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During the COVID-19 pandemic, countries imposed (partial) lockdowns that reduced viral transmission. However, these interventions may have unfavorable effects on emotional and psychological well-being. The aim of this study was to quantify possible adverse effects of the COVID-19 pandemic on psychological wellbeing in children and adolescents. Hospital admission data between January 2017 and September 2021 from eight general hospitals in the Netherlands was collected, comparing the incidences of sub-categorized psychological diagnoses, more specifically eating disorders, intentional intoxications, accidental intoxications, and excessive crying, before (2017-2019) and during the pandemic (2020-2021). Data was summarized per month and per year, and the years 2020 and 2021 were compared to 2017-2019. The relative increase or decrease in diagnoses since the start of the pandemic was calculated. Overall pediatric hospital admissions decreased with 28% since the start of the pandemic. Non-infectious diagnoses showed a decrease of 8%. Of these non-infectious diagnoses, overall psychosocial admissions were increased (+ 9%), mostly caused by an increase in admissions for eating disorders (+ 64%) and intoxications in adolescents (+ 24%). In addition, the proportion of admissions due to psychosocial diagnoses increased post-pandemic (6% vs 4%, p 0.001). Overall admissions for intoxications in children (- 3%) and excessive crying (- 1%) did not increase, although peaks in incidence were found at the start of the second lockdown.During the COVID-19 pandemic, admission rates for eating disorders and intentional intoxications showed a substantial increase, indicating a high burden of pediatric psychiatric diseases.• The COVID-19 pandemic has had an impact on psychosocial wellbeing in children and adolescents.• There was an increase in admissions due to psychosocial problems in the Netherlands in the period after the pandemic. • This was mainly caused by an increase in crisis admissions due to eating disorders and intoxications in adolescents.

Glaucoma is a common condition that relies on careful clinical assessment to diagnose and determine disease progression. There is growing evidence that glaucoma is associated not only with loss of retinal ganglion cells but also with degeneration of cortical and subcortical brain structures associated with vision and eye movements. The effect of glaucoma pathophysiology on eye movements is not well understood. In this review, we examine the evidence surrounding altered eye movements in glaucoma patients compared to healthy controls, with a focus on quantitative eye tracking studies measuring saccades, fixation, and optokinetic nystagmus in a range of visual tasks. The evidence suggests that glaucoma patients have alterations in several eye movement domains. Patients exhibit longer saccade latencies, which worsen with increasing glaucoma severity. Other saccadic abnormalities include lower saccade amplitude and velocity, and difficulty inhibiting reflexive saccades. Fixation is pathologically altered in glaucoma with reduced stability. Optokinetic nystagmus measures have also been shown to be abnormal. Complex visual tasks (eg reading, driving, and navigating obstacles), integrate these eye movements and result in behavioral adaptations. The review concludes with a summary of the evidence and recommendations for future research in this emerging field.

IntroductionConsensus is lacking on the optimal management of asymptomatic congenital pulmonary airway malformation (CPAM). For future studies, the CONNECT consortium (the COllaborative Neonatal Network for the first European CPAM Trial)—an international collaboration of specialised caregivers—has established consensus on a core outcome set of outcome parameters concerning respiratory insufficiency, surgical complications, mass effect and multifocal disease. These outcome parameters have been incorporated in the CONNECT trial, a randomised controlled trial which, in order to develop evidence-based practice, aims to compare conservative and surgical management of patients with an asymptomatic CPAM.Methods and analysisChildren are eligible for inclusion after the CPAM diagnosis has been confirmed on postnatal chest CT scan and they remain asymptomatic. On inclusion, children are randomised to receive either conservative or surgical management. Subsequently, children in both groups are enrolled into a standardised, 5-year follow-up programme with three visits, including a repeat chest CT scan at 2.5 years and a standardised exercise tolerance test at 5 years.The primary outcome is exercise tolerance at age 5 years, measured according to the Bruce treadmill protocol. Secondary outcome measures are molecular genetic diagnostics, validated questionnaires—on parental anxiety, quality of life and healthcare consumption—, repeated imaging and pulmonary morbidity during follow-up, as well as surgical complications and histopathology. This trial aims to end the continuous debate surrounding the optimal management of asymptomatic CPAM.Ethics and disseminationThis study is being conducted in accordance with the Declaration of Helsinki. The Medical Ethics Review Board of Erasmus University Medical Centre Rotterdam, The Netherlands, has approved this protocol (MEC-2022–0441). Results will be disseminated through peer-reviewed scientific journals and conference presentations.Trial registration numberNCT05701514.

OBJECTIVES When surgical resection is indicated for a congenital lung abnormality (CLA), lobectomy is often preferred over segmentectomy, mostly because the latter is associated with more residual disease. Presumably, this occurs in children because sublobar surgery often does not adhere to anatomical borders (wedge resection instead of segmentectomy), thus increasing the risk of residual disease. This study investigated the feasibility of identifying eligible cases for anatomical segmentectomy by combining virtual reality (VR) and artificial intelligence (AI). METHODS Semi-automated segmentation of bronchovascular structures and lesions were visualized with VR and AI technology. Two specialists independently evaluated via a questionnaire the informative value of regular computed tomography versus three-dimensional (3D) VR images. RESULTS Five asymptomatic, non-operated cases were selected. Bronchovascular segmentation, volume calculation and image visualization in the VR environment were successful in all cases. Based on the computed tomography images, assignment of the CLA lesion to specific lung segments matched between the consulted specialists in only 1 out of the cases. Based on the three 3D VR images, however, the localization matched in 3 of the 5 cases. If the patients would have been operated, adding the 3D VR tool to the preoperative workup would have resulted in changing the surgical strategy (i.e. lobectomy versus segmentectomy) in 4 cases. CONCLUSIONS This study demonstrated the technical feasibility of a hybridized AI–VR visualization of segment-level lung anatomy in patients with CLA. Further exploration of the value of 3D VR in identifying eligible cases for anatomical segmentectomy is therefore warranted.

