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Objective: To study the relationship between consumption of milk and milk products, calcium, lactose and vitamin D and occurrence of colorectal cancers. Design: Prospective cohort study. Subjects: A total of 9959 men and women aged 15 y or older without history of cancer at baseline. During a 24 y follow-up, 72 new cancers of the large bowel (38 in the colon and 34 in the rectum) were detected. Results: Consumption of milk and total milk products was suggested to be inversely related to colon cancer incidence, whereas no similar association was seen for rectal cancer. The relative risk between the highest and lowest quartiles of intake adjusted for potential confounding factors was 0.46 (95% confidence interval 0.14–1.46, P for trend 0.09) for milk and 0.37 (95% CI=0.12–1.39, P for trend 0.06) for total milk products. Lactose intake showed a similar inverse relationship with colon cancer: the relative risk was 0.31 (95% CI=0.08–1.15, P for trend 0.03). Intake of vitamin D or total dietary calcium was not significantly related to colorectal cancer risk, whereas calcium provided by fermented milk products was associated with increased colorectal cancer incidence; in the highest quartile the multivariate adjusted relative risk for colorectal cancer was 2.07 (95% CI=1.00–4.28). Conclusions: Our results indicate that individuals showing high consumption of milk have a potentially reduced risk of colon cancer; however, the association does not appear to be due to intake of calcium, vitamin D, or to specific effects of fermented milk. Sponsorship: This study was supported by a grant from the Swedish Cancer Foundation. European Journal of Clinical Nutrition (2001) 55, 1000–1007

It has long been proposed that nuclear RNAs might play an important role in organizing the structure of the nucleus. Initial experiments performed more than 30 years ago found that global disruption of RNA led to visible rearrangements of nuclear organization. Yet, this idea remained controversial for many years, in large part because it was unclear what specific RNAs might be involved, and which specific nuclear structures might be dependent on RNA. Over the past few years, the contributions of RNA to organizing nuclear structures have become clearer with the discovery that many nuclear bodies are enriched for specific noncoding RNAs (ncRNAs); in specific cases, ncRNAs have been shown to be essential for establishment and maintenance of these nuclear structures. More recently, many different ncRNAs have been shown to play critical roles in initiating the three-dimensional (3D) spatial organization of DNA, RNA, and protein molecules in the nucleus. These examples, combined with global imaging and genomic experiments, have begun to paint a picture of a broader role for RNA in nuclear organization and to uncover a unifying mechanism that may explain why RNA is a uniquely suited molecule for this role. In this review, we provide an overview of the history of RNA and nuclear structure and discuss key examples of RNA-mediated bodies, the global roles of ncRNAs in shaping nuclear structure, and emerging insights into mechanisms of RNA-mediated nuclear organization.

Recent years have seen a paradigm shift in the management of patients with diabetes mellitus. Rather than good glycaemic control being the sole primary aim, the therapeutic focus has broadened to consider potential additional cardiovascular and renal benefits. Sodium-glucose co-transporter 2 inhibitors, such as empagliflozin, canagliflozin and dapagliflozin, have gained increasing prominence, with evidence suggesting significant improvement in outcomes in patients with established cardiovascular and renal disease. Here, we discuss the benefits and relative risks of these novel agents and highlight important clinical issues of relevance to general physicians.

The neuraminidase (NA) of influenza A and B viruses plays a distinct role in viral replication and has a highly conserved catalytic site. Numerous sialic (neuraminic) acid analogs that competitively bind to the NA active site and potently inhibit enzyme activity have been synthesized and tested. Four NA inhibitors are now licensed in various parts of the world (zanamivir, oseltamivir, peramivir, and laninamivir) to treat influenza A and B infections. NA changes, naturally occurring or acquired under selective pressure, have been shown to reduce drug binding, thereby affecting the effectiveness of NA inhibitors. Drug resistance and other drawbacks have prompted the search for the next-generation NA-targeting therapeutics. One of the promising approaches is the identification of monoclonal antibodies (mAbs) targeting the conserved NA epitopes. Anti-NA mAbs demonstrate Fab-based antiviral activity supplemented with Fc-mediated immune effector functions. Antiviral Fc-conjugates offer another cutting-edge strategy that is based on a multimodal mechanism of action. These novel antiviral agents are composed of a small-molecule NA inhibitor and an Fc-region that simultaneously engages the immune system. The significant advancements made in recent years further support the value of NA as an attractive target for the antiviral development.

Root-knot nematode Meloidogyne incognita is among the biotic factors which has greatly affected both the yield and the quality of the tomato crop. The egg parasitic nematode, Purpureocillium lilacinum (Pl) is considered as one of the most promising agents in controlling and overcoming this plant pathogen. The nematicidal effect of the native isolate Pl AUMC 10149 on second stage juvenile’s survival and egg hatching of M. incognita at different times of exposure was tested in vitro. The obtained data showed that Pl gave a maximum percentage of J2 mortality (97.6%) and egg hatching inhibition (79.8%) after 72 hours of exposure. The potentiality of Pl as well as Bio-Nematon to control M. incognita infecting tomato was conducted using different times of application in vivo. Nine treatments with five replicates were used for such bioagents compared with the nematicide Oxamyl. Each seedling was inoculated with 1000 J2s of nematode/pot and 10 mL of Pl (1x1010 CFU/mL) or Bio-Nematon spore suspension (1x108 CFU/mL) 10mL/pot. The results indicated that the most effective treatments in reducing nematode population, number of galls and egg masses of M. incognita in plant roots was performed with treatment by Pl pre-planting and post-infection with Pl (Rf 1.9) giving a significant enhancement in plant length (64.9%), fresh weight (72.52%) and shoot dry weight (163.41%) without negatively impacting environment. Therefore, the present study confirmed that using P. lilacinum AUMC 10149 can be used as a practical supplement to environmentally friendly disease management of root-knot nematodes in Egypt. Resumo O nematoide-das-galhas Meloidogyne incognita está entre os fatores bióticos que afetaram enormemente a produção e a qualidade da cultura do tomate. O nematoide parasita de ovos, Purpureocillium lilacinum (Pl), é considerado um dos mais promissores agentes no controle e superação desse fitopatógeno. O efeito nematicida do isolado nativo Pl AUMC 10149 na sobrevivência de juvenis de segundo estágio e na eclosão dos ovos de M. incognita em diferentes momentos de exposição foi testado in vitro. Os dados obtidos mostraram que o Pl deu um percentual máximo de mortalidade de J2 (97.6%) e inibição da eclosão dos ovos (79.8%) após 72 horas de exposição. A potencialidade de Pl e de Bio-Nematon para controlar M. incognita infectando tomate foi conduzida em diferentes tempos de aplicação in vivo. Nove tratamentos com cinco repetições foram usados para tais bioagentes em comparação com o nematicida Oxamyl. Cada muda foi inoculada com 1.000 J2s de nematoide / vaso e 10 mL de Pl (1×1010 CFU/mL). Ou suspensão de esporos Bio-Nematon (1×108 CFU/mL) 10mL/pot. Os resultados indicaram que os tratamentos mais eficazes na redução da população de nematoides, número de galhas e desovas de M. incognita nas raízes das plantas foram realizados com Pl pré-plantio e pós-infecção com Pl (Rf 1.9), dando um aumento significativo no comprimento da planta (64.9%), massa fresca (72.52%) e massa seca da parte aérea (163.41%) sem impactar negativamente o meio ambiente. Portanto, o presente estudo confirmou que o uso de P. lilacinum AUMC 10149 pode ser usado como um suplemento prático para o manejo ecologicamente correto de nematoides-das-galhas no Egito.

