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1.
Opt Express ; 32(7): 11907-11915, 2024 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-38571028

RESUMO

We report on stable, long-term operation of a diode-pumped solid-state laser (DPSSL) amplifying 15 ns pulses at 1029.5 nm wavelength to 10 J energy at 100 Hz pulse rate, corresponding to 1 kW average power, with 25.4% optical-to-optical efficiency. The laser was operated at this level for over 45 minutes (∼3 · 105 shots) in two separate runs with a rms energy stability of 1%. The laser was also operated at 7 J, 100 Hz for 4 hours (1.44 · 106 shots) with a rms long-term energy stability of 1% and no need for user intervention. To the best of our knowledge, this is the first time that long-term reliable amplification of a kW-class high energy nanosecond pulsed DPSSL at 100 Hz has been demonstrated.

2.
Clin Anat ; 2024 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-38877833

RESUMO

This study aims to examine the validity and reliability of the UltraScan650™, a portable ultrasound device, used to measure BMD at the 1/3rd radius position. Fifty-two female first responders and healthcare providers were assessed using DXA (forearm, femur, lumbar, and total body) and the UltraScan650™. Fat and lean mass were also assessed using the DXA. Pearson correlations, Bland-Altman plots, t-tests, and linear regressions were used to assess validity. Intra-class correlation (ICC) coefficients were used to assess reliability. Inter-rater reliability and repeatability were good (ICC = 0.896 [0.818; 0.942], p < 0.001) and excellent (ICC = 0.917 [0.785; 0.989], p < 0.001), respectively. BMD as measured by the UltraScan650™ was weakly correlated to the DXA (r = 0.382 [0.121; 0.593], p = 0.0052). Bland-Altman plots revealed that the UltraScan650™ underestimated BMD (-0.0569 g/cm2), this was confirmed with a significant paired t-test (p < 0.001). A linear regression was performed (0.4744 × UltraScan650™ + 0.4170) to provide more information as to the issue of agreement. Bland-Altman plots revealed a negligible bias, supported by a paired t-test (p = 0.9978). Pearson's correlation revealed a significant relationship (r = -0.771 [-0.862; -0.631], p < 0.0001) between adjusted UltraScan650™-DXA and the average of the two scans (i.e., adjusted UltraScan650™ and DXA), suggesting a proportional constant error and proportional constant variability in measurements of BMD from the UltraScan650™. The UltraScan650™ is not a valid alternative to DXA for diagnostic purposes; however, the UltraScan650™ could be used as a screening tool in the clinical and research setting given the linear transformation is employed.

3.
J Strength Cond Res ; 38(2): 367-373, 2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-37815270

RESUMO

ABSTRACT: Edwards, CM, da Silva, DF, Puranda, JL, Souza, SCS, Semeniuk, K, and Adamo, KB. Associations between rank, sex, and parity with musculoskeletal injuries sustained during annual military physical fitness test. J Strength Cond Res 38(2): 367-373, 2024-Musculoskeletal injuries pose a significant threat to the well-being of military personnel. Attempts to use physical employment standard test results as predictors of injury are underway, but little is known about injuries sustained during the tests. This study sought to identify body regions most likely to be reported as injured during the annual Canadian Armed Forces (CAF) physical fitness evaluation. In addition, sex, rank, and parity status are explored as possible associated factors for injury. A total of 1,796 actively serving CAF members were categorized by sex (1,030 male participants; 766 female participants), rank (1,142 Non-Commissioned Members [NCM]; 638 Officers), and parity (314 parous female participants; 435 nulliparous female participants). Sex, rank, and parity were associated with body regions reportedly injured during an annual CAF fitness assessment (significance p ≤ 0.05). When compared with male participants, female participants were more likely to be injured {aOR: 1.797 (95% [confidence interval] CI: 1.45-2.23)} and more prone to injury of the wrist (adjusted odds ratio [aOR]: 1.933 [95% CI: 1.20-3.12]), hip (aOR: 3.445 [95% CI: 2.07-5.728]), or lower back (aOR: 1.55 [95% CI: 1.18-2.04]). Non-Commissioned Members were more likely to injure the neck (aOR: 2.14 [95% CI: 1.18-3.88]) or shoulder (aOR: 2.03 [95% CI: 1.31-3.15]), when compared with Officers. Parous female participants reported pelvis/abdomen injury at a higher rate than the nulliparous group (5 vs. 1.7%, p = 0.019). Injuries sustained during an annual CAF fitness assessment differ based on sex, rank, and parity. Canadian Armed Forces female participants, NCM, and parous female participants may require specific physical fitness support in preparation for the annual physical fitness test.


