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Purpose The Scored Patient-Generated Subjective Global Assessment (PG-SGA(C)) is a globally recognized and used nutritional screening, assessment, monitoring, and triaging tool. The aim of this study was to translate and culturally adapt the original English PG-SGA for the Japanese speaking populations and to assess its linguistic validity (i.e., comprehensibility, difficulty) and content validity, as perceived by Japanese patients and healthcare professionals. Methods In accordance with methodology used in previous Dutch, Thai, German, and Norwegian PG-SGA studies, we followed the ten steps of the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) Principles of Good Practice for Translation and Cultural Adaptation for Patient-Reported Outcome Measures. The study enrolled 50 patients and 50 healthcare professionals (HCPs) to evaluate the comprehensibility and difficulty of the translated and culturally adapted PG-SGA. The HCPs also evaluated the content validity of the translation. We evaluated each item and quantified scale indices for content validity (item content validity index (I-CVI), scale content validity index (S-CVI)), comprehensibility (item comprehensibility index (I-CI), scale comprehensibility index (S-CI)), and difficulty (item difficulty index (I-DI), scale difficulty index (S-DI)). Results Patients evaluated the comprehensibility and difficulty of the patient component as excellent (S-CI = 0.97, S-DI = 0.96). The professionals rated the Japanese version of both components of the PG-SGA as very relevant (S-CVI = 0.94). The professionals evaluated the comprehensibility of the professional component as being acceptable (S-CI = 0.88) but difficult (S-DI = 0.69), based predominantly on items related to physical examination (I-DI = 0.33-0.67). Conclusion The PG-SGA was systematically translated and culturally adapted for the Japanese setting according to the ISPOR process. The Japanese version of the PG-SGA was perceived as comprehensive, easy to use, and relevant. Perceived difficulty in professional components, specifically in the context of metabolic demand and physical examination, will require appropriate training for professionals in order to optimize implementation.

Descriptions of the clinical features of Angelman syndrome (AS) have mainly been focused on children. Here, we describe the evolution of the clinical phenotypes of AS in adulthood, using clinical data from 95 individuals (mean age 31.6 years, median 29.0 years, range 18–83 years), with genetically confirmed AS. Data was collected through physical examination and inspection of medical records, combined with questionnaires and interviews. Adults with AS experience substantial debilitating health problems. Constipation, reflux, visual problems, scoliosis, behavioral and sleeping problems occurred frequently and require appropriate attention. Epilepsy was reported in 57% of adults, negatively affecting the level of functioning. Non‐convulsive status epilepticus was not observed in the adults, however some individuals developed prolonged episodes of rhythmic shaking while awake. A decline in mobility was noted in the majority of adults. A minority of adults with AS showed microcephaly. Taken together, this first phenotypic study of adults with AS to include in person interviews with care‐givers and physical examination of patients, including the eldest adult reported to date, provides important insight in the development of the syndrome into adulthood. This knowledge is required to improve care for adult individuals with AS and to evaluate future therapies for this group.

Recently, a petition was offered to the European Commission calling for an immediate ban on animal testing. Although a Europe-wide moratorium on the use of animals in science is not yet possible, there has been a push by the non-scientific community and politicians for a rapid transition to animal-free innovations. Although there are benefits for both animal welfare and researchers, advances on alternate methods have not progressed enough to be able to replace animal research in the foreseeable future. This trend has led first and foremost to a substantial increase in the administrative burden and hurdles required to make timely advances in research and treatments for human and animal diseases. The current COVID-19 pandemic clearly highlights how much we actually rely on animal research. COVID-19 affects several organs and systems, and various animal-free alternatives currently available do not even come close to this complexity. In this Essay we therefore argue that the use of animals is essential for the advancement of human and veterinary health., In this Essay, Genzel et al. make the case for animal research in light of the COVID-19 pandemic.

Supervised exercise therapy (SET) is a first-line treatment for people with peripheral artery disease (PAD). However, data on patient adherence to SET are limited. In addition, while intermittent treadmill exercise has been widely tested, no studies have investigated recumbent total body stepping (step-ex). We examined whether exercise mode (treadmill walking [n = 17], step-ex [n = 18], or a multimodal approach [n = 18]) affected adherence to a 12-week SET program. We also investigated the potential safety and viability of step-ex for people with PAD by looking at change in exercise training capacity (highest metabolic equivalent of tasks [METs] achieved and highest total MET-minutes achieved per session). The 53 participants comprised 50% female candidates (n = 26) and were (mean [SD]) 74.2 (8.3) years old, with an ankle-brachial index of 0.70 (0.19). Overall adherence to SET was 62%. There was a difference in adherence between groups (P = .022), with the multimodal group (73.6% [21.5%]) higher than the treadmill group (50.2% [28.8%], P = .010). Treadmill participants (n [%]) (8 [47.1%]) dropped out at a higher rate than the multimodal group (3 [16.7%], P = .053). All groups increased the exercise training capacity. The multimodal group achieved greater improvement in total MET-minutes achieved per session (61.5 [45.1]) than the treadmill group (14.7 [44.3]) (P = .008).A multimodal approach to PAD exercise therapy resulted in higher adherence and greater change in exercise training capacity. Step-ex was safe for people with PAD. While further study is warranted, it is appropriate for SET programs to consider a multimodal approach using step-ex, especially given the varied health and physical ability of the PAD population.

Objective Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic disorder that is associated with cognitive disabilities. Based on studies involving animals, the hypothesized cause of these disabilities results from increased activity of inhibitory interneurons that decreases synaptic plasticity. We obtained transcranial magnetic stimulation (TMS)-based measures of cortical inhibition, excitability and plasticity in individuals with NF1. Methods We included 32 NF1 adults and 32 neurotypical controls. Cortical inhibition was measured with short-interval intracortical inhibition (SICI) and cortical silent period (CSP). Excitability and plasticity were studied with intermittent theta burst stimulation (iTBS). Results The SICI and CSP response did not differ between NF1 adults and controls. The response upon iTBS induction was significantly increased in controls (70%) and in NF1 adults (83%). This potentiation lasted longer in controls than in individuals with NF1. Overall, the TMS response was significantly lower in NF1 patients (F(1, 41) = 7.552, p = 0.009). Conclusions Individuals with NF1 may have reduced excitability and plasticity, as indicated by their lower TMS response and attenuation of the initial potentiated response upon iTBS induction. However, our findings did not provide evidence for increased inhibition in NF1 patients. Significance These findings have potential utility as neurophysiological outcome measures for intervention studies to treat cognitive deficits associated with NF1.

Carotenoids are isoprenoids widely distributed in foods that have been always part of the diet of humans. Unlike the other so-called food bioactives, some carotenoids can be converted into retinoids exhibiting vitamin A activity, which is essential for humans. Furthermore, they are much more versatile as they are relevant in foods not only as sources of vitamin A, but also as natural pigments, antioxidants, and health-promoting compounds. Lately, they are also attracting interest in the context of nutricosmetics, as they have been shown to provide cosmetic benefits when ingested in appropriate amounts. In this work, resulting from the collaborative work of participants of the COST Action European network to advance carotenoid research and applications in agro-food and health (EUROCAROTEN, www.eurocaroten.eu, https://www.cost.eu/actions/CA15136/#tabs|Name:overview) research on carotenoids in foods and feeds is thoroughly reviewed covering aspects such as analysis, carotenoid food sources, carotenoid databases, effect of processing and storage conditions, new trends in carotenoid extraction, daily intakes, use as human, and feed additives are addressed. Furthermore, classical and recent patents regarding the obtaining and formulation of carotenoids for several purposes are pinpointed and briefly discussed. Lastly, emerging research lines as well as research needs are highlighted., This article is based upon work from COST Action (European network to advance carotenoid research and applications in agro-food and health, EUROCAROTEN, CA15136, www.eurocaroten.eu, https://www.cost.eu/actions/CA15136/#tabs|Name:overview) supported by COST (European Cooperation in Science and Technology, http://www.cost.eu/).