Mammals have a limited capacity to regenerate their tissues and organs. One of the mechanisms associated with natural regeneration is dedifferentiation. Several small molecules such as vitamin C and growth factors could improve reprogramming efficiency. In this study, the NTERA2-D1 (NT2) cells were induced towards differentiation (NT2-RA) with 10-5 M retinoic acid (RA) for three days and then subjected to various amounts of vitreous humor (VH). Results show that the growth rate of these cells was reduced, while this rate was partly restored upon treatment with VH (NT2-RA-VH). Cell cycle analysis with PI method also showed that the numbers of cells at the S phase of the cell cycle in these cells were increased. The levels of SSEA3 and TRA-1-81 antigens in NT2-RA were dropped but they increased in NT2- RA-VH to a level similar to the NT2 cells. The level of SSEA1 had an opposite pattern. Expression of OCT4 gene dropped after RA treatment, but it was recovered in NT2-RA-VH cells. In conclusion, we suggest VH as a potent mixture for improving the cellular reprogramming leading to dedifferentiation. Resumo Os mamíferos têm uma capacidade limitada de regenerar seus tecidos e órgãos. Um dos mecanismos associados à regeneração natural é a desdiferenciação. Várias moléculas pequenas, como vitamina C e fatores de crescimento, podem melhorar a eficiência da reprogramação. Neste estudo, as células NTERA2-D1 (NT2) foram induzidas à diferenciação (NT2-RA) com ácido retinóico (RA) 10-5 M por três dias e depois submetidas a várias quantidades de humor vítreo (VH). Os resultados mostram que a taxa de crescimento dessas células foi reduzida, enquanto essa taxa foi parcialmente restaurada após o tratamento com VH (NT2-RA-VH). A análise do ciclo celular com o método PI também mostrou que o número de células na fase S do ciclo celular nessas células estava aumentado. Os níveis de antígenos SSEA3 e TRA-1-81 em NT2-RA diminuíram, mas aumentaram em NT2-RA-VH a um nível semelhante ao das células NT2. O nível de SSEA1 teve um padrão oposto. A expressão do gene OCT4 diminuiu após o tratamento com AR, mas foi recuperado em células NT2-RA-VH. Em conclusão, sugerimos o VH como uma mistura potente para melhorar a reprogramação celular levando à desdiferenciação.

The study was conducted to evaluate the effect of Moringa olifera on the growth and gut health of Tilapia (Oreochromis niloticus). The feed having 30% crude protein was prepared as an experimental diet with 4%, 8% and 10% M. olifera leaf supplementation, respectively. The control diet was devoid of M. olifera leaves. The 10 weeks feeding trial was carried out on 60 fish in aquaria. Fish was fed @ 3% of body weight twice a day. Diet with the high level of inclusion of M. olifera leaves significantly increased the growth rate, Survival Rate (SR), Specific Growth Rate (SGR) and Feed Conversion Efficiency (FCE) in all treatment groups compared to the control group. Similarly, Feed Conversion Ratio (FCR) gradually decreased and found highly-significant. To check the gut health of the Tilapia, random samples were selected and dissected. Nutrient agar was used as culture media to check the growth of bacteria. Pour Plate Method was used for viable colonies count by colony counter. Through staining method, the different bacteria such as Escherichia coli, Salmonella, Shigella and Pseudomonas aeruginosa were identify abundantly in the intestine of control diet fish but less number present in treatment diets groups. These results showed that M. olifera leaves up to 10% of dietary protein can be used for Nile tilapia for significant growth and healthy gut microbiota of fish. Resumo O estudo foi conduzido para avaliar o efeito da Moringa olifera no crescimento e saúde intestinal da tilápia (Oreochromis niloticus). A ração com 30% de proteína bruta foi preparada como dieta experimental com 4%, 8% e 10% de suplementação de folhas de M. olifera, respectivamente. A dieta controle foi desprovida de folhas de M. olifera. O ensaio de alimentação de 10 semanas foi realizado em 60 peixes em aquários. O peixe pesava 3% do peso corporal duas vezes ao dia. A dieta com alto nível de inclusão de folhas de M. olifera aumentou significativamente a taxa de crescimento, taxa de sobrevivência (SR), taxa de crescimento de sobrevivência (SGR) e eficiência de conversão alimentar (FCE) em todos os grupos de tratamento em comparação com o grupo de controle. Da mesma forma, a taxa de conversão de alimentação (FCR) diminuiu gradualmente e foi considerada altamente significativa. Para verificar a saúde intestinal da tilápia, amostras aleatórias foram selecionadas e dissecadas. O ágar nutriente foi usado como meio de cultura para verificar o crescimento das bactérias. O método da placa de Verter foi usado para a contagem de colônias viáveis por contador de colônias. Através do método de coloração, diferentes como Escherichia coli, Salmonella, Shigella e Pseudomonas aeruginosa foram identificados abundantemente no intestino de peixes da dieta controle, mas em menor número nos grupos de dieta de tratamento. Esses resultados mostraram que M. olifera deixa até 10% da proteína dietética e pode ser usado para tilápia do Nilo para um crescimento significativo e microbiota intestinal saudável de peixes.

