Protective effect of ischaemic preconditioning on acute and chronic renal damage following ischaemia reperfusion injury: characterisation of fibrosis development after inflammation resolution.

OBJECTIVES: Acute Kidney Injury (AKI) and Chronic Kidney Disease (CKD) are increasingly recognised as one disease continuum, rather than distinct entities, and are associated with a huge burden to healthcare services. The leading cause of AKI worldwide is Ischaemia Reperfusion Injury (IRI), most commonly seen in clinical settings of sepsis-driven hypotension. Ischaemic Preconditioning (IPC) is a strategy aimed at reducing the deleterious effects of IRI. The objectives of this study were to demonstrate an efficacious in vivo model of Kidney IRI, and the protective influence of IPC in attenuating AKI and development of renal fibrosis. METHODS: A rat model of bilateral kidney IRI was used: Male Lewis rats (n=84) were assigned to IRI, sham or IPC. In IRI, renal pedicles were clamped for 45 minutes. IPC groups underwent pulsatile IPC prior to IRI. Kidneys were retrieved at 24 hours, 48 hours, 7 days, 14 days and 28 days, and assessed histologically. RESULTS: IRI led to marked AKI (24-48 h) and renal fibrosis development by 28 days. IPC attenuated this damage, with 66% less fibrosis. Interestingly, at 14-days, the histological appearance of both IRI and IPC kidneys was rather similar, potentially representing an important transitional point at which kidneys commit to either fibrosis or recovery. This may provide a suitable inflexion point for introduction of novel anti-fibrotic therapies. CONCLUSIONS: In conclusion, we have characterised a model of kidney injury from acute to chronic phases, allowing detailed mechanistic understanding and which can be manipulated by effective treatment strategies such as IPC.

Robust Rat and Mouse Models of Bilateral Renal Ischemia Reperfusion Injury.

BACKGROUND/AIM: Acute and chronic kidney diseases are a major contributor to morbidity and mortality worldwide, with no specific treatments currently available for these. To enable understanding the pathophysiology of and testing novel treatments for acute and chronic kidney disease, a suitable in vivo model of kidney disease is essential. In this article, we describe two reliable rodent models (rats and mice) of efficacious kidney injury displaying acute to chronic kidney injury progression, which is also reversible through novel therapeutic strategies such as ischemic preconditioning (IPC). MATERIALS AND METHODS: We utilized adult male Lewis rats and adult male wildtype (C57BL/6) mice, performed a midline laparotomy, and induced warm ischemia to both kidneys by bilateral clamping of both renal vascular pedicles for a set time, to mimic the hypoxic etiology of disease commonly found in kidney injury. RESULTS: Bilateral ischemia reperfusion injury caused marked structural and functional kidney injury as exemplified by histology damage scores, serum creatinine levels, and kidney injury biomarker levels in both rodents. Furthermore, this effect displayed a dose-dependent response in the mouse model. CONCLUSION: These rodent models of bilateral kidney IRI are reliable, reproducible, and enable detailed mechanistic study of the underlying pathophysiology of both acute and chronic kidney disease. They have been carefully optimised for single operator use with a strong track record of training both surgically trained and surgically naïve operators.

Artificial Intelligence in the Diagnosis of Colorectal Cancer: A Literature Review.

BACKGROUND: The aim of this review is to explore the role of artificial intelligence in the diagnosis of colorectal cancer, how it impacts CRC morbidity and mortality, and why its role in clinical medicine is limited. METHODS: A targeted, non-systematic review of the published literature relating to colorectal cancer diagnosis was performed with PubMed databases that were scouted to help provide a more defined understanding of the recent advances regarding artificial intelligence and their impact on colorectal-related morbidity and mortality. Articles were included if deemed relevant and including information associated with the keywords. RESULTS: The advancements in artificial intelligence have been significant in facilitating an earlier diagnosis of CRC. In this review, we focused on evaluating genomic biomarkers, the integration of instruments with artificial intelligence, MR and hyperspectral imaging, and the architecture of neural networks. We found that these neural networks seem practical and yield positive results in initial testing. Furthermore, we explored the use of deep-learning-based majority voting methods, such as bag of words and PAHLI, in improving diagnostic accuracy in colorectal cancer detection. Alongside this, the autonomous and expansive learning ability of artificial intelligence, coupled with its ability to extract increasingly complex features from images or videos without human reliance, highlight its impact in the diagnostic sector. Despite this, as most of the research involves a small sample of patients, a diversification of patient data is needed to enhance cohort stratification for a more sensitive and specific neural model. We also examined the successful application of artificial intelligence in predicting microsatellite instability, showcasing its potential in stratifying patients for targeted therapies. CONCLUSIONS: Since its commencement in colorectal cancer, artificial intelligence has revealed a multitude of functionalities and augmentations in the diagnostic sector of CRC. Given its early implementation, its clinical application remains a fair way away, but with steady research dedicated to improving neural architecture and expanding its applicational range, there is hope that these advanced neural software could directly impact the early diagnosis of CRC. The true promise of artificial intelligence, extending beyond the medical sector, lies in its potential to significantly influence the future landscape of CRC's morbidity and mortality.

