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Purpose To describe a guidance on the management of post-acute COVID 19 patients in geriatric rehabilitation. Methods The guidance is based on guidelines for post-acute COVID-19 geriatric rehabilitation developed in the Netherlands, updated with recent insights from literature, related guidance from other countries and disciplines, and combined with experiences from experts in countries participating in the Geriatric Rehabilitation Special Interest Group of the European Geriatric Medicine Society. Results This guidance for post-acute COVID-19 rehabilitation is divided into a section addressing general recommendations for geriatric rehabilitation and a section addressing specific processes and procedures. The Sect. "General recommendations for geriatric rehabilitation" addresses: (1) general requirements for post-acute COVID-19 rehabilitation and (2) critical aspects for quality assurance during COVID-19 pandemic. The Sect. "Specific processes and procedures", addresses the following topics: (1) patient selection; (2) admission; (3) treatment; (4) discharge; and (5) follow-up and monitoring. Conclusion Providing tailored geriatric rehabilitation treatment to post-acute COVID-19 patients is a challenge for which the guidance is designed to provide support. There is a strong need for additional evidence on COVID-19 geriatric rehabilitation including developing an understanding of risk profiles of older patients living with frailty to develop individualised treatment regimes. The present guidance will be regularly updated based on additional evidence from practice and research. Key summary pointsAim To describe a guidance on the management of post-acute COVID 19 patients in geriatric rehabilitation. Findings This guidance addresses general requirements for post-acute COVID-19 geriatric rehabilitation and critical aspects for quality assurance during the COVID-19 pandemic. Furthermore, the guidance describes relevant care processes and procedures divided in five topics: patient selection; admission; treatment; discharge; and follow-up and monitoring. Message This guidance is designed to provide support to care professionals involved in the geriatric rehabilitation treatment of post-acute COVID-19 patients.

To determine risk factors associated with concussion among the general collegiate population using a unique data linkage methodology.Student health medical, counseling, and disability access service data were linked with university enrollment data to provide a comprehensive, deidentified dataset of students who sought care at the student health center for concussion from 2016-2020. Using chi-squared tests and logistic regression, characteristics of students with and without concussion were evaluated.During the study period, 506 concussions from 474 students were identified (cumulative incidence rate of 51.7 per 10,000 students). Significant predictors of concussion included: younger age (21 years): odds ratio (OR) = 3.52 (95% confidence intervals [CI], 2.78, 4.50), Greek affiliation: OR = 1.89 (95% CI, 1.56, 2.30), and utilization of counseling and psychological services: OR = 1.92 (95% CI 1.59, 2.32). Of the students with concussion, 47% had at least one other concussion within the preceding year. History of prior hospitalization or medical imaging for head injury increased subsequent concussion risk by 4.5 fold.Linking unique datasets provides a richer understanding of the characteristics and risk factors associated with student concussions than analysis of a single data source. This comprehensive dataset will enable future targeted interventions to prevent and treat college student concussions.

ObjectiveTo determine the small vessel disease spectrum associated with cysteine-altering NOTCH3 variants in community-dwelling individuals by analyzing the clinical and neuroimaging features of UK Biobank participants harboring such variants.MethodsThe exome and genome sequencing datasets of the UK Biobank (n = 50,000) and cohorts of cognitively healthy elderly (n = 751) were queried for cysteine-altering NOTCH3 variants. Brain MRIs of individuals harboring such variants were scored according to Standards for Reporting Vascular Changes on Neuroimaging criteria, and clinical information was extracted with ICD-10 codes. Clinical and neuroimaging data were compared to age- and sex-matched UK Biobank controls and clinically diagnosed patients from the Dutch cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) registry.ResultsWe identified 108 individuals harboring a cysteine-altering NOTCH3 variant (2.2 of 1,000), of whom 75% have a variant that has previously been reported in CADASIL pedigrees. Almost all variants were located in 1 of the NOTCH3 protein epidermal growth factor–like repeat domains 7 to 34. White matter hyperintensity lesion load was higher in individuals with NOTCH3 variants than in controls (p = 0.006) but lower than in patients with CADASIL with the same variants (p < 0.001). Almost half of the 24 individuals with brain MRI had a Fazekas score of 0 or 1 up to age 70 years. There was no increased risk of stroke.ConclusionsAlthough community-dwelling individuals harboring a cysteine-altering NOTCH3 variant have a higher small vessel disease MRI burden than controls, almost half have no MRI abnormalities up to age 70 years. This shows that NOTCH3 cysteine altering variants are associated with an extremely broad phenotypic spectrum, ranging from CADASIL to nonpenetrance.

ZusammenfassungDie Gastroenterologie bietet ein weites Feld für zukünftige „Klug-entscheiden-Empfehlungen“ (KEE), die nicht nur den gesicherten Einsatz diagnostischer Tests wie Laboruntersuchungen oder bildgebende Verfahren betreffen, sondern auch medikamentöse Therapien und die gastroenterologische Endoskopie. Dem zu häufigen Einsatz von Medikamenten wie Antibiotika und Protonenpumpenhemmern steht ihr zu seltener Einsatz bei gesicherten Indikationen gegenüber. Ähnliches trifft auf die abdominelle Bildgebung zu, insofern bei vielen Fragestellungen zu häufig der Computertomografie der Vorzug vor einer qualifizierten Sonografie gegeben wird. Laborwerte wie Lipase oder Amylase sind beim asymptomatischen Patienten nicht weiterführend und verursachen u. U. eine Vielzahl von unnötigen weiteren diagnostischen Maßnahmen. Bei akuter Pankreatitis bringt die Bestimmung beider Enzyme keinen additiven diagnostischen Nutzen. Ähnlich wenig hilfreich ist der unkritische Einsatz von weiteren für die Gastroenterologie relevanten Laborparametern wie CEA, Ammoniak oder Procalcitonin. In der Endoskopie ist eine „Vorsorgegastroskopie“ bei asymptomatischen Patienten ohne Risikofaktoren nicht sinnvoll, während die Koloskopie als Vorsorgeuntersuchung auf ein Kolonkarzinom zu selten von über 50-Jährigen wahrgenommen wird.Die sich dramatisch entwickelnde Adipositaspandemie und der damit einhergehende massive Anstieg an fortgeschrittenen nichtalkoholischen Fettlebererkrankungen mit entsprechender Morbidität und Mortalität machen KEE erforderlich, die nicht nur Empfehlungen für den einzelnen Patienten geben, sondern auch Maßnahmen zur Regulierung des Verkaufs hochverarbeiteter Lebensmittel oder zuckerreicher Softdrinks darlegen. Auch zukünftig werden sich die „Key Questions“ für KEE in der Gastroenterologie aus der Erstellung von Leitlinien heraus ergeben. Dennoch sind auch KEE für Situationen im klinischen Alltag wünschenswert, für die es keine Leitlinienempfehlungen gibt. Durch interdisziplinären Expertenkonsens und Berücksichtigung vorhandener wissenschaftlicher Daten kann diesen KEE eine sichere Basis verschafft werden.

In August 2019, the Virginia Poison Center (VPC) and the Blue Ridge Poison Center (BRPC) were contacted concerning patients experiencing repeated episodes of marked hypoglycemia following ingestion of a male enhancement supplement tablet marketed as "V8" in convenience stores in central Virginia. Over the following 3 months, the Virginia Department of Agriculture and Consumer Services (VDACS) and the Virginia Department of Health (VDH) conducted an investigation and identified 17 patients meeting the case definition (severe hypoglycemia within 48 hours of consuming an over-the-counter male enhancement supplement in a man with no history of use of insulin or other medication used to control blood glucose). Analysis of the V8 tablets revealed that most contained glyburide, a sulfonylurea oral hypoglycemic used in the treatment of diabetes and associated with prolonged hypoglycemia following overdose (1). To stem this outbreak, V8 was removed from stores when found, and public service announcements were released. The public health implications of V8 use include the potential for substantial morbidity from hypoglycemic episodes and the potential for mortality if health care services are not accessed in a timely manner when hypoglycemia occurs. The presence of V8 in the market poses a serious threat to public health because of its potentially life-threatening adverse effects.

