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To explore sociodemographic predictors for concern regarding COVID-19 transmission and how these factors interact with the identities of others, we conducted a web-based survey where we asked 568 respondents in the United States to indicate their level of COVID-19 concern in response to a series of images with short vignettes of masked and unmasked individuals of different racial/ethnic backgrounds. Using a linear mixed effects model, we found that regardless of the race of the image being presented in the vignette, concern regarding COVID-19 transmission was associated with respondents' older age (b = 0.029, p 0.001), residing in NYC (b = 0.556, p = 0.009), being heterosexual (b = 1.075, p 0.001), having higher levels of education, that is, completion of a Bachelor's degree (b = 1.10, p = 0.033) or graduate degree (b = 1.78, p 0.001), and the person in the vignette being unmasked (b = 0.822, p 0.001). Asian respondents were more likely than White respondents to be concerned regarding COVID-19. Individuals who self-reported themselves to be at high risk for COVID-19 were more likely to be concerned about COVID-19 over those who considered themselves to be low risk. These findings highlight the importance of acknowledging interactions between race, mask status, and residency in predicting COVID-19 concern.

BACKGROUND: Type 2 diabetes (T2DM) is an established risk factor for developing Parkinson's disease (PD), but its effect on disease progression is not well understood. OBJECTIVE: The aim of this study was to investigate the influence of T2DM on aspects of disease progression in PD. METHODS: We analyzed data from the Tracking Parkinson's study to examine the effects of comorbid T2DM on PD progression and quality of life by comparing symptom severity scores assessing a range of motor and nonmotor symptoms. RESULTS: We identified 167 (8.7%) patients with PD and T2DM (PD + T2DM) and 1763 (91.3%) patients with PD without T2DM (PD). After controlling for confounders, patients with T2DM had more severe motor symptoms, as assessed by Movement Disorder Society Unified Parkinson's Disease Rating Scale, Part III (25.8 [0.9] vs. 22.5 [0.3] P = 0.002), and nonmotor symptoms, as assessed by Non-Motor Symptoms Scale total (38.4 [2.5] vs. 31.8 [0.7] P < 0.001), and were significantly more likely to report loss of independence (odds ratio, 2.08; 95% confidence interval [CI]: 1.34-3.25; P = 0.001) and depression (odds ratio, 1.62; CI: 1.10-2.39; P = 0.015). Furthermore, over time, patients with T2DM had significantly faster motor symptom progression (P = 0.012), developed worse mood symptoms (P = 0.041), and were more likely to develop substantial gait impairment (hazard ratio, 1.55; CI: 1.07-2.23; P = 0.020) and mild cognitive impairment (hazard ratio, 1.7; CI: 1.24-2.51; P = 0.002) compared with the PD group. CONCLUSIONS: In the largest study to date, T2DM is associated with faster disease progression in Parkinson's, highlighting an interaction between these two diseases. Because it is a potentially modifiable metabolic state, with multiple peripheral and central targets for intervention, it may represent a target for alleviating parkinsonian symptoms and slowing progression to disability and dementia. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Smart city technologies can have detrimental effects on human rights, making it crucial to mitigate them in the R&D phase. This qualitative socio-legal study of the Helsinki metropolitan area (HMA) explores how public funding for smart city research and development (R&D), and the data protection by design principle (DPbD) of the General Data Protection Regulation (GDPR), facilitate the development of human rights compliant technology. Our study shows that the tension between the neoliberal logic of smart cities and that human rights compliance extends from the local to the global level. High compliance and localisation costs, one-sided inputs and a push for scalability in smart city technology development in Finland and other EU states may attract companies to overlook human rights risks and pursue markets outside the EU with lower standards of respect for human rights and the rule of law. We propose policy measures to facilitate human rights compliant smart city R&D, localisation and procurement, and discuss human rights due diligence and export control measures as means to mitigate the potential adverse effects of smart city technology exported from the EU. The study contributes to research on human rights-based approaches to smart city technology development and European innovation and export policy, with attention given to the role of public R&D funding agencies.

Aggregation of alpha-synuclein (α-Syn) drives Parkinson’s disease (PD), although the initial stages of self-assembly and structural conversion have not been directly observed inside neurons. In this study, we tracked the intracellular conformational states of α-Syn using a single-molecule Förster resonance energy transfer (smFRET) biosensor, and we show here that α-Syn converts from a monomeric state into two distinct oligomeric states in neurons in a concentration-dependent and sequence-specific manner. Three-dimensional FRET-correlative light and electron microscopy (FRET-CLEM) revealed that intracellular seeding events occur preferentially on membrane surfaces, especially at mitochondrial membranes. The mitochondrial lipid cardiolipin triggers rapid oligomerization of A53T α-Syn, and cardiolipin is sequestered within aggregating lipid–protein complexes. Mitochondrial aggregates impair complex I activity and increase mitochondrial reactive oxygen species (ROS) generation, which accelerates the oligomerization of A53T α-Syn and causes permeabilization of mitochondrial membranes and cell death. These processes were also observed in induced pluripotent stem cell (iPSC)–derived neurons harboring A53T mutations from patients with PD. Our study highlights a mechanism of de novo α-Syn oligomerization at mitochondrial membranes and subsequent neuronal toxicity.

