Avoiding selection bias in metabolomics studies: a tutorial.

BACKGROUND: Metabolomics techniques are increasingly applied in epidemiologic research. Many available assays are still relatively expensive and therefore measurements are often performed in small patient population studies such as case series or case-control designs with strong participant selection criteria. Subsequently, metabolomics data are frequently used to assess secondary associations for which the original study was not explicitly designed. Especially in these secondary analyses, there is a risk that the original selection criteria and the conditioning that takes place due to this selection are not properly accounted for which can lead to selection bias. AIM OF REVIEW: In this tutorial, we start with a brief theoretical introduction on the issue of selection bias. Subsequently, we demonstrate how selection bias can occur in metabolomics studies by means of an investigation into associations of metabolites with total body fat in a nested case-control study that was originally designed to study effects of elevated fasting glucose. KEY SCIENTIFIC CONCEPTS OF REVIEW: We demonstrate that standard analytical methods, such as stratification or adjustment in regression analyses, are not suited to deal with selection bias and may even induce the bias when analysing metabolite-phenotype relationships in selected groups. Finally, we show that inverse probability weighting, also known as survey weighting, can be used in some situations to make unbiased estimates of the outcomes.

The cardiothoracic ratio on post-mortem computer tomography.

In clinical practice, the cardiothoracic ratio (CTR) was first utilized on plain chest radiography, and subsequently with computed tomography (CT) to diagnose cardiomegaly with a threshold of 0.5. Using CTR in forensic practice could help to detect cardiomegaly on post-mortem CT (PMCT) prior to the autopsy. However, an adaption of the threshold could be necessary because of post-mortem changes. Our retrospective study aimed to measure the CTR on PMCT and test the possible influence of variables. We selected 109 autopsy cases in which the heart weight was within normal limits. A forensic pathologist and a radiologist measured separately the CTR on axial and scout views on PMCT. We tested the statistical concordance between the two readers and between the axial and scout view and identified factors that could be associated with a modification of the CTR. The CTR measurements revealed an overestimation of the measurements made on scout compared to axial view. The inter-reader correlation was very high for both views. Among the different variables statistically tested, heart dilatation and body mass index (BMI) were the only two factors statistically associated with an augmentation of the CTR. The CTR can be useful in the diagnosis of cardiomegaly on PMCT. However, dilatation of the cardiac chambers caused by acute heart failure may be misinterpreted radiographically as cardiomegaly. Inter-observer reliability in our study was very high. CTR may be overestimated when measured on the scout view. Further investigations with larger cohorts, including cases with cardiac hypertrophy, are necessary to better understand the relationship between radiological CTR and the morphology of the heart.

The joint contribution of tumor phenotype and education to breast cancer survival disparity between Hispanic and non-Hispanic white women.

Some studies suggest that Hispanic women are more likely to have ER- and triple-negative (ER-/PR-/HER2-) tumors and subsequently poorer prognosis than non-Hispanic white (NHW) women. In addition, only a handful of studies have examined period-specific effects of tumor phenotype and ethnicity on breast cancer survival, leaving the time-varying effects of hormonal status and ethnicity on breast cancer survival poorly defined. This study describes short and long-term breast cancer survival by ethnicity at 0-5 years and 5+ years post-diagnosis using data from the New Mexico Health, Eating, Activity, and Lifestyle cohort of Hispanic and NHW women ages 29-88 years newly diagnosed with stages I-IIIA breast cancer. The survival rate for Hispanics at 0-5 years was 82.2 % versus 94.3 % for NHW. Hispanics were more likely to have larger tumors, more advanced stage, and ER- phenotypes compared to NHW women. There was a significantly higher risk of breast cancer mortality in Hispanics over 5 years of follow-up compared to NHW (HR = 2.78, 95 % CI 1.39-5.56), adjusting for age, tumor phenotype, stage, and tumor size. This ethnic difference in survival, however, was attenuated and no longer statistically significant when additional adjustment was made for education, although a >1.5-fold increase in mortality was observed. In contrast, there was no difference between ethnic groups for survival after 5 years (HR = 1.08, 95 % CI 0.36-3.24). Our results indicate that the difference in survival between Hispanic and NHW women with breast cancer occurs in the first few years following diagnosis and is jointly associated with tumor phenotype and socio-demographic factors related to education.

Prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) in a middle-aged population with overweight and normal liver enzymes, and diagnostic accuracy of noninvasive proxies.

