While the benefits of adopting a more plant-based diet for sustainability and animal welfare are clear, its long-term health impacts, including the impact on cognitive ageing, are limited studied. Therefore, we investigated the associations between plant-based diet adherence and cognitive ageing.Data from a previous intervention study involving community-dwelling adults aged ≥ 65 years were analysed at baseline (n = 658) and after 2-year follow-up (n = 314). Global and domain-specific cognitive functioning were assessed at both timepoints. Overall, healthful and unhealthful plant-based dietary indices were calculated from a 190-item food frequency questionnaire. Multivariate-adjusted linear regression models were applied to test for associations.After full-adjustment, higher overall adherence to a plant-based diet was not associated with global cognitive function  or cognitive change . Similarly, healthful and unhealthful plant-based diet indices were not associated with cognitive functioning  or change . Interestingly, we observed fish consumption to influence the association between plant-based diet adherence and cognitive functioning (p-interaction = 0.01), with only individuals with a fish consumption of ≥ 0.93 portion/week benefitting from better overall plant-based diet adherence .We did not demonstrate associations of a more plant-based diet with cognitive ageing. However, possibly such association exists in a subpopulation with higher fish intake. This would be in line with earlier observations that diets rich in plant foods and fish, such as the Mediterranean diet, may be beneficial for cognitive ageing.Registered at clinicaltrials.gov (NCT00696514) on June 12, 2008.The online version contains supplementary material available at 10.1007/s00394-023-03130-y. Consumers are increasingly opting for more plant-based diets, for various reasons related to sustainability, animal welfare and presumed health benefits. Nevertheless, the evidence supporting health benefits of shifting to a plant-based diet remains limited. While protective associations have been demonstrated for cardiovascular disease , cancer At the same time, there is emerging evidence for beneficial effects of individual plant-derived components and foods on cognitive ageing. For example, higher consumption of polyphenols, vitamins C and E, carotenoids and unsaturated fatty acids, and plant foods rich in these plant-derived components, including vegetables, berries, nuts, olive oil, tea and coffee, have been associated to favourable brain ageing outcomes . SimilarWhereas these plant-derived components, foods and plant-centred dietary patterns have been shown to contribute to healthy cognitive ageing, there is no direct evidence to support the benefits of higher adherence to a plant-based dietary pattern. The few preliminary studies on the role of a more plant-based or vegetarian diet show promising positive associations with cognitive ageing outcomes –9, thougTo this end, the current study aims to investigate the association between plant-based diet adherence and cognitive functioning and 2-year cognitive decline in cognitively healthy older adults. To categorize plant-based diet adherence, we used the approach proposed by Satija et al.  based on. The study was approved by the Medical Ethics committee of Wageningen University & Research and has been registered at clinicaltrials.gov as NCT00696514. All participants had given written informed consent.The present study made use of data from the B-vitamins for the Prevention of Osteoporotic Fractures (B-proof) trial , a randoHabitual dietary intake was assessed at baseline by a 190-item FFQ, of which validity has been reported previously , 16. ParAs a measure of plant-based diet adherence, we calculated the overall, healthful and unhealthful plant-based diet index  . These iCognitive functioning was assessed by trained research assistants with an extensive battery of cognitive tests at baseline and after 2 years. This battery included the Rey Auditory Verbal Learning Test (RAVLT)  , the DigTo limit the number of cognition outcomes, cognitive composite scores were created. Individual cognitive test scores at baseline and after 2 yeras were converted into Z-scores based on population mean and standard deviation at baseline. The Z-scores for the TMT and Stroop Colour-Word test were reversed as lower scores represent better cognitive functioning. Individual Z-scores per test were clustered into composite scores for global and domain-specific cognitive functioning.Finally, Mini-Mental State Examination  was admi2. Physical activity was assessed using the LASA physical activity questionnaire [Information on age, gender, education level , smoking status  was collected via questionnaires. Body weight and height were measured by trained research assistants. Body mass index (BMI) was calculated as weight (kg)/(height (m))ionnaire , and exp2), physical activity (in MET h/w), smoking , alcohol intake , and margarine intake (portions/d). The longitudinal analysis was additionally adjusted for baseline cognition Z-scores. To investigate if consumption of specific animal food groups modified the association, stratified analyses by fish, meat, egg and dairy consumption (median split) were performed. P-values smaller than 0.05 were considered significant. All analyses were performed using RStudio Version 1.4.0 [Data are expressed as n (%), mean (SD) or median (IQR) unless otherwise stated. Participant characteristics between PDI tertiles were compared using ANOVA or Kruskal–Wallis test for continuous variables, and chi-square test for categorical variables. Multiple linear regression analyses were performed to investigate the association between plant-based diet adherence and cognition. For the cross-sectional analysis, we modelled cognitive function at baseline as a function of plant-based diet adherence , using data of the total study population. For the longitudinal analysis, the change in cognition Z-score between baseline and after 2 years was modelled as a function of plant-based diet adherence . Here, only data from the control group were used, to eliminate interference of the B-vitamin intervention. All analyses were adjusted for age (in years), gender, education level , BMI  Table . With reHigher adherence to an overall or healthful plant-based diet was not associated with the rate of cognitive decline over 2 years  . Better adherence to a healthful plant-based diet was associated with slower rates of cognitive decline in attention & working memory , while higher unhealthful plant-based diet adherence was associated with faster rates of decline . Overall adherence to a plant-based diet was not associated with a decline in attention & working memory (p-trend = 0.29).We did not find associations between the plant-based dietary indices and episodic memory, information processing speed, or executive functioning.To investigate if consumption of specific animal food groups modified the association between adherence to a plant-based diet and cognitive ageing, we performed stratified analyses by fish, meat, egg and dairy consumption based on a median split.For the sensitivity analysis stratified by fish intake, participants were divided into two groups, those with lower and higher fish intake than the median fish intake of 0.93 portion per week. Interestingly, fish consumption appeared to influence the association between adherence to a plant-based diet and cognition .. Interestingly, a higher consumption of fish, rich in the latter nutrients, appeared to partly influence the association between adherence to a plant-based diet and cognitive ageing.In this cohort of Dutch cognitively healthy older adults, there was no evidence for a beneficial association between adherence to a plant-based diet and cognitive ageing. While individuals who adhered better to a plant-based diet consumed more fibre and less cholesterol and saturated fatty acids, their intakes of vitamin B12, EPA and DHA were lowerTo our knowledge, the association between the degree of adherence to a plant-based or vegetarian diet with cognitive ageing has been investigated in six other studies, with mixed results. Three studies demonstrated positive associations: a more plant-based dietary pattern as derived from principle component analysis was associated with better cognitive functioning in older adults , and higWhatever the true association between plant-based diet adherence and cognitive ageing may be, the lack of beneficial association in our analysis can be explained from a nutrient perspective. A diet rich in plant foods contains many nutrients that are beneficial for healthy brain ageing, including vitamin C, vitamin E, polyphenols, carotenoids and unsaturated fatty acids. These nutrients have demonstrated anti-oxidant and anti-inflammatory properties, via which they could slow down cognitive decline during ageing . HoweverIn our sensitivity analysis, we found that fish consumption modified the association between adherence to a plant-based diet and cognition, with only individuals with a higher fish consumption seeming to benefit from adhering to a plant-based diet. While fish, rich in vitamin B12, EPA and DHA, has been shown to slow cognitive decline on its own , combiniObservational studies can confirm the combined beneficial associations of a diet rich in plant foods and fish in cognitive ageing. The MedDiet, a diet rich in vegetables, fruits, whole grains, nuts and fish, has been associated with better cognitive functioning, slower rates of cognitive decline and lower chance of dementia . SimilarWhile the modification by fish intake can be explained from a nutrient perspective and observational studies support this finding, it needs to be mentioned that our findings result from a subgroup analysis which limits the interpretability of these observations. Possibly, this is also an explanation for the inconsistency in findings, as we only demonstrated the modification by fish intake for PDI in the cross-sectional analysis, and hPDI in the longitudinal analysis. These results should be interpreted as preliminary and the analyses have to be replicated in other datasets before definite conclusions can be drawn.Finally, a remark should be made with regard to the protein content of plant-based diets. Even though protein is not considered a nutrient of prime interest for the ageing brain, adequate consumption of high-quality protein is crucial for the ageing muscle and the prevention of sarcopenia . ConsumiIn conclusion, we did not demonstrate a beneficial association of better adherence to a plant-based diet with cognitive ageing, which could be due to the lower intakes of vitamin B12, DHA and EPA in individuals with higher plant-based diet adherence. Possibly, such association between plant-based diet adherence and cognition exists in a subpopulation of fish-consumers with a fish intake of at least one portion per week. This would be in line with earlier findings that plant-centred diets that include regular fish consumption, such as the MedDiet and MIND diet, may offer benefits for the ageing brain.Supplementary file1 (DOCX 36 KB)Below is the link to the electronic supplementary material.


