Ecological context – the particular environment, and how it shapes mixing dynamics and individual susceptibility surrounding infectious disease events – can have major bearing on epidemic outcomes, yet directly comparable disease events with contrasting ecological contexts are relatively rare in wildlife systems due to concurrent differences in host genetics or pathogen strain. Here, we present a case study of one such event: a spillover of a “goat-clade” Mycoplasma ovipneumoniae strain into one bighorn sheep population that played out against two very different ecological backdrops. One event occurred on the herd’s home range near the Rio Grande Gorge in New Mexico, while the other progressed in a captive facility at Hardware Ranch in Utah. We collected data on antibody and pathogen load patterns through time at the individual level, and examined demographic responses to pathogen invasion to compare the intensity of, and in-host responses to, infection in both settings. While data collection regimens varied between the two sites, general patterns of antibody expansion and gross timing of symptoms were consistent. Symptoms emerged in the captive setting 12.9 days post-exposure, and we estimated an average time to seroconversion among the captive animals of 24.9 days. Clinical signs peaked among the captive animals at approximately 36 days post-infection, consistent with subsequent declines in symptom intensity in the free-ranging herd. At the captive site, older animals exhibited more severe declines in body condition as determined through declines in loin thickness, higher symptom burdens, and a decelerated antibody response to the pathogen. Younger animals were more likely than older animals to clear infection at or before the time of sampling at both sites. This study presents one of the richest datasets on immune responses in bighorn sheep over the course of a newly introduced M. ovipneumoniae strain available to-date.

Landslide susceptibility mapping has proved to be crucial tool for effective disaster management and planning strategies in mountainous regions. The present study is perused to investigate the changes in the landslide susceptibility of the Mandi district of Himachal Pradesh due to road construction. For this purpose, an inventory of 1723 landslides was generated from various sources. Out of these, 1199 (70%) landslides were taken in the training dataset to be used for modelling and prediction purposes, while 524 (30%) landslides were taken in the testing dataset to be used for validation purposes. Eleven landslide causative factors were selected from numerous hydrological, geological and topographical factors and were analyzed for landslide susceptibility mapping using three bivariate statistical models, namely; Frequency Ratio (FR), Certainty Factor (CF) and Shanon Entropy (SE). Two sets of LSM maps i.e. landslide susceptibility map natural (LSMN) and landslide susceptibility map road (LSMR), were generated using the above mentioned bivariate models and were divided into five landslide susceptibility classes namely; very low, low, medium, high and very high. These maps were analyzed for accuracy of prediction and validation using receiver operating characteristic (ROC) curves and area under curve (AUC) technique which indicated that all three bivariate statistical models performed satisfactorily with the SE model had the highest prediction and validation accuracy of 83-86%. Further analysis LSM maps confirmed that the percentage area in high and very high classes of land-slide susceptibility increased by 2.67-4.17% due to road construction activities in the study area.

Objective To examine the association between maternal education level and live birth after in vitro fertilization (IVF). Design Retrospective cohort study. Setting Public fertility center in China. Population 41546 women who underwent the first cycle of fresh or frozen-thawed embryo transfer between 2014 and 2019. Methods The women were divided into four educational categories according to the level of education received (elementary school graduate or less, middle school graduate, high school graduate, college graduate or higher). Main outcome measures Live birth rates. Results Patients were grouped by maternal educational level: elementary school graduate or less (n=1590), middle school graduate (n=10996), high school graduate (n=8354), and college graduate or higher (n=20606). The live birth rate, miscarriage rate, and clinical pregnancy rate in elementary school graduate or less were lower compared to other groups. In multivariate logistic regression analysis, we fail to demonstrate a statistically significant relationship between educational level and live birth in middle school graduate (adjusted odds ratio [AOR] 0.96; 95% confidence interval [CI], 0.84-1.09), high school graduate (AOR 1.01; 95% CI, 0.87-1.14) or college graduate or higher (AOR 1.01; 95% CI, 0.88-1.14) patients compared with the elementary school graduate or less reference group after adjusting for female age, infertility duration, BMI, EM thickness, no. of oocyte retrieved, infertility type, protocol in the fresh cycle, fertilization type, time of transfer and no. of embryo transferred. Conclusion No statistically significant relationship was identified between educational level and live birth in patients undergoing fresh or frozen embryo transfer.

