Development and validation of a bedside instrument to predict carbapenem resistance among gram-negative pathogens in complicated urinary tract infections

We developed a bedside instrument to predict carbapenem resistance in complicated urinary tract infections. A model assigning weighted points for admission from an extended care facility (1), history of weight loss (1), early mechanical ventilation (1), age \u3c50 years (2), male gender (3), catheter-associated urinary tract infection (4), prior antibiotics treatment (4), and prior carbapenem-resistant infection (8) exhibited good discrimination (C statistic, 0.721)

A risk score for identifying methicillin-resistant Staphylococcus aureus in patients presenting to the hospital with pneumonia.

Background Methicillin-resistant Staphylococcus aureus (MRSA) represents an important pathogen in healthcare-associated pneumonia (HCAP). The concept of HCAP, though, may not perform well as a screening test for MRSA and can lead to overuse of antibiotics. We developed a risk score to identify patients presenting to the hospital with pneumonia unlikely to have MRSA. Methods We identified patients admitted with pneumonia (Apr 2005 – Mar 2009) at 62 hospitals in the US. We only included patients with lab evidence of bacterial infection (e.g., positive respiratory secretions, blood, or pleural cultures or urinary antigen testing). We determined variables independently associated with the presence of MRSA based on logistic regression (two-thirds of cohort) and developed a risk prediction model based on these factors. We validated the model in the remaining population. Results The cohort included 5975 patients and MRSA was identified in 14%. The final risk score consisted of eight variables and a potential total score of 10. Points were assigned as follows: two for recent hospitalization or ICU admission; one each for age \u3c 30 or \u3e 79 years, prior IV antibiotic exposure, dementia, cerebrovascular disease, female with diabetes, or recent exposure to a nursing home/long term acute care facility/skilled nursing facility. This study shows how the prevalence of MRSA rose with increasing score after stratifying the scores into Low (0 to 1 points), Medium (2 to 5 points) and High (6 or more points) risk. When the score was 0 or 1, the prevalence of MRSA was \u3c 10% while the prevalence of MRSA climbed to \u3e 30% when the score was 6 or greater. Conclusions MRSA represents a cause of pneumonia presenting to the hospital. This simple risk score identifies patients at low risk for MRSA and in whom anti-MRSA therapy might be withheld

Alteration of Lung Physiology with the Administration of Convalescent Plasma in ARDS Patients Intubated with COVID-19 Pneumonia

**Background:** It remains unknown to what degree lung physiology is altered by administration of convalescent plasma in patients intubated with ARDS due to COVID-19 pneumonia. Although no longer clinically used as treatment for COVID-19, convalescent plasma therapy could be deployed again should new virus threats emerge in the future. **Aim:** To evaluate changes in ventilator physiologic variables in response to convalescent plasma transfusion using a retrospective, observational, case control study of intubated patients with COVID-19 pneumonia. **Methods:** Patients who were receiving mechanical ventilation due to COVID-19 at the time of administration of convalescent plasma therapy (CPT) were matched to control patients who did not receive convalescent plasma. Ventilatory data such as compliance, positive end-expiratory pressure (PEEP), FiO~2~ administered, PaO~2~/FiO~2~ ratio, and tidal volume were collected pre and post administration. Panel-level random-effects linear regression models were used to assess the mean difference and interactions between CPT and cases vs controls over time. **Results:** 12 patients received CPT while intubated and were matched to 35 intubated control patients who did not receive CPT. In total, 857 separate measurements of static compliance were obtained over time. No significant difference in static compliance was seen after CPT. In cases, adjusted mean static compliance was 30.8 (95% CI (23.3, 38.4))mL/cm H~2~O before CPT and 28.2 (95% CI (20.7,35.6)) mL/cm H~2~O afterwards. Controls adjusted mean static compliance was 33.9 (95% CI (29.5, 38.4)) mL/cm H~2~O before versus 32.2 (95% CI (27.9, 36.5)) mL/cm H~2~O afterwards. Variables that had small but statistically significant differences pre vs post CPT among cases and controls were systolic and diastolic blood pressure, FiO~2~, heart rate, applied PEEP, and respiratory rate. **Conclusion:** While some statistically significant physiologic effects were seen with CPT in mechanically ventilated patients, these were deemed to be small and clinically insignificant. This is consistent with prior research on less acutely ill COVID-19 patients

Cytoplasmic p53 couples oncogene-driven glucose metabolism to apoptosis and is a therapeutic target in glioblastoma.

