There is a critical skills gap on the African continent in regulatory sciences, and an acknowledged need to develop a long-term strategy for training and professional development of African regulatory personnel. Capacity building programs for African regulators should link education, training and research with career development in an approach that combines an academic base and experiential learning aligned within a competency framework. A regulatory ecosystem that engages with a broad range of stakeholders will mean that expertise in the ever-expanding field of regulatory science filters into teaching and research in a symbiotic way. In this way capacity development interventions will be a collaborative approach between the learning context (academic and training institutions) and the performance context (regulatory agencies and industry), which will ultimately best serve the patients. Monitoring and evaluation of capacity development interventions will be essential to show value of investments and ultimately guide continued funding and sustainability. This paper reviews the skills and human capacity gap and outlines a staged tactical approach for Africa that builds on previous efforts to strengthen African regulatory ecosystems.

The work reported here concerns with study a generalized nonlinear fractional boundary value problems involving ϑ-fractional derivative in the Riemann-Liouville sense. The existence and uniqueness of positive solutions to the problem at hand are proved. Our discussion relies on the properties of the Green's function, the upper and lower solutions method, and the classical fixed point theorems in a cone. Moreover, building upper and lower control functions have an effective role in the analysis. Some examples are offered to justify the validity of theoretical findings.

Mapping the genes underlying ecologically-relevant traits in natural populations is fundamental to develop a molecular understanding of species adaptation. Current sequencing technologies enable the characterisation of a species' genetic diversity across the landscape or even over its whole range. The relevant capture of the genetic diversity across the landscape is critical for a successful genetic mapping of traits and there are no clear guidelines on how to achieve an optimal sampling and which sequencing strategy to implement. Here we determine through simulation, the sampling scheme that maximises the power to map the genetic basis of a complex trait in an outbreeding species across an idealised landscape and draw genomic predictions for the trait, comparing individual and pool sequencing strategies. Our results show that QTL detection power and prediction accuracy are higher when more populations over the landscape are sampled and this is more cost-effectively done with pool sequencing than with individual sequencing. Additionally, we recommend sampling populations from areas of high genetic diversity. As progress in sequencing enables the integration of trait-based functional ecology into landscape genomics studies, these findings will guide study designs allowing direct measures of genetic effects in natural populations across the environment.

Computationally artificially derived chemical synthesis and multistep preparation processes can have a variety of use-cases. The idea of utilizing advanced computational complexity, bleu-score computational ranking type systems, and isolating different variable data is integrated in the synthesis preparation processes. Some use-cases presented include: edible polymers and the field study of printable foods, synthetic carbon capturing polymers and biomasses, and CBD Isolate for phytocannabinoids. Synthetic chemistry can tackle a variety of issues from food shortage to the opioid crisis. A computational scoring system can help with elimination reactions and non or organic reactionary mechanisms. Also, accuracy through validation-scoring and forms of molecular mechanics is crucial in the experimentation process. The same applies to various forms of variances, scattering and composition accuracy. The easiest way to demonstrate some of these concepts is through the analysis of said systems for these usecase varieties.

Background and Purpose: Hydroxychloroquine and chloroquine, alone or in combination with azithromycin, have been proposed as therapies for COVID-19. However, there is currently scant and inconsistent data regarding their proarrhythmic potential in these patients. Moreover, their risk profile in the setting of altered physiological states encountered in patients with COVID-19 (i.e. febrile state, electrolyte imbalances, and/or acidosis) is unknown. Experimental approach: Potency of hERG block was measured using high-throughput electrophysiology in the presence of variable environmental factors. These potencies informed simulations to predict population risk profiles. Effects on cardiac repolarisation were verified in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) from three separate individuals. Key Results: Chloroquine and hydroxychloroquine blocked hERG with IC50 of 1.47±0.07 µM and 3.78±0.17 µM respectively, indicating proarrhythmic risk at concentrations effective against SARS-CoV-2 in vitro and proposed in COVID-19 clinical trials. Hypokalaemia and hypermagnesemia increased potency of chloroquine and hydroxychloroquine, indicating increased proarrhythmic risk. Acidosis significantly reduced potency of all drugs (i.e. reduced proarrhythmic risk), whereas increased temperature decreased potency of chloroquine and hydroxychloroquine but increased potency for azithromycin. In silico simulations across genetically diverse populations predicted that 17% of individuals exhibit action potential durations >500 ms at the highest proposed therapeutic levels, equating to significant QT prolongation. Conclusion and Implications: Significant proarrhythmic risk is predicted for hydroxychloroquine and chloroquine at doses proposed to treat COVID-19. Clinicians should carefully consider the risk of such treatments, and implement long term QT interval monitoring in trials, particularly in patients with electrolyte imbalances.

