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We present key points from the updated Dutch-Flemish guideline on comprehensive diagnostics in disorders/differences of sex development (DSD) that have not been widely addressed in the current (inter)national literature. These points are of interest to physicians working in DSD (expert) centres and to professionals who come across persons with a DSD but have no (or limited) experience in this area. The Dutch-Flemish guideline is based on internationally accepted principles. Recent initiatives striving for uniform high-quality care across Europe, and beyond, such as the completed COST action 1303 and the European Reference Network for rare endocrine conditions (EndoERN), have generated several excellent papers covering nearly all aspects of DSD. The Dutch-Flemish guideline follows these international consensus papers and covers a number of other topics relevant to daily practice. For instance, although next-generation sequencing (NGS)-based molecular diagnostics are becoming the gold standard for genetic evaluation, it can be difficult to prove variant causality or relate the genotype to the clinical presentation. Network formation and centralisation are essential to promote functional studies that assess the effects of genetic variants and to the correct histological assessment of gonadal material from DSD patients, as well as allowing for maximisation of expertise and possible cost reductions. The Dutch-Flemish guidelines uniquely address three aspects of DSD. First, we propose an algorithm for counselling and diagnostic evaluation when a DSD is suspected prenatally, a clinical situation that is becoming more common. Referral to ultrasound sonographers and obstetricians who are part of a DSD team is increasingly important here. Second, we pay special attention to healthcare professionals not working within a DSD centre as they are often the first to diagnose or suspect a DSD, but are not regularly exposed to DSDs and may have limited experience. Their thoughtful communication to patients, carers and colleagues, and the accessibility of protocols for first-line management and efficient referral are essential. Careful communication in the prenatal to neonatal period and the adolescent to adult transition are equally important and relatively under-reported in the literature. Third, we discuss the timing of (NGS-based) molecular diagnostics in the initial workup of new patients and in people with a diagnosis made solely on clinical grounds or those who had earlier genetic testing that is not compatible with current state-of-the-art diagnostics.

It is well recognized that poor muscle function and poor physical performance are strong predictors of clinically relevant adverse events in older people. Given the large number of approaches to measure muscle function and physical performance, clinicians often struggle to choose a tool that is appropriate and validated for the population of older people they deal with. In this paper, an overview of different methods available and applicable in clinical settings is proposed. This paper is based on literature reviews performed by members of the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) working group on frailty and sarcopenia. Face-to-face meetings were organized afterwards where the whole group could amend and discuss the recommendations further. Several characteristics should be considered when choosing a tool: (1) purpose of the assessment (intervention, screening, diagnosis); (2) patient characteristics (population, settings, functional ability, etc.); (3) psychometric properties of the tool (test–retest reliability, inter-rater reliability, responsiveness, floor and ceiling effects, etc.); (4) applicability of the tool in clinical settings (overall cost, time required for the examination, level of training, equipment, patient acceptance, etc.); (5) prognostic reliability for relevant clinical outcomes. Based on these criteria and the available evidence, the expert group advises the use of grip strength to measure muscle strength and the use of 4-m gait speed or the Short Physical Performance Battery test to measure physical performance in daily practice. The tools proposed are relevant for the assessment of muscle weakness and physical performance. Subjects with low values should receive additional diagnostic workups to achieve a full diagnosis of the underlying condition responsible (sarcopenia, frailty or other).

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IL-23 is a key cytokine in the pathogenesis of spondyloarthritides, including PsA and axial spondyloarthritis, as well as related conditions, such as psoriasis and IBD. Genetic associations, animal models and translational studies in humans demonstrate the key role played by IL-23, especially when coupled with downstream overexpression of IL-17 via stimulation of T helper 17 (Th17) and other cells by IL-23. Whereas IL-23 inhibition has shown clear-cut benefit in psoriasis and peripheral manifestations of PsA, trials of IL-23 inhibitors have failed in the treatment of ankylosing spondylitis. More recently, exploratory data from PsA patients with axial symptoms suggests that improvement may occur, but needs confirmation in dedicated axial spondyloarthritis (axSpA) trials. Hypotheses for these apparently conflicting findings about IL-23 inhibition in various forms of spondylitis are discussed.

Long non-coding RNAs (lncRNAs) are a heterogeneous group of transcripts that lack protein coding potential and display regulatory functions in various cellular processes. As a result of their cell- and cancer-specific expression patterns, lncRNAs have emerged as potential diagnostic and therapeutic targets. The accurate characterization of lncRNAs in bulk transcriptome data remains challenging due to their low abundance compared to protein coding genes. To tackle this issue, we describe a unique short-read custom lncRNA capture sequencing approach that relies on a comprehensive set of 565,878 capture probes for 49,372 human lncRNA genes. This custom lncRNA capture approach was evaluated on various sample types ranging from artificial high-quality RNA mixtures to more challenging formalin-fixed paraffin-embedded tissue and biofluid material. The custom enrichment approach allows the detection of a more diverse repertoire of lncRNAs, with better reproducibility and higher coverage compared to classic total RNA-sequencing.

