Culture media affect sex after IVF treatment-a detailed analysis of explanatory variables.

PURPOSE: The purpose of this study was to provide a detailed analysis of clinical and laboratory factors associated with skewed secondary sex ratio (SSR) after ART. METHOD: Retrospective cohort study of embryos resulting in live births, from frozen and fresh single blastocyst transfers. Embryos were cultured in either G-TL (n = 686) or Sage media (n = 685). Data was analyzed using a multivariate logistic regression model and a mixed model analysis. RESULTS: Significantly more male singletons were born after culture in Sage media compared to G-TL media (odds ratio (OR) 1.34, 95% CI (1.05, 1.70), P = 0.02). Inner cell mass grade B vs A (OR 1.36 95% CI (1.05, 1.76), P = 0.02) and one previous embryo transfer (OR 1.49, 95% CI (1.03, 2.16), P = 0.03) were associated with a significantly higher probability of male child at birth. Factors associated with a reduced probability of male child were expansion grade 3 vs 5 (OR 0.66, 95% CI (10.45, 0.96), P = 0.03) and trophectoderm grade B vs A (OR 0.57, 95% CI (0.44, 0.74), P = 0.00). Male embryos developed significantly faster in Sage media compared to G-TL media for the stages of blastocyst (- 1.12 h, 95% CI (- 2.12, - 0.12)), expanded blastocyst (- 1.35 h, 95% CI (- 2.34, - 0.35)), and hatched blastocyst (- 1.75 h, 95% CI (- 2.99, - 0.52)). CONCLUSION: More male children were born after culture in Sage media compared to G-TL media. Male embryo development was affected by culture media. Our observations suggest that culture media impact male embryo quality selectively, thus potentially favoring the selection of male embryos.

Unraveling the potential clinical utility of circulating tumor DNA detection in colorectal cancer-evaluation in a nationwide Danish cohort.

BACKGROUND: Increasingly, circulating tumor DNA (ctDNA) is proposed as a tool for minimal residual disease (MRD) assessment. Digital PCR (dPCR) offers low analysis costs and turnaround times of less than a day, making it ripe for clinical implementation. Here, we used tumor-informed dPCR for ctDNA detection in a large colorectal cancer (CRC) cohort to evaluate the potential for post-operative risk assessment and serial monitoring, and how the metastatic site may impact ctDNA detection. Additionally, we assessed how altering the ctDNA-calling algorithm could customize performance for different clinical settings. PATIENTS AND METHODS: Stage II-III CRC patients (N = 851) treated with a curative intent were recruited. Based on whole-exome sequencing on matched tumor and germline DNA, a mutational target was selected for dPCR analysis. Plasma samples (8 ml) were collected within 60 days after operation and-for a patient subset (n = 246)-every 3-4 months for up to 36 months. Single-target dPCR was used for ctDNA detection. RESULTS: Both post-operative and serial ctDNA detection were prognostic of recurrence [hazard ratio (HR) = 11.3, 95% confidence interval (CI) 7.8-16.4, P < 0.001; HR = 30.7, 95% CI 20.2-46.7, P < 0.001], with a cumulative ctDNA detection rate of 87% at the end of sample collection in recurrence patients. The ctDNA growth rate was prognostic of survival (HR = 2.6, 95% CI 1.5-4.4, P = 0.001). In recurrence patients, post-operative ctDNA detection was challenging for lung metastases (4/21 detected) and peritoneal metastases (2/10 detected). By modifying the cut-off for calling a sample ctDNA positive, we were able to adjust the sensitivity and specificity of our test for different clinical contexts. CONCLUSIONS: The presented results from 851 stage II-III CRC patients demonstrate that our personalized dPCR approach effectively detects MRD after operation and shows promise for serial ctDNA detection for recurrence surveillance. The ability to adjust sensitivity and specificity shows exciting potential to customize the ctDNA caller for specific clinical settings.

Unlocking ground-based imagery for habitat mapping.

Fine-grained environmental data across large extents are needed to resolve the processes that impact species communities from local to global scales. Ground-based images (GBIs) have the potential to capture habitat complexity at biologically relevant spatial and temporal resolutions. Moving beyond existing applications of GBIs for species identification and monitoring ecological change from repeat photography, we describe promising approaches to habitat mapping, leveraging multimodal data and computer vision. We illustrate empirically how GBIs can be applied to predict distributions of species at fine scales along Street View routes, or to automatically classify and quantify habitat features. Further, we outline future research avenues using GBIs that can bring a leap forward in analyses for ecology and conservation with this underused resource.

Randomized Phase 3 trial demonstrating high efficacy, favourable safety and convenience of a novel calcipotriol and betamethasone dipropionate cream for the treatment of psoriasis.