PRECIS Nailfold capillary abnormalities are associated with primary open-angle glaucoma (POAG) and increased severity of global and central glaucomatous visual field (VF) loss. PURPOSE The purpose of this study was to investigate whether nailfold capillary abnormalities are associated with POAG and the severity of glaucomatous VF loss. MATERIALS AND METHODS A cross-sectional study of 83 POAG cases and 40 controls was conducted. Nailfold capillaroscopy images were assessed by masked graders for dilated capillaries >50 μm, crossed capillaries, tortuous capillaries, hemorrhages, avascular zones >100 μm, capillary density, and capillary distribution. VF loss in glaucoma cases was quantified using mean deviation and mean central pattern standard deviation (PSD) from the worst-affected eye. RESULTS Logistic regression analyses of cases and controls showed that avascular zones [odds ratio (OR)=1.24; 95% confidence interval (CI): 1.06, 1.47; P=0.005], capillary density (OR=0.63; 95% CI: 0.46, 0.83; P

Children with a history of regressed retinopathy of prematurity (ROP) are at increased risk of peripheral avascular retina. Wide-field digital retinal imaging and telemedicine is an effective tool for ROP screening. Ophthalmologists and Optometrists should have a high level of clinical suspicion for peripheral retinal changes in children screened for ROP.Retinopathy of prematurity, a vaso-proliferative disorder of the pre-term retina, is a preventable cause of childhood visual impairment. The Auckland Regional Telemedicine ROP (ART-ROP) network, established in 2006, utilises wide-field digital imaging and telemedicine to screen at-risk infants for ROP. This prospective observational study reports the long-term ocular outcomes of ART-ROP network infants.A comprehensive paediatric eye examination including cycloplegic autorefraction and wide-field retinal imaging was completed on all participants. Participants had been screened for ROP by the ART-ROP network between May 2008 and October 2011.A total of 69 children, with a mean age of 5 to 8 years old were assessed and divided into two groups: those with or without a history of ROP, 44 and 25 children, respectively. Infants with a history of ROP had significantly lower gestational age (26.6 ± 1.9 vs. 29.1 ± 1.6 weeks,Visual and ocular outcomes did not vary based on history of ROP, with no participant having reduced vision as a result of undetected or untreated ROP. Further research is required into the long-term implication of persistent avascular retina in regressed ROP.

Anomalías pulmonares congénitas; Consenso; Parámetros de resultado Anomalies pulmonars congènites; Consens; Paràmetres de resultat Congenital lung abnormalities; Consensus; Outcome parameters Consensus on the optimal management of asymptomatic congenital pulmonary airway malformation (CPAM) is lacking, and comparison between studies remains difficult due to a large variety in outcome measures. We aimed to define a core outcome set (COS) for pediatric patients with an asymptomatic CPAM. An online, three-round Delphi survey was conducted in two stakeholder groups of specialized caregivers (surgeons and non-surgeons) in various European centers. Proposed outcome parameters were scored according to level of importance, and the final COS was established through consensus. A total of 55 participants (33 surgeons, 22 non-surgeons) from 28 centers in 13 European countries completed the three rounds and rated 43 outcome parameters. The final COS comprises seven outcome parameters: respiratory insufficiency, surgical complications, mass effect/mediastinal shift (at three time-points) and multifocal disease (at two time-points). The seven outcome parameters included in the final COS reflect the diversity in priorities among this large group of European participants. However, we recommend the incorporation of these outcome parameters in the design of future studies, as they describe measurable and validated outcomes as well as the accepted age at measurement.

To administer the Hip Preservation Surgery Expectations Survey to a large sample of patients to ascertain the prevalence of their preoperative expectations and to assess expectations in terms of demographic and clinical characteristics.Consecutive patients were enrolled if they were ≥18 years old/spoke English and excluded if they had prior hip surgery/degenerative changes Tönnis ≥2. Patients completed the 21-item survey addressing the amount of improvement expected for each item (number of items and an overall score were determined) and the International Hip Outcome Tool (iHOT; hip score determined). Analyses included multivariable regression with survey score and number of expectations as dependent variables. Subanalyses considered collegiate/professional, competitive, and recreational sports level.Three hundred two patients participated, with a mean age of 32; 270 (89%) had cam impingement, 72 (24%) had symptoms6 months, and mean iHOT score was 41. One hundred twenty patients (40%) selected all 21 survey items, 112 (37%) selected 18 to 20, and 70 (23%) selected ≤17 items. In multivariable analysis, younger age (odds ratio [OR] = 1.3; P = .02), symptoms6 months (OR = 1.3; P = .03), and worse iHOT score (OR = 2.5; P = .0001) were associated with selecting more items. The mean survey score was 80 (range, 31-100). In multivariable analysis, younger age (P = .05), symptoms6 months (P = .01), and worse iHOT score (P = .03) were associated with greater survey scores. Collegiate/professional athletes selected more items (P = .01) and were more likely to select improvement in sports performance (OR = 7.5; P = .001), achievement of athletic potential (OR = 3.7; P = .002), and maintaining options for more demanding future activities (OR = 2.7; P = .01).Patients had multiple expectations for marked improvement in current and future physical function and psychological well-being. Younger patients, shorter symptom duration, and worse hip-specific functional status were associated with greater expectations. Understanding patients' expectations can guide preoperative education regarding realistic expectations for recovery and long-term outcome.Patients' preoperative expectations vary according to demographic and clinical characteristics as measured in a survey study.

