Annotation of Trauma-related Linguistic Features in Psychiatric Electronic Health Records for Machine Learning Applications.

Psychiatric electronic health records (EHRs) present a distinctive challenge in the domain of ML owing to their unstructured nature, with a high degree of complexity and variability. This study aimed to identify a cohort of patients with diagnoses of a psychotic disorder and posttraumatic stress disorder (PTSD), develop clinically-informed guidelines for annotating these health records for instances of traumatic events to create a gold standard publicly available dataset, and demonstrate that the data gathered using this annotation scheme is suitable for training a machine learning (ML) model to identify these indicators of trauma in unseen health records. We created a representative corpus of 101 EHRs (222,033 tokens) from a centralized database and a detailed annotation scheme for annotating information relevant to traumatic events in the clinical narratives. A team of clinical experts annotated the dataset and updated the annotation guidelines in collaboration with computational linguistic specialists. Inter-annotator agreement was high (0.688 for span tags, 0.589 for relations, and 0.874 for tag attributes). We characterize the major points relating to the annotation process of psychiatric EHRs. Additionally, high-performing baseline span labeling and relation extraction ML models were developed to demonstrate practical viability of the gold standard corpus for ML applications.

Importance of complete response for outcomes of pregnancy in patients with autoimmune hepatitis.

BACKGROUND AND AIMS: While some articles describe outcome of pregnancy in autoimmune hepatitis (AIH), there are less data evaluating influence of AIH control on maternal and perinatal outcomes. This study analysed outcomes of pregnancy and related possible risk factors in AIH. METHOD: A retrospective multicentre cohort study on pregnancy in AIH was performed in 11 hospitals in the Netherlands. Maternal and neonatal outcomes were collected from records and completed by interview. Risk factors-including incomplete response, relapse and cirrhosis-for adverse outcomes were identified using logistic regression analysis. RESULTS: Ninety-seven pregnancies in 50 women resulted in 70 deliveries (72%) with a live birth rate of 98.5%. AIH relapse occurred in 6% during pregnancy, and in 27% of post-partum episodes. Absence of complete biochemical response at conception was identified as risk factor for the occurrence of gestational and post-partum relapses. Relapse of AIH in the year before conception was a risk factor for the occurrence of both gestational relapses and post-partum relapses. No complete biochemical response increased the risk for hypertensive disorders during pregnancy and intrahepatic cholestasis of pregnancy (ICP). Cirrhosis was found to be a risk factor for miscarriages, but not for other outcomes. CONCLUSION: Pregnancy in AIH is related to an increased incidence of maternal and fetal/neonatal complications; in most cases, outcome is good. Incomplete biochemical response at conception or relapse in the year before conception are risk factors for gestational and post-partum relapses, for hypertensive disorders and for ICP. Cirrhosis was a risk factor for miscarriages.

Burn-out and employability rates are impacted by the level of job autonomy and workload among Dutch gastroenterologists.

BACKGROUND: Increasing burn-out rates among gastroenterologists make it necessary to find ways to prevent burn-out and to stimulate their ability and willingness to continue working (i.e., their employability). Understanding their antecedents might help organizations to prevent burn-out and to enhance employability among this occupational group. OBJECTIVE: The purpose of this study is to provide insight in the relationship between job characteristics and job crafting behavior on the one hand and job outcomes (burn-out symptoms and employability) on the other hand. METHODS: Data from two surveys in 2020 and 2021 were collected in a longitudinal study among 238 Dutch gastroenterologists. The data were analyzed with multiple linear regression analyses and paired-samples t-tests. RESULTS: Job characteristics, specifically job aspects that require sustained physical and/or psychological effort or skills (i.e., job demands), are important predictors of burn-out symptoms among gastroenterologists. Specifically, high quantitative and emotional workload are significantly related to more burn-out symptoms. No strong relationship was found between job crafting and burn-out symptoms. Furthermore, job aspects that reduce the negative impact of these demanding aspects and that help to achieve work goals (i.e., job resources), and job demands to some extent, significantly predict employability. In particular, high job autonomy is related to higher employability, and high quantitative workload is associated with lower employability. Job crafting does not significantly affect employability. Furthermore, levels of burn-out symptoms and employability differed only little across time. CONCLUSION: In gastroenterologists, a high quantitative workload and emotional workload are associated with a higher burn-out risk, while low job autonomy and high quantitative workload are associated with more negative perceptions of employability. To prevent burn-out and to create positive perceptions of employability, it is important to take these aspects into account.