BACKGROUND: Endovascular treatment of occlusive disease of the superficial femoral artery (SFA) has evolved from plain old balloon angioplasty (POBA) through primary stenting strategy to drug eluting technology-based approach. The RAPID trial investigates the added value of drug coated balloons (DCB, Legflow) in a primary stenting strategy (Supera stent) for intermediate (5-15 cm) and long segment (>15 cm) SFA lesions.METHODS: In this multicenter, patient-blinded trial, 160 patients with intermittent claudication, ischemic rest pain, or tissue loss due to intermediate or long SFA lesions were randomized (1:1) between Supera + DCB and Supera. Primary endpoint was primary patency at 2 years, defined as freedom from restenosis on duplex ultrasound (peak systolic velocity ratio < 2.4).RESULTS: At 2 years, primary patency was 55.1% (95%CI: 43.1%-67.1%) in the Supera + DCB group versus 48.3% (95%CI: 35.6%-61.0%) in the Supera group (P=0.957). Per protocol analysis showed a primary patency rate of 60.9% (95%CI: 48.6%-73.2%) in the Supera + DCB group versus 49.8% (95%CI: 36.9%-62.7%) in the Supera group (P=0.469). The overall mortality rate was 5% in both groups (P=0.975). Sustained functional improvement was similar in both groups.CONCLUSIONS: The 2-year results in the current trial of a primary Supera stenting strategy are consistent with other trials reporting on treatment of intermediate and long SFA lesions. A DCB supported Supera stent strategy did not improve patency rate compared to a Supera stent only strategy.

Alteplase with EVT versus EVT Alone for Stroke Trials involving Asian patients with acute stroke have suggested that endovascular treatment alone is not inferior to the usual practice of thrombolysis before endovascular treatment. This trial involving European patients did not show noninferiority or superiority of endovascular treatment alone.Background The value of administering intravenous alteplase before endovascular treatment (EVT) for acute ischemic stroke has not been studied extensively, particularly in non-Asian populations. Methods We performed an open-label, multicenter, randomized trial in Europe involving patients with stroke who presented directly to a hospital that was capable of providing EVT and who were eligible for intravenous alteplase and EVT. Patients were randomly assigned in a 1:1 ratio to receive EVT alone or intravenous alteplase followed by EVT (the standard of care). The primary end point was functional outcome on the modified Rankin scale (range, 0 [no disability] to 6 [death]) at 90 days. We assessed the superiority of EVT alone over alteplase plus EVT, as well as noninferiority by a margin of 0.8 for the lower boundary of the 95% confidence interval for the odds ratio of the two trial groups. Death from any cause and symptomatic intracerebral hemorrhage were the main safety end points. Results The analysis included 539 patients. The median score on the modified Rankin scale at 90 days was 3 (interquartile range, 2 to 5) with EVT alone and 2 (interquartile range, 2 to 5) with alteplase plus EVT. The adjusted common odds ratio was 0.84 (95% confidence interval [CI], 0.62 to 1.15; P=0.28), which showed neither superiority nor noninferiority of EVT alone. Mortality was 20.5% with EVT alone and 15.8% with alteplase plus EVT (adjusted odds ratio, 1.39; 95% CI, 0.84 to 2.30). Symptomatic intracerebral hemorrhage occurred in 5.9% and 5.3% of the patients in the respective groups (adjusted odds ratio, 1.30; 95% CI, 0.60 to 2.81). Conclusions In a randomized trial involving European patients, EVT alone was neither superior nor noninferior to intravenous alteplase followed by EVT with regard to disability outcome at 90 days after stroke. The incidence of symptomatic intracerebral hemorrhage was similar in the two groups. (Funded by the Collaboration for New Treatments of Acute Stroke consortium and others; MR CLEAN-NO IV ISRCTN number, .)

Loss of the maternal UBE3A allele causes Angelman syndrome (AS), a debilitating neurodevelopmental disorder. Here, we devised an AS treatment strategy based on reinstating dual-isoform expression of human UBE3A (hUBE3A) in the developing brain. Kozak sequence engineering of our codon-optimized vector (hUBE3Aopt) enabled translation of both short and long hUBE3A protein isoforms at a near-endogenous 3:1 (short/long) ratio, a feature that could help to support optimal therapeutic outcomes. To model widespread brain delivery and early postnatal onset of hUBE3A expression, we packaged the hUBE3Aopt vector into PHP.B capsids and performed intracerebroventricular injections in neonates. This treatment significantly improved motor learning and innate behaviors in AS mice, and it rendered them resilient to epileptogenesis and associated hippocampal neuropathologies induced by seizure kindling. hUBE3A overexpression occurred frequently in the hippocampus but was uncommon in the neocortex and other major brain structures; furthermore, it did not correlate with behavioral performance. Our results demonstrate the feasibility, tolerability, and therapeutic potential for dual-isoform hUBE3A gene transfer in the treatment of AS.

Over the past 3 decades, there have been attempts to define breastfeeding for scientific research. However, a lack of clarity remains, with concurrent ambiguity in clinical practice and insufficient inclusion of the parent perspective. Furthermore, previous concept analyses of "breastfeeding" may not fully represent what it means for an infant to be breastfed. Therefore, this concept analysis sought to define "breastfed" in the context of Western healthcare research, clinical practice, and the parent perspective. Informed by Rodgers' evolutionary method, a literature search resulted in 16 representative articles, with related terms, attributes, antecedents, and consequences identified. Analysis of the literature resulted in a theoretical definition of breastfed as a valuable process, experience, or characteristic that involves human milk consumption by an infant through a variety of delivery methods. To be breastfed relies on the existence of lactation, whether from a parent or another source, and depends upon the intentional decision of a birthing person, caregiver, or provider. It is recommended that healthcare providers and institutions adopt this inclusive definition, committing to a linguistic and conceptual distinction between a breastfed infant and direct breastfeeding. Increased clarity may improve comparability between studies, reporting to government agencies, provider communication, and supportive, family-centered care.

BackgroundStudies have suggested that some minority groups tend to have lower vaccination rates than the overall population. This study aims to examine COVID-19 vaccination rates among health care workers (HCWs) in Norway, according to immigrant background.MethodsWe used individual-level, nation-wide registry data from Norway to identify all HCWs employed full-time at 1 December 2020. We examined the relationship between country of birth and COVID-19 vaccination from December 2020 to August 2021, both crude and adjusted for e.g. age, sex, municipality of residence, and detailed occupation codes in logistic regression models.ResultsAmong all HCWs in Norway, immigrants had a 9 percentage point lower vaccination rate (85%) than HCWs without an immigrant background (94%) at 31 August 2021. The overall vaccination rate varied by country of birth, with immigrants born in Russia (71%), Serbia (72%), Lithuania (72%), Romania (75%), Poland (76%), Eritrea (77%), and Somalia (78%) having the lowest crude vaccination rates. When we adjusted for demographics and detailed occupational codes, immigrant groups that more often worked as health care assistants, such as immigrants from Eritrea and Somalia, increased their vaccination rates.ConclusionSubstantial differences in vaccination rates among immigrant groups employed in the health care sector in Norway indicate that measures to improve vaccine uptake should focus specific immigrant groups rather than all immigrants together. Lower vaccination rates in some immigrant groups appears to be largely driven by the occupational composition, suggesting that some of the differences in vaccine rates can be attributed to variation in vaccine access.

