Setting a direction for continuing professional development in anesthesiology: A synthesis of the outcome from an Utstein style meeting.

BACKGROUND: An Utstein style meeting of key stakeholders from the existing collaboration surrounding post-graduate training was arranged to set a direction for continuing professional development (CPD) of anesthesiologists in Denmark. A 2-day meeting was planned to guide discussions about competencies in anesthesiology, facilitate the development of a blueprint for a portfolio-based CPD program and provide examples of how a portfolio can be used in practice. METHODS: The meeting agenda was based on an adaptation of Kern's six-step approach to curriculum development. Twenty-four participants from the university hospitals in Denmark were invited. Prior to the meeting participants were informed of the objectives and the Utstein style process. RESULTS: Participants acknowledged a need for a more structured approach to CPD, preferably within the current organizational set up at the departmental level, and with a portfolio-based, individualized curriculum. It was recognized that CPD should contain an array of possibilities to accommodate needs and wants of both the individual and the department. It was emphasized that, while anesthesiologists are used to give feedback to trainees, many are less familiar in providing the same to peers, and psychological safety was identified as a prerequisite to support a culture where specialists can reflect openly on each other's performance. CONCLUSION: The results provide an insight into the attitudes, opportunities, and challenges of anesthesiologists in relation to continuing professional development in Denmark. Generally, participant suggestions are in line with the shift in medical education toward workplace-based learning, feedback and lifelong learning.

Hippocampal LTP and contextual learning require surface diffusion of AMPA receptors.

Long-term potentiation (LTP) of excitatory synaptic transmission has long been considered a cellular correlate for learning and memory. Early LTP (less than 1 h) had initially been explained either by presynaptic increases in glutamate release or by direct modification of postsynaptic AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor function. Compelling models have more recently proposed that synaptic potentiation can occur by the recruitment of additional postsynaptic AMPA receptors (AMPARs), sourced either from an intracellular reserve pool by exocytosis or from nearby extra-synaptic receptors pre-existing on the neuronal surface. However, the exact mechanism through which synapses can rapidly recruit new AMPARs during early LTP remains unknown. In particular, direct evidence for a pivotal role of AMPAR surface diffusion as a trafficking mechanism in synaptic plasticity is still lacking. Here, using AMPAR immobilization approaches, we show that interfering with AMPAR surface diffusion markedly impairs synaptic potentiation of Schaffer collaterals and commissural inputs to the CA1 area of the mouse hippocampus in cultured slices, acute slices and in vivo. Our data also identify distinct contributions of various AMPAR trafficking routes to the temporal profile of synaptic potentiation. In addition, AMPAR immobilization in vivo in the dorsal hippocampus inhibited fear conditioning, indicating that AMPAR diffusion is important for the early phase of contextual learning. Therefore, our results provide a direct demonstration that the recruitment of new receptors to synapses by surface diffusion is a critical mechanism for the expression of LTP and hippocampal learning. Since AMPAR surface diffusion is dictated by weak Brownian forces that are readily perturbed by protein-protein interactions, we anticipate that this fundamental trafficking mechanism will be a key target for modulating synaptic potentiation and learning.

Telestration with augmented reality for visual presentation of intraoperative target structures in minimally invasive surgery: a randomized controlled study.

AIMS: In minimally invasive surgery (MIS), intraoperative guidance has been limited to verbal communication without direct visual guidance. Communication issues and mistaken instructions in training procedures can hinder correct identification of anatomical structures on the MIS screen. The iSurgeon system was developed to provide visual guidance in the operating room by telestration with augmented reality (AR). METHODS: Laparoscopic novices (n = 60) were randomized in two groups in a cross-over design: group 1 trained only with verbal guidance first and then with additional telestration with AR on the operative screen and vice versa for group 2. Training consisted of laparoscopic basic training and subsequently a specifically designed training course, including a porcine laparoscopic cholecystectomy (LC). Outcome included time needed for training, performance with Global Operative Assessment of Laparoscopic Skills (GOALS), and Objective Structured Assessment of Technical Skills (OSATS) score for LC, complications, and subjective workload (NASA-TLX questionnaire). RESULTS: Telestration with AR led to significantly faster total training time (1163 ± 275 vs. 1658 ± 375 s, p < 0.001) and reduced error rates. LC on a porcine liver was performed significantly better (GOALS 21 ± 5 vs. 18 ± 4, p < 0.007 and OSATS 67 ± 11 vs. 61 ± 8, p < 0.015) and with less complications (13.3% vs. 40%, p < 0.020) with AR. Subjective workload and stress were significantly reduced during training with AR (33.6 ± 12.0 vs. 30.6 ± 12.9, p < 0.022). CONCLUSION: Telestration with AR improves training success and safety in MIS. The next step will be the clinical application of telestration with AR and the development of a mobile version for remote guidance.

