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Guiling Zhou,1 Stijn de Vos,1 Catharina CM Schuiling-Veninga,1 Jens Bos,1 Katrien Oude Rengerink,2 Anna Maria Gerdina Pasmooij,2 Peter GM Mol,2,3 Geertruida H de Bock,4 Eelko Hak1 1Unit of Pharmaco-Therapy, -Epidemiology and -Economics (PTEE), Department of Pharmacy, University of Groningen, Groningen, the Netherlands; 2Medicines Evaluation Board, Utrecht, the Netherlands; 3Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; 4Department of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, the NetherlandsCorrespondence: Guiling Zhou, Unit of Pharmaco-Therapy, -Epidemiology and -Economics (PTEE), Department of Pharmacy, University of Groningen, Antonius Deusinglaan 1, Groningen, 9713 AV, the Netherlands, Tel +31 503638707, Fax +31 503632772, Email g.zhou@rug.nlBackground: Repurposing registered drugs could reduce coronavirus disease (COVID-19) burden before novel drugs are authorized. Little is known about how the pandemic and imposed restrictions changed their dispensing. We aimed to investigate the impact of COVID-19 pandemic on repurposed drugs dispensing in the Netherlands.Methods: We performed interrupted time-series study using University of Groningen prescription database IADB.nl to evaluate dispensing trends of 24 repurposed drugs before (2017-February 2020) and after (March 2020– 2021) the pandemic’ start. Primary outcomes were monthly prevalence and incidence rates. An autoregressive integrated moving average model assessed the effect of pandemic and stringency index (measuring strictness of government’s restriction policies).Results: Annual number of IADB.nl population ranged from 919,697 to 952,400. Generally, dispensing of common long-term-used drugs was not significantly affected by pandemic. The prevalence of antibacterials (− 4.20 users per 1000 people), antivirals (− 0.04), corticosteroids (− 1.29), prednisolone (− 1.32), calcium channel blocker (− 0.41), and diuretics (− 1.29) was lower than expected after the pandemic’s start, while the prevalence of ivermectin (0.07), sulfonylureas (0.15), sodium-glucose co-transporter-2 (SGLT2) inhibitor (0.17), and anticoagulants (1.95) was higher than expected. The pandemic was associated with statistically significant decreases in the incidence of antibacterials (− 1.21), corticosteroids (− 0.60), prednisolone (− 0.64) and anticoagulants (− 0.02), and increases in ivermectin (0.02), aggregated antidiabetic drugs (0.13), and SGLT2 inhibitors (0.06). These trends were positively associated with pandemic and negatively associated with stringency index.Conclusion: Dispensing of most drugs was not significantly associated with pandemic and government’s response. Despite some statistically significant disruptions, these were not necessarily clinically relevant due to small absolute differences observed.Keywords: COVID-19, drug utilization, repurposed drug, stringency index

Fan Zhang,1– 3 Geertruida H de Bock,1 Petra Denig,4 Gijs W Landman,5 Qingying Zhang,2 Grigory Sidorenkov1 1Department of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; 2Department of Preventive Medicine, Shantou University Medical College, Shantou, People’s Republic of China; 3Oncology Research Laboratory, Cancer Hospital of Shantou University Medical College, Shantou, People’s Republic of China; 4Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; 5Department of Internal Medicine, Gelre Hospital, Apeldoorn, the NetherlandsCorrespondence: Grigory Sidorenkov, Department of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands, Email g.sidorenkov@umcg.nlPurpose: Women with type 2 diabetes mellitus (T2DM) have an increased risk of breast cancer. We aimed to determine the contribution of lipids, glucose and blood pressure to this risk based on the multifactorial nature of T2DM.Patients and Methods: This population-based cohort study used data from a Dutch database (the Groningen Initiative to Analyse Type 2 Diabetes Treatment) for the period 2004– 2013. The cohort included women diagnosed with T2DM, aged 30– 80 years, with no history of breast cancer and with follow-up data for at least 1 year. We used Cox proportional hazards models to estimate the associations of exposures with breast cancer occurrence, reporting adjusted hazard ratios (aHR) with 95% confidence intervals (CI). Exposures of interest included total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides, glycated hemoglobin A (HbA1c) and systolic blood pressure (SBP).Results: During a median of 4.45 years’ follow-up, 183 of 10,183 included women received a breast cancer diagnosis. We observed U-shaped associations with breast cancer incidence for total cholesterol and HDL-C at baseline. Compared with moderate elevations, women had significantly higher breast cancer risks associated with high total cholesterol (aHR, 95% CI: 1.72, 1.15– 2.55) and HDL-C (aHR, 95% CI: 1.74, 1.18– 2.58) levels, while low total cholesterol (aHR, 95% CI: 1.43, 0.94– 2.19) and HDL-C (aHR, 95% CI: 1.44, 0.95– 2.17) levels produced marginal effects without significance. Women with high LDL-C levels more often received a breast cancer diagnosis than those with medium levels (aHR, 95% CI: 1.56, 1.03– 2.35).Conclusion: This real-world dataset highlights the importance of balancing lipid profiles, particularly total cholesterol and HDL-C. Dysregulation of the lipid profile, not the glucose or blood pressure profiles, may increase the risk of breast cancer in women with T2DM.Keywords: cholesterol, triglycerides, glycated hemoglobin A, systolic blood pressure, breast cancer

