R-ketorolac ameliorates cancer-associated cachexia and prolongs survival of tumour-bearing mice.

BACKGROUND: Cancer-associated cachexia (CAC) is a debilitating syndrome associated with poor quality of life and reduced life expectancy of cancer patients. CAC is characterized by unintended body weight reduction due to muscle and adipose tissue loss. A major hallmark of CAC is systemic inflammation. Several non-steroidal anti-inflammatory drugs (NSAIDs) have been suggested for CAC treatment, yet no single medication has proven reliable. R-ketorolac (RK) is the R-enantiomer of a commonly used NSAID. The effect of RK on CAC has not yet been evaluated. METHODS: Ten- to 11-week-old mice were inoculated with C26 or CHX207 cancer cells or vehicle control (phosphate-buffered saline [PBS]). After cachexia onset, 2 mg/kg RK or PBS was administered daily by oral gavage. Body weight, food intake and tumour size were continuously measured. At study endpoints, blood was drawn, mice were sacrificed and tissues were excised. Immune cell abundance was analysed using a Cytek® Aurora spectral flow cytometer. Cyclooxygenase (COX) activity was determined in lung homogenates using a fluorometric kit. Muscle tissues were analysed for mRNA and protein expression by quantitative real-time PCR and western blotting analysis, respectively. Muscle fibre size was determined on histological slides after haematoxylin/eosin staining. RESULTS: Ten-day survival rate of C26-bearing animals was 10% while RK treatment resulted in a 100% survival rate (P = 0.0009). Chemotherapy resulted in a 10% survival rate 14 days after treatment initiation, but all mice survived upon co-medication with RK and cyclophosphamide (P = 0.0001). Increased survival was associated with a protection from body weight loss in C26 (-0.61 ± 1.82 vs. -4.48 ± 2.0 g, P = 0.0004) and CHX207 (-0.49 ± 0.33 vs. -2.49 ± 0.93 g, P = 0.0003) tumour-bearing mice treated with RK, compared with untreated mice. RK ameliorated musculus quadriceps (-1.7 ± 7.1% vs. -27.8 ± 8.3%, P = 0.0007) and gonadal white adipose tissue (-18.8 ± 49% vs. -69 ± 15.6%, P = 0.094) loss in tumour-bearing mice, compared with untreated mice. Mechanistically, RK reduced circulating interleukin-6 (IL-6) concentrations from 334 ± 151 to 164 ± 123 pg/mL (P = 0.047) in C26 and from 93 ± 39 to 35 ± 6 pg/mL (P = 0.0053) in CHX207 tumour-bearing mice. Moreover, RK protected mice from cancer-induced T-lymphopenia (+1.8 ± 42% vs. -49.2 ± 12.1% in treated vs. untreated mice, respectively). RK was ineffective in ameliorating CAC in thymus-deficient nude mice, indicating that the beneficial effect of RK depends on T-cells. CONCLUSIONS: RK improved T-lymphopenia and decreased systemic IL-6 concentrations, resulting in alleviation of cachexia and increased survival of cachexigenic tumour-bearing mice, even under chemotherapy and independent of COX inhibition. Considering its potential, we propose that the use of RK should be investigated in patients suffering from CAC.

Recruitment of Patients With Cancer for a Clinical Trial Evaluating a Web-Based Psycho-Oncological Intervention: Secondary Analysis of a Diversified Recruitment Strategy in a Randomized Controlled Trial.

