Lack of ceramide synthase 2 suppresses the development of experimental autoimmune encephalomyelitis by impairing the migratory capacity of neutrophils

Ceramide synthases (CerS) synthesise ceramides of defined acyl chain lengths, which are thought to mediate cellular processes in a chain length-dependent manner. In experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), we observed a significant elevation of CerS2 and its products, C24-ceramides, in CD11b⁺ cells (monocytes and neutrophils) isolated from blood. This result correlates with the clinical finding that CerS2 mRNA expression and C24-ceramide levels were significantly increased by 2.2- and 1.5-fold, respectively, in white blood cells of MS patients. The increased CerS2 mRNA/C24-ceramide expression in neutrophils/monocytes seems to mediate pro-inflammatory effects, since a specific genetic deletion of CerS2 in blood cells or a total genetic deletion of CerS2 significantly delayed the onset of clinical symptoms, due to a reduced infiltration of immune cells, in particular neutrophils, into the central nervous system. CXCR2 chemokine receptors, expressed on neutrophils, promote the migration of neutrophils into the central nervous system, which is a prerequisite for the recruitment of further immune cells and the inflammatory process that leads to the development of MS. Interestingly, neutrophils isolated from CerS2 null EAE mice, as opposed to WT EAE mice, were characterised by significantly lower CXCR2 receptor mRNA expression resulting in their reduced migratory capacity towards CXCL2. Most importantly, G-CSF-induced CXCR2 expression was significantly reduced in CerS2 null neutrophils and their migratory capacity was significantly impaired. In conclusion, our data strongly indicate that G-CSF-induced CXCR2 expression is regulated in a CerS2-dependent manner and that CerS2 thereby promotes the migration of neutrophils, thus, contributing to inflammation and the development of EAE and MS.     

Retinal disease in the C3 glomerulopathies and the risk of impaired vision

Background: Dense deposit disease and atypical hemolytic uremic syndrome are often caused by Complement Factor H (CFH) mutations. This study describes the retinal abnormalities in dense deposit disease and, for the first time, atypical haemolytic uremic syndrome. It also reviews our understanding of drusen pathogenesis and their relevance for glomerular disease. Methods: Six individuals with dense deposit disease and one with atypical haemolytic uremic syndrome were studied from 2 to 40 years after presentation. Five had renal transplants. All four who had genetic testing had CFH mutations. Individuals underwent ophthalmological review and retinal photography, and in some cases, optical coherence tomography, and further tests of retinal function. Results: All subjects with dense deposit disease had impaired night vision and retinal drusen or whitish-yellow deposits. Retinal atrophy, pigmentation, and hemorrhage were common. In late disease, peripheral vision was restricted, central vision was distorted, and there were scotoma from sub-retinal choroidal neovascular membranes and atypical serous retinopathy. Drusen were present but less prominent in the young person with atypical uremic syndrome due to a heterozygous CFH mutation. Conclusions: Drusen are common in forms of C3 glomerulopathy caused by compound heterozygous or heterozygous CFH mutations. They are useful diagnostically but also impair vision. Drusen have an identical composition to glomerular deposits. They are also identical to the drusen of age-related macular degeneration, and may respond to the same treatments. Individuals with a C3 glomerulopathy should be assessed ophthalmologically at diagnosis, and monitored regularly for vision-threatening complications.     

Risk-based cost-benefit analysis of alternative vaccines against COVID-19 in Brazil: Coronavac vs. Astrazeneca vs. Pfizer

We propose a probabilistic model to quantify the cost-benefit of mass Vaccination Scenarios (VSs) against COVID-19. Through this approach, we conduct a six-month simulation, from August 31st, 2021 to March 3rd, 2022, of nine VSs, i.e., the three primary vaccine brands in Brazil (CoronaVac, AstraZeneca and Pfizer), each with three different vaccination rates (2nd doses per week). Since each vaccine has different individual-level effectiveness, we measure the population-level benefit as the probability of reaching herd immunity (HI). We quantify and categorize the cost-benefit of VSs through risk graphs that show: (i) monetary cost vs. probability of reaching HI; and (ii) number of new deaths vs. probability of reaching HI. Results show that AstraZeneca has the best cost-benefit when prioritizing acquisition costs, while Pfizer is the most cost-beneficial when prioritizing the number of deaths. This work provides helpful information that can aid public health authorities in Brazil to better plan VSs. Furthermore, our approach is not restricted to Brazil, the COVID-19 pandemic, or the mentioned vaccine brands. Indeed, the method is flexible so that this study can be a valuable reference for future cost-benefit analyses in other countries and pandemics, especially in the early stages of vaccination, when data is scarce and uncertainty is high.     

