DOVER (May 9, 2019) – On May 8, 2019, the medical license and controlled substance registrations of Nihar B. Gala, MD, were permanently revoked by the Delaware Board of Medical Licensure and Discipline. The revocation was a result of allegations of unprofessional conduct related to the prescription of opioids to a patient at high risk […]

DOVER (Aug. 1, 2019) – On July 30, 2019, the medical license and controlled substance registration of Damon Cary, MD, were suspended temporarily by the Delaware Board of Medical Licensure and Discipline. The suspension was the result of a request made by the Delaware Attorney General’s Office following investigations into the prescribing and treatment practices […]

Executives and strategists try to keep their tactics under the radar, and Disney declined to provide an executive to comment on its tactics. But the studio’s answer to the online hate is there for all to see on the internet.

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Title: Leisurely Strolls More Popular, Yet Walk Times Shorter: CDC
Category: Health News
Created: 4/27/2012 2:06:00 PM
Last Editorial Review: 4/30/2012 12:00:00 AM

ABSTRACT

The protozoan parasites that cause malaria infect a wide variety of vertebrate hosts, including birds, reptiles, and mammals, and the evolutionary pressures inherent to the host-parasite relationship have profoundly shaped the genomes of both host and parasite. Here, we report that these selective pressures have resulted in unexpected alterations to one of the most basic aspects of eukaryotic biology, the maintenance of genome integrity through DNA repair. Malaria parasites that infect humans continuously generate genetic diversity within their antigen-encoding gene families through frequent ectopic recombination between gene family members, a process that is a crucial feature of the persistence of malaria globally. The continuous generation of antigen diversity ensures that different parasite isolates are antigenically distinct, thus preventing extensive cross-reactive immunity and enabling parasites to maintain stable transmission within human populations. However, the molecular basis of the recombination between gene family members is not well understood. Through computational analyses of the antigen-encoding, multicopy gene families of different Plasmodium species, we report the unexpected observation that malaria parasites that infect rodents do not display the same degree of antigen diversity as observed in Plasmodium falciparum and appear to undergo significantly less ectopic recombination. Using comparative genomics, we also identify key molecular components of the diversification process, thus shedding new light on how malaria parasites balance the maintenance of genome integrity with the requirement for continuous genetic diversification.

IMPORTANCE Malaria remains one of the most prevalent and deadly infectious diseases of the developing world, causing approximately 228 million clinical cases and nearly half a million deaths annually. The disease is caused by protozoan parasites of the genus Plasmodium, and of the five species capable of infecting humans, infections with P. falciparum are the most severe. In addition to the parasites that infect people, there are hundreds of additional species that infect birds, reptiles, and other mammals, each exquisitely evolved to meet the specific challenges inherent to survival within their respective hosts. By comparing the unique strategies that each species has evolved, key insights into host-parasite interactions can be gained, including discoveries regarding the pathogenesis of human disease. Here, we describe the surprising observation that closely related parasites with different hosts have evolved remarkably different methods for repairing their genomes. This observation has important implications for the ability of parasites to maintain chronic infections and for the development of host immunity.

ABSTRACT

Production of metallo-β-lactamases (MBLs), which hydrolyze carbapenems, is a cause of carbapenem resistance in Enterobacteriaceae. Development of effective inhibitors for MBLs is one approach to restore carbapenem efficacy in carbapenem-resistant Enterobacteriaceae (CRE). We report here that sulfamoyl heteroarylcarboxylic acids (SHCs) can competitively inhibit the globally spreading and clinically relevant MBLs (i.e., IMP-, NDM-, and VIM-type MBLs) at nanomolar to micromolar orders of magnitude. Addition of SHCs restored meropenem efficacy against 17/19 IMP-type and 7/14 NDM-type MBL-producing Enterobacteriaceae to satisfactory clinical levels. SHCs were also effective against IMP-type MBL-producing Acinetobacter spp. and engineered Escherichia coli strains overproducing individual minor MBLs (i.e., TMB-2, SPM-1, DIM-1, SIM-1, and KHM-1). However, SHCs were less effective against MBL-producing Pseudomonas aeruginosa. Combination therapy with meropenem and SHCs successfully cured mice infected with IMP-1-producing E. coli and dually NDM-1/VIM-1-producing Klebsiella pneumoniae clinical isolates. X-ray crystallographic analyses revealed the inhibition mode of SHCs against MBLs; the sulfamoyl group of SHCs coordinated to two zinc ions, and the carboxylate group coordinated to one zinc ion and bound to positively charged amino acids Lys224/Arg228 conserved in MBLs. Preclinical testing revealed that the SHCs showed low toxicity in cell lines and mice and high stability in human liver microsomes. Our results indicate that SHCs are promising lead compounds for inhibitors of MBLs to combat MBL-producing CRE.

