Toward De Novo Catalyst Discovery: Fast Identification of New Catalyst Candidates for Alcohol-Mediated Morita-Baylis-Hillman Reactions.

Recently we have demonstrated how a genetic algorithm (GA) starting from random tertiary amines can be used to discover a new and efficient catalyst for the alcohol-mediated Morita-Baylis-Hillman (MBH) reaction. In particular, the discovered catalyst was shown experimentally to be eight times more active than DABCO, commonly used to catalyze the MBH reaction. This represents a breakthrough in using generative models for catalyst optimization. However, the GA procedure, and hence discovery, relied on two important pieces of information; 1) the knowledge that tertiary amines catalyze the reaction and 2) the mechanism and reaction profile for the catalyzed reaction, in particular the transition state structure of the rate-determining step. Thus, truly de novo catalyst discovery must include these steps. Here we present such a method for discovering catalyst candidates for a specific reaction while simultaneously proposing a mechanism for the catalyzed reaction. We show that tertiary amines and phosphines are potential catalysts for the MBH reaction by screening 11 molecular templates representing common functional groups. The method relies on an automated reaction discovery workflow using meta-dynamics calculations. Combining this method for catalyst candidate discovery with our GA-based catalyst optimization method results in an algorithm for truly de novo catalyst discovery.

Drug Levels Associated With Optimal Discrimination Between Remission and Nonremission and Comparison of Antibody Assays During First Year of Stable Infliximab Maintenance Therapy in Inflammatory Bowel Disease.

BACKGROUND: To implement therapeutic drug monitoring-based strategies for infliximab (IFX) in inflammatory bowel disease, the authors assessed IFX levels for optimal discrimination between remission and nonremission and compared assays for anti-IFX antibodies (Abs). METHODS: The retrospective cohort comprised 163 bionaive patients with inflammatory bowel disease who received stable IFX maintenance therapy (5 mg/kg every 8 weeks [q8w]) for 1 year. The clinical and biochemical remission status was assessed at all infusions (weeks 14-22-30-38-46-54), and IFX and anti-IFX Abs were estimated using a time-resolved fluorometric assay (n = 690; 88% of infusions). Samples positive for anti-IFX Abs or IFX levels < limit of detection (n = 102) were analyzed by 2 binding assays [enzyme-linked immunosorbent assay (ELISA)] and functional reporter gene assay/drug-tolerant enzyme immunoassay. RESULTS: At all assessed time points, IFX levels were more than double in patients presenting clinical or biochemical remission. An IFX concentration of 4.5 mcg/mL was associated with clinical remission during the entire first year of therapy [sensitivity 54% (49-59), specificity 73% (67-78), AUCROC 0.65 (0.60-0.69), P < 0.0001]; these values were comparable with biochemical remission. Exploratory assessments for endoscopic remission (n = 131) were performed at the discretion of the treating physician. Anti-IFX Abs were associated with undetectable IFX and treatment failure [OR 2.9 (1.4-6.0), P < 0.01], irrespective of persistency or transiency. All performed assays detected anti-IFX Abs were picked up by all assays in ∼2/3 of samples. Binding assays demonstrated a higher sensitivity to anti-IFX Abs. CONCLUSIONS: IFX at ∼5 mcg/mL was associated with clinical and biochemical remission during the first year of maintenance therapy. During this phase of therapy, standard binding assays are appropriate for therapeutic drug monitoring.

Lynch syndrome-associated epithelial ovarian cancer and its immunological profile.

