CPAP resumption after a first termination and impact on all-cause mortality in France.

BACKGROUND: Continuation of continuous positive airway pressure (CPAP) therapy after initial prescription has been shown to reduce all-cause mortality versus therapy termination. However, there is a lack of data on the rates and impact of resuming CPAP in patients with obstructive sleep apnoea (OSA). This analysis determined the prevalence of CPAP resumption in the year after termination, characterised determinants of CPAP resumption, and examined the impact of CPAP resumption on all-cause mortality. METHODS: French national health insurance reimbursement system data for adults aged ≥18 years were used. CPAP prescription was identified by specific treatment codes. Patients who resumed CPAP after first therapy termination and continued to use CPAP for 1 year were matched with those who resumed CPAP then terminated therapy for a second time. RESULTS: Out of 103 091 individuals with a first CPAP termination, 26% resumed CPAP over the next 12 months, and 65% of these were still using CPAP 1 year later. Significant predictors of CPAP continuation after resumption included male sex, hypertension and CPAP prescription by a pulmonologist. In the matched population, the risk of all-cause death was 38% lower in individuals who continued using CPAP after therapy resumption versus those who had a second therapy discontinuation (hazard ratio 0.62, 95% CI 0.48-0.79; p=0.0001). CONCLUSION: These data suggest that individuals with OSA who fail initial therapy with CPAP should be offered a second trial with the device to ensure that effective therapy is not withheld from those who might benefit.

Adenoviral vectors infect B lymphocytes in vivo.

B cells are the antibody-producing arm of the adaptive immune system and play a critical role in controlling pathogens. Several groups have now demonstrated the feasibility of using engineered B cells as a therapy, including infectious disease control and gene therapy of serum deficiencies. These studies have largely utilized ex vivo modification of the cells. Direct in vivo engineering would be of utility to the field, particularly in infectious disease control where the infrastructure needs of ex vivo cell modification would make a broad vaccination campaign highly challenging. In this study we demonstrate that engineered adenoviral vectors are capable of efficiently transducing murine and human primary B cells both ex vivo and in vivo. We found that unmodified human adenovirus C5 was capable of infecting B cells in vivo, likely due to interactions between the virus penton base protein and integrins. We further describe vector modification with B cell-specific gene promoters and successfully restrict transgene expression to B cells, resulting in a strong reduction in gene expression from the liver, the main site of human adenovirus C5 infection in vivo.

Vector Strategies to Actualize B Cell-Based Gene Therapies.

Recent developments in genome editing and delivery systems have opened new possibilities for B cell gene therapy. CRISPR-Cas9 nucleases have been used to introduce transgenes into B cell genomes for subsequent secretion of exogenous therapeutic proteins from plasma cells and to program novel B cell Ag receptor specificities, allowing for the generation of desirable Ab responses that cannot normally be elicited in animal models. Genome modification of B cells or their progenitor, hematopoietic stem cells, could potentially substitute Ab or protein replacement therapies that require multiple injections over the long term. To date, B cell editing using CRISPR-Cas9 has been solely employed in preclinical studies, in which cells are edited ex vivo. In this review, we discuss current B cell engineering efforts and strategies for the eventual safe and economical adoption of modified B cells into the clinic, including in vivo viral delivery of editing reagents to B cells.

Healthcare Provider Perceptions of Causes and Consequences of ICU Capacity Strain in a Large Publicly Funded Integrated Health Region: A Qualitative Study.