Global airways â€" a novel Standard Tests for Asthma, allergic Rhinitis, and chronic Rhinosinusitis (STARR-15).

BACKGROUND: Global airway disease, with symptoms from both upper and lower airways, is a challenging problem for clinicians. Our goal is to design one single standard test for the awareness of global airway diseases to be used in clinical setting. MATERIAL AND METHODS: During 2019, rhinologists and pulmonologists generated a pool of items based on literature, patient-reported outcome measures and clinical experience. The items were administered to 206 patients with known asthma, CRS, allergic rhinitis, or a combination thereof. The patients also completed the Asthma Control Questionnaire (ACQ-5) and the Sino-Nasal Outcome Test (SNOT-22). Using a mix of clinical knowledge and data-driven methods a global airways questionnaire was developed. RESULTS: Mean ACQ score was highest in patients with all three, whereas the highest SNOT-22 score was observed in patients with CRS and asthma. After the development process, analysis of responses from 206 patients to 44 items on a new global airway’s questionnaire led to identification of 15 items that form the STARR-15 questionnaire with three underlying domains (an allergic rhinitis sub-factor, a CRS sub-factor and an asthma sub-factor). CONCLUSION: STARR-15 represents the first global airways questionnaire, to be used when examining patients with upper and lower airways symptoms. Future analyses are warranted to evaluate the clinical and psychometric properties of STARR-15.

Targeted next-generation sequencing of adult gliomas for retrospective prognostic evaluation and up-front diagnostics.

AIMS: We aimed to reclassify a population-based cohort of 529 adult glioma patients to evaluate the prognostic impact of the 2016 World Health Organization (WHO) central nervous system tumour classification. Moreover, we evaluated the feasibility of gene panel next-generation sequencing (NGS) in daily diagnostics of 225 prospective glioma patients. METHODS: The retrospective cohort was reclassified according to WHO 2016 criteria by immunohistochemistry for IDH-R132H, fluorescence in situ hybridization for 1p/19q-codeletion and gene panel NGS. All tumours of the prospective cohort were subjected to NGS analysis up-front. RESULTS: The entire population-based cohort was successfully reclassified according to WHO 2016 criteria. NGS results were obtained for 98% of the prospective patients. Survival analyses in the population-based cohort confirmed three major prognostic subgroups, that is, isocitrate dehydrogenase (IDH)-mutant and 1p/19q-codeleted oligodendrogliomas, IDH-mutant astrocytomas and IDH-wildtype glioblastomas. The distinction between WHO grade II and III was prognostic in patients with IDH-mutant astrocytoma. The survival of patients with IDH-wildtype diffuse astrocytomas carrying TERT promoter mutation and/or EGFR amplification overlapped with the poor survival of IDH-wildtype glioblastoma patients. CONCLUSIONS: Gene panel NGS proved feasible in daily diagnostics. In addition, our study confirms the prognostic role of glioma classification according to WHO 2016 in a large population-based cohort. Molecular features of glioblastoma in IDH-wildtype diffuse glioma were linked to poor survival corresponding to IDH-wildtype glioblastoma patients. The distinction between WHO grade II and III retained prognostic significance in patients with IDH-mutant diffuse astrocytic gliomas.

Testicular cancer survivors have shorter anogenital distance that is not increased by 1 year of testosterone replacement therapy.