Background Compared to HIV-negative individuals, people living with HIV have a higher risk of malignant lymphoma. To what extent hematologists miss HIV testing opportunities among lymphoma patients (LP) in the Amsterdam University Medical Centers (UMC) is currently unknown. We quantified the HIV testing rate among LP and assessed factors influencing hematologists’ HIV testing behavior in LP at both Amsterdam UMC locations. Methods In this mixed-methods study, quantitative data from 2015 to 2019 from electronic health records of LP were retrospectively collected to assess both the HIV testing rate within three months around lymphoma diagnosis and the HIV positivity prevalence. An online survey among hematologists and semi-structured interviews among hematologists and authors of hematology guidelines were conducted. Results Data from 656 LP and 21 hematologists who responded to the survey out of 40 were used. Interviews were held with four hematologists and two authors of hematology guidelines. The HIV testing rates were 56.4% and 57.6%, and the HIV positivity prevalences were 0.8% and 0.9% for both locations. Eighty-five percent (18/21) of hematologists indicated they often offered an HIV test to LP in the past year, and 42% (9/21) revealed HIV testing in LP is often discussed in their department. The type of lymphoma, lack of awareness regarding HIV testing recommendations in LP, low perceived risk of HIV among LP because of older age, and lack of guidelines recommending universal HIV testing regardless of lymphoma type, each influenced hematologists’ HIV testing behavior. Conclusion Our results show routine HIV testing among LP and hematologists’ attitudes and knowledge towards testing at the Amsterdam UMC are suboptimal, despite HIV testing being recommended in most lymphoma guidelines. This highlights the need for interventions to improve hematologists’ behavior towards testing, such as education, as well as expansion and enhanced implementation of the hematology guidelines.

Corrosion process was investigated of depleted uranium (DU) ammunition fragments buried for three years in aerobic soils continuously irrigated with water. The continuing corrosion process was triggered through formation of soluble uranyl oxyhydrate phases such as metaschoepite and becquerelite, which were identified by micro-Raman and X-ray diffraction spectroscopy. The soil was not amended by phosphates and, therefore, no uranyl phosphates were found as corrosion products on the DU surfaces by X-ray photoelectron spectroscopy. A speciation modelling at high temporal sequence (chronospeciation approach) indicated that the abundant Fe oxyhydroxides in the soil immobilized the U(IV) released through DU corrosion. During the first two years, therefore, only10 mg of U(VI) was thus found in the leachates from the soil columns, even though3 g of DU had been corroded. However, the degree of this immobilization was found to be controlled by the amount of dissolved inorganic and organic carbon (DIC and DOC) in the soil pore water providing for U(VI) complexation competing with surface complexation by the Fe hydroxides. The chronospeciation approach applied is useful to improve our understanding and ability to predict the long-term fate of U(VI) and the mechanisms controlling U(VI) mobility in soil contaminated with DU shells.

The use of animals for therapeutic benefit is well-established. For example, for individuals with a disability such as blindness, trained service dogs can enhance the ability to live independently and participate fully in society. An emotional support animal (ESA) is an untrained animal that is used to support a person disabled by an emotional or mental disorder. For an animal to qualify as an ESA, a mental health or medical professional needs to write a letter saying that the animal is needed for the mental health of the person with the disability. This article describes the legal framework for service animals and ESAs, as well as the differences between them. We summarize information about the Americans with Disabilities Act, the Fair Housing Act, the Air Carrier Access Act, and other laws governing an individual's right to be accompanied by a support animal. We also summarize the clinical research on ESAs and argue that, although there are few studies on the clinical effectiveness of ESAs, a broader body of research indicates that animals may have positive clinical effects on medical and mental illness. Finally, we suggest there is a need for further research and provider education on ESAs.

The crystal structure of indinavir sulfate, a pharmaceutical administered as an ethanol solvate, is presented, revealing a unique channel/ionic solvate structure to be characteristic of the compound. The properties of the material with regard to thermal treatment and water adsorption follow closely from the structure. The in situ amorphization of the pharmaceutical upon contacting liquid water is observed and highlights the unique dissolution enhancement of marketing the crystalline solvate dosage. Through survey of published crystal structures, an ambiguous sulfate/bisulfate ionization state is also observed in the crystal, which challenges the general understanding of the pharmaceutical. This study provides a solid-state insight into the function of a special multicomponent crystalline pharmaceutical form.

Atomically resolved crystal structures not only suffer from the inherent uncertainty in accurately locating H atoms but also are incapable of fully revealing the underlying forces enabling the formation of final structures. Therefore, the development and application of novel techniques to illuminate intermolecular forces in crystalline solids are highly relevant to understand the role of hydrogen atoms in structure adoption. Novel developments in 1H NMR MAS methodology can now achieve robust measurements of 1H chemical shift anisotropy (CSA) tensors which are highly sensitive to electrostatics. Herein, we use 1H CSA tensors, measured by MAS experiments and characterized using DFT calculations, to reveal the structure-driving factors between the two polymorphic forms of acetaminophen (aka Tylenol or paracetamol) including differences in hydrogen bonding and the role of aromatic interactions. We demonstrate how the 1H CSAs can provide additional insights into the static picture provided by diffraction to elucidate rigid molecules.

Water plays a complex and central role in determining the structural and reactive properties in numerous chemical systems. In crystalline materials with structural water, the primary focus is often to relate hydrogen bonding motifs to functional properties such as solubility, which is highly relevant in pharmaceutical applications. Nevertheless, understanding the full electrostatic landscape is necessary for a complete structure-function picture. Herein, a combination of tools including 1H magic angle spinning NMR and X-ray crystallography are employed to evaluate the local landscape of water in crystalline hydrates. Two hydrates of an anti-leukemia drug mercaptopurine, which exhibit dramatically different dehydration temperatures (by 90 °C) and a three-fold difference in the in vivo bioavailability, are compared. The results identify an electrosteric caging mechanism for a kinetically trapped water in the hemihydrate form, which is responsible for the dramatic differences in properties.

Ocular surface changes and blink abnormalities are well-established in Parkinson's disease. Blink rate may be influenced by corneal sub-basal nerve density, however, this relationship has not yet been investigated in Parkinson's disease. This case-control study examined the ocular surface in patients with moderately severe Parkinson's disease, including confocal microscopy of the cornea. Fifteen patients with moderately severe Parkinson's disease (modified Hoehn and Yahr grade 3 or 4) and fifteen control participants were recruited. Ophthalmic assessment included slit-lamp examination, blink rate assessment, central corneal aesthesiometry and in vivo corneal confocal microscopy. The effect of disease laterality was also investigated. Of the 15 patients with Parkinson's disease, ten were male and the mean age was 65.5±8.6years. The corneal sub-basal nerve plexus density was markedly reduced in patients with Parkinson's disease (7.56±2.4mm/mm2) compared with controls (15.91±2.6mm/mm2) (p

