Development of a dosimeter prototype with machine learning based 3-D dose reconstruction capabilities.

A 3-D dosimeter fills the need for treatment plan and delivery verification required by every modern radiation-therapy method used today. This report summarizes a proof-of-concept study to develop a water-equivalent solid 3-D dosimeter that is based on novel radiation-hard scintillating material. The active material of the prototype dosimeter is a blend of radiation-hard peroxide-cured polysiloxane plastic doped with scintillating agent P-Terphenyl and wavelength-shifter BisMSB. The prototype detector was tested with 6 MV and 10 MV x-ray beams at Ohio State University's Comprehensive Cancer Center. A 3-D dose distribution was successfully reconstructed by a neural network specifically trained for this prototype. This report summarizes the material production procedure, the material's water equivalency investigation, the design of the prototype dosimeter and its beam tests, as well as the details of the utilized machine learning approach and the reconstructed 3-D dose distributions.

Hyperbaric Oxygen Therapy: Descriptive Review of the Technology and Current Application in Chronic Wounds.

Hyperbaric oxygen therapy (HBOT) serves as "primary" or "adjunctive" therapy in a wide range of pathologies. It is considered the mainstay of management for potentially life-threatening conditions such as carbon monoxide poisoning, decompression illness, and gas embolisms. Moreover, HBOT has been utilized for decades as an adjunctive therapy in a variety of medical disciplines, including chronic wounds, which affect approximately 6.5 million Americans annually. In general, chronic wounds are characterized by hypoxia, impaired angiogenesis, and prolonged inflammation, all of which may theoretically be ameliorated by HBOT. Nonetheless, the cellular, biochemical, and physiological mechanisms by which HBOT achieves beneficial results in chronic wounds are not fully understood, and there remains significant skepticism regarding its efficacy. This review article provides a comprehensive overview of HBOT, and discusses its history, mechanisms of action, and its implications in management of chronic wounds. In particular, we discuss the current evidence regarding the use of HBOT in diabetic foot ulcers, while digging deeply into the roots of controversy surrounding its efficacy. We discuss how the paucity of high-quality research is a tremendous challenge, and offer future direction to address existing obstacles.

Effect of ocular hypertension on the pattern of retinal ganglion cell subtype loss in a mouse model of early-onset glaucoma.

Glaucoma is a neurodegenerative disease with elevated intraocular pressure as one of the major risk factors. Glaucoma leads to irreversible loss of vision and its progression involves optic nerve head cupping, axonal degeneration, retinal ganglion cell (RGC) loss, and visual field defects. Despite its high global prevalence, glaucoma still remains a major neurodegenerative disease. Introduction of mouse models of experimental glaucoma has become integral to glaucoma research due to well-studied genetics as well as ease of manipulations. Many established inherent and inducible mouse models of glaucoma are used to study the molecular and physiological progression of the disease. One such model of spontaneous mutation is the nee model, which is caused by mutation of the Sh3pxd2b gene. In both humans and mice, mutations disrupting function of the SH3PXD2B adaptor protein cause a developmental syndrome including secondary congenital glaucoma. The purpose of this study was to characterize the early onset nee glaucoma phenotype on the C57BL/6J background and to evaluate the pattern of RGC loss and axonal degeneration in specific RGC subtypes. We found that the B6.Sh3pxd2bnee mutant animals exhibit glaucoma phenotypes of elevated intraocular pressure, RGC loss and axonal degeneration. Moreover, the non-image forming RGCs survived longer than the On-Off direction selective RGCs (DSGC), and the axonal death in these RGCs was independent of their respective RGC subtype. In conclusion, through this study we characterized an experimental model of early onset glaucoma on a C57BL/6J background exhibiting key glaucoma phenotypes. In addition, we describe that RGC death has subtype-specific sensitivities and follows a specific pattern of cell death under glaucomatous conditions.

Added value of frailty and social support in predicting risk of 30-day unplanned re-admission or death for patients with heart failure: An analysis from OPERA-HF.

