Nirmatrelvir/ritonavir and remdesivir against symptomatic treatment in high-risk COVID-19 outpatients to prevent hospitalization or death during the Omicron era: a propensity score-matched study.

Background: Even though worldwide death rates from coronavirus disease 2019 (COVID-19) have decreased, the threat of disease progression and death for high-risk groups continues. Few direct comparisons between the available severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antivirals have been made. Objective: We aimed to compare two SARS-CoV-2 antivirals (nirmatrelvir/ritonavir and remdesivir) against all-cause hospitalization or death. Design: This is a propensity score-matched cohort study. Methods: We included all high-risk outpatients with COVID-19 in a tertiary referral center in Mexico City from 1 January 2022 to 31 July 2023. The primary outcome was all-cause hospitalization or death 28 days after symptom onset. The secondary outcome was COVID-19-associated hospitalization or death 28 days after symptom onset. Logistic regression analysis for characteristics associated with the primary outcome and a multi-group comparison with Kaplan-Meier survival estimates were performed. Results: Of 1566 patients analyzed, 783 did not receive antiviral treatment, 451 received remdesivir, and 332 received nirmatrelvir/ritonavir. The median age was 60 years (interquartile range: 46-72), 62.5% were female and 97.8% had at least one comorbidity. The use of nirmatrelvir/ritonavir was associated with an absolute risk reduction of 8.8% and a relative risk reduction of 90% for all-cause hospitalization or death. The use of remdesivir was associated with an absolute risk reduction of 6.4% and a relative risk reduction of 66% for all-cause hospitalization or death. In multivariable analysis, both antivirals reduced the odds of 28-day all-cause hospitalization or death [nirmatrelvir/ritonavir odds ratio (OR) 0.08 - 95% confidence interval (CI): 0.03-0.19, remdesivir OR 0.29 - 95% CI: 0.18-0.45]. Conclusion: In high-risk COVID-19 outpatients, early antiviral treatment with nirmatrelvir/ritonavir or remdesivir was associated with lower 28-day all-cause hospitalization or death.

Nirmatrelvir/ritonavir and remdesivir against symptomatic treatment in high-risk COVID-19 outpatients In this study, we included high-risk non-hospitalized patients with confirmed mild COVID-19. We compared those who received antiviral treatment (nirmatrelvir/ritonavir or remdesivir) against those who only received symptomatic treatment. The aim was to detect differences in hospitalization or death 28 days after symptom onset. We analyzed 1566 patients: 783 did not receive antiviral treatment, 451 received remdesivir, and 332 received nirmatrelvir/ritonavir. Most patients were female and over 60 years old. The most common comorbidities were chronic hypertension (44%), diabetes mellitus (26%), and autoimmune diseases (25%); systemic immunosuppression was registered in 35% of patients. Hospitalization or death 28 days after symptom onset occurred in 168 patients (136 in the symptomatic treatment group, 27 in the remdesivir group, and 5 in the nirmatrelvir/ritonavir group). Considering multiple variables like age, sex, comorbidities, and previous vaccination, both antivirals significantly reduced the odds of hospitalization or death (nirmatrelvir/ritonavir odds ratio 0.08, 95% confidence interval 0.03-0.19; remdesivir odds ratio 0.29, 95% confidence interval 0.18-0.45).

Designing a Local Policy to Reduce HIV in Mexico City.

The Joint United Nations Program on human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) (Joint United Nations Program on HIV/AIDS, UNAIDS) has recommended 90-90-90 goals to increase the number of patients who are aware of their status, on antiretroviral therapy, and have undetectable viral loads. Mexico City has made several achievements to aid in prevention, early diagnosis, and treatment; however, the incidence of HIV has not decreased over the past decade. This article reviews global initiatives that were successful in achieving some or all these metrics and provide a road map for Mexico to reach the desired goals.

COVID-19 pharmaceuticals in aquatic matrices: The threatening effects over cyanobacteria and microalgae.

Water contamination by pharmaceuticals is a global concern due to their potential negative effects on aquatic ecosystems and human health. This study examined the presence of three repositioned drugs used for COVID-19 treatment: azithromycin (AZI), ivermectin (IVE) and hydroxychloroquine (HCQ) in water samples collected from three urban rivers in Curitiba, Brazil, during August and September 2020. We conducted a risk assessment and evaluated the individual (0, 2, 4, 20, 100 and 200 µg.L-1) and combined (mix of the drugs at 2 µg.L-1) effects of the antimicrobials on the cyanobacterium Synechococcus elongatus and microalga Chlorella vulgaris. The liquid chromatography coupled to mass spectrometry results showed that AZI and IVE were present in all collected samples, while HCQ occurred in 78 % of them. In all the studied sites, the concentrations found of AZI (up to 2.85 µg.L-1) and HCQ (up to 2.97 µg.L-1) represent environmental risks for the studied species, while IVE (up to 3.2 µg.L-1) was a risk only for Chlorella vulgaris. The hazard quotients (HQ) indices demonstrated that the microalga was less sensitive to the drugs than the cyanobacteria. HCQ and IVE had the highest values of HQ for the cyanobacteria and microalga, respectively, being the most toxic drugs for each species. Interactive effects of drugs were observed on growth, photosynthesis and antioxidant activity. The treatment with AZI + IVE resulted in cyanobacteria death, while exposure to the mixture of all three drugs led to decreased growth and photosynthesis in the cells. On the other hand, no effect on growth was observed for C. vulgaris, although photosynthesis has been negatively affected by all treatments. The use of AZI, IVE and HCQ for COVID-19 treatment may have generated surface water contamination, which could increased their potential ecotoxicological effects. This raises the need to further investigation into their effects on aquatic ecosystems.