BACKGROUND: The fixed dose combination of calcipotriene (CAL) and betamethasone dipropionate (BDP) is a well-established topical treatment option for psoriasis based on strong scientific rationale for the single agents having complementary efficacy and safety. CAL/BDP PAD-cream is an easily spreadable cream based on PAD Technology™, an innovative formulation and drug delivery system. OBJECTIVES AND METHODS: A Phase 3, multicentre, randomized, investigator-blind, active and vehicle-controlled trial enrolling 490 patients with mild to moderate psoriasis according to the Physician Global Assessment (PGA) scale was conducted in three European countries. Products were applied once daily for 8 weeks. The aim of the trial was to evaluate the efficacy and safety of CAL/BDP PAD-cream as well as treatment acceptability compared to CAL/BDP gel and PAD-cream vehicle. Primary endpoint was percentage change in modified Psoriasis Area and Severity Index (mPASI) from baseline to Week 8. RESULTS: The percentage mean change from baseline to Week 8 in mPASI for CAL/BDP PAD-cream (67.5%) was superior compared to PAD-cream vehicle (11.7%; p < 0.0001) and non-inferior to CAL/BDP gel (63.5%). The proportion of patients achieving PGA treatment success (at least two-step improvement to clear or almost clear) after 8 weeks was superior for CAL/BDP PAD-cream (50.7%) compared to PAD-cream vehicle (6.1%, p < 0.0001) and statistically significantly greater than CAL/BDP gel (42.7%, p = 0.0442). Patient-reported psoriasis treatment convenience score (PTCS) for CAL/BDP PAD-cream was rated superior to CAL/BDP gel at Week 8 (p < 0.0001) and the mean change in DLQI from baseline to Week 8 improved statistically significantly more in the CAL/BDP PAD-cream group compared to both PAD-cream vehicle (p < 0.0001) and CAL/BDP gel (p = 0.0110). Safety assessments during the trial demonstrated that CAL/BDP PAD-cream was well-tolerated. CONCLUSION: CAL/BDP PAD-cream is a novel topical treatment of psoriasis that has a high efficacy and a favourable safety profile combined with a superior patient-reported treatment convenience.

Prevalence and characterization of treatment-refractory psoriasis and super-responders to biologic treatment: a nationwide study.

INTRODUCTION: Treatment with biologics often leads to clearance of psoriasis. However, some patients do repeatedly fail to respond and/or lose an achieved response (treatment refractory) to the biologic, whereas other patients achieve excellent response to one biologic and remain clear of psoriasis for several years (super-responders). OBJECTIVE: To identify and characterize patients with treatment refractory psoriasis and patients who are super-responders to biologic treatment. MATERIAL AND METHODS: Patients registered in DERMBIO between January 2007 and November 2019 were included. Patients were categorized as being treatment refractory if they had had treatment failure to ≥3 biologics targeting ≥2 different pathways. Super-responders were patients treated with their first biologic for minimum 5 years without an absolute psoriasis area and severity index (PASI) > 3 between 6 months and 5 years of treatment. All remaining patients from DERMBIO served as comparators. RESULTS: In total, 3280 patients were included with a mean age of 45.0 years. 1221 (37%) of the patients were females. Of the included patients, 214 (6.5%) were categorized as treatment refractory and 207 (6.3%) were categorized as super-responders. Treatment refractory patients had higher mean body weight (100.6 kg vs. 90.6 kg, P < 0.0001) and higher mean BMI (32.2 vs. 29.4, P < 0.0001) compared with the rest of patients in DERMBIO. Super-responders had higher socioeconomic status and fewer comorbidities compared with the comparator group (P < 0.0001). CONCLUSION: A small proportion of patients with psoriasis treated with biologics are either super-responders or treatment refractory. Treatment refractory patients have higher body weight, whereas super-responders have fewer comorbidities and higher socioeconomic status.

Long-term efficacy and safety of brodalumab in moderate-to-severe plaque psoriasis: a post hoc pooled analysis of AMAGINE-2 and -3.

BACKGROUND: Brodalumab is a monoclonal antibody that blocks multiple interleukin (IL)-17 family cytokines by binding to the shared A subunit of the IL-17 receptor. In Phase 3 trials, brodalumab provided high levels of skin clearance through 52 weeks in patients with moderate-to-severe psoriasis and was generally well tolerated. OBJECTIVES: To assess efficacy response rates and safety outcomes through 120 weeks for patients with moderate-to-severe psoriasis who received brodalumab. METHODS: Safety and efficacy data were pooled for patients from AMAGINE-2 and -3 who received continuous brodalumab 210 mg every 2 weeks, or brodalumab 210 mg every 2 weeks after receiving either brodalumab 140 mg or placebo through Week 12. Efficacy data are presented using observed data, non-responder imputation (NRI) and a combination of NRI and missing at random assumption to account for missing data. Absolute PASI scores are presented using mixed-effect model repeated measure modelling and multiple imputation. RESULTS: Based on observed data at Week 120, 86% of the continuous brodalumab 210 mg group achieved PASI 90 and 74% achieved PASI 100. At Week 12, 58% of this group achieved absolute PASI ≤1; this proportion increased to approximately 80% at Week 52 and persisted through Week 120. Among patients receiving continuous brodalumab 210 mg, median duration of brodalumab exposure was 747 days and the overall exposure-adjusted event rate of treatment emergent adverse events per 100 patient-years was 329. Safety through 120 weeks was comparable to the results of the primary AMAGINE-2 and -3 studies. Patients who switched to brodalumab 210 mg after receiving either brodalumab 140 mg or placebo through Week 12 showed similar skin clearance and safety profiles. CONCLUSIONS: Brodalumab treatment was well tolerated and resulted in high levels of skin clearance that were rapidly achieved and maintained through Week 120, supporting its long-term efficacy and safety profile.

