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Long-term risk for malignancy is higher among solid organ transplant (SOT) recipients compared to the general population. Four non-hepatitis viruses have been recognized as oncogenic in SOT recipients--EBV, cause of EBV-associated lymphoproliferative diseases; human herpes virus 8 (HHV8), cause of Kaposi sarcoma, primary effusion lymphoma and multicentric Castleman disease; human papilloma virus, cause of squamous cell skin cancers, and Merkel cell polyomavirus, cause of Merkel cell carcinoma. Two of these viruses (EBV and HHV8) belong to the human herpes virus family. In this review, we will discuss key aspects regarding the clinical presentation, diagnosis, treatment, and prevention of diseases in SOT recipients associated with the two herpesviruses. [ABSTRACT FROM AUTHOR]

Long-term risk for malignancy is higher among solid organ transplant (SOT) recipients compared to the general population. Four non-hepatitis viruses have been recognized as oncogenic in SOT recipients--EBV, cause of EBV-associated lymphoproliferative diseases; human herpes virus 8 (HHV8), cause of Kaposi sarcoma, primary effusion lymphoma and multicentric Castleman disease; human papilloma virus, cause of squamous cell skin cancers, and Merkel cell polyomavirus, cause of Merkel cell carcinoma. Two of these viruses (EBV and HHV8) belong to the human herpes virus family. In this review, we will discuss key aspects regarding the clinical presentation, diagnosis, treatment, and prevention of diseases in SOT recipients associated with the two herpesviruses. [ABSTRACT FROM AUTHOR]

Background This is a systematic review and meta-analysis of diagnostic test accuracy studies to assess the predictive value of both tuberculin skin test (TST) and interferon-gamma release assays (IGRA) for active tuberculosis (TB) among solid organ transplantation (SOT) recipients. Methods Medline, Embase, and the CENTRAL databases were searched from 1946 until June 30, 2022. Two independent assessors extracted data from studies. Sensitivity analyses were performed to investigate the effect of studies with high or low risk of bias. Methodological quality of each publication was assessed using QUADAS-2. Results A total of 43 studies (36 403 patients) with patients who were screened for latent TB infection (LTBI) and who underwent SOT were included: 18 were comparative and 25 noncomparative (19 TST, 6 QuantiFERON-TB Gold In-Tube [QFT-GIT]). For IGRA tests taken together, positive predictive value (PPV) and negative predictive value (NPV) were 1.2% and 99.6%, respectively. For TST, PPV was 2.13% and NPV was 95.5%. Overall, PPV is higher when TB burden is higher, regardless of test type, although still low in absolute terms. Incidence of active TB was similar between studies using LTBI prophylaxis (mean incidence 1.22%; 95% confidence interval [CI],.2179–2.221) and those not using prophylaxis (mean incidence 1.045%; 95% CI, 0.2731–1.817; P =.7717). Strengths of this study include the large number of studies available from multiple different countries; limitations include absence of gold standard for diagnosis of latent TB and low incidence of active TB. Conclusions We found both TST and IGRA had a low PPV and high NPV for the development of active TB posttransplant. Further studies are needed to better understand how to prevent active TB in the SOT population. [ABSTRACT FROM AUTHOR]

Immune response to two SARS-CoV-2 mRNA vaccine doses among kidney transplant recipients (KTRs) is limited. We aimed to evaluate humoral and cellular response to a third BNT162b2 dose. In this prospective study, 190 KTRs were evaluated before and ~3 weeks after the third vaccine dose. The primary outcomes were anti-spike antibody level >4160 AU/ml (neutralization-associated cutoff) and any seropositivity. Univariate and multivariate analyses were conducted to identify variables associated with antibody response. T-cell response was evaluated in a subset of participants. Results were compared to a control group of 56 healthcare workers. Among KTRs, we found a seropositivity rate of 70% (133/190) after the third dose (37%, 70/190, after the second vaccine dose); and 27% (52/190) achieved levels above 4160 AU/ml after the third dose, compared to 93% of controls. Variables associated with antibody response included higher antibody levels after the second dose (odds ratio [OR] 30.8 per log AU/ml, 95% confidence interval [CI]11-86.4, p < 0.001); and discontinuation of antimetabolite prior to vaccination (OR 9.1,95% CI 1.8-46.5, p = 0.008). T-cell response was demonstrated in 13% (7/53). In conclusion, third dose BNT162b2 improved immune response among KTRs, however 30% still remained seronegative. Pre-vaccination temporary immunosuppression reduction improved antibody response. [ABSTRACT FROM AUTHOR]

The purpose of this survey is to explore changes in the management of COVID-19 during the first versus the second wave, with particular emphasis on therapies, antibiotic prescriptions, and elderly care. An internet-based questionnaire survey was distributed to European Society of Clinical Microbiology and Infectious Diseases (ESCMID) members. Therapeutic approach to patients with mild-to-moderate (PiO2/FiO2 200–350) and severe (PiO2/FiO2 < 200) COVID-19, antibiotic use, and reasons for excluding patients from the intensive care unit (ICU) were investigated. A total of 463 from 21 countries participated in the study. Most representatives were infectious disease specialists (68.3%). During the second wave of pandemic, physicians abandoned the use of hydroxychloroquine, lopinavir/ritonavir, and azithromycin in favor of dexamethasone, low-molecular weight heparin (LMWH), and remdesivir in mild-to-moderate COVID-19. In critically ill patients, we detected an increased use of high-dose steroids (51%) and a decrease in tocilizumab use. The use of antibiotics at hospital admission decreased but remained high in the second wave. Age was reported to be a main consideration for exclusion of patients from ICU care by 25% of responders; a third reported that elderly were not candidates for ICU admission in their center. The decision to exclude patients from ICU care was based on the individual decision of an intensivist in 59.6% of cases. The approach of physicians to COVID-19 changed over time following evidence accumulation and guidelines. Antibiotic use at hospital admission and decision to exclude patients from ICU care remain critical aspects that should be better investigated and harmonized among clinicians. [ABSTRACT FROM AUTHOR]

