A randomized phase 2b trial examined the effects of the glucagon-like peptide-1 and glucagon receptor agonist cotadutide on kidney outcomes in patients with diabetic kidney disease.

Cotadutide is a glucagon-like peptide-1 (GLP-1) and glucagon receptor agonist that may improve kidney function in patients with type 2 diabetes (T2D) and chronic kidney disease (CKD). In this phase 2b study, patients with T2D and CKD (estimated glomerular filtration rate [eGFR] of 20 or more and under 90 mL/min per 1.73 m2 and urinary albumin-to-creatinine ratio [UACR] over 50 mg/g) were randomized 1:1:1:1:1 to 26 weeks' treatment with standard of care plus subcutaneous cotadutide uptitrated to 100, 300, or 600 µg, or placebo daily (double-blind), or the GLP-1 agonist semaglutide 1 mg once weekly (open-label).The co-primary endpoints were absolute and percentage change versus placebo in UACR from baseline to the end of week 14. Among 248 randomized patients, mean age 67.1 years, 19% were female, mean eGFR was 55.3 mL/min per 1.73 m2, geometric mean was UACR 205.5 mg/g (coefficient of variation 270.0), and 46.8% were receiving concomitant sodium-glucose co-transporter 2 inhibitors. Cotadutide dose-dependently reduced UACR from baseline to the end of week 14, reaching significance at 300 µg (-43.9% [95% confidence interval -54.7 to -30.6]) and 600 µg (-49.9% [-59.3 to -38.4]) versus placebo; with effects sustained at week 26. Serious adverse events were balanced across arms. Safety and tolerability of cotadutide 600 µg were comparable to semaglutide. Thus, our study shows that in patients with T2D and CKD, cotadutide significantly reduced UACR on top of standard of care with an acceptable tolerability profile, suggesting kidney protective benefits that need confirmation in a larger study.

Frailty indices predict mortality, complications and functional improvements in supratentorial meningioma patients over 80 years of age.

PURPOSE: To assess whether the Modified 5 (mFI-5) and 11 (mFI-11) Factor Frailty Indices associate with postoperative mortality, complications, and functional benefit in supratentorial meningioma patients aged over 80 years. METHODS: Baseline characteristics were collected from eight centers. Based on the patients' preoperative status and comorbidities, frailty was assessed by the mFI-5 and mFI-11. The collected scores were categorized as "robust (mFI=0)", "pre-frail (mFI=1)", "frail (mFI=2)", and "significantly frail (mFI≥3)". Outcome was assessed by the Karnofsky Performance Scale (KPS); functional benefit was defined as improved KPS score. Additionally, we evaluated the patients' functional independence (KPS≥70) after surgery. RESULTS: The study population consisted of 262 patients (median age 83 years) with a median preoperative KPS of 70 (range 20 to 100). The 90-day and 1-year mortality were 9.0% and 13.2%; we recorded surgery-associated complications in 111 (42.4%) patients. At last follow-up within the postoperative first year, 101 (38.5%) patients showed an improved KPS, and 183 (69.8%) either gained or maintained functional independence. "Severely frail" patients were at an increased risk of death at 90 days (OR 16.3 (CI95% 1.7-158.7)) and one year (OR 11.7 (CI95% 1.9-71.7)); nine (42.9%) of severely frail patients died within the first year after surgery. The "severely frail" cohort had increased odds of suffering from surgery-associated complications (OR 3.9 (CI 95%) 1.3-11.3)), but also had a high chance for postoperative functional improvements by KPS≥20 (OR 6.6 (CI95% 1.2-36.2)). CONCLUSION: The mFI-5 and mFI-11 associate with postoperative mortality, complications, and functional benefit. Even though "severely frail" patients had the highest risk morbidity and mortality, they had the highest chance for functional improvement.

Manifestation of site energy landscapes for ion transport in borate glasses.

The potential energy landscape of lithium borate glass of composition Li3B7O12 has been investigated by the charge attachment induced transport (CAIT) technique. Here, native lithium ions have been replaced by foreign alkali ions, M+ = K+, Rb+, Cs+. All experiments exhibit a pronounced decrease of native ion diffusion coefficients over more than 4 orders of magnitude with decreasing local population of Li+. The energy landscape is modelled by a site energy distribution (SED) with a concentration dependent Fermi energy of the native Li+ ions. The width of the populated part of the SED is found to be 250 meV (FWHM). The conclusion is made possible by a combination of a macroscopic ion replacement experiment with a Nernst-Planck-Poisson modelling of concentration depth profiles measured by secondary ion mass spectrometry (SIMS). Possible generalizations of macroscopic transport theory to match an Onsager ansatz are discussed.