Assuntos
Militares , Humanos , Masculino , Feminino , Canadá/epidemiologia , Aptidão Física , Exercício Físico
4.
Opt Lett ; 48(23): 6320-6323, 2023 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-38039257

RESUMO

We report on efficient and stable, type-I phase-matched second harmonic conversion of a nanosecond high-energy, diode-pumped, Yb:YAG laser. With a frequency-doubling crystal in an enclosed, temperature controller with optical windows, 0.5% energy stability was achieved for approximately half an hour. This resulted in 48.9 J pulses at 10 Hz (489 W) and a conversion efficiency of 73.8%. These results are particularly important for stable and reliable operation of high-energy, frequency-doubled lasers.

5.
Eur J Appl Physiol ; 123(8): 1837-1850, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-37072505

RESUMO

PURPOSE: Muscle stretching effect on the range of motion (ROM) and force deficit in non-stretched muscle, and the underlying mechanisms, is an ongoing issue. This study aimed to investigate crossover stretching effects and mechanisms on the plantar flexor muscles. METHODS: Fourteen recreationally active females (n = 5) and males (n = 9) performed six sets of 45-s static stretching (SS) (15-s recovery) to the point of discomfort of the dominant leg (DL) plantar flexors or control (345-s rest). Participants were tested for a single 5-s pre- and post-test maximal voluntary isometric contraction (MVIC) with each plantar flexor muscle and were tested for DL and non-DL ROM. They were tested pre- and post-test (immediate, 10-s, 30-s) for the Hoffman (H)-reflex and motor-evoked potentials (MEP) from transcranial magnetic stimulation in the contralateral, non-stretched muscle. RESULTS: Both the DL and non-DL-MVIC force had large magnitude, significant (↓10.87%, p = 0.027, pƞ2 = 0.4) and non-significant (↓9.53%, p = 0.15, pƞ2 = 0.19) decreases respectively with SS. The SS also significantly improved the DL (6.5%, p < 0.001) and non-DL (5.35%, p = 0.002) ROM. The non-DL MEP/MMax and HMax/MMax ratio did not change significantly. CONCLUSION: Prolonged static stretching improved the stretched muscle's ROM. However, the stretched limb's force was negatively affected following the stretching protocol. The ROM improvement and large magnitude force impairment (statistically non-significant) were transferred to the contralateral muscles. The lack of significant changes in spinal and corticospinal excitability confirms that the afferent excitability of the spinal motoneurons and corticospinal excitability may not play a substantial role in non-local muscle's ROM or force output responses.


Assuntos
Exercícios de Alongamento Muscular , Músculo Esquelético , Masculino , Feminino , Humanos , Músculo Esquelético/fisiologia , Reflexo , Contração Isométrica/fisiologia , Potencial Evocado Motor/fisiologia , Eletromiografia/métodos , Contração Muscular/fisiologia
6.
J Obstet Gynaecol Can ; 45(9): 646-654, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37268158

