[18F]FDG-PET/CT-based risk stratification in women with locally advanced uterine cervical cancer.

BACKGROUND: [18F]FDG-PET/CT is used for staging and treatment planning in patients with locally advanced cervical cancer (LACC). We studied if a PET-based prediction model could provide additional risk stratification beyond International Federation of Gynaecology and Obstetrics (FIGO) staging in our population with LACC to aid treatment decision making. METHODS: In total, 183 patients with LACC treated with chemoradiation between 2013 and 2018 were included. Patients were treated according to FIGO 2009 and retrospectively reclassified according to FIGO 2018 staging system. After validation of an existing PET-based prediction model, the predicted recurrent free survival (RFS), disease specific survival (DSS) and overall survival (OS) at 1, 3, and 5 years, based on metabolic tumor volume (MTV), maximum standardized uptake value (SUVmax) and highest level of [18F]FDG-positive node was calculated. Then the observed survival was compared to the predicted survival. An area under the curve (AUC) close to or higher than 0.7 was considered adequate for accurate prediction. The Youden (J) index defined survival chance cutoff values for low and high risk groups. RESULTS: All AUC values for the comparison between predicted and observed outcomes were > 0.7 except for 5-year RFS and for 5-year OS which were close to 0.7 (0.684 and 0.650 respectively). Cutoff values for low and high risk survival chance were 0.44 for the 3-year RFS and 0.47 for the 5-year OS. The FIGO 2009 system could not differentiate between the risk profiles. After reclassification according to FIGO 2018, all patients with stage IIIC2 and IVB fell in the high risk and almost all patients with stages IB2-IIIB and IVA in the low risk group. In patients with stage IIIC1 disease the FIGO stage cannot discriminate between the risk profiles. CONCLUSIONS: Low and high risk patients with LACC can be identified with the PET-based prediction model. In particular patients with stage IIIC1 need additional risk stratification besides the FIGO 2018 staging. The Kidd model could be a useful tool to aid treatment decision making in these patients. Our results also support the choice of [18F]FDG-PET/CT imaging in patients with LACC.

FDA-approved drug screening in patient-derived organoids demonstrates potential of drug repurposing for rare cystic fibrosis genotypes.

BACKGROUND: Preclinical cell-based assays that recapitulate human disease play an important role in drug repurposing. We previously developed a functional forskolin induced swelling (FIS) assay using patient-derived intestinal organoids (PDIOs), allowing functional characterization of CFTR, the gene mutated in people with cystic fibrosis (pwCF). CFTR function-increasing pharmacotherapies have revolutionized treatment for approximately 85% of people with CF who carry the most prevalent F508del-CFTR mutation, but a large unmet need remains to identify new treatments for all pwCF. METHODS: We used 76 PDIOs not homozygous for F508del-CFTR to test the efficacy of 1400 FDA-approved drugs on improving CFTR function, as measured in FIS assays. The most promising hits were verified in a secondary FIS screen. Based on the results of this secondary screen, we further investigated CFTR elevating function of PDE4 inhibitors and currently existing CFTR modulators. RESULTS: In the primary screen, 30 hits were characterized that elevated CFTR function. In the secondary validation screen, 19 hits were confirmed and categorized in three main drug families: CFTR modulators, PDE4 inhibitors and tyrosine kinase inhibitors. We show that PDE4 inhibitors are potent CFTR function inducers in PDIOs where residual CFTR function is either present, or created by additional compound exposure. Additionally, upon CFTR modulator treatment we show rescue of CF genotypes that are currently not eligible for this therapy. CONCLUSION: This study exemplifies the feasibility of high-throughput compound screening using PDIOs. We show the potential of repurposing drugs for pwCF carrying non-F508del genotypes that are currently not eligible for therapies. ONE-SENTENCE SUMMARY: We screened 1400 FDA-approved drugs in CF patient-derived intestinal organoids using the previously established functional FIS assay, and show the potential of repurposing PDE4 inhibitors and CFTR modulators for rare CF genotypes.

How did general practices organize care during the COVID-19 pandemic: the protocol of the cross-sectional PRICOV-19 study in 38 countries.