Rapid diagnosis by using small, simple, and portable devices could represent one of the best strategies to limit the damage and contain the spread of viral, bacterial or protozoa diseases, principally when they can be transmitted by air and are highly contagious, as some respiratory viruses are. The presence of antibodies in blood or serum samples is not the best option for deciding when a person must be quarantined to stop transmission of disease, given that cured patients have antibodies, so the best diagnosis methods rely on the use of nucleic acid amplification procedures. Here we present a very simple device and detection principle, based on paper discs coupled to contactless conductivity (C4D) sensors, can provide fast and easy diagnostics that are needed when an epidemic outbreak develops. The paper device presented here solves one of the main drawbacks that nucleic acid amplification tests have when they are performed outside of central laboratories. As the device is sealed before amplification and integrally disposed in this way, amplimers release cannot occur, allowing repetitive testing in the physician’s practice, ambulances, or other places that are not prepared to avoid cross-contamination of new samples. The use of very low volume samples allows efficient reagent use and the development of low cost, simple, and disposable point-of-care diagnostic systems., Author summary In 2005, the World Health Organization (WHO) recognized Chagas Disease as a neglected tropical disease. Meanwhile the serological tests, recommended by WHO, can be performed for chronic disease diagnosis, the nucleic acid amplification tests must be performed for the detection of the acute phase of the disease. Although the existing laboratory diagnosis tests for Chagas Disease are sensitive and highly reproducible, they cannot be performed in rural, low infrastructure environments, where this disease prevails. In this sense, the use of simple and portable analytical devices may be able to offer an affordable solution to this problem, allowing fast sampling, diagnosis and treatment prescription in one simple and fast intervention, as the performed by short term medical missions. In this study we show for the first time a diagnosis test comprising low cost materials and employing a contactless and label-free conductivity detection system that is used to read the result of a nucleic acid amplification reaction. The test showed high sensitivity for Chagas Disease diagnosis showing the potential to be used in rural and low income places.

Many microbial phenotypes are differentially or exclusively expressed on agar surfaces, including biofilms, motility, and sociality. However, agar-based assays are limited by their low throughput, which increases costs, lab waste, space requirements, and the time required to conduct experiments. Here, we demonstrate the use of wax-printed microfluidic paper-based analytical devices (μPADs) to measure linear growth rate of microbes on an agar growth media as a means of circumventing the aforementioned limitations. The main production materials of the proposed μPAD design are a wax printer, filter paper, and empty pipet boxes. A single wax-printed μPAD allowing 8 independent, agar-grown colonies costs $0.07, compared to $0.20 and $9.37 for the same number of replicates on traditional microtiter/spectrophotometry and Petri dish assays, respectively. We optimized the μPAD design for channel width (3 mm), agar volume (780 μL/channel), and microbe inoculation method (razor-blade). Comparative analyses of the traditional and proposed μPAD methods for measuring growth rate of nonmotile (Saccharomyces cerevisiae) and motile (flagellated Escherichia coli) microorganisms suggested the μPAD assays conferred a comparable degree of accuracy and reliability to growth rate measurements as their traditional counterparts. We substantiated this claim with strong, positive correlations between the traditional and μPAD assay, a significant nonzero slope in the model relating the two assays, a nonsignificant difference between the relative standard errors of the two techniques, and an analysis of inter-device reliability. Therefore, μPAD designs merit consideration for the development of enhanced-throughput, low-cost microbial growth and motility assays.

Objectives To assess hypertension prevalence and the extent and associated factors of hypertension diagnosis, follow‐up, treatment and control gaps in low‐income urban Medellin, Colombia. Methods We randomly sampled 1873 adults aged 35 or older. Unaware hypertensive individuals were defined as those without previous diagnosis whose average blood pressure was equal to or above 140/90 mmHg. For aware hypertensive patients, control was delimited as average blood pressure below 140/90 if under 59 years old or diabetic, and as less than 150/90 otherwise. We used logistic regression to identify care gap‐associated factors. Results Hypertension prevalence was 43.5% (95% CI 41.2–45.7). We found 28.2% aware and 15.3% unaware hypertensive individuals, which corresponds to a 35.1% (95% CI 31.9–38.5) underdiagnosis. This gap was determined by age, sex, education and lifestyle factors. 14.4% (95% CI 11.6–17.6) of aware hypertensive patients presented a follow‐up gap, 93.4% (95% CI 90.9–95.2) were prescribed antihypertensive drugs, but 38.9% (95% CI 34.7–43.3) were not compliant. The latter was strongly associated with follow‐up. The hypertension control gap in aware hypertensive patients, 39.0% (95% CI: 34.9–43.2), was associated with being older, having diabetes, weakly adhering to pharmacological treatment and receiving poor non‐pharmacological advice. Overall, 60.4% (95% CI 57.0–63.8) of aware and unaware hypertensive participants had either diagnosed but uncontrolled or undiagnosed hypertension. Conclusions We found high hypertension prevalence coupled with, from an international perspective, encouraging awareness and control figures. Still, there remains ample room for improvement. Our findings can assist in designing integrated primary healthcare measures that further strengthen equitable and effective access to hypertension care and control.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide. HCC typically develops on a background of chronic inflammation and fibrosis with tumor associated macrophages (TAMs) playing an important role in chronic inflammation-induced HCC and progression. However, the liver harbors unique macrophages, resident liver Kupffer cells (KCs) and monocyte-derived macrophages (Mo-Mφ), and their contribution to HCC and to the population of TAMs is incompletely known. Here, we characterized the tumor microenvironment and the proportion and transcriptional profile of hepatic macrophages (Mφ) in two commonly used HCC mouse models. A gradually increased expression of inflammatory, immune regulatory, fibrotic and cell proliferation pathways and markers was observed during diethylnitrosamine (DEN)- and non-alcoholic steatohepatitis (NASH)-induced HCC development. The transcriptional phenotypes of isolated hepatic Mφ subsets were clearly distinct and shifted during HCC development, with mixed pro-inflammatory and tumor-promoting expression profiles. There were marked differences between the models as well, with Mφ in NASH-HCC exhibiting a more immunomodulatory phenotype, in conjunction with an upregulation of lipid metabolism genes. Our data show that at least some infiltrated macrophages display expression of pro-tumoral markers, and that Kupffer cells are part of the population of TAMs and enhance tumor progression. These insights are useful to further unravel sequential pathogenic events during hepatocarcinogenesis and direct future development of new treatment strategies for HCC.

