Acute calcific periarthritis in a proximal interphalangeal joint of the hand after acute trauma: a rare case.

Acute calcific periarthritis (ACP) in the interphalangeal joints of the hand is rare, with less than 100 cases reported. A rare case of ACP in a proximal interphalangeal (PIP) joint of the hand, in a young black woman, after acute trauma, is presented. She experienced severe pain and limited range of motion, and was medicated with an oral corticoid, which was followed by a rapid resolution of the symptoms. At six months, there were no signs of clinical or radiographic recurrence. Recognition of ACP allows for avoiding unnecessary treatments. In this case, treatment with corticoids might have played a role in a faster recovery.

La periartritis calcificada aguda (PCA) en las articulaciones interfalángicas de la mano es rara, con menos de 100 casos reportados. Se presenta un caso raro de PCA en una articulación interfalángica proximal (IFP) de la mano, en una mujer joven de raza negra, después de un traumatismo agudo. Experimentó dolor intenso y rango de movimiento limitado, y fue medicada con un corticoide oral, lo que fue seguido por una rápida resolución de los síntomas. A los seis meses no hubo signos de recurrencia clínica ni radiológica. El reconocimiento de PCA permite evitar tratamientos innecesarios. En este caso, el tratamiento con corticoides podría haber contribuido a una recuperación más rápida.

Tangential velocity constraint for orbital maneuvers with Theory of Functional Connections.

Maneuvering a spacecraft in the cislunar space is a complex problem, since it is highly perturbed by the gravitational influence of both the Earth and the Moon, and possibly also the Sun. Trajectories minimizing the needed fuel are generally preferred in order to decrease the mass of the payload. A classical method to constrain maneuvers is mathematically modeling them using the Two Point Boundary Value Problem (TPBVP), defining spacecraft positions at the start and end of the trajectory. Solutions to this problem can then be obtained with optimization techniques like the nonlinear least squares conjugated with the Theory of Functional Connections (TFC) to embed the constraints, which recently became an effective method for deducing orbit transfers. In this paper, we propose a tangential velocity (TV) type of constraints to design orbital maneuvers. We show that the technique presented in this paper can be used to transfer a spacecraft (e.g. from the Earth to the Moon) and perform gravity assist maneuvers (e.g. a swing-by with the Moon). In comparison with the TPBVP, solving the TV constraints via TFC offers several advantages, leading to a significant reduction in computational time. Hence, it proves to be an efficient technique to design these maneuvers.

Prioritizing pharmaceutically active compounds (PhACs) based on occurrence-persistency-mobility-toxicity (OPMT) criteria: an application to the Brazilian scenario.

A study of Quantitative Structure Activity Relationship (QSAR) was performed to assess the possible adverse effects of 25 pharmaceuticals commonly found in the Brazilian water compartments and to establish a ranking of environmental concern. The occurrence (O), the persistence (P), the mobility (M), and the toxicity (T) of these compounds in the Brazilian drinking water reservoirs were evaluated. Moreover, to verify the predicted OPMT dataset outcomes, a quality index (QI) was also developed and applied. The main results showed that: (i) after in silico predictions through VEGA QSAR, 19 from 25 pharmaceuticals consumed in Brazil were classified as persistent; (ii) moreover, after in silico predictions through OPERA QSAR, 15 among those 19 compounds considered persistent, were also classified as mobile or very mobile. On the other hand, the results of toxicity indicate that only 9 pharmaceuticals were classified with the highest toxicity level. Ultimately, the QI of 7 from 25 pharmaceuticals were categorized as 'optimal'; 15 pharmaceuticals were categorized as 'good'; and only 3 pharmaceuticals were categorized as 'regular'. Therefore, based on the QI criteria used, it is possible to assume that this OPMT prediction dataset had a good reliability. Efforts to reduce emissions of OPMT-pharmaceuticals in Brazilian drinking water reservoirs are encouraged.

Design of experiment (DoE) as a quality by design (QbD) tool to optimise formulations of lipid nanoparticles for nose-to-brain drug delivery.

