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Provision of timely, safe, and affordable surgical care is an essential component of any high-quality health system. Increasingly, it is recognized that poor quality of care in the perioperative period (before, during, and after surgery) may contribute to significant excess mortality and morbidity. Therefore, improving access to surgical procedures alone will not address the disparities in surgical outcomes globally until the quality of perioperative care is addressed. We aimed to identify key barriers to quality perioperative care delivery for 3 "Bellwether" procedures (cesarean delivery, emergency laparotomy, and long-bone fracture fixation) in 5 low- and middle-income countries (LMICs).Ten hospitals representing secondary and tertiary facilities from 5 LMICs were purposefully selected: 2 upper-middle income (Colombia and South Africa); 2 lower-middle income (Sri Lanka and Tanzania); and 1 lower income (Uganda). We used a rapid appraisal design (pathway mapping, ethnography, and interviews) to map out and explore the complexities of the perioperative pathway and care delivery for the Bellwether procedures. The framework approach was used for data analysis, with triangulation across different data sources to identify barriers in the country and pattern matching to identify common barriers across the 5 LMICs.We developed 25 pathway maps, undertook30 periods of observation, and held40 interviews with patients and clinical staff. Although the extent and impact of the barriers varied across the LMIC settings, 4 key common barriers to safe and effective perioperative care were identified: (1) the fragmented nature of the care pathways, (2) the limited human and structural resources available for the provision of care, (3) the direct and indirect costs of care for patients (even in health systems for which care is ostensibly free of charge), and (4) patients' low expectations of care.We identified key barriers to effective perioperative care in LMICs. Addressing these barriers is important if LMIC health systems are to provide safe, timely, and affordable provision of the Bellwether procedures.

Undifferentiated pleomorphic sarcoma (UPS) and malignant peripheral nerve sheath tumor (MPNST) are aggressive soft tissue sarcomas that do not respond well to current treatment modalities. The limited availability of UPS and MPNST cell lines makes it challenging to identify potential therapeutic targets in a laboratory setting. Understanding the urgent need for improved treatments for these tumors and the limited cellular models available, we generated additional cell lines to study these rare cancers. Patient-derived tumors were used to establish 4 new UPS models, including one radiation-associated UPS-UPS271.1, UPS511, UPS0103, and RIS620, one unclassified spindle cell sarcoma-USC060.1, and 3 new models of MPNST-MPNST007, MPNST3813E, and MPNST4970. This study examined the utility of the new cell lines as sarcoma models by assessing their tumorigenic potential and mutation status for known sarcoma-related genes. All the cell lines formed colonies and migrated in vitro. The in vivo tumorigenic potential of the cell lines and corresponding xenografts was determined by subcutaneous injection or xenograft re-passaging into immunocompromised mice. USC060.1 and UPS511 cells formed tumors in mice upon subcutaneous injection. UPS0103 and RIS620 tumor implants formed tumors in vivo, as did MPNST007 and MPNST3813E tumor implants. Targeted sequencing analysis of a panel of genes frequently mutated in sarcomas identified TP53, RB1, and ATRX mutations in a subset of the cell lines. These new cellular models provide the scientific community with powerful tools for detailed studies of tumorigenesis and for investigating novel therapies for UPS and MPNST.

Surgical treatment of ileo-colic intussusception (ICI) has been reported as the second cause of emergency laparotomy in children. The performance of incidental appendectomy after surgical reduction is currently controversial. The aim is to analyse the outcomes of performing incidental appendectomy after surgical ICI reduction with or without associated bowel resection.A retrospective study was performed in patients with ICI episodes, who underwent surgical treatment in our institution between 2005-2019. Patients were divided in two groups according to the performance of associated appendectomy (AA group) or not (NA group). Subsequently, a stratified analysis was performed according to the need for bowel resection in both groups. Demographic variables, intraoperative findings, surgical time, hospital stay, postoperative complications and recurrences were analysed.A total of 101 patients (77 AA group; 24 NA group) were included, without differences in demographics or intraoperative findings. A total of 36 bowel resections were performed (24 group AA; 10 group NA), with no differences in surgical time (55.7 min in group AA vs. 61.2 min in group NA; p = 0.587) or hospital stay (median 5 days in both groups). There were also no differences in postoperative complications or recurrences between the two groups. Stratified analysis showed that bowel resection increases operative time, hospital stay and postoperative complications, regardless of whether associated appendectomy was performed or not.Incidental appendectomy during surgical treatment of ICI in children is a safe procedure that does not increase operative time, hospital stay, postoperative complications or recurrence.El tratamiento quirúrgico de la intususcepción ileocólica (IIC) es la segunda causa más frecuente de laparotomía de urgencia en niños. La realización de una apendicectomía incidental tras la reducción quirúrgica sigue siendo motivo de controversia. El objetivo de este trabajo es analizar los resultados obtenidos al llevar a cabo una apendicectomía incidental tras la reducción quirúrgica de una IIC con o sin resección intestinal asociada.Se realizó un estudio retrospectivo en pacientes con episodios de IIC sometidos a tratamiento quirúrgico en nuestro centro entre 2005 y 2019. Los pacientes se dividieron en dos grupos según se llevara a cabo apendicectomía asociada (grupo AA) o no (grupo NA). Posteriormente, se elaboró un análisis estratificado según la necesidad de practicar resección intestinal en ambos grupos. Se analizaron las variables demográficas, los hallazgos intraoperatorios, el tiempo quirúrgico, la estancia hospitalaria, las complicaciones posoperatorias y las recidivas.Se incluyeron un total de 101 pacientes (77 en el grupo AA, y 24 en el grupo NA), sin diferencias en las características demográficas ni en los hallazgos intraoperatorios. Se practicaron un total de 36 resecciones intestinales (24 en el grupo AA; 10 en el grupo NA), sin diferencias en el tiempo quirúrgico (55,7 min en el grupo AA frente a 61,2 min en el grupo NA; p = 0,587) ni en la estancia hospitalaria (mediana de 5 días en ambos grupos). Tampoco se registraron diferencias en términos de complicaciones posoperatorias o recidivas entre los dos grupos. El análisis estratificado mostró que la resección intestinal incrementa el tiempo quirúrgico, la estancia hospitalaria y las complicaciones posoperatorias, con independencia de si se lleva a cabo apendicectomía asociada o no.La apendicectomía incidental durante el tratamiento quirúrgico de la IIC en niños es un procedimiento seguro que no aumenta el tiempo quirúrgico, la estancia hospitalaria, las complicaciones posoperatorias ni las posibilidades de recidiva.

