Stevens-Johnson syndrome (SJS) is a rare and severe immunologic phenomenon characterized by rash and mucous membrane disease. SJS may be triggered by medications and, less commonly, by infections such as Mycoplasma pneumoniae (Mp). Outbreaks of SJS are exceedingly rare.

We describe the largest SJS outbreak reported in children, which was also Mp-associated. In the first case-control study of this disease, we identify predictors of Mp-associated SJS versus non–Mp-associated SJS, including fewer skin lesions, pneumonia, and elevated erythrocyte sedimentation rate. (Read the full article)

Antibiotic resistance is a global concern; however, data on antibiotic-resistant Ureaplasma spp. and Mycoplasma hominis are limited in comparison to similar data on other microbes. A total of 492 Ureaplasma spp. and 13 M. hominis strains obtained in Hangzhou, China, in 2018, were subjected to antimicrobial susceptibility testing for levofloxacin, moxifloxacin, erythromycin, clindamycin, and doxycycline using the broth microdilution method. The mechanisms underlying quinolone and macrolide resistance were determined. Meanwhile, a model of the topoisomerase IV complex bound to levofloxacin in wild-type Ureaplasma spp. was built to study the quinolone resistance mutations. For Ureaplasma spp., the levofloxacin, moxifloxacin and erythromycin resistance rates were 84.69%, 51.44% and 3.59% in U. parvum and 82.43%, 62.16% and 5.40% in U. urealyticum, respectively. Of the 13 M. hominis strains, 11 were resistant to both levofloxacin and moxifloxacin, and five strains showed clindamycin resistance. ParC S83L was the most prevalent mutation in levofloxacin-resistant Ureaplasma strains, followed by ParE R448K. The two mutations GyrA S153L and ParC S91I were commonly identified in quinolone-resistant M. hominis. A molecular dynamics-refined structure revealed that quinolone resistance-associated mutations inhibited the interaction and reduced affinity with gyrase or topoisomerase IV and quinolones. The novel mutations S21A in the L4 protein and G2654T and T2245C in 23S rRNA and ermB gene were identified in erythromycin-resistant Ureaplasma spp. Fluoroquinolone resistance in Ureaplasma spp. and Mycoplasma hominis remains high in China, the rational use of antibiotics needs to be further enhanced.

Background

Optimal concentrations of unbound antimicrobials are essential for maximum microbiological effect. Although hypoalbuminemia and albumin fluid resuscitation are common in critical care, the effects of different albumin concentrations on the unbound concentrations of highly protein-bound antimicrobials are not known. The aim of this study was to compare effects of different albumin states on total and unbound concentrations of ertapenem and ceftriaxone using an ovine model.

Methods

Design

Prospective, three phase intervention observational study.

Subjects

Healthy Merino sheep.

Interventions

Eight sheep were subject to three experimental phases; normoalbuminemia, hypoalbuminemia using plasmapheresis and albumin replacement using a 25% albumin solution. In each phase, ceftriaxone 40 mg/kg and ertapenem 15 mg/kg were given intravenously. Blood samples were collected at pre-defined intervals and analyzed using an ultra-high-performance liquid chromatography tandem mass spectrometry method. Pharmacokinetic parameters such as area under the curve (AUC_0-24), plasma clearance (CL) and apparent volume of distribution in the terminal phase (V_d) were estimated and compared between the phases.

Results

The protein and albumin concentrations were significantly different between phases. Hypoalbuminemia resulted in a significantly lower AUC_0-24 and higher CL of total and unbound concentrations of ceftriaxone compared to the other phases. Whereas albumin replacement led to higher AUC_0-24 and lower CL compared to other phases for both drugs. The V_d for total drug concentrations for both drugs were significantly lower with albumin replacement.

Conclusions

For highly protein-bound drugs such as ceftriaxone and ertapenem, both hypoalbuminemia and albumin replacement may affect unbound drug exposure.

Penn State Health has enrolled its first COVID-19 patient into an experimental treatment program called convalescent plasma therapy.

G. J. Schwartz
Aug 1, 1976; 58:259-263
ARTICLES

A multi-disciplinary collaborative relationship, developed between Penn State EMS Energy Institute researchers and a Pittsburgh-based start-up company, may hold the answer to reducing global greenhouse gas (GHG) emissions while also paving the way to disrupt the chemical and material industries.

St. Joseph Medical Center has begun using an experimental treatment program called convalescent plasma therapy with a growing number of its COVID-19 positive patients.

Researchers in Penn State’s College of Engineering, College of Agricultural Sciences and College of Medicine say direct LTP treatment and plasma-activated media are effective treatments against bacteria found in liquid cultures and have devised a way to create plasma directly in liquids.

The therapy involves taking antibodies from the blood of a person who has recovered from COVID-19 and transfusing those antibodies into an active coronavirus patient to help kickstart the immune system.

 The patient from Orai in Uttar Pradesh was admitted to the King George Medical University (KGMU) in Lucknow on April 26.