Ion molecule reactions in the HBr+ + CH4 system: a combined experimental and theoretical study.

Reactions in the system HBr+ + CH4 have been investigated inside a guided ion-beam apparatus under single-collision conditions. The HBr+ is vibrational and rotational state selected in the electronic X2Π1/2 state created by (2+1)-REMPI. Due to the exitation scheme employed different rotational states of the HBr+ are accessible. Four reaction channels have been observed. The cross section, σ, for the exothermic proton transfer channel (PT) decreases with increasing collision energy, steeper than predicted by the Langevin model. The cross section also decreases with increasing rotational energy in the HBr+, with the effect of the rotational energy being stronger than that of translational energy. The cross section for the endothermic charge transfer (CT) increased with increasing collision energy. The energy dependence is well reproduced by a simple line of center (loc) model. Although the bromine transfer (BT) is exothermic the observed cross section increased with increasing collision energy due to an activation barrier on the potential energy surface (PES). Analysis by a modified loc model suggest the relevance of an angle dependence of σ. The cross section for the endothermic hydrogen atom abstraction (HA) exhibits a maximum at 2 eV Ecm. The measured cross sections are rationalized by means of reaction dynamics simulations which show good agreement with the experimental cross sections. The dynamics simulations are carried out with a machine learning potential that is developed and benchmarked with ab initio molecular dynamics simulation. The absolute cross sections predicted by reaction dynamics simulations are well within the same order of magnitude while reproducing the trends over three different collision energies for all four reaction channels. Furthermore, the simulations demonstrate various reaction mechanisms for these reaction channels, including a very interesting HBr+ orientation selectivity for the BT reaction channel.

Electric Field Gradient Calculations for Ice VIII and IX Using Polarizable Embedding: A Comparative Study on Classical Computers and Quantum Simulators.

We test the performance of the polarizable embedding variational quantum eigensolver self-consistent field (PE-VQE-SCF) model for computing electric field gradients with comparisons to conventional complete active space self-consistent-field (CASSCF) calculations and experimental results. We compute quadrupole coupling constants for ice VIII and ice IX. We find close agreement of the quantum-computing PE-VQE-SCF results with the results from the classical PE-CASSCF calculations and with experiment. Furthermore, we observe that the inclusion of the environment is crucial for obtaining results that match the experimental data. The calculations for ice VIII are within the experimental uncertainty for both CASSCF and VQE-SCF for oxygen and lie close to the experimental value for ice IX as well. With the VQE-SCF, which is based on an adaptive derivative-assembled problem-tailored (ADAPT) ansatz, we find that the inclusion of the environment and the size of the different basis sets do not directly affect the gate counts. However, by including an explicit environment, the wavefunction and therefore the optimization problem become more complicated, which usually results in the need to include more operators from the operator pool, thereby increasing the depth of the circuit.

Divergences in classical and quantum linear response and equation of motion formulations.

Calculating molecular properties using quantum devices can be performed through the quantum linear response (qLR) or, equivalently, the quantum equation of motion (qEOM) formulations. Different parameterizations of qLR and qEOM are available, namely naïve, projected, self-consistent, and state-transfer. In the naïve and projected parameterizations, the metric is not the identity, and we show that it depends on redundant orbital rotations. This dependency may lead to divergences in the excitation energies for certain choices of the redundant orbital rotation parameters in an idealized noiseless setting. Furthermore, this leads to a significant variance when calculations include statistical noise from finite quantum sampling.

Acute-to-chronic subdural hematoma: radiographic and clinical progression from acute subdural hematoma.

INTRODUCTION: The pathogenesis of chronic subdural hematoma (CSDH) has not been completely understood. However, different mechanisms can result in space-occupying subdural fluid collections, one pathway can be the transformation of an original trauma-induced acute subdural hematoma (ASDH) into a CSDH. MATERIALS AND METHODS: All patients with unilateral CSDH, requiring burr hole trephination between 2018 and 2023 were included. The population was distributed into an acute-to-chronic group (group A, n = 41) and into a conventional group (group B, n = 282). Clinical and radiographic parameters were analyzed. In analysis A, changes of parameters after trauma within group A are compared. In analysis B, parameters between the two groups before surgery were correlated. RESULTS: In group A, volume and midline shift increased significantly during the progression from acute-to-chronic (p < 0.001, resp.). Clinical performance (modified Rankin scale, Glasgow Coma Scale) dropped significantly (p = 0.035, p < 0.001, resp.). Median time between trauma with ASDH and surgery for CSDH was 12 days. Patients treated up to the 12th day presented with larger volume of ASDH (p = 0.012). Before burr hole trephination, patients in group A presented with disturbance of consciousness (DOC) more often (p = 0.002), however less commonly with a new motor deficit (p = 0.014). Despite similar midline shift between the groups (p = 0.8), the maximal hematoma width was greater in group B (p < 0.001). CONCLUSION: If ASDH transforms to CSDH, treatment may become mandatory early due to increase in volume and midline shift. Close monitoring of these patients is crucial since DOC and rapid deterioration is common in this type of SDH.