Factores precondicionantes de secuelas en niños menores de 5 años de edad con tortícolis muscular congénita / Precondicionant factors of sequela in children under 5 years with congenital muscular wryneck

Introducción: El espectro de secuelas de la tortícolis muscular congénita es amplio. Algunos niños con dichas secuelas requieren de costosas y complejas operaciones. Objetivo: Determinar los factores precondicionantes asociados a secuelas orgánicas de la tortícolis muscular congénita en pacientes desde un mes hasta 5 años de edad. Métodos: Se realizó un estudio retrospectivo, analítico, no experimental de casos y controles que incluyó a niños con diagnóstico de tortícolis muscular congénita, atendidos en la consulta de Neurodesarrollo del Hospital Infantil Antonio María Beguez César de Santiago de Cuba, desde enero del 2017 hasta diciembre del 2020. El grupo de casos quedó conformado por todos los pacientes con complicaciones orgánicas de la tortícolis muscular congénita (24 niños) y el de control, por quienes no presentaron dichas complicaciones (72), seleccionados mediante un muestreo aleatorio simple. Resultados: El sexo masculino predominó en los pacientes con complicaciones (62,5 %). La plagiocefalia y la asimetría facial fueron las secuelas más frecuentes. La edad menor de 6 meses en el momento del diagnóstico de la entidad constituyó un factor protector (OR = 0,12; IC 95 %: 0,04-0,33; p=0,000); hubo asociación de las complicaciones con el parto distócico (OR = 0,36; IC 95 %: 0,13-1,01; p=0,049) y con la macrosomía fetal (OR = 5,7; IC 95 %: 1,44-22,2; p=0,014). También existió asociación altamente significativa de las complicaciones con la asimetría de ambos músculos esternocleidomastoideos (OR = 11,4; IC 95 %: 3,7-34,9; p=0,000) y con el inicio tardío del tratamiento (OR = 8,5; IC 95 %: 3,0-24,1; p=0,000). Conclusiones: El parto distócico, la macrosomía fetal, la asimetría entre ambos músculos esternocleidomastoideos y el inicio tardío del tratamiento rehabilitador incrementaron el riesgo de complicaciones en los integrantes de la casuística.

Introduction: The spectrum of sequela of the congenital muscular wryneck is wide. Some children with these sequela require expensive and complex operations. Objective: To determine the precondicionant factors associated with organic sequela of the congenital muscular wryneck in patients since one month to 5 years. Methods: A retrospective, analytic, non experimental of cases and controls study was carried out that included children with diagnosis of congenital muscular wryneck, assisted in the Neurodevelopment Service of Antonio María Beguez Cesar Children Hospital in Santiago de Cuba, from January, 2017 to December, 2020. The group of cases was conformed by all the patients with organic complications of the congenital muscular wryneck (24 children) and the control group, for those who didn't present these complications (72), selected by means of a simple random sampling. Results: The male sex prevailed in the patients with complications (62.5 %). The plagiocephaly and the facial asymmetry were the most frequent sequela. The age under 6 months in the moment of the diagnosis of the entity constituted a protective factor (OR = 0.12; IC 95 %: 0.04-0.33; p=0.000); there was association of the complications with the dystocic childbirth (OR = 0.36; IC 95 %: 0.13-1.01; p=0.049) and with the fetal macrosomia (OR = 5.7; IC 95 %: 1.44-22,2; p=0.014). There was also highly significant association of the complications with the asymmetry of both sternocleidomastoid muscles (OR = 11.4; IC 95 %: 3.7-34.9; p=0-000) and with the late beginning of the treatment (OR = 8.5; IC 95 %: 3.0-24.1; p=0.000). Conclusions: The dystocic childbirth, fetal macrosomia, asymmetry between both sternocleidomastoid muscles and the late beginning of the rehabilitative treatment increased the risk of complications in the members of the case material.

Favipiravir and/or nitazoxanide: a randomized, double-blind, 2×2 design, placebo-controlled trial of early therapy in COVID-19 in health workers, their household members, and patients treated at IMSS (FANTAZE).

BACKGROUND: The 2020 pandemic of SARS-CoV-2 causing COVID-19 disease is an unprecedented global emergency. COVID-19 appears to be a disease with an early phase where the virus replicates, coinciding with the first presentation of symptoms, followed by a later 'inflammatory' phase which results in severe disease in some individuals. It is known from other rapidly progressive infections such as sepsis and influenza that early treatment with antimicrobials is associated with a better outcome. The hypothesis is that this holds for COVID-19 and that early antiviral treatment may prevent progression to the later phase of the disease. METHODS: Trial design: Phase IIA randomised, double-blind, 2 × 2 design, placebo-controlled, interventional trial. RANDOMISATION: Participants will be randomised 1:1 by stratification, with the following factors: gender, obesity, symptomatic or asymptomatic, current smoking status presence or absence of comorbidity, and if the participant has or has not been vaccinated. BLINDING: Participants and investigators will both be blinded to treatment allocation (double-blind). DISCUSSION: We propose to conduct a proof-of-principle placebo-controlled clinical trial of favipiravir plus or minus nitazoxanide in health workers, their household members and patients treated at the Mexican Social Security Institute (IMSS) facilities. Participants with or without symptomatic COVID-19 or who tested positive will be assigned to receive favipiravir plus nitazoxanide or favipiravir plus nitazoxanide placebo. The primary outcome will be the difference in the amount of virus ('viral load') in the upper respiratory tract after 5 days of therapy. Secondary outcomes will include hospitalization, major morbidity and mortality, pharmacokinetics, and impact of antiviral therapy on viral genetic mutation rate. If favipiravir with nitazoxanide demonstrates important antiviral effects without significant toxicity, there will be a strong case for a larger trial in people at high risk of hospitalization or intensive care admission, for example older patients and/or those with comorbidities and with early disease. TRIAL REGISTRATION: ClinicalTrials.gov NCT04918927 . Registered on June 9, 2021.

