Labour market participation after sickness absence due to cancer: a dynamic cohort study in Catalonia (Spain).

BACKGROUND: The consequences of cancer on working until retirement age remain unclear. This study aimed to analyse working life considering all possible labour market states in a sample of workers after sickness absence (SA) due to cancer and to compare their working life paths to those of a sample of workers without SA and with an SA due to other diseases. METHODS: This was a retrospective dynamic cohort study among social security affiliates in Catalonia from 2012-2018. Cases consisted of workers with an SA due to cancer between 2012-2015 (N = 516) and were individually age- and sex-matched with those of affiliates with an SA due to other diagnoses and workers without an SA. All workers (N = 1,548, 56% women) were followed up from entry into the cohort until the end of 2018 to characterise nine possible weekly labour states. Sequence analysis, optimal matching, and multinomial logistic regression were used to identify and assess the probability of future labour market participation patterns (LMPPs). All analyses were stratified by sex. RESULTS: Compared with workers with an SA due to cancer, male workers with no SA and SA due to other causes showed a lower probability of being in the LMPP of death (aRRR 0.02, 95% CI: 0.00‒0.16; aRRR 0.17, 95% CI: 0.06‒0.46, respectively) and, among women, a lower probability of permanent disability and death (aRRR 0.24, 95% CI: 0.10‒0.57; aRRR 0.39, 95% CI: 0.19‒0.83, respectively). Compared to workers with SA due to cancer, the risk of early retirement was lower among workers with no SA (women, aRRR 0.60, 95% CI: 0.22‒1.65; men, aRRR 0.64, 95% CI: 0.27‒1.52), although these results were not statistically significant. CONCLUSIONS: Workplaces, many of which have policies common to all diagnoses, should be modified to the needs of cancer survivors to prevent an increasing frequency of early retirement and permanent disability when possible. Future studies should assess the impact of cancer on premature exit from the labour market among survivors, depending on cancer localisation and type of treatment.

Sphingolipid desaturase DEGS1 is essential for mitochondria-associated membrane integrity.

Sphingolipids function as membrane constituents and signaling molecules, with crucial roles in human diseases, from neurodevelopmental disorders to cancer, best exemplified in the inborn errors of sphingolipid metabolism in lysosomes. The dihydroceramide desaturase Δ4-dihydroceramide desaturase 1 (DEGS1) acts in the last step of a sector of the sphingolipid pathway, de novo ceramide biosynthesis. Defects in DEGS1 cause the recently described hypomyelinating leukodystrophy-18 (HLD18) (OMIM #618404). Here, we reveal that DEGS1 is a mitochondria-associated endoplasmic reticulum membrane-resident (MAM-resident) enzyme, refining previous reports locating DEGS1 at the endoplasmic reticulum only. Using patient fibroblasts, multiomics, and enzymatic assays, we show that DEGS1 deficiency disrupts the main core functions of the MAM: (a) mitochondrial dynamics, with a hyperfused mitochondrial network associated with decreased activation of dynamin-related protein 1; (b) cholesterol metabolism, with impaired sterol O-acyltransferase activity and decreased cholesteryl esters; (c) phospholipid metabolism, with increased phosphatidic acid and phosphatidylserine and decreased phosphatidylethanolamine; and (d) biogenesis of lipid droplets, with increased size and numbers. Moreover, we detected increased mitochondrial superoxide species production in fibroblasts and mitochondrial respiration impairment in patient muscle biopsy tissues. Our findings shed light on the pathophysiology of HLD18 and broaden our understanding of the role of sphingolipid metabolism in MAM function.

Epigenetic profiling linked to multisystem inflammatory syndrome in children (MIS-C): A multicenter, retrospective study.

