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OBJETIVO: Avaliar a concordância interobservador de três classificações utilizadas para a fratura do platô tibial: Schatzker, Grupo AO e Hohl. MÉTODO: Nove observadores, subdivididos de acordo com o grau de titulação (seis médicos residentes - MR - e três médicos especialistas - ME), classificaram 50 fraturas do platô tibial. A concordância interobservador foi avaliada pelo coeficiente Kappa. RESULTADOS: Comparando-se os médicos residentes (MR) com os médicos especialistas (ME), observou-se que as três classificações apresentaram concordância de grau fraco e moderado. Entre os MR, as classificações do Grupo AO e de Hohl mostraram relação direta entre aumento no grau de concordância e ano de residência médica, o que foi observado de forma parcial para a classificação de Schatzker. Para a classificação de Hohl, o Kappa variou de 0,344 a 0,577; para a classificação do Grupo AO, variou de 0,36 a 0,499; e para a classificação de Schatzker, variou de 0,278 a 0,465. CONCLUSÃO: Existe concordância significativa, ao nível de 1%, entre as três classificações para todos os pares de observadores. Comparando-se os MR com os ME, as três classificações estudadas apresentam concordância de grau fraco e moderado. A classificação de Hohl apresenta a maior concordância entre os MR.OBJECTIVE: To assess the inter-observer agreement of three tibial plateau fracture classifications: Schatzker, AO Group, and Hohl. METHODS: Nine physicians of different levels of expertise (six Orthopaedic Residents - OR - and three Orthopaedic Attendings - OA) classified 50 tibial plateau fractures. RESULTS: There was a low to moderate agreement between OR and OA on the three classification systems. A straight correlation was found between the year of Residence and an increase on the level of agreement on the AO group and Hohl classifications. This was partially seen on the Schatzker classification. Kappa ranged from 0.344 to 0.577, 0.36 to 0.499, and 0.278 to 0.465 for the Hohl, AO group, and Schatzker systems, respectively. CONCLUSION: With a level of 0.1, there was a significant agreement on the three classifications among the physicians. When comparing ORs to OAs, the three studied classifications show low to moderate consistency, with the Hohl classification showing the highest level of agreement between OR.

Sucrase isomaltase (SI) is the most prominent disaccharidase in the small intestine. Congenital sucrase-isomaltase deficiency (CSID) is an autosomal recessive disorder caused by variants in the SI gene. A homozygous frameshift mutation, c.273_274delAG (p.Gly92Leufs*8), has been identified in CSID in the Greenlandic population. This variant eliminates the luminal domain of SI and results in loss of its digestive function. Surprisingly, the truncated mutant is transport-competent and localized at the cell surface; it interacts avidly with wild type SI and negatively impacts its enzymatic function. The data propose that heterozygote carriers of p.Gly92Leufs*8 may also present with CSID symptoms., Competing Interests: Declaration of competing interest H.Y.N. has received unrestricted research grant from QOL Medical LLC, Vero Beach, Florida, USA., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

The two major intestinal α-glycosidases, sucrase-isomaltase (SI) and maltase-glucoamylase (MGAM), are active towards α-1,4 glycosidic linkages that prevail in starch. These enzymes share striking structural similarities and follow similar biosynthetic pathways. It has been hypothesized that starch digestion can be modulated via "toggling" of activities of these mucosal α-glycosidases, suggesting a possible interaction between these two enzyme complexes in the intestinal brush border membrane (BBM). Here, the potential interaction between SI and MGAM was investigated in solubilized BBMs utilizing reciprocal pull down assays, i.e., immunoprecipitation with anti-SI antibody followed by Western blotting with anti-MGAM antibody and vice versa . Our results demonstrate that SI interacts avidly with MGAM concomitant with a hetero-complex assembly in the BBMs. This interaction is resistant to detergents, such as Triton X-100 or Triton X-100 in combination with sodium deoxycholate. By contrast, inclusion of sodium deoxycholate into the solubilization buffer reduces the enzymatic activities towards sucrose and maltose substantially, most likely due to alterations in the quaternary structure of either enzyme. In view of their interaction, SI and MGAM regulate the final steps in starch digestion in the intestine, whereby SI assumes the major role by virtue of its predominant expression in the intestinal BBMs, while MGAM acts in auxiliary supportive fashion. These findings will help understand the pathophysiology of carbohydrate malabsorption in functional gastrointestinal disorders, particularly in irritable bowel syndrome, in which gene variants of SI are implicated., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Tannous, Stellbrinck, Hoter and Naim.)

