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Human dose prediction (HDP) is a useful tool for compound optimization in preclinical drug discovery. We describe here our exclusively in silico HDP strategy to triage compound designs for synthesis and experimental profiling. Our goal is a model that provides a preliminary estimate of the dose for a given exposure target based on chemical structure. First, we construct machine learning models to estimate rat pharmacokinetics, which are subsequently allometrically scaled to estimate human pharmacokinetics. Second, we establish a 10 nM free concentration target for early HDP where potency data are not yet available. Finally, we assess the uncertainty associated with each model and propagate these into the final estimate, providing us with actionable guidance on the level of accuracy of these estimates. We find that this strategy can reduce preparation of compounds with poor properties relative to an unstructured approach, but extensive experimental testing remains required.

Respiratory syncytial virus (RSV) is a major cause of hospitalization in infants, the elderly, and immune-compromised patients. While a half-life extended monoclonal antibody and 2 vaccines have recently been approved for infants and the elderly, respectively, options to prevent disease in immune-compromised patients are still needed. Here, we describe spiro-azetidine oxindoles as small molecule RSV entry inhibitors displaying favorable potency, developability attributes, and long-acting PK when injected as an aqueous suspension, suggesting their potential to prevent complications following RSV infection over a period of 3 to 6 months with 1 or 2 long-acting intramuscular (IM) or subcutaneous (SC) injections in these immune-compromised patients.

Allograft tympanoplasty was once widely used across the world but is currently only performed by a limited number of surgeons in Belgium and Germany. Allograft tympanic membranes and ossicles are procured endoscopically nowadays and are processed in specific tissue banks subject to European Union regulations on human allograft tissue to ensure the receptor will receive quality-controlled tissue. The surgical procedure via retroauricular approach can teach us how we can manage difficult cases with total, subtotal and marginal perforations, but also cases of isolated pars tensa cholesteatoma. [ABSTRACT FROM AUTHOR]

Lime stabilisation of clay soils is a widely used technique for the improvement of existing soils in the construction of embankments and sub-bases for road pavements. The mixing of clayey soils with lime initiates chemical reactions allowing a significant increase of geotechnical properties. This study aims at investigating the ability to recover strength of a conventional lime-stabilised clay soil after being distressed by multiple Freeze–Thaw (F–T) cycles. This capability was investigated as a function of the percentage of lime additive, post-compaction curing time and the presence of a disturbing element in clay-lime interaction. The stabilisation of clay soils with lime provides capability of recovering compressive strength after distress from freeze–thaw cycles,regardless of the post-compaction curing time. The percentage of lime added assumes a very important role in the extent of this capability. The presence of disturbing elements negatively affects the success of pozzolanic reactions between clay and lime.

IMPORTANCE: The past years, evidence suggested that the primary symptoms traditionally associated with bilateral vestibulopathy (BV) do not represent the full picture of this patient population. Recent literature also demonstrated cognitive impairment. However, although multitasking and dual-tasking are widely present in everyday activities, most of these studies assessed cognitive function only in single-task conditions. OBJECTIVE: To uncover the association of BV with and without hearing loss with cognitive and motor performance and cognitive-motor interference. DESIGN, SETTING, AND PARTICIPANTS: This prospective case-control study assessed persons with an isolated BV and persons with BV and a concomitant hearing loss compared with a healthy control group. Data were analyzed in December 2022. The study was conducted at Ghent University (Ghent, Belgium). Data collection took place between March 26, 2021, and November 29, 2022. MAIN OUTCOMES AND MEASURES: All participants completed the 2BALANCE dual-task protocol, comprising a static and a dynamic motor task that was combined with 5 visual cognitive tasks. These cognitive tasks assessed mental rotation, visuospatial memory, working memory, response inhibition (executive function), and processing speed. All cognitive tasks were performed in a single-task condition (while seated) and in a dual-task condition (combined with a static and a dynamic motor task). The static task comprised balancing on a force platform with foam pad, and the dynamic task comprised walking at a self-selected speed on the GAITRite Walkway. Both motor tasks were performed in the single-task and dual-task condition. RESULTS: Nineteen persons with BV and hearing loss (mean [SD] age, 56.70 [10.12] years; 10 women [52.6%]), 22 persons with an isolated BV (mean [SD] age, 53.66 [13.35] years; 7 women [31.8%]), and 28 healthy control participants were included (mean [SD] age, 53.73 [12.77] years; 12 women [42.9%]). Both patient groups had mental rotation and working memory impairment in a single-task condition and slower processing speed when walking (ie, during the dynamic dual-task condition). Additionally, the patient group with hearing loss had impaired visuospatial memory and executive function deficits in single-task and dual-task conditions, while this could only be elicited when performing a motor task in persons with isolated BV (ie, when dual-tasking). CONCLUSION AND RELEVANCE: The findings of this case-control study suggest an association between vestibular function and cognitive and motor performance, even greater in persons with a concomitant hearing loss than in persons with an isolated BV.

