Search

BACKGROUND: Lung ultrasound (LUS) can be used to monitor critically ill patients with COVID-19, but the optimal number of examined lung zones is disputed. METHODS: This was a prospective observational study. The objective was to investigate whether concise (6 zones) and extended (12 zones) LUS scoring protocols are clinically equivalent in critically ill ICU subjects with COVID-19. The primary outcome of this study was (statistical) agreement between concise and extended LUS score index evaluated in both supine and prone position. Agreement was determined using correlation coefficients and Bland-Altman plots to detect systematic differences between protocols. Secondary outcomes were difference between LUS score index in supine and prone position using similar methods. RESULTS: We included 130 LUS examinations in 40 subjects (mean age 69.0 ± 8.5y, 75% male). Agreement between concise and extended LUS score index had no clinically relevant constant or proportional bias and limits of agreement were below the smallest detectable change. Across position changes, supine LUS score index was 8% higher than prone LUS score index and had limits above the smallest detectable change, indicating true LUS score index differences between protocols may occur due to the position change itself. Lastly, inter-rater and intra-rater agreement were very good. CONCLUSIONS: Concise LUS was equally informative as extended LUS for monitoring critically ill subjects with COVID-19 in supine or prone position. Clinicians can monitor patients undergoing position changes but must be wary that LUS score index alterations may result from the position change itself rather than disease progression or clinical improvement.

Background: Endometrial cancer can be molecularly classified into POLEmut, mismatch repair deficient (MMRd), p53 abnormal (p53abn), and no specific molecular profile (NSMP) subgroups. We aimed to develop an interpretable deep learning pipeline for whole-slide-image-based prediction of the four molecular classes in endometrial cancer (im4MEC), to identify morpho-molecular correlates, and to refine prognostication. Methods: This combined analysis included diagnostic haematoxylin and eosin-stained slides and molecular and clinicopathological data from 2028 patients with intermediate-to-high-risk endometrial cancer from the PORTEC-1 (n=466), PORTEC-2 (n=375), and PORTEC-3 (n=393) randomised trials and the TransPORTEC pilot study (n=110), the Medisch Spectrum Twente cohort (n=242), a case series of patients with POLEmut endometrial cancer in the Leiden Endometrial Cancer Repository (n=47), and The Cancer Genome Atlas-Uterine Corpus Endometrial Carcinoma cohort (n=395). PORTEC-3 was held out as an independent test set and a four-fold cross validation was performed. Performance was measured with the macro and class-wise area under the receiver operating characteristic curve (AUROC). Whole-slide images were segmented into tiles of 360 μm resized to 224 × 224 pixels. im4MEC was trained to learn tile-level morphological features with self-supervised learning and to molecularly classify whole-slide images with an attention mechanism. The top 20 tiles with the highest attention scores were reviewed to identify morpho-molecular correlates. Predictions of a nuclear classification deep learning model serve to derive interpretable morphological features. We analysed 5-year recurrence-free survival and explored prognostic refinement by molecular class using the Kaplan-Meier method. Findings: im4MEC attained macro-average AUROCs of 0·874 (95% CI 0·856–0·893) on four-fold cross-validation and 0·876 on the independent test set. The class-wise AUROCs were 0·849 for POLEmut (n=51), 0·844 for MMRd (n=134), 0·883 for NSMP (n=120), and 0·928 for p53abn (n=88). POLEmut and MMRd tiles had a high density of lymphocytes, p53abn tiles had strong nuclear atypia, and the morphology of POLEmut and MMRd endometrial cancer overlapped. im4MEC highlighted a low tumour-to-stroma ratio as a potentially novel characteristic feature of the NSMP class. 5-year recurrence-free survival was significantly different between im4MEC predicted molecular classes in PORTEC-3 (log-rank pmut had an excellent prognosis, as do those with true POLEmut endometrial cancer. Interpretation: We present the first interpretable deep learning model, im4MEC, for haematoxylin and eosin-based prediction of molecular endometrial cancer classification. im4MEC robustly identified morpho-molecular correlates and could enable further prognostic refinement of patients with endometrial cancer. Funding: The Hanarth Foundation, the Promedica Foundation, and the Swiss Federal Institutes of Technology.

