非亲缘外周血造血干细胞移植治疗重型β-地中海贫血1例

患儿,女,4岁,体质量19kg。生后4个月开始进行性面色苍白伴巩膜黄染,血红蛋白65g/L,白细胞和血小板均正常,血红蛋白电泳血红蛋白A48.1%、血红蛋白A24.2%、抗碱血红蛋白47.7%,基因型为β地贫纯合子,诊断为重型β地中海贫血,以间断大量输血维持生命。于2005-12-09在厦门大学附属中山医院血液科接受非亲缘性外周血干细胞移植。预处理方案采用常规氟达拉滨、白消胺、环磷酰胺三药联合方案,以环孢菌素A、霉酚酸酯、抗胸腺淋巴细胞免疫球蛋白联合预防移植物抗宿主病,供受者人类白细胞抗原高分辨全相合,ABO血型次要不合(O-A),输入CD34 干细胞11.4×106/kg。植入成功,移植后12d中性粒细胞>0.5×109L-1,移植后37d血小板>50×109L-1,移植后35d患者血型检测转变为供者血型,患儿血红蛋白达到100g/L的时间是28d,移植后患儿未再输血,血红蛋白维持130g/L以上,整个移植过程顺利,未出现严重感染和移植物抗宿主反应,随访18个月,患儿生活正常,发育良好。     

Modelling of escalating outpatient antibiotic expenditures

OBJECTIVES: To model the relative role of old and newly introduced antibiotics in shaping increased antibiotic use. METHODS: Grouped data covering nationwide consumption and expenditure for out-of-hospital antibiotics in Greece (1990-1999) were used. The antibiotic formulations were categorized into 'common old formulations', 'old formulations with intermittent sales', 'recast formulations' and 'new substances'. The effect of each category was investigated based on index and pricing analyses. RESULTS: We estimated a 143% net increase in out-of-hospital antibiotic use during 1990-1999. The increase was 59% when all formulations of antibiotic substances available by 1990 were considered. A rapid turnaround of formulations of old substances was noticed with 669 formulations marketed during the decade. Sixteen new antibiotic substances were first introduced after 1990 and by 1999 they accounted for 34.9% of total out-of-hospital antibiotic expenditures. Three new antibiotics (a macrolide and two cephalosporins) accounted for over 90% of this amount. For all three, other less expensive alternatives were available. CONCLUSIONS: In the studied setting, out-of-hospital antibiotic use has been expanding in a highly substance-specific and non-rational fashion that is accelerated by the introduction of new drugs.     

Colistin Population Pharmacokinetics after Application of a Loading Dose of 9 MU Colistin Methanesulfonate in Critically Ill Patients

Colistin has been revived, in the era of extensively drug-resistant (XDR) Gram-negative infections, as the last-resort treatment in critically ill patients. Recent studies focusing on the optimal dosing strategy of colistin have demonstrated the necessity of a loading dose at treatment initiation (D. Plachouras, M. Karvanen, L. E. Friberg, E. Papadomichelakis, A. Antoniadou, I. Tsangaris, I. Karaiskos, G. Poulakou, F. Kontopidou, A. Armaganidis, O. Cars, and H. Giamarellou, Antimicrob Agents Chemother 53:3430–3436, 2009, http://dx.doi.org/10.1128/AAC.01361-08; A. F. Mohamed, I. Karaiskos, D. Plachouras, M. Karvanen, K. Pontikis, B. Jansson, E. Papadomichelakis, A. Antoniadou, H. Giamarellou, A. Armaganidis, O. Cars, and L. E. Friberg, Antimicrob Agents Chemother 56:4241– 4249, 2012, http://dx.doi.org/10.1128/AAC.06426-11; S. M. Garonzik, J. Li, V. Thamlikitkul, D. L. Paterson, S. Shoham, J. Jacob, F. P. Silveira, A. Forrest, and R. L. Nation, Antimicrob Agents Chemother 55:3284–3294, 2011, http://dx.doi.org/10.1128/AAC.01733-10). In 19 critically ill patients with suspected or microbiologically documented infections caused by XDR Gram-negative strains, a loading dose of 9 MU colistin methanesulfonate (CMS) (∼270 mg colistin base activity) was administered with a maintenance dose of 4.5 MU every 12 h, commenced after 24 h. Patients on renal replacement were excluded. CMS infusion was given over 30 min or 1 h. Repeated blood sampling was performed after the loading dose and after the 5th or 6th dose. Colistin concentrations and measured CMS, determined after hydrolization to colistin and including the partially sulfomethylated derivatives, were determined with a liquid chromatography-tandem mass spectrometry assay. Population pharmacokinetic analysis was conducted in NONMEM with the new data combined with data from previous studies. Measured colistimethate concentrations were described by 4 compartments for distribution and removal of sulfomethyl groups, while colistin disposition followed a 1-compartment model. The average observed maximum colistin A plus B concentration was 2.65 mg/liter after the loading dose (maximum time was 8 h). A significantly higher availability of the measured A and B forms of colistimethate and colistin explained the higher-than-expected concentrations in the present study compared to those in previous studies. Creatinine clearance was a time-varying covariate of colistimethate clearance. The incidence of acute renal injury was 20%.     

