Tumor Suppressor MicroRNAs in Clinical and Preclinical Trials for Neurological Disorders.

Cancers and neurological disorders are two major types of diseases in humans. We developed the concept called the "Aberrant Cell Cycle Disease (ACCD)" due to the accumulating evidence that shows that two different diseases share the common mechanism of aberrant cell cycle re-entry. The aberrant cell cycle re-entry is manifested as kinase/oncoprotein activation and tumor suppressor (TS) inactivation, which are associated with both tumor growth in cancers and neuronal death in neurological disorders. Therefore, some cancer therapies (e.g., kinase/oncogene inhibition and TS elevation) can be leveraged for neurological treatments. MicroRNA (miR/miRNA) provides a new style of drug-target binding. For example, a single tumor suppressor miRNA (TS-miR/miRNA) can bind to and decrease tens of target kinases/oncogenes, producing much more robust efficacy to block cell cycle re-entry than inhibiting a single kinase/oncogene. In this review, we summarize the miRNAs that are altered in both cancers and neurological disorders, with an emphasis on miRNA drugs that have entered into clinical trials for neurological treatment.

Matched three-dimensional organoids and two-dimensional cell lines of melanoma brain metastases mirror response to targeted molecular therapy.

Purpose: Despite significant advances in the treatment paradigm for patients with metastatic melanoma, melanoma brain metastasis (MBM) continues to represent a significant treatment challenge. The study of MBM is limited, in part, by shortcomings in existing preclinical models. Surgically eXplanted Organoids (SXOs) are ex vivo, three-dimensional cultures prepared from primary tissue samples with minimal processing that recapitulate genotypic and phenotypic features of parent tumors and are grown without artificial extracellular scaffolding. We aimed to develop the first matched patient-derived SXO and cell line models of MBM to investigate responses to targeted therapy. Methods: MBM SXOs were created by a novel protocol incorporating techniques for establishing glioma and cutaneous melanoma organoids. A BRAFV600K-mutant and BRAF-wildtype MBM sample were collected directly from the operating room for downstream experiments. Organoids were cultured in an optimized culture medium without an artificial extracellular scaffold. Concurrently, matched patient-derived cell lines were created. Drug screens were conducted to assess treatment response in SXOs and cell lines. Results: Organoid growth was observed within 3-4 weeks, and MBM SXOs retained histological features of the parent tissue, including pleomorphic epithelioid cells with abundant cytoplasm, large nuclei, focal melanin accumulation, and strong SOX10 positivity. After sufficient growth, organoids could be manually parcellated to increase the number of replicates. Matched SXOs and cell lines demonstrated sensitivity to BRAF and MEK inhibitors. Conclusion: Here, we describe the creation of a scaffold-free organoid model of MBM. Further study using SXOs may improve the translational relevance of preclinical studies and enable the study of the metastatic melanoma tumor microenvironment.

Mean disease alleviation between surgery and continuous positive airway pressure in matched adults with obstructive sleep apnea.

STUDY OBJECTIVES: Polysomnography parameters measure treatment efficacy for obstructive sleep apnea (OSA), such as reduction in apnea-hypopnea index (AHI). However, for continuous positive airway pressure (CPAP) therapy, polysomnography measures do not factor in adherence and thus do not measure effectiveness. Mean disease alleviation (MDA) corrects polysomnography measures for CPAP adherence and was used to compare treatment effectiveness between CPAP and multilevel upper airway surgery. METHODS: This retrospective cohort study consisted of a consecutive sample of 331 patients with OSA managed with multilevel airway surgery as second-line treatment (N = 97) or CPAP (N = 234). Therapeutic effectiveness (MDA as % change or as corrected change in AHI) was calculated as the product of therapeutic efficacy (% or absolute change in AHI) and adherence (% time on CPAP of average nightly sleep). Cardinality and propensity score matching was utilized to manage confounding variables. RESULTS: Surgery patients achieved greater MDA % than CPAP users (67 ± 30% vs. 60 ± 28%, p = 0.04, difference 7 ± 3%, 95% confidence interval 4% to 14%) in an unmatched comparison, despite a lower therapeutic efficacy seen with surgery. Cardinality matching demonstrated comparable MDA % in surgery (64%) and CPAP (57%) groups (p = 0.14, difference 8 ± 5%, 95% confidence interval -18% to 3%). MDA measured as corrected change in AHI showed similar results. CONCLUSIONS: In adult patients with OSA, multilevel upper airway surgery and CPAP provide comparable therapeutic effectiveness on polysomnography. For patients with inadequate CPAP use, surgery should be considered.

