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States have long been understood to have an obligation to protect the international legal rights and interests of others, consistent with the maxim sic utere tuo ut alienum non laedas (use what is yours in such a manner as not to injure that of another). As the world's population becomes more interdependent, this no harm obligation becomes more significant. Further, as knowledge increases about the consequences of human activity for the climate and the environment, the no harm obligation takes on greater relevance vis-à-vis the interests of the Earth's future populations. Future generations’ legal interests have been recognized in the context of sustainable development and through the principle of intergenerational equity. The no harm rule requires that these interests be properly considered and addressed appropriately, commensurate with what is at stake. At a minimum, this may require avoidance of ‘manifestly excessive adverse impacts’.

In resourced settings, adults living with perinatally acquired HIV are approaching the 5th decade of life. Their clinical and psychological outcomes highlight potential future issues for the much larger number of adolescents growing up with HIV in sub-Saharan Africa, and will inform the development of appropriate healthcare services. Lifelong exposure to HIV, and increasingly to antiretroviral therapy throughout growth and development, contrasts with adults acquiring HIV in later life. This review describes the clinical outcomes for adults living with perinatally acquired HIV including post transition mortality, morbidity and retention in care. Rates of viral suppression, drug resistance and immunological function are explored. Co-morbidities focus on metabolic, cardio- vascular, respiratory and bone health with quality-of-life data including neurocognitive functioning and mental health. Sexual and reproductive health including vaccine-preventable disease and the prevention of onward transmission to partners and infants are considered. The data gaps and future research questions to optimise outcomes for this emerging adult cohort are highlighted.

Complex challenges amongst ageing cohorts of adolescents and adults living with perinatally acquired HIV (PaHIV) may impact on hospitalisation. We report hospitalisation rates and explored predictive factors for hospitalisation in adolescents and adults (10-35 years) living with PaHIV in England. Retrospective observational cohort study over a three-year period 2016-2019. Data collected included cause and duration of hospitalisation, HIV viral load and CD4 lymphocyte count. The primary outcome was overnight hospitalisation. Patients exited at study end/ transfer of care (TOC)/ loss to follow up (LTFU) or death. Maternity/hospital admissions at other centres were excluded. Admission rates per 100 person-years (95% CI) were calculated by age group. Negative binomial regression with generalized estimating equations was performed. 255 patients contributed 689 person-years of follow up. 56% were female and 83% were of a Black, Black British, Caribbean or African ethnicity. At baseline, the median age was 19 years (IQR 16-22). 36 individuals experienced a total of 62 admissions which resulted in 558 overnight stays (median stay was 5 nights). One person died (lymphoma), six had TOC and one was LTFU by the end of the three-year study period. Crude incidence of admission for the whole cohort was 9.0 per 100 PY (6.9-11.6). The respective crude incidence rates were 1.5 PY (0.0-8.2) in those aged 10-14 years and 3.5 PY (1.5-7.0) in the 15-19-year-olds. In those aged 20-24 years it was 14.5 PY (10.1-20.2) and in those >25 years the crude incidence rate was 11.7 PY (6.9-18.5). Factors significantly associated with admission were a CD4 lymphocyte count <200 cells/uL, adjusted IRR 4.0 (1.8-8.8) and a history of a CDC-C diagnosis, adjusted IRR 2.9 (1.6-5.3). 89% admissions were HIV-related: 45% new/current CDC-C diagnoses, 76% due to infection. Hospitalisation rates were four-fold higher in adults (>20 years of age) compared to adolescents (10-19-year-olds). The continuing challenges experienced by PaHIV youth require enhanced multidisciplinary support throughout adulthood.

Poorer adherence to medication is normal in adolescence and is one of a range of risk-taking behaviours common during a developmental stage that encompasses enormous cognitive, physical, sexual, social and emotional change. For adolescents living with human immunodeficiency virus (HIV) infection, poor adherence to antiretroviral therapy (ART) confers two significant challenges: poor health, but also the specific additional burden of onward transmission to partners. Late adolescence (15–19 years) is the only age group where HIV-associated mortality is rising, driven by poor adherence to ART and lack of access to second-line therapy, particularly amongst surviving perinatally infected young people. A previous lack of well-powered randomised multimodal behavioural ART adherence interventions specifically targeting adolescents is now being addressed and ongoing studies registered to ClinicalTrials.gov are described in the context of previous data. Accepting that despite enhanced support, some adolescents will continue to struggle with adherence, we must address how best to use existing ART agents to reduce mortality and allow adolescents the time to mature into adult life. Single-tablet regimens with a high genetic barrier to resistance based on integrase inhibitors and boosted protease inhibitors exist, but global access, in resource limited settings of young people living with HIV reside, is limited. Pragmatically, such regimens tolerate the intermittent adherence so characteristic of adolescence, preserving immune function, without the rapid evolution of resistance. The potential role of long-acting injectable ART, specifically cabotegravir and rilpivirine, is discussed and future strategies including ultra-long-acting drug-delivery systems and broadly neutralising monoclonal antibodies explored.