A Perioperative Care Display for Understanding High Acuity Patients

Background  The data visualization literature asserts that the details of the optimal data display must be tailored to the specific task, the background of the user, and the characteristics of the data. The general organizing principle of a concept-oriented display is known to be useful for many tasks and data types. Objectives  In this project, we used general principles of data visualization and a co-design process to produce a clinical display tailored to a specific cognitive task, chosen from the anesthesia domain, but with clear generalizability to other clinical tasks. To support the work of the anesthesia-in-charge (AIC) our task was, for a given day, to depict the acuity level and complexity of each patient in the collection of those that will be operated on the following day. The AIC uses this information to optimally allocate anesthesia staff and providers across operating rooms. Methods  We used a co-design process to collaborate with participants who work in the AIC role. We conducted two in-depth interviews with AICs and engaged them in subsequent input on iterative design solutions. Results  Through a co-design process, we found (1) the need to carefully match the level of detail in the display to the level required by the clinical task, (2) the impedance caused by irrelevant information on the screen such as icons relevant only to other tasks, and (3) the desire for a specific but optional trajectory of increasingly detailed textual summaries. Conclusion  This study reports a real-world clinical informatics development project that engaged users as co-designers. Our process led to the user-preferred design of a single binary flag to identify the subset of patients needing further investigation, and then a trajectory of increasingly detailed, text-based abstractions for each patient that can be displayed when more information is needed.     

贵州省"5+3"模式订单定向医学毕业生的离职意愿及影响因素研究

背景 我国基层全科医生的离职意愿较高，调查其离职意愿并分析影响因素，可以为减少基层卫生人才流失提供思路。目前，完成"5+3"模式（5年临床医学本科教育+3年住院医师规范化培训）培养的订单定向医学毕业生逐步履约进入基层工作，而针对该部分全科医生离职意向的研究相对较少。 目的 调查贵州省"5+3"模式订单定向医学毕业生回归基层工作后的离职意愿及影响因素，为完善吸引卫生人才留任、建设基层全科医生队伍相关政策提供依据。 方法 以贵州省截至2020年底已完成"5+3"模式培养并履约到基层医疗卫生机构工作的2015—2017级订单定向医学毕业生为研究对象。于2021-01-20至2021-02-10对其开展电子问卷调查，内容包括毕业生的一般情况、职业满意度、离职意愿、服务期满后职业方向。共回收问卷347份，其中有效问卷311份，问卷有效回收率为89.6%。采用单因素分析及多元逐步线性回归分析全科医生离职意愿的影响因素。 结果 贵州省"5+3"订单定向医学毕业生的整体离职意愿得分为（3.98±0.98）分，具有离职倾向者229例（73.6%）。不同性别、单位地理位置、每日工作量者的离职意愿得分比较，差异有统计学意义（P<0.05）。多元逐步线性回归分析显示，单位负责人对待下属的方式、在工作中获得的成就感、对当前收入满意程度、家人对工作的支持程度、当地激励政策执行程度是"5+3"订单定向医学毕业生离职意愿的影响因素（P<0.05）。服务期满后，计划留任原基层医疗卫生机构者12例（3.9%），计划去其他基层医疗卫生机构者21例（6.7%），计划离开基层去上级医院工作者196例（63.0%），计划攻读全日制硕士学位者60例（19.3%）。 结论 贵州省"5+3"模式订单定向医学毕业生的离职意愿较高，预计服务期满后基层全科人才流失较多，需从提高收入、重视全科医生心理需求、优化全科医生培养与使用、发展基层医疗卫生机构、加强全科宣传等方面着手改善。     

Proteases and their inhibitors as prognostic factors for high-grade serous ovarian cancer