Pregnancy outcomes in patients with psoriasis, psoriatic arthritis, or axial spondyloarthritis receiving ixekizumab.

BACKGROUND: Psoriasis, psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA) are chronic inflammatory diseases that often affect women of childbearing age. Detailed information about pregnancy and related outcomes across these indications in patients exposed to ixekizumab is lacking. OBJECTIVES: To evaluate pregnancy outcomes after maternal or paternal exposure to ixekizumab in patients with psoriasis, PsA, or axSpA. METHODS: Pregnancy cases from clinical trials and post-marketing reports, associated with either maternal or paternal exposure to ixekizumab cumulatively through 22 March 2019, were identified in the Eli Lilly Global Safety Database and described separately. RESULTS: One hundred and ninety-three ixekizumab-exposed pregnancies were identified. Maternal exposure occurred in 51.3% of pregnancies (clinical trials: n = 58; post-marketing: n = 41). The majority of paternal exposure pregnancies occurred in clinical trials (91 of 94). Live births were reported for 53.8 and 61.1% of known outcomes in maternal exposure pregnancies during clinical trials and post-marketing surveillance, respectively. No congenital malformations resulting from maternal exposure were reported in clinical trials: one case, not causally related to ixekizumab therapy, was recorded in the post-marketing setting. CONCLUSIONS: This integrated safety analysis provides relevant information for clinicians treating patients with psoriasis, PsA, or axSpA with ixekizumab. No new safety signals were identified in patients receiving ixekizumab.

HSP90 inhibitor RGRN-305 for oral treatment of plaque-type psoriasis: efficacy, safety and biomarker results in an open-label proof-of-concept study.

BACKGROUND: HSP90 is a downstream regulator of tumour necrosis factor (TNF)-α and interleukin (IL)-17A signalling and may therefore serve as a novel target in the treatment of psoriasis. OBJECTIVES: This phase Ib proof-of-concept study was undertaken to evaluate the safety and efficacy of a novel HSP90 inhibitor (RGRN-305) in the treatment of plaque psoriasis. METHODS: We conducted an open-label, single-arm, dose-selection, single-centre proof-of-concept study. Patients with plaque psoriasis were treated with 250 mg or 500 mg RGRN-305 daily for 12 weeks. Efficacy was evaluated clinically using the Psoriasis Area and Severity Index (PASI), body surface area (BSA), Physician's Global Assessment (PGA) scores and the Dermatology Life Quality Index (DLQI). Skin biopsies collected at baseline and at 4, 8 and 12 weeks after initiation of treatment were used for immunohistochemical staining and for gene expression analysis. Safety was monitored via laboratory tests, vital signs, electrocardiogram and physical examinations. RESULTS: Six of the 11 patients who completed the study responded to RGRN-305 with a PASI improvement between 71% and 94%, whereas five patients were considered nonresponders with a PASI response < 50%. No severe adverse events were reported. Four of seven patients treated with 500 mg RGRN-305 daily experienced a mild-to-moderate exanthematous drug-induced eruption owing to the study treatment. Two patients chose to discontinue the study because of this exanthematous eruption. RGRN-305 treatment resulted in pronounced inhibition of the IL-23, TNF-α and IL-17A signalling pathways and normalization of both histological changes and psoriatic lesion gene expression profiles in patients who responded to treatment. CONCLUSIONS: Treatment with RGRN-305 showed acceptable safety, especially in the low-dose group, and was associated with clinically meaningful improvement in a subset of patients with plaque psoriasis, indicating that HSP90 may serve as a novel future target in psoriasis treatment.

Efficacy and safety of mogamulizumab by patient baseline blood tumour burden: a post hoc analysis of the MAVORIC trial.