Face masks are recommended as a means of reducing the spread of COVID-19, but there are practically no studies of interventions to increase face mask use. Over three weeks, nine grocery stores in the Stovner District of Oslo were randomly selected each day to have distribution of free face masks outside their entrance. Free face mask distribution increased the proportion of customers wearing a mask by 6.0 percentage points (adjusted, 95% CI 3.5–8.5). Mean mask usage was 91.7% in the control group and 97.1% in the treatment group (pooled SD 5.3%). Practically all those who wore masks had both nose and mouth covered. We conclude that free distribution of face masks increased their use. Similar trials can be conducted within a short period of time.

Background RASopathies are a group of disorders that result from mutations in genes coding for proteins involved in regulating the Ras-MAPK signaling pathway, and have an increased incidence of autism spectrum disorder (ASD). Legius syndrome is a rare RASopathy caused by loss-of-function mutations in the SPRED1 gene. The patient phenotype is similar to, but milder than, Neurofibromatosis type 1—another RASopathy caused by loss-of-function mutations in the NF1 gene. RASopathies exhibit increased activation of Ras-MAPK signaling and commonly manifest with cognitive impairments and ASD. Here, we investigated if a Spred1-/- mouse model for Legius syndrome recapitulates ASD-like symptoms, and whether targeting the Ras-MAPK pathway has therapeutic potential in this RASopathy mouse model. Methods We investigated social and communicative behaviors in Spred1-/- mice and probed therapeutic mechanisms underlying the observed behavioral phenotypes by pharmacological targeting of the Ras-MAPK pathway with the MEK inhibitor PD325901. Results Spred1-/- mice have robust increases in social dominance in the automated tube test and reduced adult ultrasonic vocalizations during social communication. Neonatal ultrasonic vocalization was also altered, with significant differences in spectral properties. Spred1-/- mice also exhibit impaired nesting behavior. Acute MEK inhibitor treatment in adulthood with PD325901 reversed the enhanced social dominance in Spred1-/- mice to normal levels, and improved nesting behavior in adult Spred1-/- mice. Limitations This study used an acute treatment protocol to administer the drug. It is not known what the effects of longer-term treatment would be on behavior. Further studies titrating the lowest dose of this drug that is required to alter Spred1-/- social behavior are still required. Finally, our findings are in a homozygous mouse model, whereas patients carry heterozygous mutations. These factors should be considered before any translational conclusions are drawn. Conclusions These results demonstrate for the first time that social behavior phenotypes in a mouse model for RASopathies (Spred1-/-) can be acutely reversed. This highlights a key role for Ras-MAPK dysregulation in mediating social behavior phenotypes in mouse models for ASD, suggesting that proper regulation of Ras-MAPK signaling is important for social behavior.

This study presents a broad overview of health issues and psychomotor development of 100 children with Angelman syndrome (AS), seen at the ENCORE Expertise Center for AS in Rotterdam, the Netherlands. We aimed to further delineate the phenotype of AS, to evaluate the association of the phenotype with genotype and other determinants such as epilepsy and to get insight in possible targets for intervention. We confirmed the presence of a more severe phenotype in the 15q11.2‐q13 deletion subtype. Novel findings were an association of (early onset of) epilepsy with a negative effect on development, a high occurrence of nonconvulsive status epilepticus, a high rate of crouch gait in the older children with risk of deterioration of mobility, a relatively low occurrence of microcephaly, a higher mean weight for height in all genetic subtypes with a significant higher mean in the nondeletion children, and a high occurrence of hyperphagia across all genetic subtypes. Natural history data are needed to design future trials. With this large clinical cohort with structured prospective and multidisciplinary follow‐up, we provide unbiased data on AS to support further intervention studies to optimize outcome and quality of life of children with AS and their family.

Several studies suggest that the extractive industry has negative consequences for gender equality despite the often positive growth impact of natural resources. We re-examine this claim at the sub-state level in sub-Saharan Africa and argue that we need to differentiate between ownership arrangements in the extractive industry. To test our argument on the gender dimension of the resource curse, this article employs unique data on the control rights of minerals within sub-Saharan countries as well as data from Afrobarometer and Demographic and Health Surveys (DHS). Our quantitative analyses explore how international vs. domestic ownership of copper, diamond and gold mines affects the labor market integration of females and intimate partner violence. The regression results suggest in line with our theoretical expectations that gender-specific structural labor market shifts within extractive industries are contingent on mineral control rights. Our models show that within mining areas, only domestic ownership reduces male unemployment. While domestic mining seems to reinforce the traditional male breadwinner model, internationally owned mineral extraction induces structural labor market changes: women abandon subsistence farming activities and migrate to the service sector. Our results further indicate that this shift of traditional gender roles within rural mining areas is associated with less intimate partner violence.

ObjectiveTo investigate whether mammalian target of rapamycin inhibitor everolimus can improve intellectual disability, autism, and other neuropsychological deficits in children with tuberous sclerosis complex (TSC).MethodsIn this 12-month, randomized, double-blind, placebo-controlled trial, we attempted to enroll 60 children with TSC and IQ ResultsThirty-two children with TSC were randomized. Intention-to-treat analysis showed no benefit of everolimus on full-scale IQ (treatment effect −5.6 IQ points, 95% confidence interval −12.3 to 1.0). No effect was found on secondary outcomes, including autism and neuropsychological functioning, and questionnaires examining behavioral problems, social functioning, communication skills, executive functioning, sleep, quality of life, and sensory processing. All patients had adverse events. Two patients on everolimus and 2 patients on placebo discontinued treatment due to adverse events.ConclusionsEverolimus did not improve cognitive functioning, autism, or neuropsychological deficits in children with TSC. The use of everolimus in children with TSC with the aim of improving cognitive function and behavior should not be encouraged in this age group.Clinicaltrials.gov identifierNCT01730209.Classification of evidenceThis study provides Class I evidence that for children with TSC, everolimus does not improve intellectual disability, autism, behavioral problems, or other neuropsychological deficits.

Purpose This case series presents 3 patients with acute kidney injury taking apixaban or rivaroxaban and transitioning to a heparin infusion. Summary Case 1 was a 78-year-old man admitted with respiratory failure, acute decompensated heart failure, and acute kidney injury. He was taking apixaban for atrial flutter. He was transitioned to an i.v. heparin infusion and had 2 consecutive heparin antifactor-Xa levels greater than 2 units/mL. Heparin was held and resumed about 36 hours later when the apixaban anti-Xa level was less than 50 ng/mL. Case 2 was a 55-year-old man admitted with acute kidney injury, taking apixaban for a recent deep vein thrombosis. Apixaban anti-Xa levels were monitored and i.v. heparin was initiated when the level was less than 100 ng/mL, about 56 hours after the last apixaban dose. Case 3 was a 64-year-old woman admitted with sepsis and acute kidney injury taking rivaroxaban for pulmonary embolism, which occurred 2 weeks prior to admission. Rivaroxaban anti-Xa levels were monitored and i.v. heparin was initiated about 36 hours after the last dose when the level was less than 100 ng/mL. The management strategy did not lead to any thrombotic outcomes; however, 1 patient experienced bleeding. Conclusion Specific anti-Xa levels for rivaroxaban and apixaban appeared to be helpful in the transition of 3 patients to unfractionated heparin infusions in the setting of acute kidney injury. These levels provided enhanced, individualized care and likely helped avoid over and under anticoagulation.