The idea of aircraft being powered by plasma drives might sound like something from a science fiction film, but a group of Chinese scientists has developed a prototype that might one day make it a reality.The team, from the Institute of Technological Sciences at Wuhan University, said in a paper published on Tuesday that they had developed a prototype of a plasma jet device capable of lifting a 1kg (2.2lb) steel ball over a 24mm (one inch) diameter quartz tube.While that might not sound like…

Zoa took to Instagram and shared photos from the hospital while donating the blood.

Title: After Teeth Are Pulled, Platelet-Rich Plasma May Speed Healing
Category: Health News
Created: 4/23/2010 12:10:00 PM
Last Editorial Review: 4/26/2010 12:00:00 AM

The formation and properties of liquid-ordered (Lo) lipid domains (rafts) in the plasma membrane are still poorly understood. This limits our ability to manipulate ordered lipid domain-dependent biological functions. Giant plasma membrane vesicles (GPMVs) undergo large-scale phase separations into coexisting Lo and liquid-disordered lipid domains. However, large-scale phase separation in GPMVs detected by light microscopy is observed only at low temperatures. Comparing Förster resonance energy transfer-detected versus light microscopy-detected domain formation, we found that nanodomains, domains of nanometer size, persist at temperatures up to 20°C higher than large-scale phases, up to physiologic temperature. The persistence of nanodomains at higher temperatures is consistent with previously reported theoretical calculations. To investigate the sensitivity of nanodomains to lipid composition, GPMVs were prepared from mammalian cells in which sterol, phospholipid, or sphingolipid composition in the plasma membrane outer leaflet had been altered by cyclodextrin-catalyzed lipid exchange. Lipid substitutions that stabilize or destabilize ordered domain formation in artificial lipid vesicles had a similar effect on the thermal stability of nanodomains and large-scale phase separation in GPMVs, with nanodomains persisting at higher temperatures than large-scale phases for a wide range of lipid compositions. This indicates that it is likely that plasma membrane nanodomains can form under physiologic conditions more readily than large-scale phase separation. We also conclude that membrane lipid substitutions carried out in intact cells are able to modulate the propensity of plasma membranes to form ordered domains. This implies lipid substitutions can be used to alter biological processes dependent upon ordered domains.

ABSTRACT

The ubiquitous parasite Toxoplasma gondii exhibits an impressive ability to maintain chronic infection of its host for prolonged periods. Despite this, little is known regarding whether and how T. gondii bradyzoites, a quasi-dormant life stage residing within intracellular cysts, manipulate the host cell to maintain persistent infection. A previous proteomic study of the cyst wall, an amorphous layer of proteins that forms underneath the cyst membrane, identified MYR1 as a putative cyst wall protein in vitro. Because MYR1 is known to be involved in the translocation of parasite-derived effector proteins into the host cell, we sought to determine whether parasites transitioning toward the bradyzoite life stage retain the capacity to translocate proteins via this pathway. By epitope tagging the endogenous loci of four known effectors that translocate from the parasitophorous vacuole into the host cell nucleus, we show, by immunofluorescence assays, that most effectors accumulate in the host nucleus at early but not late time points after infection, during the tachyzoite-to-bradyzoite transition and when parasites further along the bradyzoite differentiation continuum invade a new host cell. We demonstrate that the suppression of interferon gamma signaling, which was previously shown to be mediated by the effector TgIST, also occurs in the context of prolonged infection with bradyzoites and that TgIST export is a process that occurs beyond the early stages of host cell infection. These findings have important implications regarding how this highly successful parasite maintains persistent infection of its host.

IMPORTANCE Toxoplasma bradyzoites persist within tissue cysts and are refractory to current treatments, serving as a reservoir for acute complications in settings of compromised immunity. Much remains to be understood regarding how this life stage successfully establishes and maintains persistent infection. In this study, we investigated whether the export of parasite effector proteins into the host cell occurs during the development of in vitro tissue cysts. We quantified the presence of four previously described effectors in host cell nuclei at different time points after bradyzoite differentiation and found that they accumulated largely during the early stages of infection. Despite a decline in nuclear accumulation, we found that one of these effectors still mediated its function after prolonged infection with bradyzoites, and we provide evidence that this effector is exported beyond early infection stages. These findings suggest that effector export from within developing tissue cysts provides one potential mechanism by which this parasite achieves chronic infection.

Blue-light-induced chloroplast movements play an important role in maximizing light utilization for photosynthesis in plants. Under a weak light condition, chloroplasts accumulate to the cell surface to capture light efficiently (chloroplast accumulation response). Conversely, chloroplasts escape from strong light and move to the side wall to reduce photodamage (chloroplast avoidance response). The blue light receptor phototropin (phot) regulates these chloroplast movements and optimizes leaf photosynthesis by controlling other responses in addition to chloroplast movements. Seed plants such as Arabidopsis (Arabidopsis thaliana) have phot1 and phot2. They redundantly mediate phototropism, stomatal opening, leaf flattening, and the chloroplast accumulation response. However, the chloroplast avoidance response is induced by strong blue light and regulated primarily by phot2. Phots are localized mainly on the plasma membrane. However, a substantial amount of phot2 resides on the chloroplast outer envelope. Therefore, differentially localized phot2 might have different functions. To determine the functions of plasma membrane- and chloroplast envelope-localized phot2, we tethered it to these structures with their respective targeting signals. Plasma membrane-localized phot2 regulated phototropism, leaf flattening, stomatal opening, and chloroplast movements. Chloroplast envelope-localized phot2 failed to mediate phototropism, leaf flattening, and the chloroplast accumulation response but partially regulated the chloroplast avoidance response and stomatal opening. Based on the present and previous findings, we propose that phot2 localized at the interface between the plasma membrane and the chloroplasts is required for the chloroplast avoidance response and possibly for stomatal opening as well.

