Simultaneous and synergistic effect of heavy metal adsorption on the enhanced photocatalytic performance of a visible-light-driven RS-TONR/TNT composite.

A hydrothermally synthesized rhodium/antimony co-doped TiO2 nanorod and titanate nanotube (RS-TONR/TNT) composite was prepared for removal of heavy metals and organic pollutants from water under visible light irradiation. The composite provides the dual function of simultaneous adsorption of heavy metal ions and enhanced degradation of dissolved organic compounds. Acid treatment transformed titanate nanotubes to irregular tubular structures distributed homogeneously over untransformed RS/TONRs. Synergistic removal and degradation was studied with various heavy metals, Orange (II) dye, and Bisphenol A. The adsorption capacity of the composite for heavy metal ions was Pb(II) > Cd(II) > Cu(II) > Zn(II). The adsorbed metals enhanced photocatalytic degradation of the organic pollutants, but Cu was most effective, with degradation exceeding 70% for the dye and 80% for Bisphenol A after 5 h of treatment. Photocatalytic activity was enhanced more by adsorption than photodeposition of Cu ions. A decrease in XRD rutile peak intensity with adsorbed metal indicates a change in crystallinity which may enhance photocatalytic activity. Thick and bulging nanostructures in FE-SEM images signify ion adsorption within titanate pores. BET analysis indicated titanate nanotubes with adsorbed metal are mesoporous but their tubular structure persists. XPS showed more active Cu 2p3/2 states under light, supporting an active role of Cu+ in photocatalytic ROS generation. Detection of ROS and Cu species using methanol, EDTA, pCBA, and benzoic acid probes provided strong evidence for degradation via a charge transfer mechanism. Findings demonstrate the potential of the RS-TONR/TNT composite for simultaneous removal of heavy metals and degradation of organic pollutants.

Agricultural waste materials enhance protease production by Bacillus subtilis B22 in submerged fermentation under blue light-emitting diodes.

Bacillus bacteria have major utility in large-scale production of industrial enzymes, among which proteases have particular importance. B. subtilis B22, an aerobic and chemotrophic strain, was isolated from kimchi and identified by 16S rRNA gene sequencing. Extracellular protease production was determined in basic medium, with 1% (w/v) casein as substrate, by submerged fermentation at 37 °C under blue, green, red and white light-emitting diodes (LEDs), white fluorescent light and darkness. Fermentation under blue LEDs maximized protease production (110.79 ± 1.8 U/mL at 24 h). Various agricultural waste products enhanced production and groundnut oil cake yielded the most protease (334 ± 1.8 U/mL at 72 h). Activity and stability of the purified protease were optimum at pH 7-10 and 20-60 °C. Activity increased in the presence of Ca2+, Mg2+ and Mn2+, while Fe2+, Zn2+, Co2+ and Cu2+ moderated activity, and Ni2+ and Hg2+ inhibited activity. Activity was high (98%) in the presence of ethylenediaminetetraacetic acid (EDTA) but inhibited by phenylmethanesulfonyl fluoride (PMSF). The protease was unaffected by nonionic surfactants, tolerated an anionic surfactant and oxidizing agents, and was compatible with multiple organic solvents. These properties suggest utility of protease produced by B. subtilis B22 under blue LEDs for industrial applications.

Arsenic exposure and perception of health risk due to groundwater contamination in Majuli (river island), Assam, India.

Island populations are rarely studied for risk of arsenic (As) poisoning. As poisoning, multimetal contamination and people's perceptions of health risks were assessed on India's Majuli Island, the largest inhabited river island in the world. This holistic approach illustrated the association of groundwater contamination status with consequent health risk by measuring levels of inorganic arsenic (iAs) in groundwater, borehole sediment and biological samples (hair, nails and urine). Piper and Gibbs's plots discerned the underlying hydrogeochemical processes in the aquifer. Demographic data and qualitative factors were evaluated to assess the risks and uncertainties of exposure. The results exhibited significant enrichment of groundwater with As, Mn and Fe along with significant body burden. Maximum Hazard Index values indicated severe non-carcinogenic health impacts as well as a significantly elevated risk of cancer for both adults and children. Most (99%) of the locally affected population did not know about the adverse health impacts of metal contamination, and only 15% understood bodily ailments and health issues. Various aspects of the island environment were used to elucidate the status of contamination and future risk of disease. A projection showed adverse health outcomes rising significantly, especially among the young population of Majuli, due to overexposure to not only As but also Ba, Mn and Fe.

