Early Experience with a Novel Treatment for Menière's Disease: A Long Acting Dexamethasone Formulation for Precise Delivery to the Round Window Membrane.

OBJECTIVE: To investigate the safety and feasibility of precise delivery of a long-acting gel formulation containing 6% dexamethasone (SPT-2101) to the round window membrane for the treatment of Menière's disease. STUDY DESIGN: Prospective, unblinded, cohort study. SETTING: Tertiary care neurotology clinic. PATIENTS: Adults 18 to 85 years with a diagnosis of unilateral definite Menière's disease per Barany society criteria. INTERVENTIONS: A single injection of a long-acting gel formulation under direct visualization into the round window niche. MAIN OUTCOME MEASURES: Procedure success rate, adverse events, and vertigo control. Vertigo control was measured with definitive vertigo days (DVDs), defined as any day with a vertigo attack lasting 20 minutes or longer. RESULTS: Ten subjects with unilateral Menière's disease were enrolled. Precise placement of SPT-2101 at the round window was achieved in all subjects with in-office microendoscopy. Adverse events included one tympanic membrane perforation, which healed spontaneously after the study, and two instances of otitis media, which resolved with antibiotics. The average number of DVDs was 7.6 during the baseline month, decreasing to 3.3 by month 1, 3.7 by month 2, and 1.9 by month 3. Seventy percent of subjects had zero DVDs during the third month after treatment. CONCLUSIONS: SPT-2101 delivery to the round window is safe and feasible, and controlled trials are warranted to formally assess efficacy.

Prevalence, associated risk factors; and patient and economic impact of multiple sensory impairment in a multi-ethnic elderly population in Singapore: the PIONEER study.

BACKGROUND: To determine the prevalence, risk factors; and impact on patient health and economic outcomes across the laterality spectrum of multiple sensory impairment (MSI) in a multi-ethnic older Asian population. METHODS: In this population-based study of Singaporeans aged ≥ 60 years, MSI was defined as concomitant vision (visual acuity > 0.3 logMAR), hearing (pure-tone air conduction average > 25 dB), and olfactory (score < 12 on the Sniffin' Sticks test) impairments across the spectrum of laterality (any, unilateral, combination [of unilateral and bilateral], and bilateral). RESULTS: Among 2,057 participants (mean ± SD 72.2 ± 0.2 years; 53.1% female), the national census-adjusted prevalence rates of any, unilateral, combination, and bilateral MSI were 20.6%, 1.2%, 12.2%, and 7.2%, respectively. Older age, male gender, low socioeconomic status (SES), and smoking (all p < 0.05) were independently associated with higher likelihood of any MSI. Compared to those with no sensory loss, those with MSI had significantly decreased mobility (range 5.4%-9.2%), had poor functioning (OR range 3.25-3.45) and increased healthcare costs (range 4-6 folds) across the laterality spectrum. Additionally, bilateral MSI had a significant decrease in HRQoL (5.5%, p = 0.012). CONCLUSIONS: MSI is a highly prevalent medical condition, with 1 in 5; and almost 1 in 10 community-dwelling older Asians having any and bilateral MSI, respectively, with a higher likelihood in men, smokers, and those with low SES. Critically, MSI has a substantial negative impact on patient health and economic outcomes across the laterality spectrum. Sensory testing is critical to detect and refer individuals with MSI for management to improve their functional independence and QoL.

The Impact of Hearing Impairment on Health Indicators in a Multiethnic Population of Older Adults in Singapore.

