An innovative method to strengthen evidence for potential drug safety signals using Electronic Health Records.

Reports from spontaneous reporting systems (SRS) are hypothesis generating. Additional evidence such as more reports is required to determine whether the generated drug-event associations are in fact safety signals. However, underreporting of adverse drug reactions (ADRs) delays signal detection. Through the use of natural language processing, different sources of real-world data can be used to proactively collect additional evidence for potential safety signals. This study aims to explore the feasibility of using Electronic Health Records (EHRs) to identify additional cases based on initial indications from spontaneous ADR reports, with the goal of strengthening the evidence base for potential safety signals. For two confirmed and two potential signals generated by the SRS of the Netherlands Pharmacovigilance Centre Lareb, targeted searches in the EHR of the Leiden University Medical Centre were performed using a text-mining based tool, CTcue. The search for additional cases was done by constructing and running queries in the structured and free-text fields of the EHRs. We identified at least five additional cases for the confirmed signals and one additional case for each potential safety signal. The majority of the identified cases for the confirmed signals were documented in the EHRs before signal detection by the Dutch Medicines Evaluation Board. The identified cases for the potential signals were reported to Lareb as further evidence for signal detection. Our findings highlight the feasibility of performing targeted searches in the EHR based on an underlying hypothesis to provide further evidence for signal generation.

Tolerability of MenACWY-TT vaccination in adolescents in the Netherlands; a cross-sectional study.

BACKGROUND: In 2018, meningococcal ACWY-TT vaccine (MenACWY-TT) was offered to adolescents in the Netherlands within the National Immunization Programme at 14 years of age. A questionnaire study assessed the tolerability of this vaccine. METHODS: Five thousand adolescents were invited to participate and to fill in two questionnaires about systemic events in the week before vaccination and local reactions and systemic events in the week after vaccination. Frequencies of local and systemic adverse events in the week after vaccination were calculated. Association between the occurrence of systemic symptoms in the week before and after the vaccination was tested by using generalized mixed models (GLMM). RESULTS: Of all adolescents, 139 returned one or both questionnaires. Any local reaction within 7 days after vaccination was reported by 55.6% of the adolescents. Pain (50%) and reduced use of the injected arm (21.3%) were most often reported. Any systemic event was reported by 67.6% of the participants, with myalgia as the most often reported event (37.0%). Compared with the week before vaccination, there were no increased odds of experiencing systemic symptoms in the week after vaccination (OR 0.95; 95%CI 0.40-2.27). CONCLUSIONS: After vaccination with MenACWY-TT vaccine, most adolescents reported one or more adverse events, which were mostly mild and transient. Systemic symptoms were not reported more often in the week after compared to the week before vaccination. Unfortunately, due to a low response rate we were not able to detect the absolute elevated risks the sample size calculation was based on. However, despite limited data, our results are in line with results from prelicensure data, and indicate that MenACWY-TT vaccination is well tolerated in adolescents.

Faecal carriage, risk factors, acquisition and persistence of ESBL-producing Enterobacteriaceae in dogs and cats and co-carriage with humans belonging to the same household.

BACKGROUND: ESBL-producing Enterobacteriaceae (ESBL-E) are observed in many reservoirs. Pets might play an important role in the dissemination of ESBL-E to humans since they live closely together. OBJECTIVES: To identify prevalence, risk factors, molecular characteristics, persistence and acquisition of ESBL-E in dogs and cats, and co-carriage in human-pet pairs belonging to the same household. METHODS: In a nationwide study, one person per household was randomly invited to complete a questionnaire and to submit a faecal sample. Dog and cat owners were invited to also submit a faecal sample from their pet. Repeated sampling after 1 and 6 months was performed in a subset. ESBL-E were obtained through selective culture and characterized by WGS. Logistic regression analyses and random forest models were performed to identify risk factors. RESULTS: The prevalence of ESBL-E carriage in these cohorts was 3.8% (95% CI: 2.7%-5.4%) for human participants (n=550), 10.7% (95% CI: 8.3%-13.7%) for dogs (n=555) and 1.4% (95% CI: 0.5%-3.8%) for cats (n=285). Among animals, blaCTX-M-1 was most abundant, followed by blaCTX-M-15. In dogs, persistence of carriage was 57.1% at 1 month and 42.9% at 6 months. Eating raw meat [OR: 8.8, 95% CI: 4.7-16.4; population attributable risk (PAR): 46.5%, 95% CI: 41.3%-49.3%] and dry food (OR: 0.2, 95% CI: 0.1-0.5; PAR: 56.5%, 95% CI: 33.2%-66.6%) were predictors for ESBL-E carriage in dogs. Human-dog co-carriage was demonstrated in five households. Human-cat co-carriage was not observed. CONCLUSIONS: ESBL-E prevalence was higher in dogs than in humans and lowest in cats. The main risk factor for ESBL-E carriage was eating raw meat. Co-carriage in dogs and household members was uncommon.