INTRODUCTION: The nose-to-brain route has been widely investigated to improve drug targeting to the central nervous system (CNS), where lipid nanoparticles (solid lipid nanoparticles - SLN and nanostructured lipid carriers - NLC) seem promising, although they should meet specific criteria of particle size (PS) <200 nm, polydispersity index (PDI) <0.3, zeta potential (ZP) ~|20| mV and encapsulation efficiency (EE) >80%. To optimize SLN and NLC formulations, design of experiment (DoE) has been recommended as a quality by design (QbD) tool. AREAS COVERED: This review presents recently published work on the optimization of SLN and NLC formulations for nose-to-brain drug delivery. The impact of different factors (or independent variables) on responses (or dependent variables) is critically analyzed. EXPERT OPINION: Different DoEs have been used to optimize SLN and NLC formulations for nose-brain drug delivery, and the independent variables lipid and surfactant concentration and sonication time had the greatest impact on the dependent variables PS, EE, and PDI. Exploring different DoE approaches is important to gain a deeper understanding of the factors that affect successful optimization of SLN and NLC and to facilitate future work improving machine learning techniques.

Anatomical variations in the relationship between the spinal accessory nerve and internal jugular vein: a systematic review and meta-analysis.

The relationship between the spinal accessory nerve and internal jugular vein is important for modified neck dissection surgery. Therefore, the aim of this review was to investigate variations in this relationship. Through a search of the PubMed, Scopus, Web of Science, LILACS, and SciELO databases, the review authors collected anatomical data for inclusion in a meta-analysis, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Four relationship patterns were identified and classified: type 1, the nerve lies superficial to the vein; type 2, the nerve lies deep to the vein; type 3, the nerve crosses the branches of the vein; type 4, the nerve splits and its branches pass around the vein. The last pattern was not included in the meta-analysis. Eighteen studies were included (useful sample of 1491 hemi-necks). Type 1 variation had a prevalence of 79.7% (95% CI 77.6-81.7%), type 2 had a prevalence of 19.6% (95% CI 17.7-21.7%), and the type 3 had a prevalence of 0.7% (95% CI 0.0-1.4%). Significant differences were found among geographical subgroups. Normally, the spinal accessory nerve passes superficial to the internal jugular vein, but anatomical variations are common and there is a geographical influence. These findings are important for the safety of modified radical neck dissections.

Lipid nanoparticles strategies to modify pharmacokinetics of central nervous system targeting drugs: Crossing or circumventing the blood-brain barrier (BBB) to manage neurological disorders.

The main limitation to the success of central nervous system (CNS) therapies lies in the difficulty for drugs to cross the blood-brain barrier (BBB) and reach the brain. Regarding its structure and enzymatic complexity, crossing the BBB is a challenge, although several alternatives have been identified. For instance, the use of drugs encapsulated in lipid nanoparticles has been described as one of the most efficient approaches to bypass the BBB, as they allow the passage of drugs through this barrier, improving brain bioavailability. In particular, solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) have been a focus of research related to drug delivery to the brain. These systems provide protection of lipophilic drugs, improved delivery and bioavailability, having a major impact on treatments outcomes. In addition, the use of lipid nanoparticles administered via routes that transport drugs directly into the brain seems a promising solution to avoid the difficulties in crossing the BBB. For instance, the nose-to-brain route has gained considerable interest, as it has shown efficacy in 3D human nasal models and in animal models. This review addresses the state of the art on the use of lipid nanoparticles to modify the pharmacokinetics of drugs employed in the management of neurological disorders. A description of the structural components of the BBB, the role of the neurovascular unit and limitations for drugs to entry into the CNS is first addressed, along with the developments to increase drug delivery to the brain, with a special focus on lipid nanoparticles. In addition, the obstacle of BBB complexity in the creation of new effective drugs for the treatment of the most prevalent neurological disorders is also addressed. Finally, the proposed strategies for lipid nanoparticles to reach the CNS, crossing or circumventing the BBB, are described. Although promising results have been reported, especially with the nose-to-brain route, they are still ongoing to assess its real efficacy in vivo in the management of neurological disorders.