The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) is increasing at an alarming rate. Elevated liver enzymes are a primary reason to refer patients for further testing. However, liver enzymes within the normal range do not exclude the presence of MASLD. We examined the prevalence of MASLD in a middle-aged population with overweight and normal liver enzymes. In addition, we examined the accuracy of 4 sets of noninvasive proxies for MASLD. We included 1017 participants from the Netherlands epidemiology of obesity cohort study with body mass index ≥25 kg/m2 and liver enzymes (asparate aminotransferase, alanine aminotransferase, gamma-glutamyltranspeptidase) within normal range. The diagnostic accuracy of biomarker scores (fatty liver index, liver fat score [LFS], STEATO-ELSA, and hepatic steatosis index) was determined against elevated hepatic triglyceride content measured by 1proton magnetic resonance spectroscopy. Participants (mean age 56 years, 49% women), had a median body mass index of 29.6 kg/m2 and a median hepatic triglyceride content of 4.4%. MASLD was present in 42% of participants and was more common in men than women, with respectively 47% and 36% being affected. The LFS showed the highest accuracy with an area under the curve of 0.72. We identified metabolic syndrome as the prime predictor for MASLD with an odds ratio of 2.95 (95% confidence interval 2.20-3.98). The prevalence of MASLD in middle-aged men and women with overweight and liver enzymes within the normal range is over 40%. LFS showed the highest accuracy to detect MASLD, but, overall, biomarker scores performed relatively poor. The presence of metabolic syndrome was the prime predictor of MASLD.

[Development of a protocol for counseling patients starting with oral hypoglycemic agents]. / Développement d'un protocole pour l'accompagnement de la première délivrance des antidiabétiques oraux.

INTRODUCTION: Counseling of patients filling a first prescription is an essentiaL aspect of pharmaceutical care. The use of a protocol summarizing all relevant counseling aspects can be a useful tool to standardize pharmaceutical care and to promote impLementation. AIM: (1) To develop a protocol for counseling of patients starting with oral hypoglycaemic agents (OHA), and (2) to investigate current provision of counseling for these patients in Belgian community pharmacies. METHOD: Based on literature, a consensus meeting with community pharmacists and consultation with physicians, we developed a protocol for counseling patients starting OHA. Additionally, an observational study of current provision of counseling for patients starting OHA was performed in 90 community pharmacies. RESULTS: All pharmacists reported to provide the most important item of our protocol, i.e. dose and timing of OHA intake. All other protocol items were provided by a smaller proportion of pharmacists: indication (by 64.4% of pharmacists), mechanism of action (30.0%), what to do if a dose is missed (3.3%), side effects (34.4%), hypoglycaemia (24.4%) and Lifestyle advice (68.9%). About 45% of pharmacists reported to give written drug information to patients starting OHA. Reduction of the administrative workload was most frequently mentioned as measure to spend more time on patient counseling. The majority of pharmacists considered our protocol as feasible and appLicabLe in daily pharmacy practice. CONCLUSION: This study found that current counseLing practices for patients starting OHA can be improved. Our protocol could be a useful and feasible tool to facilitate implementation of first prescription counseling.

Higher severity grade of erlotinib-induced rash is associated with lower skin phototype.

BACKGROUND: Epidermal growth factor receptor inhibitors (EGFRIs) are associated with a characteristic papulopustular rash, an adverse event considered to be a class effect of these agents. Erlotinib, a small-molecule EGFRI, causes a papulopustular rash in 68-75% of patients. The limited reported data suggest that deleterious effects of ultraviolet radiation (UVR) may enhance the development of EGFRI-induced rash. Because the level of the biological pigment melanin correlates with increased protection against UVR, we hypothesized that lighter levels of skin pigmentation are associated with greater severity of rash. AIM: To characterize the relationship between skin phototype (SPT) and rash severity. METHODS: A retrospective chart review was conducted of 40 patients on erlotinib. Skin sensitivity to UVR was categorized using the Fitzpatrick SPT classification scheme. Grading of rash was performed using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), version 3. RESULTS: There was an inverse relationship between SPT and rash severity. Grade 0 was seen in the majority of patients with SPT V/VI, grade 1/2 in the majority of patients with SPT III/IV, and grade 3/4 rash in the majority of patients with SPT I/II (grade 0: 7% SPT I/II, 32% SPT III/IV and 50% SPT IV/V; grade 1/2: 33%, 63% and 50%, respectively; grade 3/4: 60%, 5% and 0%, respectively) (P < 0.01, Fisher exact test). CONCLUSIONS: Prevention and management of cutaneous side-effects from EGFR inhibitors is important to achieve maximum patient compliance and therapeutic benefit. The results of this study suggest that SPT may be an independent predictive factor for EGFRI-induced papulopustular rash, thus pre-therapy counselling and early intervention are important.