Background: Most children and adolescents infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remain asymptomatic or develop a mild coronavirus disease 2019 (COVID-19) that usually does not require medical intervention. However, a small proportion of pediatric patients develop a severe clinical condition, multisystem inflammatory syndrome in children (MIS-C). The involvement of epigenetics in the control of the immune response and viral activity prompted us to carry out an epigenomic study to uncover target loci regulated by DNA methylation that could be altered upon the appearance of MIS-C. Methods: Peripheral blood samples were recruited from 43 confirmed MIS-C patients. 69 non-COVID-19 pediatric samples and 15 COVID-19 pediatric samples without MIS-C were used as controls. The cases in the two groups were mixed and divided into discovery (MIS-C = 29 and non-MIS-C = 56) and validation (MIS-C = 14 and non-MIS-C = 28) cohorts, and balanced for age, gender and ethnic background. We interrogated 850,000 CpG sites of the human genome for DNA methylation variants. Findings: The DNA methylation content of 33 CpG loci was linked with the presence of MIS-C. Of these sites, 18 (54.5%) were located in described genes. The top candidate gene was the immune T-cell mediator ZEB2; and others highly ranked candidates included the regulator of natural killer cell functional competence SH2D1B; VWA8, which contains a domain of the Von Willebrand factor A involved in the pediatric hemostasis disease; and human leukocyte antigen complex member HLA-DRB1; in addition to pro-inflammatory genes such as CUL2 and AIM2. The identified loci were used to construct a DNA methylation profile (EPIMISC) that was associated with MIS-C in both cohorts. The EPIMISC signature was also overrepresented in Kawasaki disease patients, a childhood pathology with a possible viral trigger, that shares many of the clinical features of MIS-C. Interpretation: We have characterized DNA methylation loci that are associated with MIS-C diagnosis. The identified genes are likely contributors to the characteristic exaggerated host inflammatory response observed in these patients. The described epigenetic signature could also provide new targets for more specific therapies for the disorder. Funding: Unstoppable campaign of Josep Carreras Leukaemia Foundation, Fundació La Marató de TV3, Cellex Foundation and CERCA Programme/Generalitat de Catalunya.

The Influence of Doing Shift Work on the Lifestyle Habits of Primary Care Nurses.

Nurses' lifestyle habits play a key role in promoting healthy lifestyles; although, they may not always be entirely healthy and can be influenced by working conditions. This paper aims to analyze the influence of doing shift work on nurses' lifestyle habits. Participants (n = 219) were recruited from 27 primary health care centres in Spain. Data were collected on socio-demographic characteristics, working conditions and lifestyle behaviour, assessed by use of an adhoc questionnaire including validated measures. Descriptive analysis and logistic regression models were performed. A total of 95% of the nurses reported having an adequate diet; 45.2% did not engage in any type of physical activity; and 85.8% did not smoke, especially women. A total of 60.3% did shift work, especially the younger ones (80.8%; p < 0.001), these nurses being the ones with the worst food habits (81.8%). In contrast, nurses who did shift work, exercised more days a week (69.5%; p < 0.001). The dietary habits of the nurses were adequate. Low tobacco consumption and low adherence to physical activity were observed, especially among women. Shift work harmed eating habits and obesity rates, but was a protective factor in terms of adherence to physical exercise.

[Ausencia por enfermedad, condiciones médicas y de trabajo durante el embarazo en una cohorte de profesionales sanitarias]. / Sickness absence, medical and workplace conditions during pregnancy in a cohort of healthcare workers.

