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Extremes in FX returns and fundamentals
No full textThe likelihood of extreme FX returns is way higher than predicted by the normal distribution. Theory holds that macroeconomic fundamental shocks drive the exchange rate. If so, are there any extreme linkages between the variables? This article directly links large movements in exchange rates to economic fundamentals by means of multivariate extreme value theory (EVT). We find evidence for such a linkage between large depreciations and increases in money supply, prices, and interest rates. The relationship in the tails between the FX returns and observed monetary variables is documented during currency crisis episodes in Asian and Latin American countries.</p
Structure and function of the Achilles tendon and plantarflexors after non-surgical management of Achilles tendon rupture:A cross-sectional study
No full textBackground:Achilles tendon rupture (ATR) impacts the structure and function of the tendon and triceps surae. We aimed to describe recovery at different time points after injury using ultrasound imaging, strength testing and patient reported outcomes. Methods:Cross-sectional study design, collecting data from 15 different non-surgically managed participants at six independent rehabilitation time points (week 0, 8, 10, 16, 26, 52 post ATR). Outcomes included ultrasound tissue characterisation (UTC), isometric plantarflexor strength, Achilles tendon rupture score (ATRS), Euroqol 5-dimension, hospital anxiety and depression scale and Tampa Scale for Kinesiophobia. UTC echo type percentage is reported as aligned fibrillar structure (AFS) and disorganised fibrillar structure (DFS). Findings:Participants mean (SD) age was 48 years (15.8), 91 % male, body mass index 29kg/m2 (4.3) and 54 % was white British. Primary mechanism of injury was sport (71 %). Ruptured tendon cross-sectional area (CSA) was 303.55 mm2 (90.43) at 10 weeks and 218.18 mm2 (61.82) at 52 weeks post ATR. For the ruptured tendon, later assessment time points were associated with decreased AFS but had no association with DFS. Isometric plantarflexor strength on the ruptured limb at 52 weeks was 61.3 kg (20.8) or 0.7x bodyweight (BW). Non-ruptured plantarflexor strength was 93.3 kg (29.5) or 1.1x BW. Leg symmetry index at 52 weeks was 67 %. ATRS at 52 weeks was 75.1 (16.5). Conclusion:Substantial tendon remodelling may occur during the initial 52 weeks post ATR, CSA was 28 % lower from 10 weeks to 52 weeks. At 52 weeks there was persistence of fibrillar disorganisation, isometric plantarflexor weakness and reduced function. Trial registration: ClinicalTrials.gov ID: NCT05676632 .</p
The dynamic cost-effectiveness of lung cancer screening
No full textIn the Netherlands, as well as in most of Europe and in the U.S., lung cancer leads all other cancers in the number of deaths. The disease is often only detected when the cancer has spread to other organs. Such metastatic disease is associated with a poor prognosis, making lung cancer particularly fatal. To advance the detection of the disease to the localized, treatable phase, clinical trials have studied the use of low-dose CT as a screening instrument among high-risk individuals. This thesis studies the potential population-level effectiveness of regular, targeted CT screening among those with a history of smoking. A microsimulation model is used that mimics the smoking behavior and lung cancer epidemiology of U.S. and Dutch populations. Using this model, predictions are made on the benefits and resource use of varying screening strategies, including different age ranges, eligibility criteria, and frequencies of screening. The thesis also studies the impact of novel therapies such as immunotherapy and targeted therapy on the balance between benefits and harms in a screening program. Whilst these therapies prolong life for those with metastatic disease, they are also known to be expensive. By implementing lung cancer screening, many of these treatment costs may be avoided. For Switzerland, the U.S., and the Netherlands, model results suggest that the balance between cost and benefit for lung cancer screening is favorable. For the Netherlands, the optimal strategy when considering the required CT capacity, and the cost per life year gained, would be to screen ages 55-75 every year. Selection into screening is more efficient when a multivariate risk calculator is used with a threshold of 1.5% risk of lung cancer, rather than the 20 pack-year threshold currently used in the U.S. With this screening protocol, over 1000 deaths from lung cancer could be avoided annually, The thesis also demonstrates that treatment costs per lung cancer patient increased 52% in a five-year period. Although novel treatments also prolong survival in metastatic disease, their financial burden means that a CT screening program becomes 14% more affordable in cost per life year gained, by preventing some of these late-stage treatment costs.<br/
Short-term outcomes of endoscopic submucosal dissection for suspected T1 colorectal cancers:a European experience