Background In 2005, Bangladesh, India and Nepal agreed to eliminate visceral leishmaniasis (VL) as a public health problem. The approach to this was through improved case detection and treatment, and controlling transmission by the sand fly vector Phlebotomus argentipes, with indoor residual spraying (IRS) of insecticide. Initially, India applied DDT with stirrup pumps for IRS, however, this did not reduce transmission. After 2015 onwards, the pyrethroid alpha-cypermethrin was applied with compression pumps, and entomological surveillance was initiated in 2016. Methods Eight sentinel sites were established in the Indian states of Bihar, Jharkhand and West Bengal. IRS coverage was monitored by household survey, quality of insecticide application was measured by HPLC, presence and abundance of the VL vector was monitored by CDC light traps, insecticide resistance was measured with WHO diagnostic assays and case incidence was determined from the VL case register KAMIS. Results Complete treatment of houses with IRS increased across all sites from 57% in 2016 to 70% of houses in 2019, rising to >80% if partial house IRS coverage is included (except West Bengal). The quality of insecticide application has improved compared to previous studies, average doses of insecticide on filters papers ranged from 1.52 times the target dose of 25mg/m2 alpha-cypermethrin in 2019 to 1.67 times in 2018. Resistance to DDT has continued to increase, but the vector was not resistant to carbamates, organophosphates or pyrethroids. The annual and seasonal abundance of P. argentipes declined between 2016 to 2019 with an overall infection rate of 0.03%. This was associated with a decline in VL incidence for the blocks represented by the sentinel sites from 1.16 per 10,000 population in 2016 to 0.51 per 10,000 in 2019. Conclusion Through effective case detection and management reducing the infection reservoirs for P. argentipes in the human population combined with IRS keeping P. argentipes abundance and infectivity low has reduced VL transmission. This combination of effective case management and vector control has now brought India within reach of the VL elimination targets., Author summary Visceral Leishmaniasis (VL), also known as kala-azar, is a major parasitic disease in South Asia (Indian subcontinent), with 85% of the disease incidence in India. Historically VL had been controlled and almost eliminated with Indoor Residual Spraying (IRS) using dichlorodiphenyltrichloroethane (DDT). However, reinitiating this approach in 2015 failed due to high insecticide resistance in the sand fly vector and poor IRS quality, meaning that VL elimination targets were not met. To improve this the National Vector Borne Disease Control Programme changed to an effective insecticide, alpha-cypermethrin and altered the mode of application to compression pumps. Sentinel sites were established to monitor the entomological indicators, these showed the positive impact of these changes from 2016 to 2019. During this period the overall incidence of disease has decreased, and India is now on track to reach it’s target incidence for VL of less than 1/1000 people at the sub-district (block) level.

Atypical teratoid/rhabdoid tumors (ATRTs) are very aggressive childhood malignancies of the central nervous system. The underlying genetic cause are inactivating bi-allelic mutations in SMARCB1 or (rarely) in SMARCA4. ATRT-SMARCA4 have been associated with a higher frequency of germline mutations, younger age, and an inferior prognosis in comparison to SMARCB1 mutated cases. Based on their DNA methylation profiles and transcriptomics, SMARCB1 mutated ATRTs have been divided into three distinct molecular subgroups: ATRT-TYR, ATRT-SHH, and ATRT-MYC. These subgroups differ in terms of age at diagnosis, tumor location, type of SMARCB1 alterations, and overall survival. ATRT-SMARCA4 are, however, less well understood, and it remains unknown, whether they belong to one of the described ATRT subgroups. Here, we examined 14 ATRT-SMARCA4 by global DNA methylation analyses. We show that they form a separate group segregating from SMARCB1 mutated ATRTs and from other SMARCA4-deficient tumors like small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) or SMARCA4 mutated extra-cranial malignant rhabdoid tumors. In contrast, medulloblastoma (MB) samples with heterozygous SMARCA4 mutations do not group separately, but with established MB subgroups. RNA sequencing of ATRT-SMARCA4 confirmed the clustering results based on DNA methylation profiling and displayed an absence of typical signature genes upregulated in SMARCB1 deleted ATRT. In summary, our results suggest that, in line with previous clinical observations, ATRT-SMARCA4 should be regarded as a distinct molecular subgroup.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide. For advanced HCC, there is still an unmet need for more effective therapeutic strategies. HCC is typically associated with hypoxia and the hypoxia-inducible factor (HIF) regulatory pathway plays an important role in HCC development and progression. Therefore, we investigated the therapeutic potential of isoform-specific HIF-1α and HIF-2α antisense oligonucleotides (ASOs), along with their effect on the inflammatory and fibrotic component of the tumor microenvironment (TME), in an experimental HCC mouse model. Based on its efficacy and safety, a dosage regimen of 20 mg/kg intraperitoneal injection of HIFα ASO twice per week was selected for further investigation in a preventive and therapeutic setting in a N,N-diethylnitrous amide (DEN)-induced HCC mouse model. DEN administration resulted in 100% tumor formation and HIFα ASO administration led to effective and selective hepatic downregulation of its target genes. HIFα ASO treatment had no effect on tumor numbers, but even enhanced the increased hepatic expression of HCC tumor markers, α-fetoprotein and glypican-3, compared to scrambled control ASO treatment in HCC mice. Especially HIF-1α ASO treatment resulted in an enhanced increase of monocytes and monocyte-derived macrophages in the liver and an enhanced hepatic upregulation of inflammatory markers. Both HIFα ASOs aggravated liver fibrosis in HCC mice compared to scrambled ASO treatment. The observed effects of our dosing regimen for HIF-1α and HIF-2α ASO treatment in the DEN-induced HCC mouse model discourage the use of HIFα isoforms as targets for the treatment of HCC.

