COVID-19 is Observed in Older Children During the Omicron Wave in New York City.

BACKGROUND: The Omicron variant of SARS-CoV-2 has a predilection for the upper airways, causing symptoms such as sore throat, hoarse voice, and stridor. OBJECTIVE: We describe a series of children with COVID-19-associated croup in an urban multicenter hospital system. METHODS: We conducted a cross-sectional study of children ≤18 years of age presenting to the emergency department during the COVID-19 pandemic. Data were extracted from an institutional data repository comprised of all patients who were tested for SARS-CoV-2. We included patients with a croup diagnosis by International Classification of Diseases, 10th revision code and a positive SARS-CoV-2 test within 3 days of presentation. We compared demographics, clinical characteristics, and outcomes for patients presenting during a pre-Omicron period (March 1, 2020-December 1, 2021) to the Omicron wave (December 2, 2021-February 15, 2022). RESULTS: We identified 67 children with croup, 10 (15%) pre-Omicron and 57 (85%) during the Omicron wave. The prevalence of croup among SARS-CoV-2-positive children increased by a factor of 5.8 (95% confidence interval 3.0-11.4) during the Omicron wave compared to prior. More patients were ≥6 years of age in the Omicron wave than prior (19% vs. 0%). The majority were not hospitalized (77%). More patients ≥6 years of age received epinephrine therapy for croup during the Omicron wave (73% vs. 35%). Most patients ≥6 years of age had no croup history (64%) and only 45% were vaccinated against SARS-CoV-2. CONCLUSION: Croup was prevalent during the Omicron wave, atypically affecting patients ≥6 years of age. COVID-19-associated croup should be added to the differential diagnosis of children with stridor, regardless of age. © 2022 Elsevier Inc.

Therapeutic inhibition of FcγRIIb signaling targets leukemic stem cells in chronic myeloid leukemia.

Despite the successes achieved with molecular targeted inhibition of the oncogenic driver Bcr-Abl in chronic myeloid leukemia (CML), the majority of patients still require lifelong tyrosine kinase inhibitor (TKI) therapy. This is primarily caused by resisting leukemic stem cells (LSCs), which prevent achievement of treatment-free remission in all patients. Here we describe the ITIM (immunoreceptor tyrosine-based inhibition motif)-containing Fc gamma receptor IIb (FcγRIIb, CD32b) for being critical in LSC resistance and show that targeting FcγRIIb downstream signaling, by using a Food and Drug Administration-approved BTK inhibitor, provides a successful therapeutic approach. First, we identified FcγRIIb upregulation in primary CML stem cells. FcγRIIb depletion caused reduced serial re-plaiting efficiency and cell proliferation in malignant cells. FcγRIIb targeting in both a transgenic and retroviral CML mouse model provided in vivo evidence for successful LSC reduction. Subsequently, we identified BTK as a main downstream mediator and targeting the Bcr-Abl-FcγRIIb-BTK axis in primary CML CD34+ cells using ibrutinib, in combination with standard TKI therapy, significantly increased apoptosis in quiescent CML stem cells thereby contributing to the eradication of LSCs.. As a potential curative therapeutic approach, we therefore suggest combining Bcr-Abl TKI therapy along with BTK inhibition.

First Locally Acquired Congenital Zika Syndrome Case in the United States: Neonatal Clinical Manifestations.

In the spring of 2017, a full-term infant with microcephaly was delivered in South Florida. During first trimester, the mother presented with fever, nausea, and vomiting. She reported no foreign travel for herself or her partner. The infant's neurologic, ophthalmologic, neuroradiologic, and audiologic findings were highly suggestive of congenital Zika syndrome (CZS), confirmed by IgM antibodies and plaque reduction neutralization test. New observations, including peripheral temporal retinal avascularity and peripapillary retinal nerve fiber layer thinning, are presented from this first known case of non-travel-associated CZS in the United States. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:e93-e98.].

Simultaneous Targeting of PARP1 and RAD52 Triggers Dual Synthetic Lethality in BRCA-Deficient Tumor Cells.