Summary: There is no consensus regarding the optimal duration of antibiotic therapy for urinary tract infection (UTI) following kidney transplantation (KT). We performed a retrospective study comparing short (6–10 days) versus prolonged (11–21 days) antibiotic therapy for complicated UTI among KT recipients. Univariate and inverse probability treatment weighted (IPTW) adjusted multivariate analysis for composite primary outcome of all‐cause mortality or readmissions within 30 days and relapsed UTI 180 days were performed. Overall, 214 KT recipients with complicated UTI were included; 115 short‐course treatment (median 8, interquartile range [IQR] 6–9 days), 99 prolonged course (median 14, IQR 12–21 days). The composite outcome occurred in 33 (28.6%) in the short‐course group and 30 (30%) in the prolonged‐course group; relapsed UTI occurred in 19 (16.5%) vs. 21 (21%), respectively. Duration of antibiotic treatment was not associated with any of these outcomes. The only risk factor for mortality/readmissions in multivariate analysis was deceased donor. No differences between groups were demonstrated for length of hospital stay, rates of bacteraemia, resistance development, and serum creatinine at 30 and 90 days. In conclusion, we found no difference in clinical outcomes between KT recipients treated for complicated UTI with short‐course antibiotic (6–10 days) versus longer course (11–21 days). [ABSTRACT FROM AUTHOR]

Objectives: To assess whether results of observational studies of potential anti-COVID-19 drugs were reproduced in subsequent randomized controlled trials (RCTs).Methods: This was a retrospective cross-sectional study, including studies published online between 1 January and 27 October 2020 that evaluated potential COVID-19 treatments and reported all-cause mortality.Results: Of 133 comparisons included in 117 studies, most were non-randomized (104/133, 78%). Hydroxychloroquine was the most common drug type, combined with azithromycin (n = 27, 20%) or alone (n = 22, 16%), followed by IL-6 inhibitors (n = 36, 27%) and corticosteroids (n = 26, 20%). Seventy-one percent (74/104) of non-randomized studies reported adjusted survival results and only 8% (8/104) adjusted for immortal time bias. Only two RCTs (2/29, 7%) reported significant survival benefit, both reporting treatment with corticosteroids, while 32/104 (31%) non-randomized studies showed statistically significant survival benefit associated with the intervention arm. The results of the majority (28/32, 88%) of non-randomized studies reporting survival benefit were not replicated by large-scale RCTs.Conclusions: The results of most non-randomized studies reporting survival benefit of potential anti-COVID-19 drugs were not replicated by large RCTs. Regulators and healthcare professionals should exercise caution and resist the pressure to approve and prescribe drugs of unproven efficacy and potential toxicity to optimize patient care and maintain public trust in medical science. [ABSTRACT FROM AUTHOR]

Burden of COVID-19 on Hospitals across the globe is enormous and has clinical and economic implications. In this retrospective study including consecutive adult patients with confirmed SARS-CoV-2 who were admitted between 3/2020 and 30/9/20, we aimed to identify post-discharge outcomes and risk factors for re-admission among COVID-19 hospitalized patients. Mortality and re-admissions were documented for a median post discharge follow up of 59 days (interquartile range 28,161). Univariate and multivariate analyses of risk factors for re-admission were performed. Overall, 618 hospitalized COVID-19 patients were included. Of the 544 patient who were discharged, 10 patients (1.83%) died following discharge and 50 patients (9.2%) were re-admitted. Median time to re-admission was 7 days (interquartile range 3, 24). Oxygen saturation or treatment prior to discharge were not associated with re-admissions. Risk factors for re-admission in multivariate analysis included solid organ transplantation (hazard ratio [HR] 3.37, 95% confidence interval [CI] 2.73–7.5, p = 0.0028) and higher Charlson comorbidity index (HR 1.34, 95% CI 1.23–1.46, p < 0.0001). Mean age of post discharge mortality cases was 85.0 (SD 9.98), 80% of them had cognitive decline or needed help in ADL at baseline. In conclusion, re-admission rates of hospitalized COVID-19 are fairly moderate. Predictors of re-admission are non-modifiable, including baseline comorbidities, rather than COVID-19 severity or treatment. [ABSTRACT FROM AUTHOR]

Background Infections caused by multidrug-resistant (MDR) bacteria are a major public health threat. We aimed to assess the data supporting US Food and Drug Administration (FDA) approval of new agents aimed to treat MDR bacterial infections and the data provided by postmarketing studies. Methods We identified all drugs with in vitro activity against MDR bacteria initially approved by the FDA between January 2010 and December 2018. Characteristics of trials supporting approval and regulatory pathways were collected from Drugs@FDA. Characteristics of postmarketing studies were extracted from drug labels and ClinicalTrials.gov entries effective 1 June 2019. Results Initial approval of 11 newly approved antibiotics with anti-MDR activity was supported by 20 trials, all with noninferiority design. All initially approved indications were for common infections, mostly acute bacterial skin and skin-structure infections, regardless of causative microorganism. The proportion of MDR bacteria in most trials was low (<10% for gram-negative infections, <1% for gram-positive pneumonia). Most trials (90%) excluded immunocompromised and critically ill patients. Of 16 additional postmarketing randomized controlled trials identified through ClinicalTrials.gov , only 2 exclusively included infections caused by MDR bacteria, comprising 116 patients. No drug was granted accelerated approval, which would mandate postmarketing efficacy studies. Conclusions The approval of new drugs with potential clinical activity against MDR bacteria is supported by trials evaluating infections caused by non-MDR organisms, using noninferiority design and excluding the patients most likely to require these agents. Subsequent postmarketing efficacy data against these organisms are scarce. Healthcare professionals and regulators should demand more robust data to support clinical decision making. [ABSTRACT FROM AUTHOR]

SARS-CoV-2 RT-PCR re-positivity SARS-CoV-2 RT-PCR re-positivity describes positive RT-PCR following negative tests in an asymptomatic patient up to 90 days from the first episode. Keywords: COVID-19; PCR re-positivity; Reinfection; Relapse EN COVID-19 PCR re-positivity Reinfection Relapse 315 318 4 03/03/21 20210301 NES 210301 Introduction Defining reinfection, relapsed infection and recurrence of positive (re-positive) nucleic acid detection might have clinical and epidemiological implications for treatment and infection control measures, respectively. (b) Proof of a reinfection with two positive SARS-CoV-2 RT-PCR tests with Ct < 35 (or proof of replicating virus by cell culture or detection of subgenomic RNA) at different time-points. COVID-19 reinfection In August 2020, To et al. described an asymptomatic patient from Hong Kong with a positive SARS-CoV-2 PCR test from a sample collected 142 days after a first symptomatic COVID-19 episode. [Extracted from the article]

