Explore the vast range of titles available.

Background It has previously been reported that authors from developing countries are underrepresented in medical journals. Here, we aimed to build a comprehensive landscape of the geographical representation in medical research publications. Methods We collected bibliometric data of original research articles ( n  = 10,558) published between 2010 and 2019 in five leading medical journals and geolocated these by the institute of the corresponding authors. We introduced two simple metrics, the International Research Impact and the Domestic Self-Citation Index, to assess publishing and citing patterns by cities and countries. Results We show that only 32 countries published more than 10 publications in 10 years equaling 98.9% of all publications. English-speaking countries USA (48.2%), UK (15.9%), Canada (5.3%), and Australia (3.2%) are most represented, but with a declining trend in recent years. When normalized to citation count, 9/32 countries published ≥ 10% more than expected. In total, 85.7% of the publication excess originate from the USA and UK. We demonstrate similar geographical bias at the municipal level. Finally, we discover that journals more commonly publish studies from the country in which the journal is based and authors are more likely to cite work from their own country. Conclusions The study reveals Anglocentric dominance, domestic preference, but increased geographical representation in recent years in medical publishing. Similar audits could mitigate possible national and regional disparities in any academic field. Plain language summary Geographical representation in authorships of research articles is insufficiently understood. We analyzed data from over 10,000 research articles published between 2010–2019 in top medical journals. Anglocentric countries (USA, UK, Canada, and Australia) accounted for most publications, but their proportion has recently declined. When considering citations, i.e. formal references connecting new findings to observations from previously published articles, 1/3 of the studied countries published ≥10% more articles than expected. When publishing and citing articles, journals and researchers tended to favor publications from their own countries. While some improvement in geographical representation has occurred, our findings expose an Anglocentric bias and national preference, which might bias medical publishing. The approach used in this study may be used in future efforts to monitor geographical representation in publication authorships. Brück examines geographical representation in the authorship of leading medical journal publications between 2010 and 2019. While still dominated by authors from English-speaking countries, there is increased representation of authors from other countries over this period.

Background Monitoring gender representation is critical to achieve diversity and equity in academia. One way to evaluate gender representation in academia is to examine the authorship of research publications. This study sought to determine the gender of first and senior authors of articles in leading medical journals and assess trends in the gender gap over time. Methods We gather bibliometric data on original research articles ( n  = 10,558) published in 2010–2019 in five leading medical journals to audit publication and citation frequency by gender. We explored their association with scientific fields, geographical regions, journals, and collaboration scope. Results We show that there are fewer women as senior (24.8%) than leading authors (34.5%, p  < 0.001). The proportion of women varied by country with 9.1% last authors from Austria, 0.9% from Japan, and 0.0% from South Korea. The gender gap decreased longitudinally and faster for the last (−24.0 articles/year, p  < 0.001) than first authors (−14.5 articles/year, p  = 0.024) with pronounced country-specific variability. We also demonstrate that usage of research keywords varied by gender, partly accounting for the difference in citation counts. Conclusions In summary, gender representation has increased, although with country-specific variability. The study frame can be easily applied to any journal and time period to monitor changes in gender representation in science. Plain language summary The publishing of medical research papers has traditionally been dominated by men. To better understand whether gender diversity in the authorship of research papers has changed recently, we analyzed over 10,000 articles published between 2010 and 2019 in five top medical journals. Usually, the first author is recognized as the leading contributor, whereas the last author supervises the study. We found that there were fewer women in senior positions compared to first author positions. The percentage of women as authors varied across countries. Over time, the gender gap decreased, but at different rates depending on the author’s position and country. Keywords selected by researchers to describe their work varied between genders. Our findings show progress in gender representation, but with country-specific differences. This study can be used as a model to track gender representation in other journals and time periods. Brück observes a decrease in the gender gap in the authorship of leading medical journals between 2010 and 2019, with some country-specific variation. This study provides a model approach for tracking gender representation in academic research.

BackgroundTechnical factors can bias H&E digital slides potentially compromising computational histopathology studies. Here, we hypothesised that sample quality and sampling variation can introduce even greater and undocumented technical fallacy.MethodsUsing The Cancer Genome Atlas (TCGA) clear-cell renal cell carcinoma (ccRCC) as a model disease, we annotated ~78,000 image tiles and trained deep learning models to detect histological textures and lymphocyte infiltration at the tumour core and its surrounding margin and correlated these with clinical, immunological, genomic, and transcriptomic profiles.ResultsThe models reached 95% validation accuracy for classifying textures and 95% for lymphocyte infiltration enabling reliable profiling of ccRCC samples. We validated the lymphocyte-per-texture distributions in the Helsinki dataset (n = 64). Texture analysis indicated constitutive sampling bias by TCGA clinical centres and technically suboptimal samples. We demonstrate how computational texture mapping (CTM) can abrogate these issues by normalising textural variance. CTM-harmonised histopathological architecture resonated with both expected associations and novel molecular fingerprints. For instance, tumour fibrosis associated with histological grade, epithelial-to-mesenchymal transition, low mutation burden and metastasis.ConclusionsThis study highlights texture-based standardisation to resolve technical bias in computational histopathology and understand the molecular basis of tissue architecture. All code, data and models are released as a community resource.

