Impairment in work and activities of daily life in patients with psoriasis: results of the prospective BioCAPTURE registry.

Background: Little is known about the extent of impairments in work and activities of daily life (ADL) in patients with psoriasis, and the influence of contextual factors such as disease-related characteristics and treatment. Therefore, this study aimed to assess these impairments in patients with psoriasis who started using biologicals/small molecule inhibitors.Methods: Using data from the prospective BioCAPTURE registry, we collected patient, disease, and treatment parameters, as well as work/ADL impairments at baseline, 6 and 12 months. Changes in impairment parameters and correlations between impairment and patient/disease characteristics were assessed using generalized estimating equations.Results: We included 194 patients in our analysis. After biological initiation, disease activity decreased significantly (PASI 11.2 at baseline versus 3.9 at 12 months, p < 0.001). Work-for-pay in this cohort was lower than in the Dutch general population (53% versus 67%, p = 0.01). In patients who had work-for-pay, presenteeism improved over time (5% at baseline versus 0% at 12 months, p = 0.04). Up to half of the patients reported impairments in ADL, which did not change over time. Associations between impairments and contextual factors varied, but all impairments were associated with worse mental/physical general functioning.Conclusion: Patients with psoriasis using biologicals are less likely to have work-for-pay. Treatment improves the work productivity of employed patients, but we were unable to detect changes in ADL performance.

Precision assessment of bowel motion quantification using 3D cine-MRI for radiotherapy.

Objective. The bowel is an important organ at risk for toxicity during pelvic and abdominal radiotherapy. Identifying regions of high and low bowel motion with MRI during radiotherapy may help to understand the development of bowel toxicity, but the acquisition time of MRI is rather long. The aim of this study is to retrospectively evaluate the precision of bowel motion quantification and to estimate the minimum MRI acquisition time.Approach. We included 22 gynaecologic cancer patients receiving definitive radiotherapy with curative intent. The 10 min pre-treatment 3D cine-MRI scan consisted of 160 dynamics with an acquisition time of 3.7 s per volume. Deformable registration of consecutive images generated 159 deformation vector fields (DVFs). We defined two motion metrics, the 50th percentile vector lengths (VL50) of the complete set of DVFs was used to measure median bowel motion. The 95th percentile vector lengths (VL95) was used to quantify high motion of the bowel. The precision of these metrics was assessed by calculating their variation (interquartile range) in three different time frames, defined as subsets of 40, 80, and 120 consecutive images, corresponding to acquisition times of 2.5, 5.0, and 7.5 min, respectively.Main results. For the full 10 min scan, the minimum motion per frame of 50% of the bowel volume (M50%) ranged from 0.6-3.5 mm for the VL50 motion metric and 2.3-9.0 mm for the VL95 motion metric, across all patients. At 7.5 min scan time, the variation in M50% was less than 0.5 mm in 100% (VL50) and 95% (VL95) of the subsets. A scan time of 5.0 and 2.5 min achieved a variation within 0.5 mm in 95.2%/81% and 85.7%/57.1% of the subsets, respectively.Significance. Our 3D cine-MRI technique quantifies bowel loop motion with 95%-100% confidence with a precision of 0.5 mm variation or less, using a 7.5 min scan time.

Vector-apodizing phase plate coronagraph: design, current performance, and future development [Invited].

Over the last decade, the vector-apodizing phase plate (vAPP) coronagraph has been developed from concept to on-sky application in many high-contrast imaging systems on 8 m class telescopes. The vAPP is a geometric-phase patterned coronagraph that is inherently broadband, and its manufacturing is enabled only by direct-write technology for liquid-crystal patterns. The vAPP generates two coronagraphic point spread functions (PSFs) that cancel starlight on opposite sides of the PSF and have opposite circular polarization states. The efficiency, that is, the amount of light in these PSFs, depends on the retardance offset from a half-wave of the liquid-crystal retarder. Using different liquid-crystal recipes to tune the retardance, different vAPPs operate with high efficiencies (${\gt}96\%$) in the visible and thermal infrared (0.55 µm to 5 µm). Since 2015, seven vAPPs have been installed in a total of six different instruments, including Magellan/MagAO, Magellan/MagAO-X, Subaru/SCExAO, and LBT/LMIRcam. Using two integral field spectrographs installed on the latter two instruments, these vAPPs can provide low-resolution spectra (${\rm{R}} \sim 30$) between 1 µm and 5 µm. We review the design process, development, commissioning, on-sky performance, and first scientific results of all commissioned vAPPs. We report on the lessons learned and conclude with perspectives for future developments and applications.