Size Exclusion Chromatography with Dual Wavelength Detection as a Sensitive and Accurate Method for Determining the Empty and Full Capsids of Recombinant Adeno-Associated Viral Vectors.

Gene therapy has evolved over the past decade into a promising therapeutic class for treating many intractable diseases. Recombinant adeno-associated virus (AAV) is the most commonly used viral vector for delivering therapeutic genes. Independent of the manufacturing process for AAVs, the clinical materials are inherently heterogeneous and contain both empty and full capsids. Empty capsids can impact the safety and efficacy of AAV products and therefore their level needs to be controlled. Several analytical methods have been reported for this purpose. However, some of these methods have an insufficient assay range, or rely on instruments that cannot be readily implemented in a quality control (QC) environment. In this study, we describe a fast size exclusion chromatography (SEC) assay with dual-wavelength detection (SEC-DW) to directly determine the percent full capsids of AAV samples based on their peak area (PA) ratios. The two detection wavelengths selected to represent encapsidated transgenes and capsid proteins were 260 and 230 nm, respectively, instead of the conventionally used 260 and 280 nm. The use of 230 nm instead of 280 nm to monitor the contribution of the capsid protein results in a linear relationship between the PA260/PA230 ratio and the percent full capsids, unlike the nonlinear relationship observed when the PA260/PA280 ratio is used. As a result, the method exhibits a significantly extended assay range (up to 91% full capsids). The accuracy of the SEC-DW method was confirmed by comparing the results obtained against results from orthogonal high-resolution methods such as analytical ultracentrifugation (AUC) and cryo-electron microscopy and excellent agreement was obtained when common samples were analyzed using different methods. The SEC-DW method runs on a readily accessible high-performance liquid chromatography instrument platform, provides much higher assay throughput compared with AUC and electron microscopy, and can be implemented as a release method in a QC environment or used as a rapid screening tool to support process development and product understanding.

Capillary Electrophoresis-Sodium Dodecyl Sulfate with Laser-Induced Fluorescence Detection as a Highly Sensitive and Quality Control-Friendly Method for Monitoring Adeno-Associated Virus Capsid Protein Purity.

The capsid protein purity of adeno-associated virus (AAV) is considered a critical quality attribute of AAV-based gene therapy products. However, the analytical methods currently available to monitor the viral capsid proteins, which are present in extremely low concentrations, have limited sensitivity and robustness, thus limiting their general applicability. As a result, there is an urgent need to develop robust separation methods with highly sensitive detection. In this article, we describe the first denaturation and fluorescence labeling procedure for AAV capsid proteins using the pyrylium dye Chromeo™ P503, enabling the establishment of the first capillary electrophoresis-sodium dodecyl sulfate (CE-SDS) method combined with laser-induced fluorescence (LIF) detection for AAV. Upon optimization using a quality-by-design approach, the newly developed method features a simple and robust one-step sample preparation workflow resulting in consistently labeled and denatured viral protein samples, which can subsequently be separated and quantified by CE-LIF. The method has been validated to be accurate and precise with a linear range of 50-150% of the nominal concentration of 2.0 × 1011 vector genomes per mL (vg/mL). The detection limit and quantitation limit were established to be 8.0 × 107 vg/mL (∼0.8 ng/mL) and 4.2 × 108 vg/mL (∼4 ng/mL), respectively, representing the highest sensitivity achieved for AAV capsid protein quantitation reported to date and a linear dynamic range of 8.0 × 107-3.0 × 1011 vg/mL. A comparison of the CE-SDS LIF method with existing methods, such as CE-SDS ultraviolet and sodium dodecyl sulfate-polyacrylamide gel electrophoresis with SYPRO Ruby stain, indicated that the new method has superior resolution and a significant increase in signal intensity. Capsid protein purity analysis of multiple AAV serotypes, including AAV5, scAAVrh10, AAV2, and AAV6, has been demonstrated for the first time using the same method, indicating the newly developed AAV labeling procedure and CE-LIF analysis could serve as a Quality Control-friendly platform and best-in-class analytical method for the control of AAV capsid protein purity.