Away from home meals: associations with biomarkers of chronic disease and dietary intake in American adults, NHANES 2005-2010.

BACKGROUND: Away from home (AFH) meals are known to be energy-dense and of poor diet quality. Both direct and indirect exposure (for example, neighborhood restaurant density) to AFH meals have been implicated as contributors to higher body weight and adverse health outcomes. OBJECTIVE: To examine the association of frequency of eating AFH and fast-food meals with biomarkers of chronic disease and dietary intake. DESIGN: This cross-sectional study used frequency of AFH and fast-food meal and biomarker data from the NHANES 2005-2010. Information on weekly frequency of AFH and fast-food meals was collected via questionnaire during the household interview. The metabolic biomarkers examined included body mass index (BMI), serum cholesterol (total, high-density lipoprotein (HDL) and low-density lipoprotein (LDL)), triglycerides, glycohemoglobin and fasting glucose (n=8314, age⩾20, National Health and Nutrition Examination Surveys (NHANES) 2007-2010). Biomarkers of dietary exposure included serum concentrations of vitamins A, D, E, C, B-6, B-12, folate and carotenoids (n=4162; 2005-2006). Multiple linear and logistic regression methods adjusted for complex survey methodology and covariates. RESULTS: American adults reported a mean of 3.9 (95% confidence interval 3.7, 4.0) AFH and 1.8 (1.6, 1.9) fast-food meals/week. Over 50% of adults reported ⩾3 AFH and >35% reported ⩾2 fast-food meals/week. The mean BMI of more frequent AFH or fast-food meal reporters was higher (Ptrend⩽0.0004). Serum concentrations of total, LDL and HDL-cholesterol were related inversely with frequency of AFH meals (P<0.05). Frequencies of fast-food meals and serum HDL-cholesterol were also related inversely (P=0.0001). Serum concentrations of all examined micronutrients (except vitamin A and lycopene) declined with increasing frequency of AFH meals (P<0.05); women and ⩾50-year olds were at higher risk. CONCLUSIONS: Reporters of frequent AFH and fast-food meals had higher BMI and lower concentrations of HDL-cholesterol; however, profiles of other biomarkers did not indicate higher metabolic risk. However, the serum concentrations of nutrients with mostly plant foods as sources declined with increasing AFH meal frequency.

GP consultations for menstrual disorders after COVID-19 vaccination - A self-controlled cohort study based on routine healthcare data from the Netherlands.

INTRODUCTION: Several studies described that COVID-19 vaccinations can cause menstrual disorders. Our study aimed to describe whether this also resulted in more general practitioner (GP) consultations for menstrual disorders after COVID-19 vaccination, based on a large cohort study. METHODS: A retrospective self-controlled cohort study was performed including vaccinated women in 2021 aged 12-49 years from two large, representative GP databases in the Netherlands. Incidence rates and incidence rate ratio's (IRR) were calculated using Poisson regression, adjusting for SARS-CoV-2 infection as time-varying confounder. The exposed period was set at maximum six months after each COVID-19 vaccination and the non-exposed period was defined as all-time outside the exposed period. RESULTS: The cohort included 631,802 women, of which 18,986 (3 %) consulted the GP for a menstrual disorder during 2021. Increased GP consultations were observed among 12-14 year olds for amenorrhea/hypomenorrhea/oligomenorrhea (IRR: 1.85, 95 % CI: 1.30-2.65) and irregular/frequent menstruation (IRR: 1.33, 95 % CI: 1.06-1.69) after COVID-19 vaccination in general, and after Pfizer/BioNTech vaccination (IRR: 1.87, 95 % CI: 1.31-2.67 for amenorrhea/hypomenorrhea/oligomenorrhea and IRR: 1.35, 95 % CI: 1.06-1.70 for irregular/frequent menstruation). Persons from this age group were in general also vaccinated with Pfizer/BioNTech. No increase in the frequency of GP consultations were observed for older age groups, other vaccine brands, and potential risk groups. CONCLUSION: For the majority of women, no increased GP consultations for menstrual disorders was found. Solely for the youngest age group (12-14 year olds) increased GP consultations for specific types of menstrual disorders was found after Pfizer/BioNTech vaccination.