STUDY QUESTION: Is anogenital distance (AGD) shorter in testicular cancer (TC) survivors than in men from the general population, and is AGD affected by testosterone replacement therapy in adulthood? SUMMARY ANSWER: AGD, measured as distance from anus to scrotum (AGDas), is shorter in TC survivors and does not change as a result of testosterone replacement therapy. WHAT IS KNOWN ALREADY: Animal studies have shown that AGD is a postnatal 'read-out' of foetal androgen action, and short AGD in male offspring is considered a sign of feminization caused by in utero disruption of the reproductive system. Likewise, measurement of AGD in human studies has suggested AGD to be part of the testicular dysgenesis syndrome hypothesis, which proposes that male reproductive disorders, such as hypospadias, cryptorchidism, some cases of impaired semen quality and TC, all share a common foetal origin. STUDY DESIGN, SIZE, DURATION: The aim was to assess AGD in men with a history of TC and controls, and furthermore to examine AGD during testosterone replacement therapy in adulthood. Study participants were TC survivors with a mild Leydig cell insufficiency who participated in a randomized double-blind study of testosterone replacement therapy versus placebo for 52 weeks (N = 69). Men from the general population were prospectively included from a study on testicular function as controls (N = 67). PARTICIPANTS/MATERIALS, SETTING, METHODS: We measured two variants of AGD; as our primary outcome the anoscrotal distance (AGDas) measured from the centre of the anus to the posterior base of the scrotum, and secondarily the anopenile distance (AGDap) measured from the anus to the cephalad insertion of the penis. Using multiple regression analysis, the mean difference in AGD between TC survivors and men from the general population was assessed, adjusted for height, BMI and examiner. Next, AGD was measured before and after 52 weeks of treatment with testosterone or placebo, and with covariance analysis differences between the two groups at follow-up was assessed after adjustment for baseline AGD, examiner, BMI and change in BMI during treatment. MAIN RESULTS AND THE ROLE OF CHANCE: TC survivors had a shorter AGDas (-0.84 cm, 95% CI: -1.31; -0.37) compared to men from the general population, and AGDas did not differ between the testosterone and placebo treated group at follow-up (0.11 cm, 95% CI: -0.22; 0.44). In contrast, AGDap was not shorter in TC survivors after adjustment (0.05 cm, 95% CI: -0.30; 0.39), and was 0.48 cm longer (95% CI: 0.13; 0.82) at follow-up in the testosterone treated compared to the placebo-treated group. LIMITATIONS, REASONS FOR CAUTION: A limitation of the study is that the number of included men was limited, and results need confirmation in a larger study. Furthermore, TC survivors were significantly older than controls. For the comparison of AGD in TC survivors and controls, it was not possible to conduct the examinations with the examiner being blinded to which group he was examining, and it cannot be excluded that this can cause a bias. WIDER IMPLICATIONS OF THE FINDINGS: The shorter AGDas in TC survivors compared to controls, which did not change upon adult testosterone replacement therapy, supports the hypothesis that reduced AGD is part of the testicular dysgenesis syndrome and may be a marker of disrupted foetal testicular development. By contrast, AGDap was not shorter in TC survivors and might be modestly sensitive to adult testosterone treatment, and thus inferior to AGDas as a constant postnatal marker of the foetal androgen environment. STUDY FUNDING/COMPETING INTEREST(S): Expenses were paid by the Department of Oncology, Copenhagen University Hospital, Rigshospitalet. Kiowa Kirin International covered expenses for Tostran and placebo. The Danish Cancer Society, The Danish Cancer Research Foundation, the Preben & Anna Simonsen Foundation, and Rigshospitalet have supported the study. L.P. was financed by the Research Fund of the Capital Region of Denmark. The authors have no competing interests. TRIAL REGISTRATION NUMBER: Part of the study is based on men participating in a randomized controlled trial registered at ClinicalTrials.gov, NCT02991209, 25 November 2016.

The eHealth self-management application 'Oncokompas' that supports cancer survivors to improve health-related quality of life and reduce symptoms: which groups benefit most?

BACKGROUND: Oncokompas is a web-based self-management application that supports cancer survivors to monitor their health-related quality of life (HRQOL) and symptoms, and to obtain personalised feedback and tailored options for supportive care. In a large randomised controlled trial among survivors of head and neck cancer, colorectal cancer, and breast cancer and (non-)Hodgkin lymphoma, Oncokompas proved to improve HRQOL, and to reduce several tumour-specific symptoms. Effect sizes were however small, and no effect was observed on the primary outcome patient activation. Therefore, this study aims to explore which subgroups of cancer survivors may especially benefit from Oncokompas. MATERIALS AND METHODS: Cancer survivors (n = 625) were randomly assigned to the intervention group (access to Oncokompas, n = 320) or control group (6 months waiting list, n = 305). Outcome measures were HRQOL, tumour-specific symptoms, and patient activation. Potential moderators included socio-demographic (sex, age, marital status, education, employment), clinical (tumour type, stage, time since diagnosis, treatment modality, comorbidities), and personal factors (self-efficacy, personal control, health literacy, Internet use), and patient activation, mental adjustment to cancer, HRQOL, symptoms, and need for supportive care, measured at baseline. Linear mixed models were performed to investigate potential moderators. RESULTS: The intervention effect on HRQOL was the largest among cancer survivors with low to moderate self-efficacy, and among those with high personal control and those with high health literacy scores. Cancer survivors with higher baseline symptom scores benefitted more on head and neck (pain in the mouth, social eating, swallowing, coughing, trismus), and colorectal cancer (weight) specific symptoms. DISCUSSION: Oncokompas seems most effective in reducing symptoms in head and neck cancer and colorectal cancer survivors who report a higher burden of tumour-specific symptoms. Oncokompas seems most effective in improving HRQOL in cancer survivors with lower self-efficacy, and in cancer survivors with higher personal control, and higher health literacy.

Prevalence, incidence and presence of comorbidities in patients with prurigo and pruritus in Germany: A population-based claims data analysis.