Background and Objectives: To determine the impact of hearing impairment (HI) on health indicators in a multiethnic Singaporean population of older adults. Research Design and Methods: In this cross-sectional, population-based study, pure-tone averages of air-conduction thresholds at 500 Hz, 1,000 Hz, 2,000 Hz, and 4,000 Hz were calculated for each ear. Eight categories of HI were defined ranging from: 1: No HI to 8: Bilateral severe HI. Health indicators included hearing-related quality of life (H-QoL), depressive symptoms, frailty, gait speed, instrumental activities of daily living, sarcopenia, and cognitive impairment. Multivariable regression models determined the independent associations between HI and outcomes. Results: A total of 2,503 older adults (mean age ± SD 73.4 ± 8.4; 55.2% female participants) were enrolled. Of these, 289 (11.6%), 259 (10.4%), 798 (31.9%), 303 (12.1%), 515 (20.6%), 52 (2.1%), 155 (6.2%), and 115 (4.6%) had hearing levels in Cats 1 to 8, respectively; and 20 (0.8%) used a hearing aid. Compared to those with no HI, participants with unilateral mild HI (Cat 2) had a 107% reduction in H-QoL (ß: 0.63; CI: 0.18, 1.09, p = .006), increasing to a 2,816% reduction (ß: 16.78; CI: 13.25, 20.31, p < .001) in those with bilateral severe HI-Cat 8 (p-trend < .001). Those with Cat 8 also had lower gait speed and we observed a nonsignificant increase in odds of frailty as HI worsened. Discussion and Implications: H-QoL is affected across the spectrum of severity and laterality of HI. Interventions to alleviate the effects of HI and provision of QoL support are warranted. Other health indicators were only affected in late stages, suggesting that slowing disease progression is crucial in clinical management.

3,4-Diaminopyrazolo[3,4-d]pyrimidines: a new three-component microwave-assisted synthesis and anti-leukemic properties.

A convenient method for the synthesis of N3,N4-disubstituted 3,4-diaminopyrazolo[3,4-d]pyrimidines was developed using a three-component reaction of 3,5-diaminopyrazole-4-carbonitriles with primary amines and orthoesters. The preparation of 116 examples demonstrated the good scope of the reaction, which tolerated variations in the substrate structure and was particularly efficient under microwave irradiation. The short reaction time and chromatography-free product isolation add practicality to this method. The anti-leukemic activity was assessed in vitro using K562 and Jurkat T cells, and the selectivity of the most active compounds was evaluated using non-cancerous MRC5 cells. The most promising compound inhibited Jurkat T cells with a GI50 value of 0.5 µM and a selectivity index of 65.

Postmastoidectomy Hyperacusis Syndrome: Clinical Features and Treatment.

OBJECTIVE: We report a novel postmastoidectomy hyperacusis syndrome (PMHS) in patients who have had cortical mastoidectomies and experience hyperacusis to stimuli involving touch of the pinna and periauricular area. This report aims to describe the clinical characteristics of patients predisposed to this disabling complication after mastoid surgery and describes surgical treatment with mastoid cortex resurfacing with hydroxyapatite bone cement. PATIENTS: Three patients who have undergone intact canal wall mastoidectomies for nonchronic middle ear-related pathologies all reported a similar constellation of postoperative symptoms. None of the patients had any ossicular chain or middle ear abnormalities, and none had preoperative conductive hearing loss. All patients reported disabling hyperacusis related to light touch stimuli in the periauricular area. On examination, all three patients demonstrated synchronous movement of the tympanic membrane when the postauricular area was palpated. INTERVENTIONS: After a period of observation, none of the patients noted any improvement to their symptoms. Resurfacing of the mastoid cortex with hydroxyapatite bone cement was performed in all patients. MAIN OUTCOME MEASURES: Presence of touch-induced hyperacusis and audiometry was assessed postoperatively. Patients were also examined for synchronous movement of the tympanic membrane with palpation of the postauricular area. RESULTS: All patients experienced complete resolution of touch-induced hyperacusis postoperatively. Pure-tone audiometric hearing thresholds remained unchanged after mastoid cortex resurfacing, and there was no longer tympanic membrane movement with palpation of the postauricular area. CONCLUSIONS: PMHS can occur in patients after cortical mastoidectomy when there is no history of ossicular chain or history of chronic middle ear disease or middle ear abnormalities. PMHS can cause significant distress to patients and remain underrecognized unless synchronous tympanic membrane movement is specifically examined for. Treatment via mastoid cortex surfacing with hydroxyapatite bone cement is safe and effective.