Tocilizumab is useful for coronavirus disease 2019 patients: the key point is timing

SUMMARY OBJECTIVE: In coronavirus disease 2019, a rapidly progressive inflammatory process is considered to be the main cause of organ damage and mortality. Therefore, the importance of anti-inflammatory treatments such as tocilizumab is increasing. METHODS: A total of 107 patients who received tocilizumab between March 2020 and March 2021 were included in the study. The primary termination point was mortality. We compared surviving and deceased patients by the stage of the disease and where the drug was given (service or intensive care unit). RESULTS: The mean age was 60.8±14.6 years (minimum 29 years, maximum 96 years). According to the WHO staging system, 16 (15%) patients had moderate, 47 (43.9%) patients had severe, 44 (41.1%) patients had a critical illness. Although all patients were admitted to the service, 26 (24.3%) patients received tocilizumab in the intensive care unit. Of 107 patients, 80 (74.7%) survived and 27 (25.2%) died. Mortality was found to be significantly higher in critical patients (96.3%), severe patients (3.7%), and moderate patients (0%) (p<0.001). Peripheral oxygen saturation measured at admission was found to be significantly lower in patients who died. The initial saturations (p=0.008) were found to have independent effects on mortality. CONCLUSION: The results showed that tocilizumab is an effective treatment option for coronavirus disease 2019 disease and reduces mortality, but the key point is timing.

Diagnóstico e tratamento precoce da má oclusão de Classe III com Aparelho Disjuntor Hyrax e Máscara Facial de Petit com avaliação do tempo de uso com micro-sensor: relato de caso clínico / Early diagnosis and treatment of Class III occlusion with Hyrax Isolating Appliance and Petit Face Mask with evaluation of the time of use with micro-sensor: a clinical case report

O sucesso do tratamento precoce da classe III depende de um bom diagnóstico e da cooperação do paciente na utilização do aparelho extrabucal. Neste trabalho, por meio de um chip (Theramon) instalado na Máscara Facial de Petit da paciente, foi possível monitorar a quantidade de horas que a paciente utilizou o aparelho por dia, durante um período de quatro meses. Paciente do sexo feminino, 7 anos e 11 meses de idade portadora da má oclusão de classe III, utilizou o aparelho de disjunção da maxila (Hyrax) modificado, seguido da Máscara Facial de Petit com chip (Theramon) instalado. A média de uso foi maior do que 11 horas de uso diário. O uso deste dispositivo auxilia no monitoramento do tempo de uso do aparelho, cujo sucesso do tratamento depende da utilização deste pelo paciente(AU)

The success of early treatment of class III depends on a good diagnosis and the cooperation of the patient in the use of the extra oral appliance. In this study, the patient was able to monitor the number of hours the patient used the device per day during a period of four months using a Theramon chip installed in the Patient's Facial Mask. A 7-year, 11-month-old male with Class III malocclusion used the modified maxillary disjunction (Hyrax), followed by the Petit Facial Mask with a Theramon chip installed. The average use was greater than 11 hours of daily use. The use of this device assists in the monitoring of the time of use of the device, whose success of the treatment depends on the use of this by the patient(AU)

Corrección de una clase III esqueletal con anclaje óseo en paciente en crecimiento: Reporte de caso / Skeletal class III correction in growing patient with bone anchorage: CaseReport

Antecedentes: La clase III esqueletal, es una deformidad dentofacial donde el tercio inferior de la cara es más prominente, el tratamiento se decide según la etiología y la edad del paciente; si se encuentra en crecimiento la malformación puede ser tratada con un protocolo interceptivo y si es posible evitar la cirugía ortognática a futuro. Objetivo: Mejorar la clase esqueletal, descruzar la mordida u obtener mordida borde a borde, mejorar la posición del labio superior y evaluar el comparativo inicial-final de SNA y ANB. Reporte de caso:Paciente masculino de 13 años, sin antecedentes personales patológicos o familiares reportados; presenta clase III esqueletal responsiva bimaxilar, crecimiento vertical, clase molar I y canina III; fue tratado con el protocolo de mini placas BAMP (bone anchored maxillary protraction) por sus siglas en inglés, elásticos intermaxilares y un paladar con pistas planas. Resultados:La fase ortopédica duro cinco meses y se logró mordida borde a borde y clase I esqueletal. Discusión: Se obtuvieron resultados con el uso de mini implantes sin anclaje extraoral en menos tiempo a comparación de otros métodos que tienen que ser usados por 9-12 meses.Conclusión:El protocolo BAMP puede ser usado en pacientes en crecimiento sin máscara facial para corregir la clase III esqueletal.

Background: Skeletal class III is a dentofacial deformity where the lower third ofthe face is more prominent. The treatment is decided according to the etiology and age of the patient; If the patient is in growing, the malformation can be treated with an interceptive protocol and if possible, avoid a orthognathic surgery in the future. Objective: Improve the skeletal class, uncross the bite or obtain an edge-to-edge bite, improve the position of the upper lip and compare the initial-final relationship of ANS and ANB.Case report:13-year-old male patient, with no reported pathological or family history; presents skeletal class III, vertical growth, molar class I and canine III; he was treated with the protocol of mini BAMP (bone anchored maxillary protraction) plates, intermaxillary elastics and a palate with flat tracks. Results:The orthopedic phase lasted five months and an edge-to-edge bite and skeletal class I were achieved.Discussion:Results were obtained with the use of mini plates without extraoralanchorage in less time compared to other methods that have to be used for 9-12 months. Conclusion: The BAMP protocol can be used in growing patients without a face mask to correct skeletal class III.

