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Interferometers for the measurement of topography rely on imaging systems to map surface points to a camera. The response of an interferometer to variations in surface height depends on the filtering properties of the imaging system. Here we provide a simple and practical model of an imaging interferometer using classical Fourier optics, including the effects of partial coherence. The model is useful for understanding basic properties such as lateral resolution and error sources related to measurement principles that make assumptions regarding the fidelity of the instrument response over a range of surface spatial frequencies and light source wavelengths.

Optical non-contact, interferometric measurement strategies for mold pins and plates provide an effective means for improving the consistency of the injection molding of small lenses for consumer devices. In this presentation, we describe high-precision interferometric metrology combined with motion systems and advanced software to address the wide range of length scales and metrology requirements of mold assemblies intended for high-volume production.

Background: Positioning and fit of the knee prostheses in patients determines functional outcome. For that matter anthropometric differences between knee joints of patients, will affect function. Since most total knees implant systems are designed for caucasians, discrepancies in matching to Asian patients might exist, with consequently less optimal fit of the implant. The aim of this study was to evaluate differences in anthropometric dimensions between Caucasian and Asian knees of patients eligible for total knee arthroplasty. Materials and Methods: 134 patients were included for radiographic anthropometric measurements on distal femurs, proximal tibia and patellar dimension were measured of 67 Caucasian and 67 Asian patients. Patient groups were age and gender matched. All radiographs were obtained preoperatively prior to total knee arthroplasty at two different centers, Jakarta and Leiden. The radiographic measurements were widest anteroposterior (AP) and widest mediolateral (ML) dimensions, aspect ratio (ML/AP), patellar length and patellar tendon length, patellar tendon/patella ratio. Sizes of eight knee implant designs (Vanguard, Genesis II, Persona -standard and narrow-, GK Sphere, Gemini, Attune and Sigma PFC) were collected from manufactures brochures and compared to the anthropometric measurements. Chi-Square test, student t-test and Bayesian statistics were used to compare differences between the two populations. Results: The mean age of the Caucasian group was 68 ± 7.1 years and the Asian patients were 67 ± 7.8 years. Both groups included 14.9% males and 85.1% females. The Dutch patients had a height of 166cm (sd 8.1 cm) the Indonesian patients 156 cm (sd 8.0 cm), the Dutch being 6.4% taller. Preoperative deformities in the Asians was predominantly into varus, while the Dutch patients had a slight valgus alignment; 90% of the KL scores were grade 3 and 4, comparable in both groups. In AP and ML the Caucasian femur is larger than the Asian femur (male-AP 12%, female-AP 15%, male-ML 6%, female-ML 9%). The Caucasian tibia is larger in AP and ML dimensions compared to the Asian patient’s tibia. The ML/AP aspect ratios were significantly different (pConclusion: Absolute and relative differences of knee dimensions exist between Caucasian and Asian knees. Caucasian has larger AP and ML for both tibial and femoral but smaller in aspect ratio for both tibia and femur compared to Asian patients. With respect to the fit of the implant to the natural knee, total knee arthroplasty remains a compromise to nature

Injection molding is the leading high-volume production method for aspheric lenses used in consumer electronics. The design tolerances of these lenses require careful metrology of pins, resultant lenses and the injection molding plates themselves. Pins determine the form of the lenses, while the alignment of the pins to the mold plate determines apex distance, decenter and tilt. One key parameter of the mold plate is the overall flatness, as it is a critical datum for the pins. We demonstrate flatness metrology on a platform capable of sub-micron lateral resolution that can be used for roughness measurements as well as high resolution measurements of sub-millimeter features such as apex centration. The platform is capable of measuring the full 200 mm by 200 mm mold plate in under 30 minutes. The flatness results are correlated with measurements from a laser Fizeau interferometer and demonstrate better than ±1 μm correlation on samples with 20 microns of departure and better than ±0.2 μm correlation on plates with sub-micron departure.

Engineered functional surfaces often feature varying slopes on macro- and micro-scales. When surfaces are mirror-like, the highest surface slope that can be measured by a far-field 3D imaging optical surface measuring instrument isthe arcsine of the numerical aperture (NA) of the objective lens, i.e. the acceptance angle of the lens. However, progress in instrument design has allowed for measurement of non-specular surfaces with slopes steeper than this “traditional” NA limit. Nonetheless, there is currently a lack of understanding about the instrument response to surfaces with steep slopes beyond this limit. It is unclear over what surface spatial frequencies we can expect to accurately report fine surface-feature details. Here we present results demonstrating the capability of a commercial coherence scanning interferometer for measuring surface topography of a roughened flat and a blazed grating with tilt angles greater than the NA slope limit. We show that the surface form, i.e. the tilted plane, can be measured correctly. But, while surface texture information that can appear useful is also obtained, tilting significantly influences the measurement accuracy of micro-scale texture, and for asymmetric gratings, can depend on the tilting direction. A simplified surface scattering model suggests that the loss of scattered power captured by the instrument and a low signal-to-noise ratio causes the reduction of measurement accuracy. However, a rigorous three-dimensional instrument model is needed for a full understanding; we will develop this in our future work.