P < 0.001). We present the protocol for The Effect of Posterior Pericardiotomy on the Incidence of Atrial Fibrillation After Cardiac Surgery–Extended Follow-Up study (PALACS-EF): a prospective, extended follow-up of the original PALACS trial. The aim of PALACS-EF is to gain more data regarding the effect of posterior pericardiotomy on postdischarge clinical outcomes. The primary outcome is the time to the first occurrence of the composite of all-cause mortality or hospital cardiovascular readmission. The key secondary outcome is the time to the first occurrence of the composite of all-cause mortality and all-cause hospital readmission. Hospital readmission, myocardial infarction, stroke, transient ischaemic attack, heart failure, systemic embolism, or new arrhythmias with onset since 30-day follow-up will also be recorded.Postoperative atrial fibrillation (POAF) is the most common complication of cardiac surgery and has been associated with increased postoperative morbidity and hospital costs. The Posterior left pericardiotomy for the prevention of AtriaL fibrillation After Cardiac Surgery (PALACS) trial found that posterior pericardiotomy significantly reduced the incidence of POAF (17% vs. 32%, All 420 patients enrolled in the PALACS trial will be included; extended follow-up will be conducted via telephone by blinded research personnel utilizing a standardized script to ensure uniformity and completeness of follow-up. If an event has occurred, documentation will be obtained, and an independent adjudication committee blinded to group assignment will adjudicate outcome events. Results will be reported when a median follow-up of 5 years is achieved.PALACS-EF will provide data to answer the question of whether posterior pericardiotomy improves postdischarge outcomes in patients undergoing cardiac surgery, and it will provide information on the relationship between POAF and adverse postdischarge outcomes including mortality, hospitalization, heart failure, and stroke.PALACS: NCT02875405, PALACS-EF: NCT05903222  Institutional Review Board approval for the PALACS-EF protocol was given by Weill Cornell Medicine (IRB #1502015867) as an amendment to the original PALACS trial protocol approval, without the need for updated informed consent. No new data were generated or analysed for the present manuscript.Extended follow-up will be conducted via telephone by research personnel blinded to group assignment in the 420 patients enrolled in the initial PALACS trial. A standardized script will be used during telephone follow-up to ensure uniformity and completeness of follow-up . If an eAn independent committee made of two cardiologists and a cardiac surgeon blinded to group assignment will adjudicate all outcome events. A neurologist blinded to group assignment will confirm all neurologic events, including TIA and stroke.All data will be de-identified upon entry into the secure, password-protected, electronic data collection system, REDCap. Data will be prospectively entered by research personnel. REDCap will be hosted on a secure server on a password-protected computer, and access to the database will require a password as well as permission from the principal investigator. The secure server being used is also password-protected and only accessible to research personnel of the Department of Cardiothoracic Surgery, Weill Cornell Medicine.The primary outcome of PALACS-EF is the time to the first occurrence of the composite of all-cause mortality or hospital readmission for cardiovascular causes.The key secondary outcome is the time to the first occurrence of the composite of all-cause mortality or all-cause hospital readmission.Additional secondary outcomes include all-cause hospital readmission, hospital readmission for cardiovascular causes, heart failure, MI, stroke, TIA, new arrhythmias with onset after 30-day follow-up, and systemic embolism. All-cause hospital readmission and hospital readmission for cardiovascular causes will be analysed both as time to first occurrence and as recurrent events.Table 1.Definitions for the study outcomes are provided in The 420 patients enrolled in the primary PALACS trial will be part of PALACS-EF study. In PALACS, three patients (0.7%) died before hospital discharge or within 30 days of surgery. Those deaths will be counted towards the primary endpoint in the PALACS-EF study, but these patients will be excluded from the secondary analysis comparing the outcomes of patients with vs. without POAF. Inclusion criteria for the initial trial were as follows: patients undergoing primary, elective coronary artery bypass grafting, aortic valve replacement, ascending aortic repair, or a combination of these, who had no previous history of atrial fibrillation or other atrial arrhythmias.The exclusion criteria for the primary PALACS trial were as follows: pre-operative non-sinus rhythm, history of previous atrial arrhythmias, mitral or tricuspid valve surgery, surgery of the descending thoracic or thoraco-abdominal aorta, planned use of hypothermic circulatory arrest at surgery, off-pump operation, urgent or emergent presentation, disease of the left pleura or previous interventions in the left pleural cavity, non–cardiac-related contraindications to the intervention, repeat operation, minimally invasive operation, and chest deformity.For this reporting, the primary analysis will be performed at a median follow-up of 5 years.The primary analysis will compare the primary outcome by randomized treatment according to the intention-to-treat (ITT) principle where all participants will be included in their assigned treatment groups regardless of the actual procedure performed. The primary analysis will be performed using multivariable-adjusted Cox proportional hazards regression, adjusted for the following covariates: age, sex, diabetes status, ejection fraction, extent of coronary disease, type of surgery, and surgical priority. An as-treated (AT) analysis will also be conducted.Key secondary analyses include (i) a comparison of the primary endpoint for patients with POAF vs. patients without POAF and (ii) a mediation analysis using randomized treatment as exposure, POAF as the mediator, and the primary outcome as the outcome. Both key secondary analyses will be performed in the ITT population using multivariable-adjusted Cox proportional hazards regression. Other secondary analyses will be performed both in the ITT and AT populations.2DS2-VASc score, and type of surgery.For the primary outcome, subgroup and interaction-term analyses will be used to investigate the following possible effect modifiers: age, sex, left ventricular ejection fraction, CHAP values will be two sided.The authors expect only minimal missing data. In case of missing data, multiple imputation analysis will be utilized. The loss to follow-up is also expected to be minimal. It will be reported and compared between the groups using absolute risk differences. All 16Secondary outcomes will be analysed using Cox proportional hazards regression (time to first occurrence) and by the Lei Wei Yang Ying adaptation of the Anderson–Gil model with robust standard errors.t-test or the Mann–Whitney U test, and categorical variables will be analysed by use of the χ2 test.Pre-operative differences between groups will be assessed by univariate analysis. Continuous variables will be analysed by way of Student’s No formal sample size calculation has been performed for PALACS-EF. The 420 patients enrolled in the PALACS trial will be included in the extended follow-up study.Table 2.Based on the enrolled sample size, statistical power in different scenarios of event rates and treatment effects are provided in P = 0.0007; OR adjusted for the stratification variable 0.44, 95% CI 0.27–0.70, P = 0.0005] and pericardial effusion . There was no difference between groups in the incidence of short-term major adverse events, and there were no pericardiotomy-related complications. A 2023 meta-analysis17 including 25 RCTs comparing posterior pericardiotomy to no posterior pericardiotomy in 4467 patients undergoing cardiac surgery found that the overall risk of POAF was significantly lower in the posterior pericardiotomy group , as was the risk of supraventricular tachycardia , early  and late pericardial effusion , and cardiac tamponade . No data on mid- or long-term clinical outcomes were reported.The PALACS trial was the first adequately powered, rigorous, randomized trial to evaluate the use of posterior pericardiotomy for prevention of POAF. This single-centre, single-blind, prospective trial found that compared with the control group, patients receiving posterior pericardiotomy had significantly lower incidence of POAF [17% (37/212) vs. 32% (66/208), To date, it is not clear if posterior pericardiotomy improves postdischarge outcomes in patients undergoing cardiac surgery, and PALACS-EF will provide data on this important issue. In addition, PALACS-EF will provide information on the relationship between POAF and adverse postdischarge outcomes including mortality, hospitalization, heart failure, and stroke.