Aim The primary aim of this study is to demonstrate that 7‐tesla functional magnetic resonance imaging (7T‐fMRI) can visualize the neural representations of the male pelvic floor in the whole brain of a single subject. Methods In total, 17 healthy male volunteers (age 20‐47) were scanned in a 7T‐MRI scanner (Philips Achieva). The scanning protocol consisted of two functional runs using a multiband echo planar imaging sequence and a T1‐weighted scan. The subjects executed two motor tasks, one involving consecutive pelvic floor muscle contractions (PFMC) and a control task with tongue movements. Results In single subjects, results of both tasks were visualized in the cortex, putamen, thalamus, and the cerebellum. Activation was seen during PFMC in the superomedial and inferolateral primary motor cortex (M1), supplementary motor area (SMA), insula, midcingulate gyrus (MCG), putamen, thalamus, and in the anterior and posterior lobes of the cerebellum. During tongue movement, activation was seen in the inferolateral M1, SMA, MCG, putamen, thalamus, and anterior and posterior lobes of the cerebellum. Tongue activation was found in the proximity of, but not overlapping with, the PFMC activation. Connectivity analysis demonstrated differences in neural networks involved in PFMC and tongue movement. Conclusion This study demonstrated that 7T‐fMRI can be used to visualize brain areas involved in pelvic floor control in the whole brain of single subjects and defined the specific brain areas involved in PFMC. Distinct differences between brain mechanisms controlling the pelvic floor and tongue movements were demonstrated using connectivity analysis.

Increased opioid use and misuse have imposed large analytical demands across clinical and forensic sectors. Due to the absence of affordable, accurate, and simple on-site tests (e.g., point of interdiction and bedside), analysis is primarily conducted in centralized laboratories via time-consuming, labor-intensive methods. Many healthcare facilities do not have such analytical capabilities and must send samples to commercial laboratories, increasing turnaround time and care costs, as well as delaying public health warnings regarding the emergence of specific substances. Enzyme-linked immunosorbent assays (ELISAs) are used ubiquitously, despite lengthy workflows that require substantial manual intervention. Faster, reliable analytics are desperately needed to mitigate the mortality and morbidity associated with the current substance use epidemic. We describe one such alternative─a portable centrifugal microfluidic ELISA system that supplants repetitive pipetting with rotationally controlled fluidics. Embedded cellulosic membranes act as microvalves, permitting flow only when centrifugally generated hydraulic pressure exceeds their liquid entry pressure. These features enable stepwise reagent introduction, incubation, and removal simply by tuning rotational frequency. We demonstrate the success of this platform through sensitive, specific colorimetric detection of opiates, a subclass of opioids naturally derived from the opium poppy. Objective image analysis eliminated subjectivity in human color perception and permitted reliable detection of opiates in buffer and artificial urine at the ng/μL range. Opiates were clearly differentiated from other drug classes without interference from common adulterants known to cause false positive results in current colorimetric field tests. Eight samples were simultaneously analyzed in under 1 h, a marked reduction from the traditional multiday timeline. This approach could permit rapid, automatable ELISA-based drug detection outside of traditional laboratories by nontechnical personnel.

Objectives Determinants of cognitive functioning in individuals aged 90 years and older, the oldest-old, remain poorly understood. We aimed to establish the association of risk factors, white matter hyperintensities (WMHs), hippocampal atrophy, and amyloid aggregation with cognition in the oldest-old. Method We included 84 individuals without cognitive impairment and 38 individuals with cognitive impairment from the EMIF-AD 90+ Study (mean age 92.4 years) and tested cross-sectional associations between risk factors (cognitive activity, physical parameters, nutritional status, inflammatory markers, and cardiovascular risk factors), brain pathology biomarkers (WMH and hippocampal volume on magnetic resonance imaging, and amyloid binding measured with positron emission tomography), and cognition. Additionally, we tested whether the brain pathology biomarkers were independently associated with cognition. When applicable, we tested whether the effect of risk factors on cognition was mediated by brain pathology. Results Lower values for handgrip strength, Short Physical Performance Battery (SPPB), nutritional status, HbA1c, and hippocampal volume, and higher values for WMH volume and amyloid binding were associated with worse cognition. Higher past cognitive activity and lower body mass index were associated with increased amyloid binding, lower muscle mass with more WMH, and lower SPPB scores with more WMH and hippocampal atrophy. The brain pathology markers were independently associated with cognition. The association of SPPB with cognition was partially mediated by hippocampal volume. Discussion In the oldest-old, physical parameters, nutritional status, HbA1c, WMH, hippocampal atrophy, and amyloid binding are associated with cognitive impairment. Physical performance may affect cognition through hippocampal atrophy. This study highlights the importance to consider multiple factors when assessing cognition in the oldest-old.

A rare coding variant (rs72824905, p.P522R) conferring protection against Alzheimer’s disease (AD) was identified in the gene encoding the enzyme phospholipase-C-γ2 (PLCG2) that is highly expressed in microglia. To explore the protective nature of this variant, we employed latent process linear mixed models to examine the association of p.P522R with longitudinal cognitive decline in 3595 MCI patients, and in 10,097 individuals from population-based studies. Furthermore, association with CSF levels of pTau181, total tau, and Aβ1-42 was assessed in 1261 MCI patients. We found that MCI patients who carried the p.P522R variant showed a slower rate of cognitive decline compared to non-carriers and that this effect was mediated by lower pTau181 levels in CSF. The effect size of the association of p.P522R with the cognitive decline and pTau181 was similar to that of APOE-ε4, the strongest genetic risk factor for AD. Interestingly, the protective effect of p.P522R was more pronounced in MCI patients with low Aβ1-42 levels suggesting a role of PLCG2 in the response to amyloid pathology. In line with this hypothesis, we observed no protective effect of the PLCG2 variant on the cognitive decline in population-based studies probably due to the lower prevalence of amyloid positivity in these samples compared to MCI patients. Concerning the potential biological underpinnings, we identified a network of co-expressed proteins connecting PLCG2 to APOE and TREM2 using unsupervised co-regulatory network analysis. The network was highly enriched for the complement cascade and genes differentially expressed in disease-associated microglia. Our data show that p.P522R in PLCG2 reduces AD disease progression by mitigating tau pathology in the presence of amyloid pathology and, as a consequence, maintains cognitive function. Targeting the enzyme PLCG2 might provide a new therapeutic approach for treating AD.

ZusammenfassungDie portale Hypertension bei Patienten mit Leberzirrhose kann nicht nur durch interventionelle (TIPS: transjugulärer portosystemischer Stent-Shunt) oder operative Shuntanlagen, sondern auch medikamentös beeinflusst werden. Zahlreiche Studien beschäftigten sich mit der Frage, ob diese Substanzen bei dauerhafter Gabe zu einer Prognoseverbesserung bei Patienten mit Leberzirrhose führen können. Nicht selektive Betablocker (NSBB), Statine, Antibiotika, Enoxaparin und Albumin haben viele Angriffspunkte in der Pathogenese der portalen Hypertension oder bei Dekompensation der Leberzirrhose, sodass sie grundsätzlich als Kandidaten für eine Langzeittherapie infrage kommen. Während es für NSBB, Antibiotika und Albumin klare Indikationen in der Versorgung von Patienten mit dekompensierter Leberzirrhose gibt, ist dies weniger geklärt für den Einsatz von Statinen oder Antikoagulanzien. Neuere Untersuchungen ergaben widersprüchliche Ergebnisse, wenn der primäre Endpunkt einer Studie die Prognoseverbesserung oder die Vermeidung einer Dekompensation der Zirrhose durch eine dauerhafte medikamentöse Therapie war. Zum jetzigen Zeitpunkt ergibt sich aufgrund der aktuellen Studienlage keine Veranlassung, das bisherige, in Leitlinien abgesicherte Vorgehen im täglichen Alltag zu ändern. Diese Übersicht gibt einen Überblick zum Einsatz von NSBB, Antibiotika, Statinen, Antikoagulanzien und Albumin bei Komplikationen der portalen Hypertension insbesondere im Hinblick auf ihren dauerhaften Einsatz zur Verbesserung des Überlebens von Patienten mit Leberzirrhose.

The prevalence of brain pathologies increases with age and cognitive and physical functions worsen over the lifetime. It is unclear whether these processes show a similar increase with age. We studied the association of markers for brain pathology cognitive and physical functions with age in 288 cognitively normal individuals aged 60–102 years selected from the cross-sectional EMIF-AD PreclinAD and 90+ Study at the Amsterdam UMC. An abnormal score was consistent with a score below the 5th percentile in the 60- to 70-year-old individuals. Prevalence of abnormal scores was estimated using Generalized Estimating Equations (GEE) models. The prevalence of abnormal handgrip strength, the Digit Symbol Substitution Test, and hippocampal volume showed the fastest increase with age and abnormal MMSE score, muscle mass, and amyloid aggregation the lowest. The increase in prevalence of abnormal markers was partly dependent on sex, level of education, and amyloid aggregation. We did not find a consistent pattern in which markers of brain pathology cognitive and physical processes became abnormal with age.