Red yeast rice fermentation with Bacillus subtilis B2 under blue light-emitting diodes increases antioxidant secondary products (Manuscript ID: BPBSE-18-0387).

Light and bacteria can be used in combination to enhance secondary metabolite production during fermentation. Red yeast rice powder (RYRP) was inoculated with Bacillus subtilis (B2) isolated from freshwater seafood and incubated under light-emitting diodes (LEDs) of different colors (blue, green, red, white), fluorescent white light, and in darkness. Blue LED-mediated fermentation with B2 significantly enhanced production of phenolic compounds (68.4 ± 1 mg GAE/g DW) and flavonoids (51.7 ± 1 mg QE/g DW) compared to white light and darkness. Total antioxidant activity of RYRP extract after fermentation with B2 was > 77%; hydroxyl radical and superoxide scavenging were > 66%. DPPH (2,2-diphenyl-1-picryl-hydrazyl-hydrate) and ABTS (2,2'-azino-bis (3-ethylbenzothiazoline-6-sulphonic acid)) radical scavenging activities were 51% and > 67%, respectively. Reducing power was approximately twice that of extract from RYRP without B2. FTIR analysis showed a high content of hydroxyl, nitrile and carboxylic groups in the extract. Derivatives of cinnamic, benzoic and phophinodithioic acid, and quinazolinone were identified by GC-MS. Findings show that fermenting RYRP with B. subtilis B2 under blue LEDs enhances production of secondary metabolites, which should have applications in industrial fermentation processes.

Enhanced amylase production by a Bacillus subtilis strain under blue light-emitting diodes.

A chemotrophic, aerobic bacterial strain, Bacillus subtilis B2, was used to produce amylase by submerged fermentation under different light sources. SDS-PAGE indicated that the 55 kDa enzyme belonged to the α-amylase group. B2 was incubated in basal media with 1% soluble starch (pH 7.0) under blue, green, red, and white light-emitting diodes (LEDs), and white fluorescent light. Fermentation under blue LEDs maximized amylase production (180.59 ± 1.6 U/mL at 24 h). Production at 48 h increased to 310.56 ± 1.6 U/mL with 5% glucose as a simple carbon source and to 300.51 ± 1.7 U/mL with 5% groundnut oil cake as an agricultural waste substrate. Activity and stability of the amylase were greatest at pH 7.0 and 45-55 °C. Na+, Ca2+, Mg2+, Co2+, Ba2+, and K+ increased activity, while Ni2+, Hg2+, Mn2+, Cu2+, Fe3+, and Zn2+ inhibited activity. EDTA, PMSF and DTNB reduced activity by 50% or more, while tetrafluoroethylene and 1,10-phenanthroline reduced activity by 30%. The amylase was highly tolerant of the surfactants, compatible with organic solvents, oxidizing agents and the reducing agents reduced activity. These properties suggest utility of amylase produced by B. subtilis B2 under blue LED-mediated fermentation for industrial applications.

IAA production by Bacillus sp. JH 2-2 promotes Indian mustard growth in the presence of hexavalent chromium.

Bacillus sp. strain JH 2-2, isolated from the rhizosphere of plants at a multi-metal contaminated mine site, has the potential to reduce Cr(VI) to Cr(III) and promote plant growth by reducing Cr toxicity and producing IAA. The minimum inhibitory concentration of Cr(VI) to Bacillus sp. JH 2-2 was 1000 mg L(-1) and the strain reduced 99% of 10 mg Cr(VI) L(-1) to Cr(IV) within 24 h. Lower Cr(VI) stress (10 mg L(-1) ) stimulated IAA production, but much less IAA was produced at 30 or 50 mg Cr(VI) L(-1) . Inoculation with Bacillus sp. JH 2-2 increased the length of Brassica juncea L. roots by 364% and stems by 735% in the presence of 10 mg Cr(VI) L(-1) from those of uninoculated control plants. These findings suggest potential use of Bacillus sp. JH 2-2 to promote phytoremediation of soil contaminated with Cr(VI).