Effects of a time out consultation with the general practitioner on cancer treatment decision-making: a randomised controlled trial: Time out with the general practitioner and cancer treatment decision.

OBJECTIVE: Improving shared decision-making (SDM) enables more tailored cancer treatment decisions. We evaluated a Time Out consultation (TOC) with the general practitioner (GP), between cancer diagnosis and treatment decision, which aims at supporting SDM and improving continuity of primary care. This study aims to evaluate the effects of a TOC on perceived SDM, information provision and self-efficacy. METHODS: This randomised controlled trial included newly diagnosed patients with curable cancer (breast, lung, colorectal, gynaecologic and melanoma) from four Dutch hospitals. Primary outcome is perceived SDM and secondary outcomes are information provision and self-efficacy. RESULTS: One hundred fifty-four patients (control n = 77, intervention n = 77) - female: 75%, mean age: 61 (SD ± 11.9). In the intervention group, 80.5% (n = 62) had a TOC, of which 82.3% (n = 51) took place after treatment decision. Perceived SDM was lower in the intervention group (-8.9 [95% CI: 0.6-17.1]). Among those with a TOC before treatment decision (n = 11), perceived SDM was comparable to the control group (66.5 ± 27.2 vs. 67.9 ± 26.1). CONCLUSION: Even though patients are motivated to have a TOC, implementing a TOC between diagnosis and treatment decision is challenging. Effects of a timely TOC could not be established. Non-timely TOC decreased perceived SDM. Planning of the TOC should be optimised, and future research should establish if adequately timed TOC results in improved SDM in cancer patients.

Introducing hepatitis C virus healthcare pathways in addiction care in the Netherlands with a Breakthrough project: a mixed method study.

BACKGROUND: People who inject drugs (PWID) are disproportionally affected by the hepatitis C virus (HCV) infection. In the Netherlands, active HCV transmission in PWID has practically been halted but uptake of HCV testing and linkage to care remains insufficient in this risk group. A national HCV in Addiction Care (HAC) quality improvement project based on the Breakthrough methodology (i.e. Breakthrough project) aimed to secure proper linkage to care in PWID by introducing local HCV healthcare screening and treatment pathways in addiction care units. AIM: To qualitatively appraise the local HCV healthcare pathways; to evaluate the yield in terms of number of PWID screened, diagnosed, referred, and treated; and to identify best practices and barriers to successful participation in the HAC Breakthrough project. METHODS: Between 2013 and 2016, 12 units of addiction care centers throughout the Netherlands participated in two series of a HAC Breakthrough project. Local multidisciplinary teams created HCV healthcare pathways. Quality assessment of HCV healthcare pathways was performed retrospectively and data on screening results was collected. In-depth interviews were conducted to elucidate best practices and essential elements for successful participation. RESULTS: In total, six HCV healthcare pathways were submitted by ten teams of which 83% was judged to be of "good" or "sufficient" quality. Uptake of HCV-antibody screening was 40% (N = 487/1219) and uptake of HCV-RNA in HCV-antibody positives was 59% (N = 107/181). The project resulted in 76 (6%) newly detected cases of persistent HCV viremia. Of all HCV-RNA positives, 92% was referred to a hepatitis treatment center. In 39% (N = 27/70) of those referred, treatment initiation was documented and 82% (N = 22/27) achieved a sustained virological response. Teams identified several best practices including motivational counseling training, oral swabs for anti-HCV testing, facilitating complementary HCV RNA testing, and supervised hospital visits. CONCLUSION: The HAC Breakthrough project has brought about good quality HCV healthcare pathways in the majority of participating addiction care centers and has successfully linked PWID with ongoing HCV viremia to care. Uptake of HCV screening and treatment after referral were identified as the main gaps to be closed in the HCV cascade of care to achieve final HCV elimination in Dutch PWID (i.e. micro-elimination).

Clinical Course of Nodular Regenerative Hyperplasia in Thiopurine Treated Inflammatory Bowel Disease Patients.

Nodular regenerative hyperplasia (NRH) is a poorly understood liver condition, which is increasingly recognized in thiopurine-treated patients with inflammatory bowel disease (IBD).1 It is difficult to establish an optimal approach to NRH patients, because its manifestations are highly variable (from asymptomatic to symptoms of noncirrhotic portal hypertension [NCPH]) and the prognosis is unknown.2 The aim of this study was to identify NRH cases in IBD patients treated with azathioprine, mercaptopurine, and/or thioguanine, and to describe its clinical course.

