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IntroductionAcute COVID-19 infection causes significant alterations in the innate and adaptive immune systems. While most individuals recover naturally, some develop long COVID (LC) syndrome, marked by persistent or new symptoms weeks to months after SARS-CoV-2 infection. Despite its prevalence, there are no clinical tests to distinguish LC patients from those fully recovered. Understanding the immunological basis of LC is essential for improving diagnostic and treatment approaches.MethodsWe performed deep immunophenotyping and functional assays to examine the immunological profiles of LC patients, individuals with active COVID-19, recovered patients, and healthy donors. This analysis assessed both innate and adaptive immune features, identifying potential biomarkers for LC syndrome. A Binomial Generalized Linear Model (BGLM) was used to pinpoint immune features characterizing LC.ResultsCOVID-19 patients exhibited depletion of innate immune cell subsets, including plasmacytoid and conventional dendritic cells, classical, non-classical, and intermediate monocytes, and monocyte-derived inflammatory dendritic cells. Elevated basal inflammation was observed in COVID-19 patients compared to LC patients, whose immune profiles were closer to those of healthy donors and recovered individuals. However, LC patients displayed persistent immune alterations, including reduced T cell subsets (CD4, CD8, Tregs) and switched memory B cells, similar to COVID-19 patients. Through BGLM, a unique adaptive immune signature for LC was identified, featuring memory CD8 and gd T cells with low proliferative capacity and diminished expression of activation and homing receptors.DiscussionThe findings highlight a unique immunological signature associated with LC syndrome, characterized by persistent adaptive immune dysregulation. While LC patients displayed recovery in innate immune profiles comparable to healthy and Recovered individuals, deficits in T cell and memory B cell populations were evident, differentiating LC from full recovery. These findings provide insights into LC pathogenesis and may support the development of diagnostic tools and targeted therapies.

Abstract Many species communicate by combining signals into multimodal combinations. Elephants live in multi-level societies where individuals regularly separate and reunite. Upon reunion, elephants often engage in elaborate greeting rituals, where they use vocalisations and body acts produced with different body parts and of various sensory modalities (e.g., audible, tactile). However, whether these body acts represent communicative gestures and whether elephants combine vocalisations and gestures during greeting is still unknown. Here we use separation-reunion events to explore the greeting behaviour of semi-captive elephants (Loxodonta africana). We investigate whether elephants use silent-visual, audible, and tactile gestures directing them at their audience based on their state of visual attention and how they combine these gestures with vocalisations during greeting. We show that elephants select gesture modality appropriately according to their audience’s visual attention, suggesting evidence of first-order intentional communicative use. We further show that elephants integrate vocalisations and gestures into different combinations and orders. The most frequent combination consists of rumble vocalisations with ear-flapping gestures, used most often between females. By showing that a species evolutionarily distant to our own primate lineage shows sensitivity to their audience’s visual attention in their gesturing and combines gestures with vocalisations, our study advances our understanding of the emergence of first-order intentionality and multimodal communication across taxa.

Background: In the literature, female anorgasmia (AO) is closely related to obsessive–compulsive disorder (OCD), but no publication has explored the role of individual obsessive traits that may also be typical of other disorders, assuming that repetitive thoughts and compulsions must necessarily correspond to an obsessive-type neurotic profile. It is worth investigating and assessing the specific weight of other morbid conditions involved, beyond OCD. Materials and Methods: This study was conducted during 2022–2023 by selecting 208 Italian clinical patients from private databases. They submitted to individual clinical interviews and two psychometric questionnaires (Perrotta Integrative Clinical Interviews 3, PICI-3-TA, and Perrotta Individual Sexual Matrix Questionnaire, PSM-Q). Results: Among the 208 patients (M: 39.05 years), divided into subgroups by age and obsessive symptomatology, no significant differences were found between the subgroups in the comparisons of the data obtained from the administration of the PSM-Q. Conclusions: This study confirms that it is not OCD that correlates with OA but obsessive traits, which are also common to other psychopathological disorders, such as bipolar disorder, borderline disorder, manic, and psychotic disorders and, therefore, in psychotherapy, it is necessary to intervene with a clinical approach that has in mind the patient’s psychopathological personality picture and the causes that originated or reinforced OA.

