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Anthracyclines remain an essential component of the treatment of many hematologic and solid organ malignancies, but has important implications on cardiovascular disease. Anthracycline induced cardiotoxicity (AIC) ranges from asymptomatic LV dysfunction to highly morbid end- stage heart failure. As cancer survivorship improves, the detection and treatment of AIC becomes more crucial to improve patient outcomes. Current treatment modalities for AIC have been largely extrapolated from treatment of conventional heart failure, but developing effective therapies specific to AIC is an area of growing research interest. This review summarizes the current evidence behind the use of neurohormonal agents, dexrazoxane, and resynchronization therapy in AIC, evaluates the clinical outcomes of advanced therapy and heart transplantation in AIC, and explores future horizons for treatment utilizing gene therapy, stem cell therapy, and mechanism-specific targets., Competing Interests: EY reports research funding from CSL Behring, Boehringer Ingelheim, and Eli and Lilly for research outside the current manuscript, and reports consulting fees from Pfizer. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Vuong, Stein-Merlob, Cheng and Yang.)

In January and February 2015, Neisseria meningitidis serogroup B (NmB) outbreaks occurred at two universities in the United States, and mass vaccination campaigns using MenB vaccines were initiated as part of a public health response. Meningococcal carriage evaluations were conducted concurrently with vaccination campaigns at these two universities and at a third university, where no NmB outbreak occurred. Meningococcal isolates ( N = 1,514) obtained from these evaluations were characterized for capsule biosynthesis by whole-genome sequencing (WGS). Functional capsule polysaccharide synthesis ( cps ) loci belonging to one of seven capsule genogroups (B, C, E, W, X, Y, and Z) were identified in 122 isolates (8.1%). Approximately half [732 (48.4%)] of isolates could not be genogrouped because of the lack of any serogroup-specific genes. The remaining 660 isolates (43.5%) contained serogroup-specific genes for genogroup B, C, E, W, X, Y, or Z, but had mutations in the cps loci. Identified mutations included frameshift or point mutations resulting in premature stop codons, missing or fragmented genes, or disruptions due to insertion elements. Despite these mutations, 49/660 isolates expressed capsule as observed with slide agglutination, whereas 45/122 isolates with functional cps loci did not express capsule. Neither the variable capsule expression nor the genetic variation in the cps locus was limited to a certain clonal complex, except for capsule null isolates (predominantly clonal complex 198). Most of the meningococcal carriage isolates collected from student populations at three US universities were non-groupable as a result of either being capsule null or containing mutations within the capsule locus. Several mutations inhibiting expression of the genes involved with the synthesis and transport of the capsule may be reversible, allowing the bacteria to switch between an encapsulated and non-encapsulated state. These findings are particularly important as carriage is an important component of the transmission cycle of the pathogen, and understanding the impact of genetic variations on the synthesis of capsule, a meningococcal vaccine target and an important virulence factor, may ultimately inform strategies for control and prevention of disease caused by this pathogen., Competing Interests: HC, LJ, FH, MM, LR-R, and SJ were employed by the IHRC Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Whaley, Vuong, Topaz, Chang, Thomas, Jenkins, Hu, Schmink, Steward-Clark, Mathis, Rodriguez-Rivera, Retchless, Joseph, Chen, Acosta, McNamara, Soeters, Mbaeyi, Marjuki and Wang.)