Purpose The aim of this study was to evaluate the anthropometric differences between knees of Indonesian Asians and Dutch Caucasians and the fit of nine different knee implant systems. Methods A total of 268 anteroposterior (AP) and lateral knee preoperative radiographs from 134 consecutive patients scheduled for total knee arthroplasty at two different centres in Jakarta and Leiden were included. Both patient groups were matched according to age and sex and included 67 Asians and 67 Caucasians. We assessed the radiographic differences between the Asian and Caucasian anthropometric data. The dimensions of the nine knee implant designs (Vanguard, Genesis II, Persona Standard, Persona Narrow, GK Sphere, Gemini, Attune Standard, Attune Narrow, and Sigma PFC) were compared with the patients' anthropometric (distal femur and proximal tibia) measurements. Results The Dutch Caucasian patients had larger mediolateral (ML) and AP femoral and tibial dimensions than the Indonesian Asians. The aspect ratios of the distal femur and tibia were larger in Asians than in Caucasians. The AP and ML dimensions were mismatched between the tibial components of the nine knee systems and the Asian anthropometric data. Both groups had larger ML distal femoral dimensions than the knee systems. Conclusion Absolute and relative differences in knee dimensions exist not only between Asian and Caucasian knees but also within both groups. Not all TKA systems had a good fit with the Asian and Caucasian knee phenotypes. An increase in the range of available knee component sizes would be beneficial, although TKA remains an adequate compromise.

Publicado en Nature Microbiology (doi: 10.1038/s41564-020-0695-z) http://hdl.handle.net/10261/213002, The present outbreak of lower respiratory tract infections, including respiratory distress syndrome, is the third spillover, in only two decades, of an animal coronavirus to humans resulting in a major epidemic. Here, the Coronavirus Study Group (CSG) of the International Committee on Taxonomy of Viruses, which is responsible for developing the official classification of viruses and taxa naming (taxonomy) of the Coronaviridae family, assessed the novelty of the human pathogen tentatively named 2019-nCoV. Based on phylogeny, taxonomy and established practice, the CSG formally recognizes this virus as a sister to severe acute respiratory syndrome coronaviruses (SARS-CoVs) of the species Severe acute respiratory syndrome-related coronavirus and designates it as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). To facilitate communication, the CSG further proposes to use the following naming convention for individual isolates: SARS-CoV-2/Isolate/Host/Date/Location. The spectrum of clinical manifestations associated with SARS-CoV-2 infections in humans remains to be determined. The independent zoonotic transmission of SARS-CoV and SARS-CoV-2 highlights the need for studying the entire (virus) species to complement research focused on individual pathogenic viruses of immediate significance. This research will improve our understanding of virus-host interactions in an ever-changing environment and enhance our preparedness for future outbreaks., Work on DEmARC advancement and coronavirus and nidovirus taxonomies was supported by the EU Horizon2020 EVAg 653316 project, the LUMC MoBiLe program and a Mercator Fellowship by the Deutsche Forschungsgemeinschaft (to AEG) in the context of the SFB1021 (A01 to JZ)

Small World Initiative and Tiny Earth are popular citizen science programs that are implemented worldwide in response to the global antibiotic resistance crisis. When starting up the program in Albacete (Spain), we noted that rates of isolated antibiotic-producing bacteria are generally low. To make the activity more stimulating for participating students, we modified the protocol to obtain more positive results by focusing on isolation of actinomycetes, the main producers of most clinically used antibiotics. Adaptations involved redesigning culture media, incubation times and temperatures, and modification of the ESKAPE antibiosis experiment by employing an agar-transplantation step. Of 390 bacterial isolates tested, almost 6% tested positive in antibiosis experiments and DNA sequence analysis confirmed that all positives are actinomycetes, demonstrating that our protocol is efficient toward isolating antibiotic-producing actinomycetes from soil. Evaluation forms filled by participating students indicated that the program was received very positively and that our modifications contribute to make this educational program more stimulating and efficient.

The type I interferon response is an important innate antiviral pathway. Recognition of viral RNA by RIG-I-like receptors (RLRs) activates a signaling cascade that leads to type I interferon (IFN-α/β) gene transcription. Multiple proteins in this signaling pathway (e.g. RIG-I, MDA5, MAVS, TBK1, IRF3) are regulated by (de)ubiquitination events. Most viruses have evolved mechanisms to counter this antiviral response. The leader protease (Lpro) of foot-and-mouth-disease virus (FMDV) has been recognized to reduce IFN-α/β gene transcription; however, the exact mechanism is unknown. The proteolytic activity of Lpro is vital for releasing itself from the viral polyprotein and for cleaving and degrading specific host cell proteins, such as eIF4G and NF-κB. In addition, Lpro has been demonstrated to have deubiquitination/deISGylation activity. Lpro’s deubiquitination/deISGylation activity and the cleavage/degradation of signaling proteins have both been postulated to be important for reduced IFN-α/β gene transcription. Here, we demonstrate that TBK1, the kinase that phosphorylates and activates the transcription factor IRF3, is cleaved by Lpro in FMDV-infected cells as well as in cells infected with a recombinant EMCV expressing Lpro. In vitro cleavage experiments revealed that Lpro cleaves TBK1 at residues 692–694. We also observed cleavage of MAVS in HeLa cells infected with EMCV-Lpro, but only observed decreasing levels of MAVS in FMDV-infected porcine LFPK αVβ6 cells. We set out to dissect Lpro’s ability to cleave RLR signaling proteins from its deubiquitination/deISGylation activity to determine their relative contributions to the reduction of IFN-α/β gene transcription. The introduction of specific mutations, of which several were based on the recently published structure of Lpro in complex with ISG15, allowed us to identify specific amino acid substitutions that separate the different proteolytic activities of Lpro. Characterization of the effects of these mutations revealed that Lpro’s ability to cleave RLR signaling proteins but not its deubiquitination/deISGylation activity correlates with the reduced IFN-β gene transcription., Author summary Outbreaks of the picornavirus foot-and-mouth disease virus (FMDV) have significant consequences for animal health and product safety and place a major economic burden on the global livestock industry. Understanding how this notorious animal pathogen suppresses the antiviral type I interferon (IFN-α/β) response may help to develop countermeasures to control FMDV infections. FMDV suppresses the IFN-α/β response through the activity of its Leader protein (Lpro), a protease that can cleave host cell proteins. Lpro was also shown to have deubiquitinase and deISGylase activity, raising the possibility that Lpro suppresses IFN-α/β by removing ubiquitin and/or ISG15, two posttranslational modifications that can regulate the activation, interactions and localization of (signaling) proteins. Here, we show that TBK1 and MAVS, two signaling proteins that are important for activation of IFN-α/β gene transcription, are cleaved by Lpro. By generating Lpro mutants lacking either of these two activities, we demonstrate that Lpro’s ability to cleave signaling proteins, but not its deubiquitination/deISGylase activity, correlates with suppression of IFN-β gene transcription.

