Commentary-A Military Health Care Ethics Framework.

Ethical practice within military health care is a significant topic of professional and academic debate. The term "military health care ethics" enfranchises the entire health care team. Military health care professionals are subject to tension between their duties as military personnel, and their ethical duties as health care professionals, so-called "Dual Loyalty." Some military health care practitioners have suffered moral injury because of the psychological stress associated with ethical challenges on military operations. It is important to define military health care ethics and also to consider how it should be taught. The essence of ethical practice is ethical decision-making. It has become self-evident from our experience of teaching military health care ethics that a simple and agreed framework for analyzing an ethical problem is required. This paper describes the development of the King's Military Healthcare Ethics Framework in support of a military health care ethics policy on behalf of the NATO Military Healthcare Working Group. There is logic to using a stepped approach to analyze an ethical problem in military health care. These steps are: "Identify" the problem, "Analyze" the problem including consideration of perspectives, "Fuse" the analysis, and "Decide". Step 1-Identify-is intended to orientate the decision-making group, and to articulate the problem specifically and clearly in order to determine the exact ethical issue and the secondary issues that arise. Step 2-Analyse-considers the problem from 4 perspectives: patient, clinical, legal, and societal/military. These reflect the breadth of perspectives that impact on health care practice within a military context. Step 3-Fuse-is the culminating step. The conclusions from the analysis of perspectives should be summarized and key references cited. This will determine the exact decision(s) to be made. Step 4-Decide-clearly articulates the decision made and provides the record of the key reasons for making that decision. This may include areas of enduring uncertainly and any planned review of the decision. The King's Military Healthcare Ethics Analytical Framework has been evaluated for content validity through iterative discussion at 4 meetings of the NATO MHCWG and a specific workshop on military health care ethics over 2022/2023. It is included within the draft NATO Standardization Agreement on Military Healthcare Ethics.

Exploring the Dose-Response Relationship Between Estimated Resistance Training Proximity to Failure, Strength Gain, and Muscle Hypertrophy: A Series of Meta-Regressions.

BACKGROUND: The proximity to failure in which sets are terminated has gained attention in the scientific literature as a potentially key resistance training variable. Multiple meta-analyses have directly (i.e., failure versus not to failure) or indirectly (e.g., velocity loss, alternative set structures) evaluated the effect of proximity to failure on strength and muscle hypertrophy outcomes categorically; however, the dose-response effects of proximity to failure have not been analyzed collectively in a continuous manner. OBJECTIVE: To meta-analyze the aforementioned areas of relevant research, proximity to failure was quantified as the number of repetitions in reserve (RIR). Importantly, the RIR associated with each effect in the analysis was estimated on the basis of the available descriptions of the training interventions in each study. Data were extracted and a series of exploratory multilevel meta-regressions were performed for outcomes related to both strength and muscle hypertrophy. A range of sensitivity analyses were also performed. All models were adjusted for the effects of load, method of volume equating, duration of intervention, and training status. RESULTS: The best fit models for both strength and muscle hypertrophy outcomes demonstrated modest quality of overall fit. In all of the best-fit models for strength, the confidence intervals of the marginal slopes for estimated RIR contained a null point estimate, indicating a negligible relationship with strength gains. However, in all of the best-fit models for muscle hypertrophy, the marginal slopes for estimated RIR were negative and their confidence intervals did not contain a null point estimate, indicating that changes in muscle size increased as sets were terminated closer to failure. CONCLUSIONS: The dose-response relationship between proximity to failure and strength gain appears to differ from the relationship with muscle hypertrophy, with only the latter being meaningfully influenced by RIR. Strength gains were similar across a wide range of RIR, while muscle hypertrophy improves as sets are terminated closer to failure. Considering the RIR estimation procedures used, however, the exact relationship between RIR and muscle hypertrophy and strength remains unclear. Researchers and practitioners should be aware that optimal proximity to failure may differ between strength and muscle hypertrophy outcomes, but caution is warranted when interpreting the present analysis due to its exploratory nature. Future studies deliberately designed to explore the continuous nature of the dose-response effects of proximity to failure in large samples should be considered.

Global incidence trends of early-onset colorectal cancer and related exposures in early-life: an ecological analysis based on the GBD 2019.

