International Collaborative Study Research Articles

Skull base surgery for malignant tumors: The 2nd international collaborative study (1995-2015).

The current study presents the effort of a global collaborative group to review the management and outcomes of malignant tumors of the skull base worldwide. A total of 28 institutions contributed data on 3061 patients. Analysis evaluated clinical variables, survival outcomes, and multivariable factors associated with outcomes. The median age was 56 years (IQR 44-67). The open surgical approach was used in 55% (n = 1680) of cases, endoscopic resection was performed in 36% (n = 1087), and the combined approach in 9.6% (n = 294). With a median follow-up of 7.1 years, the 5-year OS DSS and RFS were 65%, 71.7% and 53%, respectively. On multivariable analysis, older age, comorbidities, histology, dural/intracranial involvement, positive margins, advanced stage, and primary site were independent prognostic factors for OS, DSS, and RFS. Adjuvant RT was a protective prognostic factor. The progress across various disciplines may have contributed to improved OS and DSS in this study compared to previous reports.

A host community’s experiences of an international teaching practicum: “They taught … and they left”

ABSTRACT This collaborative international study centres the perspectives of a Kenyan host community on a recurring international teaching practicum from Canada. Although there was general community support for the international practicum, the visiting groups’ knowledge and decision-making were prioritized and preferentially benefitted some community members. Interculturality theory and the African philosophy of Ubuntu were used as complementary frameworks to challenge the dominance of Global-North practices that positioned the Kenyan community as recipients relying on the goodwill of their external benefactors – namely, the practicum group and the non-governmental organization that facilitated the placement. We propose a reciprocity framework to counter capitalist discourses that direct powerful psychic desires for education and development into alignment with post-colonial ideals. Engaging with the dreams and desires of local peoples, we posit that thinking in terms of reciprocity can provide a practical, interdependent, and mutually beneficial approach to the planning and implementation of international teaching practicums.

Cognitive impairment in children and adolescents living with perinatal HIV disease in the ART era: a meta-analysis

Despite improved survival and overall health outcomes from modern antiretroviral therapy (ART), children and adolescents living with HIV are facing pervasive impairments in neurodevelopment including cognitive impairment, but there remains a lack of consensus on the cognitive domains that are affected in those children and adolescents. The objective of this meta-analysis was to evaluate the impact of perinatal HIV-infection on executive function, working memory, and speed of information processing in the ART era. The PubMed database was searched for studies published between 1997 and 2024, plus additional search with the ScienceDirect, bioRxiv, and medRxiv databases. A meta-analysis was conducted on thirty-five studies published between 2012 and 2023 that encompassed a total of 4066 perinatally-infected HIV patients, 2349 HIV-exposed uninfected (HEU) controls, and 2466 HIV-unexposed, uninfected (HUU) controls. Performance scores on executive function, working memory, and processing speed were pooled using random-effects meta-analysis. Compared to HEU and HUU controls, perinatally HIV-infected children and adolescents presented with significant impairments in processing speed (Hedges g=-0.64, p<0.00001), working memory (Hedges g=-0.69, p<0.00001), and to a lesser degree, executive function (Hedges g=-0.35, p=0.02). Meta-regression analysis suggested that the effect estimate of processing speed impairment negatively correlated with Gross National Income (GNI) per capita of the study countries (CALHIV vs HUU, p=0.0016; CALHIV vs HEU, p=0.0019), even though HIV-infected cases were compared to sociodemographically matched HUU controls from the same countries. Sub-group meta-analyses with participants from high-income or low-/middle-income countries provided further evidence suggesting that the performance gap between HIV-infected cases and HUU/HEU controls may be larger in low-/middle-income countries than high-income countries. In the ART era, cognitive impairment (especially reduced processing speed and working memory) persists in children and adolescents living with HIV. These impairments may be more pronounced among those children and adolescents living with HIV in low-income countries, suggesting that there may be global health inequities in treatment outcomes with perinatal HIV-infection. However, meta-analysis and meta-regression analysis have their limitations, which calls for future collaborative multi-country international studies to directly investigate this important topic. Nevertheless, there is an unmet need to assure equity in timely assessments and interventions to optimize neurocognitive development and outcomes among children and adolescents with perinatal HIV globally. This research was supported in part by NIH R01MH108466, NIH R56NS124422, and NIH R01NS124422.