The International X-ray Observatory IXO, a candidate follow-on mission for XMM/Newton and CHANDRA, has been studied in Europe in the frame of two parallel industrial assessment studies commissioned by ESA as part of the Cosmic Vision 2015-2025 programme. One of these studies was successfully carried out by EADS Astrium. The present paper is focussed on the results obtained by Astrium GmbH in this study, i.e. on the optical, mechanical and thermal design of the IXO telescope mirror and on the predicted telescope performance. The IXO telescope mirror consists of nearly 1700 Silicon Pore Optics (SPO) mirror modules [1] accommodated on eight identical petal-shaped support structures. These petals are themselves supported by an optical bench. Design drivers proved to be the allowable mass, the required optical throughput as well as the axial and lateral stiffness required by the launch vehicle. To ensure light-weighting, low thermal gradients as well as robustness during AIV, the petals and the optical bench are deliberately made of a high-modulus carbon fibre material with high thermal conductivity. The telescope optical performance achievable with this design has been analysed based on rigorous finite element, thermal and optical modelling. It has been found to be fully compliant with the required optical throughput and image quality, thus enabling the scientific benefit of the IXO mission.

Background and Objectives: Demographic trends show an increasing older adult population. Therefore, family medicine training programs may need to reevaluate how well their residents perform clinic procedures essential to older adults. Our objective was to compare the rates of the most frequently performed clinic procedures for Medicare patients in a large multiregional health care system (MRHCS) with those in a family medicine residency clinic. Methods: In this retrospective cohort study, Current Procedural Terminology coding data were queried from the billing systems of an MRHCS (the control group) and a family medicine residency clinic (the study group) for a 3-year period. The primary outcome was the procedural rate ratios per 1,000 office visits for the 10 most common clinic procedures in the MRHCS billed to Medicare. Results: The study group consisted of 19,099 office visits by Medicare patients to the residency clinic; the control group consisted of 2,034,188 visits to the MRHCS. Except for large joint injection, procedural rates were significantly different for the other nine procedures (destruction of benign skin lesions, nail care, punch or shave skin biopsy, removal of impacted cerumen, wound debridement of skin, Unna boot application, excision of skin lesion, paring of corn or callus, and insertion of bladder catheter). The rate of skin excision was higher in the residency clinic than in the MRHCS but lower for the other eight procedures. Conclusions: These data suggest that teaching programs may need to adapt to meet the current and future practice needs of this increasing patient population.

Contact-less vital-sign monitoring is enabling in situations where traditional contact-based vital sign monitoring is prohibitive, such as neonatal and burn care where electrodes and attachments risk patient infection or complications. To make vital-sign monitoring available for the consumer market, these algorithms shall use COTS cameras and run on COTS systems. In this paper, we report upon the results of an experiment to improve the performance of a contact-less respiration algorithm on a resource-constrained COTS multi-core system, in our case a Raspberry Pi 3 running Linux, using a state-of-the-art tool to visualize the behavior of a system. The improvements are an increase of the CPU utilization from 72% to almost 94% and an increase of the throughput of the algorithm by more than 45%.

Gender differences were identified in experiences of the workplace and family responsibilities amongst Australian and New Zealand ophthalmologists.To survey ophthalmologists regarding their balance of career, family and workplace experiences and to identify gender differences.Online questionnaire sent to 1000 randomly selected Royal Australian and New Zealand College of Ophthalmologists (RANZCO) Fellows in 2017.The response rate was 28% (n = 282) with 192 males.Confidential questionnaire.Questionnaire responses.Gender differences were noted in working hours (59% of males worked greater than 40 hours a week vs 26% of females, P 0.001) and frequency of private practice work (mean of 6.6 half-day sessions per week for men vs 4.9 sessions for women, P0.001). Female ophthalmologists reported additional obstacles to career advancement including difficulty receiving mentorship (57% vs 40%, P = 0.027), travel difficulties due to family responsibilities (59% vs 34%, P0.001) and rigid timelines for promotion/tenure (38% vs 19%, P = 0.005). Female ophthalmologists delayed child-bearing, with 59% becoming parents after fellowship training. Women spent more time child-rearing (67% vs 8% of men cared for children20 hours per week, P0.001). Female ophthalmologists were more likely to report experiencing discrimination (31% vs 8% of men, P0.001).Female ophthalmologists worked fewer hours, mainly in the private sector, to fulfil their greater family commitments. Female ophthalmologists reported additional obstacles to career advancement and were more likely to report experiencing discrimination in the workplace.

Antimicrobial functionality is introduced into a pharmaceutical formulation of miconazole while improving solubility. The work leverages hydrate formation propensity in order to produce hydrogen peroxide solvates. The ubiquity of hydrate formation suggests that hydrogen peroxide can be broadly deployed in pharmaceuticals, rendering a liquid excipient suitable for solid pharmaceutical formulations.

Previous reports of ocular abnormalities in Huntington’s disease (HD) have detailed eye movement disorders. The objective of this case–control study was to investigate optic nerve and macular morphology in HD using optical coherence tomography (OCT). A total of 26 HD patients and 29 controls underwent a thorough ophthalmic examination including spectral domain OCT scans of the macula and peripapillary retinal nerve fibre layer (RNFL). Genetic testing results, disease duration, HD disease burden scores and Unified HD Rating Scale motor scores were acquired for HD patients. Temporal RNFL thickness was significantly reduced in the HD group (62.3 vs. 69.8 μm, p = 0.005), and there was a significant negative correlation between temporal RNFL thickness and disease duration (R 2 = −0.51, p = 0.04). Average peripapillary RNFL thickness was not significantly different between the HD and control groups. There was a significant negative correlation between macular volume and disease duration (R 2 = −0.71, p = 0.002), and motor scores (R 2 = −0.56, p = 0.01). Colour vision was significantly poorer in the HD group. Temporal RNFL is preferentially thinned in HD patients, possibly implicating mitochondrial dysfunction as the temporal RNFL is reduced in the patients with some mitochondrial disorders, including Leber’s hereditary optic neuropathy. The correlation between the decrease in macular volume and temporal RNFL, and increasing disease severity suggests that OCT may be a useful biomarker for disease progression in HD. Larger, longitudinal studies are required.