Complication rates after autologous cranioplasty following decompressive craniectomy.

OBJECTIVE: The reimplantation of autologous bone grafts after decompressive craniectomy (DC) is still up for debate. The objective of this study was to analyze the surgical revision rate for autologous cranioplasties in our center, aiming to identify predictors for procedure-related-complications. METHODS: A retrospective single-center study was conducted for adult patients who underwent autologous cranioplasty after DC. The primary endpoint was the complication rate in terms of surgical revision and removal of the bone graft: infection, new onset seizures, dislocation, haemorrhage, osteolysis, wound dehiscence and cerebrospinal fluid (CSF) fistula. Demographic data, medical records, surgical reports and imaging studies were analysed and risk factors for complications were evaluated. RESULTS: 169 consecutive patients were included. The median interval between DC and cranioplasty was 84 days. Mean age was 51 ± 12.4 years. 26 patients (15.3%) had revision surgery for following reasons. n = 9 implant dislocations (5.3%), n = 7 osteolysis (3.6%), n = 6 infections (3.6%), n = 5 had re-bleedings (3%), n = 5 wound dehiscences (3%), and n = 2 CSF fistulas (1.2%). 18 patients developed new seizures (10.7%). Bi- and multivariate analysis revealed three independent risk factors, simultaneous ventriculo-peritoneal (VP) shunting increased the risk for material dislocation (p < 0.001); large bone grafts (> 193.5 cm2) increased the risk for osteolysis (p = 0.001) and bifrontal cranioplasties were associated with higher risk for infections (p = 0.04). CONCLUSION: The complication rates in our study were comparable to previously reported data for autologous or artificial cranioplasties. As osteolysis was correlated to larger bone grafts, a synthetic alternative should be considered in selected cases.

Tumor-Specific Alterations in Motor Cortex Excitability and Tractography of the Corticospinal Tract-A Navigated Transcranial Magnetic Stimulation Study.

BACKGROUND: Non-invasive brain mapping using navigated transcranial magnetic stimulation (nTMS) is a valuable tool prior to resection of malignant brain tumors. With nTMS motor mapping, it is additionally possible to analyze the function of the motor system and to evaluate tumor-induced neuroplasticity. Distinct changes in motor cortex excitability induced by certain malignant brain tumors are a focal point of research. METHODS: A retrospective single-center study was conducted involving patients with malignant brain tumors. Clinical data, resting motor threshold (rMT), and nTMS-based tractography were evaluated. The interhemispheric rMT-ratio (rMTTumor/rMTControl) was calculated for each extremity and considered pathological if it was >110% or <90%. Distances between the corticospinal tract and the tumor (lesion-to-tract-distance - LTD) were measured. RESULTS: 49 patients were evaluated. 16 patients (32.7%) had a preoperative motor deficit. The cohort comprised 22 glioblastomas (44.9%), 5 gliomas of Classification of Tumors of the Central Nervous System (CNS WHO) grade 3 (10.2%), 6 gliomas of CNS WHO grade 2 (12.2%) and 16 cerebral metastases (32.7%). 26 (53.1%) had a pathological rMT-ratio for the upper extremity and 35 (71.4%) for the lower extremity. All patients with tumor-induced motor deficits had pathological interhemispheric rMT-ratios, and presence of tumor-induced motor deficits was associated with infiltration of the tumor to the nTMS-positive cortex (p = 0.04) and shorter LTDs (all p < 0.021). Pathological interhemispheric rMT-ratio for the upper extremity was associated with cerebral metastases, but not with gliomas (p = 0.002). CONCLUSIONS: Our study underlines the diagnostic potential of nTMS motor mapping to go beyond surgical risk stratification. Pathological alterations in motor cortex excitability can be measured with nTMS mapping. Pathological cortical excitability was more frequent in cerebral metastases than in gliomas.