According to FAO reports, the global mule population counts about 9 million mules. This hybrid cross of a male donkey and a female horse is mainly used for draft purposes because they are thought to be strong and hardy animals. Most consider mules to be less susceptible to disease and fatigue compared to horses. Therefore, the aim of this study was to investigate the effects of fieldwork on biochemical variables and serum amyloid A in working mules. Blood samples were collected from 10 healthy, female, working mules before and after 8 h of fieldwork. According to statistical analysis, a significant influence (p < 0.05) of fieldwork was found on mules’ electrolyte profile with increased levels of sodium, chloride, and calcium, as well as on blood urea nitrogen and creatinine. After a day of fieldwork, serum sodium, chloride, calcium, urea, and creatinine concentrations were increased, supporting decreases in body water and renal blood flow. However, without comparison to a group of mules that were not exercised yet maintained under similar ambient conditions, it is uncertain whether these changes can be attributed to exercise. Further, no change in SAA concentration was found after exercise, indicating that the work performed did not result in systemic inflammation.

Abstract Mutations in SNCA, the gene encoding α-synuclein (αSyn), cause familial Parkinson’s disease (PD) and aberrant αSyn is a key pathological hallmark of idiopathic PD. This α-synucleinopathy leads to mitochondrial dysfunction, which may drive dopaminergic neurodegeneration. PARKIN and PINK1, mutated in autosomal recessive PD, regulate the preferential autophagic clearance of dysfunctional mitochondria (“mitophagy”) by inducing ubiquitylation of mitochondrial proteins, a process counteracted by deubiquitylation via USP30. Here we show that loss of USP30 in Usp30 knockout mice protects against behavioral deficits and leads to increased mitophagy, decreased phospho-S129 αSyn, and attenuation of SN dopaminergic neuronal loss induced by αSyn. These observations were recapitulated with a potent, selective, brain-penetrant USP30 inhibitor, MTX115325, with good drug-like properties. These data strongly support further study of USP30 inhibition as a potential disease-modifying therapy for PD.

According to the World Health Organization and the World Association for Sexual Health (WAS) Declaration of Sexual Rights, sex education aims to provide children and adolescents with comprehensive knowledge, skills, attitudes, and values, promoting equality and nondiscrimination while upholding freedom of thought and expression. However, current school curricula often focus on dichotomous sexual identity and hetero-cis-normative prevention strategies, neglecting the needs of gender minority (GM) and sexual minority (SM) youths. In family settings, discussions typically revolve around sexual risk reduction and basic contraception, omitting relational aspects and components of sexual identity such as orientations and gender expressions. This discrepancy highlights a gap between the official goals of sex education and its practical implementation, reflecting a cultural deficit in familial sex education. This study reviews the scientific literature on sexual health promotion interventions from 2015 to 2024 to identify inclusive approaches that enhance the participation of all youths, not just hetero-cis-normative individuals. The hypothesis is that most interventions primarily serve heterosexual and cisgender youths, indicating a need for more inclusive strategies to achieve better sexual health and educational outcomes. The study also suggests expanding curricula to align with recognized guidelines and the diverse needs of youth.