Central Retinal Artery Occlusion: Time to Presentation and Diagnosis.

OBJECTIVE: To evaluate the presentation patterns of patients diagnosed with central retinal artery occlusion (CRAO) from 2011 to 2020. DESIGN: Retrospective cohort study SUBJECTS: The present study was conducted in 484 patients presenting within 30 days of symptom onset with accurate documentation of time of symptom onset, time of presentation to the health care system, and time of presentation to an ophthalmologist. METHODS: An independent chart review of patients with CRAO was conducted. MAIN OUTCOME MEASURES: Demographic information including age, sex, and race were collected. Presentation patterns such as time of first symptoms, time of first contact with the health care system, and time of evaluation by an ophthalmologist were analyzed. Additionally, information regarding the medical venue or specialty of initial patient contact was collected. RESULTS: A total of 247 (51%) patients contacted the health care system within 4.5 hours of system onset, whereas 86 (17.8%) patients waited over 24 hours. Only 81 (32.8%) of the 247 patients who presented within 4.5 hours saw an ophthalmologist within that time frame, whereas 172 (35.5%) of the entire cohort of 484 did not present to an ophthalmologist within 24 hours of vision loss. There was significant variability with regards to medical specialty of initial patient contact, with 292 (60.3%) patients first presenting to an emergency department and 133 (27.5%) patients first presenting to an ophthalmologist. Black and Hispanic patients presented later than patients of White, Asian, or other racial backgrounds (40.4 ± 10.2 hours versus 23.0 ± 3.4 hours, P = 0.05). CONCLUSIONS: Although no level 1 evidence-based treatment is currently available for CRAO, thrombolytic therapy may be promising. Even though over half of patients with CRAO within our institution connected with the health care system within a potential window for thrombolytic therapy, most did not receive a definitive ophthalmic diagnosis within that time frame. Public health educational campaigns and infrastructure optimization must speed up presentation times, decrease the time to ophthalmic diagnosis, and target vulnerable populations to offer and research timely administration of thrombolytic therapy. FINANCIAL DISCLOSURE(S): The authors have no proprietary or commercial interest in any materials discussed in this article.

Caution in Transnasal Balloon Dilation of the Eustachian Tube: Middle Ear Penetration of Catheter Tip in a Cadaveric Model.

OBJECTIVE: To investigate the degree to which transnasal eustachian tube (ET) dilation balloon catheters are able to be passed through the ET in a cadaver model. PATIENTS AND INTERVENTIONS: A cadaveric study of 8 cadaver heads (16 ears), which underwent transnasal ET insertion with a 3 × 20-mm balloon catheter with transtympanic endoscopic visualization and grading. RESULTS: Catheter tip incursion into the protympanum or mesotympanum occurred in all ears. Radiological validation was obtained with correlation to published ET length data. CONCLUSION: Middle ear incursion of balloon catheter tips can be demonstrated in a cadaver model and highlights the ongoing need for both caution in novel surgical techniques and evolution in device design.

Neuro-ophthalmic features of patients with spontaneous cerebrospinal fluid leaks.

