贵港市急性脑炎及脑膜炎症候群病原体监测

目的 了解华南地区急性脑炎及急性脑膜炎的发病强度、病原谱和流行病学特征,为急性脑炎、脑膜炎的临床诊治和预防控制提供参考依据。方法 在广西贵港市建立涵盖市辖区、桂平市和平南县的急性脑炎、脑膜炎流行病学监测网络,按照筛检标准评估疑似病例,进行流行病学调查和采样,对标本开展细菌学培养和10种常见病毒检测。结果 2007年5月—2008年10月监测期内,共评估急性脑炎及急性脑膜炎症候群病例 883例,死亡 41例,细菌学培养和PCR检测发现存在肺炎链球菌、流脑、Hib、猪链球菌等致病菌,病毒学检测发现肠道病毒、腮腺炎病毒和乙脑病毒是病毒性脑炎脑膜炎的主要病原,贵港市确诊的细菌性、病毒性脑炎脑膜炎年均发病率分别为0.92/10万和6.42/10万,细菌性、病毒性脑炎脑膜炎均以夏秋季多见,10岁以下儿童为主,职业分布细菌性脑炎脑膜炎以散居儿童和农民为主,分别占48.65%和29.73%,病毒性脑炎脑膜炎以散居儿童和学生为主,分别占59.64%和21.08%。结论 广西贵港市急性脑炎脑膜炎病例以病毒性感染占多数,病原诊断的细菌性脑炎脑膜炎发病率处于较低水平。     

Explainable machine learning model for predicting furosemide responsiveness in patients with oliguric acute kidney injury

BackgroundAlthough current guidelines didn’t support the routine use of furosemide in oliguric acute kidney injury (AKI) management, some patients may benefit from furosemide administration at an early stage. We aimed to develop an explainable machine learning (ML) model to differentiate between furosemide-responsive (FR) and furosemide-unresponsive (FU) oliguric AKI.MethodsFrom Medical Information Mart for Intensive Care-IV (MIMIC-IV) and eICU Collaborative Research Database (eICU-CRD), oliguric AKI patients with urine output (UO) < 0.5 ml/kg/h for the first 6 h after ICU admission and furosemide infusion ≥ 40 mg in the following 6 h were retrospectively selected. The MIMIC-IV cohort was used in training a XGBoost model to predict UO > 0.65 ml/kg/h during 6–24 h succeeding the initial 6 h for assessing oliguria, and it was validated in the eICU-CRD cohort. We compared the predictive performance of the XGBoost model with the traditional logistic regression and other ML models.Results6897 patients were included in the MIMIC-IV training cohort, with 2235 patients in the eICU-CRD validation cohort. The XGBoost model showed an AUC of 0.97 (95% CI: 0.96–0.98) for differentiating FR and FU oliguric AKI. It outperformed the logistic regression and other ML models in correctly predicting furosemide diuretic response, achieved 92.43% sensitivity (95% CI: 90.88–93.73%) and 95.12% specificity (95% CI: 93.51–96.3%).ConclusionA boosted ensemble algorithm can be used to accurately differentiate between patients who would and would not respond to furosemide in oliguric AKI. By making the model explainable, clinicians would be able to better understand the reasoning behind the prediction outcome and make individualized treatment.     

肝移植术后急性肺损伤/急性呼吸窘迫综合征的研究进展

急性肺损伤/急性呼吸窘迫综合症（ALI/ARDS）是肝移植术后常见的并发症,可延长受者术后重症监护室入住时间,影响肝移植手术疗效,病情严重可致受者死亡,临床中引起了肝移植外科医师的高度重视。肝移植术后ALI/ARDS可由肺源性因素（例如机械通气相关肺损伤、肺部感染、误吸等）直接导致,也可由非肺源性因素（例如肺部以外的严重感染、输血、缺血-再灌注损伤等）间接导致。本文对肝移植术后ALI/ARDS的诊断标准及发生情况、发生机制、危险因素、实验室及临床诊断方法以及治疗方法等进行综述,加深对肝移植围手术期ALI/ARDS的理解与认知,以期为肝移植术后ALI/ARDS的诊治提供借鉴。     