BACKGROUND: Mogamulizumab was compared with vorinostat in the phase 3 MAVORIC trial (NCT01728805) in 372 patients with relapsed/refractory mycosis fungoides (MF) or Sézary syndrome (SS) who had failed ≥1 prior systemic therapy. Mogamulizumab significantly prolonged progression-free survival (PFS), with a superior objective response rate (ORR) vs. vorinostat. OBJECTIVES: This post hoc analysis was performed to evaluate the effect of baseline blood tumour burden on patient response to mogamulizumab. METHODS: PFS, ORR, time to next treatment (TTNT), skin response (modified Severity-Weighted Assessment Tool [mSWAT]) and safety were assessed in patients stratified by blood classification (B0 [n = 126], B1 [n = 62], or B2 [n = 184], indicating increasing blood involvement). RESULTS: Investigator-assessed PFS was longer for mogamulizumab versus vorinostat across all blood classes, significantly so for B1 and B2 patients. ORR was higher with mogamulizumab than with vorinostat in all blood classification groups and more markedly so with escalating B class (B0: 15.6% vs. 6.5%, P = 0.0549; B1: 25.8% vs. 6.5%, P = 0.2758; B2: 37.4% vs. 3.2%, P < 0.0001). TTNT was significantly longer for patients treated with mogamulizumab versus vorinostat with B1 (12.63 vs. 3.07 months; HR 0.32 [95% CI 0.16-0.67]; P = 0.0018) and B2 (13.07 vs. 3.53 months; HR 0.30 [95% CI 0.21-0.43]; P < 0.0001) blood involvement. In the mogamulizumab arm, 81 patients (43.5%) had ≥50% change in the mSWAT vs. 41 patients (22.0%) with vorinostat; mSWAT improvements with mogamulizumab occurred most often in B1 and B2 patients. Rapid, sustained reductions were seen in CD4+ CD26- cell counts and CD4:CD8 ratios in mogamulizumab patients for all B classes. Treatment-emergent adverse events were less frequent overall with mogamulizumab and similar in frequency regardless of B class. CONCLUSIONS: This post hoc analysis indicates greater clinical benefit with mogamulizumab vs. vorinostat in patients with MF and SS classified as having B1 and B2 blood involvement.

Prevalence and severity of coronary artery disease linked to prognosis in psoriasis and psoriatic arthritis patients: a multi-centre cohort study.

OBJECTIVES: (i) To estimate the prevalence and severity of coronary artery disease and (ii) to assess the risk of cardiovascular events and mortality, in patients with psoriasis and psoriatic arthritis (PsA) in a large-scale cohort of patients referred to coronary computed tomography angiography (CTA). METHODS: This was a cross-sectional study with follow-up of 46,022 patients based on data from a Danish national CTA registry. Exposure was defined as psoriasis or PsA. A group of patients without psoriasis, PsA or any other inflammatory disease was used as reference. Cross-sectional primary outcomes were a coronary artery calcium score (CACS) >0 and CACS ≥400, and secondary outcome was obstructive CAD. At follow-up, the primary outcome was a composite endpoint of cardiovascular events and all-cause mortality. All outcomes were adjusted for traditional cardiovascular risk factors. RESULTS: We identified 1356 psoriasis and 370 PsA patients. The adjusted odds ratio (OR) for psoriasis patients for CACS >0, CACS ≥400 and obstructive CAD was 1.26 (1.10-1.46), 1.25 (1.04-1.50) and 1.14 (0.98-1.33), respectively. For PsA patients, OR for CACS >0 was 1.28 (1.00-1.64). We found a crude hazard ratio (HR) of 1.49 (1.21-1.85) and adjusted HR of 1.14 (0.92-1.41) for the primary outcome in psoriasis patients. CONCLUSIONS: In this population, both psoriasis and PsA were associated with an increased prevalence of coronary calcification. Psoriasis patients also showed an increased prevalence of severe calcification. Psoriasis patients were at increased risk for cardiovascular events and death, however not after adjusting for the effect of other predictors.

Early efficacy and safety data with fixed-dose combination calcipotriol/betamethasone dipropionate foam attributed to mechanism of absorption and steroid potency.

Topical therapy is the mainstay of treatment for the majority of patients with psoriasis vulgaris (chronic plaque psoriasis), with combinations of vitamin D analogues and glucocorticoids having been shown to negate many of the negative effects associated with either monocomponent individually. Following the established efficacy of fixed-dose combination calcipotriol (Cal; 50 µg/g) plus betamethasone dipropionate (BD; 0.5 mg/g) ointment and gel formulations, a novel Cal/BD foam formulation was developed. When applied, Cal/BD foam forms a supersaturated solution on the skin, increasing the penetration and bioavailability of Cal and BD. Early data indicate that this results in improved efficacy outcomes versus Cal/BD ointment, without negatively affecting safety outcomes (such as the incidence/severity of side effects or impacted calcium homeostasis or hypothalamic-pituitary-adrenal axis). This article discusses the potency and absorption of fixed-dose combination Cal/BD foam, as well as the positive early efficacy and safety data associated with its utilisation in the treatment of psoriasis vulgaris.

Topical treatment of psoriasis: questionnaire results on topical therapy as long-term continuous treatment and use on specific body sites.