The time course of smooth muscle contraction can be divided into two phases, the initial phase is associated with force development, whereas the sustained phase is associated with force maintenance. Cumulative evidence suggests that the two phases are regulated by different signaling pathways and that ρ-kinase (ROCK) and protein kinase C (PKC) play an important role in regulating isometric force in sustained contractions. Since the maintenance of sustained force is critical to the function of vascular smooth muscle, unraveling the complex mechanism of force maintenance is crucial for understanding the cell biology of the muscle. The present study examined the effects of ROCK and PKC on the level of phosphorylation of the 20-kD myosin light chain (MLC20) and isometric force during a sustained contraction. We used partial activation and inhibition of ROCK and PKC to reduce the isometric force by 50% of the maximal isometric force in fully activated muscle, F

Background Occupational exposure to soluble chlorinated platinum (Pt) salts, commonly called chloroplatinates, is a known cause of Pt salt sensitisation (PSS) and occupational asthma. We aimed to model inhalable soluble Pt salts exposure levels based on measurements in precious metal refineries for use in a retrospective cohort study on PSS. Methods Five platinum refineries located in the United Kingdom (3 sites), United States, and South Africa provided time weighted average inhalable soluble Pt salts exposure data, measured in 2,982 personal air samples over a 17-year period (2000-2016). We used a Bayesian hierarchical model to estimate geometric mean (GM) exposure levels for each refinery and job title over time. Results The GM of measured exposure levels over all facilities was 92 ng/m3 with a geometric standard deviation (GSD) of 9.07. Facility-specific GMs ranged from 48 ng/m3 (GSD 15.3) to 242 ng/m3 (GSD 5.99). Exposure modelling showed that soluble Pt salts exposure levels declined approximately 10% per year in two of the five facilities, but there were no clear time trends in the other facilities. A priori specified exposure groups captured most of the between-jobs differences, which helps to accurately predict exposures for jobs with no measurement data available. Conclusions We applied exposure modelling to estimate time, refinery, and job-specific soluble Pt salts exposures. A significant annual decline in exposure levels was observed in two of the five participating facilities. Modelled exposure levels can be linked to individual workers’ job history for exposure–response analysis of PSS in an epidemiological study.

Background. Diagnosing and discriminating non-cardiogenic interstitial syndrome (NCIS) and cardiogenic pulmonary edema (CPE) is notoriously difficult in a mixed intensive care unit (ICU) population. We hypothesized that a comprehensive lung ultrasound exam can be used to accurately diagnose interstitial syndrome and can discriminate between NCIS and CPE.Methods. A single center prospective diagnostic accuracy study was used as derivation cohort and a post-hoc analysis of a multi-center prospective observational study as validation cohort. Consecutive adult ICU patients that received a lung ultrasound examination for clinical or study purposes were included. The reference standard was the diagnosis interstitial syndrome (NCIS or CPE) or non-interstitial syndromes (other pulmonary diagnoses and no pulmonary diagnoses) at the moment of examination based on full post-hoc clinical chart review except lung ultrasound. The index test was a comprehensive lung ultrasound examination performed and scored by a researcher blinded to clinical information.Results. 101 patients were included in the derivation and 125 in validation cohort. In the derivation cohort, patients with interstitial syndrome (n=56) were reliably discriminated from other patients based on the presence of a B-pattern (defined as ≥3 B-lines in one frame) with an accuracy of 94.7% (sens 90.9%, spec 91.1%), while specificity was higher for a bilateral B-pattern (accuracy 86.0%; sens 74.5%, spec 100%). For the discrimination of NCIS (n=29) from CPE (n=27), the presence of bilateral pleural line abnormalities had the highest diagnostic accuracy (94.6%; sens 89.3%, spec 100%) followed by consolidation (76.8%; sens 69.0%, spec 85.2%) and subtle lung sliding (67.9%; sens 62.1%, spec 74.1%). A diagnostic algorithm (BLUISH protocol) using B-pattern and bilateral pleural abnormalities had an accuracy of 0.86 (95%CI 0.77-0.95) for diagnosis and discrimination of interstitial syndromes. In the validation cohort, which included 125 patients with interstitial syndrome, pleural line abnormalities discriminated NCIS (n=101) from CPE (n=24) with a sensitivity of 30% (95%CI 21-40%) and a specificity of 100% (95%CI: 86-100%). Conclusions. Lung ultrasound can be used to diagnose and discriminate interstitial syndromes in ICU patients with moderate to good accuracy. Pleural line abnormalities are highly specific for NCIS, but sensitivity is limited.