Age-Stratified Model to Assess Health Outcomes of COVID-19 Vaccination Strategies,Ghana

We assessed the effect of various COVID-19 vaccination strategies on health outcomes in Ghana by using an age-stratified compartmental model. We stratified the population into 3 age groups: <25 years, 25–64 years, and ≥65 years. We explored 5 vaccination optimization scenarios using 2 contact matrices, assuming that 1 million persons could be vaccinated in either 3 or 6 months. We assessed these vaccine optimization strategies for the initial strain, followed by a sensitivity analysis for the Delta variant. We found that vaccinating persons <25 years of age was associated with the lowest cumulative infections for the main matrix, for both the initial strain and the Delta variant. Prioritizing the elderly (≥65 years of age) was associated with the lowest cumulative deaths for both strains in all scenarios. The consensus between the findings of both contact matrices depended on the vaccine rollout period and the objective of the vaccination program.     

Blinatumomab治疗急性B淋巴细胞白血病的研究进展*

急性B淋巴细胞白血病（B-cell acute lymphoblastic leukemia,B-ALL）是一种恶性血液病。研究发现,以CD19作为治疗靶点的贝林妥欧单抗（blinatumomab）作为异基因造血干细胞移植（allogeneic hematopoietic stem cell transplantation,allo-HSCT）的桥梁显著改善了复发/难治性急性B淋巴细胞白血病（relapsed/refractory acute lymphoblastic leukemia,R/R B-ALL）患者的预后,其在新诊断急性淋巴细胞白血病（acute lymphoblastic leukemia,ALL）中与细胞毒性化疗药物或其他免疫治疗药物联用,在确保疗效的同时降低了方案的不良反应,在费城染色体阳性（Philadelphia chromosome-positive,Ph⁺）ALL患者中与二代/三代酪氨酸激酶抑制剂（tyrosine kinase inhibitors,TKIs）联合应用,有望使患者后期无需移植治疗。此外,治疗后微小残留病变（minimal residual disease,MRD）对患者的复发和长期生存（overall survival,OS）具有显著影响,blinatumomab可提高ALL患者的MRD转阴率,保障了患者的远期预后。本综述重点介绍blinatumomab在B-ALL不同患者群体中的临床研究及相关进展。     

134例老年急性髓系白血病的临床特点及预后分析

  目的  分析老年急性髓系白血病（acute myeloid leukemia,AML）（非早幼粒细胞白血病）的临床特点,治疗方式以及疗效和预后特点。  方法  收集2015年1月至2023年2月北京大学国际医院收治的134例老年AML患者资料,回顾性分析患者初诊时的白细胞计数、骨髓原始细胞计数、细胞遗传学及分子学特点、ELN危险分层,根据不同治疗方案将患者分为高强度化疗组和低剂量治疗组,观察在治疗过程中强化疗是否能给患者带来生存获益以及影响老年患者生存的因素。  结果  高强度化疗患者36例,22例完全缓解（complete response,CR）（61.1%）,低剂量治疗90例中46例获得CR（51.1%）,其中19例阿扎胞苷（AZA）联合维奈克拉（VEN）治疗换着中14例获得CR（73.7%）;高强度化疗与低剂量治疗的总生存期（overall survival,OS）分别为15个月和14.5个月（P=0.226）。欧洲白血病网（ELN）危险分层低、中、高危组患者OS分别为18、14、9个月（P=0.009）,低危组高强度化疗和低剂量治疗的OS分别为22个月和15个月（P=0.745）,中危组分别为9个月和15个月（P=0.783）,高危组分别为9个月和8个月（P=0.739）。强化疗（36例）与阿扎胞苷+维奈克拉治疗（19例）相比OS分别为15个月和17个月（P=0.689）。TP53基因突变者6例,预后明显差于无突变者,中位生存期分别为2个月和14个月（P=0.004）。低、中、高危患者的1年生存率为79%、53%和44%,3年生存率分别为41%、20%和3%。多因素分析显示外周血高白细胞计数（P=0.034）、ELN危险分层（P=0.002）、合并症（P=0.017）与OS相关,而治疗强度、年龄、性别、骨髓原始细胞计数与OS 无明显相关性。  结论  高强度化疗在老年AML中没有显示明显的生存获益,但这一结果在低危患者中有待于进一步观察。TP53突变者预后较差。多因素分析预测老年AML的生存期时,基线的分子学特征、白细胞计数、合并症比治疗强度更重要。     

