Measuring cognitive impairment and monitoring cognitive decline in Huntington's disease:a comparison of assessment instruments

Background Progressive cognitive decline is an inevitable feature of Huntington’s disease (HD) but specific criteria and instruments are still insufficiently developed to reliably classify patients into categories of cognitive severity and to monitor the progression of cognitive impairment. Methods We collected data from a cohort of 180 positive gene-carriers: 33 with premanifest HD and 147 with manifest HD. Using a specifically developed gold-standard for cognitive status we classified participants into those with normal cognition, those with mild cognitive impairment, and those with dementia. We administered the Parkinson’s Disease-Cognitive Rating Scale (PD-CRS), the MMSE and the UHDRS cogscore at baseline, and at 6-month and 12-month follow-up visits. Cutoff scores discriminating between the three cognitive categories were calculated for each instrument. For each cognitive group and instrument we addressed cognitive progression, sensitivity to change, and the minimally clinical important difference corresponding to conversion from one category to another. Results The PD-CRS cutoff scores for MCI and dementia showed excellent sensitivity and specificity ratios that were not achieved with the other instruments. Throughout follow-up, in all cognitive groups, PD-CRS captured the rate of conversion from one cognitive category to another and also the different patterns in terms of cognitive trajectories. Conclusion The PD-CRS is a valid and reliable instrument to capture MCI and dementia syndromes in HD. It captures the different trajectories of cognitive progression as a function of cognitive status and shows sensitivity to change in MCI and dementia

Clonal chromosomal mosaicism and loss of chromosome Y in elderly men increase vulnerability for SARS-CoV-2

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome alterations (mCA) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (mCA and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, mCA and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, individuals with clonal mosaic events (clonal mosaicism for chromosome alterations and/or loss of chromosome Y) showed an increased risk of COVID-19 lethality

Heterogeneous contributions of change in population distribution of body mass index to change in obesity and underweight NCD Risk Factor Collaboration (NCD-RisC)

From 1985 to 2016, the prevalence of underweight decreased, and that of obesity and severe obesity increased, in most regions, with significant variation in the magnitude of these changes across regions. We investigated how much change in mean body mass index (BMI) explains changes in the prevalence of underweight, obesity, and severe obesity in different regions using data from 2896 population-based studies with 187 million participants. Changes in the prevalence of underweight and total obesity, and to a lesser extent severe obesity, are largely driven by shifts in the distribution of BMI, with smaller contributions from changes in the shape of the distribution. In East and Southeast Asia and sub-Saharan Africa, the underweight tail of the BMI distribution was left behind as the distribution shifted. There is a need for policies that address all forms of malnutrition by making healthy foods accessible and affordable, while restricting unhealthy foods through fiscal and regulatory restrictions