The influence of socioeconomic deprivation on outcomes in transplant patients infected with SARS-CoV-2 in Wales.

INTRODUCTION: SARS-CoV-2 infection has had a significant impact on vulnerable individuals including transplant patients. Socioeconomic deprivation negatively affects outcomes of many health conditions. The aim of this study was to evaluate the effect of socioeconomic deprivation on the incidence and severity of SARS-CoV-2 infection among Welsh transplant patients. METHODS: This study is a retrospective, cross-sectional study on the transplant population of Wales. The Welsh Index of Multiple Deprivation (WIMD) was used to assess the influence of socioeconomic deprivation on outcomes of Welsh transplant patients who developed SARS-CoV-2 infection. Outcome measures were the incidence of SARS-CoV-2 infection, rates of hospital and ICU admission, development of acute kidney injury (AKI) and mortality. A logistic binomial regression analysis was used to correlate the various risk factors with the incidence of SARS-CoV-2 infection. RESULTS: Two hundred and sixty-six (25%) of regular follow up patients had SARS-CoV-2 infection; of these 55 (20.7%) were admitted, 15 (5.6%) to ICU, 37 (13.9%) developed AKI, and 23 (8.6%) died. In a regression analysis, patients of younger age were associated with more (p = .001) and those with SPK (simultaneous pancreas kidney) transplant less chance of infection (p = .038), whereas social deprivation was not associated with the chance of infection (p = .14). In regression analysis increased social deprivation was associated with higher chance of AKI post SARS-CoV-2 (p = .049). CONCLUSIONS: Socioeconomic deprivation did not affect the rates or severity of SARS-CoV-2 infection apart from the degree of AKI in Welsh Transplant patients. Adherence to the preventive measures for this high-risk population must continue to remain a priority.

Experimental and numerical techniques to evaluate coal/biomass fly ash blend characteristics and potentials.

Fossil and renewable fuels are used by industrial units that produce energy-intensive products. Competitive fuel pricing encourages these fuel sources' usage globally, particularly in developing nations, which leads to large volumes of byproducts like fly ash among thermal power plant operators. The elements and compounds found in coal fly ash (CFA) and biomass fly ash (BFA) can be utilized through several engineering applications. This study aims to assess typical CFA and BFA samples quantitatively and qualitatively via techniques such as ultimate analysis (CH-S), Fourier transform infrared spectroscopy (FTIR), thermogravimetric analysis (TGA), X-ray diffraction (XRD), X-ray fluorescence (XRF) elemental analysis, and ash fusion temperature (AFT), to anticipate the ideal ratios of coal to biomass blends for combustion applications while adhering to environmental regulations. The optimal blend, consisting of 75 % CFA and 25 % BFA, exhibited improved carbon (C%) and hydrogen (H%) percentages, increasing from 2.5 % to 4.67 % and from 0 % to 0.12 %, respectively. These improvements were further confirmed by the observed functional groups in FTIR, indicating a rising trend in both carbon and hydroxyl groups from BFA to CFA. XRF and XRD also confirmed it and TGA also showed optimum mass loss (ML%) behavior of 14.55 % for 75CFA + 25BFA. According to slagging and fouling indices, the values of RB/A, Rs, and Fu indicate a reduction in slagging and fouling issues through the blending of CFA with BFA. Simultaneously, the fusion temperature increased from 1181 °C to 1207 °C. CFA was found to increase the AFT of the BFA from 1197 °C to 1247 °C, mitigating their propensity. This suggests that a blend of 75CFA + 25BFA results in lower to medium range of slagging and fouling. However, AFI and BAI indicate a slightly higher range. AFT analysis further validates the conclusions drawn from the indices. The ternary phase diagram shows that the ash's melting point increases in the optimum blend. This is attributed to a reduced content of K2O (<15 %) and increased proportions of >50 % CaO and SiO2, effectively inhibiting slagging, agglomeration, and deposition. Meanwhile, the blend maintains a medium level of acidity and susceptively to corrosion, as observed in the case of 75CFA + 25BFA. The identification of optimal blend ratios can be anticipated to offer essential solutions for future research, aiming to ensure smooth industrial operations and regulatory compliance in power plants.