This first-in-human study (NCT03032588), conducted in Belgium, evaluated a new inactivated poliovirus vaccines (IPV) candidate based on Sabin poliovirus strains grown on the high-yield PER.C6 (R) cell line. Healthy adults (N = 32) were randomized (1:1) to receive a single dose of PER.C6-based Sabin-IPV (sIPV, 15:35:112.5 DU/dose) or conventional Salk-IPV (cIPV, 40:8:32 DU/dose). Reactogenicity was assessed up to 7 days after vaccination, immunogenicity 28 days after vaccination, and safety up to 6 months after vaccination. Solicited adverse events (AEs) were mild to moderate, no changes of concern in vital signs or safety laboratory values were observed, and no severe AEs (SAEs) or vaccine-related unsolicited AEs were reported after vaccination. A trend to more frequent solicited AEs after sIPV than after cIPV administration was observed. Most participants had preexisting neutralizing antibodies against poliovirus types (titer >= 8), which were strongly boosted by sIPV. Post-vaccination geometric mean titers were high (>= 12,000) and similar across the two vaccination groups. Only participants with very high preexisting antibody levels did not show a vaccine-induced response, defined in seropositive participants as a 4-fold titer increase. The 10 initially seronegative (titer

Objective:To examine current dietary fat intakes and compliance in Irish children and to examine changes in intakes from 2005 to 2019.Design:Analyses were based on data from the Irish National Children’s Food Survey (NCFS) and the NSFS II, two cross-sectional studies that collected detailed food and beverage intake data through 7-day and 4-day weighed food diaries, respectively.Setting:NCFS and NCFS II, Republic of Ireland.Participants:A nationally representative sample of 594 (NCFS) and 600 (NCFS II) children aged 5–12 years. Current intakes from the NCFS II were compared with those previously reported in the NCFS (www.iuna.net).Results:Current intakes of total fat, SFA, MUFA, PUFA and trans fat as a percentage of total energy are 33·3, 14·0, 13·6, 5·6 and 0·5 %, respectively. Total fat, SFA and trans fat intakes since 2005 remained largely stable over time with all displaying minor decreases of Conclusion:Children in Ireland continue to meet the total fat and trans fat target goals. Adherence to MUFA and PUFA recommendations has also significantly improved. However, deviations for some fats remain, in particular SFA. These findings are useful for the development of dietary strategies to improve compliance with current recommendations.

Background The European Commission is funding projects that aim to establish data-sharing platforms. These platforms are envisioned to enhance and facilitate the international sharing of cohort data. Nevertheless, broad data sharing may be restricted by the lack of adequate recognition for those who share data. Objective The aim of this study is to describe in depth the concerns about acquiring credit for data sharing within epidemiological research. Methods A total of 17 participants linked to European Union–funded data-sharing platforms were recruited for a semistructured interview. Transcripts were analyzed using inductive content analysis. Results Interviewees argued that data sharing within international projects could challenge authorship guidelines in multiple ways. Some respondents considered that the acquisition of credit for articles with extensive author lists could be problematic in some instances, such as for junior researchers. In addition, universities may be critical of researchers who share data more often than leading research. Some considered that the evaluation system undervalues data generators and specialists. Respondents generally looked favorably upon alternatives to the current evaluation system to potentially ameliorate these issues. Conclusions The evaluation system might impede data sharing because it mainly focuses on first and last authorship and undervalues the contributor’s work. Further movement of crediting models toward contributorship could potentially address this issue. Appropriate crediting mechanisms that are better aligned with the way science ought to be conducted in the future need to be developed.

The highly contagious nature of SARS-CoV-2 has led to several studies on the transmission of the virus. A little studied potential fomite of great concern in the community is currency, which has been shown to harbor microbial pathogens in several studies. Since the onset of the COVID-19 pandemic, many businesses in the United States have limited the use of banknotes in favor of credit cards. However, SARS-CoV-2 has shown greater stability on plastic in several studies. Herein, the stability of SARS-CoV-2 at room temperature on banknotes, money cards and coins was investigated. In vitro studies with live virus suggested SARS-CoV-2 was highly unstable on banknotes, showing an initial rapid reduction in viable virus and no viral detection by 24 hours. In contrast, SARS-CoV-2 displayed increased stability on money cards with live virus detected after 48 hours. Environmental swabbing of currency and money cards on and near the campus of Brigham Young University supported these results, with no detection of SARS-CoV-2 RNA on banknotes, and a low level on money cards. However, no viable virus was detected on either. These preliminary results suggest that the use of money cards over banknotes in order to slow the spread of this virus may be ill-advised. These findings should be investigated further through larger environmental studies involving more locations.

BackgroundCongestive heart failure (CHF) is a disease that requires complex management involving multiple medications, exercise, and lifestyle changes. It mainly affects older patients with depression and anxiety, who commonly find management difficult. Existing mobile apps supporting the self-management of CHF have limited features and are inadequately validated.ObjectiveThe HeartMan project aims to develop a personal health system that would comprehensively address CHF self-management by using sensing devices and artificial intelligence methods. This paper presents the design of the system and reports on the accuracy of its patient-monitoring methods, overall effectiveness, and patient perceptions.MethodsA mobile app was developed as the core of the HeartMan system, and the app was connected to a custom wristband and cloud services. The system features machine learning methods for patient monitoring: continuous blood pressure (BP) estimation, physical activity monitoring, and psychological profile recognition. These methods feed a decision support system that provides recommendations on physical health and psychological support. The system was designed using a human-centered methodology involving the patients throughout development. It was evaluated in a proof-of-concept trial with 56 patients.ResultsFairly high accuracy of the patient-monitoring methods was observed. The mean absolute error of BP estimation was 9.0 mm Hg for systolic BP and 7.0 mm Hg for diastolic BP. The accuracy of psychological profile detection was 88.6%. The F-measure for physical activity recognition was 71%. The proof-of-concept clinical trial in 56 patients showed that the HeartMan system significantly improved self-care behavior (P=.02), whereas depression and anxiety rates were significantly reduced (PConclusionsThe HeartMan project combined a range of advanced technologies with human-centered design to develop a complex system that was shown to help patients with CHF. More psychological than physical benefits were observed.Trial RegistrationClinicalTrials.gov NCT03497871; https://clinicaltrials.gov/ct2/history/NCT03497871.International Registered Report Identifier (IRRID)RR2-10.1186/s12872-018-0921-2