Cross-talk among oncogenic signaling and metabolic pathways may create opportunities for new therapeutic strategies in cancer. Here we show that although acute inhibition of EGFR-driven glucose metabolism induces only minimal cell death, it lowers the apoptotic threshold in a subset of patient-derived glioblastoma (GBM) cells. Mechanistic studies revealed that after attenuated glucose consumption, Bcl-xL blocks cytoplasmic p53 from triggering intrinsic apoptosis. Consequently, targeting of EGFR-driven glucose metabolism in combination with pharmacological stabilization of p53 with the brain-penetrant small molecule idasanutlin resulted in synthetic lethality in orthotopic glioblastoma xenograft models. Notably, neither the degree of EGFR-signaling inhibition nor genetic analysis of EGFR was sufficient to predict sensitivity to this therapeutic combination. However, detection of rapid inhibitory effects on [18F]fluorodeoxyglucose uptake, assessed through noninvasive positron emission tomography, was an effective predictive biomarker of response in vivo. Together, these studies identify a crucial link among oncogene signaling, glucose metabolism, and cytoplasmic p53, which may potentially be exploited for combination therapy in GBM and possibly other malignancies

Improved Outcomes Associated With the Use of Intravenous Acetaminophen for Management of Acute Post-Surgical Pain in Cesarean Sections and Hysterectomies

Background: Post-surgical pain impacts many patient outcomes. Effective pain management increasingly relies on multimodal analgesia regimens in which acetaminophen (APAP) is a key component. The aim of our study was to examine the impact of oral APAP versus intravenous (IV) APAP as a component of post-surgical pain management after Cesarean sections and hysterectomies. Methods: A retrospective analysis of the Cerner HealthFacts® database (from January, 2011 to December, 2015) was conducted to compare outcomes of Cesarean section and hysterectomy surgery patients who received oral APAP to those who received IV APAP post-surgically. Length of stay (LOS), daily morphine milligram equivalent (MME) consumption, the presence of potential opioid-related adverse events (ORADEs), and total pharmacy costs were assessed. Adjusted results were derived using inverse probability weighted regression adjustment (IPW-RA) estimators based on covariates that included demographics, comorbidities, patient clinical characteristics, and hospital characteristics. Results: The study identified 29,124 Cesarean section patients (24,612 oral APAP; 4,512 IV APAP) and 9,767 hysterectomy surgery patients (5,586 oral APAP; 4,181 IV APAP). Compared to the oral APAP group, the IV APAP group had reductions in adjusted LOS (Cesarean section: -11.7% days (P < 0.001), hysterectomy: -11.8% days (P = 0.005)), lowered adjusted daily MME consumption from day 0 to day 3 (Cesarean section: -1.6 mg (P < 0.001), hysterectomy: -1.7 mg (P = 0.014)), and reduced risk of ORADEs for Cesarean sections (relative risk of 0.45, P < 0.001). Total pharmacy costs were not significantly different between the two APAP groups. Conclusions: Post-surgical pain managed with IV APAP in patients undergoing Cesarean section or hysterectomy was associated with shorter LOS, reduced risk of ORADEs, and lower opioid consumption compared to patients managed with oral APAP, without adversely impacting total pharmacy costs

Multidrug resistance, inappropriate empiric treatment and hospital mortality in Acinetobacter baumannii pneumonia and sepsis