This pre-specified analysis of DAPA-CKD assessed the impact of sodium-glucose cotransporter 2 inhibition on abrupt declines in kidney function in high-risk patients based on having chronic kidney disease (CKD) and substantial albuminuria. DAPA-CKD was a randomized, double-blind, placebo-controlled trial that had a median follow-up of 2.4 years. Adults with CKD (urinary albumin-to-creatinine ratio 200-5000 mg/g and estimated glomerular filtration rate 25-75 mL/min/1.73m2) were randomized to dapagliflozin 10 mg/day matched to placebo (2152 individuals each). An abrupt decline in kidney function was defined as a pre-specified endpoint of doubling of serum creatinine between two subsequent study visits. We also assessed a post-hoc analysis of investigator-reported acute kidney injury-related serious adverse events. Doubling of serum creatinine between two subsequent visits (median time-interval 100 days) occurred in 63 (2.9%) and 91 (4.2%) participants in the dapagliflozin and placebo groups, respectively (hazard ratio 0.68 [95% confidence interval 0.49, 0.94]). Accounting for the competing risk of mortality did not alter our findings. There was no heterogeneity in the effect of dapagliflozin on abrupt declines in kidney function based on baseline subgroups. Acute kidney injury-related serious adverse events were not significantly different and occurred in 52 (2.5%) and 69 (3.2%) participants in the dapagliflozin and placebo groups, respectively (0.77 [0.54, 1.10]). Thus, in patients with CKD and substantial albuminuria, dapagliflozin reduced the risk of abrupt declines in kidney function. HJLH and DC are co-primary authors. The DAPA-CKD Trial Committees and Investigators are listed in the Appendix.

Objectives This study aimed to develop mapping algorithms from the Expanded Prostate Cancer Index Composite (EPIC) and the Short-Form (SF) Health Surveys to the Patient-Oriented Prostate Utility Scale (PORPUS), an econometric instrument specifically developed for patients with prostate cancer. Methods Data were drawn from 2 cohorts concurrently administering PORPUS, EPIC-50, and SF-36v2. The development cohort included patients who had received a diagnosis of localized or locally advanced prostate cancer from 2017 to 2019. The validation cohort included men who had received a diagnosis of localized prostate cancer from 2014 to 2016. Linear regression models were constructed with ln(1 − PORPUS utility) as the dependent variable and scores from the original and brief versions of the EPIC and SF as independent variables. The predictive capacity of mapping models constructed with all possible combinations of these 2 instruments was assessed through the proportion of variance explained (R2) and the agreement between predicted and observed values. Validation was based on the comparison between estimated and observed utility values in the validation cohort. Results Models constructed with EPIC-50 with and without SF yielded the highest predictive capacity (R2 = 0.884, 0.871, and 0.842) in comparison with models constructed with EPIC-26 (R2 = 0.844, 0.827, and 0.776). The intraclass correlation coefficient was excellent in the 4 models (>0.9) with EPIC and SF. In the validation cohort, predicted PORPUS utilities were slightly higher than those observed, but differences were not statistically significant. Conclusions Mapping algorithms from both the original and the abbreviated versions of the EPIC and the SF Health Surveys allow estimating PORPUS utilities for economic evaluations with cost-utility analyses in patients with prostate cancer.

Resumen: La pandemia COVID ha hecho de las consultas telemáticas una herramienta básica en la práctica diaria. El objetivo principal del estudio es valorar los resultados de la aplicación de consultas telemáticas para limitar la movilidad de los pacientes.Son objetivos operativos: proponer un plan de consultas, conocer cómo limita la asistencia a las consultas, definir qué patologías se benefician más con este plan. Material y métodos: Se propone un esquema con la creación de consultas previas a las agendadas para valorar idoneidad y posibilidad de realizarla en acto único no presencial. Resultados: Se han realizado 5.619 consultas con una falta de respuesta telefónica del 19%. El 74% de los pacientes fueron resueltos de forma virtual. Existe diferencia entre unidades, siendo más probable la respuesta telefónica para las consultas de unidad, OR = 0,60 o de traumatología general, OR = 0,67 y menos para los derivados desde urgencias.El 20% de las consultas no se acompañaban de pruebas complementarias. Las consultas de traumatología general, OR = 0,34, control postoperatorio, OR = 0,49, y unidades, OR = 0,40, cumplieron mejor este requisito. De los pacientes restantes, las consultas de traumatología general, OR = 0,50, y las derivadas a unidades, OR = 0,54 fueron las que más se resolvieron sin acudir presencialmente. Conclusiones: Se han resuelto de forma no presencial el 74% de los pacientes que atendieron a la llamada telefónica. El 20% de los pacientes acuden a la visita sin pruebas complementarias. Las consultas de seguimiento de osteosíntesis y postoperatorio de cirugía artroscópica son las que más precisan de ser realizadas de forma presencial. Abstract: The COVID pandemic has made telematic consultations a basic tool in daily practice. Aims: The main objective of the study is to assess the results of the application of telematic consultations to limit the mobility of patients. The operational objectives are; to propose a consultation plan, to know how attendance limits consultations and to define which pathologies benefit the most from this plan. Methods: A scheme is proposed with the creation of pre-scheduled clinic to assess suitability and the possibility of carrying them out in a single non face-to-face act. Results: Phone call to 5,619 patients were made with a lack of response of 19%.The cases of 74% of the patients that answered were resolved virtually. There is a difference between units, obtaining a higher answering rate from patients appointed to specific clinic units, OR = 0.60, or to general trauma ones, OR = 0.67. The lowest answering rate was obtained from those derived from the emergency department. Twenty per cent of the consultations were not accompanied by complementary tests that would have favored the resolution in a single act. The general trauma consultations, OR = 0.34, postoperative control, OR = 0.49, and specific unit ones, OR = 0.40, were the ones that better met this requirement. Out of the remaining patients, the general trauma consultations, OR = 0.50, and those referred to units, OR = 0.54, were the ones that had a higher resolution rate without in- person consultation. Conclusions: The cases of 74% of the patients who answered the phone call were resolved virtually. Cases of 20% of the patients cannot be solved in a single act because they are derived without complementary tests.Osteosynthesis and postoperative arthroscopic follow-up consultations are the ones that need to be carried out in person the most.