BACKGROUND: There are currently no published population-based data on prurigo and pruritus epidemiology in Germany. OBJECTIVES: We present the prevalence, incidence and comorbidity frequency of prurigo and pruritus in Germany. METHODS: This was a retrospective healthcare research study based on anonymized routine data from the German health insurance company DAK-Gesundheit. Evaluations were carried out for 2 006 003 adults who were insured as of 31 December 2010. Prurigo and pruritus diagnoses were based on International Classification of Diseases, Tenth Revision, German Modification (ICD-10-GM) codes. RESULTS: Prevalence was determined to be 0.21% (adjusted for sex and age 0.19%) for prurigo and 2.21% (adjusted 2.14%) for pruritus in 2010. The adjusted rates extrapolated to the total German population in 2010 show that 130 685 adults would have received a prurigo diagnosis and 1 461 024 a diagnosis of pruritus. In 2011, incidence of new prurigo and pruritus cases was 0.13% (adjusted 0.12%, extrapolated 77 263 cases) and 1.51% (adjusted 1.46%, extrapolated 978 885), respectively. Adults with prurigo suffered most frequently from hypertension (35.16%), hyperlipidaemia (24.95%) and depression (21.97%); all were reported more frequently in patients with prurigo compared with the general population (P < 0.001). Similarly, adults with pruritus suffered most frequently from hypertension (31.28%), hyperlipidaemia (23.52%) and depression (18.91%) compared with patients without pruritus (P < 0.001). CONCLUSIONS: Our data show that prurigo is a relatively rare but significant disease and that pruritus is frequent and very variable in appearance, and both have a high comorbidity burden.

Brain tumour diagnostics using a DNA methylation-based classifier as a diagnostic support tool.

AIMS: Methylation profiling (MP) is increasingly incorporated in the diagnostic process of central nervous system (CNS) tumours at our centres in The Netherlands and Scandinavia. We aimed to identify the benefits and challenges of MP as a support tool for CNS tumour diagnostics. METHODS: About 502 CNS tumour samples were analysed using (850 k) MP. Profiles were matched with the DKFZ/Heidelberg CNS Tumour Classifier. For each case, the final pathological diagnosis was compared to the diagnosis before MP. RESULTS: In 54.4% (273/502) of all analysed cases, the suggested methylation class (calibrated score ≥0.9) corresponded with the initial pathological diagnosis. The diagnosis of 24.5% of these cases (67/273) was more refined after incorporation of the MP result. In 9.8% of cases (49/502), the MP result led to a new diagnosis, resulting in an altered WHO grade in 71.4% of these cases (35/49). In 1% of cases (5/502), the suggested class based on MP was initially disregarded/interpreted as misleading, but in retrospect, the MP result predicted the right diagnosis for three of these cases. In six cases, the suggested class was interpreted as 'discrepant but noncontributory'. The remaining 33.7% of cases (169/502) had a calibrated score <0.9, including 7.8% (39/502) for which no class indication was given at all (calibrated score <0.3). CONCLUSIONS: MP is a powerful tool to confirm and fine-tune the pathological diagnosis of CNS tumours, and to avoid misdiagnoses. However, it is crucial to interpret the results in the context of clinical, radiological, histopathological and other molecular information.

European Academy of Neurology guideline on the management of medication-overuse headache.

BACKGROUND: The frequent use of medication to treat migraine attacks can lead to an increase in migraine frequency and is called medication-overuse headache (MOH). METHODS: Based on the available literature in this guideline, the first step in patient management is education and counselling. RESULTS: Patients with MOH should be managed by a multidisciplinary team of neurologists or pain specialists and behavioral psychologists. Patients in whom education is not effective should be withdrawn from overused drugs and should receive preventive treatment with drugs of proven efficacy. Patients with MOH in whom preventive treatment is not effective should undergo drug withdrawal. Drug intake can be abruptly terminated or restricted in patients overusing simple analgesics, ergots or triptan medication. In patients with long-lasting abuse of opioids, barbiturates or tranquilizers, slow tapering of these drugs is recommended. Withdrawal can be performed on an outpatient basis or in a daycare or inpatient setting.

Phylogenetic origins and family classification of typhuloid fungi, with emphasis on Ceratellopsis, Macrotyphula and Typhula (Basidiomycota).