Immune checkpoint inhibitor therapy has revolutionized the treatment of advanced malignancies in recent years. Numerous reports have detailed the myriad of possible adverse inflammatory effects of immune checkpoint therapies, including within the cardiovascular system. However, these reports have been largely limited to myocarditis. The critical role of inflammation and adaptive immunity in atherosclerosis has been well characterized in preclinical studies, and several emerging clinical studies indicate a potential role of immune checkpoint targeting therapies in the development and exacerbation of atherosclerosis. In this review, we provide an overview of the role of T-cell immunity in atherogenesis and describe the molecular effects and clinical associations of both approved and investigational immune checkpoint therapy on atherosclerosis. We also highlight the role of cholesterol metabolism in oncogenesis and discuss the implications of these associations on future treatment and monitoring of atherosclerotic cardiovascular disease in the oncologic population receiving immune checkpoint therapy., Competing Interests: Funding Support and Author Disclosures Drs Stein-Merlob and Nayeri are supported by the National Institutes of Health Cardiovascular Scientist Training Program (grant T32HL007895). Dr Sallam is supported by the American Heart Association Transformational Project Award and the National Institutes of Health grant HL149766. Dr Neilan is supported by a gift from A. Curt Greer and Pamela Kohlberg, and grants from the National Institutes of Health/National Heart, Lung, and Blood Institute grants R01HL130539, R01HL137562, and K24HL150238. Dr Yang is supported by a grant from CSL Behring. Dr Neilan has been a consultant to and received fees from Amgen, H3-Biomedicine, and AbbVie outside of the current work; has received consultant fees from Bristol Myers Squibb for a Scientific Advisory Board focused on myocarditis related to immune checkpoint inhibitors; and has received grant funding from AstraZeneca on atherosclerosis with immune checkpoint inhibitors. All other authors have 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: Coronavirus disease 2019 (COVID-19) continues to cause significant morbidity and mortality worldwide. Correctional and detention facilities are at high risk of experiencing outbreaks. We aimed to evaluate cohort-based testing among detained persons exposed to laboratory-confirmed cases of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in order to identify presymptomatic and asymptomatic cases., Methods: During 1-19 May 2020, 2 testing strategies were implemented in 12 tiers or housing units of the Cook County Jail, Chicago, Illinois. Detained persons were approached to participate in serial testing (n = 137) and offered tests at 3 time points over 14 days (day 1, days 3-5, and days 13-14). The second group was offered a single test and interview at the end of a 14-day quarantine period (day 14 group) (n = 87)., Results: 224 detained persons were approached for participation and, of these, 194 (87%) participated in ≥1 interview and 172 (77%) had ≥1 test. Of the 172 tested, 19 were positive for SARS-CoV-2. In the serial testing group, 17 (89%) new cases were detected, 16 (84%) on day 1, 1 (5%) on days 3-5, and none on days 13-14; in the day 14 group, 2 (11%) cases were identified. More than half (12/19; 63%) of the newly identified cases were presymptomatic or asymptomatic., Conclusions: Our findings highlight the utility of cohort-based testing promptly after initiating quarantine within a housing tier. Cohort-based testing efforts identified new SARS-CoV-2 asymptomatic and presymptomatic infections that may have been missed by symptom screening alone., (Published by Oxford University Press for the Infectious Diseases Society of America 2020.)

In 2015 and 2016, meningococcal carriage evaluations were conducted at two universities in the United States following mass vaccination campaigns in response to Neisseria meningitidis serogroup B (NmB) disease outbreaks. A simultaneous carriage evaluation was also conducted at a university near one of the outbreaks, where no NmB cases were reported and no mass vaccination occurred. A total of ten cross-sectional carriage evaluation rounds were conducted, resulting in 1,514 meningococcal carriage isolates collected from 7,001 unique participants; 1,587 individuals were swabbed at multiple time points (repeat participants). All isolates underwent whole-genome sequencing. The most frequently observed clonal complexes (CC) were CC198 (27.3%), followed by CC1157 (17.4%), CC41/44 (9.8%), CC35 (7.4%), and CC32 (5.6%). Phylogenetic analysis identified carriage isolates that were highly similar to the NmB outbreak strains; comparative genomics between these outbreak and carriage isolates revealed genetic changes in virulence genes. Among repeat participants, 348 individuals carried meningococcal bacteria during at least one carriage evaluation round; 50.3% retained N. meningitidis carriage of a strain with the same sequence type (ST) and CC across rounds, 44.3% only carried N. meningitidis in one round, and 5.4% acquired a new N. meningitidis strain between rounds. Recombination, point mutations, deletions, and simple sequence repeats were the most frequent genetic mechanisms found in isolates collected from hosts carrying a strain of the same ST and CC across rounds. Our findings provide insight on the dynamics of meningococcal carriage among a population that is at higher risk for invasive meningococcal disease than the general population. IMPORTANCE U.S. university students are at a higher risk of invasive meningococcal disease than the general population. The responsible pathogen, Neisseria meningitidis , can be carried asymptomatically in the oropharynx; the dynamics of meningococcal carriage and the genetic features that distinguish carriage versus disease states are not completely understood. Through our analyses, we aimed to provide data to address these topics. We whole-genome sequenced 1,514 meningococcal carriage isolates from individuals at three U.S. universities, two of which underwent mass vaccination campaigns following recent meningococcal outbreaks. We describe the within-host genetic changes among individuals carrying a strain with the same molecular type over time, the primary strains being carried in this population, and the genetic differences between closely related outbreak and carriage strains. Our results provide detailed information on the dynamics of meningococcal carriage and the genetic differences in carriage and outbreak strains, which can inform future efforts to reduce the incidence of invasive meningococcal disease.

