David Y. Zhang and Allen S. Anderson Heart failure (HF) is a syndrome characterized by upregulation of the sympathetic nervous system and abnormal responsiveness of the parasympathetic

nervous system. Studies in the 1980s and 1990s demonstrated that inhibition of the renin-angiotensin-aldosterone system with angiotensin-converting enzyme inhibitors improved symptoms and mortality in HF resulting from systolic dysfunction, thus providing a framework to consider the use of β-blockers for HF therapy, contrary to the prevailing wisdom of the time. Against this backdrop, this article reviews the contemporary understanding of the sympathetic nervous system and the failing heart. Maria Patarroyo-Aponte and Monica Colvin-Adams Heart failure is one of the most prevalent cardiovascular diseases in the United States, and is associated with significant morbidity, mortality, and costs. Prompt diagnosis may help decrease mortality, hospital R428 stay, and costs related to treatment. A complete heart failure evaluation comprises a comprehensive history and physical examination, echocardiogram, and diagnostic tools that provide information regarding the etiology of heart failure, related complications, and prognosis in order to prescribe appropriate therapy, monitor response to therapy, and transition expeditiously

to advanced Androgen Receptor Antagonist therapies when needed. Emerging technologies and biomarkers may provide better risk stratification and more accurate determination of cause and progression. Faiz Subzposh, Ashwani Gupta, Shelley R. Hankins,

and Howard J. Eisen Heart failure remains a major health problem in the United States, affecting 5.8 million Americans. Its prevalence continues to rise due to the improved survival of patients. Despite advances in treatment, morbidity and mortality remain very high, with a median survival of about 5 years after the first clinical symptoms. This article describes the causes, classification, and management goals of heart failure in Stages A and B. Sasikanth Adigopula, Rey P. Vivo, Eugene C. DePasquale, Ali Nsair, and Mario C. Deng ACC Stage C heart failure includes those patients with prior or current symptoms of heart failure in the context of an underlying structural heart problem second who are primarily managed with medical therapy. Although there is guideline-based medical therapy for those with heart failure with reduced ejection fraction (HFrEF), therapies in heart failure with preserved ejection fraction (HFpEF) have thus far proven elusive. Emerging therapies such as serelaxin are currently under investigation and may prove beneficial. The role of advanced surgical therapies, such as mechanical circulatory support, in this population is not well defined. Further investigation is warranted for these therapies in patients with Stage C heart failure. Michelle M.

Les effets secondaires des corticostéroïdes inhalés sont surtout locaux : candidoses, dysphonie. Toutefois, la possibilité d’effets généraux aux posologies recommandées dans la BPCO ne doit Selleckchem beta-catenin inhibitor pas être négligée.

Notamment, les corticoïdes inhalés augmentent le risque d’infections respiratoires basses, en particulier de pneumonies, sans conséquence sur la mortalité. Il est par ailleurs important de rappeler que la sévérité de l’obstruction bronchique et le tabagisme sont des facteurs indépendants de risques d’infections respiratoires basses et de pneumonies. Le risque de développer une pneumonie sous corticothérapie inhalée est plus élevé chez les patients dès l’âge de 55 ans, avec un VEMS inférieur à 50 % de la valeur théorique, une dyspnée de stade 3 et 4 (MMRC) et si l’IMC est inférieur à 25 kg/m2. La survenue d’une pneumonie chez un patient atteint de BPCO doit conduire à réévaluer la pertinence du traitement comportant un corticoïde inhalé [31], [32] and [33]. Une réduction de la densité osseuse voire une ostéoporose et une augmentation du risque de fracture ont été aussi suggérées. Ces données n’ont pas été confirmées dans l’étude TORCH sur trois ans de

suivi [34]. Un risque accru de fragilité cutanée est bien démontré [35]. Concernant le risque de cataracte, il serait essentiellement observé chez les patients traités par corticoïdes inhalés et recevant des cures de corticothérapie orale [36]. Il n’y a pas assez d’études comparatives pour préciser la place des associations fixes d’un corticoïde inhalé et d’un β2-adrénergique de longue durée ADAMTS5 PF-06463922 in vitro d’action par rapport à un anticholinergique de longue durée d’action, ou de l’association de deux bronchodilatateurs de longue durée d’action [37] and [38]. Force est donc d’en rester aux indications mentionnées précédemment (Tableau I, Tableau II and Tableau III). Enfin, les corticoïdes par voie générale au long cours ne sont pas recommandés dans les BPCO à l’état

