Ultrafast spin-lasers.

Lasers have both ubiquitous applications and roles as model systems in which non-equilibrium and cooperative phenomena can be elucidated1. The introduction of novel concepts in laser operation thus has potential to lead to both new applications and fundamental insights2. Spintronics3, in which both the spin and the charge of the electron are used, has led to the development of spin-lasers, in which charge-carrier spin and photon spin are exploited. Here we show experimentally that the coupling between carrier spin and light polarization in common semiconductor lasers can enable room-temperature modulation frequencies above 200 gigahertz, exceeding by nearly an order of magnitude the best conventional semiconductor lasers. Surprisingly, this ultrafast operation of the resultant spin-laser relies on a short carrier spin relaxation time and a large anisotropy of the refractive index, both of which are commonly viewed as detrimental in spintronics3 and conventional lasers4. Our results overcome the key speed limitations of conventional directly modulated lasers and offer a prospect for the next generation of low-energy ultrafast optical communication.

Remdesivir and Mortality in Patients With Coronavirus Disease 2019.

BACKGROUND: The impact of remdesivir (RDV) on mortality rates in coronavirus disease 2019 (COVID-19) is controversial, and the mortality effect in subgroups of baseline disease severity has been incompletely explored. The purpose of this study was to assess the association of RDV with mortality rates in patients with COVID-19. METHODS: In this retrospective cohort study we compared persons receiving RDV with those receiving best supportive care (BSC). Patients hospitalized between 28 February and 28 May 2020 with laboratory-confirmed severe acute respiratory syndrome coronavirus 2 infection were included with the development of COVID-19 pneumonia on chest radiography and hypoxia requiring supplemental oxygen or oxygen saturation ≤94% with room air. The primary outcome was overall survival, assessed with time-dependent Cox proportional hazards regression and multivariable adjustment, including calendar time, baseline patient characteristics, corticosteroid use, and random effects for hospital. RESULTS: A total of 1138 patients were enrolled, including 286 who received RDV and 852 treated with BSC, 400 of whom received hydroxychloroquine. Corticosteroids were used in 20.4% of the cohort (12.6% in RDV and 23% in BSC). Comparing persons receiving RDV with those receiving BSC, the hazard ratio (95% confidence interval) for death was 0.46 (.31-.69) in the univariate model (P < .001) and 0.60 (.40-.90) in the risk-adjusted model (P = .01). In the subgroup of persons with baseline use of low-flow oxygen, the hazard ratio (95% confidence interval) for death in RDV compared with BSC was 0.63 (.39-1.00; P = .049). CONCLUSION: Treatment with RDV was associated with lower mortality rates than BSC. These findings remain the same in the subgroup with baseline use of low-flow oxygen.

Selective NFAT targeting in T cells ameliorates GvHD while maintaining antitumor activity.

Graft-versus-host disease (GvHD) is a life-threatening immunological complication after allogenic hematopoietic stem cell transplantation (allo-HCT). The intrinsic graft-versus-leukemia (GvL) effect, however, is the desirable curative benefit. Patients with acute GvHD are treated with cyclosporine A (CsA) or tacrolimus (FK506), which not only often causes severe adverse effects, but also interferes with the anticipated GvL. Both drugs inhibit calcineurin, thus at first suppressing activation of the nuclear factor of activated T cells (NFAT). Therefore, we explored the specific contribution of individual NFAT factors in donor T cells in animal models of GvHD and GvL. Ablation of NFAT1, NFAT2, or a combination of both resulted in ameliorated GvHD, due to reduced proliferation, target tissue homing, and impaired effector function of allogenic donor T cells. In contrast, the frequency of Foxp3(+) regulatory T (Treg) cells was increased and NFAT-deficient Tregs were fully protective in GvHD. CD8(+) T-cell recall response and, importantly, the beneficial antitumor activity were largely preserved in NFAT-deficient effector T cells. Thus, specific inhibition of NFAT opens an avenue for an advanced therapy of GvHD maintaining protective GvL.

NFATc1 induction in peripheral T and B lymphocytes.