Background: The incidence of early-onset colorectal cancer (EOCRC) is increasing globally. This study aims to describe the temporal trends of incidence and explore related risk exposures in early-life at the country level based on the GBD 2019. Methods: Data on the incidence and attributable risk factors of EOCRC were obtained from the GBD 2019. Temporal trends of age-standardized incidence were evaluated by average annual percentage change (AAPC). Early-life exposures were indicated as summary exposure values (SEV) of selected factors, SDI and GDP per capita in previous decades and at ages 0-4, 5-9, 10-14 and 15-19 years. Weighted linear or non-linear regressions were applied to evaluate the ecological aggregate associations of the exposures with incidences of EOCRC. Results: The global age-standardized incidence of EOCRC increased from 3.05 (3.03, 3.07) to 3.85 (3.83, 3.86) per 100,000 during 1990 and 2019. The incidence was higher in countries with high socioeconomic levels, and increased drastically in countries in East Asia and Caribbean, particularly Jamaica, Saudi Arabia and Vietnam. The GDP per capita, SDI, and SEVs of iron deficiency, alcohol use, high body-mass index, and child growth failure in earlier years were more closely related with the incidences of EOCRC in 2019. Exposures at ages 0-4, 5-9, 10-14 and 15-19 years were also associated with the incidences, particularly for the exposures at ages 15-19 years. Conclusion: The global incidence of EOCRC increased during past three decades. The large variations at regional and national level may be related with the distribution of risk exposures in early life.

Executive Summary: The Pediatric Extracorporeal Membrane Oxygenation Anticoagulation CollaborativE (PEACE) Consensus Conference.

OBJECTIVES: To present recommendations and consensus statements with supporting literature for the clinical management of neonates and children supported with extracorporeal membrane oxygenation (ECMO) from the Pediatric ECMO Anticoagulation CollaborativE (PEACE) consensus conference. DATA SOURCES: Systematic review was performed using PubMed, Embase, and Cochrane Library (CENTRAL) databases from January 1988 to May 2021, followed by serial meetings of international, interprofessional experts in the management ECMO for critically ill children. STUDY SELECTION: The management of ECMO anticoagulation for critically ill children. DATA EXTRACTION: Within each of eight subgroup, two authors reviewed all citations independently, with a third independent reviewer resolving any conflicts. DATA SYNTHESIS: A systematic review was conducted using MEDLINE, Embase, and Cochrane Library databases, from January 1988 to May 2021. Each panel developed evidence-based and, when evidence was insufficient, expert-based statements for the clinical management of anticoagulation for children supported with ECMO. These statements were reviewed and ratified by 48 PEACE experts. Consensus was obtained using the Research and Development/UCLA Appropriateness Method. Results were summarized using the Grading of Recommendations Assessment, Development, and Evaluation method. We developed 23 recommendations, 52 expert consensus statements, and 16 good practice statements covering the management of ECMO anticoagulation in three broad categories: general care and monitoring; perioperative care; and nonprocedural bleeding or thrombosis. Gaps in knowledge and research priorities were identified, along with three research focused good practice statements. CONCLUSIONS: The 91 statements focused on clinical care will form the basis for standardization and future clinical trials.

Prophylactic Transfusion Strategies in Children Supported by Extracorporeal Membrane Oxygenation: The Pediatric Extracorporeal Membrane Oxygenation Anticoagulation CollaborativE Consensus Conference.

OBJECTIVES: To derive systematic-review informed, modified Delphi consensus regarding prophylactic transfusions in neonates and children supported with extracorporeal membrane oxygenation (ECMO) from the Pediatric ECMO Anticoagulation CollaborativE. DATA SOURCES: A structured literature search was performed using PubMed, EMBASE, and Cochrane Library (CENTRAL) databases from January 1988 to May 2020, with an update in May 2021. STUDY SELECTION: Included studies assessed use of prophylactic blood product transfusion in pediatric ECMO. DATA EXTRACTION: Two authors reviewed all citations independently, with a third independent reviewer resolving conflicts. Thirty-three references were used for data extraction and informed recommendations. Evidence tables were constructed using a standardized data extraction form. MEASUREMENTS AND MAIN RESULTS: The evidence was evaluated using the Grading of Recommendations Assessment, Development and Evaluation system. Forty-eight experts met over 2 years to develop evidence-informed recommendations and, when evidence was lacking, expert-based consensus statements or good practice statements for prophylactic transfusion strategies for children supported with ECMO. A web-based modified Delphi process was used to build consensus via the Research And Development/University of California Appropriateness Method. Consensus was based on a modified Delphi process with agreement defined as greater than 80%. We developed two good practice statements, 4 weak recommendations, and three expert consensus statements. CONCLUSIONS: Despite the frequency with which pediatric ECMO patients are transfused, there is insufficient evidence to formulate evidence-based prophylactic transfusion strategies.

