Entry motion sickness (EMS) affects crewmembers upon return to Earth following extended adaptation to microgravity. Anticholinergic pharmaceuticals (e.g., Meclizine) are often taken prior to landing; ...however, they have operationally adverse side effects (e.g., drowsiness). There is a need to develop non-pharmaceutical countermeasures to EMS. We assessed the efficacy of a technological countermeasure providing external visual cues following splashdown, where otherwise only nauseogenic internal cabin visual references are available. Our countermeasure provided motion-congruent visual cues of an Earth-fixed scene in virtual reality, which was compared to a control condition with a head-fixed fixation point in virtual reality in a between-subject design with 15 subjects in each group. We tested the countermeasure’s effectiveness at mitigating motion sickness symptoms at the end of a ground-based reentry analog: approximately 1 h of 2Gx centrifugation followed by up to 1 h of wave-like motion. Secondarily, we explored differences in vestibular-mediated balance performance between the two conditions. While Motion Sickness Questionnaire outcomes did not differ detectably between groups, we found significantly better survival rates (with dropout dictated by reporting moderate nausea consecutively over 2 min) in the visual countermeasure group than the control group (79% survival vs. 33%, t(14) = 2.50, p = 0.027). Following the reentry analogs, subjects demonstrated significantly higher sway prior to recovery (p = 0.0004), which did not differ between control and countermeasure groups. These results imply that providing motion-congruent visual cues may be an effective mean for curbing the development of moderate nausea and increasing comfort following future space missions.
Full text
Available for:
EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, ODKLJ, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The brain is able to determine angular self-motion from visual, vestibular, and kinesthetic information. There is compelling evidence that both humans and non-human primates integrate visual and ...inertial (i.e., vestibular and kinesthetic) information in a statistically optimal fashion when discriminating heading direction. In the present study, we investigated whether the brain also integrates information about angular self-motion in a similar manner. Eight participants performed a 2IFC task in which they discriminated yaw-rotations (2-s sinusoidal acceleration) on peak velocity. Just-noticeable differences (JNDs) were determined as a measure of precision in unimodal inertial-only and visual-only trials, as well as in bimodal visual–inertial trials. The visual stimulus was a moving stripe pattern, synchronized with the inertial motion. Peak velocity of comparison stimuli was varied relative to the standard stimulus. Individual analyses showed that data of three participants showed an increase in bimodal precision, consistent with the optimal integration model; while data from the other participants did not conform to maximum-likelihood integration schemes. We suggest that either the sensory cues were not perceived as congruent, that integration might be achieved with fixed weights, or that estimates of visual precision obtained from non-moving observers do not accurately reflect visual precision during self-motion.
Full text
Available for:
EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, ODKLJ, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The occurrence of distant metastases and metastases to mediastinal lymph nodes profoundly affects the prognosis of non–small-cell lung cancer, making accurate staging crucial for selecting ...appropriate treatment. When used alone, the results of most staging methods, such as computed tomography (CT), ultrasonography, and radionuclide bone scanning, are far from ideal. Whole-body positron-emission tomography (PET) with 18F-fluorodeoxyglucose (fludeoxyglucose F 18) as a tracer is a new metabolic imaging technique that relies on the fact that there is increased metabolism of glucose in tumor cells.
1
,
2
Pulmonary tumors actively metabolize the tracer, and several studies have shown that the method has about . . .
Without visual feedback, humans perceive tilt when experiencing a sustained linear acceleration. This tilt illusion is commonly referred to as the somatogravic illusion. Although the physiological ...basis of the illusion seems to be well understood, the dynamic behavior is still subject to discussion. In this study, the dynamic behavior of the illusion was measured experimentally for three motion profiles with different frequency content. Subjects were exposed to pure centripetal accelerations in the lateral direction and were asked to indicate their tilt percept by means of a joystick. Variable-radius centrifugation during constant angular rotation was used to generate these motion profiles. Two self-motion perception models were fitted to the experimental data and were used to obtain the time constant of the somatogravic illusion. Results showed that the time constant of the somatogravic illusion was on the order of two seconds, in contrast to the higher time constant found in fixed-radius centrifugation studies. Furthermore, the time constant was significantly affected by the frequency content of the motion profiles. Motion profiles with higher frequency content revealed shorter time constants which cannot be explained by self-motion perception models that assume a fixed time constant. Therefore, these models need to be improved with a mechanism that deals with this variable time constant. Apart from the fundamental importance, these results also have practical consequences for the simulation of sustained accelerations in motion simulators.
Full text
Available for:
EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, ODKLJ, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
•Introduction of immunotherapy did not change quality of care between hospitals.•Patients underrepresented in trials received immunotherapy in routine practice.•Patients with brain metastases ...survived as long as those without this disorder.•Patients with selected auto immune disorders survived longer.
Phase III studies of checkpoint inhibitors changed the therapeutic landscape for lung cancer. In 2015 the Dutch Society of Chest Physicians (NVALT) introduced a national immunotherapy registry for patients with lung cancer; quality standards for hospitals were implemented. At population level we studied clinical benefit in daily practice and in patients who are underrepresented in phase III trials.