OBJECTIVES: Discrepancy in the supply-demand relationship for critical care services precipitates a strain on ICU capacity. Strain can lead to suboptimal quality of care and burnout among providers and contribute to inefficient health resource utilization. We engaged interprofessional healthcare providers to explore their perceptions of the sources, impact, and strategies to manage capacity strain. DESIGN: Qualitative study using a conventional thematic analysis. SETTING: Nine ICUs across Alberta, Canada. SUBJECTS: Nineteen focus groups (n = 122 participants). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Participants' perspectives on strain on ICU capacity and its perceived impact on providers, families, and patient care were explored. Participants defined "capacity strain" as a discrepancy between the availability of ICU beds, providers, and ICU resources (supply) and the need to admit and provide care for critically ill patients (demand). Four interrelated themes of contributors to strain were characterized (each with subthemes): patient/family related, provider related, resource related, and health system related. Patient/family-related subthemes were "increasing patient complexity/acuity," along with patient-provider communication issues ("paucity of advance care planning and goals-of-care designation," "mismatches between patient/family and provider expectations," and "timeliness of end-of-life care planning"). Provider-related factor subthemes were nursing workforce related ("nurse attrition," "inexperienced workforce," "limited mentoring opportunities," and "high patient-to-nurse ratios") and physician related ("frequent turnover/handover" and "variations in care plan"). Resource-related subthemes were "reduced service capability after hours" and "physical bed shortages." Health system-related subthemes were "variable ICU utilization," "preferential "bed" priority for other services," and "high ward bed occupancy." Participants perceived that strain had negative implications for patients ("reduced quality and safety of care" and "disrupted opportunities for patient- and family-centered care"), providers ("increased workload," "moral distress," and "burnout"), and the health system ("unnecessary, excessive, and inefficient resource utilization"). CONCLUSIONS: Engagement with frontline critical care providers is essential for understanding their experiences and perspectives regarding strained capacity and for the development of sustainable strategies for improvement.

Focused Critical Care Echocardiography: Development and Evaluation of an Image Acquisition Assessment Tool.

OBJECTIVES: Little attention has been placed on assessment tools to evaluate image acquisition quality for focused critical care echocardiography. We designed a novel assessment tool to objectively evaluate the image acquisition skills of critical care trainees learning focused critical care echocardiography and examined the tool for evidence of validity. DESIGN: Prospective observational study. SETTING: Medical-surgical ICUs at a tertiary care teaching hospital. SUBJECTS: Trainees in our critical care medicine fellowship program. INTERVENTIONS: Six trainees completed a focused critical care echocardiography training curriculum followed by performing 20 transthoracic echocardiograms on patients receiving invasive mechanical ventilation. At three assessment intervals (the 1st and 2nd examinations, 10th and 11th examinations, and 19th and 20th examinations), echocardiograms performed by trainees were compared with those of critical care physicians certified in echocardiography and scored according to the focused critical care echocardiography assessment tool. The primary outcome was an efficiency score (overall assessment tool score divided by examination time). Differences in mean efficiency scores between echocardiographers of differing skill levels and changes in trainees' mean efficiency scores with increasing focused critical care echocardiography experience were compared by using t tests. MEASUREMENTS AND MAIN RESULTS: On the initial assessment, mean efficiency scores (SD) for trainees and experienced physicians were 1.55 (0.95) versus 2.78 (1.38), respectively (p = 0.02), and for the second and third assessments, the corresponding efficiency ratings for trainees and experienced physicians were 2.48 (0.97) versus 4.55 (1.32) (p < 0.01) and 2.61 (1.37) versus 4.17 (2.12) (p = 0.04), respectively. CONCLUSIONS: Trainees' efficiency in focused critical care echocardiography image acquisition improved quickly in the first 10 studies, yet, it could not match with the performance of experienced physicians after 20 focused critical care echocardiography studies. The focused critical care echocardiography assessment tool demonstrated evidence of validity and could discern changes in trainees' image acquisition performance with increasing experience.

Dynamic Projection of Medication Nonpersistence and Nonadherence Among Patients With Early Breast Cancer.