Type 1 sialidosis is a metabolic storage disorder characterised by the accumulation of sialylated oligosaccharides. The condition is also known as macular cherry-red spot and myoclonus syndrome due to the characteristic macular appearance in affected individuals. This case outlines the presentation of a patient with type 1 sialidosis, including ophthalmological assessment with retinal photography and spectral domain optical coherence tomography (OCT). OCT scans showed thickening of the perimacular and peripapillary retinal nerve fibre layer, thought to be due to the abnormal accumulation of metabolic products. The cherry-red spot appearance is due to the normal appearing macula being seen in contrast to the abnormally pale surrounding, thickened retinal nerve fibre layer.

Item does not contain fulltext STUDY QUESTION: What is the percentage of overtreatment, i.e. fertility treatment started too early, in couples with unexplained infertility who were eligible for tailored expectant management? SUMMARY ANSWER: Overtreatment occurred in 36% of couples with unexplained infertility who were eligible for an expectant management of at least 6 months. WHAT IS KNOWN ALREADY: Prognostic models in reproductive medicine can help to identify infertile couples that would benefit from fertility treatment. In couples with unexplained infertility with a good chance of natural conception within 1 year, based on the Hunault prediction model, an expectant management of 6-12 months, as recommended in international fertility guidelines, prevents unnecessary treatment. STUDY DESIGN, SIZE, DURATION: A retrospective cohort study in 25 participating clinics, with follow-up of all couples who were seen for infertility in 2011-2012. PARTICIPANTS/MATERIALS, SETTING, METHODS: In all, 9818 couples were seen for infertility in the participating clinics. Couples were eligible to participate if they were diagnosed with unexplained infertility and had a good prognosis of natural conception (>30%) within 1 year based on the Hunault prediction model. Data to assess overtreatment were collected from medical records. Multilevel regression analyses were performed to investigate associations of overtreatment with patient and clinic characteristics. MAIN RESULTS AND THE ROLE OF CHANCE: Five hundred and forty-four couples eligible for expectant management were included in this study. Among these, overtreatment, i.e. starting medically assisted reproduction within 6 months, occurred in 36%. The underlying quality indicators showed that in 34% no prognosis was calculated and that in 42% expectant management was not recommended. Finally, 16% of the couples for whom a correct recommendation of expectant management for at least 6 months was made, started treatment within 6 months anyway. Overtreatment was associated with childlessness, higher female age and a longer duration of infertility. No associations between overtreatment and clinic characteristics were found. LIMITATIONS, REASONS FOR CAUTION: The response rate was low compared with other fertility studies. Evaluation of possible selection bias showed that responders had a higher socio-economic status than non-responders. WIDER IMPLICATIONS OF THE FINDINGS: Our findings show that developing and publishing guideline recommendations on tailored expectant management (TEM) is not enough and that overtreatment still occurs frequently. Future research should focus on tailored efforts to implement guideline recommendations on TEM. STUDY FUNDING/COMPETING INTERESTS: Supported by Netherlands Organisation for Health Research and Development (ZonMW). ZonMW had no role in designing the study, data collection, analysis and interpretation of data or writing of the report. Competing interests: none. TRIAL REGISTRATION NUMBER: www.trialregister.nl NTR3405.

Ophthalmic findings are common features of neurodegenerative disorders and, in addition to being clinically important, have emerged as potentially useful biomarkers of disease progression in several conditions. Clinically, these visual system abnormalities can be a clue to diagnosis, as well as being a prominent cause of disability in affected patients. In this Review, we describe the various afferent visual system and other ophthalmic features of inherited neurodegenerative disorders, including the muscular dystrophies, Friedreich ataxia, the spinocerebellar ataxias, hereditary spastic paraplegia, Charcot-Marie-Tooth disease, and other conditions. We focus on the expanding role of optical coherence tomography in diagnostic imaging of the retina and optic nerve head, and the possible use of ophthalmic findings as biomarkers of disease severity in hereditary neurodegenerative disorders. In addition, we discuss the ophthalmic manifestations and treatment implications of mitochondrial dysfunction, which is a feature of many inherited neurodegenerative diseases.

A wide range of ocular abnormalities have been documented to occur in patients with myotonic dystrophy type 1. The objectives of this study were to investigate the macular and optic nerve morphology using optical coherence tomography in patients with myotonic dystrophy type 1. A total of 30 myotonic dystrophy type 1 patients and 28 controls were recruited for participation. All participants underwent a thorough ophthalmologic examination, including spectral-domain optical coherence tomography of the macula and retinal nerve fibre layer. Images were reviewed by a retinal specialist ophthalmologist, masked to the diagnosis of the participants. Average macular thickness was significantly greater in the myotonic dystrophy group compared to controls [327.3 μm vs. 308.5 μm (p < 0.001)]. Macular thickness was significantly greater (p < 0.005) in five of the nine macular regions. The increase in macular thickness was due to the increased prevalence of epiretinal membranes in the myotonic dystrophy patient group (p = 0.0002): 48.2 % of myotonic dystrophy patient eyes had evidence of epiretinal membrane, compared with 12.5 % of control eyes. Examination revealed that 56.7 % of myotonic dystrophy patients had an epiretinal membrane in at least one eye. Visual acuity was reduced due to the presence of epiretinal membrane in six patient eyes and none of the control eyes. The presence of an epiretinal membrane was significantly correlated with increasing age in the patient group. We report an increased prevalence of epiretinal membrane in the myotonic dystrophy type 1 group. This may be a previously under-recognised form of visual impairment in this group. Epiretinal membranes can be treated surgically. We suggest that, in addition to a comprehensive clinical examination, optical coherence tomography examination is implemented as part of an ophthalmological assessment for the myotonic dystrophy type 1 patient with reduced visual acuity.