Pitfalls of predicting age-related traits by polygenic risk scores.

Polygenic risk scores (PRS) are a method increasingly used to capture the combined effect of genome-wide significant variants and those which individually do not show genome-wide significant association but are likely to contribute to the risk of developing diseases. However, their practical use incurs complications and inconsistencies that so far limit their clinical applicability. The aims of the present review are to discuss the PRS for age-related diseases and to highlight pitfalls and limitations of PRS prediction accuracy due to ageing and mortality effects. We argue that the PRS is widely used but the individual's PRS values differ substantially depending on the number of genetic variants included, the discovery GWAS and the method employed to generate them. Moreover, for neurodegenerative disorders, although an individual's genetics do not change with age, the actual score depends on the age of the sample used in the discovery GWAS and is likely to reflect the individual's disease risk at this particular age. Improvement of PRS prediction accuracy for neurodegenerative disorders will come from two sides, both the precision of clinical diagnoses, and a careful attention to the age distribution in the underlying samples and validation of the prediction in longitudinal studies.

Ion-molecule reactions in the HBr+ + HCl (DCl) system: a combined experimental and theoretical study.

Reactions in the system HBr+ + HCl (DCl) were investigated inside a guided ion-beam apparatus under single-collision conditions. In the HBr+ + HCl system, the proton transfer (PTHCl) and charge transfer (CT) are observable. In the HBr+ + DCl system, proton transfer (PTDCl) and deuterium abstraction (DA) are accessible. The cross sections for all reaction channels were measured as a function of the collision energy Ecm and of the rotational energy Erot of the ion. The rotationally state-selective formation of the ionic species was realized by resonance-enhanced multiphoton ionization (REMPI). As expected, the PT-channels are exothermic, and the cross section decreases with increasing collision energy for both PTHCl and PTDCl. The cross section for DA also decreases with an increasing Ec.m.. In the case of a considerably endothermic CT-channel, the reaction efficiency increases with increasing collision energy but has an overall much smaller cross sections compared to PT and DA reactions. Both PT-reactions are hindered by ion rotation, whereas DA is independent of Erot. The CT-channel shows a rotational enhancement near the thermochemical threshold. The experiment is complemented by theory, using ab initio molecular dynamics (AIMD, also known as direct dynamics) simulations and taking the rotational enhancement of HBr+ into account. The simulations show good agreement with the experimental results. The cross section of PTHCl decreases with an increase of the rotational energy. Furthermore, the absolute cross sections are in the same order of magnitude. The CT channel shows no reactions in the simulation.

The contribution of Compton ionization to ultrafast x-ray scattering.

We investigate the role of Compton ionization in ultrafast non-resonant x-ray scattering using a molecular model system, which includes the ionization continuum via an orthonormalized plane wave ansatz. Elastic and inelastic components of the scattering signal, as well as coherent-mixed scattering that arises from electron dynamics, are calculated. By virtue of a near-quantitative distinction between scattering related to electronic transitions into bound and continuum states, we demonstrate how Compton ionization contributes to the coherent-mixed component. Analogous to inelastic scattering, the contribution to the coherent-mixed signal is significant and particularly manifests at intermediate and high-momentum transfers. Strikingly, for molecules with inversion symmetry, the exclusion of bound or continuum transitions may lead to the prediction of spurious coherent-mixed signals. We conclude that qualitative and quantitative accuracies of predicted scattering signals on detectors without energy resolution require that elements of the two-electron density operator are used. This approach inherently accounts for all accessible electronic transitions, including ionization.

Self-management interventions for children and young people with sickle cell disease: A systematic review.