INTRODUCTION: Lynch syndrome is a multi-tumor syndrome characterized by mismatch repair deficiency (MMR-d), microsatellite instability (MSI), and increased tumor-infiltrating lymphocytes (TILs) making these tumors candidates for treatment with immune checkpoint inhibitors. However, response may depend on tumor-induced immune evasion mechanisms, e.g. loss of Beta-2-Microglobulin (B2M) or upregulation of programmed death protein ligand 1 (PD-L1). We investigated the immune response and B2M and PD-L1 expression in Lynch syndrome-associated ovarian cancers. METHODS: We successfully analyzed 30 Lynch syndrome-associated epithelial ovarian cancers collected through the Danish Hereditary Non-Polyposis Colorectal Cancer (HNPCC) register. MMR-d, MSI, immune response (CD3, CD8, and CD68), and immune evasion mechanisms (B2M and PD-L1) were investigated. Statistical associations between these markers were evaluated in addition to survival in relation to B2M/PD-L1. RESULTS: Of the 29 evaluable tumors, 27 were MMR-d (93.1%). Likewise of 26 evaluable tumors, 14 were MSI (53.8%). MMR-d/MMR-proficiency associated with MSI/MSS in 60.0%. Half of the ovarian tumors presented with high levels of TILs. Loss of B2M expression was observed in 46.7% of the tumors, while expression of PD-L1 was seen in 28.0% of the cases. There was no association between B2M/PD-L1 and MSI/TILs/survival. Loss of B2M was often seen in tumors with low TILs (p = 0.056 or p = 0.059 for CD3 and CD8 positive cells, respectively). CONCLUSION: MMR-d, MSI, and TILs are also seen in Lynch syndrome-associated ovarian cancers making these potential candidates for checkpoint-based immunotherapy. The clinical impact from immune evasion through loss of B2M needs to be investigated further in larger cohorts.

Broadening risk profile in familial colorectal cancer type X; increased risk for five cancer types in the national Danish cohort.

BACKGROUND: Familial colorectal cancer type X (FCCTX) is a phenotypically defined subset of hereditary colorectal cancer with unknown and potentially heterogeneous genetic aetiology. FCCTX has been characterized as a colorectal cancer-specific syndrome, which we herein challenge by estimating the risk for extra-colorectal cancer in the Danish FCCTX cohort. METHODS: Through the national hereditary non-polyposis colorectal cancer (HNPCC) register, 213 families fulfilling the Amsterdam I criteria and showing retained mismatch repair (MMR) function were identified. In here, sex and age-specific incidence rate ratios (IRR) were calculated for 30 extra-colorectal cancer types in comparison with the general Danish population. RESULTS: In total, 494 extra-colorectal cancers developed with significantly increased risks for cancers of the urinary tract, breast, stomach, pancreas, and eye tumours. The age groups at increased risks were 30-49 years for gastric cancer, 30-69 years for female breast cancer, 50-69 years for ocular melanoma and above age 70 for pancreatic cancer and urothelial cancer. CONCLUSIONS: Danish FCCTX families show an increased risk of several extra-colorectal cancer types. This observation may indicate unidentified disease-predisposing genetic variants in this phenotypically defined subset of hereditary colorectal cancer and calls for awareness during genetic counselling and follow-up.

Therapeutic thresholds and mechanisms for primary non-response to infliximab in inflammatory bowel disease.

BACKGROUND: Primary non-response to infliximab (IFX) inherits a poor prognosis in inflammatory bowel disease (IBD). We explored underlying mechanisms and therapeutic thresholds in an effort to provide basis for optimizing therapy. METHODS: A prospectively followed cohort of 166 IBD patients having received standard IFX induction therapy (5 mg/kg at weeks 2, 6, and 14) had trough IFX and anti-IFX antibodies (Abs) retrospectively assessed at weeks 2 (n = 148) and 6 (n = 108). Circulating TNFα was measured in matched primary non-responders (n = 29) and responders (n = 21) at baseline and weeks 6 and 14. Clinical outcome at week 14 was supported by disease activity scores in half of patients. RESULTS: In all, 18 patients (11%) had primary non-response. Infliximab was consistently lower throughout the induction phase in non-responders as compared to responders (Week 2: IFX median 18.9 µg/mL vs. 23.3, p < .05. Week 6: 8.4 vs. 17.0, p < .05). Optimal IFX thresholds associated with response was 22.9 µg/mL at week 2 (sensitivity 51%, specificity 80%, AUCROC 0.67, p < .05) and 11.8 at week 6 (72%, 77%, 0.71, p < .05). Anti-IFX Abs occurred in 28% of primary non-responders and associated with low IFX and treatment failure (OR 13.7 [2.8-67.5], p < .01). Markers of disease activity (disease activity scores, albumin, CRP) also associated with low IFX. Circulating TNFα was higher throughout induction in non-responders with ulcerative colitis but not Crohn's disease. CONCLUSION: IBD patients with primary IFX failure generally have lower IFX trough than responders during early induction phase. Pharmacokinetic failure seems common in ulcerative colits, whereas pharmacodynamic failure appears common in Crohn's disease.

P-wave indices as predictors of atrial fibrillation.