Introduction:. Higher breast cancer risks among California teachers1 and school employees2 have been documented in mortality studies and a large cohort study, the California Teacher’s Study (CTS).3 Reasons for the risk are only partially explained by known risk factors, and predictive models such as the Rosner-Colditz and Gail model explain only a part of the risk in the CTS.4 Here we analyze data from the State of Virginia Tumor Registry on 394,837 female cancer cases diagnosed from 1995-2018 to explore breast cancer risk in teachers and to generate hypotheses on the etiology of this risk. Methods:. Data on 394,837 female cancer patients from the State of Virginia Cancer Registry were evaluated. Cancer diagnoses were available in all, but occupational data was incomplete; 219,807 were listed as unknown, 18,123 unemployed, 32,714 retired. Among employed cases, 16,001 were homemakers, 14,306 employed in teaching or related school occupations, and 93,921 were employed in non-teaching occupations. The data allowed subdividing of teachers into K-Elementary, Middle-High School, and teachers NOS. School system employees were also evaluated. Registered Nurses (RNs) were used as a comparison group, given similar education levels with teachers. Comparisons were made using Pearson’s Χ2 with Yates correction. Results:. Among all cancer diagnoses, breast cancers were diagnosed in 28.06% of the unemployed, 29.50% of retirees, 30.96% of homemakers, 39.23% of employed non-teachers, and 44.30% of teachers (for teachers vs. employed non-teachers Χ2=52.45, p Citation Format: Jonathan Gagnon, Meredith H. Wernick. Breast cancers are overrepresented in school teachers, particularly of young students [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-12-07.

Across the globe, the emergence of COVID-19 led to widespread, sudden suspension of in-person instruction, displacing more than 1.5 billion learners (Capilla et al., 2020). Addressing the gap in research on emergency remote teaching (ERT), this empirical study draws on insights from semi-structured interviews with 10 in-service and five pre-service teachers, who navigated the transition both as K–12 teachers and graduate students, participating in weekly mentoring for English language learners, online curricular modules, face-to-face discussions (until the transition to ERT), mixed-reality simulation teaching with coaching, and written reflections. Using a sensemaking theoretical framework, our study examines the following questions: (1) What were the main challenges and opportunities of ERT as experienced by this cohort of language teachers? (2) How did the dual role of being a K–12 teacher and graduate student provide a unique lens for navigating these challenges and opportunities? (3) What tools or supports helped these language teachers through the transition to ERT? Thematic analysis revealed three themes (emotion, shared meaning, and technology) and illuminated connection as an overarching theme. Findings suggest that the experience of navigating the transition from both positions led to greater empathy, increased facility using technology, and a growing support network of fellow teacher-learners.

In the transition to sustainability, innovation will play a crucial role. As the latter follows intricate paths and processes, IPRs might impede further innovation and slow down the transition to sustainability by blocking innovative technologies – or making it harder to access them. Yet, when adequately used, IPRs may foster knowledge exchange and shared learning. Open innovation - particularly open licensing – can support follow-on innovation by allowing for the circulation and combination of inputs from different actors and help solving the wicked problem of sustainability. Aside from the mere practice of sharing one's IPRs to foster further innovations in an open innovation setting, the sustainable financing of follow-on innovation will be essential in the coming decades. Indeed, in a crisis-laden world and considering the - presumably - future economic downturns, the question of the financing of follow-on innovation will be critical. There is certainly a need to identify how and under which conditions intellectual property, follow-on innovation and financing models can work together towards a more sustainable world. As the R&D funding in the post-pandemic world might become scarce, uneven, and unpredictable, this article reviews whether some alternative means of funding innovation –particularly emerging blockchain-based solutions – could succeed at supporting follow-on innovation for the greater goal of sustainability.

While the GDPR and other EU laws seek to mitigate a range of potential harms associated with smart cities, the compliance with and enforceability of these regulations remain an issue. In addition, these proposed regulations do not sufficiently address the collective harms associated with the deployment of biometric technologies and artificial intelligence. Another relevant question is whether the initiatives put forward to secure fundamental human rights in the digital realm account for the issues brought on by the deployment of technologies in city spaces. In this special issue, we employ the smart city notion as a point of connection for interdisciplinary research on the human rights implications of the algorithmic, biometric and smart city technologies and the policy responses to them. The articles included in the special issue analyse the latest European regulations as well as soft law, and the policy frameworks that are currently at work in the regions where the GDPR does not apply.

As more young people feel safe to outwardly identify as transgender or gender expansive (TGE), meaning that their gender identity does not align with the sex they were assigned at birth, an increasing number of youth who identify as TGE seek gender-affirming medical care (GAMC). GAMC raises a number of ethical questions, such as the capacity of a minor to assent or consent, the role of parents or legal guardians in decisions about treatment, and implications for equitable access to care when differing parental or custodial viewpoints are present. These questions are further complicated by the difficulties in explaining the limits of long-term research in GAMC, with regard to the preservation of fertility, for example. We present two de-identified composite case studies to highlight dilemmas that may arise and offer recommendations to better support patient- and family-centered decision making for GAMC. These include employing a multidisciplinary shared decision-making approach, disentangling informed consent and assent from chronological age, developing a consistent approach to the assessment of decisional capacity, and developing age-appropriate informational materials.

Youth of Color in the United States are often leaders in movements for social justice. Evidence suggests that organizing has a positive macro-therapeutic effect on the mental health of young organizers; however, they can also experience strain and become targets of the very systems they are trying to change. In a community-based participatory action research study, three organizations that train youth of Color in organizing in Brooklyn, New York City held focus groups with youth and adult staff. The focus groups examined the strains experienced by youth organizers and the strategies adult partners use to prepare organizers to maintain hope and well-being. Findings suggest four key emergent strategies: (a) provide an emotional homespace to process the rub between worlds, (b) actively shape the long view on systems change, (c) increase self-care skills and emotional preparation for organizing, and (d) promote healing by building leader(full) communities.