From the initial introduction of checkpoint inhibitors in the Netherlands patients were centrally registered. Educational programs and quality control were provided under supervision of NVALT. The largest immunotherapy providing hospitals were compared to hospitals who provided less checkpoint inhibitors as marker of experience. Patients characteristics, treatment and side effects, response rate and survival were studied.
A total of 2676 patients were registered, 2302 with follow up data were evaluated. Between October 2015 and December 2017 a gradual increase from 12 to 30 qualified hospitals showed no major toxicity differences. Toxicity led to a hospital admission rate of 9.1 with an average duration of 10.4 days.
Overall tumor response was 21.8 % and median overall survival 12.6 months. Overall survival was not significantly different for patients aged ≥ 75 years, those having brain metastases or selected auto-immune diseases before start checkpoint inhibitors compared to younger patients or those without, respectively. Survival outcomes were worse in patients with PS 2+, non-smokers, and patients who received any palliative radiotherapy (HR 2.1, 95 % CI 1.7–2.7; 1.3, 95 % CI 1.0–1.6 and 1.2, 95 % CI 1.1–1.4, respectively).
Changes in the therapeutic landscape did not lead to major differences in quality of care between hospitals. Elderly patients, those with brain metastases or selected auto-immune disease underrepresented in clinical trials did not do worse on checkpoint inhibitors, except for those with PS 2 + .
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
•Loss of PGC-1α in PNs enhances glutamatergic transmission in the neocortex and hippocampus.•Deletion of PGC-1α from pyramidal neurons (PNs) caused ambulatory hyperactivity in response to a novel ...environment.•Extent of downregulation in metabolic and neuron-specific transcripts regulated by PGC-1α in PNs are regionally distinct.
The transcriptional coactivator peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) is a critical regulator of genes involved in neuronal metabolism, neurotransmission, and morphology. Reduced PGC-1α expression has been implicated in several neurological and psychiatric disorders. An understanding of PGC-1α’s roles in different cell types will help determine the functional consequences of PGC-1α dysfunction and/or deficiency in disease. Reports from our laboratory and others suggest a critical role for PGC-1α in inhibitory neurons with high metabolic demand such as fast-spiking interneurons. Here, we document a previously unrecognized role for PGC-1α in maintenance of gene expression programs for synchronous neurotransmitter release, structure, and metabolism in neocortical and hippocampal excitatory neurons. Deletion of PGC-1α from these neurons caused ambulatory hyperactivity in response to a novel environment and enhanced glutamatergic transmission in neocortex and hippocampus, along with reductions in mRNA levels from several PGC-1α neuron-specific target genes. Given the potential role for a reduction in PGC-1α expression or activity in Huntington Disease (HD), we compared reductions in transcripts found in the neocortex and hippocampus of these mice to that of an HD knock-in model; few of these transcripts were reduced in this HD model. These data provide novel insight into the function of PGC-1α in glutamatergic neurons and suggest that it is required for the regulation of structural, neurosecretory, and metabolic genes in both glutamatergic neuron and fast-spiking interneuron populations in a region-specific manner. These findings should be considered when inferring the functional relevance of changes in PGC-1α gene expression in the context of disease.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract
Background
a suspected urinary tract infection (UTI) is the most common reason to prescribe antibiotics in a frail older patient. Frequently, antibiotics are prescribed unnecessarily. To ...increase appropriate antibiotic use for UTIs through antibiotic stewardship interventions, we need to thoroughly understand the factors that contribute to these prescribing decisions.
Objectives
(1) to obtain insight into factors contributing to antibiotic prescribing for suspected UTIs in frail older adults. (2) To develop an overarching model integrating these factors to guide the development of antibiotic stewardship interventions for UTIs in frail older adults.
Methods
we conducted an exploratory qualitative study with 61 semi-structured interviews in older adult care settings in Poland, the Netherlands, Norway and Sweden. We interviewed physicians, nursing staff, patients and informal caregivers.
Results
participants described a chain of decisions by patients, caregivers and/or nursing staff preceding the ultimate decision to prescribe antibiotics by the physician. We identified five themes of influence: (1) the clinical situation and its complexity within the frail older patient, (2) diagnostic factors, such as asymptomatic bacteriuria, (3) knowledge (gaps) and attitude, (4) communication: interprofessional, and with patients and relatives and (5) context and organisation of care, including factors such as availability of antibiotics (over the counter), antibiotic stewardship efforts and factors concerning out-of-hours care.
Conclusions
decision-making on suspected UTIs in frail older adults is a complex, multifactorial process. Due to the diverse international setting and stakeholder variety, we were able to provide a comprehensive overview of factors to guide the development of antibiotic stewardship interventions.
•The cost-effectiveness of PCI compared to no PCI was assessed in stage III NSCLC.•A cohort partitioned survival model was developed including five health states.•PCI was more effective (0.443 QALYs) ...and costly (€10,123) than no PCI.•The probability of PCI being cost-effective was 93%.