ABC transporters, a family of ATP-dependent transmembrane proteins, are responsible for the active transport of a wide range of molecules across cell membranes, including drugs, toxins, and nutrients. Nematodes possess a great diversity of ABC transporters; however, only P-glycoproteins have been well-characterized compared to other classes. The ABC transport proteins have been implicated in developing resistance to various classes of anthelmintic drugs in parasitic nematodes; their role in plant and human parasitic nematodes still needs further investigation. Therefore, ABC transport proteins offer a potential opportunity to develop nematode control strategies. Multidrug resistance inhibitors are becoming more attractive for controlling nematodes due to their potential to increase drug efficacy in two ways: (i) by limiting drug efflux from nematodes, thereby increasing the amount of drug that reaches its target site, and (ii) by reducing drug excretion by host animals, thereby enhancing drug bioavailability. This article reviews the role of ABC transporters in the survival of parasitic nematodes, including the genes involved, their regulation and physiological roles, as well as recent developments in their characterization. It also discusses the association of ABC transporters with anthelmintic resistance and the possibility of targeting them with next-generation inhibitors or nutraceuticals  to control parasitic infections. ATP binding cassette (ABC) transport systems, one of the largest protein superfamilies, are found in all three domains of life (prokaryotes (archaea and bacteria) and eukaryotes). Eukaryotic ABC transporters typically consist of two conserved domains, a transmembrane domain (TMD) and a nucleotide-binding domain (NBD) . Based oABC transporters transport a wide range of chemical entities, including lipids, proteins, sugars, amino acids, xenobiotics, drugs and inorganic ions. Most of the family members act as transport proteins in which the ATP-binding domains bind and hydrolyse ATP to provide energy to translocate a variety of solutes across the biological membrane; however, the energising module is also involved in non-transport processes, for example, cellular processes ,10. In mCaenorhabditis elegans [Haemonchus contortus and Cooperia oncophora worms collected from treated animals compared to those collected from untreated animals [The involvement of ABC transporters in the development of anthelmintic resistance has also been identified in animal parasitic nematodes ,14; howe elegans . In addi elegans ,16, and  elegans ,18. In c animals ,20. ThisHelminths possess a larger number of ABC transporter genes than mammals, which have only a few multidrug resistance (MDR) transporters . In contC. elegans is known to have 15 P-gp genes (pgp), eight MRP (mrp) and nine Half transporter genes (haf) [Nematodes possess a greater diversity of ABC transporters compared to mammals; for example, es (haf) . Table 1es (haf) .H. contortus and the difference between the isolates. Therefore, the transport mechanism mediated through MDR transporters may vary in different developmental stages of nematodes. For example, Kerboeuf and Guegnard [H. contortus isolate compared to other MLs. In contrast, Godoy et al. [H. contortus expressed in mammalian cells. The difference in the interaction of anthelmintics across various life stages in nematodes also proposes that there might be variation in expression patterns of ABC transporters between developmental stages of nematodes. These studies suggest the important roles of ABC transporters for helminth survival; however, further work is required to better characterize these roles in the development of different helminth parasites.All the stages of helminths do not express all ABC transporters, and their expression patterns may vary in different developmental stages. For example, Sarai et al.  describeGuegnard  reportedy et al.  showed tToxoplasma gondii [As described earlier, ABC systems are divided into three major classes based on their functions; Classes 1 and 2 are involved in the translocation of substrates across the cell membrane and are found in prokaryotes and eukaryotes. Class 3 ABC systems do not function in the membrane and are mainly associated with cellular processes, for example, DNA repair, translation, and regulation of gene expression in cells . Class 1a gondii . Class 2a gondii , reviewea gondii . Althouga gondii . Mammalia gondii ,50.C. elegans worms against natural toxins [pgp-3 in H. contortus exposed to sheep eosinophil granules, suggesting a role in the detoxification of host immune cell products. Similarly, the expression of some P-gp genes (including pgp-3 and pgp-9) in intestinal excretory cells of the closely related model organism C. elegans further suggests a role for them in protecting worms against toxic substances [Bursaphelenchus xylophilus was reported in response to α-pinene, a monoterpene produced by plants in response to attack [C. elegans to some anthelmintics, particularly IVM, provides evidence for their role in protection against anthelmintics [Tc-abcg-5 may indicate an essential role for this transporter in the reproduction of Toxocara canis. Previously, we observed relatively higher expression levels of ABCF transporters (abcf-1 and abcf-2) compared to many of the other genes in H. contortus [3) and arrested growth, as well as the death as pharate adults in RNA interference studies with L3 and pupae of Tribolium castaneum, respectively. In Schistosoma mansoni, disruption of egg production following knockdown of SMDR2 or SmMRP1 expression using RNA interference further indicated an important role of ABC transporters in parasite reproduction [In nematodes, P-gps (ABCB1), one of the most studied ABC transporters, have been reported to play an important role in protecting nematodes against environmental toxins. The protective functions of several of these ABC transporters have been reported previously. For example, Pgp-3 protects l toxins . In addil toxins  describebstances . Similaro attack . In addilmintics ,54. Morelmintics  suggesteontortus . ABCF trontortus . The absontortus , who obsoduction . HoweverH. contortus [C. elegans [Brugia malayi [T. circumcinta [O. volvulus [Of the various ABC transporters found in nematodes, ABCB1 (previously known as P-gp) has been of particular interest due to its role in drug resistance and its potential as a therapeutic target. However, the identification/localization of ABCB1 in nematodes is challenging due to the complex nature of these organisms, with different life stages and protective structures. Confirming ABCB1 expression in different body tissues of nematodes requires a laborious and careful approach, and differentiation between ABCB1 and other ABC transporter proteins can be difficult. Sometimes, differentiation between P-gps and other proteins of the ABC transporters family is difficult due to the nature of methodologies employed or the abundance of other ABC transporters that may be found in every selected location . Furtherontortus , C. eleg elegans , Brugia a malayi , T. circcumcinta  and O. vvolvulus ,39.mdr-1 gene products has been documented, while in H. contortus, UIC2 also confirmed both the presence and activity of P-gps, as it was reported earlier in tumor cells [H. contortus [mdr1 monocloncal antibody staining showed that P-gps are also present in the eggshells [H. contortus [Hc-pgp-13 was expressed in pharyngeal, neuronal and epithelial tissues. Similarly, Chelladurai and Brewer [Peq-P-gps in the intestine, body wall, nerves, lateral cords, and reproductive tissues of adult male and female Parascaris equorum worms. In T. canis, detection of tissue distribution and transcription of TcABCG-5 showed that this ABC transporter was predominantly expressed in the reproductive tract of female worms, suggesting an essential role of ABCG-5 in the reproduction of this parasitic nematode [Several studies have reported the use of specific monoclonal antibodies for the detection of P-gps in nematodes. Different localisation studies have shown that ABC transporters are expressed in excretory cells, the intestine, amphids, neurons, muscles, pharynx, hypodermis, and other tissues, including the vulva in female worms . The useor cells ,63. Furtontortus , while aontortus . In addiontortus  recentlyd Brewer  revealednematode .H. contortus in the presence of P-gp inhibitors, especially verapamil. The results showed that P-gp inhibitors increase the accumulation of R-123 in the eggs of H. contortus, indicating partial or complete inhibition of drug efflux by these inhibitors [+ ATPases, K-ATPases and mitochondrial ATPases are inhibited by specific ATPase inhibitors [Certain biochemical assays are available to detect P-gps that are based on measurement or inhibition of the activity of trans-membrane transport proteins and are classified as functional assays. Accumulation studies are based on the uptake of a radiolabeled or fluorescent probe into the cell in the presence of ABC transporter inhibitors, which block the efflux proteins leading to increased accumulation of the probe and evidence of the presence of these transport proteins. The studies in mammalian cells have been conducted using transfected cell lines that over-express a specific transporter protein of interest compared to wild-type cells . Rhodamihibitors ,71. ATPahibitors . This ashibitors . Currenthibitors ,74.MDR genes (mdr-1 and mdr-2) that encode P-gps in mice. The results showed increased absorption/accumulation of various drugs in different body tissues of mice lacking P-gps compared to the control group of mice [C. elegans, genetic modification has also been used as a tool to study the role of P-gps in anthelmintic sensitivity. Deletion of some P-gp genes in C. elegans resulted in increased sensitivity of the worms to IVM compared to wild-type worms [Somechanged, in vivo methods are currently being used in mammalian studies to detect the presence of specific transport proteins. Transgenic animal models are a well-established means of evaluating genes and their protein products. Animals can be genetically modified such that a specific protein can be over-expressed or blocked by adding or deleting a gene(s). The phenomenon of the removal or silencing of a gene is called homologous recombination or, more commonly, gene knockout . The rol of mice ,76. The pe worms . HoweverH. contortus [H. contortus expressed in mammalian cells [H. contortus. Similarly, our previous studies have shown that multidrug resistance inhibitors significantly increase the in vitro toxicity of IVM and LEV in H. contortus; and exposure to IVM and LEV induces transcription of various ABC transporter genes in H. contortus larvae [H. contortus larvae to IVM and LEV also increased the efflux of rhodamine-123, suggesting the stimulatory effects of these anthelmintics on ABC transporters.The absorption, distribution and elimination of the anthelmintics, especially MLs in hosts and parasites, are influenced by multidrug resistance transporters, including P-gps ,77. The ontortus , as suggan cells ,82,83, ws larvae ,18. In aH. contortus have shown that multi-drug resistance is associated with increased P-gp mRNA expression levels in IVM-resistant strain [pgp-2 and pgp-9 in a multi-drug resistant isolate compared to a susceptible isolate of H. contortus. Our previous studies also showed that pgp-1, pgp-9.1 and pgp-9.2 expressed at significantly higher levels in drug-resistant larvae of