BackgroundAs in other countries, the coronavirus disease 2019 (COVID-19) pandemic has affected Norway’s immigrant population disproportionately with significantly higher infection rates and hospitalizations. The reasons for this are uncertain.MethodsThrough the national emergency preparedness register, BeredtC19, we have studied laboratory-confirmed infections with SARS-CoV-2 and related hospitalizations in the entire Norwegian population, by birth-country background for the period 15 June 2020 – 31 March 2021, excluding the first-wave due to limited test capacity and restrictive test criteria. Straightforward linkage of individual-level data allowed adjustment for demographics, socioeconomic factors (occupation, household crowding, education, and household income), and underlying medical risk for severe COVID-19 in regression models.ResultsThe sample comprised 5.49 million persons, of which 0.91 million born outside of Norway, 82 532 confirmed cases, and 3088 hospitalizations. Confirmed infections in this period (per 100 000): foreign-born 3140, Norwegian-born with foreign-born parents 4799, Norwegian-born with Norwegian-born parent(s) 1011. Hospitalizations (per 100 000): foreign-born 147, Norwegian-born with foreign-born parents 47, Norwegian-born with Norwegian-born parent(s) 37. The addition of socioeconomic and medical factors to the base-model (age, sex, municipality of residence) attenuated excess infection rates by 12.0% and hospitalizations by 3.8% among foreign-born, and 10.9% and 46.2% respectively among Norwegian-born with foreign parents, compared to Norwegian-born with Norwegian-born parent(s).ConclusionThere were large differences in infection rates and hospitalizations by country background, and these do not appear to be fully explained by socioeconomic and medical factors. Our results may have implications for health policy, including the targeting of mitigation strategies.

Objective:To determine clinical consensus and non-consensus in regard to evidence-based statements about feeding infants with complex CHD, with a focus on human milk. Areas of non-consensus may indicate discrepancies between research findings and practice, with consequent variation in feeding management.Materials and Methods:A modified Delphi survey validated key feeding topics (round 1), and determined consensus on evidence-based statements (rounds 2 and 3). Patients (n=25) were an interdisciplinary group of clinical experts from across the United States of America. Descriptive analysis used SPSS Statistics (Version 26.0). Thematic analysis of qualitative data provided context for quantitative data.Results:Round 1 generated 5 key topics (human milk, developing oral feeding skills, clinical feeding practice, growth failure, and parental concern about feeding) and 206 evidence-based statements. The final results included 110 (53.4%) statements of consensus and 96 (46.6%) statements of non-consensus. The 10 statements of greatest consensus strongly supported human milk as the preferred nutrition for infants with complex CHD. Areas of non-consensus included the adequacy of human milk to support growth, need for fortification, safety, and feasibility of direct breastfeeding, issues related to tube feeding, and prevention and treatment of growth failure.Conclusions:The results demonstrate clinical consensus about the importance of human milk, but reveal a need for best practices in managing a human milk diet for infants with complex CHD. Areas of non-consensus may lead to clinical practice variation. A sensitive approach to these topics is needed to support family caregivers in navigating feeding concerns.

The 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMG-CoA reductase) inhibitors lovastatin and simvastatin have both been investigated in clinical trials designed to treat the cognitive deficits associated with neurodevelopmental disorders such as neurofibromatosis type 1, fragile X and autism. In a recent study, the therapeutic efficacy of lovastatin and simvastatin were compared in a fragile X ( Fmr1 ) mouse model. The authors concluded that lovastatin was superior to simvastatin in rescuing the Fmr1 phenotypes, and cautioned against considering simvastatin as treatment for neurodevelopmental disorders. We discuss these findings in the context of published literature and argue that more support is needed for this potentially far-reaching conclusion. We further provide recommendations to improve the translation of pre-clinical studies of cognitive disorders into the clinical domain. The potential use of statins for antagonizing RAS (rat sarcoma viral oncogene homolog) signaling was first recognized nearly three decades ago (Mendola and Backer, 1990; Sebti et al., 1991). Functional RAS requires post-translational farnesylation to become membrane bound and active. Since farnesyl (like cholesterol) is a product of the mevalonate synthesis pathway, its synthesis can be reduced by interfering with the rate-limiting enzyme, 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMG-CoA reductase). Statins, designed as high-affinity HMG-CoA reductase inhibitors, are commonly prescribed for hypercholesterolemia. Over the past several decades, various types of statins have been extensively investigated as potential cancer therapeutics using cellular models, mouse studies, and human clinical trials (Gazzerro et al., 2012; Pisanti et al., 2014; Sopkova et al., 2017). On the basis of these findings, Alcino Silva and colleagues explored whether statins might have efficacy in the treatment of RASopathies, a group of neurodevelopmental disorders resulting from mutations that lead to …

Identifying predictors of depression recurrence may highlight targets for relapse prevention. This study tested the hypothesis that strength of implicit and explicit self-depressed associations (SDA) following recovery would lower the threshold for the recurrence of depression. Two main analyses were conducted to test: (i) predictive validity of SDA for recurrence in individuals with a history of depression (at least six months depression free; n = 616, six-year follow-up); (ii) predictive validity of both post-depression SDA and the extent of change in SDA following recovery for recurrence in individuals who recovered in the first two years of the study (n = 220, four-year follow-up). Further exploratory analysis tested the scar model of SDA in participants without a history of depression at baseline. Recurrence rate was 49% in both the first and second analysis. In the first analysis, implicit SDA and explicit SDA were related to recurrence in the unadjusted models, but not when controlling for baseline symptoms. In the second analysis, post-depression explicit SDA predicted recurrence over and above baseline residual depressive symptomatology. There was no support that implicit SDA following depression related to recurrence. However, there was support that stronger explicit SDA following a recent depression increased risk for recurrence.

5T4 is an oncofetal antigen with low expression in healthy tissues which is frequently overexpressed in different tumor types. Despite its overexpression in various malignancies and its association with poor prognosis, there are currently no marketed drugs that target this tumor antigen. We developed a novel antibody-drug conjugate (ADC), named SYD1875, comprising a humanized, HC41-cysteine-engineered IgG1 monoclonal antibody directed against 5T4, site-specifically conjugated to a proprietary cleavable synthetic duocarmycin-based linker-drug (vc-seco-DUBA). SYD1875 showed sub-nanomolar binding affinity to human and cynomolgus 5T4, rapid internalization, and induction of both target- and bystander-mediated cell killing. SYD1875 showed superior in vitro cytotoxicity and in vivo activity compared to A1-mcMMAF -also known as PF-6263507-, a 5T4-targeting ADC that is no longer in clinical development. A single dose of SYD1875 induced strong anti-tumor activity in patient-derived xenograft models of multiple tumor types with low, moderate and high 5T4 expression. The GLP toxicity study in cynomolgus monkey showed an acceptable toxicity and PK profile. A first-in-human dose-finding trial was initiated to evaluate safety and explore efficacy (NCT04202705). Citation Format: Patrick Groothuis, Danielle Jacobs, Kim Berentsen, Monique van der Vleuten, Ruud Coumans, Ronald Elgersma, Marion Blomenrohr, Diels van den Dobbelsteen, Patrick Beusker, Ruud Ubink, Miranda van der Lee, Wim H.A. Dokter. Introduction to the preclinical profile of SYD1875, a novel site-specifically conjugated duocarmycin-based 5T4-targeting antibody-drug conjugate [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 925.