Gamma interferon (IFN-)-induced innate immune responses play important roles in the inhibition of Toxoplasma gondii infection. It has been reported that IFN- stimulates non-acidification-dependent growth restriction of T. gondii in HeLa cells, but the mechanism remains unclear. Here, we found that -aminobutyric acid (GABA) receptor-associated protein-like 2 (GABARAPL2) plays a critical role in parasite restriction in IFN--treated HeLa cells. GABARAPL2 is recruited to membrane structures surrounding parasitophorous vacuoles (PV). Autophagy adaptors are required for the proper localization and function of GABARAPL2 in the IFN- -induced immune response. These findings provide further understanding of a noncanonical autophagy pathway responsible for IFN--dependent inhibition of T. gondii growth in human HeLa cells and demonstrate the critical role of GABARAPL2 in this response.

Mycoplasma gallisepticum is the primary etiological agent of chronic respiratory disease in chickens. Live attenuated vaccines are most commonly used in the field to control the disease, but current vaccines have some limitations. Vaxsafe MG (strain ts-304) is a new vaccine candidate that is efficacious at a lower dose than the current commercial vaccine strain ts-11, from which it is derived. In this study, the transcriptional profiles of the trachea of unvaccinated chickens and chickens vaccinated with strain ts-304 were compared 2 weeks after challenge with M. gallisepticum strain Ap3AS during the chronic stage of infection. After challenge, genes, gene ontologies, pathways, and protein classes involved in inflammation, cytokine production and signaling, and cell proliferation were upregulated, while those involved in formation and motor movement of cilia, formation of intercellular junctional complexes, and formation of the cytoskeleton were downregulated in the unvaccinated birds compared to the vaccinated birds, reflecting immune dysregulation and the pathological changes induced in the trachea by infection with M. gallisepticum. Vaccination appears to protect the structural and functional integrity of the tracheal mucosa 2 weeks after infection with M. gallisepticum.

In mammalian cells, alphavirus replication complexes are anchored to the plasma membrane. This interaction with lipid bilayers is mediated through the viral methyl/guanylyltransferase nsP1 and reinforced by palmitoylation of cysteine residue(s) in the C-terminal region of this protein. Lipid content of membranes supporting nsP1 anchoring remains poorly studied. Here, we explore the membrane binding capacity of nsP1 with regard to cholesterol. Using the medically important chikungunya virus (CHIKV) as a model, we report that nsP1 cosegregates with cholesterol-rich detergent-resistant membrane microdomains (DRMs), also called lipid rafts. In search for the critical factor for cholesterol partitioning, we identify nsP1 palmitoylated cysteines as major players in this process. In cells infected with CHIKV or transfected with CHIKV trans-replicase plasmids, nsP1, together with the other nonstructural proteins, are detected in DRMs. While the functional importance of CHIKV nsP1 preference for cholesterol-rich membrane domains remains to be determined, we observed that U18666A- and imipramine-induced sequestration of cholesterol in late endosomes redirected nsP1 to these compartments and simultaneously dramatically decreased CHIKV genome replication. A parallel study of Sindbis virus (SINV) revealed that nsP1 from this divergent alphavirus displays a low affinity for cholesterol and only moderately segregates with DRMs. Behaviors of CHIKV and SINV with regard to cholesterol, therefore, match with the previously reported differences in the requirement for nsP1 palmitoylation, which is dispensable for SINV but strictly required for CHIKV replication. Altogether, this study highlights the functional importance of nsP1 segregation with DRMs and provides new insight into the functional role of nsP1 palmitoylated cysteines during alphavirus replication.

IMPORTANCE Functional alphavirus replication complexes are anchored to the host cell membranes through the interaction of nsP1 with the lipid bilayers. In this work, we investigate the importance of cholesterol for such an association. We show that nsP1 has affinity for cholesterol-rich membrane microdomains formed at the plasma membrane and identify conserved palmitoylated cysteine(s) in nsP1 as the key determinant for cholesterol affinity. We demonstrate that drug-induced cholesterol sequestration in late endosomes not only redirects nsP1 to this compartment but also dramatically decreases genome replication, suggesting the functional importance of nsP1 targeting to cholesterol-rich plasma membrane microdomains. Finally, we show evidence that nsP1 from chikungunya and Sindbis viruses displays different sensitivity to cholesterol sequestering agents that parallel with their difference in the requirement for nsP1 palmitoylation for replication. This research, therefore, gives new insight into the functional role of palmitoylated cysteines in nsP1 for the assembly of functional alphavirus replication complexes in their mammalian host.

Background

After accounting for known risk factors for CKD progression in children, clinical outcomes among children with CKD still vary substantially. Biomarkers of tubular injury (such as KIM-1), repair (such as YKL-40), or inflammation (such as MCP-1, suPAR, TNF receptor-1 [TNFR-1], and TNFR-2) may identify children with CKD at risk for GFR decline.