H. contortus compared to the susceptible larvae [T. circumcincta, pgp-9 showed significantly higher transcription in multidrug-resistant isolate compared to susceptible isolate [haf-9 and mrp-1 were also higher in the eggs of IVM-resistant C. oncophora [C. elegans isolate showed upregulation of pgp-12 and pgp-13 with downregulation of all other P-gp genes, whereas Yan et al. [C. elegans compared to the wild-type susceptible isolate. On the other hand, Williamson and Wolstenholme [P-gps have been implicated in resistance to anthelmintics, with several studies describing an increased transcription of specific transporter genes in drug-resistant nematodes compared to their counterparts . For exat strain . Williamt strain  reportede larvae ,43. Simi isolate . In addincophora . In addincophora  recentlyn et al.  reportedtenholme  observedC. elegans, whereas the inactivation of certain pgps  resulted in increased sensitivity to IVM compared to the wild-type C. elegans. There is also accumulating evidence that exposure to anthelmintics increases gene transcription for ABC transporters in parasitic nematodes . In contrast, no significant differences were observed between the expression patterns of P-gp genes before and after IVM treatment in Parascaris univalens, C. oncophora and H. contortus [Furthermore, De Graef et al.  also repontortus ,37,99. TH. contortus following selection with IVM and moxidectin [H. contortus [Tci-pgp-9 has also been reported in multidrug-resistant T. circumcincta [Tci-pgp-9 in a multidrug-resistant T. circumcincta strain compared to the “near-isogenic” drug-susceptible sister strain. Recently, Turnbull et al. [Tci-pgp-9 sequence variants shared by the multiple-resistant UK and New Zealand isolates were not observed in their drug-susceptible counterpart. These studies suggest that increased expression of Tci-pgp-9, as well as higher sequence polymorphism may play an essential role in anthelmintic resistance in T. circumcincta.In addition to transcriptional upregulation, allelic polymorphisms in ABC transporters can potentially increase drug efflux from the cells, thus changing the drug distribution within the parasite’s tissue and moving anthelmintics away from target sites . Table 4xidectin . Similarontortus . Furtherumcincta . Choi etumcincta  also desl et al.  supporteD. immitis resistant populations with reduced efficacy to MLs [O. volvulus. However, the samples collected in 2002 showed less genetic variability than those collected in 1999, and the reasons for this still need to be clarified [Furthermore, specific SNPs have also been reported in y to MLs . The autlarified . The autABC transporters are critical in maintaining cellular homeostasis and essential for many physiological processes. Due to their broad substrate specificity and importance in cellular function, ABC transporters have become an attractive target for developing new antiparasitic drugs. For example, the characterization of ABC transporter genes may contribute to identifying gene targets for silencing and provide novel strategies for nematode control. In addition, the efficacy of existing drugs can be enhanced to overcome drug resistance in nematodes by modulation of ABC transporters.mrp-1 and pgp-1 knock-down in C. elegans led to increased sensitivity to drugs or heavy metal ions compared to the wild-type [C. elegans increases the sensitivity of genetically modified worms to MLs compared to wild-type worms [H. contortus, as described by some of the previous studies [Gene silencing at the gene expression level of ABC transporters using anti-sense oligonucleotides or double-stranded small interference RNAs (siRNA) to regulate mRNA levels or target the signaling pathways that induce ABC transporters expression has been reported to counter multi-drug resistance in mammalian cancer research ,111. Simild-type . Furtherpe worms ,54. The  studies ,114,115.The studies reporting non-specific mechanisms of anthelmintic resistance in nematodes show that P-gps are the only member of the ABC transporter family that is well understood for its role in anthelmintic resistance. The research directions to overcome the MDR in nematodes are still less advanced, and further work is required to counter this mechanism. Increased efficacy of anthelmintics against parasites could result from modifying the pharmacokinetics in the host or by blocking the resistance-conferring transport mechanism in parasites . TherefoIdeally, an effective MDRI would be a non-toxic, potent and specific inhibitor of the relevant ABC transporters and would have no adverse effects on the pharmacokinetics of anthelmintic agents . SeveralThe first-generation inhibitors were developed for some other use, such as verapamil (anti-hypertensive), cyclosporine A (immunosuppressant) and quinine . Verapamil is a well-studied multidrug resistance inhibitor and has been shown to inhibit mainly the functions of P-gps in mammalian tumor cells and nematodes ,59. HoweH. contortus and C. oncophora to anthelmintic agents by decreasing the IC50 values compared to anthelmintics alone. Verapamil also increased the thiabendazole (TBZ) toxicity in EHA and showed a partial reversal of the resistance [H. contortus only, whereas it increased LEV toxicity to both resistant and susceptible isolates and showed no effect on IC50 values of thiabendazole. In contrast, using verapamil in larval migration assay (LMA) did not show any effects on the toxicity of IVM and LEV. The authors suggested that these patterns could be attributed to variations in life-stage dependent expression levels of specific P-gp genes between early larval life stages (examined in LDA) compared to later infective-stage larvae (as examined in LMA). Furthermore, some in vivo studies showed that verapamil, when co-administered with anthelmintic agents, increased the bioavailability of IVM in jirds and sheep [H. placei-resistant isolate in LMIA [In nematodes, it has been shown that verapamil can reverse the anthelmintic resistance either partially or completely when co-administered with anthelmintics ,71,97. Vsistance . Interessistance  showed tnd sheep ,127. In  in LMIA . The inv in LMIA  reportedThis group of MDR inhibitors were designed to counter the major drawbacks of first-generation inhibitors (reduced specificity and increased toxicity). Valspodar, a derivative of cyclosporine A, is characterized by higher in vitro specificity and potency than its precursor and no immunosuppressive effects, but it failed to improve the outcome of phase II clinical trials when administered with anticancer agents. Valspodar also inhibited cytochrome P450 (CYP450), which led to higher systemic concentrations of both the inhibitor and the therapeutic drug resulting in increased toxicity ,130. BirH. contortus and T. circumcincta in larval feeding inhibition assay. The authors also suggested that the combination of P-gp inhibitors with drugs could be useful to counter the emergence of anthelmintic resistance either by increasing the drug’s efficacy or by shortening the course of treatment in livestock. Valspodar has also been reported to reverse the resistance in IVM-selected C. elegans (free-living nematode) isolate. This isolate also showed increased expression of P-gps and MRPs following IVM selection, and reversal of resistance on the addition of valspodar clearly suggested that it interferes with the functions of ABC transporters, thus ultimately reversing the resistance [H. contortus larvae in LDA and increased IVM toxicity in LMA. This increased efficacy of valspodar was more marked in LMA for IVM with both resistant and susceptible isolates  [Information on the role of second-generation inhibitors in nematodes is limited. Bartley et al.  reportedsistance . In addi values) . HoweverThe third-generation MDR inhibitors were specifically designed to counter the limitations of first two generation inhibitors; therefore, inhibitor development was focused on the compounds that avoided the inhibition of CYP450 and did not alter the pharmacokinetics of the drugs. The members of third-generation inhibitors include tariquidar , elacridar (an acridone caroxamide), zosuquidar (LY 335979), CBT-1 (quinolone derivative) and laniquidar (piperidine) . They haSchistosoma mansoni in vitro and in vivo. It eliminated egg production in vitro at a concentration of 12.5 µM. The reduction in egg production was due to the association of MDR transporters with normal cellular physiology, evidenced by the disruption of parasite egg deposition in worms due to SMDR2 and SmMRP1 genetic knockdown. In H. contortus, the use of third-generation inhibitors, zosuquidar and tariquidar rendered the resistant larvae more sensitive to IVM than susceptible larvae [50 for both susceptible and resistant isolates, zosuquidar only reduced the IC50 for resistant larvae. These inhibitors resulted in a 5–6-fold increase in IVM toxicity, highlighting the potential usefulness of combination therapy (anthelmintics and MDRIs) in restoring the sensitivity of resistant worms (resistant-breaking strategy) and reducing the recommended dose of an anthelmintic while maintaining 100% efficacy against susceptible worms.There are limited reports available on the use of third-generation inhibitor tariquidar in pathogenic parasites. Kasinathan et al.  showed te larvae . InteresH. contortus and Ascaris suum may be more susceptible to IVM and LEV following exposure to polyphenols [Rising levels of anthelmintic resistance stimulated significant research into the principle of integrated parasite management to complement regular drug treatment. One alternative control option is the use of nutraceuticals or bioactive forages containing bioactive compounds which can antagonize enteric nematodes . Such acyphenols ,148. Wheyphenols . Howeveryphenols  reportedABC transporters play a crucial role in regulating the transport of various chemical entities in nematodes. The ABC transporter superfamily is diverse in structure and function, with some members acting as transporters for a wide range of substrates, including anthelmintic drugs, while others are associated with cellular processes such as DNA repair and gene regulation. In nematodes, ABC transporters have been implicated in developing anthelmintic resistance by functioning as efflux pumps, reducing drug concentration at their target sites. The activity of these transporters can be inhibited by MDRIs, leading to increased efficacy of anthelmintic drugs. Repurposing of existing drugs can save significant time and resources in drug development and may lead to the discovery of novel mechanisms that can be exploited in combination with existing anthelmintics. Although numerous MDR inhibitors have been developed, most of these have limited efficacy, high toxicity or have shown poor efficacy in vivo. Therefore, developing novel MDR inhibitors with improved potency and safety profiles is essential for improving clinical outcomes against parasitic nematodes. For example, natural products/nutraceuticals have been considered as important sources of new drugs due to their high biodiversity, oral bioavailability, and relatively low intrinsic toxicity. Therefore, natural products/nutraceuticals are appealing candidates for combining with chemotherapy to increase the cytotoxic effects of chemotherapeutic agents and reverse MDR. However, further research is required to fully understand the role of ABC transporters in parasitic nematodes and their potential as targets for controlling parasitic nematodes.