Background: The relationship between multidrug resistance (MDR), inappropriate empiric therapy (IET), and mortality among patients with Acinetobacter baumannii (AB) remains unclear. We examined it using a large U.S. database. Methods: We conducted a retrospective cohort study using the Premier Research database (2009–2013) of 175 U.S. hospitals. We included all adult patients admitted with pneumonia or sepsis as their principal diagnosis, or as a secondary diagnosis in the setting of respiratory failure, along with antibiotic administration within 2 days of admission. Only culture-confirmed infections were included. Resistance to at least three classes of antibiotics defined multidrug-resistant AB (MDR-AB). We used logistic regression to compute the adjusted relative risk ratio (RRR) of patients with MDR-AB receiving IET and IET’s impact on mortality. Results: Among 1423 patients with AB infection, 1171 (82.3 %) had MDR-AB. Those with MDR-AB were older (63.7 ± 15.4 vs. 61.0 ± 16.9 years, p = 0.014). Although chronic disease burden did not differ between groups, the MDR-AB group had higher illness severity than those in the non-MDR-AB group (intensive care unit 68.0 % vs. 59. 5 %, p < 0.001; mechanical ventilation 56.2 % vs. 42.1 %, p < 0.001). Patients with MDR-AB were more likely to receive IET than those in the non-MDR-AB group (76.2 % MDR-AB vs. 13.8 % non-MDR-AB, p < 0.001). In a regression model, MDR-AB strongly predicted receipt of IET (adjusted RRR 5.5, 95 % CI 4.0–7.7, p < 0.001). IET exposure was associated with higher hospital mortality (adjusted RRR 1.8, 95 % CI 1.4–2.3, p < 0.001). Conclusions: In this large U.S. database, the prevalence of MDR-AB among patients with AB infection was > 80 %. Harboring MDR-AB increased the risk of receiving IET more than fivefold, and IET nearly doubled hospital mortality

BRCA2 polymorphic stop codon K3326X and the risk of breast, prostate, and ovarian cancers

Background: The K3326X variant in BRCA2 (BRCA2*c.9976A&gt;T; p.Lys3326*; rs11571833) has been found to be associated with small increased risks of breast cancer. However, it is not clear to what extent linkage disequilibrium with fully pathogenic mutations might account for this association. There is scant information about the effect of K3326X in other hormone-related cancers. Methods: Using weighted logistic regression, we analyzed data from the large iCOGS study including 76 637 cancer case patients and 83 796 control patients to estimate odds ratios (ORw) and 95% confidence intervals (CIs) for K3326X variant carriers in relation to breast, ovarian, and prostate cancer risks, with weights defined as probability of not having a pathogenic BRCA2 variant. Using Cox proportional hazards modeling, we also examined the associations of K3326X with breast and ovarian cancer risks among 7183 BRCA1 variant carriers. All statistical tests were two-sided. Results: The K3326X variant was associated with breast (ORw = 1.28, 95% CI = 1.17 to 1.40, P = 5.9x10- 6) and invasive ovarian cancer (ORw = 1.26, 95% CI = 1.10 to 1.43, P = 3.8x10-3). These associations were stronger for serous ovarian cancer and for estrogen receptor–negative breast cancer (ORw = 1.46, 95% CI = 1.2 to 1.70, P = 3.4x10-5 and ORw = 1.50, 95% CI = 1.28 to 1.76, P = 4.1x10-5, respectively). For BRCA1 mutation carriers, there was a statistically significant inverse association of the K3326X variant with risk of ovarian cancer (HR = 0.43, 95% CI = 0.22 to 0.84, P = .013) but no association with breast cancer. No association with prostate cancer was observed. Conclusions: Our study provides evidence that the K3326X variant is associated with risk of developing breast and ovarian cancers independent of other pathogenic variants in BRCA2. Further studies are needed to determine the biological mechanism of action responsible for these associations

Protection of Stem Cell-Derived Lymphocytes in a Primate AIDS Gene Therapy Model after In Vivo Selection