Efficient genome editing in the olive fruit fly,Bactrocera oleae

The olive fruit fly, Bactrocera oleae, causes great damage to the quality and quantity of olive production worldwide. Pest management approaches have proved difficult for a variety of reasons, a fact that has brought about a need for alternative tools and approaches. Here we report for the first time in B. oleae the development of the clustered regularly interspaced palindromic repeats (CRISPR)/CRISPR associated protein 9 (Cas9) gene editing tool, using the well‐known eye colour marker gene scarlet. Two synthetic guide RNAs targeting the coding region of the scarlet gene were synthesized and shown to work efficiently in vitro. These reagents were then microinjected along with purified Cas9 protein into early‐stage embryos. Successful CRISPR‐induced mutations of both copies of the scarlet gene showed a striking yellow eye phenotype, indicative of gene disruption. Multiple successful CRISPR events were confirmed by PCR and sequencing. The establishment of an efficient CRISPR‐based gene editing tool in B. oleae will enable the study of critical molecular mechanisms in olive fruit fly biology and physiology, including the analysis of insecticide resistance mechanisms and the discovery of novel insecticide targets, as well as facilitate the development of novel biotechnology‐based pest control strategies.     

Global perspective of COVID-19 epidemiology for a full-cycle pandemic

As of October 2020, there are >1 million documented deaths with COVID-19. Excess deaths can be caused by both COVID-19 and the measures taken. COVID-19 shows extremely strong risk stratification across age, socioeconomic factors, and clinical factors. Calculation of years-of-life-lost from COVID-19 is methodologically challenging and can yield misleading over-estimates. Many early deaths may have been due to suboptimal management, malfunctional health systems, hydroxychloroquine, sending COVID-19 patients to nursing homes, and nosocomial infections; such deaths are partially avoidable moving forward. About 10% of the global population may be infected by October 2020. Global infection fatality rate is 0.15-0.20% (0.03-0.04% in those <70 years), with large variability across locations with different age-structure, institutionalization rates, socioeconomic inequalities, population-level clinical risk profile, public health measures, and health care. There is debate on whether at least 60% of the global population must be infected for herd immunity, or, conversely, mixing heterogeneity and pre-existing cross-immunity may allow substantially lower thresholds. Simulations are presented with a total of 1.58-8.76 million COVID-19 deaths over 5-years (1/2020-12/2024) globally (0.5-2.9% of total global deaths). The most favorable figures in that range would be feasible if high risk groups can be preferentially protected with lower infection rates than the remaining population. Death toll may also be further affected by potential availability of effective vaccines and treatments, optimal management and measures taken, COVID-19 interplay with influenza and other health problems, reinfection potential, and any chronic COVID-19 consequences. Targeted, precise management of the pandemic and avoiding past mistakes would help minimize mortality.