Transcriptome and microbiome-immune changes across preinvasive and invasive anal cancer lesions.

Anal squamous cell carcinoma (ASCC) is a rare gastrointestinal malignancy linked to high-risk Human papillomavirus (HPV) infection, which develops from precursor lesions like Low-Grade Squamous Intraepithelial Lesions (LGSIL) and High-Grade Squamous Intraepithelial Lesions (HGSIL). ASCC incidence varies across populations, posing increased risk for People Living with HIV (PLWH). Our investigation focused on transcriptomic and metatranscriptomic changes from Squamous Intraepithelial Lesions (SILs) to ASCC. Metatranscriptomic analysis highlighted specific bacterial species (e.g., Fusobacterium nucleatum, Bacteroides fragilis) more prevalent in ASCC than precancerous lesions. These species correlated with gene encoding enzymes (Acca, glyQ, eno, pgk, por) and oncoproteins (FadA, dnaK), presenting potential diagnostic or treatment markers. Unsupervised transcriptome analysis identified distinct sample clusters reflecting histological diagnosis, immune infiltrate, HIV/HPV status, and pathway activities, recapitulating anal cancer progression's natural history. Our study unveiled molecular mechanisms in anal cancer progression, aiding in stratifying HGSIL cases based on low- or high-risk progression to malignancy.

MENSA, a Media Enriched with Newly Synthesized Antibodies, to Identify SARS-CoV-2 Persistence and Latent Viral Reactivation in Long-COVID.

Post-acute sequelae of SARS-CoV-2 (SARS2) infection (PASC) is a heterogeneous condition, but the main viral drivers are unknown. Here, we use MENSA, Media Enriched with Newly Synthesized Antibodies, secreted exclusively from circulating human plasmablasts, to provide an immune snapshot that defines the underlying viral triggers. We provide proof-of-concept testing that the MENSA technology can capture the new host immune response to accurately diagnose acute primary and breakthrough infections when known SARS2 virus or proteins are present. It is also positive after vaccination when spike proteins elicit an acute immune response. Applying the same principles for long-COVID patients, MENSA is positive for SARS2 in 40% of PASC vs none of the COVID recovered (CR) patients without any sequelae demonstrating ongoing SARS2 viral inflammation only in PASC. Additionally, in PASC patients, MENSAs are also positive for Epstein-Barr Virus (EBV) in 37%, Human Cytomegalovirus (CMV) in 23%, and herpes simplex virus 2 (HSV2) in 15% compared to 17%, 4%, and 4% in CR controls respectively. Combined, a total of 60% of PASC patients have a positive MENSA for SARS2, EBV, CMV, and/or HSV2. MENSA offers a unique antibody snapshot to reveal the underlying viral drivers in long-COVID thus demonstrating the persistence of SARS2 and reactivation of viral herpes in 60% of PASC patients.

Multi-omics analysis of green lineage osmotic stress pathways unveils crucial roles of different cellular compartments.

Maintenance of water homeostasis is a fundamental cellular process required by all living organisms. Here, we use the single-celled green alga Chlamydomonas reinhardtii to establish a foundational understanding of osmotic-stress signaling pathways through transcriptomics, phosphoproteomics, and functional genomics approaches. Comparison of pathways identified through these analyses with yeast and Arabidopsis allows us to infer their evolutionary conservation and divergence across these lineages. 76 genes, acting across diverse cellular compartments, were found to be important for osmotic-stress tolerance in Chlamydomonas through their functions in cytoskeletal organization, potassium transport, vesicle trafficking, mitogen-activated protein kinase and chloroplast signaling. We show that homologs for five of these genes have conserved functions in stress tolerance in Arabidopsis and reveal a novel PROFILIN-dependent stage of acclimation affecting the actin cytoskeleton that ensures tissue integrity upon osmotic stress. This study highlights the conservation of the stress response in algae and land plants, and establishes Chlamydomonas as a unicellular plant model system to dissect the osmotic stress signaling pathway.