BACKGROUND: Currently, no formalized international consensus guidelines exist to direct optimal topical treatment including long-term treatment. OBJECTIVE: In this survey, we aim to examine if and which topicals are used in clinical practice in long-term continuous treatment of psoriasis and how topicals are used in treating specific sites of the body. METHODS: A questionnaire was distributed electronically to dermatologists from the International Psoriasis Council (IPC) representing 26 countries. RESULTS: The top three topicals used across all severities of disease were topical corticosteroids, vitamin D analogs, and potent topical corticosteroids in combination with vitamin D analogs. On locations where the skin is thin, flexural and genital psoriasis, lower potency topical corticosteroids were used, whereas on other sites, in particular in palmoplantar psoriasis, superpotent topical corticosteroids and combination vitamin D analogs/corticosteroids were used. CONCLUSIONS: It is relevant to optimize localized therapy for all severities of psoriasis reconciling disease activity (stable vs. unstable disease), localization of the lesions and the individual patient and his/her perspectives on disease control. Topical therapies are valuable treatments for classical mild disease and may have a position in some patients with more severe manifestations.

Stoma reversal after intended restorative rectal cancer resection in Denmark: nationwide population-based study.

BACKGROUND: Data on stoma reversal following restorative rectal resection (RRR) with a diverting stoma are conflicting. This study investigated a Danish population-based cohort of patients undergoing RRR to evaluate factors predictive of stoma reversal during 3 years of follow-up. METHODS: Patients from national registries with rectal cancer undergoing RRR or Hartmann's procedure with curative intent between May 2001 and April 2012 were included. Patients with a diverting stoma were followed from the time of primary rectal cancer resection to date of stoma reversal, death, emigration, or end of 3-year follow-up. The cumulative incidence proportion (CIP) of stoma reversal at 1 and 3 years was calculated, treating death as a competing risk. Factors predictive of stoma reversal were explored using Cox regression analysis. RESULTS: Of 6859 patients included, 35·7, 41·9 and 22·4 per cent respectively had a RRR with a diverting stoma, RRR without a stoma, and Hartmann's procedure with an end-colostomy. In patients with a diverting stoma, the CIP of stoma reversal was 70·3 (95 per cent c.i. 68·4 to 72·1) per cent after 1 year, and 74·3 (72·5 to 76·0) per cent after 3 years. Neoadjuvant treatment (hazard ratio (HR) 0·75, 95 per cent c.i. 0·66 to 0·85), blood loss greater than 300 ml (HR 0·86, 0·76 to 0·97), anastomotic leak (HR 0·41, 0·33 to 0·50), T3 category (HR 0·63, 0·47 to 0·83), T4 category (HR 0·62, 0·42 to 0·90) and UICC stage IV (HR 0·57, 0·41 to 0·80) were possible predictors of delayed stoma reversal. CONCLUSION: In one-quarter of the patients the diverting stoma had not been reversed 3 years after the intended RRR procedure.

ANTECEDENTES: Los datos sobre el cierre del estoma (stoma reversal, SR) tras la exéresis el recto con intención reconstructiva (restorative rectal resection, RRR) y estoma derivativo (diverting stoma, DS) son contradictorios. Este estudio analizó los factores predictivos del SR en una cohorte danesa de base poblacional de pacientes sometidos a RRR con un seguimiento de 3 años. MÉTODOS: Los pacientes con cáncer de recto a los que se realizó una RRR o una operación de Hartmann (Hartmann's operation, HO) con intención curativa desde mayo de 2001 hasta abril de 2012, se seleccionaron a partir de registros nacionales. Los pacientes con SD fueron seguidos desde la resección primaria del cáncer rectal hasta la fecha del SR, del fallecimiento, de su cambio de residencia o hasta el final del seguimiento (3 años). Se calculó la tasa de incidencia acumulada (cumulative incidence proportion, CIP) de RS a 1 y 3 años utilizando la muerte como factor de riesgo competitivo. Se identificaron los factores predictivos de SR mediante regresión múltiple de Cox. RESULTADOS: De los 6.859 pacientes incluidos, el 35,7%, 41,9% y 22,4% tenían una RRR con DS, una RRR sin estoma y una HO con colostomía terminal, respectivamente. En pacientes con SD, el CIP de SR fue del 70,3% (i.c. del 95%: 68,4-72,1) al año y del 74,3% (i.c. del 95%: 72,5-76,0) a los 3 años. Se identificaron como posibles factores predictivos relacionados con el retraso del SR, el tratamiento neoadyuvante (cociente de riesgos instantáneos, hazard ratio, HR 0,75; i.c. del 95% 0,66-0,85), una pérdida de sangre > 300 mL (HR 0,86; i.c. del 95% 0,76-0,97), la fuga anastomótica (HR 0,41; i.c. del 95% 0,33-0,50), las categorías T3 (HR 0,63; i.c. del 95% 0,47-0,83) y T4 (HR 0,62; i.c. del 95% 0,42-0,90) y el estadio IV UICC (HR 0,57; i.c. del 95%: 0,41-0,80). CONCLUSIÓN: En una cuarta parte de los pacientes no se había cerrado el estoma derivativo tres años después de la resección de cáncer rectal con intención reconstructiva.