International Collaborative Study Comparing Outcomes of Fenestrated Endovascular Aortic Repair in OCtogenarian vs Non-Octogenarian Patients: The FEVOC study.

With an increasing life expectancy, more octogenarian patients are referred with complex aortic aneurysms (cAAA). The aim of this study was to evaluate short and mid-term outcomes following fenestrated aortic repair (FEVAR) in octogenarians. Few studies looking at octogenarian-specific outcomes with diverging results. Retrospective, multicentre cohort study including consecutive patients undergoing elective FEVAR for cAAAs or type IV thoracoabdominal aortic aneurysms between 2007-2022 in eight high-volume centres. Octogenarians vs. non-octogenarians were compared. The primary outcome was 30-day mortality. Secondary outcomes included 1, 2 and 5-year survival and reintervention rates. A total of 729 patients (median age of 74.8 years [IQR 69.2 - 79.14]) were included, 169 (23%) of which were octogenarians, with 316 (43.3%) patients undergoing juxta/pararenal aneurysm repair. Although octogenarians presented less complex but larger (61mm vs. 58mm) aneurysms, the number of fenestrations was similar across groups. No differences in in-hospital mortality (4.1 vs. 3.0%), MAE (16.6% vs 12.2%) or reintervention rates (11.2 vs. 10%) were found. Multivariable logistic regression of in-hospital mortality identified BMI (OR 0.66, 95% CI 0.51-0.95, P=0.003), chronic heart failure (OR 7.70, 95% CI 1.36-36.15, P=0.003) and GFR<45ml/min/1.73m2 (OR 5.25, 95% CI 1.20-22.86, P=0.027) as independent predictors. Median follow-up was 41 months. The 1, 2 and 5-year survival rates were 91.3%, 81.8% and 49.5% in octogenarians vs 90.6%, 86.5% and 68.8% in non-octogenarian patients (Log-rank: =0.001). Freedom from aortic-related death and freedom from reintervention at five-years were similar across groups (log-rank=0.94 and .76, respectively). Age>80 was not an independent predictor of 30-day or long-term mortality on multivariable and Cox regression analysis. Elective FEVAR in octogenarians appears to be safe, with similar outcomes as in younger patients. Future studies looking at improved patient selection methods to ensure long-term survival benefits in both octogenarians and younger patients are warranted.

The 1000 Mitoses Project: A Consensus-Based International Collaborative Study on Mitotic Figures Classification.

Introduction. The identification of mitotic figures is essential for the diagnosis, grading, and classification of various different tumors. Despite its importance, there is a paucity of literature reporting the consistency in interpreting mitotic figures among pathologists. This study leverages publicly accessible datasets and social media to recruit an international group of pathologists to score an image database of more than 1000 mitotic figures collectively. Materials and Methods. Pathologists were instructed to randomly select a digital slide from The Cancer Genome Atlas (TCGA) datasets and annotate 10-20 mitotic figures within a 2 mm2 area. The first 1010 submitted mitotic figures were used to create an image dataset, with each figure transformed into an individual tile at 40x magnification. The dataset was redistributed to all pathologists to review and determine whether each tile constituted a mitotic figure. Results. Overall pathologists had a median agreement rate of 80.2% (range 42.0%-95.7%). Individual mitotic figure tiles had a median agreement rate of 87.1% and a fair inter-rater agreement across all tiles (kappa = 0.284). Mitotic figures in prometaphase had lower percentage agreement rates compared to other phases of mitosis. Conclusion. This dataset stands as the largest international consensus study for mitotic figures to date and can be utilized as a training set for future studies. The agreement range reflects a spectrum of criteria that pathologists use to decide what constitutes a mitotic figure, which may have potential implications in tumor diagnostics and clinical management.