Importance: Oral endocrine treatments have been shown to be effective when carefully adhered to. However, in patients with early breast cancer, adherence challenges are notable, with 17% experiencing nonpersistence and 41% nonadherence at least once. Objective: To model the persistence of and adherence to oral anticancer treatment of a patient with localized breast cancer. Design, Setting, and Participants: This cohort study was conducted using anonymous reimbursement data belonging to French female patients with breast cancer, extracted from the French Health Insurance database from January 2013 to December 2018. Data analysis was conducted from January 2021 to May 2022. Main Outcomes and Measures: The main outcome was the detection of episodes of nonpersistence and nonadherence 6 months before they happened. Adherence was defined as the ratio between the time covered by a drug purchase and the time between 2 purchases; patients were considered nonadherent if the ratio of their next 3 purchases was less than 80%. Disparities in persistence and adherence based on criteria such as age, treatment type, and income were identified. Results: A total of 229 695 female patients (median [IQR] age, 63 [52-72] years) with localized breast cancer were included. A deep learning model based on a gated-recurrent unit architecture was used to detect episodes of nonpersistence or nonadherence. This model demonstrated an area under the receiving operating curve of 0.71 for persistence and 0.73 for adherence. Analyzing the Shapley Additive Explanations values also gave insights into the contribution of the different features over the model's decision. Patients older than 70 years, with past nonadherence, taking more than 1 treatment in the previous 3 months, and with low income had greater risk of episodes of nonpersistence. Age and past nonadherence, including regularity of past adherence, were also important features in the nonadherence model. Conclusions and Relevance: This cohort study found associations of patient age and past adherence with nonpersistence or nonadherence. It also suggested that regular intervals in treatment purchases enhanced adherence, in contrast to irregular purchasing patterns. This research offers valuable tools for improving persistence of and adherence to oral anticancer treatment among patients with early breast cancer.

Engineering a Novel Modular Adenoviral mRNA Delivery Platform Based on Tag/Catcher Bioconjugation.

mRNA vaccines have attracted widespread research attention with clear advantages in terms of molecular flexibility, rapid development, and potential for personalization. However, current mRNA vaccine platforms have not been optimized for induction of CD4/CD8 T cell responses. In addition, the mucosal administration of mRNA based on lipid nanoparticle technology faces challenges in clinical translation. In contrast, adenovirus-based vaccines induce strong T cell responses and have been approved for intranasal delivery. To leverage the inherent strengths of both the mRNA and adenovirus platforms, we developed a novel modular adenoviral mRNA delivery platform based on Tag/Catcher bioconjugation. Specifically, we engineered adenoviral vectors integrating Tag/Catcher proteins at specific locales on the Ad capsid proteins, allowing us to anchor mRNA to the surface of engineered Ad viruses. In proof-of-concept studies, the Ad-mRNA platform successfully mediated mRNA delivery and could be optimized via the highly flexible modular design of both the Ad-mRNA and protein bioconjugation systems.

PPRX-1701, a nanoparticle formulation of 6'-bromoindirubin acetoxime, improves delivery and shows efficacy in preclinical GBM models.

Derivatives of the Chinese traditional medicine indirubin have shown potential for the treatment of cancer through a range of mechanisms. This study investigates the impact of 6'-bromoindirubin-3'-acetoxime (BiA) on immunosuppressive mechanisms in glioblastoma (GBM) and evaluates the efficacy of a BiA nanoparticle formulation, PPRX-1701, in immunocompetent mouse GBM models. Transcriptomic studies reveal that BiA downregulates immune-related genes, including indoleamine 2,3-dioxygenase 1 (IDO1), a critical enzyme in the tryptophan-kynurenine-aryl hydrocarbon receptor (Trp-Kyn-AhR) immunosuppressive pathway in tumor cells. BiA blocks interferon-γ (IFNγ)-induced IDO1 protein expression in vitro and enhances T cell-mediated tumor cell killing in GBM stem-like cell co-culture models. PPRX-1701 reaches intracranial murine GBM and significantly improves survival in immunocompetent GBM models in vivo. Our results indicate that BiA improves survival in murine GBM models via effects on important immunotherapeutic targets in GBM and that it can be delivered efficiently via PPRX-1701, a nanoparticle injectable formulation of BiA.

The Cost of ARDS: A Systematic Review.

