Navigating beyond associations: Opportunities to establish causal relationships between the gut microbiome and colorectal carcinogenesis.

The gut microbiota has been recognized as an important determinant in the initiation and progression of colorectal cancer (CRC), with recent studies shining light on the molecular mechanisms that may contribute to the interactions between microbes and the CRC microenvironment. Despite the increasing wealth of associations being established in the field, proving causality remains challenging. Obstacles include the high variability of the microbiome and its context, both across individuals and across time. Additionally, there is a lack of large and representative cohort studies with long-term follow-up and/or appropriate sampling methods for studying the mucosal microbiome. Finally, most studies focus on CRC, whereas interactions between host and bacteria in early events in carcinogenesis remain elusive, reinforced by the heterogeneity of CRC development. Here, we discuss these current most prominent obstacles, the recent developments, and research needs.

The most important problems and needs of rasopathy patients with a noonan syndrome spectrum disorder.

BACKGROUND: Noonan syndrome spectrum disorders (NSSDs) constitute a group within the Rasopathies, and are one of the largest groups of syndromes with impact on multi-organ involvement known. The extreme variability of the clinical phenotype is, among others, due to the numerous different genes that are involved, and the differences in clinical presentation over the life span. We have studied the needs of patients and their relatives aiming to develop, evaluate and choose focus in research, medical care and policy to better meet their perspectives. METHODS: Using the participatory and interactive Dialogue method, 80 patients and relatives mentioned 53 different problems or needs (topics) that were categorized into eight themes. These themes and the topics within each theme, were subsequently prioritized by putting them in order of importance methodologically. RESULTS: The four highest prioritized themes were: (1) Physical problems (non-musculoskeletal related); (2) Social, emotional and behavioral problems; (3) Cognitive functioning and information processing; and (4) Problems related to the musculoskeletal system. Nineteen out of the 53 topics were physical problems. According to the total group of respondents, the top 3 prioritized topics within theme 1 were coagulation problems, heart problems, and feeding problems. Also data stratified by age groups, phenotype (NS and other NSSDs) and gender showed some remarkable results. For instance, feeding problems were prioritized as the most important topic of the highest prioritized theme, according to patients aged 0-12 years. Also feeding problems show a significant difference in its prioritization according to female patients (2) compared to male patients (7). On the other hand, heart problems were not mentioned in the top three prioritized topics in the youngest age groups, although heart problems are generally considered most important for patients with NSSD. CONCLUSIONS: With our results we underline the importance of methodologically inventorying the needs of NSSD patients, not only at the group level, but to also focus on specific needs according to e.g. age, phenotype and gender. For instance, it is remarkable that both the current Clinical Guidelines and the Noonan Syndrome diagnostic criteria give little to no attention to feeding problems, though our results indicate that, to the youngest patients, these problems have top priority. A similar situation appears to apply to the clinical management of e.g. coagulation, neuropsychological and musculoskeletal problems (like physiotherapy or occupational therapy) and to a need for (educational) tools to support patients at school or at work. Our study may help to shape targeted (clinical) management, research and policy inside and outside medical (research) institutes and shed light on the complex phenotypes of NSSDs, the families' and patients' perspectives on the everyday consequences of the many different problems, as well as their needs.

Genetic Diagnosis in Hereditary Hemochromatosis: Discovering and Understanding the Biological Relevance of Variants.

BACKGROUND: Hereditary hemochromatosis (HH) is a genetic disease, leading to iron accumulation and possible organ damage. Patients are usually homozygous for p. Cys282Tyr in the homeostatic iron regulator gene but may have mutations in other genes involved in the regulation of iron. Next-generation sequencing is increasingly being utilized for the diagnosis of patients, leading to the discovery of novel genetic variants. The clinical significance of these variants is often unknown. CONTENT: Determining the pathogenicity of such variants of unknown significance is important for diagnostics and genetic counseling. Predictions can be made using in silico computational tools and population data, but additional evidence is required for a conclusive pathogenicity classification. Genetic disease models, such as in vitro models using cellular overexpression, induced pluripotent stem cells or organoids, and in vivo models using mice or zebrafish all have their own challenges and opportunities when used to model HH and other iron disorders. Recent developments in gene-editing technologies are transforming the field of genetic disease modeling. SUMMARY: In summary, this review addresses methods and developments regarding the discovery and classification of genetic variants, from in silico tools to in vitro and in vivo models, and presents them in the context of HH. It also explores recent gene-editing developments and how they can be applied to the discussed models of genetic disease.