Assessment of the bioavailability of topically applied drugs designed to act within or beneath the skin is a challenging objective. A number of different, but potentially complementary, techniques are under evaluation. The objective of this work was to evaluate in vitro skin penetration and stratum corneum tape-stripping in vivo as tools with which to measure topical diclofenac bioavailability from three approved and commercialized products (two gels and one solution). Drug uptake into, and its subsequent clearance from, the stratum corneum of human volunteers was used to estimate the input rate of diclofenac into the viable skin layers. This flux was compared to that measured across excised porcine skin in conventional diffusion cells. Both techniques clearly demonstrated (a) the superiority in terms of drug delivery from the solution, and (b) that the two gels performed similarly. There was qualitative and, importantly, quantitative agreement between the in vitro and in vivo measurements of drug flux into and beyond the viable skin. Evidence is therefore presented to support an in vivo − in vitro correlation between methods to assess topical drug bioavailability. The potential value of the stratum corneum tape-stripping technique to quantify drug delivery into (epi)dermal and subcutaneous tissue beneath the barrier is demonstrated.

Purpose To examine the potential of stratum corneum (SC) sampling via tape-stripping in humans to assess bioequivalence of topical acyclovir drug products, and to explore the potential value of alternative metrics of local skin bioavailability calculable from SC sampling experiments. Methods Three acyclovir creams were considered in two separate studies in which drug amounts in the SC after uptake and clearance periods were measured and used to assess bioequivalence. In each study, a “reference” formulation (evaluated twice) was compared to the “test” in 10 subjects. Each application site was replicated to achieve greater statistical power with fewer volunteers. Results SC sampling revealed similarities and differences between products consistent with results from other surrogate bioequivalence measures, including dermal open-flow microperfusion experiments. Further analysis of the tape-stripping data permitted acyclovir flux into the viable skin to be deduced and drug concentration in that ‘compartment’ to be estimated. Conclusions Acyclovir quantities determined in the SC, following a single-time point uptake and clearance protocol, can be judiciously used both to objectively compare product performance in vivo and to assess delivery of the active into skin tissue below the barrier, thereby permitting local concentrations at or near to the site of action to be determined.

Background: Oral semaglutide is the first oral glucagon-like peptide-1 (GLP-1) receptor agonist for glycaemic control in patients with type 2 diabetes. Type 2 diabetes is commonly associated with renal impairment, restricting treatment options. We aimed to investigate the efficacy and safety of oral semaglutide in patients with type 2 diabetes and moderate renal impairment. Methods: This randomised, double-blind, phase 3a trial was undertaken at 88 sites in eight countries. Patients aged 18 years and older, with type 2 diabetes, an estimated glomerular filtration rate of 30–59 mL/min per 1·73 m2, and who had been receiving a stable dose of metformin or sulfonylurea, or both, or basal insulin with or without metformin for the past 90 days were eligible. Participants were randomly assigned (1:1) by use of an interactive web-response system, with stratification by glucose-lowering medication and renal function, to receive oral semaglutide (dose escalated to 14 mg once daily) or matching placebo for 26 weeks, in addition to background medication. Participants and site staff were masked to assignment. Two efficacy-related estimands were defined: treatment policy (regardless of treatment discontinuation or rescue medication) and trial product (on treatment without rescue medication) in all participants randomly assigned. Endpoints were change from baseline to week 26 in HbA1c (primary endpoint) and bodyweight (confirmatory secondary endpoint), assessed in all participants with sufficient data. Safety was assessed in all participants who received at least one dose of study drug. This trial is registered on ClinicalTrials.gov, number NCT02827708, and the European Clinical Trials Registry, number EudraCT 2015-005326-19, and is now complete. Findings: Between Sept 20, 2016, and Sept 29, 2017, of 721 patients screened, 324 were eligible and randomly assigned to oral semaglutide (n=163) or placebo (n=161). Mean age at baseline was 70 years (SD 8), and 168 (52%) of participants were female. 133 (82%) participants in the oral semaglutide group and 141 (88%) in the placebo group completed 26 weeks on treatment. At 26 weeks, oral semaglutide was superior to placebo in decreasing HbA1c (estimated mean change of −1·0 percentage point (SE 0·1; −11 mmol/mol [SE 0·8]) vs −0·2 percentage points (SE 0·1; −2 mmol/mol [SE 0·8]); estimated treatment difference [ETD]: −0·8 percentage points, 95% CI −1·0 to −0·6; p1c −1·1 percentage points (SE 0·1; −12 mmol/mol [SE 0·8] versus −0·1 percentage points (SE 0·1; −1 mmol/mol [SE 0·8]; ETD −1·0 percentage points, 95% CI −1·2 to −0·8; p