RESUMO

OBJECTIVES: Urinary incontinence (UI) and pelvic organ prolapse (POP) are prevalent pelvic floor disorders (PFDs) among the female population. In the military environment, being a non-commissioned member (NCM), and physically demanding occupations are factors associated with higher PFD risk. This study seeks to characterize the profile of female Canadian Armed Forces (CAF) members reporting symptoms of UI and/or POP. METHODS: Present CAF members (18-65 years) responded to an online survey. Only current members were included in the analysis. Symptoms of UI and POP were collected. Multivariate logistic regressions analyzed the relationships between PFD symptoms and associated characteristics. RESULTS: 765 active members responded to female-specific questions. The prevalence of self-reported POP and UI symptoms were 14.5% and 57.0%, respectively, with 10.6% of respondents reporting both. Advanced age (adjusted odds ratio [aOR]: 1.062, CI 1.038-1.087), a body mass index (BMI) categorized as obese (aOR: 1.909, [1.183-3.081]), parity ≥1 (e.g., aOR for 1: 2.420, [1.352-4.334]) and NCMs (aOR: 1.662, [1.144-2.414]) were factors associated with urine leakage. Parity of ≥2 (aOR: 2.351, [1.370-4.037]) compared to nulliparous and having a perception of a physically demanding job (aOR: 1.933, [1.186-3.148]) were associated with experiencing POP symptoms. Parity of ≥2 increased the odds of reporting both PFD symptoms (aOR: 5.709, [2.650-12.297]). CONCLUSION: Parity was associated with greater odds of experiencing symptoms of UI and POP. Higher age, higher BMI, and being an NCM were associated with more symptoms of UI, and the perception of having a physically demanding role increased the likelihood of reporting POP symptoms.


Assuntos
Militares , Distúrbios do Assoalho Pélvico , Prolapso de Órgão Pélvico , Incontinência Urinária , Gravidez , Feminino , Humanos , Distúrbios do Assoalho Pélvico/etiologia , Distúrbios do Assoalho Pélvico/complicações , Canadá/epidemiologia , Incontinência Urinária/epidemiologia , Obesidade/epidemiologia , Obesidade/complicações , Prolapso de Órgão Pélvico/complicações , Inquéritos e Questionários
7.
J Obstet Gynaecol Can ; 44(12): 1262-1270, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36216221

RESUMO

OBJECTIVE: Maternal serum and umbilical cord (UC) lipid and glucose levels are influenced by a variety of maternal factors over the course of pregnancy, including maternal physical activity (PA) levels and gestational weight gain (GWG). However, previous research has not assessed the interaction of these 2 variables. This study investigated mid-gestation (24-28 weeks) and late gestation (34-38 weeks) maternal and UC serum lipid and glucose profiles in relation to maternal PA status and GWG, independently and in combination. METHODS: This study had a longitudinal design. Pregnant participants (n = 40) were categorized as active or inactive based on the 2019 Canadian Guideline for Physical Activity throughout Pregnancy, and GWG was categorized as insufficient, appropriate, or excessive based on 2009 Institute of Medicine recommendations. Fasting maternal serum was taken in mid- and late gestation, and venous UC serum was taken at birth. RESULTS: No relationship was found between maternal serum values and PA and/or GWG. Infants born to individuals who were physically active across pregnancy, or who were active in mid-pregnancy and had their activity status drop in late gestation, had lower UC total cholesterol levels than those who were inactive throughout pregnancy (P < 0.0001). Participants who had gained weight appropriately at mid-gestation had significantly lower UC glucose levels than those who gained weight insufficiently (P = 0.040) or excessively (P = 0.021). CONCLUSION: In our study, PA, and GWG (independently and in combination) may not have affected maternal serum; however, meeting PA recommendations at mid-gestation may provide prophylactic effects on UC serum, potentially providing long-term health benefits to the newborn.