Recent research on Gut-Brain Axis (GBA) has suggested that the gut luminal environment, including the dietary components and commensal microbiota, could affect behavior, emotion, and cognitive abilities in the brain. The research on GBA has heavily relied on animal models, which makes the research challenging. Recent advances in organ-on-a-chip technology could be a solution for GBA research. In present work, we developed a modular microfluidic chip, where gut epithelial and brain endothelial cells were co-cultured to form the gut epithelial barrier and the Blood-Brain Barrier (BBB). Cell responses to microbial byproducts were examined by TEER measurement for each barrier, and we observed the transport of fluorescently labeled exosome across the gut barrier towards the BBB. Our results suggest this model can be used as a novel in vitro model of GBA for studying the interaction between the gut and the brain.

Introduction:Cardiac anxiety(CA) is a common finding in patients in the pre- and postoperative period of coronary artery bypass graft(CABG) surgery. Ventilatory restriction generated by pain and reduced muscle strength is associated with increased CA level. Inspiratory muscle training(IMT) for generating increased muscle strength can cause a decrease in CA in the postoperative period. Objective:To evaluate the impact of IMT on inspiratory muscle strength and its relationship with cardiac anxiety in patients undergoing CABG. Methodology:This is a randomized controlled clinical trial. In the preoperative moment, all patients answered a cardiac anxiety questionnaire, composed of two domains: fear and vigilance and avoidance. In addition, their maximum inspiratory pressure(MIP) was assessed. After the surgical procedure, the patients were divided into a control group(CG) that received routine hospital care and a training group(TG) who underwent an IMT protocol until the moment of hospital discharge. Results:80 patients were evaluated,40 in each group. The IMT group showed a 17% decrease in MIP while the CG decreased 43%(p <0.01). The fear and vigilance domain had a decrease of -16±3 in the CG while in the TG the reduction was -8±3(p <0.01). The avoidance domain reduced -17±4 in the CG vs -10±4 in the TG(p <0.01). In addition, there was a strong correlation between the MIP of the TG with the domains of fear/vigilance(r -0.77) and avoidance(r -0.72). Conclusion:IMT is associated with a reduction in the loss of inspiratory muscle strength, resulting in a reduced level of cardiac anxiety in patients undergoing CABG.

Abstract Background: Habitual snoring (HS), a prominent symptom of sleep-disordered breathing , is important to also consider the associated, multidimensional risk factors for HS in children. Aim: To identify risk factors for HS in children. Methods: A cross-sectional survey was performed in Chengdu. Children aged 2–14 years from four districts were randomly chosen to participate.Questionnaires were voluntarily completed by the children’s guardians. Results: The survey included 926 boys and 622 girls, who were an average of 7.11 5.25 years old. The sample included 463 habitual snorers (30.38%), 683 occasional snorers (44.82%), and 402 non-snorers (26.38%). HS was found in 51.84% of preschool children and 26.6% of school children.Among the HS group, 31.3% had a maternal education of a college degree or higher and 86.6%had an immediate family member who snores. Breastfeeding duration among the HS group was significantly less than among the occasional snoring and non-snoring groups. History of symptoms of allergic rhinitis, rhinosinusitis, tonsillitis, and pneumonia/bronchitis in the past six months were associated with HS. Likewise, maternal smoking during pregnancy, maternal exposure to secondhand smoke during pregnancy , and child exposure to secondhand smoke were also associated with HS. Conclusion: The prevalence of HS was higher in preschool children. Having a mother with more education, a family history of snoring, a shorter period of breastfeeding, upper respiratory tract inflammation, and passive smoking are important risk factors for HS.

