International Observational Studies Research Articles

Cardiac Resynchronization Therapy. Long-Term Evolution of Responder and Non-Responder Patients

Background: Cardiac resynchronization therapy (CRT) is an effective treatment in patients with heart failure (HF), low left ventricular ejection fraction (LVEF) and wide QRS. However, there are a percentage of these patients who are non-responders, implying worse clinical outcomes. Objectives: The aim of this study was to assess the differences in echocardiographic parameters of reverse remodeling and event rates [hospitalization for heart failure (HHF), all-cause mortality (ACM), heart transplantation (HTX) and appropriate therapies (AT)] between responder vs. non-responder patients to CRT. Methods: A total of 343 patients with CRT, classified into responders and non-responders according to clinical and echocardiographic parameters, were included in the study. A 2-year follow-up was performed, in which reverse remodeling and the incidence of HHF, ACM, HTX and AT were evaluated. Results: Among the 343 patients, 17% were non-responders and 83% responders. At 6 and 12 months there were no significant differences in ventricular diameters, but significant differences in LVEF (p<0.001), with greater increase in responders. At 24 months, responders had smaller diastolic diameter (p=0.004), smaller systolic diameter (p=0.003) and higher LVEF (p<0.001). Non-responders had significantly higher incidence of HHF (p<0.001), HTX (p=0.001) and AT (p=0.002), and an excess of ACM at the limit of statistical significance (p= 0.056). Conclusions: Patients responding to CRT presented greater reverse remodeling and better clinical evolution, in accordance with the results of international observational studies.

“Quality of Life in Epidermolysis Bullosa” and “Epidermolysis Bullosa Burden of Disease”: Italian translation, cultural adaptation, and pilot testing of two disease-specific questionnaires

BackgroundInherited epidermolysis bullosa (EB) is a clinically and genetically heterogeneous group of skin fragility disorders characterized by blister formation following minor trauma. Four major types are distinguished based on the level of cleavage within the skin. Most EB forms present severely disabling cutaneous and systemic signs and symptoms. Management relies on daily time-consuming and distressing topical medications, and symptomatic treatment of systemic findings. Disease manifestations, symptoms, and daily care strongly affect patient and caregiver quality of life (QoL). To date, there are two validated EB-specific questionnaires, the “Quality of Life in Epidermolysis Bullosa” (QOLEB) and the “Epidermolysis Bullosa Burden of Disease” (EB-BoD) for the evaluation of patient and family disease burden, respectively. The aim of our study was to develop an Italian translation of the two questionnaires and to pilot-test them.MethodsThe guidelines for translation and cross-cultural adaptation of health-related QoL measures were followed. Initially, two separate translations were generated for each questionnaire, and subsequently reconciled by an expert committee. This was followed by a back-translation process. The original texts and all translations underwent revision by the expert committee, resulting in definitive versions. The final versions were then tested in a pilot study involving cognitive debriefing in a group of 17 families, representative of all EB major types.ResultsThe translation and reconciliation process led to minor changes to obtain semantic/idiomatic/cultural equivalence of the Italian versions with the original ones and to reconcile the questions with the answer options. The cognitive debriefing process showed a good understanding and did not require text modifications.ConclusionsThe Italian versions of the QOLEB and EB-BoD provide valuable tools in everyday clinical practice of reference centers, and they allow the participation in multicenter international real-life observational studies as well as in controlled clinical trials. They enable the identification of disease-specific psychological and socioeconomic challenges for EB patients and their families, guiding targeted interventions to ensure appropriate and timely care.

ECLIM-SEHOP: how to develop a platform to conduct academic trials for childhood cancer