BACKGROUND: Oral semaglutide is the first oral formulation of a glucagon-like peptide-1 (GLP-1) receptor agonist developed for the treatment of type 2 diabetes. We aimed to compare the efficacy and safety of flexible dose adjustments of oral semaglutide with sitagliptin 100 mg. METHODS: In this 52-week, multicentre, randomised, open-label, phase 3a trial, we recruited patients with type 2 diabetes from 81 sites in ten countries. Patients were eligible if they were aged 18 years or older (19 years or older in South Korea), had type 2 diabetes (diagnosed ≥90 days before screening), HbA1c of 7·5-9·5% (58-80 mmol/mol), and were inadequately controlled on stable daily doses of one or two oral glucose-lowering drugs (for 90 days or more before screening). Participants were randomly assigned (1:1) by use of an interactive web-response system, stratified by background glucose-lowering medication at screening, to oral semaglutide with flexible dose adjustments to 3, 7, or 14 mg once daily or sitagliptin 100 mg once daily. To approximate treatment individualisation in clinical practice, oral semaglutide dose could be adjusted on the basis of prespecified HbA1c and tolerability criteria. Two efficacy-related estimands were prespecified: treatment policy (regardless of treatment discontinuation or use of rescue medication) and trial product (on treatment and without use of rescue medication) for participants randomly assigned to treatment. The primary endpoint was achievement of HbA1c of less than 7% (53 mmol/mol) at week 52 and the confirmatory secondary efficacy endpoint was change in bodyweight from baseline to week 52. Safety was assessed in all participants who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT02849080, and European Clinical Trials Database, EudraCT number 2015-005593-38, and an open-label extension is ongoing. FINDINGS: Between Sept 20, 2016, and Feb 7, 2017, of 804 patients assessed for eligibility, 504 were eligible and randomly assigned to oral semaglutide (n=253) or sitagliptin (n=251). Most participants were male (285 [57%] of 504) with a mean age of 57·4 years (SD 9·9). All participants were given at least one dose of their allocated study drug except for one participant in the sitagliptin group. From a mean baseline HbA1c of 8·3% (SD 0·6%; 67 mmol/mol [SD 6·4]), a greater proportion of participants achieved an HbA1c of less than 7% with oral semaglutide than did with sitagliptin (treatment policy estimand: 58% [134 of 230] vs 25% [60 of 238]; and trial product estimand: 63% [123 of 196] vs 28% [52 of 184]). The odds of achieving an HbA1c of less than 7% was significantly better with oral semaglutide than sitagliptin (treatment policy estimand: odds ratio [OR] 4·40, 95% CI 2·89-6·70, p

Screening plays an important role in women with a high risk of breast cancer. Given this population's high incidence of breast cancer and younger age of onset compared to the general population, it is recommended that screening starts earlier. There is ample evidence that magnetic resonance imaging (MRI) is the most sensitive diagnostic tool, and American and the European guidelines both recommend annual MRI screening (with supplementary annual mammography) as the optimum screening modality. Nevertheless, the current guidelines do not totally agree about the recommendations for MRI screening in some subgroups of patients. The first part of this article on screening in women with increased risk of breast cancer reviews the literature to explain and evaluate the advantages of MRI screening compared to screening with mammography alone: increased detection of smaller cancers with less associated lymph node involvement and a reduction in the rate of interval cancers, which can have an impact on survival and mortality (with comparable effects to other preventative measures). At the same time, however, we would like to reflect on the drawbacks of MRI screening that affect its applicability.

For women with a high risk of breast cancer, early detection plays an important role. Due to the high incidence of breast cancer, and at a younger age than in the general population, screening begins earlier, and there is considerable evidence that magnetic resonance is the most sensitive diagnostic tool, and the principal American and European guidelines agree on the recommendation to perform annual magnetic resonance (with supplemental annual mammography) as an optimal mode of screening. In addition to the absence of current consensus on which patients should be included in the recommendation for magnetic resonance screening (widely discussed in the introduction of part 1 of this work), there are other aspects that are different between guidelines, that are not specified, or that are susceptible to change based on the evidence of several years of experience, that we have called «controversies», such as the age to begin screening, the possible advisability of using a different strategy in different subgroups, performing alternate versus synchronous magnetic resonance and mammography, the age at which to terminate the two techniques, or how to follow up after risk reduction surgery.The aim of the second part of the paper is, by reviewing the literature, to provide an update in relation to some of the main «controversies» in high risk screening with magnetic resonance. And finally, based on all this, to propose a possible model of optimal and updated screening protocol.

Dentistry is recognised as a stressful profession and dentists perceive their profession to be more stressful than other healthcare professions. While earlier studies have shown a link between stress and well-being among dentists, whether stress negatively impacts their clinical performance is an important and open question. We do know, however, that stress is associated with reduced performance in other health (and non-health) related professions.This systematic review aimed to answer the question: how does stress impact on dentists' clinical performance?This systematic review was registered in PROSPERO (CRD42016045756). The CINHAL, Embase, Medline, PsycINFO, EThOS and OpenGrey electronic databases were searched according to PRISMA guidelines. Two reviewers independently screened the citations for relevance. The citation list of potentially eligible papers was also searched. Prospective empirical studies were considered for inclusion. The inclusion criteria were applied at the full-text stage by the two same reviewers independently.The search yielded 3535 titles and abstracts. Twelve publications were considered potentially eligible, eleven of which were excluded as they did not meet the predefined inclusion criteria.This systematic review identified a gap in the literature as it found no empirical evidence quantifying the impact of stress on dentists' clinical performance. Prospective well-designed experimental simulation studies, comparing stress with non-stress situations on clinical performance and decision making, as well studies evaluating prospectively real-life dentists' performance under stress are warranted.