BACKGROUND: Models for predicting the outcome of patients hospitalized for heart failure (HF) rarely take a holistic view. We assessed the ability of measures of frailty and social support in addition to demographic, clinical, imaging and laboratory variables to predict short-term outcome for patients discharged after a hospitalization for HF. METHODS: OPERA-HF is a prospective observational cohort, enrolling patients hospitalized for HF in a single center in Hull, UK. Variables were combined in a logistic regression model after multiple imputation of missing data to predict the composite outcome of death or readmission at 30 days. Comparisons were made to a model using clinical variables alone. The discriminative performance of each model was internally validated with bootstrap re-sampling. RESULTS: 1094 patients were included (mean age 77 [interquartile range 68-83] years; 40% women; 56% with moderate to severe left ventricular systolic dysfunction) of whom 213 (19%) had an unplanned re-admission and 60 (5%) died within 30 days. For the composite outcome, a model containing clinical variables alone had an area under the receiver-operating characteristic curve (AUC) of 0.68 [95% CI 0.64-0.72]. Adding marital status, support from family and measures of physical frailty increased the AUC (p < 0.05) to 0.70 [95% CI 0.66-0.74]. CONCLUSIONS: Measures of physical frailty and social support improve prediction of 30-day outcome after an admission for HF but predicting near-term events remains imperfect. Further external validation and improvement of the model is required.

Nimodipine improves vocal fold and facial motion recovery after injury: A systematic review and meta-analysis.

INTRODUCTION: Nimodipine is a calcium channel blocker that has been used to treat hypertension and vasospasm. Emerging evidence in the literature suggests that it is neuroprotective by reducing cellular apoptosis after neuronal injury and promoting axonal sprouting at the nodes of Ranvier. OBJECTIVES: To conduct a systematic review of the usage of nimodipine in cranial nerve injury and to perform a meta-analysis to estimate the efficacy of nimodipine on functional recovery of the injured cranial nerves. METHODS: Literature search was performed in eight databases using preferred reporting items for systematic reviews and meta analyses (PRISMA) guidelines. Human studies that used nimodipine as a monotherapy for treating cranial nerve injury were included for review. Cranial nerve function recovery was the primary outcome measure. RESULTS: 672 records were screened and 58 full texts in English were assessed. Nine studies were included in the final review. 5 of these, including 110 participants who received nimodipine for either recurrent laryngeal nerve or facial nerve injury and 556 controls, were used for meta-analysis. Nimodipine significantly increased the odds of vocal fold motion recovery (odds ratio [OR] 13.73, 95% confidence interval [CI] 6.21, 30.38, P < .01), and the odds of facial motion recovery (OR 2.78, 95% CI 1.20, 6.44, P = .02). Overall, nimodipine-treated patients had significantly higher odds of recovering vocal fold or facial motion compared with controls (OR 6.09, 95% CI 3.41, 10.87, P < .01). CONCLUSION: Existing evidence supports the positive effect of nimodipine on vocal fold and facial motion recovery after injury. Future research should focus on randomized clinical trials comparing recovery rates between nimodipine- and placebo-treated groups. Laryngoscope, 129:943-951, 2019.

Phytophotodermatitis related to carrot extract-containing sunscreen.

Phytophotodermatitis is a clinical diagnosis from phototoxicity of the skin induced by contact with plants or their extracts. Phytophotodermatitis maypresent with burning, erythema, patches, plaques, vesicles, bullae, or hyperpigmented patches in welldemarcated and unusual shapes. Inquiring about occupation, hobbies, and plant or plant extract contact is essential to establishing the diagnosis. Herein we present a case of phytophotodermatitisafter use of carrot extract-containing sunscreen presenting as a hyperpigmented patch in a geometric distribution with accentuation of pigment within the dynamic rhytides.

Nifedipine maintenance tocolysis and perinatal outcome: an individual participant data meta-analysis.