Objectives: In this study, we aimed to compare the outcomes and complication rates of percutaneous nephrolithotomy (PCNL) and retrograde intrarenal surgery (RIRS) in geriatric patients according to Charlson comorbidity index (CCI). Materials and Methods: Between April 2011 and January 2020, patients who underwent PCNL and RIRS for renal stone between 10 and 30 mm in geriatric patients were retrospectively evaluated. All patients’ Pre-surgery comorbidities were recorded and the CCI was calculated. The two groups’ perioperative values, stone free rates and complication rates were compared. Postoperative complications were noted according to the Clavien scoring system. Results: There were 89 and 72 patients in the PCNL and RIRS group, respectively. The median age was 67 years in both of groups (p=0.192). The stone size were 22.2 ± 3.5 and 19.9 ± 7.1 in the PCNL and RIRS group, respec¬tively ( p = 0.082). CCI scores were similar in both groups (p=0.098). Stone free and complication rates were significantly higher in PCNL group (p = 0.021, p = 0.034). Also we found that overall complication and major complication rates were statistically significant difference with especially Charlson comorbidity index score ≥2 in PCNL group (p = 0,016, p = 0,029). According to correlation analysis of intraoperative and postoperative results with Charlson comorbidity index, there was positive correlation between total complication with PCNL and RIRS group, respectively (p < 0,001, p = 0.024). In addition, there was positive correlation between lenght of hospital stay with PCNL and RIRS group, respectively (p = 0,007, p < 0,001). Also there was positive correlation between blood transfusion requirement with PCNL group (p=0,009). Conclusion: Despite there was higher stone clearence in PCNL, the complication rates were higher compared to RIRS. So RIRS might be a safe alternative treatment method to PCNL in older patients with a high CCI score.

Leaf rust of wheat caused by Puccinia triticina (Pt) is one of the most common and widespread fungal diseases which has a wide incidence area, especially in the southwest and northwest of China, the middle and lower reaches of the Yangtze river, and the southern part of the Huang-huai-hai river basin. To explore the relationship between the epidemic flora of leaf rust and transmission, a total of 709 isolates from Beijing, Hebei, Henan, Shandong, Shanxi, Shaanxi, Anhui, Jiangsu, Hubei, Yunnan, Sichuan, Gansu, Qinghai, Heilongjiang, Inner Mongolia 15 provinces was genotyped using 13 simple sequence repeat (SSR) markers. The Puccinia triticina populations from the 15 provinces were obviously divided into three predominant populations including the eastern Pt populations consisting of Pt samples from eight eastern provinces of Beijing, Hebei, Shandong, Anhui, Henan, Shanxi, Shaanxi and Heilongjiang; the four western Pt populations from Gansu, Sichuan, Qinghai and Inner Mongolia provinces; and the bridge Pt populations including Pt samples from Jiangsu, Hubei and Yunnan provinces which were communicated with the other two populations as a “bridge”. And the pathogen source transmission of eastern Pt populations was more frequent than western Pt populations. The linkage disequilibrium test indicated that the whole Pt population was linkage disequilibrium. Beijing, Hebei, Shaanxi, Jiangsu, Henan and Heilongjiang provinces were showed obviously linkage equilibrium phenomena while the five provinces of Qinghai, Hubei, Anhui, Shandong and Inner Mongolia were supported clonal mode of reproductions. In addition, provinces of Shanxi, Yunnan, Gansu, and Sichuan showed weak linkage disequilibrium phenomena. We systematically revealed the genotypic diversities, population differentiation and reproduction of P. triticina in 15 wheat producing areas in China.

Paraganglioma is a very rare extraadrenal nonepithelial tumor. The number of cases of laparoscopic surgery in Paraganglioma is small and controversial. This study encountered a case of successful transperitoneal laparoscopic surgery for a 56mm paraganglioma . Moreover, previous reports on laparoscopic surgery for paraganglioma are reviewed .

MF is a low-grade lymphoma, but on reaching the tumor stage, it can cause cardiac tamponade owing to epicardial infiltration. Myocardial infiltration, even in the absence of abnormal imaging findings, requires attention because it can lead to arrhythmia and cardiac arrest.

Outflow cannula occlusion is an infrequent complication occurring among recipients of continuous flow left ventricular assist devices (LVAD). Hereby, we present a case of intrinsic and extrinsic outflow cannula obstruction resulting in cardiogenic shock and multiorgan failure.