REtrieval And cure of Chronic Hepatitis C (REACH): Results of micro-elimination in the Utrecht province.

BACKGROUND: The Netherlands is one of the six European countries considered on track to eliminate hepatitis C virus by 2030. To achieve this goal, continuous efforts have to be put into designing efficient case-finding strategies, including the retrieval of previously diagnosed hepatitis C virus-infected who are lost to follow-up. AIMS: To trace and treat all lost to follow-up hepatitis C virus patients in the Utrecht region and create an efficient retrieval strategy that can be used in future (national) retrieval initiatives. METHODS: Positive hepatitis C virus diagnostic tests (anti-hepatitis C virus IgG or hepatitis C virus-RNA) from the laboratory of all four hospitals and one central laboratory for primary care diagnostics in the province of Utrecht from 2001 to 2015 were linked to clinical records. Untreated patients with available contact information were deemed eligible for retrieval and invited for reevaluation with (virology) blood tests, fibroscan measurement and possible direct-acting antiviral therapy. MAIN RESULTS: After screening all hepatitis C virus diagnostics, 1913 chronic hepatitis C virus-infected were identified of which 14.1% (n = 269) were invited back into care. Overall, 17.4% was traced with the highest yield (28.3%) in those who lived in the Utrecht province. Through renewed patient assessments, 42 chronic hepatitis C virus infections were re-identified (76% with a history of intravenous drug use, 24% with Metavir F3-F4). Until now, 59% has either scheduled or initiated direct-acting antiviral therapy. CONCLUSION: The retrieval of previously diagnosed hepatitis C virus patients through screening of laboratory diagnostics from the past is feasible and should be pursued for further control and reduction of hepatitis C virus infection. Retrieval is most successful when performed regionally. LAY SUMMARY: To completely eliminate chronic hepatitis C virus (HCV) infection and prevent complications, undiagnosed and also previously diagnosed but lost to follow-up (LFU) HCV patients have to be brought (back) into care for therapy. Retrieval of LFU HCV patients through screening of laboratory diagnostics from the past is feasible and most successful when performed regionally.

Is Textbook Outcome a valuable composite measure for short-term outcomes of gastrointestinal treatments in the Netherlands using hospital information system data? A retrospective cohort study.

OBJECTIVE: To develop a feasible model for monitoring short-term outcome of clinical care trajectories for hospitals in the Netherlands using data obtained from hospital information systems for identifying hospital variation. STUDY DESIGN: Retrospective analysis of collected data from hospital information systems combined with clinical indicator definitions to define and compare short-term outcomes for three gastrointestinal pathways using the concept of Textbook Outcome. SETTING: 62 Dutch hospitals. PARTICIPANTS: 45 848 unique gastrointestinal patients discharged in 2015. MAIN OUTCOME MEASURE: A broad range of clinical outcomes including length of stay, reintervention, readmission and doctor-patient counselling. RESULTS: Patients undergoing endoscopic retrograde cholangiopancreatography (ERCP) for gallstone disease (n=4369), colonoscopy for inflammatory bowel disease (IBD; n=19 330) and colonoscopy for colorectal cancer screening (n=22 149) were submitted to five suitable clinical indicators per treatment. The percentage of all patients who met all five criteria was 54%±9% (SD) for ERCP treatment. For IBD this was 47%±7% of the patients, and for colon cancer screening this number was 85%±14%. CONCLUSION: This study shows that reusing data obtained from hospital information systems combined with clinical indicator definitions can be used to express short-term outcomes using the concept of Textbook Outcome without any excess registration. This information can provide meaningful insight into the clinical care trajectory on the level of individual patient care. Furthermore, this concept can be applied to many clinical trajectories within gastroenterology and beyond for monitoring and improving the clinical pathway and outcome for patients.

Variation in palliative care of esophageal cancer in clinical practice: factors associated with treatment decisions.