Validity of the Mini-Mental State Examination-2 in Diagnosing Mild Cognitive Impairment and Dementia in Patients Visiting an Outpatient Clinic in the Netherlands.

This study examined the utility of the recently published MMSE-2:SV in detecting cognitive impairment. We used receiver operating characteristics to test the discriminative power of the MMSE-2:SV for distinguishing between older adults without mild cognitive impairment (MCI) or dementia (n=67) and patients with MCI (n=76) or dementia (n=79). The results show that the MMSE-2:SV had excellent discriminative ability in distinguishing older controls from patients with dementia, with cut-off scores of 26 and 27 (max=30) yielding appropriate sensitivity (0.810 and 0.924, respectively) and specificity (0.940 and 0.806). Discriminative power was close to good in distinguishing between older controls and patients with MCI. Here, however, no optimal cut-off point could be determined. Even though this study shows good sensitivity and adequate specificity for the MMSE-2:SV in discriminating individuals without MCI or dementia from those with dementia, its validity is limited for identifying patients with MCI.

Attitude toward livestock farming does not influence the earlier observed association between proximity to goat farms and self-reported pneumonia.

Attitudes toward environmental risks may be a source of bias in environmental health studies because concerns about environmental hazards may influence self-reported outcomes. OBJECTIVE: The main aim was to assess whether earlier observed associations between proximity to goat farms and self-reported pneumonia were biased by participants' attitude toward farming. METHODS: We developed an attitude-score for 2,457 participants of the Dutch Livestock Farming and Neighbouring Residents' Health Study (veehouderij en gezondheid omwonenden) by factor analysis of 13 questionnaire items related to attitude toward livestock farming. Linear regression analysis was used to assess associations between attitude and potential determinants. The effect of attitude on the association between goat farm proximity and pneumonia was analyzed by evaluating (1) misclassification of the outcome, (2) effect modification by attitude, and (3) exclusion of participants reporting health problems due to farms in their environment. RESULTS: In general, the study population had a positive attitude toward farming, especially if participants were more familiar with farming. Older participants, females, ex-smokers, and higher-educated individuals had a more negative attitude. Both self-reported respiratory symptoms and exposure to livestock farms were associated with a more negative attitude. Misclassification of self-reported pneumonia was nondifferential with regard to participants' attitude. Furthermore, no indication was found that the association between proximity to goat farms and pneumonia was modified by attitude. Excluding subjects who attributed their health symptoms to livestock farms did also not change the association. CONCLUSIONS: The association between goat farm proximity and pneumonia was not substantially biased by study participants' attitude toward livestock farming.

Combination of a six microRNA expression profile with four clinicopathological factors for response prediction of systemic treatment in patients with advanced colorectal cancer.

BACKGROUND: First line chemotherapy is effective in 75 to 80% of patients with metastatic colorectal cancer (mCRC). We studied whether microRNA (miR) expression profiles can predict treatment outcome for first line fluoropyrimidine containing systemic therapy in patients with mCRC. METHODS: MiR expression levels were determined by next generation sequencing from snap frozen tumor samples of 88 patients with mCRC. Predictive miRs were selected with penalized logistic regression and posterior forward selection. The prediction co-efficients of the miRs were re-estimated and validated by real-time quantitative PCR in an independent cohort of 81 patients with mCRC. RESULTS: Expression levels of miR-17-5p, miR-20a-5p, miR-30a-5p, miR-92a-3p, miR-92b-3p and miR-98-5p in combination with age, tumor differentiation, adjuvant therapy and type of systemic treatment, were predictive for clinical benefit in the training cohort with an AUC of 0.78. In the validation cohort the addition of the six miR signature to the four clinicopathological factors demonstrated a significant increased AUC for predicting treatment response versus those with stable disease (SD) from 0.79 to 0.90. The increase for predicting treatment response versus progressive disease (PD) and for patients with SD versus those with PD was not significant. in the validation cohort. MiR-17-5p, miR-20a-5p and miR-92a-3p were significantly upregulated in patients with treatment response in both the training and validation cohorts. CONCLUSION: A six miR expression signature was identified that predicted treatment response to fluoropyrimidine containing first line systemic treatment in patients with mCRC when combined with four clinicopathological factors. Independent validation demonstrated added predictive value of this miR-signature for predicting treatment response versus SD. However, added predicted value for separating patients with PD could not be validated. The clinical relevance of the identified miRs for predicting treatment response has to be further explored.

Accuracy of MRI in Restaging Locally Advanced Rectal Cancer After Preoperative Chemoradiation.

