Video-assisted thoracoscopic surgery (VATS) lobectomy is a commonly employed surgical technique for the management of operable early stage non-small cell lung cancer (NSCLC). This procedure, however, is dependent on the patient’s ability to tolerate surgery. In light of this, stereotactic ablative radiotherapy (SABR) has emerged as a viable alternative treatment strategy for patients who are inoperable or who refuse surgery. Considering the lack of randomised controlled trials and the increased risk of bias in observational cohort studies, this study protocol proposes an emulated target trial design to investigate the causal effect of SABR, in comparison to VATS, on overall survival in operable early stage NSCLC patients.

Data on NSCLC patients will be collected from routinely collected university hospital records linked with German cancer registry data. This study protocol was developed using the target trial methodology outlined by Hernan et al. The protocol establishes specific parameters for key trial components in order to mitigate bias in the analysis of observational data and to facilitate the calculation of causal estimands. The target trial design that would be emulated is a multicentre open-label two-parallel arm superiority randomised trial. Mediators and confounding variables were determined through the use of a directed acyclic graph. The statistical analysis aims to measure the per-protocol and intention to treat effect of SABR versus VATS within 3 months of diagnosis, on survival, through the difference in restricted mean survival times, using weighted non-parametric Kaplan-Meier curves.

The Ethics Committee of the Medical Faculty of Martin Luther University Halle-Wittenberg with an approved addendum with Dnr 2023–112 has approved this study. The study uses anonymised routinely collected hospital and cancer registry data in accordance with applicable data protection regulations. Results will be disseminated through peer-reviewed publications and presentations at scientific conferences.

Men, particularly those belonging to gender minority groups, often experience poorer physical health outcomes. This study examined global health and quality of life (QoL) across diverse male gender subgroups in Switzerland. While emphasising male gender diversity, we aimed to identify key sociodemographic risk factors associated with reduced global health and QoL.

We analysed a subset of the Swiss Health Survey 2022, a cross-sectional nationally representative health-related dataset from the general Swiss population. Our sample included individuals falling into one of the three groups: cisgender men, transgender men (assigned female at birth with male gender identity) and men with ‘other’ gender identities (assigned male at birth but identifying as non-binary or non-specified gender identity). Global health and QoL were assessed using the Minimum European Health Module (MEHM) and the global QoL item of the WHOQOL-Bref. Four binary logistic regression models examined the association between male gender identities, sociodemographic data and MEHM and QoL outcomes.

Our study comprised 3 505 801 male cases after weighting. Of these, 12.9% reported fair to very poor health. Key risk factors included being unemployed, migration background and being a transgender man. The strongest protective factor was higher education. Chronic conditions were reported by 33.3% men, with unemployment again being the most relevant risk factor. Identifying as a man with ‘other’ gender identities emerged as a protective factor. Regarding QoL, 8% stated impaired QoL, while the male gender identity ‘other’ was the strongest risk factor and tertiary school education the most relevant protective factor.

Risk and protective factors vary across different global health outcomes and QoL in men. These findings highlight the importance of disaggregating male gender categories beyond the binary to better understand the complexity of health disparities. A differentiated, gender-inclusive approach is essential for accurately identifying vulnerable groups and tailoring public health interventions accordingly.

Post-COVID-19 syndrome (PCS) is characterised by persistent symptoms, such as fatigue, dyspnoea, depression and sleep problems, following SARS-CoV-2 infection. The long-term course and impact on quality of life remain unclear. This review aims to synthesise evidence on longitudinal changes in symptom prevalence, severity and health-related quality of life (HRQoL) in adults with PCS.

This systematic review will include longitudinal studies (randomised controlled trials, non-randomised trials, prospective and retrospective cohort studies) of adults (≥18 years) with PCS, defined by symptoms persisting beyond 4 weeks after acute infection. Eligible studies must report changes in prevalence or severity of fatigue, dyspnoea, depression, sleep problems or HRQoL from baseline to at least one follow-up visit.