BACKGROUND: Participant recruitment poses challenges in psycho-oncological intervention research, such as psycho-oncological web-based intervention studies. Strict consecutive recruitment in clinical settings provides important methodological benefits but is often associated with low response rates and reduced practicability and ecological validity. In addition to preexisting recruitment barriers, the protective measures owing to the COVID-19 pandemic restricted recruitment activities in the clinical setting since March 2020. OBJECTIVE: This study aims to outline the recruitment strategy for a randomized controlled trial evaluating the unguided emotion-based psycho-oncological online self-help (epos), which combined traditional and web-based recruitment. METHODS: We developed a combined recruitment strategy including traditional (eg, recruitment in clinics, medical practices, cancer counseling centers, and newspapers) and web-based recruitment (Instagram, Facebook, and web pages). Recruitment was conducted between May 2020 and September 2021. Eligible participants for this study were adult patients with any type of cancer who were currently receiving treatment or in posttreatment care. They were also required to have a good command of the German language and access to a device suitable for web-based interventions, such as a laptop or computer. RESULTS: We analyzed data from 304 participants who were enrolled in a 17-month recruitment period using various recruitment strategies. Web-based and traditional recruitment strategies led to comparable numbers of participants (151/304, 49.7% vs 153/304, 50.3%). However, web-based recruitment required much less effort. Regardless of the recruitment strategy, the total sample did not accurately represent patients with cancer currently undergoing treatment for major types of cancer in terms of various sociodemographic characteristics, including but not limited to sex and age. However, among the web-recruited study participants, the proportion of female participants was even higher (P<.001), the mean age was lower (P=.005), private internet use was higher (on weekdays: P=.007; on weekends: P=.02), and the number of those who were currently under treatment was higher (P=.048). Other demographic and medical characteristics revealed no significant differences between the groups. The majority of participants registered as self-referred (236/296, 79.7%) instead of having followed the recommendation of or study invitation from a health care professional. CONCLUSIONS: The combined recruitment strategy helped overcome general and COVID-19-specific recruitment barriers and provided the targeted participant number. Social media recruitment was the most efficient individual recruitment strategy for participant enrollment. Differences in some demographic and medical characteristics emerged, which should be considered in future analyses. Implications and recommendations for social media recruitment based on personal experiences are presented. TRIAL REGISTRATION: German Clinical Trials Register DRKS00021144; https://drks.de/search/en/trial/DRKS00021144. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.1016/j.invent.2021.100410.

Physiological stress reactivity and self-harm: A meta-analysis.

OBJECTIVE: Self-harm is associated with alterations in the psychobiological stress response. Specifically, the reactivity of the autonomic nervous system (ANS) and the endocrine hypothalamic-pituitary-adrenal (HPA) axis may differ in individuals who engage in self-harm. However, evidence in this regard is inconsistent. BACKGROUND: We conducted a preregistered random-effects meta-analysis of sympathetic ANS, parasympathetic ANS, sympathetic-parasympathetic, i.e., mixed-influence ANS, and HPA axis reactivity following laboratory stress exposure in individuals who engage in self-harm and controls. Stress exposure consisted of paradigms using either social-evaluative (e.g., TSST), emotional (e.g., negatively valenced visual stimuli), or physical (e.g., cold pressor test) challenges. A total of 29 studies (self-harm: n = 954, controls: n = 1122, 74% females) were included in the analysis. RESULTS: Regarding ANS reactivity to stress, no differences emerged between the two groups. However, parasympathetic ANS activity was lower before stress (g = -0.30, CI -0.51 to -0.09) and after stressor cessation (g = 0.54, CI -1.07 to -0.01) in the self-harm group compared to controls. Regarding HPA axis reactivity, individuals who engage in self-harm showed significantly lower cortisol responses to stress than did controls (g = -0.26, CI -0.45 to -0.08). After stressor cessation (i.e., during stress recovery), cortisol was also lower in individuals who engage in self-harm compared to controls (g = -0.26, CI -0.43 to -0.08). CONCLUSIONS: Lower basal parasympathetic ANS activity and flattened cortisol responses indicate dysregulation of psychobiological stress systems in individuals who engage in self-harm. A better understanding of the psychobiological underpinnings of self-harm may allow for the establishment of biomarkers of risk stratification and treatment monitoring in affected individuals.

What is in the news today? How media-related affect shapes adolescents' stance towards the EU.

INTRODUCTION: Adolescence is regarded as a formative period for political development. One important developmental context is media. Negatively perceived political media content can foster populistic attitudes, which in turn decreases support of political institutions, such as the European Union (EU). As media valence effects are short-lived, this study examined intra-individual associations of media valence with European identity commitment and affect towards the EU, as well as indirect effects via populistic attitudes across 10 days. METHODS: We implemented a 10-day daily diary study with 371 adolescents from Germany (January to February 2022). Adolescents were on average 14.24 years old (SD = 0.55) and 60.4% were female. We estimated the hypothesized associations using multilevel structural equation models and dynamic structural equation models. RESULTS: We found significant associations between populistic attitudes and negative affect towards the EU on the same day and the next day. The lagged effect became nonsignificant, when including both same day and lagged effects into one model. Populistic attitudes were not significantly associated with European identity commitment within days or across days. Negative media content was associated with higher populistic attitudes on the same day and indirectly associated with negative affect towards the EU (b = -.01, 95% credible interval [-0.010, -0.004]). CONCLUSION: Negatively perceived political media content was associated with higher populistic attitudes and more negative affect towards the EU concurrently. Our results imply that media plays an important role for adolescents' development.