BACKGROUND: Increasing numbers of interventions are being developed to support self-management for children and young people (CYP) with sickle cell disease (SCD), but no systematic review has systematically synthesized this evidence regarding their characteristics, effectiveness, acceptability and feasibility for all published intervention types. METHODS: The Joanna Briggs Institute guidelines for mixed-method reviews were followed. A systematic search of eight databases and key journals was conducted from their inception to November 2021. Primary research of self-management interventions targeting CYP with SCD aged 8-24 years and reporting any health/social outcome and acceptability data were included. Design-specific standardized critical appraisal instruments were used. Two independent reviewers screened and appraised the articles. A third reviewer resolved disagreements. RESULTS: Of 1654 articles identified, 38 studies were included. Methodological quality was moderate. Most studies evaluated SCD education, psycho-behavioural, psychosocial and skills training and/or social support interventions. They appear to demonstrate short-term improvements in knowledge, social functioning and medical adherence outcomes. Interventions that were multifaceted in content, combined technological platforms and in-person group-based formats and involved peers, family and care providers were more acceptable and effective. The long-term impact of interventions was limited, including CYP's involvement in the intervention development and implementation. CONCLUSIONS: There is inconclusive evidence for any self-management programme. Nonetheless, support from family, peers and care providers appears to be important for self-management interventions' effectiveness and acceptability. Future research needs to prioritize CYP involvement in both intervention design and delivery, their wider social context and include CYP with SCD from non-Black backgrounds. PATIENT AND PUBLIC CONTRIBUTION: Three young people with SCD recruited acted as the review advisors. They were formally trained in the review process and involved in every aspect of the review: the design, conduct and interpretation of the findings. CYP involvement in the interventions' development and implementation was analysed as part of the review. This systematic review was conducted as part of a wider research project titled: Understanding fatigue experiences of CYP with SCD to guide the co-development of a fatigue self-management intervention. Two of the young advisors involved in the review were also involved in the development of the project funding application.

The use of the sodium fluorescein and YELLOW 560 nm filter for the resection of pediatric posterior fossa lesions.

PURPOSE: This study aimed to verify the feasibility, safety, and benefit of using fluorescein sodium (FL) and a YELLOW 560 nm filter in posterior fossa tumors in children. METHODS: All cases of pediatric posterior fossa tumors that have undergone surgery using fluorescein (2018-2022) have been included and were examined retrospectively. In those cases where resection of the tumor was planned, a blinded neuroradiologist distinguished gross total resection and subtotal resection according to the postoperative MRI findings. The surgical report and medical files were reviewed regarding the intraoperative staining grade and adverse events. The grade of fluorescent staining of the targeted lesion was assessed as described in the surgical reports. The screening was conducted for any reference to the degree of fluorescent staining: "intense," "medium," "slight," and "no staining." RESULTS: 19 cases have been included. In 14 cases, a complete resection was initially intended. In 11 of these cases, a gross total resection could be achieved (78.6%). Staining was described as intense in most cases (58.8%). Except for yellow-colored urine, no side effects obviously related to FL were found throughout the observation period. CONCLUSION: In combination with a specific filter, FL is a reliable, safe, and feasible tool in posterior fossa surgery in children.

Brain metastasis resection: the impact of fluorescence guidance (MetResect study).

OBJECTIVE: Maximal resection of brain metastases (BMs) improves both progression-free survival and overall survival (OS). Fluorescein sodium (FL) in combination with the YELLOW 560-nm filter is a safe and feasible method for visualizing residual tumor tissue during BM resection. The authors of this study aimed to show that use of FL would positively influence the volumetric extent of resection (EOR) and thus the survival outcome in patients undergoing BM resection. METHODS: Analyzing their institution's prospective brain tumor registry, the authors identified 539 consecutive patients with BMs (247 women, mean age 62.8 years) by using preoperative high-quality MR images for volumetric analysis. BMs were resected under white light (WL) in 293 patients (54.4%; WL group) and under FL guidance in 246 patients (45.6%; FL group). Sex, age, presurgical Karnofsky Performance Status (KPS), recursive partitioning analysis class, and adjuvant treatment modalities were well balanced between the two groups. Volumetric analysis was performed in a blinded fashion by quantifying pre- and postoperative tumor volume based on gadolinium-enhanced T1-weighted sequences. RESULTS: In the FL group, the postoperative tumor volume was significantly smaller (p = 0.01), and hence the quantitative EOR was significantly larger (p = 0.024) and OS was significantly longer (p = 0.0001) (log-rank testing). Multivariate Cox regression modeling showed that age, presurgical KPS, metastasis status, and FL-guided resection are independent prognostic factors for survival. CONCLUSIONS: Compared with WL resection, FL-guided BM resection increased resection quality, significantly improved EOR, and prolonged OS.

Deep demersal fish communities respond rapidly to warming in a frontal region between Arctic and Atlantic waters.