(1) Background: The effects of lockdown repetition on work-related stress, expressed through Effort-Reward Imbalance (ERI), during the COVID-19 pandemic are poorly documented. We investigated the effect of repetitive lockdowns on the ERI in French workers, its difference across occupations, and the change in its influencing factors across time. (2) Methods: Participants were included in a prospective cross-sectional observational study from 30 March 2020 to 28 May 2021. The primary outcome was the ERI score (visual analog scale). The ERI score of the population was examined via Generalized Estimating Equations. For each period, the factors influencing ERI were studied by multivariate linear regression. (3) Results: In 8121 participants, the ERI score decreased in the first 2 lockdowns (53.2 ± 0.3, p < 0.001; 50.5 ± 0.7, p < 0.001) and after lockdown 2 (54.8 ± 0.8, p = 0.004) compared with the pre-pandemic period (59 ± 0.4). ERI was higher in medical than in paramedical professionals in the pre-pandemic and the first 2 lockdowns. Higher workloads were associated with better ERI scores. (4) Conclusions: In a large French sample, Effort-Reward Imbalance worsened during the COVID-19 pandemic until the end of the 2nd lockdown. Paramedical professionals experienced a higher burden of stress compared with medical professionals.

The study aim was to examine the incidence and risk factors of respiratory syncytial virus (RSV) bronchiolitis hospitalisations and disease severity among infants. We compared demographic and health characteristics of children aged 0-23 hospitalised for RSV bronchiolitis (cases, n = 1227) during 2008-2018 and control children (n = 554) of the same age admitted for non-respiratory disease. RSV antigen was detected in nasal swabs by immunochromatography. Multiple logistic regression models were applied. The average annual incidence of hospitalisation for RSV bronchiolitis was 12.6 per 1000 and 1.7 per 1000 (P < 0.001) among infants and toddlers, respectively, with winter seasonality (November-March). The risk of hospitalisation for RSV bronchiolitis increased among children aged 0-5 months (OR 7.66; 95% CI 5.61-10.45) and 6-11 months (OR 12.88, 95% CI 8.48-19.55), compared to those aged 12-23 months. Additional risk factors were living in low vs. higher socio-economic status towns (OR 1.49; 95% CI 1.14-1.95), having chronic medical conditions (OR 2.75; 95% CI 1.61-4.70), birth month (October-January vs. June-September) (OR 2.19; 95% CI 1.60-2.99) and history of stay in neonatal intensive care unit at birth (OR 2.37; 95% CI 1.27-4.41). Male children and those who had pneumonia were more likely to have severe RSV bronchiolitis. In conclusion, the burden of hospitalisations for RSV bronchiolitis is high, especially in young infants. Effective preventive measures such as RSV active vaccines can reduce the risk of hospitalisations for RSV bronchiolitis among these vulnerable groups.