It is common practice in the early drug discovery process to conduct in vitro screening experiments using liver microsomes in order to obtain an initial assessment of test compound metabolic stability. Compounds which bind to liver microsomes are unavailable for interaction with the drug metabolizing enzymes. As such, assessment of the unbound fraction of compound available for biotransformation is an important factor for interpretation of in vitro experimental results and to improve prediction of the in vivo metabolic clearance. Various in silico methods have been proposed for the prediction of test compound binding to microsomes, from various simple lipophilicity-based models with moderate performance to sophisticated machine learning models which demonstrate superior performance at the cost of increased complexity and higher data requirements. In this work, we attempt to strike a middle ground by developing easily implementable equations with improved predictive performance. We employ a symbolic regression approach based on a medium-size in-house data set of fraction unbound in human liver microsomes measurements allowing the identification of novel equations with improved performance. We validate the model performance on an in-house held-out test set and an external validation set.

IMPORTANCE: Given the rapidly rising dementia incidence, management of modifiable risk factors, such as hearing loss, is vital. Multiple studies have demonstrated an improvement of cognitive functioning in older adults with severe hearing loss after cochlear implantation; however, few of these studies, to the authors’ knowledge, specifically analyzed participants achieving poor cognitive results preoperatively. OBJECTIVE: To evaluate the cognitive functioning of older adults with severe hearing loss at risk for mild cognitive impairment (MCI) before and after cochlear implantation. DESIGN, SETTING, AND PARTICIPANTS: This prospective, longitudinal cohort study performed at a single center reports data obtained over a 6-year period (April 2015 to September 2021) of an ongoing prospective, longitudinal cohort study on cochlear implant outcomes in older adults. A consecutive sample of older adults with severe hearing loss eligible for cochlear implantation was included. All participants obtained a Repeatable Battery for the Assessment of Neuropsychological Status for hearing-impaired patients (RBANS-H) total score indicative of MCI preoperatively. Participants were assessed before cochlear implant activation and 12 months after cochlear implant activation. INTERVENTION: The intervention consisted of cochlear implantation. MAIN OUTCOME AND MEASURE: The primary outcome measure was cognition, measured by the RBANS-H. RESULTS: A total of 21 older adult cochlear implant candidates were included in the analysis (mean [SD] age, 72 [9] years; 13 [62%] men). Cochlear implantation was associated with an improvement of overall cognitive functioning 12 months after activation (median [IQR] percentile, 5 [2-8] vs 12 [7-19]; difference, 7 [95% CI, 2-12]). Eight participants (38%) surpassed the MCI cutoff (16th percentile) postoperatively, while the overall median cognitive score remained under this cutoff. In addition, participants’ speech recognition in noise improved, with a lower score indicating improvement (mean [SD] score, +17.16 [5.45] vs +5.67 [6.3]; difference, −11.49 [95% CI, −14.26 to −8.72]), after cochlear implant activation. Improvement of speech recognition in noise was positively associated with improvement in cognitive functioning (rs, −0.48 [95% CI, −0.69 to −0.19]). Years of education, sex, RBANS-H version, and symptoms of depression and anxiety were not related to the evolution in RBANS-H scores. CONCLUSIONS AND RELEVANCE: In this prospective, longitudinal cohort study, cognitive functioning and speech perception in noise showed a clinically meaningful improvement 12 months after cochlear implant activation in older adults with severe hearing loss at risk for MCI, suggesting that cochlear implantation is not contraindicated in cochlear implant candidates with cognitive decline and should be considered after multidisciplinary evaluation.