Statement of problem Oral rehabilitation after maxillectomy can be performed by prosthetic obturation or with a free fibula flap. Successful prosthetic obturation of large maxillectomy defects can be difficult, and masticatory function is at risk in these patients. Surgical reconstruction might provide adequate masticatory function, but the literature is lacking evidence regarding this topic. Purpose The purpose of this pilot clinical study was to assess masticatory functions and health-related quality of life (HR-QoL) outcomes in patients after maxillectomy reconstructed by using the Rohner or the Alberta Reconstructive Technique and to compare outcomes with patients rehabilitated with an obturator prosthesis. Material and methods Mixing ability, maximum occlusal force, maximum mouth opening, and HR-QoL were assessed. Differences between the 2 groups were analyzed by using the Kruskal-Wallis tests for continuous variables and chi-squared tests for categorical variables. Results The reconstructed patients (n=11) showed better mixing ability, occlusal force (nonoperated side), and overall mean HR-QoL. The nonreconstructed group (n=13) did not differ from the reconstructed groups in terms of maximum mouth opening, overall mean occlusal force, occlusal force on the operated side, and most HR-QoL questionnaire domains. Conclusions Maxillary reconstruction might be beneficial for masticatory performance in patients undergoing maxillectomy. A larger study is justified to support the possible benefit of the reconstruction of maxillary defects regarding mixing ability, occlusal force (nonoperated side), and HR-QoL.

The emerging multidrug-resistant pathogenic yeast Candida auris causes life-threatening invasive infections and shows a capacity for hospital transmission that is uncommon in other Candida species. Rapid and accurate diagnosis of C. curls infections is crucial; however, the fungus is frequently misidentified. Here, we present a rapid and easily applicable PCR assay for reliable identification of C. auris by designing primers from unique GPI protein-encoding genes. Specificity of the used primers for C. auris was verified with a panel of 19 different Candida species including the clinically most relevant and phylogenetically closely related species. Efficacy of the PCR approach was validated by correctly identifying 112 C. auris isolates from an outbreak in a Spanish hospital, 20% of which were not reliably identified by MALDI-TOF MS, and 27 genotypically diverse C. auris isolates originating from hospitals in various countries, in a test that included (blind) negative controls. By employing two GPI protein primer pairs in a single PCR, a double screening can be performed, which enhances the robustness of the PCR assay and avoids potential false negatives due to recent evolutionary events, as was observed for two isolates. Our PCR method, which is based on the uniqueness of selected GPI protein-encoding genes, is useful for easy, low-cost, and accurate identification of C. auris infections in a clinical setting.

Round window membrane (RWM) application of ouabain is known to selectively destroy type I spiral ganglion cells (SGCs) in cochleas of several rodent species, while leaving hair cells intact. This protocol has been used in rats and Mongolian gerbils, but observations in the guinea pig are conflicting. This is why we reinvestigated the effect of ouabain on the guinea pig cochlea. Ouabain solutions of different concentrations were placed, in a piece of gelfoam, upon the RWM of the right cochleas. Auditory function was assessed using acoustically evoked auditory brainstem responses (aABR). Finally, cochleas were fixed and processed for histological examination. Due to variability within treatment groups, histological data was pooled and three categories based upon general histological observations were defined: cochleas without outer hair cell (OHC) and SGC loss (Category 1), cochleas with OHC loss only (Category 2), and cochleas with OHC and SGC loss (Category 3). Animals treated with 1 mM or 10 mM ouabain showed shifts in hearing thresholds, corresponding with varying histological changes in their cochleas. Most cochleas exhibited complete outer hair cell loss in the basal and middle turns, while some had no changes, together with either moderate or near-complete loss of SGCs. Neither loss of inner hair cells nor histological changes of the stria vascularis were observed in any of the animals. Cochleas in Category 1 had normal aABRs and morphology. On average, in Category 2 OHC loss was 46.0±5.7%, SGC loss was below threshold, ABR threshold shift was 44.9±2.7 dB, and ABR wave II amplitude was decreased by 17.1±3.8 dB. In Category 3 OHC loss was 68.3±6.9%, SGC loss was 49.4±4.3%, ABR threshold shift was 39.0±2.4 dB, and ABR amplitude was decreased by 15.8±1.6 dB. Our results show that ouabain does not solely destroy type I SGCs in the guinea pig cochlea.

OBJECTIVE: To evaluate the feasibility of a study on the content and effect of comprehensive geriatric care (CGC) at home for frail elderly.METHOD: Case managers invited new CGC patients of one care organization for participation in the study. At two moments, questionnaires were conducted on (social) functioning, quality of life, perceived problems, perceived informal caregiver burden, and self-management. Information on received care was collected from the patients' medical records, In addition, a questionnaire was administered to the referring physician. Feasibility was evaluated descriptively on three domains; inclusion, follow up, and data collection.RESULTS: The intended number of 25 participants was not reached, mostly because clients did not comply with inclusion criteria, and because case managers felt uncomfortable asking patients for participation in the study. Of the 14 participants, 12 were followed until the follow-up measurement. Several questionnaire domains appeared difficult to answer for participants. It also appeared difficult to collect information on received care from the medical records. Questionnaire response among general practitioners was 6 out of 11.CONCLUSION: Due to the vulnerability of the targeted group and logistical challenges, the inclusion of participants for the study was more difficult than originally thought. In combination with the difficulties in data collection, this suggests that a large-scale study on the content and effect of CGC is not feasible. Qualitative research methodologies, preferably combined with quantitative methods, offer better opportunities to understand the value of CGC for frail elderly living at home.