IntroductionECLIM-SEHOP platform was created in 2017. Its main objective is to establish the infrastructure to allow Spanish participation into international academic collaborative clinical trials, observational studies, and registries in pediatric oncology. The aim of this manuscript is to describe the activity conducted by ECLIM-SEHOP since its creation.MethodsThe platform’s database was queried to provide an overview of the studies integrally and partially supported by the organization. Data on trial recruitment and set-up/conduct metrics since its creation until November 2023 were extracted.ResultsECLIM-SEHOP has supported 47 studies: 29 clinical trials and 18 observational studies/registries that have recruited a total of 5250 patients. Integral support has been given to 25 studies: 16 trials recruiting 584 patients and nine observational studies/registries recruiting 278 patients. The trials include front-line studies for leukemia, lymphoma, brain and solid extracranial tumors, and other key transversal topics such as off-label use of targeted therapies and survivorship. The mean time from regulatory authority submission to first patient recruited was 12.2 months and from first international site open to first Spanish site open was 31.3 months.DiscussionECLIM-SEHOP platform has remarkably improved the availability and accessibility of international academic clinical trials and has facilitated the centralization of resources in childhood cancer treatment. Despite the progressive improvement on clinical trial set-up metrics, timings should still be improved. The program has contributed to leveling survival rates in Spain with those of other European countries that presented major differences in the past.

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.

Adverse effects of frailty on the outcomes of surgery for degenerative cervical myelopathy: results from a prospective multicenter international data set of 757 patients.

The goal of this study was to determine the effect of the degree of frailty on long-term neurological and functional outcomes after surgery for degenerative cervical myelopathy (DCM). A combined database of patients enrolled in the Cervical Spondylotic Myelopathy-North America and Cervical Spondylotic Myelopathy-International prospective international multicenter observational studies who underwent surgery for DCM was used as the source data. All patients underwent baseline and follow-up assessment at 2 years after surgery for functional, disability, and quality of life measurements (modified Japanese Orthopaedic Association [mJOA] scale, Neck Disability Index, SF-36 physical and mental component summary scores). Patients were separated into 4 groups according to their baseline modified frailty index 5-point scale score: not frail, pre-frail, frail, and severely frail. Differences among groups were analyzed at baseline and at 2 years after surgery, including change in scores (delta values) and the odds ratio of achieving the minimum clinically important difference (MCID) through univariate and multivariable logistic regression adjusting for age, approach, number of levels treated, and sex. A total of 757 patients (63% male) with a mean age of 56 (95% CI 55.5-57.2) years were included: 470 patients underwent an anterior approach, 310 had a posterior approach, and 23 had a combined anterior/posterior approach. A total of 50% (n = 378) of patients were classified as not frail, with 33% (n = 250) pre-frail, 13% (n = 101) frail, and 4% (n = 28) severely frail. The baseline mJOA score was significantly lower with increasing frailty (14.00 [95% CI 13.75-14.19] for not frail vs 9.71 [95% CI 9.01-10.42] for severely frail patients; p < 0.05), but the change at 2 years was not significantly different among all groups (2.43 [95% CI 2.16-2.71] for not frail vs 2.56 [95% CI 1.10-4.02] for severely frail). The SF-36 delta values were also not different among groups, but significantly worse at baseline with increasing frailty. The odds ratio of achieving MCID for mJOA was significantly higher in the not frail group (1.89 [95% CI 1.36-2.61]; p < 0.05) compared to the other frailty cohorts, which remained after adjusting for age, approach, levels treated, and sex. The odds ratio of achieving MCID for the SF-36 domains was similar among all frailty groups. Increasing frailty is associated with worse baseline functional and quality of life measures in patients undergoing surgery for DCM. Frailty does not affect the magnitude of improvement in outcome measures after surgery, but reduces the chance of achieving the MCID for functional impairment significantly. Preoperative frailty assessment can therefore help guide clinicians in managing expectations after surgery for DCM. Potentially modifiable factors should be optimized in frail patients preoperatively to enhance functional outcomes.

Depression, cardiometabolic disease, and their co-occurrence after childhood maltreatment: an individual participant data meta-analysis including over 200,000 participants

