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Background: Omicron is the current predominant variant of concern of SARS-CoV-2. We hypothesized that vaccination alters outcomes of patients hospitalized with COVID-19 during the Omicron wave and that these patients have different characteristics and outcomes than in previous waves. Methods: This is a substudy of the Host Response Mediators in Coronavirus (COVID-19) Infection (ARBs CORONA I) trial, which included adults admitted to hospital with acute COVID-19 up to July 2022 from 9 hospitals in British Columbia, Ontario and Quebec. We excluded emergency department visits without hospital admission, readmissions and admissions for another reason. Using adjusted regression analysis, we compared mortality and organ dysfunction between vaccinated (≥ 2 doses) and unvaccinated patients during the Omicron wave, as well as between all patients in the Omicron and first 3 waves of the COVID-19 pandemic. Results: During the Omicron wave, 28-day mortality was significantly lower in vaccinated (n = 19/237) than unvaccinated hospitalized patients (n = 12/127) (adjusted odds ratio [OR] 0.36, 95% confidence interval [CI] 0.15--0.89); vaccinated patients had lower risk of admission to the intensive care unit, invasive ventilation and acute respiratory distress syndrome and shorter hospital length of stay. Patients hospitalized during the Omicron wave had more comorbidities than in previous waves, and lower 28-day mortality than in waves 1 and 2 (adjusted OR 0.38, 95% CI 0.24--0.59; and 0.42, 95% CI 0.26--0.65) but not wave 3 (adjusted OR 0.81, 95% CI 0.43--1.51) and had less organ dysfunction than in the first 2 waves. Interpretation: Patients who were at least double vaccinated had lower mortality than unvaccinated patients hospitalized during the Omicron wave. Patients hospitalized during the Omicron wave had more chronic disease and lower mortality than in the first 2 waves, but not wave 3. Changes in vaccination, treatments and predominant SARS-CoV-2 variant may have decreased mortality in patients hospitalized during the Omicron wave. [ABSTRACT FROM AUTHOR]

Objectives There is clinical uncertainty over the optimal treatment for penicillin-susceptible Staphylococcus aureus (PSSA) infections. Furthermore, there is concern that phenotypic penicillin susceptibility testing methods are not reliably able to detect some blaZ -positive S. aureus. Methods Nine S. aureus isolates, including six genetically diverse strains harbouring blaZ , were sent in triplicate to 34 participating laboratories from Australia (n  = 14), New Zealand (n  = 6), Canada (n  = 12), Singapore (n  = 1) and Israel (n  = 1). We used blaZ PCR as the gold standard to assess susceptibility testing performance of CLSI (P10 disc) and EUCAST (P1 disc) methods. Very major errors (VMEs), major error (MEs) and categorical agreement were calculated. Results Twenty-two laboratories reported 593 results according to CLSI methodology (P10 disc). Nineteen laboratories reported 513 results according to the EUCAST (P1 disc) method. For CLSI laboratories, the categorical agreement and calculated VME and ME rates were 85% (508/593), 21% (84/396) and 1.5% (3/198), respectively. For EUCAST laboratories, the categorical agreement and calculated VME and ME rates were 93% (475/513), 11% (84/396) and 1% (3/198), respectively. Seven laboratories reported results for both methods, with VME rates of 24% for CLSI and 12% for EUCAST. Conclusions The EUCAST method with a P1 disc resulted in a lower VME rate compared with the CLSI methods with a P10 disc. These results should be considered in the context that among collections of PSSA isolates, as determined by automated MIC testing, less than 10% harbour blaZ. Furthermore, the clinical relevance of phenotypically susceptible, but blaZ -positive S. aureus , remains unclear. [ABSTRACT FROM AUTHOR]

Background: There have been multiple waves in the COVID-19 pandemic in many countries. We sought to compare mortality and respiratory, cardiovascular and renal dysfunction between waves in 3 Canadian provinces. Methods: We conducted a substudy of the ARBs CORONA I study, a multicentre Canadian pragmatic observational cohort study that examined the association of pre-existing use of angiotensin receptor blockers with outcomes in adults admitted to hospital with acute COVID-19 up to April 2021 from 9 community and teaching hospitals in 3 Canadian provinces (British Columbia, Ontario and Quebec). We excluded emergency department admissions without hospital admission, readmissions and admissions for another reason. We used logistic and 0–1-inflated β regression models to compare 28-day and in-hospital mortality, and the use of invasive mechanical ventilation, vasopressors and renal replacement therapy (RRT) between the first 3 waves of the COVID-19 pandemic in these provinces. Results: A total of 520, 572 and 245 patients in waves 1, 2 and 3, respectively, were included. Patients in wave 3 were on average younger and had fewer comorbidities than those in waves 1 and 2. The unadjusted 28-day mortality rate was significantly lower in wave 3 (7.8%) than in wave 1 (18.3%) (odds ratio [OR] 0.43, 95% confidence interval [CI] 0.24–0.78) and wave 2 (16.3%) (OR 0.46, 95% CI 0.27–0.79). After adjustment for differences in baseline characteristics, the difference in 28-day mortality remained significant (adjusted OR wave 3 v. wave 1: 0.46, 95% CI 0.26–0.81; wave 3 v. wave 2: 0.52, 95% CI 0.29–0.91). In-hospital mortality findings were similar. Use of invasive mechanical ventilation or vasopressors was less common in waves 2 and 3 than in wave 1, and use of RRT was less common in wave 3 than in wave 1. Interpretation: Severity of illness decreased (lower mortality and less use of organ support) across waves among patients admitted to hospital with acute COVID-19, possibly owing to changes in patient demographic characteristics and management, such as increased use of dexamethasone. Continued application of proven therapies may further improve outcomes. Study registration: ClinicalTrials.gov, no. NCT04510623 [ABSTRACT FROM AUTHOR]