The enhanced recovery after surgery (ERAS) protocol in elderly patients with acute cholecystitis: A retrospective study

Enhanced recovery after surgery (ERAS) protocol is a perioperative management theory aimed at reducing the injury of surgical patients and accelerating postoperative recovery. It has been widely recognized and applied in elective surgery. This study aimed to evaluate the clinical value of the ERAS protocol during the perioperative period of laparoscopic cholecystectomy in elderly patients with acute cholecystitis. This study aimed to evaluate the clinical value of the ERAS protocol during the perioperative period of laparoscopic cholecystectomy in elderly patients with acute cholecystitis. We collected medical data from 126 elderly patients with acute cholecystitis from October 2018 to August 2021. Among the 126 patients, 70 were included in the ERAS group and 56 in the traditional group. We analyzed the clinical data and postoperative indicators of the 2 groups. No significant differences were observed regarding the general characteristics of the 2 groups (P > .05). The ERAS group had significantly earlier time to first flatus, time to first ambulation, and time to solid intake, compared with the traditional group (P < .001); additionally, the ERAS group had significantly shorter stay and gentler feeling of postoperative pain (P < .001). Furthermore, the ERAS group had significant incidences of lower postoperative lung (P = .029) and abdominal cavity infection (P = .025) compared to the traditional group. No significant difference was observed regarding the incidences of other postoperative complications between the 2 groups (P > .05). The ERAS protocol helps reduce elderly patients’ stress reactions and accelerate postoperative recovery. Thus, it is effective and beneficial to implement the ERAS protocol during the perioperative period of elderly patients with acute cholecystitis.     

Microfluidic study of retention and elimination of abnormal red blood cells by human spleen with implications for sickle cell disease

The spleen clears altered red blood cells (RBCs) from circulation, contributing to the balance between RBC formation (erythropoiesis) and removal. The splenic RBC retention and elimination occur predominantly in open circulation where RBCs flow through macrophages and inter-endothelial slits (IESs). The mechanisms underlying and interconnecting these processes significantly impact clinical outcomes. In sickle cell disease (SCD), blockage of intrasplenic sickled RBCs is observed in infants splenectomized due to acute splenic sequestration crisis (ASSC). This life-threatening RBC pooling and organ swelling event is plausibly triggered or enhanced by intra-tissular hypoxia. We present an oxygen-mediated spleen-on-a-chip platform for in vitro investigations of the homeostatic balance in the spleen. To demonstrate and validate the benefits of this general microfluidic platform, we focus on SCD and study the effects of hypoxia on splenic RBC retention and elimination. We observe that RBC retention by IESs and RBC–macrophage adhesion are faster in blood samples from SCD patients than those from healthy subjects. This difference is markedly exacerbated under hypoxia. Moreover, the sickled RBCs under hypoxia show distinctly different phagocytosis processes from those non-sickled RBCs under hypoxia or normoxia. We find that reoxygenation significantly alleviates RBC retention at IESs, and leads to rapid unsickling and fragmentation of the ingested sickled RBCs inside macrophages. These results provide unique mechanistic insights into how the spleen maintains its homeostatic balance between splenic RBC retention and elimination, and shed light on how disruptions in this balance could lead to anemia, splenomegaly, and ASSC in SCD and possible clinical manifestations in other hematologic diseases.

