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Background: Patients with rare, pathogenic cardiomyopathy (CM) and arrhythmia variants can present with atrial fibrillation (AF). The efficacy of AF ablation in these patients is unknown., Objective: This study tested the hypotheses that: 1) patients with a pathogenic variant in any CM or arrhythmia gene have increased recurrence following AF ablation; and 2) patients with a pathogenic variant associated with a specific gene group (arrhythmogenic left ventricular CM [ALVC], arrhythmogenic right ventricular CM, dilated CM, hypertrophic CM, or a channelopathy) have increased recurrence., Methods: We performed a prospective, observational, cohort study of patients who underwent AF catheter ablation and whole exome sequencing. The primary outcome measure was ≥30 seconds of any atrial tachyarrhythmia that occurred after a 90-day blanking period., Results: Among 1,366 participants, 109 (8.0%) had a pathogenic or likely pathogenic (P/LP) variant in a CM or arrhythmia gene. In multivariable analysis, the presence of a P/LP variant in any gene was not significantly associated with recurrence (HR 1.15; 95% CI 0.84-1.60; P = 0.53). P/LP variants in the ALVC gene group, predominantly LMNA, were associated with increased recurrence (n = 10; HR 3.75; 95% CI 1.84-7.63; P < 0.001), compared with those in the arrhythmogenic right ventricular CM, dilated CM, hypertrophic CM, and channelopathy gene groups. Participants with P/LP TTN variants (n = 46) had no difference in recurrence compared with genotype-negative-controls (HR 0.93; 95% CI 0.54-1.59; P = 0.78)., Conclusions: Our results support the use of AF ablation for most patients with rare pathogenic CM or arrhythmia variants, including TTN. However, patients with ALVC variants, such as LMNA, may be at a significantly higher risk for arrhythmia recurrence., Competing Interests: Funding Support and Author Disclosures This work was supported by grants from the American Heart Association (AHA20SCG35540034 [Dr Shoemaker]) and the National Institutes of Health (R01HL155197 [Dr Shoemaker]). It was also supported by CTSA award (UL1TR000445) from the National Center for Advancing Translational Sciences. Its contents are solely the responsibility of the authors and do not necessarily represent official views of the AHA or NIH. Dr Shoemaker serves on the advisory board and has received sponsored research funds from Roche Diagnostics. Dr Kanagasundram has received speaking fees from Biosense Webster and Janssen. Dr Crossley has received consulting fees or honoraria from Bayer Healthcare, Boston Scientific, Janssen Pharmaceuticals, Medtronic, and Spectranetics. Dr Richardson has received research funding from Medtronic Inc, Abbott Inc and served as a consultant for Philips Inc and Biosense Webster. Dr Montgomery has received research funding from Medtronic Inc. Dr Ellis has received research funding from Boston Scientific, Medtronic, and Boehringer Ingelheim; and consulting fees from Medtronic, Boston Scientific, Abbott Medical, and Atricure. Dr Michaud has received consulting fees or honoraria from Boston Scientific, Medtronic, Biotronik, Abbott, and Biosense Webster. Vanderbilt receives fellowship support from Medtronic inc., Boston Scientific inc., Abbott Labs, Biotronik, and Johnson & Johnson. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Recurrence after atrial fibrillation (AF) ablation remains common. We evaluated the association between recurrence and levels of biomarkers of cardiac remodeling, and their ability to improve recurrence prediction when added to a clinical prediction model., Methods and Results: Blood samples collected before de novo catheter ablation were analyzed. Levels of bone morphogenetic protein-10, angiopoietin-2, fibroblast growth factor-23, insulin-like growth factor-binding protein-7, myosin-binding protein C3, growth differentiation factor-15, interleukin-6, N-terminal pro-brain natriuretic peptide, and high-sensitivity troponin T were measured. Recurrence was defined as ≥30 seconds of an atrial arrhythmia 3 to 12 months postablation. Multivariable logistic regression was performed using biomarker levels along with clinical covariates: APPLE score (Age >65 years, Persistent AF, imPaired eGFR [<60 ml/min/1.73m 2 ], LA diameter ≥43 mm, EF <50%; which includes age, left atrial diameter, left ventricular ejection fraction, persistent atrial fibrillation, and estimated glomerular filtration rate), preablation rhythm, sex, height, body mass index, presence of an implanted continuous monitor, year of ablation, and additional linear ablation. A total of 1873 participants were included. A multivariable logistic regression showed an association between recurrence and levels of angiopoietin-2 (odds ratio, 1.08 [95% CI, 1.02-1.15], P =0.007) and interleukin-6 (odds ratio, 1.02 [95% CI, 1.003-1.03]; P =0.02). The area under the receiver operating characteristic curve of a model that only contained clinical predictors was 0.711. The addition of any of the 9 studied biomarkers to the predictive model did not result in a statistically significant improvement in the area under the receiver operating characteristic curve., Conclusions: Higher angiopoietin-2 and interleukin-6 levels were associated with recurrence after atrial fibrillation ablation in multivariable modeling. However, the addition of biomarkers to a clinical prediction model did not significantly improve recurrence prediction.