Analysis of a non-lethal biallelic frameshift mutation in ZMPSTE24 reveals utilization of alternative translation initiation codons.

Restrictive dermopathy (RD) is a lethal condition caused by biallelic loss-of-function mutations in ZMPSTE24, whereas mutations preserving residual enzymatic activity of the ZMPSTE24 protein lead to the milder mandibuloacral dysplasia with type B lipodystrophy (MADB) phenotype. Remarkably, we identified a homozygous, presumably loss-of-function mutation in ZMPSTE24 [c.28_29insA, p.(Leu10Tyrfs*37)] in two consanguineous Pakistani families segregating MADB. To clarify how lethal consequences are prevented in affected individuals, functional analysis was performed. Expression experiments supported utilization of two alternative translation initiation sites, preventing complete loss of protein function consistent with the relatively mild phenotypic outcome in affected patients. One of these alternative start codons is newly formed at the insertion site. Our findings indicate that the creation of new potential start codons through N-terminal mutations in other disease-associated genes should generally be taken into consideration in the variant interpretation process.

Adherence and effectiveness of an emotion-based psychodynamic online self-help during and after inpatient and day-care psychotherapy: Results of a naturalistic study.

Background: Internet-based mental health interventions are considered effective in providing low-threshold support for people with mental health disorders. However, there is a lack of research investigating the transferability of such online programs into routine care settings. Low treatment adherence and problems with technical implementation often limit a successful transfer into clinical routines. This naturalistic study aims to identify influencing factors on program adherence in patients who participated in an online intervention during inpatient or day-clinic psychotherapeutic treatment. Methods and findings: In a naturalistic study, we investigated the transferability of the transdiagnostic psychodynamic online self-help program KEN-Online, which includes eight consecutive units. Between May 2017 and October 2018, patients who received inpatient or day-clinic psychotherapeutic treatment at the Department of Psychosomatic Medicine and Psychotherapy in the University Medical Center Mainz have been offered to use KEN-Online. Of the n = 749 patients who were admitted to the clinic, n = 239 patients (32%) registered for participation in KEN-Online. While 46.9% of the participants did not complete any unit (inactive participants), 53.1% completed at least the first unit (active participants). Age, number of diagnoses, and symptom severity were associated with (in)active participation. Adherence decreased over time resulting in only 17 participants (7.6%) who completed all units. None of the sociodemographic and medical characteristics proved to be significant predictors of adherence. Analyses of effectiveness showed a significant reduction of anxiety and depression in active participants in the course of participation, with higher improvements in participants that completed more than half of the units. Conclusion: Adherence to the online self-help program KEN-Online was lower in the naturalistic setting than in a previous clinical trial, but was still associated with greater program effectiveness. Adherence-promoting measures are crucial to increase the effectiveness of such interventions in clinical settings.

Partnership in Promoting Community Health Research: Ten-Year Evaluation of the Little Village Community Advisory Board.

BACKGROUND: Few have examined factors associated with community advisory board (CAB) sustainability from the perspective of members. OBJECTIVES: We aimed to provide insight into the formation of a CAB and attributes and challenges to sustaining it in addressing Latino health disparities in Chicago. METHODS: The Little Village CAB was formed in 2009 with members representing a wide range of local organizations, including churches, nonprofit organizations, and health centers. We analyzed annual survey results sent to members over a 10-year period. Likert-type questions assessed five domains: mission, commitment, communication, respect/trust, and teamwork/balance of power. We also analyzed free-text responses to determine prevalent themes. Ten years of CAB monthly meeting minutes were used to form word clouds which were assessed for changes across years. RESULTS: Survey questions demonstrated high averages across all years for each domain with minimal variation. Free-text responses indicated that members initially joined the CAB owing to request or interest in community health. CAB attributes included mission, community focus, openness/respect, teamwork, and leadership. Areas for improvement included broadening membership, clarifying goals periodically, and meeting structure. Meeting minutes demonstrated a progression from program creation to maintenance across the years. CONCLUSIONS: The CAB rated openness/respect, community focus, and commitment to mission high across all 10 years. Areas for improvement included broadening membership and clarifying goals periodically. In forming a CAB to address health disparities in a Latino community, researchers must be aware of factors that motivated members to join and remain engaged with an academic team using an iterative evaluative process.