Introduction: Obesity is highly prevalent, comes with serious health burden and is difficult to treat. In a minority, there is a genetic cause for the obesity. In these patients, therapy-resistant obesity is often observed despite intensive lifestyle treatment. Moreover, it is still unclear whether bariatric surgery is less successful in genetic obesity. Liraglutide is a Glucagon-Like-Peptide-1 (GLP-1) receptor agonist or GLP-1 analogue, showing positive effects on metabolic parameters, satiety and weight loss in lifestyle-induced obesity. We present our experiences of GLP-1 analogue treatment in patients with genetic obesity disorders. Methods: Adults with overweight or severe obesity and a molecularly proven genetic cause were treated with liraglutide 3,0 mg daily, in addition to ongoing intensive supportive lifestyle treatment. Anthropometrics, metabolic parameters, resting energy expenditure (REE), side effects, and subjectively reported satiety and quality of life were assessed. Results: Two patients with a heterozygous pathogenic melanocortin 4 recepter variant and two patients with 16p11.2 deletion syndrome, ranging in age between 21 and 32 years and in BMI between 28.1 and 55.7 kg/m2 at baseline, were treated. At end of follow-up, ranging between 33 weeks and 12 years, a mean change in BMI and waist circumference was observed of -5.7 ± 3.8 kg/m2 and -15.2 ± 21.1 cm, respectively. All patients reported better quality of life, three of them also reported improved satiety. Moreover, improvement of metabolic parameters was seen. No clear effect on REE was observed. Two patients experienced mild side effects, e.g. nausea and stomach pain, for a brief period. Conclusion: We here show beneficial effects of GLP-1 analogues on weight, metabolic parameters, and quality of life in four patients with genetic obesity. Satiety improved in three of the four patients. All patient achieved at least the clinically relevant 5–10% weight loss. Our findings suggest that GLP-1 analogue treatment might be an effective treatment option, in addition to a healthy lifestyle, for patients with genetic obesity.

The aim of this study was to evaluate the anthropometric differences between knees of Indonesian Asians and Dutch Caucasians and the fit of nine different knee implant systems.A total of 268 anteroposterior (AP) and lateral knee preoperative radiographs from 134 consecutive patients scheduled for total knee arthroplasty at two different centres in Jakarta and Leiden were included. Both patient groups were matched according to age and sex and included 67 Asians and 67 Caucasians. We assessed the radiographic differences between the Asian and Caucasian anthropometric data. The dimensions of the nine knee implant designs (Vanguard, Genesis II, Persona Standard, Persona Narrow, GK Sphere, Gemini, Attune Standard, Attune Narrow, and Sigma PFC) were compared with the patients' anthropometric (distal femur and proximal tibia) measurements.The Dutch Caucasian patients had larger mediolateral (ML) and AP femoral and tibial dimensions than the Indonesian Asians. The aspect ratios of the distal femur and tibia were larger in Asians than in Caucasians. The AP and ML dimensions were mismatched between the tibial components of the nine knee systems and the Asian anthropometric data. Both groups had larger ML distal femoral dimensions than the knee systems.Absolute and relative differences in knee dimensions exist not only between Asian and Caucasian knees but also within both groups. Not all TKA systems had a good fit with the Asian and Caucasian knee phenotypes. An increase in the range of available knee component sizes would be beneficial, although TKA remains an adequate compromise.III.

Purpose To compare oral function and health-related quality of life (HRQoL) in patients reconstructed with either a reconstruction plate or a free vascularized bone flap with or without 3D planning. Materials and methods Patients from the Institute for Reconstructive Sciences in Medicine, University Medical Center Utrecht, and Radboud University Medical Center were included. This cross-sectional study assessed objective masticatory performance with the mixing ability test (mixing ability index [MAI]), maximum bite force, maximum mouth opening, and HRQoL. Differences between groups were analyzed using analysis of variance or Kruskal-Wallis test for continuous variables and chi-square test for categorical variables. Results Six patients with digitally planned resections and reconstructions were included. For comparison, five patients treated with freehand bone reconstruction and four patients treated with plate reconstruction were also included. Mixing ability was superior in 3D-planned reconstructions (MAI: 20.7 ± 6.7) compared to plate reconstructions (MAI: 30.0 ± 0.1, P = .017) and freehand reconstructions (MAI: 29.5 ± 1.1, P = .017). Maximum mouth opening, bite force, and HRQoL differences did not reach statistical significance. Conclusion This study indicated a possible benefit to masticatory performance of adequate surgical planning for one-phase reconstruction using 3D technology. A larger prospective study is necessary to gain more evidence regarding this finding.

An important characterization for surface topography instruments is a traceable calibration of the height scale. We calibrate our coherence scanning interference microscopes using a natural spectral emission line in place of a sequence of material measures such as step-height specimens. The uncertainty budget for our approach includes estimates for several error sources associated with long term drift. Here we summarize results collected over 3 years’ experience from our laboratories to provide statistical support for confirming and refining these uncertainty contributions. We find that the source wavelength stability is < 0.005% RMS and the stability of the height scaling factor (the amplification coefficient) is < 0.02% RMS over 900 days. Both values are better than our original estimates. We also show < 0.13% RMS reproducibility of the complete traceable process using acceptance test data for over 100 manufactured instruments. Finally, we report results of 3 years of experience in certifying step-height specimens using the traceable wavelength method.

