Ronald Reagan UCLA Medical Center

The Infectious Diseases Society of America (IDSA) continues to view with concern the lean pipeline for novel therapeutics to treat drug-resistant infections, especially those caused by gram-negative pathogens. Infections now occur that are resistant to all current antibacterial options. Although the IDSA is encouraged by the prospect of success for some agents currently in preclinical development, there is an urgent, immediate need for new agents with activity against these panresistant organisms. There is no evidence that this need will be met in the foreseeable future. Furthermore, we remain concerned that the infrastructure for discovering and developing new antibacterials continues to stagnate, thereby risking the future pipeline of antibacterial drugs. The IDSA proposed solutions in its 2004 policy report, "Bad Bugs, No Drugs: As Antibiotic R&D Stagnates, a Public Health Crisis Brews," and recently issued a "Call to Action" to provide an update on the scope of the problem and the proposed solutions. A primary objective of these periodic reports is to encourage a community and legislative response to establish greater financial parity between the antimicrobial development and the development of other drugs. Although recent actions of the Food and Drug Administration and the 110th US Congress present a glimmer of hope, significant uncertainly remains. Now, more than ever, it is essential to create a robust and sustainable antibacterial research and development infrastructure--one that can respond to current antibacterial resistance now and anticipate evolving resistance. This challenge requires that industry, academia, the National Institutes of Health, the Food and Drug Administration, the Centers for Disease Control and Prevention, the US Department of Defense, and the new Biomedical Advanced Research and Development Authority at the Department of Health and Human Services work productively together. This report provides an update on potentially effective antibacterial drugs in the late-stage development pipeline, in the hope of encouraging such collaborative action.

BACKGROUND: The combination of fluorouracil and leucovorin has until recently been standard therapy for metastatic colorectal cancer. Irinotecan prolongs survival in patients with colorectal cancer that is refractory to treatment with fluorouracil and leucovorin. In a multicenter trial, we compared a combination of irinotecan, fluorouracil and leucovorin with bolus doses of fluorouracil and leucovorin as first-line therapy for metastatic colorectal cancer. A third group of patients received irinotecan alone. METHODS: Patients were randomly assigned to receive irinotecan (125 mg per square meter of body-surface area intravenously), fluorouracil (500 mg per square meter as an intravenous bolus), and leucovorin (20 mg per square meter as an intravenous bolus) weekly for four weeks every six weeks; fluorouracil (425 mg per square meter as an intravenous bolus) and leucovorin (20 mg per square meter as an intravenous bolus) daily for five consecutive days every four weeks; or irinotecan alone (125 mg per square meter intravenously) weekly for four weeks every six weeks. End points included progression-free survival and overall survival. RESULTS: Of 683 patients, 231 were assigned to receive irinotecan, fluorouracil, and leucovorin; 226 to receive fluorouracil and leucovorin; and 226 to receive irinotecan alone. In an intention-to-treat analysis, as compared with treatment with fluorouracil and leucovorin, treatment with irinotecan, fluorouracil, and leucovorin resulted in significantly longer progression-free survival (median, 7.0 vs. 4.3 months; P=0.004), a higher rate of confirmed response (39 percent vs. 21 percent, P<0.001), and longer overall survival (median, 14.8 vs. 12.6 months; P=0.04). Results for irinotecan alone were similar to those for fluorouracil and leucovorin. Grade 3 (severe) diarrhea was more common during treatment with irinotecan, fluorouracil, and leucovorin than during treatment with fluorouracil and leucovorin, but the incidence of grade 4 (life-threatening) diarrhea was similar in the two groups (<8 percent). Grade 3 or 4 mucositis, grade 4 neutropenia, and neutropenic fever were less frequent during treatment with irinotecan, fluorouracil, and leucovorin. Adding irinotecan to the regimen of fluorouracil and leucovorin did not compromise the quality of life. CONCLUSIONS: Weekly treatment with irinotecan plus fluorouracil and leucovorin is superior to a widely used regimen of fluorouracil and leucovorin for metastatic colorectal cancer in terms of progression-free survival and overall survival.