The lower lignin content in plants species with energy potential results in easier cellulose breakdown, making glucose available for ethanol generation. However, higher lignin levels can increase resistance to insect attack. The objective of this work was to evaluate the susceptibility of a bmr-6 biomass sorghum (a mutant genotype with a lower concentration of lignin) to important pests of energy sorghum, Diatraea saccharalis and Spodoptera frugiperda. Experiments were performed in the laboratory and greenhouse to evaluate the development of these pests on the biomass sorghum bmr hybrids BR007, BR008, and TX635 and their respective conventional near-isogenic genotypes (without the bmr gene). The lignin content was higher in non-bmr hybrids, but the evaluated insect variables varied between treatments, not being consistent in just one hybrid or because it is bmr or not. The lowest survival of S. frugiperda was observed in the BR008 hybrid, both bmr and non-bmr. The S. frugiperda injury scores on plants in the greenhouse were high (>7) in all treatments. For D. saccharalis, there was no difference in larval survival in the laboratory, but in the greenhouse, the BR007 hybrid, both bmr and non-bmr, provided greater survival. Due the need to diversify the energy matrix and the fact that greater susceptibility of the bmr hybrids to either pests was not found in this study, these results hold promise for cultivation of these biomass sorghum hybrids for the production of biofuels. Resumo O menor teor de lignina em espécies de plantas com potencial energético resulta na maior facilidade de quebra da celulose, disponibilizando glicose para geração de etanol. Porém, maiores teores de lignina representa um fator de resistência ao ataque de insetos. O objetivo deste trabalho foi avaliar como importantes pragas do sorgo energia, Diatraea saccharalis e Spodoptera frugiperda, se comportam quanto à alimentação e desempenho em sorgo bmr-6, um genótipo mutante com menor concentração de lignina. Foram realizados experimentos em laboratório e casa de vegetação, avaliando o desenvolvimento destas pragas nos híbridos de sorgo biomassa bmr 007, 008, TX635 e seus respectivos genótipos isogênicos convencionais (sem o gene bmr). O teor de lignina foi maior nos híbridos não bmr, mas nos parâmetros avaliados nos insetos, houve variação entre os tratamentos, não sendo consistente em apenas um híbrido e nem por ser ou não bmr. A menor sobrevivência de S. frugiperda foi verificada no híbrido BR008 tanto bmr quanto não bmr. As notas de injúria por S. frugiperda no sorgo em casa de vegetação foram altas (>7) em todos os tratamentos. Para D. saccharalis, não houve diferença significativa para a sobrevivência larval em laboratório, mas em casa de vegetação o híbrido BR007 tanto bmr quanto não bmr proporcionaram maior sobrevivência. Diante da necessidade de diversificar a matriz energética e o fato de que não foi comprovada neste estudo maior suscetibilidade dos híbridos bmr a ambas as pragas, estes resultados são promissores para o cultivo desses híbridos de sorgo biomassa para produção de biocombustíveis.

Chemotherapy can result in toxic side effects in the brain. Intake of marine-based omega-3 polyunsaturated fatty acids (n-3 PUFAs), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), alter brain fatty acids, potentially improving brain function. However, it is unclear if alpha-linolenic acid (ALA), the plant-based n-3, affects brain PUFAs during chemotherapy. The objective of this study was to examine the effects of dietary ALA, EPA and DHA, with high or low sucrose, on brain PUFAs in a mouse model of chemotherapy. Secondarily, the use of liver PUFAs as surrogate measures of brain PUFAs was examined. Lipid peroxidation (4-HNE) and neurotrophic markers (BDNF) were assessed. Female C57Bl/6 mice (n = 90) were randomized to 1 of 5 diets (high EPA + DHA/high or low sucrose, high ALA/high or low sucrose, or control with no EPA + DHA/low ALA/low sucrose) and injected with doxorubicin-based chemotherapy or saline. Brain EPA and DHA were greater (p < 0.0001) with high EPA + DHA diets, regardless of sucrose; there were no significant differences in brain PUFAs between high ALA diets and control. Chemotherapy-treated mice had higher brain and liver DHA (p < 0.05) and lower brain and liver linoleic acid (p < 0.0001). Brain n-3 and n-6 PUFAs were strongly correlated with liver n-3 (r = 0.8214, p < 0.0001) and n-6 PUFAs (r = 0.7568, p < 0.0001). BDNF was correlated with brain total PUFAs (r = 0.36; p < 0.05). In conclusion, dietary ALA in proportions approximately two times greater than consumed by humans did not appreciably increase brain n-3 PUFAs compared to low ALA intake. Liver PUFAs may be a useful surrogate marker of brain PUFAs in this mouse model.

Leukemia and lymphoma are cancers affecting children, adolescents, and young adults and may affect reproductive outcomes and maternal metabolism. We evaluated for metabolic changes in newborns of mothers with a history of these cancers.A cross-sectional study was conducted on California births from 2007 to 2011 with linked maternal hospital discharge records, birth certificate, and newborn screening metabolites. History of leukemia or lymphoma was determined using ICD-9-CM codes from hospital discharge data and newborn metabolite data from the newborn screening program.A total of 2,068,038 women without cancer history and 906 with history of leukemia or lymphoma were included. After adjusting for differences in maternal age, infant sex, age at metabolite collection, gestational age, and birthweight, among newborns born to women with history of leukemia/lymphoma, several acylcarnitines were significantly (The varied metabolite levels suggest history of leukemia or lymphoma has metabolic impact on newborn offspring, which may have implications for future metabolic consequences such as necrotizing enterocolitis and urea cycle enzyme disorders in children born to mothers with a history of leukemia or lymphoma.

We present the case of a female teenager who sustained nitrous oxide burns to the medial aspect of both thighs from contact with a nitrous oxide canister being used to fill balloons. There was a delay in presentation as the injury was not initially recognised. These burns were initially assessed as being superficial partial-thickness burns but took a prolonged time to heal despite regular wound care. This was complicated by a lack of adherence to recommended treatment for much of the patient care as well as the patient testing positive for COVID-19 during their management, which prevented surgery and significantly extended time to healing. While small numbers of similar cases have been previously described this is the first reported case outside of the Netherlands and in a child. Being aware of such cases ensures early referral to specialist burn care for appropriate management to give patients the best possible outcome.

Occurrence of biogenic amines in fresh fish and fishery products constitute a significant safety concern. Ingestion of histamine is identified as the causative agent of several food poisoning incidences on an annual basis. In addition, cadaverine, putrescine and tyramine have been recognized as potentiators of histamine poisoning. Accumulation of biogenic amines in fresh fish and fishery products has been mainly attributed to growth of bacteria possessing amino acid decarboxylase activity, which is facilitated by lack of hygienic conditions and strict temperature control during their storage. To this end, the effectiveness of traditional and modern approaches to control biogenic amine accumulation has been in the epicenter of intensive study. The aim of the present review article is to update and integrate current knowledge regarding the biogenic amine content of fresh fish and fishery products as well as the capacity of traditional and emerging control strategies.

