Related carbapenemase-producing <Emphasis Type="Italic">Klebsiella</Emphasis> isolates detected in both a hospital and associated aquatic environment in Sweden

Carbapenem antibiotics are one of the last-resort agents against multidrug-resistant (MDR) bacteria. The occurrence of carbapenemase-producing Enterobacteriaceae (CPE) in wastewater and aquatic environments is an indication of MDR bacteria in the community. This study evaluated CPE in aquatic environments and compared them to the local hospital isolates in Sweden. Phenotypic and genotypic analyses of antibiotic resistance of environmental and clinical CPE were performed. The relatedness of the isolates and possible clonal dissemination was evaluated using phylogenetic and phyloproteomic analysis. Klebsiella oxytoca carrying carbapenemase genes (bla_VIM-1, bla_IMP-29) were isolated from wastewater and the recipient river, while K. oxytoca (bla_VIM-1) and Klebsiella pneumoniae (bla_VIM-1, bla_OXA-48, bla_NDM-1, bla_KPC-3) were isolated from patients at the local clinics or hospital. The K. oxytoca classified as sequence type 172 (ST172) isolated from the river was genotypically related to two clinical isolates recovered from patients. The similarity between environmental and clinical isolates suggests the dispersion of bla_VIM-1 producing K. oxytoca ST172 from hospital to aquatic environment and the likelihood of its presence in the community. This is the first report of CPE in aquatic environments in Sweden; therefore, surveillance of aquatic and hospital environments for CPE in other urban areas is important to determine the major transfer routes in order to formulate strategies to prevent the spread of MDR bacteria.     

Synthesis and functionalization of chitosan built hydrogel with induced hydrophilicity for extended release of sparingly soluble drugs

Addressing the functional biomaterials as next-generation therapeutics, chitosan and alginic acid were copolymerized in the form of chemically crosslinked interpenetrating networks (IPNs). The native hydrogel was functionalized via carbodiimide (EDC), catalyzed coupling of soft ligand (1,2-Ethylenediamine) and hard ligand (4-aminophenol) to replace –OH groups in alginic acid units for extended hydrogel- interfaces with the aqueous and sparingly soluble drug solutions. The chemical structure, Lower solution critical temperature (LCST ≈ 37.88 °C), particle size (Z_h,app ≈ 150–200 nm), grain size (160–360 nm), surface roughness (85–250 nm), conductivity (37–74 mv) and zeta potential (16–32 mv) of native and functionalized hydrogel were investigated by using FT-IR, solid state-¹³C-NMR, TGA, DSC, FESEM, AFM and dynamic light scattering (DLS) measurements. The effective swelling, drug loading (47–78%) and drug release (53–86%) profiles were adjusted based on selective functionalization of hydrophobic IPNs due to electrostatic complexation and extended interactions of hydrophilic ligands with the aqueous and drug solutions. Drug release from the hydrogel matrices with diffusion coefficient n ≈ 0.7 was established by Non- Fickian diffusion mechanism. In vitro degradation trials of the hydrogel with a 20% loss of wet mass in simulated gastric fluid (SGF) and 38% loss of wet mass in simulated intestinal fluid (SIF), were investigated for 400 h through bulk erosion. Consequently, a slower rate of drug loading and release was observed for native hydrogel, due to stronger H-bonding, interlocking and entanglement within the IPNs, which was finely tuned and extended by the induced hydrophilic and functional ligands. In the light of induced hydrophilicity, such functional hydrogel could be highly attractive for extended release of sparingly soluble drugs.     

Haploidentical Peripheral Blood Stem Cell Transplantation Demonstrates Stable Engraftment in Adults with Sickle Cell Disease

We report on the screening and development of haploidentical hematopoietic stem cell transplantation (HSCT) for adult patients with clinically aggressive sickle cell disease (SCD) at our institution. Of 50 adult SCD patients referred for HSCT between January 2014 and March 2017, 20% were denied by insurance. Of 41 patients initially screened, 10% lacked an available haploidentical donor, 29% had elevated donor-specific antibodies (DSAs), and 34% declined to proceed to HSCT. All 10 patients who were transplanted received peripheral blood stem cells. The initial 2 were conditioned with alemtuzumab/total body irradiation (TBI) 3?Gy followed by post-transplant cyclophosphamide and failed to engraft. The next 8 patients received the regimen developed at Johns Hopkins University with TBI 3?Gy. Granulocyte colony-stimulating factor was administered from day +12 in those with HbS < 30%. All 8 patients engrafted with a median time to neutrophil >.5 × 10⁹/L of 22 days (range, 18 to 23). One patient subsequently lost the graft, and 7 (87.5%) maintained >95% donor cell chimerism at 1-year post-HSCT. Two patients developed acute graft-versus-host disease (GVHD) of at least grade II. One had chronic GVHD and died >1 year after HSCT of unknown causes. With a median follow-up of 16 months (range, 11 to 29), 7 patients (87.5%) are alive. Our findings suggest that limited insurance coverage, high rate of DSAs, and patient declining HSCT may limit the availability of haploidentical HSCT in adult SCD patients. The modified Hopkins regimen used here demonstrates high engraftment and low morbidity rates and should be tested in larger, multicenter, prospective clinical trials.     