A recent Molecular Ecology editorial made a proactive statement of support for the “Nagoya Protocol” and the principle of benefit-sharing (Marden et al. 2020) by requiring authors to provide a “Data Accessibility and Benefit‐Sharing Statement” in their articles. Here, we encourage another step that enables Indigenous communities to provide their own definitions and aspirations for access and benefit-sharing alongside the author’s “Statement”. We invite the Molecular Ecology research community to use Biocultural-, Traditional Knowledge-, and Cultural Institution Notices to help Indigenous communities gain visibility within our research structures. Notices are one of the tools offered by the Biocultural Labels Initiative (part of the Local Contexts system) designed specifically for researchers and institutions. The Notices are highly visible, machine-readable icons that signal the Indigenous provenance of genetic resources, and rights of Indigenous communities to define the future use of genetic resources and derived benefits. The Notices invite collaboration with Indigenous communities and create spaces within our research systems for them to define the provenance, protocols, and permissions associated with genetic resources using Labels. Authors contributing to Molecular Ecology can apply Notices to their articles by providing the persistent unique identifier and an optional use-statement associated with the Notice in their “Data Accessibility and Benefit‐Sharing Statement”. In this way, our research community has an opportunity to accelerate support for the principles of the Nagoya Protocol, to alleviate concerns regarding Indigenous Data Sovereignty and equitable outcomes, and to build better relationships with Indigenous collaborators to enhance research, biodiversity, and conservation outcomes.

Molecular Dynamics (MD) simulations are widely used to predict the behavior of molecular systems over time. However, one of the great challenges of MD simulations is how to treat the thousands of configurations obtained from calculations, since the number of the quantum calculations (QM) required for evaluating electronic parameters is too high and, sometimes, computationally impracticable. Thus, an efficient and accurate sampling protocol is essential for combining classical MD and QM calculations. In this article, based on the OWSCA methodology, 93 wavelet signals were analyzed in order to further refine the methodology and identify the best wavelet family for [Fe(H2O)6]2+ and [Mn(H2O)6]2+ complexes in solution. Our results point out that the bior1.3 was the best wavelet, values closest to the experimental data were obtained for both studied systems.

A chest x-ray cannot diagnose pneumonia, it only shows shadows. Pneumonia then becomes a clinical diagnosis for which antibiotics should be considered primarily after careful clinical assessment of how sick the child appears, the presence of fever, an elevated CRP, an elevated procalcitonin, and a radiologic image of a distinct lobar or lobular infiltrate.

The biodiversity in montane ecosystems is high but is threatened by rapid environmental change. Urbanization and other anthropogenic activities in the mountains surrounding cities can affect changes in land use and habitat heterogeneity. Moreover, patterns of habitat heterogeneity are closely related to elevation and have a major effect on montane biodiversity. The aim of this study was to analyze the effects of habitat heterogeneity on the vertical distribution pattern of bird diversity by characterizing the structure of the bird community, biodiversity, and landscape factors at different altitudes. Continuous monitoring of the breeding birds at Mount Tai from 2016 to 2019 revealed that forest reduced the diversity and abundance of birds and favored montane birds. Habitat composition varied at different altitudes. In the high-mountain belt and the middle-mountain belt, the habitat was primarily composed of forest. In contrast, artificial habitat was more common in the low-mountain belt. Bird abundance, species richness, and the Shannon-Wiener index decreased as the altitude increased, and the structure of the bird community significantly differed in the different belts. Some rare species tended to only occupy specific belts. Road density, number of habitat patches, patch density, and the percentage of forest significantly affected bird diversity. The effect of patch density was higher compared with other landscape factors. The “habitat amount hypothesis” was more suitable for explaining the elevational distribution pattern of bird diversity at Mount Tai. Sufficient habitat and more patches in the low-mountain belt supported higher bird diversity. The middle-mountain belt and high-mountain belt showed contrasting patterns. Our results highlight the effects of ongoing urbanization and human activities on montane biodiversity and emphasize the need for artificial habitats in the mountains surrounding cities to be managed.

