Prolonged-release pirfenidone in patients with pulmonary fibrosis as a phenotype of post-acute sequelae of COVID-19 pneumonia. Safety and efficacy.

INTRODUCTION: One of the major concerns with post-acute sequelae of COVID-19 (PASC) is the development of pulmonary fibrosis, for which no approved pharmacological treatment exists. Therefore, the primary aim of this open-label study was to evaluate the safety and the potential clinical efficacy of a prolonged-release pirfenidone formulation (PR-PFD) in patients having PASC-pulmonary fibrosis. METHODS: Patients with PASC-pulmonary fibrosis received PR-PFD 1800 mg/day (1200 mg in the morning after breakfast and 600 mg in the evening after dinner) for three months. Blood samples were taken to confirm the pharmacokinetics of PR-PFD, and adverse events (AEs) were evaluated monthly using a short questionnaire. Symptoms, dyspnea, and pulmonary function tests (spirometry, diffusing capacity for carbon monoxide, plethysmography, and 6-min walk test [6MWT]) were evaluated at baseline, and one and three months after having started the PR-PFD treatment. RESULTS: Seventy subjects with mild to moderate lung restriction were included. The most common AEs were diarrhea (23%), heartburn (23%), and headache (16%), for which no modifications in the drug study were needed. Two patients died within the first 30 days of enrolment, and three opted not to continue the study, events which were not associate with PR-PFD. Pulmonary function testing, 6MWT, dyspnea, symptoms, and CT scan significantly improved after three months of treatment with PR-PFD. CONCLUSION: In patients with PASC pulmonary fibrosis, three months' treatment with PR-PFD was safe and showed therapeutic efficacy. Still, it remains to be seen whether the pulmonary fibrotic process remains stable, becomes progressive or will improve.

Using two dyes to observe the competition of Ca2+ trapping mechanisms and their effect on intracellular Ca2+ signals.

The specificity and universality of intracellular [Formula: see text] signals rely on the variety of spatio-temporal patterns that the [Formula: see text] concentration can display. [Formula: see text] liberation through inositol 1,4,5-trisphosphate receptors ([Formula: see text]) is key for this variety. In this paper, we study how the competition between buffers of different kinetics affects [Formula: see text] signals that involve [Formula: see text] release through [Formula: see text]. The study also provides insight into the underlying spatial distribution of the channels that participate in the signals. Previous works on the effects of [Formula: see text] buffers have drawn conclusions 'indirectly' by observing the [Formula: see text]-bound dye distributions in the presence of varying concentrations of exogenous buffers and using simulations to interpret the results. In this paper, we make visible the invisible by observing the signals simultaneously with two dyes, [Formula: see text] and [Formula: see text], each of which plays the role of a slow or fast [Formula: see text] buffer, respectively. Our observations obtained for different concentrations of [Formula: see text] highlight the dual role that fast buffers exert on the dynamics, either reducing the intracluster channel coupling or preventing channel inhibition and allowing the occurrence of relatively long cycles of [Formula: see text] release. Our experiments also show that signals with relatively high [Formula: see text] release rates remain localized in the presence of large [Formula: see text] concentrations, while the mean speed of the elicited waves increases. We interpret this as a consequence of the more effective uncoupling between [Formula: see text] clusters as the slow dye concentration increases. Combining the analysis of the experiments with numerical simulations, we also conclude that [Formula: see text] release not only occurs within the close vicinity of the centers of the clearly identifiable release sites ([Formula: see text] clusters) but there are also functional [Formula: see text] in between them.

Magnitude and frequency variations of vector-borne infection outbreaks using the Ross-Macdonald model: explaining and predicting outbreaks of dengue fever.