Gender-related alcohol and drug abuse problems are related not only to biological differences, but also to social and environmental factors, which can influence the clinical presentation, consequences of use, and treatment approaches. Women are becoming the fastest-growing population of substance abusers in the United States. Given that women experience a more rapid progression of their addiction than men, it is important that we understand and address the differences to help develop prevention and treatment programs that are tailored for women, incorporating trauma assessment and management, identification and intervention for medical and psychiatric comorbidities, financial independence, pregnancy, and child care.

ZusammenfassungDie Leitlinie Komplikationen der Leberzirrhose der Deutschen Gesellschaft für Gastroenterologie, Verdauungs- und Stoffwechselkrankheiten (DGVS) ersetzt die Leitlinie aus dem Jahr 2011. Sie basiert auf den Empfehlungen der Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften (AWMF) für eine evidenzbasierte Konsensus-Leitlinie der Entwicklungsstufe S2k und wurde interdisziplinär unter Beteiligung aller relevanten Fachgesellschaften und der Patientenvertretung erstellt. Neben den in der Vorgängerversion behandelten Kapiteln Aszites, spontan bakterielle Peritonitis, hepatorenales Syndrom, hepatischer Hydrothorax und hepatopulmonales Syndrom wurden die Kapitel Diagnostik und Therapie der Hepatischen Enzephalopathie neu aufgenommen.

Background This study aimed to develop a predictive model to quantify the risk of student harmful drinking associated with emergency department (ED) visits and/or campus-wide incidents reported to campus authorities in a U.S. public university. Methods Six-year (2010/11–2015/16) student enrollment data were linked to subsequent harmful drinking events defined as either alcohol intoxication associated with ED visits or alcohol-related incidents reported to authorities within 1 year following the annual (index) enrollment. Multivariable logistic regression analysis was used to develop a risk predictive model based on the first 3-year student cohort (n = 93,289), which was then validated in the following 3-year student cohort (n = 85,876). Results A total of 2609 students in the derivation cohort and 2617 students in the validation cohort had at least 1 harmful drinking event within 1 year following the index enrollment, providing an incidence of 2.8% and 3.1%, respectively. Student demographics (gender, age, ethnicity, parental tax dependency), academic level, Greek life member, transfer students, first-time enrolled students, having been diagnosed with depression or injury, and violence involvement were statistically significant predictors. C-statistics of the model were 0.86 in both cohorts, with excellent calibration and no evidence of over- or under-prediction observed from calibration plots. Conclusions By linking routinely collected student data, a robust risk predictive model was developed and validated to quantify absolute risk of harmful drinking for every student. This model can provide a useful tool for clinicians or health educators to make real time decision to plan target interventions for students at elevated risk.

Objectives The fraction of the population that reaches the age of 100 years is growing. At this age, dementia incidence is high and cognitive functioning is highly variable across individuals. Normative data for neuropsychological tests are lacking in centenarians, which hampers the ability to evaluate their cognitive functioning for both research and clinical practice. Here, we generated norms for neuropsychological tests in a sample of cognitively healthy centenarians while taking sensory impairments into account. Design Cross-sectional cohort study. Setting Centenarians who participate in the prospective 100-plus Study. Participants A total of 235 centenarians (71.5% female), who self-reported to be cognitively healthy, which was confirmed by an informant and a trained researcher. Measurements We generated normative data for 15 cognitive tests, measuring global cognition (Mini-Mental State Examination [MMSE]), premorbid intelligence, attention, language, memory, executive function, and visuospatial function by multiple linear regressions and/or by reporting percentiles. Results Normative data for global cognition resulted in a mean MMSE score of 25.6 ± 3.1 (range = 17-30; interquartile range = 24-28). Vision problems and fatigue often complicated the ability to complete tests, and these problems explained 41% and 22% of the missing test scores, respectively. In contrast, hearing problems (4%) and task incomprehension (6%) rarely complicated test performance. While educational level was associated with performance on the majority of the tests, sex and age were only weakly associated with test performance. Conclusions We generated normative data for 15 common neuropsychological tests in a large sample of cognitively healthy centenarians, while taking age-related sensory impairments into consideration. These normative data allow the detection of deficits across a wide range of cognitive domains. Our results suggest that, next to education level, vision ability and the level of fatigue should be taken into account when evaluating cognitive functioning in centenarians. J Am Geriatr Soc 67:759-767, 2019.

Integrated disease management with self-management for Chronic Obstructive Pulmonary Disease (COPD) is effective to improve clinical outcomes. eHealth can improve patients' involvement to be able to accept and maintain a healthier lifestyle. Eventhough there is mixed evidence of the impact of eHealth on quality of life (QoL) in different settings.The primary aim of the e-Vita-COPD-study was to investigate the effect of use of eHealth patient platforms on disease specific QoL of COPD patients.We evaluated the impact of an eHealth platform on disease specific QoL measured with the clinical COPD questionnaire (CCQ), including subscales of symptoms, functional state and mental state. Interrupted time series (ITS) design was used to collect CCQ data at multiple time points. Multilevel linear regression modelling was used to compare trends in CCQ before and after the eHealth intervention.Of 742 invited COPD patients, 244 signed informed consent. For the analyses, we only included patients who actually used the eHealth platform (n = 123). The decrease of CCQ-symptoms was 0,20% before the intervention and 0,27% after the intervention; this difference was statistically significant (P=0.027). The decrease of CCQ-mental was 0,97% before the intervention and after the intervention there was an increase of 0,017%; this difference was statistically significant (P=0,01). No significant difference was found in the slopes of CCQ (P=0,12) and CCQ-function (P=0,11) before and after the intervention.The e-Vita eHealth platform had a potential beneficial impact on the CCQ-symptoms of COPD patients, but not on functional state. The CCQ-mental state remained stable after the intervention, but this was a deterioration compared to the improving situation before the start of the eHealth platform. In conclusion, this study shows that after the introduction of the COPD platform, patients experienced fewer symptoms, but their mental state deteriorated slightly at the same time. Therefore, health care providers should be aware that, although symptoms improve, there might be a slight increase in anxiety and depression after introducing an eHealth intervention to support self-management.Achtergrond: Een integrale behandeling inclusief zelfmanagement bij chronisch obstructieve longziekte (COPD) leidt tot betere klinische resultaten. eHealth kan zorgen voor meer betrokkenheid bij patiënten waardoor ze in staat zijn een gezondere levensstijl aan te nemen en vast te houden. Desondanks is er geen eenduidig bewijs van de impact van eHealth op de kwaliteit van leven (quality of life (QoL)). Doel: Het primaire doel van de e-Vita COPD-studie was om te onderzoeken wat de effecten zijn van het gebruik van een eHealth-platform voor patiënten op de verschillende domeinen van ziektespecifieke kwaliteit van leven van COPD-patiënten (CCQ). Methoden: We hebben de impact beoordeeld van het gebruik van een eHealth-platform op de klinische COPD-vragenlijst (CCQ). Deze vragenlijst omvatte subschalen van symptomen, functionele en mentale toestand. Een design met onderbroken tijdreeksen (interrupted time series (ITS)) is gebruikt om CCQ-gegevens op verschillende tijdstippen te verzamelen. Er is gebruik gemaakt van multilevel lineaire regressieanalyse om de CCQ-trends vóór en na de interventie te vergelijken. Resultaten: Van de 742 uitgenodigde COPD-patiënten hebben er 244 het document voor ‘informed consent’ ondertekend. In de analyses hebben we uitsluitend patiënten opgenomen die daadwerkelijk gebruik hebben gemaakt van het eHealth-platform (n=123). De afname van CCQ-symptomen was 0,20% vóór de interventie en 0,27% na de interventie; dit was een statistisch significant verschil (P=0,027). De daling van CCQ-mentale toestand was 0,97% vóór de interventie en na de interventie was er sprake van een stijging van 0,017%; dit verschil was statistisch significant (P=0,01). Er werd geen significant verschil vastgesteld in het verloop van CCQ (P=0,12) en CCQ-functionele toestand (P=0,11) vóór en na de interventie. Conclusie: Het e-Vita eHealth-platform had een gunstig effect op de CCQ-symptomen van COPD-patiënten, maar niet op de functionele status. De CCQ-mentale toestand bleef stabiel na de interventie, maar dit was een verslechtering in vergelijking met de verbeterende situatie voorafgaand aan de start van het eHealth-platform. Deze studie laat dus zien dat patiënten na de introductie van het COPD-platform minder symptomen ervaarden, maar dat hun mentale toestand tegelijkertijd licht verslechterde. Zorgprofessionals moeten zich ervan bewust zijn dat, ondanks de verbetering van symptomen, er een lichte toename van angst en depressie kan optreden na invoering van een eHealth-interventie.

