The emergence of SARS-CoV-2 lineages and associated saliva antibody responses among asymptomatic individuals in a large university community.

SARS-CoV-2 (CoV2) infected, asymptomatic individuals are an important contributor to COVID transmission. CoV2-specific immunoglobulin (Ig)-as generated by the immune system following infection or vaccination-has helped limit CoV2 transmission from asymptomatic individuals to susceptible populations (e.g. elderly). Here, we describe the relationships between COVID incidence and CoV2 lineage, viral load, saliva Ig levels (CoV2-specific IgM, IgA and IgG), and ACE2 binding inhibition capacity in asymptomatic individuals between January 2021 and May 2022. These data were generated as part of a large university COVID monitoring program in Ohio, United States of America, and demonstrate that COVID incidence among asymptomatic individuals occurred in waves which mirrored those in surrounding regions, with saliva CoV2 viral loads becoming progressively higher in our community until vaccine mandates were established. Among the unvaccinated, infection with each CoV2 lineage (pre-Omicron) resulted in saliva Spike-specific IgM, IgA, and IgG responses, the latter increasing significantly post-infection and being more pronounced than N-specific IgG responses. Vaccination resulted in significantly higher Spike-specific IgG levels compared to unvaccinated infected individuals, and uninfected vaccinees' saliva was more capable of inhibiting Spike function. Vaccinees with breakthrough Delta infections had Spike-specific IgG levels comparable to those of uninfected vaccinees; however, their ability to inhibit Spike binding was diminished. These data are consistent with COVID vaccines having achieved hoped-for effects in our community, including the generation of mucosal antibodies that inhibit Spike and lower community viral loads, and suggest breakthrough Delta infections were not due to an absence of vaccine-elicited Ig, but instead limited Spike binding activity in the face of high community viral loads.

Navigating Breast Cancer Oligometastasis and Oligoprogression: Current Landscape and Future Directions.

PURPOSE: We examine the potential for curative approaches among metastatic breast cancer (MBC) patients by exploring the recent literature on local ablative therapies like surgery and stereotactic body radiation therapy (SBRT) in patients with oligometastatic (OM) breast cancer. We also cover therapies for MBC patients with oligoprogressive (OP) disease. KEY FINDINGS: Surgery and SBRT have been studied for OM and OP breast cancer, mainly in retrospective or non-randomized trials. While many studies demonstrated favorable results, a cooperative study and single-institution trial found no support for surgery/SBRT in OM and OP cases, respectively. CONCLUSION: While there is interest in applying local therapies to OM and OP breast cancer, the current randomized data does not back the routine use of surgery or SBRT, particularly when considering the potential for treatment-related toxicities. Future research should refine patient selection through advanced imaging and possibly explore these therapies specifically in patients with hormone receptor-positive or HER2-positive disease.

Racial Disparities in Breast Cancer: from Detection to Treatment.

PURPOSE OF REVIEW: Update on current racial disparities in the detection and treatment of breast cancer. RECENT FINDINGS: Breast cancer remains the leading cause of cancer death among Black and Hispanic women. Mammography rates among Black and Hispanic women have surpassed those among White women, with studies now advocating for earlier initiation of breast cancer screening in Black women. Black, Hispanic, Asian, and American Indian and Alaskan Native women continue to experience delays in diagnosis and time to treatment. Further, racial discrepancies in receipt of guideline-concordant care, access to genetic testing and surgical reconstruction persist. Disparities in the initiation, completion, toxicity, and efficacy of chemotherapy, endocrine therapy, and targeted drug therapy remain for racially marginalized women. Efforts to evaluate the impact of race and ethnicity across the breast cancer spectrum are increasing, but knowledge gaps remain and further research is necessary to reduce the disparity gap.

Acquisition of Gonococcal AniA-NorB Pathway by the Neisseria meningitidis Urethritis Clade Confers Denitrifying and Microaerobic Respiration Advantages for Urogenital Adaptation.

