ALVR109, an off-the-shelf partially HLA matched SARS-CoV-2-specific T cell therapy, to treat refractory severe COVID-19 pneumonia in a heart transplant patient: Case report.

An unvaccinated adult male heart transplant recipient patient with recalcitrant COVID-19 due to SARS-CoV-2 delta variant with rising nasopharyngeal quantitative viral load was successfully treated with ALVR109, an off-the-shelf SARS-CoV-2-specific T cell therapy. Background immunosuppression included 0.1 mg/kg prednisone, tacrolimus, and mycophenolate mofetil 1 gm twice daily for historical antibody-mediated rejection. Prior therapies included remdesivir, corticosteroids, and tocilizumab, with requirement for high-flow nasal oxygen. Lack of clinical improvement and acutely rising nasopharyngeal viral RNA more than 3 weeks into illness prompted the request of ALVR109 through an emergency IND. The day following the first ALVR109 infusion, the patient's nasopharyngeal SARS-CoV-2 RNA declined from 7.43 to 5.02 log10 RNA copies/ml. On post-infusion day 4, the patient transitioned to low-flow oxygen. Two subsequent infusions of ALVR109 were administered 10 and 26 days after the first; nasopharyngeal SARS-CoV-2 RNA became undetectable on Day 11, and he was discharged the following day on low-flow oxygen 5 weeks after the initial diagnosis of COVID-19. The clinical and virologic improvements observed in this patient following administration of ALVR109 suggest a potential benefit that warrants further exploration in clinical trials.

Effect of Adjunctive Dexmedetomidine in the Treatment of Alcohol Withdrawal Compared to Benzodiazepine Symptom-Triggered Therapy in Critically Ill Patients: The EvADE Study.

OBJECTIVE: This study evaluated the safety and efficacy of adjunctive dexmedetomidine for alcohol withdrawal syndrome (AWS) treatment compared to symptom-triggered benzodiazepine therapy. METHODS: This single-center, retrospective, cohort study evaluated patients admitted to an intensive care unit (ICU) with AWS. Patients were divided into 2 groups: adjunctive dexmedetomidine or symptom-triggered therapy (control). Primary outcome was change in Clinical Institute Withdrawal Assessment for Alcohol (CIWA-Ar) score. Secondary outcomes assessed cumulative ICU benzodiazepine requirement and ICU/hospital length of stay (LOS). Safety outcomes evaluated incidence of adverse events, new onset seizures, and intubation. Propensity matching was performed to minimize differences between study groups. RESULTS: Overall, 147 patients were included, 56 in the dexmedetomidine group and 91 in the control group. Patient demographics were similar, however baseline CIWA-Ar score was statistically higher in the dexmedetomidine group. Following propensity matching, 55 patients were included in each group. No significant difference was noted for change in CIWA-Ar score (median, IQR) [3.8 (-0.4-12.3) dexmedetomidine vs. 5.4 (1.4-12.9) control, p = 0.223]. Secondary endpoints revealed increased benzodiazepine requirements (p = 0.001), prolonged ICU LOS (p = 0.050), and more frequent use of physical restraints (p = 0.001) in the dexmedetomidine group. While not statistically significant, the development of new onset seizures (p = 0.775) and intubation (p = 0.294) occurred more frequently in the dexmedetomidine group. CONCLUSION: The addition of dexmedetomidine to symptom-triggered benzodiazepines for AWS did not produce a significant change in CIWA-Ar scores from baseline compared to symptom-triggered therapy alone. The increased rate of new onset seizures and intubation warrant further investigation into the safety of dexmedetomidine in AWS.

Local production of lactate, ribose phosphate, and amino acids within human triple-negative breast cancer.

BACKGROUND: Upregulated glucose metabolism is a common feature of tumors. Glucose can be broken down by either glycolysis or the oxidative pentose phosphate pathway (oxPPP). The relative usage within tumors of these catabolic pathways remains unclear. Similarly, the extent to which tumors make biomass precursors from glucose, versus take them up from the circulation, is incompletely defined. METHODS: We explore human triple negative breast cancer (TNBC) metabolism by isotope tracing with [1,2-13C]glucose, a tracer that differentiates glycolytic versus oxPPP catabolism and reveals glucose-driven anabolism. Patients enrolled in clinical trial NCT03457779 and received IV infusion of [1,2-13C]glucose during core biopsy of their primary TNBC. Tumor samples were analyzed for metabolite labeling by liquid chromatography-mass spectrometry (LC-MS). Genomic and proteomic analyses were performed and related to observed metabolic fluxes. FINDINGS: TNBC ferments glucose to lactate, with glycolysis dominant over the oxPPP. Most ribose phosphate is nevertheless produced by oxPPP. Glucose also feeds amino acid synthesis, including of serine, glycine, aspartate, glutamate, proline and glutamine (but not asparagine). Downstream in glycolysis, tumor pyruvate and lactate labeling exceeds that found in serum, indicating that lactate exchange via monocarboxylic transporters is less prevalent in human TNBC compared with most normal tissues or non-small cell lung cancer. CONCLUSIONS: Glucose directly feeds ribose phosphate, amino acid synthesis, lactate, and the TCA cycle locally within human breast tumors.