The classical Ross-Macdonald model is often utilized to model vector-borne infections; however, this model fails on several fronts. First, using measured (or estimated) parameters, which values are accepted from the literature, the model predicts a much greater number of cases than what is usually observed. Second, the model predicts a single large outbreak that is followed by decades of much smaller outbreaks, which is not consistent with what is observed. Usually towns or cities report a number of recurrences for many years, even when environmental changes cannot explain the disappearance of the infection between the peaks. In this paper, we continue to examine the pitfalls in modelling this class of infections, and explain that, if properly used, the Ross-Macdonald model works and can be used to understand the patterns of epidemics and even, to some extent, be used to make predictions. We model several outbreaks of dengue fever and show that the variable pattern of yearly recurrence (or its absence) can be understood and explained by a simple Ross-Macdonald model modified to take into account human movement across a range of neighbourhoods within a city. In addition, we analyse the effect of seasonal variations in the parameters that determine the number, longevity and biting behaviour of mosquitoes. Based on the size of the first outbreak, we show that it is possible to estimate the proportion of the remaining susceptible individuals and to predict the likelihood and magnitude of the eventual subsequent outbreaks. This approach is described based on actual dengue outbreaks with different recurrence patterns from some Brazilian regions.

Interpretations and pitfalls in modelling vector-transmitted infections.

In this paper we propose a debate on the role of mathematical models in evaluating control strategies for vector-borne infections. Mathematical models must have their complexity adjusted to their goals, and we have basically two classes of models. At one extreme we have models that are intended to check if our intuition about why a certain phenomenon occurs is correct. At the other extreme, we have models whose goals are to predict future outcomes. These models are necessarily very complex. There are models in between these classes. Here we examine two models, one of each class and study the possible pitfalls that may be incurred. We begin by showing how to simplify the description of a complicated model for a vector-borne infection. Next, we examine one example found in a recent paper that illustrates the dangers of basing control strategies on models without considering their limitations. The model in this paper is of the second class. Following this, we review an interesting paper (a model of the first class) that contains some biological assumptions that are inappropriate for dengue but may apply to other vector-borne infections. In conclusion, we list some misgivings about modelling presented in this paper for debate.

Pregnancy and kidney transplantation, triple hazard? Current concepts and algorithm for approach of preconception and perinatal care of the patient with kidney transplantation.

INTRODUCTION: Kidney transplantation (KT) increases fertility in patients with chronic kidney disease (CKD); their pregnancies are considered of high risk because of higher incidence of complications. The objective of this study was to propose, based on current concepts, an algorithm for preconception and perinatal care of KT recipients with a desire for parity. MATERIALS AND METHODS: We searched for literature published within the last 10 years related to pregnancy and KT. Based on the results, we developed an algorithm for the approach to preconception/perinatal care of these patients. RESULTS: Preconception care begins with pre-KT study of women of childbearing age, continues with contraception, and ends with the proper selection of candidates; an exhaustive study of health condition, function of renal graft, and infections that may affect the fetus is required; fetotoxic drugs must be suspended, immunosuppression must be based in corticosteroids, azathioprine, and tacrolimus or cyclosporine. Once conception is achieved, prenatal care should be done by a multidisciplinary team; follow-up of graft function and maternal-fetal health must be strict. Pregnancy has no deleterious effect on graft function; pelvic localization of graft does not contraindicate vaginal delivery; breastfeeding is indicated if immunosuppressive levels in the newborn are low. CONCLUSIONS: KT returns the possibility of motherhood to women with CKD. Proper selection and optimal care of patients determines success in maternal, fetal, and graft results.

Growth, chronic kidney disease and pediatric kidney transplantation: is it useful to use recombinant growth hormone in Colombian children with renal transplant?

Kidney transplantation has become the best treatment for children with chronic kidney disease (CKD). In recent times, knowledge concerning the effect of CKD and kidney transplantation over the normal growth rate has increased; now it is known that 40% of children with CKD do not reach the expected height for age. Growth retardation has been associated with the type of nephropathy, metabolic and endocrine disorders that are secondary to kidney disease, immunosuppressive therapy with glucocorticoids, and suboptimal function of renal allograft. Nowadays, we know better the role of the growth hormone/insulin-like growth factor 1 axis in growth retardation we can see it in children with CKD or recipients of renal allograft. Several studies have shown that administration of recombinant growth hormone (rhGH) has a positive effect on the longitudinal growth of children and teenagers who have received a kidney transplant. On the other hand, there have been reported side effects associated with using rhGH; however, these are not statistically significant. In this article, we show a small review about growth in children with CKD and/or recipients of renal allografts the growth pattern of three children who were known by the Transplant Group of National University of Colombia, and the results obtained with the use of rhGH in one of these cases. We want to show the possibility of achieving a secure use of rhGH in children with CKD and its use as a therapeutic option for treating the growth retardation in children with kidney transplantation, and set out the need of typifying the growth pattern of Colombian children with CKD and/or who are recipients of renal allografts through multicenter studies to propose and analyze the inclusion of rhGH in the therapeutic scheme of Colombian children with these two medical conditions. rhGH could be a useful tool for treating children with CKD or kidney transplantation who have not reached the expected longitudinal growth for age. However, it is necessary to know the growth pattern standards for Colombian children with CKD or kidney transplant in Bogotá-Colombia to include the rhGH in clinical protocols for treatment of these patients.

