Use of human predictive patch test (HPPT) data for the classification of skin sensitization hazard and potency.

Since the 1940s, patch tests in healthy volunteers (Human Predictive Patch Tests, HPPTs) have been used to identify chemicals that cause skin sensitization in humans. Recently, we reported the results of a major curation effort to support the development of OECD Guideline 497 on Defined Approaches (DAs) for skin sensitization (OECD in Guideline No. 497: Defined Approaches on Skin Sensitisation, 2021a. https://doi.org/10.1787/b92879a4-en ). In the course of this work, we compiled and published a database of 2277 HPPT results for 1366 unique test substances (Strickland et al. in Arch Toxicol 97:2825-2837, 2023. https://doi.org/10.1007/s00204-023-03530-3 ). Here we report a detailed analysis of the value of HPPT data for classification of chemicals as skin sensitizers under the United Nations' Globally Harmonized System of Classification and Labelling of Chemicals (GHS). As a result, we propose the dose per skin area (DSA) used for classification by the GHS to be replaced by or complemented with a dose descriptor that may better reflect sensitization incidence [e.g., the DSA causing induction of sensitization in one individual (DSA1+) or the DSA leading to an incidence of induction in 5% of the tested individuals (DSA05)]. We also propose standardized concepts and workflows for assessing individual HPPT results, for integrating multiple HPPT results and for using them in concert with Local Lymph Node Assay (LLNA) data in a weight of evidence (WoE) assessment. Overall, our findings show that HPPT results are often not sufficient for deriving unambiguous classifications on their own. However, where they are, the resulting classifications are reliable and reproducible and can be integrated well with those from other skin sensitization data, such as the LLNA.

Effectiveness and safety of Ivermectin in COVID-19 patients: A prospective study at a safety-net hospital.

Ivermectin has been found to inhibit severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication in vitro. It is unknown whether this inhibition of SARS-CoV-2 replication correlates with improved clinical outcomes. To assess the effectiveness and safety of ivermectin in hospitalized patients with COVID-19. A total of 286 patients with COVID-19 were included in the study. Univariate analysis of the primary mortality outcome and comparisons between treatment groups were determined. Logistic regression and propensity score matching (PSM) was used to adjust for confounders. Patients in the ivermectin group received 2 doses of Ivermectin at 200 µg/kg in addition to usual clinical care on hospital Days 1 and 3. The ivermectin group had a significantly higher length of hospital stay than the control group; however, this significance did not maintain on multivariable logistic regression analysis. The length of intensive care unit (ICU) stay and duration of mechanical ventilation were longer in the control group. However, a mortality benefit was not seen with ivermectin treatment before and after PSM (p values = 0.07 and 0.11, respectively). ICU admission, and intubation rate were not significantly different between the groups (p = 0.49, and p = 1.0, respectively). No differences were found between groups regarding the length of hospital stay, ICU admission, intubation rate, and in-hospital mortality.

Research and Development Prospects for Sugarcane Industry in Vietnam.

Sugarcane is one of the most important industrial crops in Vietnam and covers a total of 127,000 hectares of plantation area. In the season 2020-2021, Vietnam has produced 0.763 million tons of sugar (accounting for 0.34% total world sugar production). A current sugarcane production of 7.498 million tons is being used mainly for sugar production for direct consumption, ethanol production, bio-electricity and fertilization. To ensure crop sustainability, various policies and plans have been implemented. Crop breeding and zoning improvement programme significantly influence sugarcane production and sugar yield. Over 25 years since the programme "one million ton of sugar" was promoted, Vietnam currently possesses 25 sugar mills with a total capacity of 110,000 tons of sugarcane per day. Major problems of sugarcane industry as well as research and development have been discussed in this review. Recent research and development work focused on the added values of co-products to ensure sustainability of the sugarcane industry. Molasses will be used for ethanol production, and bagasse is used as the biomass for the alternative energy. Sugarcane and sugar would be the main feedstocks for those bio-economy growths in Vietnam. To keep the sustainable development of the sugar industry, and to meet the demand of the food and non-food requirements, it is necessary to upgrade the sugar value chain through the adoption and the development of co-products of the sugar industry.