Hereditary Amyloidosis: Insights Into a Fibrinogen A Variant Protein.

Amyloidosis are a group of diseases in which soluble proteins aggregate and deposit in fibrillar conformation extracellularly in tissues. The effectiveness of therapeutic strategies depends on the specific protein involved, being crucial to accurately determine its nature. Moreover, following the diagnosis, the search for the mutation within relatives allows the clinical advice. Here we report the precise diagnosis and explored the possible reasons of the structural pathogenicity for a renal amyloidosis related to a fibrinogen Aα-chain variant. Whole-exome sequencing and GATK calling pipeline were leveraged to characterize the protein variant present in a patient with kidney failure. Bioinformatics strategies were applied to suggest potential explanations of the variants aggregation. Our pipeline allowed the identification of a single-point variant of fibrinogen Aα-chain, which opened the possibility of curative transplantation. In silico structural analysis suggested that the pathogenicity of the variant may be attributed to a heightened susceptibility to yield a peptide prone to deposit as an oligomer with a ß-sheet structure. Exploiting the comprehensive coverage of whole-genome sequencing, we managed to fill a vacant stage in the diagnosis of hereditary amyloidosis and to stimulate the advancement in biomedicine.

Regenerative treatments for scleroderma in cutaneous manifestations of the face: a systematic review.

OBJECTIVES: Scleroderma is a heterogeneous chronic autoimmune disease affecting connective tissue, characterised by chronic inflammation and fibrosis, particularly affecting internal organs and skin. Orofacial involvement is common, leading to facial atrophy, mask-like appearance and difficulties in function that significantly impact patients' quality of life. This systematic review evaluates different autologous regenerative treatments of facial manifestations of scleroderma, aiming to provide comprehensive understanding of their effectiveness in reducing fibrosis, and thereby improving function and skin quality. METHODS: A search in PubMed, Embase, Web of Science Core Collection, Cochrane CENTRAL, and CINAHL was conducted. Studies assessing autologous regenerative treatments in cutaneous manifestations of the face in scleroderma patients were included. Outcomes of interest were treatment characteristics, characterisation of biomaterials, outcome measurements and patient satisfaction. Methodological quality was assessed with the Effective Public Health Practice Project tool. RESULTS: In total 18 studies were included. Methodological quality of studies was weak (n=15) and moderate (n=3). Treatments consisted of autologous fat grafting, platelet-rich plasma, stromal vascular fraction, and adipose-derived stem cells. In general, most studies showed improvements of symptoms, but no treatment was considered superior. CONCLUSIONS: Autologous regenerative treatments hold potential for alleviating cutaneous manifestations of the face in scleroderma. Further clinical trials should be well-designed to improve the quality of clinical evidence.

Targeting valine catabolism to inhibit metabolic reprogramming in prostate cancer.

Metabolic reprogramming and energetic rewiring are hallmarks of cancer that fuel disease progression and facilitate therapy evasion. The remodelling of oxidative phosphorylation and enhanced lipogenesis have previously been characterised as key metabolic features of prostate cancer (PCa). Recently, succinate-dependent mitochondrial reprogramming was identified in high-grade prostate tumours, as well as upregulation of the enzymes associated with branched-chain amino acid (BCAA) catabolism. In this study, we hypothesised that the degradation of the BCAAs, particularly valine, may play a critical role in anapleurotic refuelling of the mitochondrial succinate pool, as well as the maintenance of intracellular lipid metabolism. Through the suppression of BCAA availability, we report significantly reduced lipid content, strongly indicating that BCAAs are important lipogenic fuels in PCa. This work also uncovered a novel compensatory mechanism, whereby fatty acid uptake is increased in response to extracellular valine deprivation. Inhibition of valine degradation via suppression of 3-hydroxyisobutyryl-CoA hydrolase (HIBCH) resulted in a selective reduction of malignant prostate cell proliferation, decreased intracellular succinate and impaired cellular respiration. In combination with a comprehensive multi-omic investigation that incorporates next-generation sequencing, metabolomics, and high-content quantitative single-cell imaging, our work highlights a novel therapeutic target for selective inhibition of metabolic reprogramming in PCa.