Two-phase orthodontic treatment of two different types of tooth transposition in the same patient.

Orthodontic treatment is thoroughly planned considering the patient's facial and dental characteristics, the main complaint, treatment time and the orthodontist's experience. Transposition is a form of ectopia, in which two adjacent teeth exchange positions in the dental arch. Transposition can be partial or complete. This article reports the treatment of a female patient with two kinds of tooth transposition managed in the mixed and permanent dentitions. A girl, aged eight years and three months, came to routine paediatric consultation with an ectopic permanent mandibular left lateral incisor in the mixed dentition. Radiographic analysis indicated partial transposition of the permanent mandibular left lateral incisor and canine (Md.L2.C), and development of a complete tooth transposition between the permanent maxillary right first pre-molar and canine (Mx.C.P1). The patient was treated in two phases. The first, in the mixed dentition, and the second, in the permanent dentition with a three-year follow-up between them. These challenging treatment approaches are described in detail, including the mechanics used. The key points of this treatment were early diagnosis of the ectopic mandibular lateral incisor, use of light forces and interphase patient follow-up. These determined the best time to start the second treatment phase, enabling achievement of aesthetic and functional outcomes, and the results remained stable one year after the end of orthodontic treatment.

Randomized clinical trial to compare the efficacy of ivermectin versus placebo to negativize nasopharyngeal PCR in patients with early COVID-19 in Peru (SAINT-Peru): a structured summary of a study protocol for randomized controlled trial.

OBJECTIVES: The primary objective is to determine the effect of a daily dose of ivermectin administered in three consecutive days to non-severe COVID-19 patients with no more than 96 hours of symptoms, on the detection of SARS-CoV-2 RNA by PCR from nasopharyngeal swabs at day seven post-treatment initiation. The secondary objectives are: 1. To assess the efficacy of ivermectin to reduce the SARS-CoV-2 viral load in the nasopharyngeal swab on days 4, 7, 14 and 21 post-treatment initiation 2. To assess the efficacy of ivermectin on the improvement of symptoms 3. To assess the proportion of seroconversions at day 21 4. To assess the safety of ivermectin at the proposed dose 5. To determine the magnitude of the immune response against SARS-CoV-2 6. To assess correlation of the presence of intestinal helminths on participants on baseline and day 14 with COVID-19 progression and treatment. TRIAL DESIGN: SAINT PERU is a triple-blinded, randomized, placebo-controlled trial with two parallel arms to evaluate the efficacy of ivermectin in negativizing nasopharyngeal PCR in patients with SARS-CoV-2 infection. PARTICIPANTS: The trial is conducted in two national hospitals in Lima-Peru. The study population is patients with a positive PCR test for SARS-CoV-2 in a nasopharyngeal specimen, symptomatic for 96 hours or less, with non-severe COVID-19 disease at baseline, regardless of the presence of risk factors for progression to severity. The study will not include pregnant women or minors (17 years old or younger). Inclusion criteria 1. COVID-19 symptomatology (cough, fever, anosmia, etc.) lasting no more than 96 hours, with a positive nasopharyngeal swab PCR test for SARS-CoV-2. 2. 18 years or older. 3. No use of ivermectin in the month prior to the visit. 4. No known history of ivermectin allergy. 5. Capable to give informed consent. 6. Not current use of CYP 3A4 or P-gp inhibitor drugs such as quinidine, amiodarone, diltiazem, spironolactone, verapamil, clarithromycin, erythromycin, itraconazole, ketoconazole, cyclosporine, tacrolimus, indinavir, ritonavir, cobicistat or critical CYP3A4 substrate drugs such as warfarin. Exclusion criteria 1. COVID-19 pneumonia diagnosed by the attending physician (oxygen saturation < 95% or lung examination) 2. Positive pregnancy test for women at childbearing age. 3. Positive IgG against SARS-CoV-2 by rapid diagnostic test at screening. Participants will be recruited by the investigators at the emergency services of the study sites. They are expected to remain in the trial for a period of 21 days. Follow-up visits will be conducted by the trial medical staff at the participant's home or at a hospital in case of hospitalization. Follow-up visits will assess clinical and laboratory parameters of the patients. INTERVENTION AND COMPARATOR: Ivermectin (300 mcg/kg) or placebo will be administered in one daily dose for three consecutive days. Currently, there is no solid data on the efficacy of ivermectin against the virus in vivo; therefore the use of placebo in the control group is ethically justified. MAIN OUTCOMES: Primary Proportion of patients with a positive SARS-CoV-2 PCR from a nasopharyngeal swab at day 7 post-treatment. Secondary 1. Mean viral load as determined by PCR cycle threshold (Ct) on days 4, 7, 14, and 21 2. Proportion of patients with fever and cough at days 4, 7, 14, and 21 as well as proportion of patients progressing to severe disease or death during the trial 2. Proportion of patients with a positive rapid diagnostic test at day 21 3. Proportion of drug-related adverse events during the trial 4. Median levels of IgG, IgM, IgA measured by Luminex RANDOMIZATION: Participants will be randomized to receive one dose of 300 mcg/kg ivermectin or placebo daily for three consecutive days. The epidemiologist will generate a list of correlative numbers, in randomized blocks of size 4, with the assignment to the treatment groups (a and b). The randomization list will be kept in an encrypted file accessible only to the trial statistician. This list will be handed directly to the pharmacist. Independently, the principal investigator will randomly assign the intervention (ivermectin) to one of the two groups (a or b) by tossing a coin, and will inform the pharmacist of the result of this process. The pharmacist will prepare and label the treatment vials according to the randomization list prepared by the epidemiologist and the treatment assignment given by the principal investigator. Eligible patients will be allocated in a 1:1 ratio using this randomization list. BLINDING (MASKING): The clinical trial team, the statistician, and the patients will be blinded as to arm allocation. The vials with placebo will be visibly identical to the ones with the active drug. Treatment will be administered by staff not involved in the clinical care or participant's follow up. NUMBERS TO BE RANDOMIZED (SAMPLE SIZE): The planned sample size is 186 SARS-CoV-2 PCR positive patients: 93 patients to treatment and 93 to the placebo group. TRIAL STATUS: Current protocol version: 2.0 dated January 15th, 2021. Recruitment started on Aug 29th, 2020. Recruitment is expected to be completed April 30th 2021. TRIAL REGISTRATION: "Ensayo Clínico aleatorizado de Fase IIa para comparar la efectividad de la ivermectina versus placebo en la negativización del PCR en pacientes en fase temprana de COVID-19" Peru National Health Institute REPEC with number: PER-034-20 , registered July 17th 2020 (National Peruvian Registration before the first participant enrolled). "Randomized Phase IIA Clinical Trial to Evaluate the Efficacy of Ivermectin to Obtain Negative PCR Results in Patients With Early Phase COVID-19" Clinicaltrials.gov: NCT04635943 , retrospectively registered in November 19th 2020 FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest of expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