Introduction: Guidelines for treatment of multidrug-resistant (MDR) bacteria rely on newly approved antibiotics, with limited evidence of their effectiveness for treating these infections. Data regarding cost of such an approach are lacking. We aimed to evaluate estimated cost of using newly approved antibiotic drugs compared to older antibiotics for the treatment of difficult-to-treat pathogens. Methods: MDR bacteria of interest included those defined by the World Health Organization as critical or of high priority for research. Old and newly approved antibiotics for these bacteria, defined as approved before or after January 2010, respectively, were evaluated for treatment cost and for 14-day treatment course. Estimated annual costs were calculated based on the Centers for Disease Control and Prevention's' report on MDR bacteria prevalence in US hospitalized patients. Old and new drugs costs were compared. Results: The cost of a 14-day treatment course for methicillin-resistant Staphylococcus aureus bacteremia with a newly approved drug was found to be 6 to 60 times higher than that of older drugs. Similarly, the cost of a 14-day course for carbapenem-resistant Enterobacterales or MDR Pseudomonas aeruginosa was doubled with new drugs; and for carbapenem-resistant Acinetobacter baumannii, ~ 20 times higher with newer drugs. Annual incremental costs of treating difficult-to-treat Gram-negative bacteria with new drugs ranged from 30 million to over 500 million USD. Conclusions: Using newly approved antibiotic drugs for MDR infections carries a large incremental cost. Additional data to support survival benefit of these drugs are required to justify the price differences. Subgroups of patients who would benefit most from treatment should be defined. [ABSTRACT FROM AUTHOR]

Background: Vaccines are one of the greatest achievements in public health. Prevalence and clinical significance of emerging postapproval, vaccine-related safety issues have not been systematically studied.Objective: To explore postmarketing safety modifications in U.S. Food and Drug Administration (FDA)-approved vaccine labels.Design: Retrospective cohort study.Setting: United States.Participants: Initial and subsequent labels of all vaccines that were FDA-approved between 1 January 1996 and 31 December 2015.Measurements: The primary aim was a descriptive analysis of the prevalence and characteristics of postapproval, safety-related label changes. The secondary aim was to describe the distribution of data sources triggering these modifications.Results: The study cohort comprised 57 FDA-approved vaccines. Initial approval for 53 (93%) of the vaccines was supported by randomized controlled trials, with a median cohort size of 4161 participants (interquartile range, 2204 to 8634 participants). There were 58 postapproval, safety-related label modifications associated with 25 vaccines (49 warnings and precautions, 8 contraindications, and 1 safety-related withdrawal). The initial approval trial characteristics were similar in vaccines with and without postmarketing, safety-related label modifications. The most common safety issue triggering label modifications was expansion of population restrictions (n = 21 [36%]), followed by allergies (n = 13 [22%]). The most common source of safety data was postmarketing surveillance (n = 28 of 58 [48%]).Limitation: The data source of the initial signal triggering safety-related label changes may not necessarily represent all safety data received and processed by the FDA.Conclusion: Over a 20-year period, vaccines were found to be remarkably safe. A large proportion of safety issues were identified through existing postmarketing surveillance programs and were of limited clinical significance. These findings confirm the robustness of the vaccine approval system and postmarketing surveillance.Primary Funding Source: None. [ABSTRACT FROM AUTHOR]

Background little is known on the clinical implications of vancomycin trough levels among older patients. Objective to evaluate the association between vancomycin levels and outcomes among older versus younger patients. Design retrospective study. Subjects patients aged 18–64 and ≥65 years treated with vancomycin for documented methicillin resistant Staphylococcus aureus (MRSA) infections. Methods we compared the effectiveness and toxicity of vancomycin according to trough levels in older versus younger patients. Subgroup analysis of patients with glomerular filtration rate (GFR) > 60 ml/min/1.73 m2 was performed. Results we included 181 patients aged ≥65 years and 104 younger patients. Mean age in the older group was 76.9 ± 8 years versus 50.9 ± 12.4 in the younger group. Vancomycin trough levels and 24-hours area under the curve to minimal inhibitory concentrations (AUC/MIC) were significantly higher in older patients who were also significantly more likely to achieve trough levels of ≥15 mg/l within 4 days, (98/181 (54.1%) vs. 38/104 (36.5%) in younger patients, P  = 0.004). Results were similar among patients with GFR > 60. Thirty-day mortality was significantly higher in older (74/181, 40.9% vs. 13/104, 12.5%, respectively, P  < 0.001). There was no association between vancomycin trough levels and mortality among older patients. No significant differences were demonstrated in clinical or microbiological success or nephrotoxicity. Conclusions applying uniform dosing recommendations across age groups among adults with MRSA infections results in higher vancomycin levels and AUC/MIC in older versus younger patients. Yet, mortality rates remain higher among older adults. Prospective studies are needed to define the optimal approach for using this drug in older patients. [ABSTRACT FROM AUTHOR]

Modifications of primary outcome measures after trial initiation can undermine their scientific validity. We aimed to quantify these changes and to characterize potential predictors in clinical drug trials published in high impact factor general medicine journals. The study cohort included all prospective, adult drug clinical trials published in the New England Journal of Medicine, JAMA and Lancet between June 2017 and May 2018. The matching ClinicalTrials.gov entries effective at trial initiation were compared with those effective on July 2018, thereby identifying amendments to primary outcome definitions and assessment timeframes and the planned sample size (defined as >10% change). The primary publications were reviewed for reporting of these amendments. Associations between identified changes and trial characteristics were explored using logistic regression. Of the 147 included trials, modifications to primary outcome measures were identified in 80 (54%). Primary outcome definitions, outcome assessment timeframes and the planned sample size were modified in 28 (19%), 12 (8%) and 65 (45%) of registry entries, respectively; of which 21 (75%), 11 (92%), and 33 (51%), respectively, were not reported in the related publications. There were no significant associations between modifications in registry entries and study characteristics. Approximately half of trials published in influential medical journals present changes to the design while patient accrual is ongoing, and two thirds of them are unreported. Justification for such modifications should be reported more clearly. Reviewers, editors and readers should consult ClinicalTrials.gov for a more comprehensive report of the evolution of key study methods. • Modifications of trial design after initiation can undermine scientific validity. • Design changes were identified in most drug trials published in influential journals. • Most modifications were not reported in the related publications. • Justification for such modifications should be reported more clearly. [ABSTRACT FROM AUTHOR]