BackgroundChildhood maltreatment is associated with depression and cardiometabolic disease in adulthood. However, the relationships with these two diseases have so far only been evaluated in different samples and with different methodology. Thus, it remains unknown how the effect sizes magnitudes for depression and cardiometabolic disease compare with each other and whether childhood maltreatment is especially associated with the co-occurrence (“comorbidity”) of depression and cardiometabolic disease. This pooled analysis examined the association of childhood maltreatment with depression, cardiometabolic disease, and their comorbidity in adulthood.MethodsWe carried out an individual participant data meta-analysis on 13 international observational studies (N = 217,929). Childhood maltreatment comprised self-reports of physical, emotional, and/or sexual abuse before 18 years. Presence of depression was established with clinical interviews or validated symptom scales and presence of cardiometabolic disease with self-reported diagnoses. In included studies, binomial and multinomial logistic regressions estimated sociodemographic-adjusted associations of childhood maltreatment with depression, cardiometabolic disease, and their comorbidity. We then additionally adjusted these associations for lifestyle factors (smoking status, alcohol consumption, and physical activity). Finally, random-effects models were used to pool these estimates across studies and examined differences in associations across sex and maltreatment types.ResultsChildhood maltreatment was associated with progressively higher odds of cardiometabolic disease without depression (OR [95% CI] = 1.27 [1.18; 1.37]), depression without cardiometabolic disease (OR [95% CI] = 2.68 [2.39; 3.00]), and comorbidity between both conditions (OR [95% CI] = 3.04 [2.51; 3.68]) in adulthood. Post hoc analyses showed that the association with comorbidity was stronger than with either disease alone, and the association with depression was stronger than with cardiometabolic disease. Associations remained significant after additionally adjusting for lifestyle factors, and were present in both males and females, and for all maltreatment types.ConclusionsThis meta-analysis revealed that adults with a history of childhood maltreatment suffer more often from depression and cardiometabolic disease than their non-exposed peers. These adults are also three times more likely to have comorbid depression and cardiometabolic disease. Childhood maltreatment may therefore be a clinically relevant indicator connecting poor mental and somatic health. Future research should investigate the potential benefits of early intervention in individuals with a history of maltreatment on their distal mental and somatic health (PROSPERO CRD42021239288).

Striving and Thriving: Predictors of Burnout and Resilience Among Alzheimer's Caregivers

Caregivers play an essential role in the lives of patients with Alzheimer's Disease (AD). Caregiving is emotionally and physically demanding, and is a evolving target in AD as new functional, physical, medical, and psychiatric needs emerge. Numerous studies have demonstrated that caregiver well-being affects patient outcomes; therefore, it is imperative to understand what factors contribute to caregiver burnout as well as caregiver resilience. The goal of this talk is to review results from a systematic review (performed by the presenting authors) on determinants of burnout and resilience among caregivers of patients with AD. The systematic review includes a compilation of international observational studies with patients with AD who are 65 or older.Although presenting on both resilience and burnout may seem like a broad topic for a general session, the authors feel it is impossible to discuss caregiver resilience without addressing burnout and vice-versa, as the themes are intertwined. Within a given caregiver-care recipient dyad, there may be some factors that are associated with burnout and other factors that are associated with resilience. The ultimate goal in working with caregivers is to maximize caregiver resilience and minimize caregiver burnout for the best possible outcomes for patient and caregiver alike.The first section of this talk will introduce literature on caregiver burnout and resilience, providing definitions and case examples. The second section will examine factors associated specifically with caregiver burnout and will delve into findings from the systematic review. Similarly, the third section will discuss factors associated with caregiver resilience as identified by the systematic review. Finally, we will conclude with a discussion of evidence-based interventions to best support caregivers that boost resilience and mitigate burnout. Attendees will gain an understanding of the multiplicity of factors involved in caregiver outcomes as well as strategies to support these caregivers. Discussion among session attendees will be encouraged.

An ETL-process design for data harmonization to participate in international research with German real-world data based on FHIR and OMOP CDM

BackgroundInternational studies are increasingly needed in order to gain more unbiased evidence from real-world data. To achieve this goal across the European Union, the EMA set up the DARWIN EU project based on OMOP CDM established by the OHDSI community. The harmonization of heterogeneous local health data in OMOP CDM is an essential step to participate in such networks. Using the widespread communication standard HL7 FHIR can reduce the complexity of the transformation process to OMOP CDM. Enabling German university hospitals to participate in such networks requires an Extract, Transform and Load (ETL)-process that satisfies the following criteria: 1) transforming German patient data from FHIR to OMOP CDM, 2) processing huge amount of data at once and 3) flexibility to cope with changes in FHIR profiles. MethodA mapping of German patient data from FHIR to OMOP CDM was accomplished, validated by an interdisciplinary team and checked through the OHDSI Data Quality Dashboard (DQD). To satisfy criteria 2–3, we decided to use SpringBatch-Framework according to its chunk-oriented design and reusable functions for processing large amounts of data. ResultsWe have successfully developed an ETL-process that fulfills the defined criteria of transforming German patient data from FHIR into OMOP CDM. To measure the validity of the mapping conformance and performance of the ETL-process, it was tested with 392,022 FHIR resources. The ETL execution lasted approximately-one minute and the DQD result shows 99% conformance in OMOP CDM. ConclusionsOur ETL-process has been successfully tested and integrated at 10 German university hospitals. The data harmonization utilizing international recognized standards like FHIR and OMOP fosters their ability to participate in international observational studies. Additionally, the ETL process can help to prepare more German hospitals with their data harmonization journey based on existing standards.