Background: Scarce data exist on the evolution of device-related thrombus (DRT) after left atrial appendage closure (LAAC)., Objectives: This study sought to assess the incidence, predictors, and clinical impact of persistent and recurrent DRT in LAAC recipients., Methods: Data were obtained from an international multicenter registry including 237 patients diagnosed with DRT after LAAC. Of these, 214 patients with a subsequent imaging examination after the initial diagnosis of DRT were included. Unfavorable evolution of DRT was defined as either persisting or recurrent DRT., Results: DRT resolved in 153 (71.5%) cases and persisted in 61 (28.5%) cases. Larger DRT size (OR per 1-mm increase: 1.08; 95% CI: 1.02-1.15; P = 0.009) and female (OR: 2.44; 95% CI: 1.12-5.26; P = 0.02) were independently associated with persistent DRT. After DRT resolution, 82 (53.6%) of 153 patients had repeated device imaging, with 14 (17.1%) cases diagnosed with recurrent DRT. Overall, 75 (35.0%) patients had unfavorable evolution of DRT, and the sole predictor was average thrombus size at initial diagnosis (OR per 1-mm increase: 1.09; 95% CI: 1.03-1.16; P = 0.003), with an optimal cutoff size of 7 mm (OR: 2.51; 95% CI: 1.39-4.52; P = 0.002). Unfavorable evolution of DRT was associated with a higher rate of thromboembolic events compared with resolved DRT (26.7% vs 15.1%; HR: 2.13; 95% CI: 1.15-3.94; P = 0.02)., Conclusions: About one-third of DRT events had an unfavorable evolution (either persisting or recurring), with a larger initial thrombus size (particularly >7 mm) portending an increased risk. Unfavorable evolution of DRT was associated with a 2-fold higher risk of thromboembolic events compared with resolved DRT., Competing Interests: Funding Support and Author Disclosures Dr Rodés-Cabau holds the Research Chair “Fondation Famille Jacques Larivière” for the Development of Structural Heart Disease Interventions (Laval University, Quebec City, Canada). He also has received institutional research grants from Boston Scientific. Dr Maarse has received an unrestricted grant from Boston Scientific. Dr Pérez de Prado has served as a proctor for Boston Scientific. Dr Gupta has served as a proctor for Abbott. Dr Sanchez has served as a speaker and proctor for Boston Scientific. Dr Wang has served as a consultant for Edwards Lifesciences, Boston Scientific, and Neochord; and received research grant support from Boston Scientific assigned to his employer, the Henry Ford Health System. Dr Demkow has served as a proctor for Abbott and Boston Scientific. Dr Alkhouli has served as a consultant for Boston Scientific. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Purpose: A case of loperamide-induced recurrent torsades de pointes is reported to raise awareness of an increasingly common phenomenon that could be encountered by medical providers during the current opioid epidemic., Summary: A 40 year-old-man with a prior history of opioid abuse who presented to the emergency department after taking up to 100 tablets of loperamide 2 mg daily for 5 years to blunt opioid withdrawal symptoms and was subsequently admitted to the intensive care unit for altered mental status and hyperthermia. The patient had prolonged QTc and 2 episodes of torsades de pointes (TdP) that resulted in cardiac arrest with return of spontaneous circulation. He was managed with isoproterenol, overdrive pacing, and methylnatrexone with no other events of TdP or cardiac arrest., Conclusion: A 40-year-old male who developed torsades de pointes from loperamide overdose effectively treated with overdrive pacing, isoproterenol, and methylnatrexone.