BACKGROUND: Preterm birth is the leading cause of neonatal mortality and morbidity in developed countries. Whether continued tocolysis after 48 hours of rescue tocolysis improves neonatal outcome is unproven. OBJECTIVES: To evaluate the effectiveness of maintenance tocolytic therapy with oral nifedipine on the reduction of adverse neonatal outcomes and the prolongation of pregnancy by performing an individual patient data meta-analysis (IPDMA). SEARCH STRATEGY: We searched PubMed, Embase, and Cochrane databases for randomised controlled trials of maintenance tocolysis therapy with nifedipine in preterm labour. SELECTION CRITERIA: We selected trials including pregnant women between 24 and 36(6/7)  weeks of gestation (gestational age, GA) with imminent preterm labour who had not delivered after 48 hours of initial tocolysis, and compared maintenance nifedipine tocolysis with placebo/no treatment. DATA COLLECTION AND ANALYSIS: The primary outcome was perinatal mortality. Secondary outcome measures were intraventricular haemorrhage (IVH), necrotising enterocolitis (NEC), infant respiratory distress syndrome (IRDS), prolongation of pregnancy, GA at delivery, birthweight, neonatal intensive care unit admission, and number of days on ventilation support. Pre-specified subgroup analyses were performed. MAIN RESULTS: Six randomised controlled trials were included in this IPDMA, encompassing data from 787 patients (n = 390 for nifedipine; n = 397 for placebo/no treatment). There was no difference between the groups for the incidence of perinatal death (risk ratio, RR 1.36; 95% confidence interval, 95% CI 0.35-5.33), intraventricular haemorrhage (IVH) ≥ grade II (RR 0.65; 95% CI 0.16-2.67), necrotising enterocolitis (NEC) (RR 1.15; 95% CI 0.50-2.65), infant respiratory distress syndrome (IRDS) (RR 0.98; 95% CI 0.51-1.85), and prolongation of pregnancy (hazard ratio, HR 0.74; 95% CI 0.55-1.01). CONCLUSION: Maintenance tocolysis is not associated with improved perinatal outcome and is therefore not recommended for routine practice. TWEETABLE ABSTRACT: Nifedipine maintenance tocolysis is not associated with improved perinatal outcome or pregnancy prolongation.

Practices in prescribing protein substitutes for PKU in Europe: No uniformity of approach.

BACKGROUND: There appears little consensus concerning protein requirements in phenylketonuria (PKU). METHODS: A questionnaire completed by 63 European and Turkish IMD centres from 18 countries collected data on prescribed total protein intake (natural/intact protein and phenylalanine-free protein substitute [PS]) by age, administration frequency and method, monitoring, and type of protein substitute. Data were analysed by European region using descriptive statistics. RESULTS: The amount of total protein (from PS and natural/intact protein) varied according to the European region. Higher median amounts of total protein were prescribed in infants and children in Northern Europe (n=24 centres) (infants <1 year, >2-3g/kg/day; 1-3 years of age, >2-3 g/kg/day; 4-10 years of age, >1.5-2.5 g/kg/day) and Southern Europe (n=10 centres) (infants <1 year, 2.5 g/kg/day, 1-3 years of age, 2 g/kg/day; 4-10 years of age, 1.5-2 g/kg/day), than by Eastern Europe (n=4 centres) (infants <1 year, 2.5 g/kg/day, 1-3 years of age, >2-2.5 g/kg/day; 4-10 years of age, >1.5-2 g/kg/day) and with Western Europe (n=25 centres) giving the least (infants <1 year, >2-2.5 g/kg/day, 1-3 years of age, 1.5-2 g/kg/day; 4-10 years of age, 1-1.5 g/kg/day). Total protein prescription was similar in patients aged >10 years (1-1.5 g/kg/day) and maternal patients (1-1.5 g/kg/day). CONCLUSIONS: The amounts of total protein prescribed varied between European countries and appeared to be influenced by geographical region. In PKU, all gave higher than the recommended 2007 WHO/FAO/UNU safe levels of protein intake for the general population.

The effects of glucuronic acid and N-acetyl-D-glucosamine on in vitro fertilisation of porcine oocytes.

High incidences of polyspermic penetration continue to challenge researchers during porcine in vitro fertilisation (IVF). The aim of this study was to reduce the incidence of polyspermy by increasing the perivitelline space thickness with glucuronic acid and N-acetyl-D-glucosamine (GlcNAc) supplementation during oocyte maturation. After maturation, zona pellucida and perivitelline space thicknesses, intracellular glutathione concentrations and fertilisation kinetics were measured, in addition to embryonic cleavage and blastocyst formation at 48h and 144h after IVF, respectively. There were no significant differences between the treatments for zona pellucida thickness, penetration rates, male pronuclear formation or cortical granule exocytosis. Glucuronic acid supplementation significantly increased (PPPP<0.05) of cleavage and blastocyst formation by 48 and 144h after IVF compared with all other groups. These results indicate that supplementing with 0.005mM glucuronic acid and 0.005mM GlcNAc during oocyte maturation decreases the incidence of polyspermic penetration by increasing perivitelline space thickness and improving embryo development in pigs.

