Predicting the likelihood of successful medical treatment of early pregnancy loss: development and internal validation of a clinical prediction model.

STUDY QUESTION: What are clinical predictors for successful medical treatment in case of early pregnancy loss (EPL)? SUMMARY ANSWER: Use of mifepristone, BMI, number of previous uterine aspirations and the presence of minor clinical symptoms (slight vaginal bleeding or some abdominal cramps) at treatment start are predictors for successful medical treatment in case of EPL. WHAT IS KNOWN ALREADY: Success rates of medical treatment for EPL vary strongly, between but also within different treatment regimens. Up until now, although some predictors have been identified, no clinical prediction model has been developed yet. STUDY DESIGN, SIZE, DURATION: Secondary analysis of a multicentre randomized controlled trial in 17 Dutch hospitals, executed between 28 June 2018 and 8 January 2020. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women with a non-viable pregnancy between 6 and 14 weeks of gestational age, who opted for medical treatment after a minimum of 1 week of unsuccessful expectant management. Potential predictors for successful medical treatment of EPL were chosen based on literature and expert opinions. We internally validated the prediction model using bootstrapping techniques. MAIN RESULTS AND THE ROLE OF CHANCE: 237 out of 344 women had a successful medical EPL treatment (68.9%). The model includes the following variables: use of mifepristone, BMI, number of previous uterine aspirations and the presence of minor clinical symptoms (slight vaginal bleeding or some abdominal cramps) at treatment start. The model shows a moderate capacity to discriminate between success and failure of treatment, with an AUC of 67.6% (95% CI = 64.9-70.3%). The model had a good fit comparing predicted to observed probabilities of success but might underestimate treatment success in women with a predicted probability of success of ∼70%. LIMITATIONS, REASONS FOR CAUTION: The vast majority (90.4%) of women were Caucasian, potentially leading to less optimal model performance in a non-Caucasian population. Limitations of our model are that we have not yet been able to externally validate its performance and clinical impact, and the moderate accuracy of the prediction model of 0.67. WIDER IMPLICATIONS OF THE FINDINGS: We developed a prediction model, aimed to improve and personalize counselling for medical treatment of EPL by providing a woman with her individual chance of complete evacuation. STUDY FUNDING/COMPETING INTEREST(S): The Triple M Trial, upon which this secondary analysis was performed, was funded by the Healthcare Insurers Innovation Foundation (project number 3080 B15-191). TRIAL REGISTRATION NUMBER: Clinicaltrials.gov: NCT03212352.

An evaluation of DistillerSR's machine learning-based prioritization tool for title/abstract screening - impact on reviewer-relevant outcomes.

BACKGROUND: Systematic reviews often require substantial resources, partially due to the large number of records identified during searching. Although artificial intelligence may not be ready to fully replace human reviewers, it may accelerate and reduce the screening burden. Using DistillerSR (May 2020 release), we evaluated the performance of the prioritization simulation tool to determine the reduction in screening burden and time savings. METHODS: Using a true recall @ 95%, response sets from 10 completed systematic reviews were used to evaluate: (i) the reduction of screening burden; (ii) the accuracy of the prioritization algorithm; and (iii) the hours saved when a modified screening approach was implemented. To account for variation in the simulations, and to introduce randomness (through shuffling the references), 10 simulations were run for each review. Means, standard deviations, medians and interquartile ranges (IQR) are presented. RESULTS: Among the 10 systematic reviews, using true recall @ 95% there was a median reduction in screening burden of 47.1% (IQR: 37.5 to 58.0%). A median of 41.2% (IQR: 33.4 to 46.9%) of the excluded records needed to be screened to achieve true recall @ 95%. The median title/abstract screening hours saved using a modified screening approach at a true recall @ 95% was 29.8 h (IQR: 28.1 to 74.7 h). This was increased to a median of 36 h (IQR: 32.2 to 79.7 h) when considering the time saved not retrieving and screening full texts of the remaining 5% of records not yet identified as included at title/abstract. Among the 100 simulations (10 simulations per review), none of these 5% of records were a final included study in the systematic review. The reduction in screening burden to achieve true recall @ 95% compared to @ 100% resulted in a reduced screening burden median of 40.6% (IQR: 38.3 to 54.2%). CONCLUSIONS: The prioritization tool in DistillerSR can reduce screening burden. A modified or stop screening approach once a true recall @ 95% is achieved appears to be a valid method for rapid reviews, and perhaps systematic reviews. This needs to be further evaluated in prospective reviews using the estimated recall.