Background: Increased intracranial pressure is a potential cause of spontaneous cerebrospinal fluid (sCSF) leak. Associated neuro-ophthalmic features have not been well studied, particularly relationships with idiopathic intracranial hypertension (IIH). We hypothesized that neuro-ophthalmic features routinely used in evaluations for IIH can be useful in the investigation of a causal relationship between IIH and sCSF leak. We reviewed the neuro-ophthalmic examination and office-based ophthalmic imaging data of all consecutive patients with sCSF leaks and at least one repair to investigate the clinical and neuro-ophthalmic features of increased intracranial pressure. Methods: We conducted a retrospective longitudinal study at a single institution by querying the electronic medical record system for CSF leak Current Procedural Terminology (CPT) codes (G96.00 and G96.01) from June 1, 2019, to July 31, 2022. For patients with a confirmed diagnosis of sCSF leak, demographic information, eye examination results, and ophthalmic imaging details for both eyes were collected. Results: A total of 189 patients with CSF leaks were identified through CPT coding; 159 had iatrogenic or traumatic CSF leaks, and 30 individuals (3 male, 27 female) had confirmed sCSF leaks. The mean age of patients with sCSF leaks was 46 years (range: 29 - 81), with a mean body mass index of 35.2 kg/m2 (range: 18.2 - 54.1). Only 11 of 30 underwent eye examinations (8 before surgical repair and 10 after). The mean pre-repair and post-repair best-corrected visual acuity were 20/30 (range: 20/20 - 20/55) and 20/25 (range: 20/20 - 20/40), respectively (P = 0.188). The mean retinal nerve fiber layer thickness was 99 µm (range: 96 - 104) pre-repair and 97 µm (range: 84 - 103) post-repair (P = 0.195). The mean ganglion cell complex thickness was 84 µm (range: 72 - 94) pre-repair and 82 µm (range: 71 - 94) post-repair (P = 0.500). Humphrey visual field average mean deviation was -5.1 (range: -12.4 - -1.8) pre-repair and -1.0 (range: -10.1 - 2.1) post-repair (P = 0.063). Conclusions: Serial neuro-ophthalmic examinations are recommended for patients with sCSF leaks to screen for signs of current or prior increased intracranial pressure. Larger studies are required to clarify the longitudinal changes in neuro-ophthalmic features, to investigate the incidence of IIH in cases of sCSF leak development or recurrence after surgical repair, and to explore potential causal relationships to guide post-repair management and prevent recurrent leaks. A multicenter consortium is also suggested to develop a standard clinical protocol for comprehensive management of sCSF leaks.

FDA-Approved Kinase Inhibitors in Preclinical and Clinical Trials for Neurological Disorders.

Cancers and neurological disorders are two major types of diseases. We previously developed a new concept termed "Aberrant Cell Cycle Diseases" (ACCD), revealing that these two diseases share a common mechanism of aberrant cell cycle re-entry. The aberrant cell cycle re-entry is manifested as kinase/oncogene activation and tumor suppressor inactivation, which are hallmarks of both tumor growth in cancers and neuronal death in neurological disorders. Therefore, some cancer therapies (e.g., kinase inhibition, tumor suppressor elevation) can be leveraged for neurological treatments. The United States Food and Drug Administration (US FDA) has so far approved 74 kinase inhibitors, with numerous other kinase inhibitors in clinical trials, mostly for the treatment of cancers. In contrast, there are dire unmet needs of FDA-approved drugs for neurological treatments, such as Alzheimer's disease (AD), intracerebral hemorrhage (ICH), ischemic stroke (IS), traumatic brain injury (TBI), and others. In this review, we list these 74 FDA-approved kinase-targeted drugs and identify those that have been reported in preclinical and/or clinical trials for neurological disorders, with a purpose of discussing the feasibility and applicability of leveraging these cancer drugs (FDA-approved kinase inhibitors) for neurological treatments.

Secondary Bariatric Surgery-Does the Type of Index Procedure Affect Outcomes After Conversion?

BACKGROUND: Although revisions account for 17% of cases performed at bariatric centers of excellence, scarce data exists on whether index operation type influences outcomes after secondary operations. OBJECTIVE: We designed a study investigating the effect of primary procedure type on weight loss and perioperative complications after conversion bariatric surgery. SETTING: Tertiary Referral Hospital, USA. METHODS: We performed a retrospective review of patients undergoing conversion from sleeve gastrectomy (SG) or adjustable gastric band (AGB) to Roux-en-Y gastric bypass (RYGB) from 2009 to 2019. Post-operatively, we measured short- and medium-term complications and changes in body weight at various time points. Univariate and regression analyses were performed. RESULTS: Forty-two (SG) patients and 116 (AGB) patients underwent conversion to RYGB, most commonly for GERD (57.1%) in SG patients vs. weight regain (77.6%) in AGB patients. Mean pre-conversion BMI was 36.7 kg/m2 (SG) vs 43.8 kg/m2 (AGB). Mean time to conversion (months) was 52.9 (SG) vs 94.7 (AGB). Complication rate was 9.5% (SG) vs 6% (AGB) at 30 days (p = 0.48) and 31%(SG) vs 14.5% (AGB) (p = 0.02) at 2 years. Mean post conversion %TWL was 11.6% (SG) vs 24.6% (AGB) in patients with GERD/dysphagia (p = 0.014) and 20.7% (SG) vs 27.6% (AGB) in patients converted for weight-related reasons (p = 0.027) at 1 year. Overall mean %TWL was 13.2% (SG) vs 24.7% (AGB) at 2 years (p < 0.0035). CONCLUSION: After conversion to RYGB, patients with AGB experience better short- and medium-term weight loss than those with SG, even after accounting for conversion indications. SG to RYGB conversions have a higher resolution of reflux disease.

