Wound healing and antioxidant properties of <i>Launaea procumbens</i> supported by metabolomic profiling and molecular docking

Wounds adversely affect people’s quality of life and have psychological, social, and economic impacts. Herbal remedies of Launaea procumbens (LP) are used to treat wounds. In an excision wound model, topical application of LP significantly promoted wound closure (on day 14, LP-treated animals had the highest percentages of wound closure in comparison with the other groups, as the wound was entirely closed with a closure percentage of 100%, p < 0.05). Histological analysis revealed a considerable rise in the number of fibroblasts, the amount of collagen, and its cross-linking in LP-treated wounds. Gene expression patterns showed significant elevation of TGF-β levels (2.1-fold change after 7 days treatment and 2.7-fold change in 14 days treatment) and downregulation of the inflammatory TNF-α and IL-1β levels in LP-treated wounds. Regarding in vitro antioxidant activity, LP extract significantly diminished the formation of H(2)O(2) radical (IC(50) = 171.6 μg/mL) and scavenged the superoxide radical (IC(50) of 286.7 µg/mL), indicating antioxidant potential in a dose-dependent manner. Dereplication of the secondary metabolites using LC-HRMS resulted in the annotation of 16 metabolites. The identified compounds were docked against important wound-healing targets, including vascular endothelial growth factor (VEGF), collagen α-1, tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and transforming growth factor-β (TGF-β). Among dereplicated compounds, luteolin 8-C-glucoside (orientin) demonstrated binding potential to four investigated targets (VEGF, interleukin 1β, TNF-α, and collagen α-1). To conclude, Launaea procumbens extract could be regarded as a promising topical therapy to promote wound healing in excisional wounds, and luteolin 8-C-glucoside (orientin), one of its constituents, is a potential wound-healing drug lead

Design, synthesis, and biological investigation of new thiazole-based derivatives as multi-targeted inhibitors endowed with antiproliferative, antioxidant, and antibacterial properties

IntroductionA novel series of thiazole-based derivatives 11a-f and 12a-f was developed, synthesized, and tested for antiproliferative activity as dual EGFR/VEGFR-2 inhibitors, antioxidants, and antibacterial agents.MethodsThe structures of the new compounds 11a-f and 12a-f were validated using NMR spectroscopy and elemental microanalysis. The antiproliferative activity of 11a-f and 12a-f was tested against a panel of four cancer cell lines using MTT assay.Results and DiscussionCompounds 11d and 11f had the highest antiproliferative activity, with GI50 values of 30 and 27 nM, respectively, making them more potent than erlotinib (GI50 = 33 nM). Inhibitory studies for EGFR and VEGFR-2 demonstrated that compounds 11d and 11f were the most potent derivatives with dual inhibitory activity. Furthermore, compounds 11d and 11f exhibited significant antioxidant activity at 10 μM, with radical scavenging activity of 71% and 73%, respectively, compared to the reference Trolox (78%). Moreover, compounds 11a-f and 12a-f exhibit significant inhibitory activity against E. coli DNA gyrase, with compounds 11b, 11e, and 12b displaying the highest inhibitory efficacy, yielding IC50 values of 182, 190, and 197 nM, respectively, in comparison to the reference novobiocin (IC50 = 170 nM). Compounds 11b and 11e have significant antibacterial efficacy against both Gram-positive and Gram-negative bacterial strains, as demonstrated by a twofold serial dilution experiment. They exhibit similar efficacy against S. aureus, E. coli, and P. aeruginosa, demonstrating more potency than ciprofloxacin, however displaying reduced effectiveness against B. subtilis compared to ciprofloxacin

Global Andrology Forum (GAF) Clinical Guidelines on the Management of Infertile Men with Varicocele