Diagnostic magnetic resonance imaging characteristics of congenital mesoblastic nephroma: a retrospective multi-center International Society of Pediatric Oncology-Renal Tumor Study Group (SIOP-RTSG) radiology panel study

BackgroundCongenital mesoblastic nephroma is the most common solid renal tumor in neonates. Therefore, patients <3 months of age are advised to undergo upfront nephrectomy, whereas invasive procedures at diagnosis in patients ≥3 months of age are discouraged by the International Society of Pediatric Oncology-Renal Tumor Study Group (SIOP-RTSG). Nevertheless, discriminating congenital mesoblastic nephroma, especially from the more common Wilms tumor, solely based on imaging remains difficult. Recently, magnetic resonance imaging (MRI) has become the preferred modality. Studies focusing on MRI characteristics of congenital mesoblastic nephroma are limited.ObjectiveThis study aims to identify diagnostic MRI characteristics of congenital mesoblastic nephroma in the largest series of patients to date.Materials and methodsIn this retrospective multicenter study, five SIOP-RTSG national review radiologists identified 52 diagnostic MRIs of histologically proven congenital mesoblastic nephromas. MRI was performed following SIOP-RTSG protocols, while radiologists assessed their national cases using a validated case report form.ResultsPatients (24/52 classic, 11/52 cellular, and 15/52 mixed type congenital mesoblastic nephroma, 2/52 unknown) had a median age of 1 month (range 1 day–3 months). Classic type congenital mesoblastic nephroma appeared homogeneous with a lack of hemorrhage, necrosis and/or cysts, showing a concentric ring sign in 14 (58.3%) patients. Cellular and mixed type congenital mesoblastic nephroma appeared more heterogeneous and were larger (311.6 and 174.2 cm3, respectively, versus 41.0 cm3 for the classic type (P<0.001)). All cases were predominantly T2-weighted isointense and T1-weighted hypointense, and mean overall apparent diffusion coefficient values ranged from 1.05–1.10×10−3 mm2/s.ConclusionThis retrospective international collaborative study showed classic type congenital mesoblastic nephroma predominantly presented as a homogeneous T2-weighted isointense mass with a typical concentric ring sign, whereas the cellular type appeared more heterogeneous. Future studies may use identified MRI characteristic of congenital mesoblastic nephroma for validation and for exploring the discriminative non-invasive value of MRI, especially from Wilms tumor.Graphical

International Collaborative Study of Tele-rehabiltation in Italy and India in Patients with Parkinson’s Disease: ICTRIP-PD Study (P8-11.018)

International Collaborative Study of Tele-rehabiltation in Italy and India in Patients with Parkinson’s Disease: ICTRIP-PD Study (P8-11.018)

Small cell carcinoma esophagus-A tertiary cancer center experience of a rare variant.

Esophageal cancer is quite prevalent worldwide and usually carries a poor prognosis. Histologically, although squamous cell carcinoma and adenocarcinoma predominate, small cell carcinoma (SmCC) cases have been reported. Overall, there is a paucity of literature regarding this variant. In this article, we aim to highlight this uncommon entity of carcinoma esophagus and share our experience of SmCC patients seen over a decade at our institute. Records of patients with SmCC histology from 2010 to 2020 were assessed. Patients' demographic characteristics, clinical characteristics, treatment received, and outcomes were taken into consideration. Results were analyzed statistically using SPSS version 22. Fourteen patients (nine males and five females) with a median age of 57 years (range: 35 - 72 years) were analyzed. The majority of the patients 10/14 (71.4%) received palliative radiotherapy of either 30Gy/10 fractions or 35Gy/15 fractions. Only 1/14 (7.14%) patients received neoadjuvant chemotherapy and concurrent chemoradiation (CCRT). Overall, partial response was noted in all 11 patients (78.6%) who received treatment. The average median survival was 5 months (range: 1-11 months). Although the small sample size of the study prevents us from drawing a firm conclusion, we propose national and international collaborative prospective studies for framing definitive oncologic management strategies for this rare histological variant of esophageal cancer.