Typhuloid fungi are a very poorly known group of tiny clavarioid homobasidiomycetes. The phylogenetic position and family classification of the genera targeted here, Ceratellopsis, Macrotyphula, Pterula sensu lato and Typhula, are controversial and based on unresolved phylogenies. Our six-gene phylogeny with an expanded taxon sampling shows that typhuloid fungi evolved at least twice in the Agaricales (Pleurotineae, Clavariineae) and once in the Hymenochaetales. Macrotyphula, Pterulicium and Typhula are nested within the Pleurotineae. The type of Typhula (1818) and Sclerotium (1790), T. phacorrhiza and S. complanatum (synonym T. phacorrhiza), are encompassed in the Macrotyphula clade that is distantly related to a monophyletic group formed by species usually assigned to Typhula. Thus, the correct name for Macrotyphula (1972) and Typhula is Sclerotium and all Typhula species but those in the T. phacorrhiza group need to be transferred to Pistillaria (1821). To avoid undesirable nomenclatural changes, we suggest to conserve Typhula with T. incarnata as type. Clavariaceae is supported as a separate, early diverging lineage within Agaricales, with Hygrophoraceae as a successive sister taxon to the rest of the Agaricales. Ceratellopsis s. auct. is polyphyletic because C. acuminata nests in Clavariaceae and C. sagittiformis in the Hymenochaetales. Ceratellopsis is found to be an earlier name for Pterulicium, because the type, C. queletii, represents Pterulicium gracile (synonym Pterula gracilis), deeply nested in the Pterulicium clade. To avoid re-combining a large number of names in Ceratellopsis we suggest to conserve it with C. acuminata as type. The new genus Bryopistillaria is created to include C. sagittiformis. The families Sarcomyxaceae and Phyllotopsidaceae, and the suborder Clavariineae, are described as new. Six new combinations are proposed and 15 names typified.

Psychiatric healthcare utilisation among refugee adolescents and their peers in Denmark.

PURPOSE: To investigate the psychiatric healthcare utilisation of refugees vis-à-vis their peers in Denmark during the ages 15-22. METHODS: This paper utilises comprehensive full-population registry data from 1995 to 2016 to explore the psychiatric healthcare utilisation during the transition from childhood to adulthood for refugees (N = 13,027), a comparison group of children of labour migrants from Morocco, Pakistan, and Turkey (N = 13,413), and the majority population (N = 693,043) in Denmark. To test for population differences in types of admission for particular types of disorders, odds ratios for a first contact during ages 15-22 were calculated using logistic regression. For those with at least one diagnosis-specific hospital contact, differences in the amount and type of treatment were tested using negative binomial regression to estimate means ratios of days hospitalised, days in outpatient care, number of outpatient contacts, consultations with psychiatrists in private practice, and prescribed medicine purchases. RESULTS: Refugees and the comparison group were generally less likely than the majority population to have a first contact for most disorders (adjusted ORs 0.03-0.88), but not for schizophrenia for boys (adjusted ORs 0.92-2.13). Among those who did have a first contact, youths from the ethnic minority groups tended to have more or similar inpatient and emergency room contacts (MRs 0.89-2.10), hospitalisations of refugee girls being an exception (MR 0.46; CI [0.23-0.94]), but fewer outpatient contacts, consultations with psychiatrists in private practice, and prescribed medicine purchases (MRs 0.23-0.94). CONCLUSIONS: The results suggest that refugee and other ethnic minority groups may face barriers both to initial contact and to completing adequate treatment beyond the first contact.

Epidemiology of hidradenitis suppurativa in Germany - an observational cohort study based on a multisource approach.

BACKGROUND: Hidradenitis suppurativa (HS) is a chronic, debilitating inflammatory skin disease. In Germany, there are no population-based data on the epidemiology of HS. OBJECTIVES: The objective of this study was to examine the occurrence of HS in inpatient as well as in outpatient settings. METHODS: We used three data sources for analysing the prevalence, incidence and case-related occurrence of HS in different settings: data of two German statutory health insurance (SHI) companies and hospital discharge data provided by the Federal Statistical Office. The studied period was from 2010 to 2015. RESULTS: In a representative sample of about 2.3 million insurees (out of 5.9 million total persons) of the SHI DAK-Gesundheit, 791 were diagnosed with HS in 2010. This coding prevalence of 0.03% is in accordance with the data of another SHI (Barmer) on about 9 million total insurees. In 2015, at least 34.7% of incident persons with HS had one potential misdiagnosis in 2014. CONCLUSION: This population-based study analyses the prevalence and incidence of HS in Germany. The coding prevalence of 0.03% observed in two independent SHI data sets is lower than expected. The findings of considerable potential misdiagnosis add to the underdiagnosis of HS in general and underline the need for future strategies to early detection and valid diagnosis of HS.

Molecular pathology of tumors of the central nervous system.