PURPOSE: Varicocele is among the most common reversible causes of male infertility. Although varicocele is prevalent and there is a growing body of literature on the subject, there are still numerous debates surrounding the matter. This study presents Global Andrology Forum (GAF) clinical guidelines on the management of infertile men with varicocele.MATERIALS AND METHODS: A team of clinicians and reproductive experts reviewed contemporary evidence on all aspects of varicocele, including systematic reviews, meta-analyses, and the results of the GAF global survey of practices. They then formulated expert statements and recommendations, subject to a modified Delphi process until a consensus was reached. The final statements and recommendations were rated using the GRADE system.RESULTS: A total of 31 statements and recommendations on the evaluation and management of varicocele were introduced and scored by 24 experts. All experts agreed with the final statements. Varicocele is a significant contributor to male infertility. Its diagnosis is based mainly on physical examination, although imaging can be used in certain cases. Clinical varicocele associated with abnormal sperm parameters is the primary unanimous indication of varicocele repair. However, other indications can still be considered, and recommendations for a tailored approach to controversial situations have been presented. There is inadequate evidence on the use of medical therapy for varicocele.CONCLUSIONS: These clinical guidelines on the management of infertile men with varicocele, based on the GAF surveys, systematic reviews, and meta-analyses, point out the pivotal importance of varicocele in modern Andrology. Continued research is crucial to improving diagnostic accuracy and treatment outcomes, ultimately enhancing reproductive health for men with varicocele. Therefore, the current guidelines allow clinicians to develop effective management strategies for a common issue and address practical questions where evidence is lacking.</p

Global Andrology Forum (GAF) Clinical Guidelines on the Management of Non-obstructive Azoospermia:Bridging the Gap between Controversy and Consensus

PURPOSE: Non-obstructive azoospermia (NOA), defined as the absence of sperm in the ejaculate due to testicular failure, is observed in 5% to 15% of infertile men and accounts for two-thirds of azoospermia cases. The management of NOA is marked by significant controversy and global variation in diagnostic and therapeutic approaches, highlighting the crucial need for well-designed and standardized clinical practice guidelines. We present comprehensive graded clinical practice recommendations and statements for diagnosing and treating NOA, aiming to establish standardized strategies that can globally help guide practitioners in their practice.MATERIALS AND METHODS: A comprehensive literature review was conducted to gather evidence on the epidemiological, diagnostic, and therapeutic aspects of NOA. The Global Andrology Forum (GAF) recommendations were developed through the collaboration of a global panel of experts using the Delphi method and surveys to achieve consensus. Statements were graded according to the Oxford Centre for Evidence-Based Medicine "GRADE" classification as either "Strong" or "Weak." Statements receiving at least 80% expert consensus were graded as "Strong," while others were categorized as "Weak."RESULTS: The GAF has formulated a total of 49 recommendations and statements on the diagnosis and treatment of NOA, including 21 for diagnosis and 28 for treatment. The recommendations and statements were evaluated and graded by a panel of 48 GAF experts from 25 countries worldwide. The majority of experts (60.5%) had more than 10 years of clinical experience in managing NOA.CONCLUSIONS: The GAF guidelines address discrepancies in NOA management across diverse clinical settings and provide comprehensive graded recommendations to guide clinicians in its diagnosis and treatment. Developed and graded by a large worldwide panel of experts, the current guidelines present simplified, high-standard strategies that can be seamlessly integrated into the daily global practice, offering practitioners a clear framework for managing NOA.</p

Global Andrology Forum Clinical Guidelines on the Relevance of Sperm DNA Fragmentation in Reproductive Medicine