Mutations in the SNCA gene cause autosomal dominant Parkinson’s disease (PD), with loss of dopaminergic neurons in the substantia nigra, and aggregation of α-synuclein. The sequence of molecular events that proceed from an SNCA mutation during development, to end-stage pathology is unknown. Utilising human-induced pluripotent stem cells (hiPSCs), we resolved the temporal sequence of SNCA-induced pathophysiological events in order to discover early, and likely causative, events. Our small molecule-based protocol generates highly enriched midbrain dopaminergic (mDA) neurons: molecular identity was confirmed using single-cell RNA sequencing and proteomics, and functional identity was established through dopamine synthesis, and measures of electrophysiological activity. At the earliest stage of differentiation, prior to maturation to mDA neurons, we demonstrate the formation of small β-sheet-rich oligomeric aggregates, in SNCA-mutant cultures. Aggregation persists and progresses, ultimately resulting in the accumulation of phosphorylated α-synuclein aggregates. Impaired intracellular calcium signalling, increased basal calcium, and impairments in mitochondrial calcium handling occurred early at day 34–41 post differentiation. Once midbrain identity fully developed, at day 48–62 post differentiation, SNCA-mutant neurons exhibited mitochondrial dysfunction, oxidative stress, lysosomal swelling and increased autophagy. Ultimately these multiple cellular stresses lead to abnormal excitability, altered neuronal activity, and cell death. Our differentiation paradigm generates an efficient model for studying disease mechanisms in PD and highlights that protein misfolding to generate intraneuronal oligomers is one of the earliest critical events driving disease in human neurons, rather than a late-stage hallmark of the disease.

Mutations in theSNCAgene cause autosomal dominant Parkinson’s disease (PD), with progressive loss of dopaminergic neurons in the substantia nigra, and accumulation of aggregates of α-synuclein. However, the sequence of molecular events that proceed from theSNCAmutation during development, to its end stage pathology is unknown. Utilising human induced pluripotent stem cells (hiPSCs) withSNCAmutations, we resolved the temporal sequence of pathophysiological events that occur during neuronal differentiation in order to discover the early, and likely causative, events in synucleinopathies. We adapted a small molecule-based protocol that generates highly enriched midbrain dopaminergic (mDA) neurons (>80%). We characterised their molecular identity using single-cell RNA sequencing and their functional identity through the synthesis and secretion of dopamine, the ability to generate action potentials, and form functional synapses and networks. RNA velocity analyses confirmed the developmental transcriptomic trajectory of midbrain neural precursors into mDA neurons using our approach, and identified key driver genes in mDA neuronal development. To characterise the synucleinopathy, we adopted super-resolution methods to determine the number, size and structure of aggregates inSNCA-mutant mDA neurons. At one week of differentiation, prior to maturation to mDA neurons of molecular and functional identity, we demonstrate the formation of small aggregates; specifically, β-sheet rich oligomeric aggregates, inSNCA-mutant midbrain immature neurons. The aggregation progresses over time to accumulate phosphorylated aggregates, and later fibrillar aggregates. When the midbrain neurons were functional, we observed evidence of impaired physiological calcium signalling, with raised basal calcium, and impairments in cytosolic and mitochondrial calcium efflux. Once midbrain identity fully developed,SNCA-mutant neurons exhibited bioenergetic impairments, mitochondrial dysfunction and oxidative stress. During the maturation of mDA neurons, upregulation of mitophagy and autophagy occured, and ultimately these multiple cellular stresses lead to an increase in cell death by six weeks post-differentiation. Our differentiation paradigm generates an efficient model for studying disease mechanisms in PD, and highlights that protein misfolding to generate intraneuronal oligomers is one of the earliest critical events driving disease in human neurons, rather than a late-stage hallmark of the disease.

The human genome contains numerous duplicated regions, such as parent-pseudogene pairs, causing sequencing reads to align equally well to either gene. The extent to which this ambiguity complicates transcriptomic analyses is currently unknown. This is concerning as many parent genes have been linked to disease, includingGBA1,causally linked to both Parkinson’s and Gaucher disease. We find that most of the short sequencing reads that map toGBA1, also map to its pseudogene,GBAP1. Using long-read RNA-sequencing in human brain, where all reads mapped uniquely, we demonstrate significant differences in expression compared to short-read data. We identify novel transcripts from bothGBA1andGBAP1, including protein-coding transcripts that are translatedin vitroand detected in proteomic data, but that lack GCase activity. By combining long-read with single-nuclear RNA-sequencing to analyse brain-relevant cell types we demonstrate that transcript expression varies by brain region with cell-type-selectivity. Taken together, these results suggest a non-lysosomal function for both GBA1 and GBAP1 in brain. Finally, we demonstrate that inaccuracies in annotation are widespread among parent genes, with implications for many human diseases.

Background Current femoral bone loss classification systems in revision total hip arthroplasty were created at a time when the predominant reconstructive methods used cylindrical porous-coated cobalt-chrome stems. As these stems have largely been replaced by fluted-tapered titanium stems, the ability of these classification systems to help guide implant selection is limited. The purpose of this study was to describe a novel classification system based on contemporary reconstructive techniques. Methods We reviewed the charts of all patients who underwent femoral component revision at our institution from 2007 through 2019. Preoperative images were reviewed, and FBL was rated according to the Paprosky classification and compared to ratings using our institution’s NCS. Rates of reoperation at the time of most recent follow-up were determined and compared. Results Four-hundred and forty-two femoral revisions in 330 patients with a mean follow-up duration of 2.7 years were identified. Femoral type according to Paprosky and NCS were Paprosky I (36, 8.1%), II (61, 13.8%), IIIA (180, 40.7%), IIIB (116, 26.2%), and IV (49 11.1%) and NCS 1 (35, 7.9%), 2 (364, 82.4%), 3 (8, 1.8%), 4 (27, 6.1%), and 5 (8, 1.8%). Of the 353 nonstaged rTHAs, there were 42 cases requiring unplanned reoperation (11.9%), including infection (18, 5.1%), instability (10, 2.8%), femoral loosening (5, 1.4%), and various other causes (9, 2.5%). The NCS was more predictive of reoperation than the Paprosky classification (Fisher’s exact test, P = .008 vs P = ns, respectively). Conclusion We present a novel femoral classification system that can help guide contemporary implant selection.

