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Background: Photodynamic Therapy (PDT) is a therapeutic modality that combines the application of a photoactive compound (photosensitizer, PS) with low-power light to generate reactive oxygen species in the target tissue, resulting in cytotoxic damage and cell death, while sparing adjacent tissues. The objective of this study was to evaluate the phototoxicity of a cyanine dye with two chromophores (biscyanines, BCD) in systems with varying levels of cellular organization, and we used the Photogem® (a photosensitizer approved by the Brazilian ANVISA agency for clinical use in Photodynamic Therapy) as a positive control., Materials and Methods: The cytotoxicity of the compounds was assessed in vitro in 2D monolayers, 3D spheroid cultures, and artificial skin models. Four tumoral cell lines A375 (melanoma), HCB-541 (cutaneous squamous cell carcinoma), Vu120T and Vu147T (head and neck cancer), and two normal cell lines fibroblastic HFF-1 and keratinocyte HACAT were used in this study. Cell viability, migration, production of reactive oxygen species, expression of proteins linked to DNA damage and repair, internalization, and skin permeation of PS agents., Results: Light irradiation in the presence of the PS resulted in greater cytotoxic effects for BCD as compared to Photogem®, which was accompanied by an increase in the production of reactive oxygen species including H 2 O 2 , elevated levels of cleaved PARP, and a higher rate of phosphorylated H2AX protein. BCD demonstrated enhanced internalization and bioaccumulation in the spheroids and equivalent skin models., Conclusion: BCD, as a photosensitizer, showed higher cytotoxicity, with an increased ability to generate reactive oxygen species. This led to reduced cell viability, inhibited migration, and upregulated DNA damage-related proteins. Additionally, its enhanced cellular uptake improved skin barrier permeability, making BCD a strong candidate for in vivo Photodynamic Therapy., 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 © 2024. Published by Elsevier B.V.)

Current quantum systems have significant limitations affecting the processing of large datasets with high dimensionality, typical of high energy physics. In the present paper, feature and data prototype selection techniques were studied to tackle this challenge. A grid search was performed and quantum machine learning models were trained and benchmarked against classical shallow machine learning methods, trained both in the reduced and the complete datasets. The performance of the quantum algorithms was found to be comparable to the classical ones, even when using large datasets. Sequential Backward Selection and Principal Component Analysis techniques were used for feature's selection and while the former can produce the better quantum machine learning models in specific cases, it is more unstable. Additionally, we show that such variability in the results is caused by the use of discrete variables, highlighting the suitability of Principal Component analysis transformed data for quantum machine learning applications in the high energy physics context., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor ML declared a past co-authorship/collaboration with authors NC and IO. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2023 Peixoto, Castro, Crispim Romão, Oliveira and Ochoa.)

Objective: To objectively evaluate acoustic sensitivity of the implanted microphone, and maximum stable gain of a totally implantable active middle ear implant., Design: Prospective, single centre evaluation., Study Sample: Fourteen adult patients., Results: Microphone sensitivity is approx. 10 dB lower than an externally worn conventional hearing aid, at frequencies up to 4000 Hz, and substantially lower at higher frequencies. The masking level due to microphone noise, which determines the softest test tones that can be detected, is estimated at <20 to <30 dB HL up to 1000 Hz, and <40 dB HL at higher frequencies. Maximum stable effective gain is the maximum amplification achievable without causing feedback whistling. In sensorineural hearing loss (SNHL) cases, it is 30-40 dB at frequencies up to 2000 Hz, allowing to compensate for even the maximum recommended hearing loss (60-70 dB HL). In both SNHL and mixed hearing loss (MHL) cases, maximum stable effective gain is lower (+20 to -30 dB) around 3000-6000 Hz., Conclusions: Microphone sensitivity is high enough to achieve aided thresholds of 20-40 dB HL. A strong correlation between actuator coupling efficiency and maximum stable effective gain implies that any effort to improve actuator efficiency should also increase the available gain.