Opioid-related deaths are a leading cause of accidental deaths in the United States (U.S.). This study aims to examine the national trends in opioid exposures reported to U.S. poison centers (PCs).The National Poison Data System (NPDS) was queried for opioid exposures between 2011 and 2018. We descriptively assessed the demographic and clinical characteristics. Trends in opioid frequencies and rates were analyzed using Poisson regression. Independent predictors of serious adverse events in opioid exposures were studied.There were a total of 604,183 opioid exposure calls made to the PCs during the study period. The frequency of opioid exposures decreased by 28.9% (95% CI: -29.6%, -28.1%;Analysis of calls to PCs indicated a decreasing trend of opioid exposures. However, the proportion of SAEs due to such exposures increased. There was a high proportion of intentional exposures and occurred in older age groups. PCs are a vital component of real-time public health surveillance of overdoses in the current opioid crisis.

Studying the genome of centenarians may give insights into the molecular mechanisms underlying extreme human longevity and the escape of age-related diseases. Here, we set out to construct polygenic risk scores (PRSs) for longevity and to investigate the functions of longevity-associated variants. Using a cohort of centenarians with maintained cognitive health (N = 343), a population-matched cohort of older adults from 5 cohorts (N = 2905), and summary statistics data from genome-wide association studies on parental longevity, we constructed a PRS including 330 variants that significantly discriminated between centenarians and older adults. This PRS was also associated with longer survival in an independent sample of younger individuals (p = .02), leading up to a 4-year difference in survival based on common genetic factors only. We show that this PRS was, in part, able to compensate for the deleterious effect of the APOE-ε4 allele. Using an integrative framework, we annotated the 330 variants included in this PRS by the genes they associate with. We find that they are enriched with genes associated with cellular differentiation, developmental processes, and cellular response to stress. Together, our results indicate that an extended human life span is, in part, the result of a constellation of variants each exerting small advantageous effects on aging-related biological mechanisms that maintain overall health and decrease the risk of age-related diseases.

Objective: To investigate the relationship between amyloid-beta (A beta) deposition and markers of brain structure on cognitive decline in oldest-old individuals with initial normal cognition. Methods: We studied cognitive functioning in four domains at baseline and change over time in fifty-seven cognitively intact individuals from the EMIF-AD 90+ study. Predictors were A beta status determined by [F-18]-flutemetamol PET (normal = A beta - vs. abnormal = A beta+), cortical thickness in 34 regions and hippocampal volume. Mediation analyses were performed to test whether effects of A beta on cognitive decline were mediated by atrophy of specific anatomical brain areas. Results: Subjects had a mean age of 92.7 +/- 2.9 years, of whom 19 (33%) were A beta+. Compared to A beta-, A beta+ individuals showed steeper decline on memory (beta +/- SE = -0.26 +/- 0.09), and processing speed (beta +/- SE = -0.18 +/- 0.08) performance over 1.5 years (P < 0.05). Furthermore, medial and lateral temporal lobe atrophy was associated with steeper decline in memory and language across individuals. Mediation analyses revealed that part of the memory decline observed in A beta+ individuals was mediated through parahippocampal atrophy. Interpretation: These results show that A beta abnormality even in the oldest old with initially normal cognition is not part of normal aging, but is associated with a decline in cognitive functioning. Other pathologies may also contribute to decline in the oldest old as cortical thickness predicted cognitive decline similarly in individuals with and without A beta pathology.

© 2021 American Medical Association. All rights reserved.Importance: Understanding mechanisms associated with prolonged cognitive health in combination with exceptional longevity might lead to approaches to enable successful aging. Objective: To investigate trajectories of cognitive functioning in centenarians across domains, and to examine the association of these trajectories with factors underlying cognitive reserve, physical health, and postmortem levels of Alzheimer disease (AD)-associated neuropathology. Design, Setting, and Participants: This cohort study used neuropsychological test data and postmortem neuropathological reports from Dutch centenarians who were drawn from the 100-plus Study between January 2013 and April 2019. Eligible participants self-reported being cognitively healthy, which was confirmed by a proxy. Data analysis was performed between June 2019 and June 2020. Exposures: Age, sex, APOE ϵ genotype, factors of cognitive reserve, physical health, and AD-associated neuropathology (ie, amyloid-β, neurofibrillary tangles, and neuritic plaques). Main Outcomes and Measures: In annual visits (until death or until participation was no longer possible), centenarians underwent an extensive neuropsychological test battery, from which an mean z score of global cognition, memory, executive functions, verbal fluency, visuospatial functions, and attention/processing speed was calculated. Linear mixed models with a random intercept and time as independent variable were used to investigate cognitive trajectories, adjusted for sex, age, education, and vision and hearing capacities. In a second step, linear mixed models were used to associate cognitive trajectories with factors underlying cognitive reserve, physical health at baseline, and AD-associated neuropathology. Results: Of the 1023 centenarians approached, 340 were included in the study. We analyzed 330 centenarians for whom cognitive tests were available at baseline (239 [72.4%] women; median [interquartile range] age of 100.5 [100.2-101.7] years), with a mean (SD) follow-up duration of 1.6 (0.8) years. We observed no decline across investigated cognitive domains, with the exception of a slight decline in memory function (β, -0.10 SD per year; 95% CI, -0.14 to -0.05 SD; P

Introduction: We investigated relationships among genetic determinants of Alzheimer's disease (AD), amyloid/tau/neurodegenaration (ATN) biomarkers, and risk of dementia.Methods: We studied cognitively normal individuals with subjective cognitive decline (SCD) from the Amsterdam Dementia Cohort and SCIENCe project. We examined associations between genetic variants and ATN biomarkers, and evaluated their predictive value for incident dementia. A polygenic risk score (PRS) was calculated based on 39 genetic variants. The APOE gene was not included in the PRS and was analyzed separately.Results: The PRS and APOE ε4 were associated with amyloid-positive ATN profiles, and APOE ε4 additionally with isolated increased tau (A-T+N-). A high PRS and APOE ε4 separately predicted AD dementia. Combined, a high PRS increased while a low PRS attenuated the risk associated with ε4 carriers.Discussion: Genetic variants beyond APOE are clinically relevant and contribute to the pathophysiology of AD. In the future, a PRS might be used in individualized risk profiling.

Infants with MLL-rearranged infant acute lymphoblastic leukemia (MLL-r iALL) undergo intense therapy to counter a highly aggressive malignancy with survival rates of only 30–40%. The majority of patients initially show therapy response, but in two-thirds of cases the leukemia returns, typically during treatment. The glucocorticoid drug prednisone is established as a major player in the treatment of leukemia and the in vivo response to prednisone monotreatment is currently the best indicator of risk for MLL-r iALL. We used two different single-cell RNA sequencing technologies to analyze the expression of a prednisone-dependent signature, derived from an independent study, in diagnostic bone marrow and peripheral blood biopsies. This allowed us to classify individual leukemic cells as either resistant or sensitive to treatment and show that quantification of these two groups can be used to better predict the occurrence of future relapse in individual patients. This work also sheds light on the nature of the therapy-resistant subpopulation of relapse-initiating cells. Leukemic cells associated with high relapse risk are characterized by basal activation of glucocorticoid response, smaller size, and a quiescent gene expression program with cell stemness properties. These results improve current risk stratification and elucidate leukemic therapy-resistant subpopulations at diagnosis.

Kidney tumours are among the most common solid tumours in children, comprising distinct subtypes differing in many aspects, including cell-of-origin, genetics, and pathology. Pre-clinical cell models capturing the disease heterogeneity are currently lacking. Here, we describe the first paediatric cancer organoid biobank. It contains tumour and matching normal kidney organoids from over 50 children with different subtypes of kidney cancer, including Wilms tumours, malignant rhabdoid tumours, renal cell carcinomas, and congenital mesoblastic nephromas. Paediatric kidney tumour organoids retain key properties of native tumours, useful for revealing patient-specific drug sensitivities. Using single cell RNA-sequencing and high resolution 3D imaging, we further demonstrate that organoid cultures derived from Wilms tumours consist of multiple different cell types, including epithelial, stromal and blastemal-like cells. Our organoid biobank captures the heterogeneity of paediatric kidney tumours, providing a representative collection of well-characterised models for basic cancer research, drug-screening and personalised medicine., Pre-clinical cell culture models capturing the heterogeneity of childhood kidney tumours are limited. Here, the authors establish and characterise an organoid biobank of tumour and matched normal organoid cultures from over 50 children with different subtypes of kidney cancer.