Surgical A1 pulley release can considerably reduce pain and improve hand function, but individual outcomes are highly variable. This study aimed to identify factors contributing to self-reported pain and hand function 3 months postoperatively. We included 2681 patients who had received surgical treatment for a trigger finger or thumb and who completed the Michigan Hand outcomes Questionnaire (MHQ). Hierarchical linear regression models were used to investigate patient and clinical characteristics associated with postoperative pain and hand function. For both pain and hand function, the most influential factors associated with worse outcomes were worse MHQ scores at baseline (β 0.38 and 0.33, respectively) and ≥3 preoperative steroid injections (β –0.36 and –0.35). These factors indicated that patients with severe preoperative symptoms represent a group with a more advanced disease that is more difficult to treat. These findings can assist clinicians in patient counselling, expectation management and decision-making about the timing of the intervention. Level of evidence: II

In order to improve molecular response for a discontinuation attempt in chronic myeloid leukemia (CML) patients in chronic phase, who had not achieved at least a molecular response IS (MR 4.0) after at least 2 years of imatinib therapy, we prospectively evaluated whether they could attain MR 4.0 after a switch to a combination of nilotinib and 9 months of pegylated interferon-α2b (PegIFN). The primary endpoint of confirmed MR 4.0 at month 12 (a BCR-ABL1 IS level ≤ 0.01% both at 12 and 15 months) was reached by 44% (7/16 patients, 95% confidence interval (CI): 23- 67%) of patients, with 81% (13/16 patients, 95% CI: 57-93%) of patients achieving an unconfirmed MR 4.0. The scheduled combination was completed by 56% of the patients, with premature discontinuations, mainly due to mood disturbances after the introduction of PegIFN, questioning the feasibility of the combination of nilotinib and PegIFN for this patient population and treatment goal. A comprehensive clinical substudy program was implemented to characterize the impact of the treatment changes on the immunological profile. This trial was registered at www.clinicaltrials.gov as #NCT01866553.

Arthritogenic alphaviruses, including chikungunya virus (CHIKV), preferentially target joint tissues and cause chronic rheumatic disease that adversely impacts the quality of life of patients. Viruses enter target cells via interaction with cell surface receptor(s), which determine the viral tissue tropism and pathogenesis. Although MXRA8 is a recently identified receptor for several clinically relevant arthritogenic alphaviruses, its detailed role in the cell entry process has not been fully explored. We found that in addition to its localization on the plasma membrane, MXRA8 is present in acidic organelles, endosomes, and lysosomes. Moreover, MXRA8 is internalized into cells without a requirement for its transmembrane and cytoplasmic domains. Confocal microscopy and live cell imaging revealed that MXRA8 interacts with CHIKV at the cell surface and then enters cells along with CHIKV particles. At the moment of membrane fusion in the endosomes, many viral particles are still colocalized with MXRA8. These findings provide insight as to how MXRA8 functions in alphavirus internalization and suggest possible targets for antiviral development. IMPORTANCE The globally distributed arthritogenic alphaviruses have infected millions of humans and induce rheumatic disease, such as severe polyarthralgia/polyarthritis, for weeks to years. Alphaviruses infect target cells through receptor(s) followed by clathrin-mediated endocytosis. MXRA8 was recently identified as an entry receptor that shapes the tropism and pathogenesis for multiple arthritogenic alphaviruses, including chikungunya virus (CHIKV). Nonetheless, the exact functions of MXRA8 during the process of viral cell entry remain undetermined. Here, we have provided compelling evidence for MXRA8 as a bona fide entry receptor that mediates the uptake of alphavirus virions. Small molecules that disrupt MXRA8-dependent binding of alphaviruses or internalization steps could serve as a platform for unique classes of antiviral drugs.