PARP inhibitors (PARPis) have been used to induce synthetic lethality in BRCA-deficient tumors in clinical trials with limited success. We hypothesized that RAD52-mediated DNA repair remains active in PARPi-treated BRCA-deficient tumor cells and that targeting RAD52 should enhance the synthetic lethal effect of PARPi. We show that RAD52 inhibitors (RAD52is) attenuated single-strand annealing (SSA) and residual homologous recombination (HR) in BRCA-deficient cells. Simultaneous targeting of PARP1 and RAD52 with inhibitors or dominant-negative mutants caused synergistic accumulation of DSBs and eradication of BRCA-deficient but not BRCA-proficient tumor cells. Remarkably, Parp1-/-;Rad52-/- mice are normal and display prolonged latency of BRCA1-deficient leukemia compared with Parp1-/- and Rad52-/- counterparts. Finally, PARPi+RAD52i exerted synergistic activity against BRCA1-deficient tumors in immunodeficient mice with minimal toxicity to normal cells and tissues. In conclusion, our data indicate that addition of RAD52i will improve therapeutic outcome of BRCA-deficient malignancies treated with PARPi.

IGH/MYC Translocation Associates with BRCA2 Deficiency and Synthetic Lethality to PARP1 Inhibitors.

Burkitt lymphoma/leukemia cells carry t(8;14)(q24;q32) chromosomal translocation encoding IGH/MYC, which results in the constitutive expression of the MYC oncogene. Here, it is demonstrated that untreated and cytarabine (AraC)-treated IGH/MYC-positive Burkitt lymphoma cells accumulate a high number of potentially lethal DNA double-strand breaks (DSB) and display low levels of the BRCA2 tumor suppressor protein, which is a key element of homologous recombination (HR)-mediated DSB repair. BRCA2 deficiency in IGH/MYC-positive cells was associated with diminished HR activity and hypersensitivity to PARP1 inhibitors (olaparib, talazoparib) used alone or in combination with cytarabine in vitro Moreover, talazoparib exerted a therapeutic effect in NGS mice bearing primary Burkitt lymphoma xenografts. In conclusion, IGH/MYC-positive Burkitt lymphoma/leukemia cells have decreased BRCA2 and are sensitive to PARP1 inhibition alone or in combination with other chemotherapies.Implications: This study postulates that IGH/MYC-induced BRCA2 deficiency may predispose Burkitt lymphoma cells to synthetic lethality triggered by PARP1 inhibitors.Visual Overview: http://mcr.aacrjournals.org/content/molcanres/15/8/967/F1.large.jpgMol Cancer Res; 15(8); 967-72. ©2017 AACR.

Mutations That Alter the Bacterial Cell Envelope Increase Lipid Production.

Lipids from microbes offer a promising source of renewable alternatives to petroleum-derived compounds. In particular, oleaginous microbes are of interest because they accumulate a large fraction of their biomass as lipids. In this study, we analyzed genetic changes that alter lipid accumulation in Rhodobacter sphaeroides By screening an R. sphaeroides Tn5 mutant library for insertions that increased fatty acid content, we identified 10 high-lipid (HL) mutants for further characterization. These HL mutants exhibited increased sensitivity to drugs that target the bacterial cell envelope and changes in shape, and some had the ability to secrete lipids, with two HL mutants accumulating ~60% of their total lipids extracellularly. When one of the highest-lipid-secreting strains was grown in a fed-batch bioreactor, its lipid content was comparable to that of oleaginous microbes, with the majority of the lipids secreted into the medium. Based on the properties of these HL mutants, we conclude that alterations of the cell envelope are a previously unreported approach to increase microbial lipid production. We also propose that this approach may be combined with knowledge about biosynthetic pathways, in this or other microbes, to increase production of lipids and other chemicals.IMPORTANCE This paper reports on experiments to understand how to increase microbial lipid production. Microbial lipids are often cited as one renewable replacement for petroleum-based fuels and chemicals, but strategies to increase the yield of these compounds are needed to achieve this goal. While lipid biosynthesis is often well understood, increasing yields of these compounds to industrially relevant levels is a challenge, especially since genetic, synthetic biology, or engineering approaches are not feasible in many microbes. We show that altering the bacterial cell envelope can be used to increase microbial lipid production. We also find that the utility of some of these alterations can be enhanced by growing cells in bioreactor configurations that can be used industrially. We propose that our findings can inform current and future efforts to increase production of microbial lipids, other fuels, or chemicals that are currently derived from petroleum.

