Plasmid-encoded insertion sequences promote rapid adaptation in clinical enterobacteria.

Plasmids are extrachromosomal genetic elements commonly found in bacteria. Plasmids are known to fuel bacterial evolution through horizontal gene transfer (HGT), but recent analyses indicate that they can also promote intragenomic adaptations. However, the role of plasmids as catalysts of bacterial evolution beyond HGT remains poorly explored. In this study, we investigate the impact of a widespread conjugative plasmid, pOXA-48, on the evolution of various multidrug-resistant clinical enterobacteria. Combining experimental and within-patient evolution analyses, we unveil that plasmid pOXA-48 promotes bacterial evolution through the transposition of plasmid-encoded insertion sequence 1 (IS1) elements. Specifically, IS1-mediated gene inactivations expedite the adaptation rate of clinical strains in vitro and foster within-patient adaptation in the gut microbiota. We decipher the mechanism underlying the plasmid-mediated surge in IS1 transposition, revealing a negative feedback loop regulated by the genomic copy number of IS1. Given the overrepresentation of IS elements in bacterial plasmids, our findings propose that plasmid-mediated IS transposition represents a crucial mechanism for swift bacterial adaptation.

Destruction of the brush border by Salmonella enterica sv. Typhimurium subverts resorption by polarized epithelial cells.

Salmonella enterica serovar Typhimurium is an invasive, facultative intracellular gastrointestinal pathogen that destroys the brush border of polarized epithelial cells (PEC). The brush border is critical for the functions of PEC because it resorbs nutrients from the intestinal lumen and builds a physical barrier to infecting pathogens. The manipuation of PEC during infection by Salmonella was investigated by live-cell imaging and ultrastructural analysed of the brush border. We demonstrate that the destruction of the brush border by Salmonella significantly reduces the resorption surface of PEC along with the abrogation of endocytosis at the apical side of PEC. Both these changes in the physiology of PEC were associated with the translocation of type III secretion system effector protein SopE. Additionally, the F-actin polymerization rate at the apical side of PEC was highly altered by SopE, indicating that reduced endocytosis observed in infected PEC is related to the manipulation of F-actin polymerization mediated by SopE and, to a lesser extent, by effectors SopE2 or SipA. We further observed that in the absence of SopE, Salmonella effaced microvilli and induced reticular F-actin by bacterial accumulation during prolonged infection periods. In contrast to strains translocating SopE, strains lacking SopE did not alter resorption by PEC. Finally, we observed that after engulfment of Salmonella, ezrin was lost from the apical side of PEC and found later in early endosomes containing Salmonella. Our observations suggest that the destruction of the brush border by Salmonella may contribute to the pathogenesis of diarrhea.

Association of specific nutritional intake with periodontitis.

BACKGROUND: The present study aimed to evaluate nutritional intake among a group of male patients in the dental clinic with and without periodontal disease to search for associations between nutritional profile and periodontal health. METHODS: To this purpose, nutritional intake of macronutrients, fiber, vitamins, and minerals were compared evaluating both clinical parameters and periodontal status. Non periodontitis patients were compared with stage III and IV periodontitis and its extension according to the 2017 classification. RESULTS: After multivariate analysis, statistically significant associations were found between the dietary intake of energy, total fat, cholesterol, calcium, saturated fat, monounsaturated fat and folic acid and iodine and periodontitis status. This study reports an inverse association between cholesterol and iodine and periodontitis and a direct association with saturated fat, monounsaturated fat, and folic acid. CONCLUSIONS: Maintaining an adequate intake of fat, iodine, calcium, and cholesterol and avoiding an excessive intake of energy, saturated fat, monounsaturated fat, and folic acid could be important to controlling periodontitis.

Estimated Loss of Productivity Attributed to Cardiovascular Diseases in South America. / Estimativa de Produtividade Perdida Atribuída a Doenças Cardiovasculares na América do Sul.