The ionic pair self-assembly (IPSAM) composed of poly(ethyleneimine) (PEI) and (phenylthio)acetic acid (PTA) was prepared and the effect of phenolic acids (PAs) (e.g. cinnamic acid (CA), hydroxycinnamic acid (HCA), and dihydroxycinnamic acid (DHCA)) on the upper critical solution temperature (UCST) and the temperature-responsive releasing property of IPSAM were investigated. PEI/PTA ionic pair showed a UCST behavior and the PAs decreased the UCST effective in the order of DHCA > HCA > CA. The PAs were thought to attach to the PEI chain of PEI/PTA ionic pair as pendants. According to the interfacial tensiometry, PEI/PTA(3/7) ionic pair was found to be air/water interface-active due to their amphiphilic property. CA had little effect on the interfacial activity of the ionic pair. HCA and HDCA significantly decreased the interfacial activity possibly because they are more polar than CA thus the hydrophilic and lipophilic balance of PEI/PTA ionic pair could be broken by their attachment to PEI chains. IPSAM was found as nanoparticles whose diameter was tens of nanometer and PAs had little effect on the shape and the size of IPSAM, once the UCST of PEI/PTA/PA ionic pair was above room temperature where the TEM micrographs were taken. If the UCST of PEI/PTA/PA ionic pair was below room temperature, no particulate matters were found on the TEM micrographs. The release degree of cargo loaded in IPSAM increased slowly with time lapse below UCST. Whereas, the release degree increased rapidly with time lapse above UCST, possibly because of the thermally-induced disintegration of IPSAM.

Metal-Organic Frameworks (MOFs) have been developed as solid sorbents for CO2 capture applications and their properties can be controlled by tuning the chemical blocks of their crystalline units. A number of MOFs (e.g., HKUST-1) have been developed but the question remains how to deploy them for gas–solid contact. Unfortunately, the direct use of MOFs as nanocrystals would lead to serious problems and risks. Here, for the first time, we report a novel MOF-based hybrid sorbent that is produced via an innovative in-situ microencapsulated synthesis. Using a custom-made double capillary microfluidic assembly, double emulsions of the MOF precursor solutions and UV-curable silicone shell fluid are produced. Subsequently, HKUST-1 MOF is successfully synthesized within the droplets enclosed in the gas permeable microcapsules. The developed MOF-bearing microcapsules uniquely allow the deployment of functional nanocrystals without the challenge of handling ultrafine particles, and further, can selectively reject undesired compounds to protect encapsulated MOFs.

Despite wide applications of noble metal-based catalysts in 5-hydroxymethylfurfural (HMF) oxidation, promoting the catalytic performance at low loading amounts still remains a significant challenge. Herein, a series of metal oxide modified MOx-Au/TiO2 (M = Fe, Co, Ni) catalysts with low Au loading amount of 0.5 wt% were synthesized. Addition of transition metal oxides promotes electron transfer and generation of the Auδ−–Ov–Ti3+ interface. A combination study reveals that the dual-active site (Auδ−-Ov-Ti3+) governs the catalytic performance of the rate-determining step, namely hydroxyl group oxidation. Auδ− site facilitates chemisorption and activation of O2 molecules. At the same time, Ov-Ti3+ site acts as the role of “killing two birds with one stone”: enhancing adsorption of both reactants, accelerating the activation and dissociation of H2O, and facilitating activation of the adsorbed O2. Besides, superoxide radicals instead of base is the active oxygen species during the rate-determining step. On this basis, a FDCA yield of 71.2% was achieved under base-free conditions, complying with the “green chemistry” principle. This work provides a new strategy for the transition metal oxides modification of Au-based catalysts, which would be constructive for the rational design of other heterogeneous catalysts.

Background Ibrutinib is an oral inhibitor of Bruton’s tyrosine kinase (BTK) that is FDA-approved for several lymphoproliferative disorders and chronic GVHD. Objective To characterize cutaneous eruptions arising from ibrutinib and highlight overlap with epidermal growth factor receptor inhibitor (EGFRi)-induced dermatologic adverse events (dAEs). Methods Single-center retrospective cohort of patients referred to the Skin Toxicities Program for management of cutaneous eruptions while taking ibrutinib. Results Among 19 patients, cutaneous eruptions manifested as facial-predominant papulopustular eruptions, petechiae or ecchymoses, photosensitivity, panniculitis, xerosis, and clinical staphylococcal overgrowth. The majority of patients were able to continue ibrutinib therapy with focused management of their cutaneous toxicities. Limitations This study represents cases at a single tertiary care center and is limited to patients referred for toxicity. Conclusions With the exception of petechiae, the cutaneous toxicities of ibrutinib overlap with those associated with selective EGFR inhibitors. We observed that these reactions can be successfully managed using approaches for EGFR inhibitor-induced cutaneous adverse events.

Takotsubo cardiomyopathy is characterised by left ventricular apical ballooning, in the absence of coronary artery disease, and classically occurs at times of intense stress. Due to the striking preponderance of Takotsubo cardiomyopathy occurring in postmenopausal women, it has been postulated that female sex hormones may also be implicated in its pathogenesis. This case report describes the first case of Takotsubo cardiomyopathy associated with the initiation of dydrogesterone (a synthetic retroprogesterone) in a premenopausal woman.

This is a case of a young woman who developed neurological and psychiatric symptoms 3 days after resection of an immature teratoma. She was diagnosed with anti-NMDA receptor encephalitis via positive serum antibody titres, which was later confirmed with cerebrospinal fluid antibody titres. Given her cancer diagnosis, she underwent treatment with bleomycin, etoposide and cisplatin chemotherapy in addition to 5 days of high-dose steroids (1 g of intravenous methylprednisolone) for the encephalitis. This treatment regimen led to significant clinical improvement 3 weeks after completion of one cycle of chemotherapy.