Three-component microwave-assisted synthesis of 3,5-disubstituted pyrazolo[3,4-d]pyrimidin-4-ones.

A practical three-component method for the synthesis of pyrazolo[3,4-d]pyrimidin-4-ones was developed. The reaction was performed in a one-pot manner under controlled microwave irradiation using easily accessible methyl 5-aminopyrazole-4-carboxylates, trimethyl orthoformate, and primary amines. Under the optimized conditions, challenging substrates, such as N-1 unsubstituted 5-aminopyrazole-4-carboxylates with another substituted amino group in position 3, reacted selectively affording 5-substituted 3-arylamino-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-ones. The reaction tolerated a range of primary amines, including anilines. The advantages of the developed protocol include short reaction time, pot- and step-economy, and convenient chromatography-free product isolation. The structural features of representative products were explored by X-ray crystallography.

Post-operative healing and long-term stability after mastoid cavity reconstruction using the middle temporal artery and inferior musculoperiosteal flaps.

PURPOSE: This study aims to evaluate the surgical outcomes with the use of a combination of the middle temporal artery (MTA) flap and the inferior musculoperiosteal (IMP) flap for mastoid obliteration after canal wall down mastoidectomy. METHODS: Seventy-five patients who have undergone canal wall down mastoidectomy and mastoid obliteration with the MTA and the IMP flaps at a single tertiary hospital were included. Surgical outcomes measured included the creation of a dry mastoid cavity as measured by a previously developed semi-quantitative scale, mastoid cavity epithelization time, rate of revision surgery needed, and rate of recurrent cholesteatoma. RESULTS: Patients were followed up for a median of 29 months. The median time to epithelization of the mastoid cavity was 2 months. At 1 and 3 months, 36.0% and 76.0% of patients had grade 0 and grade 1 cavities, respectively, with either a dry cavity or one or less episodes of mild otorrhea or sensation of wetness. Hundred percent of the patients achieved a grade 2 (more than one episode of otorrhea or the presence of granulation tissue that promptly resolved with simple treatment) or better cavity at 3 months. One patient re-presented with a grade 3 cavity with uncontrolled infection and daily otorrhea secondary to an attic perforation that manifested at 6 months, requiring revision surgery. There were no recurrent cholesteatomas during the follow-up period. CONCLUSIONS: The use of the MTA and the IMP flaps for mastoid obliteration may be considered as an adjunct to achieving a safe, dry ear after canal wall down mastoidectomy.

Eye Protection in ENT Practice During the COVID-19 Pandemic.

OBJECTIVES: There is a lack of evidence-based guidelines with regard to eye protection for aerosol-generating procedures in otolaryngology practice. In addition, some recommended personal protective equipment (PPE) is not compatible with commonly used ENT equipment. This study aims to investigate the degree of eye protection that commonly used PPE gives. STUDY DESIGN: Simulation model. SETTING: Simulation laboratory. METHODS: A custom-built setup was utilized to simulate the clinical scenario of a patient cough in proximity of a health care worker. A system that sprays a xanthan-fluorescein mixture was set up and calibrated to simulate a human cough. A mannequin with cellulose paper placed on its forehead, eyes, and mouth was fitted with various PPE combinations and exposed to the simulated cough. The degree of contamination on the cellulose papers was quantified with a fluorescent microscope able to detect aerosols ≥10 µm. RESULTS: When no eye protection was worn, 278 droplets/aerosols reached the eye area. The use of the surgical mask with an attached upward-facing shield alone resulted in only 2 droplets/aerosols reaching the eye area. In this experiment, safety glasses and goggles performed equally, as the addition of either brought the number of droplets/aerosols reaching the eye down to 0. CONCLUSION: When used with an upward-facing face shield, there was no difference in the eye protection rendered by safety goggles or glasses in this study. Safety glasses may be considered a viable alternative to safety goggles in aerosol-generating procedures.