Background Systematic annual screening for sight-threatening diabetic retinopathy is established in several countries but is resource intensive. Personalised (individualised) medicine offers the opportunity to extend screening intervals for people at low risk of progression and to target high-risk groups. However, significant concern exists among all stakeholders around the safety of changing programmes. Evidence to guide decisions is limited, with, to the best of our knowledge, no randomised controlled trials to date. Objectives To develop an individualised approach to screening for sight-threatening diabetic retinopathy and test its acceptability, safety, efficacy and cost-effectiveness. To estimate the changing incidence of patient-centred outcomes. Design A risk calculation engine; a randomised controlled trial, including a within-trial cost-effectiveness study; a qualitative acceptability study; and an observational epidemiological cohort study were developed. A patient and public group was involved in design and interpretation. Setting A screening programme in an English health district of around 450,000 people. Participants People with diabetes aged ≥ 12 years registered with primary care practices in Liverpool. Interventions The risk calculation engine estimated each participant’s risk at each visit of progression to screen-positive diabetic retinopathy (individualised intervention group) and allocated their next appointment at 6, 12 or 24 months (high, medium or low risk, respectively). Main outcome measures The randomised controlled trial primary outcome was attendance at first follow-up assessing the safety of individualised compared with usual screening. Secondary outcomes were overall attendance, rates of screen-positive and sight-threatening diabetic retinopathy, and measures of visual impairment. Cost-effectiveness outcomes were cost/quality-adjusted life year and incremental cost savings. Cohort study outcomes were rates of screen-positive diabetic retinopathy and sight-threatening diabetic retinopathy. Data sources Local screening programme (retinopathy), primary care (demographic, clinical) and hospital outcomes. Methods A seven-person patient and public involvement group was recruited. Data were linked into a purpose-built dynamic data warehouse. In the risk assessment, the risk calculation engine used patient-embedded covariate data, a continuous Markov model, 5-year historical local population data, and most recent individual demographic, retina and clinical data to predict risk of future progression to screen-positive. The randomised controlled trial was a masked, two-arm, parallel assignment, equivalence randomised controlled trial, with an independent trials unit and 1 : 1 allocation to individualised screening (6, 12 or 24 months, determined by risk calculation engine at each visit) or annual screening (control). Cost-effectiveness was assessed using a within-trial analysis over a 2-year time horizon, including NHS and societal perspectives and costs directly observed within the randomised controlled trial. Acceptability was assessed by purposive sampling of 60 people with diabetes and 21 healthcare professionals with semistructured interviews analysed thematically; this was a constant comparative method until saturation. The cohort was an 11-year retrospective/prospective screening population data set. Results In the randomised controlled trial, 4534 participants were randomised: 2097 out of 2265 in the individualised arm (92.6%) and 2224 out of 2269 in the control arm (98.0%) remained after withdrawals. Attendance rates at first follow-up were equivalent (individualised 83.6%, control 84.7%) (difference –1.0%, 95% confidence interval –3.2% to 1.2%). Sight-threatening diabetic retinopathy detection rates were non-inferior: individualised 1.4%, control 1.7% (difference –0.3%, 95% confidence interval –1.1% to 0.5%). In the cost-effectiveness analysis, the mean differences in complete-case quality-adjusted life years (EuroQol-5 Dimensions, five-level version, and Health Utilities Index Mark 3) did not significantly differ from zero. Incremental cost savings per person not including treatment costs were from the NHS perspective £17.34 (confidence interval £17.02 to £17.67) and the societal perspective £23.11 (confidence interval £22.73 to £23.53). In the individualised arm, 43.2% fewer screening appointments were required. In terms of acceptability, changing to variable intervals was acceptable for the majority of people with diabetes and health-care professionals. Annual screening was perceived as unsustainable and an inefficient use of resources. Many people with diabetes and healthcare professionals expressed concerns that 2-year screening intervals may detect referable eye disease too late and might have a negative effect on perceptions about the importance of attendance and diabetes care. The 6-month interval was perceived positively. Among people with dementia, there was considerable misunderstanding about eye-related appointments and care. In the cohort study, the numbers of participants (total 28,384) rose over the 11 years (2006/7, n = 