The human spleen is a unique organ that plays an important role in our immune and circulatory systems. The spleen is composed primarily of two distinct functional regions, the red pulp and the white pulp, which are intermingled by the marginal/perifollicular zone (1). It contains complex vascular pathways involving direct and indirect connections. Direct connections exist between the fast perifollicular microcirculation and venous sinuses drained in splenic veins (“closed circulation”), whereas indirect connections exist between red pulp arterioles and veins through the reticular meshwork (“open circulation”) and across the wall of sinuses (1). As much as about 80% of the spleen parenchyma is populated with the red pulp, which mainly comprises the vascular sinuses and cords of Billroth (1, 2). Approximately 3 to 10% of blood from cardiac output flows through the spleen, and about 10% of splenic inflow passes through slow open circulation in the red pulp (1, 3–5).Splenic filtration of abnormal red blood cells (RBCs) is predominately performed in the open circulation, through macrophage-rich zones (M-filter) and across splenic inter-endothelial slits (IESs) in the wall of sinuses (S-filter), as shown in Fig. 1A. The specialized elongated shape of littoral cells in the splenic sinuses and their three-dimensional (3D) barrel-like structure impose sub-micrometer scale physical barriers or constraints on RBCs navigating the open circulation (6). Prior to returning to the systemic circulation through the IESs across the spleen, circulating RBCs are checked for surface integrity by a scattered collection of resident macrophages (7). These two structural and functional spleen filters, S-filter and M-filter (Fig. 1B), sustain the remarkable capacity of the spleen to retain and destroy abnormal RBCs. Consequently, they contribute to the fine balance between RBC production in the bone marrow and the removal of abnormal RBCs from the blood circulation (1).Open in a separate windowFig. 1.Splenic filtration of altered RBCs. (A) Schematic diagram of blood circulation through splenic red pulp, including closed circulation and open circulation. The splenic filtration of altered RBCs is achieved in the open circulation in the red pulp, through macrophages (M-filter) and the splenic IESs (S-filter). (B) Schematic diagram of the oxygen gradient near the sinus. The two structural and functional spleen filters, the S-filter and M-filter, respectively, are modeled in vitro using the S-Chip and M-Chip, respectively. Created with BioRender.com.Healthy human RBCs (AA RBCs) have an average life span of 100 to 120 d (8), indicating that about 1% of the RBCs are recycled each day by the human body (9). Senescent RBCs typically have reduced deformability (10) and send signals to macrophages by expressing higher phosphatidylserine (PS), higher band-3, and reduced CD47 levels (11, 12), on their external cell surface. Senescent RBCs could exhibit a higher propensity to be sequestered at the IESs due to their reduced deformability and then cleared by macrophages, or trapped by adhesion and phagocytosed in the meshwork (13). Here, a balance between RBC retention rate and RBC elimination rate (by post-retention processing) should be dynamically maintained to ascertain homeostasis. Such homeostatic balance, however, can be severely disrupted due to hemolytic disorders, resulting in serious, and sometimes life-threatening, complications such as splenomegaly and/or hypersplenism (14). As a result, the RBC retention rate can significantly surpass the RBC post-retention elimination rate in the spleen. It is, therefore, important to investigate systematically and quantitatively both the RBC retention rate and the elimination rate in the spleen, and to compare their relative changes, as a function of disease state, with the baseline condition of healthy hemostasis.The spleen is generally in a hypoxic (low oxygen level) condition owing to its slow and open blood circulation in the red pulp (see the brief review of splenic oxygen level and transit time/velocity of RBCs in SI Appendix, Table S2). An oxygen gradient exists in the spleen from locations nearest to the arteriolar end of capillaries to the distal locations in the proximity of the IESs, as shown schematically in Fig. 1B (15). Under normal circumstances, hypoxia is mild due to continuous oxygen delivery by the RBCs through splenic circulation. However, it deepens with the reduction in oxygen delivery arising from the obstruction of RBC flow or anemia in many hemolytic blood disorders. For instance, in sickle cell disease (SCD), such obstruction/anemia-induced local hypoxia