The Effectiveness and Safety of Romosozumab and Teriparatide in Postmenopausal Women with Osteoporosis.

PURPOSE: The purpose of this observational study was to investigate the effectiveness and safety of romosozumab (ROMO) and teriparatide (TPTD) in a clinical setting. METHODS: 315 postmenopausal women were included based on the reimbursement criteria for ROMO and TPTD at the Department of Endocrinology at Aarhus University Hospital. ROMO: Bone Mineral Density (BMD) T-score <-2.5 (femoral neck (FN), total hip (TH), or lumbar spine (LS)) + a fragility fracture (hip, spine, pelvis, distal forearm, or proximal humerus) within 3 years. TPTD: Within 3 years ≥2 vertebral fractures or 1 vertebral fracture + BMD T-score (FN, TH, or LS) <-3. Data was collected from medical records. The primary end point was percentage change from baseline in BMD (FN, TH, and LS) at month 12. BMD was measured by DXA. RESULTS: At month 12 ROMO led to significantly (p<0.001) larger increases than TPTD in BMD (FN: 4.8% vs. 0.2%, TH: 5.7% vs. 0.3%, and LS: 13.7% vs. 9.3%). Discontinuation rate was lower with ROMO than with TPTD. Lower incidence of cardiovascular adverse events was observed with ROMO compared to TPTD. Treatment-naïve patients had non-significantly higher BMD increases compared to previously treated patients with both ROMO and TPTD. CONCLUSION: Treatment with romosozumab yields larger increases in bone mineral density than teriparatide after 12 months and a higher rate of completion.

New Lipophilic Hydroxamates as Promising Trypanocidal Agents: Design, Synthesis, SAR, and Conformational Behavior Studies.

A series of novel hydroxamic acid derivatives was designed and synthesized, and their growth inhibitory activity against bloodstream form Trypanosoma brucei was evaluated. These compounds are based on conformationally constrained, lipophilic, spiro carbocyclic 2,6-diketopiperazine (2,6-DKP) scaffolds and bear a side pharmacophoric functionality that contains an acetohydroxamic acid moiety (CH2CONHOH) linked with the imidic nitrogen atom of the 2,6-DKP ring via an acetamido portion [CH2CON(R), R = H, CH3]. Most of these analogues were active in the midnanomolar to low micromolar range against T. brucei. (S)-Isobutyl- or (S)-benzyl-substitution on the methylene carbon located between the amine nitrogen atom and carbonyl of the 2,6-DKP ring was studied. The effect of the methyl-substitution on the nitrogen atom of the acetamido portion in the side pharmacophoric functionality was also examined. Compounds 22 and 23, bearing an isobutyl- or benzyl-substituent, respectively, and concurrently a methyl-substituent, were found to be the most potent hydroxamates of this series (IC50 = 34 and 53 nM, respectively). Both had promising selectivity over the parasite compared to mammalian cells (SI = 940 and 470, respectively). Moreover, an E/Z conformational behavior study on hydroxamic acid 18 and its methyl-substituted counterpart 21 was undertaken using NMR spectroscopy and theoretical calculations.

Prevalence and associated factors of overweight in Chinese adolescents: A cross-sectional study.