Patient Safety, Clinical Microbiology, and Collaborative Healthcare

“Right to health” is a universal right inclusive of a culture of safety. This review aims to highlight how clinical microbiology laboratories can contribute to patient safety. They can bring down medical errors through clinical collaboration and quality control. Timely and accurate inputs from microbiology laboratory help in clinical correlation and aid in safe patient care. Through internet search, using keywords such as “medical errors” and “quality assurance,” global burden of medical errors has been compiled. References have been taken from guidelines and documents of standard national and international agencies, systematic reviews, observational studies, retrospective analyses, meta-analyses, health bulletins and reports, and personal views. Safety in healthcare should lay emphasis on prevention, reporting, analysis, and correction of medical errors. If not recorded, medical errors are regarded as occasional or chance events. Global data show adverse events are as high as 10% among hospitalized patients, and approximately two-thirds of these are reported from low- to middle-income countries (LMICs). This includes errors in laboratories as well. Clinical microbiology can impact patient safety when practiced properly with an aim to detect, control, and prevent infections at the earliest. It is a science that integrates a tripartite relationship between the patient, clinician, and a microbiology specialist. Through collaborative healthcare, all stakeholders benefit by understanding common errors and mitigate them through quality management. However, errors tend to happen despite standardization and streamlining all processes. The aim should be to minimize them, have fair documentation, and learn from mistakes to avoid repetition. Local targets should be set and then extended to meet national and global benchmarks.

Extracorporeal Membrane Oxygenation during Respiratory Pandemics: Past, Present, and Future.

The role of extracorporeal membrane oxygenation (ECMO) in the management of severe acute respiratory failure, including acute respiratory distress syndrome, has become better defined in recent years in light of emerging high-quality evidence and technological advances. Use of ECMO has consequently increased throughout many parts of the world. The coronavirus disease (COVID-19) pandemic, however, has highlighted deficiencies in organizational capacity, research capability, knowledge sharing, and resource use. Although governments, medical societies, hospital systems, and clinicians were collectively unprepared for the scope of this pandemic, the use of ECMO, a highly resource-intensive and specialized form of life support, presented specific logistical and ethical challenges. As the pandemic has evolved, there has been greater collaboration in the use of ECMO across centers and regions, together with more robust data reporting through international registries and observational studies. Nevertheless, centralization of ECMO capacity is lacking in many regions of the world, and equitable use of ECMO resources remains uneven. There are no widely available mechanisms to conduct large-scale, rigorous clinical trials in real time. In this critical care review, we outline lessons learned during COVID-19 and prior respiratory pandemics in which ECMO was used, and we describe how we might apply these lessons going forward, both during the ongoing COVID-19 pandemic and in the future.

Collaboration in colorectal surgical research.

Surgical research has been under-powered, under-funded and under-delivered for decades. A solution may be to form large research collaborations and thereby enable implementation of successful interventional trials as well as robust international observational studies with thousands of patients. There are many such research collaborations in colorectal surgery, and in this paper we have highlighted the experiences from the West Midlands Research Collaborative (WMRC), the Scandinavian Surgical Outcomes Research Group (SSORG) and the European Society of Coloproctology. With active research networks, it is possible to deliver large, high-quality studies and provide high-level evidence for solving important clinical questions in an efficient and timely manner.