OBJECTIVE: To develop an evidence-based guideline for the comprehensive management of osteoarthritis (OA) as a collaboration between the American College of Rheumatology (ACR) and the Arthritis Foundation, updating the 2012 ACR recommendations for the management of hand, hip, and knee OA. METHODS: We identified clinically relevant population, intervention, comparator, outcomes questions and critical outcomes in OA. A Literature Review Team performed a systematic literature review to summarize evidence supporting the benefits and harms of available educational, behavioral, psychosocial, physical, mind-body, and pharmacologic therapies for OA. Grading of Recommendations Assessment, Development and Evaluation methodology was used to rate the quality of the evidence. A Voting Panel, including rheumatologists, an internist, physical and occupational therapists, and patients, achieved consensus on the recommendations. RESULTS: Based on the available evidence, either strong or conditional recommendations were made for or against the approaches evaluated. Strong recommendations were made for exercise, weight loss in patients with knee and/or hip OA who are overweight or obese, self-efficacy and self-management programs, tai chi, cane use, hand orthoses for first carpometacarpal (CMC) joint OA, tibiofemoral bracing for tibiofemoral knee OA, topical nonsteroidal antiinflammatory drugs (NSAIDs) for knee OA, oral NSAIDs, and intraarticular glucocorticoid injections for knee OA. Conditional recommendations were made for balance exercises, yoga, cognitive behavioral therapy, kinesiotaping for first CMC OA, orthoses for hand joints other than the first CMC joint, patellofemoral bracing for patellofemoral knee OA, acupuncture, thermal modalities, radiofrequency ablation for knee OA, topical NSAIDs, intraarticular steroid injections and chondroitin sulfate for hand OA, topical capsaicin for knee OA, acetaminophen, duloxetine, and tramadol. CONCLUSION: This guideline provides direction for clinicians and patients making treatment decisions for the management of OA. Clinicians and patients should engage in shared decision-making that accounts for patients' values, preferences, and comorbidities. These recommendations should not be used to limit or deny access to therapies.

Objective To develop an evidence‐based guideline for the comprehensive management of osteoarthritis ( OA ) as a collaboration between the American College of Rheumatology ( ACR ) and the Arthritis Foundation, updating the 2012 ACR recommendations for the management of hand, hip, and knee OA . Methods We identified clinically relevant population, intervention, comparator, outcomes questions and critical outcomes in OA . A Literature Review Team performed a systematic literature review to summarize evidence supporting the benefits and harms of available educational, behavioral, psychosocial, physical, mind‐body, and pharmacologic therapies for OA . Grading of Recommendations Assessment, Development and Evaluation methodology was used to rate the quality of the evidence. A Voting Panel, including rheumatologists, an internist, physical and occupational therapists, and patients, achieved consensus on the recommendations. Results Based on the available evidence, either strong or conditional recommendations were made for or against the approaches evaluated. Strong recommendations were made for exercise, weight loss in patients with knee and/or hip OA who are overweight or obese, self‐efficacy and self‐management programs, tai chi, cane use, hand orthoses for first carpometacarpal ( CMC ) joint OA , tibiofemoral bracing for tibiofemoral knee OA , topical nonsteroidal antiinflammatory drugs ( NSAID s) for knee OA , oral NSAID s, and intraarticular glucocorticoid injections for knee OA . Conditional recommendations were made for balance exercises, yoga, cognitive behavioral therapy, kinesiotaping for first CMC OA , orthoses for hand joints other than the first CMC joint, patellofemoral bracing for patellofemoral knee OA , acupuncture, thermal modalities, radiofrequency ablation for knee OA , topical NSAID s, intraarticular steroid injections and chondroitin sulfate for hand OA , topical capsaicin for knee OA , acetaminophen, duloxetine, and tramadol. Conclusion This guideline provides direction for clinicians and patients making treatment decisions for the management of OA . Clinicians and patients should engage in shared decision‐making that accounts for patients’ values, preferences, and comorbidities. These recommendations should not be used to limit or deny access to therapies.