Psychosocial and pharmacologic interventions for methamphetamine addiction: protocol for a scoping review of the literature.

BACKGROUND: Methamphetamine use and harms are rising rapidly. Management of patients with methamphetamine use disorder (MUD) and problematic methamphetamine use (PMU) is challenging, with no clearly established best approach; both psychosocial and pharmacologic interventions have been described. Furthermore, given the diversity of individuals that use methamphetamines, there is a need to assess evidence for treatments for subgroups including youths; gay, bisexual, and other men who have sex with men; individuals with mental health comorbidities; and individuals in correction services. Establishing awareness of the messages regarding treatment from recent clinical practice guidelines (CPG) in the field is also of value. The first study objective will be to establish a greater understanding of the methods, populations, and findings of controlled studies for psychosocial and pharmacologic treatments for MUD and PMU. Investigation of this information can help establish the potential for advanced syntheses of the evidence (such as network meta-analysis) to compare therapies for this condition and to identify gaps related to key populations where more primary research is needed. Summarizing the recommendations regarding treatment of MUD/PMU from recent CPGs and systematic reviews will be an important secondary objective. METHODS: A scoping review will be performed. Using the OVID platform, MEDLINE, Embase, PsycINFO, and relevant Cochrane databases from EBM Reviews will be searched (from databases' inception onwards). Eligibility criteria will include individuals described as having MUD or PMU, with designs of interest including randomized trials, non-randomized trials, and controlled cohort studies with three or more months of follow-up; systematic reviews and CPGs will also be sought. Two reviewers (with support from automation tools) will independently screen all citations, full-text articles, and chart data. Different approaches to handling and summarizing the data will be implemented for each type of study design. Tables and graphics will be used to map evidence sources and identify evidence gaps. DISCUSSION: This research will enhance awareness of evidence addressing the effects of psychosocial and pharmacologic interventions for MUD/PMU overall and in sub-populations, both in terms of recent CPGs/reviews and primary studies; inspection of the latter will also help establish the feasibility of future syntheses to compare treatments, such as network meta-analysis. SYSTEMATIC REVIEW PROTOCOL REGISTRATION: Open Science Framework ( https://osf.io/9wy8p ).

Knowledge Synthesis in Evidence-Based Medicine.

Systematic reviews are the most common form of knowledge synthesis and remain a cornerstone of the practice of evidence-based medicine. They offer enhanced rigor and validity relative to traditional narrative review articles by reducing bias and increasing objectivity. In answering focused research questions, systematic reviews are directly applicable to clinical practice as well as the development of clinical guidelines and the identification of knowledge gaps, which may drive future primary research directions. Typically, such a rigorous process necessarily requires substantive time to carefully and systematically identify, screen, and synthesize all relevant available primary research on a topic. Further, other knowledge synthesis methods have emerged to address the varying needs of decision makers with respect to condensed timelines and more diverse research questions, as well as to allow incorporation of already synthesized evidence into reviews. These alternative methods include rapid reviews, scoping reviews, and overviews of systematic reviews, which are being used with increasing frequency by clinicians, decision-makers, and researchers. We encourage clinicians and researchers in nuclear medicine and other imaging sciences to acquire a greater familiarity with these methods and to consider them in clinical decision making, the development of clinical guidelines, and the planning of future research activities.

[Thoracic endometriosis with aspecific manifestation]. / Thoracale endometriose met een aspecifieke uiting.