Background and Aim: Obesity has been a global public health issue due to the increasing mortality rate and prevalence among children. However, there are scarce studies on obesity prevalence in Hong Kong children. The study aims to identify the risk factors of obesity among primary and secondary school students by assessing the relationship between sociodemographic factors, health-related behaviors, and social relationships. Methods: Self-administrated surveys were collected from 30 primary schools and 25 secondary schools participating in the "Quality Education Fund Thematic Network on Health Schools" project. Descriptive analysis was conducted to examine the proportions of different characteristics and to compare the disparity between primary and secondary school students with obesity. Results: A total of 4884 responses were collected. A larger proportion of primary school students with obesity were male (adjusted odds ratio [aOR]: 2.55, 95% confidence interval [CI]: 1.77-3.67, p < 0.001) and actively gamed (aOR: 1.64, 95% CI: 1.07-2.51, p = 0.024). Secondary school students with obesity were male (aOR: 1.61, 95% CI: 1.21-2.13, p = 0.001), had poor self-perceived academic performance (aOR:1.51, 95% CI: 1.10-2.08, p = 0.011) and expressed higher life satisfaction (family) (aOR: 1.13, 95% CI: 1.01-1.26, p = 0.032). There were negative associations found between obesity and physical activity, high consumption of sugary drinks, chocolate or candies, and insufficient consumption of vegetables. Conclusion: Male sex, physical inactivity, low self-perecived academic performance, and poor dietary behaviors were the risk factors for obesity among primary and secondary school students. The findings highlighted the importance of identifying younger individuals who were at risk of becoming clinically obese. Further studies should explore the effectiveness of various interventions through longitudinal study.

No evidence for metabolic adaptation during exercise-related energy compensation.

The constrained energy model posits that the increased total daily energy expenditure (TDEE) in response to exercise is often less than the energy cost of the exercise prescribed. The mechanisms behind this phenomenon, coined "exercise-related energy compensation" (ExEC), are poorly understood, and it is unknown if ExEC is coupled with metabolic adaptation. Using a randomized controlled 24-week exercise intervention, individuals who demonstrated ExEC were identified. Changes to all components of TDEE and metabolic adaptation were assessed using doubly labeled water over 14 days and room calorimetry over 24-h 48% of individuals exhibited ExEC (-308 ± 158 kcals/day). There were no statistically significant differences in sex, age, or BMI between ExEC and non-ExEC. ExEC was associated with baseline TDEE (r = -0.50, p = 0.006). There were no statistically significant differences in metabolic adaptations for 24 h, sleep, or resting expenditures. These findings reveal that ExEC occurs independent of metabolic adaptation in sedentary components of EE.

Development of a cellular assay as a personalized model for testing chronic wound therapeutics.

Exudates of non-healing wounds contain drivers of pathogenicity. We utilized >800 exudates from non-healing and healing wounds of diverse etiologies, collected by three different methods, to develop a wound-specific, cell-based functional biomarker assay. Human dermal fibroblast proliferation served as readout to a) to differentiate between healing and non-healing wounds, b) follow the healing process of individual patients, and c) assess the effects of therapeutics for chronic wounds ex vivo. We observed a strong correlation between wound chronicity and inhibitory effects of individual exudates on fibroblast proliferation, with good diagnostic sensitivity (76-90%, depending on the sample collection method). Transition of a clinically non-healing to a healing phenotype restored fibroblast proliferation and extracellular matrix formation while reducing inflammatory cytokine production. Transcriptional analysis of fibroblasts exposed to ex vivo non-healing wound exudates revealed an induction of inflammatory cytokine- and chemokine pathways and the unfolded protein response, indicating that these changes may contribute to the pathology of non-healing wounds. Testing the wound therapeutics platelet derived growth factor and silver sulfadiazine yielded responses in line with clinical experience and indicate the usefulness of the assay to search for and profile new therapeutics.

Associations of short-term changes in obesity indices with all-cause mortality and cardiovascular disease.

OBJECTIVE: This study aimed to investigate how short-term changes (1-, 3-, and 5-year) in obesity measures affect mortality and cardiovascular disease (CVD) risk. METHODS: We analyzed longitudinal data from the MJ Health Centre (n = 43,304 for the 1-year study; 24,295 for the 3-year study; 16,138 for the 5-year study) with median follow-up periods of 15.8, 13.9, and 12.3 years, respectively. Associations of short-term obesity indices changes with mortality and Framingham Risk Score changes were explored using time-dependent coefficient Cox regression models, restricted cubic splines, and multivariable linear regression models. RESULTS: All-cause mortality was negatively associated with short-term weight and BMI changes, with greater reductions causing poorer outcomes. Compared with stable groups, short-term reduced weight and BMI were associated with greater risks of all-cause mortality and CVD-specific mortality (5-year study only). Also, either 1- and 3-year reduced or 3-year increased waist circumference and waist to height ratio were related to higher all-cause and CVD deaths than stable groups, respectively. Nonlinear relationships indicated lower cutoff values for short-term changes in obesity indices in predicting all-cause mortality. Decreased obesity indices significantly improved CVD profiles. CONCLUSIONS: Short-term changes in obesity indices show complex mortality risks, urging personalized approaches beyond a simple weight loss focus.