may in turn trigger sickling of homozygous sickle cell disease (HbSS) RBCs (SS RBCs) and subsequently lead to further reduction in deformability and increase in the expression of adhesion molecules (16, 17). Therefore, sickled RBCs have a higher propensity to be retained by the venous sinuses as well as cords of Billroth, thereby contributing further to a reduction in the oxygen level in the spleen (18). The splenic retention of SS RBCs depends on a trade-off between the local oxygen level (which determines the sickling kinetics) and the transit time of RBCs through the spleen (19). Excessive retention of stiff and sickled SS RBCs in the patient’s spleen has been considered a dominant cause of acute splenic sequestration crisis (ASSC), a life-threatening complication, in SCD (17, 20, 21). This process might involve a vicious cycle: the more RBCs the spleen traps, the larger the spleen grows, and the larger the spleen grows, the deeper the hypoxia is, resulting in more and more sickled SS RBCs that are consequently being trapped and destroyed. Indeed, following splenectomy in young SCD children with still functional spleen, sickled RBCs have been found retained and congested upstream of IESs during ASSC (17, 22, 23). On the other hand, surface modulations such as PS externalization (24), decreased levels of CD47 (25), and elevated binding of autologous immunoglobulin (26), as well as increased membrane rigidity of sickled RBCs may also promote the retention and elimination of SS RBCs by the splenic macrophages (27–29). From these considerations, we postulate that both increased mechanical retention and hyperactive phagocytosis elimination of abnormal RBCs can exacerbate significantly under some extreme conditions such as hypoxia in SCD. These factors could, in turn, play a key role in disrupting the homeostatic balance thereby causing spleen dysfunction in hemolytic disorders.Recent in vitro studies based on microfluidic spleen-on-a-chip platforms, which simulate the micro-constrictions of IESs and hydrodynamic conditions, have advanced the functional study of RBC filtration in the spleen (30–33). However, to our knowledge, no prior in vitro assays have effectively integrated a controlled gaseous microenvironment within a microfluidic system to enable the quantitative investigation of the hypoxic effect on splenic retention and post-retention elimination of RBCs, especially for SS RBCs. Moreover, there is a compelling need for an in vitro assay that elucidates the mechanisms underlying the interaction of RBCs with splenic phagocytes during the low-velocity microcirculation through the red pulp. Most existing erythrophagocytosis (RBC elimination) assays measure phagocytic activity in a static condition, which does not faithfully replicate in vivo conditions (27, 28). To this end, the development and validation of an oxygen-mediated in vitro assay for investigating the kinetics of both splenic retention of RBCs and erythrophagocytosis under hypoxia are critically needed for a better understanding of the mechanisms responsible for splenic functions in physiology and disease.Here we present a general microfluidic platform to systematically probe the retention and elimination functions undertaken by IESs and macrophages in the human spleen, by developing and validating two functional modules of an oxygen-mediated spleen-on-a-chip. This platform entails the S-Chip and the M-Chip, which model the S-filter for RBC retention through splenic IESs and the M-filter for RBC adhesion and elimination by splenic resident macrophages, respectively. While the microfluidic platform and assays presented in this work can, by design, potentially provide mechanistic insights into a wide spectrum of hereditary and acquired human diseases, we focus particular attention here on the study of homeostatic processes in SCD. We make comparisons with healthy subjects as a negative control group. We additionally use heated AA RBCs as a positive control, while considering it as a generic model for exploring different controlled concentrations of altered RBCs in hemolytic disorders. We demonstrate that our microfluidic platform can also be used to mimic in vitro the two major components of the spleen filtering unit, namely surface sensing by macrophages and mechanical sensing by splenic IESs under controlled oxygen pressure. We further show that this approach enables systematic investigations of the cellular mechanisms underlying anemia and ASSC in SCD, while also providing potential pathways to explore, with appropriate modifications, splenomegaly and hypersplenism in other diseases such as Plasmodium falciparum malaria.