BACKGROUND: Endometriosis is a common disease, especially in subfertile women. The most common location is in the pelvis, but extragenital locations are also possible. This far less common condition has been described in almost all tissues in the body. Symptoms occurring cyclically are characteristic of endometriosis. CASE DESCRIPTION: A 37-year-old woman was discovered by chance to have ascites and pleural effusion. She had no symptoms of this. Thoracoscopy showed an image consistent with thoracic endometriosis. After initial drug therapy was unsuccessful, surgical intervention was performed. CONCLUSION: Thoracic endometriosis is a rare disease, in which the cyclical nature of the symptoms often leads to correct diagnosis. Drug therapy is the preferred treatment for patients.

Loss of function of Ywhah in mice induces deafness and cochlear outer hair cells' degeneration.

In vertebrates, 14-3-3 proteins form a family of seven highly conserved isoforms with chaperone activity, which bind phosphorylated substrates mostly involved in regulatory and checkpoint pathways. 14-3-3 proteins are the most abundant protein in the brain and are abundantly found in the cerebrospinal fluid in neurodegenerative diseases, suggesting a critical role in neuron physiology and death. Here we show that 14-3-3eta-deficient mice displayed auditory impairment accompanied by cochlear hair cells' degeneration. We show that 14-3-3eta is highly expressed in the outer and inner hair cells, spiral ganglion neurons of cochlea and retinal ganglion cells. Screening of YWHAH, the gene encoding the 14-3-3eta isoform, in non-syndromic and syndromic deafness, revealed seven non-synonymous variants never reported before. Among them, two were predicted to be damaging in families with syndromic deafness. In vitro, variants of YWHAH induce mild mitochondrial fragmentation and severe susceptibility to apoptosis, in agreement with a reduced capacity of mutated 14-3-3eta to bind the pro-apoptotic Bad protein. This study demonstrates that YWHAH variants can have a substantial effect on 14-3-3eta function and that 14-3-3eta could be a critical factor in the survival of outer hair cells.

Prepared for practice? a national survey of UK foundation doctors and their supervisors.

BACKGROUND: Mandatory induction for foundation year 1 trainees (F1s) was introduced in 2012 to ease the transition from student to doctor. The aims of this national study were to assess anxiety levels and preparedness in the 2012 F1 cohort and whether these varied according to medical school of graduation and foundation school of practice. METHODS: Online surveys were completed anonymously and voluntarily by F1s and F1 supervisors from participating foundation schools. Questions assessed how prepared F1s were for practice and how well they coped with the transition from medical school. A validated screening tool was used to assess anxiety levels. RESULTS: 1829 F1s and 1145 supervisors participated. 27.8% of F1s screened positive for pathological anxiety. Increased time spent in a 'shadowing' type role during medical school and each additional day of induction reduced anxiety levels. How prepared F1s were for different aspects of their jobs varied according to medical and foundation school, from both the F1 and supervisor perspective. CONCLUSIONS: How prepared F1s feel can vary according to the medical school of graduation and foundation school of practice. F1 anxiety may be reduced with a prolonged F1 induction programme and an extended shadowing period during the final year of medical school.

[Hereditary optic neuropathies: from clinical signs to diagnosis]. / Les neuropathies optiques héréditaires: du signe clinique au diagnostic.

Inherited optic atrophy must be considered when working up any optic nerve involvement and any systemic disease with signs of optic atrophy, even with a negative family history. There are two classical forms: dominant optic atrophy, characterized by insidious, bilateral, slowly progressive visual loss and temporal disc pallor, and Leber's optic atrophy, characterized by acute loss of central vision followed by the same event in the fellow eye within a few weeks to months, with disc hyperemia in the acute phase. Family history is critical for diagnosis. In the absence of family history, the clinician must rule out an identifiable acquired cause, i.e. toxic, inflammatory, perinatal injury, traumatic or tumoral, with orbital and brain imaging (MRI). Recessive optic atrophies are more rare and more severe and occur as part of multisystemic disorders, particularly Wolfram syndrome (diabetes mellitus, diabetes insipidus, and hearing loss). Effective treatments are limited; alcohol and smoking should be avoided. A cyclosporine trial (taken immediately upon visual loss in the first eye) is in progress in Leber's optic atrophy to prevent involvement of the fellow eye.