In traditional treatment modalities and standard clinical practices, FLASH radiotherapy (FL-RT) administers radiation therapy at an exceptionally high dosage rate. When compared to standard dose rate radiation therapy, numerous preclinical investigations have demonstrated that FL-RT provides similar benefits in conserving normal tissue while maintaining equal antitumor efficacy, a phenomenon possible due to the 'FLASH effect' (FE) of FL-RT. The methodologies involve proton radiotherapy, intensity-modulated radiation treatment, and managing high-throughput damage by radiation to solid tissues. Recent results from animal studies indicate that FL-RT can reduce radiation-induced tissue damage, significantly enhancing anticancer potency. Focusing on the potential benefits of FL proton beam treatment in the years to come, this review details the FL-RT research that has been done so far and the existing theories illuminating the FL effects. This subject remains of interest, with many issues still needing to be answered. We offer a brief review to emphasize a few of the key efforts and difficulties in moving FL radiation research forward. The existing research state of FL-RT, its affecting variables, and its different specific impacts are presented in this current review. Key topics discussed include the biochemical mechanism during FL therapy, beam sources for FL therapy, the FL effect on immunity, clinical and preclinical studies on the protective effect of FL therapy, and parameters for effective FL therapy. The majority of patients, with approximately 50% of all malignant cases, receive radiation using X-rays (photons). Ionizing radiation used in radiation treatment destroys cancer cells by inflicting damage on both healthy and malignant cells. Local solid tumors, such as those found in neck and head cancer, skin cancer, lymphoma, lung cancer, and esophageal cancer, are most commonly treated with this form of radiotherapy. Additionally, radiotherapy can serve as an adjuvant therapy, complementing chemotherapy and surgery in treating various conditions, including gastrointestinal tumors, breast cancer, and cervical cancer . RadiatiFLASH effect (FE)When dosage is administered using FT at extremely high dose rates as compared to the typical dose rates used in clinical practice, the FE reduces the tissue toxicities precipitated by radiation. According to Normal Tissue Sparing, the FT preserved the neurogenic milieu in an early study. It supported neurogenesis in the normal mice, whereas mice exposed to standard dose rate radiation showed significantly lower levels of undeveloped and mature neural cells within four months after exposure . AdditioMechanism of FEDespite the precise biochemical processes that cause the FE, which are still not fully understood, the emerging paradigm suggests that oxygen plays a crucial role in the biological reaction to FL irradiation. In general, indirect DNA damage from ionizing radiation happens when water undergoes radiolysis, producing reactive oxygen species (ROS) such as hydroxyl radicals that target DNA . AccordiEffective FL beam sourceThe FE has mostly been shown in low-energy electron linacs (linear accelerators). Platforms for experimental and medical electron accelerator research are easily accessible. The Kinetron and the Oriatron eRT6 are two specialized electron systems that produce pulsed beams of 4-5 MeV and 4.9-6 MeV electrons, respectively . Using eFE on immunityLymphopenia usually results from high-dose clinical radiation. The most radiosensitive cell types among adult hematopoietic cell populations are lymphocytes, such as T, B, and NK cells. When human peripheral blood mononuclear cells are exposed ex vivo to 2 Gy of radiation, approximately 50% of the T cells undergo apoptosis 24 hours post-exposure . The numParameters for effective FL-RTIn order to produce the FE, radiation dosage rates that are several orders of magnitude greater than usual must be used. Several other considerations must also be taken into account. These variables encompass the total dosage given, pulse rate, length, width, number, and total delivery time. The radiation's source, utilized in numerous contemporary FL experiments employing electron linear accelerators, is another crucial factor. A long-term function for the FL impact, particularly on chronic inflammation, has been suggested by the observation that the rising dosage rate decreased the amount of prematurely senescent cells  and reduced the stimulation of TGF- expression . SubsequClinical and preclinical studiesIn recent studies, the antitumor efficiency of FL-RT gave many promising results that are summarized below.BrainIn a study by Montay-Gruel P et al. (2020), FL-RT had a similar antitumor effect to conventional RT in mice with glioblastoma but with a protective effect on cognitive function . In anotIntestineIn a study by Venkatesulu BP et al. (2019), FL-RT did not have a protective effect on toxicity or survival in mice with intestinal cancer . In a stLungIn a study by Fouillade C et al., FL-RT was found to have a protective effect on normal lung tissue in mice with lung cancer . In a stSkinIn a study by Bourhis J et al., FL-RT effectively treated a patient's lymphoma . In a stBloodIn a study by Chabi S et al., FL-RT was found to have a similar antitumor effect to conventional RT in mice with leukemia but with a protective effect on normal hematopoiesis . The proOther CancersIn a preclinical study by Bubley G et al., FL-RT effectively killed prostate cancer cells . In a stRapid oxygen depletion induced by FL-RT leads to momentary hypoxia. However, the distinct responses between healthy and malignant tissues remain unclear. FL-RT may reduce radiation dosages to healthy tissue, and innovative and promising strategies for combining radiotherapy with other anticancer therapies may be encouraged. More animal studies are required before FL-RT can become the primary radiation technique utilized in clinical settings. The transition should be altered to accommodate larger radiotherapy fields, conformal radiation across multiple fields, redefinition of safe dose limits for healthy tissue, and radical cancer dosage irradiation. More studies are necessary for FL-RT to be applied to medical practice to benefit cancer patients, especially at physiological oxygen concentrations.


The antenna’s key characteristics are compact size, wide-band sub-GHz operation, dual sense CP, polarization bandwidth reconfigurability and good MIMO performance. Thus, it is a suitable candidate to be utilized in CubeSats applications in sub-GHz bands.In this letter, a compact, planar circularly polarized (CP) sub-GHz slot-based multiple-input-multiple-output (MIMO) antenna with dual sense CP along with polarization bandwidth reconfigurability is presented. The pentagonal reactively loaded slot is fed by two folded tapered feedlines to achieve CP. The antenna offers left-hand-circular polarization (RHCP) with the as well as right hand circular polarization (LHCP). The antenna exhibit linearly polarization (LP) by exciting two ports simultaneously. Moreover, the antenna CP resonance can be reconfigured by varying the capacitance of the varactor diode. The antenna has a wide −10 dB operating frequency band from 578–929 MHz. while the axial ratio (AR) bandwidth ranges from 490–810 MHz. Moreover, the two elements MIMO are optimized and placed on compact dimensions 100 × 100 × 0.76 mm Slit-slot and microstrip patch-based antennas offer bidirectional CP radiation, where the rotating senses of CP in the front and back sides are presented in9.Circular polarized (CP) antenna offers many advantages over the linearly polarized (LP) antennas due to their decreased polarization mismatch losses, and ability to provide freedom of antenna orientation. Therefore CP antennas are desired for satellite applications, WiMax, WLAN, RFID-tags, and 5G applications. Several efforts have been put in the literature to design CP antennas10. The CP senses can be reconfigured in single port antennas by switching the states of at least two p-i-n diodes16 and MEMS17. These kinds of antennas need additional complex biasing circuitry to control the diode, which increases the cost and reduces the antenna efficiency and CP bandwidth. Alternatively, CP sense reconfigurable antennas utilizing dual-ports have also been presented due to their wide-band characteristics20.Moreover, various methods have been employed to achieve polarization reconfigurable antennas that offer right-handed circular polarization (RHCP) and left-handed circular polarization (LHCP). The ability to operate with both senses (RHCP and LHCP) enables frequency reuse and doubles the capacity of the communication system23. In these designs, varactor and p-i-n diodes are utilized to achieve continuous frequency-polarization agility. At the same time, the switching between three polarization states and tunable working frequency bands are accomplished by microfluidic injection in24.Most importantly, if the antenna can be switched between two senses of CP (RHCP and LHCP) and LP, as well as the operating frequency, it will allow the user to roam to virtually any existing communication network system. Therefore, some works have been reported to designing the frequency and polarization reconfigurable antennas27, they do not offer polarization bandwidth reconfigurability. Additionally, multiple-input-multiple-output (MIMO) configurations are essential for high data rates with seamless connectivity. None of the aforementioned CP antenna with reconfigurability has MIMO capabilities. The proposed polarization bandwidth reconfigurable antenna is compared with state-of-the-art CP antennas. The proposed design is compared with other reference CP designs as shown in Table It is worth noting that most of the CP antenna designs as discussed are operating at frequency bands above 1 GHz band. The design of CP antenna with the features of frequency-polarization reconfigurability with wide-band and compact size characteristics is always challenging at the sub-GHz spectrum. Although many CP antennas have