Treating cartilage injuries and degenerations represents an open surgical challenge. The recent advances in cell therapies have raised the need for a potent off-the-shelf cell source. Intra-articular injections of TGF-β transduced polydactyly chondrocytes have been proposed as a chronic osteoarthritis treatment but despite promising results, the use of gene therapy still raises safety concerns. In this study, we characterized infant, polydactyly chondrocytes during in vitro expansion and chondrogenic re-differentiation. Polydactyly chondrocytes have a steady proliferative rate and re-differentiate in 3D pellet culture after up to five passages. Additionally, we demonstrated that polydactyly chondrocytes produce cartilage-like matrix in a hyaluronan-based hydrogel, namely transglutaminase cross-linked hyaluronic acid (HA-TG). We utilized the versatility of TG cross-linking to augment the hydrogels with heparin moieties. The heparin chains allowed us to load the scaffolds with TGF-β1, which induced cartilage-like matrix deposition both in vitro and in vivo in a subcutaneous mouse model. This strategy introduces the possibility to use infant, polydactyly chondrocytes for the clinical treatment of joint diseases.

Treatment responses of patients with acute myeloid leukemia (AML) are known to be heterogeneous, posing challenges for risk scoring and treatment stratification. In this retrospective multi-cohort study, we investigated whether combining pyroptosis- and immune-related genes improves prognostic classification of AML patients. Using a robust gene pairing approach, which effectively eliminates batch effects across heterogeneous patient cohorts and transcriptomic data, we developed an immunity and pyroptosis-related prognostic (IPRP) signature that consists of 15 genes. Using 5 AML cohorts (n = 1327 patients total), we demonstrate that the IPRP score leads to more consistent and accurate survival prediction performance, compared with 10 existing signatures, and that IPRP scoring is widely applicable to various patient cohorts, treatment procedures and transcriptomic technologies. Compared to current standards for AML patient stratification, such as age or ELN2017 risk classification, we demonstrate an added prognostic value of the IPRP risk score for providing improved prediction of AML patients. Our web-tool implementation of the IPRP score and a simple 4-factor nomogram enables practical and robust risk scoring for AML patients. Even though developed for AML patients, our pan-cancer analyses demonstrate a wider application of the IPRP signature for prognostic prediction and analysis of tumor-immune interplay also in multiple solid tumors.

Increasing evidence suggests that the immune system affects prognosis of chronic myeloid leukemia (CML), but the detailed immunological composition of the leukemia bone marrow (BM) microenvironment is unknown. We aimed to characterize the immune landscape of the CML BM and predict the current treatment goal of tyrosine kinase inhibitor (TKI) therapy, molecular remission 4.0 (MR4.0). Using multiplex immunohistochemistry (mIHC) and automated image analysis, we studied BM tissues of CML patients (n = 56) and controls (n = 14) with a total of 30 immunophenotype markers essential in cancer immunology. CML patients’ CD4+ and CD8+ T-cells expressed higher levels of putative exhaustion markers PD1, TIM3, and CTLA4 when compared to control. PD1 expression was higher in BM compared to paired peripheral blood (PB) samples, and decreased during TKI therapy. By combining clinical parameters and immune profiles, low CD4+ T-cell proportion, high proportion of PD1+TIM3−CD8+ T cells, and high PB neutrophil count were most predictive of lower MR4.0 likelihood. Low CD4+ T-cell proportion and high PB neutrophil counts predicted MR4.0 also in a validation cohort (n = 52) analyzed with flow cytometry. In summary, the CML BM is characterized by immune suppression and immune biomarkers predicted MR4.0, thus warranting further testing of immunomodulatory drugs in CML treatment.

Tumor microenvironment and immune escape affect pathogenesis and survival in classical Hodgkin lymphoma (cHL). While tumor-associated macrophage (TAM) content has been associated with poor outcomes, macrophage-derived determinants with clinical impact have remained undefined. Here, we have used multiplex immunohistochemistry and digital image analysis to characterize TAM immunophenotypes with regard to expression of checkpoint molecules programmed cell death ligand 1 (PD-L1) and indoleamine 2,3-dioxygenase 1 (IDO-1) from the diagnostic tumor tissue samples of 130 cHL patients, and correlated the findings with clinical characteristics and survival. We show that a large proportion of TAMs express PD-L1 (CD68+, median 32%; M2 type CD163+, median 22%), whereas the proportion of TAMs expressing IDO-1 is lower (CD68+, median 5.5%; CD163+, median 1.4%). A high proportion of PD-L1 and IDO-1 expressing TAMs from all TAMs (CD68+), or from CD163+ TAMs, is associated with inferior outcome. In multivariate analysis with age and stage, high proportions of PD-L1+ and IDO-1+ TAMs remain independent prognostic factors for freedom from treatment failure (PD-L1+CD68+/CD68+, HR = 2.63, 95% CI 1.17–5.88, p = 0.019; IDO-1+CD68+/CD68+, HR = 2.48, 95% CI 1.03–5.95, p = 0.042). In contrast, proportions of PD-L1+ tumor cells, all TAMs or PD-L1− and IDO-1− TAMs are not associated with outcome. The findings implicate that adverse prognostic impact of TAMs is checkpoint-dependent in cHL.