A new digital evaluation protocol applied in a retrospective analysis of periodontal plastic surgery of gingival recessions.

This research aimed to develop a new digital evaluation protocol to objectively quantify the volumetric changes of root coverage periodontal plastic surgery when combined with connective tissue graft. Consecutive patients with Cairo recession type 1 (RT1) or Cairo recession type 2 (RT2) were treated. Accurate study models obtained at baseline and follow-ups were optically scanned. Healing dynamics were measured by calculating volume differences between time points. Nineteen patients were treated between December 2014 and January 2019. At 3-month follow-up, root coverage was 95.6% (± 14.5%) with tunnel and connective tissue graft (TUN + CTG) technique, and 88.9% (± 20.5%) with the vestibular incision subperiosteal tunnel access and connective tissue graft (VISTA + CTG) technique. Recession decreased 1.33 (± 0.86) mm and 1.42 (± 0.92) mm, respectively (p = 0.337). At 6-month follow-up, root coverage was 96.5% (± 10.4%) with the TUN + CTG and 93.9% (± 10.3%) with the VISTA + CTG. Recession decreased 1.35 (± 0.85) mm and 1.45 (± 0.82) mm, respectively (p = 0.455). Complete root coverage was achieved in 86.7% (± 0.4%) with TUN + CTG and 70.6% (± 0.5%) with VISTA + CTG. No statistically significant differences were found between techniques. The digital protocol presented proved to be a non-invasive technique for accurate measurements of clinical outcomes. Both techniques reduce gingival recessions, with no statistically significant differences.

Effect of bone loss on the fracture resistance of narrow dental implants after implantoplasty. An in vitro study.

BACKGROUND: Implantoplasty (IP) involves polishing of the exposed surface of implants affected by peri-implantitis (PI). A study was made to determine whether the degree of bone loss influences the fracture resistance of implants with or without IP. MATERIAL AND METHODS: An in vitro study was carried out on 32 narrow (3.5 mm) dental implants with a rough surface and external hexagonal connection. Implantoplasty was performed in half of the implants of the sample. Both the IP and control implants were divided into two subgroups according to the amount of bone loss (3 mm or 7.5 mm). Standardized radiographic assessment of implant width was performed using specific software. The main outcome variable was the maximum compression force (Fmax) of implants when subjected to static resistance to fracture tests. Implant fractures were subsequently analyzed by scanning electron microscopy. A descriptive and bivariate analysis of the data was performed. RESULTS: Significant changes in implant width were observed after IP (p<0.05). No significant differences between IP and control implants were recorded in terms of the Fmax values in the two bone loss subgroups (3 mm: control 854.37N 195.08 vs. IP 752.12N 186.13; p=0.302, and 7.5 mm: control 548.82N 80.02 vs. IP 593.69N 111.07; p=0.370). Greater bone loss was associated to a decrease in Fmax, which proved significant for the control implants (p=0.001). Fractures were more frequently located in the platform (n=13). CONCLUSIONS: Implants with more apical bone levels appear to be more susceptible to fracture. On the other hand, IP does not seem to significantly decrease the fracture resistance of narrow (3.5 mm) platform dental implants with external hexagonal connections. The fact that most fractures occur in the platform area indicates that the latter is exposed to more mechanical stress.

The role of feedback projections in feature tuning and neuronal excitability in the early primate visual system.

A general assumption in visual neuroscience is that basic receptive field properties such as orientation and direction selectivity are constructed within intrinsic neuronal circuits and feedforward projections. In addition, it is assumed that general neuronal excitability and responsiveness in early visual areas is to a great extent independent of feedback input originating in areas higher in the stream. Here, we review the contribution of feedback projections from MT, V4 and pulvinar to the receptive field properties of V2 neurons in the anesthetized and paralyzed monkey. Importantly, our results contradict both of these assumptions. We separately inactivated each of these three brain regions using GABA pressure injections, while simultaneously recording V2 single unit activity before and hours after inactivation. Recordings and GABA injections were carried out in topographically corresponding regions of the visual field. We outline the changes in V2 activity, responsiveness and receptive field properties for early, mid and late post-injection phases. Immediately after injection, V2 activity is globally suppressed. Subsequently, there is an increase in stimulus-driven relative to spontaneous neuronal activity, which improves the signal-to-noise coding for the oriented moving bars. Notably, V2 tuning properties change substantially relative to its pre-injection selectivity profile. The resulting increase or decrease in selectivity could not be readily predicted based on the selectivity profile of the inactivated site. Finally, V2 activity rebounds before returning to it pre-injection profile Our results show that feedback projections profoundly impact neuronal circuits in early visual areas, and may have been heretofore largely underestimated in their physiological role.