Validation of the Danish Colorectal Cancer Group (DCCG.dk) database - on behalf of the Danish Colorectal Cancer Group.

AIM: The aim of this study was to validate the clinical quality database of the Danish Colorectal Cancer Group. The validation is meant to focus on core data regarding staging of the disease, treatment provided, patient-related factors and key complications. METHOD: This was a database validation study assessing the completeness of the database and the accuracy of the data by re-entering core variables into an online module in a blinded fashion and comparing re-entered data with the original database data. A sample of 5% of patients from the years 2014-2017 was randomly selected. RESULTS: The sample of 936 patients was identified and data were re-entered. The completeness of the data retrieved was a median of 96%, 100% and 99% for preoperative, intra-operative and postoperative variables, respectively. The overall accuracy was a median of 95%. The least accurate variable was date of diagnosis (50% perfect agreement), with agreement rising to 96% when near matches defined as correct date ± 30 days were included. Intra-operative variables were of high quality, as were data on surgical complications including anastomotic leakage, where agreement was 97%. CONCLUSION: This was the first major validation of the Danish Colorectal Cancer Group's database. Overall, the completeness and quality of data were high, but the validation process also identified weaknesses, which can be crucial for future users to acknowledge and consider.

Overall risk and risk factors for metachronous peritoneal metastasis after colorectal cancer surgery: a nationwide cohort study.

BACKGROUND: This study aimed to identify the cumulative incidence and risk factors of metachronous peritoneal metastasis (M-PM) from colorectal cancer in patients who had intended curative treatment. METHODS: Patients with colorectal cancer were identified using the Danish Colorectal Cancer Group database for 2006-2015. The Danish Pathology Registry and the Danish National Patient Registry were used to identify M-PM to 2017. Risk factors were estimated by multivariable absolute risk regression, treating death and other cancers as competing risks. Overall risk and risk differences (RDs) were estimated at 1, 3 and 5 years. RESULTS: In 22 586 patients with colorectal cancer, the overall risk of M-PM was reported to be 0·9 (95 per cent c.i. 0·8 to 1·0) per cent at 1 year, 1·9 (1·8 to 2·1) per cent at 3 years and 2·2 (2·0 to 2·4) per cent at 5 years. Advanced tumour category ((y)pT4 versus (y)pT1) increased the RD of both M-PM (2·9 (95 per cent c.i. 2·1 to 3·7) at 1 year and 6·0 (4·9 to 7·2) at 3 years) and lymph node involvement ((y)pN2 versus (y)pN0) (2·5 (1·8 to 3·2) at year and 4·3 (3·2 to 5·3) at 3 years). No further increase in risk was observed at 5 years. In a subanalysis, tumour-involved resection margin (R1 versus R0) was associated with M-PM with a RD of 3·9 (1·6 to 6·2) at 1 year and 5·9 (2·6 to 9·3) at 3 years. CONCLUSION: The overall risk of M-PM in patients with colorectal cancer is low, but is increased in advanced T and N status. Follow-up of at least 3 years after colorectal cancer surgery may be necessary, given the potential curative treatment of early diagnosed M-PM.

ANTECEDENTES: Este estudio tuvo como objetivo identificar la incidencia acumulada y los factores de riesgo de metástasis peritoneales metacrónicas (metachronous peritoneal metastases, M-PM) del cáncer colorrectal en pacientes que se sometieron al tratamiento curativo previsto. MÉTODOS: Se identificaron los pacientes con cáncer colorrectal a partir de la base de datos del grupo danés de cáncer colorrectal (Danish Colorectal Cancer Group) durante el periodo 2006-2015. El Registro Danés de Patología (Danish Pathology Registry) y el Registro Nacional Danés de Pacientes (Danish National Patient Registry) se utilizaron para identificar los casos de M-PM hasta el 2017. Los factores de riesgo se estimaron mediante una regresión de riesgo absoluto multivariable, tratando la muerte y otros tipos de cáncer como riesgos competitivos. El riesgo general y las diferencias de riesgo (risk differences, RD) se estimaron a 1, 3 y 5 años. RESULTADOS: De los 22.586 pacientes con CCR, el riesgo global de M-PM fue del 0,9% (i.c. del 95%: 0,8 a 1,0) al año, 1,9 (i.c. del 95%: 1,8 a 2,1) a los 3 años y 2,2 (i.c. del 95%: 2,0 a 2.4) después de 5 años. El estadio T tumoral avanzado ((y) pT4 versus (y) pT1) aumentó el riesgo de M-PM, DR a 1 año: 2,9% (i.c. del 95%: 2,1 a 3,), 3 años: 6,0 (i.c. 95% 4,9 a 7,2), así como la afectación de los ganglios linfáticos ((y) pN2 versus (y) pN0), 1 año: 2,5 (i.c. 95% 1,8 a 3,2), 3 años: 4,3 (i.c. 95% 3,2 a 5,3). No se observó un aumento adicional en la DR después de 5 años. Los márgenes de resección tumoral (R1 versus R0) se asociaron con una DR a 1 año de 3,9 (i.c. del 95% 1,6 a 6,2), y a 3 años de 5,9 (i.c. del 95% 2,6 a 9,3) de riesgo de M-PM en un subanálisis. CONCLUSIÓN: El riesgo global de M-PM en el cáncer colorrectal en pacientes es bajo, pero aumenta en las categorías de estadios T y N avanzados. Puede ser necesario un seguimiento de al menos 3 años después de la cirugía de CCR, dado el tratamiento potencialmente curativo de la M-PM diagnosticada precozmente.