stable et sont même contre-indiqués, notamment du fait des effets secondaires fréquents et majeurs. Il a ainsi été montré que la corticothérapie orale est associée à une réduction des bénéfices de la réhabilitation et à une surmortalité. Il existe peu de preuve que les dérivés xanthiques puissent modifier le cours de la maladie. Le mécanisme d’action pharmacologique de la théophylline reste à préciser aux concentrations d’intérêt thérapeutique. En effet, l’inhibition des phosphodiestérases classiquement mises en avant n’est obtenue qu’à des concentrations supra-thérapeutiques. Une théophylline, par voie orale à libération prolongée, peut être prescrite en deuxième intention si le patient a de réelles difficultés à utiliser les bronchodilatateurs inhalés ou si ces derniers améliorent insuffisamment la dyspnée après en avoir vérifié le bon usage. En effet, le rapport efficacité/tolérance de la théophylline est inférieur à celui des bronchodilatateurs inhalés.

6% with partial sight certification, 0% blind). Our study population was nearly 4 years older at the time of the last visit than that of Ang and Eke, and our follow-up time was also longer (11.2 vs 7.4 years). Both of these factors may contribute to higher numbers of visually disabled patients in Malmö. Goh and associates10 also found lower rates of visual disability, but defined low vision and blindness by VA alone, which leads to falsely

low rates. In accordance with findings in several other BKM120 studies,4, 8, 21 and 22 approximately 35% (33 of 97) of all blind patients would have been missed if impairment had been based on VA alone. Over the last 15 years some longitudinal studies have reported

rates of blindness caused by OAG at different points in time after diagnosis. Hattenhauer and associates4 found a 54% risk for unilateral blindness and a 22% risk for bilateral blindness after 20 years in treated patients Nintedanib with “classic glaucoma” (defined as patients with field loss). The estimated risks for blindness in 1 or both eyes 10 years after diagnosis were 26% and 7%, respectively. Kwon and associates5 reported a cumulative rate of unilateral blindness for glaucoma patients followed with Goldmann perimetry (40 patients) of 19% at 22 years. More recently, Chen3 analyzed 186 patients with open-angle glaucoma diagnosed in 1975 or later and found a 14.6% risk for unilateral blindness and a 6.4% risk for bilateral blindness after 15 years. Considering that improved methods both for diagnosis Bay 11-7085 and for treatment have certainly become available after the late 1970s, one would expect lower rates of low vision and blindness in our study compared to those of Hattenhauer and perhaps similar numbers to those of Chen. Instead, our results are similar to those found

in the Olmsted population4 when comparing our cumulative incidence rates calculated with the Kaplan-Meier method. On the other hand, impairment rates in the present study calculated by the competing risk method are approximately twice as high as those reported by Chen. One explanation is that we followed patients to death, in contrast to Chen. In our population blindness almost always occurred at high ages and only 13 patients became blind before 80 years of age. We also had a higher percentage of patients with exfoliative glaucoma in our study population (40.2%) than both Hattenhauer and associates (8.5%) and Chen (14 %), which could contribute to the high rates of blindness in our study. The mean duration of diagnosed disease of 11.2 years in the current study is similar to the estimate of 12.8 years reported in 1997 by Quigley and Vitale.11 Mean duration of blindness was only 3 years.

Data were missing for some variables in the cohort: maternal age (29.7%); gestational age (33.9%); and childhood vaccinations (21.1%). We carried out a complete case analysis and analysis that included the missing data as a separate category. The results were similar in both models so we have presented FK228 order the results with

missing data as a separate category. The analyses were restricted to cases with available social deprivation data based on the Townsend score for deprivation quintile [20], therefore excluded 12 women resident in Wales on 1st April 2012 for whom data on area of residence was missing. There were 33,601 women on the NHS AR for the study cohort and time period. Data were available for 30,882 women from the CSW and 24,351 women from the NCCHD (Fig. 1). 14,966/30,882 (48.5%) women had HPV partial or full vaccination and 14,164/30,882 (45.9%) women had attended for cervical screening. 2427/30,882 (7.9%) women had HPV partial vaccination and attended for cervical screening and 5579/30,882 (18.1%) women had HPV full vaccination and attended for cervical screening. Table 1 describes the characteristics of women according this website to HPV vaccine uptake. HPV vaccination status was defined as (i) full HPV vaccination with 3 or more recorded doses (n = 10,109/30,882; 32.7%); (ii) partial HPV vaccination with 1–2 doses (n = 4857/30,882; 15.7%); (iii) not HPV vaccinated