BACKGROUND: ARDS is an inflammatory condition of the lungs and is a common condition in adult ICUs. The resources required and costs of care for patients with ARDS are significant because of the severity of the illness and extended ICU lengths of stay. RESEARCH QUESTION: What are the costs associated with ARDS? STUDY DESIGN AND METHODS: We systematically searched the literature through April 29, 2021, for articles relevant to ARDS and costs. MEDLINE, Embase, Central, and EconLit databases were searched, and articles that reported on cost data from an original publication in adult patients with ARDS were included. Two authors independently assessed articles for inclusion and extracted data elements related to costs, methodology, health care system type, economic perspective, and clinical data. Publication quality was assessed using a modified version of the Quality of Health Economic Studies Instrument. RESULTS: Four thousand six hundred sixty-three publications were found, of which 110 were included for full-text review (κ = 0.72). A total of 22 publications (49,483 patients) were suitable for data extraction. The publications represented a broad range of health care systems, economic perspectives, costing methodology, and time frames. Mean inpatient costs ranged from $8,476 (2021 US dollars [USD]) to $547,974 (2021 USD) and were highest in publications of lower quality and in American health systems and were associated with trauma cohorts. Outpatient costs were highest in publications with higher readmission rates, longer durations of follow-up, and in American health systems. INTERPRETATION: A wide range of costing data is available for ARDS. A comprehensive synthesis of this literature frames the reasons for this and allows estimates to reflect the context in which they were assessed. This information will be of value to researchers and administrators interested in the economics of caring for patients with ARDS. TRIAL REGISTRY: PROSPERO; No.: CRD42020192487 https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=192487.

A Novel Piggyback Strategy for mRNA Delivery Exploiting Adenovirus Entry Biology.

Molecular therapies exploiting mRNA vectors embody enormous potential, as evidenced by the utility of this technology for the context of the COVID-19 pandemic. Nonetheless, broad implementation of these promising strategies has been restricted by the limited repertoires of delivery vehicles capable of mRNA transport. On this basis, we explored a strategy based on exploiting the well characterized entry biology of adenovirus. To this end, we studied an adenovirus-polylysine (AdpL) that embodied "piggyback" transport of the mRNA on the capsid exterior of adenovirus. We hypothesized that the efficient steps of Ad binding, receptor-mediated entry, and capsid-mediated endosome escape could provide an effective pathway for transport of mRNA to the cellular cytosol for transgene expression. Our studies confirmed that AdpL could mediate effective gene transfer of mRNA vectors in vitro and in vivo. Facets of this method may offer key utilities to actualize the promise of mRNA-based therapeutics.

Relationship Between CPAP Termination and All-Cause Mortality: A French Nationwide Database Analysis.

BACKGROUND: Randomized controlled trials have failed to demonstrate an effect of CPAP therapy on mortality. However, these studies have a number of important limitations, including low CPAP adherence, patient selection, and a small number of mortality events. RESEARCH QUESTION: What are the effects of CPAP therapy termination in the first year on all-cause mortality in patients with OSA from the Nationwide Claims Data Lake for Sleep Apnea study? STUDY DESIGN AND METHODS: Data from the Système National des Données de Santé (SNDS) database, the French national health insurance reimbursement system, for all new CPAP users ≥ 18 years of age were analyzed. The SNDS contains comprehensive, individualized, and anonymized data on health spending reimbursements for > 99% of all individuals living in France. OSA diagnosis was based on specific disease codes, whereas CPAP prescription was identified using specific treatment method codes. CPAP therapy termination was defined as the cessation of CPAP reimbursements triggered by the respiratory physician or sleep specialist in charge of follow-up. Patients who terminated therapy in the first year were propensity score matched with those who continued to use CPAP. The primary outcome was all-cause mortality. Three-year survival was visualized using Kaplan-Meier curves. Contributors to mortality also were determined. RESULTS: Data from two matched groups each including 88,007 patients were included (mean age, 60 years; 64% men). Continuation of CPAP therapy was associated with a significantly lower risk of all-cause death compared with CPAP therapy termination (hazard ratio [HR], 0.61; 95% CI, 0.57-0.65; P < .01, log-rank test). Incident heart failure also was less common in patients who continued vs terminated CPAP therapy (HR, 0.77; 95% CI, 0.71-0.82; P < .01). INTERPRETATION: These real-world data from a comprehensive, unbiased database highlight the potential for ongoing use of CPAP treatment to reduce all-cause mortality in patients with OSA.

Adenoviral vector vaccine platforms in the SARS-CoV-2 pandemic.