Graphical Abstract:

IMPORTANCE: Recent literature suggests there may be a significant effect of the vestibular system on cognition and visuospatial processing. Given the increasing prevalence of dementia and individuals at risk for it, exploring possible modifiable risk factors, including vestibular dysfunction, is vital. OBJECTIVES: To explore the association of bilateral vestibulopathy (BV) with cognitive function in older adults, taking hearing status into account, and to explore multiple vestibular characteristics and their potential associations with cognition in patients with BV. DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional study assessed older adults (age 55-84 years) with diagnosed BV from a single center using baseline measurements from the Gehoor, Evenwicht en Cognitie (GECKO) study, an ongoing prospective longitudinal cohort study. Each participant was individually matched with a healthy control based on age, sex, and hearing performance. Data were analyzed in January 2022. MAIN OUTCOMES AND MEASURES: The primary outcome measure was cognition, measured by the Repeatable Battery for the Assessment of Neuropsychological Status for Hearing-Impaired Individuals (RBANS-H). RESULTS: A total of 68 patients were assessed, including 34 patients with BV (mean [SD] age, 63.3 [6.0] years; 18 [53%] men) matched with 34 control individuals without BV. Overall, participants with BV had a clinically meaningful lower score on the RBANS-H total scale compared with those without BV (mean [SD] score, 98.62 [12.70] vs 105.91 [11.03]). This decline was most pronounced in the subdomains of immediate memory (mean [SD] score, 107.74 [10.66] vs 112.26 [10.66]), visuospatial cognition (mean [SD] score, 90.06 [13.34] vs 100.47 [13.91]), and attention (mean [SD] score, 94.79 [16.39] vs 102.06 [12.97]). There were no differences in language or delayed memory subdomains. Within the BV population, 1 vestibular parameter (the Performance-Oriented Mobility Assessment, in particular the balance subscale) was associated with lower cognitive scores (r32 = 0.51; 95% CI, 0.20 to 0.72; η2 = 0.26). Other vestibular parameters, including measurements of the peripheral vestibular end organ and questionnaires, showed no association. CONCLUSIONS AND RELEVANCE: These findings suggest there was an association between vestibular loss and cognitive impairment. Further research on the causal mechanisms underlying this association and the possible impact of vestibular rehabilitation on cognition is needed.

Cities in sub-Saharan Africa are characterised by rapid urban sprawl, which has implications for urban food accessibility. Urban sprawl results in inefficient structures of cities, and is often related to patterns of socioeconomic segregation. An important research gap in food accessibility studies is that these local socioeconomic imbalances are not considered in broad-scale studies. This research analyses how the dimensions of food access (physical, social and economic) relate to the food insecurity and dietary diversity of inhabitants of different socioeconomic groups in the rapidly growing Greater Kampala Metropolitan Area (Uganda). We use the Food Insecurity Experience Scale and Household Dietary Diversity Score to assess the overall state of food consumption. To measure physical accessibility, we geographically map the formal food system potential. A radar chart was used to visualise the vulnerability of different socioeconomic groups within the city food system. The results show that more established urban dwellers experience different access vulnerabilities than newly migrated residents, depending on their income. Lower income groups compensate their limited economic accessibility by participating in food sharing networks. Obtaining a better understanding of the dimensions of urban food accessibility can aid stakeholders in the urban food system in their policy making processes towards a more food secure and sustainable future.

A thermodynamic description of the ternary system Co–Nb–Ta is obtained by combining the descriptions of the lower-order systems according to the CALPHAD method. The thermodynamic data set for the binary Co–Nb system is taken from [1], where a new thermodynamic model for the μ-phase was introduced. The μ-phase appears in several transition metal systems, including Co–Ta. The model is applied to the Co–Ta system and extended to the ternary Co–Nb–Ta system. The thermodynamic descriptions of the systems Co–Ta, Nb–Ta and Co–Nb–Ta are reported in the present work.

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ABSTRACTObjectivesPulmonary lymphomatoid granulomatosis (PLG) is a rare angiocentric and angiodestructive EBV-associated lymphoproliferative disorder which almost always affects the lungs. PLG is more commonly diagnosed in patients with immunodeficiency and is associated with Epstein-Barr virus (EBV). ‘Drug induced PLG’ or ‘iatrogenic immunodeficiency-associated lymphoproliferative disorder’ is a special form of PLG described in patient with inflammatory bowel diseases treated with Azathioprine.MethodsWe report a case of drug-induced PLG in a 68-year-old patient with Crohn’s disease presenting with pain at the right hemithorax, fatigue and shortness of breath with a pulmonary mass.ResultsAlthough initial diagnostic findings were misleading, an open lung biopsy eventually led to the diagnosis of drug-induced PLG.ConclusionThe diagnosis of PLG is challenging because the disease is rare and the histological features can be very subtle. Correct diagnosis relies on histopathology and immunohistochemical staining and EBV RNA in situ hybridization with sampling of large and different amounts of pathologic tissue in the hands of expert pathologists. In drug-induced PLG specifically, withdrawal of the immunosuppressive agent can lead to disease regression.