Vacío construido, espacio representado

Space cannot be seen directly, and it cannot be compared to movement or light. Our gaze –our strictly human dimension of vision– is defined by its intentionality and finality. Architecture, as “thought about space”, makes us reconsider its own concepts. A building can be regarded as a representation of the project, thus inverting the usual perception of the project as the representation of the building. This is connected to the idea of space that Bachelard inspired: a “space beneath the space”. Architectural space is a theoretical fiction constructed upon the information that experience gives us. Through photography, the analysis of architecture’s representation enables us to understand the generation of its design, by looking at its voids and its visual syntax. Voids have become an essential category in this analytical process. In themselves, they are capable of qualifying and giving meaning to the image for the sake of the viewer, and they are crucial to unravel its experience. Since voids are placed actively and in a particular order by the creator, they organize and define the representation of a place and its transformation through architecture. To direct our attention to these gaps and nothingness, in a kind of interpretation of an architectural image’s negative, does not construct a supplementary or rhetorical narrative. Its goal is to produce an original account, defined by its visual nature and articulated, within a specific format, by its coherence, homogeneity, and graphical unity. For architectural theory and critique, this implies a new discourse, the goal if which is to communicate architectural thought by using the language of photography. Photography expresses perceptions and study, sensations and analysis. If nowadays, it can be understood critically –once it has been liberated from the way it qualifies the creative process– it is because we can assert its nature as an instrument that can deconstruct the invisible, that can explain voids. Itineraries, parentheses, and silences modify each image as a unique object, one that emits signals the dissection and translation of which entail a learning exercise of a new expressive dimension for architecture.El espacio no es directamente visto, no es comparable al movimiento o a la luz. La mirada –la dimensión propiamente humana de la visión– se define en su intencionalidad y finalidad. La arquitectura como “pensamiento del espacio” nos hace replantear sus propios conceptos. El edificio puede ser considerado una representación del proyecto, invirtiendo así la imagen habitual del proyecto como representación del edificio. Conecta con la idea del espacio inspirada por Bachelard: un “espacio bajo el espacio”. El espacio arquitectónico es ficción teórica construida sobre los datos de la experiencia. Con la fotografía, el análisis de su representación hace posible comprenderlo en su generación proyectual a partir de los vacíos y la sintaxis visual. El vacío resulta categoría esencial en este proceso de análisis, capaz por sí misma de cualificar y significar la imagen para el observador, clave para desentrañar su experiencia. Dispuestos activamente por el creador en un determinado orden, los vacíos organizan y definen la representación del lugar y su transformación por la arquitectura. Dirigir la atención hacía los huecos y la nada, en una especie de lectura en negativo de las imágenes de arquitectura, no construye un relato complementario o retórico. Su finalidad es la elaboración de un ensayo original, definido por su naturaleza visual, articulado en un formato concreto por la unidad gráfica, la coherencia y la homogeneidad. Para la teoría y la crítica de arquitectura, un nuevo discurso con el objetivo de comunicar la reflexión acerca del hecho arquitectónico utilizando el lenguaje fotográfico. Expresión de percepción y de estudio, de sensación y de análisis, si la fotografía se propone hoy como forma crítica, depurada en su cualificación del proceso de creación, es porque se afirma su naturaleza de instrumento para deconstruir lo invisible, de explicar los vacíos. Recorridos, paréntesis y silencios adjetivan cada imagen como objeto único, emisor de señales cuya disección y traducción significará el ejercicio de aprendizaje de una nueva dimensión expresiva para la arquitectura

Vacío construido, espacio representado

Space cannot be seen directly, and it cannot be compared to movement or light. Our gaze –our strictly human dimension of vision– is defined by its intentionality and finality. Architecture, as “thought about space”, makes us reconsider its own concepts. A building can be regarded as a representation of the project, thus inverting the usual perception of the project as the representation of the building. This is connected to the idea of space that Bachelard inspired: a “space beneath the space”. Architectural space is a theoretical fiction constructed upon the information that experience gives us. Through photography, the analysis of architecture’s representation enables us to understand the generation of its design, by looking at its voids and its visual syntax. Voids have become an essential category in this analytical process. In themselves, they are capable of qualifying and giving meaning to the image for the sake of the viewer, and they are crucial to unravel its experience. Since voids are placed actively and in a particular order by the creator, they organize and define the representation of a place and its transformation through architecture. To direct our attention to these gaps and nothingness, in a kind of interpretation of an architectural image’s negative, does not construct a supplementary or rhetorical narrative. Its goal is to produce an original account, defined by its visual nature and articulated, within a specific format, by its coherence, homogeneity, and graphical unity. For architectural theory and critique, this implies a new discourse, the goal if which is to communicate architectural thought by using the language of photography. Photography expresses perceptions and study, sensations and analysis. If nowadays, it can be understood critically –once it has been liberated from the way it qualifies the creative process– it is because we can assert its nature as an instrument that can deconstruct the invisible, that can explain voids. Itineraries, parentheses, and silences modify each image as a unique object, one that emits signals the dissection and translation of which entail a learning exercise of a new expressive dimension for architecture.El espacio no es directamente visto, no es comparable al movimiento o a la luz. La mirada –la dimensión propiamente humana de la visión– se define en su intencionalidad y finalidad. La arquitectura como “pensamiento del espacio” nos hace replantear sus propios conceptos. El edificio puede ser considerado una representación del proyecto, invirtiendo así la imagen habitual del proyecto como representación del edificio. Conecta con la idea del espacio inspirada por Bachelard: un “espacio bajo el espacio”. El espacio arquitectónico es ficción teórica construida sobre los datos de la experiencia. Con la fotografía, el análisis de su representación hace posible comprenderlo en su generación proyectual a partir de los vacíos y la sintaxis visual. El vacío resulta categoría esencial en este proceso de análisis, capaz por sí misma de cualificar y significar la imagen para el observador, clave para desentrañar su experiencia. Dispuestos activamente por el creador en un determinado orden, los vacíos organizan y definen la representación del lugar y su transformación por la arquitectura. Dirigir la atención hacía los huecos y la nada, en una especie de lectura en negativo de las imágenes de arquitectura, no construye un relato complementario o retórico. Su finalidad es la elaboración de un ensayo original, definido por su naturaleza visual, articulado en un formato concreto por la unidad gráfica, la coherencia y la homogeneidad. Para la teoría y la crítica de arquitectura, un nuevo discurso con el objetivo de comunicar la reflexión acerca del hecho arquitectónico utilizando el lenguaje fotográfico. Expresión de percepción y de estudio, de sensación y de análisis, si la fotografía se propone hoy como forma crítica, depurada en su cualificación del proceso de creación, es porque se afirma su naturaleza de instrumento para deconstruir lo invisible, de explicar los vacíos. Recorridos, paréntesis y silencios adjetivan cada imagen como objeto único, emisor de señales cuya disección y traducción significará el ejercicio de aprendizaje de una nueva dimensión expresiva para la arquitectura