OBJECTIVES: To assess the association between sickness absence (SA) trajectories by medical diagnoses and exposure to occupational risk factors during pregnancy.  Methods: SA trajectories were identified in a cohort of 367 pregnant workers from a healthcare institution (period 2010-2014), based on most frequent diagnosis using sequence analysis. Trajectory 1 included SA episodes due mainly to musculoskeletal disorders (58.86%), trajectory 2 included SA episodes due to pregnancy-related disorders (25.07%) and trajectory 3 included absences mainly covered by pregnancy-related occupational risk benefits (POR) and few SA episodes (16.08%). Exposure to occupational risk factors was assessed by experts and their association with trajectories was analysed using logistic regression. Relative risks (RR) and their 95% confidence intervals (95%CI) were adjusted for age, type of contract and work shift. RESULTS: Trajectory 1 was negatively associated with exposure to safety and ergonomic risks (RR=0.56, 95%CI=0.35-0.90; RR=0.50, 95%CI=0.33-0.77, respectively) and with the highest global risk index (RR=0.68, 95%CI=0.49-0.96). Trajectory 3 was associated with safety and ergonomic risks (RR=2.75, 95%CI=1.59-4.75; RR=3.64, 95%CI=2.18-6.06, respectively) and with the highest global risk index (RR=2.69, 95%CI=1.43-5.01). Nursing aides and nurses had a higher probability of belonging to trajectory 3 (RR 5.58, 95%CI=2.09-14.95 and RR 5.00, 95%CI 2.18-6.06, respectively). CONCLUSIONS: Pregnancy-related and musculoskeletal disorders are the most frequent sickness absence diagnosis during pregnancy. Low levels of occupational risk factors exposure were related to absences from work covered mainly by sickness absence. Current social benefits seem to be used as a complementary way to balance work and health during pregnancy.

OBJETIVO: Evaluar la asociación entre trayectorias de ausencia por enfermedad (SA) según diagnóstico y exposición a factores de riesgo laborales durante el embarazo. Métodos: Estudio de cohortes (367 trabajadoras sanitarias embarazadas). Se identificaron trayectorias de ausencia por enfermedad según los diagnósticos más frecuentes mediante análisis de secuencias (2010-2014). La trayectoria 1 incluía SA principalmente por trastornos musculoesqueléticos (58,86%), la 2 por trastornos relacionados con el embarazo (25,07%) y la 3 incluía ausencias por la prestación por riesgo durante el embarazo (POR) y pocas SA (16,08%). La exposición a factores de riesgo laborales fue evaluada por expertos y se analizó la asociación con las trayectorias mediante regresión logística. Los riesgos relativos (RR) y sus intervalos de confianza (IC95%) se ajustaron por edad, contrato y turno. RESULTADOS: La trayectoria 1 se asoció negativamente con la exposición a riesgos de seguridad y ergonómicos (RR=0,56, IC95%=0,35-0,90; RR=0,50, IC95%=0,33-0,77) y con índice de riesgo global más bajo (RR=0,68, IC95%=0,49-0,96). La tercera se asoció a riesgos de seguridad y ergonómicos (RR=2,75, IC 95 %=1,59-4,75; RR=3,64, IC 95 %=2,18-6,06) y con el riesgo más alto (RR=2,69, 95 % IC=1,43-5,01). El personal de enfermería tuvo mayor probabilidad de pertenecer a la trayectoria 3 (RR 5,58, IC95%=2,09-14,95 y RR 5,00, IC95% 2,18-6,06). CONCLUSIONES: Los trastornos musculoesqueléticos y por trastornos relacionados con el embarazo son los grupos diagnósticos de SA más frecuentes. Bajos niveles de exposición a riesgos laborales se relacionaron con ausencias cubiertas principalmente por SA. Las prestaciones sociales parecen utilizarse complementariamente para equilibrar el trabajo y la salud.

Returning to work after a sickness absence due to cancer: a cohort study of salaried workers in Catalonia (Spain).

Cancer incidence and survival rates have increased in the last decades and as a result, the number of working age people diagnosed with cancer who return to work. In this study the probability of accumulating days of employment and employment participation trajectories (EPTs) in a sample of salaried workers in Catalonia (Spain) who had a sickness absence (SA) due to cancer were compared to salaried workers with SA due to other diagnoses or without SA. Each individual with SA due to cancer between 2012 and 2015 was matched by age, sex, and onset of time at risk to a worker with SA due to other diagnoses and another worker without SA. Accumulated days of employment were measured, and negative binomial models were applied to assess differences between comparison groups. Latent class models were applied to identify EPTs and multinomial regression models to analyse the probability of belonging to one EPT of each group. Men and women without SA or with SA due to other diagnoses had at least a 9% higher probability of continuing in employment compared to workers who had a SA due to cancer, especially among men without SA (adjusted IRR 1.27, 95% CI 1.06‒1.53). Men without SA had the highest probability of having high stable EPT compared to workers who had a SA due to cancer (adjusted RRR 3.21, 95% CI 1.87‒5.50). Even though workers with SA due to cancer continue working afterwards, they do it less often than matched controls and with a less stable employment trajectory. Health and social protection systems should guaranty cancer survivors the opportunity to continue voluntary participation in the labour market.