Inhaled antibiotics are commonly used to treat persistent airway infection with Pseudomonas aeruginosa that contributes to lung damage in people with cystic fibrosis. Current guidelines recommend inhaled tobramycin for individuals with cystic fibrosis and persistent Pseudomonas aeruginosa infection who are aged six years or older. The aim is to reduce bacterial load in the lungs so as to reduce inflammation and deterioration of lung function. This is an update of a previously published review.To evaluate the effects of long-term inhaled antibiotic therapy in people with cystic fibrosis on clinical outcomes (lung function, frequency of exacerbations and nutrition), quality of life and adverse events (including drug-sensitivity reactions and survival).We searched the Cochrane Cystic Fibrosis Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. We also searched ongoing trials registries. Date of last search: 28 June 2022.We selected trials where people with cystic fibrosis received inhaled anti-pseudomonal antibiotic treatment for at least three months, treatment allocation was randomised or quasi-randomised, and there was a control group (either placebo, no placebo or another inhaled antibiotic).Two authors independently selected trials, judged the risk of bias, extracted data from these trials and judged the certainty of the evidence using the GRADE system.The searches identified 410 citations to 125 trials; 18 trials (3042 participants aged between five and 45 years) met the inclusion criteria. Limited data were available for meta-analyses due to the variability of trial design and reporting of results. A total of 11 trials (1130 participants) compared an inhaled antibiotic to placebo or usual treatment for a duration between three and 33 months. Five trials (1255 participants) compared different antibiotics, two trials (585 participants) compared different regimens of tobramycin and one trial (90 participants) compared intermittent tobramycin with continuous tobramycin alternating with aztreonam. One trial (18 participants) compared an antibiotic to placebo and also to a different antibiotic and so fell into both groups. The most commonly studied antibiotic was tobramycin which was studied in 12 trials. Inhaled antibiotics compared to placebo We found that inhaled antibiotics may improve lung function measured in a variety of ways (4 trials, 814 participants). Compared to placebo, inhaled antibiotics may also reduce the frequency of exacerbations (risk ratio (RR) 0.66, 95% confidence interval (CI) 0.47 to 0.93; 3 trials, 946 participants; low-certainty evidence). Inhaled antibiotics may lead to fewer days off school or work (quality of life measure) (mean difference (MD) -5.30 days, 95% CI -8.59 to -2.01; 1 trial, 245 participants; low-certainty evidence). There were insufficient data for us to be able to report an effect on nutritional outcomes and there was no effect on survival. There was no effect on antibiotic resistance seen in the two trials that were included in meta-analyses. We are uncertain of the effect of the intervention on adverse events (very low-certainty evidence), but tinnitus and voice alteration were the only events occurring more often in the inhaled antibiotics group. The overall certainty of evidence was deemed to be low for most outcomes due to risk of bias within the trials and imprecision due to low event rates. Different antibiotics or regimens compared Of the eight trials comparing different inhaled antibiotics or different antibiotic regimens, there was only one trial for each unique comparison. We found no differences between groups for any outcomes except for the following. Aztreonam lysine for inhalation probably improved forced expiratory volume at one second (FEVsub1/sub) % predicted compared to tobramycin (MD -3.40%, 95% CI -6.63 to -0.17; 1 trial, 273 participants; moderate-certainty evidence). However, the method of defining the endpoint was different to the remaining trials and the participants were exposed to tobramycin for a long period making interpretation of the results problematic. We found no differences in any measure of lung function in the remaining comparisons. Trials measured pulmonary exacerbations in different ways and showed no differences between groups except for aztreonam lysine probably leading to fewer people needing treatment with additional antibiotics than with tobramycin (RR 0.66, 95% CI 0.51 to 0.86; 1 trial, 273 participants; moderate-certainty evidence); and there were fewer hospitalisations due to respiratory exacerbations with levofloxacin compared to tobramycin (RR 0.62, 95% CI 0.40 to 0.98; 1 trial, 282 participants; high-certainty evidence). Important treatment-related adverse events were not very common across comparisons, but were reported less often in the tobramycin group compared to both aztreonam lysine and colistimethate. We found the certainty of evidence for these comparisons to be directly related to the risk of bias within the individual trials and varied from low to high.Long-term treatment with inhaled anti-pseudomonal antibiotics probably improves lung function and reduces exacerbation rates, but pooled estimates of the level of benefit were very limited. The best evidence available is for inhaled tobramycin. More evidence from trials measuring similar outcomes in the same way is needed to determine a better measure of benefit. Longer-term trials are needed to look at the effect of inhaled antibiotics on quality of life, survival and nutritional outcomes.

Various bowel preparation agents have been developed for effective and safe bowel cleansing before colonoscopy. Polyethylene glycol (PEG) is widely used in the elderly. A 2 L PEG solution with ascorbic acid (PEG-Asc) was developed to reduce the volume of standard 4 L PEG. Several cases of

We describe a 9-day-old baby with coarctation of the aorta who required urgent resuscitation including intubation and cardiac compressions. Despite the commencement of prostaglandin E1 (PGE1) to reopen the ductus arteriosus via the intraosseous route, postductal saturations remained unrecordable for a further 45 min. Within 3 min of administration of PGE1 via an umbilical venous catheter (UVC), saturations were recordable at 92%. UVC access was the sentinel intervention that irrevocably altered the clinical prognosis. This baby boy has survived with excellent neurodevelopmental outcome. Clinicians are less familiar with UVCs outside of the newborn period. Our data demonstrate successful placement in neonates up to 28 days of age. We hope this case encourages clinicians to consider the UVC as first-line central venous access in collapsed neonates. In cases of suspected left heart obstruction, we argue that UVCs are the optimal route.

Gambierdiscus spp. are epi-benthic dinoflagellates that have been associated with ciguatera poisoning. These microalgae can have complex secondary metabolite profiles including ciguatoxins, maitotoxins, and gambierones, with varying compositions and toxicities across species and strains. Given this chemical diversity there is a need to develop selective and sensitive methods for secondary metabolite profiling. In this study, we used a cultured Caribbean strain of Gambierdiscus silvae to develop sample preparation and analysis strategies for characterizing vic-diol containing secondary metabolites. A pooled cellular extract was first screened by liquid chromatography–high–resolution mass spectrometry (LC–HRMS) for ciguatoxin-related compounds, which resulted in the confirmation of gambierone (1) and tentative identification of 29-methylgambierone (3). Treatment of the extract with periodate confirmed that the gambierones each contained one reactive vic-diol, which was exploited for the development of a selective extraction procedure using m-aminophenylboronic acid gel and the non-aqueous binding solvent chloroform. Using this non-traditional boronate affinity procedure, LC-HRMS also revealed the presence of additional sulfated polycyclic ethers in the gambierone-containing vic-diol fraction, while pigments and other contaminants were removed. The developed tools could be applied to screen collections of Gambierdiscus and other benthic algae to provide additional chemical characterization of gambierone-related compounds. The selective extraction procedure may also prove useful as a step in the isolation of these sulfated polyethers for structural, toxicological and biotransformation studies.

Objectives. To assess cannabis and alcohol involvement among motor vehicle crash (MVC) fatalities in the United States. Methods. In this repeated cross-sectional analysis, we used data from the Fatality Analysis Reporting System from 2000 to 2018. Fatalities were cannabis-involved if an involved driver tested positive for a cannabinoid and alcohol-involved based on the highest blood alcohol concentration (BAC) of an involved driver. Multinomial mixed-effects logistic regression models assessed cannabis as a risk factor for alcohol by BAC level. Results. While trends in fatalities involving alcohol have remained stable, the percentage of fatalities involving cannabis and cannabis and alcohol increased from 9.0% in 2000 to 21.5% in 2018, and 4.8% in 2000 to 10.3% in 2018, respectively. In adjusted analyses, fatalities involving cannabis had 1.56 (95% confidence interval [CI] = 1.48, 1.65), 1.62 (95% CI = 1.52, 1.72), and 1.46 (95% CI = 1.42, 1.50) times the odds of involving BACs of 0.01% to 0.049%, 0.05% to 0.079%, and 0.08% or higher, respectively. Conclusions. The percentage of fatalities involving cannabis and coinvolving cannabis and alcohol doubled from 2000 to 2018, and cannabis was associated with alcohol coinvolvement. Further research is warranted to understand cannabis- and alcohol-involved MVC fatalities. (Am J Public Health. 2021;111(11):1976–1985. https://doi.org/10.2105/AJPH.2021.306466 )