Neisseria meningitidis historically has been an infrequent and sporadic cause of urethritis and other urogenital infections. However, a nonencapsulated meningococcal clade belonging to the hyperinvasive clonal complex 11.2 lineage has recently emerged and caused clusters of urethritis cases in the United States and other countries. One of the genetic signatures of the emerging N. meningitidis urethritis clade (NmUC) is a chromosomal gene conversion event resulting in the acquisition of the Neisseria gonorrhoeae denitrification apparatus-the N. gonorrhoeae alleles encoding the nitrite reductase AniA, the nitric oxide (NO) reductase NorB, and the intergenic promoter region. The biological importance of the N. gonorrhoeae AniA-NorB for adaptation of the NmUC to a new environmental niche is investigated herein. We found that oxygen consumption, nitrite utilization, and NO production were significantly altered by the conversion event, resulting in different denitrifying aerobic and microaerobic growth of the clade. Further, transcription of aniA and norB in NmUC isolates differed from canonical N. meningitidis, and important polymorphisms within the intergenic region, which influenced aniA promoter activity of the NmUC, were identified. The contributions of three known meningococcal regulators (NsrR, FNR, and NarQP) in controlling the denitrification pathway and endogenous NO metabolism were distinct. Overall, transcription of aniA was dampened relative to canonical N. meningitidis, and this correlated with the lower NO accumulation in the clade. Denitrification and microaerobic respiration were bolstered, and protection against host-derived NO was likely enhanced. The acquisition of the N. gonorrhoeae denitrification pathway by the NmUC supports the clade's adaptation and survival in a microaerobic urogenital environment.

Implementation of a Breast Intraoperative Oncoplastic Form to Aid Management of Oncoplastic Surgery.

INTRODUCTION: Oncoplastic breast conservation surgery (BCS) uses concurrent reduction and/or mastopexy with lumpectomy to improve aesthetic outcomes. However, tissue rearrangement can shift the original tumor location site in relation to external breast landmarks, resulting in difficulties during re-excision for a positive margin and accurate radiation targeting. We developed the Breast Intraoperative Oncoplastic (BIO) form to help depict the location of the tumor and breast reduction specimen. This study seeks to assess physician perspectives of the implementation outcomes. METHODS: From February 2021 to April 2021, the BIO form was used in 11 oncoplastic BCS cases at a single institution. With institutional review board approval, surgical oncologists (SOs), plastic surgeons (PSs), and radiation oncologists (ROs) were administered a 12-question validated survey on Acceptability of Intervention Measure (AIM), Intervention Appropriateness Measure (IAM), and Feasibility of Intervention Measure (FIM), using a 5-point Likert scale during initial implementation and at 6-month reassessment. RESULTS: Twelve physicians completed the survey initially (4 SOs, 4 PSs, and 4 ROs). The mean scores for Acceptability of Intervention Measure, Intervention Appropriateness Measure, and Feasibility of Intervention Measure were high (4.44, 4.56, and 4.56, respectively). Twelve completed the second survey (5 SOs, 3 PSs, and 4 ROs). The mean scores were marginally lower (4.06, 4.21, and 4.25). There were no significant differences when stratified by number of years in practice or specialty. Free text comments showed that 75% of physicians found the form helpful in oncoplastic BCS. CONCLUSIONS: The data indicate high feasibility, acceptability, and appropriateness of the BIO form. Results of this study suggest multidisciplinary benefits of implementing the BIO form in oncoplastic BCS.

Infection With the US Neisseria meningitidis Urethritis Clade Does Not Lower Future Risk of Urethral Gonorrhea.