Background Gram-negative bacteremia is a major cause of morbidity and mortality in hospitalized patients. Data to guide the duration of antibiotic therapy are limited. Methods This was a randomized, multicenter, open-label, noninferiority trial. Inpatients with gram-negative bacteremia, who were afebrile and hemodynamically stable for at least 48 hours, were randomized to receive 7 days (intervention) or 14 days (control) of covering antibiotic therapy. Patients with uncontrolled focus of infection were excluded. The primary outcome at 90 days was a composite of all-cause mortality; relapse, suppurative, or distant complications; and readmission or extended hospitalization (>14 days). The noninferiority margin was set at 10%. Results We included 604 patients (306 intervention, 298 control) between January 2013 and August 2017 in 3 centers in Israel and Italy. The source of the infection was urinary in 411 of 604 patients (68%); causative pathogens were mainly Enterobacteriaceae (543/604 [90%]). A 7-day difference in the median duration of covering antibiotics was achieved. The primary outcome occurred in 140 of 306 patients (45.8%) in the 7-day group vs 144 of 298 (48.3%) in the 14-day group (risk difference, –2.6% [95% confidence interval, –10.5% to 5.3%]). No significant differences were observed in all other outcomes and adverse events, except for a shorter time to return to baseline functional status in the short-course therapy arm. Conclusions In patients hospitalized with gram-negative bacteremia achieving clinical stability before day 7, an antibiotic course of 7 days was noninferior to 14 days. Reducing antibiotic treatment for uncomplicated gram-negative bacteremia to 7 days is an important antibiotic stewardship intervention. Clinical Trials Registration NCT01737320. [ABSTRACT FROM AUTHOR]

Background Early reports described an increased risk of herpes zoster following receipt of mRNA-based COVID-19 vaccines. The objective was to assess whether COVID-19 vaccine is associated with varicella-zoster virus–induced neurologic disease (VZV-ND). Methods This multicenter retrospective case-control study with a test-negative design was conducted at 12 hospitals in Israel. We included all patients admitted with VZV-ND between January 2020 and December 2021 and matched controls with a negative polymerase chain reaction result for VZV in cerebrospinal fluid. Results We identified 188 patients meeting the case definition of VZV-ND who were admitted during the study period. Cases were matched with 376 controls. There was no significant variation in the incidence of VZV-ND between 1 year preceding and 1 year following the deployment of BNT162b2 in Israel. Analysis of persons who had received at least 1 dose of COVID-19 vaccine (n = 259) showed similar proportions of VZV-ND and non–VZV-ND in 4 intervals (30, 42, 50, 60 days) following the last vaccine dose. The median time from the last vaccine dose to hospitalization with a neurologic syndrome was 53 days (IQR, 25–128) and 82 days (IQR, 36–132) for VZV-ND and non–VZV-ND, respectively, not reaching statistical significance (P =.056). The rate of VZV-ND in vaccinated patients was no different from the rate in the unvaccinated group (30.9% vs 35.4%, P =.2). Conclusions We did not find an association between COVID-19 vaccine and VZV-ND. Since COVID-19 vaccine is now recommended yearly, every fall and winter, establishing the safety of the vaccine is of great importance. [ABSTRACT FROM AUTHOR]

Data regarding presentation and management of human herpes virus 6 (HHV-6) reactivation among autologous hematopoietic cell transplantation (HCT) recipients are limited. We retrospectively reviewed medical charts of all autologous HCT patients tested for HHV-6 reactivation due to suspected clinical presentation between 1/2012 and 8/2017. Among 328 autologous HCT recipients, 44 patients were tested for HHV-6 reactivation. Thirty patients tested positive; 29 (97%) had sustained fever, six (20%) had rash and four (13%) had pneumonia. Median C-reactive protein was significantly lower in HHV-6 positive patients compared to negative patients (3.6 (range, 0.4–11) vs. 9.6 (range, 3.2–30) mg/dL, respectively, p =.004). Ganciclovir formulations were administrated in 29 (97%) patients with median time to fever resolution of one (range, 1–2) day. HHV-6 should be considered as an important cause of post engraftment fever in autologous HCT. Larger studies are warranted to evaluate incidence of HHV-6 reactivation and optimal treatment regimen. [ABSTRACT FROM AUTHOR]

Introduction: Current guidelines recommend maintaining vancomycin trough concentrations between 15–20 mg/L for serious methicillin resistant staphylococcus aureus (MRSA) infections. This recommendation is based on limited evidence. Methods: A retrospective study including patients with vancomycin susceptible MRSA infections (MIC< = 2 mg/L), treated with vancomycin. We compared outcomes among patients attaining high (> = 15mg/L) vs low (<15mg/L) trough vancomycin levels. We used a propensity score to matching patients achieving low and high levels and conducted an adjusted analysis in the propensity score (PS)-matched cohort using regression analysis. Primary outcome was 30-day all-cause mortality. Results: Among 285 patients included, there were no significant differences between patients achieving high and low vancomycin levels in mortality (46/131, 35.1% vs 41/154, 26.6%), clinical success, microbiological success, or nephrotoxicity. Similarly, in the PS-matched cohort (n = 162), there was no significant difference in mortality between patients with high and low vancomycin levels (24/53, 45.3% vs 57/109, 52.3%, respectively), adjusted odds ratio for mortality with high levels 0.63 (95% confidence interval 0.28–1.43). In both cohorts, patients with pneumonia achieving high levels had significantly higher clinical and microbiological success (PS-matched cohort: clinical success: 16/32, 50.0% vs 5/27, 18.5%, p = 0.012; microbiological success: 19/32, 59.4% vs 7/27, 25.9%, p = 0.010), without significant differences in mortality. Conclusions: We found no association between vancomycin levels > = 15 mg/L and clinical outcomes in patients with MRSA infections. In patients with MRSA pneumonia, vancomycin levels > = 15 mg/L were associated with higher clinical success rates. Further larger cohort studies are needed to define optimal vancomycin levels according to the site of infection. [ABSTRACT FROM AUTHOR]