DNA Reference Reagents for Genotyping RH Variants

Patients who carry RH blood group variants may develop Rh alloantibodies requiring matched red cell transfusions. Serologic reagents for Rh variants often fail to specifically identify variant Rh antigens and are in limited supply. Therefore, red cell genotyping assays are essential for managing transfusions in patients with clinically relevant Rh variants. Well-characterized DNA reference reagents are needed to ensure quality and accuracy of the molecular tests. Eight lyophilized DNA reference reagents, representing 21 polymorphisms in RHD and RHCE, were produced from an existing repository of immortalized B-lymphoblastoid cell lines at CBER/U.S. FDA. The material was validated through an international collaborative study involving 17 laboratories that evaluated each DNA candidate using molecular assays to characterize RHD and RHCE alleles including commercial platforms and laboratory developed testing such as Sanger sequencing, next generation sequencing, and third generation sequencing. The genotyping results showed 99.4% agreement with the expected results for the target RH polymorphisms and 87.9% for RH allele agreement. Most of the discordant RH alleles results were explained by a limited polymorphism coverage in some genotyping methods. Results of stability and accelerated degradation studies support the suitability of these reagents for use as reference standards. The collaborative study results demonstrate the qualification of these eight DNA reagents for use as reference standards for RH blood group genotyping assay development and analytical validation.

Clinical decision-making processes among graduate nurses, specialist nurses and nurse practitioners A collaborative international study.

To explore clinical decision-making by comparing the processes used by three groups of nurses in the emergency departments of three hospitals: in Norway, Finland and Ireland. Clinical decision-making in an emergency department environment is a complex process often occurring in times of crisis. It is an important aspect contributing to the quality of care. However, empirical research is limited regarding the decision-making process in different nursing roles. In accordance with the consolidated criteria for reporting qualitative research, a qualitative and observational study was conducted to explore clinical decision-making by comparing the processes used by three groups of nurses in the emergency departments of three hospitals: in Norway, Finland and Ireland. Six Registered Nurses, six Nurse Specialists and six Nurse Practitioners were observed. A total of 40hours of observation was made at each setting according to a structured observation guideline, followed by clarifying questions. The data material was analysed by means of a qualitative manifest and latent content analysis. Three themes arose: acting in accordance with routines, previous experience and intuition; considering patient experience; and facilitating new alternatives based on critical thinking. The Registered Nurses mainly used the first approach, the Nurse Specialists used the first and the second approaches, and the Nurse Practitioners used all three approaches. The results highlight the differences in decision-making processes between these groups. Nurse Practitioners were the only group that facilitated and evaluated new alternatives using their clinical autonomy, such as stepping up and making independent and collaborative decision-making. The results can be used in countries developing advanced practice nursing education and defining their scope of practice to inform stakeholders.

How Safe Is Anesthesia Management by Dentist Anesthesiologists? The Need for an International Collaborative Study on the Safety of Anesthesia Management by Dentist Anesthesiologists

How Safe Is Anesthesia Management by Dentist Anesthesiologists? The Need for an International Collaborative Study on the Safety of Anesthesia Management by Dentist Anesthesiologists

Abstract IA18: Genetic susceptibility to breast cancer: Recent advances and application to personalised prevention

Abstract The past two decades have seen dramatic progress in our understanding of the inherited basis of breast cancer, driven by large international collaborative epidemiological studies. Genetic factors identified include rare coding variants in susceptibility genes, and more than 200 common polymorphisms, identified through genome-wide association studies (GWAS) and largely in non-coding regions, that confer more moderate risks. The majority of the common variants are more strongly associated with ER-positive disease, but a subset is specifically associated with ER-negative disease. Variants are strongly enriched for regulatory regions and transcription factor binding sites, and the putative target genes are strongly enriched for known breast cancer drivers: however, the underlying target genes and mechanisms remain largely obscure. The associations for common variants appear to be largely independent of each other and can be summarised by a polygenic risk score (PRS) that is strongly predictive of risk. The most extensively validated PRS, comprising 313 SNPs, is associated with a relative risk of approximately 1.6 per standard deviation; women in the top 1% of the risk distribution have an approximately 4-fold risk of ER-positive disease and 3-fold risk of ER-negative disease. The PRS was developed in women of European ancestry but is also predictive of risk in Asian ancestry women, though less so in African ancestry women. In contrast, despite their widespread use, the evidence for association with cancer for coding variants in genes on genetic testing panels is often weak. Recent very large-scale targeted sequencing studies, however, have clarified the position, providing strong evidence for an association between protein truncating or missense variants and breast cancer risk for nine genes: BRCA1, BRCA2, ATM, CHEK2, PALB2, BARD1, RAD51C, RAD51D and TP53. Recent large-scale exome-wide sequencing analysis has shown that rare variants in several additional genes are also risk associated, with the majority being tumour suppressor genes: these include MAP3K1, ATRIP and SAMHD1. These analyses also demonstrate, however, that the contribution of coding variation, beyond the known genes, is likely to be small. The currently identified variants explain about half of the familial risk of breast cancer. Part of the “missing” heritability is due to weaker common variants, many of which should be identified in ongoing larger GWAS. The causes of the remainder are obscure and may include rare non-coding variants, repeat polymorphisms, and epistatic interactions. Risk discrimination is most powerful when all risk factors are considered. The BOADICEA model, implemented in the CanRisk tool, provides a well validated model that incorporates the effects of gene variants, polygenic risk scores, lifestyle factors and breast density to predict breast and ovarian cancer risk. Multiple translational studies are ongoing to evaluate the feasibility and utility of such personalised risk prediction for stratifying screening and prevention. Citation Format: Douglas F Easton. Genetic susceptibility to breast cancer: Recent advances and application to personalised prevention [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr IA18.