COVID-19 economic stimulus packages, tourism industry and external debt: The influence of extreme poverty.

The COVID-19 outbreak has had a catastrophic effect on the tourism sector and poverty alleviation efforts. This is especially the case, given the crucial role the tourism sector plays in poverty alleviation and the generation of foreign exchange earnings. This study investigates the moderating influence of extreme poverty on the underlying link between the size of the tourism industry and COVID-19 Economic Stimulus Packages (ESPs) while accounting for the influence of external debt. The results show that tourism-dependent economies with a larger share of individuals living in extreme poverty introduced larger ESPs to cushion the impacts of the COVID-19 outbreak. In addition, economies with larger external debt have less fiscal and monetary leeway to alleviate the negative effects of the COVID-19 outbreak.

Quality improvement through audit: Zuclopenthixol acetate prescribing, monitoring and patient outcomes in a regional health service.

OBJECTIVE: Prescribers' expectations of Zuclopethixol Acetate's (ZA) efficacy and tolerability are shaped by clinical experience and organisational culture; however, these expectations may not be consistent with current evidence and best practice. METHODS: Quality improvement project (QIP) through a process audit of ZA prescribing, monitoring and patient outcomes (adverse events) in order to identify issues requiring intervention to align with service standards and practices. RESULTS: QIP interventions resulted in a statistically significant shift in psychiatrist oversight, identifying high dose ZA with adverse outcomes and cessation of prescribing/administration within the Emergency Department. Clinically significant changes in patterns of prescribing were observed between pre-post intervention audits. CONCLUSION: Entrenching an evidence-based QIP approach to clinical practice can effect clinically significant patterns of practice change to improve safe prescribing and drug monitoring.

Removal of ceftriaxone sodium antibiotic from pharmaceutical wastewater using an activated carbon based TiO2 composite: Adsorption and photocatalytic degradation evaluation.

The water pollution becomes a serious concern for the sustainability of ecosystems due to the existence of pharmaceutical products (ceftriaxone (CEF) antibiotic). Even in low concentration of CEF has lethal effects on ecosystem and human health. To remove CEF, TiO2 is considered as an effective and efficient nanoparticles, however its performance is reduced due to wider energy gap and rapid recombination of charge carriers. In this study, activated carbon based TiO2 (ACT-X) heterogeneous nanocomposites were synthesized to improve the intrinsic properties of TiO2 and their adsorption-photocatalytic performance for the removal of CEF. The characterization results revealed that ACT-X composites have slower recombination of charge carriers, lower energy band gap (3.05 eV), and better light absorption under visible region of light. From ACT-X composites, the ACT-4 photocatalyst has achieved highest photocatalytic degradation (99.6%) and COD removal up (99.2%). The results of radical scavengers showed that photocatalytic degradation of CEF is mainly occurred due to superoxide and hydroxyl radicals. Meanwhile, the reusability of ACT-4 up to five cycles shows more than 80% photocatalytic degradation, which make the process more economical. The highest experimental adsorption capacity is achieved up to 844.8 mg g-1 using ACT-4. The favorable and multilayer heterogeneous adsorption is carried out according to the well-fitted data with pseudo-second-order and Freundlich models, respectively. These results indicate that the carbon-based TiO2 composites can be used as a green, stable, efficient, effective, reusable, renewable, and sustainable photocatalyst to eliminate the pharmaceutical pollutants (antibiotics) via adsorption and photocatalytic degradation processes.