Yu Pu,1,* Xiuxiu Zhou,1,* Di Zhang,1,* Yu Guan,1,* Yi Xia,1 Wenting Tu,1 Yang Lu,2 Weidong Zhang,2 Chi-Cheng Fu,2 Qu Fang,2 Geertruida H de Bock,3 Shiyuan Liu,1 Li Fan1 1Department of Radiology, Changzheng Hospital, Naval Medical University, Shanghai, People’s Republic of China; 2Department of Scientific Research, Shanghai Aitrox Technology Corporation Limited, Shanghai, People’s Republic of China; 3Department of Epidemiology, University Medical Center Groningen, Groningen, the Netherlands*These authors contributed equally to this workCorrespondence: Shiyuan Liu; Li Fan, Department of Radiology, ChangZheng Hospital, Naval Medical University, No. 415 Fengyang Road, Shanghai, 200003, People’s Republic of China, Tel +86 21 81886012 ; Tel +86 21 81886012, Fax +86 21 63587668, Email cjr.liushiyuan@vip.163.com; fanli0930@163.comPurpose: To explore optimal threshold of FEV1% predicted value (FEV1%pre) for high-risk chronic obstructive pulmonary disease (COPD) using the parameter response mapping (PRM) based on machine learning classification model.Patients and Methods: A total of 561 consecutive non-COPD subjects who were screened for chest diseases in our hospital between August and October 2018 and who had complete questionnaire surveys, pulmonary function tests (PFT), and paired respiratory chest CT scans were enrolled retrospectively. The CT quantitative parameter for small airway remodeling was PRM, and 72 parameters were obtained at the levels of whole lung, left and right lung, and five lobes. To identify a more reasonable thresholds of FEV1% predicted value for distinguishing high-risk COPD patients from the normal, 80 thresholds from 50% to 129% were taken with a partition of 1% to establish a random forest classification model under each threshold, such that novel PFT-parameter-based high-risk criteria would be more consistent with the PRM-based machine learning classification model.Results: Machine learning-based PRM showed that consistency between PRM parameters and PFT was better able to distinguish high-risk COPD from the normal, with an AUC of 0.84 when the threshold was 72%. When the threshold was 80%, the AUC was 0.72 and when the threshold was 95%, the AUC was 0.64.Conclusion: Machine learning-based PRM is feasible for redefining high-risk COPD, and setting the optimal FEV1% predicted value lays the foundation for redefining high-risk COPD diagnosis.Keywords: chronic obstructive pulmonary disease, computed tomography, pulmonary function test, quantitative imaging, artificial intelligence

Justine M Briët,1 Marian JE Mourits,1 Barbara L van Leeuwen,2 Edwin R van den Heuvel,3 Monique JA Kenkhuis,1 Henriette JG Arts,1 Geertruida H de Bock3 1Department of Gynecologic Oncology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; 2Department of Surgical Oncology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; 3Department of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands Purpose: A prospective, multicenter cohort study was performed on the implementation of laparoscopic hysterectomy (LH) in the Netherlands. The aim of this study was to evaluate the impact of LH on quality of life (QOL) with respect to age up to 6 months postoperatively. Patients and methods: Women with an indication for LH, either for benign conditions or early-stage low-risk endometrial cancer were included. QOL was measured before and 6 weeks and 6 months after surgery, using the 36-item Short Form Health Survey. Mean QOL values were compared to an unselected, female, Dutch reference population. A longitudinal linear mixed model was applied to assess changes in QOL over time after LH and to determine if in patients ≥65 years of age QOL scores were different. Results: Data on 116 patients were available for analysis. The median age was 54 years at time of surgery (range 34–83) with an interquartile range of 43–65 years. Six months after LH, all QOL values were higher than before surgery and were equal to or higher than those of the reference population. Older women tend to score higher on QOL preoperatively, and these scores remain high postoperatively. Conclusion: After LH, QOL improves. Older women report higher QOL values preoperatively and QOL is still high 6 months after the operation. Age does not confer a negative impact on QOL following LH and should not be the reason to refrain from laparoscopic surgery. Keywords: quality of life, laparoscopic surgery, hysterectomy, elderly