BACKGROUND: Cross-protective immunity between Neisseria meningitidis (Nm) and Neisseria gonorrhoeae (Ng) may inform gonococcal vaccine development. Meningococcal serogroup B (MenB) outer membrane vesicle (OMV) vaccines confer modest protection against gonorrhea. However, whether urethral Nm infection protects against gonorrhea is unknown. We examined gonorrhea risk among men with US Nm urethritis clade (US_NmUC) infections. METHODS: We conducted a retrospective cohort study of men with urethral US_NmUC (n = 128) between January 2015 and April 2018. Using diagnosis date as the baseline visit, we examined Ng status at return visits to compute urethral Ng risk. We compared these data to 3 referent populations: men with urethral Ng (n = 253), urethral chlamydia (Ct) (n = 251), and no urethral Ng or Ct (n = 255). We conducted sensitivity analyses to assess varied approaches to censoring, missing data, and anatomical site of infection. We also compared sequences of protein antigens in the OMV-based MenB-4C vaccine, US_NmUC, and Ng. RESULTS: Participants were primarily Black (65%) and heterosexual (82%). Over follow-up, 91 men acquired urethral Ng. Men with urethral US_NmUC had similar Ng risk to men with prior urethral Ng (adjusted hazard ratio [aHR]: 1.27; 95% CI: .65-2.48). Men with urethral US_NmUC had nonsignificantly increased Ng risk compared with men with urethral Ct (aHR: 1.51; 95% CI: .79-2.88), and significantly increased Ng risk compared with men without urethral Ng or Ct (aHR: 3.55; 95% CI: 1.27-9.91). Most of the protein antigens analyzed shared high sequence similarity. CONCLUSIONS: Urethral US_NmUC infection did not protect against gonorrhea despite substantial sequence similarities in shared protein antigens.

Evaluation of Urethrotropic-Clade Meningococcal Infection by Urine Metagenomic Shotgun Sequencing.

Urethral infections caused by an emerging nongroupable (NG) urethrotropic clade of Neisseria meningitidis were first reported in the United States in 2015 (the "U.S. NmNG urethritis clade"). Here, we evaluate for the presence of other urethral pathogens in men with U.S. NmNG urethritis clade infection. We evaluated 129 urine specimens collected from men at a sexual health clinic, including 33 from patients with culture-confirmed or suspected urethral N. meningitidis infection and 96 specimens in which nucleic acid amplification test detected Neisseria gonorrhoeae, Chlamydia trachomatis, both pathogens, or neither pathogen. N. meningitidis was detected first by real-time PCR, followed by metagenomic shotgun sequencing of 91 specimens to identify coinfections. N. meningitidis genomes were sequenced following selective whole-genome amplification when possible. Metagenomic sequencing detected N. meningitidis in 16 of 17 specimens from culture-confirmed N. meningitidis cases, with no coinfection by other conventional urethral pathogens. Metagenomic sequencing also detected N. meningitidis in three C. trachomatis-positive specimens, one specimen positive for both N. gonorrhoeae and C. trachomatis, and nine specimens with negative N. gonorrhoeae and C. trachomatis results, eight of which had suspected Neisseria infections. N. meningitidis from culture-confirmed N. meningitidis cases belonged to the U.S. NmNG urethritis clade, while N. meningitidis identified in other specimens belonged to multiple clonal complexes. Additional urethral pathogens were predominant in non-N. meningitidis specimens, including N. gonorrhoeae, C. trachomatis, Mycoplasma genitalium, Ureaplasma urealyticum, and herpes simplex virus 2. Coinfection with other conventional urethral pathogens is rare in men with culture-confirmed U.S. NmNG urethritis clade infection and points to the strong association of this clade with disease.

Modified Radical Mastectomy in De Novo Stage IV Inflammatory Breast Cancer.