Objectives: Severe acute respiratory syndrome-related coronavirus-2 binds and inhibits angiotensin-converting enzyme-2. The frequency of acute cardiac injury in patients with coronavirus disease 2019 is unknown. The objective was to compare the rates of cardiac injury by angiotensin-converting enzyme-2-binding viruses from viruses that do not bind to angiotensin-converting enzyme-2.Data Sources: We performed a systematic review of coronavirus disease 2019 literature on PubMed and EMBASE.Study Selection: We included studies with ten or more hospitalized adults with confirmed coronavirus disease 2019 or other viral pathogens that described the occurrence of acute cardiac injury. This was defined by the original publication authors or by: 1) myocardial ischemia, 2) new cardiac arrhythmia on echocardiogram, or 3) new or worsening heart failure on echocardiogram.Data Extraction: We compared the rates of cardiac injury among patients with respiratory infections with viruses that down-regulate angiotensin-converting enzyme-2, including H1N1, H5N1, H7N9, and severe acute respiratory syndrome-related coronavirus-1, to those with respiratory infections from other influenza viruses that do not bind angiotensin-converting enzyme-2, including Influenza H3N2 and influenza B.Data Synthesis: Of 57 studies including 34,072 patients, acute cardiac injury occurred in 50% (95% CI, 44-57%) of critically ill patients with coronavirus disease 2019. The overall risk of acute cardiac injury was 21% (95% CI, 18-26%) among hospitalized patients with coronavirus disease 2019. In comparison, 37% (95% CI, 26-49%) of critically ill patients with other respiratory viruses that bind angiotensin-converting enzyme-2 (p = 0.061) and 12% (95% CI, 7-22%) of critically ill patients with other respiratory viruses that do not bind angiotensin-converting enzyme-2 (p < 0.001) experienced a cardiac injury.Conclusions: Acute cardiac injury may be associated with whether the virus binds angiotensin-converting enzyme-2. Acute cardiac injury occurs in half of critically ill coronavirus disease 2019 patients, but only 12% of patients infected by viruses that do not bind to angiotensin-converting enzyme-2. [ABSTRACT FROM AUTHOR]

Background Severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) surrogate neutralization assays that obviate the need for viral culture offer substantial advantages regarding throughput and cost. The cPass SARS-CoV-2 Neutralization Antibody Detection Kit (GenScript) is the first such commercially available assay that detects antibodies that block receptor-binding domain (RBD)/angiotensin-converting enzyme (ACE)-2 interaction. We aimed to evaluate cPass to inform its use and assess its added value compared with anti-RBD enzyme-linked immunosorbent assays (ELISAs). Methods Serum reference panels comprising 205 specimens were used to compare cPass to plaque-reduction neutralization test (PRNT) and a pseudotyped lentiviral neutralization (PLV) assay for detection of neutralizing antibodies. We assessed the correlation of cPass with an ELISA detecting anti-RBD immunoglobulin (Ig)G, IgM, and IgA antibodies at a single timepoint and across intervals from onset of symptoms of SARS-CoV-2 infection. Results Compared with PRNT-50, cPass sensitivity ranged from 77% to 100% and specificity was 95% to 100%. Sensitivity was also high compared with the pseudotyped lentiviral neutralization assay (93%; 95% confidence interval [CI], 85–97), but specificity was lower (58%; 95% CI, 48–67). Highest agreement between cPass and ELISA was for anti-RBD IgG (r = 0.823). Against the pseudotyped lentiviral neutralization assay, anti-RBD IgG sensitivity (99%; 95% CI, 94–100) was very similar to that of cPass, but overall specificity was lower (37%; 95% CI, 28–47). Against PRNT-50, results of cPass and anti-RBD IgG were nearly identical. Conclusions The added value of cPass compared with an IgG anti-RBD ELISA was modest. [ABSTRACT FROM AUTHOR]

Background Bloodstream infections (BSIs) with methicillin-susceptible Staphylococcus aureus (MSSA) are associated with significant morbidity and mortality. Our objective in this study was to determine the efficacy of synergistic treatment with daptomycin when given with either cefazolin or cloxacillin for the treatment of MSSA BSI. Methods A randomized, double-blind, placebo-controlled trial was performed at 2 academic hospitals in Montreal, Canada. Patients aged ≥18 years with MSSA BSI receiving either cefazolin or cloxacillin monotherapy were considered for inclusion. In addition to the standard-of-care treatment, participants received a 5-day course of adjunctive daptomycin or placebo. The primary outcome was the duration of MSSA BSI in days. Results Of 318 participants screened, 115 were enrolled and 104 were included in the intention-to-treat analysis (median age, 67 years; 34.5% female). The median duration of bacteremia was 2.04 days among patients who received daptomycin vs 1.65 days in those who received placebo (absolute difference, 0.39 days; P  = .40). In a modified intention-to-treat analysis that involved participants who remained bacteremic at the time of enrollment, we found a median duration of bacteremia of 3.06 days among patients who received daptomycin vs 3.0 days in those who received placebo (absolute difference, 0.06 days; P  = .77). Ninety-day mortality in the daptomycin arm was 18.9% vs 17.7% in the placebo arm (P  = 1.0). Conclusions Among patients with MSSA BSIs, the administration of adjunctive daptomycin therapy to standard-of-care treatment did not shorten the duration of bacteremia and should not be routinely considered. Clinical Trials Registration NCT02972983. [ABSTRACT FROM AUTHOR]

Background The effect of participation in a clinical trial on concomitant off-study investigational drug use has not been described. We sought to determine if participation in the Daptomycin as Adjunctive Therapy for Staphylococcus aureus bacteremia (DASH) trial increased overall daptomycin prescribing at study sites. Methods We retrospectively analyzed daptomycin use for 8 years preceding the trial, off-study daptomycin use during the trial itself (31 months), and daptomycin use for 6 fiscal months after trial completion. We used a segmented linear regression analysis of an interrupted time series to analyze changes in each drug's defined daily doses (DDD) per 1000 patient-days. As a control, we analyzed use of linezolid over these periods and also accounted for rates of methicillin-resistant S. aureus (MRSA) and vancomycin-resistant Enterococcus (VRE) infections. Results For 1.5 years before the DASH trial, daptomycin use was decreasing by –0.30 DDD per 1000 patient-days per fiscal period (95% CI, –0.52 to –0.07). Following the initiation of the study, there was a statistically significant increase in daptomycin use of 0.28 DDD per 1000 patient-days per fiscal period (95% CI, 0.03 to 0.52), despite low, stable rates of MRSA and VRE infections. Following trial completion, daptomycin use decreased back toward prestudy rates. Use of linezolid remained stable throughout. Conclusions Despite the DASH trial being a negative study, it impacted the prescribing habits of local clinicians during recruitment. Trialists should be aware of potential off-target study effects, and prescribers should be wary of early uptake of interventions before definitive study results. [ABSTRACT FROM AUTHOR]