Semaglutide improves cardiometabolic risk factors in adults with overweight or obesity: STEP 1 and 4 exploratory analyses.

AIMS: Evaluate the effects of once-weekly subcutaneous semaglutide 2.4 mg on cardiometabolic risk factors in people with overweight/obesity without diabetes in the STEP 1 and 4 trials. MATERIALS AND METHODS: STEP 1 and 4 were phase III, 68-week, placebo-controlled trials of once-weekly semaglutide 2.4 mg combined with lifestyle intervention; STEP 4 had a 20-week semaglutide run-in and 48-week randomized withdrawal period. Participants had a body mass index ≥30 kg/m2 or ≥27 kg/m2 with one or more weight-related comorbidity, without diabetes. Pre-specified endpoints were changes in waist circumference, systolic/diastolic blood pressure (SBP/DBP), lipids, fasting plasma glucose (FPG), fasting serum insulin and antihypertensive/lipid-lowering medication use. Post-hoc assessments included non-high-density lipoprotein (HDL) cholesterol, homeostatic model assessment of insulin resistance (HOMA-IR; STEP 1 only), atherosclerotic cardiovascular disease (ASCVD) risk (American College of Cardiology/American Heart Association algorithm; STEP 1 only) and cardiometabolic risk factors by weight loss achieved (<5%, 5% to <10%, 10% to <15%, or ≥15%) (STEP 1 only). RESULTS: Of the 1961 participants in STEP 1 and 803 in STEP 4, most had one or more complication/comorbidity at baseline, with dyslipidaemia and hypertension most prevalent. In STEP 1, reductions in waist circumference, SBP, DBP, FPG, fasting serum insulin, lipids and HOMA-IR were greater with semaglutide versus placebo (p ≤ .001). Reductions in SBP, non-HDL cholesterol, low-density lipoprotein cholesterol and FPG were generally greater with semaglutide than placebo within weight-loss categories. Non-significant ASCVD risk reductions were observed with semaglutide versus placebo (p > .05). In STEP 4, improvements in waist circumference, SBP, FPG, fasting serum insulin and lipids during the semaglutide run-in (week 0-20) were maintained over week 20-68 with continued semaglutide, but deteriorated following the switch to placebo (p < .001 [week 20-68]). Net reductions in antihypertensive/lipid-lowering medication use occurred with semaglutide versus placebo (both trials). CONCLUSIONS: Semaglutide may improve cardiometabolic risk factors and reduce antihypertensive/lipid-lowering medication use versus placebo in adults with overweight/obesity without diabetes. These potential benefits were not maintained after treatment discontinuation. GOV NUMBERS: STEP 1 NCT03548935, STEP 4 NCT03548987.

Surgical Innovations in Tracheal Reconstruction: A Review on Synthetic Material Fabrication.

Background and Objectives: The aim of this review is to explore the recent surgical innovations in tracheal reconstruction by evaluating the uses of synthetic material fabrication when dealing with tracheomalacia or stenotic pathologies, then discussing the challenges holding back these innovations. Materials and Methods: A targeted non-systematic review of published literature relating to tracheal reconstruction was performed within the PubMed database to help identify how synthetic materials are utilised to innovate tracheal reconstruction. Results: The advancements in 3D printing to aid synthetic material fabrication have unveiled promising alternatives to conventional approaches. Achieving successful tracheal reconstruction through this technology demands that the 3D models exhibit biocompatibility with neighbouring tracheal elements by encompassing vasculature, chondral foundation, and immunocompatibility. Tracheal reconstruction has employed grafts and scaffolds, showing a promising beginning in vivo. Concurrently, the integration of resorbable models and stem cell therapy serves to underscore their viability and application in the context of tracheal pathologies. Despite this, certain barriers hinder its advancement in surgery. The intricate tracheal structure has posed a challenge for researchers seeking novel approaches to support its growth and regeneration. Conclusions: The potential of synthetic material fabrication has shown promising outcomes in initial studies involving smaller animals. Yet, to fully realise the applicability of these innovative developments, research must progress toward clinical trials. These trials would ascertain the anatomical and physiological effects on the human body, enabling a thorough evaluation of post-operative outcomes and any potential complications linked to the materials or cells implanted in the trachea.