BACKGROUND: There are few studies on surgical management in patients with de novo metastatic inflammatory breast cancer (IBC). The objective of this study is to examine the association between modified radical mastectomy (MRM) and disease-specific survival (DSS) in patients with de novo stage IV IBC. PATIENTS AND METHODS: The Surveillance, Epidemiology, and End Result Program was queried for patients ≥18 years old with cT4d/pT4d pathology, histology type 8530 and 8533 with distant disease between 2010 and 2016. The sample was divided into two groups: (1) the MRM group, defined as MRM or mastectomy with at least ten lymph nodes removed, and (2) the no-surgery group. Sociodemographic and clinical variables were compared between the groups on bivariable analysis. After propensity score matching, Kaplan-Meier curves and a Cox proportional-hazards model examined DSS. RESULTS: 1293 patients were included in the study, of whom 240 underwent MRM. A higher percentage in the MRM group had only one metastatic site (69.8% versus 52.2%), received chemotherapy (88.3% versus 66.1%) and radiation (58.8% versus 26.0%) compared with the no-MRM group. MRM was associated with an increase in DSS compared with no MRM [HR 0.63 (95% CI 0.50-0.80), p < 0.001]. Patients with MRM had a 5-year DSS rate of 31.4% compared with 17.7% for patients not undergoing surgery (p = 0.001). Survival time was 38 months (range 27-45 months) for the MRM group versus 27 months (22-29 months) for the no-MRM group. CONCLUSION: MRM in patients with de novo metastatic IBC may improve DSS in a subset of patients.

A Collaborative Intervention Between Emergency Medicine and Infectious Diseases to Increase Syphilis and HIV Screening in the Emergency Department.

BACKGROUND: Sexually transmitted infections (STIs) are a common reason for evaluation in the emergency department (ED). Given the overlapping risk factors for STIs, patients screened for gonorrhea and chlamydia should be tested for syphilis and HIV. Syphilis and HIV testing rates in the ED have been reported to be low. The study objective was to examine whether collaboration between emergency medicine (EM) and infectious disease (ID) providers improved syphilis and HIV testing in the ED. METHODS: A multidisciplinary team of EM and ID providers was formed to identify and address barriers to syphilis and HIV testing in the ED. Syphilis, HIV, chlamydia, and gonorrhea testing and infection rates were calculated and compared during 2 time periods: preintervention (January 1, 2012-December 30, 2017) and postintervention (November 1, 2018-November 30, 2019). We also extracted clinical and laboratory data from patients with positive syphilis and HIV results during the study period. RESULTS: The most commonly cited barrier to syphilis and HIV testing was concern about follow-up of positive results. Compared with the preintervention period, syphilis and HIV testing rates increased significantly in the postintervention period (incidence rate ratios, 30.70 [P < 0.0001] and 28.99 [P < 0.0001] for syphilis and HIV, respectively). The postintervention period was also associated with a significant increase in the identification of patients with positive syphilis and HIV results (incidence rate ratios, 7.02 [P < 0.0001] and 2.34 [P = 0.03], respectively). CONCLUSIONS: Collaboration between EM and ID providers resulted in a significant increase in syphilis and HIV testing and diagnosis in the ED.

Emergence of a novel urogenital-tropic Neisseria meningitidis.

PURPOSE OF REVIEW: Neisseria meningitidis (Nm) is primarily associated with asymptomatic nasopharyngeal carriage and invasive meningococcal disease (sepsis and meningitis), but like N. gonorrhoea (Ng), Nm can colonize urogenital and rectal mucosal surfaces and cause disease. First noted in 2015, but with origins in 2011, male urethritis clusters caused by a novel Nm clade were reported in the USA (the US_NmUC). This review describes research developments that characterize this urogenital-tropic Nm. RECENT FINDINGS: The US_NmUC evolved from encapsulated Nm serogroup C strains. Loss of capsule expression, lipooligosaccharide (LOS) sialylation, genetic acquisition of gonococcal alleles (including the gonococcal anaerobic growth aniA/norB cassette), antimicrobial peptide heteroresistance and high surface expression of a unique factor-H-binding protein, can contribute to the urethra-tropic phenotype. Loss-of-function mutations in mtrC are overrepresented in clade isolates. Similar to Ng, repeat US_NmUC urethritis episodes can occur. The US_NmUC is now circulating in the UK and Southeast Asia. Genomic sequencing has defined the clade and rapid diagnostic tests are being developed for surveillance. SUMMARY: The US_NmUC emerged as a cause of urethritis due to acquisition of gonococcal genetic determinants and phenotypic traits that facilitate urogenital tract infection. The epidemiology and pathogenesis of this urogenital-tropic pathogen continues to be defined.