(n = 15,916/30,882; 51.5%). There was a statistically significant relationship between uptake of the HPV vaccine and social deprivation quintile (Table 1). Women from the most affluent quintile (Quintile 1) were more likely to have had partial (19.2%) or full (39.5%) HPV vaccination. Conversely women from the most deprived quintile (Quintile 5) had the highest number of women that had not been HPV vaccinated and the lowest number of women with reported partial and full HPV vaccination (59.2%, 14.4% and 26.3%, respectively). The highest proportion of women not vaccinated was observed for the groups with maternal age under 20 years and 20–24 years (55.4% and 48.7%, respectively) compared to groups whose mothers GBA3 were older and this was statistically significant (OR 0.62; 95% CI (0.56, 0.68) and OR 0.80; 95%

CI (0.75, 0.86), respectively). There was no clear relationship between gestational age and HPV vaccination. Table 2 describes the uptake of cervical screening according to characteristics of women. There was a significant relationship between uptake of cervical screening and social deprivation score. Women from the most deprived areas (Quintile 5) were less likely to have attended for cervical screening than women from the least deprived areas (Quintile 1) (41.3% compared to 50.1%, respectively; univariate OR 0.69; 95% CI (0.65, 0.75)). Women who were fully vaccinated were more likely to have attended for cervical screening than women who had not been vaccinated and this was statistically significant (55.2% compared to 38.7%, respectively, OR 0.

The authors would like to thank IFPMA IVS and EVM members for their input into this paper. The authors also wish to acknowledge the support provided by the IFPMA IVS and EVM secretariats, in particular Janis Bernat and Magdalena Rodriguez de Azero respectively. Finally, the authors acknowledge I-BET151 chemical structure Rob Budge for his assistance

with preparing the manuscript. “
“The HIV pandemic continues to be a major global health priority, and while there has been good progress in the development of antiretroviral drugs that have contributed to longer survival of infected individuals, prospects of an effective vaccine against HIV remain largely elusive [1] and [2]. Different strategies to induce effective immune responses to HIV have been attempted in both animal and human models but with little success and controversial results PI3K inhibitor [3] and [4], although some protective

responses have been reported [5] and [6]. A critical goal of HIV vaccination is the induction of mucosal humoral immune responses. This is predicated on the production of antibodies (Abs) with capacity of hindering the entrance of HIV and its subsequent interaction with target cells at mucosal sites either by viral neutralization, aggregation, or Fc receptor mediated mechanisms [7]. Because HIV antigens (Ags) alone induce very low if any immune responses, the use of adjuvants is of paramount importance. Adjuvants being molecules, compounds or macromolecular complexes that boost the potency and longevity of specific immune responses to Ag with little toxicity and long-lasting immune effects [8]. Biodegradable nanoparticles

(NP, <700 nm) have been studied extensively as vehicles for delivery of Ag to antigen presenting cells (APCs) making them good adjuvant candidates [9], [10], [11], [12], [13] and [14]. NP can enhance the effectiveness of Ag uptake, which then increases Ag delivery to intracellular compartments of APC such as dendritic cells (DCs) and macrophages tuclazepam [15]. Hence, NP may increase Ag presentation capacity, thus boosting cellular and humoral immune responses. The Ag delivery capacity of NP has been shown both in vitro and in vivo for a wide array of Ags such as tetanus toxoid [16], Neisseria meningitides [17], Bacillus anthracis [18], and HIV Ags [19], [20], [21] and [22]. These studies provide evidence that NP may be an important tool for Ag delivery and subsequent induction of cellular and humoral immune responses, critical for development of vaccines. However, success in the development of NP as delivery systems of vaccines has been previously hampered by their low level of colloidal stability and wide limitations in manufacturing scale-up. We have developed NP made of yellow carnauba (YC) wax with high colloidal stability, low cost and scalable manufacture that would provide a rapid product development pathway.