The most frequent sequelae following a translabyrinthine approach for vestibular schwannoma resection is complete hearing loss on the affected side. Such patients could benefit from a cochlear implant, provided that two essential requisites are met before surgery: a preserved cochlear nerve and a patent cochlea to accommodate the electrode array. The goal of our study is to determine the prevalence and extent of cochlear ossification following a translabyrinthine approach. Postoperative MRI of 41 patients were retrospectively reviewed. Patients were classified according to the degree of cochlear obliteration into three groups (patent cochlea, partially obliterated cochlea and totally obliterated cochlea). The interval between surgery and the first MRI was studied as well as its relationship with the rate of cochlear ossification. At first postoperative MRI (mean interval of 20 months), 78% of patients showed some degree of cochlear ossification. Differences were found in the time interval between surgery and first MRI for each group, showing a smaller interval of time the patent cochlea group (p0.05). When MRI was performed before the first year after surgery, a larger rate of patent cochlea was found (p0.05). The present study suggests that cochlear ossification is a time-depending process, whose grounds are still to be defined.Ossificazione cocleare dopo l’approccio translabirintico e le sue implicazioni per l’impianto cocleare.La conseguenza piú frequente dopo un approccio translabirintico per uno schwannoma vestibolare è la completa perdita uditiva dal lato affetto. Questi pazienti possono trarre beneficio da un impianto cocleare, qualora però vengano soddisfatti due importanti requisiti prima della chirurgia: un nervo cocleare intatto e una coclea permeabile per accomodare l’elettrodo. L’obiettivo del nostro studio è quello di determinare la prevalenza e l’estensione dell’ossificazione cocleare dopo l’approccio translabirintico. Pertanto, sono state rivisitate retrospettivamente le immagini della risonanza magnetica (RM) post-chirurgica di 41 pazienti. I pazienti sono stati classificati secondo il grado di obliterazione cocleare in tre gruppi (coclea permeabile, coclea parzialmente obliterata e coclea completamente obliterata). È stato studiato l’intervallo tra la chirurgia e la prima RM post-chirurgica ed anche la sua relazione con il tasso di ossificazione cocleare. Alla prima RM post-chirurgica (intervallo medio: 20 mesi), il 78% dei pazienti ha mostrato un certo grado di obliterazione cocleare. Sono state trovate differenze nell’intervallo di tempo tra la chirurgia e la prima RM per ogni gruppo, mostrandosi l’intervallo di tempo piú breve nel gruppo con la coclea permeabile (p0,05). Questo studio suggerisce, quindi, che l’ossificazione cocleare è un processo tempo-dipendente, rimanendo, peró, i motivi di ció ancora sconosciuti.

Topical drug delivery to treat nail diseases such as onychomycosis and psoriasis is receiving increasing attention. Topical nail delivery is challenged by the complicated structure of the nail and the low permeability of most drugs across the nail plate. Considerable effort has been directed at developing methods to promote drug permeation across the nail plate. Iontophoresis efficiently enhances molecular transport across the skin and the eye and is now being tested for its potential in ungual delivery.This review covers the basic mechanisms of transport (electro-osmosis and -migration) and their relative contribution to nail iontophoresis as well as the key factors governing nail permselectivity and ionic transport numbers. Methodological issues concerning research in this area are summarized. The data available in vivo on nail iontophoresis of terbinafine specifically are reviewed in separate sections.Our understanding of nail iontophoresis has improved considerably since 2007; most decisively, the feasibility of nail iontophoresis in vivo has been clearly demonstrated. Future work is required to establish the adequate implementation of the technique so that its clinical efficacy to treat onychomycosis and nail psoriasis can be unequivocally determined.

Malathion is a pesticide used on a large scale and with high potential risk for human exposure. However, it is reasonable to hypothesize that while the malathion is metabolizing reactive oxygen species (ROS) can be generated and subsequently there is onset of an oxidative stress in central nervous system (CNS) structures: hippocampus, cortex, striatum and cerebellum of intoxicated rats due to mitochondrial respiratory chain disfunctions. The present study was therefore undertaken to evaluate malathion-induced lipid peroxidation (LPO), superoxide production from sub-mitochondrial particles and the activity of complexes II and IV of the mitochondrial respiratory chain. Malathion was administered in doses of 25, 50, 100 and 150 mg malathion/kg. After malathion administration LPO increased in hippocampus and striatum. This was accompanied by an increase in the formation of superoxide in submitochondrial particles in the hippocampus. Complex IV suffered significant inhibition of its activity. We could demonstrate in this study that malathion induces oxidative stress and it could be due to inactivation of mitochondrial respiratory complexes.

Apoptotic bodies are frequently found in oligodendrogliomas, particularly in the anaplastic subtype. A range of proteins, such as those of the Bcl family, are implicated in the control of apoptosis. The ratio of antagonists of apoptosis, such as Bcl-2, to agonists, such as Bax, is thought to determine the outcome for a particular cell. This study aimed to determine the expression of Bcl-2 and Bax proteins in a series of oligodendrogliomas and to relate the expression of these to measures of apoptosis. Immunohistochemistry was used to detect the expression of Bcl-2 and Bax in an archival series of 32 oligodendrogliomas. The results were scored semiquantitatively for the extent and intensity of tumour staining. Apoptosis indices were determined by counting apoptotic bodies on haematoxylin and eosin staining and the percentage of cells showing a positive reaction with the TdT-mediated dUTP-biotin nick end-labelling technique (TUNEL). Granular cytoplasmic staining for Bcl-2 was seen in tumour cells in 81% of cases. Cases with a strong intensity (but not extent) of staining showed a lower TUNEL index (P=0.038). Bcl-2 expression was identified in the walls of intratumoural blood vessels in 55% of cases and in peri-tumoural neurones (where present) in 87%. Bax expression was detected in tumour cells in 69% of cases but no relationship to TI was detected. Bax positivity was seen in blood vessels in 44% of cases and peri-tumoural neurones in 60%. Bcl-2 and Bax were concluded to be expressed in a high proportion of oligodendrogliomas, suggesting that they may exert a regulatory role in cell death in these tumours.

We aim to define which patients make up the populations with high and intermediate risk of developing breast cancer, to review the studies of screening with magnetic resonance imaging in addition to mammography in high risk patients (describing the imaging characteristics of the cancers in this group), to review the studies of screening with magnetic resonance imaging in patients with intermediate risk, and to update the guidelines for screening in patients with high or intermediate risk (based on the recent recommendations of the main scientific societies/American and European guidelines).

