International Collaborative Study Research Articles

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.

A Multicenter Study Validates the WHO 2022 Classification for Conjunctival Melanocytic Intraepithelial Lesions With Clinical and Prognostic Relevance

Several nomenclature and grading systems have been proposed for conjunctival melanocytic intraepithelial lesions (C-MIL). The fourth “WHO Classification of Eye Tumors” (WHO-EYE04) proposed a C-MIL classification, capturing the progression of noninvasive neoplastic melanocytes from low- to high-grade lesions, onto melanoma in situ (MIS), and then to invasive melanoma. This proposal was revised to the WHO-EYE05 C-MIL system, which simplified the high-grade C-MIL, whereby MIS was subsumed into high-grade C-MIL. Our aim was to validate the WHO-EYE05 C-MIL system using digitized images of C-MIL, stained with hematoxylin and eosin and immunohistochemistry. However, C-MIL cases were retrieved from 3 supraregional ocular pathology centers. Adequate conjunctival biopsies were stained with hematoxylin and eosin, Melan-A, SOX10, and PReferentially expressed Antigen in Melanoma. Digitized slides were uploaded on the SmartZoom platform and independently scored by 4 ocular pathologists to obtain a consensus score, before circulating to 14 expert eye pathologists for independent scoring. In total, 105 cases from 97 patients were evaluated. The initial consensus diagnoses using the WHO-EYE04 C-MIL system were as follows: 28 benign conjunctival melanoses, 13 low-grade C-MIL, 37 high-grade C-MIL, and 27 conjunctival MIS. Using this system resulted in 93% of the pathologists showing only fair-to-moderate agreement (kappa statistic) with the consensus score. The WHO-EYE05 C-MIL system (with high-grade C-MIL and MIS combined) improved consistency between pathologists, with the greatest level of agreement being seen with benign melanosis (74.5%) and high-grade C-MIL (85.4%). Lowest agreements remained between pathologists for low-grade C-MIL (38.7%). Regarding WHO-EYE05 C-MIL scoring and clinical outcomes, local recurrences of noninvasive lesions developed in 8% and 34% of the low- and high-grade cases. Invasive melanoma only occurred in 47% of the cases that were assessed as high-grade C-MIL. This extensive international collaborative study is the first to undertake a comprehensive review of the WHO-EYE05 C-MIL scoring system, which showed good interobserver agreement and reproducibility.

The association of insomnia with long COVID: An international collaborative study (ICOSS-II)

There is evidence of a strong association between insomnia and COVID-19, yet few studies have examined the relationship between insomnia and long COVID. This study aimed to investigate whether COVID-19 patients with pre-pandemic insomnia have a greater risk of developing long COVID and whether long COVID is in turn associated with higher incident rates of insomnia symptoms after infection. Data were collected cross-sectionally (May-Dec 2021) as part of an international collaborative study involving participants from 16 countries. A total of 2311 participants (18-99 years old) with COVID-19 provided valid responses to a web-based survey about sleep, insomnia, and health-related variables. Log-binomial regression was used to assess bidirectional associations between insomnia and long COVID. Analyses were adjusted for age, sex, and health conditions, including sleep apnea, attention and memory problems, chronic fatigue, depression, and anxiety. COVID-19 patients with pre-pandemic insomnia showed a higher risk of developing long COVID than those without pre-pandemic insomnia (70.8% vs 51.4%; adjusted relative risk [RR]: 1.33, 95% confidence interval [CI]: 1.07-1.65). Among COVID-19 cases without pre-pandemic insomnia, the rates of incident insomnia symptoms after infection were 24.1% for short COVID cases and 60.6% for long COVID cases (p<.001). Compared with short COVID cases, long COVID cases were associated with an increased risk of developing insomnia symptoms (adjusted RR: 2.00; 95% CI: 1.50-2.66). The findings support a bidirectional relationship between insomnia and long COVID. These findings highlight the importance of addressing sleep and insomnia in the prevention and management of long COVID.

Global, regional, and national time trends in myocarditis-related mortality, 1990-2019: An age-period-cohort analysis.

The aim of this study was to analyze the tendency of myocarditis mortality in 204 countries and areas during the lastthreedecades and its connection with age, epoch, and birth cohort. The Global Burden of Disease 2019 Study acquired a cause-specific myocarditis mortality estimate. The net drift, as well as the influence caused by age, period, and birth cohort, were evaluated by the age-period-cohort model. Additionally, we analyzed the tendency in research intensity and international collaboration across countries using 3,983 myocarditis-related publications from four periods during 1990-2019. During the last three decades, 101 of 204 countries and areas experienced an increase (net drifts ≥0.0%) or stagnant declines (≥-0.5%) in the death rate. In particular, increasing death rate was generally discovered in most countries whose Socio-demographic indexes (SDIs) are high and middle-high, such as the United States [net drift=2.11% (95% CI 1.71-2.51)] and Italy [2.65% (1.24-4.08)]. Countries with a higher number of deaths were more active in this field of study, such as the United States (237 publications), China (120), and Italy (73). The United States and Italy, whose total link strengths were 209 and 135, respectively, were more active in international collaborative studies. Despite the global decrease in myocarditis death rate during the last three decades, negative period and cohort effects and elevated mortality were discovered in numerous countries, especially in those whose SDIs were high, and the age distribution of deaths shifted from adolescent to middle-aged and older populations. We also observed a decline in myocarditis research in some countries with increased mortality.