We will systematically search MEDLINE, Embase, PsycINFO, Web of Science, Scopus, CINAHL and Epistemonikos, with no restrictions on language, date or publication status. Two reviewers will independently screen studies, extract data and assess risk of bias using validated tools appropriate to study design. Disagreements will be resolved by consensus or a third reviewer.

A narrative synthesis will summarise study characteristics and symptom trajectories. Where sufficient data are available, random-effects meta-analyses will be conducted to estimate pooled changes in symptom prevalence (ORs), severity ((standardised) mean differences) and HRQoL ((standardised) mean differences). Meta-regression and subgroup analyses will explore potential effect modifiers. Certainty of evidence will be evaluated using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.

No ethical approval is required. Findings will be disseminated via peer-reviewed publication, conference presentations and plain language summaries.

CRD420251011612.

Current evidence is unclear due to methodological limitations. We bridge critical knowledge gaps by quantifying the longitudinal changes in movement behaviours and their correlates from early childhood through adolescence.

Longitudinal observational cohort study.

General healthy child and adolescent sample in Singapore.

Growing Up in Singapore Towards healthy Outcomes study participants.

We used wrist-worn accelerometry and proxy-reported data to examine movement behaviours (sleep, inactivity, light physical activity (PA; LPA) and moderate-to-vigorous PA (MVPA) and screen-viewing) at ages 5.5, 8, 10 and 12 years and the sociodemographic and maternal lifestyle-related correlates using linear regression models with generalised estimating equations.

Among 837 children, sleep, LPA and MVPA declined by 3% (from 9.1 to 8.8 hours/day), 24% (from 5.8 to 4.4 hours/day) and 44% (from 71.3 to 40.1 min/day), respectively, while inactivity and screen viewing increased by 26% (from 8.0 to 10.1 hours/day) and 155% (from 1.8 to 4.6 hours/day), respectively, from ages 5.5 to 12 years. The greatest annual increase in inactivity (0.6 hour/annum) and screen-viewing (0.8 hour/annum) and decrease in LPA (0.3 hour/annum) and MVPA (10.4 min/annum) occurred from ages 8 to 10 years. Girls of Malay ethnicity and lower socioeconomic status, and whose mothers had less favourable movement behaviours, had significantly less sleep, higher inactivity and screen-viewing and/or lower PA. Maternal PA levels and/or sitting time were associated with children’s sleep, inactivity and MVPA up to age 8 years, while maternal sitting and screen-viewing behaviours were associated with children’s screen-viewing at all ages.

Using contemporaneous datasets relevant to the present day, we confirmed that children become less physically active and have longer screen-viewing as they transition into adolescence and highlighted characteristics to be prioritised in future interventions.

The Happy Healthy Active Children (HHAC) initiative is a multicomponent community-based initiative aimed at promoting physical activity, food literacy and nature literacy among children in early childhood kindergarten and primary school settings. Developed in collaboration between Activity Experts and Community Stakeholders, HHAC integrates thematic activities (Play, Nature, Food) across kindergartens, schools and the broader community. The initiative responds to growing concerns about declining physical activity levels, insufficient contact with nature and poor dietary habits in childhood, factors known to influence long-term health and well-being. This protocol outlines the design, implementation and planned evaluation of the HHAC initiative.

HHAC is carried out within the long-term strategic initiative Tingbjerg Changing Diabetes. Following the Supersetting approach, HHAC addresses inequity in health by mobilising resources across local settings (kindergartens, schools and the local community arenas) and population groups (children, parents, staff and other community members) to develop and implement contextually relevant activities promoting outdoor play, cooking and nature experiences. Activities are evaluated using a within-subject design in kindergartens, while in schools a quasi-experimental design with matched control groups is applied. Data is collected at baseline and follow-up through accelerometry, validated questionnaires and structured observations. Primary outcomes include physical activity levels, food literacy and nature literacy. Analyses apply linear mixed-effects models to account for repeated measures and clustering at the institutional level. The evaluation also investigates implementation processes and context-mechanism configurations through a comprehensive realist evaluation. This includes developing a programme theory, conducting interviews with children, parents, staff and other local stakeholders and participant observations aiming to explore experiences and the mechanisms through which the activities contribute to changes in behaviour and well-being. All data will be analysed and condensed for a model for transferability.