Objectives: The aim of this study was to assess temporal changes and clinical implications of peridevice leak (PDL) after left atrial appendage closure., Background: Endocardial left atrial appendage closure devices are alternatives to long-term oral anticoagulation (OAC) for patients with atrial fibrillation. PDL >5 mm may prohibit discontinuation of OAC., Methods: Patients included in the study had: 1) successful Watchman device implantation without immediate PDL; 2) new PDL identified at 45 to 90 days using transesophageal echocardiography; 3) eligibility for OAC; and 4) 1 follow-up transesophageal echocardiographic study for PDL surveillance. Relevant clinical and imaging data were collected by chart review. The combined primary outcome included failure to stop OAC after 45 to 90 days, transient ischemic attack or stroke, device-related thrombi, and need for PDL closure., Results: Relevant data were reviewed for 1,039 successful Watchman device implantations. One hundred eight patients (10.5%) met the inclusion criteria. The average PDL at 45 to 90 days was 3.2 ± 1.6 mm. On the basis of a median PDL of 3 mm, patients were separated into ≤3 mm (n = 73) and >3 mm (n = 35) groups. In the ≤3 mm group, PDL regressed significantly (2.2 ± 0.8 mm vs 1.6 ± 1.4 mm; P = 0.002) after 275 ± 125 days. In the >3 mm group, there was no significant change in PDL (4.9 ± 1.4 mm vs 4.0 ± 3.0 mm; P = 0.12) after 208 ± 137 days. The primary outcome occurred more frequently (69% vs 34%; P = 0.002) in the >3 mm group. The incidence of transient ischemic attack or stroke in patients with PDL was significantly higher compared with patients without PDL, irrespective of PDL size., Conclusions: New PDL detected by transesophageal echocardiography at 45 to 90 days occurred in a significant percentage of patients and was associated with worse clinical outcomes. PDL ≤3 mm tended to regress over time., Competing Interests: Funding Support and Author Disclosures Dr Ellis has received research grants (to Vanderbilt University) from Boehringer-Ingelheim, Medtronic, and Boston Scientific; is a consultant or adviser to Medtronic, Abbott Medical, Boston Scientific, and Atricure. All other authors reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Device-related thrombus (DRT) has been considered an Achilles' heel of left atrial appendage occlusion (LAAO). However, data on DRT prediction remain limited., Objectives: This study constructed a DRT registry via a multicenter collaboration aimed to assess outcomes and predictors of DRT., Methods: Thirty-seven international centers contributed LAAO cases with and without DRT (device-matched and temporally related to the DRT cases). This study described the management patterns and mid-term outcomes of DRT and assessed patient and procedural predictors of DRT., Results: A total of 711 patients (237 with and 474 without DRT) were included. Follow-up duration was similar in the DRT and no-DRT groups, median 1.8 years (interquartile range: 0.9-3.0 years) versus 1.6 years (interquartile range: 1.0-2.9 years), respectively (P = 0.76). DRTs were detected between days 0 to 45, 45 to 180, 180 to 365, and >365 in 24.9%, 38.8%, 16.0%, and 20.3% of patients. DRT presence was associated with a higher risk of the composite endpoint of death, ischemic stroke, or systemic embolization (HR: 2.37; 95% CI, 1.58-3.56; P < 0.001) driven by ischemic stroke (HR: 3.49; 95% CI: 1.35-9.00; P = 0.01). At last known follow-up, 25.3% of patients had DRT. Discharge medications after LAAO did not have an impact on DRT. Multivariable analysis identified 5 DRT risk factors: hypercoagulability disorder (odds ratio [OR]: 17.50; 95% CI: 3.39-90.45), pericardial effusion (OR: 13.45; 95% CI: 1.46-123.52), renal insufficiency (OR: 4.02; 95% CI: 1.22-13.25), implantation depth >10 mm from the pulmonary vein limbus (OR: 2.41; 95% CI: 1.57-3.69), and non-paroxysmal atrial fibrillation (OR: 1.90; 95% CI: 1.22-2.97). Following conversion to risk factor points, patients with ≥2 risk points for DRT had a 2.1-fold increased risk of DRT compared with those without any risk factors., Conclusions: DRT after LAAO is associated with ischemic events. Patient- and procedure-specific factors are associated with the risk of DRT and may aid in risk stratification of patients referred for LAAO., Competing Interests: Funding Support and Author Disclosures Dr Maarse has received an unrestricted grant from Boston Scientific. Dr Pérez de Prado has served as a proctor for Boston Scientific. Dr Gupta has served as a proctor for Abbott. Dr Sanchez has served as a speaker and proctor for Boston Scientific. Dr Demkow has served as a proctor for Abbott and Boston Scientific. Dr Alkhouli has served as a consultant for Boston Scientific. Dr Wang has been a consultant for Edwards LifeSciences, Boston Scientific, and Neochord; and has received research grant support from Boston Scientific assigned to employer Henry Ford health system. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Watchman 2.5 (Boston Scientific Inc, Marlborough, MA) implant success approaches 95% in registries, yet many patients are not attempted because of complex left atrial appendage (LAA) anatomy. Watchman FLX can expand the range of ostium width (14-31.5 mm) and depth available for LAA closure., Objective: The purpose of this study was to evaluate the safety and efficacy of Watchman FLX in patients with a failed Watchman 2.5 attempt or prohibitive LAA anatomy., Methods: The roll-in (n = 58) and primary effectiveness (n = 400) cohorts of the PINNACLE FLX trial comprised the study population. Subjects were identified who previously failed implantation of Watchman 2.5 (n = 11) or were not attempted because of prohibitive LAA anatomy (n = 88). Demographic characteristics, implant procedure details, and TEE follow-up data were compared to controls composed of enrollees not meeting these criteria (n = 359)., Results: Watchman FLX LAA closure was successfully implanted in all subjects with a prior failed Watchman 2.5 attempt (n = 11 of 11). Subjects with previously failed Watchman 2.5 were more likely to receive a 35 mm FLX device than controls (27.3% vs 7.3%; P = .047). Patients with prohibitive anatomy had smaller LAA dimensions than did controls (diameter 18.0 ± 4 mm vs 20.4 ± 3 mm; P < .001 and length 23.7 ± 5 mm vs 28.9 ± 5 mm; P < .001). There was no difference in age, sex, CHA 2 DS 2 -VASc score, HAS-BLED score, or primary efficacy between