IMPORTANCE Carbapenem antibiotics are the last resort for control of severe infectious diseases, bloodstream infections, and pneumonia caused by Gram-negative bacteria, including Enterobacteriaceae. However, carbapenem-resistant Enterobacteriaceae (CRE) strains have spread globally and are a critical concern in clinical settings because CRE infections are recognized as a leading cause of increased mortality among hospitalized patients. Most CRE produce certain kinds of serine carbapenemases (e.g., KPC- and GES-type β-lactamases) or metallo-β-lactamases (MBLs), which can hydrolyze carbapenems. Although effective MBL inhibitors are expected to restore carbapenem efficacy against MBL-producing CRE, no MBL inhibitor is currently clinically available. Here, we synthesized 2,5-diethyl-1-methyl-4-sulfamoylpyrrole-3-carboxylic acid (SPC), which is a potent inhibitor of MBLs. SPC is a remarkable lead compound for clinically useful MBL inhibitors and can potentially provide a considerable benefit to patients receiving treatment for lethal infectious diseases caused by MBL-producing CRE.

The vertebrate limb serves as an experimental paradigm to study mechanisms that regulate development of the stereotypical skeletal elements. In this study, we simultaneously inactivated Sall4 using Hoxb6Cre and Plzf in mouse embryos, and found that their combined function regulates development of the proximal-anterior skeletal elements in hindlimbs. The Sall4; Plzf double knockout exhibits severe defects in the femur, tibia, and anterior digits, distinct defects compared to other allelic series of Sall4; Plzf. We found that Sall4 regulates Plzf expression prior to hindlimb outgrowth. Further expression analysis indicated that Hox10 genes and GLI3 are severely downregulated in the Sall4; Plzf double knockout hindlimb bud. In contrast, PLZF expression is reduced but detectable in Sall4; Gli3 double knockout limb buds, and SALL4 is expressed in the Plzf; Gli3 double knockout limb buds. These results indicate that Plzf, Gli3, and Hox10 genes downstream of Sall4, regulate femur and tibia development. In the autopod, we show that Sall4 negatively regulates Hedgehog signaling, which allows for development of the most anterior digit. Collectively, our study illustrates genetic systems that regulate development of the proximal-anterior skeletal elements in hindlimbs.

BACKGROUND:Ventilator-associated pneumonia (VAP) is a common and serious complication of mechanical ventilation. We conducted a meta-analysis of published randomized controlled trials to evaluate the efficacy and safety of probiotics for VAP prevention in patients who received mechanical ventilation.METHODS:We searched a number of medical literature databases to identify randomized controlled trials that compared probiotics with controls for VAP prevention. The results were expressed as odds ratios (OR) or mean differences with accompanying 95% CIs. Study-level data were pooled by using a random-effects model. Data syntheses were accomplished by using statistical software.RESULTS:Fourteen studies that involved 1,975 subjects met our inclusion criteria. Probiotic administration was associated with a reduction in VAP incidence among all 13 studies included in the meta-analysis (OR 0.62, 95% CI 0.45–0.85; P = .003; I2 = 43%) but not among the 6 double-blinded studies (OR 0.72, 95% CI 0.44–1.19; P = .20; I2 = 55%). We found a shorter duration of antibiotic use for VAP (mean difference −1.44, 95% CI −2.88 to −0.01; P = .048, I2 = 30%) in the probiotics group than in the control group, and the finding comes from just 2 studies. No statistically significant differences were found between the groups in terms of ICU mortality (OR 0.95, 95% CI 0.67–1.34; P = .77; I2 = 0%), ICU stay (mean difference –0.77, 95% CI –2.58 to 1.04; P = .40; I2 = 43%), duration of mechanical ventilation (mean difference –0.91, 95% CI –2.20 to 0.38; P = .17; I2 = 25%), or occurrence of diarrhea (OR 0.72, 95% CI 0.45–1.15; P = .17; I2 = 41%).CONCLUSIONS:The meta-analysis results indicated that the administration of probiotics significantly reduced the incidence of VAP. Furthermore, our findings need to be verified in large-scale, well-designed, randomized, multi-center trials.