Thymoglobulin Versus Alemtuzumab Versus Basiliximab Kidney Transplantation From Donors After Circulatory Death.

Introduction: The Campath, Calcineurin inhibitor (CNI) reduction, and Chronic allograft nephropathy (3C), a study comparing alemtuzumab versus basiliximab induction immunosuppression in kidney transplants, has found lower acute rejection rate with alemtuzumab but same graft survival. The aim of the current study is to evaluate the effect of induction immunosuppression (thymoglobulin, alemtuzumab, basiliximab) on the outcome of kidneys of donors after circulatory death (DCD). Methods: Data of the 274 DCD patients of the 3C obtained from the sponsor were compounded with the 140 DCD patients who received thymoglobulin in a single center with the same entry criteria as the 3C, giving 414 patients on 3 induction regimes. Results: There were more male donors (P < 0.05) and human leukocyte antigen and DR mismatched patients in the thymoglobulin group (P < 0.001). Death-censored graft survival at 6 months was 98.6% in the thymoglobulin, 95.5% in the alemtuzumab (P = 0.08), and 95.7% in the basiliximab group (P = 0.09) and at 2 years 97.9% versus 94.8% (P = 0.13, hazard ratio [HR] 2.8, 95% CI 0.7-10.9) versus 94.3% (P = 0.06, HR 3.5, 95% CI 0.9-13.6), respectively.The 2-year overall graft survival was 95% in the thymoglobulin versus 88% in the alemtuzumab (unadjusted P = 0.038, adjusted HR 2.4, 95% CI 0.99-5.9) and 91.4% in the basiliximab group (P = 0.21). The 2-year patient survival was numerically less in the alemtuzumab compared with the thymoglobulin group (91.8% vs. 97.1%, P = 0.052, HR 2.90, 95% CI 0.93-9.2). Acute rejection was 17% in the basiliximab, 4.3% in the thymoglobulin, and 6% in the alemtuzumab group (P < 0.001). Conclusion: In DCD transplants, thymoglobulin induction may provide advantage over alemtuzumab in patient survival and the same advantage as alemtuzumab over basiliximab in terms of acute rejection. Differing maintenance immunosuppression may contribute to the difference found.

SARS-CoV-2 Infection Can Lead to an Increase in Tacrolimus Levels in Renal Transplant Patients: A Cohort Study.

The aim of this study is to evaluate the effect of SARS-CoV-2 infection on serum tacrolimus levels. Tacrolimus levels of 34 transplant patients diagnosed with SARS-CoV-2 in 2020 were compared with their pre-infection values and those of a control group with alternative infections. 20 out of 34 (59%) had high levels. At diagnosis, median tacrolimus level in the SARS-CoV-2 cohort was 9.6 µg/L (2.7-23) compared to 7.9 µg/L in the control group (p = 0.07, 95% CI for difference -0.3-5.8). The ratio of post-infection to pre-infection tacrolimus values was higher in the SARS-CoV-2 group (1.7) compared to the control group (1.25, p = 0.018, 95% CI for difference 0.08-0.89). The acute kidney injury rate was 65% (13 of 20) in SARS-CoV-2 patients with a level >8 µg/dl, compared to 29% (4 of 14) in those with lower levels (p = 0.037). Median length of stay was 10 days among SARS-CoV-2 infected patients with high tacrolimus levels compared to 0 days in the rest (p = 0.04). Four patients with high levels died compared to 2 in the control group. Clinicians should be aware of this potential effect on tacrolimus levels and take appropriate measures.