Since the update of the 4th edition of the WHO Classification of Central Nervous System (CNS) Tumors published in 2016, particular molecular characteristics are part of the definition of a subset of these neoplasms. This combined 'histo-molecular' approach allows for a much more precise diagnosis of especially diffuse gliomas and embryonal CNS tumors. This review provides an update of the most important diagnostic and prognostic markers for state-of-the-art diagnosis of primary CNS tumors. Defining molecular markers for diffuse gliomas are IDH1/IDH2 mutations, 1p/19q codeletion and mutations in histone H3 genes. Medulloblastomas, the most frequent embryonal CNS tumors, are divided into four molecularly defined groups according to the WHO 2016 Classification: wingless/integrated (WNT) signaling pathway activated, sonic hedgehog (SHH) signaling pathway activated and tumor protein p53 gene (TP53)-mutant, SHH-activated and TP53-wildtype, and non-WNT/non-SHH-activated. Molecular characteristics are also important for the diagnosis of several other CNS tumors, such as RELA fusion-positive subtype of ependymoma, atypical teratoid rhabdoid tumor (AT/RT), embryonal tumor with multilayered rosettes, and solitary fibrous tumor/hemangiopericytoma. Immunohistochemistry is a helpful alternative for further molecular characterization of several of these tumors. Additionally, genome-wide methylation profiling is a very promising new tool in CNS tumor diagnostics. Much progress has thus been made by translating the most relevant molecular knowledge into a more precise clinical diagnosis of CNS tumors. Hopefully, this will enable more specific and more effective therapeutic approaches for the patients suffering from these tumors.

Characteristics and prevalence of plaque psoriasis in patients with palmoplantar pustulosis.

BACKGROUND: Palmoplantar pustulosis (PPP) is a chronic pustular skin condition on the palms and soles. The disease is often seen in combination with plaque psoriasis, and whether PPP is a variant of psoriasis has been debated. The disease prevalence of PPP and co-occurring psoriasis is not yet established and the patient group remains understudied. OBJECTIVES: To estimate the prevalence of PPP and co-occurring psoriasis in three population-based cohorts and to provide information on patient demographics and characteristics. METHODS: Administrative healthcare registries and insurance databases from the U.S.A., Denmark and Germany were used as data sources. Patients with PPP were defined by a single International Classification of Diseases 10th Revision code for PPP during a 1-year period. Information regarding co-occurring plaque psoriasis and other comorbidities was extracted. Furthermore, use of antipsoriatic medication was identified. RESULTS: In total 1435, 751 and 1832 patients with PPP were identified in the U.S., Danish and German populations, with estimated 1-year prevalences of 0·009%, 0·005% and 0·08%, respectively. Plaque psoriasis was present in 14·2-61·3% of patients with PPP. Patients with co-occurring psoriasis had an overall higher prevalence of psoriatic arthritis. Similarly, medication use was more prevalent in patients with PPP with co-occurring psoriasis, and especially pronounced was the use of biologic therapies. CONCLUSIONS: This large observational study on patients with PPP provides detailed information regarding patient demographics, comorbidities and medication use. The 1-year prevalence of PPP varied in the three studied populations, possibly due to differences in diagnostics and recording practices. Psoriasis frequently co-occurred in patients with PPP. What's already known about this topic? Palmoplantar pustulosis (PPP) is a skin disease of the palms of the hands and soles of the feet and is known to be related to psoriasis. Whether PPP is a distinct disease or a variant of psoriasis is not yet established. The condition is understudied in terms of disease prevalence, disease predictors, patient characteristics and comorbidity. What does this study add? In this study using data from three large population-based cohorts we found low prevalence rates (< 0·1%) of PPP. The prevalence of psoriasis was estimated at between 14·2% and 61·3% in patients with psoriasis. Patients with PPP with co-occurring psoriasis have a higher prevalence of psoriatic arthritis and use of antipsoriatic drugs.

Predicting responsiveness to fampridine in gait-impaired patients with multiple sclerosis.

BACKGROUND AND PURPOSE: Fampridine leads to significant improvements in walking in many people with multiple sclerosis (PwMS). However, a relevant proportion of PwMS does not respond to fampridine and predictors of initial drug responsiveness are unknown. METHODS: Drug response to prolonged-release (PR)-fampridine was assessed in 55 PwMS using the timed 25-foot walk (T25FW), 6-min walk test (6MWT) and 12-item multiple sclerosis walking scale as outcome parameters. Patients were treated with PR-fampridine and placebo for 6 weeks each in a randomized, double-blind, placebo-controlled trial with crossover design (NCT01576354). Possible predictors of drug responsiveness were investigated by multiple correlation analysis and binary logistic regression models. An additional longitudinal analysis followed the drug responses of 32 patients treated with PR-fampridine over 3 years to identify potential predictors of long-term drug responsiveness. RESULTS: Severity of walking disability was positively correlated with enhanced responses to PR-fampridine. The strongest single predictor of drug responsiveness was poor 6MWT performance at baseline, which was positively correlated with enhanced drug response in the 6MWT (R = -0.541; P < 0.001). A multivariable logistic regression model including 6MWT and T25FW baseline performances predicted PR-fampridine responder status with an accuracy of 85.5% (specificity, 90.0%; sensitivity, 73.3%), with a threshold of 211 m in the 6MWT best separating responders from non-responders. Enhanced drug responsiveness after 3 years correlated with decline in walking endurance during this period (R = -0.634; P = 0.001). CONCLUSIONS: Initial walking impairment is a good predictor of therapeutic responsiveness to PR-fampridine. Valid predictors of patients' responsiveness to PR-fampridine are essential for patient stratification and optimization of multiple slcerosis treatment.