Various treatments are available for the palliation of esophageal cancer, but the optimal therapeutic approach is unclear. This study aimed to assess the palliative treatment modalities used in patients with inoperable esophageal cancer and to identify factors associated with treatment decisions. A population-based, retrospective cohort study was conducted using data from the nationwide Netherlands Cancer Registry and medical records of seven participating hospitals. Patients diagnosed with stage III-IV inoperable esophageal or gastric cardia cancer in the central part of the Netherlands between 2001 and 2010 were included. Logistic regression analyses were performed to identify determinants of treatment choices. In total, 736 patients were initially treated with best supportive care (21%), stent placement (19%), chemotherapy (18%), external beam radiotherapy (EBRT) (16%), brachytherapy (6%), a combination of EBRT and brachytherapy (6%), a combination of chemotherapy and EBRT (5%) or another treatment (9%). The palliative approach varied for disease stage (P < 0.01) and hospital of diagnosis (P < 0.01). Independent factors affecting treatment decisions were age, degree of dysphagia, tumor histology, tumor localization, disease stage, and hospital of diagnosis. For example, patients diagnosed in one hospital were less likely to be treated with EBRT than with stent placement compared to patients in another hospital (odds ratio 0.20, 95% confidence interval 0.07-0.59). In conclusion, the initial palliative approach of patients with inoperable esophageal cancer varies widely and is not only associated with patient- and disease-related factors, but also with hospital of diagnosis. These findings suggest a lack of therapeutic guidance and highlight the need for more evidence on palliative care strategies for esophageal cancer.

Clinical impact of five large-scale screening projects for chronic hepatitis B in Chinese migrants in the Netherlands.

BACKGROUND & AIMS: In low-endemic countries it is debated whether first-generation migrants should be screened for chronic hepatitis B infection. We describe the clinical impact of five large-scale Dutch screening projects for hepatitis B in first-generation Chinese migrants. METHODS: Between 2009 and 2013 five independent outreach screening projects for hepatitis B targeting first-generation Chinese migrants were conducted in five main Dutch regions. To explore the relevance of our screening we defined clinical impact as the presence of an indication for: (i) antiviral therapy, (ii) strict follow-up because of high hepatitis B DNA levels and/or (iii) surveillance for hepatocellular carcinoma. RESULTS: In total, 4423 persons participated in the projects of whom 6.0% (n = 264) were HBsAg positive. One hundred and twenty-nine newly diagnosed HBsAg-positive patients were analysed in specialist care. Among these patients prevalence of cirrhosis was 6.9% and antiviral therapy for hepatitis B was started in 32 patients (25%). In patients without a treatment indication, strict follow-up because of high hepatitis B DNA levels and/or surveillance for hepatocellular carcinoma was considered indicated in 64 patients (50%). CONCLUSIONS: In our screening project in first-generation Chinese migrants, antiviral treatment, strict follow-up because of high hepatitis B DNA levels and/or surveillance for hepatocellular carcinoma were considered indicated in three of four analysed HBsAg-positive patients. These data show that detection of hepatitis B in Chinese migrants can have considerable impact on patient care.

Tuberculosis during TNF-α inhibitor therapy, despite screening.

As part of a prospective study on the safety of TNF-α inhibitor therapy after screening for and treatment of latent tuberculosis infection (LTBI), we report two patients who developed active tuberculosis (TB) infection during TNF-α inhibitor therapy, despite negative screening for LTBI. The clinical history is suggestive of a primary infection acquired during travelling to TB-endemic countries. In this lesson of the month we would like to highlight the risk of travelling to TB-endemic areas in patients treated with TNF-α inhibitor therapy. Screening for latent tuberculosis infection is not enough to prevent tuberculosis in patients treated with TNF-α inhibitor therapy.

Enriching regulatory networks by bootstrap learning using optimised GO-based gene similarity and gene links mined from PubMed abstracts.

Increasingly, reverse engineering methods have been employed to infer transcriptional regulatory networks from gene expression data. Enrichment with independent evidence from sources such as the biomedical literature and the Gene Ontology (GO) is desirable to corroborate, annotate and expand these networks as well as manually constructed networks. In this paper, we explore a novel approach for computer-assisted enrichment of regulatory networks. GO-based gene similarity is first tuned to an initial network augmented with gene links mined from PubMed and then used to drive network construction using a bootstrapping algorithm. We describe two applications of this approach and discuss its added value in terms of corroboration, annotation and expansion of manually constructed and reversed engineered networks.

Subunit stoichiometry of the Clostridium botulinum type A neurotoxin complex determined using denaturing capillary electrophoresis.