The identification of causal BRCA1/2 pathogenic variants (PVs) in epithelial ovarian carcinoma (EOC) aids the selection of patients for genetic counselling and treatment decision‐making. Current recommendations therefore stress sequencing of all EOCs, regardless of histotype. Although it is recognised that BRCA1/2 PVs cluster in high‐grade serous ovarian carcinomas (HGSOC), this view is largely unsubstantiated by detailed analysis. Here, we aimed to analyse the results of BRCA1/2 tumour sequencing in a centrally revised, consecutive, prospective series including all EOC histotypes. Sequencing of n = 946 EOCs revealed BRCA1/2 PVs in 125 samples (13%), only eight of which were found in non‐HGSOC histotypes. Specifically, BRCA1/2 PVs were identified in high‐grade endometrioid (3/20; 15%), low‐grade endometrioid (1/40; 2.5%), low‐grade serous (3/67; 4.5%), and clear cell (1/64; 1.6%) EOCs. No PVs were identified in any mucinous ovarian carcinomas tested. By re‐evaluation and using loss of heterozygosity and homologous recombination deficiency analyses, we then assessed: (1) whether the eight 'anomalous' cases were potentially histologically misclassified and (2) whether the identified variants were likely causal in carcinogenesis. The first 'anomalous' non‐HGSOC with a BRCA1/2 PV proved to be a misdiagnosed HGSOC. Next, germline BRCA2 variants, found in two p53‐abnormal high‐grade endometrioid tumours, showed substantial evidence supporting causality. One additional, likely causal variant, found in a p53‐wildtype low‐grade serous ovarian carcinoma, was of somatic origin. The remaining cases showed retention of the BRCA1/2 wildtype allele, suggestive of non‐causal secondary passenger variants. We conclude that likely causal BRCA1/2 variants are present in high‐grade endometrioid tumours but are absent from the other EOC histotypes tested. Although the findings require validation, these results seem to justify a transition from universal to histotype‐directed sequencing. Furthermore, in‐depth functional analysis of tumours harbouring BRCA1/2 variants combined with detailed revision of cancer histotypes can serve as a model in other BRCA1/2‐related cancers. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland. [ABSTRACT FROM AUTHOR]

Objective: To assess the short- and long-term effects of mindfulness-based stress reduction (MBSR) on the resulting quality of life, sexual functioning, and sexual distress after risk-reducing salpingo-oophorectomy (RRSO).Design: Randomised controlled trial.Setting: A specialised family cancer clinic of the university medical center Groningen.Population: Sixty-six women carriers of the BRCA1/2 mutation who developed at least two moderate-to-severe menopausal symptoms after RRSO.Methods: Women were randomised to an 8-week MBSR training programme or to care as usual (CAU).Main Outcome Measures: Change in the Menopause-Specific Quality of Life Questionnaire (MENQOL), the Female Sexual Function Index, and the Female Sexual Distress Scale, administered from baseline at 3, 6, and 12 months. Linear mixed modelling was applied to compare the effect of MBSR with CAU over time.Results: At 3 and 12 months, there were statistically significant improvements in the MENQOL for the MBSR group compared with the CAU group (both P = 0.04). At 3 months, the mean MENQOL scores were 3.5 (95% confidence interval, 95% CI 3.0-3.9) and 3.8 (95% CI 3.3-4.2) for the MBSR and CAU groups, respectively; at 12 months, the corresponding values were 3.6 (95% CI 3.1-4.0) and 3.9 (95% CI 3.5-4.4). No significant differences were found between the MBSR and CAU groups in the other scores.Conclusion: Mindfulness-based stress reduction was effective at improving quality of life in the short- and long-term for patients with menopausal symptoms after RRSO; however, it was not associated with an improvement in sexual functioning or distress.Tweetable Abstract: Mindfulness improves menopause-related quality of life in women after risk-reducing salpingo-oophorectomy. [ABSTRACT FROM AUTHOR]