ATENCIÓ: la correcció està també al DDD, cal relacionar??? https://ddd.uab.cat/record/226203 Altres ajuts: The following studies and consortia have contributed to this manuscript. Amsterdam dementia Cohort (ADC): Research of the Alzheimer center Amsterdam is part of the neurodegeneration research program of Amsterdam Neuroscience. The Alzheimer Center Amsterdam is supported by Stichting Alzheimer Nederland and Stichting VUmc fonds. The clinical database structure was developed with funding from Stichting Dioraphte. Genotyping of the Dutch case-control samples was performed in the context of EADB (European Alzheimer DNA biobank) funded by the JPco-fuND FP-829-029 (ZonMW projectnumber 733051061). 100-Plus study: We are grateful for the collaborative efforts of all participating centenarians and their family members and/or relations. This work was supported by Stichting Alzheimer Nederland (WE09.2014-03), Stichting Diorapthe, horstingstuit foundation, Memorabel (ZonMW projectnumber 733050814) and Stichting VUmc Fonds. Genotyping of the 100-Plus Study was performed in the context of EADB (European Alzheimer DNA biobank) funded by the JPco-fuND FP-829-029 (ZonMW projectnumber 733051061). German Study on Ageing, Cognition and Dementia in Primary Care Patients (AgeCoDe): This study/publication is part of the German Research Network on Dementia (KND), the German Research Network on Degenerative Dementia (KNDD; German Study on Ageing, Cognition and Dementia in Primary Care Patients; AgeCoDe), and the Health Service Research Initiative (Study on Needs, health service use, costs and health-related quality of life in a large sample of oldest-old primary care patients (85+; AgeQualiDe)) and was funded by the German Federal Ministry of Education and Research (grants KND: 01GI0102, 01GI0420, 01GI0422, 01GI0423, 01GI0429, 01GI0431, 01GI0433, 01GI0434; grants KNDD: 01GI0710, 01GI0711, 01GI0712, 01GI0713, 01GI0714, 01GI0715, 01GI0716; grants Health Service Research Initiative: 01GY1322A, 01GY1322B, 01GY1322C, 01GY1322D, 01GY1322E, 01GY1322F, 01GY1322G). Alfredo Ramirez was partly supported by the ADAPTED consortium: Alzheimer's disease Apolipoprotein Pathology for Treatment Elucidation and Development, which has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 115975. Brain compendium: This work was funded by the UK Medical Research Council (13044). P.F.C. is a Wellcome Trust principal Fellow (212219/Z/18/Z) and a UK NIHR Senior Investigator, who receives support from the Medical Research Council Mitochondrial Biology Unit (MC_UU_00015/9), and the National Institute for Health Research (NIHR) Biomedical Research Centre based at Cambridge University Hospitals NHS Foundation Trust and the University of Cambridge. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health.Clinical AD, Sweden: We would like to thank UCL Genomics for performing the genotyping analyses. Danish data: The studies behind the Danish long-lived cases received funding from The National Program for Research Infrastructure 2007 (grant no. 09-063256), the Danish Agency for Science Technology and Innovation, the Velux Foundation, the US National Institute of Health (P01 AG08761), the Danish Agency for Science, Technology and Innovation/The Danish Council for Independent Research (grant no. 11-107308), the European Union's Seventh Framework Programme (FP7/2007-2011) under grant agreement no. 259679, the INTERREG 4 A programme Syddanmark-Schleswig-K.E.R.N. (by EU funds from the European Regional Development Fund), the CERA Foundation (Lyon), the AXA Research Fund, Paris, and The Health Foundation (Helsefonden), Copenhagen, Denmark. The GOYA study was conducted as part of the activities of the Danish Obesity Research Centre (DanORC, www.danorc.dk) and The MRC centre for Causal Analyses in Translational Epidemiology (MRC CAiTE). The genotyping for GOYA was funded by the Wellcome Trust (WT 084762). GOYA is a nested study within The Danish National Birth Cohort which was established with major funding from the Danish National Research Foundation. Additional support for this cohort has been obtained from the Pharmacy Foundation, the Egmont Foundation, The March of Dimes Birth Defects Foundation, the Augustinus Foundation, and the Health Foundation. Fundació ACE (FACE): We would like to thank patients and controls who participated in this project. We are indebted to Trinitat Port-Carbó and her family for their support of Fundació ACE research programs. Fundació ACE collaborates with the Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, Spain) and is one of the participating centers of the Dementia Genetics Spanish Consortium (DEGESCO). Agustín Ruiz has received support from the EU/EFPIA Innovative Medicines Initiative Joint Undertaking ADAPTED Grant No. 115975 and by grants PI13/02434 and PI16/01861. Acción Estratégica en Salud, integrated in the Spanish National R + D + I Plan and financed by ISCIII (Instituto de Salud Carlos III)-Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER- "Una manera de Hacer Europa"), by Fundación bancaria "La Caixa" and Grifols SA (GR@ACE project). Genetics of Healthy Ageing Study (GEHA - NL): The work described in this paper was funded mainly by the EU GEHA Project contract no. LSHM-CT-2004-503-270. Gothenburg Birth Cohort (GBC) Studies: We would like to thank UCL Genomics for performing the genotyping analyses. The studies were supported by The Stena Foundation, The Swedish Research Council (2015-02830, 2013-8717), The Swedish Research Council for Health, Working Life and Wellfare (2013-1202, 2005-0762, 2008-1210, 2013-2300, 2013-2496, 2013-0475), The Brain Foundation, Sahlgrenska University Hospital (ALF), The Alzheimer's Association (IIRG-03-6168), The Alzheimer's Association Zenith Award (ZEN-01-3151), Eivind och Elsa K:son Sylvans Stiftelse, The Swedish Alzheimer Foundation. International FTD-Genomics Consortium (IFGC): International FTD-Genomics Consortium (IFGC): The authors thank the IFGC for providing relevant data to support the analyses presented in this manuscript. Further acknowledgments for IFGC (https://ifgcsite.wordpress.com/), e.g. full members list and affiliations, are found in the online supplementary files. IPDGC (​The International Parkinson Disease Genomics Consortium): We also would like to thank all members of the International Parkinson Disease Genomics Consortium (IPDGC). See for a complete overview of members, acknowledgements and funding http://pdgenetics.org/partners. Kompetenznetz Multiple Sklerose (KKNMS): This work was supported by the German Ministry for Education and Research (BMBF) as part of the "German Competence Network Multiple Sclerosis" (KKNMS) (grant nos. 01GI0916 and 01GI0917) and the Munich Cluster for Systems Neurology (SyNergy). TA was supported by the BMBF through the Integrated Network IntegraMent, under the auspices of the e:Med Programme (01ZX1614J). BH was supported by the EU Horizon 2020 project MultipleMS.Longitudinal Aging Study Amsterdam (LASA) is largely supported by a grant from the Netherlands Ministry of Health, Welfare and Sports, Directorate of Long-Term Care. The authors are grateful to all LASA participants, the fieldwork team and all researchers for their ongoing commitment to the study. Leiden Longevity Study: This study was supported by a grant from the Innovation-Oriented Research Program on Genomics (SenterNovem IGE05007), the Centre for Medical Systems Biology, and the Netherlands Consortium for Healthy Ageing (Grant 050-060-810), all in the framework of the Netherlands Genomics Initiative/Netherlands Organization for Scientific Research (NWO) and by Unilever Colworth.Maria Carolina Dalmasso: Georg Forster Research Award (Alexander von Humboldt Foundation). Mayo Clinic AD, DLB, PD, PSP: We thank the patients and their families for their participation, without whom these studies would not have been possible. Funding for this work was supported by National Institute on Aging [RF AG051504 to NET.; U01 AG046139 to NET]; and National Institute of Neurological Disorders and Stroke [R01 NS080820 to NET; P50 NS072187]. The Mayo Clinic is a Lewy Body Dementia Association (LBDA) Research Center of Excellence, American Parkinson Disease Association (APDA) Information and Referral Center and Center for Advanced Research, NINDS Tau Center without Walls (U54-NS100693) and is supported by Mayo Clinic AD and related dementias genetics program, The Little Family Foundation, the Mangurian Foundation for Lewy body research and NINDS R01 NS078086 (to OAR). The PD program at the Mayo Clinic Florida is also supported by the Mayo Clinic Center for Regenerative Medicine, Mayo Clinic Center for Individualized Medicine, Mayo Clinic Neuroscience Focused Research Team (Cecilia and Dan Carmichael Family Foundation, and the James C. and Sarah K. Kennedy Fund for Neurodegenerative Disease Research at Mayo Clinic in Florida), the gift from Carl Edward Bolch, Jr., and Susan Bass Bolch, and The Sol Goldman Charitable Trust. Samples included in this study are from the brain bank at Mayo Clinic in Jacksonville which is supported by CurePSP The online version of this article (10.1007/s00401-019-02026-8) contains supplementary material, which is available to authorized users.