Nationwide cohort study of the impact of education, income and social isolation on survival after acute colorectal cancer surgery.

BACKGROUND: Acute colorectal cancer surgery has been associated with a high postoperative mortality. The primary aim of this study was to examine the association between socioeconomic position and the likelihood of undergoing acute versus elective colorectal cancer surgery. A secondary aim was to determine 1-year survival among patients treated with acute surgery. METHODS: All patients who had undergone a surgical procedure according to the Danish Colorectal Cancer Group (DCCG.dk) database, or who were registered with stent or diverting stoma in the National Patient Register from 2007 to 2015, were reviewed. Socioeconomic position was determined by highest attained educational level, income, urbanicity and cohabitation status, obtained from administrative registries. Co-variables included age, sex, year of surgery, Charlson Co-morbidity Index score, smoking status, alcohol consumption, BMI, stage and tumour localization. Logistic regression analysis was performed to determine the likelihood of acute colorectal cancer surgery, and Kaplan-Meier and Cox proportional hazards regression methods were used for analysis of 1-year overall survival. RESULTS: In total, 35 661 patients were included; 5310 (14·9 per cent) had acute surgery. Short and medium education in patients younger than 65 years (odds ratio (OR) 1·58, 95 per cent c.i. 1·32 to 1·91, and OR 1·34, 1·15 to 1·55 respectively), low income (OR 1·12, 1·01 to 1·24) and living alone (OR 1·35, 1·26 to 1·46) were associated with acute surgery. Overall, 40·7 per cent of patients died within 1 year of surgery. Short education (hazard ratio (HR) 1·18, 95 per cent c.i. 1·03 to 1·36), low income (HR 1·16, 1·01 to 1·34) and living alone (HR 1·25, 1·13 to 1·38) were associated with reduced 1-year survival after acute surgery. CONCLUSION: Low socioeconomic position was associated with an increased likelihood of undergoing acute colorectal cancer surgery, and with reduced 1-year overall survival after acute surgery.

ANTECEDENTES: La cirugía urgente del cáncer colorrectal se ha asociado con una mortalidad postoperatoria elevada. El objetivo principal de este estudio fue determinar la relación entre el estatus socioeconómico y la probabilidad de indicación de cirugía de cáncer colorrectal de forma urgente o electiva. El objetivo secundario fue determinar la supervivencia a 1 año en los pacientes tratados con cirugía urgente. MÉTODOS: Se revisaron todos los pacientes en los que se había realizado un procedimiento quirúrgico recogidos en la base de datos Danish Colorectal Cancer (DCCG.dk) o que se hubiera colocado una prótesis o efectuado un estoma de derivación que constasen en el National Patient Register entre 2007 y 2015. El estatus socioeconómico se estableció según el nivel más alto de educación alcanzado, los ingresos, el lugar de residencia y la situación de convivencia, datos que se obtuvieron de registros administrativos. Las covariables analizadas fueron el género, la edad, el año de la cirugía, el índice de comorbilidad de Charlson, el hábito tabáquico, el consumo de alcohol, el índice de masa corporal, el estadio y la localización del tumor. Se calcularon las regresiones logísticas según la probabilidad de cirugía de cáncer colorrectal urgente y se utilizó el método de Kaplan Meier y Cox para el análisis de la supervivencia global a 1 año. RESULTADOS: Se incluyeron 35.661 pacientes, de los que a 5.310 (15%) se realizó un procedimiento quirúrgico de urgencia. Los factores que se asociaron a cirugía urgente fueron un nivel educativo bajo o medio en menores de 65 años (razón de oportunidades, odds ratio, OR = 1,58, i.c del 95% 1,32-1,91 y OR = 1,34, i.c. del 95% 1,15-1,55, respectivamente), los bajos ingresos (OR = 1,12, i.c del 95% 1,01 -1,24) y vivir solo (OR = 1,35, i.c. del 95% 1,26-1,46). El 41,0% de los pacientes a los que se realizó cirugía urgente fallecieron en el primer año postoperatorio. Los factores asociados con una baja tasa de supervivencia al año de la cirugía urgente fueron un nivel educativo bajo (cociente de riesgos instantáneos, hazard ratio, HR = 1,18, i.c. del 95% 1,03-1,36), unos ingresos bajos (HR = 1,16, i.c. del 95% 1,01-1,34) y vivir solo (HR = 1,25, i.c. del 95% 1,13-1,38). CONCLUSIÓN: La probabilidad de ser sometido a cirugía urgente por un cáncer colorrectal y ver reducida la probabilidad de supervivencia en el primer año postoperatorio es mayor en pacientes con un estatus socioeconómico bajo.