PGC-1α Methylation, miR-23a, and miR-30e Expression as Biomarkers for Exercise- and Diet-Induced Mitochondrial Biogenesis in Capillary Blood from Healthy Individuals: A Single-Arm Intervention.

Healthy mitochondria and their epigenetic control are essential to maintaining health, extending life expectancy, and improving cardiovascular performance. Strategies to maintain functional mitochondria during aging include training; cardiovascular exercise has been suggested as the best method, but strength training has also been identified as essential to health and healthy aging. We therefore investigated the effects of concurrent exercise training and dietary habits on epigenetic mechanisms involved in mitochondrial (mt) functions and biogenesis. We analyzed epigenetic biomarkers that directly target the key regulator of mitochondrial biogenesis, PGC-1α, and mtDNA content. Thirty-six healthy, sedentary participants completed a 12-week concurrent training program. Before and after the intervention, dried blood spot samples and data on eating habits, lifestyle, and body composition were collected. MiR-23a, miR-30e expression, and mtDNA content were analyzed using real-time quantitative polymerase chain reaction (qPCR) analysis. PGC-1α methylation was analyzed using bisulfite pyrosequencing. MiR-23a, miR-30e expression, and PGC-1α methylation decreased after the intervention (p < 0.05). PGC-1α methylation increased with the consumption of red and processed meat, and mtDNA content increased with the ingestion of cruciferous vegetables (p < 0.05). Our results indicate that concurrent training could improve mitochondrial biogenesis and functions by altering the epigenetic regulation. These alterations can also be detected outside of the skeletal muscle and could potentially affect athletic performance.

Informant-based assessment instruments for dementia in people with intellectual disability: A systematic review and standardised evaluation.

BACKGROUND: Dementia in people with intellectual disability (ID) is frequent but hard to recognise. Evidence-based recommendations for suitable instruments are lacking. AIMS: The present study set out to evaluate informant-based dementia assessment instruments and to provide evidence-based recommendations for instruments most suitable in clinical practice and research. METHOD AND PROCEDURES: A systematic review was conducted across ten international electronic databases. The COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) guidelines, including a risk of bias assessment, was applied to extract information and to evaluate measurement properties and the quality of available evidence. OUTCOMES AND RESULTS: In total, 42 studies evaluating 18 informant-based assessment instruments were analysed. For screening purposes, we recommend the Behavioral and Psychological Symptoms of Dementia in Down Syndrome Scale (BPSD-DS), the Cognitive Scale for Down Syndrome (CS-DS), and the Dementia Screening Questionnaire for Individuals with Intellectual Disabilities (DSQIID). For a more thorough dementia assessment, we recommend the Cambridge Examination for Mental Disorders of Older People with Down's Syndrome and Others with Intellectual Disabilities (CAMDEX-DS). CONCLUSIONS AND IMPLICATIONS: Our study informs clinicians and researchers about adequate, well-evaluated dementia assessment instruments for people with ID, and highlights the need for high quality studies, especially regarding content validity.

An emotion-based online intervention for reducing anxiety and depression in cancer patients: Study protocol for a randomized controlled trial.