Despite significant advances in the research domain of continuous twin screw granulation, limited information is currently available on the impact of raw material properties, especially considering batch-to-batch variability. The importance of raw material variability and subsequent mitigation of the impact of this variability on the manufacturing process and drug product was recently stressed in the Draft Guidance for Industry on Quality Considerations for Continuous Manufacturing by the U.S. Food and Drug Administration (FDA). Therefore, this study assessed the impact of microcrystalline cellulose (MCC) batch-to-batch variability and process settings in a continuous twin screw wet granulation and semi-continuous drying line. Based on extensive raw material characterization and subsequent principal component analysis, raw material variability was quantitatively introduced in the design of experiments approach by means of t1 and t2 scores. L/S ratio had a larger effect on critical granule attributes and processability than screw speed and drying time. A large impact of the t1 and t2 scores was found, indicating the importance of raw material attributes. For the studied formulation, it was concluded that MCC batches with a low water binding capacity, low moisture content and high bulk density generated granules with the most desirable quality attributes. Additionally, an innovative and quantitative approach towards mitigating batch-to-batch variability of raw materials was proposed, which is also applicable for additional excipients and APIs., Graphical abstract Unlabelled Image

Background: The European Association for Palliative Care White Paper defined optimal palliative care in dementia based on evidence and expert consensus. Yet, we know little on how to achieve this for people with dementia living and dying at home. Aims: To examine evidence on home palliative care interventions in dementia, in terms of their effectiveness on end-of-life care outcomes, factors influencing implementation, the extent to which they address the European Association for Palliative Care palliative care domains and evidence gaps. Design: A systematic review of home palliative care interventions in dementia. Data sources: The review adhered to the PRISMA guidelines and the protocol was registered with PROSPERO (CRD42018093607). We searched four electronic databases up to April 2018 (PubMed, Scopus, Cochrane library and CINAHL) and conducted lateral searches. Results: We retrieved eight relevant studies, none of which was of high quality. The evidence, albeit of generally weak quality, showed the potential benefits of the interventions in improving end-of-life care outcomes, for example, behavioural disturbances. The interventions most commonly focused on optimal symptom management, continuity of care and psychosocial support. Other European Association for Palliative Care domains identified as important in palliative care for people with dementia, for example, prognostication of dying or avoidance of burdensome interventions were under-reported. No direct evidence on facilitators and barriers to implementation was found. Conclusions: The review highlights the paucity of high-quality dementia-specific research in this area and recommends key areas for future work, for example, the need for process evaluation to identify facilitators and barriers to implementing interventions.

The aim of this study was to determine the frequency of upper respiratory tract symptoms (URS) in elite female gymnasts during a training season. In addition, we aimed to observe the extent to which salivary immunoglobulin A (sIgA) is associated with URS in these athletes, including potential effects of the season and timing of sample collection. Over one year, 18 elite female gymnasts completed URS and fatigue questionnaires weekly and provided 1 mL of saliva after a minimum 36 h of rest (morning or afternoon) to measure relative sIgA concentration (= mean absolute sIgA value of the week divided by the mean absolute sIgA value of the weeks without URS). Mean weekly URS and mean relative sIgA values per gymnast correlated negatively (r = -0.606, P = 0.022). Most URS were noted in the most fatigued gymnasts (7.4 ± 10.1 vs. 2.5 ± 5.6 (P < 0.001) for ‘normal’ and 2.1 ± 3.7 (P = 0.001) for ‘better than normal’ rested). In spring, relative sIgA was higher compared to autumn (112 ± 55 vs. 89 ± 41%, P < 0.001) and winter (92 ± 35%, P = 0.001), while during summer, relative sIgA appeared higher compared to autumn (110 ± 55 vs. 89 ± 41%, P = 0.016). The interaction effect with timing of sample collection showed higher relative sIgA values in morning samples in spring and summer compared to afternoon samples, with the inverse observed in autumn and winter (F = 3.565, P = 0.014). During a gymnastics season, lower relative sIgA values were linked to higher susceptibility to URS in elite gymnasts. However, relative sIgA values were influenced by season and timing of sample collection and thus should be considered when interpreting sIgA data.

Acta crystallographica / Section D 76(12), 1244 - 1255 (2020). doi:10.1107/S2059798320013753, Structural studies of glycoproteins and their complexes provide critical insights into their roles in normal physiology and disease. Most glycoproteins contain N-linked glycosylation, a key post-translation modification that critically affects protein folding and stability and the binding kinetics underlying protein interactions. However, N-linked glycosylation is often an impediment to yielding homogeneous protein preparations for structure determination by X-ray crystallography or other methods. In particular, obtaining diffraction-quality crystals of such proteins and their complexes often requires modification of both the type of glycosylation patterns and their extent. Here, we demonstrate the benefits of producing target glycoproteins in the GlycoDelete human embryonic kidney 293 cell line that has been engineered to produce N-glycans as short glycan stumps comprising N-acetylglucosamine, galactose and sialic acid. Protein fragments of human Down syndrome cell-adhesion molecule and colony-stimulating factor 1 receptor were obtained from the GlycoDelete cell line for crystallization. The ensuing reduction in the extent and complexity of N-glycosylation in both protein molecules compared with alternative glyco­engineering approaches enabled their productive deployment in structural studies by X-ray crystallography. Furthermore, a third successful implementation of the GlycoDelete technology focusing on murine IL-12B is shown to lead to N-glycosylation featuring an immature glycan in diffraction-quality crystals. It is proposed that the GlycoDelete cell line could serve as a valuable go-to option for the production of homogeneous glycoproteins and their complexes for structural studies by X-ray crystallography and cryo-electron microscopy., Published by Wiley, Bognor Regis