Objective Hyperglycaemia in type 2 diabetes is caused by varying degrees of two defects: low insulin sensitivity and beta-cell dysfunction. We assessed if subgrouping of patients into three pathophysiological phenotypes according to these defects could identify individuals with high or low risk of future cardiovascular events. Design This is a prospective cohort study. Methods We assessed estimates of insulin sensitivity and beta-cell function from the homeostasis model assessment-2 in 4209 individuals with recently diagnosed type 2 diabetes enrolled from general practitioners and outpatient clinics in Denmark. Individuals were followed for a composite cardiovascular endpoint (either atherosclerotic outcomes (myocardial infarction, unstable angina pectoris, stroke, coronary or peripheral revascularization), heart failure, or cardiovascular death) and all-cause mortality. Results Totally 417 individuals with the insulinopenic phenotype (high insulin sensitivity and low beta-cell function) had substantially lower risk of cardiovascular events (5-year cumulative incidence: 4.6% vs 10.1%; age-/sex-adjusted hazard ratio (aHR): 0.49; 95% CI: 0.30–0.82) compared with 2685 individuals with the classical phenotype (low insulin sensitivity and low beta-cell function), driven by atherosclerotic events. Conversely, 1107 individuals with the hyperinsulinaemic phenotype (low insulin sensitivity and high beta-cell function) had more cardiovascular events (5-year cumulative incidence: 12.6%; aHR: 1.33; 95% CI: 1.05–1.69), primarily driven by increased heart failure and cardiovascular death and increased all-cause mortality. Conclusions Simple phenotyping based on insulin sensitivity and beta-cell function predicts distinct future risks of cardiovascular events and death in patients with type 2 diabetes. These results suggest that precision medicine according to underlying type 2 pathophysiology potentially can reduce diabetes complications.

Aggregation of α-Synuclein (α-Syn) drives Parkinson’s disease, although the initial stages of self-assembly and structural conversion have not been captured inside neurons. We track the intracellular conformational states of α-Syn utilizing a single-molecule FRET biosensor, and show that α-Syn converts from its monomeric state to form two distinct oligomeric states in neurons in a concentration dependent, and sequence specific manner. 3D FRET-CLEM reveals the structural organization, and location of aggregation hotspots inside the cell. Notably multiple intracellular seeding events occur preferentially on membrane surfaces, especially mitochondrial membranes. The mitochondrial lipid, cardiolipin triggers rapid oligomerization of A53T α-Syn, and cardiolipin is sequestered within aggregating lipid-protein complexes. Mitochondrial aggregates impair complex I activity and increase mitochondrial ROS generation, which accelerates the oligomerization of A53T α-Syn, and ultimately causes permeabilization of mitochondrial membranes, and cell death. Patient iPSC derived neurons harboring A53T mutations exhibit accelerated oligomerization that is dependent on mitochondrial ROS, early mitochondrial permeabilization and neuronal death. Our study highlights a mechanism of de novo oligomerization at the mitochondria and its induction of neuronal toxicity.

In the transition to sustainability, innovation will play a crucial role. As the latter follows intricate paths and processes, IPRs might impede further innovation and slow down the transition to sustainability by blocking innovative technologies – or making it harder to access them. Yet, when adequately used, IPRs may foster knowledge exchange and shared learning. Open innovation - particularly open licensing – can support follow-on innovation by allowing for the circulation and combination of inputs from different actors and help solving the wicked problem of sustainability. Aside from the mere practice of sharing one's IPRs to foster further innovations in an open innovation setting, the sustainable financing of follow-on innovation will be essential in the coming decades. Indeed, in a crisis-laden world and considering the - presumably - future economic downturns, the question of the financing of follow-on innovation will be critical. There is certainly a need to identify how and under which conditions intellectual property, follow-on innovation and financing models can work together towards a more sustainable world. As the R&D funding in the post-pandemic world might become scarce, uneven, and unpredictable, this article reviews whether some alternative means of funding innovation –particularly emerging blockchain-based solutions – could succeed at supporting follow-on innovation for the greater goal of sustainability.

Planting new forests has received scientific and political attention as a measure to mitigate climate change. Large, new forests have been planted in places like China and Ethiopia and, over time, a billion hectares could become available globally for planting new forests. Sustainable management of forests, which are available to wood production, has received less attention despite these forests covering at least two billion hectares globally. Better management of existing forests would improve forest growth and help mitigate climate change by increasing the forest carbon (C) stock, by storing C in forest products, and by generating wood-based materials substituting fossil C based materials or other CO2-emission-intensive materials. Some published research assumes a trade-off between the timber harvested from existing forests and the stock of C in those forest ecosystems, asserting that both cannot increase simultaneously. We tested this assumption using the uniquely detailed forest inventory data available from Finland, Norway and Sweden, hereafter denoted northern Europe. We focused on the period 1960 - 2017, that saw little change in the total area covered by forests in northern Europe. At the start of the period, rotational forestry practices began to diffuse, eventually replacing selective felling management systems as the most common management practice. Looking at data over the period we find that despite significant increases in timber and pulp wood harvests, the growth of the forest C stock accelerated. Over the study period, the C stock of the forest ecosystems in northern Europe increased by nearly 70%, while annual timber harvests increased at the about 40% over the same period. This increase in the forest C stock was close to on par with the CO2-emissions from the region (other greenhouse gases not included). Our results suggest that the important effects of management on forest growth allows the forest C stock and timber harvests to increase simultaneously. The development in northern Europe raises the question of how better forest management can improve forest growth elsewhere around the globe while at the same time protecting biodiversity and preserving landscapes.