Additively manufactured space-filling meta-implants.

The unprecedented properties of meta-biomaterials could pave the way for the development of life-lasting orthopedic implants. Here, we used non-auxetic meta-biomaterials to address the shortcomings of the current treatment options in acetabular revision surgery. Due to the severe bone deficiencies and poor bone quality, it can be very challenging to acquire adequate initial implant stability and long-term fixation. More advanced treatments, such as patient-specific implants, do guarantee the initial stability, but are formidably expensive and may eventually fail due to stress shielding. We, therefore, developed meta-implants furnished with a deformable porous outer layer. Upon implantation, this layer plastically deforms into the defects, thereby improving the initial stability and homogeneously stimulating the surrounding bone. We first studied the space-filling behavior of additively manufactured pure titanium lattices, based on six different unit cells, in a compression test complemented with full-field strain measurements. The diamond, body-centered cubic, and rhombic dodecahedron unit cells were eventually selected for the design of the deformable porous outer layer. Each design came in three different relative density profiles, namely maximum (MAX), functionally graded (FG), and minimum (MIN). After their compression in bone-mimicking molds with simulated acetabular defects, the space-filling behavior of the implants was evaluated using load-displacement curves, micro-CT images, and 3D reconstructions. The meta-implants with an FG diamond infill exhibited the most promising space-filling behavior. However, the required push-in forces exceed the impact forces currently applied in surgery. Future research should, therefore, focus on design optimization, to improve the space-filling behavior and to facilitate the implantation process for orthopedic surgeons. STATEMENT OF SIGNIFICANCE: Ideally, orthopedic implants would last for the entire lifetime of the patient. Unfortunately, they rarely do. Critically sized defects are a common sight in the revision of acetabular cups, and rather difficult to treat. The permanent deformation of lattice structures can be used to create shape-morphing implants that would fill up the defect site, and thereby restore the physiological loading conditions. Bending-dominated structures were incorporated in the porous outer layer of the space-filling meta-implants for their considerable lateral expansion in response to axial compression. A functionally graded density offered structural integrity at the joint while enhancing the deformability at the bone-implant interface. With the use of a more ductile metal, CP-Ti, these meta-implants could be deformed without strut failure.

Simultaneous assessment of colon motility in children with functional constipation by cine-MRI and colonic manometry: a feasibility study.

BACKGROUND: Colonic manometry is the current reference standard for assessing colonic neuromuscular function in children with intractable functional constipation (FC). Recently, cine magnetic resonance imaging (cine-MRI) has been proposed as a non-invasive alternative. We compared colonic motility patterns on cine-MRI with those obtained by manometry in children, by stimulating high-amplitude propagating contractions (HAPCs) with bisacodyl under manometric control while simultaneously acquiring cine-MRI. METHODS: After Institutional Review Board approval, adolescents with FC scheduled to undergo colonic manometry were included. A water-perfused 8-lumen catheter was used for colonic manometry recordings. After an intraluminal bisacodyl infusion, cine-MRI sequences of the descending colon were acquired for about 30 min simultaneously with colonic manometry. Manometry recordings were analysed for HAPCs. MRI images were processed with spatiotemporal motility MRI techniques. The anonymised motility results of both techniques were visually compared for the identification of HAPCs in the descending colon. RESULTS: Data regarding six patients (three males) were analysed (median age 14 years, range 12-17). After bisacodyl infusion, three patients showed a total of eleven HAPCs with colonic manometry. Corresponding cine-MRI recorded high colonic activity during two of these HAPCs, minimal activity during seven HAPCs, while two HAPCs were not recorded. In two of three patients with absent HAPCs on manometry, colonic activity was recorded with cine-MRI. CONCLUSIONS: Simultaneous acquisition of colonic cine-MRI and manometry in children with FC is feasible. Their motility results did not completely overlap in the identification of HAPCs. Research is needed to unravel the role of cine-MRI in this setting.