Title: Notch4, uncovering an immunomodulator in allergic asthmaAuthors: Beatriz Moyaa, Manali Mukherjeeb and Parameswaran Nairba. Department of Allergy, Hospital Universitario 12 de Octubre, Madrid, Spainb. Division of Respirology, Department of Medicine, McMaster University, Hamilton & Firestone Institute for Respiratory Health, St Joseph’s Healthcare, Hamilton, ON, CanadaCorrespondence to : Beatriz Moya. Allergy Department. Hospital Universitario 12 de Octubre, Madrid, SpainEmail:drbeatrizmoya@gmail.comAcknowledgements : Dr. Mukherjee is supported by investigator award from Canadian Institutes of Health Research and Canadian Allergy, Asthma, and Immunology Foundation. She has received honorarium from AZ, GSK and her university has received grants from Methapharm Speciality Pharmaceuticals. Dr. Nair is supported by the Frederick E. Hargreave Teva Innovation Chair in Airway Diseases. He has received honoraria from AZ, Sanofi, Teva, Merck, Novartis and Equillium and his university has received research grants from AZ, Teva, Sanofi, Novartis, BI and Methapharm. The authors recognize Dr. Anna Globinska for graphical abstract design and Dr. Rodrigo Jiménez-Saiz for critical review of the manuscript.Keywords: Allergic asthma; Airway inflammation; Th2 cell; Th17 cell; Treg cell; Notch4 receptorAbbreviations: Th, T helper; UFPs, pollutant ultrafine particles; AMs, alveolar macrophages; Treg cells, regulatory T cells; ILC2s, type 2 innate lymphoid cells; GDF15, cytokine growth and differentiation factor 15; IL, interleukin; IL-6R, interleukin-6 receptor; IL-4R, interleukin-4 receptorWord count: 918/1000

S.T.E.M  Challenge - The Tow ChallengeGrade/Level: 7thTime Allotment: The total duration of The Tow Challenge is 60 minutes. In this time, the person in charge of the class will allocate time as follows:5 minutes: explanation of the challenge and QA off from such explanation. 5 minutes: present the materials that can be used in the challenge. 45 minutes: students completing the challenge. 5 minutes: open discussion among the students. Type of Technology: Construction, forces, Math, and PhysicsChallenge: Each group within the class is challenged to Tow a 4-wheeled dolly with the rest of the class standing on it. Essential Question or Problem to be Solved: Can you build a towing mechanism using only the provided materials?Student Learning Outcomes:Understand the science and physics behind pull forces. Understand the different strengths of materials. Calculate the force needed to pull a given weight. Use and understand the Engineering Design Process when creating a structure.Openly discuss their experimentation findings with their classmates to reiterate and come up with a better solution. Materials: Teacher Materials: Masking Tape (2)Measuring Tape (1)Sharpie/Marker (1)4 wheeled dolly (1 - big enough to hold at least 4 students/2 teachers on top of it)Team Materials:Sheets of newspaper (50 pages of US Broadsheet newspapers) Sharpie/Marker (1)Straws (10) Scissors (1) Rope  (1 foot) Masking Tape (3 Feet) Aluminum Foil (1) Letter-sized sheets (3)

Accurate chemical kinetics are essential for reactor design and operation. However, despite recent advances in “big data” approaches, availability of kinetic data is often limited in industrial practice. Herein, we present a comparative proof-of-concept study for kinetic parameter estimation from limited data. Cross-validation (CV) is implemented to nonlinear least-squares (LS) fitting and evaluated against Markov chain Monte Carlo (MCMC) and genetic algorithm (GA) routines using synthetic data generated from a simple model reaction. As expected, conventional LS is fastest but least accurate in predicting true kinetics. MCMC and GA are effective for larger data sets but tend to overfit to noise for limited data. Cross-validation least-square (LS-CV) strongly outperforms these methods at much reduced computational cost, especially for significant noise. Our findings suggest that implementation of cross-validation with conventional regression provides an efficient approach to kinetic parameter estimation with high accuracy, robustness against noise, and only minimal increase in complexity.