Modulation of proteasome function by pharmacological interventions and molecular biology tools is an active area of research in cancer biology and neurodegenerative diseases. Curcumin (diferuloylmethane) is a naturally occurring polyphenol that affects multiple signaling pathways and known to modulate PKC activities. The therapeutic significance of curcumin is often considered to reside in its anti-inflammatory, antioxidant, anti-angiogenic, or anti-apoptotic properties. However, recent research suggests that the therapeutic efficacy of curcumin may be due to its activity as a potent inhibitor of the proteasome. In this study, we show that both curcumin and its synthetic polyphenolic derivative (didemethylcurcumin), CUIII modulated proteasome activity in a biphasic manner. Curcumin and CUIII increased proteasome activity at nanomolar concentrations but inhibited proteasome activity at micromolar concentrations. Curcumin was more effective than CUIII in relative proteasome activity increase at nanomolar concentrations. Also, curcumin was more effective than CUIII in relative proteasome activity inhibition at micromolar concentration. The docking study was conducted on the 20S proteasome catalytic subunit. Estimated Kd values for curcumin and didemethylcurcumin are 0.0054μM and 1.3167μM, respectively. These values correlate well with the results of the effectiveness of modulation by curcumin compare to CUIII. The small size of CUIII makes its dock to the narrow cavity of the active site, but the binding interaction is not strong compare to curcumin. This study suggests that curcumin and its didemethyl derivative can be used to modulate proteasome activity. This communication implicates the reason why curcumin and its didemethyl derivative can be used to two different disease mechanisms, neurodegeneration, and cancer.

Background Vitamin D deficiency is now recognized as an independent risk factor and is involved in the pathogenesis of carpal tunnel syndrome (CTS). The purpose of this study was to evaluate the effects of vitamin D3 supplementation on functional and symptomatic outcomes in CTS patients with vitamin D deficiency. Methods This was a prospective, single-arm study with a pretreatment or posttreatment quasi-experimental design. Carpal tunnel syndrome patients with vitamin D deficiency were treated with vitamin D3 (60 000 IU/week) plus standard treatment for a period of 3 months. Carpal tunnel syndrome–related pain and functional and symptomatic outcomes were assessed at baseline and at 3 months posttreatment using the Visual Analogue Scale (VAS) and the Boston Carpal Tunnel Questionnaire, respectively, along with serum vitamin D. Results A total of 42 patients were analyzed. At 3 months posttreatment, there was a significant reduction in the severity of pain (VAS score) from baseline ( Z = −5.71, P < .001). Similarly, the functional and symptomatic outcomes (Boston symptoms severity scale [SSS] and Boston functional status scale [FSS] score) at 3 months posttreatment significantly improved in comparison with baseline (Boston SSS: Z = −5.66, P < .001; Boston FSS: Z = −5.68, P < .001). Conclusions Vitamin D3 supplementation was associated with improvement in functional and symptomatic outcomes and CTS-related pain in CTS with vitamin deficiency. However, further robust randomized controlled trials are warranted to validate the results.

In this study, CO₂ conversion to acetate and CH₄ was achieved in a flow-through laboratory-scale microbial electrosynthesis (MES) cell composed of a 3D conductive polylactic acid (cPLA) lattice cathode with electrodeposited metal electrocatalyst coatings. The MES cell with a bare cPLA cathode showed the poorest performance with the lowest H₂ and CH₄ production rates and low Coulombic efficiency. This was ascribed to a poor electrocatalytic activity of cPLA towards H₂ production and high electrode resistivity. When the cPLA electrode was modified with metal coatings, the CH₄, acetate and H₂ production rate increased significantly, with the following trend: cPLA < Ni < NiFe < NiFeMn. The better performance of the metal-coated cPLA in terms of CH₄ production was attributed to the lower electrical resistance, enhanced H₂ production and enhanced electron transfer between the cathode and the biofilm. At the cell potential of 2.8 V, the best-performing NiFeMn cPLA cathode showed stable production of CH₄ (50 ± 6 mL d⁻¹), acetate (185 ± 27 mg d⁻¹), and H₂ (545 ± 175 mL d⁻¹) at close to 100% Coulombic efficiency.

Background: Endogenous and synthetic cannabinoids have been shown to induce cancer cell death through the accumulation of the sphingolipid, ceramide (Cer). Recently, we have demonstrated that Cer accumulation enhances the induction of immunogenic cell death (ICD). Objectives: The primary objective of this study was to demonstrate that (±) 5-epi CP 55,940 (5-epi), a by-product of the chemical synthesis of the synthetic cannabinoid CP 55,940, induces ICD in colorectal cancer (CRC) cells, and that modulation of the sphingolipid metabolic pathway through inhibition of the sphingosine kinases (SphKs) enhances these effects. Methods: A cell culture model system of human CRC cell lines was employed to measure the cell surface and intracellular production of markers of ICD. The effects of 5-epi, alone and in combination with SphK inhibitors, on production of Cer through the de novo sphingolipid synthesis pathway were measured by Liquid Chromatography - Tandem Mass Spectrometry (LC/MS/MS)-based sphingolipidomic analysis. Cell surface exposure of calreticulin (ectoCRT), a hallmark of ICD, was measured by flow cytometry. Examination of the effects of 5-epi, alone and in combination with SphK inhibitors, on the intracellular signaling pathway associated with ICD was conducted by immunoblot analysis of human CRC cell lines. Results: Sphingolipidomic analysis indicated that 5-epi induces the de novo sphingolipid synthetic pathway. 5-epi dose dependently induces cell surface exposure of ectoCRT, and inhibition of Cer metabolism through inhibition of the SphKs significantly enhances 5-epi-induced ectoCRT exposure in multiple CRC cell lines. 5-epi induces and SphK inhibition enhances activation of the cell death signaling pathway associated with ICD. Conclusions: This study is the first demonstration that cannabinoids can induce the cell surface expression of ectoCRT, and potentially induce ICD. Moreover, this study reinforces our previous observation of a role for Cer accumulation in the induction of ICD and extends this observation to the cannabinoids, agents not typically associated with ICD. Inhibition of SphKs enhanced the 5-epi-induced signaling pathways leading to ICD and production of ectoCRT. Overexpression of SphK1 has previously been associated with chemotherapy resistance. Thus, targeting the SphKs has the potential to reverse chemotherapy resistance and simultaneously enhance the antitumor immune response through enhancement of ICD induction.