Analysis of Potassium Titanyl Phosphate Laser Settings and Voice Outcomes in the Treatment of Reinke's Edema.

OBJECTIVE: Despite increased clinical utility of the 532-nm potassium titanyl phosphate (KTP) laser, no studies have examined outcomes for Reinke's edema (RE) as a function of laser parameters and initial treatment effects. Variability in delivery parameters, fiber-to-tissue distance, and immediate end-tissue effects limits universal application of existing study outcomes. We examine voice outcomes using standardized treatment classification, providing justification for laser parameter selection and immediate tissue effect in clinical use. METHODS: Retrospective review of 9 patients who underwent KTP laser treatment for RE. Demographics, RE severity, laser settings, total laser energy, and immediate tissue effects were correlated with quantified voice outcomes. RESULTS: An average of 157 joules (6-640 J) was delivered over a 0.369-second exposure time (0.1-0.9 seconds). Immediate tissue effects varied from nonablative treatment (type I and type II) to ablation without tissue removal (type III). Overall, Voice Handicap Index-10 (VHI-10) decreased by 8.23; improvement was most pronounced with type II treatments (delta VHI-10=12). No complications were encountered. CONCLUSION: Potassium titanyl phosphate laser can be safely and effectively used to improve voice in RE patients regardless of severity. This is the first study to provide detailed information on laser settings, energy delivery, and treatment effect in RE management; these results may guide clinical use of this modality, especially for novice laser surgeons.

Timing of nimodipine therapy for the treatment of vocal fold paralysis.

OBJECTIVES/HYPOTHESIS: To retrospectively determine optimal timing for initiation of nimodipine within a cohort of patients with acute vocal fold paralysis (VFP). STUDY DESIGN: Retrospective patient review. METHODS: Subjects were divided into three groups: initiation within 15 days postinjury (n = 19), between 15 and 30 days postinjury (n = 23), or greater than 30 days postinjury (n = 11). RESULTS: Fifty-one patients (53 paralyzed vocal folds [VFs]) met entrance criteria and were offered and started off-label nimodipine treatment. Thirty-six of 53 VFs recovered purposeful motion (67.9%). There was no significant difference in the rate of VF recovery among patients who began nimodipine within 15 days (68.4%), patients who started nimodipine between 15 and 30 days (73.9%) of nerve injury (P = .1405), and patients who initiated nimodipine after 30 days postinjury (54.5%). CONCLUSIONS: Nimodipine treatment for acute VFP yielded equal VF motion recovery rates regardless of when the medication was initiated. Time to recovery of motion was not different between groups studied.

Prospective investigation of nimodipine for acute vocal fold paralysis.

INTRODUCTION: Nimodipine has been shown to be beneficial for recovery from acute vocal fold paralysis (AVFP) in an animal model. METHODS: prospective, open-label trial of patients with AVFP was performed using nimodipine. Consecutive patients were evaluated and offered nimodipine therapy. RESULTS: Fifty-three patients were considered for treatment with nimodipine. Thirteen did not qualify for inclusion, 5 were lost to follow-up, and 7 had side effects requiring cessation of treatment. Thus 28 patients (30 paralyzed vocal folds) were analyzed. Eighteen of the paralyzed vocal folds experienced recovery of purposeful motion (60%). Historical controls and laryngeal electromyography meta-analysis suggest no more than a 20% recovery rate from AVFP. CONCLUSIONS: This open label study using nimodipine for treatment of AVFP demonstrates tripling of the recovery rate of vocal fold motion compared with historical controls. Further study in a randomized, controlled manner is warranted.

Comparison of tolerance and cost-effectiveness of two nasal anesthesia techniques for transnasal flexible laryngoscopy.