In accordance with the opinion of the World Health Organization and the World Water Council the development of effective technologies for the treatment of wastewater from heavy metals for their discharge into water bodies or reuse is an urgent task nowadays. Phytoremediation biotechnologies is the most environmentally friendly and cheapest way of the treatment of wastewater, suitable for sustainable development principals. The main disadvantage of the phytoremediation is the slow speed of the process. A method for accelerating the process of phytoremediation by the combined effect of magnetic and weak electric fields is proposed. The purpose of this study is to determine the values of the parameters of the magnetic and weak electric fields that are most suitable for extracting cuprum ions from wastewater using the higher aqua plants (Lemna minor). A corresponding technological process based on the results of the study is proposed. The results have shown that the removal of copper cations from sulfate solutions effectively occurs in the initial period of time (1–5 hours) under the influence of a magnetic field with an intensity of H = 2 kA/m. Under the combined influence of an electrical current with density j = 240 μA/cm2 and a magnetic field (H = 2 kA/m) the highest rate of copper extraction by duckweed leaves is achieved. Under these conditions, the greatest growth and development of plant leaves occurs. The paper presents the results of determining of the parameters of the electrochemical release from the eluate of the spent phytomass of duckweed. It has been determined that the release of metal occurs at E = 0.32 V. An original scheme for wastewater treatment from copper with subsequent separation of copper from the spent phytomass of duckweed is proposed. In general, the presented results are a scientific justification of wastewater treatment technologies and a contribution to resolving the crisis in the field of fresh water supply. An important contribution in the circular economy is a technology recommendation proposed for recovering copper from duckweed after wastewater treatment.

Background: Targeting of MDSCs is a major clinical challenge in the era of immunotherapy. Antibodies which deplete MDSCs in murine models can reactivate T cell responses. In humans such approaches have not developed due to difficulties in identifying targets amenable to clinical translation. Methods: RNA-sequencing of M-MDSCs and G-MDSCs from cancer patients was undertaken. Flow cytometry and immunohistochemistry of blood and tumours determined MDSC CD33 expression. MDSCs were treated with Gemtuzumab ozogamicin and internalisation kinetics, and cell death mechanisms determined by flow cytometry, confocal microscopy and electron microscopy. Effects on T cell proliferation and CAR-T cell anti-tumour cytotoxicity were identified in the presence of Gemtuzumab ozogamicin. Findings: RNA-sequencing of human M-MDSCs and G-MDSCs identified transcriptomic differences, but that CD33 is a common surface marker. Flow cytometry indicated CD33 expression is higher on M-MDSCs, and CD33+ MDSCs are found in the blood and tumours regardless of cancer subtype. Treatment of human MDSCs leads to Gemtuzumab ozogamicin internalisation, increased p-ATM, and cell death; restoring T cell proliferation. Anti-GD2-/mesothelin-/EGFRvIII-CAR-T cell activity is enhanced in combination with the anti-MDSC effects of Gemtuzumab ozogamicin. Interpretation: The study identifies that M-MDSCs and G-MDSCs are transcriptomically different but CD33 is a therapeutic target on peripheral and infiltrating MDSCs across cancer subtypes. The immunotoxin Gemtuzumab ozogamicin can deplete MDSCs providing a translational approach to reactivate T cell and CAR-T cell responses against multiple cancers. In the rare conditions of HLH/MAS gemtuzumab ozogamicin provides a novel anti-myeloid strategy. Fund: This work was supported by Cancer Research UK, CCLG, Treating Children with Cancer, and the alumni and donors to the University of Birmingham. (c) 2019 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

In recent years, the number of reported Human African Trypanosomiasis (HAT) cases caused by Trypanosoma brucei (T.b.) gambiense has been markedly declining, and the goal of ‘elimination as a public health problem’ is within reach. For the next stage, i.e. interruption of HAT transmission by 2030, intensive screening and surveillance will need to be maintained, but with tools and strategies more efficiently tailored to the very low prevalence. We assessed the sequential use of ELISA and Immune Trypanolysis (ITL) on dried blood spot (DBS) samples as an alternative to the traditional HAT field testing and confirmation approach. A cross-sectional study was conducted in HAT endemic and previously endemic zones in Kongo Central province, and a non-endemic zone in Haut Katanga province in the Democratic Republic of the Congo (DRC). Door-to-door visits were performed to collect dried blood spot (DBS) samples on filter paper. ELISA/T.b. gambiense was conducted followed by ITL for those testing positive by ELISA and in a subset of ELISA negatives. In total, 11,642 participants were enrolled. Of these, 11,535 DBS were collected and stored in appropriate condition for ELISA testing. Ninety-seven DBS samples tested positive on ELISA. In the endemic zone, ELISA positivity was 1.34% (95%CI: 1.04–1.64). In the previously endemic zone and non-endemic zone, ELISA positivity was 0.34% (95% CI: 0.13–0.55) and 0.37% (95% CI: 0.15–0.60) respectively. Among the ELISA positives, only two samples had a positive ITL result, both from the endemic zone. One of those was from a former HAT patient treated in 2008 and the other from an individual who unfortunately had deceased prior to the follow-up visit. Our study showed that a surveillance strategy, based on DBS samples and centralized testing with retracing of patients if needed, is feasible in DRC. ELISA seems well suited as initial test with a similar positivity rate as traditional screening tests, but ITL remains complex. Alternatives for the latter, also analyzable on DBS, should be further explored., Author summary Human African Trypanosomiasis (HAT), also known as sleeping sickness is a parasitic disease, transmitted by tsetse flies, that is usually fatal if untreated. The number of cases have been rapidly declining over the past years indicating that elimination of the disease as a public health problem is within reach. To achieve the next stage, i.e. interruption of HAT transmission by 2030, intensive screening and surveillance will need to be maintained, but with tools and strategies more efficiently tailored to the very low prevalence. In contrast to the traditional approach of sending laboratory expertise to the field, we assessed an alternative approach based on the collection of dried blood samples on filter paper that were tested in a regional laboratory. Samples were taken in endemic, previously endemic and non-endemic villages and tested by ELISA and Immune Trypanolysis. The ELISA positivity rates were similar to those of other screening techniques currently used and Immune Trypanolysis was highly specific. Hence for surveillance in HAT endemic areas, collecting dried blood samples followed by centralized testing could become an alternative to the current strategy of active screening by mobile teams with on the spot confirmation. It has also potential for post-elimination surveillance to monitor resurgence and for exploratory surveillance in historic foci. Though highly specific, Immune Trypanolysis remains too complex for use in intermediate level laboratories, to further expand this strategy an alternative second step test is required.