Findings will be disseminated through peer-reviewed journals, conference presentations and public engagement activities targeting educators, policymakers and health professionals. The intervention materials will also be made freely available to support broader implementation. The study procedures were registered and approved by The Capital Region’s centre for data reviews ‘Videnscenter for Dataanmeldelser’ (Reference: P-2023–14277). All procedures were carried out under relevant regulations and guidelines. Written information about the study was given to all school principals, teachers and parents/guardians before the start of the study, and written informed consent is obtained from all legal guardians of all participants in their native language prior to child enrolment.

The objective was to assess whether frailty is associated with an increased risk of postoperative delirium (POD) in intensive care unit (ICU) patients aged 65 years and older.

A systematic review was conducted in accordance with Preferred Reporting Items for Systematic Review and Meta-Analysis guidelines. MEDLINE (via PubMed) and the Cochrane Library were searched for studies published between August 2014 and January 2025, assessing frailty with validated instruments and reporting POD during ICU stay. While the search strategy was not limited to a specific study design, only observational studies met the inclusion criteria. Study quality was appraised using the Newcastle-Ottawa Scale (NOS). Due to methodological heterogeneity, results were synthesised narratively.

This review targeted the intensive care setting specifically, including studies conducted in hospital-based ICUs in various countries.

Of 655 records, five studies (n=3045) met inclusion criteria. Frailty prevalence ranged from 10% to 34.9%. Tools used included the Fried Frailty Scale, modified Frailty Index (mFI), FRAIL Scale (Fatigue, Resistance, Ambulation, Illnesses, and Loss of weight), Comprehensive Assessment of Frailty and Edmonton Frailty Scale. Frail patients had higher POD incidence and experienced more complications such as acute kidney injury, prolonged mechanical ventilation and reoperation. NOS scores ranged from 5 to 7, indicating moderate quality.

Frailty appears to be associated with an increased risk of POD in ICU patients aged 65 and older. Given the limited number and heterogeneity of studies, further research is needed to validate this relationship and to inform targeted prevention strategies in critical care.

https://doi.org/10.17605/OSF.IO/7TWQ8

Salivary gland carcinomas (SGC) are rare tumours. The term SGC is not more than an umbrella for a variety of histogenetically, morphologically and biologically distinct entities. Accordingly, SGCs have not been sufficiently investigated to date. Their rarity makes it difficult to reach high patient numbers for individual entities in clinical studies, leading to pooling patients with different histological subtypes to attain sufficient participants. The different histological subtypes of SGC differ significantly in their clinicopathological features, such as their grading, their occurrence and their outcome. SGCs are usually stratified into low-grade, intermediate-grade or high-grade tumours. In most kinds of SGC, specific targetable molecular markers are lacking. The inclusion of immunotherapy (IT), however, might improve the outcome of patients suffering from high-grade SGCs. In order to integrate IT as a therapeutic option for SGC and to facilitate therapeutic decisions based on tumour (immune) biology, predictive and prognostic immunological biomarkers are indispensable.

In this prospective study, 500 patients will be enrolled, who are distributed in three arms. The observational cohort includes patients with malignant salivary gland tumours, whereas patients with benign tumours of a salivary gland are grouped in the control group 1. In the control cohort, 2 patients do not have a salivary gland tumour but have a planned functional surgery of the nose or ear or a maxillofacial surgery. The local immune status from the tumour tissue and the microbiome will be sampled before treatment. In addition, the systemic immune status from peripheral blood will be analysed before and after surgery and after the adjuvant and definitive chemoradiotherapy, if applicable. Clinical baseline characteristics and outcome parameters will additionally be collected. Data mining and modelling approaches will finally be applied to identify interactions of local and systemic immune parameters and to define predictive and prognostic immune signatures based on the evaluated immune markers.