OBJECTIVE: (1) Compare tolerance of aerosolized spray versus syringe administration of topical anesthesia for transnasal flexible laryngoscopy (TFL), (2) analyze cost-effectiveness of both techniques. STUDY DESIGN: Prospective, blinded, randomized trial. SETTING: Tertiary academic laryngology practice. METHODS: One hundred and eight patients underwent TFL over 3 months. Patients were randomized to receive equivalent dose 1:1 neosynephrine/4% plain lidocaine mixture via aerosolized spray ("spray") or application with 1-cc syringe ("syringe"). Patients and physicians independently rated comfort of TFL on 5-point scale (1 = not at all comfortable to 5 = very comfortable). Data were collected on patient and endoscopist experience with TFL and reasons for poor tolerance of laryngoscopy. Cost analyses of disposable spray tips and syringes were calculated. RESULTS: Both patients and physicians reported very high tolerance of TFL. Patient tolerance appears to be similar between spray- versus syringe-administered anesthesia, although study limitations preclude definitive analysis. Poor tolerance of laryngoscopy was reported in 6.5% with comparable distribution between anesthetic delivery methods. There was no impact of patient prior experience with TFL, and there was no difference between anesthetic methods for TFL performed by resident, fellow, or attending. The difference between costs of the disposable spray tip versus syringe was $1.32 per unit. CONCLUSIONS: Use of a 1-cc syringe is an effective method to provide topical nasal anesthesia for TFL and saves $1.32 per unit compared to disposable spray tips. In our practice, transition to syringe-administered nasal anesthesia is projected to save $1300 per 1000 patients, or an anticipated $1000 per year per physician, with excellent patient tolerance of TFL.

The role of voice therapy in the treatment of dyspnea and dysphonia in a patient with a vagal nerve stimulation device.

Vagal nerve stimulators (VNS) are implanted to treat medically refractory epilepsy and depression. The VNS stimulates the vagus nerve in the left neck. Laryngeal side effects are common and include dysphagia, dysphonia, and dyspnea. The current case study represents a patient with severe dyspnea and dysphonia, persisting even with VNS deactivation. The case demonstrates the use of voice and respiratory retraining therapy for the treatment of VNS-induced dysphonia and dyspnea. It also highlights the importance of a multidisciplinary approach, including laryngology, neurology, and speech-language pathology, in the treatment of these challenging patients.

Melanocortin receptor accessory proteins in adrenal gland physiology and beyond.

The melanocortin receptor (MCR) family consists of five G-protein-coupled receptors (MC1R-MC5R) with diverse physiological roles. MC1R controls pigmentation, MC2R is a critical component of the hypothalamic-pituitary-adrenal axis, MC3R and MC4R have a vital role in energy homeostasis and MC5R is involved in exocrine function. The melanocortin receptor accessory protein (MRAP) and its paralogue MRAP2 are small single-pass transmembrane proteins that have been shown to regulate MCR expression and function. In the adrenal gland, MRAP is an essential accessory factor for the functional expression of the MC2R/ACTH receptor. The importance of MRAP in adrenal gland physiology is demonstrated by the clinical condition familial glucocorticoid deficiency, where inactivating MRAP mutations account for ∼20% of cases. MRAP is highly expressed in both the zona fasciculata and the undifferentiated zone. Expression in the undifferentiated zone suggests that MRAP could also be important in adrenal cell differentiation and/or maintenance. In contrast, the role of adrenal MRAP2, which is highly expressed in the foetal gland, is unclear. The expression of MRAPs outside the adrenal gland is suggestive of a wider physiological purpose, beyond MC2R-mediated adrenal steroidogenesis. In vitro, MRAPs have been shown to reduce surface expression and signalling of all the other MCRs (MC1,3,4,5R). MRAP2 is predominantly expressed in the hypothalamus, a site that also expresses a high level of MC3R and MC4R. This raises the intriguing possibility of a CNS role for the MRAPs.

Frequency-dependent effects of background noise on subcortical response timing.

The addition of background noise to an auditory signal delays brainstem response timing. This effect has been extensively documented using manual peak selection. Peak picking, however, is impractical for large-scale studies of spectrotemporally complex stimuli, and leaves open the question of whether noise-induced delays are frequency-dependent or occur across the frequency spectrum. Here we use an automated, objective method to examine phase shifts between auditory brainstem responses to a speech sound (/da/) presented with and without background noise. We predicted that shifts in neural response timing would also be reflected in frequency-specific phase shifts. Our results indicate that the addition of background noise causes phase shifts across the subcortical response spectrum (70-1000 Hz). However, this noise-induced delay is not uniform such that some frequency bands show greater shifts than others: low-frequency phase shifts (300-500 Hz) are largest during the response to the consonant-vowel formant transition (/d/), while high-frequency shifts (720-1000 Hz) predominate during the response to the steady-state vowel (/a/). Most importantly, phase shifts occurring in specific frequency bands correlate strongly with shifts in the latencies of the predominant peaks in the auditory brainstem response, while phase shifts in other frequency bands do not. This finding confirms the validity of phase shift detection as an objective measure of timing differences and reveals that this method detects noise-induced shifts in timing that may not be captured by traditional peak latency measurements.