Background Soluble CD13 (sCD13), generated through cleavage of membrane-bound CD13 by matrix metalloproteinase-14 (MMP14), exhibits proinflammatory, angiogenic, and arthritogenic properties. Its known receptors include bradykinin receptor B1 (B1R) and protease-activated receptor 4 (PAR4). Building on our previous findings that the sCD13-B1R axis contributes to fibrosis in systemic sclerosis (SSc), we investigated whether plasma sCD13 levels and gene expression by peripheral blood cells are associated with clinical features of SSc. Methods Plasma sCD13 levels were quantified by ELISA in SSc patients and healthy controls enrolled at the University of Michigan Scleroderma Program. Three independent patient cohorts were analyzed to assess associations with disease subtype, vascular complications, and early-stage disease. Public transcriptomic datasets were used to evaluate the expression of CD13-related genes in peripheral blood cells. Statistical analyses included t-tests, one-way ANOVA, chi-square tests, and correlation analyses, with significance defined as p  < 0.05. Results Plasma sCD13 levels were significantly elevated in SSc patients compared to healthy controls but showed no association with vascular complications or baseline severity of skin disease as shown by mRSS, interstitial lung disease, pulmonary function, and autoantibody profiles. In early-stage SSc, higher baseline sCD13 predicted greater improvement in skin fibrosis over one year ( r = -0.42, p  = 0.001), and longitudinal decline in sCD13 corelated with changes in DLCO% ( r  = 0.53, p  = 0.04). Transcriptomic analysis revealed upregulation of ANPEP (CD13), MMP14 , and F2RL3 (PAR4) in SSc blood, with strong positive correlations between ANPEP and both MMP14 and F2RL3 . In addition, ANPEP and MMP14 expression correlated with TGFB1 and IL6 , key cytokines in SSc pathogenesis. Single-cell data further localized ANPEP and MMP14 expression to myeloid cells, particularly CD14⁺ and CD16⁺ monocytes and dendritic cells. Conclusions Our results demonstrate that circulating sCD13 reflects dynamic disease activity rather than static severity in SSc. Its expression in myeloid cells and linkage to fibrotic cytokines suggest an active role in disease pathogenesis. While systemic sCD13 alone may have limited biomarker utility, longitudinal monitoring and integration with tissue-level markers could enhance prediction of disease trajectory and therapeutic response.

Objectives Neutrophils and neutrophil extracellular traps (NETs) contribute to the vascular complications of multiple diseases, but their role in systemic sclerosis (SSc) is understudied. We sought to test the hypothesis that NETs are implicated in SSc vasculopathy and that treatment with prostacyclin analogs may ameliorate SSc vasculopathy not only through vasodilation but also by inhibiting NET release. Methods Blood from 125 patients with SSc (87 diffuse cutaneous SSc and 38 limited cutaneous SSc) was collected at a single academic medical center. Vascular complications such as digital ulcers, pulmonary artery hypertension, and scleroderma renal crisis were recorded. The association between circulating NETs and vascular complications was determined using in vitro and ex vivo assays. The impact of the synthetic prostacyclin analog epoprostenol on NET release was determined. Results Neutrophil activation and NET release were elevated in patients with SSc-associated vascular complications compared to matched patients without vascular complications. Neutrophil activation and NETs positively correlated with soluble E-selectin and VCAM-1, circulating markers of vascular injury. Treatment of patients with digital ischemia with a synthetic prostacyclin analog boosted neutrophil cyclic AMP, which was associated with the blunting of NET release and reduced NETs in circulation. Conclusion Our study demonstrates an association between NETs and vascular complications in SSc. We also identified the potential for an additional therapeutic benefit of synthetic prostacyclin analogs, namely to reduce neutrophil hyperactivity and NET release in SSc patients. Key message • Neutrophils and NETs are understudied in the pathogenesis of SSc. • Plasma NETs are associated with SSc vascular complications and may identify patients deserving proactive treatments. • Prostacyclin analogs potentially protect against SSc vasculopathy-related NET release by boosting intracellular cyclic AMP.

Introduction Low bone mineral density (BMD) has been described in children and young people with perinatally acquired HIV (PHIV), which may be related to both traditional (e.g. low body mass index and malnutrition) and HIV‐related risk factors (e.g. longstanding exposure to HIV and antiretroviral therapy [ART], with immune suppression, chronic immune activation and inflammation). Here, we evaluate BMD in a U.K. cohort of young people with PHIV by age and ART. Methods This longitudinal, observational study was conducted at a U.K. tertiary PHIV service between November 2018 and March 2022. Bone health was assessed in 130 individuals aged 15–19 (n = 50), 20−24 (n = 50) and 25 years and older (n = 30) by dual‐energy X‐ray absorptiometry, bone mineralization and turnover markers. Low BMD was defined as lumbar spine (LS) and/or femur‐BMD z‐score below −2, relative to age, sex and ethnicity‐matched U.K. population‐based normative controls. Two‐year follow‐up evaluation was performed in those aged 15−19 (n = 42) and 20−24 years (n = 43) at enrolment, which included a group who switched from tenofovir disoproxil fumarate (TDF) to tenofovir alafenamide (TAF) ART at baseline. Bayesian logistic regression models examined predictors of low BMD and the effect of ART‐backbone on BMD accrual. Results At baseline, 57% were female and 82% of black ethnicity, with 31 (24%) on TDF‐ART. Sixteen (12%) had low baseline BMD. Over a median follow‐up duration of 26 (interquartile range [IQR] 25–29) months, BMD accrual was lower‐than‐expected in those aged 15−19 years (mean change LS‐BMD z‐score −0.15 (standard deviation [SD] 0.44)), when compared to normative controls. No associations were seen with HIV parameters or the ART regimen. Participants who switched to TAF‐ART had similar BMD accrual 26 (IQR 24–32) months post switch, when compared to those on non‐TAF/TDF‐ART (mean change LS‐BMD z‐score TAF −0.01 [SD 0.41] vs. non‐TAF/TDF −0.03 [SD 0.54]). Conclusions While rates of low BMD were reassuringly low in this cohort, lower‐than‐expected BMD accrual was observed in younger individuals, relative to normative controls. Overall, BMD accrual on TAF‐ART was non‐inferior to non‐TAF/TDF‐ART.