Assuntos
Complicações na Gravidez , Feminino , Recém-Nascido , Gravidez , Humanos , Complicações na Gravidez/prevenção & controle , Canadá , Aumento de Peso , Parto , Lipídeos , Exercício Físico , Glucose , Cordão Umbilical , Índice de Massa Corporal , Peso ao Nascer
8.
BMC Immunol ; 22(1): 78, 2021 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-34920698

RESUMO

BACKGROUND: Phosphoinositide-3-kinase-delta (PI3Kδ) inhibition is a promising therapeutic approach for inflammatory conditions due to its role in leucocyte proliferation, migration and activation. However, the effect of PI3Kδ inhibition on group 2 innate lymphoid cells (ILC2s) and inflammatory eosinophils remains unknown. Using a murine model exhibiting persistent airway inflammation we sought to understand the effect of PI3Kδ inhibition, montelukast and anti-IL5 antibody treatment on IL33 expression, group-2-innate lymphoid cells, inflammatory eosinophils, and goblet cell metaplasia. RESULTS: Mice were sensitised to house dust mite and after allowing inflammation to resolve, were re-challenged with house dust mite to re-initiate airway inflammation. ILC2s were found to persist in the airways following house dust mite sensitisation and after re-challenge their numbers increased further along with accumulation of inflammatory eosinophils. In contrast to montelukast or anti-IL5 antibody treatment, PI3Kδ inhibition ablated IL33 expression and prevented group-2-innate lymphoid cell accumulation. Only PI3Kδ inhibition and IL5 neutralization reduced the infiltration of inflammatory eosinophils. Moreover, PI3Kδ inhibition reduced goblet cell metaplasia. CONCLUSIONS: Hence, we show that PI3Kδ inhibition dampens allergic inflammatory responses by ablating key cell types and cytokines involved in T-helper-2-driven inflammatory responses.


Assuntos
Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Eosinófilos/imunologia , Hipersensibilidade/imunologia , Inflamação/imunologia , Interleucina-33/metabolismo , Linfócitos/imunologia , Sistema Respiratório/imunologia , Acetatos/uso terapêutico , Animais , Antígenos de Dermatophagoides/imunologia , Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Ciclopropanos/uso terapêutico , Citocinas/metabolismo , Feminino , Células Caliciformes/efeitos dos fármacos , Células Caliciformes/patologia , Hipersensibilidade/tratamento farmacológico , Inflamação/tratamento farmacológico , Interleucina-5/antagonistas & inibidores , Camundongos , Camundongos Endogâmicos BALB C , Pyroglyphidae , Quinolinas/uso terapêutico , Sulfetos/uso terapêutico , Células Th2/imunologia
9.
Opt Express ; 29(4): 5607-5623, 2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-33726095

RESUMO

In this paper, we present a model to predict thermal stress-induced birefringence in high energy, high repetition rate diode-pumped Yb:YAG lasers. The model calculates thermal depolarisation as a function of gain medium geometry, pump power, cooling parameters, and input polarisation state. We show that model predictions are in good agreement with experimental observations carried out on a DiPOLE 100 J, 10 Hz laser amplifier. We show that single-pass depolarisation strongly depends on input polarisation state and pumping parameters. In the absence of any depolarisation compensation scheme, depolarisation varies over a range between 5% and 40%. The strong dependence of thermal stress-induced depolarisation on input polarisation indicates that, in the case of multipass amplifiers, the use of waveplates after every pass can reduce depolarisation losses significantly. We expect that this study will assist in the design and optimisation of Yb:YAG lasers.

10.
Opt Lett ; 46(22): 5771-5773, 2021 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-34780458

RESUMO

We report on obtaining output energy of 146 J in 10 ns long pulses at 10 Hz repetition rate from Bivoj, a multi-Joule multi-slab cryogenic gas-cooled diode pumped solid state laser, by overcoming its damage threshold bottleneck. This is a 40% energy and power increase of the laser system in comparison to our previous publication and to the most powerful multi-Joule high power laser system.