BACKGROUND: General practitioners (GPs) play a crucial role in the fight against the COVID-19 pandemic as the first point of contact for possibly infected patients and are responsible for short and long-term follow-up care of the majority of COVID-19 patients. Nonetheless, they experience many barriers to fulfilling this role. The PRICOV-19 study investigates how GP practices in 38 countries are organized during the COVID-19 pandemic to guarantee safe, effective, patient-centered, and equitable care. Also, the shift in roles and tasks and the wellbeing of staff members is researched. Finally, PRICOV-19 aims to study the association with practice- and health care system characteristics. It is expected that both characteristics of the GP practice and health care system features are associated with how GP practices can cope with these challenges. This paper describes the protocol of the study. METHODS: Using a cross-sectional design, data are collected through an online questionnaire sent to GP practices in 37 European countries and Israel. The questionnaire is developed in multiple phases, including a pilot study in Belgium. The final version includes 53 items divided into six sections: patient flow (including appointments, triage, and management for routine care); infection prevention; information processing; communication; collaboration and self-care; and practice and participant characteristics. In the countries where data collection is already finished, between 13 and 636 GP practices per country participated in the study. Questionnaire data are linked with OECD and HSMR data regarding national policy responses to the pandemic and analyzed using multilevel models considering the system- and practice-level. DISCUSSION: To the best of our knowledge, the PRICOV-19 study is the largest and most comprehensive study that examines how GP practices function during the COVID-19 pandemic. Its results can significantly contribute to better preparedness of primary health care systems across Europe for future major outbreaks of infectious diseases.

Functional Restoration of CFTR Nonsense Mutations in Intestinal Organoids.

BACKGROUND: Pharmacotherapies for people with cystic fibrosis (pwCF) who have premature termination codons (PTCs) in the cystic fibrosis transmembrane conductance regulator (CFTR) gene are under development. Thus far, clinical studies focused on compounds that induce translational readthrough (RT) at the mRNA PTC location. Recent studies using primary airway cells showed that PTC functional restoration can be achieved through combining compounds with multiple mode-of-actions. Here, we assessed induction of CFTR function in PTC-containing intestinal organoids using compounds targeting RT, nonsense mRNA mediated decay (NMD) and CFTR protein modulation. METHODS: Rescue of PTC CFTR protein was assessed by forskolin-induced swelling of 12 intestinal organoid cultures carrying distinct PTC mutations. Effects of compounds on mRNA CFTR level was assessed by RT-qPCRs. RESULTS: Whilst response varied between donors, significant rescue of CFTR function was achieved for most donors with the quintuple combination of a commercially available pharmacological equivalent of the RT compound (ELX-02-disulfate or ELX-02ds), NMD inhibitor SMG1i, correctors VX-445 and VX-661 and potentiator VX-770. The quintuple combination of pharmacotherapies reached swelling quantities higher than the mean swelling of three VX-809/VX-770-rescued F508del/F508del organoid cultures, indicating level of rescue is of clinical relevance as VX-770/VX-809-mediated F508del/F508del rescue in organoids correlate with substantial improvement of clinical outcome. CONCLUSIONS: Whilst variation in efficacy was observed between genotypes as well as within genotypes, the data suggests that strong pharmacological rescue of PTC requires a combination of drugs that target RT, NMD and protein function.

The relation between cardiac 123I-mIBG scintigraphy and functional response 1 year after CRT implantation.

AIMS: Cardiac resynchronization therapy (CRT) is a disease-modifying therapy in patients with chronic heart failure (CHF). Current guidelines ascribe CRT eligibility on three parameters only: left ventricular ejection fraction (LVEF), QRS duration, and New York Heart Association (NYHA) functional class. However, one-third of CHF patients does not benefit from CRT. This study evaluated whether 123I-meta-iodobenzylguanidine (123I-mIBG) assessed cardiac sympathetic activity could optimize CRT patient selection. METHODS AND RESULTS: A total of 78 stable CHF subjects (age 66.8 ± 9.6 years, 73% male, LVEF 25.2 ± 6.7%, QRS duration 153 ± 23 ms, NYHA 2.2 ± 0.7) referred for CRT implantation were enrolled. Subjects underwent 123I-mIBG scintigraphy prior to implantation. Early and late heart-to-mediastinum (H/M) ratio and 123I-mIBG washout were calculated. CRT response was defined as either an increase of LVEF to >35%, any improvement in LVEF of >10%, QRS shortening to <150 ms, or improvement in NYHA class of >1 class. In 33 patients LVEF increased to >35%, QRS decreased <150 ms in 36 patients, and NYHA class decreased in 33 patients. Late H/M ratio and hypertension were independent predictors of LVEF improvement to >35% (P = 0.0014 and P = 0.0149, respectively). In addition, early H/M ratio, LVEF, and absence of diabetes mellitus (DM) were independent predictors for LVEF improvement by >10%. No independent predictors were found for QRS shortening to <150 ms or improvement in NYHA class. CONCLUSION: Early and late H/M ratio were independent predictors of CRT response when improvement of LVEF was used as measure of response. Therefore, cardiac 123I-mIBG scintigraphy may be used as a tool to optimize selection of subjects that might benefit from CRT.