Approval from the institutional review board of the Friedrich-Alexander-Universität Erlangen-Nürnberg was granted in September 2023 (application number 23-292-B). The results will be disseminated to the scientific audience and the general public via presentations at conferences and publication in peer-reviewed journals.

NCT06047236.

Research for pandemic response needs to be timely to inform evidence-based decision making. The lack of epidemiological data at the start of the COVID-19 pandemic led experts to call for cohorts that could rapidly supply data about newly emerging infectious diseases. The ‘Bern, get ready’ (BEready) study aims to establish a prospective ‘pandemic preparedness cohort’ in the canton of Bern, Switzerland. This cohort can be pivoted to the needs of a new pandemic pathogen. The aim of this pilot study was to investigate the potential response and to test the feasibility of procedures for BEready.

Closed population-based cohort study.

Random sample of private households in the canton of Bern, Switzerland, that had previously responded to an online survey.

Adults, children and pets.

Enrolment as a percentage, associations between the agreement to participate and the demographic and socioeconomic variables of the invited household member, number of social contacts, proportion of samples collected, proportion of complete questionnaires and proportion of participants responding after 12 months.

After the initial in-person visit with venous blood sampling, participants were followed up for 1 year. We tested remote data collection methods, with online questionnaires and self-collected capillary blood and nasopharyngeal samples, and established a biobank.

The pilot study enrolled 106/1138 (9%) of invited households plus two additional households that had proactively contacted us. In total, we enrolled 193 people in 108 households (1.8 per household) and 44 pets between April and September 2023. We obtained and stored at least one venous and/or capillary baseline blood sample from 184/193 (95%) people and 40/44 (91%) pets. After 1 year, 172/193 (89%) people in 101/108 (94%) of households completed a follow-up survey, as did 22 owners of 34/44 (77%) pets. 151/172 (88%) respondents returned a follow-up capillary blood sample.

The response rate to the pilot study shows that obtaining high levels of participant enrolment in a pandemic preparedness cohort study is challenging. Data collection without face-to-face contact with a study team is feasible for household members and will be needed in BEready if control measures during a pandemic prevent in-person studies.

Despite the growing volume of research in surgical education (SurgED), the integration of evidence into teaching practice remains fragmented and inconsistent. A structured and continuously updated synthesis is needed to support data-informed curriculum development and promote best practices across training programmes.

This protocol describes the development of a living systematic review and evidence map of SurgED research. Studies will be identified through comprehensive searches of CENTRAL, PubMed and Web of Science, and screened independently by two reviewers, supported by an Artificial Intelligence (AI)-assisted screening tool to improve efficiency. Eligible studies will include both quantitative and qualitative designs involving medical students, surgical residents and faculty. Studies will be categorised across key educational domains such as simulation-based training, competency-based assessment, feedback, mentoring and technology-enhanced learning. The evidence map will be updated at least quarterly, with new studies screened and added in near real-time to ensure that the map remains current and actionable.

As this study does not involve human participants, ethical approval is not required. Findings will be disseminated through peer-reviewed publications, presentations at national and international conferences and open access integration into the Evidence at a glance (EVIglance) evidence platform.

Delirium is a critical and complex neuropsychiatric syndrome that significantly affects older adults in general hospital wards. Although multicomponent interventions have been shown to be effective in preventing delirium, the consistent implementation remains a challenge. Also, to manage the complex pathway of patients from admission to discharge in hospital, the involvement of the nursing staff is essential. Developing a nurse-led clinical pathway for delirium prevention could provide a structured approach to improving care quality. For intervention development taking account of the complexity of the clinical environment, the UK Medical Research Council framework is frequently used. A core element of this framework is mapping a programme theory that explains how, for whom and in what circumstances an intervention may work. The realist review methodology is well suited to uncovering the underlying mechanisms, contexts and outcomes of interventions, translating these into a programme theory.