Pro-Angiogenic Effects of Low Dose Ethoxidine in a Murine Model of Ischemic Hindlimb: Correlation between Ethoxidine Levels and Increased Activation of the Nitric Oxide Pathway.

Ethoxidine, a benzo[c]phenanthridine derivative, has been identified as a potent inhibitor of topoisomerase I in cancer cell lines. Our group has reported paradoxical properties of ethoxidine in cellular processes leading to angiogenesis on endothelial cells. Because low concentration ethoxidine is able to favor angiogenesis, the present study aimed to investigate the ability of 10-9 M ethoxidine to modulate neovascularization in a model of mouse hindlimb ischemia. After inducing unilateral hindlimb ischemia, mice were treated for 21 days with glucose 5% or with ethoxidine, to reach plasma concentrations equivalent to 10-9 M. Laser Doppler analysis showed that recovery of blood flow was 1.5 fold higher in ethoxidine-treated mice in comparison with control mice. Furthermore, CD31 staining and angiographic studies confirmed an increase of vascular density in ethoxidine-treated mice. This ethoxidine-induced recovery was associated with an increase of NO production through an enhancement of eNOS phosphorylation on its activator site in skeletal muscle from ischemic hindlimb. Moreover, real-time RT-PCR and western blots have highlighted that ethoxidine has pro-angiogenic properties by inducing a significant enhancement in vegf transcripts and VEGF expression, respectively. These findings suggest that ethoxidine could contribute to favor neovascularization after an ischemic injury by promoting the NO pathway and VEGF expression.

The surgical approach to managing differentiated thyroid cancer.

In recent decades, our understanding of thyroid cancer has improved significantly with the recognition that differentiated thyroid cancer (DTC) has good survival and oncological outcomes. Along with the recent rise in the detection of otherwise subclinical tumours due to improved diagnostics, there has been much debate on how aggressive one should be when performing thyroid and lymph node surgery. The use of risk stratification to categorize patients into low, intermediate and high risk has led to a more tailored approach to treating differentiated thyroid cancer. This ensures patients are not subject to preventable morbidity from overtreatment while maintaining good outcomes. We discuss the approach to primary thyroid and lymph node surgery by reviewing the current literature.

Impact of aluminum chloride on process performance and microbial community structure of granular sludge in an upflow anaerobic sludge blanket reactor for natural rubber processing wastewater treatment.

In this study, granular sludge formation was carried out using an aluminum chloride supplement in an upflow anaerobic sludge blanket (UASB) reactor treating natural rubber processing wastewater. Results show that during the first 75 days after the start-up of the UASB reactor with an organic loading rate (OLR) of 2.65 kg-COD·m(-3)·day(-1), it performed stably with a removal of 90% of the total chemical oxygen demand (COD) and sludge still remained in small dispersed flocs. However, after aluminum chloride was added at a concentration of 300 mg·L(-1) and the OLR range was increased up to 5.32 kg-COD·m(-3)·day(-1), the total COD removal efficiency rose to 96.5 ± 2.6%, with a methane recovery rate of 84.9 ± 13.4%, and the flocs began to form granules. Massively parallel 16S rRNA gene sequencing of the sludge retained in the UASB reactor showed that total sequence reads of Methanosaeta sp. and Methanosarcina sp., reported to be the key organisms for granulation, increased after 311 days of operation. This indicates that the microbial community structure of the retained sludge in the UASB reactor at the end of the experiment gave a good account of itself in not only COD removal, but also granule formation.

A decade with nucleic acid-based microbiological methods in safety control of foods.

In the last decade, nucleic acid-based methods gradually started to replace or complement the culture-based methods and immunochemical assays in routine laboratories involved in food control. In particular, real-time polymerase chain reaction (PCR) was technically developed to the stage of good speed, sensitivity and reproducibility, at minimized risk of carry-over contamination. Basic advantages provided by nucleic acid-based methods are higher speed and added information, such as subspecies identification, information on the presence of genes important for virulence or antibiotic resistance. Nucleic acid-based methods are attractive also to detect important foodborne pathogens for which no classical counterparts are available, namely foodborne pathogenic viruses. This review briefly summarizes currently available or developing molecular technologies that may be candidates for involvement in microbiological molecular methods in the next decade. Potential of nonamplification as well as amplification methods is discussed, including fluorescent in situ hybridization, alternative PCR chemistries, alternative amplification technologies, digital PCR and nanotechnologies.