been presented at the sub-GHz band for RFID tags, the internet of things, CubeSat, and several other applicationsCP antennas have several advantages in sub-GHz wireless communication systems, particularly in CubeSat applications. These antennas improve signal propagation, reduce the impact of orientation, mitigate polarization mismatch, and find use in RFID, IoT, and satellite communication systems. The proposed antenna design is suitable for CubeSats operating in sub-GHz bands with CP characteristics. CP antennas are beneficial for satellite communication systems in the sub-GHz frequency range as they enhance signal reception and transmission, compensating for polarization mismatch caused by satellite orientation and ground station antennas. The specific frequency range of 578 to 929 MHz is mentioned as a potential range where circularly polarized antennas are commonly used. This range includes VHF and UHF bands, which are utilized by CubeSats, wireless microphone systems, UHF RFID systems, and certain satellite communication systems. Circularly polarized antennas help maintain consistent signal quality and improve performance in these applications.This letter focuses on the design of compact circularly polarized antenna for CubeSat applications. Most of the sub-GHz antenna for CubeSat operation are 3D structure which needs additional deployment mechanism. Thus, adding more complexity to the CubeSat design. However, the proposed antenna is low profile and planar and doesn’t need any additional deployment structure.This work is based on dual-port slot-based antenna with multiple polarization . A single antenna structure is being utilized to obtain 3 different types of CP at sub-GHz operation.The proposed antenna design is optimized in MIMO configuration with good MIMO performance metrics.The proposed antenna design has the 3-dB axial ratio (AR) bandwidth that can be tuned from 490–810 MHz by utilizing a single varactor diode. This is the prominent feature of the antenna design to provide switching flexibility between narrow-band and wide-band CP operation in wide-band antennas structure.The 2-element MIMO antenna offers a good isolation within a compact size and stable radiation patterns.To the best of the author’s knowledge, this design is the first of its kind that combines the advantages of compact size (100 mm × 100 mm × 0.76 mm), polarization bandwidth reconfigurability, narrow & wide bands CP configuration, and MIMO operation at sub-GHz bands.The distinguishing features as described above show the uniqueness and appropriateness of the proposed antenna design to be utilized in CubeSat applications operating at sub-GHz bands.This letter focuses on the design of a dual-port slot-based MIMO antenna with multiple polarization  along with polarization bandwidth reconfigurable MIMO antenna. The novelty and unique features of the proposed antenna design are given below: The schematic diagram of the proposed dual-feed single-element antenna is shown in Fig. The single element was then rotated along the axis with 360-degree for the MIMO configuration while keeping the parameters same of the antenna, as shown in Fig. For the proposed antenna design, a sub-GHz band communications was selected due to its numerous advantages. The slot-based antenna design are quite popular due to its ease of manufacturing, integration with other circuit components, planar structure, wide-band attributes, and omni-directional radiation patterns, all of which are well suited for the proposed antenna design.The proposed slot has been configured in a meandering closed loop pattern to achieve compact size, resembling a non-uniform pentagonal shape as depicted in Fig. Furthermore, a parametric analysis are performed to enhance performance in terms of size reduction and bandwidth expansion. The slot antenna is coupled with a capacitor (Cap), as shown in Fig. The E-field distribution on the antenna for two ports is investigated to explain the CP mechanism of the MIMO antenna Fig. . For porTo understand the circular polarization (CP) mechanism of the MIMO antenna with two ports, the distribution of the electric field (E-field) on the antenna is thoroughly investigated. This investigation aims to analyze the behavior of the E-field and its impact on the radiation characteristics of the antenna. Figure In contrast, when port-2 is excited, the E-field exhibits a counter-clockwise rotation. This counter-clockwise rotation of the E-field generates left-hand circularly polarized (LHCP) radiation. LHCP polarization involves the rotation of the electric field vector in a left-handed circular pattern as the wave propagates. One crucial observation made during this investigation is that during the excitation of ports 1 and 2, there is a negligible effect on antenna 2. In other words, no significant E-field is detected on antenna 2 when both ports 1 and 2 are excited simultaneously. This negligible effect leads to a high level of isolation between the MIMO elements. Isolation is an essential characteristic in MIMO (Multiple-Input Multiple-Output) systems, as it ensures that the signals transmitted from one antenna element do not interfere with the signals received by the other elements. The high isolation achieved in this MIMO antenna configuration helps minimize cross-interference and improves the overall performance and reliability of the system.By investigating the E-field distribution and the resulting polarization characteristics of the MIMO antenna, a comprehensive understanding of the CP mechanism is obtained. This knowledge is valuable for designing and optimizing MIMO antenna systems in various applications, such as wireless communications, radar systems, and satellite communications, where efficient signal transmission and reception are essential.iiThe simulated and measured . The antenna gives RHCP when port-1 (left port) is excited, while it gives LHCP when port-2 (right port) is excited. The simulated AR as a function of the frequency is shown in Fig. The proposed antenna design is capable of radiating in three different polarization modes: LP, RHCP, and LHCP. Unlike other antennas, this design doesn’t require any switching circuitry like p-i-n diodes or MEMS to switch between polarization modes. Typically, polarization reconfigurable antennas use switching mechanisms involving active components, which adds complexity and requires additional circuitry and control mechanisms.In this antenna’s case, LP radiation is achieved by simultaneously feeding both ports (port-1 and port-2) with the desired signals. This results in LP radiation with an Axial Ratio (AR) value exceeding 40 dB. The Axial Ratio measures the circular polarization of the antenna’s radiation, with lower values indicating better circular polarization. By configuring the feeding of the antenna ports appropriately, LP radiation is achieved without the need for switching circuits. This sets it apart from other antennas that rely on additional components for polarization switching.Overall, this antenna design offers the advantage of radiating in different polarization modes  without the complexity and potential drawbacks of switching circuitry. It provides versatility in terms of polarization selection and bandwidth reconfiguration, making it suitable for various applications.The antenna also has the additional advantage of AR bandwidth reconfigurability. The central frequency of the AR can be tuned by varying the capacitance of the diode. The resonance of AR can be shifted from 490 to 810 MHz by changing the capacitance values of varactor diode As shown in Fig. The gain of the antenna for port-1 and port-2 (LHCP and RHCP gain) plots are shown in Fig. The radiation patterns for each polarization scenario are also shown in Fig. The proposed MIMO antenna is also investigated for co-pol and cross-pol patterns at 650 MHz as shown in Fig. The proposed antenna design exhibited omni-directional radiation patterns and providing 360-degree coverage pattern in the azimuth plane, thus enabling communication with multiple ground stations without requiring precise pointing or alignment. This can be particularly beneficial for CubeSats operating in low earth orbit, due to limited resources or maneuvering capabilities.The diversity of the MIMO antenna in terms of envelope correlation coefficient (ECC) is calculated to show how much antenna elements are independent in their performance. The values are found to be very low, less than 0.02, ideal for the MIMO operation.24 do not offer sub-GHz operation and only a few designs24 offer frequency reconfigurability. Although most of the antennas are offering polarization reconfigurability, none of them have the extra advantages of the MIMO configuration. Thus, the proposed antenna outperforms its competitor designs with its operating capability in the sub-GHz band, polarization bandwidth reconfigurability, and MIMO configuration in a single design.The proposed polarization-frequency reconfigurable antenna is compared with state-of-the-art antennas in terms of their typical functionalities. Most of the antennasA low-profile 2-elements MIMO antenna at sub-GHz with polarization-frequency agility is presented. The primary single-element antenna consists of a pentagonal slotline having a varactor diode in its center to obtain a compact antenna design. The unique capacitive loaded slot-line with the folded feedlines gives a broadband impedance bandwidth of 46.58% (578   929 MHz), and a 3dB AR bandwidth from 490 to 810 MHz. The proposed dual-feed antenna offers RHCP as well as LHCP radiations. Additionally, the AR bandwidth can be reconfigured by varying the capacitance of the varactor diode. The AR can be tuned over the operating bandwidth of 490 to 810 MHz. Furthermore, the antenna gives a high RHCP and LHCP gain of 1.079 dBi, and 1.078 dBi, respectively. The two-element MIMO antenna is realized on compact board size of 100 mm × 100 mm. The attractive features of this design are compact size and wide operating bandwidth in the sub-GHz band, polarization-bandwidth reconfigurability, and good isolation.