TB management in the European Union/European Economic Area: a multi-centre survey.

BACKGROUND: Essential TB care in the European Union/European Economic Area (EU/EEA) comprises 21 standards for the diagnosis, treatment and prevention of TB that constitute the European Union Standards for Tuberculosis Care (ESTC).METHODS: In 2017, we conducted an audit on TB management and infection control measures against the ESTC standards. TB reference centres in five EU/EEA countries were purposely selected to represent the heterogeneous European TB burden and examine geographic variability.RESULTS: Data from 122 patients, diagnosed between 2012 and 2015 with multidrug-resistant TB (n = 49), extensively drug-resistant TB (XDR-TB) (n = 11), pre-XDR-TB (n = 29) and drug-susceptible TB (n = 33), showed that TB diagnosis and treatment practices were in general in agreement with the ESTC.CONCLUSION: Overall, TB management and infection control practices were in agreement with the ESTC in the selected EU/EEA reference centres. Areas for improvement include strengthening of integrated care services and further implementation of patient-centred approaches.

REALMS study: real-world effectiveness and safety of fingolimod in patients with relapsing-remitting multiple sclerosis in Portugal.

BACKGROUND: Fingolimod, an oral sphingosine 1-phosphate receptor modulator, is approved by EMA for relapsing-remitting multiple sclerosis (RRMS). OBJECTIVES: To assess the effectiveness and safety of fingolimod in patients with RRMS in real-world clinical practice in Portugal. METHODS: Retrospective, multicentre, non-interventional study, reporting 3 years follow-up of data collected from October 2015 to July 2016. Sociodemographic data and previous treatments at baseline and data regarding disease evolution, including number of relapses, annualised relapse rates (ARR) and Expanded Disability Status Scale (EDSS), were collected. RESULTS: Two-hundred and seventy-five participants were enrolled in the REALMS study. Results showed that the main reason to switch to fingolimod was failure of previous treatment (56.7%) and only 3.6% were naïve patients. In the total population, there was a significant decrease in ARR of 64.6% in the first year of treatment, 79.7% in the second year and 82.3% in the third year, compared with baseline. More than 67.0% of patients had no relapses during the 3 years after switching to fingolimod. EDSS remained stable throughout the study. CONCLUSIONS: Therapy with fingolimod showed a sustained effectiveness and safety over the 3 years, particularly on patients switched from first-line drugs (BRACE). No new safety issues were reported.

Acute and chronic effects of environmental realistic concentrations of simvastatin in danio rerio: evidences of oxidative alterations and endocrine disruptive activity.