Disparate Use of Chemoradiation in Elderly Patients With Localized Anal Cancer.

BACKGROUND: The incidence of squamous cell carcinoma of the anus (SCCA) is increasing, particularly among the elderly (age ≥65 years). We sought to compare patterns of care for the treatment of SCCA in elderly versus nonelderly patients. METHODS: Data for patients with stages I-III SCCA diagnosed from 2004 through 2015 were obtained from the National Cancer Database. Patients were categorized as having received standard-of-care (SOC) chemoradiation (CRT) with multiagent chemotherapy, non-SOC therapy, palliative therapy, or no treatment. Differences in treatment groups were tested using the chi-square test. We used logistic regression to identify predictors of SOC CRT and multiagent versus single-agent chemotherapy in patients receiving CRT. Propensity score matching was used to compare overall survival (OS) in elderly patients receiving multiagent versus single-agent chemotherapy for those receiving CRT. RESULTS: We identified 9,156 elderly and 17,640 nonelderly patients. A lower proportion of elderly versus nonelderly patients (54.5% vs 65.0%; P<.0001) received SOC CRT than other treatments or no treatment. In multivariate analysis, elderly patients were 38% less likely than nonelderly patients to receive SOC CRT (odds ratio, 0.62; 95% CI, 0.58-0.65; P<.0001). A higher proportion of the elderly were treated with single-agent versus multiagent chemotherapy (16.9% vs 11.8%; P<.0001), which resulted in a >1.5-fold increase in the likelihood of elderly patients receiving single-agent chemotherapy (odds ratio, 1.52; 95% CI, 1.39-1.66) in multivariate analysis. After propensity score matching, 3-year OS was higher in elderly patients who received CRT with multiagent versus single-agent chemotherapy (77.1% vs 67.5%; hazard ratio, 0.78; 95% CI, 0.68-0.89; P=.0002). CONCLUSIONS: In this comprehensive study of patients with stages I-III SCCA, elderly patients were less likely than nonelderly patients to receive SOC CRT. The low proportion of elderly patients receiving SOC CRT with multiagent chemotherapy for localized anal cancer suggests that the optimal treatment approach for this vulnerable population remains undefined.

Heteroresistance to the model antimicrobial peptide polymyxin B in the emerging Neisseria meningitidis lineage 11.2 urethritis clade: mutations in the pilMNOPQ operon.

Clusters of Neisseria meningitidis (Nm) urethritis among primarily heterosexual males in multiple US cities have been attributed to a unique non-encapsulated meningococcal clade (the US Nm urethritis clade, US_NmUC) within the hypervirulent clonal complex 11. Resistance to antimicrobial peptides (AMPs) is a key feature of urogenital pathogenesis of the closely related species, Neisseria gonorrhoeae. The US_NmUC isolates were found to be highly resistant to the model AMP, polymyxin B (PmB, MICs 64-256 µg ml-1 ). The isolates also demonstrated stable subpopulations of heteroresistant colonies that showed near total resistant to PmB (MICs 384-1024 µg ml-1 ) and colistin (MIC 256 µg ml-1 ) as well as enhanced LL-37 resistance. This is the first observation of heteroresistance in N. meningitidis. Consistent with previous findings, overall PmB resistance in US_NmUC isolates was due to active Mtr efflux and LptA-mediated lipid A modification. However, whole genome sequencing, variant analyses and directed mutagenesis revealed that the heteroresistance phenotypes and very high-level AMP resistance were the result of point mutations and IS1655 element movement in the pilMNOPQ operon, encoding the type IV pilin biogenesis apparatus. Cross-resistance to other classes of antibiotics was also observed in the heteroresistant colonies. High-level resistance to AMPs may contribute to the pathogenesis of US_NmUC.