BACKGROUND: P-wave duration (PDURATION ) and P-wave area (PAREA ) have been linked to risk of atrial fibrillation (AF), but they do not improve the efficacy of Framingham AF risk score. We suggest the incorporation of both variables in one index, the P-wave area/P-wave duration (PAREA/DURATION ) index, which may be considered an expression of the average amplitude of the P wave that reflects aspects of P-wave morphology. OBJECTIVE: To assess the prognostic value of P-wave area/P-wave duration index (PAREA/DURATION index) in lead II together with other P-wave indices (PWIs) in incidence of AF in the Copenhagen Holter Study. METHODS: The study included 632 men and women, between 55 and 75 years with no apparent heart disease or AF. Baseline standard 12-lead Electrocardiography (ECGs) were analyzed manually. RESULTS: The median follow-up time was 14.7 (14.5;14.9) years. A total of 68 cases of AF and 233 cases of death were recorded. The restricted cubic spline method showed a U-shaped association between PAREA/DURATION and rate of AF. The lowest quintile of PAREA/DURATION index in lead II was associated with increased rate of AF, HR 2.80 (1.64-4.79). The addition of the new index to the Framingham model for AF improved the model in this population. The PAREA in lead II in its lowest quintile was also associated with increased rate of AF, HR 2.16 (1.25-3.75), but did not improve the Framingham model. PDURATION and P-wave terminal force (PTF) were not significantly associated with AF. CONCLUSION: A flat P wave as expressed by a small PAREA/DURATION index in lead II is associated with increased rate of incident AF beyond known AF risk factors.

Social ties between team members affect patient satisfaction: a data-driven approach to handling complex network analyses.

Research from outside the medical field suggests that social ties between team-members influence knowledge sharing, improve coordination, and facilitate task completion. However, the relative importance of social ties among team-members for patient satisfaction remains unknown. In this study, we explored the association between social ties within emergency teams performing simulated caesarean sections (CS) and patient-actor satisfaction. Two hundred seventy-two participants were allocated to 33 teams performing two emergency CSs in a simulated setting. We collected data on social ties between team-members, measured as affective, personal and professional ties. Ties were rated on 5-point Likert scales. In addition, participants' clinical experience, demographic data and their knowledge about team members' roles were surveyed. Perceived patient satisfaction was measured on a 5-point Likert scale. Data was analysed with a linear regression model using elastic net regularization. In total, 109 predictor variables were analysed including 84 related to social ties and 25 related to clinical experience, demographics and knowledge test scores. Of the 84 variables reflecting social ties, 34 (41%) had significant association with patient satisfaction, p < 0.01. By contrast, a significant association with patient satisfaction was found for only one (4%) of the 25 variables reflecting clinical experience, demographics and knowledge of team roles. Affective ties and personal ties were found to be far more important predictors in the statistical model than professional ties and predictors relating to clinical experience. Social ties between emergency team members may be important predictors of patient satisfaction. The results from this study help to enhance our conceptual understanding of social ties and their implications for team-dynamics. Our study challenges existing views of team-performance by placing emphasis on achieving collective competence through affective and personal social ties, rather than focusing on traditional measures of expertise.

Social ties influence teamwork when managing clinical emergencies.

BACKGROUND: Our current understanding of medical team competence is traditionally influenced by an individualistic perspective focusing on individual team members' knowledge, skills as well as on effective communication within the team. However, team dynamics may influence team performance more than previously anticipated. In particular, recent studies in other academic disciplines suggest that social ties between team members may impact team dynamics but this has not been explored for medical teams. We aimed to explore intensive care staff's perceptions about teamwork and performance in clinical emergencies focusing particularly on the teams' social ties. METHODS: Semi-structured interviews were conducted with a purposive sample of intensive care staff. We used a thematic analysis approach to data interpretation. RESULTS: Thematic saturation was achieved after three group interviews and eight individual interviews. Findings demonstrated that social ties influenced teamwork by affecting the teams' ability to co-construct knowledge, coordinate tasks, the need for hierarchy, the degree to which they relied on explicit or implicit communication, as well as their ability to promote adaptive behavior. CONCLUSIONS: Social ties may be an important factor to consider and acknowledge in the design of future team training, as well as for work planning and scheduling of team activities during clinical practice. More research is needed into the causal effect of social ties on team performance and outcome.

Computational construction of the electronic Hamiltonian for photoinduced electron transfer and Redfield propagation.