Dependence of drug metabolism on dosing time has long been recognized. However, only recently are the underlying mechanisms for circadian drug metabolism being clarified. Diurnal rhythmicity in expression of drug-metabolizing enzymes is believed to be a key factor determining circadian metabolism. Supporting the notion that biological rhythms are generated and maintained by the circadian clock, a number of diurnal enzymes are under the control of the circadian clock. In general, circadian clock genes generate and regulate diurnal rhythmicity in drug-metabolizing enzymes via transcriptional actions on one or two of three cis-elements (i.e., E-box, D-box, and Rev-erb response element or RAR-related orphan receptor response element). Additionally, cycling or clock-controlled nuclear receptors such as hepatocyte nuclear factor 4α and peroxisome proliferator–activated receptor are contributors to diurnal enzyme expression. These newly discovered mechanisms for each of the rhythmic enzymes are reviewed in this article. We also discuss how the rhythms of enzymes are translated to circadian pharmacokinetics and drug chronotoxicity, which has direct implications for chronotherapeutics. Our discussion is also extended to two diurnal transporters (P-glycoprotein and multidrug resistance-associated protein 2) that have an important role in drug absorption. Although the experimental evidence is lacking in metabolism-based chronoefficacy, circadian genes (e.g., Rev-erbα) as drug targets are shown to account for diurnal variability in drug efficacy.

Reactive immunization with a single-dose cholera vaccine that could rapidly (within days) protect immunologically naive individuals during virgin soil epidemics, when cholera reaches immunologically naive populations that have not experienced cholera for decades, would facilitate cholera control. One dose of attenuated Vibrio cholerae O1 classical Inaba vaccine CVD 103-HgR (Vaxchora) containing ≥2 x 10⁸ CFU induces vibriocidal antibody seroconversion (a correlate of protection) in >90% of U.S. adults. A previous CVD 103-HgR commercial formulation required ≥2 x 10⁹ CFU to elicit high levels of seroconversion in populations in developing countries. We compared the vibriocidal responses of Malians (individuals 18 to 45 years old) randomized to ingest a single ≥2 x 10⁸-CFU standard dose (n = 50) or a ≥2 x 10⁹-CFU high dose (n = 50) of PaxVax CVD 103-HgR with buffer or two doses (n = 50) of Shanchol inactivated cholera vaccine (the immunologic comparator). To maintain blinding, participants were dosed twice 2 weeks apart; CVD 103-HgR recipients ingested placebo 2 weeks before or after ingesting vaccine. Seroconversion (a ≥4-fold vibriocidal titer rise) between the baseline and 14 days after CVD 103-HgR ingestion and following the first and second doses of Shanchol were the main outcomes measured. By day 14 postvaccination, the rates of seroconversion after ingestion of a single standard dose and a high dose of CVD 103-HgR were 71.7% (33/46 participants) and 83.3% (40/48 participants), respectively. The rate of seroconversion following the first dose of Shanchol, 56.0% (28/50 participants), was significantly lower than that following the high dose of CVD 103-HgR (P = 0.003). The vibriocidal geometric mean titer (GMT) of the high dose of CVD 103-HgR exceeded the GMT of the standard dose at day 14 (214 versus 95, P = 0.045) and was ~2-fold higher than the GMT on day 7 and day 14 following the first Shanchol dose (P > 0.05). High-dose CVD 103-HgR is recommended for accelerated evaluation in developing countries to assess its efficacy and practicality in field situations. (This study has been registered at ClinicalTrials.gov under registration no. NCT02145377.)