Various forms of organic and inorganic P fertilizers did not negatively affect soil- and root-inhabiting AM fungi in a maize-soybean rotation system.

Arbuscular mycorrhizal (AM) fungi are key components of most agricultural ecosystems. Therefore, understanding the impact of agricultural practices on their community structure is essential to improve nutrient mobilization and reduce plant stress in the field. The effects of five different organic or mineral sources of phosphorus (P) for a maize-soybean rotation system on AM fungal diversity in roots and soil were assessed over a 3-year period. Total DNA was extracted from root and soil samples collected at three different plant growth stages. An 18S rRNA gene fragment was amplified and taxa were detected and identified using denaturing gradient gel electrophoresis followed by sequencing. AM fungal biomass was estimated by fatty acid methyl ester analysis. Soil P fertility parameters were also monitored and analyzed for possible changes related with fertilization or growth stages. Seven AM fungal ribotypes were detected. Fertilization significantly modified soil P flux, but had barely any effect on AM fungi community structure or biomass. There was no difference in the AM fungal community between plant growth stages. Specific ribotypes could not be significantly associated to P treatment. Ribotypes were associated with root or soil samples with variable detection frequencies between seasons. AM fungal biomass remained stable throughout the growing seasons. This study demonstrated that roots and soil host distinct AM fungal communities and that these are very temporally stable. The influence of contrasting forms of P fertilizers was not significant over 3 years of crop rotation.

TRPV4 channels mediate the infrared laser-evoked response in sensory neurons.

Infrared laser irradiation has been established as an appropriate stimulus for primary sensory neurons under conditions where sensory receptor cells are impaired or lost. Yet, development of clinical applications has been impeded by lack of information about the molecular mechanisms underlying the laser-induced neural response. Here, we directly address this question through pharmacological characterization of the biological response evoked by midinfrared irradiation of isolated retinal and vestibular ganglion cells from rodents. Whole cell patch-clamp recordings reveal that both voltage-gated calcium and sodium channels contribute to the laser-evoked neuronal voltage variations (LEVV). In addition, selective blockade of the LEVV by micromolar concentrations of ruthenium red and RN 1734 identifies thermosensitive transient receptor potential vanilloid channels as the primary effectors of the chain reaction triggered by midinfrared laser irradiation. These results have the potential to facilitate greatly the design of future prosthetic devices aimed at restoring neurosensory capacities in disabled patients.

Genetic variability in arbuscular mycorrhizal fungi compatibility supports the selection of durum wheat genotypes for enhancing soil ecological services and cropping systems in Canada.

Crop nutrient- and water-use efficiency could be improved by using crop varieties highly compatible with arbuscular mycorrhizal fungi (AMF). Two greenhouse experiments demonstrated the presence of genetic variability for this trait in modern durum wheat ( Triticum turgidum L. var. durum Desf.) germplasm. Among the five cultivars tested, 'AC Morse' had consistently low levels of AM root colonization and DT710 had consistently high levels of AM root colonization, whereas 'Commander', which had the highest colonization levels under low soil fertility conditions, developed poor colonization levels under medium fertility level. The presence of genetic variability in durum wheat compatibility with AMF was further evidenced by significant genotype × inoculation interaction effects in grain and straw biomass production; grain P, straw P, and straw K concentrations under medium soil fertility level; and straw K and grain Fe concentrations at low soil fertility. Mycorrhizal dependency was an undesirable trait of 'Mongibello', which showed poor growth and nutrient balance in the absence of AMF. An AMF-mediated reduction in grain Cd under low soil fertility indicated that breeding durum wheat for compatibility with AMF could help reduce grain Cd concentration in durum wheat. Durum wheat genotypes should be selected for compatibility with AMF rather than for mycorrhizal dependency.

Nontarget effects of foliar fungicide application on the rhizosphere: diversity of nifH gene and nodulation in chickpea field.