This work aimed to (a) characterize the microstructure and porosity of human nail and bovine hoof by mercury intrusion porosimetry and SEM image analysis, (b) study the effects of hydration and of N-acetyl-l-cysteine treatment on the microstructure of both membranes, and (c) determine whether the microstructural modifications were associated with changes in drug penetration measured by standard diffusion studies. Bovine hoof surface is more porous than nail surface although there were no differences between the mean surface pore sizes. Hydration and N-acetyl-l-cysteine increased the roughness and apparent surface porosity, and the porosity determined by mercury intrusion porosimetry of both membranes. Pore-Cor TM was used to generate tridimensional structures having percolation characteristics comparable to nail and hooves. The modeled structures were horizontally banded having an inner less-porous area which disappeared upon treatment. Treatment increased the predicted permeability of the simulated structures. Triamcinolone permeation increased significantly for hooves treated N-acetyl-l-cysteine, i.e., the membranes for which microstructural and permeability changes were the largest. Thus, microstructural changes determined via mercury intrusion porosimetry and subsequently modeled by Pore-Cor TM were related to drug diffusion. Further refinement of the technique will allow fast screening of penetration enhancers to be used in ungual drug delivery.

DQA1, DQB1 and DPB1 alleles were investigated in a large panel of samples carrying HLA-DQ2- and HLA-DQ9-bearing extended haplotypes. Every instance of the [HLA-B8, SCO1, DR3, DQ2a] and [HLA-B18, F1C3, DR3, DQ2b] extended haplotypes carried the DQA1*-0501 allele, while every instance of [HLA-844, F1C31, DR7, DQ2c], (HLA-B47, FC91,0, DR7, DQ2c] and [HLA-B57, SC61, DR7, DQ2d] carried the DQA1*0201 allele. All HLA-DR3, DQ2 and HLA-DR7, DQ2 extended haplotypes carried the DQB1*0201 allele. Every example of [HLA-B57, SC61, DR7, DQ9] carried the DQB1*0303 allele. Several associations between the DPB1 alleles and some HLA-DQ2- and DQ9-carrying extended haplotypes were identified. HLA-DPw2-encoding alleles. DPB1*0202 (50%, p < 0.001) and 0201 (30%). were found on the [HLA-B18, F1C30, DR3, DQ2b] extended haplotype. Every instance of the [HLA-B57, SC61, DR7, DQ9] extended haplotype carried the DPB 1*0401 allele. Also, we have confirmed the associations of the DPB1*0101 and DPB1*0401 alleles with the [HLA-B8, SC01. DR3, DQ2a] extended haplotype. The analysis of hornozygous typing cells carrying the [HLA-B44. FC31, DR7, DQ2c] extended haplotype showed that the DPB1*0401 and 0201 alleles were present at similar frequencies (37.5%). while the DPB1*1101 allele was found in only 25% of these haplotypes analyzed. Our results suggest that the constancy of the DNA of the HLA-B, DR, DQ regions may extend to the DP region and that the extent of such fixity varies, perhaps as the result of ethnic variability of the population studied.

This work investigates the reverse iontophoretic extraction of lactate, a widely used marker of tissue distress in critically ill patients and of sports performance. In vitro experiments were performed to establish the relationship between subdermal lactate levels and lactate iontophoretic extraction fluxes. Subsequently, the iontophoretic extraction of lactate was performed in vivo in healthy volunteers. Lactate was quickly and easily extracted by iontophoresis both in vitro and in vivo. During a short initial phase, iontophoresis extracts the lactate present in the skin reservoir, providing information of relevance, perhaps, for dermatological and cosmetic applications. In a second step, lactate is extracted from the interstitial subdermal fluid allowing local lactate kinetics to be followed in a completely non-invasive way. The simultaneous in vivo extraction of chloride, and its possible role as an internal standard to calibrate lactate reverse iontophoretic fluxes, was also demonstrated. Despite these positive findings, however, considerably more research is necessary to eliminate potential artefacts and to facilitate interpretation of the data.

Reverse iontophoresis extracts glucose across the skin in the GlucoWatch Biographer, a device to monitor glycemia in diabetes. However, the device must first be calibrated with an invasive "fingerstick" and this has been perceived as a disadvantage. Here, urea, a neutral "internal standard" is extracted simultaneously in an attempt to render the technique completely non-invasive.In a 5-h experiment in human volunteers, reverse iontophoretic fluxes of glucose and urea (J(glu) and J(urea), respectively) were measured periodically and correlated with the corresponding blood levels. In the case of glucose, a finger-tip blood sample was taken at the beginning of each collection interval; for urea, three blood samples were assayed: one before, one during, and one at the end of iontophoresis.The ratio J(glu)/J(urea) divided by the ratio of the systemic concentrations (C(glu)/C(urea)) yielded an extraction coefficient (K) that could be compared between subjects. Though J(glucose) tracked C(glu) faithfully when the volunteers were challenged with an oral glucose load, J(urea) remained quite stable reflecting the fact that C(urea) did not change appreciably during the experiment. However, whereas the variability (expressed as the coefficient of variation) in the normalized extraction flux of urea (J(urea)/C(urea)) was on the order of 25%, that for glucose was greater (45%), with the result that the values of K (0.45 +/- 0.25) were less constant than anticipated.Although urea performed quite reasonably as an internal standard, in that its extraction flux and systemic concentration both remained quite constant, the normalized, transdermal, iontophoretic flux of glucose showed interindividual variability due to mechanisms that were not entirely governed by electrotransport. That is, despite good qualitative tracking to blood levels, there appear to be other (biochemical, metabolic, contamination?) factors that impact upon the quantitative results obtained.

To evaluate the causes, degree of injury and localization of the hepatic trauma in thoracic-abdominal injuries: surgical solution and its results, as well as to explain the liver damages according to the cause of the injury.Patients with thoracic-abdominal trauma often evidence liver lesions that must be treated quickly and promptly.Retrospective study of the cases of liver trauma undergoing surgery during the years 1995/2000 at the Jos Casimiro Ulloa , Emergency Hospital in Lima, Peru.164 patients underwent surgery with a mortality rate of 13.4% (22). Injuries were caused by direct contusion in 58% of the cases and by aggression in 42% of the cases. The liver was repaired with suture in 121 cases, by tamponing in 40 cases, by hepatectomy in 1 case and no treatment in 2 cases. There were 38 re-interventions. The relation between the degrees of liver injuries and mortality were: 1 Degree: 9 cases, with no deaths, 2 Degree: 97 cases with 4 deaths (4.1%); 3rd Degree: 37 cases with 2 deaths (5%), 4 Degree: 12 cases with 7 deaths (58%); 5 Degree: 9 cases with 9 deaths (100%).In our experience, liver complications in thoracic-abdominal injuries are high,. Total mortality was 13.6%, of which 70% were due to a closed wound and 30% due to an open wound. Resuscitation, vital support, quick and timely surgery, whichever the technique used to reduce liver bleeding, gives positive results. Often the accompanying lesions determine the patient s evolution. The symptoms of liver injuries are predictable in cases of direct trauma or deceleration. In wounds inflicted by bullets or sharp and penetrating objects, the trajectory determines the damages to the anatomy.