Positron emission tomography (PET) can be used with nitrogen-13-ammonia (13NH3) to estimate regional myocardial blood flow, and with fluorine-18-deoxyglucose (18FDG) to measure exogenous glucose uptake by the myocardium. We used PET to predict whether preoperative abnormalities in left ventricular wall motion in 17 patients who underwent coronary-artery bypass surgery were reversible. The abnormalities were quantified by radionuclide or contrast angiography or both, before and after grafting. PET images were obtained preoperatively. Abnormal wall motion in regions in which PET images showed preserved glucose uptake was predicted to be reversible, whereas abnormal motion in regions with depressed glucose uptake was predicted to be irreversible. According to these criteria, abnormal contraction in 35 of 41 segments was correctly predicted to be reversible (85 percent predictive accuracy), and abnormal contraction in 4 of 26 regions was correctly predicted to be irreversible (92 percent predictive accuracy). In contrast, electrocardiograms showing pathological Q waves in the region of asynergy predicted irreversibility in only 43 percent of regions. We conclude that PET imaging with 13NH3 to assess blood flow and 18FDG to assess the metabolic viability of the myocardium is an accurate method of predicting potential reversibility of wall-motion abnormalities after surgical revascularization.

BACKGROUND: Whether closure of a patent foramen ovale reduces the risk of recurrence of ischemic stroke in patients who have had a cryptogenic ischemic stroke is unknown. METHODS: In a multicenter, randomized, open-label trial, with blinded adjudication of end-point events, we randomly assigned patients 18 to 60 years of age who had a patent foramen ovale (PFO) and had had a cryptogenic ischemic stroke to undergo closure of the PFO (PFO closure group) or to receive medical therapy alone (aspirin, warfarin, clopidogrel, or aspirin combined with extended-release dipyridamole; medical-therapy group). The primary efficacy end point was a composite of recurrent nonfatal ischemic stroke, fatal ischemic stroke, or early death after randomization. The results of the analysis of the primary outcome from the original trial period have been reported previously; the current analysis of data from the extended follow-up period was considered to be exploratory. RESULTS: We enrolled 980 patients (mean age, 45.9 years) at 69 sites. Patients were followed for a median of 5.9 years. Treatment exposure in the two groups was unequal (3141 patient-years in the PFO closure group vs. 2669 patient-years in the medical-therapy group), owing to a higher dropout rate in the medical-therapy group. In the intention-to-treat population, recurrent ischemic stroke occurred in 18 patients in the PFO closure group and in 28 patients in the medical-therapy group, resulting in rates of 0.58 events per 100 patient-years and 1.07 events per 100 patient-years, respectively (hazard ratio with PFO closure vs. medical therapy, 0.55; 95% confidence interval [CI], 0.31 to 0.999; P=0.046 by the log-rank test). Recurrent ischemic stroke of undetermined cause occurred in 10 patients in the PFO closure group and in 23 patients in the medical-therapy group (hazard ratio, 0.38; 95% CI, 0.18 to 0.79; P=0.007). Venous thromboembolism (which comprised events of pulmonary embolism and deep-vein thrombosis) was more common in the PFO closure group than in the medical-therapy group. CONCLUSIONS: Among adults who had had a cryptogenic ischemic stroke, closure of a PFO was associated with a lower rate of recurrent ischemic strokes than medical therapy alone during extended follow-up. (Funded by St. Jude Medical; RESPECT ClinicalTrials.gov number, NCT00465270 .).

BACKGROUND AND METHODS: To define better the bacteria responsible for infections of dog and cat bites, we conducted a prospective study at 18 emergency departments. To be eligible for enrollment, patients had to meet one of three major criteria for infection of a bite wound (fever, abscess, and lymphangitis) or four of five minor criteria (wound-associated erythema, tenderness at the wound site, swelling at the site, purulent drainage, and leukocytosis). Wound specimens were cultured for aerobic and anaerobic bacteria at a research microbiology laboratory and, in some cases, at local hospital laboratories. RESULTS: The infected wounds of 50 patients with dog bites and 57 patients with cat bites yielded a median of 5 bacterial isolates per culture (range, 0 to 16) at the reference laboratory. Significantly more isolates grew at the reference laboratory than at the local laboratories (median, 1; range, 0 to 5; P<0.001). Aerobes and anaerobes were isolated from 56 percent of the wounds, aerobes alone from 36 percent, and anaerobes alone from 1 percent; 7 percent of cultures had no growth. Pasteurella species were the most frequent isolates from both dog bites (50 percent) and cat bites (75 percent). Pasteurella canis was the most common isolate of dog bites, and Past. multocida subspecies multocida and septica were the most common isolates of cat bites. Other common aerobes included streptococci, staphylococci, moraxella, and neisseria. Common anaerobes included fusobacterium, bacteroides, porphyromonas, and prevotella. Isolates not previously identified as human pathogens included Reimerella anatipestifer from two cat bites and Bacteroides tectum, Prevotella heparinolytica, and several porphyromonas species from dog and cat bites. Erysipelothrix rhusiopathiae was isolated from two cat bites. Patients were most often treated with a combination of a beta-lactam antibiotic and a beta-lactamase inhibitor, which, on the basis of the microbiologic findings, was appropriate therapy. CONCLUSIONS: Infected dog and cat bites have a complex microbiologic mix that usually includes pasteurella species but may also include many other organisms not routinely identified by clinical microbiology laboratories and not previously recognized as bite-wound pathogens.