Skin, soft tissue, bone, and joint infections in hospitalized patients: epidemiology and microbiological, clinical, and economic outcomes.

BACKGROUND: Infections involving skin, soft tissue, bone, or joint (SSTBJ) are common and often require hospitalization. There are currently few published studies on the epidemiology and clinical and economic outcomes of these infections, whether acquired in the community or healthcare setting, in a large population. OBJECTIVE: To characterize outcomes of culture-proven SSTBJ infection in hospitalized patients, using information from a large database. DESIGN: We identified patients hospitalized in 134 institutions during 2002-2003 for whom specific International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis codes and a culture-positive SSTBJ specimen were recorded. Patients were classified into 4 clinical groups based on the type and clinical severity of infection. Patients in each group were further classified on the basis of whether their infection was community acquired or healthcare associated and whether it was complicated or uncomplicated. RESULTS: We identified 12,506 patients with culture-positive infections and categorized them as having cellulitis (37.3%), osteomyelitis or septic arthritis (22.4%), surgical wound infection (26.1%), device-associated or prosthesis infection (7.2%), or other SSTBJ infection (6.9%). Monomicrobial infection was reported for 59% of patients, 54.6% of whom had Staphylococcus aureus as the etiologic agent. Of all S. aureus isolates recovered, 1,121 (28.0%) of 4,007 were resistant to methicillin. Healthcare-associated infections accounted for 27.2% of cases and were associated with a significantly greater mortality rate, a longer length of stay, and greater hospital charges, compared with community-acquired infections. Patients with a complicated infection (78.4%) had a significantly greater mortality rate, a longer length of stay, and greater hospital charges, compared with patients with an uncomplicated infection. CONCLUSIONS: SSTBJ infections are frequent among hospitalized patients. S. aureus caused infection in more than 50% of the patients studied, and 28.0% of the S. aureus isolates recovered were resistant to methicillin. Healthcare-associated and complicated infections are associated with a significantly higher mortality rate and more prolonged and expensive hospitalizations. These findings could assist in projects to revise current management strategies in order to optimize outcomes while restraining costs.

Fluctuations in vancomycin CNS tissue concentrations following intermittent and continuous infusions in the rat.

The purpose of this investigation was to compare the variability of vancomycin concentrations in the serum and CNS when administered continuously or as intermittent intravenous infusions in the rat. The hypothesis for this investigation was that the magnitude of change in serum vancomycin concentrations directly relates to the extent of vancomycin concentration fluctuations in the CNS. Microdialysis and serum sampling techniques were employed and biologic samples were analysed for vancomycin using HPLC. Over the dosing interval, the mean changes in concentrations were 71.8 +/- 9.8% and 13.6 +/- 9.3% for serum and 61.7 +/- 7.8% and 6.8 +/- 3.5% for brain extracellular fluid in the intermittent and continuously infused groups, respectively. Accordingly, the relative changes in vancomycin concentrations in brain extracellular fluid were closely associated with corresponding changes in serum concentrations (R2=0.94). Thus, continuous intravenous administration of vancomycin results in minimal serum and CNS tissue concentration changes as compared to traditional intermittent dosing methods and allows for more consistent vancomycin concentrations in the CNS.

Comparison of force exerted on the sternum during a sneeze versus during low-, moderate-, and high-intensity bench press resistance exercise with and without the valsalva maneuver in healthy volunteers.

Sternal precautions are intended to prevent complications after median sternotomy, but little data exist to support the consensus recommendations. To better characterize the forces on the sternum that can occur during everyday events, we conducted a prospective nonrandomized study of 41 healthy volunteers that evaluated the force exerted during bench press resistance exercise and while sneezing. A balloon-tipped esophageal catheter, inserted through the subject's nose and advanced into the thoracic cavity, was used to measure the intrathoracic pressure differential during the study activities. After the 1 repetition maximum (1-RM) was assessed, the subject performed the bench press at the following intensities, first with controlled breathing and then with the Valsalva maneuver: 40% of 1-RM (low), 70% of 1-RM (moderate), and 1-RM (high). Next, various nasal irritants were used to induce a sneeze. The forces on the sternum were calculated according to a cylindrical model, and a 2-tailed paired t test was used to compare the mean force exerted during a sneeze with the mean force exerted during each of the 6 bench press exercises. No statistically significant difference was found between the mean force from a sneeze (41.0 kg) and the mean total force exerted during moderate-intensity bench press exercise with breathing (41.4 kg). In conclusion, current guidelines and recommendations limit patient activity after a median sternotomy. Because these patients can repeatedly withstand a sneeze, our study indicates that they can withstand the forces from more strenuous activities than are currently allowed.