There have been many attempts to define the key relationships between passive drug diffusion across the skin and the molecular and physicochemical properties of the permeant. At the present time, the importance of lipophilicity (or hydrogen bond donor and acceptor properties) and of molecular volume are well established, and useful predictive relationships for passive percutaneous permeability exist. With respect to iontophoresis, on the other hand, the situation is far less clear and the mechanisms involved have not been completely defined. The roles of electromigration and electroosmosis (current-induced convective solvent flow) are now beginning to be understood and experimentally separated. In turn, this allows the manner in which certain physicochemical parameters influence the efficiency of drug electrotransport to be deduced. An initial examination of a database drawn from the literature and from our own work (for which the experimental conditions employed were reasonably constant) suggests a rather sharp dependence of cationic drug delivery via electromigration upon molecular size. We suggest that the analysis reveals useful paths for further investigation.

A 52-year-old woman was admitted because of lower abdominal pain. Physical examination showed a 5-cm bulky barrel-shaped uterine cervix, a 10-week sized uterus and a 10-cm right adnexal mass. Colpo...

The use of enemas during labor usually depends on the preference of the attending physician and available resources. However enemas cause discomfort in women and increase the costs of delivery.The objective of this review was to assess the effects of enemas during the first stage of labor on infection rates in mothers and newborns, duration of labor, perineal wound dehiscence in the mother, perineal pain, faecal soiling and costs.We searched the Cochrane Pregnancy and Childbirth Group trials register, the Cochrane Controlled Trials Register, Database of Abstracts of Reviews of Effectiveness, Medline and reference lists of articles.Randomised trials in which an enema was administered during the first stage of labor and which included assessment of possible neonatal or puerperal morbidity or mortality.Selected studies were assessed by three reviewers independently.Two trials involving 665 women were included. These showed no clear difference in infection rates for puerperal mothers (odds ratio 0.61, 95% confidence interval 0.36 to 1.04) or newborn children.There is not enough evidence to evaluate the use of routine enemas during the first stage of labor.

To evaluate the transport number of Na+, and the isoelectric point, of two skin membranes frequently used for iontophoretic in vitro research.Na+ transport numbers were determined by the Hittorf method or by the measurement of membrane potential. The skin isoelectric point was deduced from the electroosmosis of mannitol (a polar non-electrolyte) as a function of pH.The Na+ transport number across porcine skin, like that for hairless mouse, indicated a modest cation permselectivity. Consistent with this observation, the isoelectric points of porcine and hairless mouse skin were determined to be in the ranges of 3.5-3.75 and 4.5-4.6, respectively. That is, at physiological pH, both of these model membranes supports a net negative charge.The permselective properties of porcine and hairless mouse skin are similar (but with the porcine membrane having apparently fewer basic or more weakly-acidic groups than that of the mouse) and consistent with the characteristics, which have been deduced elsewhere, of human skin.

Interleukin-8 (IL-8) acts on human neutrophils via two receptors, CXCR1 and CXCR2. It shares CXCR2 with all neutrophil-activating chemokines, which like IL-8 have a conserved Glu-Leu-Arg (ELR) N-terminal motif, but is generally considered to be the only relevant agonist for CXCR1. IL-8 has a basic residue at the sixth position after the second cysteine, which was suggested to contribute to CXCR1 specificity. Among the other ELR chemokines, only granulocyte chemotactic protein 2 (GCP-2) has such a basic determinant. Using Jurkat cells that stably express either CXCR1 or CXCR2, we studied receptor activation by IL-8, GCP-2 epithelial neutrophil-activating protein 2 (ENA-78) (which shares 77% identical amino acids with GCP-2) and growth-regulated oncogene alpha (GRO alpha). At 10 nM and higher concentrations, GCP-2 and IL-8 induced significant activation of CXCR1-expressing cells, but no activity was found with GRO alpha and ENA-78. As expected, however, all four chemokines had similar activities on CXCR2-expressing cells. A variant of GCP-2 in which the basic residue, Arg20, was replaced by a glycine was synthesized. This derivative was ineffective on CXCR1, but was as active as wild-type GCP-2 in CXCR2-expressing cells. GCP-2 displaced radiolabeled IL-8 from both receptors with low affinity, and in this respect resembled ENA-78 and GRO alpha. Our data show that GCP-2 acts via both IL-8 receptors and thus appears to be functionally more similar to IL-8 than to the other ELR chemokines. Activation of CXCR1 appears to depend significantly on the presence of a basic binding determinant close to the second cysteine.

We report the results of 23 patients with aplastic anemia (AA) treated with a program of 14 lymphocytapheresis (LC). Treatments were performed with apheresis machines, models Haemonetics 30-S and Baxter CS3000, using the standard program. This procedure was done because AA in many cases appears as a result of the action of a T cell population that inhibits hematopoiesis. Theoretically, removal of this clonal population would produce hematopoietic recovery. Of the total of 23 patients, 9 were excluded for final evaluation of treatment results because 7 died during or shortly after treatment (0.7-3 months); one patient abandoned treatment after three LC and another died 7 months later because of transformation to acute leukemia. The remaining 14 patients were included in the final evaluation of treatment; seven females and seven males, average age 46.1 years (range 22-69); 13 with severe, and one with moderate AA; 11 with recently diagnosed, and 3 with chronic AA; 12 without previous treatment and two treated before with antilymphocyte globulin + oxymetholone (OXM) + cyclosporine A (CsA) with transient partial remission (PR). Besides lymphocytapheresis, 13 patients received OXM; 4 of them GM-CSF and one low dose CsA. Four patients had complete remission lasting59.5 months (range 42-78); eight PR (average duration of38.6 months), and two minimal remission (37 and 29 months). Platelet, reticulocyte and granulocyte counts increased on average at 48.7, 73.3 and 91.4 days, respectively. In conclusion, 14 (60.8%) of 23 patients with AA showed an improvement related to LC treatment, with a survival probability of 63% from the fourth month, the latter with an added beneficial effect of the other therapies used. Larger numbers of patients have to be treated with LC to determine its real usefulness, mechanism of action and the best conditions for its use.