The present crisis in male reproductive health: an urgent need for a political, social, and research roadmap.

BACKGROUND: There is a global crisis in male reproductive health. Evidence comes from globally declining sperm counts and increasing male reproductive system abnormalities, such as cryptorchidism, germ cell tumors, and onset of puberty. Male factor infertility occurs in ~40% of couples experiencing infertility. Data demonstrate an association between male infertility and overall health. Associated significant health conditions include diabetes mellitus, metabolic disorders, and cardiovascular disease. Adding to the complexity is that men typically do not seek health care unless there is acute medical need or, as in the case of the infertile couple, the male goes for a reproductive examination and semen analysis. However, 25% of the time a reproductive health examination does not occur. Couples are increasingly utilizing IVF at more advanced ages, and advanced paternal age is associated with increased risk for (i) adverse perinatal outcomes for both offspring and mother; (ii) early child mortality, cancer, and mental health issues. In addition to age, paternal lifestyle factors, such as obesity and smoking, impact not only the male fertility but also the offspring wellness. OBJECTIVES: The purpose of this paper was (i) to spotlight emerging and concerning data on male reproductive health, the relationship(s) between male reproductive and somatic health, and the heritable conditions father can pass to offspring, and (ii) to present a strategic roadmap with the goals of increasing (a) the awareness of men and society on the aforementioned, (b) the participation of men in healthcare seeking, and (c) advocacy to invigorate policy and funding agencies to support increased research into male reproductive biology. CONCLUSIONS: The Male Reproductive Health Initiative (MRHI) is a newly established and rapidly growing global consortium of key opinion leaders in research, medicine, funding and policy agencies, and patient support groups that are moving forward the significant task of accomplishing the goals of the strategic roadmap.

Metabolic improvement in obese patients after duodenal-jejunal exclusion is associated with intestinal microbiota composition changes.

BACKGROUND: Intestinal microbiota have been suggested to play an important role in the pathogenesis of obesity and type 2 diabetes. Bariatric surgery improves both conditions and has been associated with changes in intestinal microbiota composition. We investigated the effect of a nonsurgical bariatric technique on intestinal microbiota composition in relation to metabolic improvement. METHODS: Seventeen patients with obesity and type 2 diabetes were treated with the nonsurgical duodenal-jejunal bypass liner, which excludes the proximal 60 cm small intestine from food. Fecal samples as well as metabolic parameters reflecting obesity and type 2 diabetes were obtained from the patients at baseline, after 6 months with the device in situ, and 6 months after explantation. RESULTS: After 6 months of treatment, both obesity and type 2 diabetes had improved with a decrease in weight from 106.1 [99.4-123.5] to 97.4 [89.4-114.0] kg and a decrease in HbA1c from 8.5% [7.6-9.2] to 7.2% [6.3-8.1] (both p < 0.05). This was paralleled by an increased abundance of typical small intestinal bacteria such as Proteobacteria, Veillonella, and Lactobacillus spp. in feces. After removal of the duodenal-jejunal bypass liner, fecal microbiota composition was similar to that observed at baseline, despite persistent weight loss. CONCLUSION: Improvement of obesity and type 2 diabetes after exclusion of the proximal 60 cm small intestine by treatment with a nonsurgical duodenal-jejunal bypass liner may be promoted by changes in fecal microbiota composition.

Evaluation of compressed sensing MRI for accelerated bowel motility imaging.

BACKGROUND: To investigate the feasibility of compressed sensing and parallel imaging (CS-PI)-accelerated bowel motility magnetic resonance imaging (MRI) and to compare its image quality and diagnostic quality to conventional sensitivity encoding (SENSE) accelerated scans. METHODS: Bowel MRI was performed in six volunteers using a three-dimensional balanced fast field-echo sequence. Static scans were performed after the administration of a spasmolytic agent to prevent bowel motion artefacts. Fully sampled reference scans and multiple prospectively 3× to 7× undersampled CS-PI and SENSE scans were acquired. Additionally, fully sampled CS-PI and SENSE scans were retrospectively undersampled and reconstructed. Dynamic scans were performed using 5× to 7× accelerated scans in the presence of bowel motion. Retrospectively, undersampled scans were compared to fully sampled scans using structural similarity indices. All reconstructions were visually assessed for image quality and diagnostic quality by two radiologists. RESULTS: For static imaging, the performance of CS-PI was lower than that of fully sampled and SENSE scans: the diagnostic quality was assessed as adequate or good for 100% of fully sampled scans, 95% of SENSE, but only for 55% of CS-PI scans. For dynamic imaging, CS-PI image quality was scored similar to SENSE at high acceleration. Diagnostic quality of all scans was scored as adequate or good; 55% of CS-PI and 83% of SENSE scans were scored as good. CONCLUSION: Compared to SENSE, current implementation of CS-PI performed less or equally good in terms of image quality and diagnostic quality. CS-PI did not show advantages over SENSE for three-dimensional bowel motility imaging.