In Vitro Exposure of Leukocytes to HIV Preexposure Prophylaxis Decreases Mitochondrial Function and Alters Gene Expression Profiles.

The use of antiretroviral therapy (ART) as preexposure prophylaxis (PrEP) is an effective strategy for preventing HIV acquisition. The cellular consequences of PrEP exposure, however, have not been sufficiently explored to determine potential effects on health in individuals without HIV. In this study, peripheral blood mononuclear cells (PBMCs) from people without HIV were exposed to tenofovir disoproxil fumarate (TDF) or emtricitabine (FTC) overnight. Mitochondrial mass and function were measured by flow cytometry and an Agilent XFp analyzer. Monocyte-derived macrophages (MDMs) were differentiated in 20% autologous serum for 5 days in the presence or absence of TDF or FTC, and surface markers, lipid uptake, and efferocytosis were measured by flow cytometry. MDM gene expression was measured using transcriptome sequencing (RNA-seq). Plasma lipids were measured using mass spectrometry. PBMCs exposed to TDF or FTC had decreased maximal oxygen consumption rate (OCR) and reduced mitochondrial mass. Exposure to PrEP also increased reactive oxygen species (ROS) production from monocyte subsets. Compared to MDMs cultured in medium alone, cells differentiated in the presence of TDF (829 genes) or FTC (888 genes) had significant changes in gene expression. Further, PrEP-exposed MDMs had decreased mitochondrial mass and displayed increased lipid uptake and reduced efferocytosis. Plasma biomarkers and lipid levels were also altered in vivo in individuals receiving a PrEP regimen. In conclusion, exposure of leukocytes to TDF or FTC resulted in decreased mitochondrial function and altered functional and transcriptional profiles. These findings may have important implications for the metabolic and immunologic consequences of PrEP in populations at risk for HIV acquisition.

Full Molecular Typing of Neisseria meningitidis Directly from Clinical Specimens for Outbreak Investigation.

Neisseria meningitidis is a leading cause of bacterial meningitis and sepsis worldwide and an occasional cause of meningococcal urethritis. When isolates are unavailable for surveillance or outbreak investigations, molecular characterization of pathogens needs to be performed directly from clinical specimens, such as cerebrospinal fluid (CSF), blood, or urine. However, genome sequencing of specimens is challenging because of low bacterial and high human DNA abundances. We developed selective whole-genome amplification (SWGA), an isothermal multiple-displacement amplification-based method, to efficiently enrich, sequence, and de novo assemble N. meningitidis DNA from clinical specimens with low bacterial loads. SWGA was validated with 12 CSF specimens from invasive meningococcal disease cases and 12 urine specimens from meningococcal urethritis cases. SWGA increased the mean proportion of N. meningitidis reads by 2 to 3 orders of magnitude, enabling identification of at least 90% of the 1,605 N. meningitidis core genome loci for 50% of the specimens. The validated method was used to investigate two meningitis outbreaks recently reported in Togo and Burkina Faso. Twenty-seven specimens with low bacterial loads were processed by SWGA before sequencing, and 12 of 27 were successfully assembled to obtain the full molecular typing and vaccine antigen profile of the N. meningitidis pathogen, thus enabling thorough characterization of outbreaks. This method is particularly important for enhancing molecular surveillance in regions with low culture rates. SWGA produces enough reads for phylogenetic and allelic analysis at a low cost. More importantly, the procedure can be extended to enrich other important human bacterial pathogens.

Reverse Sequence Syphilis Screening and Discordant Results in Pregnancy.

A "reverse sequence syphilis screening" algorithm is widely used for syphilis testing. This retrospective study showed that most (65%) pregnant women with discordant screening results (treponemal multiplex flow immunoassay IgG+/rapid plasma reagin-) had a nonreactive confirmatory Treponema pallidum-particle agglutination assay, likely indicative of a false-positive reaction.

Repeat Episodes of Symptomatic Urethritis Due to a Uropathogenic Meningococcal Clade.