Methods

We investigated whether plasma KIM-1, YKL-40, MCP-1, suPAR, TNFR-1, and TNFR-2 are associated with GFR decline in children with CKD and in subgroups defined by glomerular versus nonglomerular cause of CKD. We studied participants of the prospective CKiD Cohort Study which enrolled children with an eGFR of 30–90 ml/min per 1.73 m² and then assessed eGFR annually. Biomarkers were measured in plasma collected 5 months after study enrollment. The primary endpoint was CKD progression, defined as a composite of a 50% decline in eGFR or incident ESKD.

Results

Of the 651 children evaluated (median age 11 years; median baseline eGFR of 53 ml/min per 1.73 m²), 195 (30%) had a glomerular cause of CKD. Over a median follow-up of 5.7 years, 223 children (34%) experienced CKD progression to the composite endpoint. After multivariable adjustment, children with a plasma KIM-1, TNFR-1, or TNFR-2 concentration in the highest quartile were at significantly higher risk of CKD progression compared with children with a concentration for the respective biomarker in the lowest quartile (a 4-fold higher risk for KIM-1 and TNFR-1 and a 2-fold higher risk for TNFR-2). Plasma MCP-1, suPAR, and YKL-40 were not independently associated with progression. When stratified by glomerular versus nonglomerular etiology of CKD, effect estimates did not differ significantly.

Conclusions

Higher plasma KIM-1, TNFR-1, and TNFR-2 are independently associated with CKD progression in children.

Paclitaxel has been considered to cause OATP1B-mediated drug-drug interactions at therapeutic doses; however, its clinical relevance has not been demonstrated. This study aimed to elucidate in vivo inhibition potency of paclitaxel against OATP1B1 and OATP1B3 using endogenous OATP1B biomarkers. Paclitaxel is an inhibitor of OATP1B1 and OATP1B3, with K_i of 0.579 ± 0.107 and 5.29 ± 3.87 μM, respectively. Preincubation potentiated its inhibitory effect on both OATP1B1 and OATP1B3, with K_i of 0.154 ± 0.031 and 0.624 ± 0.183 μM, respectively. Ten patients with non–small cell lung cancer who received 200 mg/m² of paclitaxel by a 3-hour infusion were recruited. Plasma concentrations of 10 endogenous OATP1B biomarkers—namely, coproporphyrin I, coproporphyrin III, glycochenodeoxycholate-3-sulfate, glycochenodeoxycholate-3-glucuronide, glycodeoxycholate-3-sulfate, glycodeoxycholate-3-glucuronide, lithocholate-3-sulfate, glycolithocholate-3-sulfate, taurolithocholate-3-sulfate, and chenodeoxycholate-24-glucuronide—were determined in the patients with non–small cell lung cancer on the day before paclitaxel administration and after the end of paclitaxel infusion for 7 hours. Paclitaxel increased the area under the plasma concentration-time curve (AUC) of the endogenous biomarkers 2- to 4-fold, although a few patients did not show any increment in the AUC ratios of lithocholate-3-sulfate, glycolithocholate-3-sulfate, and taurolithocholate-3-sulfate. Therapeutic doses of paclitaxel for the treatment of non–small cell lung cancer (200 mg/m²) will cause significant OATP1B1 inhibition during and at the end of the infusion. This is the first demonstration that endogenous OATP1B biomarkers could serve as surrogate biomarkers in patients.

SIGNIFICANCE STATEMENT

Endogenous biomarkers can address practical and ethical issues in elucidating transporter-mediated drug-drug interaction (DDI) risks of anticancer drugs clinically. We could elucidate a significant increment of the plasma concentrations of endogenous OATP1B biomarkers after a 3-hour infusion (200 mg/m²) of paclitaxel, a time-dependent inhibitor of OATP1B, in patients with non–small cell lung cancer. The endogenous OATP1B biomarkers are useful to assess the possibility of OATP1B-mediated DDIs in patients and help in appropriately designing a dosing schedule to avoid the DDIs.

Human granulocytic anaplasmosis (HGA) is a tick-borne disease caused by the obligate intracellular Gram-negative bacterium Anaplasma phagocytophilum. The disease often presents with nonspecific symptoms with negative serology during the acute phase. Direct pathogen detection is the best approach for early confirmatory diagnosis. Over the years, PCR-based molecular detection methods have been developed, but optimal sensitivity is not achieved by conventional PCR while real-time PCR requires expensive and sophisticated instruments. To improve the sensitivity and also develop an assay that can be used in resource-limited areas, an isothermal DNA amplification assay based on recombinase polymerase amplification (RPA) was developed. To do this, we identified a 171-bp DNA sequence within multiple paralogous copies of msp2 within the genome of A. phagocytophilum. Our novel RPA assay targeting this sequence has an analytical limit of detection of one genome equivalent copy of A. phagocytophilum and can reliably detect 125 bacteria/ml in human blood. A high level of specificity was demonstrated by the absence of nonspecific amplification using genomic DNA from human or DNA from other closely-related pathogenic bacteria, such as Anaplasma platys, Ehrlichia chaffeensis, Orientia tsutsugamushi, and Rickettsia rickettsii, etc. When applied to patient DNA extracted from whole blood, this new RPA assay was able to detect 100% of previously diagnosed A. phagocytophilum cases. The sensitivity and rapidness of this assay represents a major improvement for early diagnosis of A. phagocytophilum in human patients and suggest a role for better surveillance in its reservoirs or vectors, especially in remote regions where resources are limited.