The construction of open-system diabatic Hamiltonians relevant for investigation of electron transfer processes is a computational challenge. In this paper, we present how the full system Hamiltonian, as well as relevant system-bath coupling parameters can be computed from a purely computational starting point. We have investigated two methods for calculating electronic couplings, Generalized Mulliken Hush (GMH) and Fock Matrix Reconstruction (FMR). We apply these methods to calculate the couplings in a model molecular triad, thus constructing the system-Hamiltonian in a diabatic basis. The triad is constructed with a donor-antenna-acceptor type architecture, and a two-step photoinduced electron transfer is expected in this system. With the calculated electronic couplings in combination with Huang-Rhys type electron-phonon couplings, we are able to construct two open-system Hamiltonians from a computational bottom-up approach, where the phonon-reservoir is approximated as harmonic oscillators. Based on these Hamiltonians, two separate propagations of populations are performed using the Redfield formalism. Based on the dynamics, we observe small differences between the results from the GMH and FMR simulations. The overall picture is similar for the two methods. Thereby, we conclude that the FMR approach is suitable as an initial screening tool for identifying long-lived photoinduced charge separated states and that a GMH based Hamiltonian can then be constructed to scrutinize promising candidate molecules. Furthermore, either method can be used to construct all relevant operators needed for the Redfield tensor, without prior knowlegde from experimental data.

The riddle of the forbidden UV absorption of aqueous nitrate: the oscillator strength of the n →π* transition in NO3- including second order vibronic coupling.

The environmentally relevant n →π* transition in the nitrate anion is doubly forbidden by symmetry, as the Franck-Condon and first order vibronic coupling terms are both zero in the gas phase. Inclusion of the second order vibronic coupling term is therefore essential when calculating the oscillator strength. Here we have calculated an oscillator strength of 5.7 × 10-6. The second order vibronic coupling term is included by manually displacing the ground-state geometry simultaneously along two normal modes, Ql and Qk, in 19 × 19 steps, and calculating the transition dipole moment at each point by TD-DFT/ωB97XD/aug-cc-pVTZ and fitting to a polynomial in order to evaluate the second derivative with respect to Ql and Qk. In the aqueous phase the high symmetry of NO3- is broken and the first order term is no longer forbidden. However, the calculated solvated geometry still resembles the gas phase geometry and the calculated first order term does not contribute significantly to the overall oscillator strength of 1.9 × 10-6. This is a rare example of higher order vibronic coupling being more important than the lowest order term.

Common source of miscalculation and misclassification of P-wave negativity and P-wave terminal force in lead V1.

BACKGROUND: P-wave terminal force (PTF) > 4000 ms·µV and deep terminal negativity (DTN) are ECG markers of left atrial abnormality associated with both atrial fibrillation and stroke. When the precordial lead V1 is placed higher than the correct position in the fourth intercostal space, it may cause increased PTF and DTN. Several studies have documented that electrode misplacement, especially high placement, is common. The influence of electrode misplacement on these novel ECG markers has not previously been quantified. OBJECTIVE: The objective was to assess the influence of electrode misplacement on PTF and DTN. METHOD: 12-Lead ECGs were recorded in 29 healthy volunteers from the Department of Cardiology at the Copenhagen University Hospital of Bispebjerg. The precordial electrode V1 was placed in the fourth, third and second intercostal space, giving a total of 3 ECGs per subject. Continuous variables were compared using Dunnett's post-hoc test and categorical variables were compared using Fischer's exact test. RESULTS: High placement of V1 electrodes resulted in a more than three-fold increase of PTF (IC4 = 2267 ms·µV, IC2 = 7996 ms·µV, p-value < 0.001). There was a similar increase of DTN (IC4 = 0%, IC2 = 28%, p-value < 0.001). P-wave area and amplitude of the negative deflection increased, and P-wave area and amplitude of the positive deflection decreased. The P-wave shape changed from being predominantly positive or biphasic in IC4 to 90% negative in IC2. The PR-duration and P-wave duration were not altered by electrode placement. CONCLUSION: High electrode placement results in significant alteration of PTF and DTN in lead V1.

Outcome of continued infliximab therapy in Crohn's disease patients with response but without remission after one year of infliximab - a retrospective cohort study.