Objectives: Respiratory syncytial virus (RSV) is a leading cause of respiratory tract infections, especially in young children. Antibiotics are often unnecessarily prescribed for the treatment of RSV. Such treatments affect antibiotic resistance in future bacterial infections of treated patients and the general population. This study aimed to understand risk factors for and patterns of unnecessary antibiotic prescription in children with RSV., Methods: In a single-centre, retrospective study in Israel, we obtained data for children aged ≤2 years (n = 1016) hospitalised for RSV bronchiolitis during 2008-2018 and ascertained not to have bacterial co-infections. Antibiotic misuse was defined as prescription of antibiotics during hospitalisation of the study population. Demographic and clinical variables were assessed as predictors of unnecessary antibiotic treatment in a multivariable logistic regression model., Results: The unnecessary antibiotic treatment rate of children infected with RSV and ascertained not to have a bacterial co-infection was estimated at 33.4% (95% CI 30.5-36.4%). An increased likelihood of antibiotic misuse was associated with drawing bacterial cultures and with variables indicative of a severe patient status such as lower oxygen saturation, higher body temperature, tachypnoea and prior recent emergency room visit. Older age and female sex were also associated with an increased likelihood of unnecessary antibiotic treatment., Conclusions: Unnecessary antibiotic treatment in RSV patients was very common and may be largely attributed to physicians' perception of patients' severity. Improving prescription guidelines, implementing antibiotic stewardship programmes and utilising decision support systems may help achieve a better balance between prescribing and withholding antibiotic treatment., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Annonaceae family has broad uses in herbal medicine for treatment of several diseases, whether through seeds' or leaves' extracts. The present study investigates the antiproliferative and antitumor activity of Annona cherimola aqueous leaf (AAL) extract/infusion in acute myeloid leukemia (AML) cell lines in vitro. High-resolution LC-MS was first used to analyze the composition of the aqueous extract. Cell proliferation assay, Annexin V staining, cell cycle analysis, dual Annexin V/PI staining, cell death quantification by ELISA, ROS level detection and Western Blotting were then performed to elucidate the therapeutic effects of AAL extract. The results obtained revealed a potent antioxidant activity of AAL extract. Moreover, the extract exhibited dose- and time-dependent antiproliferative effects on AML cell lines by decreasing cell viability with an IC 50 of 5.03% (v/v) at 24 h of treatment of KG-1 cells. This decrease in viability was accompanied with a significant increase in apoptotic cell death with cell cycle arrest and flipping of the phosphatidylserine from the inner to the outer leaflet of the cell membrane. The respective overexpression and downregulation of proapoptotic proteins like cleaved caspase-8, cleaved PARP-1 and Bax and antiapoptotic proteins like Bcl-2 further validated the apoptotic pathway induced by AAL on AML cells. Finally, LC-MS revealed the presence of several compounds like fatty acids, terpenes, phenolics, cinnamic acids and flavonoids that could contribute to the antioxidant and anti-cancer effects of this herbal infusion. In addition to the generally known nutritional effects of the Annona cherimola fruit and leaves, the presented data validates the antioxidant and anti-cancerous effects of the leaf infusion on AML cell lines, proposing its potential therapeutic use against acute myeloid leukemia with future in vivo and clinical trials., (Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Rationale: Tobacco products are very addictive, partly because they contain nicotine which is reinforcing, but also because they include appealing aromas and tastes. Flavor additives are such sensory stimuli which enhance attractiveness, as well as use and abuse of tobacco and vaping products. Yet, the interaction between these flavor additives and nicotine remains poorly understood., Objectives: We want to understand how flavors may reduce nicotine' aversive taste and how it may enhance its voluntary oral self-administration in mice., Methods: We first studied the effect of flavor additives on nicotine solution palatability in a free bottle choice paradigm. Second, we investigated the effect of vanilla flavoring on the different stages of nicotine (40 μg/ml) oral self-administration in mice., Results: We show that adding flavors increase nicotine palatability and facilitate acquisition and maintenance of oral self-administration when compared to nicotine-alone group. Mice adapt their operant behavior depending on changes in nicotine concentration. All mice reinstate nicotine seeking upon presentation of associated cues. Nevertheless, vanilla-flavored nicotine was not more reinforcing than vanilla-flavored water which was reinforcing enough to drive similar operant response rates., Conclusions: Flavor additives increase nicotine oral consumption and help maintaining operant behavior in mice. Moreover, flavors can be very attractive and can have high reinforcing value by themselves. Thus, it is crucial that the investigation on how taste signals play an important role in modulating oral nicotine intake in rodent models remains explored., (© 2021. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

Flaxseeds have been known for their anti-cancerous effects due to the high abundance of lignans released upon ingestion. The most abundant lignan, secoisolariciresinol diglucoside (SDG), is ingested during the dietary intake of flax, and is then metabolized in the gut into two mammalian lignan derivatives, Enterodiol (END) and Enterolactone (ENL). These lignans were previously reported to possess anti-tumor effects against breast, colon, and lung cancer. This study aims to investigate the potential anti-cancerous effect of the flaxseed lignans SDG, END and ENL on acute myeloid leukemia cells (AML) in vitro and to decipher the underlying molecular mechanism. AML cell lines, (KG-1 and Monomac-1) and a normal lymphoblastic cell line were cultured and treated with the purified lignans. ENL was found to be the most promising lignan, as it exhibits a significant selective dose- and time-dependent cytotoxic effect in both AML cell lines, contrary to normal cells. The cytotoxic effects observed were attributed to apoptosis induction, as revealed by an increase in Annexin V staining of AML cells with increasing ENL concentrations. The increase in the percentage of cells in the pre-G phase, in addition to cell death ELISA analysis, validated cellular and DNA fragmentation respectively. Analysis of protein expression using western blots confirmed the activation of the intrinsic apoptotic pathway upon ENL treatment. This was also accompanied by an increase in ROS production intracellularly. In conclusion, this study demonstrates that ENL has promising anti-cancer effects in AML cell lines in vitro, by promoting DNA fragmentation and the intrinsic apoptotic pathway, highlighting the protective health benefits of flax seeds in leukemia., (Copyright © 2020. Published by Elsevier Masson SAS.)