Mucormycosis is a life-threatening infection that occurs in patients who are immunocompromised because of diabetic ketoacidosis, neutropenia, organ transplantation, and/or increased serum levels of available iron. Because of the increasing prevalence of diabetes mellitus, cancer, and organ transplantation, the number of patients at risk for this deadly infection is increasing. Despite aggressive therapy, which includes disfiguring surgical debridement and frequently adjunctive toxic antifungal therapy, the overall mortality rate is high. New strategies to prevent and treat mucormycosis are urgently needed. Understanding the pathogenesis of mucormycosis and the host response to invading hyphae ultimately will provide targets for novel therapeutic interventions. In this supplement, we review the current knowledge about the virulence traits used by the most common etiologic agent of mucormycosis, Rhizopus oryzae. Because patients with elevated serum levels of available iron are uniquely susceptible to mucormycosis and these infections are highly angioinvasive, emphasis is placed on the ability of the organism to acquire iron from the host and on its interactions with endothelial cells lining blood vessels. Several promising therapeutic strategies in preclinical stages are identified.

IMPORTANCE: In retrospective studies, 68Ga-PSMA-11 positron emission tomographic (PET) imaging improves detection of biochemically recurrent prostate cancer compared with conventional imaging. OBJECTIVE: To assess 68Ga-PSMA-11 PET accuracy in a prospective multicenter trial. DESIGN, SETTING, AND PARTICIPANTS: In this single-arm prospective trial conducted at University of California, San Francisco and University of California, Los Angeles, 635 patients with biochemically recurrent prostate cancer after prostatectomy (n = 262, 41%), radiation therapy (n = 169, 27%), or both (n = 204, 32%) underwent 68Ga-PSMA-11 PET. Presence of prostate cancer was recorded by 3 blinded readers on a per-patient and per-region base. Lesions were validated by histopathologic analysis and a composite reference standard. MAIN OUTCOMES AND MEASURES: Endpoints were positive predictive value (PPV), detection rate, interreader reproducibility, and safety. RESULTS: A total of 635 men were enrolled with a median age of 69 years (range, 44-95 years). On a per-patient basis, PPV was 0.84 (95% CI, 0.75-0.90) by histopathologic validation (primary endpoint, n = 87) and 0.92 (95% CI, 0.88-0.95) by the composite reference standard (n = 217). 68Ga-PSMA-11 PET localized recurrent prostate cancer in 475 of 635 (75%) patients; detection rates significantly increased with prostate-specific antigen (PSA): 38% for <0.5 ng/mL (n = 136), 57% for 0.5 to <1.0 ng/mL (n = 79), 84% for 1.0 to <2.0 ng/mL (n = 89), 86% for 2.0 to <5.0 ng/mL (n = 158), and 97% for ≥5.0 ng/mL (n = 173, P < .001). Interreader reproducibility was substantial (Fleiss κ, 0.65-0.78). There were no serious adverse events associated with 68Ga-PSMA-11 administration. PET-directed focal therapy alone led to a PSA drop of 50% or more in 31 of 39 (80%) patients. CONCLUSIONS AND RELEVANCE: Using blinded reads and independent lesion validation, we establish high PPV for 68Ga-PSMA-11 PET, detection rate and interreader agreement for localization of recurrent prostate cancer. TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT02940262 and NCT03353740.