Accurate serologic tests to detect host antibodies to severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) will be critical for the public health response to the coronavirus disease 2019 pandemic. Many use cases are envisaged, including complementing molecular methods for diagnosis of active disease and estimating immunity for individuals. At the population level, carefully designed seroepidemiologic studies will aid in the characterization of transmission dynamics and refinement of disease burden estimates and will provide insight into the kinetics of humoral immunity. Yet, despite an explosion in the number and availability of serologic assays to test for antibodies against SARS-CoV-2, most have undergone minimal external validation to date. This hinders assay selection and implementation, as well as interpretation of study results. In addition, critical knowledge gaps remain regarding serologic correlates of protection from infection or disease, and the degree to which these assays cross-react with antibodies against related coronaviruses. This article discusses key use cases for SARS-CoV-2 antibody detection tests and their application to serologic studies, reviews currently available assays, highlights key areas of ongoing research, and proposes potential strategies for test implementation. [ABSTRACT FROM AUTHOR]

Diagnostic testing to identify persons infected with severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) infection is central to control the global pandemic of COVID-19 that began in late 2019. In a few countries, the use of diagnostic testing on a massive scale has been a cornerstone of successful containment strategies. In contrast, the United States, hampered by limited testing capacity, has prioritized testing for specific groups of persons. Real-time reverse transcriptase polymerase chain reaction-based assays performed in a laboratory on respiratory specimens are the reference standard for COVID-19 diagnostics. However, point-of-care technologies and serologic immunoassays are rapidly emerging. Although excellent tools exist for the diagnosis of symptomatic patients in well-equipped laboratories, important gaps remain in screening asymptomatic persons in the incubation phase, as well as in the accurate determination of live viral shedding during convalescence to inform decisions to end isolation. Many affluent countries have encountered challenges in test delivery and specimen collection that have inhibited rapid increases in testing capacity. These challenges may be even greater in low-resource settings. Urgent clinical and public health needs currently drive an unprecedented global effort to increase testing capacity for SARS-CoV-2 infection. Here, the authors review the current array of tests for SARS-CoV-2, highlight gaps in current diagnostic capacity, and propose potential solutions. [ABSTRACT FROM AUTHOR]

Diagnostic testing to identify persons infected with severe acute respiratory syndrome–related coronavirus 2 (SARS-CoV-2) infection is central to control the global pandemic of COVID-19 that began in late 2019. In a few countries, the use of diagnostic testing on a massive scale has been a cornerstone of successful containment strategies. In contrast, the United States, hampered by limited testing capacity, has prioritized testing for specific groups of persons. Real-time reverse transcriptase polymerase chain reaction–based assays performed in a laboratory on respiratory specimens are the reference standard for COVID-19 diagnostics. However, point-of-care technologies and serologic immunoassays are rapidly emerging. Although excellent tools exist for the diagnosis of symptomatic patients in well-equipped laboratories, important gaps remain in screening asymptomatic persons in the incubation phase, as well as in the accurate determination of live viral shedding during convalescence to inform decisions to end isolation. Many affluent countries have encountered challenges in test delivery and specimen collection that have inhibited rapid increases in testing capacity. These challenges may be even greater in low-resource settings. Urgent clinical and public health needs currently drive an unprecedented global effort to increase testing capacity for SARS-CoV-2 infection. Here, the authors review the current array of tests for SARS-CoV-2, highlight gaps in current diagnostic capacity, and propose potential solutions. Diagnostic testing to identify infected persons is central to efforts to control the COVID-19 pandemic. This review synthesizes current knowledge of diagnostic options available to clinicians, highlights key gaps in current diagnostic capacity, and discusses potential solutions. [ABSTRACT FROM AUTHOR]

Summary: In a 3‐year cohort study of adult patients with proven or probable IA, fewer patients initially treated with isavuconazole experienced adverse events compared with voriconazole, but more patients required a change in therapy due to lack of clinical efficacy. [ABSTRACT FROM AUTHOR]

Background: Administering antimicrobial agents before obtaining blood cultures could potentially decrease time to treatment and improve outcomes, but it is unclear how this strategy affects diagnostic sensitivity.Objective: To determine the sensitivity of blood cultures obtained shortly after initiation of antimicrobial therapy in patients with severe manifestations of sepsis.Design: Patient-level, single-group, diagnostic study. (ClinicalTrials.gov: NCT01867905).Setting: 7 emergency departments in North America.Participants: Adults with severe manifestations of sepsis, including systolic blood pressure less than 90 mm Hg or a serum lactate level of 4 mmol/L or more.Intervention: Blood cultures were obtained before and within 120 minutes after initiation of antimicrobial treatment.Measurements: Sensitivity of blood cultures obtained after initiation of antimicrobial therapy.Results: Of 3164 participants screened, 325 were included in the study (mean age, 65.6 years; 62.8% men) and had repeated blood cultures drawn after initiation of antimicrobial therapy (median time, 70 minutes [interquartile range, 50 to 110 minutes]). Preantimicrobial blood cultures were positive for 1 or more microbial pathogens in 102 of 325 (31.4%) patients. Postantimicrobial blood cultures were positive for 1 or more microbial pathogens in 63 of 325 (19.4%) patients. The absolute difference in the proportion of positive blood cultures between pre- and postantimicrobial testing was 12.0% (95% CI, 5.4% to 18.6%; P < 0.001). Sensitivity of postantimicrobial culture was 52.9% (CI, 42.8% to 62.9%). When the results of other microbiological cultures were included, microbial pathogens were found in 69 of 102 (67.6% [CI, 57.7% to 76.6%]) patients.Limitation: Only a proportion of screened patients were recruited.Conclusion: Among patients with severe manifestations of sepsis, initiation of empirical antimicrobial therapy significantly reduces the sensitivity of blood cultures drawn shortly after treatment initiation.Primary Funding Source: Vancouver Coastal Health, St. Paul's Hospital Foundation Emergency Department Support Fund, the Fonds de recherche Santé-Québec, and the Maricopa Medical Foundation. [ABSTRACT FROM AUTHOR]

There were no cases of tuberculosis in a cohort of 2531 patients who underwent hematopoietic cell transplantation from 2010 to 2015 after 7323 person-years of follow up (95% confidence interval [CI], 0.0–0.05 cases/100 person-years), including 29 (1.15%) patients with untreated latent tuberculosis after 89 person-years of follow-up (95% CI, 0.0–4.06 cases/100 person-years). [ABSTRACT FROM AUTHOR]

