objective: The purpose of our study was to compare Merocel (Merocel Hemox 10 cm) and BNP (biodegradable nasopore) during a septoturbinoplasty procedure in terms of efficiency and patient comfort., Patients and Methods: We carried out a retrospective review of 72 patients who had undergone septoturbinoplasty between January 2015 and January 2016. Each group, packed with BNP or Merocel Hemox 10 cm was composed of 36 patients. A standard visual analogue scale ranging from zero (no symptoms) to 10 (the most severe symptoms) was used to assess subjective symptoms. To compare the usefulness of materials we evaluated the postoperative bleeding, infection and adhesion after the removal of packing with and endoscopic examination using a 5-point scale (zero, absent; 1, mild; 2, moderate; 3, severe; and 4, very severe). Secretions and crusts were evaluated 1 week and 4 weeks after surgery in both groups using a 5-point scale (zero, absent; 1, mild; 2, moderate; 3, severe; and 4, very severe)., Results: A total of 72 patients were enrolled in the study, 45 women and 27 men; age range 15-78 with a mean age of 47 years. In the group A (Merocel group), 21 cases showed grade 1 bleeding (58%), 11 cases grade 2 (30%) and 4 patients grade 0 (11.1%). In the group B (BNP group), 29 cases showed grade 0 bleeding (80.56%) and 7 cases showed grade 1 bleeding (19.44%). There was a statistical significant difference between the Merocel group and the BNP group in terms of bleeding after removal of packing material (p < 0.05). In the group A, 16 patients developed mild adhesion (44%), 8 patients moderate adhesion (22.2%), 3 patients severe adhesion (8.33%) and 1 patient very severe adhesion (2.77%). BNP nasal packing didn't cause any adhesion in 25 patients (69.4%), 11 patients developed mild adhesion (30.5%). So there was a statistical significant difference between group A and group B regarding the adhesion (p < 0.05). There was a statistically significance reduction of nasal secretions and crusts at a week after surgery in the BNP group vs. Merocel group. The difference is not statistically significant 4 weeks after surgery. About the severity of symptoms related to nasal packing, we found a statistically significant difference (p < 0.05) between Merocel and BNP group regarding the pain during packing removal, the general satisfaction and the pressure., Conclusions: Biodegradable nasopore reduced pain and patient discomfort during packing removal and causes less bleeding compared to Merocel hemox 10 cm. This type of material can be used after septoturbinolplasty.

Background: Nearly eleven years have passed since the International Agency for Research on Cancer classified Formaldehyde (FA) as a known human carcinogen (group 1), yet the safety of anatomy pathology workers who are currently exposed to FA is still a matter of concern., Objective: The purpose of this study was to evaluate the literature to discover which topics have been focused on and what the latest developments are in managing FA indoor pollution in anatomy pathology departments. which topics have been focused on and what the latest developments in managing FA indoor pollution in anatomy pathology departments., Methods: For the purpose of this review, we searched for publications in PubMed and Web of Science using selected keywords. The articles were reviewed and categorized into one or more of the following three categories based on subject matter: exposure levels exposure controls and alternatives., Results: Our search resulted in a total of 31 publications that matched our inclusion criteria. The topics discussed, in order of frequency (from highest to lowest), were: "exposure controls", "exposure levels" and "alternatives". The most frequently suggested intervention was to improve local exhaust ventilation systems to minimize FA levels in gross anatomy laboratories., Conclusions: We found a lack of evidence-based improvement interventions that aimed to control exposure to FA. According to this finding, and pending a valid chemical substitute for FA, we suggest the need for more in-depth studies targeting measures to minimize exposures to FA in pathology departments.

Introduction: The aim of this study was to systematically review and evaluate the literature regarding the prognosis of altered sensation after extrusion of root canal filling materials and the possible factors influencing it., Methods: A systematic search of the literature was performed to identify studies that reported on altered sensation after extrusion of root canal filling materials during endodontic treatments. The articles were evaluated for their relevance based on strict inclusion criteria, and the identified suitable articles were subject to data extraction and analysis., Results: Initially, 109 possibly relevant articles were identified. After screening and full-text evaluations, 28 articles that met the inclusion criteria were analyzed, reporting on a total of 84 patients with altered sensation after extrusion of root canal filling materials. All the included studies, except 1 case series, were case reports. Under the limited available data, the extracted data showed that 91% of the patients had fully or partially recovered over time. Most of the cases in the lower molars as well as most of the cases in which the obturation was performed using paraformaldehyde-containing sealer or cases in which an immediate treatment was not performed did not fully recover., Conclusions: The current scientific knowledge regarding the prognosis of nerve injuries caused by overextruded endodontic materials relies primarily on case reports. Within the limitations of the published data, it seems that the tooth locations, types of extruded materials and the obturation technique, and treatment after the injury may affect the nerve injury prognosis., (Copyright © 2016 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.)