NFAT transcription factors control the proliferation and survival of peripheral lymphocytes. We have reported previously that the short isoform NFATc1/αA whose generation is induced by immune receptor stimulation supports the proliferation and inhibits the activation-induced cell death of peripheral T and B cells. We will show in this study that in novel bacterial artificial chromosome transgenic mice that express EGFP under the control of entire Nfatc1 locus the Nfatc1/Egfp transgene is expressed as early as in double-negative thymocytes and in nonstimulated peripheral T and B cells. Upon immune receptor stimulation, Nfatc1/Egfp expression is elevated in B, Th1, and Th2 cells, but only weakly in T regulatory, Th9, and Th17 cells in vitro whose generation is affected by TGFß. In naive lymphocytes, persistent immune receptor signals led to a 3-5 increase in NFATc1/αA RNA levels during primary and secondary stimulation, but a much stronger induction was observed at the protein level. Whereas anti-CD3(+)CD28 stimulation of primary T cells induces both NFATc1/αA and their proliferation and survival, anti-IgM stimulation of B cells induces NFATc1/αA and proliferation, but activation-induced cell death after 3-d incubation in vitro. The anti-IgM-mediated activation-induced cell death induction of B cells in vitro is suppressed by anti-CD40-, LPS-, and CpG-mediated signals. In addition to inducing NF-κB factors, together with anti-IgM, these signals also support the generation of NFATc1/αA. According to these data and the architecture of its promoter region, the Nfatc1 gene resembles a primary response gene whose induction is affected at the posttranscriptional level.

Therapy duration and long-term outcomes in extra-pulmonary tuberculosis.

BACKGROUND: Tuberculosis is classified as either pulmonary or extra-pulmonary (EPTB). While much focus has been paid to pulmonary tuberculosis, EPTB has received scant attention. Moreover, EPTB is viewed as one wastebasket diagnosis, as "the other" which is not pulmonary. METHODS: This is a retrospective cohort study of all patients treated for EPTB in the state of Texas between January 2000 and December 2005, who had no pulmonary disease. Clinical and epidemiological factors were abstracted from electronic records of the Report of Verified Case of Tuberculosis. The long-term outcome, which is death by December 2011, was established using the Social Security Administration Death Master File database. Survival in EPTB patients was compared to those with latent tuberculosis, as well as between different types of EPTB, using Cox proportional hazard models. A hybrid of the machine learning method of classification and regression tree analyses and standard regression models was used to identify high-order interactions and clinical factors predictive of long-term all-cause mortality. RESULTS: Four hundred and thirty eight patients met study criteria; the median study follow-up period for the cohort was 7.8 (inter-quartile range 6.0-10.1) years. The overall all-cause mortality rate was 0.025 (95% confidence interval [CI]: 0.021-0.030) per 100 person-year of follow-up. The significant predictors of poor long-term outcome were age (hazard ratio [HR] for each year of age-at-diagnosis was 1.05 [CI: 1.04-1.06], treatment duration, type of EPTB and HIV-infection (HR = 2.16; CI: 1.22, 3.83). Mortality in genitourinary tuberculosis was no different from latent tuberculosis, while meningitis had the poorest long-term outcome of 46.2%. Compared to meningitis the HR for death was 0.50 (CI: 0.27-0.91) for lymphatic disease, 0.42 (CI: 0.21-0.81) for bone/joint disease, and 0.59 (CI: 0.27-1.31) for peritonitis. The relationship between mortality and therapy duration for each type of EPTB was a unique "V" shaped curve, with the lowest mortality observed at different therapy durations for each, beyond which mortality increased. CONCLUSIONS: EPTB is comprised of several different diseases with different outcomes and durations of therapy. The "V" shaped relationship between therapy duration and outcome leads to the hypothesis that longer duration of therapy may lead to higher patient mortality.

Impact of a Laboratory-Developed Phenotypic Rapid Susceptibility Test Directly From Positive Blood Cultures on Time to Narrowest Effective Therapy in Patients With Gram-Negative Bacteremia: A Prospective Randomized Trial.

Background: Antimicrobial susceptibility testing (AST) is often needed prior to antimicrobial optimization for patients with gram-negative bloodstream infections (GN-BSIs). Rapid AST (rAST) in combination with antimicrobial stewardship (AS) may decrease time to administration of narrower antibiotics. Methods: This was a prospective, nonblinded, randomized trial evaluating the impact of a phenotypic rAST method vs conventional AST (cAST) in hospitalized patients with GN-BSI and source control. The primary outcome was time to narrowest effective therapy. Results: Two hundred seventy-four patients were randomized and 205 underwent analysis (97 cAST, 108 rAST). Median (interquartile range [IQR]) time to susceptibility results was 23 hours shorter in the rAST group (cAST: 62 [59-67] hours vs rAST: 39 [IQR, 35-46] hours; P < .001). Median (IQR) time to narrowest effective therapy was similar between groups (cAST: 73 [44-138] hours vs rAST: 64 [42-92] hours; P = .10). Median (IQR) time to narrowest effective therapy was significantly shorter in a prespecified subgroup of patients not initially on narrowest therapy and during AS working hours (cAST: 93 [56-154] hours vs rAST: 62 [43-164] hours; P = .004). Significant decreases were observed in median (IQR) time to oral therapy (cAST: 126 [76-209] hours vs rAST: 91 [66-154] hours; P = .02) and median (IQR) length of hospital stay (cAST: 7 [4-13] days vs rAST: 5 [4-8] days; P = .04). Conclusions: In patients with GN-BSI, rAST did not significantly decrease time to narrowest effective therapy but did decrease time to oral antibiotics and length of hospital stay. Rapid AST using existing microbiology platforms has potential to optimize patient outcomes.