Potential use of Pseudomonas koreensis AGB-1 in association with Miscanthus sinensis to remediate heavy metal(loid)-contaminated mining site soil.

Endophytic bacteria have the potential to promote plant growth and heavy metal(loid) (HM) removal from contaminated soil. Pseudomonas koreensis AGB-1, isolated from roots of Miscanthus sinensis growing in mine-tailing soil, exhibited high tolerance to HMs and plant growth promoting traits. Transmission electron microscope (TEM) analysis revealed that AGB-1 sequestered HMs extracellularly and their accumulation was visible as dark metal complexes on bacterial surfaces and outside of the cells. DNA sequencing of HM resistance marker genes indicated high homology to the appropriate regions of the arsB, ACR3(1), aoxB, and bmtA determinants. Inoculating mining site soil with AGB-1 increased M. sinensis biomass by 54%, chlorophyll by 27%, and protein content by 28%. High superoxide dismutase and catalase activities, and the lower malondialdehyde content of plants growing in AGB-1-inoculated soil indicate reduced oxidative stress. Metal(loid) concentrations in roots and shoots of plants grown in inoculated soil were higher than those of the controls in pot trials with mine tailing soil. Results suggest that AGB-1 can be used in association with M. sinensis to promote phytostabilization and remediation of HM-contaminated sites.

Trichoderma virens PDR-28: a heavy metal-tolerant and plant growth-promoting fungus for remediation and bioenergy crop production on mine tailing soil.

A heavy metal-tolerant fungus, Trichoderma virens PDR-28, was isolated from rhizosphere soil and evaluated for use in remediating mine tailing soil and for plant biomass production. PDR-28 exhibited plant growth-promoting traits, including 1-aminocyclopropane-1-carboxylic acid (ACC) deaminase, acid phosphatase and phytase activity, siderophore production, and P solubilization. HMs were more available in mine tailing soil inoculated soil with PDR-28 than in uninoculated soil; the order of HM bioleaching was Cd > As > Zn > Pb > Cu. PDR-28 effectively removed HMs in the order of Pb > Cd > As > Zn > Cu from liquid media containing 100 mg HM L(-1). Inoculating HM-contaminated mine tailing soil with the fungus significantly increased the dry biomass of maize roots (64%) and shoots (56%). Chlorophyll, total soluble sugars (reducible and nonreducible), starch, and protein contents increased by 46%, 28%, 30%, and 29%, respectively, compared to plants grown in uninoculated soil. Inoculation increased heavy metal concentrations in maize roots by 25% (Cu) to 62% (Cd) and in shoots by 35% (Cu) to 64% (Pb) compared to uninoculated plants. Results suggest that PDR-28 would be beneficial for phytostabilization and plant biomass production as a potential source of biofuel in the quest for renewable energy.

Pseudomonas fluorescens JH 70-4 promotes pb stabilization and early seedling growth of sudan grass in contaminated mining site soil.

A bacterial strain (JH 70-4) exhibiting plant growth promoting characteristics (indoleacetic acid production and 1-aminocyclopropane-1-carboxylate deaminase activity), as well as heavy metal(loid) (HM) tolerance and Pb precipitation, was isolated from HM-contaminated soil at an abandoned mine site. The bacterium was identified as Pseudomonas fluorescens based on 16S rDNA sequencing. The JH 70-4 strain induced precipitation of Pb as PbS nanoparticles, confirmed by X-ray diffraction. Solution pH, incubation time, and Pb concentration influenced removal and PbS formation. Inoculating contaminated soil with JH 70-4 decreased Pb availability; exchangeable Pb decreased while organic- and sulphide-bound Pb increased. The toxicity characteristic leaching procedure showed a 65% decrease in Pb in leachate 60 d after inoculating soil with JH 70-4. Shoot and root lengths of Sudan grass grown in the inoculated soil were greater than in the uninoculated soil. Findings suggest that microbial Pb fixation is a viable strategy for remediating soil and promoting plant growth for phytostabilization of contaminated sites.

Sex and gender differences in adverse events following influenza and COVID-19 vaccination.