Ten years of the horse reference genome: insights into equine biology, domestication and population dynamics in the post-genome era.

The horse reference genome from the Thoroughbred mare Twilight has been available for a decade and, together with advances in genomics technologies, has led to unparalleled developments in equine genomics. At the core of this progress is the continuing improvement of the quality, contiguity and completeness of the reference genome, and its functional annotation. Recent achievements include the release of the next version of the reference genome (EquCab3.0) and generation of a reference sequence for the Y chromosome. Horse satellite-free centromeres provide unique models for mammalian centromere research. Despite extremely low genetic diversity of the Y chromosome, it has been possible to trace patrilines of breeds and pedigrees and show that Y variation was lost in the past approximately 2300 years owing to selective breeding. The high-quality reference genome has led to the development of three different SNP arrays and WGSs of almost 2000 modern individual horses. The collection of WGS of hundreds of ancient horses is unique and not available for any other domestic species. These tools and resources have led to global population studies dissecting the natural history of the species and genetic makeup and ancestry of modern breeds. Most importantly, the available tools and resources, together with the discovery of functional elements, are dissecting molecular causes of a growing number of Mendelian and complex traits. The improved understanding of molecular underpinnings of various traits continues to benefit the health and performance of the horse whereas also serving as a model for complex disease across species.

Genetic diversity and relationships among native Japanese horse breeds, the Japanese Thoroughbred and horses outside of Japan using genome-wide SNP data.

Eight horse breeds-Hokkaido, Kiso, Misaki, Noma, Taishu, Tokara, Miyako and Yonaguni-are native to Japan. Although Japanese native breeds are believed to have originated from ancient Mongolian horses imported from the Korean Peninsula, the phylogenetic relationships among these breeds are not well elucidated. In the present study, we compared genetic diversity among 32 international horse breeds previously evaluated by the Equine Genetic Diversity Consortium, the eight Japanese native breeds and Japanese Thoroughbreds using genome-wide SNP genotype data. The proportion of polymorphic loci and expected heterozygosity showed that the native Japanese breeds, with the exception of the Hokkaido, have relatively low diversity compared to the other breeds sampled. Phylogenetic and cluster analyses demonstrated relationships among the breeds that largely reflect their geographic distribution in Japan. Based on these data, we suggest that Japanese horses originated from Mongolian horses migrating through the Korean Peninsula. The Japanese Thoroughbreds were distinct from the native breeds, and although they maintain similar overall diversity as Thoroughbreds from outside Japan, they also show evidence of uniqueness relative to the other Thoroughbred samples. This is the first study to place the eight native Japanese breeds and Japanese Thoroughbred in context with an international sample of diverse breeds.

Changes to country-specific hepatitis A travel vaccination recommendation for UK travellers in 2017-responding to a vaccine shortage in the national context.