Due to their wide use, pharmaceuticals can be discarded, metabolized and excreted into the environment, potentially affecting aquatic organisms. Lipid-regulating drugs are among the most prescribed medications around the world, to control human cholesterol levels, in more than 20 million patients. Despite this massive use of lipid-regulating drugs, particularly simvastatin, the role of these drugs is not fully characterized and understood in terms of its potential toxicological effects at the environmental level. This work intended to characterize the toxicity of an acute (120 h post-fertilization) and chronic (60 days) exposure to the antihyperlipidemic drug simvastatin (in concentrations of 92.45, 184.9, 369.8, 739.6 and 1479.2 ng L-1), in the freshwater species zebrafish (Danio rerio). The concentrations hereby mentioned were implemented in both exposures, and were based on levels found in wastewater treatment plant influents (11.7 ± 3.2 µg L-1), effluents (2.65 ± 0.8 µg L-1) and Apies River (1.585 ± 0.3 µg L-1), located in Pretoria, South Africa and, particularly in the maximum levels found in effluents from wastewater treatment plants in Portugal (369.8 ng L-1). The acute effects were analysed focusing on behavioural endpoints (erratic and purposeful swimming), total distance travelled and swimming time), biomarkers of oxidative stress (the activities of the enzymes superoxide dismutase, catalase, glutathione peroxidase), biotransformation (the activity of glutathione S-transferases) and lipid peroxidation (levels of thiobarbituric acid reactive substances). Animals chronically exposed were also histologically analysed for sex determination and gonadal developmental stages identification. In terms of acute exposure, significant alterations were reported in terms of behavioural alterations (hyperactivity), followed by a general reduction in all tested biomarkers. Also, the analysis of chronically exposed fish evidenced no alterations in sex ratio and maturation stages. In addition, the analysis of chronically exposed fish evidenced no alterations in terms of sexual characteristics, suggesting that the chronic exposure of Danio rerio to simvastatin does not alter the sex ratio and maturation stages of individuals. This assumption suggests that simvastatin did not act as an endocrine disruptor. Moreover, the metabolism, neuronal interactions and the antioxidant properties of SIM seem to have modulated the hereby-mentioned results of toxicity. Results from this assay allow inferring that simvastatin can have an ecologically relevant impact in living organisms.

Completeness of TB notification in Portugal, 2015: an inventory and capture-recapture study.

BACKGROUND: Despite the steady decline in the last few decades, Portugal remains the Western European country with the highest TB notification rates. The aim of this study was to estimate the completeness of notification to the National Tuberculosis Programme (NTP) Surveillance System (SVIG-TB) in 2015.METHODS: We implemented an inventory study and a three-source log-linear capture-recapture analysis using two additional data sources that were deterministic and probabilistically linked: the national notifiable diseases surveillance system (Sistema Nacional de Vigilância Epidemiológica SINAVE) and the national hospital discharge database (Grupos de Diagnósticos Homogéneos GDH).RESULTS: We identified 2328 unique probable/confirmed TB cases across the three data sources. We found a positive dependency between SVIG-TB and SINAVE (incidence rate ratio IRR 8.9, 95%CI 6.6-12.0) and between GDH and SINAVE (IRR 2.6, 95%CI 2.0-3.4). After adjusting for these dependencies, we estimated that 266 cases (95%CI 198-358) were not reported, indicating a notification (to SVIG-TB) completeness rate of 77.0%.CONCLUSION: True incidence rate of TB in Portugal in 2015 could have been as high as 26.1 per 100 000. This could be an overestimation because of false-positive cases recorded in both SINAVE and GDH or on a smaller scale, false non-matches. Studies aimed at validating potentially false-positive cases should be implemented to address these limitations.

Acute and chronic effects of environmental realistic concentrations of clofibric acid in Danio rerio: Behaviour, oxidative stress, biotransformation and lipid peroxidation endpoints.