Introduction: The coronavirus 2019 (COVID-19) pandemic has demanded care changes for patients with chronic disease. Patients with CF are considered at higher risk of developing severe manifestations in the case of SARS-CoV-2 infection, and a need for new ways of safer care delivery has been required to avoid transmission. Objectives: To assess the impact of the lockdown during the first wave of the COVID-19 pandemic and remote monitoring on patient’s health status and daily maintenance therapy in a middle-income resource setting. Methods: During the first wave of the pandemic period, we changed from regular clinic visits to telephone visit calls to monitor our patients’ health condition and adherence to physiotherapy and physical exercise. Results: A total of 120 patients or their caregivers have been contacted by telephone call visits over ten weeks. During this period, 38 patients (28.33%) were identified to have pulmonary exacerbation; 89.5% were prescribed oral antibiotics, 3% were hospitalized to get iv antibiotics, and 8% of the patients presented other CF complications. Most of the patients did not change the frequency of the daily physiotherapy. Moreover, 71% of the patients who performed regular physical exercise changed the frequency and the type of exercise during the quarantine period. Interestingly, mean FEV1 and body weight increased significantly and after the lockdown period. Conclusions: During the COVID-19 pandemic, the implementation of telephone contact processes aiming for CF patients’ appropriate care is of great importance. Further studies are needed to evaluate patient outcomes when transitioning from face-to-face clinics to telemedicine clinics.

In this paper we describe an additional newborn patient with craniofacial dysmorphisms, congenital heart disease, hypotonia and a 2q13 deletion of 1.7 Mb, whose clinical and genomic findings are consistent with the diagnosis of 2q13 microdeletion syndrome.

Free light chains (FLC), considered a biomarker of B cell activity, are frequently elevated in different systemic inflammatory-autoimmune diseases. As systemic sclerosis (SSc) clinical course may be variable, this study aimed to assess FLCs levels in serum and urine of affected individuals, as biomarkers of disease activity. We assessed FLC levels in serum and urine of 72 SSc patients and 30 healthy controls (HC). Results were analyzed in comparison with overall clinical and laboratory findings, disease activity index (DAI) and disease severity scale (DSS). SSc patients displayed increased levels of k and λ FLC in serum, significantly higher than HC (p=0.0001) alongside with the mean levels of free k/λ ratio and of the k+λ sum (p=0.0001). In addition, SSc patients had significant higher levels in the urine of free k and of k/λ ratio than HC (p=0.0001). SSc patients with increased k+λ sum in serum showed a statistically higher levels of erythro-sedimentation rate (p=0.034), C-reactive protein (p=0.003), higher DAI (p=0.024) and DSS (p=0.015) than SSc patients with normal levels of FLC. A positive linear correlation was found between serum levels of free k and DAI (r=0.29, p=0.014). SSc patients with increased free k in urine had statistically higher DAI (p=0.048) than SSc patients with normal level of free k. The significant increased levels of FLC correlated with disease activity in SSc patients. Our results strengthen the role of FLC as useful biomarkers in clinical practice to early diagnosis and monitor disease activity with an improvement of SSc patients’ management.

Rationale, aims and objectives: The available evidence on the existence and consequences of the use of heuristics in the clinical decision process is very scarce. The purpose of this study is to measure the use of the Representativeness, Availability and Overconfidence heuristics in real conditions with Primary Care physicians in cases of dyspnea and to study the possible correlation with diagnostic error. Methods: A prospective cohort study was carried out in 4 Primary Care centers in which 371 new cases or dyspnea were registered. The use of the three heuristics in the diagnostic process is measured through an operational definition of the same. Subsequently, the statistical correlation with the identified clinical errors is analyzed. Results: In 9.97% of the registered cases a diagnostic error was identified. In 49.59% of the cases, the physicians used the representativeness heuristic in the diagnostic decision process. The availability heuristic was used by 82.38% of the doctors and finally, in more than 50% of the cases the doctors showed excess confidence. None of the heuristics showed a statistically significant correlation with diagnostic error. Conclusion: The three heuristics have been used as mental shortcuts by Primary Care physicians in the clinical decision process in cases of dyspnea, but their influence on the diagnostic error is not significant. New studies based on the proposed methodology will allow confirming both its importance and its association with diagnostic error.

