Fanconi syndrome after a single exposure to intravenous zoledronic acid

Bisphosphonates are commonly used to reduce fracture risk in patients with osteoporosis, in those with malignant metastatic bone disease and for treatment of malignant hypercalcaemia. We present the case of a woman in her 80s admitted with recurrent falls who developed Fanconi syndrome after a single dose of intravenous Zoledronic acid despite normal renal function. In this report, we review the literature exploring nephrotoxicity secondary to Zoledronic acid use recognising that there are other reported cases of Fanconi syndrome however, all in patients with malignancy rather than for osteoporosis. We also present one of the first cases of Fanconi syndrome after just a single exposure to Zoledronic acid in a patient who had normal preceding renal function. This highlights the need to be aware of the possibility of significant nephrotoxicity after a single exposure to Zoledronic acid even without the recognised risk factors of chronic or acute kidney disease

Identifying correlates of risk for future tuberculosis disease progression in South African children (intrepid): a protocol paper

Introduction Young children and children living with HIV are at high risk of progressing to tuberculosis (TB) disease following Mycobacterium tuberculosis (Mtb) exposure and infection, and also of developing severe forms of disease and TB-related mortality. Identifying children who have very early (sub-clinical) TB disease, prior to progression to clinically apparent TB, would mean that TB preventive treatment (TPT) could be more efficiently targeted to this group. Identifying biomarker changes on drug therapy in children with Mtb infection or very early disease could pave the way for the development of tests that can identify which children have viable bacilli and are therefore at increased risk of disease progression. Methods and analysis The INTREPID study will utilize already collected samples taken from well-phenotyped paediatric cohorts in three clinical studies conducted in South Africa in children <5 years, including a drug-resistant TPT trial (TB-CHAMP), an observational household contact study (IGRA studies), and a prospective diagnostic study (Umoya), all conducted in a setting with a high burden of TB and HIV. We will employ transcriptomic, proteomic, metabolomic, and serology approaches to analyse changes in host blood profiles at every stage along the TB continuum, from Mtb exposure to disease and from children treated for Mtb infection and early TB disease, as well as targeted Mtb antibody analysis. Data on viral co-infections and relevant clinical and epidemiological parameters will be integrated and evaluated to identify the optimal biosignatures that can predict future progression to clinically overt disease in children below 5 years of age, including those living with HIV. Ethics and dissemination The study protocol received ethical approval from the Stellenbosch University Health Research Ethics Committee (N23/03/025). The study findings will be disseminated through peer-reviewed publications, scientific conferences, and formal presentations to healthcare professionals and to local communities, in collaboration with the Desmond Tutu TB Centre Community Advisory Board (DTTC CAB)

Social networking site use, depressive and anxiety symptoms in adolescents: evidence from a longitudinal cohort study (SCAMP)

Background The growing and pervasive use of social network sites (SNS) has raised concerns about their impact on adolescent mental health during this sensitive developmental phase. Existing longitudinal studies are constrained by methodological limitations and limited exploration of underlying mechanisms. We investigated the longitudinal associations between SNS use and depressive and anxiety symptoms in adolescents and whether sleep mediated these associations. Methods We analysed longitudinal data from 2350 adolescents from 31 schools in London, participating in the Study of Cognition, Adolescents, and Mobile Phones (SCAMP). The exposure was self-reported duration of SNS use at baseline (aged 11–12 years). Outcomes were depressive and anxiety symptoms at follow-up, analysed as symptom severity and clinically significant symptoms (aged 13–15 years). The associations between SNS use and depressive and anxiety symptoms were assessed via multi-level ordinal logistic regression (symptom severity) and logistic regression (clinically significant symptoms). The mediation effects of insufficient sleep, sleep onset latency, and sleep disturbance were assessed by mediation analysis. Results Compared to 0–30 min per day, more than 3 h per day of SNS use at baseline was associated with higher severity levels of depressive and anxiety symptoms (adjusted odds ratio (OR) = 1.47, 95% CI 1.12, 1.93 and OR = 1.40, 95% CI 1.06, 1.83, respectively) and clinically significant depressive and anxiety symptoms at follow-up (OR = 1.70, 95% CI 1.19, 2.42 and OR = 1.60, 95% CI 1.11, 2.31, respectively). The associations between total and weekend SNS use and depressive symptom severity were stronger in girls than boys. Other associations were similar by gender. Insufficient sleep duration (particularly on weekdays) and sleep onset latency at baseline partly mediated the associations of SNS use and depressive and anxiety symptoms (proportion of mediation ranged between 11.1% and 33.1%). The mediation effects of sleep disturbance were less marked. Conclusions In a large longitudinal cohort, we found that SNS use exceeding 3 h per day is associated with increased risks of depressive and anxiety symptoms in adolescents. Findings from mediation analysis suggest that addressing poor sleep hygiene in relation to SNS use might mitigate the negative impact of high SNS use. Our findings may inform the development of early secondary school curricula incorporating digital literacy and sleep hygiene education