6637; 2016/17, n = 14,864). Annual incidences ranged as follows: screen-positive 4.4–10.6%, due to diabetic retinopathy 2.3–4.6% and sight-threatening diabetic retinopathy 1.3–2.2%. The proportions of screen-positive fell steadily but sight-threatening diabetic retinopathy rates remained stable. Limitations Our findings apply to a single city-wide established English screening programme of mostly white people with diabetes. The cost-effectiveness analysis was over a short timeline for a long-standing disease; the study, however, was designed to test the safety and effectiveness of the screening regimen, not the cost-effectiveness of screening compared with no screening. Cohort data collection was partly retrospective: data were unavailable on people who had developed sight-threatening diabetic retinopathy or died prior to 2013. Conclusions Our randomised controlled trial can reassure stakeholders involved in diabetes care that extended intervals and personalised screening is feasible, where data linkage is possible, and can be safely introduced in established screening programmes with potential cost savings compared with annual screening. Rates of screen-positive diabetic retinopathy and sight-threatening diabetic retinopathy are low and show consistent falls over time. Involvement of patients in research is crucial to success. Future work Future work could include external validation with other programmes followed by scale-up of individualised screening outside a research setting and economic modelling beyond the 2-year time horizon. Trial registration This trial is registered as ISRCTN87561257. Funding This project was funded by the National Institute for Health and Care Research (NIHR) Programme Grants for Applied Research programme and will be published in full in Programme Grants for Applied Research; Vol. 11, No. 6. See the NIHR Journals Library website for further project information. Plain language summary Diabetic retinopathy remains a leading cause of vision loss for people with diabetes. Annual photographic screening allows early detection and prompt treatment in many countries. A new approach is to vary how often this is undertaken at each visit, after calculating each person’s risk of progression; we have called this ‘individualised’ screening. We tested this variable-interval risk-based approach against annual screening in a randomised controlled trial of 4534 people in Liverpool. Six-, 12- or 24-month intervals represented high, medium and low risks, respectively, of becoming screen-positive by the next appointment. With our patient and public involvement group, we designed a computer-based risk-calculation system using personal information from screening, general practitioners and hospitals. Attendance rates at the next screening appointment were similar in the individualised (84%) and annual (control) (85%) groups. Similar amounts of sight-threatening diabetic retinopathy were detected in the two arms (1.4% individualised, 1.7% control), with 43% fewer visits. In this study in a single geographical region, savings estimated to accrue to the NHS per person over 2 years were £17.34 and £23.11 for wider society, but estimates did not include treatment costs. During interviews, 60 people with diabetes and 21 healthcare professionals said that individualised screening would be acceptable because of increasing rates of diabetes and the chance to target high-risk people. Patients had anxieties about the reliability of the risk-calculation and restricting access, requesting opportunities for earlier screening if risks changed. Varying screening intervals based on a person’s own risk of progression appears feasible and safe. Low-risk people would be spared unnecessary appointments. Introducing an individualised approach could now move to wider testing and validation in other UK and international settings. The trial only ran for 2 years and was in a long-established programme with low rates of disease, so monitoring of attendance and retinopathy rates should be included as part of wider testing. Scientific summary Background Diabetic retinopathy remains the most common cause of visual impairment in working populations worldwide. Systematic annual screening to detect and treat sight-threatening diabetic retinopathy (STDR) is established in several countries including the United Kingdom (UK) and has greatly improved the detection of treatable disease. With the rapid increase in the prevalence of diabetes, new approaches to screening are required. Risk stratification, personalised (individualised) medicine, and clinical bioinformatics offer opportunities to extend the screening interval for people at low risk of progression and to target those at high risk. However there is significant concern among people with diabetes, healthcare professionals and health commissioners in the UK around the safety and acceptability of changing an established and successful programme. To ensure that health care is available for all it is imperative that it is not only efficacious but cost-efficient, that is, it delivers care at an affordable cost for commissioners. Evidence to guide these