INTRODUCTION: Active and passive surveillance studies have found that a greater proportion of females report adverse events (AE) following receipt of either the COVID-19 or seasonal influenza vaccine compared to males. In a predominately young adult female population of healthcare workers, we sought to determine the intersection of biological sex and sociocultural gender differences in prospective active reporting of vaccine outcomes, which remains poorly characterized. METHODS: This cohort study enrolled Johns Hopkins Health System healthcare workers (HCWs) who were recruited from the mandatory annual fall 2019-2022 influenza vaccine and the fall 2022 COVID-19 bivalent vaccine campaigns. Vaccine recipients were enrolled the day of vaccination and AE surveys were administered two days post-vaccination for bivalent COVID-19 and influenza vaccine recipients. Data were collected regarding the presence of a series of solicited local and systemic AEs. Open-ended answers about participants' experiences with AEs also were collected for the COVID-19 vaccine recipients. RESULTS: Females were more likely to report local AEs after either influenza (OR = 2.28, p = 0.001) or COVID-19 (OR = 2.57, p = 0.008) vaccination compared to males, regardless of age or race. Males and females had comparable probabilities of reporting systemic AEs after either influenza (OR = 1.18, p = 0.552) or COVID-19 (OR = 0.96, p = 0.907) vaccination. Hormonal birth control use did not impact the rates of reported AEs following influenza vaccination among reproductive-aged female HCWs. Women reported more interruptions in their daily routine following COVID-19 vaccination than men and were more likely to seek out self-treatment. More women than men scheduled their COVID-19 vaccination before their days off in anticipation of AEs. CONCLUSIONS: Our findings highlight the need for sex- and gender-inclusive policies to inform more effective mandatory occupational health vaccination strategies. Further research is needed to evaluate the potential disruption of AEs on occupational responsibilities following mandated vaccination for healthcare workers, a predominately female population, and to more fully characterize the post-vaccination behavioral differences between men and women.

Research that addresses both the sex and gender differences of vaccine outcomes and behaviors is lacking. In this survey study of healthcare workers, comprised of mostly reproductive-aged females/women, we investigated biological sex (male/female) and gender (man/woman) differences in vaccine adverse events and outcomes following either influenza or bivalent COVID-19 vaccination.Regardless of age or race, females were more likely to report local (at injection site), but not systemic (whole body), adverse events than males, consistent across influenza and bivalent COVID-19 vaccine cohorts. Sex hormones are hypothesized to play a role in the differences in immune response following vaccination between males and females. We investigated if hormonal birth control use among females may be associated with differences in vaccine adverse events among the influenza vaccine cohort. However, there was no difference in the likelihood of reporting adverse events between birth control users and non-users. Based on open-ended responses to survey questions, women were found to report more interruptions to their daily routine than men following COVID-19 vaccination. Women were also more likely to seek out self-treatment with over-the-counter medication and intentionally schedule their vaccination around days off in anticipation of adverse events.With nearly 80% of healthcare jobs held by women, even higher for direct patient care positions like nursing, females/women may be disproportionately impacted by mandated annual vaccinations. Vaccinations are necessary for the prevention of disease transmission; however, our findings highlight a need for more equitable occupational vaccine strategies that consider both sex and gender differences.

Sex and gender differences in adverse events following receipt of influenza and COVID-19 vaccination among healthcare workers.