Introduction: COVID-19 is a severe respiratory syndrome caused by the SARS-CoV-2 virus. In Brazil the highest infection rates are associated with socially vulnerable populations. This study therefore sought to analyze the spatial distribution of the disease and its relation with geographic, socioeconomic and public health policy characteristics associated with quilombola communities in Salvaterra municipality, state of Pará, for the period of March to September, 2020., Methodology: This cross-sectional and ecological study used data from the Disease Notification System and the National Registry of Health Establishments of the Ministry of Health, the Income Transfer Registry of the Ministry of Citizenship and the 2010 census of the Brazilian Institute of Geography and Statistics. Statistical and spatial analysis of the data was done through percentages of cases and Flow and Kernel map techniques., Results: Seventy-five notified cases of COVID-19 distributed among 7 quilombola communities in the municipality were analyzed. The epidemiological profile followed a national trend, with a higher percentage of cases among persons who were female, adults with low schooling levels, working as family farmers and with an outcome ending in recovery. The spatial distribution of the disease was not homogenous and showed clusters of cases and high incidence rates, especially in communities close to the municipal seat or to highways., Conclusions: The use of data analysis techniques was satisfactory for providing an understanding of the socioeconomic production of the disease in the areas studied. Accordingly, the need for intensifying epidemiological survey actions in the quilombola communities of the municipality is emphasized., Competing Interests: No Conflict of Interest is declared, (Copyright (c) 2021 Nelson Veiga Goncalves, Joao Simao de Melo Neto, Selma Kazumi da Trindade Noguchi, Andrey Silva Machado, Alcindo da Silva Martins Junior, Maira Cibelle da Silva Peixoto, Alba Lucia Ribeiro Raithy, Camylle Maia Costa Faria, Tainara Carvalho Garcia Miranda Filgueiras, Alex Baima Amaral Junior, Claudia do Socorro Carvalho Miranda.)

Objective: Evaluation of the audiological patient performance with an upgrade of the firmware from the fixed feedback canceller (FFC) to the adaptive feedback canceller (AFC) on an active middle ear implant., Study Design: Retrospective observational nonrandomized group study., Setting: Private hospital., Patients/interventions: From March 2018 to September 2019, 15 patients implanted with an active middle ear implant, with 6 or more months of experience with a FFC system, were upgraded to an AFC algorithm., Main Outcome Measures: Functional gain, speech perception in silence and in noise, and sound localization capacities were examined. Feedback reduction was also analyzed., Results: Thirteen patients were analyzed. Pure tone audiometric evaluation with FFC (mean value of 48.02 dB) compared with AFC at 1 (mean value of 49.12 dB) and 6 months (mean value of 42.75 dB) revealed no statistically significant differences (p = 0.889 and p = 0.358 respectively).In speech discrimination in silence, clinically relevant improvements were observed with AFC at 1 and 6 months, with a mean value of 41.5 and 38.3 dB, respectively (p = 0.03 and p = 0.021 correspondingly). In speech discrimination in noisy environments, we observed an improvement of the different conditions tested. No differences were found in localization capacities between FFC and AFC at the two different moments of evaluation., Conclusions: AFC is more effective than FFC in cancelling feedback and improving sound quality, allowing for better speech understanding in silence and in noise., Competing Interests: The authors disclose no conflicts of interest., (Copyright © 2020, Otology & Neurotology, Inc.)

Purpose: This paper reports the surgical and audiological outcomes of a large series of patients who received a fully implantable middle ear implant (MEI): carina (Cochlear, Australia)., Methods: This is a multicentre retrospective study involving three tertiary referral centres. Patient data were collected for the first 42 consecutive patients who were fitted with the MEI between 2014 and 2019 (Sheffield from February 2017 to January 2019; São Paulo from April 2015 to September 2017; Porto from December 2014 to May 2017). The main outcome measures included surgical results, free field speech testing with speech recognition thresholds (SRT) and audiological gain., Results: There was one major complication due to infection resulting in a brain abscess and explantation of the device. Three other patients had minor skin infections; no other complications were reported. Results show a functional gain of 19.5 dB (p < 0.05) with the MEI versus unaided condition. SRT improved from 57.4 dB to 44.6 dB with the MEI (p < 0.05)., Conclusions: This fully implanable active MEI offers a reliable option for patients with moderate-to-severe sensorineural or mixed hearing losses especially for those do not tolerate or cannot use conventional hearing aids. It provides significant improvement in hearing as shown in the audiological outcomes. The surgery is relatively straightforward but there is a steep learning curve. The devices are well tolerated by all patients.