Comparison between coelioscopy and coeliotomy for liver biopsy in channel catfish.

OBJECTIVE: To evaluate endoscopic liver biopsy and compare that technique with a standard coeliotomy biopsy technique in fish. DESIGN: Randomized controlled clinical trial. ANIMALS: 30 channel catfish (Ictalurus punctatus). PROCEDURES: 10 fish were randomly assigned into control, coeliotomy, and coelioscopy groups. Anesthesia was performed with a recirculating anesthesia machine. Body weight, PCV, and total protein (TP) concentration in blood as well as plasma activities of aspartate aminotransferase, creatinine phosphokinase, lactate dehydrogenase, and sorbitol dehydrogenase were measured before and after surgery. Standard ventral coeliotomy or coelioscopy was performed, and the biopsy specimens were scored histologically. RESULTS: Coeliotomy and coelioscopy procedures were well tolerated without acute deaths. Blood TP concentration and PCV decreased after surgery in the coelioscopy group because of intracoelomic fluid administration to aid visualization. Minor changes in activities for hepatic and muscular enzyme activities were apparent, but were not significantly different between the coelioscopy and coeliotomy groups. Coelioscopy and coeliotomy yielded biopsy specimens of similar diagnostic quality. However, coelioscopy permitted a more extensive evaluation of the viscera, and all 10 surgical wounds healed completely, compared with severe wound dehiscence in 3 of 10 fish that underwent coeliotomy. CONCLUSIONS AND CLINICAL RELEVANCE: Both coelioscopy and coeliotomy were capable of yielding antemortem liver biopsy specimens of diagnostic quality in catfish. Coelioscopy permitted a more detailed examination of the coelomic viscera through a smaller surgical incision, was less traumatic, and resulted in decreased wound dehiscence.

Follicular mycosis fungoides: a histopathologic, immunohistochemical, and genotypic review.

Follicular mycosis fungoides (FMF) is a recognized variant of mycosis fungoides. In this review, the authors characterize the distinct histopathological and immunohistochemical patterns of FMF that have been reported in the literature. This article is an extensive review of the literature cited in Medline and own data of the authors. The major patterns of FMF histopathology, immunohistochemistry, and molecular genetics are summarized in this review. Histologically, the quintessential finding in FMF is small to medium atypical CD3+ CD4+ CD8- T lymphocytes around and within the epithelium of the hair follicles. This finding is requisite to the diagnosis. However, this finding may be obscured by a host of other patterns often identified in FMF. This includes basaloid folliculo-lymphoid hyperplasia, a granulomatous reaction, eosinophilic folliculitis, and follicular cystic changes with subtle atypical lymphocytes in the cyst wall. Follicular mucinosis (MF) and syringo-tropism are also variably present. Immunohistochemistry of all reported cases uniformly show a CD4+ T cell infiltrate. This review emphasizes and discusses the broad spectrum of histologic changes which may be seen in FMF, clues to the diagnosis, and some potential mimickers.

Inhibition of human malignant neuroblastoma cell DNA synthesis by lipoxygenase metabolites of arachidonic acid.

In vivo studies have shown that inhibitors of cyclooxygenase metabolism of arachidonic acid may diminish growth and metastasis of certain tumors. Because cyclooxygenase inhibition may increase the production of lipoxygenase products of arachidonic acid metabolism, we have investigated the effect of two such products, 12-hydroxyeicosatetraenoic acid (12-HETE) and 15-hydroxyeicosatetraenoic acid (15-HETE) on tumor cell proliferation in vitro. When neuroblastoma cells (SK-N-SH) in culture were treated with 12-HETE for 18 hr, incorporation of [3H]thymidine was inhibited up to 64% at concentrations from 20 to 50 microM. Under the same conditions, 15-HETE resulted in inhibition of up to 46%, while arachidonic acid had no apparent effect. When evaluated in the presence of serum, 12-HETE at a concentration of 120 microM produced a 20.6 +/- 2.8% (S.E.) inhibition of the increase in total DNA content over 48 hr, while 15-HETE at this concentration produced a 16.5 +/- 5.3% inhibition. We conclude that 12-HETE, the product of platelet lipoxygenase, and 15-HETE, a product of neutrophil and lymphocyte lipoxygenases, can inhibit human neuroblastoma cell growth in vitro and may play a role in the effect of cyclooxygenase inhibitors on tumor growth in vivo.