Background: The MenAfriNet Consortium supports strategic implementation of case-based meningitis surveillance in key high-risk countries of the African meningitis belt: Burkina Faso, Chad, Mali, Niger, and Togo. We describe bacterial meningitis epidemiology in these 5 countries in 2015-2017., Methods: Case-based meningitis surveillance collects case-level demographic and clinical information and cerebrospinal fluid (CSF) laboratory results. Neisseria meningitidis, Streptococcus pneumoniae, or Haemophilus influenzae cases were confirmed and N. meningitidis/H. influenzae were serogrouped/serotyped by real-time polymerase chain reaction, culture, or latex agglutination. We calculated annual incidence in participating districts in each country in cases/100 000 population., Results: From 2015-2017, 18 262 suspected meningitis cases were reported; 92% had a CSF specimen available, of which 26% were confirmed as N. meningitidis (n = 2433; 56%), S. pneumoniae (n = 1758; 40%), or H. influenzae (n = 180; 4%). Average annual incidences for N. meningitidis, S. pneumoniae, and H. influenzae, respectively, were 7.5, 2.5, and 0.3. N. meningitidis incidence was 1.5 in Burkina Faso, 2.7 in Chad, 0.4 in Mali, 14.7 in Niger, and 12.5 in Togo. Several outbreaks occurred: NmC in Niger in 2015-2017, NmC in Mali in 2016, and NmW in Togo in 2016-2017. Of N. meningitidis cases, 53% were NmC, 30% NmW, and 13% NmX. Five NmA cases were reported (Burkina Faso, 2015). NmX increased from 0.6% of N. meningitidis cases in 2015 to 27% in 2017., Conclusions: Although bacterial meningitis epidemiology varied widely by country, NmC and NmW caused several outbreaks, NmX increased although was not associated with outbreaks, and overall NmA incidence remained low. An effective low-cost multivalent meningococcal conjugate vaccine could help further control meningococcal meningitis in the region., (Published by Oxford University Press for the Infectious Diseases Society of America 2019. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

In 2016, Mali reported a bacterial meningitis outbreak consisting of 39 suspected cases between epidemiologic weeks 9 and 17 with 15% case fatality ratio in the health district of Ouéléssebougou, 80 kilometers from the capital Bamako. Cerebrospinal fluid specimens from 29 cases were tested by culture and real-time polymerase chain reaction; 22 (76%) were positive for bacterial meningitis pathogens, 16 (73%) of which were Neisseria meningitidis (Nm). Of the Nm-positive specimens, 14 (88%) were N meningitidis serogroup C (NmC), 1 was NmW, and 1 was nongroupable. Eight NmC isolates recovered by culture from the outbreak were characterized using whole genome sequencing. Genomics analysis revealed that all 8 isolates belonged to a new sequence type (ST) 12446 of clonal complex 10217 that formed a distinct clade genetically similar to ST-10217, a NmC strain that recently caused large epidemics of meningitis in Niger and Nigeria. The emergence of a new ST of NmC associated with an outbreak in the African meningitis belt further highlights the need for continued molecular surveillance in the region., (Published by Oxford University Press for the Infectious Diseases Society of America 2019. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Background: Heart failure and dementia are diseases of the elderly that result in billions of dollars in annual health care expenditure. With the aging of the United States population and increasing evidence of shared risk factors, there is a need to understand the conditions' shared contributions to nationwide mortality. The objectives of this study were to estimate the burden of mortality from heart failure and dementia and characterize the demographics of affected individuals., Methods and Results: This retrospective study used National Vital Statistics Data from 1999 to 2016 provided by the Centers for Disease Control and International Classification of Diseases (10th edition) codes for heart failure and dementia as defined by the Medicare Chronic Conditions Data Warehouse. From 1999 to 2016, deaths contributed to by both heart failure and dementia totaled 214,706 and constituted 4.00% of all heart failure deaths and 9.04% of all dementia deaths. Women were more affected than men, with higher age-adjusted mortality rates (per 1,000,000 person-years): 38.67 (95% confidence interval [CI] 38.47-38.87) versus 32.90 (95% CI 32.65-33.15; P < .001). Whites were affected more than blacks, with age-adjusted mortality rates (per 1,000,000 person-years) of 38.00 (95% CI 37.83-38.16) versus 31.06 (95% CI 30.54-31.59; P < .001). However, under the age of 65 years, higher crude mortality rates (per 1,000,000 person-years) were reported in men (0.20, 95% CI 0.18-0.22) compared with women (0.15, 95% CI 0.13-0.16; P < .001)., Conclusions: This study provides insight into temporal trends and nationwide mortality rates reported for heart failure and dementia. Our results suggest a disproportionate burden on populations over 85 years of age, whites, and women., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Increases in pneumococcal meningitis were reported from Ghanaian regions that lie in the meningitis belt in 2016-2017, despite introduction of 13-valent pneumococcal conjugate vaccine (PCV13) in 2012 using a 3-dose schedule (6, 10, and 14 weeks). We describe pneumococcal meningitis epidemiology in the Ghanaian Northern and Upper West regions across two meningitis seasons., Methods: Suspected meningitis cases were identified using World Health Organization standard definitions. Pneumococcal meningitis was confirmed if pneumococcus was the sole pathogen detected by polymerase chain reaction, culture, or latex agglutination in cerebrospinal fluid collected from a person with suspected meningitis during December 2015-March 2017. Pneumococcal serotyping was done using PCR. Annual age-specific pneumococcal meningitis incidence (cases per 100,000 population) was calculated, adjusting for suspected meningitis cases lacking confirmatory testing., Findings: Among 153 pneumococcal meningitis cases, 137 (89.5%) were serotyped; 100 (73.0%) were PCV13-type, including 85 (62.0%) that were serotype 1, a PCV13-targeted serotype. Persons aged ≥5 years accounted for 96.7% (148/153) of cases. Comparing 2015-2016 and 2016-2017 seasons, the proportion of non-serotype 1 PCV13-type cases decreased from 20.0% (9/45) to 4.1% (3/74) (p = 0.008), whereas the proportion that was serotype 1 was stable (71.1% (32/45) vs. 58.1% (43/74); p = 0.16). Estimated adjusted pneumococcal meningitis incidence was 1.8 in children aged <5 years and ranged from 6.8-10.5 in older children and adults., Conclusions: High pneumococcal meningitis incidence with a large proportion of serotype 1 disease in older children and adults suggests infant PCV13 vaccination has not induced herd protection with this schedule in this high-transmission setting., Competing Interests: The authors have declared that no competing interests exist.