Aim A robust and user-friendly software tool was developed for the prediction of dopamine D2 receptor occupancy (RO) in patients with schizophrenia treated with either olanzapine or risperidone. This tool can facilitate clinician exploration of the impact of treatment strategies on RO using sparse plasma concentration measurements. Methods Previously developed population pharmacokinetic (PPK) models for olanzapine and risperidone were combined with a PD model for D2 receptor occupancy (RO) and implemented in the R programming language. MAP Bayesian estimation was used to provide predictions of plasma concentration and receptor occupancy and based on sparse PK measurements. Results The average (standard deviation) response times of the tools were 2.8 (3.1) and 5.3 (4.3) seconds for olanzapine and risperidone, respectively. The mean error (95% confidence interval) and root mean squared error (RMSE, 95% CI) of predicted versus observed concentrations were 3.73 ng/mL (-2.42 – 9.87) and 10.816 (6.71 – 14.93) for olanzapine, and 0.46 ng/mL (-4.56 – 5.47) and 6.68 (3.57 – 9.78) for risperidone and its active metabolite (9-OH risperidone). Mean error and RMSE of RO were -1.47% (-4.65 – 1.69) and 5.80 (3.89 – 7.72) for olanzapine and -0.91% (-7.68 – 5.85) and 8.87 (4.56 – 13.17) for risperidone. Conclusion Treatment of schizophrenia with antipsychotics offers unique challenges and requires careful monitoring to establish the optimal dosing regimen. Our monitoring software predicts RO in a reliable and accurate form.

The coexistence of granular liquid-like phase (cluster) and gas-like phase (void) in fluidization, a spontaneous symmetry-breaking dissipative state, contributes to excellent mixing behavior in multi-phase reactors. In present study, a universal granular state equation to describe phase coexistence far from critical point is developed, where both the inelastic solid-collision and asymmetrical instability is taken into consideration. Catastrophe theory is applied to find the stable boundary of phase coexistence, and verified by cold-flow experiment with different solid pressure. A phase diagram, based on both theoretical analysis and experimental study, is given as a useful guideline of design and operation of efficient multi-phase reactors.

Background: Resolution of inflammation is now recognized as a tightly regulated and active process. Lipoxins (LX) are lead members of a larger family of specialized pro-resolving mediators with unique anti-inflammatory and pro-resolving properties. Recent studies implicated natural killer (NK) cells in the resolution of allergic airway inflammation, notably in promoting eosinophil apoptosis. The aim of the study was to better understand the pro-resolving actions of NK cells and LXA4 during allergic eosinophilic airway inflammation. Methods: 20 subjects with grass pollen allergic rhinitis were included. A nasal provocation test with either a single grass pollen allergen threshold dose or diluent was used. Nasal lavage fluid and cells were collected at baseline and at different time points after challenge. For in vitro assays, eosinophils were incubated with NK cells. Results: We observed that NK cells were recruited to the nasal mucosa shortly after the initiation of the allergic inflammatory response. This recruitment correlated with eosinophilic inflammation. In vitro assays demonstrated that direct contact and a combined action of CD56bright and CD56dim NK cells were needed to promote autologous eosinophil apoptosis. We furthermore observed that local LXA4 production correlated with the peak of neutrophil nasal mucosal infiltration, suggesting a potential role of neutrophils in LXA4 biosynthesis during the early phase of the allergic inflammatory response. Last, LXA4 appeared as essential to inhibit the in vitro release of eosinophil superoxide triggered by NK cells. Conclusion: Together, these findings indicate a synergistic role for NK cells and LXA4 in the resolution of allergic eosinophilic inflammation.

Based on an analysis of anonymized medical records from four hospitals in Asia and Africa, we succeeded in identifying symptoms typical for narcolepsy (with cataplexy) that are regularly overlooked because they are masked by the two severe leading symptoms. Our results do not differ between primary and secondary cases of narcolepsy. 