BACKGROUND: Cardiovascular diseases (CVD) have significant health and economic burdens. In South America, the loss of productivity related to these diseases has not yet been well explored. OBJECTIVE: Estimate the potentially productive years of life lost (PPYLL) and loss of productivity related to premature mortality associated with CVD in South America, in 2019. METHODS: Mortality data available from the 2019 Global Burden of Disease Study were used to estimate the burden of disease attributable to CVD. For monetary calculations of productivity loss, a proxy of the human capital approach was used. Data were stratified by sex, in working age groups. RESULTS: The total number of deaths due to CVD in South America in 2019 was 754,324, and the total number of PPYLL was 2,040,973. The total permanent loss of productivity was approximately US$ 3.7 billion and US$ 7.8 billion in purchasing power parity, equivalent to 0.11% of the gross domestic product. The cost per death was US$ 22,904, and the ratio between men and women for the cost per death was 1.45. The variation in scenarios indicates that the estimates are robust, even with important differences between countries. CONCLUSIONS: CVD impose a significant economic burden on countries in South America. The characterization of this burden can support governments in the allocation of resources for the planning and execution of health policies and interventions in promotion, prevention, and recovery.

FUNDAMENTO: As doenças cardiovasculares (DCV) têm ônus sanitário e econômico significativos. Na América do Sul (AS), a perda de produtividade relacionada a estas enfermidades ainda não foi bem explorada. OBJETIVO: Estimar os anos de vida produtiva perdidos (AVPP) e a perda de produtividade relacionados a mortalidade prematura associada as DCV na AS, em 2019. MÉTODOS: Empregou-se dados de mortalidade disponíveis no Global Burden of Disease Study 2019 na estimativa da carga de doença atribuível a DCV. Para os cálculos monetários da perda da produtividade usou-se uma proxy da abordagem de capital humano. Estratificou-se por sexo, nas faixas etárias de trabalho. RESULTADOS: O número total de mortes por DCV na AS no ano de 2019 foi de 754.324 e os AVPP foram 2.040.973. A perda permanente de produtividade total foi de aproximadamente US$ 3,7 bilhões e US$ 7,8 bilhões em paridade do poder de compra, equivalente a 0,11% do produto interno bruto. O custo por morte foi de US$ 22.904, e a razão desse custo por óbito, entre homens e mulheres foi 1,45. A variação dos cenários aponta robustez nas estimativas, mesmo com diferenças importantes entre os países. CONCLUSÕES: As DCV impõem um ônus econômico significativo a este bloco de países. A caracterização deste fardo pode amparar os governos na alocação de recursos destinados ao planejamento e execução de políticas e intervenções sanitárias, sejam de promoção, prevenção ou recuperação.

Typhoon- and pollution-driven enhancement of reactive bromine in the mid-latitude marine boundary layer.

Tropospheric reactive bromine is important for atmospheric chemistry, regional air pollution, and global climate. Previous studies have reported measurements of atmospheric reactive bromine species in different environments, and proposed their main sources, e.g. sea-salt aerosol (SSA), oceanic biogenic activity, polar snow/ice, and volcanoes. Typhoons and other strong cyclonic activities (e.g. hurricanes) induce abrupt changes in different earth system processes, causing widespread destructive effects. However, the role of typhoons in regulating reactive bromine abundance and sources remains unexplored. Here, we report field observations of bromine oxide (BrO), a critical indicator of reactive bromine, on the Huaniao Island (HNI) in the East China Sea in July 2018. We observed high levels of BrO below 500 m with a daytime average of 9.7 ± 4.2 pptv and a peak value of ∼26 pptv under the influence of a typhoon. Our field measurements, supported by model simulations, suggest that the typhoon-induced drastic increase in wind speed amplifies the emission of SSA, significantly enhancing the activation of reactive bromine from SSA debromination. We also detected enhanced BrO mixing ratios under high NOx conditions (ppbv level) suggesting a potential pollution-induced mechanism of bromine release from SSA. Such elevated levels of atmospheric bromine noticeably increase ozone destruction by as much as ∼40% across the East China Sea. Considering the high frequency of cyclonic activity in the northern hemisphere, reactive bromine chemistry is expected to play a more important role than previously thought in affecting coastal air quality and atmospheric oxidation capacity. We suggest that models need to consider the hitherto overlooked typhoon- and pollution-mediated increase in reactive bromine levels when assessing the synergic effects of cyclonic activities on the earth system.

Anthropogenic short-lived halogens increase human exposure to mercury contamination due to enhanced mercury oxidation over continents.