Epigenome-wide association study of COVID-19 severity with respiratory failure.

BACKGROUND: Patients infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), responsible for the coronavirus disease 2019 (COVID-19), exhibit a wide spectrum of disease behaviour. Since DNA methylation has been implicated in the regulation of viral infections and the immune system, we performed an epigenome-wide association study (EWAS) to identify candidate loci regulated by this epigenetic mark that could be involved in the onset of COVID-19 in patients without comorbidities. METHODS: Peripheral blood samples were obtained from 407 confirmed COVID-19 patients ≤ 61 years of age and without comorbidities, 194 (47.7%) of whom had mild symptomatology that did not involve hospitalization and 213 (52.3%) had a severe clinical course that required respiratory support. The set of cases was divided into discovery (n = 207) and validation (n = 200) cohorts, balanced for age and sex of individuals. We analysed the DNA methylation status of 850,000 CpG sites in these patients. FINDINGS: The DNA methylation status of 44 CpG sites was associated with the clinical severity of COVID-19. Of these loci, 23 (52.3%) were located in 20 annotated coding genes. These genes, such as the inflammasome component Absent in Melanoma 2 (AIM2) and the Major Histocompatibility Complex, class I C (HLA-C) candidates, were mainly involved in the response of interferon to viral infection. We used the EWAS-identified sites to establish a DNA methylation signature (EPICOVID) that is associated with the severity of the disease. INTERPRETATION: We identified DNA methylation sites as epigenetic susceptibility loci for respiratory failure in COVID-19 patients. These candidate biomarkers, combined with other clinical, cellular and genetic factors, could be useful in the clinical stratification and management of patients infected with the SARS-CoV-2. FUNDING: The Unstoppable campaign of the Josep Carreras Leukaemia Foundation, the Cellex Foundation and the CERCA Programme/Generalitat de Catalunya.

Shorter androgen receptor polyQ alleles protect against life-threatening COVID-19 disease in European males.

BACKGROUND: While SARS-CoV-2 similarly infects men and women, COVID-19 outcome is less favorable in men. Variability in COVID-19 severity may be explained by differences in the host genome. METHODS: We compared poly-amino acids variability from WES data in severely affected COVID-19 patients versus SARS-CoV-2 PCR-positive oligo-asymptomatic subjects. FINDINGS: Shorter polyQ alleles (≤22) in the androgen receptor (AR) conferred protection against severe outcome in COVID-19 in the first tested cohort (both males and females) of 638 Italian subjects. The association between long polyQ alleles (≥23) and severe clinical outcome (p = 0.024) was also validated in an independent cohort of Spanish men <60 years of age (p = 0.014). Testosterone was higher in subjects with AR long-polyQ, possibly indicating receptor resistance (p = 0.042 Mann-Whitney U test). Inappropriately low serum testosterone level among carriers of the long-polyQ alleles (p = 0.0004 Mann-Whitney U test) predicted the need for intensive care in COVID-19 infected men. In agreement with the known anti-inflammatory action of testosterone, patients with long-polyQ and age ≥60 years had increased levels of CRP (p = 0.018, not accounting for multiple testing). INTERPRETATION: We identify the first genetic polymorphism that appears to predispose some men to develop more severe disease. Failure of the endocrine feedback to overcome AR signaling defects by increasing testosterone levels during the infection leads to the polyQ tract becoming dominant to serum testosterone levels for the clinical outcome. These results may contribute to designing reliable clinical and public health measures and provide a rationale to test testosterone as adjuvant therapy in men with COVID-19 expressing long AR polyQ repeats. FUNDING: MIUR project "Dipartimenti di Eccellenza 2018-2020" to Department of Medical Biotechnologies University of Siena, Italy (Italian D.L. n.18 March 17, 2020) and "Bando Ricerca COVID-19 Toscana" project to Azienda Ospedaliero-Universitaria Senese. Private donors for COVID-19 research and charity funds from Intesa San Paolo.