Introduction: Active and passive surveillance studies have found that a greater proportion of females report adverse events (AE) following receipt of either the COVID-19 or seasonal influenza vaccine compared to males. We sought to determine the intersection of biological sex and sociocultural gender differences in prospective active reporting of vaccine outcomes, which remains poorly characterized. Methods: This cohort study enrolled Johns Hopkins Health System healthcare workers (HCWs) who were recruited from the annual fall 2019-2022 influenza vaccine and the fall 2022 COVID-19 bivalent vaccine campaigns. Vaccine recipients were enrolled the day of vaccination and AE surveys were administered two days post-vaccination (DPV) for bivalent COVID-19 and Influenza vaccine recipients. Data were collected regarding the presence of a series of solicited local and systemic AEs. Open-ended answers about participants' experiences with AEs also were collected for the COVID-19 vaccine recipients. Results: Females were more likely to report local AEs after influenza (OR=2.28, p=0.001) or COVID-19 (OR=2.57, p=0.008) vaccination compared to males, regardless of age or race. Males and females had comparable probabilities of reporting systemic AEs after influenza (OR=1.18, p=0.552) or COVID-19 (OR=0.96, p=0.907) vaccination. Exogenous hormones from birth control use did not impact the rates of reported AEs following COVID-19 vaccination among reproductive-aged female HCWs. Women reported more interruptions in their daily routine following COVID-19 vaccination than men and were more likely to seek out self-treatment. More women than men scheduled their COVID-19 vaccination before their days off in anticipation of AEs. Conclusions: Our findings highlight the need for sex- and gender-inclusive policies to inform more effective occupational health vaccination strategies. Further research is needed to evaluate the potential disruption of AEs on occupational responsibilities following mandated vaccination for healthcare workers and to more fully characterize the post-vaccination behavioral differences between men and women. KEY MESSAGE: What is already known on this topic: ⇒ Among diversely aged adults 18-64 years, females report more AEs to vaccines, including the influenza and COVID-19 vaccines, than males.⇒ Vaccine AEs play a role in shaping vaccine hesitancy and uptake.⇒ Vaccine uptake related to influenza and COVID-19 are higher among men than women.⇒ Research that addresses both the sex and gender disparities of vaccine outcomes and behaviors is lacking.What this study adds: ⇒ This prospective active reporting study uses both quantitative and qualitative survey data to examine sex and gender differences in AEs following influenza or COVID-19 vaccination among a cohort of reproductive-aged healthcare workers.How this study might affect research, practice, or policy: ⇒ Sex and gender differences in AEs and perceptions relating to vaccination should drive the development of more equitable and effective vaccine strategies and policies in occupational health settings.

Advanced bone formation in mice with a dominant-negative mutation in the thyroid hormone receptor ß gene due to activation of Wnt/ß-catenin protein signaling.

Thyroid hormone (T(3)) acts in chondrocytes and bone-forming osteoblasts to control bone development and maintenance, but the signaling pathways mediating these effects are poorly understood. Thrb(PV/PV) mice have a severely impaired pituitary-thyroid axis and elevated thyroid hormone levels due to a dominant-negative mutant T(3) receptor (TRß(PV)) that cannot bind T(3) and interferes with the actions of wild-type TR. Thrb(PV/PV) mice have accelerated skeletal development due to unknown mechanisms. We performed microarray studies in primary osteoblasts from wild-type mice and Thrb(PV/PV) mice. Activation of the canonical Wnt signaling in Thrb(PV/PV) mice was confirmed by in situ hybridization analysis of Wnt target gene expression in bone during postnatal growth. By contrast, T(3) treatment inhibited Wnt signaling in osteoblastic cells, suggesting that T(3) inhibits the Wnt pathway by facilitating proteasomal degradation of ß-catenin and preventing its accumulation in the nucleus. Activation of the Wnt pathway in Thrb(PV/PV) mice, however, results from a gain of function for TRß(PV) that stabilizes ß-catenin despite the presence of increased thyroid hormone levels. These studies demonstrate novel interactions between T(3) and Wnt signaling pathways in the regulation of skeletal development and bone formation.

Human stem cell osteoblastogenesis mediated by novel glycogen synthase kinase 3 inhibitors induces bone formation and a unique bone turnover biomarker profile in rats.