Dyslipidemias: new therapeutic targets and relevance of combination therapies

Based on growing evidence showing a better prognosis in individuals with lower levels of low-density lipoprotein cholesterol (LDL-C), updated 2019 European Society of Cardiology guidelines have further reduced LDL-C targets in patients with higher cardiovascular risk. National and international observational clinical studies demonstrated a significant gap between goals recommended by international guidelines and LDL-C levels achieved in the real world, especially in patient populations at higher risk. Combination treatment strategies with more lipid-lowering drugs represent effective and safe options for the achievement of recommended targets. The introduction of new drugs, such as bempedoic acid, further expands the available therapeutic armamentarium for hypercholesterolemia management.

Knee osteoarthritis and time-to all-cause mortality in six community-based cohorts: an international meta-analysis of individual participant-level data

BackgroundOsteoarthritis (OA) is a chronic joint disease, with increasing global burden of disability and healthcare utilisation. Recent meta-analyses have shown a range of effects of OA on mortality, reflecting different OA definitions and study methods. We seek to overcome limitations introduced when using aggregate results by gathering individual participant-level data (IPD) from international observational studies and standardising methods to determine the association of knee OA with mortality in the general population.MethodsSeven community-based cohorts were identified containing knee OA-related pain, radiographs, and time-to-mortality, six of which were available for analysis. A two-stage IPD meta-analysis framework was applied: (1) Cox proportional hazard models assessed time-to-mortality of participants with radiographic OA (ROA), OA-related pain (POA), and a combination of pain and ROA (PROA) against pain and ROA-free participants; (2) hazard ratios (HR) were then pooled using the Hartung–Knapp modification for random-effects meta-analysis.Findings10,723 participants in six cohorts from four countries were included in the analyses. Multivariable models (adjusting for age, sex, race, BMI, smoking, alcohol consumption, cardiovascular disease, and diabetes) showed a pooled HR, compared to pain and ROA-free participants, of 1.03 (0.83, 1.28) for ROA, 1.35 (1.12, 1.63) for POA, and 1.37 (1.22, 1.54) for PROA.DiscussionParticipants with POA or PROA had a 35–37% increased association with reduced time-to-mortality, independent of confounders. ROA showed no association with mortality, suggesting that OA-related knee pain may be driving the association with time-to-mortality.FundingVersus Arthritis Centre for Sport, Exercise and Osteoarthritis and Osteoarthritis Research Society International.

A total blood volume or more transfused during pregnancy or after childbirth: Individual patient data from six international population-based observational studies.

BackgroundThis study aimed to compare incidence, management and outcomes of women transfused their blood volume or more within 24 hours during pregnancy or following childbirth.MethodsCombined analysis of individual patient data, prospectively collected in six international population-based studies (France, United Kingdom, Italy, Australia, the Netherlands and Denmark). Massive transfusion in major obstetric haemorrhage was defined as transfusion of eight or more units of red blood cells within 24 hours in a pregnant or postpartum woman. Causes, management and outcomes of women with massive transfusion were compared across countries using descriptive statistics.FindingsThe incidence of massive transfusion was approximately 21 women per 100,000 maternities for the United Kingdom, Australia and Italy; by contrast Denmark, the Netherlands and France had incidences of 82, 66 and 69 per 100,000 maternities, respectively. There was large variation in obstetric and haematological management across countries. Fibrinogen products were used in 86% of women in Australia, while the Netherlands and Italy reported lower use at 35–37% of women. Tranexamic acid was used in 75% of women in the Netherlands, but in less than half of women in the UK, Australia and Italy. In all countries, women received large quantities of colloid/crystalloid fluids during resuscitation (>3·5 litres). There was large variation in the use of compression sutures, embolisation and hysterectomy across countries. There was no difference in maternal mortality; however, variable proportions of women had cardiac arrests, renal failure and thrombotic events from 0–16%.InterpretationThere was considerable variation in the incidence of massive transfusion associated with major obstetric haemorrhage across six high-income countries. There were also large disparities in both transfusion and obstetric management between these countries. There is a requirement for detailed evaluation of evidence underlying current guidance. Furthermore, cross-country comparison may empower countries to reference their clinical care against that of other countries.