An Analysis of Serological Response and Infection Outcomes Following Oxford-AstraZeneca (AZD1222) and Pfizer-BioNTech (mRNA BNT162b2) SARS-CoV-2 Vaccines in Kidney and Kidney-pancreas Transplants.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 is associated with high mortality among transplant recipients. Comparative data that define humoral responses to the Oxford-AstraZeneca (AZ) and BNT162b2 (Pfizer-BioNTech) vaccines are limited. METHODS: We recruited 920 kidney transplant patients receiving at least 1 dose of severe acute respiratory syndrome coronavirus 2 vaccine, excluding patients with virus pre-exposure. Serological status was determined with the COVID-SeroKlir ELISA (Kantaro-EKF Diagnostics). Patients with a corrected antibody level of <0.7 AU/mL were considered seronegative. RESULTS: Four hundred ninety-five AZ and 141 Pfizer patients had a sample analyzed after first dose and 593 after second dose (346 AZ versus 247 Pfizer). After first dose, 25.7% of patients seroconverted (26.6% AZ, 22.8% Pfizer). After second dose, 148 (42.8%) of AZ seroconverted compared with 130 (52.6%) of Pfizer (P = 0.02; hazard ratio, 1.48; 95% confidence interval, 1.07-2.06). When negative responders were excluded, Pfizer patients were shown to have significantly higher response than AZ patients (median 2.6 versus 1.78 AU/mL, P = 0.005).Patients on mycophenolate had a reduced seroconversion rate (42.2% versus 61.4%; P < 0.001; hazard ratio, 2.17) and reduced antibody levels (0.47 versus 1.22 AU/mL, P = 0.001), and this effect was dose dependent (P = 0.05). Prednisolone reduced the seroconversion from 58.2% to 43.6% (P = 0.03) among Pfizer but not AZ recipients. Regression analysis showed that antibody levels were reduced by older age (P = 0.002), mycophenolate (P < 0.001), AZ vaccine (versus Pfizer, P = 0.001), and male gender (P = 0.02). Sixteen of 17 serious postvaccine infections occurred to patients who did not seroconvert. CONCLUSIONS: Both seroconversion and antibody levels are lower in AZ compared with Pfizer vaccinated recipients following 2 vaccine doses. Mycophenolate was associated with lower antibody responses in a dose-dependent manner. Serious postvaccine infections occurred among seronegative recipients.

Semaglutide once a week in adults with overweight or obesity, with or without type 2 diabetes in an east Asian population (STEP 6): a randomised, double-blind, double-dummy, placebo-controlled, phase 3a trial.

BACKGROUND: Semaglutide 2·4 mg once weekly has been investigated for weight management in global populations. Differences exist between Asian and non-Asian populations in terms of body composition and definitions of obesity. In the Semaglutide Treatment Effect in People with obesity (STEP) 6 trial, we assessed the effect of semaglutide versus placebo for weight management in adults from east Asia with obesity, with or without type 2 diabetes. METHODS: This randomised, double-blind, double-dummy, placebo-controlled, phase 3a superiority trial was done at 28 outpatient clinics in Japan and South Korea. Eligible participants were adults (aged ≥18 years in South Korea; ≥20 years in Japan) with a BMI of at least 27·0 kg/m2 with two or more weight-related comorbidities or a BMI of 35·0 kg/m2 or more with one or more weight-related comorbidity (one comorbidity had to be either hypertension, dyslipidaemia, or, in Japan only, type 2 diabetes) who had at least one self-reported unsuccessful dietary attempt to lose bodyweight. Participants were randomly assigned (4:1:2:1) to once-weekly subcutaneous semaglutide 2·4 mg or matching placebo, or semaglutide 1·7 mg or matching placebo, plus lifestyle recommendations for 68 weeks. Data for the placebo groups were pooled in statistical analyses. The primary endpoints were percentage change in bodyweight from baseline at week 68 and the proportion of participants who had achieved a reduction of at least 5% of baseline bodyweight at week 68. Change in abdominal visceral fat area was assessed as a supportive secondary endpoint using computed tomography scanning in a subset of participants. Efficacy outcomes were assessed in the full analysis set, which included all randomly assigned participants according to the intention-to-treat principle. Safety was assessed in all participants who received at least one dose of the study drug. This trial was registered with ClinicalTrials.gov, NCT03811574. FINDINGS: Between Jan 21, 2019 and June 4, 2019, 437 participants were screened, of whom 401 were randomly assigned to semaglutide 2·4 mg (n=199), semaglutide 1·7 mg (n=101), or placebo (n=101) and included in the intention-to-treat analysis. Estimated mean change in bodyweight from baseline to week 68 was -13·2% (SEM 0·5) in the semaglutide 2·4 mg group and -9·6% (0·8) in the semaglutide 1·7 mg group versus -2·1% (0·8) in the placebo group (estimated treatment difference [ETD] -11·1 percentage points [95% CI -12·9 to -9·2] for semaglutide 2·4 mg vs placebo; -7·5 percentage points [95% CI -9·6 to -5·4] for semaglutide 1·7 mg vs placebo; both p<0·0001). At week 68, a larger proportion of participants had achieved a 5% or higher reduction in baseline bodyweight in the semaglutide 2·4 mg group (160 [83%] of 193 participants) and semaglutide 1·7 mg group (71 [72%] of 98 participants) than in the placebo group (21 [21%] of 100 participants); odds ratio [OR] 21·7 [95% CI 11·3 to 41·9] for semaglutide 2·4 mg vs placebo; OR 11·1 [95% CI 5·5 to 22·2] for semaglutide 1·7 mg vs placebo; both p<0·0001). Abdominal visceral fat area was reduced by 40·0% (SEM 2·6) among participants in the semaglutide 2·4 mg group and 22·2% (3·7) among participants in the semaglutide 1·7 mg group versus 6·9% (3·8) in the placebo group (ETD -33·2% [95% CI -42·1 to -24·2] for semaglutide 2·4 mg vs placebo; -15·3% [95% CI -25·6 to -4·9] for semaglutide 1·7 mg vs placebo). 171 (86%) of 199 participants in the semaglutide 2·4 mg group, 82 (82%) of 100 participants in the semaglutide 1·7 mg group, and 80 (79%) of 101 participants in the placebo group reported adverse events. Gastrointestinal disorders, which were mostly mild to moderate, were reported in 118 (59%) of 199 participants in the semaglutide 2·4 mg group, 64 (64%) of 100 participants in the semaglutide 1·7 mg group, and 30 (30%) of 101 participants in the placebo group. Adverse events leading to trial product discontinuation occurred in five (3%) of 199 participants in the semaglutide 2·4 mg group, three (3%) of 100 participants in the semaglutide 1·7 mg group, and one (1%) of 101 participants in the placebo group. INTERPRETATION: Adults from east Asia with obesity, with or without type 2 diabetes, given semaglutide 2·4 mg once a week had superior and clinically meaningful reductions in bodyweight, and greater reductions in abdominal visceral fat area compared with placebo, representing a promising treatment option for weight management in this population. FUNDING: Novo Nordisk. TRANSLATIONS: For the Korean and Japanese translations of the abstract see Supplementary Materials section.