A 12-gene pharmacogenetic panel to prevent adverse drug reactions: an open-label, multicentre, controlled, cluster-randomised crossover implementation study

© 2023Background: The benefit of pharmacogenetic testing before starting drug therapy has been well documented for several single gene–drug combinations. However, the clinical utility of a pre-emptive genotyping strategy using a pharmacogenetic panel has not been rigorously assessed. Methods: We conducted an open-label, multicentre, controlled, cluster-randomised, crossover implementation study of a 12-gene pharmacogenetic panel in 18 hospitals, nine community health centres, and 28 community pharmacies in seven European countries (Austria, Greece, Italy, the Netherlands, Slovenia, Spain, and the UK). Patients aged 18 years or older receiving a first prescription for a drug clinically recommended in the guidelines of the Dutch Pharmacogenetics Working Group (ie, the index drug) as part of routine care were eligible for inclusion. Exclusion criteria included previous genetic testing for a gene relevant to the index drug, a planned duration of treatment of less than 7 consecutive days, and severe renal or liver insufficiency. All patients gave written informed consent before taking part in the study. Participants were genotyped for 50 germline variants in 12 genes, and those with an actionable variant (ie, a drug–gene interaction test result for which the Dutch Pharmacogenetics Working Group [DPWG] recommended a change to standard-of-care drug treatment) were treated according to DPWG recommendations. Patients in the control group received standard treatment. To prepare clinicians for pre-emptive pharmacogenetic testing, local teams were educated during a site-initiation visit and online educational material was made available. The primary outcome was the occurrence of clinically relevant adverse drug reactions within the 12-week follow-up period. Analyses were irrespective of patient adherence to the DPWG guidelines. The primary analysis was done using a gatekeeping analysis, in which outcomes in people with an actionable drug–gene interaction in the study group versus the control group were compared, and only if the difference was statistically significant was an analysis done that included all of the patients in the study. Outcomes were compared between the study and control groups, both for patients with an actionable drug–gene interaction test result (ie, a result for which the DPWG recommended a change to standard-of-care drug treatment) and for all patients who received at least one dose of index drug. The safety analysis included all participants who received at least one dose of a study drug. This study is registered with ClinicalTrials.gov, NCT03093818 and is closed to new participants. Findings: Between March 7, 2017, and June 30, 2020, 41 696 patients were assessed for eligibility and 6944 (51·4 % female, 48·6% male; 97·7% self-reported European, Mediterranean, or Middle Eastern ethnicity) were enrolled and assigned to receive genotype-guided drug treatment (n=3342) or standard care (n=3602). 99 patients (52 [1·6%] of the study group and 47 [1·3%] of the control group) withdrew consent after group assignment. 652 participants (367 [11·0%] in the study group and 285 [7·9%] in the control group) were lost to follow-up. In patients with an actionable test result for the index drug (n=1558), a clinically relevant adverse drug reaction occurred in 152 (21·0%) of 725 patients in the study group and 231 (27·7%) of 833 patients in the control group (odds ratio [OR] 0·70 [95% CI 0·54–0·91]; p=0·0075), whereas for all patients, the incidence was 628 (21·5%) of 2923 patients in the study group and 934 (28·6%) of 3270 patients in the control group (OR 0·70 [95% CI 0·61–0·79]; p <0·0001). Interpretation: Genotype-guided treatment using a 12-gene pharmacogenetic panel significantly reduced the incidence of clinically relevant adverse drug reactions and was feasible across diverse European health-care system organisations and settings. Large-scale implementation could help to make drug therapy increasingly safe. Funding: European Union Horizon 2020