PURPOSE: Post-reconstruction filtering is often applied for noise suppression due to limited data counts in myocardial perfusion imaging (MPI) with single-photon emission computed tomography (SPECT). We study a deep learning (DL) approach for denoising in conventional SPECT-MPI acquisitions, and investigate whether it can be more effective for improving the detectability of perfusion defects compared to traditional post-filtering. METHODS: Owing to the lack of ground truth in clinical studies, we adopt a noise-to-noise (N2N) training approach for denoising in SPECT-MPI images. We consider a coupled U-Net (CU-Net) structure which is designed to improve learning efficiency through feature-map reuse. For network training we employ a bootstrap procedure to generate multiple noise realizations from list-mode clinical acquisitions. In the experiments we demonstrated the proposed approach on a set of 895 clinical studies, where the iterative OSEM algorithm with 3D Gaussian post-filtering was used to reconstruct the images. We investigated the detection performance of perfusion defects in the reconstructed images using the non-prewhitening matched filter (NPWMF), evaluated the uniformity of left ventricular (LV) wall in terms of image intensity, and quantified the effect of smoothing on the spatial resolution of the reconstructed left ventricular wall by using its full-width at half-maximum (FWHM). RESULTS: Compared to OSEM with Gaussian post-filtering, the DL denoised images with CU-Net significantly improved the detection performance of perfusion defects at all contrast levels (65%, 50%, 35%, and 20%). The signal-to-noise ratio (SNR(D)) in the NPWMF output was increased on average by 8% over optimal Gaussian smoothing (p-value < 10(−4), paired t-test), while the inter-subject variability was greatly reduced. The CU-Net also outperformed a 3D non-local means (NLM) filter and a convolutional autoencoder (CAE) denoising network in terms of SNR(D). In addition, the FWHM of the LV wall in the reconstructed images was varied by less than 1%. Furthermore, CU-Net also improved the detection performance when the images were processed with less post-reconstruction smoothing (a trade-off of increased noise for better LV resolution), with SNR(D) improved on average by 23%. CONCLUSIONS: The proposed DL with N2N training approach can yield additional noise suppression in SPECT-MPI images over conventional post-filtering. For perfusion defect detection, DL with CU-Net could outperform conventional 3D Gaussian filtering with optimal setting as well as NLM and CAE.

Lowering the administered dose in SPECT myocardial perfusion imaging (MPI) has become an important clinical problem. In this study we investigate the potential benefit of applying a deep learning (DL) approach for suppressing the elevated imaging noise in low-dose SPECT-MPI studies. We adopt a supervised learning approach to train a neural network by using image pairs obtained from full-dose (target) and low-dose (input) acquisitions of the same patients. In the experiments, we made use of acquisitions from 1,052 subjects and demonstrated the approach for two commonly used reconstruction methods in clinical SPECT-MPI: 1) filtered backprojection (FBP), and 2) ordered-subsets expectation-maximization (OSEM) with corrections for attenuation, scatter and resolution. We evaluated the DL output for the clinical task of perfusion-defect detection at a number of successively reduced dose levels (1/2, 1/4, 1/8, 1/16 of full dose). The results indicate that the proposed DL approach can achieve substantial noise reduction and lead to improvement in the diagnostic accuracy of low-dose data. In particular, at 1/2 dose, DL yielded an area-under-the-ROC-curve (AUC) of 0.799, which is nearly identical to the AUC = 0.801 obtained by OSEM at full-dose ( ${p}$ -value = 0.73); similar results were also obtained for FBP reconstruction. Moreover, even at 1/8 dose, DL achieved AUC = 0.770 for OSEM, which is above the AUC = 0.755 obtained at full-dose by FBP. These results indicate that, compared to conventional reconstruction filtering, DL denoising can allow for additional dose reduction without sacrificing the diagnostic accuracy in SPECT-MPI.

Summary This study aimed to evaluate 2 phytases, at 2 supplementation doses, in broiler diets with nutritional matrices with reduction in Ca:total P (tP) ratio. One-day-old male chicks (n = 3,960) were distributed in an arrangement of 12 treatments, with 10 replicates each; the experimental unit consisted of a floor pen with 33 birds each. Trial lasted up to 42 D, and birds were given the experimental diets: T1—positive control 1 (high Ca:tP ratio—recommended amount); T2—negative control 1 (reduction of 0.16% Ca and 0.16% available P-AP); T3–T2 + 500 FTU/kg enzyme A; T4–T2 + 500 FTU/kg enzyme B; T5–T2 + 1000 FTU/kg enzyme A; T6–T2 + 1000 FTU/kg enzyme B; T7–positive control 2 (low Ca:tP ratio); T8—negative control 2 (reduction of 0.16% Ca and 0.16% AP); T9–T8 + 500 FTU/kg enzyme A; T10–T8 + 500 FTU/kg enzyme B; T11–T8 + 1000 FTU/kg enzyme A; and T12–T8 + 1000 FTU/kg enzyme B. At 21 and 42 D of age, performance variables were recorded (body weight, body weight gain, feed intake, and feed conversion ratio) and tibial bone composition (Ca and P) and resistance was determined (strength at rupture). Results indicate that enzyme supplementation was efficient, regardless of Ca:tP ratio. The highest phytase dose presented superior results, especially for the 21-D evaluation. Phytase “B,” a bacterial product, showed superior response on performance and bone quality.