Mercury (Hg) is a contaminant of global concern, and an accurate understanding of its atmospheric fate is needed to assess its risks to humans and ecosystem health. Atmospheric oxidation of Hg is key to the deposition of this toxic metal to the Earth's surface. Short-lived halogens (SLHs) can provide halogen radicals to directly oxidize Hg and perturb the budget of other Hg oxidants (e.g., OH and O3). In addition to known ocean emissions of halogens, recent observational evidence has revealed abundant anthropogenic emissions of SLHs over continental areas. However, the impacts of anthropogenic SLHs emissions on the atmospheric fate of Hg and human exposure to Hg contamination remain unknown. Here, we show that the inclusion of anthropogenic SLHs substantially increased local Hg oxidation and, consequently, deposition in/near Hg continental source regions by up to 20%, thereby decreasing Hg export from source regions to clean environments. Our modeling results indicated that the inclusion of anthropogenic SLHs can lead to higher Hg exposure in/near Hg source regions than estimated in previous assessments, e.g., with increases of 8.7% and 7.5% in China and India, respectively, consequently leading to higher Hg-related human health risks. These results highlight the urgent need for policymakers to reduce local Hg and SLHs emissions. We conclude that the substantial impacts of anthropogenic SLHs emissions should be included in model assessments of the Hg budget and associated health risks at local and global scales.

East Asian summer monsoon delivers large abundances of very-short-lived organic chlorine substances to the lower stratosphere.

Deep convection in the Asian summer monsoon is a significant transport process for lifting pollutants from the planetary boundary layer to the tropopause level. This process enables efficient injection into the stratosphere of reactive species such as chlorinated very-short-lived substances (Cl-VSLSs) that deplete ozone. Past studies of convective transport associated with the Asian summer monsoon have focused mostly on the south Asian summer monsoon. Airborne observations reported in this work identify the East Asian summer monsoon convection as an effective transport pathway that carried record-breaking levels of ozone-depleting Cl-VSLSs (mean organic chlorine from these VSLSs ~500 ppt) to the base of the stratosphere. These unique observations show total organic chlorine from VSLSs in the lower stratosphere over the Asian monsoon tropopause to be more than twice that previously reported over the tropical tropopause. Considering the recently observed increase in Cl-VSLS emissions and the ongoing strengthening of the East Asian summer monsoon under global warming, our results highlight that a reevaluation of the contribution of Cl-VSLS injection via the Asian monsoon to the total stratospheric chlorine budget is warranted.

Familial bilateral macronodular adrenal hyperplasia due to a novel ARMC 5 germline mutation: Clinical status and possible association with other neoplasms.

INTRODUCTION/OBJECTIVES: Mutations in the ARMC5 (armadillo repeat containing 5, OMIM 615549) gene, a putative tumor suppressor gene, have recently been identified as a common cause of sporadic and familial bilateral macronodular adrenal hyperplasia (BMAH). Familial BMAH is thought to be caused by two mutations, one germline and the other somatic, as suggested by the 2-hit theory. The objective is to describe a new mutation and develop its clinical characteristics and implications. METHODS, RESULTS AND CONCLUSIONS: We present an affected family with 11 members carrying a novel mutation of the ARMC5 gene (NM_001288767.1): c.2162T>C p. (Leu721Pro). Two of the carriers developed clinical Cushing's syndrome (CS), two mild autonomous cortisol secretion (MACS) and one presented with autonomous cortisol secretion (ACS). Four patients developed other tumors, three of whom died from this cause. It is not known whether these tumors could be related to the described mutation.

Effect of olive leaf phytochemicals on the anti-acetylcholinesterase, anti-cyclooxygenase-2 and ferric reducing antioxidant capacity.

In this study, the phytochemical profile of fifty olive leaves (OL) extracts from Spain, Italy, Greece, Portugal, and Morocco was characterized and their anti-cholinergic, anti-inflammatory, and antioxidant activities were evaluated. Luteolin-7-O-glucoside, isoharmnentin, and apigenin were involved in the acetylcholinesterase (AChE) inhibitory activity, while oleuropein and hydroxytyrosol showed noteworthy potential. Secoiridoids contributed to the cyclooxygenase-2 inhibitory activity and antioxidant capacity. Compounds such as oleuropein, ligstroside and luteolin-7-O-glucoside, may exert an important role in the ferric reducing antioxidant capacity. It should be also highlighted the role of hydroxytyrosol, hydroxycoumarins, and verbascoside concerning the antioxidant activity. This research provides valuable insights and confirms that specific compounds within OL extracts contribute to distinct anti-cholinergic, anti-inflammatory, and anti-oxidative effects.