The same food formulation processed to obtain two different starch gelatinisations (SG) and resistant starch (RS) contents was evaluated in old and adult dogs, regarding apparent total tract digestibility (ATTD) of nutrients, fermentation products in faeces, and postprandial glucose and insulin responses. A diet with corn was ground and extruded in two different ways, obtaining Low RS (2.2 g/kg DM; 99.9% of SG) and High RS (15.3 g/kg DM; 62.6% of SG). Each diet was fed to adults (4.0 ± 0.7 years) or old beagle dogs (11.5 ± 0.4 years) in a 2 (ages) x 2 (RS amounts) factorial arrangement with 8 dogs per food. Data were evaluated by analysis of variance, and postprandial responses by analysis of variance of repeated measurements over time ( p  < 0.05). Diet × age interaction was observed for protein ATTD, with lower values for old dogs fed High RS than those for the other treatments ( p  < 0.05). No age or diet effect was verified for the ATTD of other nutrients and faecal score. Faecal moisture and pH were higher for adults than that for old dogs ( p  < 0.05). The High RS food increased acetate, propionate and butyrate concentrations in faeces, regardless of age ( p  < 0.01). Old dogs presented lower acetate and total short-chain fatty acids (SCFA) and higher lactate and ammonia than adults ( p  < 0.05). Only for old dogs the intake of the High RS food reduced ammonia and increased faecal lactate ( p  < 0.05). An age × diet interaction was verified for glucose postprandial response, with lower values for old dogs fed High RS food ( p  < 0.05), while no differences were found for the other treatments. Old dogs had higher postprandial insulin secretion regardless of the diet ( p  < 0.05), and lower insulin increment at 180 min after the meal when fed the Low RS than when fed the High RS food ( p  < 0.05). In conclusion, the diet with lower SG and higher RS improved the intestinal microenvironment, with higher butyrate and total SCFA without altering faeces production or score. Old dogs presented less acetate and total SCFA and higher lactate and ammonia in faeces than adults. The High RS food increased lactate and reduced ammonia in faeces of old dogs, with possible positive influences for gut health. Old dogs had higher postprandial insulin secretion than that of adults to maintain blood glucose, and the diet with higher RS content reduced the postprandial glucose response of old dogs.

Captive parrots show a high incidence of obesity and other metabolic disorders due to the consumption of unbalanced diets. Therefore, this study evaluated the digestibility and metabolic effects of transitioning blue-fronted amazons from a high fat diet (sunflower seeds) to processed diets with three degrees of starch gelatinization (SG). The same feed formulation was processed to obtain pelletized feed (PEL) at 27.1% SG; low-cooked extruded feed (EXT L ) at 81.6% SG; and high-cooked extruded feed (EXT H ) at 98.5% SG. Thirty adult parrots were fed sunflower seeds for 90 days, then were distributed in a completely randomized design with 10 repetitions per treatment, and fed one of the three prepared diets for 160 days. Feed palatability, apparent digestibility, excreta concentrations of volatile fatty acids, lactate and ammonia, initial and final radiographic examinations, blood cell counts and glucose, triglycerides, cholesterol, total protein, albumin, aspartate aminotransferase (AST) and uric acid levels were evaluated. The data were analysed by an analysis of variance and compared by Tukey's test (p < 0.05). Sunflower seed was more digestible than processed feeds (p < 0.05). Diet processing interfered with fat and starch digestibility (p < 0.001), being higher in the PEL than in the EXT H and EXT L respectively. Transitioning from sunflower seeds to balanced diets reduced serum glucose, triglycerides, cholesterol and AST (p < 0.05) and increased red blood cell, haemoglobin, lymphocyte, monocyte and leucocyte counts (p < 0.01). Radiographs indicated a decreased hourglass (p = 0.015) and a reduced heart-liver ratio after ingesting the processed feeds (p < 0.05). Feed processing did not affect blood cell counts, serum biochemistry or radiographic examinations. In conclusion, parrots preferred the extruded diet and did not require an extensive SG to properly digest the feed. Consuming the processed diets improved the birds' metabolism and health., (© 2018 Blackwell Verlag GmbH.)