Effect of Weekly Subcutaneous Semaglutide vs Daily Liraglutide on Body Weight in Adults With Overweight or Obesity Without Diabetes: The STEP 8 Randomized Clinical Trial.

Importance: Phase 3 trials have not compared semaglutide and liraglutide, glucagon-like peptide-1 analogues available for weight management. Objective: To compare the efficacy and adverse event profiles of once-weekly subcutaneous semaglutide, 2.4 mg, vs once-daily subcutaneous liraglutide, 3.0 mg (both with diet and physical activity), in people with overweight or obesity. Design, Setting, and Participants: Randomized, open-label, 68-week, phase 3b trial conducted at 19 US sites from September 2019 (enrollment: September 11-November 26) to May 2021 (end of follow-up: May 11) in adults with body mass index of 30 or greater or 27 or greater with 1 or more weight-related comorbidities, without diabetes (N = 338). Interventions: Participants were randomized (3:1:3:1) to receive once-weekly subcutaneous semaglutide, 2.4 mg (16-week escalation; n = 126), or matching placebo, or once-daily subcutaneous liraglutide, 3.0 mg (4-week escalation; n = 127), or matching placebo, plus diet and physical activity. Participants unable to tolerate 2.4 mg of semaglutide could receive 1.7 mg; participants unable to tolerate 3.0 mg of liraglutide discontinued treatment and could restart the 4-week titration. Placebo groups were pooled (n = 85). Main Outcomes and Measures: The primary end point was percentage change in body weight, and confirmatory secondary end points were achievement of 10% or more, 15% or more, and 20% or more weight loss, assessed for semaglutide vs liraglutide at week 68. Semaglutide vs liraglutide comparisons were open-label, with active treatment groups double-blinded against matched placebo groups. Comparisons of active treatments vs pooled placebo were supportive secondary end points. Results: Of 338 randomized participants (mean [SD] age, 49 [13] years; 265 women [78.4%]; mean [SD] body weight, 104.5 [23.8] kg; mean [SD] body mass index, 37.5 [6.8]), 319 (94.4%) completed the trial, and 271 (80.2%) completed treatment. The mean weight change from baseline was -15.8% with semaglutide vs -6.4% with liraglutide (difference, -9.4 percentage points [95% CI, -12.0 to -6.8]; P < .001); weight change with pooled placebo was -1.9%. Participants had significantly greater odds of achieving 10% or more, 15% or more, and 20% or more weight loss with semaglutide vs liraglutide (70.9% of participants vs 25.6% [odds ratio, 6.3 {95% CI, 3.5 to 11.2}], 55.6% vs 12.0% [odds ratio, 7.9 {95% CI, 4.1 to 15.4}], and 38.5% vs 6.0% [odds ratio, 8.2 {95% CI, 3.5 to 19.1}], respectively; all P < .001). Proportions of participants discontinuing treatment for any reason were 13.5% with semaglutide and 27.6% with liraglutide. Gastrointestinal adverse events were reported by 84.1% with semaglutide and 82.7% with liraglutide. Conclusions and Relevance: Among adults with overweight or obesity without diabetes, once-weekly subcutaneous semaglutide compared with once-daily subcutaneous liraglutide, added to counseling for diet and physical activity, resulted in significantly greater weight loss at 68 weeks. Trial Registration: ClinicalTrials.gov Identifier: NCT04074161.