We recently reported that restoring the CYP27A1–27hydroxycholesterol axis had antitumor properties. Thus, we sought to determine the mechanism by which 27HC exerts its anti–prostate cancer effects. As cholesterol is a major component of membrane microdomains known as lipid rafts, which localize receptors and facilitate cellular signaling, we hypothesized 27HC would impair lipid rafts, using the IL6–JAK–STAT3 axis as a model given its prominent role in prostate cancer. As revealed by single molecule imaging of DU145 prostate cancer cells, 27HC treatment significantly reduced detected cholesterol density on the plasma membranes. Further, 27HC treatment of constitutively active STAT3 DU145 prostate cancer cells reduced STAT3 activation and slowed tumor growth in vitro and in vivo. 27HC also blocked IL6-mediated STAT3 phosphorylation in nonconstitutively active STAT3 cells. Mechanistically, 27HC reduced STAT3 homodimerization, nuclear translocation, and decreased STAT3 DNA occupancy at target gene promoters. Combined treatment with 27HC and STAT3 targeting molecules had additive and synergistic effects on proliferation and migration, respectively. Hallmark IL6–JAK–STAT gene signatures positively correlated with CYP27A1 gene expression in a large set of human metastatic castrate-resistant prostate cancers and in an aggressive prostate cancer subtype. This suggests STAT3 activation may be a resistance mechanism for aggressive prostate cancers that retain CYP27A1 expression. In summary, our study establishes a key mechanism by which 27HC inhibits prostate cancer by disrupting lipid rafts and blocking STAT3 activation.

Implications:

Collectively, these data show that modulation of intracellular cholesterol by 27HC can inhibit IL6–JAK–STAT signaling and may synergize with STAT3-targeted compounds.

Capture bioprocessing unit operations were previously shown to clear or kill several log₁₀ of a model mycoplasma Acholeplasma laidlawii in lab-scale spike/removal studies. Here, we confirm this observation with two additional mollicute species relevant to biotechnology products for human use: Mycoplasma orale and Mycoplasma arginini. Clearance of M. orale and M. arginini from protein A column purification was similar to that seen with A. laidlawii, though some between cycle carryover was evident, especially for M. orale. However, on-resin growth studies for all three species revealed that residual mycoplasma in a column slowly die off over time rather than expanding further. Solvent/detergent exposure completely inactivated M. arginini though detectable levels of M. orale remained. A small-scale model of a commercial low-pH hold step did inactivate live M. orale, but this inactivation required a lower pH set point and occurred with slower kinetics than previously seen with A. laidlawii. Additionally, ultraviolet-C irradiation was shown to be effective for A. laidlawii and M. orale inactivation whereas virus-retentive filters for upstream and downstream processes, as expected, cleared A. laidlawii. These data argue that M. orale and M. arginini overall would be largely cleared by early bioprocessing steps as shown previously for A. laidlawii, and that barrier technologies can effectively reduce the risk from media components. For some unit operations, M. orale and M. arginini may be hardier, and require more stringent processing or equipment cleaning conditions to assure effective mycoplasma reduction. By exploring how some of the failure modes in commercial antibody manufacturing processes can still eliminate mycoplasma burden, we demonstrate that required best practices assure biotechnology products will be safe for patients.

S100A8/A9 is implicated in inflammation mechanisms related to atherosclerosis and plaque vulnerability, but it remains unclear whether S100A8/A9 is associated with the prognosis of ischemic stroke. The aim of this study was to investigate these associations in 2 independent multicenter cohorts.Plasma S100A8/A9 concentrations at baseline were measured among 4785 patients with ischemic stroke from 2 independent cohorts: Infectious Factors, Inflammatory Markers, and Prognosis of Acute Ischemic Stroke (IIPAIS) and China Antihypertensive Trial in Acute Ischemic Stroke (CATIS). The primary outcome was a composite outcome of death or major disability at 3 months after ischemic stroke. Secondary outcomes were major disability, death, and a composite outcome of death or vascular events.Among the combined participants of IIPAIS and CATIS, the adjusted odds ratios associated with the highest quartile of plasma S100A8/A9 were 2.11 (95% CI, 1.66–2.68) for the primary outcome and 1.62 (95% CI, 1.27–2.07) for the secondary outcome of major disability; adjusted hazard ratios were 4.14 (95% CI, 2.10–8.15) for the secondary outcome of death and 2.08 (95% CI, 1.38–3.13) for the composite outcome of death or vascular events. Each SD increase of log-transformed S100A8/A9 was associated with 28% (95% CI, 18%–39%; P < 0.001) increased risk of the primary outcome. Multivariable-adjusted spline regression analyses showed a linear association between plasma S100A8/A9 concentrations and primary outcome (P < 0.001 for linearity). Subgroup analyses further confirmed these associations.High plasma S100A8/A9 concentrations at baseline were independently associated with increased risks of adverse clinical outcomes at 3 months after ischemic stroke, suggesting that S100A8/A9 might have a role as a prognostic marker of ischemic stroke.