Long-term efficacy and safety of tildrakizumab for moderate-to-severe psoriasis: pooled analyses of two randomized phase III clinical trials (reSURFACE 1 and reSURFACE 2) through 148 weeks.

BACKGROUND: Tildrakizumab is a specific anti-interleukin-23p19 monoclonal antibody approved for the treatment of plaque psoriasis. OBJECTIVES: To evaluate the long-term efficacy and safety of tildrakizumab treatment for patients with moderate-to-severe psoriasis for up to 148 weeks. METHODS: Pooled analysis from two double-blind, randomized controlled trials: reSURFACE 1 and reSURFACE 2. Efficacy was assessed for responders (≥ 75% improvement in Psoriasis Area and Severity Index; PASI 75) and partial responders (PASI 50-75) to tildrakizumab 100 mg and 200 mg at week 28 who were maintained on the same dose (administered every 12 weeks), and for partial responders or nonresponders (PASI < 50) to etanercept 50 mg at week 28 who, after a 4-week washout, were switched to tildrakizumab 200 mg (administered at weeks 32 and 36, and every 12 weeks thereafter). Safety was assessed in the all-patients-as-treated population. Three different methods of imputing missing data were used: nonresponder imputation (NRI), multiple imputation and observed cases. The Clinicaltrials.gov numbers are NCT01722331 (reSURFACE 1) and NCT01729754 (reSURFACE 2). RESULTS: At week 148 (NRI), 72·6%, 53·8% and 28·9% of tildrakizumab 100-mg responders and 80·2%, 59·9% and 32·6% of tildrakizumab 200-mg responders had PASI 75, 90 and 100 responses, respectively. For partial responders to tildrakizumab 100 mg and 200 mg, the proportions of patients achieving PASI 75, 90 and 100 responses were 32·5%, 25·0% and 10·0%; and 47·1%, 27·5% and 12·8%, respectively. For patients who were partial responders or nonresponders to etanercept, the proportions of patients achieving PASI 75, 90 and 100 responses were 66·9%, 43·8% and 14·9% at week 148. Rates of discontinuations due to adverse events [tildrakizumab 100 mg: 1·7 per 100 patient-years (PYs); tildrakizumab 200 mg: 1·2 per 100 PYs] and exposure-adjusted rates of serious adverse events (5·9 per 100 PYs; 5·5 per 100 PYs), severe infections (1·1 per 100 PYs; 1·1 per 100 PYs), malignancies (0·6 per 100 PYs; 0·4 per 100 PYs) and major adverse cardiovascular events (0·4 per 100 PYs; 0·5 per 100 PYs) were low. CONCLUSIONS: Tildrakizumab was well tolerated and efficacy was well maintained in week 28 responders who continued tildrakizumab treatment through 3 years, or improved among etanercept partial responders or nonresponders who switched to tildrakizumab. What's already known about this topic? Tildrakizumab 100 mg and 200 mg are efficacious and well tolerated with short-term use in the treatment of patients with moderate-to-severe plaque psoriasis. What does this study add? High levels of efficacy are maintained for up to 3 years of psoriasis treatment with tildrakizumab. There is a favourable long-term safety profile with both tildrakizumab 100 mg and 200 mg, with a low incidence of adverse events of special interest through 3 years.

Catchment properties and the photosynthetic trait composition of freshwater plant communities.

Unlike in land plants, photosynthesis in many aquatic plants relies on bicarbonate in addition to carbon dioxide (CO2) to compensate for the low diffusivity and potential depletion of CO2 in water. Concentrations of bicarbonate and CO2 vary greatly with catchment geology. In this study, we investigate whether there is a link between these concentrations and the frequency of freshwater plants possessing the bicarbonate use trait. We show, globally, that the frequency of plant species with this trait increases with bicarbonate concentration. Regionally, however, the frequency of bicarbonate use is reduced at sites where the CO2 concentration is substantially above the air equilibrium, consistent with this trait being an adaptation to carbon limitation. Future anthropogenic changes of bicarbonate and CO2 concentrations may alter the species compositions of freshwater plant communities.