cohorts. Transesophageal echocardiography (TEE) at 12 months showed zero leak in 90.9% in the failed Watchman 2.5 cohort, 91.3% in the prohibitive anatomy cohort, and 89.5% in the control cohort (P = .84). Overall and cardiovascular mortality was lower in the prohibitive anatomy cohort (1.2% vs 8.8% in controls; P = .02)., Conclusion: Watchman FLX implantation in patients with a prior failed Watchman 2.5 attempt or prohibitive LAA anatomy remained safe and highly effective. The association of reduced overall mortality with smaller LAA dimension warrants future study., (Copyright © 2021 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Objectives: The aim of this study was to assess the safety and efficacy of a new subxiphoid hybrid epicardial-endocardial atrial fibrillation (AF) ablation and left atrial appendage (LAA) ligation approach for the treatment of persistent AF., Background: Surgical hybrid ablation procedures have shown promise for maintaining sinus rhythm versus catheter ablation but are associated with increased periprocedural adverse events., Methods: Patients with symptomatic persistent AF (n = 33, mean age 64 ± 9 years, 25 men) who had antiarrhythmic drug therapy or prior catheter ablation was unsuccessful were referred for hybrid epicardial-endocardial AF ablation and LAA exclusion. LAA closure was confirmed by transesophageal echocardiographic Doppler flow and/or computed tomographic angiography 1 to 3 months post-ligation. The incidence of atrial tachycardia or AF recurrence, LAA closure, thromboembolic events, and post-operative complications were assessed., Results: All 33 patients underwent successful LAA ligation with epicardial ablation of the posterior left atrial wall, as well as endocardial pulmonary vein isolation and cavotricuspid isthmus ablation. Freedom from atrial tachycardia or AF was 91% (20 of 22 patients) at 6 months, 90% (18 of 20 patients) at 12 months, 92% (11 of 12 patients) at 18 months, and 92% (11 of 12) at 24 months. There were no acute periprocedural complications (<7 days). Thirty-day adverse events included 2 patients with pericardial effusion requiring pericardiocentesis and 1 incisional hernia repair. There were no long-term complications, strokes, or deaths. LAA ligation was complete in 27 of 33 subjects (82%), with 6 subjects having leaks of <5 mm., Conclusions: Subxiphoid hybrid epicardial-endocardial ablation with LAA ligation is feasible, safe, and effective. Future prospective studies are needed to validate these initial findings., Competing Interests: Author Disclosures Dr. Lee is a consultant for and equity holder in SentreHEART/AtriCure. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Referring patients with nonvalvular atrial fibrillation (NVAF) for left atrial appendage closure (LAAC) device should be based on bleeding risks, poor anticoagulation compliance, and patient goals. Patient selection should consider overall prognosis and risk of implant procedure. We detail specific clinical scenarios where LAAC could be considered, based on FDA-approved indications. The indications for LAAC are different in Europe. High-risk scenarios in which LAA occlusion may be preferred alone, or in addition to oral anticoagulation use, are reviewed. Ongoing clinical trials and newer device designs will help change the appropriate post-implant drug regimen which will affect patient and device selection., Competing Interests: Disclosure Consulting and Advisory Board; (All <$10,000 per annum); Boston Scientific Inc, Abbott Medical Inc, Medtronic Inc Research funding; Investigator Initiated studies (funding paid to Vanderbilt University Medical Center); Boston Scientific Inc, Medtronic Inc, Atricure Inc, Boehringer-Ingelheim Pharmaceuticals Inc (C.R. Ellis). No disclosures (G.G. Jackson)., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Importance: Hypoglycemia-related emergency department (ED) or hospital use among patients with type 2 diabetes (T2D) is clinically significant and possibly preventable., Objective: To develop and validate a tool to categorize risk of hypoglycemic-related utilization in patients with T2D., Design, Setting, and Participants: Using recursive partitioning with a split-sample design, we created a classification tree based on potential predictors of hypoglycemia-related ED or hospital use. The resulting model was transcribed into a tool for practical application and tested in 1 internal and 2 fully independent, external samples. Development and internal testing was conducted in a split sample of 206 435 patients with T2D from Kaiser Permanente Northern California (KPNC), an integrated health care system. The tool was externally tested in 1 335 966 Veterans Health Administration and 14 972 Group Health Cooperative patients with T2D., Exposures: Based on a literature review, we identified 156 candidate predictor variables (prebaseline exposures) using data collected from electronic medical records., Main Outcomes and Measures: Hypoglycemia-related ED or hospital use during 12 months of follow-up., Results: The derivation sample (n = 165 148) had a mean (SD) age of 63.9 (13.0) years and included 78 576 (47.6%) women. The crude annual rate of at least 1 hypoglycemia-related ED or hospital encounter in the KPNC derivation sample was 0.49%. The resulting hypoglycemia risk stratification tool required 6 patient-specific inputs: number of prior episodes of hypoglycemia-related utilization, insulin use, sulfonylurea use, prior year ED use, chronic kidney disease stage, and age. We categorized the predicted 12-month risk of any hypoglycemia-related utilization as high (>5%), intermediate (1%-5%), or low (<1%). In the internal validation sample, 2.0%, 10.7%, and 87.3% were categorized as high, intermediate, and low risk, respectively, with observed 12-month hypoglycemia-related utilization rates of 6.7%, 1.4%, and 0.2%, respectively. There was good discrimination in the internal validation KPNC sample (C statistic = 0.83) and both external validation samples (Veterans Health Administration: C statistic = 0.81; Group Health Cooperative: C statistic = 0.79)., Conclusions and Relevance: This hypoglycemia risk stratification tool categorizes the 12-month risk of hypoglycemia-related utilization in patients with T2D using only 6 inputs. This tool could facilitate targeted population management interventions, potentially reducing hypoglycemia risk and improving patient safety and quality of life.