No full textBackground and Aims:The indication for primary surgery on suspected deep submucosal invasive colorectal carcinoma (d-SMIC) is debatable. Consequently, local excision techniques, such as endoscopic submucosal dissection (ESD), are increasingly attempted in such patients. This study retrospectively evaluated the effectiveness of ESD in obtaining a free vertical margin (VM)-R0 in suspected d-SMIC compared with suspected superficial SMIC (s-SMIC). Methods:ESDs for suspected T1 colorectal cancer (CRC) in treatment-naïve polyps were included between 2011 and 2022 in 5 European tertiary referral centers. Based on optical assessment, lesions were categorized into suspected d-SMIC or s-SMIC. Main outcomes were the VM-R0 rate, en bloc resection rate, and adverse event rate. An adjusted risk ratio for VM-R1 resections within the suspected d-SMIC group was calculated.Results:In the suspected s-SMIC group (n = 1063), en bloc resection rate, VM-R0 rate, proportion of pT1 CRC, and adverse even rate were 90.5% (95% CI, 88-92), 90.6% (95% CI, 88-92), 18.0%, and 3.6% (IQR, 2-5), respectively. In the suspected d-SMIC group (n = 139), these values were 61.9% (IQR, 54-70), 55.4% (IQR, 47-63), 74.8%, and 5.8% (IQR, 2-10), respectively. Compared with suspected s-SMIC cases, the VM-R0 rate of suspected d-SMIC cases particularly decreased for pT1Sm2-3 (75.9% vs 55.7%). None of the investigated features (age, sex, polyp location, size, morphology, and Hiroshima classification) predicted a VM-R1 resection in suspected d-SMIC cases.Conclusions:ESD performed on polyps with suspected d-SMIC showed lower VM-R0 rates for pT1Sm2-3 cases compared with suspected s-SMIC cases. This should be taken into account when selecting the optimal resection technique for suspected d-SMIC cases.</p
Urban environment in early-life and brain morphology in preadolescents
No full textRapid urbanization leads to increased exposure to air pollution, limited greenness, and denser built environments. However, evidence on how these urban factors influence brain development remains limited. We investigated associations between urban characteristics during pregnancy and childhood and brain morphology in preadolescence. The study included 2895 children from the Dutch Generation R Study, with replication in 92 children from the French PELAGIE cohort. Twelve built environment and four urban natural space indicators were estimated at residential addresses during pregnancy and childhood. Brain outcomes included cortical gray matter, cerebral white matter, cerebellum, corpus callosum, subcortical structures volumes, cortical thickness, and surface area assessed at 9–12 years. We applied multi-exposure regression models with data-driven variable selection and assessed mediation by air pollution and road-traffic noise, adjusting for confounders. In Generation R, higher NDVI during pregnancy was associated with smaller cortical gray matter volume (-5132 mm3; 95 % CI: -8611, -1652), and higher facility richness with larger nucleus accumbens volume. During childhood, higher distance to blue space was associated with larger cortical gray matter volume, and higher transport land use with smaller hippocampus. No mediation by air pollution or road-traffic noise was observed. In PELAGIE, associations were consistent but not statistically significant. Cortical thickness was associated with several built environment indicators during childhood, and surrounding greenness was linked to smaller surface area in specific cortical regions. Our findings suggest that early-life exposure to urban environments may influence brain morphology, with distinct contributions from green space, blue space, and built environment factors.</p
A robust method for primary cerebellar culture and genetic manipulation of Purkinje cells from postnatal mice
No full textBackground:Primary cerebellar cultures are a powerful system for studying genes and pathways involved in development and disease. However, maintaining the survival of Purkinje cells in vitro remains challenging. These neurons represent a small fraction of the cerebellar population and are highly sensitive to culture conditions, making genetic manipulation difficult. Existing protocols often use more than one culture medium, vary in the developmental stage of the cerebellar tissue used, and may require supplementary support cell cultures. New method:We describe a robust method for dissociated cerebellar cultures that supports Purkinje cell development and enables efficient genetic manipulation using two techniques. Results:Our protocol supports the development of Purkinje cells from embryonic day 18 and postnatal day 1 mouse cerebellar tissue, with P1-derived neurons more closely resembling their in vivo counterparts. Genetic manipulation was achieved via cell-specific adeno-associated viral transduction and non-cell-specific antisense oligonucleotide transfection. Functional neuronal activity was confirmed using calcium imaging with Fluo-4 AM.Comparison with existing methods:Our approach unifies key aspects of existing protocols. It uses a single-medium composition, eliminating the need for separate seeding and maintenance media. Culturing each cerebellum individually preserves the intrinsic number of supporting cells, eliminating the need for parallel cultures. Using postnatal tissue also reduces animal usage. Additionally, gene expression can be successfully modulated using antisense oligonucleotides. Conclusions:This protocol provides an efficient framework for the culture, development, and genetic manipulation of Purkinje cells, facilitating their application in molecular, cellular, and functional studies of cerebellar development and disease models.</p
Translating physicians’ intuition into quantifiable data:clinical hospital-based surveillance to complement existing methods to address gaps in current surveillance systems