Item does not contain fulltext STUDY QUESTION: What is the effectiveness of a multifaceted implementation strategy compared to usual care on improving the adherence to guideline recommendations on expectant management for couples with unexplained infertility? SUMMARY ANSWER: The multifaceted implementation strategy did not significantly increase adherence to guideline recommendations on expectant management compared to care as usual. WHAT IS KNOWN ALREADY: Intrauterine insemination (IUI) with or without ovarian hyperstimulation has no beneficial effect compared to no treatment for 6 months after the fertility work-up for couples with unexplained infertility and a good prognosis of natural conception. Therefore, various professionals and policy makers have advocated the use of prognostic profiles and expectant management in guideline recommendations. STUDY DESIGN, SIZE, DURATION: A cluster randomized controlled trial in 25 clinics in the Netherlands was conducted between March 2013 and May 2014. Clinics were randomized between the implementation strategy (intervention, n = 13) and care as usual (control, n = 12). The effect of the implementation strategy was evaluated by comparing baseline and effect measurement data. Data collection was retrospective and obtained from medical record research and a patient questionnaire. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 544 couples were included at baseline and 485 at the effect measurement (247 intervention group/238 control group). MAIN RESULTS AND THE ROLE OF CHANCE: Guideline adherence increased from 49 to 69% (OR 2.66; 95% CI 1.45-4.89) in the intervention group, and from 49 to 61% (OR 2.03; 95% CI 1.38-3.00) in the control group. Multilevel analysis with case-mix adjustment showed that the difference of 8% was not statistically significant (OR 1.31; 95% CI 0.67-2.59). The ongoing pregnancy rate within six months after fertility work-up did not significantly differ between intervention and control group (25% versus 27%: OR 0.72; 95% CI 0.40-1.27). LIMITATIONS REASONS FOR CAUTION: There is a possible selection bias, couples included in the study had a higher socio-economic status than non-responders. How this affects guideline adherence is unclear. Furthermore, when powering for this study we did not take into account the unexpected improvement of adherence in the control group. WIDER IMPLICATIONS OF THE FINDINGS: Generalization of our results to other countries with recommendations on expectant management might be questionable because barriers for expectant management can be very different in other countries. Furthermore, due to a large variation in improved adherence rate in the intervention group it will be interesting to further analyse the process of implementation in each clinic with a process evaluation on professionals and couples' exposure to and experiences with the strategy. STUDY FUNDING/COMPETING INTEREST(S): Supported by Netherlands Organisation for Health Research and Development (ZonMW, project number 171203005). No competing interests. TRIAL REGISTRATION NUMBER: Dutch trial Register, www.trialregister.nl NTR3405. TRIAL REGISTRATION DATE: 19 April 2012. DATE OF FIRST PATIENT'S ENROLMENT: 10 July 2012.

Structural and thermal data were obtained for a novel hemihydrate of 6-mercaptopurine. The hemihydrate shows increased solubility and bioavailability when compared to the monohydrate form, better stability against conversion in aqueous media than the anhydrate form, and a dehydration temperature of 240 °C, the highest of any known hydrate crystal.

Food provisioning to chicks of Little Egret Egretta garzetta in a colony at Ligagneau in the Camargue, southern France, was measured using electronic nest balances. Both pair members supplied food to the chicks, and each performed three to five alternating foraging trips. The loading rate during the first trip of the day (1.09 g/min) was more than three times as high as that during later trips (0.32 g/min) and accounted for 20% of the daily amount of food delivered. This food was collected while the birds were feeding in dense aggregations on mosquitofish which had become temporarily concentrated due to hypoxic conditions overnight in the surrounding marsh. Later in the day, when this concentrated food source was no longer available, the birds fed solitarily. The total amount of food delivered per day remained constant at 385 g as chick age increased from 10 to 20 days. Given the observed loading rates, 385 g is near the maximum amount of food the pair can deliver during a 16.5-h daylight period when they forage continuously throughout the day but only one parent at a time. This indicates that a time constraint limits the amount of food delivered to a brood during this stage of the breeding cycle. Given this time constraint, the total amount of food delivered per day would have been reduced by 25% if the birds had not been able to benefit from the concentrations of mosquitofish during the early morning. Breeding success was significantly higher at Ligagneau (3.25 chicks/nest) than in other Camargue colonies (2.69 chicks/nest). In addition, post-fledging survival of chicks with a low rank in the brood hierarchy was probably better at Ligagneau than elsewhere in the Camargue. We attribute this elevated reproductive output at Ligagneau to the exceptionally large amount of food collected by egrets during the early morning aggregations, which were probably formed in response to predictable concentrations of mosquitofish in the permanent marshes surrounding this colony. Such aggregations were rarely observed in the temporary marshes surrounding the other colonies, probably because the occurrence and location of fish concentrations are difficult to predict in this habitat due to rapidly falling water levels.

Item does not contain fulltext STUDY QUESTION: Do couples who were eligible for tailored expectant management (TEM) and did not start treatment within 6 months after the fertility work-up, have different experiences with the quality of care than couples that were also eligible for TEM but started treatment right after the fertility work-up? SUMMARY ANSWER: Tailored expectant management of at least 6 months in couples with unexplained infertility is not associated with the experiences with quality of care or trust in their physician. WHAT IS KNOWN ALREADY: In couples with unexplained infertility and a good prognosis of natural conception within 1 year, expectant management for 6-12 months does not compromise ongoing birth rates and is equally as effective as starting medically assisted reproduction immediately. Therefore, TEM is recommended by various international clinical guidelines. Implementation of TEM is still not optimal because of existing barriers on both patient and professional level. An important barrier is the hesitance of professionals to counsel their patients for TEM because they fear that patients will be dissatisfied with care. However, if and how adherence to TEM actually affects the couples' experience with care is unknown. Experiences with the quality care can be measured by evaluating the patient-centredness of care and the patients' trust in their physician. STUDY DESIGN, SIZE, DURATION: This is a retrospective cross-sectional study. A survey with written questionnaires was performed among all couples who participated in the retrospective audit of guideline adherence on TEM in 25 Dutch clinics. PARTICIPANTS/MATERIALS, SETTING, METHODS: Couples were eligible to participate if they were diagnosed with unexplained infertility and had a good prognosis (>30%) of natural conception within 1 year based on the Hunault prediction model. We used patient's questionnaires to collect data on the couples' experience with the quality of care and possible confounders for their experiences other than having undergone TEM or not. Multilevel regression analyses were performed to investigate case-mix adjusted association of TEM with the patient-centredness of care (PCQ-Infertility) and the patients' trust in their physician (Wake Forest Trust Scale). MAIN RESULTS AND THE ROLE OF CHANCE: Couples who adhered to TEM experienced the quality of care on the same level as couples who were exposed to early treatment, i.e. started fertility treatment within 6 months after fertility work-up. There were no associations between adherence to TEM and the patient-centredness of care or the patients' trust in their physician. LIMITATIONS, REASONS FOR CAUTION: Because this study is retrospective, recall bias might occur. Furthermore, we were unable to measure the difference in experience with care over time. Therefore, our results have to be interpreted carefully. WIDER IMPLICATIONS OF THE FINDINGS: Prospective research on couples undergoing TEM have to be performed to provide more detailed insight in the patients' experiences with the decision making process and subsequently the expectant period. Tackling the barriers surrounding TEM, i.e. better counselling and more patient information material, could further improve patient experiences with the quality of care for couples who are advised TEM. STUDY FUNDING/COMPETING INTERESTS: Supported by Netherlands Organisation for Health Research and Development (ZonMW). ZonMW had no role in designing the study, data collection, analysis and interpretation of data or writing of the report. Competing interests: none. TRIAL REGISTRATION NUMBER: www.trialregister.nl NTR3405.