Developing a policy maturity model for prescription digital therapeutics based on expert consensus: protocol for an eDelphi study

Introduction Prescription Digital Therapeutics (PDTx) represent an emerging frontier in healthcare, leveraging software-based solutions to treat or manage specific medical conditions. However, despite rising interest and encouraging evidence of clinical benefits, the policy landscape remains fragmented. Jurisdictions vary widely in their regulatory approaches, reimbursement pathways, and processes for clinical integration, thus creating uncertainties for developers, payers, and healthcare providers. This protocol outlines a eDelphi study to develop and validate a comprehensive policy maturity framework guiding systematic assessment of national or regional readiness for PDTx adoption. Methods and analysis We will conduct an eDelphi study with up to three rounds to refine and validate a PDTx policy maturity framework. Experts will be recruited purposively from six stakeholder groups (regulators, healthcare providers, payers/health economists, developers, researchers, and patient advocates), prioritising Europe while seeking variation across health system types and levels of economic development; a small number of non-European experts may be invited to broaden perspectives. An optional pilot round will gather initial feedback on the prototype framework, followed by iterative rounds to assess and revise domains, scoring criteria, and maturity thresholds. A five-point Likert scale (from “strongly disagree” to “strongly agree”) will collect quantitative data, while open-text prompts will capture qualitative insights. Consensus will be defined as ≥70% agreement and/or an interquartile range (IQR) ≤1 for critical items. Quantitative summaries and thematic analysis will guide iterative revisions of the model. This Delphi protocol aims to produce a consensus-driven framework that captures the essential elements of PDTx policy development and implementation. If validated, the framework can serve as a reference for policymakers, industry leaders, healthcare providers and researchers seeking to benchmark or advance the adoption of PDTx within health systems. Ethics and dissemination Ethical approval for this study was obtained from the Ethics Committee of the Faculty of Medicine of the University of Porto (reference: 320/CEFMUP/2025). Panellists will provide electronic informed consent, and data will be kept confidential. The finalized framework will be disseminated via peer-reviewed publications, conference presentations, and policy briefs targeting stakeholders involved in digital health governance

Validation of the measure of case-discussion complexity (MeDic) and the metric for the observation of decision-making (MODe) for streamlining workflow and evaluating decision-making in US tumor boards

Background. Clinical guidelines for cancer care recognize multidisciplinary tumour boards (MTBs) as a gold standard for providing quality of care for cancer patients. However, the requirements and workflow for MTBs varies across countries, influencing their roles in decision making, care efficiency and medical education. This study compares validity and performance of MDT evaluation tools, Measure of case-Discussion Complexity (MeDiC) and Metric for the Observation of Decision-Making (MODe) in the UK vs US. Methods. MeDiC, developed to assess case complexity, and MODe, designed to evaluate decision making quality, were applied to 555 cases and 104 MTB meetings, from urological and gynecological tumor boards at an academic cancer center between December 2021 and June 2024. MeDiC was used to assess clinical complexity through pathology, patient, and treatment factors, while MODe evaluated decision-making quality based on patient information and team contributions. All assessors underwent formal training. Data analysis included reliability testing using intraclass correlation coefficients (ICCs), Kappa, Cronbach's alpha, and bootstrapping was used to estimate confidence intervals for correlation estimates. Results. MeDiC demonstrated good reliability (ICC=0.849) in the US MDT and identified key factors contributing to complexity, such as malignancy and significant comorbidities. The tool also revealed that case discussion duration was not significantly associated with complexity levels. MODe similarly showed moderate reliability (ICC=0.628), with high correlations between decision-making quality and contributions from core specialties such as medical oncologists. Conclusions. The validity of MeDiC and MODe in US were similar to the tools performance in the UK settings. However, case complexity metrics demonstrated significant selection of more complex cases for US MDT presentation compared to UK MDTs