Intestinal organoids for Cystic Fibrosis research.

Significant progress has been made in the development of CFTR modulator therapy; however, current CFTR modulator therapies are only available for a minority of the CF-patient population. Additionally, heterogeneity in in vivo modulator response has been reported among individuals carrying homozygous F508del-CFTR, adding to the desire for an optimal prediction of response-to-therapy on an individual level. In the last decade, a lot of progress has been made in the development of primary cell cultures into 3D patient-derived disease models. The advantage of these models is that the endogenous CFTR function is affected by the patient's mutation as well as other genetic or environmental factors. In this review we focus on intestinal organoids as in vitro model for CF, enabling for CF disease classification, drug development and treatment optimization in a personalized manner, taking into account rare CFTR mutations and clinical heterogeneity among individuals with CF.

Microsatellite diversity of the Nordic type of goats in relation to breed conservation: how relevant is pure ancestry?

In the last decades, several endangered breeds of livestock species have been re-established effectively. However, the successful revival of the Dutch and Danish Landrace goats involved crossing with exotic breeds and the ancestry of the current populations is therefore not clear. We have generated genotypes for 27 FAO-recommended microsatellites of these landraces and three phenotypically similar Nordic-type landraces and compared these breeds with central European, Mediterranean and south-west Asian goats. We found decreasing levels of genetic diversity with increasing distance from the south-west Asian domestication site with a south-east-to-north-west cline that is clearly steeper than the Mediterranean east-to-west cline. In terms of genetic diversity, the Dutch Landrace comes next to the isolated Icelandic breed, which has an extremely low diversity. The Norwegian coastal goat and the Finnish and Icelandic landraces are clearly related. It appears that by a combination of mixed origin and a population bottleneck, the Dutch and Danish Land-races are separated from the other breeds. However, the current Dutch and Danish populations with the multicoloured and long-horned appearance effectively substitute for the original breed, illustrating that for conservation of cultural heritage, the phenotype of a breed is more relevant than pure ancestry and the genetic diversity of the original breed. More in general, we propose that for conservation, the retention of genetic diversity of an original breed and of the visual phenotype by which the breed is recognized and defined needs to be considered separately.

[Distinguishing temporomandibular pain from other types of orofacial pain based on a questionnaire]. / Onderscheid tussen temporomandibulaire pijn en andere vormen van orofaciale pijn op basis van een vragenlijst.

This study investigated whether, apart from the usual tools for the diagnosis of temporomandibular pain, a questionnaire can distinguish between temporomandibular pain and other types of orofacial pain, based on the biopsychosocial model. 509 patients, who reported orofacial pain in an online questionnaire, were divided into 2 groups based on a clinical examination: patients with temporomandibular pain and patients with orofacial pain in whom temporomandibular pain was excluded. Logistic regression analyses showed that the 2 patient groups did not differ from each other with regard to the majority of biological and psychological aspects of the biopsychosocial model. However, patients with temporomandibular pain reported bruxism and non-specific pain more often, and reported a higher intensity of pain. This study showed that a questionnaire can aid in distinguishing patients with temporomandibular pain from patients with other types of orofacial pain.

Practical measurement of affordability: an application to medicines.