BACKGROUND: Sunitinib, a vascular endothelial growth factor pathway inhibitor, is an effective treatment for metastatic renal-cell carcinoma. We sought to determine the efficacy and safety of sunitinib in patients with locoregional renal-cell carcinoma at high risk for tumor recurrence after nephrectomy. METHODS: In this randomized, double-blind, phase 3 trial, we assigned 615 patients with locoregional, high-risk clear-cell renal-cell carcinoma to receive either sunitinib (50 mg per day) or placebo on a 4-weeks-on, 2-weeks-off schedule for 1 year or until disease recurrence, unacceptable toxicity, or consent withdrawal. The primary end point was disease-free survival, according to blinded independent central review. Secondary end points included investigator-assessed disease-free survival, overall survival, and safety. RESULTS: The median duration of disease-free survival was 6.8 years (95% confidence interval [CI], 5.8 to not reached) in the sunitinib group and 5.6 years (95% CI, 3.8 to 6.6) in the placebo group (hazard ratio, 0.76; 95% CI, 0.59 to 0.98; P=0.03). Overall survival data were not mature at the time of data cutoff. Dose reductions because of adverse events were more frequent in the sunitinib group than in the placebo group (34.3% vs. 2%), as were dose interruptions (46.4% vs. 13.2%) and discontinuations (28.1% vs. 5.6%). Grade 3 or 4 adverse events were more frequent in the sunitinib group (48.4% for grade 3 events and 12.1% for grade 4 events) than in the placebo group (15.8% and 3.6%, respectively). There was a similar incidence of serious adverse events in the two groups (21.9% for sunitinib vs. 17.1% for placebo); no deaths were attributed to toxic effects. CONCLUSIONS: Among patients with locoregional clear-cell renal-cell carcinoma at high risk for tumor recurrence after nephrectomy, the median duration of disease-free survival was significantly longer in the sunitinib group than in the placebo group, at a cost of a higher rate of toxic events. (Funded by Pfizer; S-TRAC ClinicalTrials.gov number, NCT00375674 .).

BACKGROUND: Heart failure with preserved ejection fraction (EF) is a common syndrome, but trends in treatments and outcomes are lacking. METHODS AND RESULTS: We analyzed data from 275 hospitals in Get With the Guidelines-Heart Failure from January 2005 to October 2010. Patients were stratified by EF as reduced EF (EF <40% [HF-reduced EF]), borderline EF (40%≤EF<50% [HF-borderline EF]), or preserved (EF ≥50% [HF-preserved EF]). Using multivariable models, we examined trends in therapies and outcomes. Among 110 621 patients, 50% (55 083) had HF-reduced EF, 14% (15 184) had HF-borderline EF, and 36% (40 354) had HF-preserved EF. From 2005 to 2010, the proportion of hospitalizations for HF-preserved EF increased from 33% to 39% (P<0.0001). In multivariable analyses, use of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers at discharge decreased in all EF groups, and β-blocker use increased. Patients with HF-preserved EF less frequently achieved blood pressure control (adjusted odds ratio, 0.44 versus HF-reduced EF; P<0.001) and were more likely discharged to skilled nursing (adjusted odds ratio, 1.16 versus HF-reduced EF; P<0.001). In-hospital mortality for HF-preserved EF decreased from 3.32% in 2005 to 2.35% in 2010 (adjusted odds ratio, 0.89 per year; P=0.01) but was stable for patients with HF-reduced EF (3.03%-2.83%; adjusted odds ratio, 0.93 per year; P=0.10). CONCLUSIONS: Hospitalization for HF-preserved EF is increasing relative to HF-reduced EF. Although in-hospital mortality for patients with HF-preserved EF declined over the study period, an important opportunity remains for identifying evidence-based therapies in patients with HF-preserved EF.

Invasive fungal infections are increasingly common in the nosocomial setting. Furthermore, because risk factors for these infections continue to increase in frequency, it is likely that nosocomial fungal infections will continue to increase in frequency in the coming decades. The predominant nosocomial fungal pathogens include Candida spp., Aspergillus spp., Mucorales, Fusarium spp., and other molds, including Scedosporium spp. These infections are difficult to diagnose and cause high morbidity and mortality despite antifungal therapy. Early initiation of effective antifungal therapy and reversal of underlying host defects remain the cornerstones of treatment for nosocomial fungal infections. In recent years, new antifungal agents have become available, resulting in a change in standard of care for many of these infections. Nevertheless, the mortality of nosocomial fungal infections remains high, and new therapeutic and preventative strategies are needed.