Baclofen, a γ-amino-butyric acid type-B receptor agonist with exponentially increased use at high-dose to facilitate abstinence in chronic alcoholics, is responsible for increasing poisonings. Baclofen overdose may induce severe encephalopathy and electroencephalographic (EEG) abnormalities. Whether prior prolonged baclofen treatment may influence the severity of baclofen-induced encephalopathy in overdose has not been established. We designed a rat study to characterize baclofen-induced encephalopathy, correlate its severity with plasma concentrations and investigate the contribution of tolerance. Baclofen-induced encephalopathy was assessed using continuous EEG and scored based on a ten-grade scale. Following the administration by gavage of 116 mg/kg baclofen, EEG rapidly and steadily impaired resulting in the successive onset of deepening sleep followed by generalized periodic epileptiform discharges and burst-suppressions. Thereafter, encephalopathy progressively recovered following similar phases in reverse. Periodic triphasic sharp waves, non-convulsive status epilepticus and even isoelectric signals were observed at the most critical stages. Prior repeated baclofen administration resulted in reduced severity (peak: grade 7 versus 9; peak effect length: 382 ± 40 versus 123 ± 14 min, P = 0.008) and duration of encephalopathy (18 versus > 24 h, P = 0.0007), supporting the acquisition of tolerance. The relationship between encephalopathy severity and plasma baclofen concentrations fitted a sigmoidal E max model with an anticlockwise hysteresis loop suggesting a hypothetical biophase site of action. The baclofen concentration producing a response equivalent to 50% of E max was significantly reduced (8947 μg/L, ±11.3% versus 12,728 μg/L, ±24.0% [mean, coefficient of variation], P = 0.03) with prior prolonged baclofen administration. In conclusion, baclofen overdose induces early-onset and prolonged marked encephalopathy that is significantly attenuated by prior repeated baclofen treatment. Our findings suggest a possible role for the blood-brain barrier in the development of tolerance; however, its definitive involvement remains to be demonstrated., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Baclofen, a γ-amino-butyric acid type-B receptor agonist with exponentially increased use at high-dose to facilitate abstinence in chronic alcoholics, is responsible for increasing poisonings. Tolerance and withdrawal syndromes have been reported during prolonged treatment but their contribution to the variability of baclofen-induced neurotoxicity in overdose is unknown. We studied baclofen-induced effects on rat sedation, temperature, and ventilation and modeled baclofen pharmacokinetics and effect/concentration relationships aiming to investigate the consequences of repeated baclofen pretreatment and to characterize withdrawal syndrome. Baclofen-induced dose-dependent sedation (p <0.01), hypothermia (p <.001) and respiratory depression (p <.01) were altered in repeatedly baclofen-pretreated rats (p <.05). Repeatedly baclofen-pretreated rats did not exhibit respiratory depression following baclofen overdose due to limitations on baclofen-induced increase in inspiratory (p <.01) and expiratory times (p <.01). Only slight hypoxemia without respiratory acidosis was observed. Baclofen discontinuation resulted in hyperlocomotion and non-anxiogenic withdrawal symptoms. Regarding pharmacokinetics, repeated baclofen pretreatment increased the peak concentration (p <.05) and absorption constant rate (p <.05) and reduced the distribution volume (p <.0001) and elimination half-life (p <.05). Analysis of the effect/concentration relationships indicated that plasma baclofen concentration decreases more rapidly than all studied neuro-respiratory effects, in tolerant and non-tolerant rats. Taken together, our findings supported the role of brain distribution in baclofen-induced neurotoxicity expression and its probable involvement in tolerance-related attenuation in addition to physiological adaptations of ventilation. In conclusion, repeated pretreatment attenuates baclofen-attributed neurotoxicity in overdose and results in post-discontinuation withdrawal syndrome. Our findings suggest both pharmacodynamic and pharmacokinetic mechanisms whose relative contributions to the variability of baclofen-induced neurotoxicity in overdose remain to be established.