Wnt activation by inhibiting glycogen synthase kinase 3 (GSK-3) causes bone anabolism in rodents making GSK-3 a potential therapeutic target for osteoporotic and osteolytic metastatic bone disease. To understand the wnt pathway related to human disease translation, the ability of 3 potent inhibitors of GSK-3 (AZD2858, AR79, AZ13282107) to 1) drive osteoblast differentiation and mineralisation using human adipose-derived stem cells (hADSC) in vitro; and 2) stimulate rat bone formation in vivo was investigated. Bone anabolism/resorption was determined using clinically relevant serum biomarkers as indicators of bone turnover and bone formation assessed in femurs by histopathology and pQCT/µCT imaging. GSK-3 inhibitors caused ß-catenin stabilisation in human and rat mesenchymal stem cells, stimulated hADSC commitment towards osteoblasts and osteogenic mineralisation in vitro. AZD2858 produced time-dependent changes in serum bone turnover biomarkers and increased bone mass over 28 days exposure in rats. After 7 days, AZD2858, AR79 or AZ13282107 exposure increased the bone formation biomarker P1NP, and reduced the resorption biomarker TRAcP-5b, indicating increased bone anabolism and reduced resorption in rats. This biomarker profile was differentiated from anabolic agent PTH1-34 or the anti-resorptive Alendronate-induced changes. Increased bone formation in cortical and cancellous bone as assessed by femur histopathology supported biomarker changes. 14 day AR79 treatment increased bone mineral density and trabecular thickness, and decreased trabecular number and connectivity assessed by pQCT/µCT. GSK-3 inhibition caused hADSC osteoblastogenesis and mineralisation in vitro. Increased femur bone mass associated with changes in bone turnover biomarkers confirmed in vivo bone formation and indicated uncoupling of bone formation and resorption.

Developmental abnormalities in chicken embryos exposed to N-nitrosoatrazine.

Nitrate and atrazine (ATR) occur in combination in some drinking-water supplies and might react to form N-nitrosoatrazine (NNAT), which is reportedly more toxic than nitrate, nitrite, or ATR. Current evidence from population-based studies indicates that exposure to nitrate, nitrite, and nitrosatable compounds increases the risk of congenital defects and/or rate of embryo lethality. To test the hypothesis that NNAT induces malformations during embryogenesis, chicken embryos were examined for lethality and developmental abnormalities after treating fertilized eggs with 0.06-3.63 µg NNAT. After 5 d of incubation (Hamburger and Hamilton stage 27), 90% of embryos in NNAT-treated eggs were alive, of which 23% were malformed. Malformations included heart and neural-tube defects, caudal regression, gastroschisis, microphthalmia, anophthalmia, and craniofacial hypoplasia. The findings from this investigation suggest further studies are needed to determine the mechanisms underlying NNAT-induced embryotoxicity.

Biodegradation of BTEX mixture by Pseudomonas putida YNS1 isolated from oil-contaminated soil.

The presence of mixed contaminants, such as BTEX (benzene, toluene, ethylbenzene and xylene isomers) can affect the biodegradation, fate and environmental impacts of each compound. To understand the influence of interactions among BTEX compounds on their biodegradation, four bacteria were isolated from oil-contaminated soil and assayed for BTEX biodegradation in vitro. The isolate exhibiting maximum biodegradation was identified as Pseudomonas putida based on the 16S rDNA sequence. The biodegradation of the BTEX compounds was greatly influenced by pH, temperature, and salinity. Substrate mixture studies (binary, tertiary and quaternary) revealed that the presence of toluene increased the biodegradation rate of benzene, ethylbenzene, and xylene.

First- versus Third-Generation EGFR Tyrosine Kinase Inhibitors in EGFR-Mutated Non-Small Cell Lung Cancer Patients with Brain Metastases.