PEGylation or covalent attachment of poly(ethylene glycol) improves the pharmacokinetic properties of protein drugs. In vivo circulation lifetimes are increased and dosages are decreased, resulting in improved patient quality of life. PEG may be attached to proteins using a variety of different chemical reactions. This review discusses currently available FDA-approved PEGylated protein drugs, their intended use and target, and the PEG attachment chemistry utilized.

BACKGROUND: Management algorithms for adult severe traumatic brain injury (sTBI) were omitted in later editions of the Brain Trauma Foundation's sTBI Management Guidelines, as they were not evidence-based. METHODS: We used a Delphi-method-based consensus approach to address management of sTBI patients undergoing intracranial pressure (ICP) monitoring. Forty-two experienced, clinically active sTBI specialists from six continents comprised the panel. Eight surveys iterated queries and comments. An in-person meeting included whole- and small-group discussions and blinded voting. Consensus required 80% agreement. We developed heatmaps based on a traffic-light model where panelists' decision tendencies were the focus of recommendations. RESULTS: We provide comprehensive algorithms for ICP-monitor-based adult sTBI management. Consensus established 18 interventions as fundamental and ten treatments not to be used. We provide a three-tier algorithm for treating elevated ICP. Treatments within a tier are considered empirically equivalent. Higher tiers involve higher risk therapies. Tiers 1, 2, and 3 include 10, 4, and 3 interventions, respectively. We include inter-tier considerations, and recommendations for critical neuroworsening to assist the recognition and treatment of declining patients. Novel elements include guidance for autoregulation-based ICP treatment based on MAP Challenge results, and two heatmaps to guide (1) ICP-monitor removal and (2) consideration of sedation holidays for neurological examination. CONCLUSIONS: Our modern and comprehensive sTBI-management protocol is designed to assist clinicians managing sTBI patients monitored with ICP-monitors alone. Consensus-based (class III evidence), it provides management recommendations based on combined expert opinion. It reflects neither a standard-of-care nor a substitute for thoughtful individualized management.

OBJECTIVE: CD40-CD40 ligand (CD40L) interactions play a significant role in the production of autoantibodies and tissue injury in lupus nephritis. We performed an open-label, multiple-dose study to evaluate the safety, efficacy, and pharmacokinetics of BG9588, a humanized anti-CD40L antibody, in patients with proliferative lupus nephritis. The primary outcome measure was 50% reduction in proteinuria without worsening of renal function. METHODS: Twenty-eight patients with active proliferative lupus nephritis were scheduled to receive 20 mg/kg of BG9588 at biweekly intervals for the first 3 doses and at monthly intervals for 4 additional doses. Safety evaluations were performed on all patients. Eighteen patients receiving at least 3 doses were evaluated for efficacy. RESULTS: The study was terminated prematurely because of thromboembolic events occurring in patients in this and other BG9588 protocols (2 myocardial infarctions in this study). Of the 18 patients for whom efficacy could be evaluated, 2 had a 50% reduction in proteinuria without worsening of renal function. Mean reductions of 38.9% (P < 0.005), 50.1% (P < 0.005), and 25.3% (P < 0.05) in anti-double-stranded DNA (anti-dsDNA) antibody titers were observed at 1, 2, and 3 months, respectively, after the last treatment. There was a significant increase in serum C3 concentrations at 1 month after the last dose (P < 0.005), and hematuria disappeared in all 5 patients with significant hematuria at baseline. There were no statistically significant reductions in lymphocyte count or serum immunoglobulin, anticardiolipin antibody, or rubella IgG antibody concentrations after therapy. CONCLUSION: A short course of BG9588 treatment in patients with proliferative lupus nephritis reduces anti-dsDNA antibodies, increases C3 concentrations, and decreases hematuria, suggesting that the drug has immunomodulatory action. Additional studies will be needed to evaluate its long-term effects.