In stage III non-small cell lung cancer (NSCLC), prophylactic cranial irradiation (PCI) reduces the brain metastases incidence and prolongs the progression-free survival without improving overall survival. PCI increases the risk of toxicity and is currently not adopted in routine care. Our objective was to assess the cost-effectiveness of PCI compared with no PCI in stage III NSCLC from a Dutch societal perspective.
A cohort partitioned survival model was developed based on individual patient data from three randomized phase III trials (N = 670). Quality-adjusted life years (QALYs) and costs were estimated over a lifetime time horizon. A willingness-to-pay (WTP) threshold of €80,000 per QALY was adopted. Sensitivity and scenario analyses were performed to address parameter uncertainty and to explore what parameters had the greatest impact on the cost-effectiveness results.
PCI was more effective and costly (0.443 QALYs, €10,123) than no PCI, resulting in an incremental cost-effectiveness ratio (ICER) of €22,843 per QALY gained. The probability of PCI being cost-effective at a WTP threshold of €80,000 per QALY was 93%. The probability of PCI gaining three and six additional months of life were 76% and 56%. The scenario analysis adding durvalumab increased the ICER to €35,159 per QALY gained. Using alternative survival distributions had little impact on the ICER. Assuming fewer PCI fractions and excluding indirect costs decreased the ICER to €18,263 and €5554 per QALY gained.
PCI is cost-effective compared to no PCI in stage III NSCLC, and could therefore, from a cost-effectiveness perspective, be considered in routine care.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Introduction
Prevalence of obesity and associated diseases, including type 2 diabetes mellitus, dyslipidaemia and non‐alcoholic fatty liver disease (NAFLD), are increasing. Underlying mechanisms, ...especially in humans, are unclear. Bariatric surgery provides the unique opportunity to obtain biopsies and portal vein blood‐samples.
Methods
The BARIA Study aims to assess how microbiota and their metabolites affect transcription in key tissues and clinical outcome in obese subjects and how baseline anthropometric and metabolic characteristics determine weight loss and glucose homeostasis after bariatric surgery. We phenotype patients undergoing bariatric surgery (predominantly laparoscopic Roux‐en‐Y gastric bypass), before weight loss, with biometrics, dietary and psychological questionnaires, mixed meal test (MMT) and collect fecal‐samples and intra‐operative biopsies from liver, adipose tissues and jejunum. We aim to include 1500 patients. A subset (approximately 25%) will undergo intra‐operative portal vein blood‐sampling. Fecal‐samples are analyzed with shotgun metagenomics and targeted metabolomics, fasted and postprandial plasma‐samples are subjected to metabolomics, and RNA is extracted from the tissues for RNAseq‐analyses. Data will be integrated using state‐of‐the‐art neuronal networks and metabolic modeling. Patient follow‐up will be ten years.
Results
Preoperative MMT of 170 patients were analysed and clear differences were observed in glucose homeostasis between individuals. Repeated MMT in 10 patients showed satisfactory intra‐individual reproducibility, with differences in plasma glucose, insulin and triglycerides within 20% of the mean difference.
Conclusion
The BARIA study can add more understanding in how gut‐microbiota affect metabolism, especially with regard to obesity, glucose metabolism and NAFLD. Identification of key factors may provide diagnostic and therapeutic leads to control the obesity‐associated disease epidemic.
Full text
Available for:
BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Introduction:
Approximately 80% of non-small cell lung cancer (NSCLC) patients with bone metastases have cancer induced bone pain (CIBP).
Methods:
The NVALT-9 was an open-label, single arm, phase II, ...multicenter study. Main inclusion criterion: bone metastasized NSCLC patients with uncontrolled CIBP brief pain inventory BPI ≥ 5 over last 7 days. Patients were treated with six milligram ibandronate intravenously (day 1–3) once a day. Main exclusion criteria: active secondary malignancy, systemic anti-tumor treatment and radiotherapy ≤4 weeks before study start, previous bisphosphonate treatment. Statistics: Simon's Optimal two-stage design with a 90% power to declare the treatment active if the pain response rate is ≥ 80% and 95% confidence to declare the treatment inactive if the pain response rate is ≤ 60%. If pain response is observed in ≤ 12 of the first 19 patients further enrollment will be stopped. Primary endpoint: bone pain response, defined as 25% decrease in worst pain score (PSc) over a 3-day period (day 5–7) compared to baseline PSc with maximum of 25% increase in mean analgesic consumption during the same period. Secondary endpoints: BPI score, quality of life, toxicity and World Health Organization Performance Score.
Results:
Of the 19 enrolled patients in the first stage, 18 were evaluable for response. All completed ibandronate treatment according to protocol. In 4 (22.2%), a bone pain response was observed. According to the stopping rule, further enrollment was halted.
Discussion:
Ibandronate loading doses lead to insufficient pain relief in NSCLC patients with CIBP.
PDF