M. tuberculosis (Mtb) are able to control the infection, co-infection with HIV increases the risk of TB infection progressing to TB disease by over 20-fold. While antiretroviral therapy (ART), the cornerstone of HIV care, decreases the incidence of TB in HIV-uninfected people, this remains 4- to 7-fold higher after ART in HIV-co-infected individuals in TB-endemic settings, regardless of the duration of therapy. Thus, the immune control of Mtb infection in Mtb/HIV-co-infected individuals is not fully restored by ART. We do not fully understand the reasons why Mtb/HIV-co-infected individuals maintain a high susceptibility to the reactivation of LTBI, despite an effective viral control by ART. A deep understanding of the molecular mechanisms that govern HIV-induced reactivation of TB is essential to develop improved treatments and vaccines for the Mtb/HIV-co-infected population. We discuss potential strategies for the mitigation of the observed chronic immune activation in combination with both anti-TB and anti-retroviral approaches.HIV and TB are the cause of significant worldwide mortality and pose a grave danger to the global public health. TB is the leading cause of death in HIV-infected persons, with one in four deaths attributable to TB. While the majority of healthy individuals infected with  Despite the advent of COVID-19, the tuberculosis (TB) and human immunodeficiency virus (HIV) co-pandemic continues to be a major healthcare issue in resource-limited countries ,3. The r+ T cells that also express the coreceptor CCR5 are the first cells infected by the virus + T cell-d by ART . These id by ART . The expd by ART . The expd by ART  was locad by ART . The pred by ART . Hence, ART alone does not completely resolve chronic immune activation during Mtb/SIV co-infection. As mentioned above, Mtb/SIV co-infection models have been developed in different NHP species . Our gro+ T cells [+ T cell reconstitution, but also allowed the control of the clinical reactivation of LTBI to TB [+ interstitial macrophages [During our NHP studies, we made interesting discoveries. Initiating ART at a time when signs of TB reactivation were already apparent did not lead to any control of TB reactivation, despite an effective control of viral replication in the periphery, alveoli and lungs and despite the reconstitution of CD4 T cells . The iniBI to TB . Even inBI to TB , thus miBI to TB  and receBI to TB . Interesrophages . Thus, irophages  and macrrophages , causingInhibition of IDO in the NHP model of TB. The inhibition of IDO was initially attempted in SIV-infected macaques . Boasso + myeloid cells. Further, these reactivating animals are characterized by the presence of high levels of type I IFN.IDO inhibition in Mtb/SIV co-infection and the intersection of the IDO pathway with other important immunometabolic networks. The results discussed in the preceding sections have positive implications for experiments conducted with both Mtb/SIV-co-infected RMs and Mtb/HIV-co-infected individuals. While only a handful of experiments have been performed in Mtb/SIV- (or SIV/Mtb)-co-infected NHPs, modeling the human co-infection, emerging data from these model systems suggest a critical role for type I IFN  and IDO,+ metabolism are critical for host–pathogen interactions in the presence of Mtb infection [+ glycohydrolase [+-degrading enzyme CD38, Mtb encodes an NAD+ hydrolase that is released into the cytoplasm of host macrophages, thus inducing the necrotic death of the host cells and enabling its own escape [+ through salvage pathway precursors may prevent necrotic host cell death and potentially stimulate Mtb-specific immune responses. Low NAD+ levels, on the other hand, may favor the survival of Mtb. It is therefore possible that therapeutic approaches that result in an increase in intracellular NAD+ levels could adjunctively promote a better control of pathogens like Mtb and SIV, especially in the context of co-infection. Alterations in NADnfection . Mtb infnfection ,90, whicydrolase . In addin escape . Mtb is n escape . While a+ and IDO–kynurenine pathways are linked, as the latter represents the de novo pathway for NAD+ synthesis. Earlier studies showed the potential utility of inhibiting tryptophan catabolism by IDO inhibition [+ synthesis via Kyn as an unintended consequence. It is likely that such inhibition accounts for the compensatory, counter-regulatory, and counter intuitive results that were obtained in some studies using IDO knockout mice [+ pathways, it is also possible that NAD+ precursors will synergize with IDO inhibitors in the control of Mtb infection. Furthermore, the IDO pathway is also connected to the signaling by Sirtuin1 (SIRT1) and AMP-activated protein kinase (AMPK) [+-dependent protein deacetylases involved in the control of Mtb and are activated by AMPK [+ precursors with SIRT1/AMPK activators should provide for optimum NAD+ levels and the control of Mtb replication in vivo. Further, NAD+ replenishment could not only optimize the effect of IDO blockade but also synergize with SIRT1/AMPK activators to control Mtb infection.The NADhibition . There iout mice . Considee (AMPK) . Sirtuin by AMPK . There i by AMPK . The mec by AMPK . Studies by AMPK . NAD rep by AMPK . Thus, tIt may be possible to inhibit IDO activity by D-1MT in Mtb/SIV-co-infected RMs on ART, with and without ATT, in order to answer the question as to whether this checkpoint inhibitor plays a key role in mediating the immunosuppressive effects arising from type I IFN induction due to chronic immune activation. It may be possible to inhibit IDO activity via multiple and diverse strategies. As discussed in the preceding sections, IDO is induced by SIV infection as well . TreatmeNew approaches are urgently needed to treat the TB/HIV syndemic. Defining the molecular mechanisms that govern the reactivation of TB in the presence of Mtb/HIV co-infection is a critical research priority for developing improved therapeutic regimens in combination with ART . Many crThe NHP model of TB, HIV, and Mtb/HIV co-infection has been instrumental in advancing our knowledge to this level, especially with respect to the immunosuppressive nature of the granuloma. Answering the critical questions highlighted in this review would allow us to gain a deep mechanistic understanding of complex immune networks and pathways in lung compartments, which is virtually impossible to do in humans but can be attempted in the NHP model. NHPs, including RMs, are particularly amenable to such studies. The ability to administer ART and block specific host pathways in vivo offers an unprecedented and unique opportunity for obtaining mechanistic insights, with translational potential for TB/HIV treatment.


Mammography, or breast X-ray imaging, is the most widely used imaging modality to detect cancer and other breast diseases. Recent studies have shown that deep learning-based computer-assisted detection and diagnosis (CADe/x) tools have been developed to support physicians and improve the accuracy of interpreting mammography. A number of large-scale mammography datasets from different populations with various associated annotations and clinical data have been introduced to study the potential of learning-based methods in the field of breast radiology. With the aim to develop more robust and more interpretable support systems in breast imaging, we introduce VinDr-Mammo, a Vietnamese dataset of digital mammography with breast-level assessment and extensive lesion-level annotations, enhancing the diversity of the publicly available mammography data. The dataset consists of 5,000 mammography exams, each of which has four standard views and is double read with disagreement (if any) being resolved by arbitration. The purpose of this dataset is to assess Breast Imaging Reporting and Data System (BI-RADS) and breast density at the individual breast level. In addition, the dataset also provides the category, location, and BI-RADS assessment of non-benign findings. We make VinDr-Mammo publicly available as a new imaging resource to promote advances in developing CADe/x tools for mammography interpretation. Treatment is most successful when breast cancer is at its early stage. Biennial screening can reduce breast cancer mortality rate by 30%2. Among standard imaging examinations for breast cancer diagnosis, namely mammography, ultrasound, digital breast tomosynthesis, and magnetic resonance, mammography is the recommended modality for cancer screening3. Interpreting mammography for breast cancer screening is a challenging task. The recall rate of mammogram screening is around 11% with a sensitivity of 86.9%, while the cancer detection rate is 5.1 per 1,000 screens4. It means that a large portion of cases called back for further examinations eventually result in non-cancer. Improving cancer screening results may help reduce the cost of follow-up examinations and unnecessary mental burdens on patients.Breast cancer is among the most prevalent cancers and accounts for the largest portion of cancer deaths, with an estimated 2.2 million new cases in 20206, several works have adapted deep learning networks for mammography interpretation and showed potential to use in clinical practices12. In retrospective settings, the CAD tool as an independent reader can achieve a performance comparable to an average mammographer8. It can be leveraged as a decision support tool that helps enhance radiologists’ cancer detection with the reading time being unchanged9. In another human-machine hybrid setting, where radiologists and machine-learning algorithm independently estimate the malignancy of the lesions, the linear combination of human and machine prediction show higher performance than a single human or machine reader10. The improvement as a result human-machine combination is also witnessed in screening mammography interpretation11. Furthermore, there was evidence that shows a machine learning model developed by training on data from a specific population (UK) can generalize and perform well on another population (US)12.With recent advancements of learning-based algorithms for image analysis19  dataset19 are the two earliest public datasets that provide digitalized scans of screen-film mammograms with precise annotations of breast abnormalities. The MIAS dataset was released in 1994 with 161 studies collected in the United Kingdom while the DDSM dataset consisted of 2,620 exams collected from institutions in the United States. Compared to the former one, the DDSM dataset has a significantly larger scale and follows the BI-RADS standard. To the best of our knowledge, INbreast17, released in 2012 with 115 exams from Portugal, is the very first public dataset that provides digital mammograms with lesions annotations and overall exam assessment following the BI-RADS standard. In 2019, the NYU Breast Cancer Screening Dataset16 was introduced with 229,426 screening exams, consisting of 1,001,093 images, from 141,473 women screened at NYU Langone Health. The dataset contains breast-level cancer based on biopsy results, exam-level assessment of BI-RADS, breast density, and biopsied finding annotations. While the dataset is not public, the subsequent work10 based on this dataset showed evidence that a large-scale dataset of mammography can enable a computer-aided system that helps improve radiologist performance. At around the same time, the Cohort of Screen-Aged Women Case-Control (CSAW-CC)20 was opened for evaluating AI tools for breast cancer, including 1303 cancer cases and 10,000 randomly selected controls from Karolinska University Hospital. The CSAW-CC dataset is a subset of the full CSAW dataset including women screened in the Stockholm region between 2008 and 2015. In cancer cases, visible tumors in mammography were manually annotated on a pixel level. Another large-scale dataset is the OPTIMAM mammography image database13 (OMI-DB) which consists of images and clinical data of 172 282 women screened and diagnosed in several institutions in the United Kingdom since 2011. To access to the OMI-DB dataset, the research group must submit an application to elaborate the scientific purpose based on the dataset which will be reviewed by the OPTINAM steering committee. In addition, the Chinese Mammography Database was recently introduced, containing 1,775 studies from several Chinese institutions. All cases have breast-level benign and malignant confirmed by biopsy, and molecular subtypes are available for 749 cases. A summary of the characteristics of these datasets is given in Table The recent progress in the study of mammography interpretation has drawn much attention with an increasing number of