Due to their widespread use, pharmaceuticals can be metabolized, excreted and ultimately discarded in the environment, thereby affecting aquatic organisms. Lipid-regulating drugs are among the most prescribed medications around the world, controlling human cholesterol levels, in more than 20 million patients. Despite this growing use of lipid-regulating drugs, particularly those whose active metabolite is clofibric acid, the potential toxicological effects of these pharmaceuticals in the environment is not fully characterized. This work intended to characterize the toxicity of an acute (120 hours post-fertilization) and chronic (60 days post-fertilization) exposures to clofibric acid in concentrations of 10.35, 20.7, 41.4, 82.8, and 165.6 µg L-1 in zebrafish (Danio rerio). The concentrations which were implemented in both exposures were based on predicted environmental concentrations for Portuguese surface waters. The acute effects were analysed focusing on behavioural endpoints (small and large distance travelled, swimming time and total distance travelled), biomarkers of oxidative stress (activity of the enzymes superoxide dismutase, Cu/Zn- and Mn SOD; catalase, CAT; glutathione peroxidase, Se- and total GPx), biotransformation (activity of glutathione S-transferases, GSTs) and lipid peroxidation (thiobarbituric acid reactive substances, TBARS). Chronically exposed individuals were also histologically analysed for sex determination and gonadal developmental stages. In terms of acute exposure, significant alterations were reported, in terms of behavioural alterations (hypoactivity), followed by an overall increase in all tested biomarkers. Chronically exposed organisms did not show alterations in terms of sex ratio and maturation stages, suggesting that clofibric acid did not act as an endocrine disruptor. Moreover, the metabolism of clofibric acid resulted in increased levels of both forms of SOD activity, especially for animals exposed to higher levels of this drug. An increase of CAT activity was observed in fish exposed to low levels, and a decrease in those exposed to higher amounts of clofibric acid. Both GPx forms had their activities increased. The enzyme of biotransformation GSTs were increased at low levels of clofibric acid but inhibited at higher amounts of this substance. Lipid peroxidation levels were also changed, with an induction of this parameter with increasing amounts of clofibric acid. Changes also occurred in behavioural endpoints and patterns for control organisms and for those exposed to clofibric acid were significantly distinct, for all types (light and darkness) of exposure, and for the two analysed endpoints (small and large distance). Results from this assay allow inferring that clofibric acid can have an ecologically relevant impact in living organisms exposed to this substance, with putative effects on the metabolism of individuals, affecting their behaviour and ultimately their survival.

Pessaries containing nanostructured lipid carriers (NLC) for prolonged vaginal delivery of progesterone.

Progesterone (PRG) plays a crucial role in the female reproductive system, being the vaginal route the most adequate for its administration, as this drug has an extensive hepatic first pass effect. Nonetheless, vaginal PRG dosage forms originate immediate drug release and requires repeated administrations, which is unpleasant. Thereby, it is necessary to develop alternative delivery systems for prolonged vaginal release of PRG. The objective of this work was the development of pessaries for the prolonged vaginal delivery of PRG. Studies began with the preparation of an aqueous dispersion of PRG-loaded NLC (NLC_PRG), followed by the evaluation of its biocompatibility in human immortalized keratinocytes (HaCat cells), using three different methods (neutral red uptake, resazurin reduction and sulforhodamine B assays). Finally, the NLC_PRG was incorporated into pessaries, which were further characterized according to the European Pharmacopoeia to assess their suitability to prolong PRG release through the vaginal route. The results showed that, after preparation, 90% of the NLC_PRG had sizes equal or lower than 315.60 ± 0.01 nm, and an EE of 96.42 ± 0.00%. All the assays used to assess the biocompatibility of NLC_PRG showed the absence of cytotoxicity towards HaCaT cells for concentrations up to 10 µg/mL. In all cytotoxicity assays, a cytotoxic effect was only observed for concentrations equal or higher than 25 µg/mL, which provides high confidence in the obtained results. The outcomes of this study suggest the suitability of using pessaries containing PRG-loaded NLC for sustained drug release, which is an innovative therapeutic strategy and constitutes a promising alternative for the vaginal use of PRG. However, further ex vivo and in vivo studies are needed to fully clarify the pharmacokinetic and toxicological profile before reaching the clinical use.

Photochemical mechanism of DEACM uncaging: a combined time-resolved spectroscopic and computational study.

The elementary steps of photocleavage in (coumarin-4-yl)methyl photoremovable protecting groups (PPGs) are elucidated by a combined electronic structure and time-resolved visible pump infrared probe (VIS-pump IR-probe) spectroscopic study. We specifically focus on the [7-(diethylamino)coumarin-4-yl]methyl (DEACM) PPG which has found increasing interest in biological applications over recent years. A series of leaving groups (LGs) are investigated, including azide (DEACM-N3), thiocyanate (DEACM-SCN), carbonate (DEACM-Carb), and a thymine nucleobase (DEACM-T) representing a model system for caged DNA. These systems are found to exhibit vastly different photocleavage time scales, ranging from the subpicosecond scale in the case of DEACM-SCN to ∼35 picoseconds in the case of DEACM-N3 and ∼540 picoseconds in the case of DEACM-Carb. In the case of DEACM-SCN, the appearance of the product is biphasic, with a fast (