Contains fulltext : 273921.pdf (Publisher’s version ) (Open Access) BACKGROUND: T4-classified squamous cell carcinoma (SCC) of external auditory canal (EAC) can potentially involve different anatomical structures, which could translate into different treatment strategies and survival outcomes within one classification. Our aim is to evaluate the clinical added value of T4-subclasses proposed by Lavieille and by Zanoletti. METHODS: Retrospective data, including patients with primary operated cT4-classified EAC SCC, was obtained from 12 international hospitals. We subclassified according to the T4-subclasses. The treatment strategies, disease-free survival (DFS) and overall survival per subclass were calculated. RESULTS: A total of 130 T4-classified EAC SCC were included. We found commonly used treatment strategies per subclass according to Lavieille and the DFS seems also to differ per subclass. Subclass according to Zanoletti showed comparable treatment strategies and survival outcomes per subclass. CONCLUSION: Our study suggests that the subclass according Lavieille might have added value in clinical practice to improve care of T4-classified EAC SCC.

Increasingly, researchers in developed economies are associating the exponential growth in share repurchases with executives’ desire to increase company share price and thus the value of their own share-based compensation. As research on this topic in emerging economies is sparse, this paper investigates the relationship between share repurchases and executive share-based compensation in South Africa. Certain weaknesses in South African corporate governance relating to share repurchases exacerbate the risk of camouflaged rent extraction and unethical behaviour. Regression analyses were executed, using data on share repurchases and executive share-based compensation variables for listed South African companies for the period 2002–2017. Statistically significant positive relationships were identified between share repurchases and executive share-based compensation. The results support the proposition that South African executives may be repurchasing shares in a bid to increase the value of their share-based compensation (in line with the managerial power theory), rather than maximising long-term shareholder value. This paper emphasises the need for improved corporate governance relating to share repurchases in South Africa. Given the income inequality in South Africa, the findings also have social justice implications.

In this paper, we show that magnetic skyrmion nucleation can be controlled using Ga+ ion irradiation, which manipulates the magnetic interface effects (in particular the magnetic anisotropy and Dzyaloshinskii-Moriya interaction) that govern the stability and energy cost of skyrmions in thin film systems. We systematically and quantitatively investigated what effect these changes have on the nucleation of magnetic skyrmions. Our results indicate that the energy cost of skyrmion nucleation can be reduced up to 26% in the studied dose range and that it scales approximately linearly with the square root of the domain-wall energy density. Moreover, the total number of nucleated skyrmions in irradiated devices after nucleation was found to depend linearly on the ion dose and could be doubled compared to nonirradiated devices. These results show that ion irradiation cannot only be used to enable local nucleation of skyrmions, but that it also allows for fine control of the threshold and efficiency of the nucleation process., Comment: Main: 17 pages, 3 figures; Supplemental Material: 7 pages, 5 figures

Objectives: To investigate the impact of thoracic ultrasound (TUS) examinations on clinical management in adult ICU patients. Design: A prospective international observational study. Setting: Four centers in The Netherlands and Italy. Patients: Adult ICU patients (> 18 yr) that received a clinically indicated lung ultrasound examination. Interventions: None. Measurements and Main Results: Clinicians performing TUS completed a pre-and post-examination case report form. Patient characteristics, TUS, and resulting clinical effects were recorded. First, change of management, defined as a TUS-induced change in clinical impression leading to a change in treatment plan, was reported. Second, execution of intended management changes within 8 hours was verified. Third, change in fluid balance after 8 hours was calculated. A total of 725 TUS performed by 111 operators across 534 patients (mean age 63 ± 15.0, 70% male) were included. Almost half of TUS caused a change in clinical impression, which resulted in change of management in 39% of cases. The remainder of TUS confirmed the clinical impression, while a minority (4%) did not contribute. Eighty-nine percent of management changes indicated by TUS were executed within 8 hours. TUS examinations that led to a change in fluid management also led to distinct and appropriate changes in patient's fluid balance. Conclusions: In this international observational study in adult ICU patients, use of TUS had a major impact on clinical management. These results provide grounds for future randomized controlled trials to determine if TUS-induced changes in decision-making also lead to improved health outcomes.