AIMS: This study explores nontarget effects of fungicide application on field-grown chickpea. METHODS AND RESULTS: Molecular methods were used to test the effects of foliar application of fungicide on the diversity and distribution of nifH genes associated with two chickpea cultivars and their nodulation. Treatments were replicated four times in a split-plot design in the field, in 2008 and 2009. Chemical disease control did not change the richness of the nifH genes associated with chickpea, but selected different dominant nifH gene sequences in 2008, as revealed by correspondence analysis. Disease control strategies had no significant effect on disease severity or nifH gene distribution in 2009. Dry weather conditions rather than disease restricted plant growth that year, suggesting that reduced infection rather than the fungicide is the factor modifying the distribution of nifH gene in chickpea rhizosphere. Reduced nodule size and enhanced N(2) -fixation in protected plants indicate that disease control affects plant physiology, which may in turn influence rhizosphere bacteria. The genotypes of chickpea also affected the diversity of the nifH gene in the rhizosphere, illustrating the importance of plant selective effects on bacterial communities. CONCLUSIONS: We conclude that the chemical disease control affects nodulation and the diversity of nifH gene in chickpea rhizosphere, by modifying host plant physiology. A direct effect of fungicide on the bacteria cannot be ruled out, however, as residual amounts of fungicide were found to accumulate in the rhizosphere soil of protected plants. SIGNIFICANCE AND IMPACT OF THE STUDY: Systemic nontarget effect of phytoprotection on nifH gene diversity in chickpea rhizosphere is reported for the first time. This result suggests the possibility of manipulating associative biological nitrogen fixation in the field.

Audiological findings in 100 USH2 patients.

Bilateral sensorineural hearing loss (HL), classically described as mild to severe with a typically down-sloping audiometric configuration, is the earliest symptom occurring in Usher syndrome type II (USH2). Audiological findings were analyzed in a total of 100 USH2 patients (92 families) divided into three groups according to the gene involved: 88 USH2A, 10 GPR98 and 2 DFNB31 patients. A fine analysis of audiograms was performed (pure tone average, degree of severity, configuration). The median age of HL diagnosis was 5 years (range 8 months-31 years) although the median age at USH2 diagnosis was 34.5 (range 8-76). Moderate HL was predominant (76%) and a gently down-sloping configuration characterized most audiograms (66%). No statistically significant difference was found between USH2A and GPR98 patients but a tendency was clearly noted for more GPR98 patients to present with severe hearing loss. It is not possible to predict the mutated gene from audiograms.

[Screening for retinal detachment using wide-field retinal imaging]. / Dépistage du décollement de rétine par l'utilisation d'une imagerie panrétinienne.

PURPOSE: The wide-field retinal imaging device (200°) (P200 Optomap Plus, Optos, Edinburgh, Scotland, UK), using a scanning laser ophthalmoscope (SLO), makes it possible to visualize a wide retinal area including the retinal periphery. The present study was designed to evaluate the ability to detect peripheral rhegmatogenous lesions using SLO wide-field image reading. METHODS: Between 2 November 2007 and 30 April 2008, all patients presenting with a retinal detachment were prospectively enrolled. Retinal ophthalmoscopy and drawing of retinal detachment, breaks, and holes were performed by a single retinal surgeon. SLO imaging was performed by an orthoptist and image reading by a senior resident. The orthoptist and the resident were both unaware of the results of the clinical examination. The extension of the retinal detachment in clock hours as well as the number of breaks and holes were compared between the retinal drawing and the image reading results. RESULTS: During the study period, 6053 images were taken, in 56 eyes with retinal detachment documented. Retinal breaks and holes were detected in seven of 10 cases with SLO image reading, only those situated superiorly between 11 and 1 o'clock and inferiorly between 5 and 7 o'clock were missed. Retinal detachments (one situated superiorly and one situated inferiorly) were detected in nine of 10 cases. CONCLUSIONS: The sensitivity of retinal detachment detection with the wide-field imaging device appears to be satisfactory for screening purposes, although it cannot replace retinal ophthalmoscopy.

The retinal pigment epithelium in health and disease.