Magnaporthe oryzae effectors MoHEG13 and MoHEG16 interfere with host infection and MoHEG13 counteracts cell death caused by Magnaporthe-NLPs in tobacco.

KEY MESSAGE: Adapted pathogens are able to modulate cell responses of their hosts most likely due to the activity of secreted effector molecules thereby enabling colonisation by ostensible nonhost pathogens. It is postulated that host and nonhost pathogens of a given plant species differ in their repertoire of secreted effector molecules that are able to suppress plant resistance. We pursued the strategy of identifying novel effectors of Magnaporthe oryzae, the causal agent of blast disease, by comparing the infection process of closely related host vs. nonhost Magnaporthe species on barley (Hordeum vulgare L.). When both types of pathogen simultaneously attacked the same cell, the nonhost isolate became a successful pathogen possibly due to potent effectors secreted by the host isolate. Microarray studies led to a set of M. oryzae Hypothetical Effector Genes (MoHEGs) which were classified as Early- and LateMoHEGs according to the maximal transcript abundance during colonization of barley. Interestingly, orthologs of these MoHEGs from a nonhost pathogen were similarly regulated when investigated in a host situation, suggesting evolutionary conserved functions. Knockout mutants of MoHEG16 from the group of EarlyMoHEGs were less virulent on barley and microscopic studies revealed an attenuated transition from epidermal to mesophyll colonization. MoHEG13, a LateMoHEG, was shown to antagonize cell death induced by M. oryzae Necrosis-and ethylene-inducing-protein-1 (Nep1)-like proteins in Nicotiana benthamiana. MoHEG13 has a virulence function as a knockout mutant showed attenuated disease progression when inoculated on barley.

Pathologic correlates of false positive breast magnetic resonance imaging findings: which lesions warrant biopsy?

BACKGROUND: Contrast-enhanced breast magnetic resonance imaging (MRI) is highly sensitive for breast cancer. However, adoption of breast MRI is hampered by frequent false positive (FP) findings. Though ultimately proven benign, these suspicious findings require biopsy due to abnormal morphology and/or kinetic enhancement curves that simulate malignancy on MRI. We hypothesized that analysis of a series of FP MRI findings could reveal a pattern of association between certain "suspicious" lesions and benign disease that might help avoid unnecessary biopsy of such lesions in the future. METHODS: A retrospective chart review identified women undergoing breast MRI between June 1995 and March 2002 with FP findings identified by MRI alone. Lesions were retrospectively characterized according to an MRI Breast Imaging-Reporting and Data System lexicon and matched to pathology. RESULTS: Twenty-two women were identified with 29 FP lesions. Morphology revealed 1 focus (3.5%), 5 masses less than 5 mm (17%), 11 masses greater than 5 mm (38%), 1 (3.5%) linear enhancement, and 11 (38%) non-mass-like enhancement. Kinetic curves were suspicious in 15 (52%). Histology demonstrated 20 (69%) variants of normal tissue and 9 (31%) benign masses. MRI lesions less than 5 mm (n = 6, 20.5%) were small, well-delineated nodules of benign breast tissue. CONCLUSION: Suspicious MRI lesions less than 5 mm often represent benign breast tissue and could potentially undergo surveillance instead of biopsy.

Lymphatic mapping improves staging and reduces morbidity in women undergoing total mastectomy for breast carcinoma.