mammogram datasets with various characteristics, while some datasets are publicly available to the research community, some have restricted access or are not open21. Breast abnormalities that need short-term follow-up or are suspicious of malignancy are marked by bounding rectangles. Following European guideline22, mammography exams were independently double-read. Any discordance between the two radiologists would be resolved by arbitration with the involvement of a third radiologist. To the best of our knowledge, VinDr-Mammo is currently the largest public dataset  of full-field digital mammography that provides breast-level BI-RADS assessment category along with suspicious or probably benign findings that need follow-up examination. By introducing the dataset, we contribute a benchmarking imaging dataset to evaluate and compare algorithmic support systems for breast cancer screening based on FFDM.Along with the existing mammography datasets, we introduce and release the VinDr-Mammo dataset, an open-access large-scale Vietnamese dataset of full-field digital mammography consisting of 5,000 four-view exams with breast-level assessment and extensive lesion-level annotations. Our aims is to enhance the diversity of the publicly available mammography data for a more robust AI system and to lean towards a more interpretable system via extensive lesion-level annotations. Mammographies were acquired retrospectively from two primary hospitals in Hanoi, Vietnam, namely Hospital 108 (H108) and Hanoi Medical University Hospital (HMUH). Breast cancer assessment and density are reported following Breast Imaging Reporting and Data SystemThis study was approved by the Institutional Review Board of the HMUH and H108. All the personally identifiable information and protected health information of patients were removed. Additionally, this project did not affect clinical care at these two hospitals; hence patient consent was waived. The creation of the VinDr-Mammo dataset involves three stages: data acquisition, mammography reading, and data stratification. An overview of the data creation process is illustrated in Fig. https://hmu.edu.vn/) and Hospital 108 (H108–https://www.benhvien108.vn/home.htm). As the exams were randomly selected, the dataset includes both screening and diagnostic exams and represents the real distribution of patient cohorts in these hospitals. All images have the image presentation intent type of “FOR PRESENTATION” as those of for-processing were not stored by the hospitals. Images were acquired on equipments from 3 vendors, namely SIEMENS, IMS, and Planmed. All radiographers working at these hospitals were trained and certified by HMUH. To ensure patient privacy is protected, identifiable patient information in DICOM tags is fully removed via a Python script. Only necessary information used for loading and processing DICOM images and patient demographic information, i.e., age, is retained. Besides DICOM meta-data, associated information might appear in the images, such as laterality and view of the image and sometimes the patient’s name. As this textual information usually appears in the corners of the image, we remove them by setting to black all pixels in a rectangle at each corner. The size of the rectangle is determined by visually inspecting a subset of the collected dataset. To validate the pseudonymization stage, both DICOM metadata and image are manually reviewed by human readers.In this step, 20,000 mammography images in DICOM format from 5,000 mammography examinations were randomly sampled from the pool of all mammography examinations taken between 2018 and 2020 via the Picture Archiving and Communication System (PACS) of Hanoi Medical University Hospital  are provided. There are seven BI-RADS assessment categories, namely BI-RADS 0 , BI-RADS 1 (negative), BI-RADS 2 (benign), BI-RADS 3 (probably benign), BI-RADS 4 (Suspicious), BI-RADS 5  and BI-RADS 6 (known biopsy-proven). Since the biopsy results are not available, there is no presence of BI-RADS 6 in the re-reading process. Regarding the breast density level, its four categories are A , B (scattered areas of fibroglandular), C (heterogeneously dense), and D (extremely dense). For the mammography findings, the list of findings provided in this dataset includes the mass, calcification, asymmetries, architectural distortion, and other associated features, namely suspicious lymph node, skin thickening, skin retraction, and nipple retraction. Each finding is marked by a bounding box to localize the abnormal finding. In the given finding list, BI-RADS assessment is provided for mass, calcification, asymmetries, and architectural distortion. Since the purpose of this dataset is for breast cancer screening, benign findings, i.e., findings of BI-RADS 2, are not reported to reduce the annotating time. Only findings of BI-RADS categories greater than 2, which are not confident of benign or likely to be malignant, are marked. More details of the reading reports are provided in supplementary materials. Figure The reading results follow the schema and lexicon of the Breast Imaging Reporting and Data Systemhttps://github.com/vinbigdata-medical/vindr-lab), which was specifically designed for viewing and annotating medical images with the medical image viewer being based on the Open Health Imaging Foundation project (https://ohif.org/). The three participating radiologists were able to remotely access the data for reading and annotating. All three radiologists hold healthcare professional certificates, which require up to eight years of training program, and are approved by the Joint Review Committee on Education in Radiology, Vietnamese Ministry of Health. Furthermore, each reader has more than ten years of experience in the field. Specifically, all three radiologists received training in mammography interpretation and had an average of 19 years of clinical experience interpreting mammography (range 14–22 years). Additionally, each annotator reviewed an average of 13,333 mammography exams annually . Table The mammography reading process was facilitated by a web-based annotation tool called VinDr Lab  format. Subsequently, we parsed the exported file to discard unnecessary information, namely annotation timestamp, and radiologist’s identifier then simplified the file’s structure and transformed it to comma-separated values (CSV) file so that it could be easily parsed.23 which bases on a relaxed target that only retains a fraction of the appearance of each attribute while ignoring their co-occurrence. One-fifth of the dataset, equivalent to 1,000 exams, is for testing and the rest for training. The attributes that are taken into account for splitting include breast-level BI-RADS categories, breast composition, findings categories, and the attached BI-RADS categories (if any). The distribution of breast-level BI-RADS categories, breast composition, and findings for each subset are provided in Tables Recent CADx and CADe solutions are mostly learning-based approaches that require separating the dataset into disjoint subsets for training and evaluation. A pre-defined training/test split would help guarantee that different research works will use the same exams for training and testing. Otherwise, inconsistent or unstated splits in different research works might hinder the reproducibility and comparison of these works. For an appropriate stratification, both the training and test sets should reflex the assessment, composition, and distribution of findings of the whole dataset. However, stratifying that dataset while preserving the correlation between various data characteristics is challenging as the number of combinations of different attributes grows exponentially with the number of attributes . Hence, we split the dataset by an algorithm called iterative stratification24 for public access. Breast-level and lesion-level annotations of the whole dataset are stored in CSV files breast-level_annotations.csv and finding_annotations.csv, respectively. The images are structured into subfolders according to the encoded study identifiers, each of which contains four images corresponding to four views of the exam. The subfolder name and image file name are named following the study identifier and image identifier. The information of the breast-level annotations is provided for each image even though there is redundancy since each breast is associated with two images of different view positions, i.e., MLO and CC. We find this representation more convenient because other metadata of the image, namely laterality and view position, can also be included, eliminating the need to parse this information from the DICOM tags. Metadata for each image in the breast-level_annotations.csv file includes:study_id: The encoded study identifier.series_id: The encoded series identifier.image_id: The encoded image identifier.laterality: Laterality of the breast depicted in the image. Either L or R.view_position: Breast projection. Standard views are CC and MLO.height: Height of the image.width: Width of the image.breast_birads: BI-RADS assessment of the breast that the image depicts.breast_density: Density category of the breast that the image depicts.split: Indicating the split to which the image belongs. Either training or test.Both DICOM images and radiologists’ annotations of the dataset are available on PhysioNetimage_id: The encoded identifier of the image in which the finding appears.study_id: The encoded identifier of the associated study.series_id: The encoded identifier of the associated series.laterality: Laterality of the breast in which the finding appears.view_position: Orientation with respect to the breast of the image.height: Height of the image.width: Width of the image.breast_birads: BI-RADS assessment of the breast that the image depicts.breast_density: Density category of the breast that the image depicts.finding_categories: List of finding categories attached to the region, e.g., mass with skin retraction.finding_birads: BI-RADS assessment of the marked finding.xmin: Left boundary of the box.ymin: Top boundary of the box.xmax: Right boundary of the box.ymax: Bottom boundary of the box.split: Indicating the split to which the image belongs. Either training or test.Regarding breast findings, each annotation represents the occurrence of breast abnormality at a region, represented by a bounding box, in a specific image. This means that a single finding may associate with annotations from different views, yet this linking information is not acquired in the annotation process. Metadata for each finding annotation in the finding_annotations.csv file contains:25 of the patients has been fully removed to meet data privacy regulations such as the U.S. HIPAA26 and the European GDPR27. In addition, the image content of all mammograms was manually reviewed case-by-case by human readers to ensure that no patient information remained. We developed a set of rules underlying our labeling tool to reduce mislabeling. These rules allowed us to verify the radiologist-generated labels automatically. Specifically, they prevent annotators from mechanical mistakes like forgetting to choose global labels or marking lesions on the image while choosing “BI-RADS 1” as the breast-level assessment.The data pseudonymization procedure and the quality of the labeling process were strictly controlled. First, all meta-data was manually reviewed to ensure that all individually identifiable health information or PHIhttps://www.physionet.org/about/licenses/physionet-credentialed-health-data-license-150/). By accepting this DUA, users agree that the dataset can be used for scientific research and educational purposes only and will not attempt to re-identify any patients, institutions or hospitals. Additionally, the authors should cite this original paper for any publication that explores this dataset.The VinDr-Mammo dataset was created for the purpose of developing and evaluating computer-aided detection and diagnosis algorithms based on full-field digital mammography. In addition, it can also be used for general tasks in computer vision, such as object detection and multiple-label image classification. To download and explore this dataset, users are required to accept a Date Usage Agreement (DUA) called PhysioNet Credentialed Health Data License 1.5.0 , BI-RAS 1 , BI-RAS 2 . Additionally, some abnormalities, such as skin and nipple retraction, have less than 40 samples, making studying these abnormalities on this dataset less reliable. Finally, the introduced dataset is not DICOM-compliant and it would fail to be processed properly by DICOM processing libraries.Supplementary materials