decisions is very limited and there are no randomised controlled trials (RCTs). Much of the data on prevalence and incidence of diabetic retinopathy and progression to more severe stages of disease come from the 1980s to 1990s and before the introduction of systematic screening and improvements in diabetes and blood pressure control. Data on the current progression rates in screening populations are limited and are reported variably. We conducted a programme of quantitative and qualitative research to develop and test the acceptability, safety, efficacy and cost-effectiveness of an individualised approach to screening for STDR. To provide data for future planning of early detection programmes and the design of future research studies we designed a longitudinal observational cohort study of the population of people with diabetes in Liverpool. We aimed to investigate the prevalence and incidence of the stages in the natural history of diabetic retinopathy, namely screen-positive, sight-threatening and treatable disease, and visual impairment, all key patient-centred outcomes in the disease. Changes to the programme and their implications A number of changes to the programme occurred in the early years. A systematic review was published at around the time of the programme start. We used these data to design aspects of the study and conducted a literature review instead. Data for the cohort study proved not to be available on people who had died prior to programme start. We adopted a mixed retrospective and prospective analysis but this added some difficulty in interpreting the findings. In 2016 resources were repurposed from the cohort study to support recruitment of the RCT, which was behind schedule. The scope of the cohort study was narrowed to focus only on the data available from the screening programme, meaning that we were unable to complete data collection on the patient-centred outcomes after sight-threatening retinopathy had been confirmed, namely treatment and visual impairment. Recruitment of non-attenders proved beyond the resources available and was abandoned. Further research is needed to address these unanswered questions. Methods The programme included the development of a bespoke data warehouse, the development of a risk-calculation engine, a RCT, a within-trial cost-effectiveness study, a qualitative study of acceptability, and an observational cohort study. We recruited and fully embedded a seven-person patient and public involvement group which was maintained throughout the programme. The setting was the screening programme of a single English health district (clinical commissioning group). All people with diabetes aged 12 years and over registered with general practices in the Liverpool city area were invited by letter to participate in the research programme. Consent was through an opt-out process. A purpose-built dynamic data warehouse was developed to support all aspects of the programme including bespoke processes addressing inconsistency in routinely collected data, multiple data platforms and lack of technical manuals. Data on eligible participants were sourced from primary care (demographic, clinical), Liverpool Diabetes Eye Screening Programme (retinopathy) and hospital outcomes (true screen-positive, STDR). Data were cross referenced against opt-out records before further use within the programme. A risk-calculation engine was developed for the assessment of individual risk of progressing to screen-positive using patient-focused covariate selection, a continuous-time Markov model, 5-year historical local population data, and the most recent individual demographic, retina and clinical data. The risk-calculation engine was linked to the data warehouse. The Patient and Public Involvement group determined the risk criterion of

Alzheimer’s disease is a neurodegeneration with protein deposits, altered proteolysis, and inflammatory and oxidative processes as major hallmarks. Despite the continuous search for potential therapeutic treatments, no cure is available to date. The use of natural molecules as adjuvants in the treatment of Alzheimer’s disease is a very promising strategy. In this regard, ginsenosides from ginseng root show a variety of biological effects. Here, we dissected the role of ginsenosides Rg1 and Rg2 in modulating autophagy and oxidative stress in neuroblastoma cells overexpressing Aβ(1-42). Key hallmarks of these cellular processes were detected through immunomethods and fluorometric assays. Our findings indicate that ginsenosides are able to upregulate autophagy in neuronal cells as demonstrated by increased levels of LC3II and Beclin-1 proteins and decreased amounts of p62. Simultaneously, an activation of lysosomal hydrolases was observed. Furthermore, autophagy activation promoted the clearance of Aβ(1-42). Rg1 and Rg2 also reduced oxidative stress sources and macromolecule oxidation, promoting NRF2 nuclear translocation and the expression of antioxidant enzymes. Our data further clarify the mechanisms of action of Rg1 and Rg2, indicating new insights into their role in the management of disorders like Alzheimer’s disease.