Background: There is currently no effective AIDS vaccine, emphasizing the importance of developing alternative therapies. Recently, a patient was successfully transplanted with allogeneic, naturally resistant CCR5-negative (CCR5 delta 32) cells, setting the stage for transplantation of naturally resistant, or genetically modified stem cells as a viable therapy for AIDS. Hematopoietic stem cell (HSC) gene therapy using vectors that express various anti-HIV transgenes has also been attempted in clinical trials, but inefficient gene transfer in these studies has severely limited the potential of this approach. Here we evaluated HSC gene transfer of an anti-HIV vector in the pigtailed macaque (Macaca nemestrina) model, which closely models human transplantation. Methods and Findings: We used lentiviral vectors that inhibited both HIV-1 and simian immunodeficiency virus (SIV)/HIV-1 (SHIV) chimera virus infection, and also expressed a P140K mutant methylguanine methyltransferase (MGMT) transgene to select gene-modified cells by adding chemotherapy drugs. Following transplantation and MGMT-mediated selection we demonstrated transgene expression in over 7% of stem-cell derived lymphocytes. The high marking levels allowed us to demonstrate protection from SHIV in lymphocytes derived from gene-modified macaque long-term repopulating cells that expressed an HIV-1 fusion inhibitor. We observed a statistically significant 4-fold increase of gene-modified cells after challenge of lymphocytes from one macaque that received stem cells transduced with an anti-HIV vector (p<0.02, Student's t-test), but not in lymphocytes from a macaque that received a control vector. We also established a competitive repopulation assay in a second macaque for preclinical testing of promising anti-HIV vectors. The vectors we used were HIV-based and thus efficiently transduce human cells, and the transgenes we used target HIV-1 genes that are also in SHIV, so our findings can be rapidly translated to the clinic. Conclusions: Here we demonstrate the ability to select protected HSC-derived lymphocytes in vivo in a clinically relevant nonhuman primate model of HIV/SHIV infection. This approach can now be evaluated in human clinical trials in AIDS lymphoma patients. In this patient setting, chemotherapy would not only kill malignant cells, but would also increase the number of MGMTP140K-expressing HIV-resistant cells. This approach should allow for high levels of HIV-protected cells in AIDS patients to evaluate AIDS gene therapy

Genome-Wide Association Study in East Asians Identifies Novel Susceptibility Loci for Breast Cancer

Genetic factors play an important role in the etiology of both sporadic and familial breast cancer. We aimed to discover novel genetic susceptibility loci for breast cancer. We conducted a four-stage genome-wide association study (GWAS) in 19,091 cases and 20,606 controls of East-Asian descent including Chinese, Korean, and Japanese women. After analyzing 690,947 SNPs in 2,918 cases and 2,324 controls, we evaluated 5,365 SNPs for replication in 3,972 cases and 3,852 controls. Ninety-four SNPs were further evaluated in 5,203 cases and 5,138 controls, and finally the top 22 SNPs were investigated in up to 17,423 additional subjects (7,489 cases and 9,934 controls). SNP rs9485372, near the TGF-β activated kinase (TAB2) gene in chromosome 6q25.1, showed a consistent association with breast cancer risk across all four stages, with a P-value of 3.8×10−12 in the combined analysis of all samples. Adjusted odds ratios (95% confidence intervals) were 0.89 (0.85–0.94) and 0.80 (0.75–0.86) for the A/G and A/A genotypes, respectively, compared with the genotype G/G. SNP rs9383951 (P = 1.9×10−6 from the combined analysis of all samples), located in intron 5 of the ESR1 gene, and SNP rs7107217 (P = 4.6×10−7), located at 11q24.3, also showed a consistent association in each of the four stages. This study provides strong evidence for a novel breast cancer susceptibility locus represented by rs9485372, near the TAB2 gene (6q25.1), and identifies two possible susceptibility loci located in the ESR1 gene and 11q24.3, respectively