Zika virus: what we need to know?

Zika virus is one of the emerging viruses and is of significant threat to human health globally. It is a mosquito borne flavivirus similar to dengue, yellow fever, and West Nile viruses. It was reported about 5 decades ago and then it spreads to different parts of the world. Large outbreaks were reported on Yap Islands in 2007. Now it has gained wide attention globally by health communities. Major vector for virus transmission is Aedes aegypti mosquito. ZIKV infection is mostly asymptomatic but it is also responsible to cause mild influenza like illness to serious manifestations. There is no specific anti‐viral treatment is available for ZIKV infection. The virus disseminates very fast due to which it possesses a serious threat especially in those areas where there is lack of specific immunity against virus. Little knowledge is available on its transmission and pathogenicity. Although virus was discovered years ago but its genomic structure is not clearly understood yet. In this review we focus on the current knowledge of epidemiology of ZIKV, its transmission, its structural biology, different aspects of diagnosis and diagnostic challenges as well as highlighted appropriates antiviral drugs and vaccines regarding treatment.     

Clinicopathological analysis of ATRX,DAXX and NOTCH receptor expression in angiosarcomas

Aims

Multiple genetic alterations, including alternative lengthening of telomeres (ALT) and NOTCH mutations, have been described in angiosarcoma. Loss of α‐thalassaemia/mental retardation syndrome X‐linked (ATRX) and death domain‐associated protein 6 (DAXX) expression is frequently associated with the ALT phenotype. Additionally, inhibition of NOTCH signalling induces the development of malignant vascular tumours in mice, indicating a tumour suppressive role of the NOTCH pathway in the pathogenesis of angiosarcoma. The aim of this study was to evaluate the immunohistochemical expression of ATRX, DAXX and NOTCH receptors (NOTCH1 and NOTCH2) in a large cohort of angiosarcomas, and study their clinicopathological and prognostic significance.

Methods and results

One hundred and forty cases of angiosarcoma were stained for ATRX, DAXX, NOTCH1 and NOTCH2. ATRX loss (<10% labelling) was seen in seven of 118 (6%) cases, and was more frequent in deep soft tissue tumours than in other body sites (P = 0.004). Angiosarcomas with ATRX loss were associated with worse event‐free survival than angiosarcomas with retained ATRX expression (P = 0.003). DAXX was retained in all specimens examined. Decreased NOTCH1 expression (≤1+ intensity) was seen in 29 of 123 (24%) cases, and was associated with a cutaneous site of origin (P = 0.013) and advanced disease (P = 0.026). NOTCH2 expression was decreased in 16 of 103 (16%) cases, was associated with visceral tumours (P = 0.001), and correlated with worse disease‐specific survival (P = 0.033).

Conclusions

ATRX, NOTCH1 and NOTCH2 expression varies in angiosarcomas and shows significant correlations with site of origin and poor clinical outcome, thus highlighting the biological heterogeneity within this tumour type.     

Impact of persistent and cleared preformed HLA DSA on kidney transplant outcomes

Preformed HLA donor-specific antibodies (DSA) only detected with Luminex have been associated with increased risk of antibody-mediated rejection (ABMR) and graft failure after kidney transplantation (KT). Their evolution after KT may modify this risk. We analyzed postransplant evolution of preformed DSA identified retrospectively and their impact on outcomes of 370 KT performed 2006–2014. Antibodies were monitored prospectively at 1-3-5?years after KT and if any dysfunction. Early acute ABMR was more frequent among patients with preformed DSA class-I or I?+?II than isolated class-II (29.4% vs 4.5%, p?=?0.02). One year post-KT, 20 of 34 patients with functioning KT had persistent DSA. Preformed DSA class-II persisted more frequently than class-I/I?+?II (66.7% vs 33.3%; p?=?0.031). The only risk factor independently associated with persistence was pretransplant MFI. Patients with de novo DSA had the highest risk of ABMR (HR 22.2 [CI 6.1–81.2]). Although recipients with persisting preformed DSA had significantly increased ABMR risk (HR 14.7 [CI 6.5–33.0]), those with cleared preformed DSA also had a higher risk than those without DSA (HR 7.01 [CI 2.2–21.8]).Preformed DSA are a very important risk factor for ABMR and graft loss. Patients who clear preformed DSA still show an increased risk of ABMR and graft loss after KT.