BACKGROUND: Optimal management of Crohn's disease patients having responded to infliximab but without achieving remission is not well defined. The present study examined if these patients benefit from continued long-term infliximab maintenance therapy. METHOD: Retrospective cohort study including all patients treated with infliximab for 1 year until the end of 2017 who have had a response but not reached remission on infliximab. Clinical outcomes were defined by the physicians' global evaluation, supported by clinical indices and objective markers of disease activity. RESULTS: In total, 376 Crohn's disease patients received infliximab. Among these, 76 (20%) were classified as having response but non-remission (RNR) after 1 year of therapy. A great majority (n = 54; 71%) experienced no additional therapeutic benefit after a further year of infliximab maintenance therapy, thus still having RNR. Nineteen patients (25%) obtained remission during continued infliximab, whereas only 4% (n = 3) experienced treatment failure. Although infliximab therapy beyond 2 years (follow-up median 35 months, IQR: 23-55) was accompanied by a higher proportion attaining remission (40%), nearly half (46%) still failed to improve. Among patients who had discontinued infliximab while having RNR (n = 21), half (n = 11) experienced disease flare within five months (median 22 weeks, IQR: 12-31). CONCLUSION: Most patients (71%) had no additional therapeutic benefit after an additional year of infliximab therapy, and after a median maintenance infliximab treatment period of 3 years, half still failed to improve further. Considering the importance of achieving complete remission, these patients appear to have an unmet medical need.

Density Functional Theory Investigation on Boron Subphthalocyanine-Ferrocene Dyads.

Twelve dyad structures were investigated using time-dependent density functional theory (TD-DFT). The dyads are all functionalized boron subphthalocyanines (SubPcs), where the SubPc unit acts as an acceptor, and ferrocene was chosen as the donor. Both axial and peripheral functionalization was investigated using four different linker groups between the SubPc unit and the ferrocene unit. The calculated molecular orbitals were compared for the 12 structures and discussed in the context of possible electron transport through the system and the use in organic photovoltaics. Optical properties of the 12 structures were investigated using a TD-DFT approach with the generalized gradient approximation type exchange correlation functional BP86 and using the Pople style basis set 6-31++G(d,p). Both changes in absorption properties by changing the linker group and changes in absorption properties when changing the position of the linker group were considered.

Effect of urban design on microclimate and thermal comfort outdoors in warm-humid Dar es Salaam, Tanzania.

Due to the complexity of built environment, urban design patterns considerably affect the microclimate and outdoor thermal comfort in a given urban morphology. Variables such as building heights and orientations, spaces between buildings, plot coverage alter solar access, wind speed and direction at street level. To improve microclimate and comfort conditions urban design elements including vegetation and shading devices can be used. In warm-humid Dar es Salaam, the climate consideration in urban design has received little attention although the urban planning authorities try to develop the quality of planning and design. The main aim of this study is to investigate the relationship between urban design, urban microclimate, and outdoor comfort in four built-up areas with different morphologies including low-, medium-, and high-rise buildings. The study mainly concentrates on the warm season but a comparison with the thermal comfort conditions in the cool season is made for one of the areas. Air temperature, wind speed, mean radiant temperature (MRT), and the physiologically equivalent temperature (PET) are simulated using ENVI-met to highlight the strengths and weaknesses of the existing urban design. An analysis of the distribution of MRT in the areas showed that the area with low-rise buildings had the highest frequency of high MRTs and the lowest frequency of low MRTs. The study illustrates that areas with low-rise buildings lead to more stressful urban spaces than areas with high-rise buildings. It is also shown that the use of dense trees helps to enhance the thermal comfort conditions, i.e., reduce heat stress. However, vegetation might negatively affect the wind ventilation. Nevertheless, a sensitivity analysis shows that the provision of shade is a more efficient way to reduce PET than increases in wind speed, given the prevailing sun and wind conditions in Dar es Salaam. To mitigate heat stress in Dar es Salaam, a set of recommendations and guidelines on how to develop the existing situation from microclimate and thermal comfort perspectives is outlined. Such recommendations will help architects and urban designers to increase the quality of the outdoor environment and demonstrate the need to create better urban spaces in harmony with microclimate and thermal comfort.

Cupriavidus pinatubonensis AEO106 deals with copper-induced oxidative stress before engaging in biodegradation of the herbicide 4-chloro-2-methylphenoxyacetic acid.