Auxin is a crucial growth regulator that governs plant development and responses to environmental perturbations. It functions at the heart of many developmental processes, from embryogenesis to organ senescence, and is key to plant interactions with the environment, including responses to biotic and abiotic stimuli. As remarkable as auxin is, it does not act alone, but rather solicits the help of, or is solicited by, other endogenous signals, including the plant hormones abscisic acid, brassinosteroids, cytokinins, ethylene, gibberellic acid, jasmonates, salicylic acid, and strigolactones. The interactions between auxin and other hormones occur at multiple levels: hormones regulate one another's synthesis, transport, and/or response; hormone-specific transcriptional regulators for different pathways physically interact and/or converge on common target genes; etc. However, our understanding of this crosstalk is still fragmentary, with only a few pieces of the gigantic puzzle firmly established. In this review, we provide a glimpse into the complexity of hormone interactions that involve auxin, underscoring how patchy our current understanding is.

Simultaneous alcohol and marijuana (SAM) use is common, but it exacerbates negative consequences. Individuals use alcohol and cannabis products in different ways and have distinct reasons for use. The present study examines day-level effects of motives on consequences on SAM-use days, accounting for consumption, and tests whether using multiple alcohol (e.g., beer + liquor) and/or cannabis (e.g., concentrate + leaf) products on the same day mediates these relations. College students engaging in SAM use at least once in the past month (N = 281; Mage = 20.17) completed two bursts of 28 consecutive days of data collection. We examined within-person effects of motives (effect-enhancement, social, offered [it was offered], coping) on number of negative consequences and on experiencing hangover, nausea, or blackout; and indirect effects via two concurrent mediators: using multiple alcohol products and multiple cannabis products. Total effect models showed effect-enhancement motives were related to nausea, social motives to number of total consequences and hangover, and coping motives to blackout. Effect-enhancement, social, and offered motives evinced significant indirect effects on consequence outcomes via multiple alcohol, but not cannabis, product use. Coping motives did not exhibit significant indirect effects, and were related to multiple cannabis, but not alcohol, product use, although all other motives were related to both mediators. Findings support recent work demonstrating within-person relations between social motives and negative consequences on SAM-use days. Limiting the number of alcohol products consumed on SAM-use days may be beneficial, particularly for young adults using to enhance intoxication or for social reasons. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Over the past 30 years, the significance of nitric oxide (NO) has become increasingly apparent in mammalian physiology. It is biosynthesized by three isoforms of nitric oxide synthases (NOS): neuronal (nNOS), endothelial (eNOS), and inducible (iNOS). Neuronal and eNOS both produce low levels of NO (nM) as a signaling agent and vasodilator, respectively. Inducible (iNOS) is present in activated macrophages at sites of infection to generate acutely toxic (μM) levels of NO as part of the mammalian immune defense mechanism. These discoveries have led to numerous animal and clinical studies to evaluate the potential therapeutic utility of NO in various medical operations/treatments, primarily using NO gas (via gas-cylinders) as the NO source. In this review, we focus specifically on recent advances in the electrochemical generation of NO (E-NOgen) as an alternative means to generate NO from cheap and inert sources, and the fabrication and testing of biomedical devices that utilize E-NOgen to controllably generate NO for medical applications.

Neonatal hyperbilirubinaemia is a very common entity witnessed in most of the newborns. Rarely are there events where the bilirubin levels reach extreme values mandating invasive therapy. Unconjugated hyperbilirubinaemia when solely present is easy to manage and diagnose the common aetiological factors associated with it. The issue arises when we come across a mixed picture of conjugated with unconjugated hyperbilirubinaemia and puts us in a dilemma as to what are we treating. Our case highlights a similar picture where we witnessed the highest documented levels of total bilirubin but to our surprise the major component of which was direct bilirubin. This report takes us through the differentials which were ruled out and our management strategies for solving this rare mystery.

Our patient was a 57-year-old woman with a history of bilateral retropectoral silicone breast augmentation and axillary hyperhidrosis who underwent a bilateral thoracic sympathectomy via video-assisted thoracoscopic surgery by a surgeon at an outside hospital approximately 20 years ago. The left side required an open thoracotomy. Shortly after the surgery, she developed a left-sided Baker 4 capsular contracture and the left implant was noted to be ruptured. Both implants were exchanged. Several years later the patient began to experience progressive fatigue. Work-up revealed a left lung nodule and she underwent a biopsy that confirmed silicone granulomas. It was hypothesised that at the time of her initial thoracotomy the implant was violated resulting in silicone spillage into the thoracic cavity. The patient was referred to our institution for advanced management of her intrathoracic silicosis. The patient underwent bilateral removal of her silicone implants, total capsulectomy and needle-localised removal of her left thoracic silicone masses. She had an uneventful postoperative course with resolution of her fatigue.

Youth living with perinatally acquired HIV (YLPHIV) have been found to have a range of mental disorders. Some adult HIV studies have linked mental health to adverse metabolic outcomes due to dysregulation of the sympathetic nervous system and hypothalamic-pituitary-adrenal axis, but this association has not previously been explored in YLPHIV.We investigated the association of mental health measures with metabolic outcomes in YLPHIV and HIV-uninfected youth (HIV-U) and linear regression was used to assess the adjusted associations.Overall, 203 YLPHIV (median age = 10.7years; 52% female; mean duration on ART 8 years, 12% CD4 count 50 copies/mL) and 44 HIV-U (median age = 10.3 years; 55% female) were enrolled. YLPHIV had higher median total cholesterol (4.2 vs 3.9 mmol/L, p = 0.049) and triglyceride (0.9 vs 0.7 mmol/L, p < 0.001) compared to HIV-U. We found higher percentage of poor functional competence (40% vs 25%, p = 0.02) and self-concept (23% vs 9%, p = 0.03) and higher depression (6% vs 2%, p < 0.01), anger (6% vs 2%, p = 0.04) and disruptive behaviour (4% vs 0%, p < 0.01) in YLPHIV as compared to HIV-U. Among YLPHIV, higher scores of anger were associated with higher total cholesterol and higher low-density lipoprotein (s = 0.010, p = 0.041 and s = 0.012, p = 0.048 respectively) and disruptive behaviour with higher low-density lipoprotein (s = 0.010, p = 0.043) after adjusting for age, sex and BMIZ.This is the one of first study to investigate the association of mental health with metabolic outcomes among YLPHIV. The association of increased anger and disruptive behaviour with increased lipid concentration is a novel finding. Further longitudinal studies are needed to evaluate the causal relationships between mental health and metabolic outcomes.

Influenza polymerase (FluPol) plays a key role in the viral infection cycle by transcribing and replicating the viral genome. FluPol is a multifunctional, heterotrimeric enzyme with cap-binding, endonuclease, RNA-dependent RNA polymerase and polyadenylation activities. It performs its functions in the context of the viral ribonucleoprotein particle (RNP), wherein the template viral RNA is coated by multiple copies of viral nucleoprotein. Moreover, it interacts with a number of host proteins that are essential cofactors and, consequently, adaptive mutations in the polymerase are required for crossing the avian-human species barrier. In this review, we show how mechanistic understanding of how FluPol performs its multiple functions has greatly advanced over the last decade through determination of high-resolution structures by X-ray crystallography and cryo-electron microscopy. These have revealed not only the detailed architecture of FluPol but highlighted the remarkably conformational flexibility that is inherent to its functioning as a dynamic RNA synthesis machine. Structural studies are also underpinning current attempts to develop next-generation anti-influenza drugs that directly target FluPol.