Ovarian carcinoma is one of the most lethal malignancies, but only very few prognostic biomarkers are known. The degradome, comprising proteases, protease non-proteolytic homologues and inhibitors, have been involved in the prognosis of many cancer types, including ovarian carcinoma. The prognostic significance of the whole degradome family has not been specifically studied in high-grade serous ovarian cancer. A targeted DNA microarray known as the CLIP-CHIP microarray was used to identify potential prognostic factors in ten high-grade serous ovarian cancer women who had early recurrence (<1.6 years) or late/no recurrence after first line surgery and chemotherapy. In women with early recurrence, we identified seven upregulated genes (TMPRSS4, MASP1/3, SPC18, PSMB1, IGFBP2, CFI – encoding Complement Factor I – and MMP9) and one down-regulated gene (ADAM-10). Using immunohistochemistry, we evaluated the prognostic effect of these 8 candidate genes in an independent cohort of 112 high-grade serous ovarian cancer women. Outcomes were progression, defined according to CA-125 criteria, and death. Multivariate Cox proportional hazard regression models were done to estimate the associations between each protein and each outcome. High ADAM-10 expression (intensity of 2–3) was associated with a lower risk of progression (adjusted hazard ratio (HR): 0.51; 95% confidence interval (CI): 0.29-0.87). High complement factor I expression (intensity 2–3) was associated with a higher risk of progression (adjusted HR: 2.30, 95% CI: 1.17–4.53) and death (adjusted HR: 3.42; 95% CI: 1.72–6.79). Overall, we identified the prognostic value of two proteases, ADAM-10 and complement factor I, for high-grade serous ovarian cancer which could have clinical significance.     

Association of regional socioeconomic deprivation and rurality with global developmental delay in early childhood: Data from mandatory school entry examinations in Germany

BackgroundFrom birth to young adulthood, health and development of young people are strongly linked to their living situation, including their family’s socioeconomic position (SEP) and living environment. The impact of regional characteristics on development in early childhood beyond family SEP has been rarely investigated. This study aimed to identify regional predictors of global developmental delay at school entry taking family SEP into consideration.MethodWe used representative, population-based data from mandatory school entry examinations of the German federal state of Brandenburg in 2018/2019 with n=22,801 preschool children. By applying binary multilevel models, we hierarchically analyzed the effect of regional deprivation defined by the German Index of Socioeconomic Deprivation (GISD) and rurality operationalized as inverted population density of the children’s school district on global developmental delay (GDD) while adjusting for family SEP (low, medium and high).ResultsFamily SEP was significantly and strongly linked to GDD. Children with the highest family SEP showed a lower odds for GDD compared to a medium SEP (female: OR=4.26, male: OR=3.46) and low SEP (female: OR=16.58, male: OR=12.79). Furthermore, we discovered a smaller, but additional and independent effect of regional socioeconomic deprivation on GDD, with a higher odds for children from a more deprived school district (female: OR=1.35, male: OR=1.20). However, rurality did not show a significant link to GDD in preschool children beyond family SEP and regional deprivation.ConclusionFamily SEP and regional deprivation are risk factors for child development and of particular interest to promote health of children in early childhood and over the life course.     

Communication practices in conversations about sexual health in medical healthcare settings: A systematic review

ObjectiveMany healthcare professionals experience difficulties in discussing sexual health with their patients. The aim of this review was to synthesize results of studies on communication practices in interactions about sexual health in medical settings, to offer healthcare professionals suggestions on how to communicate about this topic.MethodsWe searched for studies using five databases. Reference lists and specialist bibliographies were searched to identify additional studies. We included discourse analytic studies that used recordings of medical consultations.ResultsWe identified five studies that met the inclusion criteria. Findings were synthesized into seven categories of practices deployed by patients and healthcare professionals when talking about sexual health: avoiding delicate terms (1), delaying potentially delicate words and issues (2), using assumptive talk (3), generalized advice-giving (4), deploying patients’ talk (5), depersonalization (6), and patient-initiated advice (7).ConclusionPractices indicate the delicacy associated with discussing sexual health issues, but results also shed light on practices that can help professionals to deal with this delicacy, and to be responsive to patients’ needs and concerns.Practice implicationsFindings will assist healthcare professionals in broaching topics related to sexual health so they can help patients deal with challenges that affect their sexual health and overall well-being.