Precision Medicine in Adult Obstructive Sleep Apnea and Home Diagnostic Testing: Caution in Interpretation of Home Studies Without Clinician Input Is Necessary.

Purpose: To assess the validity of home sleep apnea test directed diagnosis and treatment of obstructive sleep apnea (OSA) in a real-life clinical setting and establish the extent to which clinical evaluation alters diagnosis and therapeutic intervention, in the context of the evolving realm of precision medicine. Methods: Retrospective consecutive cohort study of 505 patients referred to a single center between 15th September 2015 to 14th September 2016, multidisciplinary specialist sleep clinic presenting with a home sleep apnea test prior to referral. We evaluated the effect of sleep medicine practitioner (SMP) and ear, nose, and throat surgeon (ENTS) review on patient diagnoses, disease severity, and management options in OSA. Results: Hundred and fifteen patients were included. Repeat evaluation with in-lab polysomnogram (PSG) was required in 46/115 (40.0%) of patients, of which 20/46 (43.5%) had OSA severity changed. Sleep medicine practitioner review decreased the need for repeat testing with formal in-lab PSG (p < 0.05) and increased patient acceptance of continuous positive airway pressure (CPAP) as a long-term management option for OSA. Sleep medicine practitioner/ENTS review resulted in discovery of a non-OSA related sleep disorder or change in OSA severity in 47.8% (55/115). Ear, nose, and throat surgeon review resulted in additional or changed diagnosis in 75.7% (87/115) of patients. Conclusion: In the clinical assessment and diagnosis of OSA, patients should be reviewed by medical practitioners with an interest in sleep disorders to better navigate the complexities of assessment, as well as the identification of co-morbid conditions.

Astrocytes Do Not Forfeit Their Neuroprotective Roles After Surviving Intense Oxidative Stress.

In order to fulfill their evolutionary role as support cells, astrocytes have to tolerate intense oxidative stress under conditions of brain injury and disease. It is well known that astrocytes exposed to mild oxidative stress are preconditioned against subsequent stress exposure in dual hit models. However, it is unclear whether severe oxidative stress leads to stress tolerance, stress exacerbation, or no change in stress resistance in astrocytes. Furthermore, it is not known whether reactive astrocytes surviving intense oxidative stress can still support nearby neurons. The data in this Brief Report suggest that primary cortical astrocytes surviving high concentrations of the oxidative toxicant paraquat are completely resistant against subsequent oxidative challenges of the same intensity. Inhibitors of multiple endogenous defenses (e.g., glutathione, heme oxygenase 1, ERK1/2, Akt) failed to abolish or even reduce their stress resistance. Stress-reactive cortical astrocytes surviving intense oxidative stress still managed to protect primary cortical neurons against subsequent oxidative injuries in neuron/astrocyte co-cultures, even at concentrations of paraquat that otherwise led to more than 80% neuron loss. Although our previous work demonstrated a lack of stress tolerance in primary neurons exposed to dual paraquat hits, here we show that intensely stressed primary neurons can resist a second hit of hydrogen peroxide. These collective findings suggest that stress-reactive astroglia are not necessarily neurotoxic, and that severe oxidative stress does not invariably lead to stress exacerbation in either glia or neurons. Therefore, interference with the natural functions of stress-reactive astrocytes might have the unintended consequence of accelerating neurodegeneration.

Patient-reported olfaction improves following outside-in Draf III frontal sinus surgery for chronic rhinosinusitis.