Introduction: Up to 50% of non-small cell lung cancer (NSCLC) harbor EGFR alterations, the most common etiology behind brain metastases (BMs). First-generation EGFR-directed tyrosine kinase inhibitors (EGFR-TKI) are limited by blood-brain barrier penetration and T790M tumor mutations, wherein third-generation EGFR-TKIs, like Osimertinib, have shown greater activity. However, their efficacy has not been well-studied in later therapy lines in NSCLC patients with BMs (NSCLC-BM). We sought to compare outcomes of NSCLC-BM treated with either first- or third-generation EGFR-TKIs in first-line and 2nd-to-5th-line settings. Methods: A retrospective review of NSCLC-BM patients diagnosed during 2010-2019 at Cleveland Clinic, Ohio, US, a quaternary-care center, was performed and reported following 'strengthening the reporting of observational studies in epidemiology' (STROBE) guidelines. Data regarding socio-demographic, histopathological, molecular characteristics, and clinical outcomes were collected. Primary outcomes were median overall survival (mOS) and progression-free survival (mPFS). Multivariable Cox proportional hazards modeling and propensity score matching were utilized to adjust for confounders. Results: 239 NSCLC-BM patients with EGFR alterations were identified, of which 107 received EGFR-TKIs after diagnosis of BMs. 77.6% (83/107) received it as first-line treatment, and 30.8% (33/107) received it in later (2nd-5th) lines of therapy, with nine patients receiving it in both settings. 64 of 107 patients received first-generation (erlotinib/gefitinib) TKIs, with 53 receiving them in the first line setting and 13 receiving it in the 2nd-5th lines of therapy. 50 patients received Osimertinib as third-generation EGFR-TKI, 30 in first-line, and 20 in the 2nd-5th lines of therapy. Univariable analysis in first-line therapy demonstrated mOS of first- and third-generation EGFR-TKIs as 18.2 and 19.4 months, respectively (p = 0.57), while unadjusted mPFS of first- and third-generation EGFR-TKIs was 9.3 and 13.8 months, respectively (p = 0.14). In 2nd-5th line therapy, for first- and third-generation EGFR-TKIs, mOS was 17.3 and 11.9 months, (p = 0.19), while mPFS was 10.4 and 6.08 months, respectively (p = 0.41). After adjusting for age, performance status, presence of extracranial metastases, whole-brain radiotherapy, and presence of leptomeningeal metastases, hazard ratio (HR) for OS was 1.25 (95% CI 0.63-2.49, p = 0.52) for first-line therapy. Adjusted HR for mOS in 2nd-to-5th line therapy was 1.60 (95% CI 0.55-4.69, p = 0.39). Conclusions: No difference in survival was detected between first- and third-generation EGFR-TKIs in either first or 2nd-to-5th lines of therapy. Larger prospective studies are warranted reporting intracranial lesion size, EGFR alteration and expression levels in primary tumor and brain metastases, and response rates.

Combination of EGFR-Directed Tyrosine Kinase Inhibitors (EGFR-TKI) with Radiotherapy in Brain Metastases from Non-Small Cell Lung Cancer: A 2010-2019 Retrospective Cohort Study.

INTRODUCTION: Traditionally, brain metastases have been treated with stereotactic radiosurgery (SRS), whole-brain radiation (WBRT), and/or surgical resection. Non-small cell lung cancers (NSCLC), over half of which carry EGFR mutations, are the leading cause of brain metastases. EGFR-directed tyrosine kinase inhibitors (TKI) have shown promise in NSCLC; but their utility in NSCLC brain metastases (NSCLCBM) remains unclear. This work sought to investigate whether combining EGFR-TKI with WBRT and/or SRS improves overall survival (OS) in NSCLCBM. METHODS: A retrospective review of NSCLCBM patients diagnosed during 2010-2019 at a tertiary-care US center was performed and reported following the 'strengthening the reporting of observational studies in epidemiology' (STROBE) guidelines. Data regarding socio-demographic and histopathological characteristics, molecular attributes, treatment strategies, and clinical outcomes were collected. Concurrent therapy was defined as the combination of EGFR-TKI and radiotherapy given within 28 days of each other. RESULTS: A total of 239 patients with EGFR mutations were included. Of these, 32 patients had been treated with WBRT only, 51 patients received SRS only, 36 patients received SRS and WBRT only, 18 were given EGFR-TKI and SRS, and 29 were given EGFR-TKI and WBRT. Median OS for the WBRT-only group was 3.23 months, for SRS + WBRT it was 3.17 months, for EGFR-TKI + WBRT 15.50 months, for SRS only 21.73 months, and for EGFR-TKI + SRS 23.63 months. Multivariable analysis demonstrated significantly higher OS in the SRS-only group (HR = 0.38, 95% CI 0.17-0.84, p = 0.017) compared to the WBRT reference group. There were no significant differences in overall survival for the SRS + WBRT combination cohort (HR = 1.30, 95% CI = 0.60, 2.82, p = 0.50), EGFR-TKIs and WBRT combination cohort (HR = 0.93, 95% CI = 0.41, 2.08, p = 0.85), or the EGFR-TKI + SRS cohort (HR = 0.46, 95% CI = 0.20, 1.09, p = 0.07). CONCLUSIONS: NSCLCBM patients treated with SRS had a significantly higher OS compared to patients treated with WBRT-only. While sample-size limitations and investigator-associated selection bias may limit the generalizability of these results, phase II/III clinicals trials are warranted to investigate synergistic efficacy of EGFR-TKI and SRS.