The assessment of climate impact on marine communities dwelling deeper than the well-studied shelf seas has been hampered by the lack of long-term data. For a long time, the prevailing expectation has been that thermal stability in deep ocean layers will delay ecosystem responses to warming. Few observational studies have challenged this view and indicated that deep organisms can respond exceptionally fast to physical change at the sea surface. To address the depth-specific impact of climate change, we investigated spatio-temporal changes in fish community structure along a bathymetry gradient of 150-1500 m between 1998 and 2016 in East Greenland. Here, the Arctic East Greenland Current and the Atlantic Irminger Current meet and mix, representing a sub-Arctic transition zone. We found the strongest signals of community reorganizations at depths between 350 and 1000 m and only weak responses in the shallowest and deepest regions. Changes were in synchrony with atmospheric warming, loss in sea ice and variability in physical sea surface conditions both within our study region and North of the Denmark Strait. These results suggest that interannual variability and long-term climate trends of the larger ecoregion can rapidly affect fish communities down to 1000-m depth through atmospheric ocean coupling and food web interactions.

Reclassification of Clostridium aurantibutyricum Hellinger 1944 and Clostridium roseum (ex McCoy and McClung 1935) Cato et al. 1988.

Clostridium aurantibutyricum, Clostridium felsineum and Clostridium roseum share a very high similarity based on multi-locus sequence analysis. In this study, their correct taxonomic status was determined using genomic and phenotypic investigations. Average nucleotide identity based on MUMmer alignment of the genomes and in silico DNA-DNA hybridization resulted in values of 98.55-100 and 78.7-100 %, respectively, strongly indicating that all strains are members of the same species. In addition, morphological investigations, fatty acid analyses and substrate utilization tests revealed no striking differences between the strains. Therefore, we propose the reclassification of C. aurantibutyricum and C. roseum as later heterotypic synonyms of C. felsineum. The type strain is lodged in several culture collections (ATCC 17788T=DSM 794T=NCIMB 10690T).

Coincident measurement of photo-ion circular dichroism and photo-electron circular dichroism in 1-phenylethylamine.

Here, we report the coincident measurement of PICD and PECD effects in 1-phenylethylamine upon multiphoton ionization. Both photo-ion circular dichroism (PICD) and photo-electron circular dichroism (PECD) are methods to distinguish enantiomers. In PICD, a difference in total ion yields upon multiphoton ionization with circular polarized light is measured, whereas, in PECD, circular dichroism is observed in the angular distribution of the photoelectrons. Here, we report on our continuous effort to measure the PICD and PECD effects in coincidence, i.e. simultaneously under the same measurement conditions using a home-built photoion-photoelectron coincidence spectrometer. Pure samples of R-(+)-1-phenylethylamine and S-(-)-1-phenylethylamine have been photo-ionized using a femtosecond laser operated at 394 nm.

The Potential Energy Profile of the HBr+ + HCl Bimolecular Collision.

Recently, the HBr+ + HCl bimolecular reaction has been exploited by guided ion beam studies to probe the effect of rotational excitations and collision energies on the dynamics of the ion-molecule reactions. The current manuscript employs high-level ab initio calculations and reports the potential energy of pathways leading to various products, including HBr + HCl+, H2Cl+ + Br, H2Br+ + Cl, and H2 + BrCl+. The study shows that the intermediates involved in this reaction are connected by low-lying transition states, thus frequent isomerizations and diverse products are expected. Further, this manuscript screens the performance of 192 different combinations of computationally efficient methods and basis sets in order to identify the optimal quantum chemical method for further dynamics simulations.

Challenges of Adjusting Single-Nucleotide Polymorphism Effect Sizes for Linkage Disequilibrium.

BACKGROUND: Genome-wide association studies (GWAS) were successful in identifying SNPs showing association with disease, but their individual effect sizes are small and require large sample sizes to achieve statistical significance. Methods of post-GWAS analysis, including gene-based, gene-set and polygenic risk scores, combine the SNP effect sizes in an attempt to boost the power of the analyses. To avoid giving undue weight to SNPs in linkage disequilibrium (LD), the LD needs to be taken into account in these analyses. OBJECTIVES: We review methods that attempt to adjust the effect sizes (ß-coefficients) of summary statistics, instead of simple LD pruning. METHODS: We subject LD adjustment approaches to a mathematical analysis, recognising Tikhonov regularisation as a framework for comparison. RESULTS: Observing the similarity of the processes involved with the more straightforward Tikhonov-regularised ordinary least squares estimate for multivariate regression coefficients, we note that current methods based on a Bayesian model for the effect sizes effectively provide an implicit choice of the regularisation parameter, which is convenient, but at the price of reduced transparency and, especially in smaller LD blocks, a risk of incomplete LD correction. CONCLUSIONS: There is no simple answer to the question which method is best, but where interpretability of the LD adjustment is essential, as in research aiming at identifying the genomic aetiology of disorders, our study suggests that a more direct choice of mild regularisation in the correction of effect sizes may be preferable.