The Transcription Factor NFATc1 Supports the Rejection of Heterotopic Heart Allografts.

The immune suppressants cyclosporin A (CsA) and tacrolimus (FK506) are used worldwide in transplantation medicine to suppress graft rejection. Both CsA and FK506 inhibit the phosphatase calcineurin (CN) whose activity controls the immune receptor-mediated activation of lymphocytes. Downstream targets of CN in lymphocytes are the nuclear factors of activated T cells (NFATs). We show here that the activity of NFATc1, the most prominent NFAT factor in activated lymphocytes supports the acute rejection of heterotopic heart allografts. While ablation of NFATc1 in T cells prevented graft rejection, ectopic expression of inducible NFATc1/αA isoform led to rejection of heart allografts in recipient mice. Acceptance of transplanted hearts in mice bearing NFATc1-deficient T cells was accompanied by a reduction in number and cytotoxicity of graft infiltrating cells. In CD8+ T cells, NFATc1 controls numerous intracellular signaling pathways that lead to the metabolic switch to aerobic glycolysis and the expression of numerous lymphokines, chemokines, and their receptors, including Cxcr3 that supports the rejection of allogeneic heart transplants. These findings favors NFATc1 as a molecular target for the development of new strategies to control the cytotoxicity of T cells upon organ transplantation.

NFATc1 controls the cytotoxicity of CD8+ T cells.

Cytotoxic T lymphocytes are effector CD8+ T cells that eradicate infected and malignant cells. Here we show that the transcription factor NFATc1 controls the cytotoxicity of mouse cytotoxic T lymphocytes. Activation of Nfatc1 -/- cytotoxic T lymphocytes showed a defective cytoskeleton organization and recruitment of cytosolic organelles to immunological synapses. These cells have reduced cytotoxicity against tumor cells, and mice with NFATc1-deficient T cells are defective in controlling Listeria infection. Transcriptome analysis shows diminished RNA levels of numerous genes in Nfatc1 -/- CD8+ T cells, including Tbx21, Gzmb and genes encoding cytokines and chemokines, and genes controlling glycolysis. Nfatc1 -/- , but not Nfatc2 -/- CD8+ T cells have an impaired metabolic switch to glycolysis, which can be restored by IL-2. Genome-wide ChIP-seq shows that NFATc1 binds many genes that control cytotoxic T lymphocyte activity. Together these data indicate that NFATc1 is an important regulator of cytotoxic T lymphocyte effector functions.NFAT nuclear translocation has been shown to be required for CD8+ T cell cytokine production in response to viral infection. Here the authors show NFATc1 controls the cytotoxicity and metabolic switching of activated CD8+ T cells required for optimal response to bacteria and tumor cells.

Controlling outbreak of vancomycin-resistant Enterococcus faecium among infants caused by an endemic strain in adult inpatients.

BACKGROUND: Vancomycin-resistant Enterococcus faecium (VREfm) is commonly associated with hospital outbreaks and has been found to be associated with increased morbidity, mortality, length of stay, and health care costs. METHODS: We sought to investigate and control an outbreak of VREfm in the neonatal intensive care unit (NICU) of a public academic hospital with a level III NICU. The index case was an infant in the NICU incidentally identified with urinary colonization with VREfm. Aggressive control measures were initiated promptly. Investigation included active surveillance cultures in infants, parents of colonized infants, and birth mothers of newborn admitted to NICU; molecular strain typing of available isolates of VREfm including adult inpatients; and medical record review. RESULTS: After identification of index case, 13 additional infants were identified with VREfm colonization. Age at culture was 6 to 87 days; birth weight was 1,070 to 2,834 g. VREfm isolated from majority of infants (12/14 [85.7%]), the birth mother of a pair of colonized twins, and a pulse oximeter device used in adult inpatients belonged to a single strain. Outbreak control measures were successful in the NICU. The outbreak-causing strain was found to be endemic among adult inpatients. Adult patients with the outbreak-causing strain of VREfm were more likely to have received previous therapy with meropenem (Mann-Whitney 2-tailed P value = .038). VRE colonization was identified in 0.3% (1/310) of birth mothers with newborn admitted to NICU. CONCLUSION: An endemic strain of VREfm among adult inpatients was responsible for a subsequently controlled outbreak in the NICU.