HtrA1, Ddr-2, and Mmp-13 are reliable biomarkers for osteoarthritis (OA), yet the exact mechanism for the upregulation of HtrA-1 is unknown. Some have shown that chondrocyte hypertrophy is associated with early indicators of inflammation including TGF-β and the Receptor for Advanced Glycation End-products (RAGE). To examine the correlation of inflammation with the expression of biomarkers in OA, we performed right knee destabilization surgery on 4-week-old-wild type and RAGE knock-out (KO) mice. We assayed for HtrA-1, TGF-β1, Mmp-13, and Ddr-2 in articular cartilage at 3, 7, 14, and 28 days post-surgery by immunohistochemistry on left and right knee joints. RAGE KO and wild type mice both showed staining for key OA biomarkers. However, RAGE KO mice were significantly protected against OA compared to controls. We observed a difference in the total number of chondrocytes and percentage of chondrocytes staining positive for OA biomarkers between RAGE KO and control mice. The percentage of cells staining for OA biomarkers correlated with severity of cartilage degradation. Our results indicate that the absence of RAGE did protect against the development of advanced OA. We conclude that HtrA-1 plays a role in lowering TGF-β1 expression in the process of making articular cartilage vulnerable to damage associated with OA progression.

Animal model studies and human epidemiological studies have shown that some infectious diseases develop primarily in individuals with an inherited predisposition. A heritable contribution to the development of severe influenza virus infection (i.e., that which results in death) has not previously been hypothesized or tested. Evidence for a heritable contribution to death due to influenza was examined using a resource consisting of a genealogy of the Utah population linked to death certificates in Utah over a period of 100 years. The relative risks of death due to influenza were estimated for the relatives of 4,855 individuals who died of influenza. Both close and distant relatives of individuals who died of influenza were shown to have a significantly increased risk of dying of influenza, consistent with a combination of shared exposure and genetic effects. These data provide strong support for a heritable contribution to predisposition to death due to influenza.

Multiple mutations in the reverse transcriptase (RT) gene were observed in a drug-resistant isolate of human immunodeficiency virus type 1 (HIV1) from an individual having prolonged (greater than 2 years) zidovudine (AZT) therapy. The virus replicated in PBMC's in the presence of very high concentrations of AZT (125 microM). Drug-sensitive strains were curtailed by 0.01 microM AZT. Eleven defined mutations were observed as compared with published sequences of RT for eight strains of HIV1. Eight of these mutations were found in the domain involved in nucleotide recognition and enzyme function. Only one of the mutations, giving a Thr--Tyr change at amino acid 215, matched those previously ascribed (67, 70, 215, and 219) to the generation of high-level resistance to AZT. Therefore additional amino acid changes may have significance in the emergence of super-resistant viruses.

The first exposure of gram-negative bacilli to an aminoglycoside antibiotic in vitro induces a biphasic bactericidal response and adaptive drug resistance (G. L. Daikos, G. G. Jackson, V. T. Lolans, and D. M. Livermore, J. Infect. Dis. 162:414-420, 1990; G. G. Jackson, G. L. Daikos, and V. T. Lolans, J. Infect. Dis. 162:408-413, 1990). The therapeutic implications were examined in netilmicin treatment of a Pseudomonas aeruginosa infection of normal and neutropenic mice. For 2 h after the first dose, the bactericidal rates were rapid, 0.75, 1.0, and 1.5 log10 CFU/h with doses of 10, 30, and 60 mg/kg, respectively. Each twofold increase in dosage reduced the number of surviving bacteria fivefold. Between 2 and 6 h, the second-phase bactericidal rate was slow, less than or equal to 0.3 log10 CFU/h, regardless of the dose. In a multiple-dose regimen, the same amount of netilmicin given in one dose was 70 and 90% more effective than two or three doses, respectively. Doses calculated to keep the drug level in plasma above the MIC were less effective than regimens giving first exposure to a high drug concentration. Adaptive resistance occurred when doses were given more than 2 h after the start of treatment. Temporary survival of bacteremic neutropenic mice was 60 to 70% greater with a second dose at 2 h than after a longer interval. In a thigh infection of neutropenic mice treated every 2 h, doses 4, 6, and 8 h after the first one showed no bactericidal effect. A drug-free interval of 8 h (20 times the drug half-life) renewed bacterial susceptibility to drug action. The results in vivo confirm the biphasic bactericidal action and induction of adaptive resistance that characterized first exposure of gram-negative bacilli to aminoglycoside antibiotics. The phenomena have meaning for the optimum clinical use of aminoglycosides.

Adaptive resistance to the bactericidal effect of an aminoglycoside antibiotic was induced in Pseudomonas aeruginosa and other aerobic gram-negative bacilli by initial exposure to the drug. Both subinhibitory and inhibitory concentrations produced resistance in bacterial cells surviving the effects of the initial ionic binding. Development of drug refractoriness required an adaptive period of growth, was enhanced by the continued presence of drug, and reversed after several hours of growth in drug-free medium. Unstable resistance was not explained by selection of mutants. The mechanism of adaptive resistance was down-regulation of aminoglycoside uptake during the period of accelerated energy dependent drug transport (EDP II). Down-regulation induced by gentamicin or tobramycin produced cross-resistance to other aminoglycosides. The kinetics of unstable first-exposure resistance suggests that a continuous drug level might not provide the most effective therapy with aminoglycosides and gives rationale to larger initial and longer interval bolus dosing.

Gram-negative bacilli precooled to 4 degrees C to inactivate energy-dependent drug transport were exposed to an aminoglycoside antibiotic to assess the antibacterial effect of passive ionic binding of drug. Removal of free drug and energizing the cells by incubation at 37 degrees C showed the postexposure effect to be bactericidal. The effect was directly related to the amount and concentration of drug in the initial exposure medium proportional to the bacterial density. Binding was nonsaturable at the highest drug:bacteria ratio tested. Elution, exposure of spheroplasts, and inhibition by divalent cations indicated binding sites in the outer bacterial membrane. Different bacterial species had variable efficiency but similar patterns of binding different aminoglycosides reflecting in vitro susceptibility. The self-promoted postexposure internalization of ionically bound aminoglycoside accounts for the early drug-concentration-dependent rapid bactericidal action of aminoglycosides. The phenomenon has implications for effective initial dosing with aminoglycoside antibiotics.