Effect of ice on pain after corticosteroid injection in the hand and wrist: a randomized controlled trial.

This prospective, randomized controlled study was designed to determine if applying ice to the site of corticosteroid injections in the hand and wrist reduces post-injection pain. Patients receiving corticosteroid injections in the hand or wrist at a tertiary institution were enrolled. Subjects were randomized to apply ice to the injection site and take scheduled over-the-counter analgesics ( n = 36) or take scheduled over-the-counter analgesics alone ( n = 32). There were no significant differences in the mean pain score between the two groups at any time-point (pre-injection or 1-5 days post-injection). In regression modelling, the application of ice did not predict pain after injection. Visual analogue pain scores increased at least 2 points (0-10 scale) after injection in 17 out of 36 patients in the ice group versus ten out of 32 control patients. We conclude that the application of ice in addition to over-the-counter analgesics does not reduce post-injection pain after corticosteroid injection in the hand or wrist. LEVEL OF EVIDENCE: I Therapeutic Study.

The surgical anastomoses after orthotopic heart transplantation: clinical complications and morphologic observations.

From May 1984 through June 1993, 162 patients have undergone orthotopic heart transplantation at the University of Ottawa Heart Institute. Thirty-three deaths occurred, and postmortem examinations were performed in 29 of these cases. This study evaluated the surgical anastomoses of these patients' hearts, an aspect of orthotopic heart transplantation that has not been well described in the literature. The major findings encountered were two cases of stenosis at the left atrial anastomosis, one case of aortic anastomotic tear, one case of pulmonary artery anastomotic kinking, one case of left atrial suture line mural thrombus and possible coronary embolism, and one case of extramural compression of a coronary artery by an anastomotic suture. Other findings when the suture lines were examined included residual native valve remnants, protruding tissue tags or other tissue remnants, mural thrombi, and protruding free suture ends. These findings are described, illustrated, and discussed in the context of the published literature on the subject.

Analysis of deaths after heart transplantation: the University of Ottawa Heart Institute experience.

This study reviews the clinical outcome of the 132 orthotopic heart transplantations performed at our institute from 1984 through 1991 and focuses on the pathology of those patients who died. The study comprised 124 adults (mean age, 45.6 +/- 0.9 years) and eight children. Twenty-six adult and one pediatric deaths occurred. Operative mortality (within 30 days) was 10.6%, with 84.8% of patients surviving to discharge. Actuarial probabilities of survival at 1 and 5 years were 84% +/- 3% and 71% +/- 6%, respectively. Of the 27 deaths, six (22.2%) occurred in the operating room (from hemorrhage, graft failure, and hyperacute rejection); 14 (51.9%) occurred in-hospital after surgery (from sepsis, rejection, cytomegalovirus disease, or myocardial infarct), and seven (25.9%) occurred after discharge (from rejection and/or recurrent coronary artery disease). Two groups of patients were at higher risk: patients in cardiogenic shock requiring pretransplantation mechanical support, with in-hospital mortality of 39.1%; and patients with previous valve replacement who were taking oral anticoagulants, with intraoperative mortality of 50.0%. Pathologic examination revealed occasional instances of unsuspected coronary artery disease in the donor hearts with more than 50% stenoses of the left anterior descending coronary arteries in three of 21 (14.3%) of cases. Complications of the transplantation or related therapeutic procedures were common among those who died. The complications ranged from functionally insignificant anatomic curiosities to life-threatening problems. These complications are tabulated and shown.

Sixth nerve palsy complicating percutaneous thermal ablation of the trigeminal nerve rootlet.

Two patients, an 81-year-old man and a 77-year-old woman, developed sixth nerve palsies after radiofrequency trigeminal gangliolysis for trigeminal neuralgia. Both sixth nerve palsies resolved spontaneously within four to seven months. The combination of postoperative trigeminal nerve deficits and transient oculomotor nerve palsies can mimic parasellar mass lesions and lead to unnecessary neuroradiologic investigation in the early postoperative period.

Extracranial-intracranial (EC-IC) arterial bypass: past performance and current concepts.

The authors present a review of published experience with intracranial-extracranial arterial bypass grafting. The procedure is technically feasible and has a relatively low morbidity and mortality when performed by experienced microvascular surgeons. However, its therapeutic value is still unproven.

Metastasis of a rectal carcinoid to the posterior fossa.