BACKGROUND AND PURPOSE: Diffusion MRI has established value in patients with ischemic stroke but has not been systematically investigated in patients with transient ischemic attack (TIA). METHODS: Clinical, conventional MRI, and diffusion MRI data were collected on 42 consecutive patients with symptoms of cerebral TIA. TIA imaging data were compared with those from a contemporaneous group of 23 completed stroke patients. RESULTS: Twenty of the 42 TIA patients (48%) demonstrated neuroanatomically relevant focal abnormalities on diffusion-weighted imaging (DWI) and apparent diffusion coefficient (ADC) imaging. When present, DWI/ADC signal changes in TIA patients were less pronounced and smaller in volume than those in completed stroke patients. TIA symptom duration was significantly longer for DWI-positive than for DWI-negative patients, 7.3 versus 3.2 hours. Diffusion MRI information changed the suspected anatomic and vascular TIA localization and the suspected etiologic mechanism in over one third of patients with diffusion MRI abnormalities. Of the 20 TIA patients with identifiable lesions on diffusion MRI, 9 had follow-up imaging studies; of these, 4 did not show a relevant infarct on follow-up imaging. CONCLUSIONS: Diffusion MRI demonstrates ischemic abnormalities in nearly half of clinically defined TIA patients. The percentage of patients with a DWI lesion increases with increasing total symptom duration. In nearly half, the diffusion MRI changes may be fully reversible, while in the remainder the diffusion MRI findings herald the development of a parenchymal infarct despite transient clinical symptoms. Finally, diffusion imaging results have significant clinical utility, frequently changing the presumed localization and etiologic mechanism.

BACKGROUND: Maternal, obstetrical, and infant-related factors associated with the risk of perinatal transmission of human immunodeficiency virus type 1 (HIV-1) were identified before the widespread use of zidovudine therapy in pregnant women. The risk factors for transmission when women and infants receive zidovudine are not well characterized. METHODS: We examined the effects of maternal, obstetrical, and infant-related characteristics and maternal virologic and immunologic variables on the risk of perinatal transmission of HIV-1 among 480 women and their infants, all of whom received zidovudine. The women and infants were participating in a phase 3 trial of passive immunoprophylaxis for the prevention of perinatal transmission. RESULTS: In univariate analyses, the risk of perinatal transmission was associated with each of the following: decreased maternal CD4+ lymphocyte counts at base line; decreased maternal HIV p24 antibody levels at base line and delivery; increased maternal HIV-1 titer at base line and delivery; increased maternal HIV-1 RNA levels at base line and delivery; and the presence of chorioamnionitis at delivery. In multivariate analyses, the only independent risk factor was the maternal HIV-1 RNA level at base line (odds ratio for transmission, 2.4 per log increase in the number of copies; 95 percent confidence interval, 1.2 to 4.7; P=0.02) and at delivery (odds ratio, 3.4; 95 percent confidence interval, 1.7 to 6.8; P=0.001). There was no perinatal transmission of HIV-1 among the 84 women who had HIV-1 levels below the limit of detection (500 copies per milliliter) at base line or the 107 women who had undetectable levels at delivery. CONCLUSIONS: Among pregnant women and their infants, all treated with zidovudine, the maternal plasma HIV-1 RNA level was the best predictor of the risk of perinatal transmission of HIV-1. Antiretroviral therapy that reduces the HIV-1 RNA level to below 500 copies per milliliter appears to minimize the risk of perinatal transmission as well as improve the health of the women.