Anti-PD1 treatment has improved the survival of metastatic melanoma patients, yet it is unknown which patients benefit from the treatment. In this exploratory study, we aimed to understand the effects of anti-PD1 therapy on the patients’ immune system and discover the characteristics that would result in successful treatment. We collected peripheral blood (PB) samples from 17 immuno-oncology-naïve metastatic melanoma patients before and after 1 and 3 months of anti-PD1 therapy. In addition, matching tumor biopsies at the time of diagnosis were collected for tissue microarray. The complete blood counts, PB immunophenotype, serum cytokine profiles, and tumor-infiltrating lymphocytes were analyzed and correlated with the clinical data. Patients were categorized based on their disease control into responders (complete response, partial response, stable disease > 6 months, N = 11) and non-responders (progressive disease, stable disease ≤ 6 months, N = 6). During therapy, the PB natural killer T (NKT) cell frequency, expression of CD25 and CD45RO on cytotoxic natural killer (NK) cells, and serum CXC chemokine levels were significantly increased in responders. Furthermore, higher age together with age-associated characteristics from PB, lower frequency of PB-naïve CD8+ T cells, and elevated levels of serum MCP-4 and OPG were discovered as baseline predictors of treatment response. We therefore propose that in addition to T cells, anti-PD1 treatment is associated with NK- and NKT-cell population dynamics, and that the age-associated characteristics from PB together with older age may contribute to prolonged PFS in anti-PD1-treated melanoma patients.

Background The European Health Data Space (EHDS) regulation has been proposed to harmonize health data processing. Given its parallels with the Act on Secondary Use of Health and Social Data (Secondary Use Act) implemented in Finland in 2020, this study examines the consequences of heightened privacy constraints on registry-based medical research. Methods We collected study permit counts approved by university hospitals in Finland in 2014–2023 and the data authority Findata in 2020‒2023. The changes in the study permit counts were analysed before and after the implementation of the General Data Protection Regulation (GDPR) and the Secondary Use Act. By fitting a linear regression model, we estimated the deficit in study counts following the Secondary Use Act. Results Between 2020 and 2023, a median of 5.5% fewer data permits were approved annually by Finnish university hospitals. On the basis of linear regression modelling, we estimated a reduction of 46.9% in new data permits nationally in 2023 compared with the expected count. Similar changes were neither observed after the implementation of the GDPR nor in permit counts of other medical research types, confirming that the deficit was caused by the Secondary Use Act. Conclusions This study highlights concerns related to data privacy laws for registry-based medical research and future patient care. Key Points Given its parallels with the European Health Data Space regulation, we modelled its possible consequences for registry-based medical research using data from Finland, where the Act on the Secondary Use of Health and Social Data (Secondary Use Act) has been implemented since 2020. Adjusted for the historical trend of increasing registry-based research conducted in Finnish university hospitals, the data permit count was almost 50% lower than expected in 2023. Similar changes were not observed post-GDPR or in other medical research types. This study demonstrates how increased data privacy regulations might reduce medical research, innovations and advances in future patient care.

Flow cytometric immunophenotyping of lymphocytes and dendritic cells, and functional lymphocyte mitogen response tests are used in the diagnostics of inborn errors of immunity (IEI), especially in pediatrics. These routinely used tests lack sufficient age-matched reference values in children. We established reference values for lymphocyte and dendritic cell subsets for four age groups from 68 healthy children under 12 years of age. These values were then compared to prior publicly available articles and 46 clinical samples from children with confirmed IEI diagnosis. Mitogen response results were also compared between 27 children and 177 adults. In the literature review, we found considerable variability in lymphocyte subset definitions and statistical approaches. Most IEI patients had increased transitional and naïve B, and decreased memory B cells. CHH patients had increased γδ T and DNTs. Lymphocyte stimulation via FASCIA method provides weaker stimulation results in children than in adults, which seems to result from a larger proportional count of naïve lymphocytes in children. The established reference values can be used in diagnostics of pediatric immunological conditions in laboratories that use similar analytic methods. Lower lymphocyte mitogen response results in children need to be taken into consideration when interpreting the results of lymphocyte functional tests.