Autonomous in silico optimization framework for high-performance micromixers

Effective mixing at the microscale is essential for lab-on-a-chip systems, yet designing micromixers that achieve both high mixing efficiency and low pressure drop remains challenging and resource-intensive. Here, we introduce an autonomous in silico framework for designing obstacle-based micromixers through integrating 3D geometry generation, computational fluid dynamics (CFD) simulations and a multi-objective artificial intelligence optimization algorithm within a fully automated close-loop workflow. A constraint-aware NSGA-II variant is used, incorporating a repair operator to ensure design feasibility. Experimentally validated against hyperspectral imaging-based mixing characterization and pressure-drop measurements, the framework eliminates manual trial-and-error workload and alleviates researchers from the tedious tasks of navigating across 3D modeling, CFD simulations, and optimization algorithms, reducing optimization time by 48% compared to the conventional simulation-assisted approach. By autonomously screening hundreds of designs, it identifies Pareto-optimal micromixers and generates an extensive database that supports inverse design and reveals the mixing structure-performance relationship, facilitating the establishment of general design guidelines. The framework is generally applicable to a wide range of passive micromixers

The protective stepping response in patients with bilateral vestibular hypofunction

Objective: Protective stepping following postural instability is a defence mechanism that prevents falls. Vestibular patients have increased risk of falling but little is known about their stepping response. Here, we investigate whether the protective stepping response is preserved in patients with bilateral vestibular hypofunction (BVH). Methods: This cross-sectional study, conducted in a balance-research facility, measured body sway and protective stepping responses during a dynamic postural task (platform oscillations at different velocities). Patients diagnosed with BVH were recruited from neuro-otology clinics. As stepping may be dictated by instability perception, objective sway and subjective instability were also analysed for each participant. Results: 12 patients (4 males, age:65.1, SD:14.2 years) and 12 healthy age and gender matched controls (age:64.8, SD:5.3) were recruited. Patients swayed more than controls (t:-2.153,p=0.03,d=-0.39) and showed marginally steeper objective-subjective instability curves than controls (t:-2.082,p=0.053,d=-0.85), meaning they felt slightly more unstable than controls for the same amount of sway. However, stepping velocity thresholds (t:-1.013,p=0.324,d=0.45) and latencies (t:0.062,p=0.951,d=-0.02) were not different between patients and controls. Discussion: These results indicate that the protective stepping response is preserved in BVH patients, hence not critically dependent on vestibular input. Only chronic patients were included, which limits the generalisation of the results to acute phases of the vestibular loss