PURPOSE: To evaluate the evidence on sperm DNA fragmentation (SDF) and its clinical applications in reproductive medicine, highlighting benefits, limitations, and guidelines for its use to assist clinicians in objective decision-making.MATERIALS AND METHODS: A multidisciplinary team of clinicians and reproductive experts from the Global Andrology Forum (GAF) reviewed the latest evidence on SDF, covering indications, testing methods, recurrent pregnancy loss, varicocele and its repair, assisted reproductive technologies (ART), treatment of associated conditions, antioxidant therapy, and sperm selection for ART. Expert statements and recommendations were developed and graded with the GRADE system using a modified Delphi process.RESULTS: Based on the GAF surveys, systematic reviews, and meta-analyses related to SDF, 52 experts introduced and scored 24 statements and recommendations using the GRADE system. Of these, 87.5% (21/24) achieved strong ratings, reflecting broad consensus, while 12.5% (3/24) were rated weak. The guidelines provide evidence-based recommendations for clinical scenarios, including the role of SDF in infertility, recurrent pregnancy loss, and ART outcomes.CONCLUSIONS: While there is growing interest and evidence regarding the clinical benefit of SDF testing and its utility in managing male infertility, significant gaps in the literature limit its routine use in clinical practice. The guidelines offer a structured framework for integrating SDF testing into male infertility management, emphasizing a tailored approach based on individual clinical scenarios. Clinicians must balance the benefits and limitations of SDF testing and antioxidant treatment to optimize care in reproductive medicine. These guidelines are critical for advancing evidence-based practices in male infertility management.</p

The Global State of Contemporary Andrology Practice:A Comprehensive Analysis of Clinical Practice, Training Pathways, and Emerging Challenges

PURPOSE: This study evaluates the current state of andrology practice worldwide, identifies challenges faced by clinicians, and explores training, certification, and research opportunities. It also seeks to redefine the qualifications necessary to be recognized as an andrologist and to propose areas for standardization and improvement.MATERIALS AND METHODS: A global, cross-sectional survey was conducted using a 48-question online questionnaire designed by international experts. The survey, distributed in English, covered various domains of modern andrology practice. Responses from 405 participants across 59 countries were analyzed using R version 4.1.2, with categorical variables reported as frequencies and percentages.RESULTS: Among respondents, 47.3% held medical doctor (MD) degrees, with urologists (31.1%) and clinical andrologists (25.3%) being the most represented specialties. Formal, board-certified andrological training was reported as available in only 48.1% of countries. While half of the respondents identified as andrologists based on experience, only one-third did so through certification, obtained from diverse, nationally recognized organizations. The primary areas of practice included male infertility (36.7%), male sexual dysfunction (27.2%), and sexually transmitted infections (14.5%). Many participants were actively engaged in assisted reproductive technologies, imaging, and andrological surgical emergencies. Despite strong interest in clinical, basic, and translational research, respondents highlighted significant challenges, including inconsistent training pathways, insufficient certification standards, and the complexity of managing diverse andrological conditions.CONCLUSIONS: Andrology is an evolving multidisciplinary specialty where board-certified urologists, clinical andrologists, and reproductive medicine specialists collaborate to address male reproductive and sexual health challenges. Despite their advanced competencies in medical, surgical, and laboratory interventions, specialists face significant global disparities in training and certification. This survey highlights the urgent need for standardized training, evidence-based guidelines, and unified certification to ensure consistency, enhance patient care, and advance andrology's academic and clinical excellence worldwide.</p

Pooled analysis of who surgical safety checklist use and mortality after emergency laparotomy

Background: The World Health Organization (WHO) Surgical Safety Checklist has fostered safe practice for 10 years, yet its place in emergency surgery has not been assessed on a global scale. The aim of this study was to evaluate reported checklist use in emergency settings and examine the relationship with perioperative mortality in patients who had emergency laparotomy. Methods: In two multinational cohort studies, adults undergoing emergency laparotomy were compared with those having elective gastrointestinal surgery. Relationships between reported checklist use and mortality were determined using multivariable logistic regression and bootstrapped simulation. Results: Of 12 296 patients included from 76 countries, 4843 underwent emergency laparotomy. After adjusting for patient and disease factors, checklist use before emergency laparotomy was more common in countries with a high Human Development Index (HDI) (2455 of 2741, 89⋅6 per cent) compared with that in countries with a middle (753 of 1242, 60⋅6 per cent; odds ratio (OR) 0⋅17, 95 per cent c.i. 0⋅14 to 0⋅21, P &lt; 0⋅001) or low (363 of 860, 42⋅2 percent; OR 0⋅08, 0⋅07 to 0⋅10, P &lt; 0⋅001) HDI. Checklist use was less common in elective surgery than for emergency laparotomy in high-HDI countries (risk difference −9⋅4 (95 per cent c.i. −11⋅9 to −6⋅9) per cent; P &lt; 0⋅001), but the relationship was reversed in low-HDI countries (+12⋅1 (+7⋅0 to +17⋅3) per cent; P &lt; 0⋅001). In multivariable models, checklist use was associated with a lower 30-day perioperative mortality (OR 0⋅60, 0⋅50 to 0⋅73; P &lt; 0⋅001). The greatest absolute benefit was seen for emergency surgery in low-and middle-HDI countries. Conclusion: Checklist use in emergency laparotomy was associated with a significantly lower perioperative mortality rate. Checklist use in low-HDI countries was half that in high-HDI countries