This study compares the incidence and risk-markers of student alcohol intoxication-related emergency department (ED) visits and alcohol-related incidents reported to student affairs. Methods: Enrol...

The incidence of milk leakage (ML) after dry-off (DO) and related risk factors was studied in 1,175 dairy cows from 41 commercial herds in 8 European countries: Belgium, Czech Republic, Denmark, France, Germany, Italy, the Netherlands, and Spain. Milk leakage was assessed twice for 30 s each during 3 visits at 20 to 24 h, 30 to 34 h, and 48 to 52 h after DO. Information related to dry-cow management and udder health was collected at herd and cow level, including individual somatic cell count (ISCC) from test-day controls and occurrence of clinical mastitis cases from DO until 30 d in lactation. Mixed-effect logistic regression analyses were used to identify possible risk factors for ML and to study the association between ML and new intramammary infections. Intramammary infections were defined as clinical mastitis cases during the dry period and in the first 30 d in lactation or a rise in ISCC from before to after the dry period (threshold: 200,000 cells/mL) or both. Milk leakage was observed in 24.5% of the cows between 20 and 52 h after DO, where the herd incidence varied between 0.0 and 77.8%. The reduction in number of milkings in the weeks before DO had statistically significant effect on the ML incidence. When the milking frequency was reduced from 3 times/d to 2 or maintained at twice a day, cows had 11 (95% CI = 3.43-35.46) or 9 (95% CI = 1.85-48.22) times higher odds of leaking milk, respectively, compared with cows where the milking frequency was reduced from twice to once a day. Also, the milk production 24 h before DO was associated with ML incidence. Hence, cows with a milk production between 13 and 21 L or above 21 L had 2.3 (95% CI = 1.48-3.53) and 3.1 (95% CI = 1.79-5.3) times higher odds of leaking milk, respectively, compared with cows with a milk production below 13 L. A higher ML incidence was present in the group of cows with an average ISCC in the last 3 mo before DO ≥200,000 cells/mL (odds ratio = 1.7; 95% CI = 1.13-2.41) compared with cows with an average ISCC100,000 cells/mL. Quarters with ML tended to have 2.0 times higher odds of developing clinical mastitis compared with quarters not leaking milk. Cows with ML tended to have 1.5 times higher odds of intramammary infections (i.e., an increase of ISCC or clinical mastitis) compared with cows without ML.

Alzheimer’s disease (AD) is characterized by amyloid-beta (Aβ) deposits, which come in myriad morphologies with varying clinical relevance. Previously, we observed an atypical Aβ deposit, referred to as the coarse-grained plaque. In this study, we evaluate the plaque’s association with clinical disease and perform in-depth immunohistochemical and morphological characterization. The coarse-grained plaque, a relatively large (Ø ≈ 80 µm) deposit, characterized as having multiple cores and Aβ-devoid pores, was prominent in the neocortex. The plaque was semi-quantitatively scored in the middle frontal gyrus of Aβ-positive cases (n = 74), including non-demented cases (n = 15), early-onset (EO)AD (n = 38), and late-onset (LO)AD cases (n = 21). The coarse-grained plaque was only observed in cases with clinical dementia and more frequently present in EOAD compared to LOAD. This plaque was associated with a homozygous APOE ε4 status and cerebral amyloid angiopathy (CAA). In-depth characterization was done by studying the coarse-grained plaque’s neuritic component (pTau, APP, PrPC), Aβ isoform composition (Aβ40, Aβ42, AβN3pE, pSer8Aβ), its neuroinflammatory component (C4b, CD68, MHC-II, GFAP), and its vascular attribution (laminin, collagen IV, norrin). The plaque was compared to the classic cored plaque, cotton wool plaque, and CAA. Similar to CAA but different from classic cored plaques, the coarse-grained plaque was predominantly composed of Aβ40. Furthermore, the coarse-grained plaque was distinctly associated with both intense neuroinflammation and vascular (capillary) pathology. Confocal laser scanning microscopy (CLSM) and 3D analysis revealed for most coarse-grained plaques a particular Aβ40 shell structure and a direct relation with vessels. Based on its morphological and biochemical characteristics, we conclude that the coarse-grained plaque is a divergent Aβ plaque-type associated with EOAD. Differences in Aβ processing and aggregation, neuroinflammatory response, and vascular clearance may presumably underlie the difference between coarse-grained plaques and other Aβ deposits. Disentangling specific Aβ deposits between AD subgroups may be important in the search for disease-mechanistic-based therapies.

ObjectivesThe objectives of this study were to investigate the effect of genetic and social factors on depressive symptoms and depression over time and to test whether social factors moderate the relationship between depressive symptoms and its underlying genetics in later life.MethodsThe study included 2,279 participants with a mean follow-up of 15 years from the Longitudinal Aging Study Amsterdam with genotyping data. The personal genetic loading for depression was estimated for each participant by calculating a polygenic risk scores (PRS-D), based on 23,032 single nucleotide polymorphisms associated with major depression in a large genome-wide association study. Partner status, network size, received and given emotional support were assessed via questionnaires and depressive symptoms were assessed using the CES-D Scale. A CES-D Scale of 16 and higher was considered as clinically relevant depression.ResultsHigher PRS-D was associated with more depressive symptoms whereas having a partner and having a larger network size were independently associated with less depressive symptoms. After extra adjustment for education, cognitive function and functional limitations, giving more emotional support was also associated with less depressive symptoms. No evidence for gene-environment interaction between PRS-D and social factors was found. Similar results were found for clinically relevant depression.ConclusionGenetic and social factors are independently associated with depressive symptoms over time in older adults. Strategies that boost social functioning should be encouraged in the general population of older adults regardless of the genetic liability for depression.

Infants with MLL-rearranged acute lymphoblastic leukemia (ALL) undergo intense therapy to counter a highly aggressive leukemia with survival rates of only 30-40%. The majority of patients initially show therapy response, but in two-thirds of cases the leukemia returns, typically during treatment. Accurate relapse prediction would enable treatment strategies that take relapse risk into account, with potential benefits for all patients. Through analysis of diagnostic bone marrow biopsies, we show that single-cell RNA sequencing can predict future relapse occurrence. By analysing gene modules derived from an independent study of the gene expression response to the key drug prednisone, individual leukemic cells are predicted to be either resistant or sensitive to treatment. Quantification of the proportion of cells classified by single-cell transcriptomics as resistant or sensitive, accurately predicts the occurrence of future relapse in individual patients. Strikingly, the single-cell based classification is even consistent with the order of relapse timing. These results lay the foundation for risk-based treatment of MLL-rearranged infant ALL, through single-cell classification. This work also sheds light on the subpopulation of cells from which leukemic relapse arises. Leukemic cells associated with high relapse risk are characterized by a smaller size and a quiescent gene expression program. These cells have significantly fewer transcripts, thereby also demonstrating why single-cell analyses may outperform bulk mRNA studies for risk stratification. This study indicates that single-cell RNA sequencing will be a valuable tool for risk stratification of MLL-rearranged infant ALL, and shows how clinically relevant information can be derived from single-cell genomics.Key PointsSingle-cell RNA sequencing accurately predicts relapse in MLL-rearranged infant ALLIdentification of cells from which MLL-rearranged infant ALL relapses occur

Processing of genital sensations in the central nervous system of humans is still poorly understood. Current knowledge is mainly based on neuroimaging studies using electroencephalography (EEG), magneto-encephalography (MEG), and 1.5- or 3- Tesla (T) functional magnetic resonance imaging (fMRI), all of which suffer from limited spatial resolution and sensitivity, thereby relying on group analyses to reveal significant data. Here, we studied the impact of passive, yet non-arousing, tactile stimulation of the penile shaft using ultra-high field 7T fMRI. With this approach, penile stimulation evoked significant activations in distinct areas of the primary and secondary somatosensory cortices (S1 & S2), premotor cortex, insula, midcingulate gyrus, prefrontal cortex, thalamus and cerebellum, both at single subject and group level. Passive tactile stimulation of the feet, studied for control, also evoked significant activation in S1, S2, insula, thalamus and cerebellum, but predominantly, yet not exclusively, in areas that could be segregated from those associated with penile stimulation. Evaluation of the whole-brain activation patterns and connectivity analyses indicate that genital sensations following passive stimulation are, unlike those following feet stimulation, processed in both sensorimotor and affective regions.