Interferometers for the measurement of surface form and texture have a reputation for high performance. However, the results for many types of surface features can deviate from the expectation of one cycle of phase shift per half wavelength of surface height. Here we review the fundamentals of imaging interferometry and describe ways of defining instrument response, including the linear instrument transfer function. These considerations define practical regimes of linear behavior that are usually satisfied for traditional uses of interferometers; but that are increasingly challenged by applications involving complex textures and high surface slopes. We conclude by proposing pathways for further improving performance on difficult surface structures using advanced modeling techniques.

The functional behavior of sealing surfaces and bearings depends on the texture direction with respect to the axis of rotation of a machined part, known as the twist or lead angle. We present our lead angle measurement solution using interference microscopy, multi-axis staging, and advanced software for determining surface texture direction and cylinder rotation axis.

Background Airway epithelial cells have a well-accepted role in the regulation of local inflammatory processes in allergic and innate defence responses. However, their role the pathophysiology of chronic rhinosinusitis with nasal polyps (CRSwNP) is unclear. The objective was to investigate whether potential differences in the mRNA expression profile of nasal epithelia from healthy individuals and from CRSwNP patients would shed new light on disease mechanisms. Methods Primary epithelial cells from nasal polyps of 24 affected individuals and from middle turbinates of 9 healthy controls were obtained using magnetic beat assisted isolation and were used for expression profiling using the Human Genome U133 Plus 2.0 Genechip Array. Results Multiple gene probes corresponding to 27 genes showed an aberrant expression profile in polyp epithelial cells compared to healthy controls. Most of these genes are linked to pathogenic mechanisms seen in neoplasm formation, including changes in cell-cell adhesion, metabolic processes, cell cycle control, and differentiation. Remarkably, our data additionally suggest a role for maternally expressed genes in the pathogenesis of CRSwNP and reveal two distinct states of polyp epithelium that could not be linked to the presence or absence of atopy in patients or to the level of eosinophilia or neutrophilia of the polyp. Conclusions Our data suggest new roles for nasal epithelium in the pathogenesis of CRSwNP.

Background Patient-Reported Outcome Measures (PROMs) have been proposed for benchmarking health care quality across hospitals, which requires extensive case-mix adjustment. The current study’s aim was to develop and compare case-mix models for mortality, a functional outcome, and a patient-reported outcome measure (PROM) in ischemic stroke care. Methods Data from ischemic stroke patients, admitted to four stroke centers in the Netherlands between 2014 and 2016 with available outcome information (N = 1022), was analyzed. Case-mix adjustment models were developed for mortality, modified Rankin Scale (mRS) scores and EQ-5D index scores with respectively binary logistic, proportional odds and linear regression models with stepwise backward selection. Predictive ability of these models was determined with R-squared (R2) and area-under-the-receiver-operating-characteristic-curve (AUC) statistics. Results Age, NIHSS score on admission, and heart failure were the only common predictors across all three case-mix adjustment models. Specific predictors for the EQ-5D index score were sex (β = 0.041), socio-economic status (β = − 0.019) and nationality (β = − 0.074). R2-values for the regression models for mortality (5 predictors), mRS score (9 predictors) and EQ-5D utility score (12 predictors), were respectively R2 = 0.44, R2 = 0.42 and R2 = 0.37. Conclusions The set of case-mix adjustment variables for the EQ-5D at three months differed considerably from the set for clinical outcomes in stroke care. The case-mix adjustment variables that were specific to this PROM were sex, socio-economic status and nationality. These variables should be considered in future attempts to risk-adjust for PROMs during benchmarking of hospitals.

The street food sector in Sub-Saharan Africa is a source of affordable and nutritious meals for the urban poor, while also being an important source of income for the women who dominate this sector. Despite the importance of this sector, many micro- and informal enterprises are labelled as 'survivalist', beyond the reach of common development policies, which give priority to so-called growth-oriented enterprises. When given the chance to speak for themselves, do enterprises express any aspirations to grow? Contrary to the literature, our findings show that necessity-driven enterprises do aspire to grow and that this is true for both those owned by men and women. Using contextual interaction theory, this paper explains why it is possible for previous authors to come to such a different conclusion.

The nasal cavity displays immune tolerance to commensal bacteria under homeostatic conditions, which is rapidly converted to a pro-inflammatory response upon infection. Yet, the factors that control this conversion are still largely unknown. Here, we provide evidence that Fc gamma receptor III (FcγRIII) stimulation breaks immune tolerance to bacteria in the human nasal cavity through activation of nasal epithelial cells, which are the first line of defense against invading microbes. While under steady-state conditions human nasal epithelial cells were completely non-responsive to Gram-negative bacteria P. aeruginosa or TLR4 ligand LPS, IgG opsonization of bacteria, as occurs upon infection, strongly induced production of pro-inflammatory agents such as IL-6 and IL-8. This breaking of tolerance to bacteria was completely dependent on FcγRIII, which amplified cytokine gene transcription through cross-talk with TLR4. In addition, we identified that epithelial cells from patients suffering from chronic rhinosinusitis with nasal polyps do not display LPS tolerance, thereby providing an explanation for the disturbed host defense responses of these patients. Taken together, these data are the first to identify FcγR expression on nasal epithelial cells, as well as to identify its important role in controlling the balance between tolerance and inflammation in the nasal cavity.