Allogeneic hematopoietic cell transplantation (HCT) recipients are at increased risk for varicella zoster virus (VZV) reactivation and associated complications. The incidence, timing, and risk factors for severe herpes zoster (HZ) are not well described in the era of acyclovir (ACV) prophylaxis. We performed a retrospective cohort study of all patients who underwent first allogeneic HCT between October 2006 and December 2015 at our institution. Patients were followed until December 2017 for the development of severe HZ, defined as necessitating administration of i.v. antiviral medication. Out of 2163 patients who underwent allogeneic HCT, 22 (1.0%) developed severe HZ at a rate of 1 per 228 person-years, including dermatomal/multidermatomal disease (n = 5), disseminated skin disease (n = 5), HZ ophthalmicus (n = 4), meningitis/encephalitis (n = 4), pneumonia (n = 2), viremia (n = 1), and erythema multiforme (n = 1). Severe HZ infection occurred in a bimodal distribution during the early peri-HCT period and at 12 to 24 months post-HCT (median, 12.7 months). Twelve patients (54.5%) were compliant with ACV prophylaxis at the time of HZ diagnosis. Eleven patients (50%) died during the study period, only 2 of whom (9.1%) with active VZV infection. Mortality was higher in patients on immunosuppressive therapy (62.5% versus 16.7%; P =.045) and with concurrent graft-versus-host disease (75.0% versus 35.7%; P =.044). These data suggest that severe HZ remains an important consideration despite ACV prophylaxis. [ABSTRACT FROM AUTHOR]

Background: Hepatitis B is a viral infection requiring specific serologic testing to diagnose the stage of the disease. There are many tests which can be ordered in a variety of combinations. This study aimed to assess routine Hepatitis B screening practices in a tertiary care centre and determine the diagnostic and economic benefits of protocolized ordering. Methods: We evaluated all measurements of Hepatitis B total core antibodies, core IgM antibodies, surface antibodies and surface antigens performed at our institution between January 1, 2015 and December 31, 2015. We also recorded secondary testing (envelope antigens and antibodies, and viral DNA). Costs were estimated using provincial insurance reimbursement values. Using the subset of patients who received complete testing, we developed a reflexive screening protocol to minimize costs while simultaneously improving diagnostic utility. Results: 30,335 hepatitis B tests were performed at an estimated total cost of $584,683. 53.9% of patients were screened with a single test. 29% of patients who received secondary testing had no evidence of exposure on primary testing. Using the protocol of initial testing of total core antibody and surface antibody with reflexive testing, we would save an estimated $181,632 (95% CI $154,201.90 –$208,910.50) per year while providing more complete information. Interpretation: Screening practices for Hepatitis B are frequently inadequate to diagnose and stage the infection and often included unnecessary testing. Protocolization of Hepatitis B testing could limit this practice while resulting in significantly lower costs. [ABSTRACT FROM AUTHOR]

The article focuses on the use of isavuconazole, which has drug-drug interactions in comparison to azole antifungals for invasive fungal disease in patients under the drug administration of Ibrutinib. It discusses the importance of B-cell-receptor (BCR) signaling pathway in the context of cancer-cell survival and chronic lymphocytic leukemia (CLL) and marginal zone lymphoma (MZL).

Introduction and objective: Diagnostic testing for Clostridioides difficile infection (CDI) by nucleic acid amplification test (NAAT) cannot distinguish between colonization and infection. A positive NAAT may therefore represent a false positive for infection, since diarrhea due to various aetiologies may occur in hospitalized patients. Our objective was to help answer the question: “does this medical inpatient with diarrhea have CDI?” Design: We conducted a retrospective cohort study (n = 248) on the Clinical Teaching Units of the Royal Victoria Hospital (Montréal, Canada). Patients were included if they had a NAAT between January 2014 and September 2015 and their admission diagnosis was not CDI. CDI cases and non-CDI cases were compared, and independent predictors of CDI were determined by logistic regression. Results: Several factors were independently associated with CDI, including: hemodialysis (OR: 13.5, 95% CI: 2.85–63.8), atrial fibrillation (OR: 3.70, 95% CI: 1.52–9.01), whether the patient received empiric treatment (OR: 3.01, 95% CI: 1.04–8.68), systemic antibiotic therapy prior to testing (OR: 4.23, 95% CI: 1.71–10.5), previous positive NAAT (OR: 3.70, 95% CI: 1.41–9.72), and a leukocyte count of 11x109/L or higher (OR: 3.43, 95% CI: 1.42–8.26). The area under the curve was 0.80. Conclusion: For patients presenting with hospital-onset diarrhea, various parameters can help differentiate between CDI and other causes. A clinical prediction calculator derived from our cohort () might assist clinicians in estimating the risk of CDI for inpatients; those with low pre-test probability may not require immediate testing, treatment, nor prolonged isolation. [ABSTRACT FROM AUTHOR]

When faced with a new and therefore frightening disease such as coronavirus disease 2019 (COVID-19), and given concerns over a potentially high case fatality rate, clinicians and patients will be strongly compelled to try unproven therapies. As the number of severely ill patients with coronavirus disease 2019 (COVID-19) continues to increase, we must learn as much as possible about this disease, as quickly as possible, to inform patient care. [Extracted from the article]

In multivariable analysis of associations between initial antibiotic therapy and clinical outcomes in 5005 patients with microbiologically confirmed Streptococcus pneumoniae infections,"discordant" empiric antibiotic therapy was not associated with 30-day mortality rate (hazard ratio, 0.94; 95% confidence interval, .67-1.32). [ABSTRACT FROM AUTHOR]