The International Association for the Study of Lung Cancer Thymic Epithelial Tumor Staging Project: A Re-Assessment of the International Thymic Malignancy Interest Group/International Association for the Study of Lung Cancer Lymph Node Map for Thymic Epithelial Tumors for the Forthcoming Ninth Edition of the TNM Classification of Malignant Tumors

IntroductionA lymph node map is the pillar on which accurate assignment and documentation of nodal classification stands. The International Thymic Malignancy Interest Group created the first map for thymic epithelial malignancies in conjunction with the eighth edition of the TNM classification, representing the first official TNM classification of thymic epithelial malignancies. The map was based on clinical experience and published studies, but it was largely empirical because of limited available data. Dissemination of the map and implementation of a standard thymic stage classification across the world in 2017 have provided more consistent and granular data. MethodsMore than twice as many cases of node involvement are available for analysis in the current database compared with that of the eighth edition database, allowing validation of many aspects of the eighth edition map. This article details the process and considerations for refinement of the thymic map for the ninth TNM used by the Thymic Domain of the Staging and Prognostic Factors Committee of the International Association for the Study of Lung Cancer. The committee evaluated a large international collaborative data set, published anatomical and clinical studies pertaining to lymph node spread from thymic epithelial tumors, in conjunction with the analysis underlying refinements of the TNM components for the ninth edition TNM classification. ResultsThe node map boundaries of the N1 and N2 categories remain unchanged. Visual clarifications have been added to the nomenclature of nodal stations within these regions. ConclusionsOn the basis of the recommendation to keep the N component unchanged for the ninth edition TNM classification, the lymph node map remains unchanged as well; however, clarifications have been added to facilitate clinical use.

A standardised protocol for relative SARS-CoV-2 variant severity assessment, applied to Omicron BA.1 and Delta in six European countries, October 2021 to February 2022.

Several SARS-CoV-2 variants that evolved during the COVID-19 pandemic have appeared to differ in severity, based on analyses of single-country datasets. With decreased testing and sequencing, international collaborative studies will become increasingly important for timely assessment of the severity of new variants. Therefore, a joint WHO Regional Office for Europe and ECDC working group was formed to produce and pilot a standardised study protocol to estimate relative case-severity of SARS-CoV-2 variants during periods when two variants were co-circulating. The study protocol and its associated statistical analysis code was applied by investigators in Denmark, England, Luxembourg, Norway, Portugal and Scotland to assess the severity of cases with the Omicron BA.1 virus variant relative to Delta. After pooling estimates using meta-analysis methods (random effects estimates), the risk of hospital admission (adjusted hazard ratio (aHR) = 0.41; 95% confidence interval (CI): 0.31-0.54), admission to intensive care unit (aHR = 0.12; 95% CI: 0.05-0.27) and death (aHR = 0.31; 95% CI: 0.28-0.35) was lower for Omicron BA.1 compared with Delta cases. The aHRs varied by age group and vaccination status. In conclusion, this study demonstrates the feasibility of conducting variant severity analyses in a multinational collaborative framework and adds evidence for the reduced severity of the Omicron BA.1 variant.

Research Priorities in Prehabilitation for Patients Undergoing Cancer Surgery: An International Delphi Study

BackgroundRecently, the number of prehabilitation trials has increased significantly. The identification of key research priorities is vital in guiding future research directions. Thus, the aim of this collaborative study was to define key research priorities in prehabilitation for patients undergoing cancer surgery.MethodsThe Delphi methodology was implemented over three rounds of surveys distributed to prehabilitation experts from across multiple specialties, tumour streams and countries via a secure online platform. In the first round, participants were asked to provide baseline demographics and to identify five top prehabilitation research priorities. In successive rounds, participants were asked to rank research priorities on a 5-point Likert scale. Consensus was considered if > 70% of participants indicated agreement on each research priority.ResultsA total of 165 prehabilitation experts participated, including medical doctors, physiotherapists, dieticians, nurses, and academics across four continents. The first round identified 446 research priorities, collated within 75 unique research questions. Over two successive rounds, a list of 10 research priorities reached international consensus of importance. These included the efficacy of prehabilitation on varied postoperative outcomes, benefit to specific patient groups, ideal programme composition, cost efficacy, enhancing compliance and adherence, effect during neoadjuvant therapies, and modes of delivery.ConclusionsThis collaborative international study identified the top 10 research priorities in prehabilitation for patients undergoing cancer surgery. The identified priorities inform research strategies, provide future directions for prehabilitation research, support resource allocation and enhance the prehabilitation evidence base in cancer patients undergoing surgery.