ABSTRACTRural and urban areas are often conceptualized as two separate entities and studied accordingly. However, in reality, they are related in multiple ways. Here we explore this relation between rural and urban areas from a land use perspective. We argue that land should be characterized along a gradient from rural to urban. Further, we argue that land use along this gradient typically combines both rural and urban functions. Finally, we point at the complex patterns of migration and mobility between different types of settlements, which is a multidirectional process that further blurs the distinction between rural and urban areas. These propositions are supported by examples from recent research and suggest the need for a more inclusive approach towards the analysis of rural and urban land use systems, as well as plans and policies that target these systems.

ABSTRACTUrbanization leads to a continuous loss of agricultural land, both directly under the form of land take, and indirectly through the use of agricultural land for non-productive rural activities like recreation, horse keeping or hobby farming. These urbanization processes put pressure on farmers, making farming activities harder through reduced agricultural land, negative externalities and the competition for land. To estimate possible future changes, an agricultural agent-based model was combined with spatially explicit urbanization scenarios and with different agricultural subsidizing policies for the case study of Belgium. As a result of an aging farming population and low succession rates, simulations until 2035 showed a continuous decline of farmers in all scenarios; a trend that will continue for as long as not every farmer that quits his activities is replaced. The results also showed that these declines are expected to be higher in the rural-urban fringe.

Acute myeloid leukemia (AML) is driven by leukemia stem cells (LSCs) that resist conventional chemotherapy and are the major cause of relapse1,2. Hypomethylating agents (HMAs) are the standard of care in the treatment of older or unfit patients with AML, but responses are modest and not durable3–5. Here we demonstrate that LSCs upregulate the tumor necrosis factor family ligand CD70 in response to HMA treatment resulting in increased CD70/CD27 signaling. Blocking CD70/CD27 signaling and targeting CD70-expressing LSCs with cusatuzumab, a human αCD70 monoclonal antibody with enhanced antibody-dependent cellular cytotoxicity activity, eliminated LSCs in vitro and in xenotransplantation experiments. Based on these preclinical results, we performed a phase 1/2 trial in previously untreated older patients with AML with a single dose of cusatuzumab monotherapy followed by a combination therapy with the HMA azacitidine (NCT03030612). We report results from the phase 1 dose escalation part of the clinical trial. Hematological responses in the 12 patients enrolled included 8 complete remission, 2 complete remission with incomplete blood count recovery and 2 partial remission with 4 patients achieving minimal residual disease negativity by flow cytometry at <10−3. Median time to response was 3.3 months. Median progression-free survival was not reached yet at the time of the data cutoff. No dose-limiting toxicities were reported and the maximum tolerated dose of cusatuzumab was not reached. Importantly, cusatuzumab treatment substantially reduced LSCs and triggered gene signatures related to myeloid differentiation and apoptosis.

ABSTRACTArtificial intelligence (AI) is increasingly expected to disrupt the ordinary functioning of society. From how we fight wars or govern society, to how we work and play, and from how we create to how we teach and learn, there is almost no field of human activity which is believed to be entirely immune from the impact of this emerging technology. This poses a multifaceted problem when it comes to designing and understanding regulatory responses to AI. This article aims to: (i) defend the need for a novel conceptual model for understanding the systemic legal disruption caused by new technologies such as AI; (ii) to situate this model in relation to preceding debates about the interaction of regulation with new technologies (particularly the ‘cyberlaw’ and ‘robolaw’ debates); and (iii) to set out a detailed model for understanding the legal disruption precipitated by AI, examining both pathways stemming from new affordances that can give rise to a regulatory ‘disruptive moment’, as well as the Legal Development, Displacement or Destruction that can ensue. The article proposes that this model of legal disruption can be broadly generalisable to understanding the legal effects and challenges of other emerging technologies.

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