Aim of the study. Multiple system atrophy (MSA) and spinocerebellar ataxia (SCA) share similar symptomatology. We describe a rare occurrence of familial MSA that proved to be SCA6 upon genetic analysis. Materials and methods. Eighty MSA patients were enrolled in our study; blood samples were collected and genetic screening of the familial case for known SCA loci was performed. Results. A 68-year-old woman presented with recurrent and severe episodes of light-headedness, imbalance, frequent falls, neck and lower back stiffness, subjective arm and leg weakness, and numbness and tingling in both feet. One year later, her condition had declined; she experienced more falls, worsening instability, again more generalised but still subjective weakness, impaired fine motor movements, slurred speech, difficulty swallowing, episodes of choking, bladder incontinence, and constipation. Clinical suspicion included parkinsonism, MSA, and SCA. The patient was enrolled in our MSA study and was found to have 22 and 12 CAG repeats in CACNA1A. The other 79 clinical MSA patients were negative for SCA6 screening. Conclusions and clinical implications. While MSA and SCA may have similar presentations during early disease stages, the presence of both conditions on the list of differential diagnoses can be a diagnostic dilemma. Further analysis will aid in developing a biomarker to distinguish between the two conditions and guide proper management.

Introduction Genetic variants in the glucocerebrosidase (GBA) gene have been previously associated with susceptibility to synucleinopathies. The risk is well-established in Lewy body disease but is not as confirmed for multiple system atrophy (MSA). We aim to evaluate associations between exonic variants in GBA and risk of neuropathologically-confirmed multiple system atrophy (MSA). Methods Sanger gene sequencing of GBA was performed on 167 pathologically confirmed MSA patients collected at Mayo Clinic Florida Brain Bank, and data were extracted from whole-genome sequencing of 834 clinical controls. Common GBA variants were assessed for association with MSA. Rare GBA variants (and also all GBA variants) were collapsed together and evaluated for association with MSA risk using a gene-burden test. Results A total of 17 exonic GBA variants were observed, including a novel p.Q112X variant that is likely pathogenic in a patient with mixed parkinsonism-cerebellar subtype MSA. The more common p.N409S and p.L483P variants that recessively cause Gaucher's disease (GD), and are associated with risk of Lewy body disease, were not observed. When collapsing across all GBA variants, the presence of any GBA variant was significantly more frequent in MSA patients than in controls (OR = 1.90, P = 0.031). However, this association was driven by p.T408M, which had a significantly higher frequency in MSA patients compared to controls (OR = 4.21, P = 0.002). There was no significant association with risk of MSA for the p.E365K variant (OR = 0.79, P = 0.72). Conclusions Other than the specific GBA p.T408M variant, coding GBA variants are not associated with risk of MSA.

Background: Abnormal aggregates of α‐synuclein are pathologic hallmarks of multiple system atrophy (MSA) and Lewy body disease (LBD). LBD sometimes coexists with MSA, but the impact of co‐pathology, particularly diffuse LBD, on presentation of MSA has not been studied. We aimed to determine the frequency and clinicopathologic features of MSA with LBD (MSA+LBD). Methods: Using hematoxylin & eosin and α‐synuclein‐immunostained slides, we assessed the distribution and severity of LBD in 230 autopsy‐confirmed MSA patients collected from 1998 to 2018. Alzheimer‐type pathology was assessed to assign the likelihood of clinical presentations of dementia with Lewy body (DLB) using the consensus criteria for DLB. We reviewed medical records to characterize clinicopathologic features of MSA+LBD. Genetic risk factors for LBD, including APOE ε4 allele and mutations in GBA, SNCA, LRRK2, and VPS35, were analyzed. Results: LBD was observed in 11 MSA patients (5%); seven were brainstem type, three were transitional type, and one was diffuse type. The latter four had an intermediate or high likelihood of DLB. Three of the four had an antemortem diagnosis of Parkinson’s disease with dementia (PDD) or clinically probable DLB. Two patients had neuronal loss in the substantia nigra, but not in striatal or olivocerebellar systems with widespread glial cytoplasmic inclusions, consistent with minimal change MSA. In these cases, LBD was considered the primary pathology, and MSA was considered coincidental. APOE ε4 allele frequency was not different between MSA+LBD and MSA without LBD. Two of nine MSA+LBD patients had a risk variant of GBA (p.T408M and p.E365K). Conclusions: Although rare, MSA with transitional or diffuse LBD can develop clinical features of PDD or DLB. Minimal change MSA can be interpreted as a coincidental, but distinct, α‐synucleinopathy in a subset of patients with diffuse LBD.

Recent decades have witnessed the emergence and growth of transnational higher education, a specific form of internationalization which considers education as a product which can be packaged and sold abroad. This transnationalization of higher education is especially prominent in the discipline of business, which has wide student appeal. The purpose of this chapter is to review the transnationalization of business education. The chapter begins by situating transnational higher education within the internationalization of higher education more broadly. It then characterises transnational higher education, enumerating various definitions and transnationalization modes. Finally, it rationalizes transnational higher education from a geo-political/economic perspective.