11.
Opt Lett ; 46(8): 1808-1811, 2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33857075

RESUMO

We report on the successful demonstration of second and third harmonic conversion of a high pulse energy, high average power 1030 nm diode pumped Yb-doped yttrium aluminum garnet (Yb:YAG) nanosecond pulsed laser in a large aperture lithium triborate (LBO) crystal. We demonstrated generation of 59.7 J at 10 Hz (597 W) at 515 nm (second harmonic) and of 65.0 J at 1 Hz (65 W) at 343 nm (third harmonic), with efficiencies of 66% and 68%, respectively. These results, to the best of our knowledge, represent the highest energy and power reported for frequency conversion to green and UV-A wavelengths.

12.
J Sport Rehabil ; 30(6): 952-955, 2021 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-33883300

RESUMO

Clinical Scenerio: Neck pain is a costly symptom in both civilian and military worlds. While traditional treatments include deep neck flexor stabilizing exercises, manual therapy, electrical therapy, and other nonsurgical interventions, scapular orientation and stability training has emerged as a possible tool to reduce neck pain severity. Methods that can be coached at a distance could be of value in virtual appointments or circumstances where access to a qualified manual therapist is limited. Focused Clinical Question: What is the effectiveness of including exercise programs targeting scapular kinematics and stability to decrease neck pain? Summary of Key Findings: Exercise programs targeting scapular kinematics and stability, with coaching and individualized progressions, appear to reduce neck pain severity. Clinical Bottom Line: Evidence supports the inclusion of exercises for scapular kinematics and stability at a prescription of 3 sessions per week, with a duration of 4 or 6 weeks. Exercise programs should include a "learning" or coaching phase to ensure exercises are performed as intended, and exercise progressions should be based on participant ability rather than predetermined timelines. Further research is needed to better understand the benefits of this potential strategy and the statistical impact of scapular-focused exercise interventions on neck pain in specific populations like military and athletes. Strength of Recommendation: There is 'Fair' to 'Good' evidence from 2 level 1b single-blind randomized control studies and 1 level 2b pre-post test control design study supporting the inclusion of exercise programs targeting scapular kinematics and stability to decrease chronic neck pain severity.


Assuntos
Cervicalgia , Escápula , Fenômenos Biomecânicos , Terapia por Exercício , Humanos , Cervicalgia/terapia , Método Simples-Cego
13.
Opt Lett ; 45(10): 2946-2949, 2020 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-32412507

RESUMO

We report on frequency doubling of high-energy, high-repetition-rate ns pulses from a cryogenically gas cooled, multi-slab Yb:YAG laser system, using a type-I phase-matched lithium triborate (LBO) crystal. Pulse energy of 4.3 J was extracted at 515 nm for a fundamental input of 5.4 J at 10 Hz (54 W), corresponding to a conversion efficiency of 77%. However, during long-term operation, a significant reduction of efficiency (more than 25%) was observed owing to the phase mismatch arising due to the temperature-dependent refractive index change in the crystal. This forced frequent angle tuning of the crystal to recover the second-harmonic generation (SHG) energy. More than a five-fold improvement in energy stability of SHG was observed when the LBO crystal was mounted in an oven, and its temperature was controlled at 27°C. Stable frequency doubling with 0.8% rms energy variation was achieved at a higher input power of 74 W when the LBO temperature was controlled at 50°C.