Following the analysis for the broiler sector, at the request of the poultry sector and the Ministry of Agriculture, Nature and Food Quality, an analysis of antibiotic use prescriptions was carried out at rearing farms in the broiler poultry sector. The analysis focused on associations between antibiotic use and farm and management factors from the CRA-KIP dataset in the years 2016-2018. In navolging van de analyse voor de vleeskuikensector is op verzoek van pluimveesector en ministerie LNV een analyse uitgevoerd van antibioticumgebruiksvoorschriften op opfokfok- en opfokvermeerderingsbedrijven in de vleespluimveesector. Er is gezocht naar associaties tussen antibioticumgebruik en bedrijfs- en managementfactoren uit de CRA- en KIP-databank in de periode 2016-2018.

BACKGROUND AND AIMS In the United States, access to naloxone has been expanded as a measure to address growing opioid overdose mortality. The study aimed to describe the national trends in naloxone use as reported to the US poison centers (PCs). METHODS The National Poison Data System (NPDS) was queried for cases reporting naloxone therapy from 1 January 2001 to 31 December 2016. Demographic and clinical characteristics were assessed descriptively. Trends in naloxone reports were evaluated by using generalized linear mixed models that were adjusted for age, gender and random effects of the geographical census region. Cumulative incidence rates (CIR) of naloxone reports at the state- and national-level were calculated. RESULTS There were 304 249 cases reporting naloxone therapy during the study period. The frequency of naloxone reports increased from 9498 in 2000 to 26 826 in 2016. The proportion of cases where naloxone was used prior to PC recommendation increased from 59.8% in 2000 to 81.5% in 2016. The mean number of NPDS naloxone reports per 100 000 human exposures increased from 9.6 [95% confidence interval (CI) = 6.4-14.2] to 31.7 (95% CI = 21.4-46.9, P

With aging, the incidence of neuropathological hallmarks of neurodegenerative diseases increases in the brains of cognitively healthy individuals. It is currently unclear to what extent these hallmarks associate with symptoms of disease at extreme ages. Forty centenarians from the 100-plus Study cohort donated their brain. Centenarians self-reported to be cognitively healthy at baseline, which was confirmed by a proxy. Objective ante-mortem measurements of cognitive performance were associated with the prevalence, distribution and quantity of age- and AD-related neuropathological hallmarks. Despite self-reported cognitive health, objective neuropsychological testing suggested varying levels of ante-mortem cognitive functioning. Post-mortem, we found that neuropathological hallmarks related to age and neurodegenerative diseases, such as Aβ and Tau pathology, as well as atherosclerosis, were abundantly present in most or all centenarians, whereas Lewy body and pTDP-43 pathology were scarce. We observed that increased pathology loads correlated across pathology subtypes, and an overall trend of higher pathology loads to associate with a lower cognitive test performance. This trend was carried especially by the presence of neurofibrillary tangles (NFTs) and granulovacuolar degeneration (GVD) and to a lesser extent by Aβ-associated pathologies. Cerebral Amyloid Angiopathy (CAA) specifically associated with lower executive functioning in the centenarians. In conclusion, we find that while the centenarians in this cohort escaped or delayed cognitive impairment until extreme ages, their brains reveal varying levels of disease-associated neuropathological hallmarks, some of which associate with cognitive performance. Electronic supplementary material The online version of this article (10.1186/s40478-018-0558-5) contains supplementary material, which is available to authorized users.

To examine the trends in incidence and socio-demographic, organizational, academic, and clinical risk markers of student alcohol intoxication associated with emergency department (ED) visits.Student admission data from 2009 to 2015 were linked to primary healthcare data and subsequent ED visits with alcohol intoxication identified using ICD-9 codes within one year following the first (index) enrollment each year. Incidence rate per 10,000 person-years was calculated. Cox proportional hazard regression provided adjusted hazard ratios (HR) (95 % CIs) for the association between student characteristics and subsequent ED visits with alcohol intoxication.Of 177,128 students aged 16-49 enrolled, 889 had at least one ED visit with alcohol intoxication, resulting in an incidence rate of 59/10,000 person-years. Incidence increased linearly from 45/10,000 person-years in 2009-10 to 71/10,000 person-years in the 2014-15 academic year (p 0.001). HRs (95%CIs) of student characteristics associated with this outcome were: males (versus females): 1.38 (1.21-1.58); below 20 years of age (versus 25-30 years): 3.36 (1.99-5.65); Hispanic (versus Asian) students: 1.61 (1.16-2.25); parental tax dependency: 1.49 (1.16-1.91); Greek life member: 1.96 (1.69-2.26); member of an athletic team: 0.51 (0.36-0.72); undergraduate (versus graduate) students: 2.65 (1.88-3.74). Past year alcohol use or having been diagnosed with depression or anxiety were also significant predictors. Adjustments for campus-related factors strongly attenuated the associations between student socio-demographic characteristics with this outcome.Linking student admission data with ED clinical data can help monitor student alcohol intoxication associated with ED visits and identify student groups at higher risk who subsequently can be targeted for intervention efforts.

The aim of this systematic review was to identify isolated acute cyanide poison cases and to identify reported signs, symptoms, and laboratory findings.We searched MEDLINE, Cochrane Reviews, and Web of Science case reports and series using a number of MeSH descriptors pertaining to cyanide, toxicity, and poisonings. We excluded studies on plants, laboratory analyses, smoke inhalation poisonings, animals as well as non-English language articles and those in which data were not available. Data extracted included demographics, exposure characteristics, acute signs/symptoms, and medical management and outcome.From the initial 2976 articles retrieved, 65 articles (52 case reports, 13 case series) met inclusion criteria and described 102 patients. Most patients were unresponsive (78%), hypotensive (54%), or had respiratory failure (73%); other signs and symptoms included cardiac arrest (20%), seizures (20%), cyanosis (15%), cherry red skin (11%), and had an odor present (15%). Medical management included cyanide antidote kit (20%), sodium thiosulfate (40%), and hydroxocobalamin (29%). The majority of cases (66%) required intubation with mechanical ventilation and a substantial number (39%) developed refractory hypotension requiring vasopressor support.Contrary to general reviews published on cyanide toxicity, reports of cherry red skin and bitter almond odor were rare among published cyanide cases. Consistent with other studies, metabolic acidosis with significant lactic acidosis were the laboratory values consistently associated with cyanide toxicity. Healthcare providers may overlook cyanide toxicity in the differential diagnosis, if certain expected characteristics, such as the odor of almonds or a cherry red color of the skin are absent on physical examination.

OBJECTIVETraumatic neuromas may develop after nerve injury at the proximal nerve stump, which can lead to neuropathic pain. These neuromas are often resistant to therapy, and excision of the neuroma frequently leads to recurrence. In this study, the authors present a novel surgical strategy to prevent neuroma formation based on the principle of centro-central anastomosis (CCA), but rather than directly connecting the nerve ends to an autograft, they created a loop using a 3D-printed polyethylene Y-shaped conduit with an autograft in the distal outlets.METHODSThe 3D-printed Y-tube with autograft was investigated in a model of rat sciatic nerve transection in which the Y-tube was placed on the proximal sciatic nerve stump and a peroneal graft was placed between the distal outlets of the Y-tube to form a closed loop. This model was compared with a CCA model, in which a loop was created between the proximal tibial and peroneal nerves with a peroneal autograft. Additional control groups consisted of the closed Y-tube and the extended-arm Y-tube. Results were analyzed at 12 weeks of survival using nerve morphometry for the occurrence of neuroma formation and axonal regeneration in plastic semi-thin sections.RESULTSAmong the different surgical groups, the Y-tube with interposed autograft was the only model that did not result in neuroma formation at 12 weeks of survival. In addition, a 13% reduction in the number of myelinated axons regenerating through the interposed autograft was observed in the Y-tube with autograft model. In the CCA model, the authors also observed a decrease of 17% in the number of myelinated axons, but neuroma formation was present in this model. The closed Y-tube resulted in minimal nerve regeneration inside the tube together with extensive neuroma formation before the entrance of the tube. The extended-arm Y-tube model clearly showed that the majority of the regenerating axons merged into the Y-tube arm, which was connected to the autograft, leaving the extended plastic arm almost empty.CONCLUSIONSThis pilot study shows that our novel 3D-printed Y-tube model with interposed autograft prevents neuroma formation, making this a promising surgical tool for the management of traumatic neuromas.