Context-dependent encoding in the auditory brainstem subserves enhanced speech-in-noise perception in musicians.

Musical training strengthens speech perception in the presence of background noise. Given that the ability to make use of speech sound regularities, such as pitch, underlies perceptual acuity in challenging listening environments, we asked whether musicians' enhanced speech-in-noise perception is facilitated by increased neural sensitivity to acoustic regularities. To this aim we examined subcortical encoding of the same speech syllable presented in predictable and variable conditions and speech-in-noise perception in 31 musicians and nonmusicians. We anticipated that musicians would demonstrate greater neural enhancement of speech presented in the predictable compared to the variable condition than nonmusicians. Accordingly, musicians demonstrated more robust neural encoding of the fundamental frequency (i.e., pitch) of speech presented in the predictable relative to the variable condition than nonmusicians. The degree of neural enhancement observed to predictable speech correlated with subjects' musical practice histories as well as with their speech-in-noise perceptual abilities. Taken together, our findings suggest that subcortical sensitivity to speech regularities is shaped by musical training and may contribute to musicians' enhanced speech-in-noise perception.

Protein supplementation of ruminants consuming low-quality cool- or warm-season forage: differences in intake and digestibility.

An in situ study (Exp. 1) using 4 ruminally cannulated steers (343 ± 11 kg of BW) in a completely randomized design was used to compare ruminal degradation characteristics of low-quality cool-season (C3; Kentucky bluegrass straw; Poa pratensis; 6.3% CP; DM basis) and warm-season (C4; tallgrass prairie; 5.7% CP; DM basis) forage. Four ruminally cannulated steers (252 ± 8 kg of BW; Exp. 2) and 4 wethers (38 ± 1 kg of BW; Exp. 3) were used in two 2 × 2 factorial arrangements of treatments to determine the influence of supplemental CP (CPSupp; soybean meal; 0.09 and 0.19% of BW, CP basis, for steers and lambs, respectively) on nutrient intake and digestion of C3 and C4 forages. Steers and wethers were allotted to separate 4 × 4 Latin squares that ran simultaneously with 20-d periods. In Exp. 1, C3 had a greater A fraction (fraction of total pool disappearing at a rate too rapid to measure) and effective degradability of DM and NDF compared with C4 (P < 0.01). In addition, C3 had a greater (P < 0.01) A fraction and effective degradability of N, whereas the C fraction (fraction of total pool unavailable in the rumen) was less (P < 0.01) than those for C4. Consequently, RDP accounted for 84.7% of total CP in C3 as compared with 66% for C4 (P < 0.01). In Exp. 2, a CPSupp × forage interaction (P < 0.01) was noted for forage and total DMI, with CPSupp increasing intake of C4 by 47% and intake of C3 forage by only 7%. Dry matter digestibility responded similarly, with a CPSupp × forage interaction (P = 0.05; CPSupp increased digestibility by 21% with C4 and by 9% with C3 forage). In addition, CPSupp × forage interactions were noted for ruminal liquid retention time (P = 0.02; CPSupp decreased retention by 3.6 h with C4 and by only 0.6 h with C3 forage) and particulate passage rate (P = 0.02; CPSupp increased passage by 46% with C4 and by 10% with C3 forage). As in Exp. 2, a CPSupp × forage interaction (P = 0.01; CPSupp increased digestibility by 18% with C4 and by 7% with C3 forage) was observed with DM digestibility in Exp. 3. In contrast, only N balance (P < 0.01) and N digestibility (P < 0.01) were affected by CPSupp. These data suggest that intake and digestion of low-quality C3 and C4 forages by ruminants are not similar and, more important, that the physiological response of ruminants to protein supplementation of low-quality forage is dependent on forage type.