Adenoviral vectors have been explored as vaccine agents for a range of infectious diseases, and their ability to induce a potent and balanced immune response made them logical candidates to apply to the COVID-19 pandemic. The unique molecular characteristics of these vectors enabled the rapid development of vaccines with advanced designs capable of overcoming the biological challenges faced by early adenoviral vector systems. These successes and the urgency of the COVID-19 situation have resulted in a flurry of candidate adenoviral vector vaccines for COVID-19 from both academia and industry. These vaccines represent some of the lead candidates currently supported by Operation Warp Speed and other government agencies for rapid translational development. This review details adenoviral vector COVID-19 vaccines currently in human clinical trials and provides an overview of the new technologies employed in their design. As these vaccines have formed a cornerstone of the COVID-19 global vaccination campaign, this review provides a full consideration of the impact and development of this emerging platform.

Alteration of the carbohydrate for deoxyguanosine analogs markedly changes DNA replication fidelity, cell cycle progression and cytotoxicity.

Nucleoside analogs are efficacious cancer chemotherapeutics due to their incorporation into tumor cell DNA. However, they exhibit vastly different antitumor efficacies, suggesting that incorporation produces divergent effects on DNA replication. Here we have evaluated the consequences of incorporation on DNA replication and its fidelity for three structurally related deoxyguanosine analogs: ganciclovir (GCV), currently in clinical trials in a suicide gene therapy approach for cancer, D-carbocyclic 2'-deoxyguanosine (CdG) and penciclovir (PCV). GCV and CdG elicited similar cytotoxicity at low concentrations, whereas PCV was 10-100-fold less cytotoxic in human tumor cells. DNA replication fidelity was evaluated using a supF plasmid-based mutation assay. Only GCV induced a dose-dependent increase in mutation frequency, predominantly GC-->TA transversions, which contributed to cytotoxicity and implicated the ether oxygen in mutagenicity. Activation of mismatch repair with hydroxyurea decreased mutations but failed to repair the GC-->TA transversions. GCV slowed S-phase progression and CdG also induced a G2/M block, but both drugs allowed completion of one cell cycle after drug treatment followed by cell death in the second cell cycle. In contrast, PCV induced a lengthy early S-phase block due to profound suppression of DNA synthesis, with cell death in the first cell cycle after drug treatment. These data suggest that GCV and CdG elicit superior cytotoxicity due to their effects in template DNA, whereas strong inhibition of nascent strand synthesis by PCV may protect against cytotoxicity. Nucleoside analogs based on the carbohydrate structures of GCV and CdG is a promising area for antitumor drug development.

Adenoviral vectors for in vivo delivery of CRISPR-Cas gene editors.

Harnessing the bacterial clustered regularly interspaced short palindromic repeats (CRISPR) system for genome editing in eukaryotes has revolutionized basic biomedical research and translational sciences. The ability to create targeted alterations of the genome through this easy to design system has presented unprecedented opportunities to treat inherited disorders and other diseases such as cancer through gene therapy. A major hurdle is the lack of an efficient and safe in vivo delivery system, limiting most of the current gene therapy efforts to ex vivo editing of extracted cells. Here we discuss the unique features of adenoviral vectors that enable tissue specific and efficient delivery of the CRISPR-Cas machinery for in vivo genome editing.

Hydroxyurea induces bystander cytotoxicity in cocultures of herpes simplex virus thymidine kinase-expressing and nonexpressing HeLa cells incubated with ganciclovir.