Perchlorate behavior in the context of black carbon and metal cogeneration following fireworks emission at Oak Lake, Lincoln, Nebraska, USA.

The imprints of fireworks displays on the adjacent water body were investigated from the perspective of cogeneration of black carbon, metals and perchlorate (ClO4-). In particular, the mixing and dissipation of ClO4- were studied at Oak Lake, Lincoln, Nebraska, following fireworks displays in 2015 and 2016. Following the display, ClO4- concentration in the water increased up to 4.3 µg/L and 4.0 µg/L in 2015 and 2016, respectively. A first-order model generally provided a good fit to the measured perchlorate concentrations from which the rate of dissipation was estimated as 0.07 d-1 in 2015 and 0.43 d-1 in 2016. SEM images show imprints of soot and metal particles in aerosol samples. EDS analysis of the lake sediment confirmed the presence of Si, K, Ca, Zn and Ba, most of which are components of fireworks. The δ13C range of -7.55‰ to -9.19‰ in the lake water system closely resembles fire-generated carbon. Cogeneration of black carbon and metal with perchlorate was established, indicating that ClO4- is an excellent marker of fireworks or a burning event over all other analyzed parameters. Future microcosmic, aggregation and column-based transport studies on black carbon in the presence of perchlorate and metals under different environmental conditions will help in developing transport and fate models for perchlorate and black carbon particles.

Removal of p-cresol and tylosin from water using a novel composite of alginate, recycled MnO2 and activated carbon.

For sustainable production, there is an urgent need to minimize the adverse environmental impacts of swine farming, which is a major contributor of the pollutants p-cresol and tylosin. Novel reactive composite alginate beads (CAB-MOACs) were fabricated by combining alginate with activated carbon (AC) and MnO2 recovered from spent battery waste and used for efficient removal of p-cresol and tylosin from water. Batch experiments were carried out under varying pH (3-11), temperature (15-50 °C), and agitation speed (50-200 rpm) to understand their effects on removal efficiency. The CAB-MOACs had better removal efficiency for p-cresol and tylosin than alginate beads alone or beads containing only AC or MnO2. Adsorption to CAB-MOACs followed pseudo-second-order kinetics (R2≥0.98) and Langmuir isotherm models (R2≥0.95). CAB-MOACs showed higher removal efficiency (∼99.9% after 10 h) compared to beads containing only immobilized MnO2 (60-70%) or AC (94-96%). Regeneration and reuse performance of the CAB-MOACs was excellent through five cycles, although slightly better for p-cresol than tylosin. With low-cost manufacturing and beneficial utilization of hazardous waste such as spent batteries, the newly developed composite beads show potential as an effective adsorbent for treating wastewater effluent containing emerging contaminants like p-cresol and tylosin. Future studies may focus on product refinement and large-scale testing on actual wastewaters.

Thyroid hormone excess rather than thyrotropin deficiency induces osteoporosis in hyperthyroidism.

Thyrotoxicosis is an important but under recognized cause of osteoporosis. Recently, TSH deficiency, rather than thyroid hormone excess, has been suggested as the underlying cause. To investigate the molecular mechanism of osteoporosis in thyroid disease, we characterized the skeleton in mice lacking either thyroid hormone receptor alpha or beta (TRalpha(0/0), TRbeta-/-). Remarkably, in the presence of normal circulating thyroid hormone and TSH concentrations, adult TRalpha(0/0) mice had osteosclerosis accompanied by reduced osteoclastic bone resorption, whereas juveniles had delayed endochondral ossification with reduced bone mineral deposition. By contrast, adult TRbeta-/- mice with elevated TSH and thyroid hormone levels were osteoporotic with evidence of increased bone resorption, whereas juveniles had advanced ossification with increased bone mineral deposition. Analysis of T3 target gene expression revealed skeletal hypothyroidism in TRalpha(0/0) mice, but skeletal thyrotoxicosis in TRbeta-/- mice. These studies demonstrate that bone loss in thyrotoxicosis is independent of circulating TSH levels and mediated predominantly by TRalpha, thus identifying TRalpha as a novel drug target in the prevention and treatment of osteoporosis.