OBJECTIVE: To develop two practical methods for measuring the affordability of medicines in developing countries. METHODS: The proposed methods--catastrophic and impoverishment methods--rely on easily accessible aggregated expenditure data and take into account a country's income distribution and absolute level of income. The catastrophic method quantifies the proportion of the population whose resources would be catastrophically reduced by spending on a given medicine; the impoverishment method estimates the proportion of the population that would be pushed below the poverty line by procuring a given medicine. These methods are illustrated by calculating the affordability of glibenclamide, an antidiabetic drug, in India and Indonesia. The results were validated by comparing them with the results obtained by using household micro data for India and Indonesia. FINDINGS: When accurate aggregate data are available, the proposed methods offer a practical way to obtain informative and accurate estimates of affordability. Their results are very similar to those obtained with household micro data analysis and are easily compared across countries. CONCLUSION: The catastrophic and impoverishment methods, based on macro data, can provide a suitable estimate of medicine affordability when the household level micro data needed to carry out more sophisticated studies are not available. Their usefulness depends on the availability of accurate aggregated data.

Is there a health penalty of China's rapid urbanization?

While highly pertinent to the human welfare consequences of development, the impact of rapid urbanization on population health is not obvious. This paper uses community and individual-level longitudinal data from the China Health and Nutrition Survey to estimate the net health impact of China's unprecedented urbanization. We construct an index of urbanicity from a broad set of community characteristics and define urbanization in terms of movements across the distribution of this index. We use difference-in-differences estimators to identify the treatment effect of urbanization on the self-assessed health of individuals. We find that urbanization raises the probability of reporting of poor health and that a greater degree of urbanization has a larger effect. The effect may, in part, be attributable to changed health expectations, but it also appears to operate through health behaviour. Populations experiencing urbanization tend to consume more fat and smoke more.

Dutch monitor on stress and physical load: risk factors, consequences, and preventive action.

OBJECTIVES: Due to recent changes in legislation on occupational health and safety, a national monitor on stress and physical load was developed in The Netherlands to monitor (a) risks and consequences of stress and physical load at work, (b) preventive actions in companies to reduce these risks, and (c) organisational and environmental variables that facilitate preventive actions. METHODS: Information was gathered from employers, employees, and employees' representatives. The monitor was used with a nationally representative sample of companies in industry, wholesale trade, and banking and finance, 782 companies in total. RESULTS AND CONCLUSIONS: The information from the employees, aggregated at the company level, was not found to be correlated with that from the employer from the same companies. Although many employers do recognise risk factors for both physical load and stress as a problem they often seem to underestimate the problem when compared with employees or their representatives. This is particularly the case for psychosocial risk factors. Also, the perception of outcome measures, especially employers who consider emotional exhaustion to be work related, were fewer than the employees' representatives of the same organisation. Preventive measures on physical load are much more popular than measures against stress. It is the responsibility of the employer to take more preventive action of all kinds. They need to recognise risk factors as problems and health outcomes to be related to work. Employees of larger companies should participate with employers to consider effective measures, and more use should be made of support at branch level. For specific preventive measures, specific predictors emerged. Except for measures to prevent work stress, information from employees did not sufficiently contribute to the initiation of preventive measures in the workplace.

Mental health care and the opposition movement in The Netherlands.

In The Netherlands, there is a more or less recognized movement in the field of mental health care which is referred to as the psychiatric opposition movement or the patients movement. The nucleus of the Dutch movement consists of patients and ex-patients. As far as mental health professionals are participating in the movement, they do so as more or less passive supporters of a movement dominated by patients and ex-patients. This article is dealing with two questions. The first question is how and to what degree the opposition movement in The Netherlands has succeeded in breaking through or at least questioning the closed nature of Dutch mental health care system. The second question will be whether the dilemma between resistance and dependence in the position of patients and ex-patients is visible in the activities of the opposition movement, and whether this dilemma acted as an obstacle to their efforts to influence the mental health care debate in The Netherlands. An effort is being made to answer this question by describing the position of the opposition movement with respect to the Insanity Law and with respect to the organization of mental health care. In conclusion, three stages were found to be crucial in the development of Dutch opposition movement. In the 1970s, the opposition movement appeared to operate within the borders of a closed system in which the medical profession had a high degree of autonomy.(ABSTRACT TRUNCATED AT 250 WORDS)

KIE: Dutch mental health care is described as a traditionally closed system in which the medical profession has a high degree of autonomy. Since the 1970s the traditional system has been challenged by an opposition movement that is dominated to an unusual extent by mental patients and ex-patients. A sociological analysis of the development and role of this opposition movement is presented, with particular regard to its efforts in pressing for changes in the law on compulsory hospitalization and for a reorganization of the mental health system to give patients more say in their own care and to abolish large psychiatric hospitals.