To report a randomized trial comparing the Legflow paclitaxel-eluting balloon (PEB) + Supera stenting to Supera stenting alone in patients with intermediate to long superficial femoral artery (SFA) lesions.The multicenter RAPID trial ( controlled-trials.com ; identifier ISRCTN47846578) randomized (1:1) 160 patients (mean age 67 years; 102 men) with Rutherford category 2-6 ischemia to treatment with Legflow PEB + Supera stent or Supera stent alone in intermediate to long SFA lesions (mean lesion length 15.8±7.4 vs 15.8±7.6 cm, respectively). The efficacy outcome was primary patency, defined as freedom from restenosis on duplex ultrasound or angiography.Baseline characteristics including the percentage of occlusions were similar between groups. In the intention-to-treat analysis, the estimated primary patency at 1 year was 68.3% (95% CI 56.7% to 79.9%) in the PEB + Supera group vs 62.0% (95% CI 49.1% to 74.9%) in the Supera group (p=0.900). Per-protocol analysis showed a 12-month primary patency estimate of 74.7% (95% CI 63.1% to 86.3%) in the PEB + Supera group vs 62.0% (95% CI 49.1% to 74.9%) in the control group (p=0.273). Secondary patency estimates at 12 months (per-protocol analysis) were 89.0% (95% CI 80.6% to 97.4%) vs 98.0% (95% CI 94.1% to 100%; p=0.484); the estimates for freedom from clinically driven target lesion revascularization (CD-TLR) were 83.0% (95% CI 72.8% to 93.2%) and 77.8% (95% CI 66.6% to 89.0%; p=0.277), respectively.The short-term results from the multicenter RAPID randomized controlled trial indicate that the Legflow PEB is safe and feasible for the treatment of intermediate to long SFA lesions. In this trial, at least 70% of the patients suffered an occlusion. The PEB group had higher rates of primary patency and freedom from CD-TLR, although there were no statistically significant differences vs controls.

Angelman syndrome (AS) is a neurodevelopmental disorder caused by loss of the maternally inherited allele of UBE3A. Ube3aSTOP/p+ mice recapitulate major features of AS in humans and allow conditional reinstatement of maternal Ube3a with the expression of Cre recombinase. We have recently shown that AS model mice exhibit reduced inhibitory drive onto layer (L)2/3 pyramidal neurons of visual cortex, which contributes to a synaptic excitatory/inhibitory imbalance. However, it remains unclear how this loss of inhibitory drive affects neural circuits in vivo. Here we examined visual cortical response properties in individual neurons to explore the consequences of Ube3a loss on intact cortical circuits and processing. Using in vivo patch-clamp electrophysiology, we measured the visually evoked responses to square-wave drifting gratings in L2/3 regular-spiking (RS) neurons in control mice, Ube3a-deficient mice, and mice in which Ube3a was conditionally reinstated in GABAergic neurons. We found that Ube3a-deficient mice exhibited enhanced pyramidal neuron excitability in vivo as well as weaker orientation tuning. These observations are the first to show alterations in cortical computation in an AS model, and they suggest a basis for cortical dysfunction in AS. NEW & NOTEWORTHY Angelman syndrome (AS) is a severe neurodevelopmental disorder caused by the loss of the gene UBE3A. Using electrophysiological recording in vivo, we describe visual cortical dysfunctions in a mouse model of AS. Aberrant cellular properties in AS model mice could be improved by reinstating Ube3a in inhibitory neurons. These findings suggest that inhibitory neurons play a substantial role in the pathogenesis of AS.

The neurofibromatoses are inherited, tumor suppressor disorders that are characterized by multiple, benign peripheral nerve sheath tumors and other nervous system tumors. Each disease is associated with a distinct genetic mutation and with a different pathogenesis and clinical course. Neurofibromatosis 1 (NF1) is common and epitomized by multiple neurofibromas with widespread complications. NF2 and schwannomatosis are rare diseases that are typified by multiple schwannomas that are particularly painful in people with schwannomatosis. Since 1985, the Children's Tumor Foundation (formerly the National Neurofibromatosis Foundation) has hosted an international Neurofibromatosis Conference, bringing together international participants who are focused on NF research and clinical care. The 2017 Conference, held in Washington, DC, was among the largest gatherings of NF researchers to date and included presentations from clinicians and basic scientists, highlighting new data regarding the molecular and cellular mechanisms underlying each of these diseases as well as results from clinical studies and clinical trials. This article summarizes the findings presented at the meeting and represents the current state-of-the art for NF research.

BackgroundAs depression has a recurrent course, relapse and recurrence prevention is essential.AimsIn our randomised controlled trial (registered with the Nederlands trial register, identifier: NTR1907), we found that adding preventive cognitive therapy (PCT) to maintenance antidepressants (PCT+AD) yielded substantial protective effects versus antidepressants only in individuals with recurrent depression. Antidepressants were not superior to PCT while tapering antidepressants (PCT/−AD). To inform decision-makers on treatment allocation, we present the corresponding cost-effectiveness, cost-utility and budget impact.MethodData were analysed (n = 289) using a societal perspective with 24-months of follow-up, with depression-free days and quality-adjusted life years (QALYs) as health outcomes. Incremental cost-effectiveness ratios were calculated and cost-effectiveness planes and cost-effectiveness acceptability curves were derived to provide information about cost-effectiveness. The budget impact was examined with a health economic simulation model.ResultsMean total costs over 24 months were €6814, €10 264 and €13 282 for AD+PCT, antidepressants only and PCT/−AD, respectively. Compared with antidepressants only, PCT+AD resulted in significant improvements in depression-free days but not QALYs. Health gains did not significantly favour antidepressants only versus PCT/−AD. High probabilities were found that PCT+AD versus antidepressants only and antidepressants only versus PCT/−AD were dominant with low willingness-to-pay thresholds. The budget impact analysis showed decreased societal costs for PCT+AD versus antidepressants only and for antidepressants only versus PCT/−AD.ConclusionsAdding PCT to antidepressants is cost-effective over 24 months and PCT with guided tapering of antidepressants in long-term users might result in extra costs. Future studies examining costs and effects of antidepressants versus psychological interventions over a longer period may identify a break-even point where PCT/−AD will become cost-effective.Declaration of interestC.L.H.B. is co-editor ofPLOS Oneand receives no honorarium for this role. She is also co-developer of the Dutch multidisciplinary clinical guideline for anxiety and depression, for which she receives no remuneration. She is a member of the scientific advisory board of the National Insure Institute, for which she receives an honorarium, although this role has no direct relation to this study. C.L.H.B. has presented keynote addresses at conferences, such as the European Psychiatry Association and the European Conference Association, for which she sometimes receives an honorarium. She has presented clinical training workshops, some including a fee. She receives royalties from her books and co-edited books and she developed preventive cognitive therapy on the basis of the cognitive model of A. T. Beck. W.A.N. has received grants from the Netherlands Organisation for Health Research and Development and the European Union and honoraria and speakers' fees from Lundbeck and Aristo Pharma, and has served as a consultant for Daleco Pharma.