Discovery of drug-like acetylcholinesterase inhibitors by rapid virtual screening of a 6.9 million compound database.

Cholinesterase inhibitors remain the mainstay of Alzheimer's disease treatment, and the search for new inhibitors with better efficacy and side effect profiles is ongoing. Virtual screening (VS) is a powerful technique for searching large compound databases for potential hits. This study used a sequential VS workflow combining ligand-based VS, molecular docking and physicochemical filtering to screen for central nervous system (CNS) drug-like acetylcholinesterase inhibitors (AChEIs) amongst the 6.9 million compounds of the CoCoCo database. Eleven in silico hits were initially selected, resulting in the discovery of an AChEI with a Ki of 3.2 µM. In vitro kinetics and in silico molecular dynamics experiments informed the selection of an additional seven analogues. This led to the discovery of two further AChEIs, with Ki values of 2.9 µM and 0.65 µM. All three compounds exhibited reversible, mixed inhibition of acetylcholinesterase. Importantly, the in silico physicochemical filter facilitated the discovery of CNS drug-like compounds, such that all three inhibitors displayed high in vitro blood-brain barrier model permeability.

Classification of Temporal Bone Pneumatization on High-Resolution Computed Tomography: Prevalence Patterns and Implications.

Objective The degree of pneumatization of the temporal bone has implications in the pathophysiology and surgical considerations of many temporal bone disorders. This study aims to identify common pneumatization patterns in the petrous apex, mastoid, and infralabyrinthine compartments of the temporal bone. Variables associated with temporal bone pneumatization were also identified. Study Design Case series with chart review. Setting Single tertiary hospital. Subjects and Methods In total, 299 high-resolution computed tomography scans of the temporal bone performed on patients between 2013 and 2016 were reviewed. Only normal temporal bone scans in patients aged 13 years and older were included. Previously published grading systems were used to classify pneumatization patterns in the petrous apex, mastoid, and infralabyrinthine region. Results The most common pneumatization pattern in the petrous apex was group 2 (less than half of the petrous apex medial to the labyrinth is pneumatized), that in the mastoid was group 4 (hyperpneumatization), and that in the infralabyrinthine region was type B (limited pneumatization), at 54.8%, 55.4%, and 76.0% of patients, respectively. Patients with increased pneumatization of 1 temporal bone compartment tended to have increased pneumatization of the same compartment on the contralateral side and the other compartments on the ipsilateral side ( P < .05). Younger age ( P < .001) and male sex ( P = .001) were associated with increased pneumatization in the petrous apex and infralabyrinthine compartments. Conclusion The degree of temporal bone pneumatization varies among the different compartments. Age and sex have a significant association with the degree of pneumatization of the petrous apex and infralabyrinthine compartment.

Changing epidemiology of oral squamous cell carcinoma of the tongue: A global study.

BACKGROUND: There are reports about the changing epidemiology of tongue squamous cell carcinoma (SCC), with recent reports indicating an increasing incidence in young women. METHODS: Data on incident cases of tongue SCC were collected from cancer registries worldwide. RESULTS: Data from a total of 22 cancer registries and 89,212 incident cases of tongue SCC worldwide were included. Most areas experienced an incidence increase ranging from 0.4% to 3.3% per year. There was a significant difference in the incidence increase between sexes in 11 of the 22 registries. In 14 of the 22 registries studied, the increase in incidence of tongue SCC was higher in the group of subjects <45 years old than those ≥45 years old. CONCLUSION: This study suggests a general but not universal increase in the incidence of tongue SCC worldwide. In some regions of the world, we observed a shifting trend toward women and/or younger patients. © 2016 Wiley Periodicals, Inc. Head Neck 39: 297-304, 2017.

Prevalence and associations of neuropathic pain in a cohort of multi-ethnic Asian low back pain patients.