BACKGROUND: Patients with a locally advanced rectal carcinoma benefit from preoperative chemoradiotherapy. MRI is considered the first choice imaging modality after preoperative chemoradiation, although its reliability for restaging is debatable. OBJECTIVE: The purpose of this study was to determine the accuracy of MRI in restaging locally advanced rectal cancer after preoperative chemoradiation. DESIGN: This was a retrospective study. SETTINGS: The study was conducted in a Dutch high-volume rectal cancer center. PATIENTS: A consecutive cohort of 48 patients with locally advanced rectal cancer treated with a curative intent was identified. MAIN OUTCOME MEASURES: Three readers independently evaluated the MRI both for primary staging and for restaging after preoperative chemoradiation and were blinded to results from the other readers as well as histological results. Interobserver variability was determined. Accuracy of the restaging MRI was assessed through the comparison of tumor characteristics on MRI with histopathologic outcomes. RESULTS: T stage was correctly predicted by the 3 readers in 47% to 68% and N stage in 68% to 70%. Overstaging was more common than understaging. Positive predictive values (PPV) among the 3 readers for T0 were 0%, and negative predictive values (NPVs) varied from 84% to 85%. For T1/2, PPVs and NPVs were 50% to 67% and 72% to 90%, and for T3/4 they were 54% to 62% and 33% to 78%. PPVs and NPVs for N0 stage were 81% to 95% and 58% to 73%. Tumor regression grade on MRI did not correspond with histopathologic tumor regression grade; PPVs for good response (tumor regression grade on MRI 1-2) were 48% to 61%, and NPVs were 42% to 58%. Interobserver agreement was fair to moderate for T stage, N stage, and tumor response (κ = 0.20-0.41) and fair to substantial for the relation with the mesorectal fascia (κ = 0.33-0.77). In none of the patients was the surgical plan changed after the restaging MRI. LIMITATIONS: This study was limited by its small sample size and retrospective nature. CONCLUSIONS: MRI has low accuracy for restaging locally advanced rectal cancer after preoperative chemoradiation, and the interobserver variability is significant.

Metabolic Health in Short Children Born Small for Gestational Age Treated With Growth Hormone and Gonadotropin-Releasing Hormone Analog: Results of a Randomized, Dose-Response Trial.

CONTEXT: Previously we showed that pubertal children born small for gestational age (SGA) with a poor adult height (AH) expectation can benefit from treatment with GH 1 mg/m(2) per day (∼ 0.033 mg/kg/d) in combination with 2 years of GnRH analog (GnRHa) and even more so with a double GH dose. GnRHa treatment is thought to have negative effects on body composition and blood pressure. Long-term effects and GH-dose effects on metabolic health in children treated with combined GH/GnRHa are unknown. OBJECTIVE: This study aimed to investigate body composition, blood pressure, and lipid profile during GH treatment, either with or without 2 years of additional GnRHa. To assess whether GH 2 mg/m(2) per day (∼ 0.067 mg/kg/d) results in a similar or even more favorable metabolic health at AH than GH 1 mg/m(2) per day. METHODS: This was a longitudinal, randomized, dose-response GH trial involving 107 short SGA children (58 girls) treated with GH until AH (GH randomized 1 or 2 mg/m(2)/d during puberty). Sixty-four children received additional GnRHa. At AH, metabolic parameters were compared between children treated with combined GH/GnRHa and those with only GH. The GH dose effect on metabolic health was evaluated in a subgroup of 47 children who started GH treatment in early puberty (randomized 1 or 2 mg/m(2)/d) with 2 years of GnRHa. RESULTS: At AH, fat mass percentage (FM%) SD score (SDS), lean body mass (LBM) SDS, blood pressure SDS, and lipid profile were similar between children treated with combined GH/GnRHa and those with only GH. In the pubertal subgroup, FM% SDS was lower during treatment with GH 2 mg/m(2) per day. There was no GH dose-dependent effect on LBM SDS, blood pressure, and lipid profile. CONCLUSIONS: Combined GH/GnRHa treatment has no long-term negative effects on metabolic health compared with only GH. Started in early puberty, a GH dose of 2 mg/m(2) per day results in a similar metabolic health at AH and a more favorable FM% than GH 1 mg/m(2) per day.

Outpatient cataract surgery: incident and procedural risk analysis do not support current clinical ophthalmology guidelines.