The neurofibromatoses, which include neurofibromatosis type I (NF1), neurofibromatosis type II (NF2), and schwannomatosis, are a group of syndromes characterized by tumor growth in the nervous system. The RASopathies are a group of syndromes caused by germline mutations in genes that encode components of the RAS/mitogen-activated protein kinase (MAPK) pathway. The RASopathies include NF1, Noonan syndrome, Noonan syndrome with multiple lentigines, Costello syndrome, cardio-facio-cutaneous syndrome, Legius syndrome, capillary malformation arterio-venous malformation syndrome, and SYNGAP1 autism. Due to their common underlying pathogenetic etiology, all these syndromes have significant phenotypic overlap of which one common feature include a predisposition to tumors, which may be benign or malignant. Together as a group, they represent one of the most common multiple congenital anomaly syndromes estimating to affect approximately one in 1000 individuals worldwide. The subcontinent of India represents one of the largest populations in the world, yet remains underserved from an aspect of clinical genetics services. In an effort to bridge this gap, the First International Conference on RASopathies and Neurofibromatoses in Asia: Identification and Advances of New Therapeutics was held in Kochi, Kerala, India. These proceedings chronicle this timely and topical international symposium directed at discussing the best practices and therapies for individuals with neurofibromatoses and RASopathies. Children's Tumor Foundation; Fonds De La Recherche Scientifique ‐ FNRS, Grant/Award Numbers: T002614, T024719F; Manchester NIHR Biomedical Research Centre, Grant/Award Number: IS‐BRC‐1215‐20007; NIH/NIAMS, Grant/Award Number: R01AR062165; Axis Health Biomedicals and the Doctor's Academy; Schiller India; MedGenome; Wales Gene Park; University of Wales Trinity Saint David; Cardiff University; AstraZeneca

Objective An epilepsy mouse model for Tuberous Sclerosis Complex (TSC) was developed and validated to investigate the mechanisms underlying epileptogenesis. Furthermore, the possible antiepileptogenic properties of commonly used antiepileptic drugs (AEDs) and new compounds were assessed. Methods Tsc1 deletion was induced in CAMK2A‐expressing neurons of adult mice. The antiepileptogenic properties of commonly used AEDs and inhibitors of the mTOR pathways were assessed by EEG recordings and by molecular read outs. Results Mice developed epilepsy in a narrow time window (10 ± 2 days) upon Tsc1 gene deletion. Seizure frequency but not duration increased over time. Seizures were lethal within 18 days, were unpredictable, and did not correlate to seizure onset, length or frequency, reminiscent of sudden unexpected death in epilepsy (SUDEP). Tsc1 gene deletion resulted in a strong activation of the mTORC1 pathway, and both epileptogenesis and lethality could be entirely prevented by RHEB1 gene deletion or rapamycin treatment. However, other inhibitors of the mTOR pathway such as AZD8055 and PF4708671 were ineffective. Except for ketogenic diet, none of commonly used AEDs showed an effect on mTORC1 activity. Vigabatrin and ketogenic diet treatment were able to significantly delay seizure onset. In contrast, survival was shortened by lamotrigine. Interpretation This novel Tsc1 mouse model is highly suitable to assess the efficacy of antiepileptic and ‐epileptogenic drugs to treat mTORC1‐dependent epilepsy. Additionally, it allows us to study the mechanisms underlying mTORC1‐mediated epileptogenesis and SUDEP. We found that early treatment with vigabatrin was not able to prevent epilepsy, but significantly delayed seizure onset.

In their article, Goyal et al.1 questioned the added benefit of IV thrombolysis (IVT) prior to mechanical thrombectomy (MT) in patients with ischemic stroke and a large vessel occlusion. As we await the results of ongoing randomized trials (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands [MR CLEAN–NO IV], [ISRCTN80619088][1]; Bridging Thrombolysis Versus Direct Mechanical Thrombectomy in Acute Ischemic Stroke [SWIFT DIRECT], [NCT03192332][2]; Direct Intra-arterial Thrombectomy in Order to Revascularize AIS Patients With Large Vessel Occlusion Efficiently in Chinese Tertiary Hospitals [DIRECT-MT], [NCT03469206][3]), we must rely on observational data with adequate adjustment for potential confounding variables to estimate the value of IVT in MT-eligible patients.2 Goyal et al.1 rightfully stated that no statistical method can completely adjust for allocation bias. However, current American Heart Association guidelines state that a blood pressure above 185/110 mm Hg and impaired hemostasis (direct oral anticoagulant use or international normalized ratio >1.7) are contraindications for IVT.3 These variables have also been associated with worse outcomes4 and, therefore, are true confounders. Much to our surprise, data on baseline blood pressure and hemostasis were not reported in by Goyal et al.,1 and it does not appear that these variables were used in the propensity score matching. We invite the authors to comment on why information on baseline blood pressure and hemostasis was not reported and how this may have affected their results. [1]: /external-ref?link_type=ISRCTN&access_num=ISRCTN80619088 [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT03192332&atom=%2Fneurology%2F91%2F24%2F1115.atom [3]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT03469206&atom=%2Fneurology%2F91%2F24%2F1115.atom

The RASopathies are a group of disorders due to variations of genes associated with the Ras/MAPK pathway. Some of the RASopathies include neurofibromatosis type 1 (NF1), Noonan syndrome, Noonan syndrome with multiple lentigines, cardiofaciocutaneous (CFC) syndrome, Costello syndrome, Legius syndrome, and capillary malformation-arteriovenous malformation (CM-AVM) syndrome. In combination, the RASopathies are a frequent group of genetic disorders. This report summarizes the proceedings of the 4th International Symposium on Genetic Disorders of the Ras/MAPK pathway and highlights gaps in the field. (c) 2016 Wiley Periodicals, Inc.

Objective: To investigate whether mammalian target of rapamycin complex 1 (mTORC1) inhibitors could reduce seizure frequency in children with tuberous sclerosis complex (TSC). Methods: Due to slow inclusion rate, target inclusion of 30 children was not reached. Twenty-three children with TSC and intractable epilepsy (age 1.8–10.9 years) were randomly assigned (1:1) to open-label, add-on sirolimus treatment immediately or after 6 months. Sirolimus was titrated to trough levels of 5–10 ng/mL. Primary endpoint was seizure frequency change during the sixth month of sirolimus treatment. Results: Intention-to-treat analysis showed sirolimus treatment resulted in 41% seizure frequency decrease (95% confidence interval [CI] −69% to +14%; p = 0.11) compared to the standard-care period. Per protocol analysis of 14 children who reached sirolimus target trough levels in the sixth sirolimus month showed a seizure frequency decrease of 61% (95% CI −86% to +6%; p = 0.06). Cognitive development did not change. All children had adverse events. Five children discontinued sirolimus prematurely. Conclusions: We describe a randomized controlled trial for a non–antiepileptic drug that directly targets a presumed causal mechanism of epileptogenesis in a genetic disorder. Although seizure frequency decreased, especially in children reaching target trough levels, we could not show a significant benefit. Larger trials or meta-analyses are needed to investigate if patients with TSC with seizures benefit from mTORC1 inhibition. This trial was registered at trialregister.nl (NTR3178) and supported by the Dutch Epilepsy Foundation. Classification of evidence: This study provides Class III evidence that sirolimus does not significantly reduce seizure frequency in children with TSC and intractable epilepsy. The study lacked the precision to exclude a benefit from sirolimus.