Lymphatic mapping (LM) and sentinel lymph node biopsy (SLNB) have become widely accepted in the setting of breast conservation surgery. We hypothesized that LM can be extended to women undergoing total mastectomy, being technically feasible, yielding highly accurate and sensitive results, improving axillary staging, and reducing postoperative morbidity. Between 1995 and 2003, 99 women (mean age 59 years, range 34-87) underwent 100 mastectomies with LM using blue dye alone. Fifty-nine operations (60%) were followed by a completion axillary lymph node dissection (ALND). Ninety per cent of patients had invasive carcinoma; 10 per cent had in situ carcinoma. Mean tumor size was 2.5 cm (range 0.3-8 cm). One hundred fifty-nine sentinel nodes (SNs) (mean 1.65, range 1-5) were successfully identified in 96 (96%) axillae. Twenty-five (25%) sentinel nodes revealed nodal metastases. Five of 25 (20%) SNs had micrometasteses. Three patients had a false-negative SN, yielding a sensitivity of 91 per cent. The accuracy of LM was 97 per cent. No patient who underwent SLNB alone developed lymphedema, axillary seroma formation, infection, or restricted arm movement. This was contrasted with patients undergoing ALND, where 10 (16%) developed lymphedema and 2 (3%) developed an infection. Ten (25%) patients developed axillary paresthesias after SNB compared with 47 (78%) patients after ALND (P < 0.0001). LM in the setting of mastectomy is accurate and sensitive. This technique improves axillary staging and decreases morbidity. Patients who are not candidates for breast conservation should be offered LM and SLNB at the time of mastectomy.

Does reoperation predispose to postoperative wound infection in women undergoing operation for breast cancer?

Reoperations for breast cancer predispose to a higher risk of postoperative wound infections than primary procedures. We accomplished a retrospective chart review of 320 women who underwent multiple breast cancer procedures between 10/97 and 8/02. The mean number of procedures was 2.4 (range, 2-5). The overall incidence of wound infection was 6.1 per cent. Wound infections developed, on average, 12 days after surgery (range, 2-30). There was a statistically significant difference in the incidence of wound infection comparing the initial procedure versus the subsequent operation (1.6% vs. 9.4%, P < 0.001). This was also seen with reoperation after an operative biopsy compared to operation after a core biopsy (11.1% vs. 9.7%, P < 0.01). The incidence was increased to 22.0 per cent when the initial operation involved lymph node dissection (sentinel lymph node biopsy or complete axillary lymph node dissection). Wire localization did not increase the incidence of postoperative wound infections, and prophylactic antibiotics were associated with a decreased incidence of wound infection in the reoperative setting. The incidence of wound infection is increased with reoperation after operative biopsy compared to operation after core biopsy and is further increased when the initial biopsy involved lymph node dissection.

Does fibrin sealant reduce drain output and allow earlier removal of drainage catheters in women undergoing operation for breast cancer?

Serosanguinous drainage after mastectomy and axillary lymph node dissection has traditionally been treated with the temporary use of closed suction drainage catheters. Use of drainage catheters is associated with wound infection, discomfort, nerve injury, and impaired arm movement. Commercially produced fibrin sealant has been proposed to reduce postoperative serosanguinous collections. We hypothesized that the intraoperative application of low-dose (2-5 cm3) fibrin sealant would reduce serosanguinous drainage and allow earlier removal of closed suction drainage catheters after operation for breast cancer. Fifty-five women with known breast cancer underwent either total mastectomy, modified radical mastectomy, or isolated level I and II axillary lymph node dissection. Twenty-six patients were treated with fibrin sealant and 29 served as control subjects. The application of fibrin sealant resulted in a significant reduction in overall duration catheters were needed (7 vs 8.3 days; P = 0.05). More importantly fibrin sealant reduced the time until 24-hour drain output was less than 30 cm3 (4.9 vs 6.2 days). Additionally fibrin sealant application resulted in a 60 per cent reduction in overall drainage amount after total mastectomy and a 32 per cent reduction after modified radical mastectomy. The application of fibrin sealant after axillary lymph node dissection did not decrease overall drainage amount. In conclusion fibrin sealant reduces serosanguinous drainage after total mastectomy and modified radical mastectomy and may allow earlier removal of closed suction drainage catheters.