Polymerase chain reaction (PCR) for the diagnosis of Clostridium difficile infection (CDI) might result in overdiagnosis. The clinical outcomes of symptomatic CDI patients diagnosed by PCR remain uncertain. We aimed to determine whether patients whose diagnosis of CDI was based on PCR had different characteristics and clinical outcomes than those diagnosed by toxin immunoassay. Consecutive CDI patients, hospitalized at Rabin Medical Center, Beilinson Hospital, Petah Tikva, Israel, between January 2013 and January 2016, were identified retrospectively and included in the study. Diagnosis of CDI was based on PCR or diagnosis by immunoassay for C. difficile toxin. The main outcome was 30- and 90-day all-cause mortality. The PCR group included 165 patients and the immunoassay group included 157 patients. In comparison to the immunoassay group, patients in the PCR group were more likely to be younger, to be independent, to undergo previous abdominal surgery, and to use laxatives. The 30-day mortality rate in the PCR group was significantly lower than that in the immunoassay group, 29/165 (18%) vs 49/157 (31%), respectively; p = 0.028. On multivariate analysis, PCR diagnosis was associated with reduced mortality, OR 0.48 (95% CI 0.26-0.88). PCR-based diagnosis of CDI is associated with reduced all-cause mortality rates. Further studies are needed to determine the management of patients with discrepant immunoassay and PCR diagnosis of CDI. [ABSTRACT FROM AUTHOR]

Ureteral stents are routinely used in renal transplant and are associated with reduced urological complications but increased urinary tract infections (UTIs). There is no agreement on the preferred time to removal of stents after transplantation. We performed a systematic review and meta-analysis of all randomized controlled trials (RCTs) comparing stent duration of <14 days vs > =14 days. Electronic databases were searched to identify RCTs that compared early vs late stent removal. Primary outcome was urinary tract infections. Secondary outcomes included various urological complications. No significant difference in UTI rates was demonstrated between short and long stent duration (relative risk (RR) 0.85, 95% confidence interval (CI) 0.44-1.64), with significant heterogeneity (I² = 86%). Sensitivity analysis evaluating studies with low risk of bias for allocation concealment demonstrated statistically significant lower rates of UTI with short stent duration (RR 0.48, 95% CI 0.32-0.71) with no heterogeneity. No significant difference was demonstrated for the outcome of major urological complications (RR 0.72, 95% CI 0.50-1.05), without heterogeneity. Ureteral stenosis rates were significantly lower in the short duration arm (RR 0.42, 95% CI 0.18-0.98). Early removal of ureteral stents after renal transplant may be associated with reduced rates of UTI and ureteral stenosis. Additional RCTs are needed. [ABSTRACT FROM AUTHOR]

The authors also report data suggesting that patients with hematological malignancies may be disqualified from receiving intensive treatment; hence, treating hematologists should be alert to this possibility and clarify the baseline disease prognosis to encourage ICU care when appropriate. Hence, physicians treating COVID-19 patients with hematological malignancy should be aware of the limited generalizability of data on therapeutic options for this population [[4]]. The number of COVID-19 cases worldwide has crossed 400 million cases as for February 2022. [Extracted from the article]

Bloodstream infections (BSIs) are both common and fatal in older patients. We describe data from studies evaluating older patients hospitalized with BSIs. Most older patients with BSIs present “typically” with either fever or leukocytosis. The most common source of BSI in older patients is the urinary tract, and accordingly, Gram-negative organisms predominate. A significant part of these BSIs may thus be preventable by removal of unnecessary urinary catheters. Increased long term mortality is reported following BSIs in older patients, however, data on other long-term outcomes, including functional capacity, cognitive decline and others are lacking. Management of BSIs may include less invasive procedures due to the fragility of older patients. This approach may delay the diagnosis and treatment in some cases. Older patients are probably under-represented in clinical trials assessing treatment of bacteremia. Physicians treating older patients should consider the relevance of these studies' outcomes. [ABSTRACT FROM PUBLISHER]

• Oesophageal candidiasis is a common infection among immunocompromised patients. • Available guidelines recommend fluconazole as the preferred treatment. • Data regarding the effectiveness of fluconazole have not been compiled systematically in times of increased fluconazole resistance. • No difference in efficacy or safety was demonstrated between fluconazole and other azoles for the treatment of oesophageal candidiasis. • Use of echinocandins resulted in lower mycological cure rates and higher relapse rates. Oesophageal candidiasis is a common infection among individuals with immunosuppression, associated with significant morbidity. Available guidelines recommend fluconazole as the preferred treatment; however, data regarding its effectiveness in an era of increased fluconazole resistance has not been systematically compiled. A systematic review and meta-analysis of randomized controlled trials (RCTs) addressing systemic antifungal therapy for oesophageal candidiasis was undertaken. The primary outcome was clinical response. Subgroup analysis was planned based on immune status and Candida spp. Twelve RCTs were included, of which six compared fluconazole with other azoles, four compared fluconazole with echinocandins, and two compared amphotericin deoxycholate with echinocandins. Most RCTs mainly included human-immunodeficiency-virus-positive individuals. No significant differences were found between fluconazole and comparators for the outcomes of clinical response or combined clinical and endoscopic response [relative risk (RR) 1.02, 95% confidence interval (CI) 0.97–1.07 and RR 1.06, 95% CI 0.98–1.15, respectively]. No differences were found between fluconazole and other azoles for other outcomes; however, compared with echinocandins, fluconazole had significantly higher mycological response rates and lower early relapse rates (RR 1.09, 95% CI 1.02–1.17 and RR 0.42, 95% CI 0.26–0.68, respectively). No significant differences were demonstrated between fluconazole and comparators for overall or severe adverse events. Information required for the planned subgroup analyses was not available. No differences in efficacy or safety were found between fluconazole and other azoles for the treatment of candida oesophagitis. The use of echinocandins resulted in lower mycological cure rates and higher relapse rates. Additional RCTs should evaluate these interventions among broader patient populations and a wider spectrum of Candida spp. [ABSTRACT FROM AUTHOR]