In 2015, we identified a non-groupable clade of Neisseria meningitidis that causes urethritis in men (the US_NmUC). Because repeat infection is common with Neisseria gonorrhoeae, we examined whether reinfection also occurs with the US_NmUC. We provide evidence that men are susceptible to repeat episodes of urethritis from the US_NmUC.

Emergence of a new Neisseria meningitidis clonal complex 11 lineage 11.2 clade as an effective urogenital pathogen.

Neisseria meningitidis (Nm) clonal complex 11 (cc11) lineage is a hypervirulent pathogen responsible for outbreaks of invasive meningococcal disease, including among men who have sex with men, and is increasingly associated with urogenital infections. Recently, clusters of Nm urethritis have emerged primarily among heterosexual males in the United States. We determined that nonencapsulated meningococcal isolates from an ongoing Nm urethritis outbreak among epidemiologically unrelated men in Columbus, Ohio, are linked to increased Nm urethritis cases in multiple US cities, including Atlanta and Indianapolis, and that they form a unique clade (the US Nm urethritis clade, US_NmUC). The isolates belonged to the cc11 lineage 11.2/ET-15 with fine type of PorA P1.5-1, 10-8; FetA F3-6; PorB 2-2 and express a unique FHbp allele. A common molecular fingerprint of US_NmUC isolates was an IS1301 element in the intergenic region separating the capsule ctr-css operons and adjacent deletion of cssA/B/C and a part of csc, encoding the serogroup C capsule polymerase. This resulted in the loss of encapsulation and intrinsic lipooligosaccharide sialylation that may promote adherence to mucosal surfaces. Furthermore, we detected an IS1301-mediated inversion of an ∼20-kb sequence near the cps locus. Surprisingly, these isolates had acquired by gene conversion the complete gonococcal denitrification norB-aniA gene cassette, and strains grow well anaerobically. The cc11 US_NmUC isolates causing urethritis clusters in the United States may have adapted to a urogenital environment by loss of capsule and gene conversion of the Neisseria gonorrheae norB-aniA cassette promoting anaerobic growth.

Expansion of a urethritis-associated Neisseria meningitidis clade in the United States with concurrent acquisition of N. gonorrhoeae alleles.

BACKGROUND: Increased reports of Neisseria meningitidis urethritis in multiple U.S. cities during 2015 have been attributed to the emergence of a novel clade of nongroupable N. meningitidis within the ST-11 clonal complex, the "U.S. NmNG urethritis clade". Genetic recombination with N. gonorrhoeae has been proposed to enable efficient sexual transmission by this clade. To understand the evolutionary origin and diversification of the U.S. NmNG urethritis clade, whole-genome phylogenetic analysis was performed to identify its members among the N. meningitidis strain collection from the Centers for Disease Control and Prevention, including 209 urogenital and rectal N. meningitidis isolates submitted by U.S. public health departments in eleven states starting in 2015. RESULTS: The earliest representatives of the U.S. NmNG urethritis clade were identified from cases of invasive disease that occurred in 2013. Among 209 urogenital and rectal isolates submitted from January 2015 to September 2016, the clade accounted for 189/198 male urogenital isolates, 3/4 female urogenital isolates, and 1/7 rectal isolates. In total, members of the clade were isolated in thirteen states between 2013 and 2016, which evolved from a common ancestor that likely existed during 2011. The ancestor contained N. gonorrhoeae-like alleles in three regions of its genome, two of which may facilitate nitrite-dependent anaerobic growth during colonization of urogenital sites. Additional gonococcal-like alleles were acquired as the clade diversified. Notably, one isolate contained a sequence associated with azithromycin resistance in N. gonorrhoeae, but no other gonococcal antimicrobial resistance determinants were detected. CONCLUSIONS: Interspecies genetic recombination contributed to the early evolution and subsequent diversification of the U.S. NmNG urethritis clade. Ongoing acquisition of N. gonorrhoeae alleles by the U.S. NmNG urethritis clade may facilitate the expansion of its ecological niche while also increasing the frequency with which it causes urethritis.