Evaluation of gastrointestinal motility with MRI: Advances, challenges and opportunities.

Dynamic magnetic resonance imaging (MRI) of gastrointestinal motility has developed rapidly over the past few years. The non-invasive and non-ionizing character of MRI is an important advantage together with the fact that it is fast and can visualize the entire gastrointestinal tract. Advances in imaging and quantification techniques have facilitated assessment of gastric, small intestinal, and colonic motility in a clinical setting. Automated quantitative motility assessment using dynamic MRI meets the need for non-invasive techniques. Recently, studies have begun to examine this technique in patients, including those with IBD, pseudo-obstruction and functional bowel disorders. Remaining challenges for clinical implementation are processing the large amount of data, standardization and validation of the numerous MRI metrics and subsequently assessment of the potential role of dynamic MRI. This review examines the methods, advances, and remaining challenges of evaluation of gastrointestinal motility with MRI. It accompanies an article by Khalaf et al. in this journal that describes a new protocol for assessment of pan-intestinal motility in fasted and fed state in a single MRI session.

The "omics" of human male infertility: integrating big data in a systems biology approach.

Spermatogenesis is a complex process in which >2300 genes are temporally and spatially regulated to form a terminally differentiated sperm cell that must maintain the ability to contribute to a totipotent embryo which can successfully differentiate into a healthy individual. This process is dependent on fidelity of the genome, epigenome, transcriptome, and proteome of the spermatogonia, supporting cells, and the resulting sperm cell. Infertility and/or disease risk may increase in the offspring if abnormalities are present. This review highlights the recent advances in our understanding of these processes in light of the "omics revolution". We briefly review each of these areas, as well as highlight areas of future study and needs to advance further.

Clearing of psoriasis documented by laser Doppler perfusion imaging contrasts remaining elevation of dermal expression levels of CD31.

BACKGROUND: Vascular modifications represent a key feature in psoriatic plaques. Previous research with Laser Doppler Perfusion Imaging (LDPI) revealed a remarkable heterogeneity in the cutaneous perfusion within homogenous-appearing psoriatic lesions. Insights in the relation between perfusion during treatment and related biological changes are lacking. OBJECTIVES: To study the effect of calcipotriol-betamethasone dipropionate ointment on the microcirculation and the expression levels of immunohistochemical markers in psoriatic lesions compared to the distant uninvolved skin. METHODS: Psoriatic lesions of fourteen patients were treated once a day during 8 weeks. Clinical SUM scores and the perfusion intensity by means of LDPI were assessed every 2 weeks. After 8 weeks, a biopsy from the target lesion and one from the distant uninvolved skin were taken and stained for psoriasis-related markers, like IL-17 and CD31. RESULTS: After 8 weeks, seven patients reached a SUM score of 0 or 1, and were classified as good-responders. The other patients were classified moderate-responders. The perfusion intensity decreased in all lesions during therapy. In the good-responders, all investigated psoriasis-related proteins within the treated lesions reached the expression level found within the distant uninvolved skin. The expression of CD31, however, was significantly higher in the treated lesions as compared to the distant uninvolved skin (p = 0.0156). In the moderate responders, almost all expression levels remained significantly elevated compared to the uninvolved skin. CONCLUSIONS: In the skin of good-responders the expression of dermal CD31(+) endothelium remains significantly elevated within the treated lesions compared with the distant uninvolved skin, whereas a marked reduction in the perfusion intensity and SUM score was found. This indicates that clinical improvement might outrun endothelial changes.