Dans les addictions avec substance, le topiramate a montré un intérêt principalement dans l’alcoolodépendance. Néanmoins, la fréquence des effets indésirables fait que ce médicament ne peut être utilisé en

première intention, mais après les traitements habituels. Il n’existe que peu d’études dans les autres addictions. La prudence est de mise pour les addictions pour lesquelles il n’existe pas de traitements validés, telles que la dépendance à la cocaïne et la dépendance à la méthamphétamine. Dans les addictions comportementales, le topiramate a montré un intérêt, principalement dans la boulimie et le binge eating disorder. Dans la boulimie, l’American Psychiatric Association (APA) a recommandé que le topiramate ne soit utilisé qu’en cas d’inefficacité des autres traitements en raison de ses effets indésirables fréquents. La tendance du topiramate à induire une selleckchem perte de poids a été relevée comme problématique chez les patients avec un poids normal ou inférieur à la normale (IMC < 20 kg/m2) [69]. Dans le futur, la réalisation d’essais cliniques sur l’utilisation du topiramate en addictologie chez des patients ayant une comorbidité psychiatrique permettrait de mieux refléter la réalité des pratiques

au quotidien, ce dans la mesure où la corrélation entre troubles psychiatriques et troubles liés à une substance est bien établie. les auteurs déclarent ne pas avoir de conflits Endocrinology antagonist d’intérêts en relation avec cet article. “
“Le diagnostic et la classification des hypertensions pulmonaires (HTP) ont été au centre des débats de plusieurs symposiums au cours de ces quarante dernières années : Genève 1973, Evian 1998, Venise 2003, Dana Point 2008 et Nice en 2013. La dernière définition de l’HTP tient compte de la pression artérielle pulmonaire moyenne (PAPm) mesurée au moment du cathétérisme cardiaque droit, qui doit être supérieure ou égale à 25 mmHg [1]. Pour le moment, nous ne disposons pas de suffisamment de données pour pouvoir définir une hypertension pulmonaire à l’effort [1]. L’ancienne

Terminal deoxynucleotidyl transferase définition qui parlait d’une PAPm à l’effort ≥ 30 mmHg a été abandonnée en 2008, principalement en raison d’une grande variabilité de l’hémodynamique à l’effort selon l’âge et de l’impossibilité d’imposer un standard unique pour l’épreuve d’effort. L’hypertension artérielle pulmonaire (HTAP) est définie par une PAPm ≥ 25 mmHg, une pression capillaire pulmonaire (PCP) ≤ 15 mmHg (télé-expiratoire) et des résistances vasculaires pulmonaires (RVP) > 3 unités Wood au moment du cathétérisme cardiaque droit [1]. Les RVP sont calculées en tenant compte du débit cardiaque (DC) selon la formule : (PAPm-PCP) / DC. L’examen essentiel pour le diagnostic de l’hypertension pulmonaire est le cathétérisme cardiaque droit.

Despite representing only a small percentage of ICU patients, those who fail to wean from ventilation consume a disproportionate share of

healthcare resources (Sprague and Hopkins, 2003) with an increase in mortality, morbidity, and ICU length of stay (Choi et al 2008, Epstein, 2009, Gosselink et al 2008). Weakness or fatigue of the diaphragm and the accessory muscles of inspiration is widely recognised as a cause of failure to wean from mechanical ventilation (Choi et al 2008, Petrof et al 2010). http://www.selleckchem.com/products/jq1.html There is also some evidence to suggest that mechanical ventilation may adversely affect diaphragmatic structure and function. These alterations, known as ventilator-induced diaphragmatic dysfunction, involve changes in myofibre length and rapid atrophy (Petrof et al 2010). Patients who undergo prolonged periods of ventilation also demonstrate decreases in respiratory muscle endurance (Chang et al 2005). Inspiratory muscle training is a technique Ulixertinib that loads the diaphragm and accessory inspiratory muscles with the aim of increasing their strength and endurance. Theoretically, mechanically ventilated patients could

undertake inspiratory muscle training in several ways: isocapnic/normocapnic hyperpnoea training, the application of devices that impose resistive or threshold loads, or adjustment of the ventilator sensitivity settings, such that patients need to generate greater negative intrathoracic pressures to initiate inspiratory flow (Hill et al 2010, Caruso et al 2005, Bissett and Leditschke, 2007). Inspiratory muscles respond to What is already known on this topic: Inspiratory