C-type natriuretic peptide preserves vascular and cardiac function in sepsis

BACKGROUND: Sepsis is a life-threatening condition and a major cause of mortality in intensive care units worldwide, a clear unmet medical need. CNP (C-type natriuretic peptide) regulates inflammation and cardiovascular homeostasis, but its involvement in sepsis pathogenesis is not fully elucidated. This study investigated the intrinsic role of CNP, and therapeutic potential of the peptide, in offsetting the pathogenesis of sepsis. METHODS: Plasma concentrations of CNP, and its N-terminal cleavage product NT-proCNP (N-terminal pro-CNP), were measured in sepsis patients. Cardiac function, vascular hemodynamics, endothelial integrity, and biomarkers of inflammation were analyzed in wild-type, endothelium-restricted (ecCNP−/−), or cardiomyocyte-restricted (cmCNP−/−) CNP knockout animals, or global NPR (natriuretic peptide receptor)-C−/− deficient mice, in etiologically distinct models of sepsis. CNP (0.2 mg/kg per d) was infused to rescue any adverse phenotype and probe therapeutic potential. RESULTS: Circulating (NT-proCNP) increased in sepsis patients and was associated with reduced disease severity. ecCNP−/− mice exhibited an aggravated phenotype compared with wild-type mice in experimental sepsis, exemplified by impaired microcirculatory flow, edema, and increased expression of inflammatory biomarkers. In addition, cmCNP−/− animals showed overt cardiac dysfunction following lipopolysaccharide treatment. This worsened phenotype was mirrored in NPR-C−/− mice, implying that this cognate NPR subtype underpins the salutary actions of endogenous CNP. Pharmacological CNP administration improved microvascular perfusion, cardiac output, and inflammation in wild-type and ecCNP−/−, but not NPR-C−/−, mice. CONCLUSIONS: Endogenous CNP plays a protective role in sepsis by preserving microvascular perfusion, reducing inflammation, maintaining endothelial integrity, and sustaining cardiac function via NPR-C. Pharmacologically targeting CNP signaling warrants further evaluation as a potential therapeutic opportunity in sepsis

Motion compensated spin echo cardiac diffusion tensor imaging in multiple cardiac phases using an ultrahigh gradient strength scanner

Background Cardiac diffusion tensor imaging (cDTI) has traditionally relied on inefficient stimulated echo techniques to robustly assess microstructural changes over the cardiac cycle. Ultrahigh gradient strength systems (>80mT/m) allow shorter motion compensated diffusion encoding. This study compares the ability of high and ultrahigh strength gradient systems to provide systolic and diastolic motion compensated spin echo (MCSE) cDTI. Methods Second order MCSE sequences were developed for a research-only Siemens 3T Connectom (300mT/m maximum gradient amplitude per axis) and breath hold cDTI was acquired at peak systole and end diastole. Acquisitions used the maximum achievable gradient strength (GUH, 116mT/m) and also limited to typical high gradient strengths (GH, 66mT/m based on 80mT/m maximum allowable), giving TE=48ms and 58ms respectively. Data were acquired at 2.8x2.8x8mm3, b=500s/mm2 (8 averages) and b=150s/mm2 (2 averages) in 6 encoding directions. Results 22 healthy subjects were recruited. 20/21 and 21/22 systolic acquisitions at GUH and GH respectively met the >50% criteria of the circumferential myocardium showing the expected transmural variation in helix angle. For GUH and GH (16/20) 80% and (16/22) 73% of diastolic acquisitions were successful respectively. SNR was increased using GUH compared to GH (median [IQR]: 112.9 [3.8] vs. 9.6 [2.9], p=0.0002 diastole, 15.6 [5.9] vs. 12.5 [6.7], p=0.006 systole). Using GUH fractional anisotropy was lower in systole (0.349 [0.040] vs. 0.373 [0.019], p=0.002) and GUH transmural helix angle gradient (HAG) was steeper in diastole (-0.70 [0.17] vs. -0.55 [0.12] ˚/%, p=0.04). At both GUH and GH, sheetlet angle (|E2A|) was higher in systole than in diastole (30.7 [7.3] vs. 21.3 [6.7]˚ p=10-4 and 32.6 [10.9] vs. 26.0 [7.4]˚, p=0.03 respectively). Differences in HAG between phases were only apparent with GH (-0.88 [0.23] vs. -0.55 [0.15], p=10-4) and differences in the mean diffusivity only with GUH (1.64 [0.11] vs. 1.52 [0.24] x10-3mm2/s, p=0.002). Conclusion Ultrahigh strength gradient systems deliver higher SNR for MCSE and more robust imaging in diastole. While further work is required to further improve the reliability in diastole, at ultrahigh gradient strengths, cDTI using MCSE can identify dynamic changes in the cardiac microstructure. These findings will lead to more widespread use of multiphase MCSE in cDTI clinical research

La Niña, Climate change, high exposure and vulnerability combined led to devastating floods in parts of Southern Africa

Cite as Pinto, I. et al., (2026): La Niña, Climate change, high exposure and vulnerability combined led to devastating floods in parts of Southern Africa (WWA scientific report No. 81) World Weather Attributio