A sensitivity analysis of a personalized pulse wave propagation model for arteriovenous fistula surgery. Part A: Identification of most influential model parameters.

Previously, a pulse wave propagation model was developed that has potential in supporting decision-making in arteriovenous fistula (AVF) surgery for hemodialysis. To adapt the wave propagation model to personalized conditions, patient-specific input parameters should be available. In clinics, the number of measurable input parameters is limited which results in sparse datasets. In addition, patient data are compromised with uncertainty. These uncertain and incomplete input datasets will result in model output uncertainties. By means of a sensitivity analysis the propagation of input uncertainties into output uncertainty can be studied which can give directions for input measurement improvement. In this study, a computational framework has been developed to perform such a sensitivity analysis with a variance-based method and Monte Carlo simulations. The framework was used to determine the influential parameters of our pulse wave propagation model applied to AVF surgery, with respect to parameter prioritization and parameter fixing. With this we were able to determine the model parameters that have the largest influence on the predicted mean brachial flow and systolic radial artery pressure after AVF surgery. Of all 73 parameters 51 could be fixed within their measurement uncertainty interval without significantly influencing the output, while 16 parameters importantly influence the output uncertainty. Measurement accuracy improvement should thus focus on these 16 influential parameters. The most rewarding are measurement improvements of the following parameters: the mean aortic flow, the aortic windkessel resistance, the parameters associated with the smallest arterial or venous diameters of the AVF in- and outflow tract and the radial artery windkessel compliance.

A sensitivity analysis of a personalized pulse wave propagation model for arteriovenous fistula surgery. Part B: Identification of possible generic model parameters.

Decision-making in vascular access surgery for hemodialysis can be supported by a pulse wave propagation model that is able to simulate pressure and flow changes induced by the creation of a vascular access. To personalize such a model, patient-specific input parameters should be chosen. However, the number of input parameters that can be measured in clinical routine is limited. Besides, patient data are compromised with uncertainty. Incomplete and uncertain input data will result in uncertainties in model predictions. In part A, we analyzed how the measurement uncertainty in the input propagates to the model output by means of a sensitivity analysis. Of all 73 input parameters, 16 parameters were identified to be worthwhile to measure more accurately and 51 could be fixed within their measurement uncertainty range, but these latter parameters still needed to be measured. Here, we present a methodology for assessing the model input parameters that can be taken constant and therefore do not need to be measured. In addition, a method to determine the value of this parameter is presented. For the pulse wave propagation model applied to vascular access surgery, six patient-specific datasets were analyzed and it was found that 47 out of 73 parameters can be fixed on a generic value. These model parameters are not important for personalization of the wave propagation model. Furthermore, we were able to determine a generic value for 37 of the 47 fixable model parameters.

Correlation between male age, WHO sperm parameters, DNA fragmentation, chromatin packaging and outcome in assisted reproduction technology.

In the human, male ageing results in reproductive hormonal and cellular changes that can influence semen quality (volume, motility, concentration and morphology) and ultimately result in a reduced fertilising capacity and a longer 'time to pregnancy' for ageing men as well as an increased risk for miscarriage. This prospective cohort study of 278 patients undergoing a first in vitro fertilisation or intracytoplasmic sperm injection treatment was undertaken to examine whether patient's age was reflected in sperm motility, concentration, morphology as well as in DNA fragmentation (DFI) and immature chromatin (unprocessed nuclear proteins and/or poorly condensed chromatin) as measured by the sperm chromatin structure assay. This study also investigated the possible influence of male age (after correcting for female age) on their fertilising capacity, on obtaining a pregnancy and a healthy baby at home. Logistic regression analysis did not reveal any male age-related influences on sperm parameters like concentration, motility or morphology. No significant male age-related increase in DFI or immature chromatin was demonstrable for these patients. Elevated male age, after correcting for female age, was not related to lower fertilisation rates or significant decreases in the chance for a healthy baby at home.

Reference values of skin autofluorescence.