OBJECTIVES: The Draf III frontal sinusotomy is an established surgical procedure with an important role in the surgical management of recalcitrant chronic rhinosinusitis (CRS). In 2012, the outside-in approach to the Draf III was described as a safe and efficient procedure. Smell recovery in inflammatory CRS is challenging, and to date there is limited evidence suggesting that Draf III improves patient-reported olfactory dysfunction from CRS. METHODS: A consecutive series of patients who underwent an outside-in Draf III for inflammatory CRS by a single, tertiary rhinologist were reviewed. Patients were excluded if the Draf III was performed for noninflammatory conditions. Postoperatively, patients were maintained on long-term corticosteroid irrigations, and adherence was assessed. Prospectively collected data included patient demographics, a visual analogue scale for smell, overall Sinonasal Outcome Test Score (SNOT-22), global nasal function score, and a clinician-graded clinical outcome score. RESULTS: One hundred and four patients (41.1% female) aged 54 ± 12 years underwent an outside-in Draf III. The median follow-up time was 30.6 months (range 12.2-72.1). The majority of patients rated their smell loss as moderate or worse preoperatively; however, this was significantly improved at postoperative review (71.2% vs. 27.6%; Kendall tau-b, P < 0.01). The SNOT-22 score improved after surgery (2.32 ± 1.09 vs. 0.78 ± 0.69, P < 0.0001). Medication adherence was significantly associated with improved clinical outcome score (Kendall tau-b, P < 0.004). Aspirin exacerbated respiratory disease was found to be a significant risk factor predicting poor clinical outcome on univariate analysis (Odds Ratio = 4.69 (1.03-21.2), P = 0.04). CONCLUSION: The outside-in Draf III appears to facilitate sustained, meaningful improvement in several self-reported outcomes, including smell. However, further study and comparison to less aggressive surgery will be required to confirm its true benefit. LEVEL OF EVIDENCE: Level 4 Laryngoscope, 129:25-30, 2019.

An update on neurotoxin products and administration methods.

Since onabotulinumtoxinA for nonsurgical aesthetic enhancement of glabellar lines was initially reported, the popularity of botulinum neurotoxin (BoNT) products among both clinicians and consumers has rapidly grown, and we have seen several additional BoNT formulations enter the market. As the demand for minimally invasive cosmetic procedures continues to increase, we will see the introduction of additional formulations of BoNT products as well as new delivery devices and administration techniques. In this article, we provide a brief update on current and upcoming BoNT products and also review the literature on novel administration methods based on recently published studies.

Clinical implications of mucosal remodeling from chronic rhinosinusitis.

BACKGROUND: Prognostic implications of mucosal remodeling in chronic rhinosinusitis (CRS) remain unclear. Remodeling of respiratory mucosa in asthma is associated with greater medication use and decreased function. This study investigates the implications of mucosal remodeling on long-term clinical outcomes in patients with CRS. METHODS: A case-control study of adult patients with CRS undergoing endoscopic sinus surgery (ESS) was performed. Mucosal remodeling was defined by squamous metaplasia, subepithelial fibrosis, and/or basement membrane thickening. The presence of remodeling changes were assessed relative to clinical and treatment outcomes at a minimum of 12 months postoperatively. Clinical outcomes were assessed at baseline and 12 months using a Nasal Symptom Score (NSS) and 22-item Sino-Nasal Outcome Test (SNOT-22). Treatment outcomes were assessed by oral corticosteroid usage (burst/continuous), topical corticosteroid irrigation frequency, and further surgical intervention. RESULTS: A total of 110 patients (48.73 ± 14.75 years, 48.2% female) were assessed. Significant improvements where seen for the entire population, in both NSS (2.64 ± 1.06 to 1.34 ± 1.08, p < 0.001) and SNOT-22 (2.05 ± 0.96 to 1.06 ± 0.79, p < 0.001). Patients with remodeling (n = 88) were younger (47.2 ± 14.8 vs 54.7 ± 13.5 years, p = 0.03), but had similar symptom scores. Remodeling was seen in CRS with nasal polyposis (CRSwNP) (54.5%) and eosinophilic chronic rhinosinusitis (eCRS) (59.8%). Symptom improvement at 12 months was similar between remodeled and non-remodeled groups (NSS: Δ1.34 ± 1.20 vs Δ1.12 ± 1.31, p = 0.395; SNOT-22: Δ1.05 ± 0.91 vs Δ0.73 ± 0.95, p = 0.124); however, patients with remodeling had greater corticosteroid irrigation frequency (64.0% vs 31.6% daily use, Kendall's tau-b p = 0.004). CONCLUSION: Established mucosal remodeling predicts a greater reliance on topical therapies to reach similar clinical endpoints as those without remodeling.