The business world is in a state of flux due in part to the advent of disruptive technologies such as artificial intelligence, smart robots, and nanotechnology. The dawn of this ‘Smart Machine Age' has significant implications for business education, which will need to be transformed with a new focus on imparting knowledge, skills, and abilities suitable for the new workplace environment. Among the skill sets that are in highest demand according to employers is cross-cultural competence (CC). Scholarly interest in CC has grown exponentially in recent years and there is an emerging consensus that it is best taught through non-traditional pedagogies centered on experiential learning. This chapter explores the efficacy of international service learning as a tool for teaching CC, with a focus on an innovative social entrepreneurship project undertaken at Florida International University. The project involves a partnership between a student organization, an NGO, and a women's self-help group in India.

In der vorliegenden Studie wird untersucht, wie sich die Preise für FTTB/H- und gigabitfähige Breitbandkabelprodukte auf dem deutschen Markt im internationalen Vergleich einordnen, wie sich die angebotenen Produktportfolios unterscheiden und welche Muster sich aus der länderübergreifenden Analyse ableiten lassen. Zu diesem Zweck wurden Preise und produktbezogene Parameter in Deutschland und zehn weiteren europäischen Ländern mit unterschiedlich weit entwickelten Glasfaser- und Gigabitmärkten erhoben. Die niedrigsten kaufkraftbereinigten Preise für Produkte mit sehr hohen Bandbreiten beobachten wir in Frankreich, der Schweiz und Polen. Darunter sind mit Frankreich und der Schweiz zwei Länder, in denen besonders niederschwellige Zugangsmöglichkeiten für Vorleistungsnachfrager bestehen. Zugleich weisen diese beiden Länder auch verhältnismäßig hohe Take-up-Raten bei Gigabitgeschwindigkeiten auf. Über alle Bandbreiten hinweg legen unsere Ergebnisse nahe, dass mit zunehmender Entwicklung des Marktes in der Regel eine Homogenisierung des Preisniveaus über die unterschiedlichen Anbietertypen und Bandbreiten hinweg eintritt, mutmaßlich ebenfalls gefördert durch Infrastruktur- und vorleistungsbasierten Wettbewerb. Die Preise in Deutschland bewegen sich bei den hierzulande überwiegend nachgefragten Bandbreiten von 100 Mbit/s im Mittelfeld unseres internationalen Vergleichs. Auffällig sind die Aufschläge für FTTB/H Produkte in Bandbreiten, die mit aufgerüsteten xDSL-Netzen nicht bedient werden können. Dies gilt insbesondere für Gigabitprodukte. Dieses Preissetzungsverhalten deutet auf Abschöpfungsstrategien hin und könnte ein Indiz für wenig Vorleistungs- und Infrastrukturwettbewerb bei sehr hohen Bandbreiten sein. Auch wenn dieses Preissetzungsverhalten sicherlich in Teilen auf den frühen Entwicklungsstand des Marktes zurückzuführen ist, kann davon ein Penetrationsrisiko für die neu entstehenden FTTB/H-Netze ausgehen, insbesondere, wenn diese parallel zu aufgerüsteten xDSL-Infrastrukturen entstehen. The study at hand compares product portfolios and prices for FTTB/H and gigabit-capable broadband cable products in Germany and ten European countries characterised by fibre and gigabit markets of varying degrees of development. Based on our assessment, common patterns from the cross-country analysis are derived. We observe the lowest purchasing power-adjusted prices for products with very high bandwidths in France, Switzerland and Poland. France and Switzerland are characterised by particularly low-threshold access options for wholesale customers. At the same time, these two countries show the highest take-up rates for gigabit products within our sample. Across all bandwidths, our results suggest a connection between the level of market maturity and the homogeneity of price levels across different provider types and bandwidths, presumably fostered by infrastructure and wholesale-based competition. In comparison to its peers, prices for broadband products with bandwidths of 100 Mbit/s, which are most prominent in Germany, are in the midfield of our sample. The surcharges for FTTB/H products in bandwidths that cannot be served with upgraded xDSL networks are striking, in particular with regard to gigabit products. This pricing behaviour indicates skimming strategies and could be an indication of little wholesale and infrastructure competition at very high bandwidths. Even if this pricing behaviour can be partly attributed to the early stage of development of the market, it may pose a penetration risk for the newly emerging FTTB/H networks, especially if they are built in parallel with upgraded xDSL infrastructure.