In this study, we investigated whether postburn itch in rats, after a full thickness burn, is correlated to the nervous reinnervation of the burn wound area. For this purpose, we determined scratching duration (expressed as second/hour) at 24 hours, 2, 4, 8, and 12 weeks postburn and combined this with immunohistochemistry for protein gene product 9.5 (PGP9.5) to identify all nerve fibers, calcitonin gene related peptide (CGRP) to identify peptidergic fibers, tyrosine hydroxylase (TH) for sympathetic fibers, and growth-associated protein 43 (GAP-43) for regrowing fibers. We found a modest, but highly significant, increase in scratching duration of all burn wound rats from 3 to 12 weeks postburn (maximally 63 ± 9.5 second/hour compared to sham 3.1 ± 1.4 second/hour at 9 weeks). At 24 hours postburn, all nerve fibers had disappeared from the burn area. Around 4 weeks postburn PGP 9.5- and CGRP-immunoreactive nerve fibers returned to control levels. TH- and GAP-43-IR nerve fibers, which we found to be almost completely colocalized, did not regrow. No correlation was found between scratching duration and nervous reinnervation of the skin. The present results suggest that in rat, like in human, burn wound healing will induce increased scratching, which is not correlated to the appearance of nervous reinnervation.

Dear Editor,We agree with Hoyte and Dart that the three-bag Prescott protocol for acetylcysteine is overdue for improvement [1]. We also agree that the key steps in transitioning to a new protocol ...

To the Editor,We read with interest the article by Vo et al. [1] which conducted a retrospective review of venlafaxine overdoses reported to the California Poison Control System between 2006 and 20...

Background Human psittacosis is a highly under diagnosed zoonotic disease, commonly linked to psittacine birds. Psittacosis in birds, also known as avian chlamydiosis, is endemic in poultry, but the risk for people living close to poultry farms is unknown. Therefore, our study aimed to explore the temporal and spatial patterns of human psittacosis infections and identify possible associations with poultry farming in the Netherlands. Methods We analysed data on 700 human cases of psittacosis notified between 01-01-2000 and 01-09-2015. First, we studied the temporal behaviour of psittacosis notifications by applying wavelet analysis. Then, to identify possible spatial patterns, we applied spatial cluster analysis. Finally, we investigated the possible spatial association between psittacosis notifications and data on the Dutch poultry sector at municipality level using a multivariable model. Results We found a large spatial cluster that covered a highly poultry-dense area but additional clusters were found in areas that had a low poultry density. There were marked geographical differences in the awareness of psittacosis and the amount and the type of laboratory diagnostics used for psittacosis, making it difficult to draw conclusions about the correlation between the large cluster and poultry density. The multivariable model showed that the presence of chicken processing plants and slaughter duck farms in a municipality was associated with a higher rate of human psittacosis notifications. The significance of the associations was influenced by the inclusion or exclusion of farm density in the model. Conclusions Our temporal and spatial analyses showed weak associations between poultry-related variables and psittacosis notifications. Because of the low number of psittacosis notifications available for analysis, the power of our analysis was relative low. Because of the exploratory nature of this research, the associations found cannot be interpreted as evidence for airborne transmission of psittacosis from poultry to the general population. Further research is needed to determine the prevalence of C. psittaci in Dutch poultry. Also, efforts to promote PCR-based testing for C. psittaci and genotyping for source tracing are important to reduce the diagnostic deficit, and to provide better estimates of the human psittacosis burden, and the possible role of poultry.

Gender-related alcohol and drug abuse problems are related not only to biological differences, but also to social and environmental factors, which can influence the clinical presentation, consequences of use, and treatment approaches. Women are becoming the fastest-growing population of substance abusers in the United States. Given that women experience a more rapid progression of their addiction than men, it is important that we understand and address the differences to help develop prevention and treatment programs that are tailored for women, incorporating trauma assessment and management, identification and intervention for medical and psychiatric comorbidities, financial independence, pregnancy, and child care.

Objective: To determine whether the implementation of a national program to improve quality of care in geriatric rehabilitation (GR) in the Netherlands improves successful GR in terms of independence in activities of daily living (ADL), discharge destination, and length of stay.Design: Prospective longitudinal study, comparing 2 consecutive cohorts: at the start of implementation (n = 386) and at 1 year after implementation (n = 357) of this program.Setting/Participants: Included were 16 skilled nursing facilities, 743 patients (median age 80 years, interquartile range 72-85; 64.5% females) indicated for GR and their health care professionals (elderly care physicians, physiotherapists, and nursing staff).Intervention: National program to stimulate self-organizing capacity to develop integrated care to improve GR service delivery in 4 domains: alignment with patients' (care) needs, care coordination, team cooperation, and quality of care.Measurements: Data on patients' characteristics, functional outcomes at admission and discharge, length of stay, and discharge destination were collected via an online questionnaire sent to health care professionals. The primary outcome measure was successful rehabilitation defined as independence in ADL (Barthel Index >= 15), discharge home, and a short length of stay (lowest 25% per diagnostic group). Generalized estimating equation analysis was used to adjust for age, gender, and clustering effects in the total population and for the 2 largest diagnostic subgroups, traumatic injuries and stroke. Results: In the total population, at 1 year postimplementation there was 12% more ADL independence [ odds ratio (OR) 1.59, 95% confidence interval (CI) 1.00-2.54]. Although successful rehabilitation (independence in ADL, discharge home, short length of stay) was similar in the 2 cohorts, patients with traumatic injuries were more successful 1 year postimplementation (OR 1.61, 95% CI 1.01-2.54). In stroke patients, successful rehabilitation was similar between the cohorts, but with more independence in ADL in the follow-up cohort (OR 1.99, 95% CI 1.09-3.63).Conclusions: This study shows that 1-year after the implementation of the Dutch national program to improve quality of care there was more independence in ADL at discharge, but the combined outcome of successful GR (independence in ADL, discharge home, short length of stay) was only significantly improved in patients with traumatic injuries. (C) 2016 AMDA - The Society for Post-Acute and Long-Term Care Medicine.

Lobar cerebral microbleeds are most often sporadic and associated with Alzheimer's disease. The aim of our study was to identify the underlying genetic defect in a family with cognitive complaints and multiple lobar microbleeds and a positive family history for early onset Alzheimer's disease. We performed exome sequencing followed by Sanger sequencing for validation purposes on genomic DNA of three siblings with cognitive complaints, reduced amyloid-beta-42 in CSF and multiple cerebral lobar microbleeds. We checked for the occurrence of the variant in a cohort of 363 patients with early onset dementia and/or microbleeds. A novel frameshift variant (c.236_237delAC) generating a premature stop codon in the CCM2 gene shared by all three siblings was identified. Pathogenicity of the variant was supported by the presence of cerebral cavernous malformations in two of the siblings and by the absence of the variant exome variant databases. Two siblings were homozygous for APOE-ϵ4; one heterozygous. The cognitive complaints, reduced amyloid-beta-42 in CSF and microbleeds suggest preclinical Alzheimer's disease, but the stability of the cognitive complaints does not. We hypothesize that the phenotype in this family may be due to a combination of the CCM2 variant and the APOE status. © 2016 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics Published by Wiley Periodicals, Inc.

Loperamide abuse has been increasing in the United States as a potential alternative to manage opioid withdrawal symptoms or to achieve euphoric effects of opioid use. In June 2016, the Food and Drug Administration warned health care providers and the general public about potential serious adverse outcomes, including cardiac dysrhythmias and death. The purpose of this study is to determine recent trends in intentional loperamide abuse and misuse, reported clinical effects and management, and medical outcomes as reported to poison centers across the United States.Loperamide exposures reported to the National Poison Data System indicating intentional misuse, abuse, and suspected suicide between January 1, 2010, and December 31, 2015, were assessed. Demographic and temporal trends, as well as reported clinical effects, medical management, and health outcomes, were analyzed.There was a 91% increase in reported exposures from 2010 to 2015, of which half were single-agent loperamide use only. Loperamide exposures reported to the National Poison Data System increased at approximately 38 cases per year (95% confidence interval [CI] 32.5 to 42.9; P0.0001). Fifteen deaths were reported during this time frame, of which 8 involved single-agent loperamide abuse.Loperamide abuse and misuse are projected to increase in the absence of any methods to reduce exposure or curb abuse. Health care providers should consider the potential for loperamide toxicity when managing patients with opioidlike toxicity.