The effects of resistant starch (RS) intake on nutrient digestibility, microbial fermentation products, faecal IgA, faecal pH, and histological features of the intestinal mucosa of old dogs were evaluated. The same formulation was extruded in two different conditions: one to obtain elevated starch cooking degree with low RS content (0.21%) and the other lower starch cooking with high RS content (1.46%). Eight geriatric Beagles (11.5 ± 0.38 years old) were fed each diet for 61 days in a crossover design. Food intake, nutrient digestibility, fermentation products, faecal pH, and faecal IgA were examined via variance analysis. Histological results of intestinal biopsies were assessed via Wilcoxon test for paired data. The morphometric characteristics of large intestine crypts were evaluated via paired t tests (p < .05). Protein, fat, and energy digestibilities were higher for the low-RS diet (p < .05). Dogs receiving the high-RS diet had lower faecal pH and higher values for propionate, butyrate, total volatile fatty acids, and lactate (p < .05). No differences between diets were found in the histological parameters of the gut mucosa, and only a tendency for deeper crypts in the descending colon was observed for dogs fed the high-RS diet (p = .083). The intake of a corn-based kibble diet manufactured with coarse ground raw material and low starch gelatinization to obtain 1.4% of RS affected microbial fermentation products and faecal pH and tended to increase crypt depth in the descending colon of old dogs., (© 2017 Blackwell Verlag GmbH.)

Objectives: This study aimed to evaluate the effectiveness, according to the hearing threshold and language performance, of cochlear implants through a period of 10 or more years of follow-up., Methods: A retrospective chart review was conducted. 132 patients were selected from the children's population that underwent cochlear implantation at the Department of Otorhinolaryngology, Centro Hospitalar e Universitário de Coimbra, from 1992 to 2001, with a minimum follow-up period of 10 years. A comparison of the pure-tone and speech audiometric thresholds between two periods (T0 and T1) was performed. T0 refers to the initial evaluation, immediately after the rehabilitation programme, within the first year after cochlear implantation. T1 refers to the most recent annual assessment, carried out in 2010 and 2011. Speech understanding was also evaluated through word and sentence recognition tests., Results: No statistically significant differences were found between early and late assessments, in paediatric cochlear implants users, after a 10 years period of cochlear implantation. Both speech and pure-tone audiometry seem to stabilize except for 2000 Hz where the results were even better after 10 years. Factors such as age at time of implantation, duration of deafness, aetiology and exchange of the speech processor do not seem to have a role in auditory performance after a long rehabilitation period. In tests of verbal discrimination rates of words and phrases recognition were of 84.6% and 65.1%, respectively., Conclusions: Cochlear implant is an effective treatment for severe to profound hearing loss in children, contributing to a hearing performance and an appropriate language acquisition, currently comparable to normal hearing children. These benefits appear to keep stable over the years. No deterioration was identified., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Unlabelled: Amusia is a disorder that affects the processing of music. Part of this processing happens in the primary auditory cortex. The study of this condition allows us to evaluate the central auditory pathways., Objective: To explore the diagnostic evaluation tests of amusia., Method: The authors propose an evaluation protocol for patients with suspected amusia (after brain injury or complaints of poor musical perception), in parallel with the assessment of central auditory processing, already implemented in the department. The Montreal Evaluation of Battery of amusia was the basis for the selection of the tests. From this comprehensive battery of tests we selected some of the musical examples to evaluate different musical aspects, including memory and perception of music, ability concerning musical recognition and discrimination. In terms of memory there is a test for assessing delayed memory, adapted to the Portuguese culture. Prospective study., Results and Conclusions: Although still experimental, with the possibility of adjustments in the assessment, we believe that this assessment, combined with the study of central auditory processing, will allow us to understand some central lesions, congenital or acquired hearing perception limitations.