BACKGROUND: Microbial degradation of phenoxy acid (PA) herbicides in agricultural soils is important to minimize herbicide leaching to groundwater reservoirs. Degradation may, however, be hampered by exposure of the degrader bacteria to toxic metals as copper (Cu) in the soil environment. Exposure to Cu leads to accumulation of intracellular reactive oxygen species (ROS) in some bacteria, but it is not known how Cu-derived ROS and an ensuing oxidative stress affect the degradation of PA herbicides. Based on the previously proposed paradigm that bacteria deal with environmental stress before they engage in biodegradation, we studied how the degradation of the PA herbicide 2-methyl-4-chlorophenoxyacetic acid (MCPA) by the model PA degrader Cupriavidus pinatubonensis AEO106 was affected by Cu exposure. RESULTS: Exposure of C. pinatubonensis in batch culture to sublethal concentrations of Cu increased accumulation of ROS measured by the oxidant sensing probe 2,7-dichlorodihydrofluorescein diacetate and flow cytometry, and resulted in upregulation of a gene encoding a protein belong to the Ohr/OsmC protein family. The ohr/osmC gene was also highly induced by H2O2 exposure suggesting that it is involved in the oxidative stress response in C. pinatubonensis. The increased ROS accumulation and increased expression of the oxidative stress defense coincided with a delay in the catabolic performance, since both expression of the catabolic tfdA gene and MCPA mineralization were delayed compared to unexposed control cells. CONCLUSIONS: The current study suggests that Cu-induced ROS accumulation in C. pinatubonensis activates a stress response involving the product of the ohr/osmC gene. Further, the stress response is launched before induction of the catabolic tfdA gene and mineralization occurs.

Infants with prenatally diagnosed kidney anomalies have an increased risk of urinary tract infections.

AIM: This study estimated the urinary tract infection (UTI) risk in a nationwide cohort of infants prenatally diagnosed with parenchymal kidney anomalies compared with a comparison cohort. METHODS: A Danish population-based nationwide cohort of foetuses diagnosed with parenchymal kidney anomalies between 2007 and 2012 had previously been identified. These were compared with foetuses without kidney anomalies who were prenatally scanned the same year. Live born infants were followed from birth until the diagnosis of UTI, emigration, death or two years of age. Cumulative incidences of UTIs were computed. Mortality was estimated using the Kaplan-Meier method. RESULTS: We identified 412 foetuses with parenchymal kidney anomalies out of 362 069 who underwent ultrasound scans and 277 were born alive. The overall risk of a UTI before the age of two years was 19%, and it was 14% among infants without prenatally diagnosed co-occurring urinary tract malformations. The corresponding risk in the 4074 controls was 1%. After two years, mortality was 2.2% in infants with prenatally diagnosed parenchymal kidney anomalies and 0.2% in the controls. CONCLUSION: Infants prenatally diagnosed with parenchymal kidney anomalies had a substantially increased risk of UTI. Awareness of this increased risk may facilitate earlier diagnosis of UTIs in this population.

Prevalence and patient characteristics of Mayer-Rokitansky-Küster-Hauser syndrome: a nationwide registry-based study.

STUDY QUESTION: What is the prevalence of Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome? SUMMARY ANSWER: The prevalence of MRKH syndrome in Denmark is 1 in 4982 (95% confidence interval (CI): 4216-5887) live female births. WHAT IS KNOWN ALREADY: The prevalence of MRKH syndrome has been estimated to be around 1 in 4000-5000 females. However, population-based prevalence studies of MRKH syndrome are sparse. Moreover, population-based data on patient characteristics are lacking. STUDY DESIGN, SIZE, DURATION: This retrospective cohort study used the Danish National Patient Registry (DNPR) to identify a nationwide population-based cohort of patients with MRKH syndrome. Subsequently, patients were linked to the Danish Cytogenetic Central Registry (DCCR) and patient medical records in order to validate the diagnoses. PARTICIPANTS/MATERIALS, SETTING, METHODS: Hospitalizations and outpatient visits from 1994 to April 2015 at all public hospitals in Denmark were searched for patients assigned with a diagnosis code indicative of MRKH syndrome. The diagnoses were validated by diagnostic history in the DNPR and DCCR data, and by review of patient medical records. The prevalence was estimated considering the identified patients born from 1974 to 1996. Patient characteristics were described using data collected from DNPR, DCCR and patient medical records. MAIN RESULTS AND THE ROLE OF CHANCE: The diagnosis was validated in 304 of 314 patients (96.8%) suspected with MRKH syndrome by review of diagnostic histories, DCCR data, and medical records and in 168 patients, the diagnosis of MRKH syndrome was confirmed (positive predictive value = 55.3% (95% CI: 49.5-60.9%)). The prevalence was 1 in 4982 (95% CI: 4216-5887) live female births based on 138 patients born from 1974 to 1996. Typical MRKH syndrome and atypical MRKH syndrome/Müllerian duct aplasia, Renal aplasia, and Cervicothoracic Somite dysplasia association were present in 56.5% and 43.5% of the patients, respectively. Kidney malformations were the most prevalent extragenital malformations, described in 38 of 111 patients (34.2%). However, in 57 patients (33.9%) no urinary tract imaging was performed. Three familial cases of MRKH syndrome were identified. LIMITATIONS, REASONS FOR CAUTION: We identified all patients with MRKH syndrome diagnosed at public hospitals in Denmark. When interpreting the prevalence estimate, caution must be taken due to limitations such as patients not diagnosed in public hospitals, other diagnosis codes not used in the study and the unknown impact of a net positive migration rate in Denmark. WIDER IMPLICATIONS OF THE FINDINGS: The prevalence estimate around 1 in 5000 is in accordance with a previous nationwide study. We consider the prevalence generalizable to other Caucasian populations. Prevalence studies of non-Caucasian populations are needed to investigate whether inter-ethnic differences in prevalence exist. Finally, the results of this study emphasize the need for sufficient basic examinations of patients with MRKH syndrome, including the importance of family medical history. STUDY FUNDING/COMPETING INTERESTS: None.