Modelling the control strategies against dengue in Singapore.

Notified cases of dengue infections in Singapore reached historical highs in 2004 (9459 cases) and 2005 (13,817 cases) and the reason for such an increase is still to be established. We apply a mathematical model for dengue infection that takes into account the seasonal variation in incidence, characteristic of dengue fever, and which mimics the 2004-2005 epidemics in Singapore. We simulated a set of possible control strategies and confirmed the intuitive belief that killing adult mosquitoes is the most effective strategy to control an ongoing epidemic. On the other hand, the control of immature forms was very efficient in preventing the resurgence of dengue epidemics. Since the control of immature forms allows the reduction of adulticide, it seems that the best strategy is to combine both adulticide and larvicide control measures during an outbreak, followed by the maintenance of larvicide methods after the epidemic has subsided. In addition, the model showed that the mixed strategy of adulticide and larvicide methods introduced by the government seems to be very effective in reducing the number of cases in the first weeks after the start of control.

Threshold conditions for a non-autonomous epidemic system describing the population dynamics of dengue.

A non-autonomous dynamical system, in which the seasonal variation of a mosquito vector population is modeled, is proposed to investigate dengue overwintering. A time-dependent threshold, R(t), is deduced such that when its yearly average, denoted by R, is less than 1, the disease does not invade the populations and when R is greater than 1 it does. By not invading the population we mean that the number of infected individuals always decrease in subsequent seasons of transmission. Using the same threshold, all the qualitative features of the resulting epidemic can be understood. Our model suggests that trans-ovarial infection in the mosquitoes facilitates dengue overwintering. We also explain the delay between the peak in the mosquitoes population and the peak in dengue cases.

The impact of imperfect vaccines on the evolution of HIV virulence.

A theoretical framework is proposed on which some hypotheses related to the impact of imperfect vaccines on the evolution of HIV virulence can be tested. For this, a linear increase of risk behaviour with vaccine efficacy is assumed. This is based on the hypothesis that people are prone to relax preventive measures by knowing that they and their partners are vaccinated and that this effect is more intense the more effective the vaccine is known to be. An additional, and perhaps more important hypothesis is related to the theoretical possibility that increased risk behaviour of some vaccinated individuals in partially protected populations could act as a selective pressure toward more virulent HIV strains. Those hypotheses were tested by a mathematical model that considers three different HIV strains competing against each other in a population partially protected by imperfect vaccines of distinct efficacies. Simulations of the model demonstrated that, under the above hypotheses, there is a shift in HIV virulence towards more aggressive strains with increase in vaccine efficacy, associated with a marked reduction in the total amount of transmission and, consequently, in the prevalence of HIV. Potential ways for further testing the theory/model and the implications of the results are discussed.

The Eyam plague revisited: did the village isolation change transmission from fleas to pulmonary?

Back in the 17th century the Derbyshire village of Eyam fell victim to the Black Death, which is thought to have arrived from London in some old clothes brought by a travelling tailor. The village population was 350 at the commencement of plague, of which only 83 survived. Led by the church leaders, the village community realized that the whole surrounding region was at risk from the epidemic, and therefore decided to seal themselves off from the other surrounding villages. In the first 275 days of the outbreak, transmission was predominantly from infected fleas to susceptible humans. From then onward, mortality sharply increased, which indicates a changing in transmission pattern. We hypothesize that the confinement facilitated the spread of the infection by increasing the contact rate through direct transmission among humans. This would be more consistent with pulmonary plague, a deadlier form of the disease. In order to test the above hypothesis we designed a mathematical model for plague dynamics, incorporating both the indirect (fleas-rats-humans) and direct (human-to-human) transmissions of the infection. Our results show remarkable agreement between data and the model, lending support to our hypotheses. The Eyam plague episode is celebrated as a remarkable act of collective self-sacrifice. However, to the best of our knowledge, there were no evidence before that the confinement actually increased the burden payed by the commoners. In the light of our results, it can be said that the hypothesis that confinement facilitated the spread of the infection by increasing the contact rate through direct transmission is plausible.