Bioconversion of Shrimp Waste into Functional Lipid by a New Oleaginous Sakaguchia sp.

Chitin, the second most abundant biomolecule after cellulose in nature, is a significant aquaculture by-product, and is estimated at 6-8 million tons annually. Chitin is composed of monomeric N-acetylglucosamine (NAG) which can be seen as an alternative feedstock for biotechnology. Microbial functional lipids have gained attention due to their bioactivity and sustainable production. In this study, a new oleaginous yeast strain named Sakaguchia sp. HKC2 was found to be able to use NAG as the carbon source for growth and accumulate functional lipids such as PUFAs and carotenoids. When cultured on the NAG-containing medium, strain HKC2 exhibited slower growth and slower intracellular lipid accumulation compared to those on a glucose-containing medium. However, the lipids obtained from HKC2 grown on NAG medium were richer in PUFAs. Notably, torularhodin-a powerful bioactive carotenoid-was found in all HKC2 cultures on NAG, while torulene was abundant in glucose medium. These findings highlight a novel avenue for utilizing aquatic by-products and unlocking their potential.

Removal of foreign bodies from children's ears: a nurse-led clinic.

This article presents an account of the rationale for and the introduction of a change in practice. The successful removal of foreign bodies from children's ears requires appropriate skills and experience. While traditionally a role for junior doctors, removal of foreign bodies from children's ears at the ear, nose and throat outpatient clinic at Birmingham Children's Hospital was associated with a low success rate. Therefore, it was proposed that an experienced advanced nurse practitioner would carry out this task in an attempt to improve patient outcomes. A database of outcomes was maintained and compared with those from a doctor-led clinic at Nottingham University Hospitals NHS Trust. The results highlight the benefits of nurse-led removal of foreign bodies from children's ears.

Lymphatic-draining nanoparticles deliver Bay K8644 payload to lymphatic vessels and enhance their pumping function.

Dysfunction of collecting lymphatic vessel pumping is associated with an array of pathologies. S-(-)-Bay K8644 (BayK), a small-molecule agonist of L-type calcium channels, improves vessel contractility ex vivo but has been left unexplored in vivo because of poor lymphatic access and risk of deleterious off-target effects. When formulated within lymph-draining nanoparticles (NPs), BayK acutely improved lymphatic vessel function, effects not seen from treatment with BayK in its free form. By preventing rapid drug access to the circulation, NP formulation also reduced BayK's dose-limiting side effects. When applied to a mouse model of lymphedema, treatment with BayK formulated in lymph-draining NPs, but not free BayK, improved pumping pressure generated by intact lymphatic vessels and tissue remodeling associated with the pathology. This work reveals the utility of a lymph-targeting NP platform to pharmacologically enhance lymphatic pumping in vivo and highlights a promising approach to treating lymphatic dysfunction.

The characteristics of coalbed water and coal in a coal seam situated in the Red River Basin, Vietnam.

An in-depth understanding of the hydrogeochemical characteristics of coal mines is helpful in establishing an effective and successful exploration program of coalbed methane (CBM). This study provides a comprehensive analysis of hydrogeological characteristics, characteristics of coalbed water, and characteristics of the coal sample from a coal seam located in the Red River Basin (RRB). These physicochemical characteristics along with the microbial composition of coalbed water were critically analyzed. A high concentration of chloride and sodium was found in the coalbed water, presumably due to the coal mine's stratigraphic association with marine or marine-transitional beds. A correlation between the occurrence of microbes and the chemical components in the coalbed water was established. The characteristics of the coal were systematically analyzed, including proximate, ultimate, and petrographic analyses. Based on the coal macerals, coal rank is classified as low-rank (sub-bituminous) with a vitrinite reflectance (Ro, max) of 0.36%, suggesting that this type of low-rank coal is favorable for biogenic methane generation. Pore structures and pore types were characterized using different methods, including low-temperature nitrogen adsorption/desorption (LTNA), mercury intrusion porosimetry (MIP), and scanning electron microscopy (SEM). Coal from the study area has microporous and macroporous features. Pore types of the coal were also characterized using SEM. The primary genetic pore types of the Red River coal include plant tissue holes and blowholes.