14.
Age Ageing ; 49(3): 481-486, 2020 04 27.
Artigo em Inglês | MEDLINE | ID: mdl-32040192

RESUMO

INTRODUCTION: The impact and outcome of hip fractures are well described for people living in the community, but inpatient hip fracture (IHF) have not been extensively studied. In this study, we examine the patient characteristics, common falls risk factors and clinical outcomes of this condition. METHODS: Between January 2016 and December 2017, we analysed all inpatient falls that resulted in hip fracture within Aneurin Bevan University Health Board (ABUHB) in Wales. RESULTS: The overall falls rate was 8.7/1000 occupied bed days (OBD). Over the 2 years, 118 patients sustained an IHF, giving a rate of 0.12/1000 OBD. The mean age was 81.8 ± 9.5 (range 49-97) years and 60% were women. Most patients (n = 112) were admitted from their own home. Mean Charlson Comorbidity Index and the number of medications on admission were 5.5 ± 1.9 and 8.5 ± 3.7, respectively.Fifty-three patients (45%) sustained the IHF following their first inpatient fall. Twenty-four IHF (20%) occurred within 72 h. Mean length of stay was 84.9 ± 55.8 days. Only 43% were discharged back to their original place of residence following an IHF; 27% were discharged to a care home (26 new care home discharges), and 30% died as an inpatient. One-year mortality was 54% (n = 64/118). The most common comorbidity was dementia (63%). CONCLUSION: Mortality and need for care home placement are both much higher after IHF than following community hip fracture. Most people who suffer a hip fracture in hospital have already demonstrated their need for falls risk management by having fallen previously during the same admission.


Assuntos
Fraturas do Quadril , Pacientes Internados , Acidentes por Quedas , Idoso , Idoso de 80 Anos ou mais , Feminino , Fraturas do Quadril/diagnóstico , Fraturas do Quadril/epidemiologia , Fraturas do Quadril/terapia , Hospitalização , Humanos , País de Gales/epidemiologia
15.
J Pharmacol Exp Ther ; 369(3): 443-453, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30940692

RESUMO

This study describes the pharmacokinetic (PK) and pharmaco-dynamic (PD) profile of N-(5-(4-(5-(((2R,6S)-2,6-dimethylmorpholino)methyl)oxazol-2-yl)-1H-indazol-6-yl)-2-methoxypyridin-3-yl)methanesulfonamide (GSK2292767A), a novel low-solubility inhaled phosphoinositide 3-kinase delta (PI3Kδ) inhibitor developed as an alternative to 2-(6-(1H-indol-4-yl)-1H-indazol-4-yl)-5-((4-isopropylpiperazin-1-yl)methyl)oxazole (nemiralisib), which is a highly soluble inhaled inhibitor of PI3Kδ with a lung profile consistent with once-daily dosing. GSK2292767A has a similar in vitro cellular profile to nemiralisib and reduces eosinophilia in a murine PD model by 63% (n = 5, P < 0.05). To explore whether a low-soluble compound results in effective PI3Kδ inhibition in humans, a first time in human study was conducted with GSK2292767A in healthy volunteers who smoke. GSK2292767A was generally well tolerated, with headache being the most common reported adverse event. PD changes in induced sputum were measured in combination with drug concentrations in plasma from single (0.05-2 mg, n = 37), and 14-day repeat (2 mg, n = 12) doses of GSK2292767A. Trough bronchoalveolar lavage (BAL) for PK was taken after 14 days of repeat dosing. GSK2292767A displayed a linear increase in plasma exposure with dose, with marginal accumulation after 14 days. Induced sputum showed a 27% (90% confidence interval 15%, 37%) reduction in phosphatidylinositol-trisphosphate (the product of phosphoinositide 3-kinase activation) 3 hours after a single dose. Reduction was not maintained 24 hours after single or repeat dosing. BAL analysis confirmed the presence of GSK2292767A in lung at 24 hours, consistent with the preclinical lung retention profile. Despite good lung retention, target engagement was only present at 3 hours. This exposure-response disconnect is an important observation for future inhaled drug design strategies considering low solubility to drive lung retention.