Background. Cancer is a known risk factor for developing active tuberculosis. We determined the incidence and relative risk of active tuberculosis in cancer patients compared to the general population. Methods. Medline, Medline InProcess, EMBASE, PubMed, the Cochrane Database of Systematic Reviews, Cancerlit, and Web of Science were searched up to December 1, 2015. Studies of pathologically confirmed cancer cases were included if active tuberculosis was identified concurrently or after diagnosis. Cumulative incidence rate/100 000 population (CIR) of new cases of tuberculosis occurring in cancer patients and comparative incidence rate ratios (IRRs) to the general population from the same country of origin were estimated. A random effect meta-analysis was conducted on the CIR and IRR. Results. A total of 23 studies reporting 593 tuberculosis cases occurring in 324 041 cancer patients between 1950 and 2011 were identified. In a meta-analysis of 6 studies conducted in the United States in 317 243 cancer patients (98% of all patients), the CIR of tuberculosis decreased by 3-fold and 6.5-fold in hematologic and solid cancers, respectively, before and after 1980. After 1980 the CIR of tuberculosis was highest in hematologic (219/100 000 population; IRR = 26), head and neck (143; 16), lung cancers (83; 9) and was lowest in breast and other solid cancers (38; 4). Conclusions. Individuals living in the United States with hematologic, head and neck, and lung cancers had a 9-fold higher rate of developing active tuberculosis compared to those without cancer and would benefit from targeted latent tuberculosis screening and therapy. [ABSTRACT FROM AUTHOR]

The article presents a study which explores the low risk of Pneumocystis jirovecii pneumonia and invasive aspergillosis in patients with Waldenstr€om macroglobulinaemia (WM). It discussed the association of WM with the activation of nuclear factor-jB via Bruton tyrosine kinase (BTK), which is U.S. Food and Drug Administration-approved for the treatment of chronic lymphocytic leukaemia (CLL), mantle cell lymphoma, and marginal zone lymphoma.

Background: There are increasing data regarding Terrisporobacter glycolicus as an emerging anaerobic pathogen. However, the few published cases to date usually report it as part of a polymicrobial infection. Here, we describe the first reported monomicrobial surgical site infection with this bacterium. Identification methods, taxonomy, and clinical management of this rarely identified pathogen are also discussed. Case presentation: A previously healthy 66-year-old sustained an open olecranon fracture of his left arm after trauma. He subsequently underwent open reduction and internal fixation (ORIF), with insertion of an olecranon locking plate and two locking screws. Ten days after surgery, the patient developed increasing pain at the surgical site and noted green discharge from the wound. Culture of the wound discharge yielded grew a pure Grampositive anaerobe identified by the RapidANA® microbial identification system as C. difficile (profile 000010, 99.1 % probability). Reference laboratory testing identified the isolate as T. glycolicus/mayombei (previously designated as Clostridium glycolicum/mayombei) by 16S rRNA gene sequencing and as Clostridium glycolicum by MALDI-TOF mass spectrometry. The patient received an 8-week course of moxifloxacin and metronidazole with an excellent clinical response at 12 months' follow-up. Conclusions: We describe the case of a deep surgical site infection with T. glycolicus/mayombei (formerly known as Clostridium glycolicum and Clostridium mayombei, respectively), which extends our knowledge of the clinical spectrum of this pathogen. The isolate was misidentified by phenotypic identification methods. [ABSTRACT FROM AUTHOR]

Background: The immunological literature has been redefining clinical phenomena as hypotheses emerge regarding causal links between triggers, immunologic manifestations, and their specific inflammatory cascades. Of late, autoimmune manifestations that appear to be caused by an external adjuvant have been grouped into a complex syndrome referred to as autoimmune/inflammatory syndrome induced by adjuvants (ASIA). This syndrome may present with diverse clinical problems, which may include neurocognitive impairment, inflammatory musculoskeletal changes, and constitutional symptoms. There is evidence in the literature linking vaccines to different auto-immune manifestations. Vaccines have not traditionally been reported to trigger ASIA, although reports are emerging linking the human papilloma virus and hepatitis B vaccines to it. Case presentation: We report the first suspected case of ASIA in a previously healthy patient who received the Fluad seasonal influenza vaccine, which contains the MF59 adjuvant. He presented to hospital with profound weakness and was diagnosed with severe rhabdomyolysis. He also had elevated troponin-I and extensive cardiac investigations enabled the diagnosis of myocarditis. His infectious and rheumatologic work-ups were negative. He responded well to conservative management and did not require immune suppressive therapy. Conclusion: Given the benefits of the influenza vaccine, and the low incidence of clinically significant complications, we encourage ongoing seasonal influenza immunization. However, ongoing surveillance is required to evaluate the occurrence of rare adverse events, including ASIA. [ABSTRACT FROM AUTHOR]

Background Staphylococcus aureus bloodstream infection (bacteremia) is traditionally treated with at least 2 weeks of intravenous (IV) antibiotics in adults, 3–7 days in children, and often longer for those with complicated disease. The current practice of treating S. aureus bacteremia (SAB) with prolonged IV antibiotics (rather than oral antibiotics) is based on historical observational research and expert opinion. Prolonged IV antibiotic therapy has significant disadvantages for patients and healthcare systems, and there is growing interest in whether a switch to oral antibiotics following an initial period of IV therapy is a safe alternative for clinically stable patients. Protocol The early oral switch (EOS) domain of the S. aureus Network Adaptive Platform (SNAP) trial will assess early switch to oral antibiotics compared with continued IV treatment in clinically stable patients with SAB. The primary endpoint is 90-day all-cause mortality. Hospitalised SAB patients are assessed at platform day 7 ±2 (uncomplicated SAB) and day 14 ±2 (complicated SAB) to determine their eligibility for randomization to EOS (intervention) or continued IV treatment (current standard of care). Discussion Recruitment is occurring in the EOS domain of the SNAP trial. As of August 2023, 21% of all SNAP participants had been randomized to the EOS domain, a total of 264 participants across 77 centers, with an aim to recruit at least 1000 participants. We describe challenges and facilitators to enrolment in this domain to aid those planning similar trials. [ABSTRACT FROM AUTHOR]

Background: Widespread penicillin usage rapidly resulted in the emergence of penicillin resistance in Staphylococcus aureus. However, new data suggest that penicillin susceptibility may be in a period of renaissance. The objective of our study was to quantify penicillin resistance in methicillin-susceptible Staphylococcus aureus (MSSA) bacteremia.Methods: We retrospectively reviewed all adult MSSA bacteremia from April 2010 to April 2015 at the McGill University Health Centre (Montreal, QC, Canada). Susceptibility to penicillin, erythromycin, clindamycin, and trimethoprim-sulfamethoxazole (TMP-SMX) was determined in accordance with the Clinical & Laboratory Standards Institute guidelines.Results: There were 324 unique episodes of MSSA bacteremia. Ninety (28%) isolates were susceptible to penicillin, 229 (71%) to erythromycin, 239 (74%) to clindamycin, and 317 (98%) to TMP-SMX. Isolates that were penicillin resistant were more likely to also be resistant to other antibiotics, but a statistically significant association was apparent only for erythromycin resistance (76/234, 32.2% vs 19/90, 21.1%, P = .04). The median age of patients was 67.5 years (interquartile range 52-78) and overall in-hospital 30-day mortality was 16.3% (53 deaths). After adjustment for patient age, there was no association between penicillin resistance and either intensive care unit admission or death.Conclusion: More than one-quarter of patients with MSSA bacteremia potentially could be treated with parenteral penicillin, which may offer pharmacokinetic advantages over other beta-lactam drugs and potentially improved outcomes. [ABSTRACT FROM AUTHOR]