Cervical Extraoral Traction Therapy in Early Treatment of Class II Malocclusion. A systematic review / Terapia de tracción extraoral cervical en el tratamiento temprano de la maloclusión de clase II. Una revisión sistemática / Terapia de Tração Extraoral Cervical no Tratamento Precoce da Maloclusão Classe II. Uma revisão sistemática

Abstract Introduction and objective: Cervical headgear has been used for decades as a treatment of class II malocclusion. Although the effects have been reported previously they are somewhat contradictory. The objective was to determine the available scientific evidence that supports the parameters of clinical use for therapy with cervical extraoral traction in early treatment for class II malocclusion. Materials and methods: A systematic search was conducted using Medline, Google Scholar, Cochrane, and Lilacs data-bases. The search involved articles in English, Spanish, Portuguese, and German using previously selected MeSH terms and free-text terms. The search included articles dealing with cervical extraoral traction treatment, systematic reviews, meta-analysis, clinical trials, and cohort, case-control, and cross-sectional studies. Methodological quality was evaluated using various scales according to the type of study. Results: The search generated 334 articles, 259 were eliminated because they were duplicates, and 34 were eliminated because they did not meet the inclusion criteria. 41 articles were evaluated in full text, 21 were excluded because they did not meet the inclusion criteria, leaving a total of 20 articles. Conclusions: The articles offered varied, yet clear, recommendations. According to the literature and clinical judgment, treatment timing is recommended during the pubertal growth spurt. The most efficient force is 450 to 500g per side for 12 to 14 hours per day. A long outer bow bent 15o degrees upward should be used in patients with normal and hypodivergent patterns. Maxillary growth control depends on age, force, treatment duration, etc. Changes in overjet can be expected due to changes in dental inclination, growth, or the use of additional appliances; an average molar distalization of 1 mm to 2 mm can be achieved.

Resumen Introducción y objetivo: La Tracción cervical se ha utilizado durante décadas como tratamiento para la maloclusión de clase II. Aunque los efectos se han informado previamente, son algo contradictorios. El objetivo fué determinar la evidencia científica disponible que respalde los parámetros de uso clínico para la terapia con tracción extraoral cervical en el tratamiento temprano de la maloclusión de clase II. Materiales y métodos: Se realizó una búsqueda sistemática utilizando las bases de datos Medline, Google Scholar, Cochrane y Lilacs. La búsqueda incluyó artículos en inglés, español, portugués y alemán utilizando términos MeSH previamente seleccionados y términos de texto libre. La búsqueda incluyó artículos relacionados con el tratamiento de tracción extraoral cervical, revisiones sistemáticas, metanálisis, ensayos clínicos y estudios de cohortes, casos y controles y estudios transversales. La calidad metodológica se evaluó utilizando varias escalas según el tipo de estudio. Resultados: La búsqueda generó 334 artículos, 259 fueron eliminados porque eran duplicados y 34 fueron eliminados porque no cumplían con los criterios de inclusión. Se evaluaron 41 artículos en texto completo, se excluyeron 21 porque no cumplían con los criterios de inclusión, dejando un total de 20 artículos. Conclusiones: Los artículos ofrecieron recomendaciones variadas, pero claras. De acuerdo con la literatura y el juicio clínico, se recomienda el momento del tratamiento durante el período de crecimiento puberal. La fuerza más eficiente es de 450 a 500 g por lado durante 12 a 14 horas por día. Se debe usar un arco externo largo doblado 15 grados hacia arriba en pacientes con patrones normales e hipodivergentes. El control del crecimiento maxilar depende de la edad, la fuerza, la duración del tratamiento, etc. Se pueden esperar cambios en la sobrecarga debido a cambios en la inclinación dental, el crecimiento o el uso de aparatos adicionales. Se puede lograr una distalización molar promedio de 1 mm a 2 mm.