Assuntos
Indazóis/farmacologia , Indazóis/farmacocinética , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Inibidores de Fosfoinositídeo-3 Quinase/farmacocinética , Sulfonamidas/farmacologia , Sulfonamidas/farmacocinética , Pesquisa Translacional Biomédica , Administração por Inalação , Adulto , Animais , Lavagem Broncoalveolar , Eosinofilia/tratamento farmacológico , Feminino , Humanos , Indazóis/administração & dosagem , Indazóis/efeitos adversos , Pulmão/metabolismo , Masculino , Camundongos , Pessoa de Meia-Idade , Permeabilidade , Inibidores de Fosfoinositídeo-3 Quinase/administração & dosagem , Inibidores de Fosfoinositídeo-3 Quinase/efeitos adversos , Segurança , Solubilidade , Escarro/efeitos dos fármacos , Escarro/metabolismo , Sulfonamidas/administração & dosagem , Sulfonamidas/efeitos adversos
16.
N Engl J Med ; 373(1): 48-59, 2015 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-26132941

RESUMO

BACKGROUND: Erythropoietic protoporphyria is a severe photodermatosis that is associated with acute phototoxicity. Patients with this condition have excruciating pain and a markedly reduced quality of life. We evaluated the safety and efficacy of an α-melanocyte-stimulating hormone analogue, afamelanotide, to decrease pain and improve quality of life. METHODS: We conducted two multicenter, randomized, double-blind, placebo-controlled trials of subcutaneous implants containing 16 mg of afamelanotide. Patients in the European Union (74 patients) and the United States (94 patients) were randomly assigned, in a 1:1 ratio, to receive a subcutaneous implant containing either afamelanotide or placebo every 60 days (a total of five implants in the European Union study and three in the U.S study). The type and duration of sun exposure, number and severity of phototoxic reactions, and adverse events were recorded over the respective 180-day and 270-day study periods. Quality of life was assessed with the use of validated questionnaires. A subgroup of U.S. patients underwent photoprovocation testing. The primary efficacy end point was the number of hours of direct exposure to sunlight without pain. RESULTS: In the U.S. study, the duration of pain-free time after 6 months was longer in the afamelanotide group (median, 69.4 hours, vs. 40.8 hours in the placebo group; P=0.04). In the European Union study, the duration of pain-free time after 9 months was also longer in the afamelanotide group than in the placebo group (median, 6.0 hours vs. 0.8 hours; P=0.005), and the number of phototoxic reactions was lower in the the afamelanotide group (77 vs. 146, P=0.04). In both trials, quality of life improved with afamelanotide therapy. Adverse events were mostly mild; serious adverse events were not thought to be related to the study drug. CONCLUSIONS: Afamelanotide had an acceptable side-effect and adverse-event profile and was associated with an increased duration of sun exposure without pain and improved quality of life in patients with erythropoietic protoporphyria. (Funded by Clinuvel Pharmaceuticals and others; ClinicalTrials.gov numbers, NCT01605136 and NCT00979745.).


Assuntos
Dor/prevenção & controle , Protoporfiria Eritropoética/tratamento farmacológico , Luz Solar/efeitos adversos , alfa-MSH/análogos & derivados , Adulto , Método Duplo-Cego , Implantes de Medicamento , Humanos , Pessoa de Meia-Idade , Dor/etiologia , Protoporfiria Eritropoética/complicações , alfa-MSH/efeitos adversos , alfa-MSH/uso terapêutico
17.
Pharm Res ; 34(12): 2498-2516, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28702798

RESUMO

PURPOSE: To examine if pulmonary P-glycoprotein (P-gp) is functional in an intact lung; impeding the pulmonary absorption and increasing lung retention of P-gp substrates administered into the airways. Using calculated physico-chemical properties alone build a predictive Quantitative Structure-Activity Relationship (QSAR) model distinguishing whether a substrate's pulmonary absorption would be limited by P-gp or not. METHODS: A panel of 18 P-gp substrates were administered into the airways of an isolated perfused mouse lung (IPML) model derived from Mdr1a/Mdr1b knockout mice. Parallel intestinal absorption studies were performed. Substrate physico-chemical profiling was undertaken. Using multivariate analysis a QSAR model was established. RESULTS: A subset of P-gp substrates (10/18) displayed pulmonary kinetics influenced by lung P-gp. These substrates possessed distinct physico-chemical properties to those P-gp substrates unaffected by P-gp (8/18). Differential outcomes were not related to different intrinsic P-gp transporter kinetics. In the lung, in contrast to intestine, a higher degree of non-polar character is required of a P-gp substrate before the net effects of efflux become evident. The QSAR predictive model was applied to 129 substrates including eight marketed inhaled drugs, all these inhaled drugs were predicted to display P-gp dependent pulmonary disposition. CONCLUSIONS: Lung P-gp can affect the pulmonary kinetics of a subset of P-gp substrates. Physico-chemical relationships determining the significance of P-gp to absorption in the lung are different to those operative in the intestine. Our QSAR framework may assist profiling of inhaled drug discovery candidates that are also P-gp substrates. The potential for P-gp mediated pulmonary disposition exists in the clinic.