Heterogeneity in Outcomes of Pathologic T1-2N1 Breast Cancer After Mastectomy: Looking Beyond Locoregional Failure Rates.

PURPOSE: A meta-analysis of 22 randomized trials accrued from 1964 to 1986 demonstrated significantly higher rates of locoregional failure (LRF) and breast-cancer mortality in women with 1-3 positive nodes without postmastectomy radiotherapy (PMRT) after mastectomy (mast.). Recent data demonstrate that PMRT reduces distant metastases (DM) in women with pN1 disease. The challenge today is whether all patients with pathologic T1-2pN1 disease have similar substantial LRF/DM risk that routinely warrants PMRT. METHODS: We reviewed patients with pT1-2N1 breast cancer treated with mast. ± adjuvant systemic therapy without PMRT from 2000 to 2013. The endpoints were LRF and DM rates, estimated by cumulative incidence method. RESULTS: We identified 468 patients with median follow-up of 6.3 years. Most (71%) were estrogen receptor/progesterone receptor + human epidermal growth factor receptor 2 (HER2). There were 269 patients with 1+ node, 140 patients with 2+ nodes, and 59 patients with 3+ nodes. The 6-year LRF/DM rates were 4.1%/8.4%. Patients with 1+, 2+, and 3+ nodes had 6-year LRF of 2.3, 5.1 and 8.9%, respectively (p = 0.13). The 6-year DM rate was higher in patients with 3+ nodes versus 1-2+ nodes: 15.7% versus 7.4% (p = 0.02). Several subgroups had low 6-year LRF and DM rates, including T1/1+ node (0.8%/4.1% LRF/DM) and micrometastases (0%/5.8% LRF/DM). CONCLUSIONS: Patients with pT1-2pN1 represent a heterogeneous group with a wide range of LRF/DM rates. In particular, patients with pT1 tumors and 1 + LN, and patients with micrometastases, had low event rates. These groups would derive small absolute reductions in LRF and DM with addition of PMRT, underscoring the importance of patient selection for PMRT in pT1-2pN1 breast cancer.

Large Cluster of Neisseria meningitidis Urethritis in Columbus, Ohio, 2015.

Background: Neisseria meningitidis (Nm) is a Gram-negative diplococcus that normally colonizes the nasopharynx and rarely infects the urogenital tract. On Gram stain of urethral exudates, Nm can be misidentified as the more common sexually transmitted pathogen Neisseria gonorrhoeae. Methods: In response to a large increase in cases of Nm urethritis identified among men presenting for screening at a sexually transmitted disease clinic in Columbus, Ohio, we investigated the epidemiologic characteristics of men with Nm urethritis and the molecular and phylogenetic characteristics of their Nm isolates. The study was conducted between 1 January and 18 November 2015. Results: Seventy-five Nm urethritis cases were confirmed by biochemical and polymerase chain reaction testing. Men with Nm urethritis were a median age of 31 years (interquartile range [IQR] = 24-38) and had a median of 2 sex partners in the last 3 months (IQR = 1-3). Nm cases were predominantly black (81%) and heterosexual (99%). Most had urethral discharge (91%), reported oral sex with a female in the last 12 months (96%), and were treated with a ceftriaxone-based regimen (95%). A minority (15%) also had urethral chlamydia coinfection. All urethral Nm isolates were nongroupable, ST-11 clonal complex (cc11), ET-15, and clustered together phylogenetically. Urethral Nm isolates were similar by fine typing (PorA P1.5-1,10-8, PorB 2-2, FetA F3-6), except 2, which had different PorB types (2-78 and 2-52). Conclusions: Between January and November 2015, 75 urethritis cases due to a distinct Nm clade occurred among primarily black, heterosexual men in Columbus, Ohio. Future urogenital Nm infection studies should focus on pathogenesis and modes of sexual transmission.