Occurrence and characteristics of extended-spectrum-ß-lactamase- and AmpC-producing clinical isolates derived from companion animals and horses.

OBJECTIVES: To investigate the occurrence and characteristics of extended-spectrum ß-lactamase (ESBL)- and AmpC-producing Enterobacteriaceae isolates in clinical samples of companion animals and horses and compare the results with ESBL/AmpC-producing isolates described in humans. METHODS: Between October 2007 and August 2009, 2700 Enterobacteriaceae derived from clinical infections in companion animals and horses were collected. Isolates displaying inhibition zones of ≤ 25 mm for ceftiofur and/or cefquinome by disc diffusion were included. ESBL/AmpC production was confirmed by combination disc tests. The presence of resistance genes was identified by microarray, PCR and sequencing, Escherichia coli genotypes by multilocus sequence typing and antimicrobial susceptibility by broth microdilution. RESULTS: Sixty-five isolates from dogs (n = 38), cats (n = 14), horses (n = 12) and a turtle were included. Six Enterobacteriaceae species were observed, mostly derived from urinary tract infections (n = 32). All except 10 isolates tested resistant to cefotaxime and ceftazidime by broth microdilution using clinical breakpoints. ESBL/AmpC genes observed were bla(CTX-M-1, -2, -9, -14, -15,) bla(TEM-52), bla(CMY-2) and bla(CMY-)(39). bla(CTX-M-1) was predominant (n = 17). bla(CTX-M-9) occurred in combination with qnrA1 in 3 of the 11 Enterobacter cloacae isolates. Twenty-eight different E. coli sequence types (STs) were found. E. coli carrying bla(CTX-M-1) belonged to 13 STs of which 3 were previously described in Dutch poultry and patients. CONCLUSIONS: This is the first study among a large collection of Dutch companion animals and horses characterizing ESBL/AmpC-producing isolates. A similarity in resistance genes and E. coli STs among these isolates and isolates from Dutch poultry and humans may suggest exchange of resistance between different reservoirs.

Intermediate filaments in malignant melanomas. Identification and use as marker in surgical pathology.

Intermediate-sized filaments have been studied in human malignant melanomas and in normal melanocytes by immunofluorescence microscopy with antibodies directed against keratin, vimentin, desmin, neurofilament protein, and glial filament protein. Both human melanotic and amelanotic tumor cells and tumor metastases as well as normal melanocytes in human skin and in the rat eye contain exclusively intermediate filaments of the vimentin type. No reaction was seen with antibodies to keratin, desmin, neurofilaments, or glial filaments. These latter four antisera, however, gave strong reactions in epidermis and other epithelial tissues, muscle, or neural tissues, respectively. The results favor a mesenchymal character of melanocytes, although a neuroectodermal origin in an early developmental stage is possible. The finding that melanomas contain exclusively vimentin intermediate filaments may prove useful in differential diagnosis of melanomas from other tumor types.

[A free market is unfavourable for health care]. / Marktwerking is niet gunstig voor de gezondheidszorg.

The new health care system in the Netherlands introduces a free market into the health care sector. Because health care lacks some essential conditions, a free market will not provide effective resource allocation in this sector. In addition, a free market leads to more bureaucracy and less solidarity, cooperation and freedom of choice. It also impairs the autonomy of the medical professional.

Cbl functions downstream of Src kinases in Fc gamma RI signaling in primary human macrophages.