Vascular endothelial growth factor (VEGF) has previously been demonstrated to accelerate compensatory lung growth (CLG) in mice and may be a useful therapy for pulmonary hypoplasia. Systemic administration of VEGF can result in side effects such as hypotension and edema. The aim of this study was to explore nasal delivery as a route for intrapulmonary VEGF administration. Eight-week-old C57BL/6 male mice underwent left pneumonectomy, followed by daily nasal instillation of VEGF at 0.5 mg/kg or isovolumetric saline. Lung volume measurement, morphometric analysis, and protein expression studies were performed on lung tissues harvested on postoperative day (POD) 4. To understand the mechanism by which VEGF accelerates lung growth, proliferation of human bronchial epithelial cells (HBEC) was assessed in a co-culture model with lung microvascular endothelial cells (HMVEC-L) treated with and without VEGF (10 ng/mL). The assay was then repeated with a heparin-binding EGF-like growth factor (HB-EGF) neutralizing antibody ranging from 0.5-50 μg/mL. Compared to control mice, the VEGF-treated group displayed significantly higher lung volume (P = 0.001) and alveolar count (P = 0.005) on POD 4. VEGF treatment resulted in increased pulmonary expression of HB-EGF (P = 0.02). VEGF-treated HMVEC-L increased HBEC proliferation (P = 0.002) while the addition of an HB-EGF neutralizing antibody at 5 and 50 μg/mL abolished this effect (P = 0.01 and 0.002, respectively). These findings demonstrate that nasal delivery of VEGF enhanced CLG. These effects could be mediated by a paracrine mechanism through upregulation of HB-EGF, an epithelial cell mitogen., Competing Interests: The authors have declared that no competing interests exist.

BackgroundDeficiency of vascular endothelial growth factor (VEGF) is associated with hypoplastic lung diseases, such as congenital diaphragmatic hernia. Provision of VEGF has been demonstrated to be beneficial in hyperoxia-induced bronchopulmonary dysplasia, and hence could induce lung growth and improve the outcome in hypoplastic lung diseases. We aimed to determine the effects of exogenous VEGF in a rodent model of compensatory lung growth after left pneumonectomy.MethodsEight-to-ten-week-old C57Bl6 male mice underwent left pneumonectomy, followed by daily intra-peritoneal injections of saline or VEGF (0.5 mg/kg). Lung volume measurement, pulmonary function tests, and morphometric analyses were performed on post-operative day (POD) 4 and 10. The pulmonary expression of angiogenic factors was analyzed by quantitative polymerase chain reaction and western blot.ResultsLung volume on POD 4 was higher in the VEGF-treated mice (P=0.03). On morphometric analyses, VEGF increased the parenchymal volume (P=0.001), alveolar volume (P=0.0003), and alveolar number (P<0.0001) on POD 4. The VEGF group displayed higher levels of phosphorylated-VEGFR2/VEGFR2 (P=0.03) and epidermal growth factor (EGF) messenger RNA (P=0.01).ConclusionVEGF accelerated the compensatory lung growth in mice, by increasing the alveolar units. These changes may be mediated by VEGFR2 and EGF-dependent mechanisms.