Resumo Introdução e objetivo: A tração cervical tem sido utilizada como tratamento da má oclsão de classe II. Embora os efeitos tenham sido relatados anteriormente, eles são contraditórios. O objetivo foi determinar as evidências científicas disponíveis que suportamos parâmetros de uso clínico para terapia com tração extraoral cervical no tratamentoprecoce da má oclusão de classe II. Materiais e métodos: Uma pesquisa sistemática foirealizada usando Medline, Google Scholar, Cochrane e Lilacs. Foram incluidos artigos em inglês, espanhol, português e alemão, usando termos MeSH selecionados anteriormente e termos de texto livre. A pesquisa incluiu artigos que tratavam do tratamento da tração extraoral cervical, revisões sistemáticas, meta-análise, ensaios clínicos e estudos de coorte, caso-controle e transversais. A qualidade metodológica foi avaliada usando várias escalas de acordo com o tipo de estudo. Resultados: a busca gerou 334 artigos, 259 foram eliminados por serem duplicados e 34 foram eliminados por não atenderem aos critérios de inclusão. 41 artigos foram avaliados em texto completo, 21 foram excluídos por não atenderem aos critérios de inclusão, totalizando 20 artigos. Conclusões: Os artigos oferecidos apresentaram recomendações variadas, porém claras. De acordo com a literatura e o julgamento clínico, o momento do tratamento é recomendado durante o surto de crescimento puberal. A força mais eficiente é de 450 a 500g por lado, durante 12 a 14 horas por dia. Um arco externo longo e dobrado de 15 graus deve ser usado em pacientes com padrões normais e hipodivergentes. O controle do crescimento maxilar depende da idade, força, duração do tratamento, etc. Alterações no overjet podem ser esperadas devido a alterações na inclinação dentária, crescimento ou uso de aparelhos adicionais; uma distalização molar média de 1 mm a 2 mm pode ser alcançada.

High energy density LED-based photobiomodulation inhibits squamous cell carcinoma progression in co-cultures in vitro.

Current management of oral potentially malignant disorders is careful monitoring. Unfortunately, the 'watch and wait' approach only generates anxiety and a feeling of powerlessness, especially to those caring for patients. Photobiomodulation (PBM) has emerged as a potential strategy to inhibit possible transforming cells. The aim of this study was to investigate the effect of LED-based PBM on the progression of malignant invasion into a fibroblast-based stroma. An in vitro model of carcinoma in situ (CIS) containing stromal fibroblasts and carcinoma cells in co-culture was used to study the effect of PBM on the expansion of CIS colonies. A second model of co-culture (cells separated by membrane), was used to study cell counts, viability and apoptosis following PBM at high doses (36 J/cm2). The data was analyzed using Kruskal-Wallis, Dunn's test and non-linear regression, wherever appropriate. PBM was able to inhibit the expansion of CIS colonies as well as the total number of colonies after 72 h of treatment (p < 0.05). Cell viability, apoptosis and death assays revealed an overall advantage of stromal fibroblasts over carcinoma cells after high-dose PBM. In conclusion, LED-based PBM at high doses inhibited the progression and number of oral squamous cell carcinoma colonies without affecting the surrounding stromal fibroblasts in vitro.

Long-Term Outcomes in Puerto Ricans with Rheumatoid Arthritis (RA) Receiving Early Treatment with Disease-Modifying Anti-Rheumatic Drugs using the American College of Rheumatology Definition of Early RA.

BACKGROUND: Early treatment of rheumatoid arthritis (RA) results in better long-term outcomes. However, the optimal therapeutic window has not been clearly established. OBJECTIVE: To determine the clinical outcome of Puerto Ricans with RA receiving early treatment with conventional and/or biologic disease-modifying anti-rheumatic drugs (DMARDs) based on the American College of Rheumatology (ACR) definition of early RA. METHODS: A cross-sectional study was performed in a cohort of Puerto Ricans with RA. Demographic features, clinical manifestations, disease activity, functional status, and pharmacotherapy were determined. Early treatment was defined as the initiation of DMARDs (conventional and/or biologic) in less than 6 months from the onset of symptoms attributable to RA. Patients who received early (< 6months) and late (≥6 months) treatments were compared using bivariate and multivariate analyses. RESULTS: The cohort comprised 387 RA patients. The mean age at study visit was 56.0 years. The mean disease duration was 14.9 years and 337 (87.0%) patients were women. One hundred and twenty one (31.3%) patients received early treatment. In the multivariate analysis adjusted for age and sex, early treatment was associated with better functional status, lower probability of joint deformities, intra-articular injections and joint replacement surgeries, and lower scores in the physician's assessments of global health, functional impairment and physical damage of patients. CONCLUSION: Using the ACR definition of early RA, this group of patients treated with DMARDs within 6 months of disease had better long-term outcomes with less physical damage and functional impairment.