The aim of this realist review is to develop a programme theory for a nurse-led clinical pathway to prevent delirium in older adults aged 65 years or older in general hospital wards and to identify strategies to support its effective implementation.

The realist review is based on the methodical framework developed by Pawson et al and further adapted by Rycroft-Malone et al and the reporting will follow the Realist And MEta-narrative Evidence Syntheses: Evolving Standards guidelines. The process comprises four steps: (1) defining the review scope; (2) systematically searching for and appraising the evidence; (3) extracting and synthesising findings and (4) developing a narrative synthesis. Interest holders, including clinical and academic experts, will be actively involved as an expert reference group to inform and refine the programme theory. The final programme theory will be presented in Context-Mechanism-Outcome configurations and the Implementation Research Logic Model.

Since no data are collected as part of the review, ethical approval is not required. Findings will be disseminated through academic conferences and publication in a peer-reviewed journal.

This protocol has been registered at Open Science Framework (https://doi.org/10.17605/OSF.IO/7EPTF).

To explore perceptions of digitalisation and patient safety from the view of the German general public and related sociodemographic factors.

Cross-sectional survey.

A nationwide survey was undertaken in 2024, using data from the Techniker Krankenkasse (TK) Monitor of Patient Safety. The TK Monitor of Patient Safety is an annual survey of the population on the state of patient safety in medical care.

1000 German adults (18 years and older).

Ordinal logistic regression analyses were performed to investigate the associations among sociodemographic factors (age, gender, education and household income) and perceptions on digitalisation and patient safety.

The majority of respondents expected benefits from digital applications in healthcare. Over half of the respondents (58%) believed that artificial intelligence (AI) can help reduce complications and errors, while 49% of the respondents believed that the use of AI poses serious new risks for the healthcare sector. The results showed that sociodemographic variables are important factors influencing patient safety perceptions of digitalisation and AI. Female, older, less educated and/or lower-income individuals were less likely to perceive benefits from digital care applications and AI.

In our study, the German public appears to view digital technologies and AI as tools both for improving patient safety and as potential risk factors. Our findings also highlight the importance of analysing sociodemographic factors to identify specific disparities in how different groups are affected by digitalisation. Such analysis is essential for developing targeted strategies that mitigate current patient safety risks, ensuring that digital health solutions are equitable and safe across all demographic groups.

Preterm infants, particularly those born before 29 weeks of gestation, are at increased risk of developing bronchopulmonary dysplasia (BPD) and other complications of prematurity. Substantial evidence suggests that respiratory tract colonisation with Ureaplasma species significantly contributes to pulmonary inflammation, impaired lung function and subsequent lung disease especially in very immature infants. Moreover, Ureaplasma exposure has been implicated in the pathogenesis of other inflammation-related sequelae of prematurity. Although representing a potentially actionable risk factor for adverse short-term and long-term neonatal outcome, controversies on Ureaplasma-associated morbidity remain and recommendations for screening practices in preterm infants are missing. The NEO-CONSCIOUS (Neonatal Colonisation and Infection with Ureaplasma in very immature preterm infants born Ureaplasma colonisation and infection in very preterm infants at high risk of adverse outcome, the extent of potentially accompanying inflammation and the impact on short-term and long-term morbidity.

This is a prospective observational multicentre study being conducted in level III neonatal intensive care units in Germany and Austria. In total, 400 infants born before 29 weeks of gestation are screened for Ureaplasma colonisation immediately after birth. In addition, biomarkers of systemic inflammation are determined on day 1 and day 28. The study infants are followed up until discharge and at 2 years corrected age. The primary outcome BPD and/or death is assessed at 36 weeks postmenstrual age. Secondary outcomes include systemic inflammation, secondary infections, intraventricular haemorrhage, periventricular leukomalacia, necrotising enterocolitis, retinopathy of prematurity and neurodevelopmental outcome at 24 months corrected age.