Background Acute pyelonephritis is a frequent cause of morbidity, with a wide variation in duration of therapy. We performed a systematic review of all randomized controlled trials (RCTs) comparing ≤7 days treatment with a longer course. Methods Electronic databases were searched to identify RCTs that assessed adults treated for pyelonephritis, comparing a 7 day or shorter versus longer therapy. Primary outcome was clinical failure at the end of the long treatment arm (EOT). Secondary outcomes included clinical failure at the end of follow-up (EOF), microbiological failure, all-cause mortality, the development of resistance and adverse events. Results Clinical failure at EOT did not significantly differ between the two treatment arms [relative risk (RR) 0.63, 95% CI 0.33–1.18, I² = 41%]. Results did not differ when including studies comparing only fluoroquinolones, reducing the heterogeneity (RR 0.76, 95% CI 0.49–1.17, I² = 0%). We found no difference between the short and long treatment arms regarding clinical failure at EOF, even in a small subgroup of bacteraemic patients. No difference was found between the arms regarding microbiological failure at EOF, except in a subgroup of studies with a high percentage of patients with urogenital abnormalities, where microbiological failure at EOF was significantly higher in the short treatment arm (RR 1.78, 95% CI 1.02–3.10, I2 = 21%). Adverse events were similar between the arms. Conclusions Seven days of treatment for acute pyelonephritis is equivalent to longer treatment in terms of clinical failure and microbiological failure, including in bacteraemic patients. In patients with urogenital abnormalities, the evidence, although weak, suggests that longer treatment is required. [ABSTRACT FROM AUTHOR]

Abstract: Time to first antibiotic dose (TFAD) of 4h or 8h has been suggested as a quality measure for adult patients hospitalised with community-acquired pneumonia (CAP). Clinical evidence leading to implementation of this quality measure came from two large, retrospective studies. Following these studies, several prospective studies were conducted, with variable results. In a compilation of all observational studies to date, no significant benefit for short TFAD in terms of all-cause mortality was observed [unadjusted odds ratio (OR)=1.01, 95% confidence interval (CI) 0.79–1.29, 13 studies; adjusted OR=0.95, 95% CI 0.73–1.23, 14 studies]. Implementation of a requirement for short TFAD for CAP in the emergency department or other acute medical care setting may lead to unnecessary antibiotic treatment. We believe that attention should be shifted to early appropriate empirical antibiotic treatment for severe sepsis in hospital regardless of the source of infection, rather than focusing on CAP. [Copyright &y& Elsevier]

Background Tigecycline is a novel glycylcycline that exhibits broad-spectrum antibacterial activity. Recently, the US FDA issued a warning concerning increased mortality with tigecycline in randomized controlled trials (RCTs). Methods We conducted a systematic review and meta-analysis of RCTs that compared tigecycline with any other antibiotic regimen for the treatment of any infection. A comprehensive search, without publication status or other restrictions, was conducted. The primary outcome was overall 30 day mortality. The secondary outcome included clinical and microbiological failure, superinfections and adverse events (AEs). The trials’ risks of bias and their effects on results were assessed. Two reviewers independently extracted the data. Individual trials’ relative risks (RRs) were pooled using a fixed effect meta-analysis. Results Fifteen trials (7654 patients) were included. Overall mortality was higher with tigecycline compared with other regimens [RR 1.29, 95% confidence interval (CI) 1.02–1.64, without heterogeneity]. The type of infection assessed and the trials’ reported risks of bias did not affect this result. Clinical failure was significantly higher with tigecycline (RR 1.16, 95% CI 1.06–1.27) and non-statistically significant higher rates of microbiological failure were demonstrated (RR 1.13, 95% CI 0.99–1.30). Development of septic shock was significantly more frequent with tigecycline (RR 7.01, 95% CI 1.27–38.66). Superinfections were significantly more common with tigecycline and so were AEs, including all AEs and AEs requiring discontinuation. Conclusions In the light of the increased mortality, probably explained by decreased clinical and microbiological efficacy, clinicians should avoid tigecycline monotherapy in the treatment of severe infections and reserve it as a last-resort drug. [ABSTRACT FROM PUBLISHER]

Abstract: Purpose: Antiviral prophylaxis is commonly prescribed to haematological cancer patients. We conducted a systematic review and meta-analysis to quantify its overall benefit in specific clinical scenarios. Methods: Randomised controlled trials assessing antiviral prophylaxis versus placebo, no treatment, pre-emptive treatment or another antiviral drug were included. Patients undergoing haematopoietic stem cell transplantation (HSCT) or intensive chemotherapy for acute leukaemia or high-grade lymphoma were included. No restrictions on language, year or publication status were applied. Overall mortality, herpes simplex virus (HSV) and cytomegalovirus (CMV) diseases were assessed as primary outcomes. Pooled relative risks (RRs) and numbers needed to treat (NNT) with 95% confidence intervals (CI) are reported. Results: HSCT was the condition assessed in 22 trials and intensive chemotherapy in 5 trials. In the pre-engraftment setting of autologous or allogeneic HSCT, antiviral prophylaxis (mainly acyclovir for HSV seropositive recipients) significantly reduced HSV (NNT 2, 2–2, control event rate (CER) 61.9%) and CMV disease, with no effect on overall mortality. In the allogeneic post-engraftment setting (mainly CMV-seropositive recipients/donors), antiviral prophylaxis resulted in a significant reduction in overall mortality, RR 0.79 (0.65–0.95), NNT 12 (7–50, CER 39.4%) and all viral-related outcomes. In this setting, acyclovir significantly reduced overall mortality (RR 0.71, 0.53–0.96, 4 trials) and ganciclovir/maribavir significantly reduced CMV disease (RR 0.26, 0.14–0.48, 5 trials). During chemotherapy, acyclovir significantly decreased HSV disease (NNT 3, 2–4, CER 37.4%) and infection rates, with no effect on mortality. Conclusions: Antiviral prophylaxis reduced mortality with a small NNT in the post-engraftment setting of allogeneic HSCT. In the pre-engraftment phase and during chemotherapy only viral-related morbidity was reduced. [Copyright &y& Elsevier]