Human betacoronaviruses OC43 and HKU1 are endemic respiratory pathogens and, while related, originated from independent zoonotic introductions. OC43 is in fact a host-range variant of the species Betacoronavirus-1, and more closely related to bovine coronavirus (BCoV)—its presumptive ancestor—and porcine hemagglutinating encephalomyelitis virus (PHEV). The β1-coronaviruses (β1CoVs) and HKU1 employ glycan-based receptors carrying 9-O-acetylated sialic acid (9-O-Ac-Sia). Receptor binding is mediated by spike protein S, the main determinant of coronavirus host specificity. For BCoV, a crystal structure for the receptor-binding domain S1(A) is available and for HKU1 a cryoelectron microscopy structure of the complete S ectodomain. However, the location of the receptor-binding site (RBS), arguably the single-most important piece of information, is unknown. Here we solved the 3.0-Å crystal structure of PHEV S1(A). We then took a comparative structural analysis approach to map the β1CoV S RBS, using the general design of 9-O-Ac-Sia-binding sites as blueprint, backed-up by automated ligand docking, structure-guided mutagenesis of OC43, BCoV, and PHEV S1(A), and infectivity assays with BCoV-S–pseudotyped vesicular stomatitis viruses. The RBS is not exclusive to OC43 and related animal viruses, but is apparently conserved and functional also in HKU1 S1(A). The binding affinity of the HKU1 S RBS toward short sialoglycans is significantly lower than that of OC43, which we attribute to differences in local architecture and accessibility, and which may be indicative for differences between the two viruses in receptor fine-specificity. Our findings challenge reports that would map the OC43 RBS elsewhere in S1(A) and that of HKU1 in domain S1(B).

Activation of the integrated stress response (ISR) by a variety of stresses triggers phosphorylation of the α-subunit of translation initiation factor eIF2. P-eIF2α inhibits eIF2B, the guanine nucleotide exchange factor that recycles inactive eIF2•GDP to active eIF2•GTP. eIF2 phosphorylation thereby represses translation. Persistent activation of the ISR has been linked to the development of several neurological disorders, and modulation of the ISR promises new therapeutic strategies. Recently, a small-molecule ISR inhibitor (ISRIB) was identified that rescues translation in the presence of P-eIF2α by facilitating the assembly of more active eIF2B. ISRIB enhances cognitive memory processes and has therapeutic effects in brain-injured mice without displaying overt side effects. While using ISRIB to investigate the ISR in picornavirus-infected cells, we observed that ISRIB rescued translation early in infection when P-eIF2α levels were low, but not late in infection when P-eIF2α levels were high. By treating cells with varying concentrations of poly(I:C) or arsenite to induce the ISR, we provide additional proof that ISRIB is unable to inhibit the ISR when intracellular P-eIF2α concentrations exceed a critical threshold level. Together, our data demonstrate that the effects of pharmacological activation of eIF2B are tuned by P-eIF2α concentration. Thus, ISRIB can mitigate undesirable outcomes of low-level ISR activation that may manifest neurological disease but leaves the cytoprotective effects of acute ISR activation intact. The insensitivity of cells to ISRIB during acute ISR may explain why ISRIB does not cause overt toxic side effects in vivo.

Escherichia coli has been widely used as a platform microorganism for both membrane protein production and cell factory engineering. The current methods to produce membrane proteins in this organism require the induction of target gene expression and often result in unstable, low yields. Here, we present a method combining a constitutive promoter with a library of bicistronic design (BCD) elements, which enables inducer-free, tuned translation initiation for optimal protein production. Our system mediates stable, constitutive production of bacterial membrane proteins at yields that outperform those obtained with E. coli Lemo21(DE3), the current gold standard for bacterial membrane protein production. We envisage that the continuous, fine-tunable, and high-level production of membrane proteins by our method will greatly facilitate their study and their utilization in engineering cell factories.

Summary Introduction Mastication has been assessed in several ways in the past. Both patients reported and objective assessment methods have been developed. The University Medical Center (UMC) Utrecht has developed a mixing ability test (MAT) using a two‐coloured wax tablet. The present study investigates the association between the mixing ability test and a chewing related questionnaire in patients treated for oral malignancies. Patients and methods In a cohort study, patients treated for oral malignancies were assessed 4‐6 weeks before and 4‐6 weeks after treatment, as well as 6 months, 1 year and 5 years after treatment. The mixing ability test was assessed using 10 and 20 chewing strokes and was compared to seven questions about several aspects of mastication. Regression analysis was performed and density plots were drawn for statistical analysis. Results One hundred and twenty‐three patients were included in this study. The questionnaire was less predictive for the 10‐chewing stroke test and the test was less discriminatory for different food types than the 20‐chewing stroke mixing ability test. Three questions about the ability to chew solid, soft and thickened liquid food types were found to be significantly predictive for the 20‐chewing stroke test. Threshold values on the mixing ability index were around 20 for the ability to chew solid food types and 24 for soft food types. Conclusion The 10‐chewing stroke mixing ability test is less suitable than 20‐chewing strokes for patients with and treated for oral cancer. The 20‐chewing stroke mixing ability test has a fair association with self‐reported outcomes.

Background Chewing ability is often compromised in patients with oral cancer. The aim of this study was to identify which factors affect masticatory performance in these patients. Methods Patients with primary oral cancer were assessed for up to 5 years after primary treatment. Healthy controls were assessed once. A mixed‐model analysis was performed, with masticatory performance as outcome measure. Results A total of 123 patients were included in the study. Factors positively associated with masticatory performance were number of occlusal units (OU), having functional dentures, and maximum mouth opening (MMO). The impact of tumor location and maximum bite force (MBF) differed per assessment moment. Masticatory performance declined for up to 1 year but recovered at 5 years after treatment. Conclusion Masticatory performance in patients treated for oral cancer is affected by MBF, MMO, number of OU, and dental status. These should be the focus of posttreatment therapy.