Suicide gene therapy with the herpes simplex virus thymidine kinase (HSV-TK) cDNA and ganciclovir can elicit cytotoxicity to transgene-expressing and nonexpressing bystander cells via transfer of ganciclovir phosphates through gap junctions. HeLa cells do not exhibit bystander cytotoxicity, although we showed recently that they transfer low levels of ganciclovir phosphates to bystander cells. Here, we attempted to induce bystander cytotoxicity using hydroxyurea, an inhibitor of ribonucleotide reductase, to decrease the endogenous dGTP pool, which should lessen competition with ganciclovir triphosphate for DNA incorporation. Addition of hydroxyurea to cocultures of HSV-TK-expressing and bystander cells synergistically increased ganciclovir-mediated cytotoxicity to both cell populations while producing primarily an additive effect in cultures of 100% HSV-TK-expressing cells. Whereas HSV-TK-expressing cells in coculture were approximately 50-fold less sensitive to ganciclovir compared with cultures of 100% HSV-TK-expressing cells, addition of hydroxyurea restored ganciclovir sensitivity. Quantification of deoxynucleoside triphosphate pools showed that hydroxyurea decreased dGTP pools without significantly affecting ganciclovir triphosphate levels. Although hydroxyurea significantly increased the ganciclovir triphosphate:dGTP value for 12 to 24 hours in HSV-TK-expressing and bystander cells from coculture (1.4- to 4.9-fold), this value was increased for <12 hours (2.5-fold) in 100% HSV-TK-expressing cells. These data suggest that the prolonged increase in the ganciclovir triphosphate:dGTP value in cells in coculture resulted in synergistic cytotoxicity. Compared with enhancement of bystander cytotoxicity through modulation of gap junction intercellular communication, this strategy is superior because it increased cytotoxicity to both HSV-TK-expressing and bystander cells in coculture. This approach may improve clinical efficacy.

A novel mechanism of synergistic cytotoxicity with 5-fluorocytosine and ganciclovir in double suicide gene therapy.

The combination of cytosine deaminase (CD) and herpes simplex virus thymidine kinase (HSV-TK) suicide gene protocols has resulted in enhanced antitumor activity in cultured tumor cells and animal models. In this study, we show that concurrent addition of prodrugs 5-fluorocytosine (5-FC) and ganciclovir (GCV) was less efficacious than sequential treatment in human DU145 prostate carcinoma cells infected with an adenovirus containing a CD/HSV-TK fusion gene. If cells were incubated for 24 hours with 5-FC followed by a 24-hour GCV treatment, GCV triphosphate levels were 2-fold higher, incorporation of GCV monophosphate into DNA was 2.5-fold higher, and growth inhibition was increased 4-fold compared with simultaneous treatment. As expected, cellular dTTP levels were reduced during the 5-FC preincubation. However, dGTP pools also declined parallel to the dTTP decrease. Similar results were obtained when 5-fluorouracil or 5-fluoro-2'-deoxyuridine was used instead of CD/5-FC. These data allowed us to propose a novel hypothesis for the synergistic interaction between CD/5-FC and HSV-TK/GCV treatments. We suggest that the CD/5-FC-mediated reduction of dTTP results in a concurrent decrease of dGTP due to allosteric regulation of ribonucleotide reductase. Because dGTP is the endogenous competitor of GCV triphosphate, depleted dGTP at the time of GCV addition results in increased GCV in DNA and cell kill. In fact, addition of deoxyguanosine during the 5-FC incubation reverses the dGTP depletion, reduces the amount of GCV monophosphate incorporated into DNA, and prevents the CD/5-FC-mediated enhancement of HSV-TK/GCV cytotoxicity. Understanding this mechanistic interaction may help recognize better strategies for creating more efficacious clinical protocols.

Perspectives on strained intensive care unit capacity: A survey of critical care professionals.

BACKGROUND: Strained intensive care unit (ICU) capacity represents a supply-demand mismatch in ICU care. Limited data have explored health care worker (HCW) perceptions of strain. METHODS: Cross-sectional survey of HCW across 16 Alberta ICUs. A web-based questionnaire captured data on demographics, strain definition, and sources, impact and strategies for management. RESULTS: 658 HCW responded (33%; 95%CI, 32-36%), of which 452 were nurses (69%), 128 allied health (19%), 45 physicians (7%) and 33 administrators (5%). Participants (agreed/strongly agreed: 94%) reported that strain was best defined as "a time-varying imbalance between the supply of available beds, staff and/or resources and the demand to provide high-quality care for patients who may become or who are critically ill"; while some recommended defining "high-quality care", integrating "safety", and families in the definition. Participants reported significant contributors to strain were: "inability to discharge ICU patients due to lack of available ward beds" (97%); "increases in the volume" (89%); and "acuity and complexity of patients requiring ICU support" (88%). Strain was perceived to "increase stress levels in health care providers" (98%); and "burnout in health care providers" (96%). The highest ranked strategies were: "have more consistent and better goals-of-care conversations with patients/families outside of ICU" (95%); and "increase non-acute care beds" (92%). INTERPRETATION: Strain is perceived as common. HCW believe precipitants represent a mix of patient-related and operational factors. Strain is thought to have negative implications for quality of care, HCW well-being and workplace environment. Most indicated strategies "outside" of ICU settings were priorities for managing strain.