Background. Prevention of catheter-related bloodstream infections in patients undergoing hemodialysis by use of antimicrobial catheter lock solutions has been examined in several trials, but no consensus is available for clinical practice. Methods. A systematic review and meta-analysis were performed of randomized controlled trials that compared single or combination antimicrobial catheter lock solutions with heparin or another antimicrobial for the prevention of infections in patients undergoing hemodialysis. The primary outcomes assessed were bloodstream infections, catheter-related bloodstream infections, and the need for catheter removal. Relative risks with 95% confidence intervals (CIs) for individual trials were pooled. Results. Eleven trials (924 patients) that assessed antibiotic catheter lock solutions and 5 trials (661 patients) that assessed nonantibiotic antimicrobial catheter lock solutions met inclusion criteria. None of the trials assessed all bloodstream infections. Antibiotic catheter lock solutions significantly reduced catheter-related bloodstream infections (relative risk, 0.44; 95% CI, 0.38-0.50). Significant heterogeneity for this outcome could be explained by smaller effect estimates in larger trials that reported adequate randomization methods (relative risk, 0.60; 95% CI, 0.54-0.67). Efficacy was higher when additional preventive measures were used and to prevent the first episode of catheter-related bloodstream infection. Catheter removal rates were significantly reduced (relative risk, 0.35; 95% CI, 0.23-0.55). Resistance development was documented in a single patient. Data concerning nonantibiotic antimicrobial lock solutions were limited and heterogenous. High-quality trials that used additional preventive measures showed a significant reduction in catheter-related bloodstream infections (relative risk, 0.25; 95% CI, 0.13-0.50). Conclusions. Antibiotic catheter lock solutions reduce catheter-related bloodstream infections, with a number needed to treat of 4 patients (95% CI, 4-5), and catheter removal rates in patients undergoing hemodialysis. The use of antibiotic catheter lock solutions should be considered in routine clinical practice in conjunction with other prevention modalities. [ABSTRACT FROM AUTHOR]

Objectives To determine and quantify differences in efficacy between treatment regimens for brucellosis. Design Systematic review and meta-analysis of randomised controlled trials assessing different antibiotic regimens and durations of treatment for human brucellosis. Data sources PubMed, CENTRAL, Lilacs, conference proceedings, and bibliographies with no restrictions on language, study year, or publication status. Review methods Search, application of inclusion and exclusion criteria, data extraction, and assessment of methodological quality independently performed in duplicate. Primary outcomes were relapse and overall failure resulting from primary failure or relapse. Relative risks with 95% confidence intervals were calculated and pooled with a fixed effect model. Results 30 trials and 77 treatment arms were included. Overall failure was significantly higher with doxycycline- rtfampicin compared to doxycycline-streptomycin, mainly due to a higher rate of relapse (relative risk 2.80, 95% confidence interval 1.81 to A.36; 13 trials, without heterogeneity). Results were consistent among patients with bacteraemia and complicated brucellosis. Doxycycline-streptomycin resulted in a significantly higher rate of failure than doxycycline-rifampicin- aminoglycoside (triple drug regimen) (2.50,1.26 to 5.00; two trials). Gentamicin was not inferiorto streptomycin (1.45, 0.52 to 4.00 for failure; two trials). Quinolones combined with rifampicin were significantly less effective than doxycycline combined with rifampicin or streptomycin {1.83,1.11 to 3.02, for failure; five trials). Monotherapy was associated with a higher risk of failure than combined treatment when administered fora similar duration (2.56,1.55 to 4.23; five trials). Treatment for six weeks or more offered an advantage over shorter treatment durations. Conclusions There are significant differences in effectiveness between currently recommended treatment regimens for brucellosis. The preferred treatment should be with dual or triple regimens including an arninoglycoside. [ABSTRACT FROM AUTHOR]

Summary: Cefepime is a broad-spectrum cephalosporin with enhanced coverage against Gram-positive and Gram-negative bacteria. We did a systematic review of randomised trials that compared cefepime with another β-lactam antibiotic, alone or with the addition of a non-β-lactam antibiotic to both study groups. We searched Central, PubMed, Embase, Lilacs, new US Food and Drug Administration drug applications, conference proceedings, and references of the included studies. Two reviewers independently did the search and data extraction. 57 trials were included. All-cause mortality—the primary outcome—was higher with cefepime than other β-lactams (risk ratio [RR] 1·26 [95% CI 1·08–1·49]). Sensitivity analyses by the trials'' methodological quality revealed higher RRs for trials reporting adequate allocation-sequence generation (1·52 [1·20–1·92]) and allocation concealment (1·36 [1·09–1·70]). Baseline risk factors for mortality were similar. No significant differences between groups in treatment failure, superinfection, or adverse events were found. This Review provides evidence and offers possible explanations for increased mortality among patients treated with cefepime in randomised trials. [Copyright &y& Elsevier]

We aimed to evaluate the rates of antibody response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccine among kidney transplant recipients, and to identify factors associated with reduced immunogenicity. This was a prospective cohort study including consecutive kidney transplant recipients in a single referral transplant centre. Participants were tested for anti-spike (anti-S) antibodies 2–4 weeks after a second vaccine dose. Primary outcome was rate of seropositivity. Univariate and multivariate analyses were conducted to identify factors associated with seropositivity. Of 308 kidney transplant recipients included, only 112 (36.4%) tested positive for anti-S antibodies 2–4 weeks after receiving the second dose of BNT162b2 vaccine. Median antibody titre was 15.5 AU/mL (interquartile range (IQR) 3.5–163.6). Factors associated with antibody response were higher estimated glomerular filtration rate (eGFR) (odds ratio (OR) 1.025 per mL/min/1.73 m2, 95% confidence interval (CI) 1.014–1.037, p < 0.001), lower mycophenolic acid dose (OR 2.347 per 360 mg decrease, 95%CI 1.782–3.089, p < 0.001), younger age (OR 1.032 per year decrease, 95%CI 1.015–1.05, p < 0.001) and lower calcineurin inhibitor (CNI) blood level (OR 1.987, 95%CI 1.146–3.443, p 0.014). No serious adverse events resulting from the vaccine were reported. Kidney transplant recipients demonstrated an inadequate antibody response to SARS-CoV-2 mRNA vaccination. Immunosuppression level was a significant factor in this response. Strategies to improve immunogenicity should be examined in future studies. [ABSTRACT FROM AUTHOR]

Polymicrobial endocarditis is uncommon. We present a case of polymicrobial endocarditis caused by Enterococcus faecalis and Coxiella burnetii and review previous cases of polymicrobial endocarditis involving Coxiella burnetii. Testing for Q fever should be considered in any patient with endocarditis living in an endemic area. [ABSTRACT FROM AUTHOR]