Yamamoto and Okamoto question whether the decreased sensitivity of postantimicrobial blood cultures described in our study may partially be attributable to the fact that 2 of 7 participating institutions obtained only 1 postantimicrobial blood culture set. In a sensitivity analysis of 238 patients who had an equal volume of blood drawn before and after the initiation of antimicrobial therapy, 33.6% of preantimicrobial blood cultures were positive compared with 19.3% of postantimicrobial cultures (absolute difference, 14.3% [95% CI, 6.5% to 22.1%]). [Extracted from the article]

Background Current guidelines recommend obtaining blood cultures prior to antimicrobial therapy in patients with sepsis. Administering antimicrobials immediately without waiting for blood cultures could potentially decrease time to treatment and improve outcomes, but it is unclear the degree to which this strategy impacts diagnostic yield. Methods We performed a patient-level, single-arm, diagnostic trial. Seven urban emergency departments affiliated with academic medical centers across Canada and the United States participated in the study. Adults ≥18 years of age presenting to the emergency department with evidence of severe manifestations of sepsis, including a systolic blood pressure <90 mmHg and/or a serum lactate ≥4 mmol/L were included. Study participants had 2 sets of blood cultures drawn prior to and immediately following antimicrobial administration. The primary outcome was the difference in blood culture pathogen recovery rates before and after administration of antimicrobial therapy. Results Of the 3,164 participants screened, 325 were included in the study (mean age, 65.6 years; 63.0% men) and had repeat blood cultures drawn after the initiation of antimicrobial therapy (median time of 70 minutes, IQR 50 to 110 minutes). Pre-antimicrobial blood cultures were positive for one or more microbial pathogens in 102/325 (31.4%) patients. Fifty-four participants (52.9%) had matching blood culture results after initiation of antimicrobial treatment. The absolute difference in pathogen recovery rates was 14.5% ([95% CI 8.0 to 21.0%]; P < 0.0001) between pre- and post-antimicrobial blood cultures. Results were consistent in an analysis of the per-protocol population (absolute difference, 13.3% [95% CI 6.1 to 20.4%]; P < 0.0001). Including the results of other microbiological cultures done as part of routine care, microbial pathogens were recovered in 69 of 102 (67.7%) participants (absolute difference, 10.2% [95% CI 3.4 to 16.8%]; P < 0.0001). Conclusion Among patients with severe manifestations of sepsis, the administration of empiric antimicrobial therapy significantly reduces the yield of pathogen recovery when blood cultures are drawn shortly after treatment initiation. Disclosures All Authors: No reported Disclosures. [ABSTRACT FROM AUTHOR]

Excluding pregnant people from Covid‐19 clinical trials may lead to unintended harmful consequences. For this study, an online questionnaire was sent to physicians belonging to Canadian professional medical associations in order to evaluate their perspectives on the participation of pregnant women in Covid‐19 clinical trials. The majority of respondents expressed support for including pregnant women in Covid‐19 trials (119/165; 72%), especially those investigating therapies with a prior safety record in pregnancy (139/164; 85%). The main perceived barriers to inclusion identified were unwillingness of pregnant patients to participate and of treating teams to offer participation, the burden of regulatory approval, and a general "culture of exclusion" of pregnant women from trials. We describe why some physicians may be reluctant to include pregnant individuals in trials, and we identify barriers to the appropriate participation of pregnant people in clinical research. [ABSTRACT FROM AUTHOR]

Letermovir is approved for the prevention of cytomegalovirus (CMV) reactivation and clinical disease in patients undergoing allogeneic hematopoietic‐cell transplantation (HCT). However, there is uncertainty about letermovir's ability to prevent clinical events during the period of prophylaxis as well as after the discontinuation of prophylaxis in the post‐transplant setting. We performed a retrospective cohort study in CMV‐seropositive allogeneic HCT recipients at high risk of CMV events, who received letermovir for primary prophylaxis from November 2017 through December 2019. We analyzed CMV outcomes for these patients during and after prophylaxis was discontinued. Patient outcomes were followed through June 2020. Sixty patients received letermovir for a median of 13 weeks (range, 1‐72 weeks). Thirteen (22%) patients had quantifiable CMV DNAemia (reactivation) during letermovir prophylaxis a median of 9 days (range, 1‐59 days) after starting letermovir. Five (8%) of these patients discontinued prophylaxis and received preemptive therapy (PET) with valganciclovir; eight (13%) continued letermovir as prophylaxis and CMV DNAemia resolved without PET. Thirteen patients (22%) had post‐prophylaxis CMV reactivation a median of 33 days (range, 14‐109 days) after letermovir discontinuation. In four (7%) of these patients, CMV DNAemia resolved without PET, and nine (15%) received PET. No patient developed CMV disease. Patients who developed CMV reactivation during prophylaxis did so shortly after initiation of letermovir, and most patients who developed CMV reactivation post‐prophylaxis did so within 60 days after discontinuation of letermovir. Letermovir prophylaxis has changed the presentation of CMV infection in high‐risk HCT patients. [ABSTRACT FROM AUTHOR]