BACKGROUND: Thromboses of the hepatic artery (HAT) and portal vein (PVT) may complicate orthotopic liver transplantation (OLT) and result in graft loss and mortality. Revision and retransplantation are treatment options, but their longterm outcomes remain undefined. This study was undertaken to evaluate the incidence of major vascular complications after OLT, determine efficacy of therapies, and identify factors influencing longterm outcomes. STUDY DESIGN: All patients undergoing OLT from 1984 to 2007 were evaluated. Kaplan-Meier analysis was performed to define the effects of vascular complications on posttransplant survival. Anastomotic revision and arterial thrombolysis were compared with retransplantation as treatment for HAT. After 2002, porta hepatis dissection was initiated with early occlusion of common hepatic artery (CHA) inflow; its impact on HAT incidence was determined. RESULTS: From 1984 to 2007, 4,234 OLTs were performed. HAT occurred in 203 patients (5%) and PVT in 84 (2%). Graft survival was significantly reduced by HAT or PVT; patient survival was reduced only by PVT. Retransplantation for HAT improved patient survival over revision or thrombolysis in the first year but did not provide longterm survival advantage (56% versus 56% at 5 years; p=0.53). Patients with HAT had only 10% graft salvage with anastomotic revision or thrombolysis. HAT was significantly reduced with early CHA inflow occlusion (1.1% versus 3.7%; p=0.002). Factors increasing risk of HAT included pediatric recipients, liver cancer, and aberrant arterial anatomy requiring complex reconstruction. CONCLUSIONS: Both HAT and PVT significantly reduce graft survival after OLT; PVT more adversely affects patient survival. Revision and thrombolysis rarely salvage grafts after HAT; retransplantation provides superior short-term, but not longterm, survival. Avoidance of vascular complications in OLT is critical, especially with today's scarcity of donor livers. Early atraumatic CHA occlusion significantly reduces the incidence of HAT.

Three COVID-19 vaccines are authorized or approved for use among adults in the United States (1,2). Two 2-dose mRNA vaccines, mRNA-1273 from Moderna and BNT162b2 from Pfizer-BioNTech, received Emergency Use Authorization (EUA) by the Food and Drug Administration (FDA) in December 2020 for persons aged ≥18 years and aged ≥16 years, respectively. A 1-dose viral vector vaccine (Ad26.COV2 from Janssen [Johnson & Johnson]) received EUA in February 2021 for persons aged ≥18 years (3). The Pfizer-BioNTech vaccine received FDA approval for persons aged ≥16 years on August 23, 2021 (4). Current guidelines from FDA and CDC recommend vaccination of eligible persons with one of these three products, without preference for any specific vaccine (4,5). To assess vaccine effectiveness (VE) of these three products in preventing COVID-19 hospitalization, CDC and collaborators conducted a case-control analysis among 3,689 adults aged ≥18 years who were hospitalized at 21 U.S. hospitals across 18 states during March 11-August 15, 2021. An additional analysis compared serum antibody levels (anti-spike immunoglobulin G [IgG] and anti-receptor binding domain [RBD] IgG) to SARS-CoV-2, the virus that causes COVID-19, among 100 healthy volunteers enrolled at three hospitals 2-6 weeks after full vaccination with the Moderna, Pfizer-BioNTech, or Janssen COVID-19 vaccine. Patients with immunocompromising conditions were excluded. VE against COVID-19 hospitalizations was higher for the Moderna vaccine (93%; 95% confidence interval [CI] = 91%-95%) than for the Pfizer-BioNTech vaccine (88%; 95% CI = 85%-91%) (p = 0.011); VE for both mRNA vaccines was higher than that for the Janssen vaccine (71%; 95% CI = 56%-81%) (all p<0.001). Protection for the Pfizer-BioNTech vaccine declined 4 months after vaccination. Postvaccination anti-spike IgG and anti-RBD IgG levels were significantly lower in persons vaccinated with the Janssen vaccine than the Moderna or Pfizer-BioNTech vaccines. Although these real-world data suggest some variation in levels of protection by vaccine, all FDA-approved or authorized COVID-19 vaccines provide substantial protection against COVID-19 hospitalization.

This article summarizes concepts, methods, cross‐cultural evidence, and implications of parental acceptance‐rejection theory (PARTheory). The theory focuses primarily on parental love—its expressions, impact, and origins. Nearly 2,000 studies in the United States and cross‐culturally confirm the widely held belief that children everywhere need acceptance (love) from parents and other attachment figures. Evidence has shown that when this need is not met, children worldwide—regardless of variations in culture, gender, age, or ethnicity—tend to self‐report a specific form of psychological maladjustment. Additionally, individuals who perceive themselves to be rejected appear to be more disposed than accepted persons to develop behavior problems, depression or depressed affect, substance abuse, and other mental health‐related issues. Finally, children and adults appear universally to organize their perceptions of acceptance‐rejection around the same four classes of behavior. These include warmth/affection (or coldness/lack of affection), hostility/aggression, indifference/neglect, and undifferentiated rejection.