Implementing data on targeted therapy from the INFORM registry platform for children with relapsed cancer in Sweden.

Advances in treatment of childhood malignancies have improved overall cure rates to 80%. Nevertheless, cancer is still the most common cause of childhood mortality in Sweden. The prognosis is particularly poor for relapse of high-risk malignancies. In the international INFORM registry, tumor tissue from patients with relapsed, refractory, or progressive pediatric cancer as well as from very-high risk primary tumors is biologically characterized using next-generation sequencing to identify possible therapeutic targets. We analyzed data from Swedish children included in the INFORM registry concerning patient characteristics, survival, sequencing results and whether targeted treatment was administered to the children based on the molecular findings. A registry-based descriptive analysis of 184 patients included in the INFORM registry in Sweden during 2016-2021. The most common diagnoses were soft tissue and bone sarcomas followed by high grade gliomas [including diffuse intrinsic pontine glioma (DIPG)]. Complete molecular analysis was successful for 203/212 samples originating from 184 patients. In 88% of the samples, at least one actionable target was identified. Highly prioritized targets, according to a preset scale, were identified in 48 (24%) samples from 40 patients and 24 of these patients received matched targeted treatment but only six children within a clinical trial. No statistically significant benefit in terms of overall survival or progression free survival was observed between children treated with matched targeted treatment compared to all others. This international collaborative study demonstrate feasibility regarding sequencing of pediatric high-risk tumors providing molecular data regarding potential actionable targets to clinicians. For a few individuals the INFORM analysis was of utmost importance and should be regarded as a new standard of care with the potential to guide targeted therapy.

Gender-Specific Genetic Predisposition to Breast Cancer: BRCA Genes and Beyond

Among neoplastic diseases, breast cancer (BC) is one of the most influenced by gender. Despite common misconceptions associating BC as a women-only disease, BC can also occur in men. Additionally, transgender individuals may also experience BC. Genetic risk factors play a relevant role in BC predisposition, with important implications in precision prevention and treatment. The genetic architecture of BC susceptibility is similar in women and men, with high-, moderate-, and low-penetrance risk variants; however, some sex-specific features have emerged. Inherited high-penetrance pathogenic variants (PVs) in BRCA1 and BRCA2 genes are the strongest BC genetic risk factor. BRCA1 and BRCA2 PVs are more commonly associated with increased risk of female and male BC, respectively. Notably, BRCA-associated BCs are characterized by sex-specific pathologic features. Recently, next-generation sequencing technologies have helped to provide more insights on the role of moderate-penetrance BC risk variants, particularly in PALB2, CHEK2, and ATM genes, while international collaborative genome-wide association studies have contributed evidence on common low-penetrance BC risk variants, on their combined effect in polygenic models, and on their role as risk modulators in BRCA1/2 PV carriers. Overall, all these studies suggested that the genetic basis of male BC, although similar, may differ from female BC. Evaluating the genetic component of male BC as a distinct entity from female BC is the first step to improve both personalized risk assessment and therapeutic choices of patients of both sexes in order to reach gender equality in BC care. In this review, we summarize the latest research in the field of BC genetic predisposition with a particular focus on similarities and differences in male and female BC, and we also discuss the implications, challenges, and open issues that surround the establishment of a gender-oriented clinical management for BC.