Malaria infection caused by Plasmodium parasites remains a major health burden worldwide especially in the tropics and subtropics. Plasmodium exhibits a complex life cycle whereby it undergoes a series of developmental stages in the Anopheles mosquito vector and the vertebrate human host. Malaria severity is mainly attributed to the genetic complexity of the parasite which is reflected in the sophisticated mechanisms of invasion and evasion that allow it to overcome the immune responses of both its invertebrate and vertebrate hosts. In this review, we aim to provide an updated, clear and concise summary of the literature focusing on the interactions of the vertebrate innate immune system with Plasmodium parasites, namely sporozoites, merozoites, and trophozoites. The roles of innate immune factors, both humoral and cellular, in anti-Plasmodium defense are described with particular emphasis on the contribution of key innate players including neutrophils, macrophages, and natural killer cells to the clearance of liver and blood stage parasites. A comprehensive understanding of the innate immune responses to malaria parasites remains an important goal that would dramatically help improve the design of original treatment strategies and vaccines, both of which are urgently needed to relieve the burden of malaria especially in endemic countries.

Primary membranous nephropathy is associated with increased risk of venous thromboembolic events, which are inversely correlated with serum albumin levels. To evaluate the potential benefit of prophylactic anticoagulation (venous thromboembolic events prevented) relative to the risk (major bleeds), we constructed a Markov decision model. The venous thromboembolic event risk according to serum albumin was obtained from an inception cohort of 898 patients with primary membranous nephropathy. Risk estimates of hemorrhage were obtained from a systematic literature review. Benefit-to-risk ratios were predicted according to bleeding risk and serum albumin. This ratio increased with worsening hypoalbuminemia from 4.5:1 for an albumin under 3 g/dl to 13.1:1 for an albumin under 2 g/dl in patients at low bleeding risk. Patients at intermediate bleeding risk with an albumin under 2 g/dl have a moderately favorable benefit-to-risk ratio (under 5:1). Patients at high bleeding risk are unlikely to benefit from prophylactic anticoagulation regardless of albuminemia. Probabilistic sensitivity analysis, to account for uncertainty in risk estimates, confirmed these trends. From these data, we constructed a tool to estimate the likelihood of benefit based on an individual's bleeding risk profile, serum albumin level, and acceptable benefit-to-risk ratio (www.gntools.com). This tool provides an approach to the decision of prophylactic anticoagulation personalized to the individual's needs and adaptable to dynamic changes in health status and risk profile.

Unlabelled: Osteoporosis affects the craniofacial and oral structures and has been associated with periodontal bone loss, tooth loss and reduced jaw bone mass., Objective: This study aimed to test the therapeutic efficacy of synthetic bone mineral (SBM) in minimizing alveolar bone loss induced by mineral deficiency in a rat model. SBM consists of a calcium carbonate apatite (similar to bone apatite) matrix incorporating magnesium, zinc, and fluoride ions., Design: Thirty female Sprague Dawley rats (2 months old) were randomly distributed into 3 groups (10 rats per group): GA (control), on basic diet; GB, on mineral deficient (MD) diet; and GC, on MD+SBM. The rats were sacrificed after 3 months, the jawbones were isolated and the soft tissues removed. Bone density was determined using X-ray radiography (Faxitron); mandibular cortical width, panoramic mandibular index, and alveolar resorption degree (M/M ratio) using BioquantOsteo; and bone micro-architecture micro-computed tomography and scanning electron microscopy., Results: Compared to control (GA), the rats on MD diet (GB) experienced significant mandibular bone loss while the rats on MD+SBM diet (GC) experienced significantly less bone loss compared to the GB group., Conclusion: SBM, administered orally, may have the potential as an osteoporosis therapeutic agent in minimizing or preventing alveolar bone loss induced by mineral deficiency., (Copyright © 2012 Elsevier Ltd. All rights reserved.)