Objective

To determine whether live-attenuated yellow fever vaccine (YFV) was associated with MS relapse, we evaluated the clinical courses of 23 patients in the year before and the year after immunization at the university hospital of Geneva, Switzerland.

Microscopy and rapid diagnostic tests (RDTs) are the main diagnostic tools for malaria but fail to detect low-density parasitemias that are important for maintaining malaria transmission. To complement existing diagnostic methods, an isothermal reverse transcription-recombinase polymerase amplification and lateral flow assay (RT-RPA) was developed. We compared the performance with that of ultrasensitive reverse transcription-quantitative PCR (uRT-qPCR) using nucleic acid extracts from blood samples (n = 114) obtained after standardized controlled human malaria infection (CHMI) with Plasmodium falciparum sporozoites. As a preliminary investigation, we also sampled asymptomatic individuals (n = 28) in an area of malaria endemicity (Lambaréné, Gabon) to validate RT-RPA and assess its performance with unprocessed blood samples (dbRT-RPA). In 114 samples analyzed from CHMI trials, the positive percent agreement to uRT-qPCR was 90% (95% confidence interval [CI], 80 to 96). The negative percent agreement was 100% (95% CI, 92 to 100). The lower limit of detection was 64 parasites/ml. In Gabon, RT-RPA was 100% accurate with asymptomatic volunteers (n = 28), while simplified dbRT-RPA showed 89% accuracy. In a subgroup analysis, RT-RPA detected 9/10 RT-qPCR-positive samples, while loop-mediated isothermal amplification (LAMP) detected 2/10. RT-RPA is a reliable diagnostic test for asymptomatic low-density infections. It is particularly useful in settings where uRT-qPCR is difficult to implement.

BACKGROUND

Continuous glucose monitoring (CGM) provides important information to aid in achieving glycemic targets in people with diabetes.

OBJECTIVE

Most individuals with type 2 diabetes also have obesity, and treatment with some diabetes medications, including insulin, can cause further weight gain. No approved chronic weight management medications have been prospectively investigated in individuals with overweight or obesity and insulin-treated type 2 diabetes. The primary objective of this study was to assess the effect of liraglutide 3.0 mg versus placebo on weight loss in this population.

This follow-up study of a randomized, prospective trial included 192 patients with newly diagnosed severe aplastic anemia receiving antithymoglobulin and cyclosporine, with or without granulocyte colony-stimulating factor (G-CSF). We aimed to evaluate the long-term effect of G-CSF on overall survival, event-free survival, probability of secondary myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML), clinical paroxysmal nocturnal hemoglobinuria, relapse, avascular osteonecrosis and chronic kidney disease. The median follow-up was 11.7 years (95% CI, 10.9-12.5). The overall survival rate at 15 years was 57±12% in the group given G-CSF and 63±12% in the group not given G-CSF (P=0.92); the corresponding event-free survival rates were 24±10% and 23±10%, respectively (P=0.36). In total, 9 patients developed MDS or AML, 10 only a clonal cytogenetic abnormality, 7 a solid cancer, 18 clinical paroxysmal nocturnal hemoglobinuria, 8 osteonecrosis, and 12 chronic kidney disease, without any difference between patients treated with or without G-CSF. The cumulative incidence of MDS, AML or isolated cytogenetic abnormality at 15 years was 8.5±3% for the G-CSF group and 8.2±3% for the non-G-CSF group (P=0.90). The cumulative incidence of any late event including myelodysplastic syndrome or acute myeloid leukemia, isolated cytogenetic abnormalities, solid cancer, clinical paroxysmal nocturnal hemoglobinuria, aseptic osteonecrosis, chronic kidney disease and relapse was 50±12% for the G-CSF group and 49±12% for the non-G-CSF group (P=0.65). Our results demonstrate that it is unlikely that G-CSF has an impact on the outcome of severe aplastic anemia; nevertheless, very late events are common and eventually affect the prognosis of these patients, irrespectively of their age at the time of immunosuppressive therapy (NCT01163942).