Cell death induction facilitates egress of Coxiella burnetii from infected host cells at late stages of infection.

Intracellular bacteria have evolved mechanisms to invade host cells, establish an intracellular niche that allows survival and replication, produce progeny, and exit the host cell after completion of the replication cycle to infect new target cells. Bacteria exit their host cell by (i) initiation of apoptosis, (ii) lytic cell death, and (iii) exocytosis. While bacterial egress is essential for bacterial spreading and, thus, pathogenesis, we currently lack information about egress mechanisms for the obligate intracellular pathogen C. burnetii, the causative agent of the zoonosis Q fever. Here, we demonstrate that C. burnetii inhibits host cell apoptosis early during infection, but induces and/or increases apoptosis at later stages of infection. Only at later stages of infection did we observe C. burnetii egress, which depends on previously established large bacteria-filled vacuoles and a functional intrinsic apoptotic cascade. The released bacteria are not enclosed by a host cell membrane and can infect and replicate in new target cells. In summary, our data argue that C. burnetii egress in a non-synchronous way at late stages of infection. Apoptosis-induction is important for C. burnetii egress, but other pathways most likely contribute.

Evidence of nitrate-based nighttime atmospheric nucleation driven by marine microorganisms in the South Pacific.

Our understanding of ocean-cloud interactions and their effect on climate lacks insight into a key pathway: do biogenic marine emissions form new particles in the open ocean atmosphere? Using measurements collected in ship-borne air-sea interface tanks deployed in the Southwestern Pacific Ocean, we identified new particle formation (NPF) during nighttime that was related to plankton community composition. We show that nitrate ions are the only species for which abundance could support NPF rates in our semicontrolled experiments. Nitrate ions also prevailed in the natural pristine marine atmosphere and were elevated under higher sub-10 nm particle concentrations. We hypothesize that these nucleation events were fueled by complex, short-term biogeochemical cycling involving the microbial loop. These findings suggest a new perspective with a previously unidentified role of nitrate of marine biogeochemical origin in aerosol nucleation.

Breast Cancer in Pregnant Young Women: Clinicopathological Profile, Survival, and Pregnancy Outcomes.

Background Breast cancer is one of the most common cancer types diagnosed during pregnancy; the presence of any neoplasm in pregnant women faces clinical dilemmas and challenges in cancer and pregnancy management. Pregnancy-associated breast cancer (PABC) is defined as breast cancer diagnosed during pregnancy or within one year after delivery. The aim of this study was to describe tumor clinicopathological characteristics and pregnancy outcomes in PABC patients. Materials and methods This is a retrospective cohort assessing PABC patients. Qualitative variables were compared using Fisher's exact test. Kaplan-Meier method was used to calculate survival. Cox regression and logistic regression methods were used to estimate the hazard ratio (HR) and odds ratio (OR), respectively. Results We assessed 16 PABC patients. Women ≤ 35 years of age were mainly diagnosed at advanced stage (88.8%) with ER-negative disease (77.8%). Patients with >4 pathological lymph nodes (25%; p = 0.001) and ER-negative disease (50%; p = 0.646) showed poor five-year overall survival (OS). In the multivariate analysis, nodal involvement was the main predictor associated with poorer OS (HR = 1.4, 90% confidence interval [CI]: 1.14 to 1.8). The following risk factors might influence the risk of preterm delivery: maternal older age, gestational age at diagnosis, and intrauterine exposure to chemotherapy, but an adjusted OR of 0.61 (90% CI: 0.34 to 1), 0.80 (90% CI: 0.66 to 0.9), and 0.013 (90% CI: 0.00 to 0.9), respectively, did not statistically support such an effect. Conclusions Younger women with PABC had a more aggressive pathological profile that might partly explain the poor OS. Obstetrical adverse events related to preterm delivery should be avoided with better planning of specialized strategies.

First Report of Colletotrichum chrysophilum Causing Anthracnose on Nance (Byrsonima crassifolia) in Mexico.