We report the metastasis of a rectal carcinoid to the dura mater of the posterior fossa. The clinical presentation was unusual because of a 10-year latent period between resection of the primary rectal tumor and symptoms and signs of the posterior fossa metastasis; the radiological findings were atypical of a metastasis. Gastrointestinal carcinoids, apudomas, and the concept of the APUD endocrine cell family are reviewed.

Lambl's excrescences and papillary fibroelastomas: are they different?

OBJECTIVE: To determine if Lambl's excrescences (LEs) and papillary fibroelastomas (PFEs) differ histologically. SETTING: Materials were obtained from post mortem examinations performed at the Ottawa Civic Hospital, a tertiary care teaching hospital in Ottawa, Ontario. DESIGN AND PATIENTS: Hearts with grossly 'classic' PFEs (n = 10) or 'typical' LEs (n = 20) were examined. The patients with PFEs had a mean age of 63.5 years (range 24 to 79), similar to that of 68.1 years (range 47 to 83) for those with LEs. The LEs and PFEs were compared regarding their gross characteristics, sizes, locations and microscopic appearances. MAIN RESULTS: Lesions which were termed LEs had a similar microscopic appearance to grossly categorized PFEs; however, the LEs were smaller and broader-based. Some LEs and PFEs were microscopically indistinguishable. CONCLUSIONS: As LEs and PFEs may be virtually identical microscopically in some instances, separation of these two lesions may be artificial; however, this separation remains useful because it highlights the gross appearances, unusual locations and potential clinical sequelae of papillary fibroelastomas.

Blunt cervical spine Brown-Séquard injury. A report of three cases.

Cervical spinal cord Brown-Séquard syndrome was diagnosed in three recent victims of blunt injury at the authors' Level II Trauma Center. While anatomic hemisection of the cord, resulting in ipsilateral motor and proprioception loss and contralateral pain and temperature deficit, is a fully understandable concept, in the context of the acute trauma evaluation, these findings may be confusing because they are unexpected. Penetrating trauma is far more likely to cause this uncommon syndrome than vehicular crash, fall, or crushing injury. Pediatric victims frequently have no fracture. Early neurosurgical consultation, computed tomography (CT), and magnetic resonance imaging (MRI) if plain film radiography is uninformative, and consideration for rapid decompression if the deficit and pathologic anatomy warrant, are the recommended approaches. Motor function recovery from blunt injury may be expected within six months, a better prognosis than for penetrating injury causing the syndrome.

Endothelial papillary fibroelastomas arising in and around the aortic sinus, filling the ostium of the right coronary artery.

Endothelial papillary fibroelastomas are rare endocardial and usually valvular lesions, most often found incidentally at autopsy. Occasionally these lesions cause clinical sequelae by embolizing to the heart and brain, or (in the case of valvular ones) by intermittent prolapse into a coronary artery. Papillary fibroelastomas arising in the right coronary ostium, and filling the origin of the right coronary artery are described. Other similar but smaller lesions were found on the surrounding aortic intima. To our knowledge, these are the first such lesions to be described. The case is reviewed in the context of previously published literature on the subject.

'Minimal deviation' endometrioid carcinoma with oncocytic change of the endometrium.

We report an unusual adenocarcinoma of the endometrium in an 80-year-old woman. The tumor diffusely involved the entire thickness of the myometrium. The cervix, ovaries, and fallopian tubes were unremarkable. Microscopic examination revealed an extremely well-differentiated endometrioid adenocarcinoma with mild cytologic atypia and slightly distorted glands infiltrating almost the entire thickness of the myometrium. In addition, the neoplastic endometrioid cells showed extensive oncocytic change. Endometrial curettings had been interpreted as simple endometrial hyperplasia with eosinophilic metaplasia. The significance of this lesion is discussed in terms of possible confusion with benign endometrial lesions as well as benign cervical lesions.

Observations on moyamoya disease: a case treated with superficial temporal-middle cerebral artery anastomosis.

A 24-year-old Caucasian woman with Moyamoya disease was treated by a superficial temporal, middle cerebral artery anastomosis. Her pre and postoperative angiograms revealed that the telangiectatic network in the region of the basal ganglion served as a transcerebral collateral circulation from the internal carotid artery proximal to its occlusion to the cortical branches of the middle cerebral artery. The transit through two capillary systems (basal ganglia and cortical) explains the slow circulation time. Prompt venous drainage was seen to occur once a more direct collateral supply was established by the superficial temporal-middle cerebral artery anastomosis.