An international comparison of surface topography measurement noise was carried out. The comparison involved twelve optical surface topography instruments (focus variation instruments, confocal microscopes and coherence scanning interferometers) from six European research laboratories. The purpose of this comparison was to perform a practical test of the ISO definition and procedures for determining measurement noise on a variety of instruments, and to provide good practice guidance to the user community for quantifying, specifying and interpreting measurement noise. Despite taking steps to enable an optimal comparison by supplying a variety of specimens, where the ‘best’ could be selected and the measurement area was clearly defined, an appropriate comparison of the measurement noise beyond the actual measurement conditions was complex, as the measurement time, speed and lateral resolution were difficult to establish for most of the instruments. The results that could be obtained were: (i) the measurment noise N M can be reliably estimated from two measurements, (ii) noise may vary considerably between instruments, even when they have the same measurement principle, (iii) the noise in a practical measurement may be considerably higher than the noise with a levelled flat, and (iv) the ‘rms repeatability’ has little correlation to the noise determined according to the ISO specification standard, and may lead to values that are more than a hundred times smaller.

For optical measurements of areal surface topography, the instrument transfer function (ITF) quantifies height response as a function of the lateral spatial frequency content of the surface. The ITF is used widely for optical full-field instruments such as Fizeau interferometers, confocal microscopes, interference microscopes, and fringe projection systems as a more complete way to characterize lateral resolving power than a single number such as the Abbe limit. This paper is a comprehensive review of the ITF, including standardized definitions, ITF prediction using theoretical simulations, common uses, limitations, and evaluation techniques using material measures.

The application of stem cells in the treatment of various degenerative diseases is highly promising. However, cell-based therapy could be limited by the problem of low viability of grafted cells and uncertainty about their fate. The combination of molecular imaging and contrast-enhanced MRI may give more insight into the survival and behavior of grafted stem cells. We explore hair-follicle-bulge-derived stem cells (HFBSCs) as a potential candidate for autologous cell-based therapy. HFBSCs are transduced with a lentiviral construct with genes coding for bioluminescent (Luc2) and fluorescent (copGFP) reporter proteins, and subsequently loaded with magnetic nanoparticles to enable MRI visualization. Thus, we investigate for the first time if lentiviral transduction and cellular loading with nanoparticles have a cytotoxic effect upon these stem cells. Transduction efficiency, proliferation rate, cell viability and reporter protein co-expression during long-term culture of transduced HFBSCs were studied using fluorescence and bioluminescence microscopy. In addition, the effect of TMSR50 nanoparticles on proliferation and viability was investigated using the MTS assay and bioluminescence microscopy. The amount of TMSR50-loaded HFBSCs needed to reach signal threshold for MRI was assessed using an agarose phantom. Transduction with the Luc2-copGFP construct did not influence senescence, proliferation, doubling time, and differentiation of the HFBSCs. CopGFP expression was visible immediately after transduction and persisted for at least 15 passages, concomitantly with Luc2 expression. Cellular loading with TMSR50 nanoparticles did not affect cell viability and proliferation. The results imply that combined MRI and bioluminescence imaging may enable in vivo localization and long-term monitoring of grafted viable HFBSCs. Copyright © 2016 John Wiley & Sons, Ltd.

Forest fires are an important disturbance factor of boreal forests, annually burning about 0.5% of the forested area in Canada. Wildfire regimes are influenced by climate and a number of studies project an increase in wildfire activity with climate change. Another factor influencing wildfires is human intervention (fire suppression), and one factor that has rarely been assessed is fuel fragmentation. Studies evaluating the effect of forest fire suppression concluded that in areas with strong suppression effort the burned area as well as the fire size decreased. Here we evaluate wildfire distributions over the last three decades for two areas that differ mainly in their level of forest management and fire suppression: the Boreal Shield (unmanaged) and the Boreal Plain regions (intensively managed) in the Canadian Province of Saskatchewan. We calculate a fuel fragmentation index and relate fire sizes and burned areas to fire weather. We use the concept of the characteristic fire size (CFS); hence we analyze how much burned area is contributed to the total burned area per fire size class. Both areas show a uni-modal distribution of the CFS, indicating that the majority of burned area was contributed by medium sized fires (Boreal Shield 6.39 · 104 ha, the Boreal Plain 8.79 · 104 ha). Burned area as well as fuel fragmentation is lower in the managed forest compared to the unmanaged area. The fuel fragmentation index constantly increased since the 1980s in both regions. Despite the large efforts of fire suppression in the Boreal Plains, the CFS is slightly larger in this managed region. Neither the burned area nor the fire size could be linked statistically to the weather conditions, at the time of the fire (using the Canadian Fire Weather Index). We argue that the high fragmentation over the last decades have decreased the burned area. The slightly higher characteristic fire size in the managed area might be explained by the considerably lower fragmentation, counteracting fire suppression efforts. Fuel fragmentation is likely to decrease over the next decades due re-growth. Though a strong link between fire weather and burned area at the fine scale of this study could not be detected we expect that a decrease in fragmentation in combination with an increase in fire prone weather conditions (as expected for the future) might increase the risk of large fires in both areas. We suggest that future fire risk analysis should include an assessment of the effect of fuel fragmentation.

Summary Background Children with obesity show differences in brain structure, executive function and appetitive traits when compared with lean peers. Little is known on the relationship between brain structure and these traits. Objectives To investigate the relationship between differences in brain structure and executive function and appetitive traits, in obese and lean adolescents. Methods MRI was used to measure cortical thickness and subcortical volumes. Executive function was measured by a Stop Signal-and a Choice Delay Task. Appetitive traits were measured using the Child Eating Behaviour Questionnaire. Results Adolescents with obesity had greater volumes of the pallidum; 1.78 mL (SE 0.03, p=0.014), when compared with controls; 1.65 mL (SE 0.02). In the group with obesity, greater pallidum volume was positively associated with the ability to delay reward in the Choice Delay Task (p=0.012). Conclusion The association between pallidum volumes and Choice Delay Task in obese adolescents supports the hypothesis that the pallidum plays an important role in executive dysfunction in obese children.