The anti-tumor activity of imidazolium salts is highly dependent upon the substituents on the nitrogen atoms of the imidazolium cation. We have synthesized and characterized a series of naphthalene-substituted imidazolium salts and tested them against a variety of non-smallcell lung cancer cell lines. Several of these complexes displayed anticancer activity comparable to cisplatin. These compounds induced apoptosis in the NCI-H460 cell line as determined by Annexin V staining, caspase-3, and PARP cleavage. These results strongly suggest that this class of compounds can serve as potent chemotherapeutic agents.

End-to-end (E2E) modelling and simulation, i.e. verifying the science performance of LISA Pathfinder (spacecraft and payload), is mandatory in order to minimize mission risks. In this paper, focus is on two particular applications of the E2E performance simulator currently being developed at EADS Astrium GmbH: the opto-dynamical stability and the self-gravity disturbance stability analysis. The E2E models applied here comprise the opto-dynamical modelling of the optical metrology systems (OMS) laser interferometry, the thermo-elastic distortion modelling of the OMS optical elements and the self-gravity disturbance model accounting for structural distortions. Preliminary analysis results are presented in detail, identifying shortcomings of the current LISA technology package (LTP) mounting baseline. As a consequence, the design is now being revised.

Six new structure refinements and eleven sets of polarised, single-crystal electronic absorption spectra, E‖X, Y and Z, in the energy range 35000–5000 cm–1 were obtained on natural and synthetic orthozoisite-type “thulites” and clinozoisite-type piemontites: Ca2(Al3–pMp 3+) [OH|O|SiO4|Si2O7] where M3+ = Mn3+ or (Mn1–n 3+Fen 3+) for the synthetic or natural minerals, respectively. Electron microprobe analyses of the single crystals studied revealed substitutional degrees pM3+ = 0.13 or 0.51 in natural and synthetic “thulite”, respectively, and 0.57 ≤ pM3+ ≤ 1.17 or 0.83 ≤ pM3+ ≤ 1.47 in the natural or synthetic piemontites, respectively. Manganese in “thulite” is trivalent, as it is in piemontite. In both structure types, M3+ fractionates strongly into the axially compressed [M(3)O6] polyhedra, and does not enter the M(2) sites. Mean M(3)—O and M(1)—O distances increase in both structures, compared to the M3+-free Al end members. Such distance changes in piemontite are +0.47% and +0.53% per 0.1x M3+, respectively, (x = site fraction). The bending angle of the Si2O7-group in cis-configuration, ∢Si(1)—O(9)—Si(2), decreases from 164.4° in clinozoisite to 147.4° in the most Mn3+-rich synthetic piemontite with p Mn³⁺ = 1.47 (emp) or x Mn³⁺(M3) = 0.931 and x Mn³⁺(M1) = 0.460 (from structure refinement). The detailed evaluation of the changes, due to Al→M3+ substitution, of individual bond lengths, as well as the quantitative evaluation of the intensities of the strong spinallowed dd bands of Mn3+ in M(3), prove that in natural piemontite the preference of Mn3+ for M(3) over M(1) is more pronounced than that of Fe3+. This is in accord with the Jahn-Teller effect of 3d4-configurated Mn3+. In addition, evaluation of the individual M(3)–O(i) distances with increasing x Mn³⁺(M3) in piemontite indicates that the axial compression of the [M(3)O6] polyhedra increases. This contrasts with the behaviour of Fe3+-bearing epidotes and is again in accord with the Jahn-Teller effect of Mn3+. The polarisation behaviour of the three strong spin-allowed dd-bands of Mn3+ in M(3), v I at 13000–12000 cm–1 (E‖Y), v II at 19000–18000 cm–1 (E‖Y and Z, Z > Y) and v III at 24000–22000 cm–1 (E‖X) is best interpreted by assuming a C 2 v (C 2″) pseudo-symmetry of the M(3) sites, a super-group of their site symmetry Cs . Evaluation of the energies of v I, v II and v III on the basis of the energy level diagram obtained for Mn3+ with the above pseudo-symmetry yields the crystal field parameter 10 Dq = 13540 cm–1 for x Mn³⁺(M3) = 0:931. 10 Dq increases slightly by 30 cm–1 per -0.1x Mn³⁺(M3). Such values and the Jahn-Teller splitting of the octahedral crystalfield ground-state of Mn3+, δ = v I, yield a crystal field stabilisation energy of Mn3+(M3) of 14080 cm–1 for x Mn³⁺(M3) = 0:931. CFSEMn 3+ increases slightly by 28 cm–1 per -0.1x Mn³⁺(M3). Such values are appreciably smaller than those typical of Mn3+ substituting for Al in the axially elongated [M(1)O6] octahedra in the andalusite structure type. This different behaviour of Mn3+ in the two structure types is likely due to the smaller deviation of (c=a)oct in piemontite M(3) compared to andalusite M(1) for the same site fractions of Mn3+. In addition, the axial inversion effect — compressed [M(3)O6] in the clinozoisite-type or elongated [M(1)O6] in the andalusite-type, involving the electron hole of 3d4 in d z 2 or d( x ²- y ²), respectively — may play a role.