Multi-log cytotoxicity of carbocyclic 2'-deoxyguanosine in HSV-TK-expressing human tumor cells.

Ganciclovir (GCV) is widely used as a prodrug for selective activation in tumor cells expressing herpes simplex virus thymidine kinase (HSV-TK) because of its ability to induce multi-log cytotoxicity to HSV-TK-expressing as well as nonexpressing bystander cells. We now report that another substrate for HSV-TK, D-carbocyclic 2'-deoxyguanosine (CdG), induces multi-log cytotoxicity in HSV-TK-expressing and bystander cells at concentrations

Intravenous immunoglobulin for severe infections: a survey of Canadian specialists.

PURPOSE: To survey the opinions of Canadian critical care medicine and infectious disease specialists about the use of intravenous immunoglobulin (IVIG) for the treatment of severe infections. MATERIALS AND METHODS: A scenario-based, cross-sectional survey of Canadian critical care medicine and infectious disease specialists was conducted from March to June 2003. RESULTS: The response rate was 291/487 (60%). Respondents were primarily medically trained and most (241/291; 83%) were practicing in large academic referral centers. Physicians reported that they would use IVIG in patients with streptococcal toxic shock syndrome (STSS; 218/288; 76%), streptococcal necrotizing fasciitis without STSS (143/286; 50%), staphylococcal toxic shock syndrome (75/288; 26%), streptococcal soft tissue infection without NF or STSS (31/286; 11%), and septic shock due to intra-abdominal focus (9/283; 3%). The majority (> or =67%) of respondents believed that it would be ethical to randomize patients to IVIG or placebo in a clinical trial in each of the five scenarios. One third (192/286) reported that it would not be ethical to randomize patients with STSS. Canadian specialists commonly report favoring the use of IVIG to treat STSS and necrotizing fasciitis but less commonly endorse this treatment for other infections. CONCLUSION: Specialist's beliefs surrounding the efficacy of IVIG would challenge but not preclude the conduct of future placebo controlled trials of severe streptococcal infections in Canada.

Coma, metabolic acidosis, and methemoglobinemia in a patient with acetaminophen toxicity.

We present a case of early coma, metabolic acidosis and methemoglobinemia after substantial acetaminophen toxicity in the absence of hepatic failure. A 77-year-old female presented to the emergency department with a decreased level of consciousness. She was found unresponsive by a family member in her bed, and was reported to be acting normally when she was last seen eight hours earlier. Laboratory results on arrival were: pH 7.19, sodium 139 mmol/L, chloride 106 mmol/L, potassium 3.3 mmol/L, CO2 8 mmol/L, and an anion gap of 25. Both venous lactate (10.2 mmol/L) and methemoglobin (9.4 %) were elevated. The patient's acetaminophen concentration was markedly elevated at 7138 µmol/L (1078 µg/ml). Hepatic enzymes and coagulation tests were normal [alanine transaminase (ALT) 8 U/L, international normalized ratio (INR) 1.0]. Intravenous N-acetylcysteine (NAC) was initiated at a dose of 150 mg/kg over 15 minutes, followed by 50 mg/kg over the next four hours, followed by 100 mg/kg over the next 16 hours. Twenty-four hours after admission, the anion gap metabolic acidosis had resolved, and the methemoglobin was 2.1%. Aminotransferases peaked at 44 U/L and INR peaked at 1.9. A urine 5-oxoproline assay performed five days after admission was negative, suggesting no evidence of a 5-oxoprolinase deficiency. We describe the pathophysiology and discuss the literature on acetaminophen-induced coma and metabolic acidosis in the absence of hepatic injury; and propose mechanisms for associated methemoglobinemia.