OBJECTIVES: A routine review of hepatitis A travel vaccination recommendations was brought forward in June 2017 due to hepatitis A vaccine shortages and a concurrent outbreak in men who have sex with men (MSM). There were three objectives: first, to document the review process for changing the recommendations for the UK travellers in June 2017. Second, to study the impact of these changes on prescribing in general practice in 2017 compared with the previous 5 years. Third, to study any changes in hepatitis A notifications in June-October 2017 compared with the previous 5 years. STUDY DESIGN: This is an observational study. METHODS: Travel vaccination recommendations for countries with either low-risk (<20%) or high-risk (>90%) status according to child hepatitis A seroprevalence were not changed. A total of 67 intermediate-risk countries with existing recommendations for most travellers and with new data on rural sanitation levels were shortlisted for the analysis. Data on child hepatitis A seroprevalence, country income status, access to sanitation in rural areas and traveller volumes were obtained. Information about the vaccine supply was obtained from Public Health England. Changes to the existing classification were made through expert consensus, based on countries' hepatitis A seroprevalence, sanitation levels, level of income, volume of travel and hepatitis A traveller cases. Data on the number of combined and monovalent hepatitis A-containing vaccines prescribed in England, 2012-2017, were obtained from the National Health Service Business Service Authorities. The number of monthly prescriptions for January-September 2017 was compared with the mean number of prescriptions for the same month in the previous 5 years (t-test, α = 5%, df = 4). The number of hepatitis A cases notified in June-October 2017 not related to the MSM outbreak was compared with the number of notifications in the same months in previous years. RESULTS: A total of 36 countries were downgraded based on good access (80+% of population) to sanitation in rural areas and the intermediate-risk status in terms of child hepatitis A seroprevalence. For these countries, vaccination would only be recommended to travellers staying long term, visiting friends and relatives or staying in areas without good sanitation. There was a significant decline in hepatitis A vaccine prescriptions in June-September 2017, and there was no increase in the number of notifications. CONCLUSIONS: Hepatitis A vaccination recommendations for travel were revised in 2017 following a systematic approach to maintain continuity of supply after a hepatitis A vaccine shortage and increased hepatitis A vaccine demand related to a large outbreak. Improved access to good sanitation in rural areas and low seroprevalence estimates among children have led to 36 countries to no longer require vaccination for most travellers. These changes do not seem to have impacted on hepatitis A notifications in England, although further research will be needed to quantify the impact more precisely.

Decrease in semen quality and Leydig cell function in infertile men: a longitudinal study.

STUDY QUESTION: Are infertile men with reduced semen quality at risk of a further decrease in testicular function? SUMMARY ANSWER: Infertile men with severely reduced semen quality risk further deterioration of semen quality 15 years after treatment for infertility, and a lower baseline sperm concentration was associated with a more pronounced increase in LH and decrease in testosterone/LH ratio at follow-up. WHAT IS KNOWN ALREADY: Male factors account for up to 50% of human infertility. The most common finding is spermatogenic failure (SgF) yet the life course of semen quality and testosterone production in such men has not been described. STUDY DESIGN, SIZE, DURATION: A follow-up study of men with SgF was performed 15 years after the initial infertility assessment between January 1995 and December 2000. PARTICIPANTS/MATERIALS, SETTING, METHODS: Hospital records were used to identify potential participants in the study. A total of 137 men with primary male infertility due to SgF and 70 controls with good semen quality from couples with female factor infertility who attended a tertiary referral centre were included: the participation rate was 31% and 26%, respectively. The men provided semen samples and underwent a physical examination. Blood samples were taken to measure levels of reproductive hormones (FSH, LH, testosterone, sex hormone-binding globulin, estradiol and inhibin B). Current results were compared with results from the initial assessments. MAIN RESULTS AND THE ROLE OF CHANCE: At the time of follow up the SgF men had significantly lower Leydig cell capacity than the control group as well as much lower semen quality. For the SgF men, between baseline sampling and follow up, the median sperm concentration decreased from 1.9 to 0.6 mill/ml and total sperm count from 7.7 to 2.0 million (P = 0.019 and 0.012, respectively), and 10% developed azoospermia. Calculated free testosterone (cFT), but not total testosterone (tT) decreased in the SgF group by ~0.6% (95% CI 0.1-1.2%) per year. In the SgF group, LH increased by 1.6% (CI 0.9-2.3%) annually, and consequently tT/LH and cFT/LH ratios had decreased by 1.3% (CI 0.5-2.1) and 2.1% (CI 1.2-3.0%), respectively. The increase in LH and the decreases in tT/LH and cFT/LH ratios were more pronounced in men with lower baseline sperm concentrations. LIMITATIONS, REASONS FOR CAUTION: We consider the case group as representative of infertile men not in need of testosterone treatment at baseline investigation, but do not have information on those that chose not to participate in the follow-up study. There were alterations in some hormone analysis methods during the follow-up period that may introduce uncertainty in interpretation of long-term changes in hormone levels despite rigorous quality control. The validity of the control group suffers from a lack of hormone values at baseline. Also, at follow-up, for practical reasons only one semen sample could be obtained, which makes the effect estimate more uncertain and there is a risk of non-differential misclassification. WIDER IMPLICATIONS OF THE FINDINGS: Without being able to predict individual outcomes, it is prudent to consider sperm cryopreservation or advise not to postpone fertility treatment when men present with infertility due to impaired semen quality. Whether partly compensated Leydig cell insufficiency in men with SgF will eventually develop into overt testosterone deficiency cannot be determined from our study. STUDY FUNDING/COMPETING INTEREST(s): Aase and Einar Danielsen (Grant no. 10-001053), Nordic Research Committee (Grant no. 5109), The Kirsten and Freddie Johansen Fund, and Rigshospitalet's Research Fund (grant no. R24-A812). There are no competing interests.