The prevalence of neuropathic low back pain differs in different ethnic populations. The aims of the study are to determine its frequency and associations in a multi-ethnic cohort of Asian low back pain patients. This was a cross-sectional study of low back patients seen at the University of Malaya Medical Centre, Kuala Lumpur, Malaysia. Neuropathic low back pain patients were identified using the painDETECT questionnaire and compared with non-neuropathic (unclear or nociceptive) low back pain patients, in terms of socio-demographic and clinical factors, pain severity (numerical pain rating scale, NPRS), disability (Roland Morris Disability Questionnaire, RMDQ), as well as anxiety and depression (Hospital Anxiety and Depression Scale, HADS). Of 210 patients, 26 (12.4%) have neuropathic low back pain. Neuropathic pain is associated with non-Chinese ethnicity, higher body mass index and pain radiation below the knee. Patients with neuropathic pain have significantly higher NPRS and RMDQ scores, and there are more subjects with anxiety on HADS. However, there are no differences between the groups in age, gender, pain duration or underlying diagnosis of low back pain. The prevalence of neuropathic low back pain in a multi-ethnic Malaysian cohort is lower than previously reported in other populations with possible differences between ethnic groups. It is associated with greater pain severity, disability and anxiety.

Can venous base excess replace arterial base excess as a marker of early shock and a predictor of survival in trauma?

INTRODUCTION: Arterial base excess is an established marker of shock and predictor of survival in trauma patients. However, venous blood is more quickly and easily obtained. This study aimed to determine if venous base excess could replace arterial base excess as a marker in trauma patients at presentation and if venous base excess is predictive of survival at 24 hours and one week. METHODS: This was a prospective study of 394 trauma patients presenting to the emergency department of a tertiary hospital over a 17-month period. Data on base excess at presentation, vital signs, shock index (SI), injury severity score (ISS), and mortality at 24 hours and one week was collected and analysed. RESULTS: Arterial and venous blood gas tests were performed on 260 and 134 patients, respectively. Patients were stratified into groups based on their SI and ISS for analysis. There was no statistical difference between mean venous blood gas and arterial blood gas levels at presentation when SI > 0.7, regardless of ISS (p > 0.05). The mortality rate was 4.57%. Both venous and arterial base excess was lower in nonsurvivors compared to survivors (p < 0.05). However, at 24 hours and one week, the difference in base excess values at presentation between survivors and nonsurvivors was greater when using venous base excess compared to arterial base excess (11.53 vs. 4.28 and 11.41 vs. 2.66, respectively). CONCLUSION: In conclusion, venous base excess can replace arterial base excess in trauma patients as a means of identifying and prognosticating early shock.

Open Thrombectomy for Primary Acute Mesentericoportal Venous Thrombosis--Should It Be Done?

Mesentericoportal venous thrombosis (MVT) is a rare condition, accounting for 5-15% of acute mesenteric ischemia. Primary MVT is even rarer, with some reports quoting an incidence rate of 10-30% of reported cases. It presents a diagnostic challenge and is associated with a significant mortality rate, ranging from 13% to 50%. As it is an uncommon condition, the evidence in current literature regarding the treatment of MVT is limited. We discuss our surgical experience with a case of acute primary MVT that was managed with good clinical outcome and discuss the current evidence for the treatment of acute MVT. A 50-year-old Chinese lady with no significant past medical history presented with a 2-day history of abdominal pain and epigastric tenderness on examination. Computed tomography of her abdomen and pelvis showed evidence of extensive acute thrombi present in portal confluence extending into the superior mesenteric vein, associated with submucosal edema in some central jejunal loops. Despite systemic anticoagulation therapy with intravenous heparin, the patient deteriorated clinically, and decision was made for an exploratory laparotomy, small bowel resection, and open thrombectomy. Postoperative recovery was uneventful. She was discharged on postoperative day 13 with lifelong oral anticoagulation. In conclusion, we describe the successful management of a patient with extensive acute primary MVT where open thrombectomy was performed together with small bowel resection.

Intratympanic steroids as a salvage treatment for sudden sensorineural hearing loss? A meta-analysis.