Background: During menopause women experience vasomotor and psychosexual symptoms that cannot entirely be alleviated with hormone replacement therapy (HRT). Besides, HRT is contraindicated after breast cancer. Objectives: To review the evidence on the effectiveness of psychological interventions in reducing symptoms associated with menopause in natural or treatment‐induced menopausal women. Search strategy: Medline/Pubmed, PsycINFO, EMBASE and AMED were searched until June 2017. Selection criteria: Randomised controlled trials (RCTs) concerning natural or treatment‐induced menopause, investigating mindfulness or (cognitive‐)behaviour‐based therapy were selected. Main outcomes were frequency of hot flushes, hot flush bother experienced, other menopausal symptoms and sexual functioning. Data collection and analysis: Study selection and data extraction were performed by two independent researchers. A meta‐analysis was performed to calculate the standardised mean difference (SMD). Main results: Twelve RCTs were included. Short‐term (<20 weeks) effects of psychological interventions in comparison to no treatment or control were observed for hot flush bother (SMD −0.54, 95% CI −0.74 to −0.35, P < 0.001, I2 = 18%) and menopausal symptoms (SMD −0.34, 95% CI −0.52 to −0.15, P < 0.001, I2 = 0%). Medium‐term (≥20 weeks) effects were observed for hot flush bother (SMD −0.38, 95% CI −0.58 to −0.18, P < 0.001, I2 = 16%). [Correction added on 9 July 2018, after first online publication: there were miscalculations of the mean end point scores for hot flush bother and these have been corrected in the preceding two sentences.] In the subgroup treatment‐induced menopause, consisting of exclusively breast cancer populations, as well as in the subgroup natural menopause, hot flush bother was reduced by psychological interventions. Too few studies reported on sexual functioning to perform a meta‐analysis. Conclusions: Psychological interventions reduced hot flush bother in the short and medium‐term and menopausal symptoms in the short‐term. These results are especially relevant for breast cancer survivors in whom HRT is contraindicated. There was a lack of studies reporting on the influence on sexual functioning. Systematic review: psychological interventions reduce bother by hot flushes in the short‐ and medium‐term. Systematic review: psychological interventions reduce bother by hot flushes in the short‐ and medium‐term. [ABSTRACT FROM AUTHOR]

Objective: To assess the sensitivity of detection and accuracy of volumetry by manual and semi-automated quantification of artificial pulmonary nodules in an anthropomorphic thoracic phantom on low-dose CT.Methods: Fifteen artificial spherical nodules (diameter 3, 5, 8, 10 and 12 mm; CT densities -800, -630 and +100 HU) were randomly placed inside an anthropomorphic thoracic phantom. The phantom was examined on 16- and 64-row multidetector CT with a low-dose protocol. Two independent blinded observers screened for pulmonary nodules. Nodule diameter was measured manually, and volume calculated. For solid nodules (+100 HU), diameter and volume were also evaluated by semi-automated software. Differences in observed volumes between the manual and semi-automated method were evaluated by a t-test.Results: Sensitivity was 100 % for all nodules of >5 mm and larger, 60-80 % for solid and 0-20 % for non-solid 3-mm nodules. No false-positive nodules but high inter-observer reliability and inter-technique correlation were found. Volume was underestimated manually by 24.1 ± 14.0 % for nodules of any density, and 26.4 ± 15.5 % for solid nodules, compared with 7.6 ± 8.5 % (P < 0.01) semi-automatically.Conclusion: In an anthropomorphic phantom study, the sensitivity of detection is 100 % for nodules of >5 mm in diameter. Semi-automated volumetry yielded more accurate nodule volumes than manual measurements. [ABSTRACT FROM AUTHOR]