Acute septic infective endocarditis caused by Pseudomonas aeruginosa, in two patients with conditions that made it incurable, was treated with long-term orally administered ciprofloxacin. Bacteremia and symptoms cleared, resulting in subjective well-being without cure for three and one half and 22 months, respectively. Large amounts of ciprofloxacin, 150 and 1,440 g, respectively, were given continuously without apparent adverse reactions. Blood isolates of P. aeruginosa after treatment had limited progression of resistance to ciprofloxacin. Use of orally administered ciprofloxacin provides new opportunities for the long-term treatment of serious infections with restricted risk of bacterial drug resistance and no appreciable side effects.

Cinoxacin, a new synthetic antibacterial agent with in vitro activity against all species of Enterobacteriaceae, was used in the treatment of urinary tract infections in 20 patients. The dose of cinoxacin was 250 mg orally every 6 h for 10 days. The etiological agents were Escherichia coli in fifteen, Klebsiella-Enterobacter in five, Proteus mirabilis in two, and Providencia in one. The minimal inhibitory concentration for these organisms ranged from 2 to 64 mug/ml. Eleven of the 20 patients had renal involvement by defined criteria, whereas the remaining nine were considered to have bladder bacilluria. The initial strain was eradicated during and immediately after treatment in 19 of 20 cases. At 6 weeks, 65% had sterile urine. Bactericidal urine levels of cinoxacin were obtained in all patients. No significant hematological, renal, hepatic, or gastroenterologic toxicity was noted. Cinoxacin appears to be a safe and useful drug in the treatment of urinary tract infections caused by Enterobacteriaceae.

Under double-blind protocol, a controlled comparison was made between a new cephalosporin, cephacetrile, and cephalothin or cephaloridine. The patient's primary physician determined the indications for treatment, and the dosage was uniform for each route of administration. Infecting strains of staphylococci and Proteus mirabilis had a lower median inhibitory concentration for cephalothin than cephacetrile; the opposite was true for Escherichia coli and Klebsiella species. The average peak serum level 1 h after a dose of 2 g intravenously was 74.9 +/- 21 and 21.5 +/- 8.7 mug/ml for cephacetrile and cephalothin, respectively; 6 h after the dose, the respective levels were 12.4 +/- 4.3 and 3.7 +/- 0.9 mug/ml. Renal clearances were similar and the plasma clearance was proportional to the serum levels. In the urine, the concentration of cephacetrile was three times higher than that of cephalothin. Based on a percentage of therapeutic potential, success in the treatment of infections with susceptible organisms was 42 and 44% for the two different drug regimens. Initial bacterial resistance was found in about one-fifth of infections, and concomitant therapy with other drugs was practiced in one-half of the treatment courses. Intravenous use of cephacetrile was discontinued prematurely more often than was use of cephalothin, suggesting less tolerance. Although there was no overt toxicity, more than 75% of patients on either regimen had some form of unwanted response to treatment, the most common being superinfection. From this limited but controlled experience, cephacetrile can be considered comparable to cephalothin in antimicrobial treatment and overall side reactions.

In two double-blind trials, volunteers challenged with rhinovirus were treated with aspirin or placebo. Aspirin treatment did not alter the rates of infection or illness but was associated with a moderate reduction in the frequency or severity of some symptoms. The overall benefit in rhinovirus infection was not statistically significant. Aspirin treatment appeared to cause a highly significant increase in the rate of virus shedding in treated subjects. The increase in virus shedding must be considered an adverse event that could influence the course of the disease in the individual and increase the likelihood of the spread of the infection to contacts.

Bacterial endocarditis caused by Actinobacillus actinomycetemcomitans is a rare disease. A 48-year-old man who had a Starr-Edwards aortic valve prosthesis inserted in 1972 was admitted for evaluation of confusion, headaches, anorexia, weight loss, diarrhea and weakness. Six blood cultures yielded gram-negative organisms which were subsequently identified as A. actinomycetemcomitans. Treatment with ampicillin and gentamicin resulted in cure which has been maintained after an observation period of eleven months. This represents the second report of A. actinomycetemcomitans endocarditis in a patient with a prosthetic valve.

We examined the effects and mechanisms of action of ACTH and ACTH fragments on gonadotropin secretion in immature rats. ACTH administered by daily injection or continuous infusion (osmotic minipumps) attenuated the postcastration rise in serum LH. Pituitary LH concentration was either unchanged or increased in ACTH-treated rats and pituitary sensitivity to gonadotropin-releasing hormone (GnRH) was reduced by ACTH treatment. A fragment of ACTH (ACTH 4-10), which is less steroidogenic, did not alter levels of serum LH, and ACTH did not reduce LH secretion in adrenalectomized castrates. Serum and pituitary concentrations of prolactin were normal in ACTH-treated animals. These studies demonstrate that the suppression of gonadotropin secretion by ACTH is mediated by the adrenal gland. This mechanism causes a decreased pituitary sensitivity to GnRH, but LH synthesis does not appear to be affected. Prolactin does not play a role in this mechanism.