Cost analysis of erythropoietic-stimulating therapy dosing in oncology inpatients.

BACKGROUND: Inpatient costs associated with different erythropoietic-stimulating therapy regimens have not been compared in an oncology setting. OBJECTIVE: To conduct a cost analysis of different regimens of epoetin alfa (EPO) and darbepoetin alfa (DARB) in an inpatient oncology setting. METHODS: A retrospective evaluation of oncology diagnosis-related group discharges during 2003, in 30 community hospitals, identified EPO treatment patterns. Wholesale acquisition costs were determined for patients who received EPO 40,000 units or more once weekly. Potential differences in costs were calculated using conversion ratios for an equivalent EPO dose 3 times weekly or DARB dose once weekly (EPO:DARB ratio 260:1, approximating DARB 150 microg once weekly). A sensitivity analysis was performed using an EPO:DARB ratio of 400:1, approximating DARB 100 microg once weekly (1.5 microg/kg). RESULTS: Among the 1410 EPO doses administered (n = 677 pts.), a dose of 40,000 units or more was used 44% of the time (n = 311 pts.), with dosing initiated on average 5.6 days after admission. For these 311 evaluable patients, switching from EPO 40,000 units once weekly to EPO 10,000 units 3 times weekly reduced per-patient and total drug acquisition costs by approximately 50% (704 US dollars vs 359 US dollars and 218,938 US dollars vs 111,615 US dollars, respectively). Relative to EPO once weekly, switching patients to DARB resulted in increased drug acquisition costs at the 260:1 conversion and lower costs at the 400:1 conversion. However, EPO 3 times weekly remained the least costly option by 44-63%. The cost-savings realized with EPO 10,000 units 3 times weekly increased with longer duration of hospitalization. CONCLUSIONS: In an inpatient setting, use of EPO 10,000 units 3 times weekly may minimize expenditures associated with treatment of cancer-related anemia using erythropoietic-stimulating therapies.

Healthcare-associated bloodstream infection: A distinct entity? Insights from a large U.S. database.

OBJECTIVE: To gain a better understanding of the epidemiology, microbiology, and outcomes of early-onset, culture-positive, community-acquired, healthcare-associated, and hospital-acquired bloodstream infections. DESIGN: We analyzed a large U.S. database (Cardinal Health, MediQual, formerly MedisGroups) to identify patients with bacterial or fungal bloodstream isolates from 2002 to 2003. SETTING: The data set included administrative and clinical variables (physiologic, laboratory, culture, and other clinical) from 59 hospitals. Bloodstream infections were identified in those hospitals collecting clinical and culture data for at least the first 5 days of admission. PATIENTS: Patients with bloodstream infection within 2 days of admission were classified as having community-acquired bloodstream infection. Those with a prior hospitalization within 30 days, transfer from another facility, ongoing chemotherapy, or long-term hemodialysis were classified as having healthcare-associated bloodstream infection. Bloodstream infections that developed after day 2 of admission were classified as hospital-acquired bloodstream infection. A total of 6,697 patients were identified as having bloodstream infection. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Healthcare-associated bloodstream infection accounted for more than half (55.3%) of all bloodstream infections. Nearly two thirds (62.3%) of hospitalized patients with bloodstream infection suffered from either hospital-acquired bloodstream infection or healthcare-associated bloodstream infection and had higher morbidity and mortality rates than those with community-acquired bloodstream infection. Of all bloodstream infection pathogens, fungal organisms were associated with the highest crude mortality, longest length of stay in hospital, and greatest total charges. Of all bacterial bloodstream infections, methicillin-resistant Staphylococcus aureus was associated with the highest crude mortality rate (22.5%), the longest mean length of stay (11.1 +/- 10.7 days), and the highest median total charges ($36,109). After we controlled for confounding factors, methicillin-resistant S. aureus was associated with the highest independent mortality risk (odds ratio 2.70; confidence interval 2.03-3.58). S. aureus was the most commonly encountered pathogen in all types of early-onset bacteremia. CONCLUSIONS: Healthcare-associated bloodstream infection constitutes a distinct entity of bloodstream infection with its unique epidemiology, microbiology, and outcomes. Methicillin-resistant Staphylococcus aureus carries the highest relative mortality risk among all pathogens.