Asymptomatic true gallbladder duplication: a case report and review of the literature.

Gallbladder duplication is a rare event, with an incidence at autopsy of about 1/4000, with very few documented symptomatic cases reported. Preoperative diagnosis and differentiation of this malformation are important to prevent inadvertent damage to the biliary system, a complicated postoperative course, and repeat surgery. We present a case of true gallbladder duplication found incidentally during abdominal ultrasonography (US). The diagnosis was made with US and the Y-type duplication was demonstrated with magnetic resonance cholangiopancreatography (MRCP).

[Pulmonary thromboembolism associated with glioblastoma multiforme: imaging diagnosis of a case and a review of the literature]. / Tromboembolia pulmonar asociada a glioblastoma multiforme: diagnóstico por imagen de un caso y revisión de la bibliografía.

INTRODUCTION: The incidence of deep vein thrombosis and pulmonary embolism in patients with cerebral neoplasia has been estimated at 120/100,000 (the second highest rate for any kind of malignant neoplasia). A timely diagnosis is an indispensable requisite in the clinical evaluation of neurological patients. Patients suffering from glioblastoma multiforme present a generalized state of hypercoagulability with a deep vein thrombosis incidence after surgery of between 3 and 60%. The incidence with which pulmonary embolism occurs is 5% in patients following neurosurgical operations, with a mortality rate of between 9 and 50%. CASE REPORT: We report the case of a 64 year old male patient with a suspected diagnosis of pulmonary thromboembolism and thrombosis of the right lower limb. Clinical studies included a simple chest X ray, a Doppler ultrasound recording of the lower limbs, a spiral computed tomography (CAT) scan of the thorax, and a magnetic resonance (MR) scan of the head. The spiral CAT scan showed filling defects in the main pulmonary arteries, a tram track appearance and central filling defects. All these findings are compatible with an imaging diagnosis of pulmonary thromboembolism. CONCLUSIONS: The main aim of this study was to describe the use of spiral CAT scanning as a primary tool in the diagnosis of a case. The concurrence of the spiral scan image, the abnormal increase in D dimer and the clinical information left no doubts about the diagnosis. The clinical manifestations of pulmonary thromboembolism are not specific and therefore the patient s life is at risk. In addition, few reports have been published about the association between glioblastoma multiforme and the later appearance of pulmonary thromboembolism (a search was conducted in the medical literature from the last 10 years using MEDLINE), and hence we have presented a communication dealing with this pathological association together with a brief review of the clinical diagnosis of pulmonary thromboembolism and its physiopathogenic mechanisms.

Vaccination against rubella: analysis of the temporal evolution of the age-dependent force of infection and the effects of different contact patterns.

In this paper, we analyze the temporal evolution of the age-dependent force of infection and incidence of rubella, after the introduction of a very specific vaccination program in a previously nonvaccinated population where rubella was in endemic steady state. We deduce an integral equation for the age-dependent force of infection, which depends on a number of parameters that can be estimated from the force of infection in a steady state prior to the vaccination program. We present the results of our simulations, which are compared with observed data. We also examine the influence of contact patterns among members of a community on the age-dependent intensity of transmission of rubella and on the results of vaccination strategies. As an example of the theory proposed, we calculate the effects of vaccination strategies for four communities from Caieiras (Brazil), Huixquilucan (Mexico), Finland, and the United Kingdom. The results for each community differ considerably according to the distinct intensity and pattern of transmission in the absence of vaccination. We conclude that this simple vaccination program is not very efficient (very slow) in the goal of eradicating the disease. This gives support to a mixed strategy, proposed by Massad et al., accepted and implemented by the government of the State of São Paulo, Brazil.

Modelling the natural history of HIV infection in individuals and its epidemiological implications.