P494 Efficacy and safety of Upadacitinib in moderate to severe paediatric Crohn’s disease and ulcerative colitis in a tertiary Paediatric IBD (PIBD) centre – A case series

Abstract Background Upadacitinib is a selective Janus kinase 1 inhibitor approved for the treatment of patients 18 years and older with the diagnosis of Crohn’s disease and ulcerative colitis. Although there is promising data for its use in adult inflammatory bowel disease (IBD), limited data are currently available on its use in paediatric IBD. We present our experience in this case series of patients ≤ 18 years on Upadacitinib. Methods We identified patients under the age of ≤ 18 years, started on Upadacitinib for the indication of IBD. Data on demographics, disease subtype, duration on Upadacitinib, number of biologic failures, tofacitinib use, concomitant biologic use, adverse events and clinical remission were gathered. Results 12 patients with paediatric IBD (median age at Upadacitinib start 15.5 years, range 13.9 to 17.8 years, 8 (67%) males, were identified. 7 patients had Crohn’s disease, 3 patients had ulcerative colitis and 2 patients had IBD unclassified. 4 patients (33%) were diagnosed under the age of 6 years with early onset IBD (EOIBD), 1 was 3.5 years old, 1 was 4 years old and 2 were 5 years old. 11/12 (92%) patients had failed 3 or more biologics. Upadacitinib was used as monotherapy in all patients and previous biologic treatments were stopped. 1 patient with a partial response to tofacitinib was switched to Upadacitinib. All patients had active disease at commencement of Upadacitinib. All 12 (100%) patients were started on 45 mg of Upadacitinib. 8/12 (67%) patients have been followed up for at least 8 weeks. Out of the 8 patients, 5/8 (63%) patients were in clinical remission between 8-16 weeks of therapy, 2/8 (25%) had partial response and 1/8 (13%) has been refractory to treatment. Relapse of symptoms was noted in 1 patient after dose was dropped to 30 mg; this patient had achieved remission on 45 mg. No serious adverse events occurred; 2 patients noted to have increased triglycerides (max 5.75mmol/L; range 0.38-1.58mmol/L). 1 of them had previous exposure to tofacitinib and the triglycerides were already raised prior to starting Upadacitinib. 1 patient developed headaches, as a result, Upadacitinib dose was decreased. There were no incidences of shingles or other serious infections. Abbreviations CD, Crohn's disease; UC, ulcerative colitis; IBD-U; inflammatory bowel disease unclassified; Upa, upadacitinib; AEs; adverse events Conclusion The patients in this case series, started on Upadacitinib, are a heterogeneous group with refractory disease. In these paediatric and adolescent patients Upadacitinib seemed safe and efficacious with a low side effect profile. Further national and international collaborative studies are needed to confirm our findings. Table 1. Patient Characteristics

DOP14 Proctocolectomy is associated with improved transplant-free survival in patients with primary sclerosing cholangitis: results from a pooled collaborative international study