Nance fruit [Byrsonima crassifolia (L.) HBK] is a native crop widely distributed in Mexico and South America (Medina-Torres et al. 2018). It has been reported that nance is a good source of active compounds with anti-inflammatory, neuropharmacological and antioxidant effects. In 2022, the annual production of nance fruit in Mexico was of 7,713.13 tons and average yield of 5.64 t/ha with economic value of 51,952.66 million pesos (SIAP, 2022). This production generated significant economic income for the communities at a local, regional, and national level. In January 2023, irregular necrotic spots were observed on leaves and fruit of nance in an orchard of 50 nance trees located in San Sebastián Nopalera (16°54'52.73"N; 97°47'50.35"W), Oaxaca, Mexico. The incidence of the disease ranged from 50 to 60% of the trees. Infected fruit first showed dark-brown lesions with defined borders that coalesced to form large necrotic area. Isolates were purified by single spore isolation method (Choi et al. 1999).Colletotrichum strains were grown in PDA medium and five monoconidial isolates were obtained. A representative sample was selected (CNC-NP3) and deposited in the Culture Collection of Phytopathogenic Fungi of Plant Pathology Laboratory of the CIIDIR-Oaxaca of the Instituto Politécnico Nacional. Colony on PDA was white with sparse aerial mycelium, and the center was dark grey with abundant acervuli. Conidia (n = 100) were hyaline, aseptate, cylindrical with rounded apex, 13.5 to 15.2 × 4.3 to 5.1 µm. Appressoria (n = 20) were terminal or lateral, obovoid to clavate and some with slightly lobed, 9.9 to 11.6 × 5.3 to 6.6 µm. Based on the morphology, the isolate was identified as belonging to the Colletotrichum gloeosporioides species complex (Jayawardena et al. 2016). The representative isolate CNC-NP3 was identified by multilocus phylogenetic analysis using nucleotide sequences of internal transcribed spacer (ITS), actin (ACT), ß-tubulin (TUB2), and glyceraldehyde-3-phosphate-dehydrogenase (GAPDH) (Jayawardena et al. 2016). The sequences were deposited in GenBank (accessions nos. OQ861102 (ITS), OQ870548 (ACT), OQ870549 (TUB2), OQ870550 (GAPDH). The phylogenetic analysis was carried out by Maximum likelihood method using concatenated sequences of ITS, ACT, TUB2 and GAPDH genes (Kozlov et al. 2019). The multilocus phylogenetic analysis revelated clearly the isolate CNC-NP3 as Colletotrichum chrysophilum. To confirm pathogenicity of CNC-NP3, 30 healthy fruits were inoculated. Fifteen disinfected nance with wounds and fifteen nance without wounds were inoculate with 10 µL of conidial suspension (1×105 spores/mL) from 7-day old culture. And controls were inoculated using sterile distilled water. Fruits were placed in a moist chamber covered with plastic bag at 25 °C for 48 h to maintain high humidity. After 4 days the inoculation sites development symptoms that were identical to those initially observed in the field, whereas the control group remained symptomless. The pathogenicity test was performed twice, with the same results. The pathogen was re-isolated from the lesion to fulfill Koch's postulates. Currently, Colletotrichum chrysophilum has been reported causing anthracnose disease in several crops: apple in New York (Khodadadi et al. 2020), papaya in Mexico (Pacheco- Esteva et al.2022), Blueberry (Soares et al. 2022) and banana in Brazil (Astolfi et al. 2022). To our knowledge, this is the first report of anthracnose in Byrsonima crassifolia caused by Colletotrichum chrysophilum in Oaxaca, Mexico.

Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRASG12C Inhibitor Efficacy.