Beschrijven van de haalbaarheid van een poliklinisch geriatrisch behandelprogramma, als pilotproject ontwikkeld in Vivium Naarderheem. De uitkomsten werden onderzocht in een pretest-posttest design met een groep. Haalbaarheid werd onderzocht door mondelinge afname van een patienttevredenheidsvragenlijst en door gestructureerde interviews met behandelaars en management. Het effect werd onderzocht door bij start (T0) en bij ontslag (T1) van het behandelprogramma schriftelijke vragenlijsten af te nemen: bij de patienten over het participatieniveau en de gezondheidsgerelateerde kwaliteit van leven en bij hun mantelzorgers over de ervaren belasting. Er werden 18 patienten geincludeerd. Vijftien daarvan revalideerden na een CVA. Behandelaars en managers vonden het programma uitvoerbaar, op voorwaarde dat het vervoer van de patienten, de roosterplanning en de financiering goed geregeld zijn. Het behandelprogramma werd door de patienten met een gemiddeld rapportcijfer van 8,1 gewaardeerd. Er zijn geen statistisch significante verschillen gevonden in het participatieniveau van de patienten en in de zorgbelasting van de mantelzorgers bij de start en het einde van de poliklinische behandeling. De algemene gezondheidsbeleving, gemeten met de RAND-36, was na poliklinische revalidatie achteruit gegaan. Uit deze pilotstudie blijkt dat vijftien van de achttien patienten die gebruik maken van de polikliniek, revalideert vanwege CVA. Poliklinische geriatrische revalidatie is een door de bevraagde patienten gewaardeerde aanvulling op de klinische revalidatieperiode, en de uitvoering ervan lijkt haalbaar. Een verbetering van de gezondheidstoestand of van het participatieniveau kon niet worden aangetoond.

Purpose: In mammography, the height of the image receptor is adjusted to the patient before compressing the breast. An inadequate height setting can result in an imbalance between the forces applied by the image receptor and the paddle, causing the clamped breast to be pushed up or down relative to the body during compression. This leads to unnecessary stretching of the skin and other tissues around the breast, which can make the imaging procedure more painful for the patient. The goal of this study was to implement a method to measure and minimize the force imbalance, and to assess its feasibility as an objective and reproducible method of setting the image receptor height. Methods: A trial was conducted consisting of 13 craniocaudal mammographic compressions on a silicone breast phantom, each with the image receptor positioned at a different height. The image receptor height was varied over a range of 12 cm. In each compression, the force exerted by the compression paddle was increased up to 140 N in steps of 10 N. In addition to the paddle force, the authors measured the force exerted by the image receptor and the reaction force exerted on the patient body by the ground. The trial was repeated 8 times, with the phantom remounted at a slightly different orientation and position between the trials. Results: For a given paddle force, the obtained results showed that there is always exactly one image receptor height that leads to a balance of the forces on the breast. For the breast phantom, deviating from this specific height increased the force imbalance by 9.4 ± 1.9 N/cm (6.7%) for 140 N paddle force, and by 7.1 ± 1.6 N/cm (17.8%) for 40 N paddle force. The results also show that in situations where the force exerted by the image receptor is not measured, the craniocaudal force imbalance can still be determined by positioning the patient on a weighing scale and observing the changes in displayed weight during the procedure. Conclusions: In mammographic breast compression, even small changes in the image receptor height can lead to a severe imbalance of the applied forces. This may make the procedure more painful than necessary and, in case the image receptor is set too low, may lead to image quality issues and increased radiation dose due to undercompression. In practice, these effects can be reduced by monitoring the force imbalance and actively adjusting the position of the image receptor throughout the compression.

Herein, we describe the discovery of a novel binding pocket for CYP 2C9 inhibitors. Trifluoromethanesulfonamide compounds 1 and 2, identified within a Pfizer progesterone receptor antagonist program, were found to strongly inhibit the drug metabolizing cytochrome P450 enzyme CYP 2C9. Homology modelling and subsequent X-ray co-crystal data have elucidated the binding orientation of compounds 1 and 2 in CYP 2C9. Compound 2 adopts a previously unreported binding mode. Less acidic sulfonamide analogues within these series have reduced CYP 2C9 activity, and we postulate this is due to a reduced hydrogen bonding potential with key interacting residues within CYP 2C9. This work shows that CYP 2C9 has a more flexible active site than previously reported; therefore multiple binding modes and alternative pharmacophore models must be considered when predicting CYP 2C9 affinity.

The pursuit of low noise in optical instruments for areal surface topography measurement is relevant to many surface types, ranging from super-polished optical surfaces to weakly reflecting or scattering textures that require enhanced signal sensitivity. We clarify the definition and experimental methods for quantifying random noise in areal surface topography measurements. We also propose a parameter, the topographical noise density, that concisely summarizes the effects of measurement bandwidth. To illustrate these ideas, we present results from a commercial phase-shifting interference microscope showing an RMS measurement noise of 0.03 nm for a 1-s data acquisition of 1 million surface topography image points, after application of a 3 × 3-pixel convolution filter. The results follow the expected inverse square root dependence on the data acquisition time for fast averaging of topography maps, resulting in a measurement noise of

We propose a practical theoretical model of an interference microscope that includes the imaging properties of optical systems with partially coherent illumination. We show that the effects on measured topography of a spatially extended, monochromatic light source at low numerical apertures can be approximated in a simplified model that assumes spatially coherent light and a linear, locally shift-invariant transfer function that accounts for optical aberrations and the attenuation of diffracted plane wave amplitudes with increasing spatial frequencies. Simulation of instrument response using this model agrees with methods using numerical pupil-plane integration and with an experimental measurement of surface topography.