Background Although a short course (7 days) of antibiotics has been demonstrated to be noninferior to a conventional course (14 days) in terms of mortality and infectious complications for patients with a Gram-negative bacterial bloodstream infection (GNB), it is unknown whether a shorter treatment duration can provide a better overall clinical outcome. Methods We applied a bloodstream infection-specific desirability of outcome ranking (DOOR) analysis to the results of a previously completed, randomized controlled trial comparing short versus conventional course antibiotic therapy for hospitalized patients with uncomplicated GNB. We determined the probability that a randomly selected participant in the short course group would have a more desirable overall outcome than a participant in the conventional duration group. We performed (1) partial credit analyses allowing for calculated and variable weighting of DOOR ranks and (2) subgroup analyses to elucidate which patients may benefit the most from short durations of therapy. Results For the 604 patients included in the original study (306 short course, 298 conventional course), the probability of having a more desirable outcome with a short course of antibiotics compared with a conventional course was 51.1% (95% confidence interval, 46.7% to 55.4%), indicating no significant difference. Partial credit analyses indicated that the DOOR results were similar across different patient preferences. Prespecified subgroup analyses using DOOR did not reveal significant differences between short and conventional courses of therapy. Conclusions Both short and conventional durations of antibiotic therapy provide comparable clinical outcomes when using DOOR to consider benefits and risks of treatment options for GNB. [ABSTRACT FROM AUTHOR]

Data regarding immunogenicity of mRNA severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines among kidney transplant recipients in the months following vaccination are lacking. We aimed to investigate humoral immune response at 3–4 months post-vaccination among a cohort of kidney transplant recipients, compared with a control group of dialysis patients. Anti-spike antibodies were tested at 1 and 3–4 months after vaccination. Of 259 kidney transplant recipients tested at a median time of 110 days from second vaccine dose, 99 (38%) were seropositive, compared with 83% (101/122) of control patients. Younger age, better renal function and lower immunosuppression levels were associated with seropositivity. A total of 14% (13/94) of participants seropositive at 1 month became seronegative at follow-up and 11% (18/165) became seropositive. The latter were mainly individuals with higher antibody levels at 1 month. Antibody levels at 3–4 months were significantly reduced in both study groups, although the decline was more pronounced in the control group. Kidney transplant recipients present poor antibody response to mRNA SARS-CoV-2 vaccination, with only 38% seropositive at 3–4 months. Nevertheless, the decay in antibody response over time is modest, and some patients may present delayed response, reaching adequate antibody levels at 3–4 months. Low seropositivity rates in this group call for investigating other immunization strategies. [ABSTRACT FROM AUTHOR]

Patients with specific hematological malignancies (HM) are at increased risk for severe disease and death from infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In healthy subjects, vaccination against SARS-CoV-2 has been demonstrated to be highly effective in disease prevention; however, immunocompromised patients were largely excluded from vaccine randomized controlled trials. In this review, we overview available non-randomized studies addressing effectiveness and safety of several coronavirus disease 2019 (COVID-19) vaccines in patients with HM. Overall, COVID-19 vaccines are safe in patients with HM, with adverse events similar to those in the general population. Though serology testing is not recommended as a test to evaluate vaccine effectiveness, a correlation between higher antibody levels and protection against infection has been reported. Studies evaluating humoral response to COVID-19 vaccine in HM patients demonstrate low immunogenicity, mainly in patients with lymphoproliferative disorders, as well as with certain drugs, including mainly anti-CD20 antibodies, Bruton tyrosine kinase inhibitors, and also ruxolitinib and venetoclax. Seropositivity rates of patients with non-Hodgkin lymphoma and chronic lymphocytic leukemia following mRNA vaccination reach 40%–50%. T-cell responses to vaccination are also impaired among these patients. Better humoral response rates are reported in multiple myeloma patients and hematopoietic stem-cell transplant, reaching ∼75%–80%, but not in patients following chimeric antigen receptor T-cell therapy. Patients with chronic myeloid leukemia and myeloproliferative diseases have high response rate to vaccination. Third mRNA vaccine dose is currently recommended to all HM patients. Alternative approaches for vaccination and prevention in patients unable to mount an immune response following full vaccination are provided in the review. [ABSTRACT FROM AUTHOR]

Background: Immunosuppression reduction is a common practice in the management of bacterial infection among kidney transplant recipients (KTRs). This practice, however, is based on limited evidence. Methods: Retrospective study comparing clinical outcomes of KTRs whose antimetabolite was discontinued vs continued during hospitalization due to bacterial infection, considering calcineurin inhibitors (CNI) levels. Primary outcome was a composite of clinical failure at day 5; all‐cause mortality; and/or re‐hospitalization at 90 days. Multivariable analysis of risk factors for the primary outcome was performed using a propensity‐matched cohort. Results: We included 183 KTRs hospitalized with bacterial infection. Neither discontinuation of antimetabolites nor lower levels of CNI at infection onset were associated with a significant decrease the composite primary outcome. No significant difference in graft loss or rejection was demonstrated between patients with low vs high CNI levels or discontinuation vs continuation of antimetabolite. In multivariable analysis, CNI levels and management of antimetabolite were not significantly associated with adverse outcome. Conclusions: Immunosuppression reduction in hospitalized KTRs with bacterial infection did not offer a clinical advantage in terms of mortality, re‐hospitalization, or clinical success. An interventional study evaluating continuation of immunosuppression vs reduction should be considered. [ABSTRACT FROM AUTHOR]

• The proposed AMS framework in LTCF should focus on five domains: strategic vision, team, interventions, patient-centred care and awareness. • Internists can partner with geriatrists, pharmacists and infectious disease specialists to address barriers and to improve patient care. • AMS interventions are associated with reduced side effects, lower mortality, shorter hospital stays, and reduced costs. Older adults hospitalized in internal medicine wards or long-term care facilities (LTCF) are progressively increasing. Older adults with multimorbidity are more susceptible to infections, as well as to more vulnerable to adverse effects (and interactions) of antibiotics, resulting in a need for effective and safer strategies for antimicrobial stewardship (ASM), both in hospitalization wards and long-term care facilities. Studies on antimicrobial stewardship in older patients are scarce and guidelines are required. Given the peculiarities of the optimization of antimicrobial prescription in individual older adults for common infections, tactics to overcome barriers need an update. The use of rapid diagnosis tests, biomarkers, de-escalation and switching from intravenous to oral/subcutaneous therapy strategies are examples of successful AMS interventions. AMS interventions are associated with reduced side effects, lower mortality, shorter hospital stays, and reduced costs. The proposed AMS framework in LTCF should focus on five domains: strategic vision, team, interventions, patient-centred care and awareness. Internists can partner with geriatrists, pharmacists and infectious disease specialists to address barriers and to improve patient care. [ABSTRACT FROM AUTHOR]