Cabbage and fermented vegetables: From death rate heterogeneity in countries to candidates for mitigation strategies of severe COVID-19

Large differences in COVID-19 death rates exist between countries and between regions of the same country. Some very low death rate countries such as Eastern Asia, Central Europe, or the Balkans have a common feature of eating large quantities of fermented foods. Although biases exist when examining ecological studies, fermented vegetables or cabbage have been associated with low death rates in European countries. SARS-CoV-2 binds to its receptor, the angiotensin-converting enzyme 2 (ACE2). As a result of SARS-CoV-2 binding, ACE2 downregulation enhances the angiotensin II receptor type 1 (AT1R) axis associated with oxidative stress. This leads to insulin resistance as well as lung and endothelial damage, two severe outcomes of COVID-19. The nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is the most potent antioxidant in humans and can block in particular the AT1R axis. Cabbage contains precursors of sulforaphane, the most active natural activator of Nrf2. Fermented vegetables contain many lactobacilli, which are also potent Nrf2 activators. Three examples are: kimchi in Korea, westernized foods, and the slum paradox. It is proposed that fermented cabbage is a proof-of-concept of dietary manipulations that may enhance Nrf2-associated antioxidant effects, helpful in mitigating COVID-19 severity.</p

Clinical manifestations of intermediate allele carriers in Huntington disease

Objective: There is controversy about the clinical consequences of intermediate alleles (IAs) in Huntington disease (HD). The main objective of this study was to establish the clinical manifestations of IA carriers for a prospective, international, European HD registry. Methods: We assessed a cohort of participants at risk with <36 CAG repeats of the huntingtin (HTT) gene. Outcome measures were the Unified Huntington's Disease Rating Scale (UHDRS) motor, cognitive, and behavior domains, Total Functional Capacity (TFC), and quality of life (Short Form-36 [SF-36]). This cohort was subdivided into IA carriers (27-35 CAG) and controls (<27 CAG) and younger vs older participants. IA carriers and controls were compared for sociodemographic, environmental, and outcome measures. We used regression analysis to estimate the association of age and CAG repeats on the UHDRS scores. Results: Of 12,190 participants, 657 (5.38%) with <36 CAG repeats were identified: 76 IA carriers (11.56%) and 581 controls (88.44%). After correcting for multiple comparisons, at baseline, we found no significant differences between IA carriers and controls for total UHDRS motor, SF-36, behavioral, cognitive, or TFC scores. However, older participants with IAs had higher chorea scores compared to controls (p 0.001). Linear regression analysis showed that aging was the most contributing factor to increased UHDRS motor scores (p 0.002). On the other hand, 1-year follow-up data analysis showed IA carriers had greater cognitive decline compared to controls (p 0.002). Conclusions: Although aging worsened the UHDRS scores independently of the genetic status, IAs might confer a late-onset abnormal motor and cognitive phenotype. These results might have important implications for genetic counseling. ClinicalTrials.gov identifier: NCT01590589