Sudden sensorineural hearing loss is typically treated with systemic steroids. The aim of this meta-analysis was to evaluate the efficacy of salvage intratympanic steroid treatment in patients who have initial treatment failure with systemic steroids. A MEDLINE literature search was performed, supported by searches of Web of Science, Biosis, and Science Direct. Articles of all languages were included. Selection of relevant publications was conducted independently by three authors. Only randomized controlled trials were considered. In one arm of the studies, the patients received salvage intratympanic steroids. In the other arm, patients did not receive further treatment. The standard difference in mean (SDM) amount of improvement in hearing threshold between patients who did and did not receive salvage intratympanic steroids was calculated. From an initial 184 studies found via the search strategy, 5 studies met inclusion criteria and were included. There was a statistically significant greater reduction in hearing threshold on pure-tone audiometry in patients who received salvage intratympanic steroids than in those who did not (SDM = -0.401, p = 0.005). Subgroup analysis showed that administration by intratympanic injection (SDM = -0.375, p = 0.013) rather than a round window catheter (SDM = -0.629, p = 0.160) yielded significant improvement in outcome. The usage of dexamethasone yielded better outcomes (SDM = -0.379, p = 0.039) than the use of methylprednisolone (SDM = -0.459, p = 0.187). No serious side effect of treatment was reported. In patients who have failed initial treatment with systemic steroids, additional treatment with salvage intratympanic dexamethasone injections demonstrate a statistically significant reduction in the hearing thresholds as compared to controls.

Cosmetic procedures among youths: a survey of junior college and medical students in Singapore.

INTRODUCTION: Although cosmetic procedures have become increasingly popular among the younger population in recent years, limited research on this subject has been done in the Asian context. We aimed to explore the views and knowledge regarding cosmetic procedures among junior college (JC) and medical students in Singapore. METHODS: In the first phase of the study, a cross-sectional, self-administered survey of 1,500 JC students aged 16-21 years from six JCs was conducted in 2010. The same survey was then conducted on a random sample of Year 2-5 medical students from an undergraduate medical school in 2011. RESULTS: In total, 1,164 JC and 241 medical students responded to the surveys. There was an overall female to male ratio of 1.3:1. Of all the respondents, 2.5% of the JC students and 3.0% of the medical students admitted to having undergone cosmetic procedures. Among those who claimed to have never had cosmetic procedures done, 9.0% and 44.0% of the JC and medical students, respectively, responded that they would consider such procedures in the future. Those who disapproved of their peers undergoing cosmetic surgery comprised 35.0% of JC students and 56.8% of medical students. Among the JC and medical students, 52.0% and 36.1%, respectively, were unaware of any risks associated with cosmetic procedures. CONCLUSION: The younger population is increasingly accepting of cosmetic procedures. However, there is a general lack of understanding of the risks associated with such procedures. Education of both the general public and medical students may help prevent potential medicolegal issues.

Klf2 is an essential factor that sustains ground state pluripotency.

The maintenance of mouse embryonic stem cells (mESCs) requires LIF and serum. However, a pluripotent "ground state," bearing resemblance to preimplantation mouse epiblasts, can be established through dual inhibition (2i) of both prodifferentiation Mek/Erk and Gsk3/Tcf3 pathways. While Gsk3 inhibition has been attributed to the transcriptional derepression of Esrrb, the molecular mechanism mediated by Mek inhibition remains unclear. In this study, we show that Krüppel-like factor 2 (Klf2) is phosphorylated by Erk2 and that phospho-Klf2 is proteosomally degraded. Mek inhibition hence prevents Klf2 protein phosphodegradation to sustain pluripotency. Indeed, while Klf2-null mESCs can survive under LIF/Serum, they are not viable under 2i, demonstrating that Klf2 is essential for ground state pluripotency. Importantly, we also show that ectopic Klf2 expression can replace Mek inhibition in mESCs, allowing the culture of Klf2-null mESCs under Gsk3 inhibition alone. Collectively, our study defines the Mek/Erk/Klf2 axis that cooperates with the Gsk3/Tcf3/Esrrb pathway in mediating ground state pluripotency.