Background Evidence suggests that engagement in care (EIC) may be worse in young people living with perinatal HIV (YPLPHIV) compared to adults or children living with HIV. We took a published EIC algorithm for adults with HIV, which takes patients’ clinical scenarios into account, and adapted it for use in YPLPHIV in England, to measure their EIC. Methods The adult algorithm predicts when in the next 6 months the next clinic visit should be scheduled, based on routinely collected clinical indicators at the current visit. We updated the algorithm based on the latest adult guidelines at the time, and modified it for young people in paediatric care using the latest European paediatric guidelines. Paediatric/adolescent HIV consultants from the UK reviewed and adapted the resulting flowcharts. The adapted algorithm was applied to the Adolescent and Adults Living with Perinatal HIV (AALPHI) cohort in England. Data for 12 months following entry into AALPHI were used to predicted visits which were then compared to appointment attendances, to measure whether young people were in care in each month. Proxy markers (e.g. dates of CD4 counts, viral loads (VL)) were used to indicate appointment attendance. Results Three hundred sixteen patients were in AALPHI, of whom 41% were male, 82% of black African ethnicity and 58% born abroad. At baseline (time of AALPHI interview) median [IQR] age was 17 [15–18] years, median CD4 was 597 [427, 791] cells/µL and 69% had VL ≤50c/mL. 10 patients were dropped due to missing data. 306 YPLPHIV contributed 3,585 person months of follow up across the 12 month study in which a clinic visit was recorded for 1,204 months (38/1204 dropped due to missing data). The remaining 1,166 months were classified into 3 groups: Group-A: on ART, VL ≤ 50c/mL—63%(734/1,166) visit months, Group-B: on ART, VL > 50c/mL—27%(320/1,166) Group-C: not on ART-10%(112/1,166). Most patients were engaged in care with 87% (3,126/3,585) of months fulfilling the definition of engaged in care. Conclusions The adapted algorithm allowed the varying clinical scenarios of YPLPHIV to be taken into account when measuring EIC. However availability of good quality surveillance data is crucial to ensure that EIC can be measured well.

Identifying which young people living with perinatally acquired HIV (PHIV) are less likely to engage in care is crucial to allow targeted interventions to support them to attend clinic. We adapted an existing Engagement in Care (EIC) algorithm for adults with HIV in England, for use in young people. We applied it to data from young people with PHIV in the Adolescents and Adults Living with Perinatal HIV (AALPHI) cohort. The algorithm predicts the timing of the next scheduled clinic visit, within 1–6 months of current visit, based on routine clinical data. Follow-up was 12-months from AALPHI baseline interview. Each person-month was classified as engaged in care or not. Logistic regression models (allowing for clustered data) were used to explore baseline characteristics associated with being engaged in care, adjusting for a priori variables (time from interview, sex, age, ethnicity, country of birth). Potential characteristics were across 7 domains: sociodemographic; risk behaviour practices; mental health; cognition; clinic setting; HIV management and experience; and HIV clinical markers. Of 316 young people, 187(59%) were female, 271(86%) of black ethnicity and 184(58%) born abroad. At baseline, median [IQR] age was 17[15–18] years, and 202(69%) had viral load ≤50 copies/ml(c/mL). 87% of 3,585 person-months were classified as engaged in care. Characteristics independently associated with poorer odds of being engaged in care were: Asian/mixed/other ethnicity, vs. black ethnicity (OR 0.44, 95% CI 0.25, 0.78, p = 0.02); ever self-harmed, vs. not (OR 0.55, 95% CI 0.32, 0.95, p = 0.03); on antiretroviral therapy (ART) and self-assessed bad/not so good adherence (OR 0.46, 95% CI 0.25, 0.84) or not on ART (OR 0.64, 95% CI 0.64, 1.21) vs. on ART and good/excellent adherence (p = 0.04)); baseline VL>50c/mL, vs VL≤50c/mL (OR 0.47, 95% CI 0.30, 0.75, p = 0.002). These characteristics can help identify individuals requiring enhanced support to maintain service engagement.