Non-small lung cancers (NSCLC) frequently (∼30%) harbor KRAS driver mutations, half of which are KRASG12C. KRAS-mutant NSCLC with comutated STK11 and/or KEAP1 is particularly refractory to conventional, targeted, and immune therapy. Development of KRASG12C inhibitors (G12Ci) provided a major therapeutic advance, but resistance still limits their efficacy. To identify genes whose deletion augments efficacy of the G12Cis adagrasib (MRTX-849) or adagrasib plus TNO155 (SHP2i), we performed genome-wide CRISPR/Cas9 screens on KRAS/STK11-mutant NSCLC lines. Recurrent, potentially targetable, synthetic lethal (SL) genes were identified, including serine-threonine kinases, tRNA-modifying and proteoglycan synthesis enzymes, and YAP/TAZ/TEAD pathway components. Several SL genes were confirmed by siRNA/shRNA experiments, and the YAP/TAZ/TEAD pathway was extensively validated in vitro and in mice. Mechanistic studies showed that G12Ci treatment induced gene expression of RHO paralogs and activators, increased RHOA activation, and evoked ROCK-dependent nuclear translocation of YAP. Mice and patients with acquired G12Ci- or G12Ci/SHP2i-resistant tumors showed strong overlap with SL pathways, arguing for the relevance of the screen results. These findings provide a landscape of potential targets for future combination strategies, some of which can be tested rapidly in the clinic. SIGNIFICANCE: Identification of synthetic lethal genes with KRASG12C using genome-wide CRISPR/Cas9 screening and credentialing of the ability of TEAD inhibition to enhance KRASG12C efficacy provides a roadmap for combination strategies. See related commentary by Johnson and Haigis, p. 4005.

Infections and risk factors for infection-related mortality after pediatric allogeneic hematopoietic stem cell transplantation in Mexico: A single center retrospective study.

OBJECTIVE: To identify the type of infections and risk factors for infection-related mortality (IRM) after allogeneic hematopoietic stem cell transplantation (HSCT). METHODS: Retrospective cohort study of patients <16 years of age treated in 2010-2019 was conducted. Unadjusted hazard ratios (HR) and adjusted hazard ratios (aHR) with 95% confidence intervals (95% CIs) were estimated using Cox regression. Cumulative incidence was calculated. RESULTS: Data for 99 pediatric patients were analyzed. The myeloablative conditioning was the most used regimen (78.8%) and the hematopoietic stem cell source was predominantly peripheral blood (80.8%). Primary graft failure occurred in 19.2% of patients. Frequency of acute graft-versus-host disease was 46.5%. Total of 136 infectious events was recorded, the most common of which were bacterial (76.4%) followed by viral infection (15.5%) and then fungal infection (8.1%). The best predictors for infection subtypes where the following: a) for bacterial infection (the age groups of 10.1-15 years: aHR = 3.33; 95% CI: 1.62-6.85 and. >15 years: aHR = 3.34; 95% CI: 1.18-9.45); b) for viral infection (graft versus host disease: aHR = 5.36; 95% CI: 1.62-17.68), however, for fungal infection statistically significant predictors were not identified. Related mortality was 30% (n = 12). Increased risk for infection-related mortality was observed in patients with unrelated donor and umbilical cord stem cells recipients (HR = 3.12; 95% CI: 1.00-9.85). CONCLUSIONS: Frequencies of infections and infection-related mortality appear to be similar to those reported. Unrelated donors and stem cells from umbilical cord recipients were associated with a high risk of mortality.

Direct medical cost of COVID-19 in children hospitalized at a tertiary referral healthcare center in Mexico City.

Introduction: Despite the end of the COVID-19 pandemic being declared by the WHO, the economic consequences are far from over. One of these implications was the cost of inpatient care for health institutions. To date, some studies have examined the economic burden of COVID-19 in the adult population but only a few have focused on child populations. Objective: To estimate the direct medical costs of COVID-19, focusing on children in Mexico. Method: Data about resources consumed during hospital stays were extracted from the medical records of patients hospitalized at a Mexican tertiary healthcare institution. Other sources of information were the unit prices of inputs and the salaries of health personnel. A micro-costing methodology was used to obtain cost results by age group over different hospital areas. Data analysis was performed with descriptive statistics and regression models to evaluate the predictors of total cost. Results: One hundred and ten medical records were reviewed of which 57.3% corresponded to male patients and the mean age was 7.2 years old. The estimated average cost per patient was US$5,943 (95% CI: US$4,249-7,637). When the costs of the three clinical areas were summed, only the 5-10 years old group showed a maximum cost of US$14,000. The regression analysis revealed the following factors as significant: sex, age, staying at an emergency room, having a positive bacterial culture, and having comorbidities. Discussion: The cost results were somewhat similar to those reported in children from the USA, but only regarding low severity COVID-19 cases. However, comparability between these types of studies should be done with caution due to the huge differences between the healthcare systems of countries. The study cost results may help public decision-makers in budget planning and as inputs for future cost-effectiveness studies about interventions regarding COVID-19.

Long-term cost-effectiveness analysis of sacral neuromodulation in the treatment of severe faecal incontinence.