A denaturing capillary electrophoresis method was developed to evaluate the subunit stoichiometry of the Clostridium botulinum type A neurotoxin complex. The results indicate that the neurotoxin complex contains single copies of the 150 kDa neurotoxin and the non-toxic non-hemagglutinating subunits as well as 5-6 HA17, 4-5 HA23, 3-4 HA48, and 8-9 HA34 subunits. The calculated molecular mass for a complex with this stoichiometry is between 880 and 1,000 kDa. The molecular mass of the intact complex was determined using size-exclusion HPLC (SE-HPLC) and SE-HPLC in conjunction with multi-angle laser light scattering detection. Based on a comparison to a mixture of standard proteins, SE-HPLC analysis yielded a molecular mass of 880 kDa while light scattering analysis indicated a weight average molecular mass of 925 +/- 45 kDa. The close agreement between the molecular mass values determined by the three approaches supports the subunit stoichiometry proposed for the C. botulinum type A neurotoxin complex.

High prevalence of low bone mineral density in patients with Inflammatory Bowel Disease in the setting of a peripheral Dutch hospital.

BACKGROUND AND AIMS: Osteopenia and osteoporosis are frequently encountered in patients with Inflammatory Bowel Disease (IBD). Our aims were to evaluate the actual practice of screening for low bone mineral density (BMD) by dual energy X-ray absorptiometry (DEXA), to determine the prevalence of low BMD and to investigate the risk factors associated with a low BMD in the IBD population of a regional Dutch hospital. METHODS: A retrospective chart review was performed in 474 patients (259 with ulcerative colitis, 210 with Crohn's disease and 5 with indeterminate colitis). DEXA results and potential predictive factors of low BMD were documented. Predictive factors of low BMD were assessed by logistic regression. RESULTS: DEXA was performed in 168 IBD patients (35.4%). A low BMD (T-score<-1) was present in 64.3%. Osteoporosis (T-score<-2.5) was found in 23.8%. Low BMI, older age at the moment of diagnosis and male gender were found to be predictive factors of low BMD. For patients with osteoporosis, disease duration was an additional predictive factor. After subgroup analysis predictive factors were found to be the same in patients with Crohn's disease. CONCLUSIONS: The prevalence of osteopenia and osteoporosis in IBD patients in a regional centre is as high as the prevalence rates reported from tertiary referral centres. A low BMI, an older age at the moment of diagnosis and male gender were predictive factors of low BMD. Prediction of osteoporosis and osteopenia using risk factors identified in this and previous studies is presently not feasible.

Electronic, Magnetic, and Redox Properties of [MFe(3)S(4)] Clusters (M = Cd, Cu, Cr) in Pyrococcus furiosus Ferredoxin.

The ground- and excited-state properties of heterometallic [CuFe(3)S(4)](2+,+), [CdFe(3)S(4)](2+,+), and [CrFe(3)S(4)](2+,+) cubane clusters assembled in Pyrococcus furiosus ferredoxin have been investigated by the combination of EPR and variable-temperature/variable-field magnetic circular dichroism (MCD) studies. The results indicate Cd(2+) incorporation into [Fe(3)S(4)](0,-) cluster fragments to yield S = 2 [CdFe(3)S(4)](2+) and S = (5)/(2) [CdFe(3)S(4)](+) clusters and Cu(+) incorporation into [Fe(3)S(4)](+,0) cluster fragments to yield S = (1)/(2) [CuFe(3)S(4)](2+) and S = 2 [CuFe(3)S(4)](+) clusters. This is the first report of the preparation of cubane type [CrFe(3)S(4)](2+,+) clusters, and the combination of EPR and MCD results indicates S = 0 and S = (3)/(2) ground states for the oxidized and reduced forms, respectively. Midpoint potentials for the [CdFe(3)S(4)](2+,+), [CrFe(3)S(4)](2+,+), and [CuFe(3)S(4)](2+,+) couples, E(m) = -470 +/- 15, -440 +/- 10, and +190 +/- 10 mV (vs NHE), respectively, were determined by EPR-monitored redox titrations or direct electrochemistry at a glassy carbon electrode. The trends in redox potential, ground-state spin, and electron delocalization of [MFe(3)S(4)](2+,+) clusters in P. furiosus ferredoxin are discussed as a function of heterometal (M = Cr, Mn, Fe, Co, Ni, Cu, Zn, Cd, and Tl).