The study has been approved by the ethics committees in Würzburg and Leipzig and the local ethics committees of all participating centres. Results will be disseminated through peer-reviewed international publications and conferences. The study is registered with the German Clinical Trials Register, ID DRKS00033001.

German Clinical Trials Register (DRKS00033001).

Chronic low back pain (CLBP) and depressive symptoms (DS) are highly prevalent, burdensome, costly and comorbid health conditions. Osteopathic manipulative treatment (OMT) was shown to improve pain and disability in patients with CLBP; however, the effect on comorbid DS remains less certain. Interestingly, CLBP and DS seem to be associated with changes in interoception, which may be reversed by OMT.

The study protocol proposes a single-blinded, parallel-group, randomised controlled trial to investigate the effect of OMT on clinical symptoms (depression, pain and disability) and interoceptive functions (interoceptive accuracy, sensibility and awareness) in patients with CLBP and comorbid DS. A sample of 60 adult subjects with CLBP and comorbid DS shall be recruited from osteopathic, orthopaedic and physiotherapeutic practices and educational institutes for osteopathy, sports science, psychology and medicine in Hamburg, Germany. Participants will be randomly allocated (1:1 ratio) to receive six 45 min treatment sessions of either OMT (standard-OMT group) or sham treatment imitating OMT (sham-OMT group). Primarily, symptoms of depression, pain and disability will be assessed with the Beck’s Depression Inventory, Second Edition (BDI-II), Numeric Rating Scale (NRS) and Oswestry Disability Index (ODI). Secondarily, interoceptive accuracy, sensibility and awareness will be evaluated using the Heartbeat Tracking Task (HTT), Multidimensional Assessment of Interoceptive Awareness (MAIA-2) and confidence-accuracy correspondence (CAC). Ancillary, the therapeutic alliance will be investigated with the Helping Alliance Questionnaire. Data will be collected at baseline (t₀), the first, third and sixth treatment sessions (t₁, t₃, t₆) and at 3 months follow-up (t₇). The findings will be analysed for between-group differences using descriptive (mean and SD) and inductive statistics (mixed analysis of variance). It is hypothesised that standard-OMT, compared with sham-OMT, will reduce depression, pain and disability (BDI-II, NRS, ODI) and increase interoceptive accuracy, sensibility and awareness (HTT, MAIA-2, CAC) in patients with CLBP and comorbid DS.

The study was approved by the ethics committee of the Medical School Hamburg (MSH-2023/288). The anonymised dataset will be published in an online repository, and the results will be published in peer-reviewed scientific journals.

DRKS00031694.

Exacerbations of chronic obstructive pulmonary disease (COPD) can lead to reduced lung function and worse clinical outcomes. Previous studies have reported associations between severe exacerbations and increased risk of hospitalisation and/or mortality. This meta-analysis examined the impact of moderate exacerbations on the risk of future exacerbations and all-cause mortality.

This meta-analysis included seven observational studies from the EXACOS (EXAcerbations of COPD and their OutcomeS)/AVOIDEX (Impact of AVOIDing EXacerbations of COPD) programme studies.

This meta-analysis used data from regional claims databases or electronic healthcare records from seven countries.

The individual studies included patients with a diagnosis of COPD and ≥12 months of data availability before (regarded as baseline) and after the index (ie, the date of the first COPD diagnosis), with postindex data considered the follow-up period.

The number of COPD exacerbations experienced during the baseline period (ie, the exposure variable) was used to categorise patients into the following groups: no exacerbations, one moderate exacerbation only or two or more moderate/severe exacerbations. Outcomes assessed included risk of COPD exacerbations and all-cause mortality during follow-up as a function of baseline exacerbations. For meta-analyses, all rate ratios (RRs) were log-transformed, and associations were pooled across studies using random-effects meta-analysis models.