Purpose:

Thymidine kinase 1 (TK1) is downstream to the CDK4/6 pathway, and TK activity (TKa) measured in blood is a dynamic marker of outcome in patients with advanced breast cancer (ABC). This study explores TK1 as a biomarker of palbociclib response, both in vitro and in patients with ABC.

Experimental Design:

Modulation of TK1 levels and activity by palbociclib were studied in seven estrogen receptor–positive breast cancer cell lines: sensitive (PDS) and with palbociclib acquired resistance (PDR). TKa was assayed in plasma obtained at baseline (T0), after one cycle (T1), and at disease progression on palbociclib (T2) in patients enrolled in the "To Reverse ENDocrine Resistance" (TREnd) trial (n = 46).

Results:

Among E2F-dependent genes, TK1 was significantly downregulated after short-term palbociclib. Early TKa reduction by palbociclib occurred in PDS but not in PDR cells. In patients, median TKa (mTKa) at T0 was 75 DiviTum units per liter (Du/L), with baseline TKa not proving prognostic. At T1, mTKa decreased to 35 Du/L, with a minority of patients (n = 8) showing an increase—correlating with a worse outcome than those with decreased/stable TKa (n = 33; mPFS 3.0 vs 9.0 months; P = 0.002). At T2, mTKa was 251 Du/L; patients with TKa above the median had worse outcomes on post-study treatment compared with those with lower TKa (2.9 vs 8.7 months; P = 0.05).

Conclusions:

TK is a dynamic marker of resistance to palbociclib which may lead to early identification of patients in whom treatment escalation may be feasible. In addition, TKa may stratify prognosis in patients with acquired resistance to palbociclib.

Plasma DNA fragmentomics is an emerging area of research covering plasma DNA sizes, end points, and nucleosome footprints. In the present study, we found a significant increase in the diversity of plasma DNA end motifs in patients with hepatocellular carcinoma (HCC). Compared with patients without HCC, patients with HCC showed a preferential pattern of 4-mer end motifs. In particular, the abundance of plasma DNA motif CCCA was much lower in patients with HCC than in subjects without HCC. The aberrant end motifs were also observed in patients with other cancer types, including colorectal cancer, lung cancer, nasopharyngeal carcinoma, and head and neck squamous cell carcinoma. We further observed that the profile of plasma DNA end motifs originating from the same organ, such as the liver, placenta, and hematopoietic cells, generally clustered together. The profile of end motifs may therefore serve as a class of biomarkers for liquid biopsy in oncology, noninvasive prenatal testing, and transplantation monitoring.

Significance:

Plasma DNA molecules originating from the liver, HCC and other cancers, placenta, and hematopoietic cells each harbor a set of characteristic plasma DNA end motifs. Such markers carry tissue-of-origin information and represent a new class of biomarkers in the nascent field of fragmentomics.

This article is highlighted in the In This Issue feature, p. 627

Computers, mobile phones and all other electronic devices contain thousands of transistors, linked together by thin films of metal. Scientists have developed a method that can use the electrons in a plasma to produce these films.

As interest in the application of plasma medicine -- the use of low-temperature plasma (LTP) created by an electrical discharge to address medical problems -- continues to grow, so does the need for research advancements proving its capabilities and potential impacts on the health care industry. Across the world, many research groups are investigating plasma medicine for applications including cancer treatment and the accelerated healing of chronic wounds, among others.

The United States has authorised the emergency use of the Ebola drug remdesivir for treating coronavirus, clearing the way for the potential treatment of 140,000 patients around the country.

Gay and bisexual men have reportedly been told they cannot donate their plasma to coronavirus trials at a London hospital.

And other stories from around the world.

Trials to treat COVID-19 using the blood plasma from those who have already recovered from the illness have begun.

As interest in the application of plasma medicine -- the use of low-temperature plasma (LTP) created by an electrical discharge to address medical problems -- continues to grow, so does the need for research advancements proving its capabilities and potential impacts on the health care industry. Across the world, many research groups are investigating plasma medicine for applications including cancer treatment and the accelerated healing of chronic wounds, among others.

Hospitals in London and Birmingham have been supplied with fourteen units of convalescent plasma to see if it helps people who are battling

Takeda in global licensing agreement with ProThera to develop plasma-based therapies for inflammatory conditions.

Actor Kartik Aaryan has urged all COVID-19 survivors in the country to donate their blood plasma for the recovery of those who are battling the pandemic. Kartik reposted a video of COVID-19 survivor. She is seen donating her blood plasma.

"I donated my blood plasma today A person who has recovered from COVID is able to make antibodies against it. Also if you don't have any pre-existing ailments you are considered a healthy body and CAN donate your blood plasma, if willing, for the benefit of patients in a critical condition. With great joy and pride I am able to share that I fit all the necessary criteria to donate plasma and did so today at the Red Cross Ahmedabad," she wrote in the caption of the video. She then focussed on the procedure to donate the plasma, which she said is similar to donating blood.