Background It is unclear if relevant changes in pulmonary involvement in critically ill COVID-19 patients can be reliably detected by the CT severity score (CTSS) and lung ultrasound score (LUSS), or if these changes have prognostic implications. In addition, it has been argued that adding pleural abnormalities to the LUSS could improve its prognostic value. The objective of this study was to compare LUSS and CTSS for the monitoring of COVID-19 pulmonary involvement through: first, establishing the correlation of LUSS (± pleural abnormalities) and CTSS throughout admission; second, assessing agreement and measurement error between raters for LUSS, pleural abnormalities, and CTSS; third, evaluating the association of the LUSS (± pleural abnormalities) and CTSS with mortality at different timepoints. Methods This is a prospective, observational study, conducted during the second COVID-19 wave at the AmsterdamUMC, location VUmc. Adult COVID-19 ICU patients were prospectively included when a CT or a 12-zone LUS was performed at admission or at weekly intervals according to local protocol. Patients were followed 90 days or until death. We calculated the: (1) Correlation of the LUSS (± pleural abnormalities) and CTSS throughout admission with mixed models; (2) Intra-class correlation coefficients (ICCs) and smallest detectable changes (SDCs) between raters; (3) Association between the LUSS (± pleural abnormalities) and CTSS with mixed models. Results 82 consecutive patients were included. Correlation between LUSS and CTSS was 0.45 (95% CI 0.31–0.59). ICCs for LUSS, pleural abnormalities, and CTSS were 0.88 (95% CI 0.73–0.95), 0.94 (95% CI 0.90–0.96), and 0.84 (95% CI 0.65–0.93), with SDCs of 4.8, 1.4, and 3.9. The LUSS was associated with mortality in week 2, with a score difference between patients who survived or died greater than its SDC. Addition of pleural abnormalities was not beneficial. The CTSS was associated with mortality only in week 1, but with a score difference less than its SDC. Conclusions LUSS correlated with CTSS throughout ICU admission but performed similar or better at agreement between raters and mortality prognostication. Given the benefits of LUS over CT, it should be preferred as initial monitoring tool.

Background: Childhood trauma may contribute to poorer premorbid social and academic adjustment which may be a risk factor for schizophrenia.Aim: We explored the relationship between premorbid adjustment and childhood trauma, timing of childhood trauma’s moderating role as well as the association of clinical and treatment-related confounders with premorbid adjustment.Setting: We conducted a secondary analysis in 111 patients with first-episode schizophrenia (FES) disorders that formed part of two parent studies, EONKCS study (n =73) and the Shared Roots study (n =38).Methods: Type of childhood trauma was assessed with the Childhood Trauma Questionnaire, short-form and premorbid adjustment using the Premorbid Adjustment Scale. Timing of childhood trauma was assessed using the Life Events Checklist and life events timeline. Linear regression analyses were used to assess the moderating effect of timing of childhood trauma. Clinical and treatment-related confounders were entered into sequential hierarchical regression models to identify independent predictors of premorbid adjustment across key life stages.Results: Childhood physical neglect was associated with poorer premorbid academic functioning during childhood and early adolescence, and poorer premorbid social functioning during early and late adolescence. By hierarchical regression modelling (r2 = 0.13), higher physical neglect subscale scores (p = 0.011) independently predicted poorer premorbid social adjustment during early adolescence. Timing of childhood trauma did not moderate the relationship between childhood trauma and premorbid functioning.Conclusion: In patients with FES, childhood physical neglect may contribute to poorer premorbid social functioning during early adolescence. This may provide us with an opportunity to identify and treat at-risk individuals earlier.