muscle weakness in critically ill patients appears to contribute to slow or unsuccessful weaning from mechanical ventilation. Several trials of inspiratory muscle training to facilitate weaning in intensive care have been performed, with inconsistent results. What this review adds: Pooled data from randomised trials confirm that inspiratory muscle training increases inspiratory muscle strength, but it is not yet clear whether it shortens the mechanical ventilation most period, improves weaning success, or improves survival. As no systematic appraisal of studies investigating the effect of inspiratory muscle training on weaning from mechanical ventilation has been indexed on the PEDro website or in PubMed, we undertook such a review, which aimed to answer the following specific research questions: 1. Does inspiratory muscle training improve inspiratory muscle strength and endurance in adults receiving mechanical ventilation? In addition to registration on PROSPERO, a more detailed protocol for conducting this review was submitted for peer review and publication (Moodie et al 2011) prior to commencing the review process. Five electronic databases were searched (PEDro, PubMed, CENTRAL, EMBASE, and CINAHL) from the earliest available date until April 2011.

By the end of January 2010 [1], the coverage of adults ranged from 8.7% to 34.4% (Fig. 2). States varied in their

approaches to check details implementing their H1N1 vaccination programs in an unprecedented situation. While the literature addressed factors related to uptake of seasonal influenza vaccine at the individual level [12] and [13], states and regions used their best judgment and knowledge of their jurisdictions to guide their decisions on distribution and system design, given the lack of scientific evidence in that area. The purpose of this study was to determine supply chain and system factors associated with H1N1 coverage rates at the state-wide level for adults in order to inform selleck future events of this nature. We hypothesized that characteristics of the vaccine supply chain in each state and decisions around targeting vaccine could predict uptake. One classic supply

chain study, for example, has demonstrated that a product stocked in a large number of locations increases the probability that a particular location will be stocked out, and may also reduce the distance traveled by the final consumer [14]. Some of these characteristics of the state vaccine supply included the number of locations where vaccine was available, prioritization of the ACIP-recommended target groups, the type of providers to whom vaccine was directed, and the lead-time between vaccine allocation and availability in a state, which largely reflects differences in states’ ordering processes. Because other factors affect uptake, as evidenced by state-to-state variation in seasonal influenza coverage and individual-level studies [15], [16], [17] and [18], underlying population differences such as demographic characteristics, utilization of preventive health services, and healthcare infrastructure were also examined. It is relevant to mention that individual-level studies differ from those with a regional or ecological view. Others have used this

Rolziracetam ecological approach in the analysis of other health-related problems such as water fluoridation and tooth decay [19] and [20]. Data from the centralized distribution system on vaccine shipments from October 5, 2009 through December 9, 2009 were made available for analysis, thus allowing us to focus the analysis on the period during which vaccine was in short supply. We examined the relationship between state vaccination rates in persons 18 and over with variables covering population and health-related state characteristics and state-specific vaccination campaign information. The outcome measure is state estimates of vaccination coverage, as calculated by the CDC [1]. Participants 18 and over on the Behavioral Risk Factor Surveillance System (BRFSS) and National H1N1 Flu Survey (NHFS) were asked if they had received an H1N1 vaccine during October 2009–January 2010.

Dans la dépendance au cannabis, aux benzodiazépines ou aux opiacés, il n’y a actuellement pas d’essais

cliniques contrôlés randomisés disponibles concernant l’usage du topiramate. Dans la boulimie, deux études contrôlées, randomisées, ont retrouvé une efficacité du topiramate par rapport au placebo avec diminution du nombre de crises de boulimie et des conduites de vomissements provoqués [30], [31] and [32]. Dans le binge eating disorder, plusieurs essais cliniques contrôlés randomisés ont montré une diminution des crises de boulimie et une perte de poids. Dans le jeu pathologique (gambling), il n’a pas été retrouvé de résultats significatifs. Plusieurs essais ont vu leurs résultats fragmentés au sein de plusieurs publications [15], [16], [18], [19], [20], [21], [22], selleck chemicals llc [27], [28], [30] and [31]. Enfin, de nombreux essais évaluant l’efficacité du topiramate sont en cours dans des