This article assesses the role of recipient genetics to COVID-19 vaccine responses. Vaccines represent preventative interventions suitable to an immunogenetic perspective to predict how human variability will influence their safety and efficacy. The genetic polymorphism among individuals within any population can make possible that the immunity elicited by a vaccine is variable in length and strength. The same immune challenge (either virus or vaccine) could provoke partial, complete or even failed protection for some individuals treated under the same conditions. We review genetic variants and mechanistic relationships among chemokines, chemokine receptors, interleukins, interferons, interferon receptors, toll-like receptors, histocompatibility antigens, various immunoglobulins and major histocompatibility complex antigens. These are the targets for variation among macrophages, dendritic cells, Natural Killer cells, T- and B- lymphocytes, and complement. The acute nature of vaccine reactogenicity is reminiscent of the time course of adverse drug reaction mediated by the immune system. The variety of technology platforms (mRNA, viral vectors) utilized currently to produce vaccines against SARS-CoV-2 infections may each also trigger genetically distinct immune reactogenic profiles. With biobanking of recipient genomic DNA and serum immunoprofiling, global COVID-19 vaccinations could launch a new era of research and clinical translation in personalized health.

This article proposes an analytical model to understand the rod-growth of eutectic in the bulk undercooled melt. Based on the previous derivations of the lamellar eutectic growth models, relaxing the assumptions of small Peclet numbers, the model is derived by considering melt kinetic and thermal undercoolings. The intent of this model is to predict the transitions in eutectic pattern for conditions of the low and high growth velocity. In addition to investigation of the transition between lamellar and rod eutectic pattern, mathematical simplifications of solving Bessel function are presented as well, which is the most important priority to model calculation.

In the development of personalized medicine, the ultrasensitive detection of point mutations that correlate with diseases is important to improve the efficacy of treatment and guide clinical medication. In this study, locked nucleic acid (LNA) was introduced as an amplification suppressor of a massive number of wild-type alleles in an amplification refractory mutation system (ARMS) to achieve the detection of low-abundance mutations with high specificity and sensitivity of at least 0.1%. By integrating the length of clamp, base type, number and position of LNA modifications, we have established a “shortest length with the fewest LNA bases” principle from which each LNA base would play a key role in the affinity and the ability of single base discrimination could be improve. Finally, based on this LNA design guideline, a series of the most important single point mutation sites of epidermal growth factor receptor (EGFR) was verified to achieve the optimal amplification state which as low as 0.1% mutation gene amplification was not affected under the wild gene amplification was completely inhibited, demonstrating that the proposed design principle has good applicability and versatility and is of great significance for the detection of circulating tumor DNA.

Background: The high incidence of postoperative pulmonary venous obstruction (PVO) is a major mortality-associated concern in patients with right atrial isomerism and extracardiac total anomalous pulmonary venous connection (TAPVC). We evaluated new anatomical risk factors for reducing the space behind the heart after TAPVC repair. Methods: 18 patients who underwent TAPVC repair between 2014 and 2020 were enrolled. Sutureless technique was used in 12 patients and conventional repair in six patients. The angle between the line perpendicular to the vertebral body and that from the vertebral body to the apex was defined as the “vertebral-apex angle (V-A angle).” The ratio of post- and preoperative angles, indicating the apex’s lateral rotation, was compared between patients with and without PVO. Results: The median (interquartile range) age and body weight at repair were 102 (79-176) days and 3.8 (2.6-4.8) kg, respectively. The 1-year survival rate was 83% (median follow-up, 29 [11-36] months). PVO occurred in seven patients (39%), who showed an obstruction of one or two branches in the apex side. The postoperative V-A angle (46° [45°-50°] vs. 36° [29°-38°], P = 0.001) and the ratio of post- and preoperative V-A angles (1.27 [1.24-1.42] vs. 1.03 [0.98-1.07], P = 0.001) were significantly higher in the PVO group than in the non-PVO group. The cut-off values of the postoperative V-A angle and ratio were 41° and 1.17, respectively. Conclusions: A postoperative rotation of the heart apex into the ipsilateral thorax was a risk factor for branch PVO after TAPVC repair.