Incidence and survival of Hodgkin lymphoma patients in Girona (Spain) over three decades: a population-based study.

Hodgkin lymphoma (HL) is characterized by heterogeneous histologic findings, clinical presentation and outcomes. Using the Girona population-based cancer registry data we sought to explore the incidence of HL over three decades in Girona Province (Spain) and examine the relationship between clinical features at diagnosis and survival. From 1985 to 2013, 459 cases were recorded. Patients were stratified by sex, age group, stage at diagnosis, histological subtypes and the presence of B-symptoms. The crude incidence rate (CR) was 2.7 and the corresponding European age-adjusted rate was 2.6, being higher in men than in women (sex ratio=1.6). Incidence remained constant throughout the period of study. Nodular sclerosis was the most frequent histology and showed an increasing incidence over time [estimated annual percentage change=+2.4, 95% confidence interval (CI): 0.8-4.0]. The 5-year observed survival and relative survival of patients diagnosed with HL were 73.1% (95% CI: 69.0-77.5) and 74.6% (95% CI: 70.0-79.4), respectively. No statistical differences in observed survival were observed across the three decades of study (P=0.455). Clinical parameters negatively influencing 5-year relative survival in the multivariate analysis were as follows: age at diagnosis at least 65 years; clinical stage IV; and presence of B-symptoms. These current patterns of presentation and outcomes of HL help delineate key populations in order to explore risk factors for HL and strategies to improve treatment outcomes.

Strategic lesions in the anterior thalamic radiation and apathy in early Alzheimer's disease.

BACKGROUND: Behavioural disorders and psychological symptoms of Dementia (BPSD) are commonly observed in Alzheimer's disease (AD), and strongly contribute to increasing patients' disability. Using voxel-lesion-symptom mapping (VLSM), we investigated the impact of white matter lesions (WMLs) on the severity of BPSD in patients with amnestic mild cognitive impairment (a-MCI). METHODS: Thirty-one a-MCI patients (with a conversion rate to AD of 32% at 2 year follow-up) and 26 healthy controls underwent magnetic resonance imaging (MRI) examination at 3T, including T2-weighted and fluid-attenuated-inversion-recovery images, and T1-weighted volumes. In the patient group, BPSD was assessed using the Neuropsychiatric Inventory-12. After quantitative definition of WMLs, their distribution was investigated, without an a priori anatomical hypothesis, against patients' behavioural symptoms. Unbiased regional grey matter volumetrics was also used to assess the contribution of grey matter atrophy to BPSD. RESULTS: Apathy, irritability, depression/dysphoria, anxiety and agitation were shown to be the most common symptoms in the patient sample. Despite a more widespread anatomical distribution, a-MCI patients did not differ from controls in WML volumes. VLSM revealed a strict association between the presence of lesions in the anterior thalamic radiations (ATRs) and the severity of apathy. Regional grey matter atrophy did not account for any BPSD. CONCLUSIONS: This study indicates that damage to the ATRs is strategic for the occurrence of apathy in patients with a-MCI. Disconnection between the prefrontal cortex and the mediodorsal and anterior thalamic nuclei might represent the pathophysiological substrate for apathy, which is one of the most common psychopathological symptoms observed in dementia.

Brain tissue modifications induced by cholinergic therapy in Alzheimer's disease.