Incidence distributions, risk factors and trends of vaginal cancer: A global population-based study.

OBJECTIVE: This study aimed to investigate the incidence, risk factors and trends for vaginal cancer. DESIGN: Retrospective observational design. SETTING: Data were collected from multiple sources, including the Global Cancer Observatory, Cancer Incidence in Five Continents Plus, Global Burden of Disease, World Bank and the United Nations. POPULATION: Individuals diagnosed with vaginal cancer. METHODS: The study collected data on vaginal cancer from the specified sources. The age-standardised rate (ASR) of vaginal cancer was calculated for different regions and age groups. Multivariable and univariable linear regression analyses were performed to examine the associations between risk factors and the incidence of vaginal cancer. Trend analysis was conducted using joinpoint regression analysis, and the average annual percentage change (AAPC) was calculated to quantify the temporal trend. MAIN OUTCOME MEASURES: The main outcome measures of the study were the incidence of vaginal cancer, risk factors associated with the disease and the trend of its incidence over time. RESULTS: There were 17 908 newly reported cases of vaginal cancer (ASR = 0.36, 95% CI 0.30-0.44) in 2020, with the highest ASRs reported in South-Central Asia and Southern Africa. Risk factors associated with a higher incidence of vaginal cancer included a higher prevalence of unsafe sex and human immunodeficiency virus (HIV) infection. The temporal trend showed an overall rising incidence globally, with Iceland (AAPC = 29.56, 95% CI 12.12-49.71), Chile (AAPC = 22.83, 95% CI 13.20-33.27), Bahrain (AAPC = 22.05, 95% CI 10.83-34.40) and the UK (AAPC = 1.40, 95% CI 0.41-2.39) demonstrating the most significant rising trends. CONCLUSIONS: The significant regional disparities and risk factors associated with vaginal cancer underscore the necessity for targeted interventions and education, particularly in regions with a lower human development index (HDI) and a higher prevalence of human papillomavirus (HPV) infection. The increasing incidence trend emphasises the need for enhanced HPV vaccination rates to prevent the development of vaginal cancer.

Patients taking benralizumab, dupilumab, or mepolizumab have lower postvaccination SARS-CoV-2 immunity.

BACKGROUND: Biologic therapies inhibiting the IL-4 or IL-5 pathways are very effective in the treatment of asthma and other related conditions. However, the cytokines IL-4 and IL-5 also play a role in the generation of adaptive immune responses. Although these biologics do not cause overt immunosuppression, their effect in primary severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immunization has not been studied completely. OBJECTIVE: Our aim was to evaluate the antibody and cellular immunity after SARS-CoV-2 mRNA vaccination in patients on biologics (PoBs). METHODS: Patients with severe asthma or atopic dermatitis who were taking benralizumab, dupilumab, or mepolizumab and had received the initial dose of the 2-dose adult SARS-CoV-2 mRNA vaccine were enrolled in a prospective, observational study. As our control group, we used a cohort of immunologically healthy subjects (with no significant immunosuppression) who were not taking biologics (NBs). We used a multiplexed immunoassay to measure antibody levels, neutralization assays to assess antibody function, and flow cytometry to quantitate Spike-specific lymphocytes. RESULTS: We analyzed blood from 57 patients in the PoB group and 46 control subjects from the NB group. The patients in the PoB group had lower levels of SARS-CoV-2 antibodies, pseudovirus neutralization, live virus neutralization, and frequencies of Spike-specific B and CD8 T cells at 6 months after vaccination. In subgroup analyses, patients with asthma who were taking biologics had significantly lower pseudovirus neutralization than did subjects with asthma who were not taking biologics. CONCLUSION: The patients in the PoB group had reduced SARS-CoV-2-specific antibody titers, neutralizing activity, and virus-specific B- and CD8 T-cell counts. These results have implications when considering development of a more individualized immunization strategy in patients who receive biologic medications blocking IL-4 or IL-5 pathways.