Background:Percutaneous vertebroplasty (PV) is an alternative option to treat pain after an osteoporotic vertebral compression fracture (OVCF). Controversy exists as to whether PV increases the risk of new OVCFs or prevents further vertebral height loss in treated levels. We assessed both during 1-year follow-up in patients with acute OVCF randomised to PV or a sham procedure.Mehods:VERTOS IV is a prospective, multicentre, randomised controlled trial comparing PV with sham therapy in 180 patients. NewOVCFs and further vertebral height loss were assessed at 3, 6, and 12 months.Results:After a median follow-up of 12 months (interquartile range (IQR) = 12-12) 31 new fractures were reported in 15 patients from the PV group and 28 new fractures in 19 patients from the sham group. The occurrence of new vertebral fractures did not significantly differ between the groups (χ2(1) = 0.83, p = 0.36, OR = .71, 95%CI = 0.33-1.50). There was no higher fracture risk of adjacent versus distant vertebrae. After sham procedure, further height loss of treated vertebrae occurred more frequently (7 patients (8%) in the PV group and 39 (45%) in the sham group (χ2(1) = 28.85, p Conclusions:The risk of further vertebral height loss is significantly lower after PV compared to a sham intervention, i.e. PV protectsagainst progressive vertebral height loss. In addition, PV does not increase the risk of new adjacent and distant OVCFs.

Paired associative stimulation (PAS) is a frequently used TMS paradigm that induces long-term potentiation in the human cortex. However, little is known about the within-subject consistency of PAS-induced effects. We determined PAS-induced effects and their consistency in healthy volunteers between two PAS sessions. Additionally, we assessed the benefit of applying linear mixed models (LMMs) to PAS data. Thirty-eight healthy volunteers underwent two identical PAS sessions with a >1 week interval. During each session, motor evoked potentials (MEPs) were assessed once before PAS induction and 3 times after at 30 min intervals. We did not detect any significant potentiation of MEP size after PAS induction. However, MEP size during PAS induction showed significant potentiation over time in both sessions (LR(1)=13.36, p

Background Angelman syndrome (AS) is a neurodevelopmental disorder caused by mutations affecting UBE3A function. AS is characterized by intellectual disability, impaired motor coordination, epilepsy, and behavioral abnormalities including autism spectrum disorder features. The development of treatments for AS heavily relies on the ability to test the efficacy of drugs in mouse models that show reliable, and preferably clinically relevant, phenotypes. We previously described a number of behavioral paradigms that assess phenotypes in the domains of motor performance, repetitive behavior, anxiety, and seizure susceptibility. Here, we set out to evaluate the robustness of these phenotypes when tested in a standardized test battery. We then used this behavioral test battery to assess the efficacy of minocycline and levodopa, which were recently tested in clinical trials of AS. Methods We combined data of eight independent experiments involving 111 Ube3a mice and 120 wild-type littermate control mice. Using a meta-analysis, we determined the statistical power of the subtests and the effect of putative confounding factors, such as the effect of sex and of animal weight on rotarod performance. We further assessed the robustness of these phenotypes by comparing Ube3a mutants in different genetic backgrounds and by comparing the behavioral phenotypes of independently derived Ube3a-mutant lines. In addition, we investigated if the test battery allowed re-testing the same animals, which would allow a within-subject testing design. Results We find that the test battery is robust across different Ube3a-mutant lines, but confirm and extend earlier studies that several phenotypes are very sensitive to genetic background. We further found that the audiogenic seizure susceptibility phenotype is fully reversible upon pharmacological treatment and highly suitable for dose-finding studies. In agreement with the clinical trial results, we found that minocycline and levodopa treatment of Ube3a mice did not show any sign of improved performance in our test battery. Conclusions Our study provides a useful tool for preclinical drug testing to identify treatments for Angelman syndrome. Since the phenotypes are observed in several independently derived Ube3a lines, the test battery can also be employed to investigate the effect of specific Ube3a mutations on these phenotypes.

ObjectiveTo assess whether percutaneous vertebroplasty results in more pain relief than a sham procedure in patients with acute osteoporotic compression fractures of the vertebral body.DesignRandomised, double blind, sham controlled clinical trial.SettingFour community hospitals in the Netherlands, 2011-15.Participants180 participants requiring treatment for acute osteoporotic vertebral compression fractures were randomised to either vertebroplasty (n=91) or a sham procedure (n=89).InterventionsParticipants received local subcutaneous lidocaine (lignocaine) and bupivacaine at each pedicle. The vertebroplasty group also received cementation, which was simulated in the sham procedure group.Main outcome measuresMain outcome measure was mean reduction in visual analogue scale (VAS) scores at one day, one week, and one, three, six, and 12 months. Clinically significant pain relief was defined as a decrease of 1.5 points in VAS scores from baseline. Secondary outcome measures were the differences between groups for changes in the quality of life for osteoporosis and Roland-Morris disability questionnaire scores during 12 months’ follow-up.ResultsThe mean reduction in VAS score was statistically significant in the vertebroplasty and sham procedure groups at all follow-up points after the procedure compared with baseline. The mean difference in VAS scores between groups was 0.20 (95% confidence interval −0.53 to 0.94) at baseline, −0.43 (−1.17 to 0.31) at one day, −0.11 (−0.85 to 0.63) at one week, 0.41 (−0.33 to 1.15) at one month, 0.21 (−0.54 to 0.96) at three months, 0.39 (−0.37 to 1.15) at six months, and 0.45 (−0.37 to 1.24) at 12 months. These changes in VAS scores did not, however, differ statistically significantly between the groups during 12 months’ follow-up. The results for secondary outcomes were not statistically significant. Use of analgesics (non-opioids, weak opioids, strong opioids) decreased statistically significantly in both groups at all time points, with no statistically significant differences between groups. Two adverse events occurred in the vertebroplasty group: one respiratory insufficiency and one vasovagal reaction.ConclusionsPercutaneous vertebroplasty did not result in statistically significantly greater pain relief than a sham procedure during 12 months’ follow-up among patients with acute osteoporotic vertebral compression fractures.

Previous research showed that individuals who were remitted from a depressive disorder displayed heightened attention towards negative adjectives (e.g., worthless). We tested if this attentional bias (AB) is predictive of future recurrence of depressive episodes and/or having depressive symptoms at 2- and 4-year follow-up. We used a longitudinal approach within the Netherlands Study of Depression and Anxiety (NESDA) and selected participants who were remitted from Major Depressive Disorder (MDD) (n = 918). AB was measured with a verbal Exogenous Cueing Task; using 2 presentation times (500 and 1250 ms) and 3 stimulus types (negative, positive, neutral). Over 4 years, we prospectively assessed recurrence of depressive episodes and depressive symptomatology after participants completed the ECT. Diagnosis of depressive disorder was measured with clinical rating-scales and self-report questionnaires. A heightened probability of recurrence was neither associated with (heightened) AB for negative nor with (lowered) AB for positive adjectives. Thus, the findings do not support the view that an AB toward negative stimuli or away from positive stimuli plays a critical role in the recurrence of depression.