OBJECTIVE: To evaluate whether an ophthalmologist-led, non-anesthesia-supported, limited monitoring pathway for phacoemulsification/intraocular lens cataract surgery, can be performed safely with only a medical emergency team providing support. DESIGN: Retrospective, observational, cohort study. PARTICIPANTS: All patients who underwent elective phacoemulsification/intraocular lens surgery under topical anesthesia in the ophthalmology outpatient unit between January 1, 2011, and December 31, 2012. METHODS: Cataract surgery was performed by phacoemulsification under topical anesthesia. The intake process mainly embraced ophthalmic evaluation, obtaining a medical history, and proposing the procedure. A staff ophthalmologist performed the procedure assisted by 2 registered nurses in an independent outpatient clinic operating room within the hospital. The clinical pathway was without dedicated presence of or access to anesthesia service. Perioperative monitoring was limited to blood pressure and plethysmography preoperatively and intraoperatively. Patients were offered supportive care and instructed to avoid fasting and continue all their chronic medication. MAIN OUTCOME MEASURES: The primary outcome measure was the incidence of adverse events requiring medical emergency team (MET) interventions throughout the pathway. Secondary outcome measures were surgical ocular complication rates, use of oral sedatives, and reported reasons to perform the surgery in the classical operation room complex. RESULTS: Within the cataract pathway, 6961 cases (4347 patients) were eligible for analysis. Three MET interventions related to the phacoemulsification/intraocular lens pathway occurred in the 2-year study period, resulting in an intervention rate of 0.04%. None of the interventions was intraoperative. All 3 patients were diagnosed as vasovagal collapse and recuperated uneventfully. No hospital admittance was required. Eight other incidents occurred within the general ophthalmology outpatient unit population during the study period. CONCLUSIONS: Cataract surgery can be safely performed in an outpatient clinic, in the absence of the anesthesia service and with limited workup and monitoring. Basic first aid and basic life support skills seem to be sufficient in case of an adverse event. An MET provides a generous failsafe for this low-risk procedure.

High prevalence of intratesticular varicocele in a post-orchidopexy cohort.

PURPOSE: Intratesticular varicocele (ITV) is an uncommon sonographic finding. A prevalence of up to 2% has been reported in men with testicular problems. In a cohort of men who had undergone prepubertal orchidopexy for acquired undescended testis, several cases of ITV were found. The aim of this study was to analyse the prevalence and clinical aspects of ITV in this cohort. METHODS: In a long-term follow-up study of position and growth of undescended testis after prepubertal orchidopexy, ultrasonography was used to identify men with ITV. Data on clinical presentation, testicular volume, and the location, size and Doppler aspects of intratesticular varicocele were collected and analysed. RESULTS: Of the 105 men, 9 were identified with ITV (8.6%). In all patients, the side of orchidopexy correlated with the side of the ITV, and all were left-sided. The testis with ITV had a smaller volume than the testis without ITV (p = 0.026). CONCLUSIONS: A remarkably high prevalence of ITV (8.6%) was found as well as a smaller volume of the testes with ITV in a cohort of men who had undergone prepubertal orchidopexy for acquired undescended testis.

Cancer cells in epithelial-to-mesenchymal transition and tumor-propagating-cancer stem cells: distinct, overlapping or same populations.

Cell populations of solid cancers and their distant models, the cancer cell lines, have been categorized in sub-populations: cancer stem-tumor-propagating cells (CSC-TPC) versus derived cells, epithelial- versus mesenchymal-type cells, dormant versus actively proliferating cells and so on. CSC-TPC are minimally defined by their operational properties: immortality and the ability to regenerate in vivo or in vitro the whole panel of cancer cells. The epithelial-to-mesenchymal transition (EMT), mostly observed in vitro, generates mesenchymal-type from epithelial-type cells. The converse transition is mesenchymal-to-epithelial transition. In vitro work suggests that CSC-TPC and EMT cell phenotypes overlap. An analysis of the properties of these sub-populations, as studied in vitro, shows that indeed these two phenotypes may be linked to some extent. However, the in vivo counterpart of this relation in human tumors has barely been investigated. A model in which among the EMT cells released from the tumor only the most competent CSC-TPC will succeed to metastasize is proposed. It is suggested that in the Darwinian evolution of cancer cells, many phenotypes reflecting the expression of various programs, reversible to irreversible, exclusive, overlapping or linked coexist and compete with each other.

Pilot study of a three-step diagnostic pathway for young and old patients with Parkinson's disease dementia: screen, test and then diagnose.