Background: Cancer-related cognitive impairment (CRCI) is a prevalent source of comprised quality of life in cancer survivors. This study evaluated the efficacy of Emotional Freedom Techniques (EFT) on self-reported CRCI (sr-CRCI). Methods: In this prospective multicentre randomised wait-list controlled study (ClinicalTrials.gov Identifier: NCT02771028), eligible cancer survivors had completed curative treatment, were 18 years or older and screened positive for sr-CRCI with > 43 on the Cognitive Failures Questionnaire (CFQ). Participants were randomised to the immediate treatment group (ITG) or wait-list control (WLC) group, based on age (< or > 65 years), gender, treatment (chemotherapy or not), and centre. The ITG started to apply EFT after inclusion and performed this for 16 weeks. The WLC group could only start the application of EFT after 8 weeks of waiting. Evaluations took place at baseline (T0), 8 weeks (T1) and 16 weeks (T2). The primary outcome was the proportion of patients with sr-CRCI according to the CFQ score. Findings: Between October 2016 and March 2020, 121 patients were recruited with CFQ > 43 indicating sr-CRCI. At T1, the number of patients scoring positive on the CFQ was significantly reduced in the ITG compared to the WLC group (40.8% vs. 87.3% respectively; p

Background Participation in quality controls, also called external quality assessment (EQA) schemes, is required for the ISO15189 accreditation of the Medical Centers of Human Genetics. However, directives on the minimal frequency of participation in genetic quality control schemes are lacking or too heterogeneous, with a possible impact on health care quality. Objective The aim of this project is to develop Belgian guidelines on the frequency of participation in quality controls for genetic testing in the context of rare diseases. Methods A group of experts analyzed 90 EQA schemes offered by accredited providers and focused on analyses used for the diagnosis of rare diseases. On that basis, the experts developed practical recommendations about the minimal frequencies of participation of the Medical Centers of Human Genetics in quality controls and how to deal with poor performances and change management. These guidelines were submitted to the Belgian Accreditation Body and then reviewed and approved by the Belgian College of Human Genetics and Rare Diseases and by the National Institute for Health and Disability Insurance. Results The guidelines offer a decisional algorithm for the minimal frequency of participation in human genetics EQA schemes. This algorithm has been developed taking into account the scopes of the EQA schemes, the levels of experience, and the annual volumes of the Centers of Human Genetics in the performance of the tests considered. They include three key principles: (1) the recommended annual assessment of all genetic techniques and technological platforms, if possible through EQAs covering the technique, genotyping, and clinical interpretation; (2) the triennial assessment of the genotyping and interpretation of specific germline mutations and pharmacogenomics analyses; and (3) the documentation of actions undertaken in the case of poor performances and the participation to quality control the following year. The use of a Bayesian statistical model has been proposed to help the Centers of Human Genetics to determine the theoretical number of tests that should be annually performed to achieve a certain threshold of performance (eg, a maximal error rate of 1%). Besides, the guidelines insist on the role and responsibility of the national public health authorities in the follow-up of the quality of analyses performed by the Medical Centers of Human Genetics and in demonstrating the cost-effectiveness and rationalization of participation frequency in these quality controls. Conclusions These guidelines have been developed based on the analysis of a large panel of EQA schemes and data collected from the Belgian Medical Centers of Human Genetics. They are applicable to other countries and will facilitate and improve the quality management and financing systems of the Medical Centers of Human Genetics.

Background Control of cutaneous leishmaniasis by public health systems in the Americas relies on case identification and treatment. Point-of-care diagnostics that can be performed by health workers within or near affected communities could effectively bring the health system to the resource-limited sites providing early diagnosis and treatment, reducing morbidity and the burden of disease. Methodology/principal findings A cross-sectional study was undertaken to evaluate the diagnostic test performance of Isothermal Recombinase Polymerase Amplification (RPA) targeting Leishmania kinetoplast DNA, coupled with a lateral flow (LF) immunochromatographic strip, in a field setting and a laboratory reference center. Minimally invasive swab and FTA filter paper samples were obtained by community health workers and highly trained technicians from ulcerated lesions of > 2 weeks’ evolution from 118 patients’ ≥ 2 years of age in the municipality of Tumaco, Nariño. Extracted DNA was processed by RPA-LF at a reference center or in a primary health facility in the field. Evaluation was based on a composite “gold standard” that included microscopy, culture, biopsy and real-time polymerase chain reaction detection of Leishmania 18S rDNA. Standard of care routine diagnostic tests were explored as comparators. Sensitivity and specificity of RPA-LF in the reference lab scenario were 87% (95%CI 74–94) and 86% (95%CI 74–97), respectively. In the field scenario, the sensitivity was 75% (95%CI 65–84) and specificity 89% (95%CI 78–99). Positive likelihood ratios in both scenarios were higher than 6 while negative likelihood ratios ranged to 0.2–0.3 supporting the usefulness of RPA-LF to rule-in and potentially to rule-out infection. Conclusions/significance The low complexity requirements of RPA-LF combined with non-invasive sampling support the feasibility of its utilization by community health workers with the goal of strengthening the diagnostic capacity for cutaneous leishmaniasis in Colombia. Trial registration ClinicalTrials.gov NCT04500873., Author summary Limited access to diagnosis is a critical determinant of the “neglect” that defines the so-called Neglected Tropical Diseases (NTDs) including cutaneous leishmaniasis. Diagnostic tests that can be performed close to and involve the participation of the affected communities would improve access to treatment as well as diagnosis. Using non-invasive swab and filter paper samples obtained by Community Health Workers, we evaluated the diagnostic performance of an innovative and technically simple molecular test: Isothermal Recombinase Polymerase Amplification (RPA) to detect Leishmania DNA, coupled with a lateral flow (LF) strip to read the results with the naked eye. The RPA-LF test demonstrated high sensitivity and specificity and capacity to rule in or rule out a diagnosis of cutaneous leishmaniasis in both an endemic field setting and reference laboratory. The findings encourage the further optimization of the test format for Point-of-Care diagnosis by health personnel and rural health workers in endemic settings.