Background Rhinosinusitis, malignant otitis externa, and skull base osteomyelitis represent a spectrum of cranial invasive fungal disease (IFD). These syndromes have distinct characteristics, yet they may progress to involve similar structures, resulting in inflammation and invasion of the adjacent internal carotid artery (ICA). Invasive fungal carotiditis can have devastating consequences, including cerebral infarction, subarachnoid hemorrhage, and death. Methods We retrospectively studied all patients diagnosed with cranial IFD and carotid involvement at our institution from 2003 to 2018. We also searched Medline/PubMed for reports of Aspergillus or Mucorales cranial infections with ICA involvement. All cases with mycologic evidence of cranial IFD and radiographic or pathologic evidence of ICA involvement were included. Results We identified 78 cases of invasive fungal carotiditis between 1958 and 2018, including 4 cases at our own institution. Forty-one were caused by Aspergillus and 37 by Mucorales species. Presenting symptoms included vision changes (73%), cranial nerve palsy (69%), and headache (42%). Carotid events included occlusion, aneurysm formation, and vessel rupture. Cerebral infarcts occurred in 50% of cases. Mortality at 6 weeks, 12 weeks, and 2 years was 27%, 41%, and 71% respectively. The median time from symptom onset to death was 150 days for cases due to Aspergillus and 51 days for cases due to Mucorales species. Conclusions Invasive fungal carotiditis is a rare but morbid manifestation of cranial IFD. Early suspicion of IFD and administration of antifungal treatment, vascular imaging, and endovascular interventions should be considered to reduce the high mortality of this disease. [ABSTRACT FROM AUTHOR]

The optimal treatment for potential AmpC-producing Enterobacteriaceae , including Serratia, Providencia, Citrobacter, Enterobacter , and Morganella species, remains unknown. An updated systematic review and meta-analysis of studies comparing beta-lactam/beta-lactamase inhibitors with carbapenems in the treatment of bloodstream infections with these pathogens found no significant difference in 30-day mortality (OR, 1.13; 95% CI, 0.58 – 2.20). [ABSTRACT FROM AUTHOR]

Background and Objectives: In this proof‐of‐concept study, which included blood donor samples, we aimed to demonstrate how Bayesian latent class models (BLCMs) could be used to estimate SARS‐CoV‐2 seroprevalence in the absence of a gold standard assay under a two‐phase sampling design. Materials and Methods: To this end, 6810 plasma samples from blood donors who resided in Québec (Canada) were collected from May to July 2020 and tested for anti‐SARS‐CoV‐2 antibodies using seven serological assays (five commercial and two non‐commercial). Results: SARS‐CoV‐2 seroprevalence was estimated at 0.71% (95% credible interval [CrI] = 0.53%–0.92%). The cPass assay had the lowest sensitivity estimate (88.7%; 95% CrI = 80.6%–94.7%), while the Héma‐Québec assay had the highest (98.7%; 95% CrI = 97.0%–99.6%). Conclusion: The estimated low seroprevalence (which indicates a relatively limited spread of SARS‐CoV‐2 in Quebec) might change rapidly—and this tool, developed using blood donors, could enable a rapid update of the prevalence estimate in the absence of a gold standard. Further, the present analysis illustrates how a two‐stage BLCM sampling design, along with blood donor samples, can be used to estimate the performance of new diagnostic tests and inform public health decisions regarding a new or emerging disease for which a perfect reference standard does not exist. [ABSTRACT FROM AUTHOR]

Background: Double carbapenem therapy has been promoted as an alternative treatment for infections due to carbapenemase-producing Enterobacteriaceae where carbapenemase inhibitors are unavailable or when other agents have demonstrated toxicity with equally limited evidence. The capacity of other β-lactams and β-lactamase inhibitors to provide synergistic activity with carbapenems is unclear.Objectives: This study sought to investigate the in vitro synergistic potential of other β-lactam/β-lactamase combinations with meropenem against KPC producers.Methods: Time-kill assays were performed on 24 unique strains of KPC-producing Klebsiella pneumoniae. Combinations evaluated included meropenem or imipenem with one of the following: ertapenem, piperacillin/tazobactam or ceftolozane/tazobactam. Concentrations used for each drug were those considered physiologically attainable in patients with a time above the concentration exceeding 40%-50% of the dose interval. Combinations were considered to be synergistic when they reduced bacterial cfu/mL by ≥2 log10 at 24 h as compared with the single most active agent.Results: The combination of piperacillin/tazobactam with meropenem was found to be synergistic against 70.8% of the isolates, followed by ertapenem with meropenem (58.3%) and ceftolozane/tazobactam with meropenem (41.7%). The piperacillin/tazobactam combination was found to be more bactericidal than the other combinations, with 58.3% of isolates demonstrating a ≥4 log10 cfu/mL reduction at 24 h, as compared with 37.5% for ertapenem and 20.8% for ceftolozane/tazobactam combinations.Conclusions: The combination of piperacillin/tazobactam with meropenem may be a potential therapy against KPC-producing K. pneumoniae when other therapies are unavailable or prohibitively toxic. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "Efficacy of oral vancomycin in preventing recurrent Clostridium difficile infection in patients treated with systemic antimicrobial agents" by N.W. Van Hise and others, published in a 2016 issue.

Background: Consideration to add empiric MRSA therapy with vancomycin is a common clinical dilemma. However, vancomycin overuse has important adverse events. MRSA colonization screening is commonly performed for infection control. We hypothesized that in cases of S. aureus bacteremia, a score based on patient level factors and MRSA colonization could predict the risk of MRSA infection and inform the need for empiric coverage.Methods: Using modern machine learning statistical methods (LASSO regression and random forests), we designed a predictive score for MRSA infection based on patient level characteristics, and MRSA colonization as measured by screening done 30 days before infection (30-Day criteria), or at any time before infection (Ever-Positive criteria). Patient factors (age, sex, number of previous admissions, and other medical comorbidities) were obtained through our electronic records.Results: With random forests, MRSA colonization largely surpassed all other factors in terms of accuracy and discriminatory power. Using LASSO regression, MRSA colonization was the only factor with MRSA infection predictive power with odds ratio of 10.3 (min: 5.99, max: 16.1) and 8.14 (min: 6.01, max: 14.8) for the 30-Day and Ever-Positive criteria, respectively. Further, patient comorbidities were not adequate predictors of MRSA colonization.Conclusions: In an era of community acquired MRSA, colonization status appears to be the only independent and reliable predictor of MRSA infection in cases of S. aureus bacteremia. A clinical approach based on a patient's known MRSA colonization status and on local susceptibility patterns may be appropriate. [ABSTRACT FROM AUTHOR]