Abstract Background Subaortic stenosis (SAS) was a rare congenital heart disease of left ventricular outflow tract (LVOT), ranging from “isolated” lesions to “tunnel” or “diffuse” lesions. We conducted a retrospective study to describe the characteristics of patients with different lesions and analyze the risk factors for reoperation. Methods In this study, we examined a single-center retrospective cohort of SAS patients undergoing resection from 2010 to 2019. Patients were classified as simple lesion group (n = 37) or complex lesion group (n = 28). Demographics, perioperative findings, and clinical data were analyzed. Results The surgical effect of the two groups was significantly lower than that before the operation (p <0.05). The median age at operation was 6(3-11.8) years. There was no operative mortality. In complex lesion group, extracorporeal circulation time (CPB time), aortic cross clamp time (ACC time), mechanical ventilation time and ICU stay time were longer. The median follow-up period was 2.8 years (range 1-3.8), with two late death. Six patients (9.2%) required reoperation due to restenosis or severe aortic insufficiency. The freedom from reoperation rates at 5 years was 66.7% for simple lesion but only 52.3% for complex lesion (p = 0.036). Conclusions Although the lesions include many forms, subaortic stenosis resection was still satisfactory. However, the reoperation after initial surgical treatment was not infrequent, especially in patients with complex lesion.

Background: This study aims at better defining the profile of patients with a complicated versus non-complicated postoperative course following isolated tricuspid valve (TV) surgery to identify predictors of a favourable/unfavourable hospital outcome. Methods: All patients treated with isolated tricuspid surgery from March 1997-January 2020 at our institution were retrospectively reviewed. Considering the complexity of most of these patients, a regular postoperative course was arbitrarily defined as a length-of-stay in intensive care unit <4 days and/or postoperative length-of-stay <10days. Patients were therefore divided accordingly in two groups. Results: 172 patients were considered, among whom 97 (56.3%) had a regular (REG) and 75 (43.6%) a non-regular (NEG) postoperative course. The latter had worse baseline clinical and echocardiographic characteristics, with higher rate of renal insufficiency, previous heart failure hospitalizations, cardiac operations, and right ventricular dysfunction. NEG patients more frequently needed tricuspid replacement and experienced a greater number of complications (p<0.001) and higher in-hospital mortality (13% vs 0%, p<0.001). The majority of these complications were related to more advanced stage of the tricuspid disease. Among most important predictors of a negative outcome univariate analysis identified chronic kidney disease, ascites, previous right heart failure hospitalizations, right ventricular dysfunction, previous cardiac surgeries, TV replacement and higher MELD scores. At multivariate analysis, liver enzymes and diuretics’ dose were predictors of complicated postoperative course. Conclusions: In isolated TV surgery a complicated postoperative course is observed in patients with more advanced right heart failure and organ damage. Earlier surgical referral is associated to excellent outcomes and should be recommended.

Introduction: Over-prescription of antimicrobials for patients is a major driver of bacterial resistance. The aim of the present study was to assess the knowledge, attitude and prescription in relation to antimicrobials among physicians in the Zhejiang province in China, and identify the determining factors. Methods: A total of 600 physicians in public county hospitals and township health institutions were surveyed cross-sectionally using a structured electronic questionnaire. Results: The questionnaire was completed by 580 physicians and accordingly, the response rate was 96.67%. The mean score of 11 terms related to antimicrobial knowledge was 6.81, and that an average of 32.1% of patients with upper respiratory tract infections (URIs) would be prescribed antimicrobials. Multivariate analysis indicated that young general practitioners with less training are more likely to contribute to high antimicrobial prescriptions (P<0.05). Older physicians with more trainings are more willing to provide patients with the correct knowledge regarding antimicrobials and less likely to prescribe antimicrobial s to URIs. The results of the correlation analysis showed that a positive connection was found between the doctor’s knowledge, attitude and prescription practice (P<0.05). Conclusion: Proper prescription of antimicrobials depends on adequate knowledge and regular training programs for physicians.