OBJECTIVE: To pilot a three-step diagnostic model for young and old patients with Parkinson's disease dementia (PDD). METHODS: Prospective investigator-blinded study. We developed a screening questionnaire for patients with Parkinson's disease (PD) and their caregivers. Further, patients were subjected to three screening instruments (Montreal Cognitive Assessment (MoCA), Frontal Assessment Battery (FAB), Addenbrooke's Cognitive Examination-revised (ACE-R) and a detailed neuropsychological examination (NPE). Based on the NPE, patients were divided in a PD (without dementia) and a PDD-group. RESULTS: Forty-one PD patients, aged 37-94 years, participated in this study. Patients were divided in a young group, < or = 65 (n = 22) and an old group >65 years (n = 19). In the young group (PDD, n = 5) the patient-screening questionnaire predicted PDD with a sensitivity/specificity of 100.0%/94.1%; in the old group (PDD, n = 10) the proxy-screening questionnaire predicted PDD with a sensitivity/specificity of 88.9%/66.7%. In the young group, ACE-R had the largest Area Under the Curve (AUC) 0.88 (0.70-1.00), in the old group MoCA (AUC 1.00). However, the three instruments did not differ significantly. CONCLUSIONS: It seems feasible and efficient to use three consecutive diagnostic steps for PDD: (1) a screening questionnaire, (2) if positive: MoCA, FAB or ACE-R as screening instrument and (3) if positive: a detailed NPE for diagnosing PDD.

Assessment of psychomotor development before and after strabismus surgery for infantile esotropia.

PURPOSE: To assess motor and mental development before and after strabismus surgery in children with infantile esotropia. PATIENTS AND METHODS: Mental and motor development indexes of 20 children with infantile esotropia without neurologic abnormalities and 17 age-matched healthy control subjects were prospectively tested at regular intervals before and after strabismus surgery with the Dutch version of the Bayley and ordinal scales of infant development. RESULTS: The mean age for surgery in the study group was 13.5 months. Before strabismus surgery, the Bayley scales of infant development showed a significant delay in both mental (P < .045) and motor (P < .008) development for children with infantile esotropia compared with the control group. Three weeks after surgery, the delay in mental development had disappeared. The delay in motor development persisted for months. Two of the 7 ordinal scales--object permanence (P < .01) and means-end (P < .036)--showed a statistically significant delay for children with infantile esotropia. Three weeks after strabismus surgery, there was no difference between the study group and the control group. CONCLUSIONS: Children with infantile esotropia had delayed motor and mental development compared with healthy children. After strabismus surgery, patients recovered mentally, but their motor delays persisted for months when tested with the Bayley scales of infant development.

[Questionnaires on the quality of life in other than the Dutch language used in the Nederlands Tijdschrift voor Geneeskunde (Dutch Journal of Medicine): the translation procedure and arguments for the choice of the questionnaire]. / Niet-Nederlandse vragenlijsten over levenskwaliteit gebruikt in het Nederlands Tijdschrift voor Geneeskunde: vertaalprocedure en argumenten voor de keuze van de vragenlijst.

OBJECTIVE: To determine how the authors of research published in the Nederlands Tijdschrift voor Geneeskunde (Dutch Journal of Medicine; NTvG) translated the questionnaires that they used in other than the Dutch language and to review the arguments on the basis of which the authors chose the questionnaires used. DESIGN: Bibliometric study and a survey. METHOD: All of the authors who had published an article in the NTvG up to and including January 2006 in which a questionnaire was used that was originally not in the Dutch language were approached by means ofa survey. In this survey, they were asked about the translation procedure and the factors that had contributed to the choice of the particular questionnaire. RESULTS: The authors of 38 articles in which a translated non-Dutch questionnaire had been used returned 31 survey forms (response: 82%). Among the 31 authors, who had used a total of 39 questionnaires, 24 (77%) were aware of the proper translation procedure. Of the 9 authors who had translated the questionnaire themselves, 6 had used the technique of translation and back-translation. In the choice of the questionnaire used, an important factor for many authors (64%) was the use of the questionnaire in previously published comparable research. CONCLUSION: A large proportion of the authors (77%) was aware of the current guidelines for the translation of questionnaires.

Empirical investigation of extreme single-particle behavior of nuclear quadrupole moments in highly collective A approximately 150 superdeformed bands.

The intrinsic quadrupole moment Q(0) of superdeformed rotational bands in A approximately 150 nuclei depends on the associated single-particle configuration. We have derived an empirical formula based on the additivity of effective quadrupole moments of single-particle orbitals that describes existing measurements from (142)Sm to (152)Dy. To further test the formula, the predicted Q(0) moments for two superdeformed bands in (146)Gd of 14.05 eb were confronted with a new measurement yielding 13.9+/-0.4 eb and 13.9+/-0.3 eb, respectively. This excellent agreement provides empirical evidence of extreme single-particle behavior in highly deformed, collective systems.