Multiple imputation in data that grow over time:A comparison of three strategies

Multiple imputation is a recommended technique to deal with missing data. We study the problem where the investigator has already created imputations before the arrival of the next wave of data. The newly arriving data contain missing values that need to be imputed. The standard method (RE-IMPUTE) is to combine the new and old data before imputation, and re-impute all missing values in the combined data. We study the properties of two methods that impute the missing data in the new part only, thus preserving the historic imputations. Method NEST multiply imputes the new data conditional on each filled-in old data (Formula presented.) times. Method APPEND is the special case of NEST with (Formula presented.) thus appending each filled-in data by single imputation. We found that NEST and APPEND have the same validity as RE-IMPUTE for monotone missing data-patterns. NEST and APPEND also work well when relations within waves are stronger than between waves and for moderate percentages of missing data. We do not recommend the use of NEST or APPEND when relations within time points are weak and when associations between time points are strong

Vaccines for mucosal immunity to combat emerging infectious diseases.

The mucosal immune system consists of molecules, cells, and organized lymphoid structures intended to provide immunity to pathogens that impinge upon mucosal surfaces. Mucosal infection by intracellular pathogens results in the induction of cell- mediated immunity, as manifested by CD4-positive (CD4 + ) T helper-type 1 cells, as well as CD8 + cytotoxic T-lymphocytes. These responses are normally accompanied by the synthesis of secretory immunoglobulin A (S-IgA) antibodies, which provide an important first line of defense against invasion of deeper tissues by these pathogens. New-generation live, attenuated viral vaccines, such as the cold-adapted, recombinant nasal influenza and oral rotavirus vaccines, optimize this form of mucosal immune protection. Despite these advances, new and reemerging infectious diseases are tipping the balance in favor of the parasite; continued mucosal vaccine development will be needed to effectively combat these new threats

Young offenders caught in the act:A population-based cohort study comparing internationally adopted and non-adopted adolescents

Empirical research has shown an elevated risk for externalizing behavior problems in international adoptees. To address the extent to which this risk exists for more serious externalizing problems we compared the rates of registered criminal offending of internationally adopted adolescents with those of non-adopted adolescents in the Netherlands. In a large population-based cohort study (N = 3,758,506 including n = 10,563 international adoptees) on Dutch youth with ages up to 19 years we examined registrations in the program on juvenile crime and in the national police system from 2005 to 2013. Controlling for time lapse and background variables we found that international adoptees had been in contact with the criminal justice system more frequently than non-adoptees. However, the findings differed across region of adoption: Adoptees from South America and from Africa had been in contact with the criminal justice system most frequently (and more often than non-adoptees), whereas adoptees from China (total n = 4569) had the least contacts (and less often than non-adoptees). The percentages of criminal offending of adoptees ranged between 1.16% and 15.83% across regions of adoption (versus 10.86% in non-adoptees). The large majority of adoptees – including those from South America and Africa – were not involved in criminal acts. We hypothesize that the higher and lower risks of criminal offending found for adoptees from certain countries are associated with the varying levels of pre-adoption adversity (e.g., neglect and abuse) that the adoptees have experienced

The oncological outcomes of isolated limb perfusion and neo-adjuvant radiotherapy in soft tissue sarcoma patients:A nationwide multicenter study

Introduction: Patients with locally extensive high-grade extremity soft tissue sarcomas (eSTS) are often presented in multidisciplinary teams to decide between ablative surgery (amputation) or limb-salvage surgery supplemented with either neo-adjuvant radiotherapy (RT) or induction isolated limb perfusion (ILP). In The Netherlands, ILP typically aims to reduce the size of tumors that would otherwise be considered irresectable, whereas neo-adjuvant RT aims mainly at improving local control and reducing morbidity of required marginal margins. This study presents a 15-year nationwide cohort to describe the oncological outcomes of both pre-operative treatment strategies. Methods: All consecutive patients with locally extensive primary high-grade eSTS surgically treated between 2000 and 2015 at five tertiary sarcoma centers that received neo-adjuvant ILP or RT were included. 169 patients met the inclusion criteria (89 ILP, 80 RT). Median follow-up was 7.3 years. Results: Limb salvage was achieved in 84% of cases in the ILP group (80% for patients with amputation indication) and 96% of cases in the RT group. 5-Year overall survival was 47% in the ILP group, 69% in the RT group. 5-Year local recurrence rate was 14% in the ILP group, 10% in the RT group. Distant metastasis rate was 55% in the ILP group, 36% in the RT group. Conclusion: We find oncological outcomes and limb salvage rates in line with existing literature for both treatment modalities. Whether the tumor was locally advanced with an indication for induction therapy to prevent amputation or morbid surgery appeared to be the main determinant in choosing between neo-adjuvant ILP or RT

Blood and brain biochemistry and behaviour in NTBC and dietary treated tyrosinemia type 1 mice