Objective: to evaluate current practice and outcomes of pregnancy in women previously diagnosed with Budd-Chiari syndrome and/or portal vein thrombosis, with and without concomitant portal hypertension. Design and setting: multicentre retrospective cohort study between 2008-2021 Population: Women who conceived in the predefined period after the diagnosis of Budd-Chiari syndrome and/or portal vein thrombosis Methods and main outcome measures: We collected data on diagnosis and clinical features. The primary outcomes were maternal mortality and live birth rate. Secondary outcomes included maternal, neonatal and obstetric complications. Results: Forty-five women (12 Budd-Chiari syndrome, 33 portal vein thrombosis; 76 pregnancies) were included. Underlying prothrombotic disorders were present in 23 of 45 women (51%). Thirty-eight women (84%) received low-molecular-weight heparin during pregnancy. Of 45 first pregnancies, 11 (24%) ended in pregnancy loss and 34 (76%) resulted in live birth of which 27 at term age (79% of live births and 60% of pregnancies). No maternal deaths were observed, one woman developed pulmonary embolism during pregnancy and two women (4%) had variceal bleeding requiring intervention. Conclusions: The high number of term live births (79%) and lower than expected risk of pregnancy-related maternal and neonatal morbidity in our cohort suggest that Budd-Chiari syndrome and/or portal vein thrombosis should not be considered as an absolute contra-indication for pregnancy. Individualized, nuanced counselling and a multidisciplinary pregnancy surveillance approach are essential in this patient population.

Key Points • Transnasal Oesophagoscopy (TNO) is an approach to inspect the upper aerodigestive tract, especially in the head and neck cancer (HNCA) population that present with dysphagia. • Twenty-five (25) office-based TNO procedures were performed, with a same-day discharge rate of 96% (24/25) and no reported complications. • This case series is the first to compare preoperative and postoperative outcomes (EAT-10) following stricture dilatation using TNO in the UK. Our results show a statistically significant improvement in symptom severity (EAT-10 scores) (n=11, P=0.001). In the majority of these patients, strictures were due to post-radiation complications. Biopsy in 4/5 cases was sufficient for diagnosis/ruling out disease. Of these patients, 80% had a previous HNCA. • This study identifies the remit for a new ‘one-stop’ TNO service for suspected cancer referrals, of which a large proportion are patients with a previous HNCA. Surveillance, therapeutics and diagnostics can be achieved in a single visit. • Earlier staging or treatment may be achieved due to a fast turnover in clinic

Slope gradient and vegetation cover play key roles in soil erosion process. Exploring the effects of slope gradient and vegetation cover on runoff and sediment yielding characteristics is therefore of great importance for minimizing soil erosion. In this work, based on field scouring experiments on the riparian slopes of the lower Yellow River, China, variation in total runoff, accumulative runoff sediment concentration, erosion sediment yield, and sediment particle size composition under four slope gradients (5°, 10°, 15°, 20°) and three vegetation cover levels (0%, 15%, 30%) were analyzed. Runoff and sediment yield were greatly influenced by slope gradient at steep slope gradients (15° and 20°), while they were mainly affected by vegetation cover at medium slope gradients (5° and 10°). The main enriched particle size of the eroded sediment showed a trend of first increasing and then decreasing with the increasing slope gradient. There was an interaction between slope gradient and vegetation cover, the effect of vegetation cover on erosion sediment yield weakened gradually with increasing slope gradient (at medium slope gradients of 5° and 10°), while the effect of slope gradient increased at steep slope gradients (15° and 20°).

Mycorrhizal associations are essential for orchid germination and seedling establishment, and thus may constrain the distribution and abundance of orchids under natural conditions. Previous works have shown that germination and seedling establishment in several orchids often decline with increasing distance from adult plants, resulting in nonrandom spatial patterns of seedling establishment. In contrast, individuals of the fully mycoheterotrophic orchid Gastrodia confusoides often tend to have random spatial patterns of distribution within bamboo forests. Since G. confusoides is parasitic on litter-decaying fungi, its random spatial patterns of distribution may be due to highly scattered patterns of litter-decaying fungi within bamboo forests. To test this hypothesis, we first identified the main mycorrhizal fungi associating with developing seeds and adult plants using Miseq high-throughput sequencing. Next, we combined seed germination experiments with quantitative PCR (qPCR) analyses to investigate to what extent the abundance of mycorrhizal fungi affected spatial patterns of seed germination. Our results show that seed germination and subsequent growth to an adult stage in G. confusoides required a distinct switch in mycorrhizal partners, in which protocorms associated with a single Mycena fungus, while adults associated with a fungus from the genus Gymnopus. A strong, positive relationship was observed between germination and Mycena abundance in the litter, but not between germination and Gymnopus abundance. Fungal abundance was not significantly related to the distance from the adult plants, and consequently germination was also not significantly related to the distance from adult plants. Our results provide the first evidence that the spatial distribution and abundance of litter-decaying fungi are distributed randomly within the bamboo forest and independently from G. confusoides adults.