Characterization of Latex-Clearing Protein and Aldehyde Dehydrogenases Involved in the Utilization of poly(cis-1,4-isoprene) by Nocardia farcinica NBRC 15532

Microbial degradation of natural rubber and synthetic poly(cis-1,4-isoprene) is expected to become an alternative treatment system for waste from poly(cis-1,4-isoprene) products including scrap tires. Nocardia farcinica NBRC 15,532, a gram-positive rubber-degrading bacterium, can utilize poly(cis-1,4-isoprene) as the sole source of carbon and energy to produce oligo-isoprene metabolites containing aldehyde and keto end groups. A homology-based search of the genome revealed a gene encoding a latex-clearing protein (Lcp). Gene disruption analysis indicated that this gene is essential for the utilization of poly(cis-1,4-isoprene) in this strain. Further analysis of the genome sequence identified aldehyde dehydrogenase (ALDH) genes as potential candidates for oxidative degradation of oligo-isoprene aldehydes. Based on the enzymatic activity of the ALDH candidates, NF2_RS14000 and NF2_RS14385 may be involved in the degradation of oligo-isoprene aldehydes. Analysis of the reaction products revealed that these ALDHs oxidized tri- to penta-isoprene aldehydes, which were generated by the reaction of Lcp. Based on the inability of ALDH gene deletion mutants, we concluded that NF2_RS14000 is mainly involved in the utilization of poly(cis-1,4-isoprene) and the oxidative degradation of oligo-isoprene aldehydes in Nocardia farcinica NBRC 15,532.

Identification and transcriptional analysis of poly(cis-1,4-isoprene) degradation gene in Rhodococcus sp. strain RDE2.

The microbial degradation of synthetic and natural poly(cis-1,4-isoprene) rubber is expected to become an alternative treatment technique for waste from poly(cis-1,4-isoprene) products, such as scrap tires. A gram-positive rubber-degrading bacterium, Rhodococcus sp. strain RDE2, was isolated from the waste of a rubber-processing factory in Vietnam. This strain grew on natural rubber as a sole source of carbon and energy and produced oligo-isoprenoid metabolites containing aldehyde groups from poly(cis-1,4-isoprene). To identify the genes responsible for poly(cis-1,4-isoprene) degradation, the complete genome sequence of this strain was determined. The complete genome sequence consists of a 5,715,406 bp chromosome and 6 plasmids (GenBank accession numbers AP025186.1 to AP025192.1) with an average GC content of 67.9%. The genome contains 5358 protein-coding sequences and 12 and 68 copies of rRNA and tRNA genes, respectively. Based on genome sequence analysis, the lcp gene (RDE2_08,770), responsible for the initial step of poly(cis-1,4-isoprene) degradation, was identified. The gene product obtained from Escherichia coli depolymerizes poly(cis-1,4-isoprene) to low-molecular-weight oligo-isoprenoids. The transcription of this gene is activated during the utilization of poly(cis-1,4-isoprene) in strain RDE2. The lcpR gene (RDE2_08,760), which encodes a putative transcriptional regulator, is located upstream of lcp. The lcpR gene product recognizes the promoter region of lcp. When the lcpR gene is deleted, the constitutive transcription of lcp is observed. Thus, it is inferred that the LcpR negatively regulates lcp transcription. These results strongly suggest that the lcp and lcpR genes are involved in poly(cis-1,4-isoprene) utilization in strain RDE2.

Voice Rehabilitation by Voice Prostheses After Total Laryngectomy: A Systematic Review and Network Meta-Analysis for 11,918 Patients.