Abstract Background It is hypothesized that the gut-liver axis plays a pivotal role in the aetiology of primary sclerosing cholangitis (PSC). Colectomy before liver transplantation is associated with decreased rates of recurrent PSC.1 We previously observed that proctocolectomy with permanent ileostomy is associated with better transplant-free survival in a population-based Dutch cohort.2 The aim of the present study is to confirm the effect of colectomy on PSC disease course in an international context. Methods We conducted a retrospective analysis on the International PSC Registry (IPSCR), comprising patients from Finland, Norway, Sweden, and the Netherlands. Endpoints were defined as liver transplantation (LT) and PSC-related death (excluding colorectal carcinoma) and were censored in the first year after colectomy to allow for a delayed protective effect. Cox proportional hazards regression was performed, with correction for the following known risk factors; sex, age at diagnosis, large or small duct PSC, features of auto-immune hepatitis, and inflammatory bowel disease (IBD) status (i.e. ulcerative colitis, Crohn’s disease or IBD unspecified). IBD status and colectomy status were included as time-dependent exposure variables, the latter stratified for extent and indication for colectomy. Results A total of 2595 patients were included, of which 1341 from the Netherlands, 560 from Finland, 528 from Norway, and 166 from Sweden. Of all patients 1900(73%) were diagnosed with IBD and 346(15%) had undergone a colectomy; 34(9%) hemi-, 91(26%) subtotal, and 172(50%) proctocolectomy with pouch and 65(19%) with ileostomy. During a total follow-up of 28,282 patient years, 848(33%) patients reached the endpoint LT or PSC-related death. Hazard ratio (HR) of reaching LT or PSC-related death was significantly decreased in patients with proctocolectomy (0.70(0.52-0.93)) compared to patients without colectomy with variation per country (Netherlands 0.82(0.56-1.19), Finland 0.52(0.24-1.13), Norway 0.59(0.31-1.03), Sweden 0.28(0.06-1.24)). This effect was less pronounced in case of a hemi- or subtotal colectomy (HR 0.84(059-1.20)). The effect was most pronounced in the proctocolectomy with permanent ileostomy group (HR 0.55(0.30-0.99)). Of the known risk factors only a concurrent IBD diagnosis had no significant effect on transplant-free survival. Conclusion Our extended data confirm that colectomy is associated with a decreased risk of liver transplantation and PSC-related death. An incremental effect was seen with the extent of the colectomy, with the most pronounced effect in the proctocolectomy group with permanent ileostomy. Our data support the putative role of the gut-liver axis in the disease course of PSC.

TRANSCRIPTOMIC SIGNATURES OF AGING, GENETICS, AND MORTALITY RISK: FINDINGS FROM THE LONG LIFE FAMILY STUDY

Abstract The Long Life Family Study (LLFS), funded by the National Institute on Aging, is an international collaborative study of the genetics and familial components of exceptional longevity and healthy aging. We phenotyped 4,953 individuals from 539 two-generational families (1,727 proband; 3,226 offspring) at baseline (2006-2009). A second visit (2014-2017) was conducted for 2,904 (478 proband; 2,426 offspring) participants, with a third visit ongoing. The longitudinal, comprehensive in-person visits measured domains of healthy aging, including physical performance, cognition, and blood markers. Extensive genetic analyses were performed using the baseline blood draw, including genotyping with the Illumina 2.5M Human Omni array, linkage analyses with the families, whole genome sequencing using the TopMED protocol, metabolomic assays, and trascriptomics (RNA-seq). Collectively, this symposium will present novel findings that examined differences in gene expression between those of extreme old age compared to younger participants, elucidate potential new genomic regions and variants associated with ankle brachial index, examine rare variants under linkage peaks for perceived physical fatigability, and compare mortality and cause of death between LLFS and the US population. Specifically, Ms. Li will share results on gene expression profiles in aging. Then, Ms. Ressler will share findings on the genetics of ankle brachial index with linkage and association results. Next, Ms. Gay will discuss associations under the linkage peak for perceived physical fatigability. Lastly, Ms. Yao will present mortality and patterns of death in the LLFS. As Discussant, Dr. Nalini Raghavachari from the NIA will provide insights and propose future directions for LLFS.

Ethical considerations for biobanking and use of genomics data in Africa: a narrative review

BackgroundBiobanking and genomic research requires collection and storage of human tissue from study participants. From participants’ perspectives within the African context, this can be associated with fears and misgivings due to a myriad of factors including myths and mistrust of researchers. From the researchers angle ethical dilemmas may arise especially with consenting and sample reuse during storage. The aim of this paper was to explore these ethical considerations in the establishment and conduct of biobanking and genomic studies in Africa.MethodsWe conducted a narrative synthesis following a comprehensive search of nine (9) databases and grey literature. All primary research study designs were eligible for inclusion as well as both quantitative and qualitative evidence from peer reviewed journals, spanning a maximum of 20 years (2000–2020). It focused on research work conducted in Africa, even if data was stored or analysed outside the region.ResultsOf 2,663 title and abstracts screened, 94 full texts were retrieved and reviewed for eligibility. We included 12 studies (7 qualitative; 4 quantitative and one mixed methods).Ethical issues described in these papers related to community knowledge and understanding of biobanking and genomic research, regulation, and governance of same by research ethics committees, enrolment of participants, types of informed consents, data collection, storage, usage and sharing as well as material transfer, returning results and benefit sharing. ca. Biospecimen collection and storage is given in trust and participants expect confidentially of data and results generated. Most participants are comfortable with broad consent due to trust in researchers, though a few would like to be contacted for reconsenting in future studies, and this would depend on whether the new research is for good cause. Sharing data with external partners is welcome in some contexts but some research participants did not trust foreign researchers.ConclusionBiobanking and genomic studies are a real need in Africa. Linked to this are ethical considerations related to setting up and participation in biobanks as well as data storage, export, use and sharing. There is emerging or pre-existing consensus around the acceptability of broad consent as a suitable model of consent, the need for Africans to take the lead in international collaborative studies, with deliberate efforts to build capacity in local storage and analysis of samples and employ processes of sample collection and use that build trust of communities and potential study participants. Research ethics committees, researchers and communities need to work together to work together to adapt and use clearly defined ethical frameworks, guidelines, and policy documents to harmonize the establishment and running of biobanking and genomic research in Africa.