Among 2 733 162 patients with COPD, one moderate exacerbation was significantly associated with a twofold increased risk of future exacerbations compared with having no exacerbations during baseline, with pooled RRs (95% CIs) of 2.47 (1.47 to 4.14) at 1 year, 2.49 (1.38 to 4.49) at 2 years and 2.38 (1.30 to 4.34) at 3 years postindex. The pooled RR (95% CI) for all-cause mortality was 1.30 (1.05 to 1.62), indicating a 30% increase in risk following one moderate exacerbation versus no exacerbations.

Preventing moderate exacerbations in patients with COPD should be a priority that may improve patient trajectories and outcomes.

Suicidal thoughts and behaviours are linked to a wide range of mental health conditions. New interest in the psychiatric benefits of nitrous oxide (N₂O) has only recently emerged. The broad pharmacological effects of N₂O are thought to be due in large part to N-methyl-d-aspartate antagonism and opioid effects. The purpose of this study protocol is to test whether inhalational N₂O exerts rapid antisuicidal effects as a transdiagnostic treatment for suicidal ideation.

This is the protocol of a single-centre pilot study of N₂O inhalation in 85 psychiatric inpatients. The initial 45-min double-blind, randomised, placebo-controlled inhalation session either consists of 50% N₂O and 50% oxygen (‘active treatment’) or 50% oxygen plus air. The primary outcome is the change in Beck Scale for Suicidal Ideation scores between the day before and the day after inhalation. A second inhalation containing N₂O will be administered 1 week after the first inhalation to ensure that all study participants receive the active treatment at least once. For the mechanism of action and prediction, a nested biomarker substudy will employ multimodal techniques, including analysis of hair and blood samples and electroencephalography.

This study was approved by the local ethics committee (‘Kantonale Ethikkommission—Kanton Zürich’) and by the Swiss Agency for Therapeutic Products (Swissmedic). Study results will be disseminated primarily by peer-reviewed scientific journals and also by conference presentations, patient and public events and social media.

ClinicalTrials.gov ID NCT06636357.

Persistently low serum alkaline phosphatase (ALP) activity is the hallmark of hypophosphatasia (HPP). However, low ALP values are not commonly recognised in routine clinical practice, often leading to delayed HPP diagnosis. Determining symptoms associated with persistently low ALP activity may facilitate a timelier diagnosis and improved treatment of patients with HPP. This study aimed to evaluate the signs and symptoms associated with low ALP.

Retrospective, multicentre, cross-sectional study.

Medical records of adults with low ALP activity collected in 18 German clinics and large medical centres with medical specialty in endocrinology, diabetology, rheumatology and osteology were assessed. Serum ALP activity, medical history, previous diagnoses, laboratory values and symptoms were analysed.

Records were screened to identify patients≥18 years with ALP activity below the lower limit of the normal range within the last 5 years. Exclusion criteria were oncological or haematological disorders, intensive care at the time of low ALP measurement and having more than one ALP measurement in the normal range or above. Data from 849 patients with ≥1 low ALP value (median age: 44.0, min 18.0, max 90.0), including a subset of 32 patients with documented HPP diagnosis, were analysed.

The study cohort presented with a spectrum of clinical manifestations and diagnostic profiles. Patients with HPP displayed typical symptoms, in particular musculoskeletal pain and fractures, more often than patients without HPP diagnosis (n=817). Among patients without HPP, 26.6% were diagnosed with hypothyroidism. 35 patients displayed 4+ clinical and biochemical signs typical for HPP that were attributed to differential diagnoses, such as rheumatic diseases, fibromyalgia and osteoporosis/osteopenia, suggesting the possibility of underlying HPP in some cases.

Most patients in this study had hypophosphatasemia without further evaluation, highlighting the need for greater awareness of low ALP levels in clinical practice. Recognising low ALP levels, especially when accompanied by symptoms like pain, musculoskeletal and dental abnormalities, is crucial for timely diagnosis and improved patient care.