Purpose Our aim was to assess the different voice prostheses (VPs) to identify the most efficient, safest, patient-tailored, longest lifetime, and inexpensive VPs and assess the different factors affecting their quality. Method In September 2017, 15 databases were searched to include all randomized controlled trials. A new search was done in May 2019 to include all other study design articles, which include all the new-era VPs subtypes. Network meta-analysis (NMA) was applied to all 27 outcomes, besides NMA overall and partial order setting was done by using Hasse scatter plots. p values were used in NMA, where the best VPs are approaching one and the least approaches zero. Meta-analysis was done for the rest of the outcomes. Results Two hundred one articles were eligible for inclusion in our study (N = 11,918). Provox-2 was significantly the most efficient and safest device concerning the most patient preference (odds ratio [OR] = 33.88 [0.65, 1762.24]; p = .92), the least dislodgement (risk ratio [RR] = 0.27 [0.13, 0.57]; p = .79), the least airflow resistance (RR = 0.42 [0.08, 2.11]; p = .84), the least granulation formation (RR = 0.73 [0.02, 26.32]; p = .60), and the least VPs' inaccurate size (RR = 0.77 (0.23, 2.61); p = .66). Heat and moisture exchanger addition showed a significant increase in maximum phonation time and breathing experience, with p values (1 and .59), respectively. While heat and moisture exchanger addition showed a significant decline in stoma cleaning frequency, coughing frequency, forced expectoration, sputum production, sleeping problems, and loosening of adhesive, with p values (.99, .72, .69, .96, 1, and 0.96), respectively, Groningen low resistance and Nijdam were considered the worst devices with both overall mean p value of .44. Conclusions Provox-2 is considered the best choice as being the most preferable for patients, with the least airflow resistance, dislodgment, granulation formation, and prosthesis inaccurate size. Groningen low resistance and Nijdam were considered the worst devices according to our analysis. Supplemental Material https://doi.org/10.23641/asha.14802903.

Health and safety needs in early care and education programs: what do directors, child health records, and national standards tell us?

OBJECTIVE: To identify the overlapping and unique health and safety needs and concerns identified by early care and education (ECE) directors, health records, and observed compliance with national health and safety (NHS) standards. DESIGN AND SAMPLE: Cross-sectional study. 127 ECE programs from 5 California counties participated in the study, including 118 directors and 2,498 children's health records. MEASURES: Qualitative data were collected using standardized ECE directors' interviews to identify their health and safety concerns; and objective, quantitative data were collected using child health record reviews to assess regular health care, immunizations, health insurance, special health care needs, and screening tests and an observation Checklist of 66 key NHS standards collected by research assistants. RESULTS: The overlapping health and safety needs and concerns identified by the directors and through observations were hygiene and handwashing, sanitation and disinfection, supervision, and the safety of indoor and outdoor equipment. Some of the health and safety needs identified by only one assessment method were health and safety staff training, medical plans for children with special health care needs and follow-up on positive screening tests. CONCLUSIONS: Comprehensive, multimethod assessments are useful to identify health and safety needs and develop public health nursing interventions for ECE programs.

T-type, but not L-type, voltage-gated calcium channels are dispensable for lymphatic pacemaking and spontaneous contractions.

The spontaneous contractions of collecting lymphatic vessels provide an essential propulsive force to return lymph centrally. These contractions are driven by an intrinsic electrical pacemaker, working through an unknown underlying ionic mechanism that becomes compromised in some forms of lymphedema. In previous studies, T-type voltage-gated Ca2+ channels (VGCCs) were implicated in this pacemaking mechanism, based on the effects of the reputedly selective T-type VGCC inhibitors mibefradil and Ni2+. Our goal was to test this idea in a more definitive way using genetic knock out mice. First, we demonstrated through both PCR and immunostaining that mouse lymphatic muscle cells expressed Cav3.1 and Cav3.2 and produced functional T-type VGCC currents when patch clamped. We then employed genetic deletion strategies to selectively test the roles of each T-type VGCC isoform in the regulation of lymphatic pacemaking. Surprisingly, global deletion of either, or both, isoform(s) was without significant effect on either the frequency, amplitude, or fractional pump flow of lymphatic collectors from two different regions of the mouse, studied ex vivo. Further, both WT and Cav3.1-/-; 3.2-/- double knock-out lymphatic vessels responded similarly to mibefradil and Ni2+, which substantially reduced contraction amplitudes and slightly increased frequencies at almost all pressures in both strains: a pattern consistent with inhibition of L-type rather than T-type VGCCs. Neither T-type VGCC isoform was required for ACh-induced inhibition of contraction, a mechanism by which those channels in smooth muscle are thought to be targets of endothelium-derived nitric oxide. Sharp intracellular electrode measurements in lymphatic smooth muscle revealed only subtle, but not significant, differences in the resting membrane potential and action potential characteristics between vessels from wild-type and Cav3.1-/-; 3.2-/- double knock-out mice. In contrast, smooth-muscle specific deletion of the L-type VGCC, Cav1.2, completely abolished all lymphatic spontaneous contractions. Collectively our results suggest that, although T-type VGCCs are expressed in mouse lymphatic smooth muscle, they do not play a significant role in modulating the frequency of the ionic pacemaker or the amplitude of spontaneous contractions. We conclude that the effects of mibefradil and Ni2+ in other lymphatic preparations are largely or completely explained by off-target effects on L-type VGCCs, which are essential for controlling both the frequency and strength of spontaneous contractions.