Efectos del tratamiento temprano en variables morfológicas, cinco años después de su aplicación / Effects of early treatment on morphological variables five years after application

Introducción: las pautas del tratamiento temprano propician una respuesta de desarrollo del sistema estomatognático. Objetivo: evaluar los efectos del tratamiento temprano en variables morfológicas, con técnicas de la rehabilitación neuro oclusal, cinco años después de ser aplicado durante la dentición temporal. Métodos: investigación de desarrollo, longitudinal y descriptiva, entre los años 2001 y 2010, en la Facultad de Estomatología de la Universidad de Ciencias Médicas de Villa Clara. Universo: 2 215 niños de cinco años de edad perteneciente a instituciones infantiles de la ciudad de Santa Clara (2001-2002). Se utilizó un método estratificado por etapas. Las variables de estudio se analizaron en tres etapas evolutivas: inicial, intermedia y final. La muestra fue de 59 niños con interferencias oclusales durante la dentición temporal que fueron tratados con terapias funcionales, durante el año 2002 y evaluados un año después (primera etapa). La segunda etapa se desarrollo durante los años 2007-2010; la muestra fue de 46 niños con diez años de edad. Se diseñó un modelo de consentimiento informado que estableció el compromiso de colaboración de los niños seleccionados. Se realizaron pruebas estadísticas: test de Friedman, Wilcoxon, Fisher y medida clásica de chi cuadrado. Resultados: se observó un aumento del resalte en 33 de los casos y predominó el escalón mesial (87 por ciento) al final del estudio. Se mantuvo la tendencia al aumento en la anchura intermolar temporal. Los valores medios a nivel de los primeros molares permanentes se comportaron similares a la norma descrita por Mayoral (47 mm). Conclusiones: los cambios favorables observados en las variables morfológicas objeto de estudio, cinco años después de ser aplicado el tratamiento temprano con técnicas de la rehabilitación neuro oclusal, corroboran que los cinco primeros años de la vida del niño constituye la etapa ideal para comenzar a tratar las alteraciones del sistema estomatognático(AU)

Introduction: early treatment typically obtains an adequate developmental response from the stomatognathic system. Objective: evaluate the effects of early treatment on morphological variables using neuro-occlusal rehabilitation techniques five years after application during primary dentition. Methods: adevelopmental longitudinal descriptive study was conducted from 2001 to 2010 at the School of Dentistry of the University of Medical Sciences of Villa Clara. The study universe was 2 215 five-year-old children from educational institutions of the city of Santa Clara (2001-2002). A staged stratified method was applied. Study variables were analyzed along three evolution stages: initial, intermediate and final. The study sample was composed of 59 children with occlusal interferences during primary dentition, which were treated with functional therapies in 2002 and evaluated one year later (first stage). The second stage extended from 2007 to 2010. The sample consisted of 46 ten-year-old children. An informed consent form was developed to record the commitment of the children selected with the study. The statistical tests performed were Friedman's, Wilcoxon's, Fisher's and classical chi-square measure. Results: increased overjet was found in 33 of the cases, with a predominance of the mesial step (87 percent) at the end of the study. A tendency to increased temporary intermolar width was observed throughout the study. Mean values for the first permanent molars were similar to the standard described by Mayoral (47 mm). Conclusions: the favorable changes found in the morphological variables under study five years after application of early treatment with neuro-occlusal rehabilitation confirm that the first five years in the life of a child are the ideal stage to start treating alterations of the stomatognathic system(AU)

Resultados del tratamiento de la orbitopatía tiroidea y factores que influyen sobre la respuesta terapéutica / Results of the treatment of thyroid orbinopathy and factors affecting the therapeutic response

Objetivo: evaluar los resultados del tratamiento de la orbitopatía tiroidea y determinar cuáles son los factores que influyen sobre ellos. Métodos: se realizó un estudio observacional en una cohorte de 82 pacientes con orbitopatía tiroidea, durante el período 1997-2009. Resultados: en los casos con orbitopatía tiroidea activa, la corticoterapia se inició a los 19 meses de evolución y no fue satisfactoria en la mayoría de ellos, por lo que para preservar la visión se realizaron varias intervenciones quirúrgicas. Los factores que influyeron sobre la respuesta terapéutica fueron el tabaquismo y la actividad de la orbitopatía tiroidea (OR= 30,479 y OR= 14,557, respectivamente). Se obtuvieron buenos resultados con el uso de la toxina botulínica A y con la cirugía en la corrección del estrabismo y la retracción. Conclusiones: el diagnóstico y el tratamiento precoz es la conducta terapéutica ideal para los pacientes con orbitopatía tiroidea. El tabaquismo y la actividad de la orbitopatía tiroideainterfirieren en la respuesta terapéutica. La toxina botulínica A y la cirugía son efectivas en la corrección del estrabismo y la retracción palpebral de la orbitopatía tiroidea(AU)

Objective: to evaluate the results of the treatment of thyroid orbinopathy and to determine the factors affecting them. Methods: observational study of a cohort of 82 patients with thyroid orbinopathy during the 1997-2009 period. Results: corticosteroid-bases therapy began nineteen months after the onset of disease and was unsatisfactory in most of cases with active thyroid orbitopathy, so it was necessary to perform several surgeries to preserve the vision. The influential factors on the therapeutic response were smoking and thyroid orbinopathy activity (OR= 30,479 and OR= 14,557, respectively). Good results were attained with botilinum toxin A and strabismus correction surgery and retraction. Conclusions: early diagnosis and treatment is the best therapy for patients with thyroid orbinopathy. Smoking and thyroid orbinopathy negatively affect the therapeutic response. Botulinum toxin A and surgery are effective options in the strabismus correction and palpebral retractions of thyroid orbinopathy(AU)

Early treatment with metformin induces resistance against tumor growth in adult rats.

It is known that antidiabetic drug metformin, which is used worldwide, has anti-cancer effects and can be used to prevent cancer growth. We tested the hypothesis that tumor cell growth can be inhibited by early treatment with metformin. For this purpose, adult rats chronically treated with metformin in adolescence or in adulthood were inoculated with Walker 256 carcinoma cells. Adult rats that were treated with metformin during adolescence presented inhibition of tumor growth, and animals that were treated during adult life did not demonstrate any changes in tumor growth. Although we do not have data to disclose a molecular mechanism to the preventive metformin effect, we present, for the first time, results showing that cancer growth in adult life is dependent on early life intervention, thus supporting a new therapeutic prevention for cancer.