The variation of viraemia in the natural course of HIV infection is expected to have major influence on the probability of transmission and, consequently, on the epidemiology of HIV/AIDS. In this paper we propose a model which takes into account the time evolution of HIV viraemia (measured as HIV-RNA copies per ml of blood) in an infected individual and its impact on the threshold for the establishment of an endemic level, and mainly on the relative contribution of each of the clinical phases of the infection to the total transmission of HIV per infected individual. We consider that an infected individual passes through three phases of viraemia. The first phase, which lasts for 6-7 weeks, is characterized by very high viraemia. In the second phase, which lasts about 10 years, the viraemia is much lower, increasing again in the last phase, which lasts up to two years, and ends in full-blown AIDS. We show that the relative contribution of each phase to the total transmission of HIV is very sensitive to the model we assume for the dependence of the transmissibility of HIV on the viral load. For instance, if we assume that transmissibility is proportional to the decimal logarithm of viraemia, then the second phase predominates always. Due to the epidemiological importance of this fact, it is clear that further improvement on virological research to better understand the dependence of HIV transmissibility on the viral concentration in biological fluids is necessary.

The risk of yellow fever in a dengue-infested area.

Yellow fever and dengue are viral infections that in urban centres are transmitted by the same arthropod vector, a mosquito of the genus Aedes. In order to estimate the risk of an epidemic of urban yellow fever in a dengue-infested area we calculated the threshold in the basic reproduction number, R0, of dengue, above which any single sylvatic yellow fever-infected individual will trigger an urban yellow fever epidemic. Specifically, we analysed the relationship between the extrinsic incubation period and the duration of viraemia, from which it is possible to define the R0 for dengue that would also suggest an outbreak potential for yellow fever. We also calculated the critical proportion of people to vaccinate against yellow fever in order to prevent an epidemic in a dengue-endemic area. The theory proposed is illustrated by the case of São Paulo State in southern Brazil, where dengue is endemic and the risk of urban yellow fever is already imminent.

Activation of mitochondrial oxidative phosphorylation during (+/-)-isoproterenol-induced cell injury of myocardium.

Hydrolytic and synthetic activities of mitochondrial ATPase were studied during (+/-)-isoproterenol-induced cell injury of the myocardium (67 mg/kg body weight). This research was a long-term study (72 h) in which rat heart homogenates, and a potentiometric method were used. Hydrolytic activities in homogenates from (+/-)-isoproterenol-treated rats were not statistically different, during the whole long-term study, from the hydrolytic activity in normal homogenates. The synthetic activity (mitochondrial oxidative phosphorylation) of mitochondrial ATPase increased at 3, 6, and 18 h (35, 48 and 23% respectively) after (+/-)-isoproterenol administration with regard to the control group. At 12 h and 21-72 h after drug administration, the data revealed no differences between synthetic activity of mitochondrial ATPase in control vs (+/-)-isoproterenol treated homogenates. The facts that synthetic and hydrolytic activities in homogenates from (+/-)-isoproterenol treated rats were never lower than the synthetic and hydrolytic activities in normal homogenates, and that activation of mitochondrial oxidative phosphorylation occurred at some times after (+/-)-isoproterenol treatment, suggest that no considerable and "negative" modifications occur in the active configuration of mitochondrial ATPase during (+/-)-isoproterenol-induced injury of the myocardium (67 mg/kg body weight).

A mixed ectoparasite--microparasite model for bat-transmitted rabies.

This paper considers the transmission of rabies to domestic livestock by vampire bats. Vampire bats act as ectoparasites on cattle both by ingesting a small amount of blood every night and by prolonging bleeding by the action of anticoagulant substances in their saliva. In addition to this parasitic action bats may also transmit rabies, inflicting important losses on affected herds by the inevitable mortality due to the infection. We modeled this complex interaction and we also demonstrate that bat control measures are more effective in reducing rabies prevalence and mortality by rabies than cattle vaccination.

Mitochondrial oligomycin-sensitive ATPase during isoproterenol-induced cell injury of myocardium.

The enzymatic activity of the mitochondrial oligomycin-sensitive ATPase was investigated during isoproterenol-induced cell injury of myocardium, using rat heart homogenates and a potentiometric method. The enzymatic activity of the oligomycin-sensitive ATPase and the inhibitory action of oligomycin do not show significant alterations upon treatment with isoproterenol. These results are inconsistent with the hypothesis that modifications in the active configuration of the mitochondrial ATPase take place during isoproterenol-induced injury of myocardium.