Retinal pigment epithelial cells (RPE) constitute a simple layer of cuboidal cells that are strategically situated behind the photoreceptor (PR) cells. The inconspicuousness of this monolayer contrasts sharply with its importance [1]. The relationship between the RPE and PR cells is crucial to sight; this is evident from basic and clinical studies demonstrating that primary dysfunctioning of the RPE can result in visual cell death and blindness. RPE cells carry out many functions including the conversion and storage of retinoid, the phagocytosis of shed PR outer segment membrane, the absorption of scattered light, ion and fluid transport and RPE-PR apposition. The magnitude of the demands imposed on this single layer of cells in order to execute these tasks, will become apparent to the reader of this review as will the number of clinical disorders that take origin from these cells.

[Course system of the Working Group for Gastro-intestinal Surgery Davos]. / Kurssystem der Arbeitsgemeinschaft für Gastrointestinale Chirurgie Davos.

Training in technical skills is essential for advanced surgical education. Training is moving more and more from the operating room to surgical training laboratories. A crucial impulse for this development came from Davos, where the first skills course was organized in 1984 after the formation of the Working Group for Gastro-intestinal (GI) Surgery (AGC Davos). Since this first course more than 5,000 residents have successfully completed the GI skills training course in Davos and many of the alumni are themselves teaching surgery today. The level and quality of this course has remained stable for 27 years on a high quality level although teaching has continuously been adjusted to modern techniques. The language of this international workshop is English. The number of applications exceeds the course capacity every year, which is an indication for the need of such training courses and should be principally included into the skills curriculum for surgeons.

Long-term phosphorus fertilization impacts soil fungal and bacterial diversity but not AM fungal community in alfalfa.

Soil function may be affected by cropping practices impacting the soil microbial community. The effect of different phosphorus (P) fertilization rates (0, 20, or 40 kg P(2)O(5) ha(-1)) on soil microbial diversity was studied in 8-year-old alfalfa monocultures. The hypothesis that P fertilization modifies soil microbial community was tested using denaturing gradient gel electrophoresis and phospholipids fatty acid (PLFA) profiling to describe soil bacteria, fungi, and arbuscular mycorrhizal (AM) fungi diversity. Soil parameters related to fertility (soil phosphate flux, soluble P, moisture, phosphatase and dehydrogenase assays, and carbon and nitrogen content of the light fraction of soil organic matter) were also monitored and related to soil microbial ribotype profiles. Change in soil P fertility with the application of fertilizer had no effect on crop yield in 8 years, but on the year of this study was associated with shifts in the composition of fungal and bacterial communities without affecting their richness, as evidenced by the absence of effect on the average number of ribotypes detected. However, variation in soil P level created by a history of differential fertilization did not significantly influence AM fungi ribotype assemblages nor AM fungi biomass measured with the PLFA 16:1omega5. Fertilization increased P flux and soil soluble P level but reduced soil moisture and soil microbial activity, as revealed by dehydrogenase assay. Results suggest that soil P fertility management could influence soil processes involving soil microorganisms. Seasonal variations were also recorded in microbial activity, soil soluble P level as well as in the abundance of specific bacterial and fungal PLFA indicators of soil microbial biomass.

Outcomes for 236 patients from a 2-year early intervention in psychosis service.

OBJECTIVE: To examine: i) changes in key outcome measures over time in treatment in a representative first-episode psychosis treatment cohort and ii) baseline predictors of service disengagement. METHOD: Baseline characteristics of 236 patients were examined for associations with outcomes over time using generalized estimating equation models. The data on disengagement were analysed using logistic regression. RESULTS: After controlling for admission scores, patients showed consistently improved outcomes while in treatment on functional recovery (unemployment, P < 0.01; HoNOS, P < 0.001; the Quality of Life Scale, P < 0.001; GAF, P < 0.05) but not symptomatology (as assessed by the PANSS and substance abuse). The 64 (33%) who disengaged were more likely to be unemployed (P < 0.01) and have higher HoNOS (P < 0.01) and GAF (P < 0.05) scores at baseline. CONCLUSION: This evaluation has shown significant improvements in psychosocial functioning but not psychopathology during treatment at an Early Intervention for Psychosis Service. Despite attempts to retain patients, there is a high rate of treatment discontinuation.