Association of Prediabetes and Type 2 Diabetes With Cognitive Function After Stroke

Background and Purpose- Type 2 diabetes mellitus (T2D) is associated with cognitive impairment and an increased risk of dementia, but the association between prediabetes and cognitive impairment is less clear, particularly in a setting of major cerebrovascular events. This article examines the impact of impaired fasting glucose and T2D on cognitive performance in a stroke population. Methods- Seven international observational studies from the STROKOG (Stroke and Cognition) consortium (n=1601; mean age, 66.0 years; 70% Asian, 26% white, and 2.6% African American) were included. Fasting glucose level (FGL) during hospitalization was used to define 3 groups, T2D (FGL ≥7.0 mmol/L), impaired fasting glucose (FGL 6.1-6.9 mmol/L), and normal (FGL <6.1 mmol/L), and a history of diabetes mellitus and the use of a diabetes mellitus medication were also used to support a diagnosis of T2D. Domain and global cognition Z scores were derived from standardized neuropsychological test scores. The cross-sectional association between glucose status and cognitive performance at 3 to 6 months poststroke was examined using linear mixed models, adjusting for age, sex, education, stroke type, ethnicity, and vascular risk factors. Results- Patients with T2D had significantly poorer performance in global cognition (SD, -0.59 [95% CI, -0.82 to -0.36]; P<0.001) and in all domains compared with patients with normal FGL. There was no significant difference between impaired fasting glucose patients and those with normal FGL in global cognition (SD, -0.10 [95% CI, -0.45 to 0.24]; P=0.55) or in any cognitive domain. Conclusions- Diabetes mellitus, but not prediabetes, is associated with poorer cognitive performance in patients 3 to 6 months after stroke.

Estimating treatment importance in multidrug-resistant tuberculosis using Targeted Learning: An observational individual patient data network meta-analysis.

Persons with multidrug-resistant tuberculosis (MDR-TB) have a disease resulting from a strain of tuberculosis (TB) that does not respond to at least isoniazid and rifampicin, the two most effective anti-TB drugs. MDR-TB is always treated with multiple antimicrobial agents. Our data consist of individual patient data from 31 international observational studies with varying prescription practices, access to medications, and distributions of antibiotic resistance. In this study, we develop identifiability criteria for the estimation of a global treatment importance metric in the context where not all medications are observed in all studies. With stronger causal assumptions, this treatment importance metric can be interpreted as the effect of adding a medication to the existing treatments. We then use this metric to rank 15 observed antimicrobial agents in terms of their estimated add-on value. Using the concept of transportability, we propose an implementation of targeted maximum likelihood estimation, a doubly robust and locally efficient plug-in estimator, to estimate the treatment importance metric. A clustered sandwich estimator is adopted to compute variance estimates and produce confidence intervals. Simulation studies are conducted to assess the performance of our estimator, verify the double robustness property, and assess the appropriateness of the variance estimationapproach.

Update on Li-Fraumeni syndrome

The Li-Fraumeni syndrome (LFS, online Mendelian inheritance in man, OMIM #151623) is considered to be one of the currently known most aggressive cancer predisposition syndromes. The heterogeneous spectrum of tumors is dominated by bone and soft tissue sarcomas, various brain tumors, premenopausal breast cancer and adrenocortical carcinoma (ACC). Even in childhood the cancer risk is very strongly increased and it is not uncommon for people with LFS to develop synchronous and metachronous tumors. Typical histopathological findings and molecular genetic signatures can help towards the diagnosis. Inheritance is autosomal dominant and the penetrance appears to be more variable than previously thought. The prevalence of LFS is approximately 1:5000 with ahigh interregional variance. The LFS is caused by germline mutations in the TP53 gene coding for the protein p53, an essential cellular transcription factor that initiates antitumor responses to cellular stress, such as DNA damage. In people with LFS, due to the loss of functional p53, the protective mechanism of the cells is weakened resulting in asignificantly increased cancer risk. In order to improve the survival of people with LFS, structured tumor early recognition and surveillance strategies are recommended; however, national and international longitudinal observational studies are needed to evaluate the cost-effort-benefit balance. For this reason, the authors have established the LFS cancer predisposition registry in which all patients with LFS and other syndromes predisposing to cancer can be registered. Detailed information can be found at www.cancer-predisposition.org .