Im Zusammenhang mit der wachsenden Bedeutung des Themas Nachhaltigkeit rücken Refurbishment-Geschäftsmodelle auch für Smartphones verstärkt in das öffentliche Interesse. Zunächst ist festzuhalten, dass es sich beim Markt für Refurbished-Smartphones im Vergleich zum Markt für Neugeräte um ein relativ kleines Segment handelt. Markforschern zufolge kommen Refurbished-Smartphones derzeit auf einen Anteil von etwa 10% an den in Deutschland verkauften Smartphones, mit steigender Tendenz. Das Segment ist durch eine heterogene Anbieterlandschaft geprägt. Während Unternehmen wie Rebuy oder asgoodasnew als vertikal integrierte Anbieter die Wertschöpfungsstufen Beschaffung, Wiederaufbereitung und Vertrieb abdecken, konzentrieren sich andere Unternehmen auf bestimmte Stufen. So haben sich beispielsweise als auf Refurbished-Produkte spezialisierte Marktplätze die Anbieter Back Market und Refurbed etabliert. Zwischen diesen Unternehmen und anderen Akteuren im Smartphone-Ökosystem sind verschiedene Kooperationsformen zu beobachten. Es ist zu erwarten, dass die Branche nicht nur vom Trend zum nachhaltigeren Kaufverhalten, sondern auch von den bereits eingeführten oder in Umsetzung befindlichen Maßnahmen zur Verlängerung der Lebensdauer und Erhöhung der Reparierbarkeit von Smartphones profitieren wird. Hierdurch wird sich das Potential an wiederaufbereitbaren Geräten insgesamt vergrößern. Darüber hinaus können Wiederaufbereitungsprozesse durch verbesserte Reparaturmöglichkeiten optimiert werden. Unsere Analysen zeigen darüber hinaus, dass Refurbishment-Anbieter insbesondere bei der Beschaffung geeigneter Geräte zunehmende Herausforderungen haben und hier insbesondere etablierte größere Akteure mit kontinuierlichem Kundenkontakt eine Rolle spielen können. Ein insbesondere aus Verbrauchersicht relevantes Problem besteht in der begrenzten Vergleichbarkeit der Angebote und in fehlenden anbieterübergreifenden Qualitätsstandards. Um bei Verbrauchern Vertrauen aufzubauen, bieten viele Refurbishment-Anbieter deutlich längere Garantiezeiten an als für Neugeräte üblich. Wichtiger erscheint jedoch, dass die Branche aus Eigeninteresse anbieterübergreifende Qualitätsstandards etabliert, um für Verbraucher mehr Transparenz zu schaffen und sich breitere Kundenschichten zu erschließen. Against the background of the growing importance of sustainability, refurbishment business models for smartphones are increasingly attracting public interest. First of all, it should be noted that the market for refurbished smartphones is a relatively small segment compared to the market for new devices. According to market research, refurbished smartphones account for 10% of total smartphone sales in Germany, with increasing importance. The segment is characterized by a heterogeneous supply side. While companies such as Rebuy or asgoodasnew are vertically integrated providers covering procurement, testing and refurbishment as well as distribution, other companies have specialized in certain stages of the value chain. For example, the providers Back Market and Refurbed have established themselves as marketplaces specialising in refurbished products. Various forms of cooperation can be observed between these companies and other players in the smartphone ecosystem. It is expected that the industry will benefit not only from the trend towards more sustainable customer behaviour, but also from the measures already introduced or being implemented to extend the lifespan and increase the reparability of smartphones. This will increase the overall potential of devices to be refurbished. Furthermore, refurbishment processes can be optimised through improved repair conditions. Our analyses also show that refurbishment providers face increasing challenges, particularly in the procurement of suitable devices, and that established larger players with continuous customer contact can play a role here in particular. A problem that is especially relevant from a consumer perspective is the limited comparability of offers and the lack of quality standards in the refurbishment market. In order to build consumer confidence, many refurbishment providers offer significantly longer warranty periods for refurbished smartphone than is usual for new devices. However, it seems to be more important that the industry starts to establish quality standards in order to create more transparency for consumers and to expand into broader customer groups.

Planting new forests has received scientific and political attention as a measure to mitigate climate change. Large, new forests have been planted in places like China and Ethiopia and, over time, a billion hectares could become available globally for planting new forests. Sustainable management of forests, which are available to wood production, has received less attention despite these forests covering at least two billion hectares globally. Better management of existing forests would improve forest growth and help mitigate climate change by increasing the forest carbon (C) stock, by storing C in forest products, and by generating wood-based materials substituting fossil C based materials or other CO2-emission-intensive materials. Some published research assumes a trade-off between the timber harvested from existing forests and the stock of C in those forest ecosystems, asserting that both cannot increase simultaneously. We tested this assumption using the uniquely detailed forest inventory data available from Finland, Norway and Sweden, hereafter denoted northern Europe. We focused on the period 1960 - 2017, that saw little change in the total area covered by forests in northern Europe. At the start of the period, rotational forestry practices began to diffuse, eventually replacing selective felling management systems as the most common management practice. Looking at data over the period we find that despite significant increases in timber and pulp wood harvests, the growth of the forest C stock accelerated. Over the study period, the C stock of the forest ecosystems in northern Europe increased by nearly 70%, while annual timber harvests increased at the about 40% over the same period. This increase in the forest C stock was close to on par with the CO2-emissions from the region (other greenhouse gases not included). Our results suggest that the important effects of management on forest growth allows the forest C stock and timber harvests to increase simultaneously. The development in northern Europe raises the question of how better forest management can improve forest growth elsewhere around the globe while at the same time protecting biodiversity and preserving landscapes.

Forthcoming in: T.Pihlajarinne,, J. Mähönen, P. N. Upreti (eds.): Intellectual Property Rights in the Post Pandemic World: an Integrated Framework of Sustainability, Innovation and Global Justice. Edward Elgar 2023, forthcoming., Max Planck Institute for Innovation & Competition Research Paper No. 22-07 In the transition to sustainability, innovation will play a crucial role. As the latter follows intricate paths and processes, IPRs might impede further innovation and slow down the transition to sustainability by blocking innovative technologies – or making it harder to access them. Yet, when adequately used, IPRs may foster knowledge exchange and shared learning. Open innovation - particularly open licensing – can support follow-on innovation by allowing for the circulation and combination of inputs from different actors and help solving the wicked problem of sustainability. Aside from the mere practice of sharing one's IPRs to foster further innovations in an open innovation setting, the sustainable financing of follow-on innovation will be essential in the coming decades. Indeed, in a crisis-laden world and considering the - presumably - future economic downturns, the question of the financing of follow-on innovation will be critical. There is certainly a need to identify how and under which conditions intellectual property, follow-on innovation and financing models can work together towards a more sustainable world. As the R&D funding in the post-pandemic world might become scarce, uneven, and unpredictable, this article reviews whether some alternative means of funding innovation –particularly emerging blockchain-based solutions – could succeed at supporting follow-on innovation for the greater goal of sustainability.