Background. Poor nutrition practices result in malnutrition, a public health concern that affects a third of children globally. In Zimbabwe, ~27.6% of children under-5 years old are stunted. Some of these children spend long hours in early childhood development centres (ECDCs). Children can receive half to two-thirds of their daily food intake while in care, making ECDCs an ideal entry point to influence child nutrition positively. There are no specific nutrition guidelines for ECDCs in Zimbabwe. Objective. The study aimed to investigate food provision at ECDCs of the Northern-Central District of Harare.Methods. A descriptive, cross-sectional study with an analytical component was conducted in 15 ECDCs. Fifteen ECD managers (ECDMs) and 14 food handlers (FHs) were included in the study. An observational checklist allowed recording of food preparation and hygiene practices. The Dietary Diversity Score (DDS) of the menu was calculated using the Food and Agriculture Organisation (FAO) 9-group DDS sheet.Results. Inadequate food storage facilities and food handling practices were observed. Staff had minimal nutrition-related training. Staff displayed a positive attitude towards their role in providing healthy meals. Barriers to serving healthy meals were inadequate funds, children’s food preferences, unrealistic parental expectations, and external factors. The mean DDS score for menus was 2.8. Meals consisted mainly of starchy items, legumes and meat, and lacked fruit and dairy items.Conclusion. National guidelines can improve children’s dietary intake while in day care. In alignment with Sustainable Development Goals 2 and 3, food provision at ECDCs should be a priority.

Introduction: The phase 3 PACIFIC trial established consolidation therapy with durvalumab as standard of care for patients with unresectable, stage III NSCLC and no disease progression after definitive chemoradiotherapy (CRT). The observational PACIFIC-R study assesses the real-world effectiveness of durvalumab in patients from an early access program. Here, we report treatment characteristics and a preplanned analysis of real-world progression-free survival (rwPFS).Methods: PACIFIC-R (NCT03798535) is an ongoing, international, retrospective study of patients who started durvalumab (intravenously; 10 mg/kg every 2 wk) within an early access program between September 2017 and December 2018. The primary end points are investigator-assessed rwPFS and overall survival (analyzed by Kaplan–Meier method).Results: As of November 30, 2020, the full analysis set comprised 1399 patients from 11 countries (median follow-up duration, 23.5 mo). Patients received durvalumab for a median of 11.0 months. Median rwPFS was 21.7 months (95% confidence interval: 19.1–24.5). RwPFS was numerically longer among patients who received concurrent versus sequential CRT (median, 23.7 versus 19.3 mo) and among patients with programmed cell death-ligand 1 expression greater than or equal to 1% versus less than 1% (22.4 versus 15.6 mo). Overall, 16.5% of the patients had adverse events leading to treatment discontinuation; 9.5% of all patients discontinued because of pneumonitis or interstitial lung disease.Conclusions: Consolidation durvalumab after definitive CRT was well tolerated and effective in this large, real-world cohort study of patients with unresectable, stage III NSCLC. As expected, rwPFS was longer among patients who received concurrent versus sequential CRT and patients with higher programmed cell death-ligand 1 expression. Nevertheless, favorable rwPFS outcomes were observed regardless of these factors.

Purpose: Definitive chemoradiotherapy (dCRT) is a treatment option with curative intent for patients with esophageal cancer that could result in late toxicities and affect health-related quality of life (HRQoL). This study aimed to review the literature and perform a meta-analysis to investigate the effect of dCRT on late toxicities and HRQoL in esophageal cancer. Methods and Materials: A systematic search was performed in MEDLINE, EMBASE, and PsychINFO. Prospective phase II and III clinical trials, population-based studies, and retrospective chart reviews investigating late toxicity or HRQoL after dCRT (≥50 Gy) were included. The HRQoL outcomes were analyzed using linear mixed-effect models with restricted cubic spline transformation. Any HRQoL changes of ≥10 points were considered clinically relevant. The risk of toxicities was calculated using the number of events and the total study population. Results: Among 41 included studies, 10 assessed HRQoL and 31 late toxicity. Global health status remained stable over time and improved after 36 months compared with baseline (mean change, +11). Several tumor-specific symptoms, including dysphagia, eating restrictions, and pain, improved after 6 months compared with baseline. Compared with baseline, dyspnea worsened after 6 months (mean change, +16 points). The risk of any late toxicity was 48% (95% CI, 33%-64%). Late toxicity risk of any grade for the esophagus was 17% (95% CI, 12%-21%), pulmonary 21% (95% CI, 11%-31%), cardiac 12% (95% CI, 6%-17%), and any other organ 24% (95% CI, 2%-45%). Conclusions: Global health status remained stable over time, and tumor-specific symptoms improved within 6 months after dCRT compared with baseline, with the exception of dyspnea. In addition, substantial risks of late toxicity were observed.