A previous preliminary investigation based on a novel MRI approach to map anatomical connectivity revealed areas of increased connectivity in Alzheimer's disease (AD) but not in mild cognitive impairment patients. This prompted the hypothesis tested here, that these areas might reflect phenomena of brain plasticity driven by acetylcholinesterase inhibitors (AChEIs). Thirty-eight patients with probable AD (19 under medication with AChEIs and 19 drug-naïve) were recruited together with 11 healthy controls. All subjects had MRI scanning at 3T, including volumetric and diffusion-weighted scans. Probabilistic tractography was used to initiate streamlines from all parenchymal voxels, and anatomical connectivity maps (ACMs) were obtained by counting, among the total number of streamlines initiated, the fraction passing through each brain voxel. After normalization into standard space, ACMs were used to test for between-group comparisons, and for interactions between the exposure to AChEIs and global level of cognition. Patients with AD had reduced ACM values in the fornix, cingulum, and supramarginal gyri. The ACM value was strongly associated with the AChEI dosage-x-duration product in the anterior limb (non-motor pathway) of the internal capsule. Tractography from this region identified the anterior thalamic radiation as the main white matter (WM) tract passing through it. The reduced connectivity in WM bundles connecting the hippocampi with the rest of the brain (fornix/cingulum) suggests a possible mechanism for the spread of AD pathology. An intriguing explanation for the interaction between AChEIs and ACM is related to the mechanisms of brain plasticity, partially driven by neurotrophic properties of acetylcholine replacement.

Mixed-1,10-phenanthroline-Cu(II) complexes: synthesis, cytotoxic activity versus hematological and solid tumor cells and complex formation equilibria with glutathione.

Cu(II) complexes with 1,10-orthophenanthroline (phen) show cytotoxic and antitumoral effects. To enhance and exploit these features, we studied complexes containing one or two phen units together with N,N'-substituted-imidazolidine-2-thione (L). We synthesized and structurally characterized the precursor molecule Cu(phen)(OH(2))(2)(OClO(3))(2), and determined the complex formation constants of [Cu(phen)(L)](2+). We studied the cytotoxic activity of [Cu(phen)(2)(L)](ClO(4))(2) versus human hematologic (CCRF-CEM and CCRF-SB) and solid tumor-derived cell lines (K-MES-1, DU-145). The cytotoxic activities, in the 1-3 µM range, show that our Cu(II)-complexes possess comparable inhibitory activities against both leukemia and carcinoma cells, unlike the majority of antineoplastic agents, usually more potent against hematologic cancer cells than against solid tumor cells. Because the free Cu(II) ion is reduced by glutathione (GSH), we studied the reactivity of our complexes with GSH, providing evidence that no redox reaction occurred under the chosen experimental conditions. Complex formation equilibria were present, studied by spectrophotometric titrations. The redox properties of the prepared compounds were also investigated by cyclic voltammetry, confirming that the mixed Cu(II) complexes were resistant to reduction.

Value of imaging studies after a first febrile urinary tract infection in young children: data from Italian renal infection study 1.

OBJECTIVE: We examined the diagnostic accuracy of routine imaging studies (ultrasonography and micturating cystography) for predicting long-term parenchymal renal damage after a first febrile urinary tract infection. METHODS: This study addressed the secondary objective of a prospective trial evaluating different antibiotic regimens for the treatment of acute pyelonephritis. Data for 300 children < or =2 years of age, with normal prenatal ultrasound results, who completed the diagnostic follow-up evaluation (ultrasonography and technetium-99m-dimercaptosuccinic acid scanning within 10 days, cystography within 2 months, and repeat technetium-99m-dimercaptosuccinic acid scanning at 12 months to detect scarring) were analyzed. Outcome measures were sensitivity, specificity, and negative and positive predictive values for ultrasonography and cystography in predicting parenchymal renal damage on the 12-month technetium-99m-dimercaptosuccinic acid scans. RESULTS: The kidneys and urinary tracts were mostly normal. The acute technetium-99m-dimercaptosuccinic acid scans showed pyelonephritis in 54% of cases. Renal scarring developed in 15% of cases. The ultrasonographic and cystographic findings were poor predictors of long-term damage, showing minor sonographic abnormalities for 12 and reflux for 23 of the 45 children who subsequently developed scarring. CONCLUSIONS: The benefit of performing ultrasonography and scintigraphy in the acute phase or cystourethrography is minimal. Our findings support (1) technetium-99m-dimercaptosuccinic acid scintigraphy 6 months after infection to detect scarring that may be related to long-term hypertension, proteinuria, and renal function impairment (although the degree of scarring was generally minor and did not impair renal function) and (2) continued surveillance to identify recurrent urinary tract infections that may warrant further investigation.