Frontal sinus surgery and sinus distribution of nasal irrigation.

BACKGROUND: Effective mucus lavage and delivery of topical pharmaceuticals are central to successful management of chronic rhinosinusitis (CRS). The frontal sinus remains difficult to penetrate with topical therapies. This study evaluates the benefit of Draf III frontal dissection compared to traditional Draf IIa for distribution of topical therapies. METHODS: Fresh human cadaver heads were dissected sequentially with Draf IIa frontal sinusotomy and then Draf III procedures. Each cavity was irrigated with pediatric (120 mL) and adult (240 mL) irrigation bottles with 1/1000 10% fluorescein-labeled free water in 2 fixed positions (vertex and Frankfort horizontal). An endoscope at a fixed position within the frontal sinus recorded frontal sinus and frontal recess penetration. The images then underwent blinded evaluation of fluid distribution scored as 0 to 4 (nasal cavity only, frontal recess, medial one-half, lateral one-half, and lavage). Ordinal distribution score was analyzed with Kendall's tau-b. RESULTS: Eight specimens (age 76 ± 11.2 years; 50% female) were assessed. Draf III was superior to Draf IIa in ability to achieve frontal sinus distribution of irrigation (90.6% vs 50.1%, p < 0.001). Vertex head position improved distribution (90.6% vs 50.1%, p < 0.001), was synergistic with Draf III (100% with 87.5% lavage, p < 0.001), but was unable to overcome Draf IIa (81.2% with 25% lavage, p < 0.001). Irrigation volume trended toward improved distribution with larger volume irrigations. CONCLUSION: Successful treatment of sinonasal disease may require postoperative delivery of topical therapies. Draf III frontal sinusotomy achieves superior topical access, and access to the frontal sinus with Draf IIa appears limited, despite large volumes and positioning.

Therapies for actinic keratosis with a focus on cosmetic outcomes.

Actinic keratosis (AK) is a commonly encountered premalignant epidermal lesion that has a predilection to manifest on highly visible areas such as the face, head, and hands. Lesions may be cosmetically unappealing and have been reported to reduce patients' quality of life (QOL), but appropriate treatment can resolve these issues. In this article, we review the efficacy of the most commonly utilized treatments for AKs including topical medications, procedural modalities, and light-based therapies, and we discuss the relevant cosmetic considerations and outcomes.

Improved nutrient intake following implementation of the consensus standardised parenteral nutrition formulations in preterm neonates--a before-after intervention study.

BACKGROUND: New standardised parenteral nutrition (SPN) formulations were implemented in July 2011 in many neonatal intensive care units in New South Wales following consensus group recommendations. The aim was to evaluate the efficacy and safety profile of new consensus formulations in preterm infants born less than 32 weeks. METHODS: A before-after intervention study conducted at a tertiary neonatal intensive care unit. Data from the post-consensus cohort (2011 to 2012) were prospectively collected and compared retrospectively with a pre-consensus cohort of neonates (2010). RESULTS: Post-consensus group commenced parenteral nutrition (PN) significantly earlier (6 v 11 hours of age, p 0.005). In comparison to the pre-consensus cohort, there was a higher protein intake from day 1 (1.34 v 0.49 g/kg, p 0.000) to day 7 (3.55 v 2.35 g/kg, p 0.000), higher caloric intake from day 1 (30 v 26 kcal/kg, p 0.004) to day 3 (64 v 62 kcal/kg, p 0.026), and less daily fluid intake from day 3 (105.8 v 113.8 mL/kg, p 0.011) to day 7 (148.8 v 156.2 mL/kg, p 0.025), and reduced duration of lipid therapy (253 v 475 hr, p 0.011). This group also had a significantly greater weight gain in the first 4 weeks (285 v 220 g, p 0.003). CONCLUSIONS: New consensus SPN solutions provided better protein intake in the first 7 days and were associated with greater weight gain in the first 4 weeks. However, protein intake on day 1 was below the consensus goal of 2 g/kg/day.