Objectives: A systematic review and meta-analysis to assess sensitivity and specificity of coronary CT angiography (CCTA) for significant stenosis at different degrees of coronary calcification.Methods: A literature search was performed including studies describing test characteristics of CCTA for significant stenosis, performed with at least 16-MDCT and according to calcium score (CS). Invasive coronary angiography was the reference standard. Pooled sensitivity and specificity of CCTA by CS categories and CT equipment were calculated.Results: Of 14,121 articles, 51 studies reported on the impact of calcium scoring on diagnostic performance of CCTA and could be included in the systematic review. Twenty-seven of these studies (5,203 participants) were suitable for meta-analysis. On a patient-basis, sensitivity of CCTA for significant stenosis was 95.8, 95.6, 97.6 and 99.0% for CS 0-100, 101-400, 401-1,000 and >1,000 respectively. Specificity was 91.2, 88.2, 50.6 and 84.0% respectively. Specificity of CCTA was significantly lower for CS 401-1,000 due to lack of patients without significant stenosis. Sensitivity and specificity of 16-MDCT were significantly lower compared to more modern CT systems.Conclusions: Even in cases of severe coronary calcification, sensitivity and specificity of CCTA for significant stenosis are high. With 64-MDCT and newer CT systems, a CS cut-off for performing CCTA no longer seems indicated.Key Points: Decisions about performing coronary CT angiography (CCTA) sometimes depend on calcium scoring. CCTA is highly sensitive for coronary stenosis. With 16-MDCT, however, heavy calcification reduces specificity for significant stenosis. For 64-MDCT (and above), CCTA has high specificity, even with severe coronary calcification. [ABSTRACT FROM AUTHOR]

Objective: To evaluate performance of computer-aided detection (CAD) beyond double reading for pulmonary nodules on low-dose computed tomography (CT) by nodule volume.Methods: A total of 400 low-dose chest CT examinations were randomly selected from the NELSON lung cancer screening trial. CTs were evaluated by two independent readers and processed by CAD. A total of 1,667 findings marked by readers and/or CAD were evaluated by a consensus panel of expert chest radiologists. Performance was evaluated by calculating sensitivity of pulmonary nodule detection and number of false positives, by nodule characteristics and volume.Results: According to the screening protocol, 90.9 % of the findings could be excluded from further evaluation, 49.2 % being small nodules (less than 50 mm(3)). Excluding small nodules reduced false-positive detections by CAD from 3.7 to 1.9 per examination. Of 151 findings that needed further evaluation, 33 (21.9 %) were detected by CAD only, one of them being diagnosed as lung cancer the following year. The sensitivity of nodule detection was 78.1 % for double reading and 96.7 % for CAD. A total of 69.7 % of nodules undetected by readers were attached nodules of which 78.3 % were vessel-attached.Conclusions: CAD is valuable in lung cancer screening to improve sensitivity of pulmonary nodule detection beyond double reading, at a low false-positive rate when excluding small nodules.Key Points: • Computer-aided detection (CAD) has known advantages for computed tomography (CT). • Combined CAD/nodule size cut-off parameters assist CT lung cancer screening. • This combination improves the sensitivity of pulmonary nodule detection by CT. • It increases the positive predictive value for cancer detection. [ABSTRACT FROM AUTHOR]

Objectives: To determine the correlation between CT measurements of emphysema or peripheral airways and airflow obstruction in chronic obstructive pulmonary disease (COPD).Methods: PubMed, Embase and Web of Knowledge were searched from 1976 to 2011. Two reviewers independently screened 1,763 citations to identify articles that correlated CT measurements to airflow obstruction parameters of the pulmonary function test in COPD patients, rated study quality and extracted information. Three CT measurements were accessed: lung attenuation area percentage < -950 Hounsfield units, mean lung density and airway wall area percentage. Two airflow obstruction parameters were accessed: forced expiratory volume in the first second as percentage from predicted (FEV(1) %pred) and FEV(1) divided by the forced volume vital capacity.Results: Seventy-nine articles (9,559 participants) were included in the systematic review, demonstrating different methodologies, measurements and CT airflow obstruction correlations. There were 15 high-quality articles (2,095 participants) in the meta-analysis. The absolute pooled correlation coefficients ranged from 0.48 (95 % CI, 0.40 to 0.54) to 0.65 (0.58 to 0.71) for inspiratory CT and 0.64 (0.53 to 0.72) to 0.73 (0.63 to 0.80) for expiratory CT.Conclusions: CT measurements of emphysema or peripheral airways are significantly related to airflow obstruction in COPD patients. CT provides a morphological method to investigate airway obstruction in COPD.Key Points: • Computed tomography is widely performed in patients with chronic obstructive pulmonary disease (COPD) • CT provides quantitative morphological methods to investigate airflow obstruction in COPD • CT measurements correlate significantly with the degree of airflow obstruction in COPD • Expiratory CT measurements correlate more strongly with airflow obstruction than inspiratory CT • Low-dose CT decreases the radiation dose for diagnosis and quantitative emphysema evaluation. [ABSTRACT FROM AUTHOR]