Global economic burden of unmet surgical need for appendicitis

Background: There is a substantial gap in provision of adequate surgical care in many low-and middle-income countries. This study aimed to identify the economic burden of unmet surgical need for the common condition of appendicitis. Methods: Data on the incidence of appendicitis from 170 countries and two different approaches were used to estimate numbers of patients who do not receive surgery: as a fixed proportion of the total unmet surgical need per country (approach 1); and based on country income status (approach 2). Indirect costs with current levels of access and local quality, and those if quality were at the standards of high-income countries, were estimated. A human capital approach was applied, focusing on the economic burden resulting from premature death and absenteeism. Results: Excess mortality was 4185 per 100 000 cases of appendicitis using approach 1 and 3448 per 100 000 using approach 2. The economic burden of continuing current levels of access and local quality was US $92 492 million using approach 1 and$73 141 million using approach 2. The economic burden of not providing surgical care to the standards of high-income countries was $95 004 million using approach 1 and$75 666 million using approach 2. The largest share of these costs resulted from premature death (97.7 per cent) and lack of access (97.0 per cent) in contrast to lack of quality. Conclusion: For a comparatively non-complex emergency condition such as appendicitis, increasing access to care should be prioritized. Although improving quality of care should not be neglected, increasing provision of care at current standards could reduce societal costs substantially

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

Global fertility in 204 countries and territories, 1950–2021, with forecasts to 2100: a comprehensive demographic analysis for the Global Burden of Disease Study 2021