Cloning, expression in Pichia pastoris, and characterization of a thermostable GH5 mannan endo-1,4-beta-mannosidase from Aspergillus niger BK01.

BACKGROUND: Mannans are key components of lignocellulose present in the hemicellulosic fraction of plant primary cell walls. Mannan endo-1,4-beta-mannosidases (1,4-beta-D-mannanases) catalyze the random hydrolysis of beta-1,4-mannosidic linkages in the main chain of beta-mannans. Biodegradation of beta-mannans by the action of thermostable mannan endo-1,4-beta-mannosidase offers significant technical advantages in biotechnological industrial applications, i.e. delignification of kraft pulps or the pretreatment of lignocellulosic biomass rich in mannan for the production of second generation biofuels, as well as for applications in oil and gas well stimulation, extraction of vegetable oils and coffee beans, and the production of value-added products such as prebiotic manno-oligosaccharides (MOS). RESULTS: A gene encoding mannan endo-1,4-beta-mannosidase or 1,4-beta-D-mannan mannanohydrolase (E.C. 3.2.1.78), commonly termed beta-mannanase, from Aspergillus niger BK01, which belongs to glycosyl hydrolase family 5 (GH5), was cloned and successfully expressed heterologously (up to 243 microg of active recombinant protein per mL) in Pichia pastoris. The enzyme was secreted by P. pastoris and could be collected from the culture supernatant. The purified enzyme appeared glycosylated as a single band on SDS-PAGE with a molecular mass of approximately 53 kDa. The recombinant beta-mannanase is highly thermostable with a half-life time of approximately 56 h at 70 degrees C and pH 4.0. The optimal temperature (10-min assay) and pH value for activity are 80 degrees C and pH 4.5, respectively. The enzyme is not only active towards structurally different mannans but also exhibits low activity towards birchwood xylan. Apparent Km values of the enzyme for konjac glucomannan (low viscosity), locust bean gum galactomannan, carob galactomannan (low viscosity), and 1,4-beta-D-mannan (from carob) are 0.6 mg mL-1, 2.0 mg mL-1, 2.2 mg mL-1 and 1.5 mg mL-1, respectively, while the kcat values for these substrates are 215 s-1, 330 s-1, 292 s-1 and 148 s-1, respectively. Judged from the specificity constants kcat/Km, glucomannan is the preferred substrate of the A. niger beta -mannanase. Analysis by thin layer chromatography showed that the main product from enzymatic hydrolysis of locust bean gum is mannobiose, with only low amounts of mannotriose and higher manno-oligosaccharides formed. CONCLUSION: This study is the first report on the cloning and expression of a thermostable mannan endo-1,4-beta-mannosidase from A. niger in Pichia pastoris. The efficient expression and ease of purification will significantly decrease the production costs of this enzyme. Taking advantage of its acidic pH optimum and high thermostability, this recombinant beta-mannanase will be valuable in various biotechnological applications.

Successful treatment of ventriculitis caused by Pseudomonas aeruginosa and carbapenem-resistant Klebsiella pneumoniae with i.v. ceftazidime-avibactam and intrathecal amikacin.