Rivaroxaban for non-valvular atrial fibrillation and venous thromboembolism in the Netherlands: a real-world data based cost-effectiveness analysis

Background: Non-vitamin K antagonist oral anticoagulants (NOACs) have been included in international guidelines as important alternatives to vitamin K antagonists (VKAs) for the treatment of venous thromboembolism (VTE) and stroke prevention in non-valvular atrial fibrillation (NVAF). Meanwhile, in the Netherlands, NOACs are widely used next to VKAs. The objective of this study is to estimate the cost-effectiveness of treatment with rivaroxaban compared to VKAs in NVAF and VTE patients in the Netherlands, using data from international prospective observational phase IV studies.Methods: Two models were developed to represent NVAF and VTE patients, populated with patients from the XANTUS (NCT01606995) and XALIA (NCT01619007) international prospective observational studies. The 1-year cost-effectiveness of rivaroxaban use, compared to VKAs, was explored in a population consisting of NVAF and VTE patients (base case) as well as for four scenarios with sub-populations: NVAF patients only, VTE patients only, NVAF patients with unstable international normalized ratio (INR), and NVAF patients using an INR self-measuring device.Results: In the base case, rivaroxaban saved €72,350 and gained 21 quality-adjusted life-years (QALYs) in a simulation of 2,000 patients over the use of VKAs. Ergo, rivaroxaban was dominant over VKAs. The probabilistic sensitivity analysis showed a probability of 85% for rivaroxaban being dominant and 100% at a willingness-to-pay threshold of €20,000/QALY. Rivaroxaban appeared to be dominant in all scenarios as well, except for the NVAF-patients-only scenario where the incremental cost-effectiveness ratio (ICER) was €157/QALY.Conclusions: In patients with NVAF or VTE, rivaroxaban treatment is likely to be cost-effective and a potentially cost-saving alternative to VKA in the Netherlands.

ULIS (Upper Limb International Spasticity), a 10-year Odyssey

Homer's Odyssey, one of the major Greek epic poems, tells the story of the hero Odysseus (or Ulysses in Roman versions) and his journey home to his wife Penelope. An epic poem is a long, narrative poem that is usually about heroic deeds and events that are significant to the culture of the poet. In keeping with this classic storytelling style, we describe the journey that the Upper Limb International Spasticity Study (ULIS) program has taken. The program was started in 2008 and has encountered a number of trials and obstacles along the way. This article sets out the history of development through its 10-year “Odyssey.” We use the benefit of hindsight to discuss how conducting large-scale, international observational studies can inform and influence routine practice in an area as diverse and complex as spasticity rehabilitation. We focus on the clinical pearls found within the now extensive ULIS dataset and how continually building upon the insights from each study can provide a real impetus for change.

Perinatal insults and neurodevelopmental disorders may impact Huntington's disease age of diagnosis

IntroductionThe age of diagnosis of Huntington's disease (HD) varies among individuals with the same HTT CAG-repeat expansion size. We investigated whether early-life events, like perinatal insults or neurodevelopmental disorders, influence the diagnosis age. MethodsWe used data from 13,856 participants from REGISTRY and Enroll-HD, two large international multicenter observational studies. Disease-free survival analyses of mutation carriers with an HTT CAG repeat expansion size above and including 36 were computed through Kaplan-Meier estimates of median time until an HD diagnosis. Comparisons between groups were computed using a Cox proportional hazard survival model adjusted for CAG-repeat expansion length. We also assessed whether the group effect depended on gender and the affected parent. ResultsInsults in the perinatal period were associated with an earlier median age of diagnosis of 45.00 years (95%CI: 42.07–47.92) compared to 51.00 years (95%CI: 50.68–51.31) in the reference group, with a CAG-adjusted hazard ratio of 1.61 (95%CI: 1.26–2.06). Neurodevelopmental disorders were also associated with an earlier median age of diagnosis than the reference group of 47.00 years (95% CI: 43.38–50.62) with a CAG-adjusted hazard ratio of 1.42 (95%CI: 1.16–1.75). These associations did not change significantly with gender or affected parent. ConclusionsThese results, derived from large observational datasets, show that perinatal insults and neurodevelopmental disorders are associated with earlier ages of diagnosis of magnitudes similar to the effects of known genetic modifiers of HD. Given their clear temporal separation, these early events may be causative of earlier HD onset, but further research is needed to prove causation.