Background Reduced susceptibility of mosquito vectors to currently used insecticides hampers control interventions. Recently pyriproxyfen, an insect growth regulator has been demonstrated to effectively reduce the reproductive potential in vector mosquitoes. Methods Pyriproxyfen (PPF), in different concentrations (0.75%, 0.075%, 0.0075%, and 0.00075%) was applied on papers and Indian wild type Aedes aegypti female mosquitoes (N ≥ 20 for each treatment) were exposed onto it as per WHO guidelines, to study the reproductive disruption. PPF concentration on treated papers was quantitatively cross-determined using HPLC method. Reduction in fecundity, fertility and adult emergence in exposed female Ae. aegypti was determined. Abnormal development in ovary and eggs of exposed females was studied microscopically after different time intervals. Results Eggs laid, eggs hatched, pupae formed and adults emerged per female exposed in both before blood meal and after blood meal groups declined significantly from lowest to highest concentration of PPF (F ≥ 5.2; p < 0.02). Adult emergence inhibition in females exposed to PPF before and after blood meal groups ranged from 58.8% [OR = 0.18 (95% CI = 0.09–0.36)] to 79.2% [OR = 0.04 (95% CI = 0.02–0.10)] and 64.4% [OR = 0.12 (95% CI = 0.05–0.28)] to 77.1% [OR = 0.05 (95% CI = 0.02–0.14)] respectively in different concentrations. The probit model used suggested that FI50 (50% fertility inhibition) and EI50 (50% emergence inhibition) were 0.002% (p = 0.82) and 0.0001% (p = 0.99) for females exposed before blood meal, while 0.01% (p = 0.63) and, Author summary Development of resistance against insecticides has challenged mosquito control programmes globally and prompted the research of alternative options that can complement insecticides. An insect growth regulator, pyriproxyfen (PPF) usage against mosquitoes can effectively reduce the vector population. PPF mainly inhibits the metamorphosis of mosquito larvae into pupae and prevent the adult emergence, therefore it is generally applied in mosquito breeding habitats. PPF has been shown to exhibit delayed residual effect that may impair the reproductive capacity by affecting the survival, fecundity and fertility of adult mosquito exposed through tarsal contact. Presently, the effectiveness of different concentrations of PPF intended to be delivered through contact have been evaluated against dengue vector Ae. aegypti. Results suggested that very low PPF concentration treated surfaces drastically reduce the fecundity, fertility and adult emergence in mosquitoes. Study suggests that control interventions based on PPF-treated surfaces could provide an additional route to target mosquito vector control by overall population density reduction.

The COVIPENDIUM was conceived asaliving paper on the new coronavirus disease (COVID-19). Itprovides a structured compilation of scientific data about the virus, the disease and its control.Its objective is to help scientists identify the most relevant publications on COVID-19 in the wealth of information that appears every day. It is also expected to foster a global understanding of disease control and stimulate transdisciplinary initiatives. This version dated October 20 is the final version of the document. It is a publication of the journal Transciplinary Insights.

Scholars traditionally receive career credit for a paper based on where in the author list they appear, but position in an author list often carries little information about what the contribution of each researcher was. “Contributorship” refers to a movement to formally document the nature of each researcher’s contribution to a project. We discuss the emerging CRediT standard for documenting contributions and describe a web-based app and R package called tenzing that is designed to facilitate its use. tenzing can make it easier for researchers on a project to plan and record their planned contributions and to document those contributions in a journal article.

OBJECTIVE: Even when medical treatments are limited, supporting patients' coping strategies could improve their quality of life. Greater understanding of patients' coping strategies, and influencing factors, can aid developing such support. We examined the prevalence of coping strategies and associated variables.METHODS: We used sociodemographic and baseline data from the ACTION trial, including measures of Denial, Acceptance, and Problem-focused coping (COPE; Brief COPE inventory), of patients with advanced cancer from six European countries. Clinicians provided clinical information. Linear mixed models with clustering at hospital level were used.RESULTS: Data from 675 patients with stage III/IV lung (342, 51%) or stage IV colorectal (333, 49%) cancer were used; mean age 66 (10 SD) years. Overall, patients scored low on Denial and high on Acceptance and Problem-focused coping. Older age was associated with higher scores on Denial than younger age (β = 0.05; CI[0.023; 0.074]), and patients from Italy (β = 1.57 CI[0.760; 2.388]) and Denmark (β = 1.82 CI[0.881; 2.750]) scored higher on Denial than patients in other countries.CONCLUSIONS: Patients with advanced cancer predominantly used Acceptance and Problem-focused coping, and Denial to a lesser extent. Since the studied coping strategies of patients with advanced cancer vary between subpopulations, we recommend taking these factors into account when developing tailored interventions to support patients' coping strategies.