PURPOSE: A patient with carbapenem-resistant Klebsiella pneumoniae infection is described, and treatment options are discussed. SUMMARY: Few antibiotics to treat carbapenem-resistant Enterobacteriaceae (CRE) infection are available, and treatment is further complicated by the limited ability of many antibiotics to penetrate into the cerebrospinal fluid (CSF). Currently, there is a lack of clinical data on the treatment of central nervous system CRE infections, and therapy is based on case reports, case series, and small retrospective studies. A patient was admitted to the emergency department with intracranial hemorrhage and ventriculitis due to traumatic injury. A ventriculostomy and, subsequently, a ventriculoperitoneal (VP) shunt were placed. After approximately a month of treatment with various antibiotic regimens, the patient's VP shunt was externalized, and a CSF culture speciated carbapenem-resistant K. pneumoniae and Pseudomonas aeruginosa. The patient was then switched to i.v. ceftazidime-avibactam and intrathecal amikacin therapy. His CSF cultures were sterile 3 days after initiation of those antibiotics, and subsequent CSF cultures resulted in no growth. After the patient was treated with intrathecal amikacin 30 mg daily for 4 weeks and i.v. ceftazidime-avibactam 2.5 g every 8 hours for 6 weeks, the ventriculitis resolved, the external ventricular drain was removed, and he was transferred to a long-term care facility for rehabilitation. CONCLUSION: A man with ventriculitis caused by P. aeruginosa and carbapenem-resistant K. pneumoniae was successfully treated with i.v. ceftazidime-avibactam and intrathecal amikacin.

Negative Lymph Node Count and Lymph Node Ratio Are Associated With Survival in Male Breast Cancer.

BACKGROUND: Male breast cancer (MBC) is usually diagnosed at late stages and therefore has a worse prognosis than female breast cancer (FBC). MBC is also more likely to have lymph node (LN) involvement than FBC. MATERIALS AND METHODS: We sought to determine the prognostic role of the examined lymph node (LN), negative LN (NLN), and positive LN counts and the LN ratio (LNR), defined as (positive LNs/ENLs), on the survival rate among MBC patients. We performed a large population-based study using the data from the Surveillance, Epidemiology, and End Results program. RESULTS: Older age, black race, stage IV disease, ≤ 1 NLN, and a > 31.3% LNR were significantly associated with worse survival across all prediction models. Moreover, we demonstrated a decreased risk of mortality in MBC patients across the MBC-specific survival model (hazard ratio, 0.98; 95% confidence interval, 0.96-0.998; P = .03) and 10-year MBC-specific survival model (hazard ratio, 0.98; 95% confidence interval, 0.96-0.999; P = .04). CONCLUSION: MBC has had an augmented incidence over the years. We found several independent predictors of MBC survival, including age, race, stage, NLNs, and the LNR. We strongly suggest adding the NLN count and/or LNR into the current staging system. Further studies are needed to provide information on the mechanisms underlying the association between the NLN count and MBC survival and the LNR and MBC survival.

Epsin deficiency promotes lymphangiogenesis through regulation of VEGFR3 degradation in diabetes.

Impaired lymphangiogenesis is a complication of chronic complex diseases, including diabetes. VEGF-C/VEGFR3 signaling promotes lymphangiogenesis, but how this pathway is affected in diabetes remains poorly understood. We previously demonstrated that loss of epsins 1 and 2 in lymphatic endothelial cells (LECs) prevented VEGF-C-induced VEGFR3 from endocytosis and degradation. Here, we report that diabetes attenuated VEGF-C-induced lymphangiogenesis in corneal micropocket and Matrigel plug assays in WT mice but not in mice with inducible lymphatic-specific deficiency of epsins 1 and 2 (LEC-iDKO). Consistently, LECs isolated from diabetic LEC-iDKO mice elevated in vitro proliferation, migration, and tube formation in response to VEGF-C over diabetic WT mice. Mechanistically, ROS produced in diabetes induced c-Src-dependent but VEGF-C-independent VEGFR3 phosphorylation, and upregulated epsins through the activation of transcription factor AP-1. Augmented epsins bound to and promoted degradation of newly synthesized VEGFR3 in the Golgi, resulting in reduced availability of VEGFR3 at the cell surface. Preclinically, the loss of lymphatic-specific epsins alleviated insufficient lymphangiogenesis and accelerated the resolution of tail edema in diabetic mice. Collectively, our studies indicate that inhibiting expression of epsins in diabetes protects VEGFR3 against degradation and ameliorates diabetes-triggered inhibition of lymphangiogenesis, thereby providing a novel potential therapeutic strategy to treat diabetic complications.