Background: Staphylococcus aureus bacteremia is associated with significant morbidity and mortality. To treat this infection, the current standard of care includes intravenous anti-staphylococcal beta-lactam antibiotics and obtaining adequate source control. Combination therapy with an aminoglycoside or rifampin, despite early promise, can no longer be routinely recommended due to an absence of proven benefit and risk of harm. Daptomycin is a rapidly acting bactericidal antibiotic that is approved for the treatment of Staphylococcus aureus bacteremia as monotherapy but has not been shown to be superior to the current standard of care. As demonstrated in vitro, the addition of daptomycin to beta-lactam therapy may result in enhanced anti-staphylococcal activity. Our objective is to assess the efficacy and safety of prescribing the combination of daptomycin with cefazolin or cloxacillin for the treatment of methicillin-susceptible Staphylococcus aureus (MSSA) bacteremia in adults. We hypothesize that adjunctive therapy with daptomycin will reduce the duration of bacteremia in this population.Methods: The DASH-RCT trial is a randomized, double blind, placebo-controlled trial designed per the Standard Protocol Items: Recommendation for Interventional Trials (SPIRIT) and Consolidated Standards of Reporting Trials (CONSORT) guidelines. We recruit adults with confirmed MSSA bacteremia, at the McGill University Health Center. Patients are eligible if they are 18 years or older, can receive cefazolin or cloxacillin monotherapy, and are enrolled within 72 h of the first blood culture being drawn. Exclusion criteria include anaphylaxis to study drugs, having polymicrobial bacteremia, anticipated hospital admission for < 5 days, and healthcare team refusal. While receiving standard of care, study patients are randomized to a 5-day course of adjunctive daptomycin or placebo. The trial began in December 2016 and is expected to end in December 2018, after recruiting an estimated 102 patients.Discussion: The DASH-RCT will compare the use of daptomycin as an adjunct to an anti-staphylococcal beta-lactam versus placebo in the treatment of MSSA bacteremia. We believe that a short course of dual therapy will result in earlier eradication of bacteremia and that subsequent research could evaluate effects on metastatic infection, relapse, and/or mortality. Ongoing issues in the trial include a delay between presentation of infection, enrollment in the trial, and the potential for unrecognized deep foci of infection at diagnosis.Trial Registration: ClinicalTrials.gov, NCT02972983 . Registered on 25 November 2016. Trial protocol: http://individual.utoronto.ca/leet/dash/dashprotocol.pdf. [ABSTRACT FROM AUTHOR]

Viral respiratory tract infections (VRTI) are extremely common. Considering the profound social and economic impact of COVID-19, it is imperative to identify novel mechanisms for early detection and prevention of VRTIs, to prevent future pandemics. Wearable biosensor technology may facilitate this. Early asymptomatic detection of VRTIs could reduce stress on the healthcare system by reducing transmission and decreasing the overall number of cases. The aim of the current study is to define a sensitive set of physiological and immunological signature patterns of VRTI through machine learning (ML) to analyze physiological data collected continuously using wearable vital signs sensors. A controlled, prospective longitudinal study with an induced low grade viral challenge, coupled with 12 days of continuous wearable biosensors monitoring surrounding viral induction. We aim to recruit and simulate a low grade VRTI in 60 healthy adults aged 18–59 years via administration of live attenuated influenza vaccine (LAIV). Continuous monitoring with wearable biosensors will include 7 days pre (baseline) and 5 days post LAIV administration, during which vital signs and activity-monitoring biosensors (embedded in a shirt, wristwatch and ring) will continuously monitor physiological and activity parameters. Novel infection detection techniques will be developed based on inflammatory biomarker mapping, PCR testing, and app-based VRTI symptom tracking. Subtle patterns of change will be assessed via ML algorithms developed to analyze large datasets and generate a predictive algorithm. This study presents an infrastructure to test wearables for the detection of asymptomatic VRTI using multimodal biosensors, based on immune host response signature. CliniclTrials.gov registration: NCT05290792 [ABSTRACT FROM AUTHOR]

Staphylococcus aureus bloodstream (SAB) infection is a common and severe infectious disease, with a 90-day mortality of 15%–30%. Despite this, <3000 people have been randomized into clinical trials of treatments for SAB infection. The limited evidence base partly results from clinical trials for SAB infections being difficult to complete at scale using traditional clinical trial methods. Here we provide the rationale and framework for an adaptive platform trial applied to SAB infections. We detail the design features of the Staphylococcus aureus Network Adaptive Platform (SNAP) trial that will enable multiple questions to be answered as efficiently as possible. The SNAP trial commenced enrolling patients across multiple countries in 2022 with an estimated target sample size of 7000 participants. This approach may serve as an exemplar to increase efficiency of clinical trials for other infectious disease syndromes. [ABSTRACT FROM AUTHOR]

In Staphylococcus aureus bacteremia, mortality rates in randomized controlled trials (RCTs) are consistently lower than observational studies. Stringent eligibility criteria and omission of early deaths in RCTs contribute to this mortality gap. Clinicians should acknowledge the possibility of a lower treatment effect when applying RCT results to bedside care. [ABSTRACT FROM AUTHOR]

• Styphylococcus aureus bacteremia (SAB) is common in low and middle-income countries (LMIC). • LMIC are poorly represented in SAB research. • In-hospital mortality for SAB is much higher in LMIC than in high-income countries. Staphylococcus aureus bacteremia (SAB) is a common infection worldwide. We compared SAB mortality in low- and middle-income countries (LMIC) versus high-income countries (HIC) in a meta-analysis. We searched MEDLINE, Embase, and Cochrane Database of Systematic Reviews from 1991-2021 and included observational, single-country studies on patients with positive blood cultures for S. aureus. The main outcome was the proportion of patients with SAB who died in the hospital. A generalized linear mixed random-effects model was used to pool estimates, and a meta-regression was used to adjust for study-level characteristics. A total of 332 studies involving 517,671 patients in 39 countries were included. No study was conducted in a low-income country. Only 33 (10%) studies were performed in middle-income countries (MIC), which described 6,216 patients. The pooled in-hospital mortality was 32.4% (95% confidence interval [CI] 27.2%-38.2%, T2 = 0.3063) in MIC and 22.3% (95% CI 20.1%-24.6%, T2 = 0.3257) in HIC. In a meta-regression model, MIC had higher in-hospital mortality (adjusted odds ratio 1.37, 95% CI 1.11-1.71; P = 0.0042) than HIC. In SAB studies, LMIC are poorly represented. In-hospital mortality was significantly higher in MIC than in HIC. Research should be conducted in LMIC to characterize differences in care processes driving the mortality gap. [ABSTRACT FROM AUTHOR]