populations de patients alcoolodépendants ou dépendants à la cocaïne Selleckchem Alectinib avec ou sans comorbidités psychiatriques. La posologie optimale du topiramate dans l’alcoolodépendance n’est pas clairement connue. Plusieurs experts recommandent une introduction progressive pour prévenir ses nombreux effets indésirables [4]. Pour certains auteurs, il peut être démarré à 25 mg matin et soir, augmenté de 25 mg par prise chaque semaine, afin d’obtenir la posologie cible de 150 mg matin et soir en sixième semaine [6]. Dans les essais retenus, les patients ayant une comorbidité psychiatrique, les sujets âgés de moins de 18 ans

et ceux âgés de plus de 65 ans étaient exclus, ce qui soulève le problème de la transposition des résultats de ces études en pratique courante. Certains essais n’ont inclus que des sujets de sexe masculin [11], [22], [27] and [37] ou de sexe féminin [32]. La durée des essais était très variable, de 11 semaines all [26] à neuf mois [25]. Le traitement des conduites addictives s’effectue sur le long terme, compte tenu de la fréquence des rechutes. Il est donc important que les essais aient une durée relativement longue. Une durée de six mois a été jugée par certains auteurs comme raisonnable, quelle que soit la conduite addictive [65]. Dans l’alcoolodépendance, la définition d’un critère d’évaluation pouvait varier d’une étude à une autre : un « verre standard » pouvait correspondre à 12 grammes d’éthanol [20] and [21] ou 14 grammes [18] and [19], et une journée de consommation « massive » pouvait correspondre à une consommation d’éthanol allant de 30 à 40 grammes [24] à plus de 90 grammes [22].

4). EPEC samples (E2348/69) pre-treated for 3 h with dilutions of serum or fecal extracts obtained from mice immunized with BCG-bfpA, BCG-intimin, Smeg-bfpA or Smeg-intimin, were added to HEp-2 monolayers cultivated on coverslips. As a negative control, EPEC (E2348/69) samples were similarly pre-treated with dilutions of serum

or feces collected prior to the immunizations. After incubation for click here 3 h at 37 °C, the coverslips were stained and examined by light microscopy. Untreated EPEC (E2348/69) typically displays a localized pattern of adhesion, generating tight microcolonies of bacteria on the epithelial cell surface. As shown in Fig. 5A–C, adherence of EPEC (E2348/69) cells pre-treated with dilutions of immune serum or fecal extracts was blocked by over 90%. In contrast, in EPEC (E2348/69) cells pre-treated with dilutions of serum or feces collected before immunization, adherence was blocked by less than 5%. Attenuated M. bovis BCG vaccine strains have been intensively investigated as a vehicle for delivering heterologous antigens and allowing the induction of both humoral (mucosal and systemic) and cell-mediated immune responses [21]. In this study, we used recombinant BCG that expressed BfpA or intimin ABT-199 price as vaccines against EPEC. As an alternative,

M. smegmatis was also used to present the BfpA and intimin antigens to the host. It is interesting to note that the recombinant strains of both species were able to induce systemic and mucosal BfpA and intimin-specific antibody responses with adherence-neutralizing activity following oral administration to mice. This evidence demonstrates that the different rBCG-EPEC or Smeg-EPEC vaccine strains are potential live vectors for the generation

Dipeptidyl peptidase of strategies to prevent EPEC. Three important qualities for a recombinant vaccine were positively evaluated in our study. First, a live attenuated vaccine was constructed with the ability to express two important proteins, BfpA and intimin, involved in the pathogenesis of EPEC. Second, the expression of the recombinant proteins induced specific and long lasting immune response in immunized mice, characterized by serum and mucosal IgG and IgA antibodies. The third important property of our recombinants is that the induced antibodies were able to prevent, in in vitro EPEC adherence to HEp-2 cells. IgA production was probably enhanced by the adjuvant effects of mesoporous silica SBA-15 [20]. SBA-15 is a nontoxic positive modulator of the mucosal immune response even in low immune responsive mice and is a natural candidate to be included as an adjuvant in an anti-EPEC vaccine. The anti-EPEC antibodies specifically recognize recombinant and native BfpA and intimin proteins free in solution and naturally fixed on the bacterial cell surfaces (Fig. 1A and B). The significant production of TNF-α and IFN-γ identifies BfpA and intimin as inducers of cellular immunity [22] and [23].