Cbl is a cytosolic protein that is rapidly tyrosine phosphorylated in response to Fc receptor activation and binds to the adaptor proteins Grb2, CrkL, and Nck. A few reports describe Cbl interactions in primary human hematopoietic cells. We show evidence that Cbl participates in signaling initiated by Fc gammaRI receptor cross-linking in human primary macrophages, and functions downstream of Src family kinases in this pathway. Fc gammaRI stimulation in human macrophages was associated with rapid and transient tyrosine phosphorylation of the Cbl adaptor protein. Immunoprecipitated Cbl was complexed with several tyrosine phosphorylated proteins, the most prominent of which was a 38-kDa band identified as the CrkL adaptor protein. CrkL associated with tyrosine-phosphorylated Cbl and itself became tyrosine phosphorylated after Fc gammaRI cross-linking. SLP-76, a recently cloned Grb2-associated protein, was strongly tyrosine phosphorylated after Fc gammaRI stimulation and was associated with both Cbl and Grb2. Grb2 and Cbl binding to SLP-76 were inducible after Fc gammaRI stimulation of the macrophages. Nck was inducibly bound to Cbl after Fc gammaRI stimulation, whereas Grb2 was constitutively associated with it. Shc was also inducibly tyrosine phosphorylated and bound to Grb2 after Fc gammaRI stimulation of the macrophages. PP1, a specific inhibitor of Src kinases, inhibited the Fc gammaRI-induced respiratory burst, as well as the tyrosine phosphorylation of Cbl and its inducible association with CrkL. These results suggest a fundamental role for the tyrosine phosphorylation of Cbl, CrkL, SLP-76, and Shc and the association of Cbl with CrkL, SLP-76, and Nck in Fc gammaRI signaling in human macrophages. Experiments performed with PP1, the specific Src kinase inhibitor, demonstrate the first evidence that Cbl and the Cbl-Crkl interaction are downstream targets for myeloid Src kinases required for the activation of myeloid NADPH oxidase activity.

The relation of the pleural thickening in tuberculosis pleurisy with the activity of adenosine deaminase.

BACKGROUND: Residual pleural thickening (RPT) still occurs in most patients with tuberculosis pleurisy despite advances in the treatment of tuberculosis. The aim of this study was to evaluate the significance of RPT in tuberculosis pleurisy with the patients clinical findings, biochemical and microbiological properties of pleural effusion and with the total adenosine deaminase (ADA) and isoenzymes levels. METHODS: 121 tuberculosis pleurisy patients were evaluated retrospectively. According to posteroanterior chest x-rays, the 63 (52%) cases with the thickness 2 mm or more in lower lateral hemithorax were grouped as I and the 58 (48%) cases without pleural thickness were grouped as II. The amount of pleural effusion was classified into small, medium or massive according to their chest x-rays. In both groups; sex, age, symptoms score, bacteriological and biochemical tests and ADA levels were recorded. RESULTS: 81 (67%) male and 40 (33%) female, overall 121 patients were enrolled into the study. RPT was found higher in males (p=0.014) and the increase ran parallel with the amount of cigarette smoking (p=0.014). RPT was found to be lower in small effusions (p=0.001). The group with RPT, the serum albumin was found lower (p=0.002), pleural fluid total protein (p=0.047) and the ratio of pleural fluid protein to serum protein (p=0.002) were found higher. In group I, total ADA: 69.5 +/- 38.9 IU/L and ADA2: 41.3 +/- 31.6 IU/L were higher than the cases without RPT (p=0.032, p=0.017, respectively). CONCLUSIONS: We suggest that the immunological mechanisms are effective in the development of pleural thickening.

Consumption of energy-dense, nutrient-poor foods by adult Americans: nutritional and health implications. The third National Health and Nutrition Examination Survey, 1988-1994.

BACKGROUND: Current dietary guidance recommends limiting the intake of energy-dense, nutrient-poor (EDNP) foods, but little is known about recent consumption patterns of these foods. OBJECTIVE: The contribution of EDNP foods to the American diet and the associated nutritional and health implications were examined. DESIGN: Data from the third National Health and Nutrition Examination Survey (n = 15611; age >/=20 y) were used. EDNP categories included visible fats, nutritive sweeteners and sweetened beverages, desserts, and snacks. The potential independent associations of EDNP food intake with intakes of energy, macronutrients, micronutrients, and serum vitamin, lipid, and carotenoid profiles were examined with linear and logistic regression procedures. RESULTS: EDNP foods supplied approximately 27% of energy intake; alcohol provided an additional 4%. The relative odds of consuming foods from all 5 food groups and of meeting the recommended dietary allowance or daily reference intake for protein and several micronutrients decreased with increasing EDNP food intake (P: < 0.0001). Energy intake and percentage of energy from fat were positively related to EDNP intake. Serum concentrations of vitamins A, E, C, and B-12; folate; several carotenoids; and HDL cholesterol were inversely related (P:

Dietary vitamin B-6 intake and food sources in the US population: NHANES II, 1976-1980.