BACKGROUND: A cancer diagnosis can cause severe emotional distress and affect quality of life as well as social relationships. The transition from inpatient to outpatient treatment is burdened by stressful uncertainties and a gap of psycho-oncological care. In addition, further barriers, such as information deficits or fear of stigmatization, might hinder cancer patients to use psycho-oncological face-to-face interventions. Online interventions can be a low-threshold adjunct to existing face-to-face services. This study aims to evaluate the effect of the online self-help program epos (emotion-based psycho-oncological online self-help) on improving symptoms of anxiety and depression in German-speaking cancer patients. METHODS: A randomized controlled trial (RCT) is carried out in a parallel group design. N = 325 patients will be enrolled in the trial, randomly assigned to an intervention and a control group. While the intervention group has access to nine modules of epos, the control group gets access to an informational website. Participants will complete online questionnaires at baseline (T0), after the intervention (T1) and three-month follow-up (T2). Primary outcome is a combined measure of depression and anxiety. Secondary outcomes include psychological distress, anxiety, depression, quality of life, emotional control, posttraumatic growth, and satisfaction with epos. Participants are at least 18 years old, have a cancer diagnosis, currently receive cancer treatment or aftercare, have sufficient German language competence, and have access to the Internet. Exclusion criteria are severe mental comorbidities (i.e. severe depression, suicidality) or somatic comorbidities (i.e. visual disabilities). DISCUSSION: The results of this study will provide information about acceptability, feasibility, and efficacy of epos in improving symptoms of depression and anxiety in cancer patients and thus contribute to the research on web-based interventions. If found efficacious, epos will improve psycho-oncological care in cancer patients in transition from inpatient to outpatient care and in those who struggle to find adequate psycho-oncological support due to other (perceived) barriers.

Oxytocin and vasopressin within the ventral and dorsal lateral septum modulate aggression in female rats.

In contrast to male rats, aggression in virgin female rats has been rarely studied. Here, we established a rat model of enhanced aggression in females using a combination of social isolation and aggression-training to specifically investigate the involvement of the oxytocin (OXT) and arginine vasopressin (AVP) systems within the lateral septum (LS). Using neuropharmacological, optogenetic, chemogenetic as well as microdialysis approaches, we revealed that enhanced OXT release within the ventral LS (vLS), combined with reduced AVP release within the dorsal LS (dLS), is required for aggression in female rats. Accordingly, increased activity of putative OXT receptor-positive neurons in the vLS, and decreased activity of putative AVP receptor-positive neurons in the dLS, are likely to underly aggression in female rats. Finally, in vitro activation of OXT receptors in the vLS increased tonic GABAergic inhibition of dLS neurons. Overall, our data suggest a model showing that septal release of OXT and AVP differentially affects aggression in females by modulating the inhibitory tone within LS sub-networks.

[Development of a Psychosocial Online Self-Help Program for Cancer Patients: A Patient-Oriented Approach]. / Entwicklung einer psychosozialen Online-Selbsthilfe für Krebspatienten: ein patientenorientierter Ansatz.

AIM OF THE STUDY: Involving potential end users in the development process of digital interventions makes it possible to ensure that these programs meet the needs, requirements and expectations of future users, which in turn has a positive impact on acceptance and adherence. This contribution presents a participatory development approach for the patient-centered design of the psycho-oncological online self-help epos, which aims to provide support in coping with cancer. METHODS: Patients were involved in the developmental process at two points. At an early stage of development, semi-standardized in-depth interviews were conducted with patients diagnosed by different types of cancer (N=10) and were qualitatively evaluated with regard to their view of (1) the cancer disease and (2) the design of an online self-help on the content, structural and design levels. At a later stage, a prototype of the online self-help was evaluated in a pilot phase. RESULTS: The qualitative analysis of the interviews with a total of N=742 codings resulted in five main content categories (changes in everyday life and future experience, changes in social relationships, processing mechanisms, loss of control, difficult emotions), which provide information about the central challenges and burdens of people with cancer. Participants showed particularly strong emotions around interpersonal concerns, so in addition to the emotion-based focus, the online self-help also included a focus on social relationships. Structural and design implications for development related primarily to clarity and user-friendliness. The pilot phase allowed evaluating whether the requirements for the online self-help that were described by cancer patients at an early stage of development were met. CONCLUSION: Patient participation in the development process of the digital online self-help epos provided information for the design at various levels. Involving potential end users in several development phases can ensure that the requirements and suggestions have been sufficiently considered not only from the perspective of the developers, but also from the perspective of future users. These findings confirm the importance of a patient-centered approach in the development of digital offerings.

The dipeptidyl peptidase 4 inhibitor linagliptin ameliorates renal injury and accelerated resolution in a rat model of crescentic nephritis.