Objective: To compare the effects of two regimens of GH therapy with different target IGF-1 levels on anthropometric parameters, glucose metabolism, lipid profile and cardiac function in adults with GH deficiency (GHD)., Patients and Methods: Retrospective analysis of 14 GHD adults from Clementino Fraga Filho University Hospital, Rio de Janeiro, Brazil, who were treated with a GH regimen aimed at maintaining serum IGF-1 levels between the median and upper reference limit (high dose group - HDGH) and 18 GHD adults from Federal University Hospital, Curitiba, Brazil, who received a fixed GH dose of 0.2mg/day in the first year of treatment, followed by titration to maintain serum IGF-1 levels between the median and lower reference limit (low dose group - LDGH). All patients were followed for 2 years with analysis of anthropometric parameters, serum levels of IGF-1, glucose, insulin, HOMA-IR, lipid profile, and transthoracic echocardiography., Results: Changes on weight, BMI and waist circumference were similar between the two groups. Insulin levels increased and HOMA-IR worsened in the LDGH group at 1year and improved thereafter. Total cholesterol and triglycerides did not change with therapy. LDL cholesterol reduced in both groups, while HDL-cholesterol significantly increased only in the HDGH group (p=0.007 vs LDGH). No significant variations on echocardiographic parameters were observed., Conclusion: The HDGH and LDGH regimens resulted in similar changes on anthropometric, echocardiographic, glucose and lipid parameters in GHD adults, except for increase in HDL cholesterol that was only observed in the HDGH regimen., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

The purpose of this study was to evaluate the effects of 5 years of GH substitution on cardiac structure and function, physical work capacity and blood pressure levels in adults with GH deficiency (GHD). Fourteen patients were clinically assessed every 3 months for 5 years. Transthoracic echocardiography and exercise test were performed at baseline, 24, 48 and 60 months. Blood pressure (BP) was measured by means of ambulatory monitoring of blood pressure at baseline, 6, 12, 24 and 60 months. Left ventricular mass and its index increased progressively during the 5 years of GH substitution (P = 0.008 and 0.007, respectively). There were no significant changes in all others cardiac parameters evaluated. It was observed a significant improve in functional capacity (P < 0.001) and maximal oxygen uptake (P = 0.006) during the treatment. Diurnal systolic BP increased by 15 mmHg (P = 0.024) and diurnal diastolic BP by 4.5 mmHg (P = 0.037). There was no change in dirnal systolic pressure load but a considerable but non-statistically significant reduction in diurnal diastolic pressure load was observed during the study. During the night diastolic BP increased by 4 mmHg (P = 0.012) despite a substantial but non-statistically significant reduction in diastolic pressure load. We observed an increase in the proportion of persons with a non-physiological nocturnal fall (non-dippers) throughout the study (from 36.4% at baseline to 54.6% after 60 months of therapy). We concluded that 5 years of GH replacement promoted positive effects on exercise capacity and maximum oxygen uptake in spite of a modest increase in BP levels and left ventricular mass. Continuous monitoring is mandatory to arrive at further conclusions concerning the effects of GH substitution in adults on cardiovascular parameters with respect to possible unfavorable long term effects.

The benefits of long-term effects of growth hormone (GH) substitution on carbohydrate and lipid metabolism in GH-deficient (GHD) adults are still controversial. The purpose of this study was to evaluate the effects of 5 years of GH substitution on body composition, glucose and lipid metabolism, and carotid artery intima-media thickness (IMT) in GHD adults. Fourteen patients were clinically assessed every 3 months for 5 years. Serum insulin-like growth factor 1 levels, lipid profile, oral glucose tolerance test, and ultrasonography of the carotid arteries were performed at baseline, 6 months, and every year during replacement. Visceral fat was measured by computed tomographic scan at baseline and at 6, 12, 24, and 60 months. The waist circumference was reduced after 6 months but increased during the next months toward baseline values. Visceral fat decreased during the study. Fasting glucose and insulin levels did not change, as well as the homeostasis model assessment of insulin resistance index. Despite an initial increase in frequency of abnormal glucose tolerance, mean 2-hour oral glucose tolerance test glucose levels decreased during the last 2 years. There was an increase in apolipoprotein A-1 levels during the treatment. Apolipoprotein B levels were reduced after 6 months and remained stable thereafter. A reduction in carotid artery IMT was observed during replacement. We concluded that 5 years of GH replacement therapy promoted positive effects on visceral fat, lipid profile, and carotid artery IMT in GHD adults. Long-term therapy improves insulin sensitivity through a reduction in visceral fat, and continuing monitoring is mandatory in terms of glucose metabolism.