Tyrosinemia type 1 (TT1) is a rare metabolic disease caused by a defect in the tyrosine degradation pathway. Neurocognitive deficiencies have been described in TT1 patients, that have, among others, been related to changes in plasma large neutral amino acids (LNAA) that could result in changes in brain LNAA and neurotransmitter concentrations. Therefore, this project aimed to investigate plasma and brain LNAA, brain neurotransmitter concentrations and behavior in C57 Bl/6 fumarylacetoacetate hydrolase deficient (FAH-/-) mice treated with 2-(2-nitro-4-trifluoromethylbenoyl)-1,3-cyclohexanedione (NTBC) and/or diet and wild-type mice. Plasma and brain tyrosine concentrations were clearly increased in all NTBC treated animals, even with diet (p <0.001). Plasma and brain phenylalanine concentrations tended to be lower in all FAH-/- mice. Other brain LNAA, were often slightly lower in NTBC treated FAH-/- mice. Brain neurotransmitter concentrations were usually within a normal range, although serotonin was negatively correlated with brain tyrosine concentrations (p <0.001). No clear behavioral differences between the different groups of mice could be found. To conclude, this is the first study measuring plasma and brain biochemistry in FAH-/- mice. Clear changes in plasma and brain LNAA have been shown. Further research should be done to relate the biochemical changes to neurocognitive impairments in TT1 patients

Systematic Review of Factors Affecting Quality of Life After Cytoreductive Surgery with Hyperthermic Intraperitoneal Chemotherapy

Background: Previous studies have shown that, overall, quality of life (QoL) decreases within the first 3–6 months after cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS + HIPEC), returning to baseline levels by 6–12 months. This systematic review aims to evaluate the factors affecting QoL after CRS + HIPEC within 12 months of surgery. Methods: Electronic databases were investigated searching for articles reporting QoL with validated questionnaires up to September 2019. Risk of bias was assessed with the methodological index for non-randomized studies tool. The primary outcomes were short-term (< 6 months after surgery) and medium-term (6–12 months after surgery) determinants of QoL after CRS + HIPEC. Secondary outcomes were QoL and reported symptoms over time. Results: We included 14 studies that used 12 different questionnaires. The reported data were collected prospectively or retrospectively for 1556 patients (dropout < 50% in four studies). Overall, studies showed diminished QoL within 3 months after surgery and a recovery to baseline or greater by 12 months. QoL was negatively influenced by higher age, female sex, prolonged operation time, extensive disease, residual disease, adjuvant chemotherapy, complications, stoma placement, and recurrent disease. QoL results were comparable between studies, with dropout rates above and below 50%. Conclusions: QoL returns to baseline levels within 12 months after CRS + HIPEC provided the disease does not recur, and this recovery process is influenced by several factors

Diagnostic Laparoscopy as a Selection Tool for Patients with Colorectal Peritoneal Metastases to Prevent a Non-therapeutic Laparotomy During Cytoreductive Surgery

OBJECTIVE: The aim of this study was to evaluate the introduction of diagnostic laparoscopy (DLS) in patients with colorectal peritoneal metastases (PM) to prevent non-therapeutic laparotomies during cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS + HIPEC). METHODS: Patients with histologically proven colorectal PM who underwent a laparotomy for potential CRS + HIPEC from January 2006 to January 2019 were retrospectively identified from a prospectively maintained database. In 2012, DLS was introduced in the preoperative work-up for CRS + HIPEC in our academic center. The rates of non-therapeutic laparotomies, major postoperative complications (Clavien-Dindo grade III or higher), and survival outcomes were investigated for patients who underwent a laparotomy before (cohort A) and after (cohort B) the introduction of DLS. In cohort B, the reasons to refrain from DLS were retrospectively explored from medical records. RESULTS: Overall, 172 patients were included [cohort A: 48 patients (27.9%); cohort B: 124 patients (72.1%)]. A significant drop in the rate of non-therapeutic laparotomies occurred in cohort B compared with cohort A (21.0 vs. 35.4%: p = 0.044), despite only 85 patients (68.5%) from cohort B undergoing DLS in our academic center. The most important reason to refrain from DLS was a recently performed DLS or laparotomy in the referring hospital (48.7%). Major postoperative complications, in-hospital mortality, and survival outcomes were similar for both cohorts. CONCLUSIONS: Performing DLS during the preoperative work-up for CRS + HIPEC prevents non-therapeutic laparotomies in patients with colorectal PM. We recommend performing this laparoscopic screening in an experienced HIPEC center

Catalytic activity of the membrane-bound methylcholanthrene-inducible cytochrome P-450

AbstractThe benzopyrene hydroxylase activity of the methylcholanthrene-inducible form of cytochrome P-450 (P-448) has been studied in native and reconstituted liver microsomal membranes. The data obtained show that the molecular catalytic activity of membrane-bound cytochrome P-448 depends on the molar ratio of the cytochrome to NADPH-cytochrome P-450 reductase and that the optimal ratio for maximal activity of cytochrome P-448 in the microsomal membrane essentially differs from the equimolar one