 

 

 

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So proud of @sumitisingh 👏🏻👏🏻 I urge all survivors to check with their doctors and donate their blood plasma if eligible to help critical patients who are on the road to recovery.🙏🏻 Also a big Thank You Sumiti for spreading awareness #KokiPoochega . . . #Repost @sumitisingh ・・・ I donated my blood plasma today— A person who has recovered from COVID is able to make antibodies against it . Also if you don’t have any pre existing ailments you are considered a healthy body and CAN donate your blood plasma, if willing, for the benefit of patients in a critical condition. With great joy and pride I am able to share that I fit all the necessary criteria to donate plasma and did so today at the Red Cross Ahmedabad. The procedure:- The procedure to donate plasma is the same as when you donate blood. There is one needle that is used to draw blood from your body, and the blood runs through tubes that carry it into a machine. That machine separates the plasma from the blood . The same needle sends back blood to your body while the (yellowish coloured) plasma is collected in a bag. It's all toO cool. This happens through multiple cycles. I was also informed that the body will replenish the plasma in 24 - 48 hours. Dear Positives/Now Negatives... This was my first blood plasma donation experience. My feelings were oscillating between nervousness and excitement . On one part I was unsure about the procedure and how I’d feel thereafter . On the other hand there was a desire to contribute in any way I could in the war against COVID. If it helped anyone , anywhere I was doing it . Expect 2 needle pricks. The first one to check if you have antibodies .The second one to draw blood out and transfer it back in. The procedure lasted 30-40 minutes. Most of this time I was fine, however for 3- 4 minutes I felt nauseous and light headed. My doctors at the Red Cross, immediately helped me with what I was feeling and put me at ease. I have been completely fine, thereafter. SVP hospital is the first in India to get approvals for trials for Plasma Therapy and I wish them all the luck in the world & thank them for taking me through this. If I can do it.... maybe you can too

A post shared by KARTIK AARYAN (@kartikaaryan) onApr 22, 2020 at 4:43am PDT

"There is one needle that is used to draw blood from your body, and the blood runs through tubes that carry it into a machine. That machine separates the plasma from the blood. The same needle sends back blood to your body while the (yellowish coloured) plasma is collected in a bag. It''s all too cool. This happens through multiple cycles. I was also informed that the body will replenish the plasma in 24 - 48 hours, [sic]" she explained.

"Dear Positives/Now Negatives... This was my first blood plasma donation experience. My feelings were oscillating between nervousness and excitement . On one part I was unsure about the procedure and how I''d feel thereafter . On the other hand there was a desire to contribute in any way I could in the war against COVID. If it helped anyone , anywhere I was doing it. Expect 2 needle pricks. The first one to check if you have antibodies .The second one to draw blood out and transfer it back in. The procedure lasted 30-40 minutes. Most of this time I was fine, however for 3- 4 minutes I felt nauseous and light headed. My doctors at the Red Cross, immediately helped me with what I was feeling and put me at ease. I have been completely fine, thereafter. SVP hospital is the first in India to get approvals for trials for Plasma Therapy and I wish them all the luck in the world; thank them for taking me through this. If I can do it.... maybe you can too, [sic]" she wrote.

Kartik had interviewed her on the first episode of his online chat-show Koki Poochega, and lauding her effort he urged all survivors to follow her example.

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While trials on plasma therapy for COVID-19 continue, they have sparked debate among medical professionals. While one set of experts feels that plasma therapy can work wonders with a supportive line of treatment, the other set opines that it is too premature to make such claims without thorough clinical evidence.

Interestingly, the first set of experts is now further puzzled as to whom they should administer plasma therapy. That's because of the high risk involved as COVID-19 patients may still have existing ailments that may not respond well to plasma therapy.

The concern was raised after the recent death of a 52-year-old man who was given plasma therapy at a Mumbai hospital. The man had co-morbidities and was on ventilator support.

Dr Anoop Kumar, consultant and chief of Critical Care Medicine at BM Hospital, Calicut

Premature to consider it
Dr Asha Kishore, medical director, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Thiruvananthapuram, said, "While there have been a few reports of convalescent plasma therapy being effective in treating COVID patients, unless there is a clinical study it is premature to consider it as an accepted form of treatment. It should be considered experimental therapy and should be monitored and regulated by the health ministry. Even data from China is too limited to confirm successful experiment of plasma therapy."

"Our transfusion medicine department has applied for participation in a clinical trial of convalescent plasma for the treatment for COVID-19 called by the Indian Council of Medical Research (ICMR). The ICMR's sponsored trial will be conducted to evaluate the safety and efficacy of convalescent plasma in patients with moderate COVID-19 infection. We are awaiting approval," said Dr Asha.