BACKGROUND: Skin autofluorescence (AF) as measured with the AGE Reader (DiagnOptics Technologies, Groningen, The Netherlands) is a noninvasive prognostic marker in diabetes mellitus and other diseases with increased cardiovascular risk. This study provides reference values of healthy Caucasian control subjects as a function of age, tobacco smoking, and gender. METHODS: The results of skin AF measured in 428 healthy Caucasian control subjects by the AGE Reader (n = 211) and its nonautomated but otherwise similar predecessor, the Autofluorescence Reader (n = 217), were analyzed. Linear regression analysis was performed to obtain reference values for skin AF as a function of age. Further analysis was performed on the effect of tobacco smoking (n = 96) and gender. RESULTS: Skin AF was described by a linear increase with age of approximately 0.023 arbitrary units (AU) per year for subject age up to 70 years. Tobacco smoking was associated with an absolute increase of skin AF by 0.16 AU (P < 0.01), without a significant further increase with age (P = 0.17). Gender had no influence on skin AF in nonsmokers. Among current smokers, female subjects had a 0.2 AU higher skin AF than male subjects (P = 0.02), with no further age-related increase. CONCLUSIONS: The present results provide reference values of skin AF for healthy Caucasian control subjects over a broad age range. A major contribution of age and some interaction of smoking and gender were observed, resulting in reference values of skin AF suitable for clinical settings and future studies.

The genetics of male infertility: a field of study whose time is now.

Idiopathic male infertility is often associated with genetic and epigenetic abnormalities. Such abnormalities include chromosome translocations and aneuploidies, Y chromosome microdeletions, and mutations of the CFTR gene. The unraveling of the human genome and ongoing animal transgenic studies have identified numerous other genes likely to be associated with male infertility. Initial reports from human studies have identified several candidate genes, including the protamine genes, SPO11, EIF5A2, USP26, ACT, and others. In addition to gene mutations and polymorphisms, damage to the chromatin resulting in single and double strand DNA breaks affects fertility. Recent studies are highlighting the role of such abnormalities in male infertility, and point to protamine defects as one cause of DNA damage. Epigenetic abnormalities also are being investigated, including the role of residual sperm mRNA in embryogenesis, and the effects of abnormal spermatogenesis on gene imprinting. These studies are pointing to complex etiologies and clinical ramifications in many infertile men.

Properties of a new, long-lasting vaginal delivery system (LASRS) for contraceptive and antimicrobial agents.

In view of the need for improved vaginal formulations that are contraceptive, that may prevent transmission of sexually transmitted infections, or both, a new delivery system (base formulation; called Long Acting, Sustained Release of Spermicide, or LASRS) was developed that contains bioadhesive and other ingredients with a long history of safety, and was designed to provide long-lasting vaginal retention of the formulation and to minimize possible vaginal irritation caused by incorporated active ingredients. Nonoxynol-9 (N-9) was added as an active ingredient to study the vaginal irritating properties of the formulation and to assess its long-term effectiveness by postcoital spermicidal tests. In the first series of experiments, in vitro studies showed that the formulation spreads rapidly over a cellulose membrane, forming a bioadhesive layer that remained for at least 12 hours. The second series of experiments addressed the safety of the LASRS suppository in rabbits and primates. Even with a very high concentration of N-9 (20.5%), LASRS caused only mild/moderate but acceptable irritation in the rabbit. No vaginal irritation occurred in the primate at an even higher concentration (22.5%). During the third series of experiments, the long-lasting vaginal retention properties were evaluated by postcoital spermicidal tests in the primate. LASRS with N-9 was highly spermicidal even when mating was delayed for 12 hours after placement of the formulation. Spermicidal activity was also observed when 1) mating was delayed for 24 hours after insertion of the formulation, and 2) if the females were mated 2 or even 3 times without reinsertion of the suppository before collection of the vaginal contents. In the final series of tests, the postcoital spermicidal properties of menfegol, another cytotoxic spermicide, were evaluated as were several modifications in the base formulation. Menfegol produced essentially the same results as N-9. Altering the base formulation proved to be nonbeneficial because a decrease in the long-term spermicidal effectiveness was obtained. These results suggest that the LASRS suppository has good vehicle properties for the delivery of active ingredients to the vagina.

Failure of elimination of paternal mitochondrial DNA in abnormal embryos.

Paternal mitochondrial DNA is normally eliminated from mammalian embryos. We have shown the presence of paternal mtDNA at the blastocyst stage in some abnormal human embryos.