Dietary vitamin B-6 intake and food sources were estimated from the Second National Health and Nutrition Examination Survey (NHANES II) dietary data for 11,658 adults aged 19-74 y. The average daily intake of vitamin B-6 was 1.48 +/- 0.01 mg (mean +/- SEM) for the total population, 1.85 +/- 0.02 for males and 1.14 +/- 0.01 for females. Seventy-one percent of males and 90% of females consumed less than the 1980 recommended dietary allowance (RDA) of vitamin B-6. Sixty-four percent of all survey respondents reported a ratio of vitamin B-6 to dietary protein of less than 0.02 (expressed as mg/g protein). Foods from animal and plant sources provided 48% and 52% of the total vitamin B-6, respectively. Vitamin B-6 intake decreased (P less than 0.0001) with increasing age and decreasing education and income status. Beef steaks and roasts, alcoholic beverages, potatoes, ready-to-eat cereals, and milk were important dietary sources of vitamin B-6.

Proportion of energy intake from fat and subsequent weight change in the NHANES I Epidemiologic Follow-up Study.

We examined the association of percent energy intake from fat with subsequent weight change in 2580 men and 4567 women, using data from the National Health and Nutrition Examination Survey (NHANES) I Epidemiologic Follow-up Study (NHEFS). Weight change was defined as the difference between the follow-up weight (NHEFS, 1982-1984) and the baseline weight (NHANES I, 1971-1974). Fat intake was estimated from a 24-h dietary recall obtained at baseline. Regression analyses adjusted for potential confounders showed no significant association of percent fat energy with weight change in men. Among women aged < 50 y, the inverse relation of percent fat energy with weight change was significant (beta = -0.052, P = 0.04). After exclusion of respondents with any morbidity from the analytic cohort, percent fat energy and weight change were positively associated in men (beta = 0.046, P = 0.05), but not in women. In conclusion, percent fat energy intake and weight change were inversely related in women aged < 50 y in the NHEFS cohort, but positively associated in men without any morbidity.

Effect of age on changes in plasma, erythrocyte, and urinary B-6 vitamers after an oral vitamin B-6 load.

We investigated the effect of age on indices of vitamin B-6 metabolism in 36 fasting males aged 25-35, 45-55, and 65-75 y who ingested 17.15 mumol vitamin B-6. There were no significant differences among groups in dietary vitamin B-6 intake, base-line erythrocyte pyridoxal 5'-phosphate (PLP), and total vitamin B-6 concentrations, and 24-h and base-line urinary excretion of total vitamin B-6 and 4-pyridoxic acid (4-PA). Base-line plasma PLP and total vitamin B-6 were higher (p less than 0.05) in the youngest group. Increased serum alkaline phosphatase (AP) and decreased dietary vitamin B-6 intake were correlated with decreased base-line plasma PLP and total vitamin B-6. Changes in plasma and erythrocyte PLP concentrations and excretion of 4-PA and total vitamin B-6 postload were not different among groups. Indices of vitamin B-6 absorption, phosphorylation, and excretion were not affected by age.

Dietary diversity and subsequent mortality in the First National Health and Nutrition Examination Survey Epidemiologic Follow-up Study.

We examined the relation of dietary diversity to subsequent all-cause mortality by using data from the First National Health and Nutrition Examination Survey (NHANES I) Epidemiologic Follow-up Study, 1982-1987. The analytic cohort consisted of 4160 men and 6264 women (including 2556 deaths), 25-74 y at baseline (1971-1975). Twenty-four-hour dietary recalls were evaluated for variety among the five major food groups: dairy, meat, grain, fruit, and vegetable, with a dietary diversity score (DDS); consumption of each food group contributed 1 point to a maximum possible DDS of 5. Age-adjusted risk of mortality was inversely related to DDS (P < or = 0.0009) in men and women. The inverse diversity-mortality association was adjusted for potential confounders: education, race, smoking status, and dietary fiber intake; the relative risk of mortality in men and women consuming two or fewer food groups was 1.5 (95% CI 1.2-1.8) and 1.4 (95% CI 1.1-1.9), respectively. In conclusion, diets that omitted several food groups were associated with an increased risk of mortality.