17q12 deletion and duplication syndrome in Denmark-A clinical cohort of 38 patients and review of the literature.

17q12 deletions and duplications are two distinct, recurrent chromosomal aberrations usually diagnosed by chromosomal microarray analysis (CMA). The aberrations encompass the genes, HNF1B, LHX1, and ACACA, among others. We here describe a large national cohort of 12 phenotyped patients with 17q12 deletions and 26 phenotyped patients with 17q12 duplications. The total cohort includes 19 index patients and 19 family members. We also reviewed the literature in order to further improve the basis for the counseling. We emphasize that renal disease, learning disability, behavioral abnormalities, epilepsy, autism, schizophrenia, structural brain abnormalities, facial dysmorphism, and joint laxity are features seen in both the 17q12 deletion syndrome and the reciprocal 17q12 duplication syndrome; and we extend the list of features seen in both patient categories to include strabismus, esophageal defects, and duodenal atresia. Delayed language development, learning disability, kidney involvement, and eye dysmorphism and strabismus were the most consistently shared features among patients with 17q12 deletion. Patients with 17q12 duplications were characterized by an extremely wide phenotypic spectrum, including a variable degree of learning disabilities, delayed language development, delayed motor milestones, and a broad range of psychiatric and neurological features. This patient group also included adults achieving an academic degree. Assessing index patients and non-index patients separately, our observations illustrate that an overall milder disease burden is seen, in particular in patients with 17q12 duplications who are ascertained on the duplication rather than the phenotype. This evidence may be useful in prenatal counseling. © 2016 Wiley Periodicals, Inc.

Kidney anomalies diagnosed by prenatal ultrasound screening and associated non-urinary malformations: a nationwide prevalence study.

OBJECTIVES: To estimate the prevalence of kidney anomalies at second trimester ultrasound screening, and furthermore, to investigate pregnancy outcomes and the pattern of additional malformations. METHODS: We previously identified all women attending second-trimester ultrasound scans in Denmark between 1 January 2007 and 31 December 2012. Using the Astraia databases and the Danish National Patient Registry, we identified all fetuses with kidney anomalies diagnosed prenatally in these women. In addition to the prevalence of fetuses with kidney anomalies, we estimated the live birth prevalence ratio of non-urinary malformations, comparing the prevalences in infants with and without prenatally diagnosed kidney anomalies. RESULTS: The prevalence of fetuses with kidney anomalies at second trimester scans was 11.4 per 10 000 fetuses. Among the 412 fetuses identified, 127 pregnancies were terminated. For live born children the prevalence of additional non-urinary malformations was four times higher (95% CI: 3-5) compared with the prevalence among children without prenatal kidney anomalies. Digestive system anomalies were particularly prevalent. CONCLUSION: These population-based data provide additional insight into the course of pregnancy and birth outcomes following prenatal diagnoses of kidney anomalies. © 2016 John Wiley & Sons, Ltd.