Cholesterol-rich arterial plaques characterize atherosclerosis, a significant cause of heart disease. Arterial plaques upregulate inflammatory cytokines secreted by the macrophages that finally become cholesterol-laden foam cells. Nutraceuticals have received attention over the years, demonstrating potential benefits towards treating and preventing cardiovascular diseases (CVD), including atherosclerosis. Curcumin, a potent polyphenol present in Curcuma longa, showed remarkable anti-atherosclerotic activity via anti-inflammatory and anti-oxidative properties. The bioavailability and low water solubility of curcumin limit its clinical translational purposes. These issues can be circumvented effectively by nano-drug delivery systems that can target atherosclerotic plaque sites. In this work, we chose to use curcumin and a natural bioenhancer called Bioperine (derived from Piper nigrum) inside a polymeric nano-drug delivery system for targeting atherosclerotic plaque sites. We selected two different ratios of curcumin: Bioperine to study its comparative effect on the inhibition of oxidized low-density lipoprotein (Ox-LDL) induced foam cell formation and investigated the therapeutic efficacy in THP-1 monocyte-derived macrophages via different in vitro cell studies. Our studies demonstrated that Bioperine administration alongside curcumin via PLGA nanoparticles (NPs) imparts a reduction in macrophage-mediated foam cell formation, relative cholesterol content, and the inflammatory pathways when administered as preventive medicine, highlighting the importance of natural-based compounds towards the therapeutic intervention against the atherosclerotic activity.

BJOG-20-2353.R2 What should we believe when systematic reviews disagree?For many years, uterine balloon tamponade (UBT) has been used to treat severe postpartum haemorrhage (PPH), despite a lack of randomised trials to demonstrate its effectiveness. With commercial devices being expensive, clinicians in low resource settings have made their own using 2 low-cost, widely available items (Foley catheters and condoms). Public health experts have been so confident of their benefit that large programmes have been set up to disseminate the necessary skills worldwide.Recently, however, the global maternal health community has been thrown into disarray when not one, but two randomised controlled efficacy trials suggested that outcomes with condom catheter UBTs were actuallyworse than normal care in low resource settings. The Cochrane meta-analysis concluded that “in [low resource] settings, balloon tamponade [should be] only introduced alongside multi‐system improvements in PPH care” (Kellie et al. Cochrane Database of Systematic Reviews 2020(7): CD013663).Systematic reviews may be the pinnacle of evidence-based medicine, but even they can differ in how to interpret evidence. And so, proponents of the condom catheter conducted their own systematic review with far wider inclusion criteria – they not only included the randomised trials but examined success rates from 15 non-randomised trials and 69 case series (Suarez et al. Am J Obstet Gynecol 2020;222(4):293.e1–e52). Furthermore, the primary outcome was the success rate of the technique (overall 86%) rather than the risk of morbidity and mortality compared to controls, as used in the Cochrane review. This is problematic, as reported ‘success rates’ without controls can be very difficult to interpret: in initial case series misoprostol showed similar success rates against life-threatening haemorrhage before RCTs eventually showed it to be less effective than oxytocin.A third version of the same review is published today by a WHO team (Pingray et al. BJOG 2021;XXX,XXX). This time they include only 4 high quality studies in which UBT was compared to standard care. With a composite maternal morbidity / mortality outcome, they found no evidence of benefit and concluded that “the effect … is unclear, as is the role of the type of device and the setting”. WHO studies are now underway to address this uncertainty.But why is this all so important? The difficulty comes because the World Health Organisation has been updating its guidance on PPH management, and had to declare a position on UBT. The recently-published guideline, drawn up by independent experts, accepts the validity of the RCTs but recognises that there is wide acceptability of the technique and that the evidence of harm is only for condom catheters and onlyin resource-poor settings. They put a high emphasis on minimising harm and conclude that UBTs should only be used in settings where there is already a good standard of care, including recourse to blood transfusion and surgery if needed (WHO. Geneva: World Health Organization; 2021).Until further studies are published, the debate will continue. But this episode shows how the choice of inclusion criteria and outcomes in systematic reviews are critical, both for their conclusions, and for global policy.

Is the patient choice the best choice?