Objectives: Several outbreaks of serogroup B meningococcal disease have occurred among university students in recent years. In the setting of high coverage of the quadrivalent meningococcal conjugate vaccine and prior to widespread use of serogroup B meningococcal vaccines among adolescents, we conducted surveys to characterize the prevalence and molecular characteristics of meningococcal carriage among university students., Methods: Two cross-sectional oropharyngeal carriage surveys were conducted among undergraduates at a Rhode Island university. Isolates were characterized using slide agglutination, real-time polymerase chain reaction (rt-PCR), and whole genome sequencing. Adjusted prevalence ratios and 95% confidence intervals were calculated using Poisson regression to determine risk factors for carriage., Results: A total of 1837 oropharyngeal specimens were obtained from 1478 unique participants. Overall carriage prevalence was 12.7-14.6% during the two survey rounds, with 1.8-2.6% for capsular genotype B, 0.9-1.0% for capsular genotypes C, W, or Y, and 9.9-10.8% for nongroupable strains by rt-PCR. Meningococcal carriage was associated with being male, smoking, party or club attendance, recent antibiotic use (inverse correlation), and recent respiratory infections., Conclusions: In this university setting, the majority of meningococcal carriage was due to nongroupable strains, followed by serogroup B. Further evaluation is needed to understand the dynamics of serogroup B carriage and disease among university students., (Published by Elsevier Ltd.)

Bacterial meningitis is a severe, acute infection of the fluid surrounding the brain and spinal cord that can rapidly lead to death. Even with recommended antibiotic treatment, up to 25% of infected persons in Africa might experience neurologic sequelae (1). Three regions in northern Ghana (Upper East, Northern, and Upper West), located in the sub-Saharan "meningitis belt" that extends from Senegal to Ethiopia, experienced periodic outbreaks of meningitis before introduction of serogroup A meningococcal conjugate vaccine (MenAfriVac) in 2012 (2,3). During December 9, 2015-February 16, 2016, a total of 432 suspected meningitis cases were reported to health authorities in these three regions. The Ghana Ministry of Health, with assistance from CDC and other partners, tested cerebrospinal fluid (CSF) specimens from 286 patients. In the first 4 weeks of the outbreak, a high percentage of cases were caused by Streptococcus pneumoniae; followed by an increase in cases caused by Neisseria meningitidis, predominantly serogroup W. These data facilitated Ghana's request to the International Coordinating Group* for meningococcal polysaccharide ACW vaccine, which was delivered to persons in the most affected districts. Rapid identification of the etiologic agent causing meningitis outbreaks is critical to inform targeted public health and clinical interventions, including vaccination, clinical management, and contact precautions.

Background: Meningococcal conjugate vaccines against serogroups A, C, W, and Y (MenACWY) are recommended for routine use in adolescents aged 11-18 years. The impact of these vaccines on the meningococcal population structure in the United States have yet to be evaluated., Methods: Meningococcal isolates recovered during 2006-2010 (ie, after introduction of MenACWY) collected through Active Bacterial Core surveillance (ABCs) were characterized; serogroup distribution and molecular features of these isolates were compared to previously published data on ABCs isolates recovered from 2000 to 2005 (ie, before introduction of MenACWY). P values were generated using χ(2) statistics and exact methods., Results: There was a significant change (P < .05) in serogroup distribution among all age groups between the 2 periods. A small proportion of isolates showed evidence of capsular switching in both periods. Between the 2 periods, significant changes were observed in the distribution of porin A, ferric enterobactin transport, and strain genotypes among vaccine and nonvaccine serogroups., Conclusions: The population structure of US meningococcal isolates is dynamic; some changes occurred over time, but the basic structure remained. Vaccine-induced serogroup replacement was not observed, although a small proportion of isolates had undergone capsule switching, possibly driven by non-vaccine-mediated selection. Changes in the distribution of molecular features are likely due to horizontal gene transfer and changes in serogroup distribution., (Published by Oxford University Press on behalf of the Infectious Diseases Society of America 2015. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

PCR detecting the protein D (hpd) and fuculose kinase (fucK) genes showed high sensitivity and specificity for identifying Haemophilus influenzae and differentiating it from H. haemolyticus. Phylogenetic analysis using the 16S rRNA gene demonstrated two distinct groups for H. influenzae and H. haemolyticus.