Against immunology principle
Dr Wiqar Shaikh, senior allergy and asthma specialist, who had treated the 52-year-old Byculla resident who was treated at home and recovered from COVID-19, said, "Plasma therapy means giving antibodies from a COVID cured patient to one still suffering from it. This is not within the principle of immunology. When a person has a viral infection, the first reaction of the body's immune system is to form IgM (Immuno Globulin M) antibodies and IgG (Immuno Globulin G). However, these are not the important defences against a virus. When the virus enters a body, it does so by mistake and cannot survive within the body and hence enters a cell to survive." Dr Shaikh added, "The COVID virus is an RNA virus, which cannot replicate on its own, it requires the cell apparatus to multiply. Whenever the immune system identifies a virus containing cell, two types of cells are activated. Both are T-lymphocytes, the first category is the cytotoxic T-lymphocyte and the second is the Natural Killer (NK) T-lymphocyte, both of which destroy the virus containing cell using bodily chemicals called 'perforins' and 'granzymes'. This cytotoxic and NK cells develop a memory for the virus within the body, and when the person gets infected with the same virus again, the memory cytotoxic and NK cells launch an immediate attack and kill the virus. Therefore, antibodies (plasma therapy), has a very poor role in defence against COVID and hence is of no use, claims Dr Shaikh.

Dr Asha Kishore, medical director, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Thiruvananthapuram

"There are no double-blind placebo-controlled trials anywhere in the world of plasma therapy actually helping in recovery of serious COVID patients. Moreover, such clinical research is a welcome move, but it takes months or years of painstaking research," said Dr Shaikh.

In favour of plasma therapy
Dr Anoop Kumar, consultant and chief of Critical Care Medicine at BM Hospital, Calicut, said, "The Kerala government was concerned about the rapid rise in COVID-19 cases and called for a meeting of well-known health professionals in Kerala on March 20. At the meeting it was agreed to make use of plasma therapy, as we have come across case studies of successful results in China, South Korea, and other countries. However, it is yet to be published in the international journal."

"Plasma therapy has been effective in various virus outbreaks in the past, such as Nipah virus in 2018, H1N1 in 2008 and even the 1918 flu outbreak," said Dr Anoop, adding, "We intend to collect plasma from patients who have recovered from COVID-19. For instance, a 55-year-old recovered patient can donate around 800ml of plasma from the blood, and this can save four lives with a mere 200 ml of plasma."

However, donor protocol mandates that the donor should not have any fever, or foreign travel history or respiratory infection, and should have remained in self-isolation for 14 days post discharge and the swab collected after self-quarantine period should be negative.

200
Quantity in ml of plasma required for treatment

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Bollywood singer Kanika Kapoor has now approached the King George's Medical University (KGMU), offering to donate her plasma for treatment of other Covid-19 patients. The singer called up the head of transfusion medicine department, Prof Tulika Chandra, and volunteered to help.

"She called me up and said she really wanted to help other Covid-19 patients. Vice Chancellor Prof M.L.B. Bhatt has given a go ahead on it and we will now be carrying out the tests on her to see if she is fit to donate her plasma," said Prof Chandra.

As per experts, Kanika's sample will be tested for a number of things before she can donate her plasma. These include her haemoglobin level that should be above 12.5, weight should be more than 50 kg and the patient should not have diabetes, cardiovascular issues, malaria, syphilis and other such ailments.

Kanika's sample will probably be taken on Tuesday and if found to be eligible, she will be donating her plasma on Wednesday. Kanika Kapoor had grabbed headlines last month when she became the first Bollywood celebrity to test positive for Coronavirus.

Kanika had attended two parties in Lucknow in the presence of top politicians and bureaucrats and all of them were later tested for Corona. Kanika was hospitalized for over a fortnight at the Sanjay Gandhi Post-Graduate Institute of Medical Sciences (SGPGIMS).

She had, on April 26, come out with a statement clarifying her travel and Covid-19 history declaring that she was aware of misconceptions and wrong information floating around her but she chose to remain silent until ready to speak. Kanika in her social media post had said that all persons she came in contact with in the UK, Mumbai and Lucknow had been tested negative and that she had duly followed the process.

Meanwhile, the KGMU on Sunday night, made the first plasma transfusion in a 58-year-old patient from Orai who is a government doctor whose condition was critical. The doctors now say that the patient is responding well to the transfusion.

The university has received three plasma donations from fully recovered Covid-19 patients, two from doctors and one from a Lakhimpur man.

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New Delhi: The Health Ministry on Tuesday said currently plasma therapy is at the experimental stage and there is no evidence yet to support that it can be used as a treatment for COVID-19.
Addressing a press briefing, Health Ministry Joint Secretary Lav Agarwal said currently there are no approved therapies for COVID-19 and there is not enough evidence to claim that plasma therapy can be used for the treatment of the disease.

"ICMR has launched a national-level study to study the efficacy of plasma therapy in the treatment of COVID 19," he said.

"Till ICMR concludes its study and a robust scientific proof is available, plasma therapy should be used only for research or trial purpose. If plasma therapy is not used in a proper manner under proper guidelines, then it can also cause life-threatening complications," said Agarwal.

The official said that the doubling rate of coronavirus cases now stands at 10.2 days.
He further said that in the last 24 hours, 1,543 new cases of COVID-19 have been reported, taking the total cases to 29,435.

"6,868 COVID-19 patients, which is 23.3 per cent of total cases, have recovered so far," he added.

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Scientists are working to collecting and using convalescent plasma to develop a passive immunization program to treat patients hospitalized for COVID-19.

Convalescent plasma therapy was started on a patient by doctors of King George's Medical University (KGMU) on Sunday. A 54-year-old government doctor