Assuntos
Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Pulmão/metabolismo , Preparações Farmacêuticas/metabolismo , Absorção pelo Trato Respiratório , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Animais , Masculino , Camundongos , Camundongos Knockout , Preparações Farmacêuticas/química , Especificidade por Substrato , Membro 4 da Subfamília B de Transportadores de Cassetes de Ligação de ATP
18.
Opt Express ; 24(11): 11683-93, 2016 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-27410094

RESUMO

In this paper, we extend our recent work on partially coherent quantitative phase imaging (pcQPI) from two-dimensional (2D) to three-dimensional (3D) imaging of weakly scattering samples. Due to the mathematical complexity, most theoretical modeling of quantitative phase image formation under partial coherence has focused on thin, well-focused samples. It is unclear how these abberations are affected by defocusing. Also, as 3D QPI techniques continue to develop, a better model needs to be developed to understand and quantify these aberrations when imaging thicker samples. Here, using the first order Born's approximation, we derived a mathematical framework that provides an intuitive model of image formation under varying degrees of coherence. Our description provides a clear connection between the halo effect and phase underestimation, defocusing and the 3D structure of the sample under investigation. Our results agree very well with the experiments and show that the microscope objective defines the sectioning ability of the imaging system while the condenser lens is responsible for the halo effect.

19.
Opt Express ; 24(17): 19682-94, 2016 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-27557246

RESUMO

We report on type-I phase-matched second harmonic generation (SHG) in three nonlinear crystals: DKDP (98% deuteration), YCOB (XZ plane), and LBO (XY plane), of 8 J, 10 Hz cryogenic gas cooled Yb:YAG laser operating at 1029.5 nm. DKDP exhibited an efficiency of 45% at a peak fundamental intensity of 0.24 GW/cm2 for 10 Hz operation at 10 ns. At the same intensity and repetition rate, YCOB and LBO showed 50% and 65% conversion efficiencies, respectively. Significant improvement in conversion efficiency, to a maximum of 82%, was demonstrated in LBO at 0.7 GW/cm2 and 10 Hz, generating output energy of 5.6 J at 514.75 nm, without damage or degradation. However, no improvement in conversion efficiency was recorded for YCOB at this increased intensity. Additionally, we present theoretically calculated temperature maps for both 10 J and 100 J operation at 10 Hz, and discuss the suitability of these three crystals for frequency conversion of a 100 J, 10 Hz diode pumped solid state laser (DPSSL).

20.
Opt Lett ; 41(9): 2089-92, 2016 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-27128081

RESUMO

We report on the successful demonstration of a 100 J-level, diode pumped solid state laser based on cryogenic gas cooled, multi-slab ceramic Yb:YAG amplifier technology. When operated at 175 K, the system delivered a pulse energy of 107 J at a 1 Hz repetition rate and 10 ns pulse duration, pumped by 506 J of diode energy at 940 nm, corresponding to an optical-to-optical efficiency of 21%. To the best of our knowledge, this represents the highest energy obtained from a nanosecond pulsed diode pumped solid state laser. This demonstration confirms the energy scalability of the diode pumped optical laser for experiments laser architecture.

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