A preliminary model that predicts the taste on the basis of simple instrumental measurements was used to compare the effects of different cultural methods to improve the taste of tomato fruits. The differences in taste between varieties were much bigger than those between three applied EC levels.

Despite the enormous potential repertoire of γδ T cells, there are several observations which suggest that the expressed γδ repertoire in the periphery of normal individuals is often quite restricted. To assess selective expansions among γδ T cells from both adult and newborn blood samples, PBMC from 12 normal adults and cord blood from 15 normal newborns were analyzed for TCRDV1 and TCRDV2 junctional diversity by CDR3 size spectratyping and single-strand conformational polymorphism. Although TCRBV usage showed extensive heterogeneity in adults and newborns, both populations often showed CDR3 region restriction for TCRDV1 and TCRDV2. Analysis of the CDR3 spectratype patterns of newborn twins suggested that clonal selection for TCRDV is independent of genetic background. The possible role of Gram-negative bacteria in driving selective responsiveness of γδ T cells in PBMCs from adults was examined by in vitro stimulation with Escherichia coli and Pseudomonas aeruginosa. Donors whose TCRDV repertoire was highly clonal in the unstimulated blood cells showed the same predominant clones among the bacteria-stimulated cultures. In individuals whose γδ T cells were less restricted, in vitro stimulation did not select for clonality; rather, the TCRDV repertoires were similar before and after bacterial stimulation. Together, these data indicate that γδ T cells are often clonally restricted in adults as well as in newborns and suggest that the prominent stimulatory activity of Gram-negative bacteria does not by itself account for the restriction or diversity of the γδ T cell repertoire.

The use of computer algebra in the field of differential geometry and its applications to geometric structures of partial differential equations is discussed. The differential geometric setting is shortly described; a number of programs are slightly touched, some examples given, and an application to the construction of supersymmetric extensions of the Korteweg-de Vries equation is demonstrated.

Human peripheral blood T cells proliferate in response to Escherichia coli and Pseudomonas aeruginosa. We observed that during the first few days after stimulation a large percentage of the responding PBMC were gamma delta T cells. In our study we characterized the early T cell responses of freshly isolated adult and newborn PBMC to soluble preparations of heat-killed E. coli and P. aeruginosa. Specimens from all healthy adults tested showed intense proliferation in response to both bacterial preparations; at 6 days, the responding cells were mainly T cell blasts, of which high percentages (up to 80%) were gamma delta T cells, most expressing V delta 2/V gamma 9. All newborn blood specimens tested also showed T cell proliferative responses, which included a marked expansion of gamma delta T cells, mainly of the V delta 1 subset. Populations of purified V delta 1 and V delta 2 T cells were obtained from adult PBMC following stimulation with E. coli; both subsets proliferated upon rechallenge with the bacterial preparations. Protease treatment of the bacterial preparations did not appreciably affect their ability to induce expansion of gamma delta T cells in either adult or cord blood, indicating that the stimulatory components were not proteins. The response of gamma delta T cells from newborns indicates that prior exposure to bacterial products is not necessary and suggests that gamma delta T cells are important elements in natural immunity to these extracellular organisms.

The major component in cementitious waste solidification/stabilization (S/S) systems is an amorphous calcium silicate hydroxide hydrate phase (C-S-H) phase according to cement chemistry nomenclature), but the behavior of this gel phase in aqueous solution is not well understood. In this paper, a thermodynamic model is suggested for predicting aqueous solubility of C-S-H as a function of the Ca/Si ratio based on a solid solution−aqueous solution (SSAS) subregular equilibrium model for a binary non-ideal mixing of the end-member phases calcium hydroxide and calcium silicate, with known pK values and a miscibility gap at Ca/Si > 3. A maximum in Gibbs free energy of mixing (GM) of −3.2 kJ/mol is predicted to occur at a Ca/Si ratio of 1.5. Predicted Ca and Si solubility, pH, and solid Ca/Si values agree with experimental data on C-S-H solubility reported from the literature. The thermodynamic basis of this SSAS model is superior to those based on empirical Ksp values vs Ca/Si ratio relationships or on ideal so...

We studied differences in body composition and basal metabolic rate (BMR, measured in postabsorptive birds under thermoneutral conditions at night) in two subspecies of red knots, Calidris canutus: one that spends the nonbreeding season under energetically costly climatic conditions at temperate latitudes (subspecies islandica in western Europe) and one that winters in the hot and humid tropics (subspecies canutus in West and South Africa). To examine whether the possible differences would be upheld under identical conditions, we kept both groups in captivity as well. Body composition was quantified with respect to the fat and lean components of 10 ''organs'' (breast muscles, leg muscles, stomach, intestine, liver kidneys, lungs, heart, and the skin, and skeleton and attached muscle). Captive birds had lighter lean tissues than wild birds, especially those of the stomach, intestine, kidneys, and liver (the nutritional organs). During the northern winter wild islandica knots had higher lean masses than canutus knots in tropical Africa. Tropically wintering red knots had lower BMRs than their temperate-wintering conspecifics, and birds in long-term captivity had lower BMR values than their free-living counterparts. Average BMR values per category of birds (wild or captive of either subspecies) were strongly correlated with the group averages of lean mass. Prediction of BMR on the basis of total lean mass of red knots undergoing incipient starvation follows this same relationship because metabolically active tissue is being depleted. That the two subspecies converged to similar body composition in captivity indicates that individual red knots may possess considerable flexibility. We argue that red knots, and probably most other long-distance migrants, have metabolic machinery that is able to adjust continuously, depending on the ecological conditions and food types encountered in the course of the year. We further argue that variation in (functional components of) lean mass is the vehicle for seasonal adjustments in metabolic physiology to variable demand levels. Body mass adjustments offer a flexible response enabling red knots to economize on total daily metabolic expenditure whenever conditions allow a relaxation of metabolic scope, such as during winter in the Tropics.