Early postoperative single treatment ablative fractional lasing of Mohs micrographic surgery facial scars: a split-scar, evaluator-blinded study.

BACKGROUND/OBJECTIVES: Despite precise surgical technique, some postoperative facial scars will depress and widen over time, likely due to weakened or inadequately replaced collagen fibers in the underlying dermis. The purpose of this study is to evaluate whether a 10,600 nm ablative carbon dioxide (CO2 ) fractional laser used early in the post-surgical setting results in improved postoperative facial scars after a single treatment session. STUDY DESIGN: A prospective randomized, comparative split-scar study was conducted on 20 subjects between the ages of 20-90. Subjects underwent Mohs surgery for nonmelanoma skin cancer of the face. Subsequent to tumor removal, subjects with a linear scar of 4 cm or greater were enrolled. On the day of suture removal, all subjects had one-half of their scar randomly selected and treated with a 10,600 nm CO2 fractional laser (energy = 10 mJ; density = 10%; spot size = 7 mm; pulse = 1). The untreated scar half served as a control. Scars were re-evaluated 12 weeks later. An independent blinded observer graded the scar halves with the Vancouver scar scale (VSS) immediately prior to treatment and 12 weeks after treatment. Subjects completed a visual analog scale (VAS) at the same time points. RESULTS: Three months after laser treatment, a significant decrease in VSS and 3 of the 4 of its individual parameters were detected in both control and treated halves of the scar. When comparing the laser group versus the control group, a statistically significant difference was not noted in VSS (P = 0.31) but a statistically significant difference in patient VAS was detected (P = 0.002). No side effects of the laser treatment were noted. CONCLUSION: Facial wounds sutured in a layered manner heal well. Patients prefer early fractional CO2 lasing of surgical scars, though use of the VSS failed to detect an objective difference between laser and control halves of scars. Conservative laser settings, a single session treatment, and VSS insensitivity for surgical scars may influence these findings.

Mucopolysaccharidosis type VI on enzyme replacement therapy since infancy: Six years follow-up of four children.

Clinical and biochemical improvements are reported on Mucopolysaccharidosis type VI (MPS VI) patients on Enzyme Replacement Therapy (ERT) with rhASB (galsulfase, Naglazyme®), and preclinical and clinical studies have shown clinical benefits of early initiation. We report four unrelated MPS VI children who began ERT as infants (ages 5 days­10 months). The three older patients showed the first clinical signs of MPS VI at baseline, also presenting different degrees of dysostosis multiplex, and two had mild heart disease. The two oldest also had mild facial coarseness, one had hearing conduction deficit and sleep disorder and the other corneal clouding at baseline. After six years on ERT, all four patients have normal urinary GAG values. Although they all showed normal motor and mental development, brain and cervical spine MRI images available from two of the older patients showed abnormalities, while the youngest child continues having normal images. The four patients presented slower progression of bone and joint disease when compared to their affected older siblings. It should be noticed that only two patients in this sample are currently below the 3rd percentile for height: the youngest who has a constitutional factor associated and the eldest who already presented frank dysostosis at 10 months of age. These findings confirm previous studies that report that skeletal features of the disease cannot be completely prevented despite early ERT. Heart disease already present in two of the four infants at baseline got worse over time and appeared in another patient, but the youngest child on ERT introduction still has a normal echocardiogram at six years of age; he also is the only one without corneal clouding after six years follow-up. Our results also suggest that early ERT prevented storage in spleen and liver and may also have improved or prevented progression of facial dysmorphic features, corroborating similar findings seen in previous studies. No safety concerns were identified and none of the patients experienced a serious adverse event. The baseline severity of the disorder of these four infants seems related to age and it is tempting to say that severity on the first year of life is progressive and ERT effectiveness is indirectly related to it. Despite being known that MPS VI progresses differently among patients, the fact that these infants had a slower progression than their older siblings speaks in favor of a very early start of ERT. In conclusion, this report confirms the early manifestations of the disease and provides additional evidence on safety and of the beneficial effects of ERT in patients less than 1 year of age.

Early vs late orthodontic treatment of tooth crowding by first premolar extraction: A systematic review.

OBJECTIVE: To investigate the body of evidence in the literature about the most favorable time for initiating orthodontic treatment in patients with severe crowding caused by tooth size arch length deficiency (TSALD). MATERIALS AND METHODS: Electronic databases (PubMed, Ovid Medline, Scopus, Virtual Health Library, and The Cochrane Library) were searched for articles published between 1900 and April 2014. Studies were included that evaluated treatment of patients with severe crowding caused TSALD, who were treated with first premolar extraction. The association between the stage of development of occlusion at which treatment was started, and the primary and/or secondary outcomes of early and late treatment were investigated. RESULTS: After application of the eligibility criteria and reading of the full texts, six articles were included in the final review. Of these six articles, all of which were retrospective, four showed that the primary outcome (correction of severe crowding) of the early and late groups was improved, but without statistically significant differences after treatment. Therefore, the findings of secondary outcomes in the literature (postretention crowding relapse, duration of total and active treatment [treatment with appliances], external apical root resorption, and soft tissue profile) were the target of this study. These studies presented low or moderate methodological quality and control of bias. CONCLUSIONS: Both early and late extraction had a similar effect on correction of crowding. Early treatment had two favorable secondary outcomes (less relapse and reduced active treatment time) vs late treatment. However, the levels of evidence were not sufficient to assert which protocol was superior.