BACKGROUND AND PURPOSE: Dipeptidyl peptidase 4 (DPP-4) inhibitors are a class of oral glucose-lowering drugs used in the treatment of type 2 diabetes. In a pilot study using human kidney biopsies, we observed high DPP-4 expression in early crescent formation. This glomerular lesion occurs in different kidney diseases and is a hallmark in the pathogenesis of renal dysfunction. Therefore, we investigated the potential involvement of DPP-4 in the pathogenesis of nephritis induced by anti-glomerular basement membrane (GBM) antibody in rats. EXPERIMENTAL APPROACH: Linagliptin and vehicle were used to treat anti-GBM nephritis in a 2- and 8-week regimen, that is either preventive or therapeutic (treatment started 7 days or 4 weeks after disease induction). Kidney function, morphologic changes, inflammation and fibrosis were monitored. KEY RESULTS: In the long-term experiment, linagliptin preventive treatment in anti-GBM nephritic rats significantly reduced the number of crescents, glomerulosclerosis, tubular injury and renal fibrosis, compared with those in untreated nephritic rats. Both linagliptin regimes significantly lowered the number of Pax8+ cells on the glomerular tuft in anti-GBM nephritis, indicating accelerated resolution of the cellular crescents. The linagliptin treatment did not change the podocyte stress in both therapeutic groups. Therapeutic intervention with linagliptin resulted in weaker amelioration of renal disease on Week 8 than did preventive intervention. CONCLUSION AND IMPLICATIONS: DPP-4 inhibition with linagliptin ameliorates renal injury in a rat model of anti-GBM, indicating that linagliptin not only is a secure therapy in diabetes but also can improve resolution of glomerular injury and healing in non-diabetic renal disease.

Increased soluble fms-like tyrosine kinase 1 after ischemia reperfusion contributes to adverse clinical outcomes following kidney transplantation.

Renal ischemia reperfusion injury (IRI) adversely affects clinical outcomes following kidney transplantation. Understanding the cellular mechanisms and the changes in gene/protein expression following IRI may help to improve these outcomes. Serum soluble fms-like tyrosine kinase 1 (sFlt-1), a circulating antiangiogenic protein, is increased in the first week following kidney transplantation. We evaluated the casual relationship of elevated sFlt-1 levels with renal microvascular dysfunction following IRI in a longitudinal study of 93 kidney transplant recipients and in several animal models. Transplant recipients with higher sFlt-1 levels had higher odds of delayed graft function, graft rejection, impaired graft function, and death. In a subgroup of 25 participants who underwent kidney biopsy within 4 months of kidney transplantation, peritubular capillary area was lower in those with elevated serum sFtl-1 levels. The administration of recombinant sFlt-1 into rodents resulted in significant structural and functional changes of the renal microvasculature, including reduced peritubular capillary density and intracapillary blood volume, and lead to increased expression of inflammatory genes and increased fibrosis. In a murine model of IRI, the kidney was a site of sFlt-1 production, and systemic neutralization of sFlt-1 preserved peritubular capillary density and alleviated renal fibrosis. Our data indicate that high sFlt-1 levels after IRI play an important role in the pathogenesis of microvascular dysfunction, thereby contributing to adverse clinical outcomes following kidney transplantation.

Using Community-Driven, Participatory Qualitative Inquiry to Discern Nuanced Community Health Needs and Assets of Chicago's La Villita, a Mexican Immigrant Neighborhood.

In predominately immigrant neighborhoods, the nuances of immigrant life in the ethnic enclave have important, yet underappreciated impact on community health. The complexities of immigrant experiences are essential to unpacking and addressing the impact of acculturative processes on observed racial, ethnic, and class-based health disparities in the United States. These insights because they are largely unexplored are best captured qualitatively through academic-community research partnership. We established the participatory mixed method Little Village participatory community health assessment (CHA) to explore community health in an ethnic enclave. In this paper, we share findings from our qualitative component exploring: how do Residents in a Predominately Immigrant Neighborhood Perceive Community Health Needs and Assets in Little Village. Three major themes emerged: rich, health promoting community assets inherent in the ethnic enclave; cumulative chronic stress impacting the mental health of families and intra-familial strain; and, work and occupation as important but underappreciated community health determinants in an immigrant neighborhood. These nuanced findings enhanced our community health assessment and contributed to the development of two additional tailored CHA methods, a community member-administered Community Health Survey, and an oral history component that provided deeper insight on the community's health needs and assets, and a focus for action on work as a social determinant of health at the community level. Conducting trusted community-driven health assessments that are adaptive and flexible to capture authentic needs and assets are critical, given health consequences of the new anti-immigrant rhetoric and growing socio-political tensions and fear in immigrant neighborhoods in the United States.