AIM: The aim of this study was to evaluate the long-term cost-effectiveness of sacral neuromodulation in the treatment of severe faecal incontinence as compared with symptomatic management. METHODS: In the public health field, a micro-costing evaluation method was conducted from the perspectives of the health system and the society. The incremental cost-effectiveness ratio was used as a decision index, and we considered various scenarios to evaluate the impact of the cost of symptomatic management and percutaneous nerve evaluation success rate in its calculation. Clinical data were retrieved from a consecutive cohort of 93 patients with severe faecal incontinence undergoing sacral neuromodulation after a failure of conservative (pharmacological and biofeedback) and/or surgical (sphincteroplasty) first-line treatments were considered. RESULTS: The long-term incremental cost-effectiveness ratio comparing sacral neuromodulation versus symptomatic management was 14347€/QALY and 28523€/QALY from the societal and health service provider's perspectives, respectively. If the definitive pulse generator implant success rate was 100%, incremental cost-effectiveness would correspond to 6831€/QALY and 16761€/QALY, respectively. CONCLUSIONS: Sacral neuromodulation may be considered a cost-effective technique in the long-term treatment of severe faecal incontinence from the societal and health care sector perspectives. Improving patient selection and determining the predictive outcome factors for successful sacral neuromodulation in the treatment of faecal incontinence would improve cost-effectiveness.

Exploring the Antioxidant, Neuroprotective, and Anti-Inflammatory Potential of Olive Leaf Extracts from Spain, Portugal, Greece, and Italy.

The leaves of the olive tree (Olea europaea L.) are one of the major solid wastes from the olive industry. Globally, the European Union is the largest producer of olive by-products, with Spain, Italy, Greece, and Portugal accounting for almost the entire production. Many questions remain to be solved concerning olive leaves (OL), including those related to possible differences in composition and/or biological activities depending on their geographical origin. In the present work, OL from Spain, Italy, Greece, and Portugal have been characterized according to their phytochemical profile, antioxidant capacity, neuroprotective activity, and anti-inflammatory effects. The Spanish and Italian OL samples presented the highest antioxidant and neuroprotective activities, while the Greek OL showed the lowest. These results were strongly associated with the content of oleoside methyl ester and p-hydroxybenzoic acid for the Spanish and Italian samples, respectively, whereas the content of decarboxymethyl elenolic acid dialdehyde form (hydrated) was negatively associated with the mentioned biological activities of the Greek samples. No country-related effect was observed in the anti-inflammatory activity of OL. Comprehensively, this work could provide a useful tool for manufacturers and R&D departments in making environmentally friendly decisions on how OL can be used to generate nutraceutical products based on the composition and origin of this by-product.

Photocatalytic chlorine atom production on mineral dust-sea spray aerosols over the North Atlantic.

Active chlorine in the atmosphere is poorly constrained and so is its role in the oxidation of the potent greenhouse gas methane, causing uncertainty in global methane budgets. We propose a photocatalytic mechanism for chlorine atom production that occurs when Sahara dust mixes with sea spray aerosol. The mechanism is validated by implementation in a global atmospheric model and thereby explaining the episodic, seasonal, and location-dependent 13C depletion in CO in air samples from Barbados [J.E. Mak, G. Kra, T. Sandomenico, P. Bergamaschi, J. Geophys. Res. Atmos. 108 (2003)], which remained unexplained for decades. The production of Cl can also explain the anomaly in the CO:ethane ratio found at Cape Verde [K. A. Read et al., J. Geophys. Res. Atmos. 114 (2009)], in addition to explaining the observation of elevated HOCl [M. J. Lawler et al., Atmos. Chem. Phys. 11, 7617-7628 (2011)]. Our model finds that 3.8 Tg(Cl) y-1 is produced over the North Atlantic, making it the dominant source of chlorine in the region; globally, chlorine production increases by 41%. The shift in the methane sink budget due to the increased role of Cl means that isotope-constrained top-down models fail to allocate 12 Tg y-1 (2% of total methane emissions) to 13C-depleted biological sources such as agriculture and wetlands. Since 2014, an increase in North African dust emissions has increased the 13C isotope of atmospheric CH4, thereby partially masking a much greater decline in this isotope, which has implications for the interpretation of the drivers behind the recent increase of methane in the atmosphere.