No full textInformal clinical exchanges among pediatricians frequently provide the first indications of emerging (para-)infectious diseases. However, these observations often remain anecdotal and unstructured, leaving gaps in traditional surveillance systems. In this Perspective, we advocate for the integration of active, hospital-based clinical surveillance to bolster early detection and response. Drawing on recent pediatric examples, including multisystem inflammatory syndrome in children, acute hepatitis of unknown origin, invasive group A streptococcal disease, and Mycoplasma pneumoniae , we show how frontline clinical awareness often preceded formal recognition and informed early management. We outline a model for structured data collection within pediatric hospital networks, combining routine Internation Classification of Diseases-coded reporting with eventual natural language processing to extract key clinical features from health records. This system aims to transform clinical intuition into real-time, actionable data, enabling timely intervention and more accurate public health responses. By linking informal clinical insight with formal surveillance, we can enhance preparedness, enable earlier intervention, and ultimately improve outcomes in pediatric infectious diseases.</p
An Intravenous Brain-Penetrant Enzyme Therapy for Mucopolysaccharidosis II
No full textBACKGROUND:Tividenofusp alfa, comprising iduronate-2-sulfatase fused to an engineered transferrin receptor–binding Fc domain, has been developed to treat neurologic and peripheral manifestations of mucopolysaccharidosis type II (MPS II), a rare lysosomal disorder causing progressive multisystem and neurologic decline. METHODS:We conducted a phase 1–2, open-label study in which male participants up to 18 years of age with MPS II received weekly intravenous tividenofusp alfa for 24 weeks, followed by an 80-week safety extension and a 157-week open-label extension. The primary objective was to evaluate the safety of tividenofusp alfa. Secondary objectives were to evaluate central nervous system and peripheral effects as assessed by cerebrospinal fluid (CSF) and urinary heparan sulfate levels, adaptive behavior (as assessed with the Vineland Adaptive Behavior Scales), and liver volume. RESULTS:A total of 47 male participants were enrolled. At the 24-week primary analysis, all 47 participants reported at least one adverse event that emerged during the treatment period, most commonly infusion-related reactions. Pyrexia, urticaria, and vomiting were the most frequently reported symptoms of infusion-related reactions, occurring in more than 40% of the participants, despite routine premedication. Three participants had serious treatment-related adverse events; all continued to receive treatment. CSF and urinary heparan sulfate levels appeared to be reduced from baseline by 91% and 88%, respectively. Across all study periods, adverse events remained common. Reductions in heparan sulfate levels appeared to be maintained through week 153, adaptive behavior stabilized or improved, and liver volumes normalized or remained normal. CONCLUSIONS:In participants with MPS II, tividenofusp alfa treatment was commonly associated with adverse events. Heparan sulfate, the primary substrate that accumulates in the CSF and urine in persons with MPS II, appeared to decrease to levels within the range of unaffected children. A randomized trial is ongoing to further evaluate these effects.<p/
Interpretable Neural Networks in Genomics:Opening the Black Box
No full textThe overarching goal of functional genomics research is to understand and intervene in the biological processes that connect genotype, environment, and phenotype. Using data acquired from sequencing individuals, we can model these underlying mechanisms and aim to predict outcomes of interest, such as heritable traits or disease risk. This thesis explores the use of interpretable neural networks to predict complex traits and diseases from genomic data
Early and late outcomes of patient-specific endografts with retrograde outer branches for complex aortic aneurysms involving cranially oriented target vessels
No full textObjective: To evaluate the early and late outcomes of patient-specific endografts with retrograde outer branches for the treatment of complex aortic aneurysms involving cranially oriented target vessels (TVs). Methods: This multicenter retrospective study incorporated both prospectively and retrospectively collected data from consecutive patients who underwent fenestrated-branched endovascular aortic repair using patient-specific endografts with retrograde branches for complex aortic aneurysms with cranially oriented TVs from August 1, 2015, to October 31, 2024. Cranial orientation was defined as an aorta-to-vessel origin angle greater than 30°. The primary outcome was retrograde branch-related target artery instability (TAI). Secondary outcomes included retrograde branch-related mortality, major adverse events, and reinterventions. Outcomes were categorized as early (within 30 days postoperatively or during hospitalization) or late events (occurring beyond 30 days after the index procedure and after hospital discharge). Results:Twelve patients (9 male patients; median age: 77 years; interquartile range: 70.5-80 years) were analyzed. A total of 49 vessels were targeted, and 14 (28.6%) were incorporated with retrograde branches. There were no retrograde branch-related intraoperative complications. The technical success rate was 100%. The rate of early retrograde branch-related TAI was 7.1% (1/14). There were no early major adverse events. Among the 49 TVs treated, the rate of early reintervention was 4.1% (2/49), with one case being retrograde branch-related. The median follow-up was 31 months (interquartile range: 13.5-54 months). Two-year cumulative incidence of both retrograde branch-related TAI and mortality was 0.0%; however, one right renal artery incorporated with a retrograde branch occluded at postoperative 4 years. There was one late death at 2.8 years, which was not retrograde branch-related. Conclusions: The use of patient-specific endografts with retrograde branches is a feasible technique. It enabled the incorporation of TV with cranial orientation during the fenestrated-branched endovascular aortic repair procedure and demonstrated high technical success with low incidence of retrograde branch-related adverse events.</p