Oral glucocorticoid use in patients with rheumatoid arthritis initiating TNF-inhibitors, tocilizumab or abatacept: Results from the international TOCERRA and PANABA observational collaborative studies

ObjectiveTo evaluate and compare the use of oral glucocorticoids with three classes of bDMARDs in patients with rheumatoid arthritis (RA). MethodsWe included patients from 13 observational registries treated with a TNF-inhibitor, abatacept or tocilizumab and with available information on the use of oral glucocorticoids. The main outcome was oral glucocorticoid withdrawal. A McNemar test was used to analyse the change in the use of glucocorticoids after 1 year. Kaplan-Meier estimates and Cox regressions, adjusted for patient, treatment, and disease characteristics, were used to evaluate glucocorticoid discontinuation in patients with glucocorticoids at baseline. Because of heterogeneity, analyses were done by registers and pooled using random-effects meta-analysis. ResultsA total of 12,334 participants treated with TNF-inhibitors, 2100 with tocilizumab and 3229 with abatacept were included. At one-year, oral glucocorticoid use decreased in all treatment groups (odds ratio for stopping vs. starting of 2.19 [95% CI 1.58; 3.04] for TNF-inhibitors, 2.46 [1.39; 4.35] for tocilizumab; 1.73 [1.25; 2.21] for abatacept). Median time to glucocorticoid withdrawal was ≈2 years or more in most countries, with a gradual decrease over time. Compared to TNF-inhibitors, crude hazard ratios of glucocorticoid discontinuation were 0.65[0.48–0.87] for abatacept, and 1.04 [0.76–1.43] for tocilizumab, and adjusted hazard ratios were 1.1 [0.83–1.47] for abatacept, and 1.30 [0.96–1.78] for tocilizumab. ConclusionAfter initiation of a bDMARD, glucocorticoid use decreased similarly in all treatment groups. However, glucocorticoid withdrawal was much slower than advocated by current international guidelines. More effort should be devoted to glucocorticoid tapering when low disease activity is achieved.

Real-life studies and registries of severe asthma: The advent of digital technology

Severe asthma is a chronic and heterogeneous disease that negatively affects the quality of life of our patients and health care utilization. Given the remaining burden of uncontrolled disease in many of these patients, better understanding of its epidemiology, disease mechanisms, effectiveness of novel therapies such as biologics are still highly needed. Asthma treatment guidelines are largely informed by randomized controlled trials (RCTs) and meta analyses of RCTs, however inclusion criteria of many efficacy RCTs of asthma treatments often exclude a high number of patients with asthma in the community. Data from real-life studies and registries of severe asthma can complement efficacy studies by not only providing evidence on how a treatment performs in everyday clinical practice, post marketing safety information, data to support subsequent clinical trial design, but also helping to delineate the natural history of a disease and supporting important translational research endeavors. In the current review, we summarise available national and international collaborative studies and registries, the variables studies and the novel data and insights they provide. The key source of information for most asthma registries are real-life data from patient's electronic health records. Advent of digital technology in collecting data and their analysis is obvious and we draw attention to generation of new knowledge from registries of severe asthma to improve current diagnostic and therapeutic guidelines and asthma control.