Background: Accurate assessments of current and future fertility—including overall trends and changing population age structures across countries and regions—are essential to help plan for the profound social, economic, environmental, and geopolitical challenges that these changes will bring. Estimates and projections of fertility are necessary to inform policies involving resource and health-care needs, labour supply, education, gender equality, and family planning and support. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 produced up-to-date and comprehensive demographic assessments of key fertility indicators at global, regional, and national levels from 1950 to 2021 and forecast fertility metrics to 2100 based on a reference scenario and key policy-dependent alternative scenarios. Methods: To estimate fertility indicators from 1950 to 2021, mixed-effects regression models and spatiotemporal Gaussian process regression were used to synthesise data from 8709 country-years of vital and sample registrations, 1455 surveys and censuses, and 150 other sources, and to generate age-specific fertility rates (ASFRs) for 5-year age groups from age 10 years to 54 years. ASFRs were summed across age groups to produce estimates of total fertility rate (TFR). Livebirths were calculated by multiplying ASFR and age-specific female population, then summing across ages 10–54 years. To forecast future fertility up to 2100, our Institute for Health Metrics and Evaluation (IHME) forecasting model was based on projections of completed cohort fertility at age 50 years (CCF50; the average number of children born over time to females from a specified birth cohort), which yields more stable and accurate measures of fertility than directly modelling TFR. CCF50 was modelled using an ensemble approach in which three sub-models (with two, three, and four covariates variously consisting of female educational attainment, contraceptive met need, population density in habitable areas, and under-5 mortality) were given equal weights, and analyses were conducted utilising the MR-BRT (meta-regression—Bayesian, regularised, trimmed) tool. To capture time-series trends in CCF50 not explained by these covariates, we used a first-order autoregressive model on the residual term. CCF50 as a proportion of each 5-year ASFR was predicted using a linear mixed-effects model with fixed-effects covariates (female educational attainment and contraceptive met need) and random intercepts for geographical regions. Projected TFRs were then computed for each calendar year as the sum of single-year ASFRs across age groups. The reference forecast is our estimate of the most likely fertility future given the model, past fertility, forecasts of covariates, and historical relationships between covariates and fertility. We additionally produced forecasts for multiple alternative scenarios in each location: the UN Sustainable Development Goal (SDG) for education is achieved by 2030; the contraceptive met need SDG is achieved by 2030; pro-natal policies are enacted to create supportive environments for those who give birth; and the previous three scenarios combined. Uncertainty from past data inputs and model estimation was propagated throughout analyses by taking 1000 draws for past and present fertility estimates and 500 draws for future forecasts from the estimated distribution for each metric, with 95% uncertainty intervals (UIs) given as the 2·5 and 97·5 percentiles of the draws. To evaluate the forecasting performance of our model and others, we computed skill values—a metric assessing gain in forecasting accuracy—by comparing predicted versus observed ASFRs from the past 15 years (2007–21). A positive skill metric indicates that the model being evaluated performs better than the baseline model (here, a simplified model holding 2007 values constant in the future), and a negative metric indicates that the evaluated model performs worse than baseline. Findings: During the period from 1950 to 2021, global TFR more than halved, from 4·84 (95% UI 4·63–5·06) to 2·23 (2·09–2·38). Global annual livebirths peaked in 2016 at 142 million (95% UI 137–147), declining to 129 million (121–138) in 2021. Fertility rates declined in all countries and territories since 1950, with TFR remaining above 2·1—canonically considered replacement-level fertility—in 94 (46·1%) countries and territories in 2021. This included 44 of 46 countries in sub-Saharan Africa, which was the super-region with the largest share of livebirths in 2021 (29·2% [28·7–29·6]). 47 countries and territories in which lowest estimated fertility between 1950 and 2021 was below replacement experienced one or more subsequent years with higher fertility; only three of these locations rebounded above replacement levels. Future fertility rates were projected to continue to decline worldwide, reaching a global TFR of 1·83 (1·59–2·08) in 2050 and 1·59 (1·25–1·96) in 2100 under the reference scenario. The number of countries and territories with fertility rates remaining above replacement was forecast to be 49 (24·0%) in 2050 and only six (2·9%) in 2100, with three of these six countries included in the 2021 World Bank-defined low-income group, all located in the GBD super-region of sub-Saharan Africa. The proportion of livebirths occurring in sub-Saharan Africa was forecast to increase to more than half of the world's livebirths in 2100, to 41·3% (39·6–43·1) in 2050 and 54·3% (47·1–59·5) in 2100. The share of livebirths was projected to decline between 2021 and 2100 in most of the six other super-regions—decreasing, for example, in south Asia from 24·8% (23·7–25·8) in 2021 to 16·7% (14·3–19·1) in 2050 and 7·1% (4·4–10·1) in 2100—but was forecast to increase modestly in the north Africa and Middle East and high-income super-regions. Forecast estimates for the alternative combined scenario suggest that meeting SDG targets for education and contraceptive met need, as well as implementing pro-natal policies, would result in global TFRs of 1·65 (1·40–1·92) in 2050 and 1·62 (1·35–1·95) in 2100. The forecasting skill metric values for the IHME model were positive across all age groups, indicating that the model is better than the constant prediction. Interpretation: Fertility is declining globally, with rates in more than half of all countries and territories in 2021 below replacement level. Trends since 2000 show considerable heterogeneity in the steepness of declines, and only a small number of countries experienced even a slight fertility rebound after their lowest observed rate, with none reaching replacement level. Additionally, the distribution of livebirths across the globe is shifting, with a greater proportion occurring in the lowest-income countries. Future fertility rates will continue to decline worldwide and will remain low even under successful implementation of pro-natal policies. These changes will have far-reaching economic and societal consequences due to ageing populations and declining workforces in higher-income countries, combined with an increasing share of livebirths among the already poorest regions of the world. Funding: Bill & Melinda Gates Foundation