PURPOSE

We aimed to evaluate the efficacy and safety of use of the Fasting Algorithm for Singaporeans with Type 2 Diabetes (FAST) during Ramadan.

Background and objectives

Bioelectrical impedance analysis (BIA) devices can help assess volume overload in patients receiving maintenance peritoneal dialysis. However, the effects of BIA on the short-term hard end points of peritoneal dialysis lack consistency. This study aimed to test whether BIA-guided fluid management could improve short-term outcomes in patients on peritoneal dialysis.

Background and objectives

Large, randomized, controlled trials targeting higher hemoglobin level with erythropoiesis-stimulating agents for Western patients with CKD showed harm. However, the effect of anemia correction using erythropoiesis-stimulating agents may differ between CKD subpopulations. The Prevention of ESKD by Darbepoetin Alfa in CKD Patients with Non-diabetic Kidney Disease study, a multicenter, randomized, open-label, parallel-group study, aimed to examine the effect of targeting hemoglobin levels of 11–13 g/dl using darbepoetin alfa with reference to a low-hemoglobin target of 9–11 g/dl on kidney outcome in patients with advanced CKD without diabetes in Japan.

Fnr is a transcriptional regulator that controls the expression of a variety of genes in response to oxygen limitation in bacteria. Genome sequencing revealed four genes (fnr1, fnr3, fnr5, and fnr7) coding for Fnr proteins in Paenibacillus polymyxa WLY78. Fnr1 and Fnr3 showed more similarity to each other than to Fnr5 and Fnr7. Also, Fnr1 and Fnr3 exhibited high similarity with Bacillus cereus Fnr and Bacillus subtilis Fnr in sequence and structures. Both the aerobically purified His-tagged Fnr1 and His-tagged Fnr3 in Escherichia coli could bind to the specific DNA promoter. Deletion analysis showed that the four fnr genes, especially fnr1 and fnr3, have significant impacts on growth and nitrogenase activity. Single deletion of fnr1 or fnr3 led to a 50% reduction in nitrogenase activity, and double deletion of fnr1 and fnr3 resulted to a 90% reduction in activity. Genome-wide transcription analysis showed that Fnr1 and Fnr3 indirectly activated expression of nif (nitrogen fixation) genes and Fe transport genes under anaerobic conditions. Fnr1 and Fnr3 inhibited expression of the genes involved in the aerobic respiratory chain and activated expression of genes responsible for anaerobic electron acceptor genes.

IMPORTANCE The members of the nitrogen-fixing Paenibacillus spp. have great potential to be used as a bacterial fertilizer in agriculture. However, the functions of the fnr gene(s) in nitrogen fixation and other metabolisms in Paenibacillus spp. are not known. Here, we found that in P. polymyxa WLY78, Fnr1 and Fnr3 were responsible for regulation of numerous genes in response to changes in oxygen levels, but Fnr5 and Fnr7 exhibited little effect. Fnr1 and Fnr3 indirectly or directly regulated many types of important metabolism, such as nitrogen fixation, Fe uptake, respiration, and electron transport. This study not only reveals the function of the fnr genes of P. polymyxa WLY78 in nitrogen fixation and other metabolisms but also will provide insight into the evolution and regulatory mechanisms of fnr in Paenibacillus.

Kylian Mbappe and Neymar Jr's friendship is not limited to Paris Saint Germain but also off the field. The recent example of the same could be the French footballer's recent post on social media. Mbappe posted a picture of himself on social media where he was seen playing basketball. This was quite an ideal opportunity for Neymar Jr to pull his teammate's leg and he hilariously trolled the footballer with a funny comment.

If you're always gaming on the go with your smartphone, you'll definitely want the best phone controller.

A recent study has described new states that can be found in super-cold atom experiments, which could have applications for quantum technology.

Boston Dynamics robot dog, known as Spot, is patroling Bishan-Ang Mo Kio Park in Singapore to help with social distancing practices during the coronavirus pandemic, the Singapore government announced.