Background: This is an update of a Cochrane review first published in 2002, and previously updated in 2007. Late radiation rectal problems (proctopathy) include bleeding, pain, faecal urgency, and incontinence and may develop after pelvic radiotherapy treatment for cancer., Objectives: To assess the effectiveness and safety of non-surgical interventions for managing late radiation proctopathy., Search Methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 11, 2015); MEDLINE (Ovid); EMBASE (Ovid); CANCERCD; Science Citation Index; and CINAHL from inception to November 2015., Selection Criteria: We included randomised controlled trials (RCTs) comparing non-surgical interventions for the management of late radiation proctopathy in people with cancer who have undergone pelvic radiotherapy for cancer. Primary outcomes considered were: episodes of bowel activity, bleeding, pain, tenesmus, urgency, and sphincter dysfunction., Data Collection and Analysis: Study selection, 'Risk of bias' assessment, and data extraction were performed in duplicate, and any disagreements were resolved by involving a third review author., Main Results: We identified 1221 unique references and 16 studies including 993 participants that met our inclusion criteria. One study found through the last update was moved to the 'Studies awaiting classification' section. We did not pool outcomes for a meta-analysis due to variation in study characteristics and endpoints across included studies.Since radiation proctopathy is a condition with various symptoms or combinations of symptoms, the studies were heterogeneous in their intended effect. Some studies investigated treatments targeted at bleeding only (group 1), some investigated treatments targeted at a combination of anorectal symptoms, but not a single treatment (group 2). The third group focused on the treatment of the collection of symptoms referred to as pelvic radiation disease. In order to enable some comparison of this heterogeneous collection of studies, we describe the effects in these three groups separately.Nine studies assessed treatments for rectal bleeding and were unclear or at high risk of bias. The only treatments that made a significant difference on primary outcomes were argon plasma coagulation (APC) followed by oral sucralfate versus APC with placebo (endoscopic score 6 to 9 in favour of APC with placebo, risk ratio (RR) 2.26, 95% confidence interval (CI) 1.12 to 4.55; 1 study, 122 participants, low- to moderate-quality evidence); formalin dab treatment (4%) versus sucralfate steroid retention enema (symptom score after treatment graded by the Radiation Proctopathy System Assessments Scale (RPSAS) and sigmoidoscopic score in favour of formalin (P = 0.001, effect not quantified, 1 study, 102 participants, very low- to low-quality evidence), and colonic irrigation plus ciprofloxacin and metronidazole versus formalin application (4%) (bleeding (P = 0.007, effect not quantified), urgency (P = 0.0004, effect not quantified), and diarrhoea (P = 0.007, effect not quantified) in favour of colonic irrigation (1 study, 50 participants, low-quality evidence).Three studies, of unclear and high risk of bias, assessed treatments targeted at something very localised but not a single pathology. We identified no significant differences on our primary outcomes. We graded all studies as very low-quality evidence due to unclear risk of bias and very serious imprecision.Four studies, of unclear and high risk of bias, assessed treatments targeted at more than one symptom yet confined to the anorectal region. Studies that demonstrated an effect on symptoms included: gastroenterologist-led algorithm-based treatment versus usual care (detailed self help booklet) (significant difference in favour of gastroenterologist-led algorithm-based treatment on change in Inflammatory Bowel Disease Questionnaire-Bowel (IBDQ-B) score at six months, mean difference (MD) 5.47, 95% CI 1.14 to 9.81) and nurse-led algorithm-based treatment versus usual care (significant difference in favour of the nurse-led algorithm-based treatment on change in IBDQ-B score at six months, MD 4.12, 95% CI 0.04 to 8.19) (1 study, 218 participants, low-quality evidence); hyperbaric oxygen therapy (at 2.0 atmospheres absolute) versus placebo (improvement of Subjective, Objective, Management, Analytic - Late Effects of Normal Tissue (SOMA-LENT) score in favour of hyperbaric oxygen therapy (HBOT), P = 0.0019) (1 study, 150 participants, moderate-quality evidence, retinol palmitate versus placebo (improvement in RPSAS in favour of retinol palmitate, P = 0.01) (1 study, 19 participants, low-quality evidence) and integrated Chinese traditional plus Western medicine versus Western medicine (grade 0 to 1 radio-proctopathy after treatment in favour of integrated Chinese traditional medicine, RR 2.55, 95% CI 1.30 to 5.02) (1 study, 58 participants, low-quality evidence).The level of evidence for the majority of outcomes was downgraded using GRADE to low or very low, mainly due to imprecision and study limitations. , Authors' Conclusions: Although some interventions for late radiation proctopathy look promising (including rectal sucralfate, metronidazole added to an anti-inflammatory regimen, and hyperbaric oxygen therapy), single small studies provide limited evidence. Furthermore, outcomes important to people with cancer, including quality of life (QoL) and long-term effects, were not well recorded. The episodic and variable nature of late radiation proctopathy requires large multi-centre placebo-controlled trials (RCTs) to establish whether treatments are effective. Future studies should address the possibility of associated injury to other gastro-intestinal, urinary, or sexual organs, known as pelvic radiation disease. The interventions, as well as the outcome parameters, should be broader and include those important to people with cancer, such as QoL evaluations.