Acquired amnesia in childhood: a single case study.

We report the case of C.L., an 8-year-old child who, following the surgical removal of an ependymoma from the left cerebral ventricle at the age of 4 years, developed significant difficulties in retaining day-to-day events and information. A thorough neuropsychological analysis documented in C.L. a severe anterograde amnesic syndrome, characterised by normal short-term memory, but poor performance on episodic long-term memory tests. In particular, C.L. demonstrated virtually no ability to recollect new verbal information several minutes after the presentation. As for semantic memory, C.L. demonstrated general semantic competencies, which, depending on the test, ranged from the level of a 6-year-old girl to a level corresponding to her actual chronological age. Finding a patient who, despite being severely impaired in the ability to recollect new episodic memories, still demonstrates at least partially preserved abilities to acquire new semantic knowledge suggests that neural circuits implicated in the memorisation of autobiographical events and factual information do not overlap completely. This case is examined in the light of growing literature concerned with the dissociation between episodic and semantic memory in childhood amnesia.

Drug transport mechanisms and release kinetics from molecularly designed poly(acrylic acid-g-ethylene glycol) hydrogels.

Controlled drug release devices of pH-sensitive, complexing poly(acrylic acid-g-ethylene glycol) (P(AA-g-EG)) hydrogels were prepared by free radical solution UV polymerization. The effects of hydrogel composition, polymerization conditions and surrounding environment on theophylline release kinetics and drug transport mechanisms were evaluated in these P(AA-g-EG) polymer networks. Release studies indicated a dependence of the theophylline release kinetics and diffusion coefficients on the hydrogel structure, polymerization conditions and pH of the environment. The theophylline transport mechanism was studied by fitting experimental data to five different model equations and calculating the corresponding parameters. The Akaike information criterion was also considered to elucidate the best-fit equation. Results indicated that in most release cases, the drug release mechanism was anomalous (non-Fickian). This indicates that such systems may, under certain conditions, provide release characteristics approaching zero-order release. The pH of the dissolution medium appeared to have a strong effect on the drug transport mechanism. At more basic pH values, Case II transport was observed, indicating a drug release mechanism highly influenced by macromolecular chain relaxation. The results obtained in this research work lead us to the conclusion that P(AA-g-EG) hydrogels can be successfully used as drug delivery systems. Their versatility to be designed with specifically tuned release properties renders these biomaterials promising pharmaceutical carriers for therapeutic agents.

Design of poly(ethylene glycol)-tethered copolymers as novel mucoadhesive drug delivery systems.

We developed novel acrylic-based polymers that can be used as mucoadhesive delivery systems. Poly(acrylic acid) hydrogels were modified by grafting adhesion promoter chains such as poly(ethylene glycol) (PEG) onto their back-bone chains, thus promoting the adhesive process by interpenetration. The copolymers synthesized were designated as P(AA-g-EG). Hydrogels were synthesized using PEG of two different molecular weights, 1000 and 2000, and with varying molar feed ratio of AA-EG (20:80, 40:60, 60:40, 80:20, 12:88, 25:75, 44:56, 67:33). The copolymers were synthesized by using free radical solution UV-polymerization. The effects of different PEG-tethered structures on mucoadhesion were studied using a tensiometric testing and the work of adhesion was calculated. Preswollen P(AA-g-EG) copolymer films composed of 40% acrylic acid (AA) and 60% ethylene glycol (EG), containing PEG 1000 tethers, exhibited the highest value for the work of mucoadhesion, 130 x 10(-3)+/-27 x 10(-3) mJ, that is five times higher than the formulation composed of pure PAA. Based on these results and associated molecular analysis, we conclude that the higher mucoadhesive properties of this specific copolymer were the result of the synergistic effects of both monomers. AA functional groups allowed the polymer to form multiple hydrogen bonds with the glycoproteins present in the mucus. PEG tethers possibly acted as mucoadhesive promoters, enhancing interpenetration of polymer chains into the mucus.