Mesodermal mixed tumor. Diagnosis by analysis of intermediate filament proteins.

A 58-year-old patient presented with poorly differentiated adenocarcinoma, probably primary in the ovary and, later in the course of her illness, with pure pleomorphic rhabdomyosarcoma. There was no evidence by light or electron microscopy of a mixture of these two tumor types. Further analysis by immunoperoxidase demonstrated scattered desmin-positive (muscle) cells in the adenocarcinoma portion of the tumor, establishing the diagnosis of malignant mesodermal mixed tumor.

Decreased expression of both Fc gamma RII and Fc gamma RIII mRNA in leukemic granulocytes.

Morphologically mature granulocytes from patients with chronic myeloid leukemia exhibit a defect in internalization of heat-aggregated IgG. In this study, we investigate the status of the steady-state levels of the mRNA for the two receptors for IgG, Fc gamma RII and Fc gamma RIII, as a step towards understanding the molecular basis of the defect and in turn the discordant maturation of the leukemic cells. Our data show that the mRNA for both receptors is lower in the leukemic cells relative to the normal cells. This may be one of the causes for the defective endocytosis.

Fc gamma RII and Fc gamma RIII on normal leukaemic granulocytes: a flow cytometry and northern analysis.

Morphologically mature granulocytes from patients with chronic myeloid leukaemia (CML) exhibit a defect in internalization of heat-aggregated IgG. In order to investigate this defect at the molecular level and, in turn, the discordant maturation of these granulocytes, we compared the expression of Fc gamma RII and Fc gamma RIII, the two receptors for IgG on the surface of granulocytes, in normal and CML samples. Our flow cytometric data show that the number of granulocytes expressing Fc gamma RIII is lowered in CML patients to near half that in normal individuals, with a simultaneous decrease in the steady-state levels of the mRNA for Fc gamma RIII. Mean fluorescence intensity (MFI), an indicator of the number of receptors per cell, varies widely for Fc gamma RIII in normal individuals whereas it is more localized and lowered in granulocytes from CML patients. The number of granulocytes positive for Fc gamma RII is also significantly lowered in CML samples compared to the normals, which exhibit a wide variation in the number of cells positive for the receptor, even though their nRNA levels do not vary much. The CML granulocytes, in general, exhibit lowered levels of the steady-state mRNA for Fc gamma RII. The MFI for the surface expression of Fc gamma RII is only marginally different between the two cell types. Our data indicate that the morphologically homogeneous population of CML granulocytes actually consists of at least two types of cells, one which expresses the Fc receptors and one which does not.

Heterogeneity in the expression of Fc gammaRIII in morphologically mature granulocytes from patients with chronic myeloid leukemia.

Morphologically mature granulocytes from patients with chronic myeloid leukemia exhibit a defect in receptor mediated endocytosis of FITC-conjugated heat-aggregated IgG. In our earlier studies, we have shown that transcripts for Fc gammaRII and Fc gammaRIII are lowered in CML granulocytes, while no such trend was seen for CD11b, CD18 and actin, the other molecules involved in this process. We have also shown by flow cytometry that the number of granulocytes expressing the Fc receptors on their surface is lowered in CML patients. In this report, we show that the lowered steady state level of the mRNA for the Fc receptors is due to their faster degradation and not due to any defect in transcription. A study of the expression of mRNA for Fc gammaRIII in morphologically mature CML granulocytes by in situ hybridization showed that there is heterogeneity in the expression of this receptor, with some cells positive for the message and some not. These results suggest that the Fc gammaRIII transcript reaches a stable RNA pool in only some of the granulocytes, whereas in the rest of the cells, it is probably degraded after it is transcribed and is therefore not detected. The Fc gammaRIII is probably one of the first antigens to be lost from the leukemic granulocyte surface during the transition of the disease from the chronic phase to the accelerated phase and finally to the blast crisis.