Recovery of herpes simplex virus (HSV) Type 1 from the blood buffy coat of four adults is reported for the first time. All of the patients had vesicular stomatitis and facial vesicles; two also had either keratoconjunctivitis or disseminated skin lesions. The infection was not the primary one with HSV in any of them. Two of three patients who had renal failure were receiving immunosuppressive drugs; one patient was normal except for alcoholism and diabetes. None developed signs of visceral organ infection and all recovered within 2 to 4 weeks. The findings demonstrate the occurrence of heretofore unrecognized nonfatal HSV Type 1 viremia in both healthy and immunosuppressed leukocytes, can occur regardless of the presence of serum antibody, and may or may not be associated with the disseminated lesions.

The discovery that aminosugars found in nature kill common bacteria initiated use of a new class of antibiotics that have played a key role in the management of several major medical problems over the past 40 years. The rapid bactericidal effect of the aminoglycosides on aerobic Gram-negative bacilli has expanded their use to approximately 6% of all our general hospital patients. These agents have many desirable properties, but also have the potential for producing ototoxicity and nephrotoxicity that imposes pharmacological limitations on their optimum use. The experience of earlier investigations demonstrated the need for quantitative measurements and individual patient dosing which has reduced the risk of toxicity many fold. Using sensitive measurements, toxic manifestations can be classified as detectable by laboratory means only, some that have clinical expression and rarely a lasting handicap. Semisynthetic modification of kanamycin (amikacin) and sissomicin (netilmicin) protects these compounds against inactivation by most bacterial enzymes and preserves their effectiveness. Netilmicin seems to have less potential for causing toxicity, especially ototoxicity that is irreversible, and offers the possibility of further gains through pharmacological flexibility without crippling toxicity.

One hundred fourteen articles published in the Journal of Infectious Diseases in 1982 were evaluated for the occurrence of eight commonly made statistical errors. Seventy-one percent of Original Articles and 50% of presentations in the Data Forum used statistical methods to analyze results. Almost all of the articles that used statistics contained at least one statistical error. The most common inadequacy, which occurred in 95% of the articles with statistical data, was the statement of a probability value without a complete summary of the statistical results. The most common error was the failure to include a correction for multiple comparisons. These results suggest that a more clearly stated statistical policy, a more explicit set of instructions to authors, and closer editorial attention to statistical methodology, perhaps at the prepublication phase, would improve the validity of articles published in the Journal.

Fungal and mycobacterial infections are among the most common opportunistic infections in patients infected with human immunodeficiency virus (HIV). Candida infections are the bell-wether of progression to symptomatic HIV infection and candida oesophagitis often marks the onset of the acquired immunodeficiency syndrome (AIDS). More than 80% of AIDS patients have candida disease. Candida infections remain local and respond to treatment but tend to recur. Cryptococcal infections initially affect few HIV positive patients but involve 10-30% with AIDS. Meningitis is the usual presentation and dissemination is common. Amphotericin usually produces improvement but cure is infrequent, and maintenance therapy is advisable. Mycobacteria cause intracellular infections increasing in parallel with immunodeficiency. Mycobacterium avium-intracellulare is predominant, occurring with other opportunistic pathogens causing systemic and local symptoms with high bacterial density in infected cells. Multidrug treatment is best, but the results are disappointing. Tuberculosis is prevalent in certain groups of patients. It often presents with atypical clinical and pathological features. Anti-tuberculous treatment is effective and prophylaxis should be considered. Endemic fungi with mycobacteria cause sporadic infections. Opportunistic infections are the lethal arm of HIV infection. Diligent diagnosis and persistent treatment offer benefit to HIV-infected patients.

Antiviral chemotherapy has been too long perceived as being relatively impossible. Such notions adversely affect the acquisition of important specific clinical information, whereas much new knowledge is available about viral replication and cell biology which enhances the prospects for effective chemotherapy. Some immediate goals can be recognized that will further determine the ability to influence viral infections and properly interpret the drug effects. In recent controlled observations there is reason for expectant optimism, but the demonstration of antiviral chemotherapy is both disease- and host-dependent, with important nonpharmacologic aspects. Rapid specific and sensitive diagnostic tests are of paramount importance; that they can be devised is a generally accepted conclusion among virologists. Problems in the scientific evaluation of antiviral chemotherapy in man have led to the recommendations of compounds that have no proved effect; amantadine, Ara A, and interferon, however, have been shown to be efficacious. Acyclovir and bromvinyldeoxyuridine have demonstrated virus-directed chemotherapy with impressive specificity. The frontier of antiviral chemotherapy holds great promise for additional learning and improved health through the implementation of developing knowledge.

The prevalence, incidence, and source of infections with different types of herpesviruses were determined prospectively for 25 persons undergoing hemodialysis, 30 allograft recipients, and 16 kidney donors. The prevalence of prior infections with cytomegalovirus (CMV), herpes simplex virus (HSV), and Epstein-Barr virus (EBV) was high (72%-100%) and was similar for healthy persons and those with renal failure. The incidence of infections in patients undergoing hemodialysis was no greater than that before dialysis. In allograft recipients, the incidence of infection with CMV was 73%; HSV, 57%; EBV, 30%; and varicella-zoster virus (clinical), 7%. Ninety-seven percent of the patients developed an infection with one or more herpesviruses. Transfusions, hemodialysis, the allograft, and hospital environment were not significant sources in transmission. Uremia and splenectomy were unimportant in the reactivation of infection. Immunosuppressive drugs possibly algmented by a graft rejection response account for the high incidence of recrudescent infections with CMV and HSV.