Tuberous sclerosis complex (TSC) is a rare monogenic disorder characterized by benign tumors in multiple organs as well as a high prevalence of epilepsy, intellectual disability and autism. TSC is caused by inactivating mutations in the TSC1 or TSC2 genes. Heterozygocity induces hyperactivation of mTOR which can be inhibited by mTOR inhibitors, such as rapamycin, which have proven efficacy in the treatment of TSC-associated symptoms. The aim of the present study was (1) to identify molecular changes associated with social and cognitive deficits in the brain tissue of Tsc1 +/− mice and (2) to investigate the molecular effects of rapamycin treatment, which has been shown to ameliorate genotype-related behavioural deficits. Molecular alterations in the frontal cortex and hippocampus of Tsc1 +/− and control mice, with or without rapamycin treatment, were investigated. A quantitative mass spectrometry-based shotgun proteomic approach (LC-MSE) was employed as an unbiased method to detect changes in protein levels. Changes identified in the initial profiling stage were validated using selected reaction monitoring (SRM). Protein Set Enrichment Analysis was employed to identify dysregulated pathways. LC-MSE analysis of Tsc1 +/− mice and controls (n = 30) identified 51 proteins changed in frontal cortex and 108 in the hippocampus. Bioinformatic analysis combined with targeted proteomic validation revealed several dysregulated molecular pathways. Using targeted assays, proteomic alterations in the hippocampus validated the pathways “myelination”, “dendrite,” and “oxidative stress”, an upregulation of ribosomal proteins and the mTOR kinase. LC-MSE analysis was also employed on Tsc1 +/− and wildtype mice (n = 34) treated with rapamycin or vehicle. Rapamycin treatment exerted a stronger proteomic effect in Tsc1 +/− mice with significant changes (mainly decreased expression) in 231 and 106 proteins, respectively. The cellular pathways “oxidative stress” and “apoptosis” were found to be affected in Tsc1 +/− mice and the cellular compartments “myelin sheet” and “neurofilaments” were affected by rapamycin treatment. Thirty-three proteins which were altered in Tsc1 +/− mice were normalized following rapamycin treatment, amongst them oxidative stress related proteins, myelin-specific and ribosomal proteins. Molecular changes in the Tsc1 +/− mouse brain were more prominent in the hippocampus compared to the frontal cortex. Pathways linked to myelination and oxidative stress response were prominently affected and, at least in part, normalized following rapamycin treatment. The results could aid in the identification of novel drug targets for the treatment of cognitive, social and psychiatric symptoms in autism spectrum disorders. Similar pathways have also been implicated in other psychiatric and neurodegenerative disorders and could imply similar disease processes. Thus, the potential efficacy of mTOR inhibitors warrants further investigation not only for autism spectrum disorders but also for other neuropsychiatric and neurodegenerative diseases.

Automatic milking systems record an enormous amount of data on milk yield and the cow itself. These type of big data are expected to contain indicators for health and resilience of cows. In this study, the aim was to define and estimate heritabilities for traits related with fluctuations in daily milk yield and to estimate genetic correlations with existing functional traits, such as udder health, fertility, claw health, ketosis, and longevity. We used daily milk yield records from automatic milking systems of 67,025 lactations in the first parity from 498 herds in the Netherlands. We defined 3 traits related to the number of drops in milk yield using Student t-tests based on either a rolling average (drop rolling average) or a regression (drop regression) and the natural logarithm of the within-cow variance of milk yield (LnVar). Average milk yield was added to investigate the relationships between milk yield and these new traits. ASReml was used to estimate heritabilities, breeding values (EBV), and genetic correlations among these new traits and average milk yield. Approximate genetic correlations were calculated using correlations between EBV of the new traits and existing EBV for health and functional traits correcting for nonunity reliabilities using the Calo method. Partial genetic correlations controlling for persistency and average milk yield and relative contributions to reliability were calculated to investigate whether the new traits add new information to predict fertility, health, and longevity. Heritabilities were 0.08 for drop rolling average, 0.06 for drop regression, and 0.10 for LnVar. Approximate genetic correlations between the new traits and the existing health traits differed quite a bit, with the strongest correlations (-0.29 to -0.52) between LnVar and udder health, ketosis, persistency, and longevity. This study shows that fluctuations in daily milk yield are heritable and that the variance of milk production is best among the 3 fluctuations traits tested to predict udder health, ketosis, and longevity. Using the residual variance of milk production instead of the raw variance is expected to further improve the trait to breed healthy, resilient, and long-lasting dairy cows.

Wetlands occupy a position in the landscape that makes them vulnerable to the effects of current land use and the legacies of past land use. Many wetlands in agricultural regions like the North American Midwest are strongly affected by elevated nutrient inputs as well as high rates of invasion by the hybrid cattail Typha × glauca. These two stressors also exacerbate each other: increased nutrients increase invasion success, and invasions increase nutrient retention and nutrient loads in the wetland. This interaction could create a positive feedback that would inhibit efforts to manage and control invasions, but little is known about the effects of past or present nutrient inputs on wetland invasive plant management. We augmented a previously-published community-ecosystem model (MONDRIAN) to simulate the most common invasive plant management tools: burning, mowing, and herbicide application. We then simulated different management strategies and 3 different durations in low and high nutrient input conditions, and found that the most effective management strategy and duration depends strongly on the amount of nutrients entering the wetland. In high-nutrient wetlands where invasions were most successful, a combination of herbicide and fire was most effective at reducing invasion. However, in low-nutrient wetlands this approach did little to reduce invasion. A longer treatment duration (6 years) was generally better than a 1-year treatment in high-nutrient wetlands, but was generally worse than the 1-year treatment in low-nutrient wetlands. At the ecosystem level, we found that management effects were relatively modest: there was little effect of management on ecosystem C storage, and while some management strategies decreased wetland nitrogen retention, this effect was transient and disappeared shortly after management ceased. Our results suggest that considering nutrient inputs in invaded wetlands can inform and improve management, and reducing nutrient inputs is an important component of an effective management strategy.

Bovine milk samples were collected from 30 Dutch farms and analysed by gas chromatography-mass spectrometry for phytanic acid (PHY), pristanic acid (PA) and SRR/RRR-diastereomers ratio of PHY. The samples differed in the percentage of fresh grass in the cows' daily ration (0–94%) fed either indoors or via grazing (daytime grazing or continuous grazing). Six samples were from organic/biodynamic farms. PHY and PA concentrations were not significantly higher in organic/biodynamic compared with conventional milk, nor were they correlated with the amount of fresh grass in the diet. The SRR/RRR-diastereomers ratio was correlated with the percentage of fresh grass in the diet and was lower in organic milk than in conventional milk, although the difference was not significant (p = 0.057). These results indicate that PHY and PA contents are not suitable indicators of pasture grazing or organic/biodynamic farming, whereas the SRR/RRR-diastereomers ratio may be useful for indicating fresh grass feeding and organic farming.

The urachus is a vestigial structure of the allantois and cloaca. It involutes as fetal development progresses to become a fibrous cord, which courses between the umbilicus and bladder dome within the retropubic space. Infection occasionally occurs in patients with congenital patent urachus. Here, we report a patient with infection of a previously closed urachal tract presenting as an abdominal mass. This has rarely been described in the literature. Current knowledge on imaging findings to the diagnosis is discussed.