Sarcoidosis: epidemiology, characteristics, and outcomes over 10 years - a single-center study in Pakistan.

BACKGROUND: Sarcoidosis is a multisystem granulomatous inflammatory disease which remains under-diagnosed in a tuberculosis endemic region such as Pakistan. RATIONALE: To determine the distribution, clinical characteristics, diagnostic and treatment modalities and the disease course in the Pakistani population. METHODS: A cross-sectional review of sarcoidosis patients from Jan-1,2010 to Dec-31,2019 was done. Multivariable logistic and cox-regression models were used to identify the independent risk-factors associated with disease relapse. Kaplan-Meier curves were used to assess the DFS. RESULTS: 222 patients, with mean age 44 ± 12 years, predominantly females (57.7%) and mean BMI 29 ± 6 were diagnosed sarcoidosis. Significant co-morbidities affected 36.5%, 90% were nonsmokers, and 50.3% belonged to moderate SES. Total 178 (80.2%) were symptomatic with 115 (51.8%) having multi-organ involvement. Stage-I radiological disease was predominant (52.5%). Histopathological diagnosis was obtained in 161 (72.5%) patients. Out of 113 mediastinal lymph-nodes, NNGI was present in 99, with highest yield in Station-07 (68.6%). Treatment was instituted in 108/178 (60.7%) symptomatic patients with steroids alone and in 26 (14.6%) with S+IS, with better clinical and radiological response duration in patients receiving steroid monotherapy (p-values=0.01 and 0.001,respectively, along with overall higher survival time (p-value = 0.04). Risk factors identified for relapse included high SES (AOR5.52;95%CI(1.10-28.40),0.04), steroid monotherapy (AOR0.22; 95%CI(0.10-0.87),0.03), symptomatic response after one year (AOR3.40; 95%CI(1.02-11.10),0.04), and radiological response duration (AOR1.10; 95%CI(1.05-1.20),0.04). CONCLUSION: Sarcoidosis is a dynamic disease with a variable clinical and geographical spectrum but good overall prognosis.

Do stock markets play a role in determining COVID-19 economic stimulus? A cross-country analysis.

This paper makes an innovative contribution to the extant literature by analysing the determinants of economic stimulus packages implemented by governments in response to the COVID-19 pandemic. In particular, we explore whether stock market declines observed in many countries can predict the size of COVID-19 stimulus packages. Moreover, we explore whether a country's level of income can augment the underlying relationship between stock market declines and stimulus packages. The findings reveal that a larger stock market decline results in a larger stimulus package; however, this effect is only observed in countries that have an income level greater than the mean and/or median per capita gross domestic product (GDP). Moreover, our results show that monetary policy is more responsive to a stock market decline than fiscal policy. Thus, our results underscore the importance of international donor agencies such as the World Bank and International Monetary Fund (IMF) in supporting less affluent countries in coping with the adverse impacts of the COVID-19 pandemic on their economies.