30 patients (less than 15 years old) were admitted for esophageal strictures, 16 of them secondary to corrosive injury. All the patients were treated with endoscopic dilatation with Savary-Gilliard bougie. The dilations were done with general anesthesia using an Olympus GIF-XP10 endoscope and with fluoroscopic control. In the esophageal stenosis secondary to caustic ingestion endoscopic injection with Betamethasone was also used. The most frequent site of the stenosis was the upper third of the esophagus, and the main type of stenosis was tubular in the secondary to caustic burns and annular in the other group. In the post-caustic group 385 dilations were performed in 115 sessions. In the other group 159 dilations were done in 51 sessions. Two perforations and one sepsis were reported in patients with corrosive stenosis. There was no mortality. 43.7% of the patients with corrosive stenosis and 85.7% with stenosis secondary to other causes obtained complete healing. Esophageal dilation with Savary-Gilliard bougies represents a safe and reliable method for the treatment of esophageal strictures.

30 patients (less than 15 years old) were admitted for esophageal strictures, 16 of them secondary to corrosive injury. All the patients were treated with endoscopic dilation with Savary Gilliard bougie. The dilatation were done with general anesthesia using an Olympus GIF-XP10 endoscope and with fluoroscopic control. In the esophageal stenosis secondary to caustic ingestion endoscopic injection with Betamethasone was also used. The most frequent site of the stenosis was the upper third of the esophagus, and the main type of stenosis was tubular in the secondary to caustic burns and annular in the other group. In the posteaustic group 385 dilatations were performed in 115 sessions. Two perforations and one sepsis were reported in patients with corrosive stenosis. There was no mortality. 43.7% of the patients with corrosive stenosis and 85.7% with stenosis secondary to other causes obtained complete healing. Oesophageal dilatation with Savary-Gilliary bougies represents a safe and reliable method for the treatment of esophageal strictures.

MHC class II alleles and haplotypes were determined from unrelated individuals and families of the Arhuaco ( n = 107), Kogi ( n = 42), Arsario ( n = 18), and Wayu ( n = 88) tribes located in the northern part of Colombia. Class II DRB, DQA1, and DQB1 alleles were determined by PCR-SSO and PCR-RFLP based methods. Four haplotypes, [DRB1 ∗ 0407, DRB4 ∗ 0101, DQA1 ∗ 03, DQB1 ∗ 0302]; [DRB1 ∗ 0403, DRB4 ∗ 0101, DQA1 ∗ 03, DQB1 ∗ 0302]; [DRB1 ∗ 1402/1406, DRB3 ∗ 0101, DQA1 ∗ 0501, DQB1 ∗ 0301]; and [DRB1 ∗ 0802, DQA1 ∗ 0401, DQB1 ∗ 0402], were observed among these four tribes. In addition to these haplotypes, the Wayu Indians showed a frequency of 21.3% for the [DRB1 ∗ 1602, DRB5 ∗ 02, DQA1 ∗ 0501, DQB1 ∗ 0301] haplotype, 13.1% for the [DRB1 ∗ 0411, DRB4 ∗ 0101, DQA1 ∗ 03, DQB1 ∗ 0302] haplotype, and 8.1% for the [DRB ∗ 0411, DRB4 ∗ 0101, DQA1 ∗ 03, DQB1 ∗ 0402] haplotype. Red cell antigen typing was used to calculate genetic admixture. The Kogi and Arsario showed no genetic admixture while the Arhuaco tribe showed admixture with genes of African origin and the Wayu showed admixture with Caucasians as well as genes of African origin. These findings were confirmed by the MHC class II allele and haplotype data obtained, as alleles and haplotypes of Caucasian and African origin were detected in the Wayu and Arhuaco and not in the Kogi or Arsario. These studies will be important in disease association and transplantation studies for Amerindian and Colombian populations and for correlating genetic traits with the anthropologic and linguistic data available in order to better understand the Amerindian populations.

We have developed a new PCR-RFLP method for HLA-DQB1 typing. This method was easy to follow, requiring only one DQB1 generic amplification and 5 endonucleases to assign 14 out of 15 HLA-DQB1 alleles. In addition, we determined that by using one generic amplification and two enzymes (Sau96 I and Hae III) it was possible to type the generic specificities: DQw2, DQw4, DQw5, DQw6, and DQw7, DQw8-9, providing a practical alternative for serological HLA-DQ generic typing. We also performed a side-by-side correlation with a PCR-SSO typing method and found an almost 100% concordance between the methods. The limitations of these methods were: 1) the PCR-RFLP method did not allow the differentiation between the HLA-DQB1*0602 and *0603 alleles; 2) the PCR-SSO method gave crosshybridization signals in the detection of *0302 or *0303 alleles. Our results suggested that both methods, PCR-RFLP and PCR-SSO, are useful alternatives for HLA-DQB1 typing.

This article reports the case of a large calcifying epithelial odontogenic tumor in a patient with tuberous sclerosis complex. The calcifying epithelial odontogenic tumor, one of the rarest odontogenic tumors, is reviewed in detail, as is the unusual disorder of tuberous sclerosis complex.

A case of nodular fasciitis diagnosed by fine needle aspiration cytology is described. The cytologic findings included fusiform cells, mitoses, macrophages, multinucleated giant cells and mesenchymal elements in a characteristic granular background substance. The cytopathologic diagnosis was subsequently confirmed by the histopathologic study of the tumor and by electron microscopy.