Enviroxime, an inhibitor of rhinovirus replication, was studied in a double-blind, placebo-controlled trial with 99 volunteers. The efficacy of a nasal-spray formulation of enviroxime was tested as pretreatment or as postchallenge treatment for rhinovirus type 4 infection. In the regimens used, drug administration neither prevented infection nor reduced the frequency of specific colds. The mean concentration of enviroxime in nasal washes (12 h after a dose) differentiated two groups of responders. Those in whom the drug concentration exceeded 100 ng/ml had some benefits, although these were statistically insignificant.

The development of a drug with the properties of moxalactam creates both a new class of beta-lactam antibiotics and potentially a new era in chemotherapy. The specific activity (antibacterial effect/mg), stability against enzymatic degradation, and pharmacologic advantages of moxalactam provide new promise for the treatment of some infections and for moving forward our understanding of bacterial properties and the processes of infection. Such conditions offer numerous opportunities for development of new knowledge and improved practices in antimicrobial therapy. As the quality of antibiotics is improved through modification by chemical synthesis, some biologic and clinical needs shift. Experience provides a basis for anticipation and recognition of some of the conditions that are most likely to occur. Physicians should be alert to these possibilities and to their opportunity for making observations that will establish the optimal use of moxalactam, the first of a new generation of beta-lactam antibiotics.

Among patients in general hospitals approximately one-third receive antimicrobial drugs, and nosocomial infections develop in 3 to 4 percent of them. These two events vary widely suggesting no constant relation, except that antibiotic use affects the etiology and course of nosocomial infections. There is deliberation about the benefits versus the harm of antibiotic prophylaxis. It avoids the morbidity and tissue damage from infection with the least antibiotic for the shortest time and works best when the need is brief or the microbial target is a single species. Among nonsurgical patients, a high risk of infection results from exposure to a transmissible infection, minor procedural trauma or increased host susceptibility. In clinical use, antimicrobial prophylaxis usually combines inefficiency with unproved efficacy. Prevention of nosocomial acquisition of urinary tract infection, pneumonia, catheter sepsis and cutaneous infections by antibiotic prophylaxis is ineffective. Recommendations in other conditions are derived mostly from presumed benefit, recognized failures and assessment of adverse results from drug use. Inefficient long-term prophylaxis contributes to the emergence of transmissible bacterial drug resistance. Those clinical conditions that represent need with reasonable efficiency and those that are useless and dangerous prophylactic practices should be defined. Using one and avoiding the other through education and professional discipline offers the best hope of amplifying effective antibiotic prophylaxis and minimizing unwanted effects on the recipient and hospital cohorts.

Optimal therapeutic use of aminoglycoside antibiotics requires monitoring of levels in serum. Three methods have been developed for clinical use; one yields a specific 14C-labeled product, and two are microbiologic methods in which different indicator strains are used to measure the diffusion of drug into agar. These methods were compared in assays with 200 sera from patients receiving gentamicin or sisomicin. Some specimens also contained either a beta-lactam antibiotic or clindamycin. In the presence of penicillin or cephalosporin, the level of aminoglycoside measured was accurate if the specimens were treated with beta-lactamase. The presence of clindamycin invalidated the results when Bacillus subtilis was used as the indicator strain, but not with the other microbiologic method or the enzymatic method. Under proper circumstances, the results obtained by the various methods were comparable, according to statistical analysis. The enzymatic procedure is the most specific and rapid method, but materials for agar well diffusion methods are more readily available and more economical. The procedures are practical, and their use is recommended in patients being treated with aminoglycoside antibiotics.

There are now laboratory means of screening and identifying people who, although they are free from the signs of urinary tract infection, fit into abnormal groups owing to the high numbers of bacteria and leukocytes in their urine. Chronic bacteriuria and pathologic pyuria, with or without symptoms, have important physiologic and pathologic consequences. It is the physicians opportunity to recognize and treat these asymptomatic as well as symtomatic urinary tract infections. If untreated and uncorrected the result, with progressive frequency over a period of 10-15 years, is increased morbidity, especially with pregnancies, structural damage to the kidneys, kidney stones, uremia, hypertension, and premature death.

The efficacy and toxicity of ganciclovir given by intravenous or intravenous plus intravitreal injection were studied in nine patients with cytomegalovirus (CMV) retinitis; seven with AIDS and two with drug induced immunodeficiency. Five patients had retinitis with macular involvement in six sighted eyes; six patients had only peripheral retinitis in seven eyes. In two patients (two eyes) with macular involvement intravenous plus intravitreal injection of ganciclovir preserved sight; intravenous infusion alone did not in four eyes of three other patients. In seven eyes (six patients) with peripheral retinitis vision was retained regardless of the route of ganciclovir treatment. Following intravenous ganciclovir drug levels in the vitreous fluid were 1.4-2.2 mmol/l, that is, 44 and 65% of the concomitant serum concentration. Clinically and at necropsy three eyes showed no evidence of toxicity from intravitreal injection of ganciclovir. All of five patients with AIDS who received intravenous ganciclovir for more than one week developed leucopenia. CMV retinitis of the macula may be benefited with minimal drug toxicity by intravitreal injection of ganciclovir. Treatment of peripheral CMV retinitis in patients with AIDS may be optional.