Background and Purpose: Surgery remains the first-line treatment of ovarian cancer. However, perioperative risk factors including the choice of anaesthetics may influence its recurrence after surgery. In the current study, it was hypothesised that inhalational anaesthetic sevoflurane and intravenous anaesthetic propofol might affect cancer cellular metabolism and signalling, which might interfere the malignancy of ovarian cancer cells. Experimental Approach: Cultured ovarian cancer cells were exposed to 2.5% sevoflurane or administered with 4 μg/mL propofol for 2 hours followed by 24 hours recovery. Their cell viability, proliferation, migration and invasion were assessed using cell counting kit-8, Ki-67 staining, wound healing and Transwell assay. Cellular signalling biomarkers were measured using immunofluorescent staining and/or Western blot. Cultured media were collected for 1H-NMR spectroscopy-based metabolomics analysis. Key Results: The cell viability, proliferation, migration, and invasion of ovarian cancer cells were enhanced by sevoflurane but suppressed by propofol. Sevoflurane increased the GLUT1, MPC1, GLUD1, p-Erk1/2, and HIF-1α expressions but decreased the PEDF expression. In contrast to the sevoflurane treatment, the “mirror changes” of these cellular markers were observed with propofol. Sevoflurane increased levels of isopropanol but decreased glucose and glutamine levels in the media, but the opposite changes of those metabolites were found after propofol treatment. Conclusion and Implications: These data indicated that unlike propofol, sevoflurane enhanced ovarian cancer cell metabolism and activated PEDF/Erk/HIF-1α cellular signalling pathway, suggesting that sevoflurane might have pro-tumour property but propofol might afford an anti-tumour property. The translational value of this work warrants further study.

Quantifying how multiple ecosystem services and functions are affected by different drivers of Global Change is challenging. Particularly in African savanna regions, highly integrated land-use activities created a landscape mosaic with flows of multiple resources between land use types. A framework is needed that quantifies the effects of climate change, management and policy interventions on ecosystem services that are most relevant for rural communities, such as provision of food, feed, carbon sequestration, nutrient cycling and natural pest control. In spite of progress made in ecosystem modelling, data availability and stakeholder interactions, these elements have neither been brought together in an integrated framework, nor evaluated in the context of real-world problems. Here, we propose and outline such framework as developed by a multi-disciplinary research network, the Southern African Limpopo Landscapes network (SALLnet). Components of the framework such as the crop model APSIM and the vegetation model aDGVM2 had already been parameterized and evaluated using data sets from savanna regions of eastern, western and southern Africa, and were fine-tuned using novel data sets from Limpopo. A prototype of an agent-based farm household model was developed using comprehensive farm survey information from the Limpopo Province of South Africa. A first test of the functionality of the integrated framework has been performed for alternative policy interventions on smallholder crop-livestock systems. We discuss the versatile applicability of the framework, with a focus on smallholder landscapes in the savanna regions of southern Africa that are considered hotspots of global change impacts.

Background: Quantifying age trends in healthcare costs of pediatric asthma leads to better understanding of the natural history of the disease and informed decision-making on the allocation of healthcare resources. Methods: We identified children with incident asthma from the health administrative data of British Columbia, Canada (Jan 1998 to Dec 2015), and followed them from their first diagnosis of asthma or wheezing until age 18. We estimated direct medical costs (in 2016 Canadian dollars [$]), including inpatient and outpatient encounters and pharmacy costs, attributed to asthma (primary outcome) and other respiratory diseases (secondary outcome). We assessed the impact of sex and socioeconomic status on age trends, adjusting for calendar effect. Results: The final analysis included 44,552 children with asthma (62% boys). From age 0 to 18, costs of asthma/wheezing and other respiratory conditions decreased from $1,036 to $29/child-year, and from $1,145 to $31/child-year, respectively. Children under 3 years of age incurred 4–fold higher costs for asthma/wheezing and other respiratory conditions. In particular, costs of asthma hospitalizations were 10 times higher in this age group compared to older children. Age trends were generally similar between sex groups and across socioeconomic status. However, medication costs for asthma/wheezing decreased in boys, whereas those in girls declined during childhood but increased during adolescence. Conclusions: The highest costs of pediatric asthma are concentrated in children younger than 3. Age trends were generally consistent between sex and across socioeconomic status.