Vessel shape alterations of the vertebrobasilar arteries in Mucopolysaccharidosis type IVa (Morquio A) patients.

PURPOSE: Main symptom of mucopolysaccharidosis type IVa (MPS IVa) is progressive systemic skeletal dysplasia. This is routinely monitored by cerebral and spinal MRI. The vascular system is generally not in the primary focus of interest. In our population of MPS IVa patients we observed vessel shape alterations of the vertebrobasilar arteries, which has not been described before. MATERIAL AND METHODS: MRI-datasets of 26 patients with MPS IVa acquired between 2008 and 2015 were eligible for retrospective analysis of the vertebrobasilar arteries. The vessel length and angle of the basilar artery (BA) and both vertebral arteries (VA) were analyzed. A deflection angle between 90° and 130° in the vessel course was defined as tortuosity, less than 90° as kinking. The results were compared to a matched control group of 23 patients not suffering from MPS. RESULTS: The deflection angle [°] of the VA and BA was significantly decreased in the majority (85%) of MPS IVa patients compared to the control group: BA 132±24 vs. 177±6, BA/VA transition 113±21 vs. 152±13, right VA 108±23 vs. 156±13, left VA 110± 22 vs. 157±14 (all p<0.005). Likewise, vessels of MPS IVa patients were significantly longer compared to the control group: BA 27±4 vs. 21±2, right VA 20±6 vs. 10±1, left VA 18±5 vs. 11±2 (all p<0.005). CONCLUSION: MPS IVa is associated with significantly increased tortuosity of vertebrobasilar arteries. Therefore the vascular system of MPS IVa patients should be monitored on routinely basis, as vessel shape alterations had been associated with dissections, leading to a higher risk of cerebrovascular events.

Expecting to See a Letter: Alpha Oscillations as Carriers of Top-Down Sensory Predictions.

Predictions strongly influence perception. However, the neurophysiological processes that implement predictions remain underexplored. It has been proposed that high- and low-frequency neuronal oscillations act as carriers of sensory evidence and top-down predictions, respectively (von Stein and Sarnthein 2000; Bastos et al. 2012). However, evidence for the latter hypothesis remains scarce. In particular, it remains to be shown whether slow prestimulus alpha oscillations in task-relevant brain regions are stronger in the presence of predictions, whether they influence early categorization processes, and whether this interplay indeed boosts perception. Here, we directly address these questions by manipulating subjects' prior expectations about the identity of visually presented letters while collecting magnetoencephalographic recordings. We find that predictions lead to increased prestimulus alpha oscillations in a multisensory network representing grapheme/phoneme associations. Furthermore, alpha power interacts with stimulus degradation and top-down expectations to predict visibility ratings, and correlates with the amplitude of early sensory components (P1/N1m complex), suggesting a role in the selective amplification of predicted information. Our results thus indicate that low-frequency alpha oscillations can serve as a mechanism to carry and test sensory predictions about letters.

Activation of Cardiac Fibroblast Growth Factor Receptor 4 Causes Left Ventricular Hypertrophy.

Chronic kidney disease (CKD) is a worldwide public health threat that increases risk of death due to cardiovascular complications, including left ventricular hypertrophy (LVH). Novel therapeutic targets are needed to design treatments to alleviate the cardiovascular burden of CKD. Previously, we demonstrated that circulating concentrations of fibroblast growth factor (FGF) 23 rise progressively in CKD and induce LVH through an unknown FGF receptor (FGFR)-dependent mechanism. Here, we report that FGF23 exclusively activates FGFR4 on cardiac myocytes to stimulate phospholipase Cγ/calcineurin/nuclear factor of activated T cell signaling. A specific FGFR4-blocking antibody inhibits FGF23-induced hypertrophy of isolated cardiac myocytes and attenuates LVH in rats with CKD. Mice lacking FGFR4 do not develop LVH in response to elevated FGF23, whereas knockin mice carrying an FGFR4 gain-of-function mutation spontaneously develop LVH. Thus, FGF23 promotes LVH by activating FGFR4, thereby establishing FGFR4 as a pharmacological target for reducing cardiovascular risk in CKD.