Diabetic ketoacidosis is an acute complication of Diabetes Mellitus characterized by hyperglycemia, metabolic acidosis, dehydration, and ketosis, in patients with profound insulin deficiency. It occurs predominantly in patients with type 1 diabetes and is frequently precipitated by infections, insulin withdrawal or undiagnosed type 1 diabetes. The authors review its pathophysiology, diagnostic criteria and treatment options in adults, as well as its complications.

The treatment of Graves' disease (GD) with antithyroid drugs (ATD) leads to remission of the disease in approximately half of patients treated for at least six months, and the overall relapse rate is high, ranging from 60% to 80%. The presence of prognostic features for achieving a remission after medical treatment is a matter of discussion in the literature. The aim of this study is to evaluate the effect of different ATD regimens available in Brazil (propylthiouracil--PTU and methimazole--MMI) on remission and relapse rates of GD, as well as to determine possible predictors of remission and relapse of the disease and the side effects profile. We reviewed the records from all patients submitted to medical treatment of GD (and with no report of prior treatment of the disease) for at least six months and followed for at least 12 months after the drug withdrawal at Hospital Universitário Clementino Fraga Filho (HUCFF), between October 1978 and August 2003. We identified 127 patients, with the age ranging from 18 to 88 years (mean 39.3 +/- 12.8). Remission was observed in 58 patients (45.7%) and relapse occurred in 31 (53.4%), at a mean period of 14.5 +/- 16.1 months. We verified that the duration of symptoms before the beginning of medical treatment, age and gender did not influence the rate of remission and the relapse risk, whereas the presence of large goiter size (> 40 grams), Graves' ophthalmopathy and use of high daily doses of ATD (> or = 600 mg of propylthiouracil/60 mg of methimazole MMI) were associated with a decreased remission rate. Moreover, patients who presented a TSH measurement < 0.4 microIU/mL between 4 to 5 weeks after the drug withdrawal showed an increased relapse cumulative probability. In conclusion, our results confirms that lasting remission rate of GD treated with ATD is relatively low. We concluded that the combination of goiter size > 40 g, ophthalmopathy, and use of daily doses of PTU > or = 600 mg or MMI > or = 60 mg was vigorously related to lack of remission of GD. Furthermore, TSH measurement between 4 to 5 weeks after the drug withdrawal seems to be a useful tool to determine the remission chance and the relapse risk of the disease.

Objective: To describe three patients diagnosed with somatotropinomas in whom the analgesic effect of octreotide was observed, along with dependency to the drug., Methods: These patients had pituitary macroadenomas treated with transphenoidal surgery and pituitary radiotherapy, and received high daily doses (>900 microg/day) of subcutaneous octreotide because of persistent high levels of growth hormone and insulin-like growth factor I (IGF-I)., Results: Headache occurred prior to drug administration in all three cases, with relief soon after. We also observed tolerance to octreotide's analgesic and anti-secretory actions (one patient), craving for the drug (two patients), withdrawal syndrome (one patient), and drug abuse (one patient)., Conclusion: Dependency syndrome may occur when high doses of octreotide are used, sometimes leading to drug abuse. Tolerance to the growth hormone anti-secretory effect of the drug may encourage physicians to increase doses to levels at which drug dependency has been observed. Sustained release somatostatin analogs may represent a solution to this problem.

The frequency of myopathy in hypothyroidism ranges from 30 to 80%. The major symptoms related are weakness, muscular cramps and myalgia. The pseudohyperthrophic form is called Hoffman's syndrome. The electrophysiological study reveals myopathy, neuropathy or mixed pattern. Laboratorial investigation generally shows increased levels of muscle enzymes and low serum thyroid hormones, with thyrotrophic-stimulating hormone (TSH) elevated. The treatment consists in hormone replacement and the prognosis is good in most of the cases. We report an adult male who developed muscular cramps, myalgia, weakness, pseudohyperthrophy, associated with facial edema and alteration of his voice. The muscle enzymes were increased and T4 was undetectable with a raised level of TSH. The myopathy was the initial manifestation of hypothyroidism in this case.