Proses dehidrasi merupakan salah satu proses yang sering dijumpai pada pabrik pengolahan gas alam. TEG (triethylene glycol) merupakan senyawa Glycol yang biasa digunakan pada proses dehidrasi gas alam. TEG dimanfaatkan sebagai absorben pada absorpsi air yang masih terkandung dalam gas alam yang bisa menyebabkan hydrate dan korosi. Proses absorpsi ini dilakukan di TEG contactor, TEG yang sudah digunakan akan dilakukan regenerasi, jika sudah di regenerasi maka TEG akan digunakan kembali. Tujuan dari penelitian ini yaitu melakukan proses estimasi temperatur yang sesuai untuk proses absorpsi unit regenerasi TEG, karena banyak TEG loss pada proses ini. TEG loss terjadi di TEG regenerator dan biasanya disebabkan oleh temperatur kondensor refluks yang kurang tepat sehingga menyebabkan TEG teruapkan keluar ke atmosfer bersama uap air. Kehilangan TEG adalah masalah bagi operasi yang penting dalam sistem dehidrasi. Langkah yang digunakan untuk mengurangi TEG loss adalah dengan melakukan estimasi temperatur dari condensor refluks dibuat menjadi 100°C dengan cara mengubah temperatur reboiler dari 190°C menjadi 197,3°C.

The dimethacrylate macromonomer named bis (2-hydroxy-3-(méthacryloyloxy) propyl) fumarate (HMPF) was synthesized by ring opening reaction of epoxide function of glycidyl methacrylate (GMA) with maleic anhydride (MA) in presence of Maghnite-H+ as a catalyst at room temperature and at free solvent. The Maghnite-H+ is a proton exchanged montmorillonite clay it is an Algerian clay activated by sulfuric acid 0,23M. The HMPF was characterized by FT-IR, 1H NMR and 13C NMR spectroscopic techniques. A kinetic study was carried out to determine the amount of the catalyst (5, 10, 20 and 30%) which will give abetter yield of the synthesis reaction. T he yield of the reaction was 62. 2 3% for a quantity of Maghnite-H+ (20% relative to the monomer and for a r eaction time of 72 h.

PURPOSE Cisplatin plus gemcitabine is a standard regimen for first-line treatment of advanced non–small-cell lung cancer (NSCLC). Phase II studies of pemetrexed plus platinum compounds have also shown activity in this setting. PATIENTS AND METHODS This noninferiority, phase III, randomized study compared the overall survival between treatment arms using a fixed margin method (hazard ratio [HR] < 1.176) in 1,725 chemotherapy-naive patients with stage IIIB or IV NSCLC and an Eastern Cooperative Oncology Group performance status of 0 to 1. Patients received cisplatin 75 mg/m2 on day 1 and gemcitabine 1,250 mg/m2 on days 1 and 8 (n = 863) or cisplatin 75 mg/m2 and pemetrexed 500 mg/m2 on day 1 (n = 862) every 3 weeks for up to six cycles. RESULTS Overall survival for cisplatin/pemetrexed was noninferior to cisplatin/gemcitabine (median survival, 10.3 v 10.3 months, respectively; HR = 0.94; 95% CI, 0.84 to 1.05). Overall survival was statistically superior for cisplatin/pemetrexed versus cisplatin/gemcitabine in patients with adenocarcinoma (n = 847; 12.6 v 10.9 months, respectively) and large-cell carcinoma histology (n = 153; 10.4 v 6.7 months, respectively). In contrast, in patients with squamous cell histology, there was a significant improvement in survival with cisplatin/gemcitabine versus cisplatin/pemetrexed (n = 473; 10.8 v 9.4 months, respectively). For cisplatin/pemetrexed, rates of grade 3 or 4 neutropenia, anemia, and thrombocytopenia ( P ≤ .001); febrile neutropenia ( P = .002); and alopecia ( P < .001) were significantly lower, whereas grade 3 or 4 nausea ( P = .004) was more common. CONCLUSION In advanced NSCLC, cisplatin/pemetrexed provides similar efficacy with better tolerability and more convenient administration than cisplatin/gemcitabine. This is the first prospective phase III study in NSCLC to show survival differences based on histologic type.

This study was aimed at preparing chitosan (CS)-phenolic acids copolymers to obtain better preservation effect in marine products. In this work, CS was grafted onto phenolic acids such as gallic acid (GA) and protocatechuic acid (PA) by a carbodiimide coupling method. The copolymers (CS-grafted-GA (CS-g-GA) and CS-grafted-PA (CS-g-PA)) were further confirmed through physicochemical properties including ultraviolet–visible (UV–Vis) spectrophotography, fourier transform infrared (FTIR) spectrometry, differential scanning calorimetry (DSC) thermogram, rheological behaviour, scanning electron microscope (SEM) and antioxidant activity analysis. Subsequently, the effects of copolymers on preservation of refrigerated sea bass (Lateolabrax japonicus) fillets were investigated. The results showed that the CS-g-GA (110.82 mg GA/g) exhibited higher grafting rate than CS-g-PA (62.63 mg PA/g). According to the assessment of UV–Vis and FTIR spectrometry, both the GA and PA were grafted onto CS successfully. SEM analysis demonstrated that the microstructure of copolymers became irregular. Meanwhile, both the CS-g-GA and CS-g-PA copolymers displayed superior thermal stability, rheological properties and antioxidant capacity than the pure CS. Furthermore, the copolymers also revealed a significantly stronger preservation effect on sea bass fillets including inhibiting microbial growth and delaying the deterioration of color, texture and sensory quality. Therefore, CS-g-GA and CS-g-PA could be used as promising preservatives for seafood.

Purpose To highlight a case of chorioretinitis sclopetaria, with concomitant macular hole formation and orbital emphysema, caused by a commercial-grade pressure washer. Patient A 19-year-old male presented to the emergency department with a left eye injury, incurred after being sprayed with a commercial-grade pressure washer. He endorsed ipsilateral blurred vision, pain, and linear floaters. Left eye visual acuity was 20/40. Dilated fundus exam showed inferior vitreous hemorrhage, retinal whitening, and pre-, intra-, and sub-retinal hemorrhages, consistent with chorioretinitis sclopetaria. Optical coherence tomography revealed a full-thickness macular hole. Computed tomography scan of the orbits showed subcutaneous and post-septal orbital emphysema. Two months following injury, vitreous and retinal hemorrhages and macular hole resolved. Five months following injury, visual acuity improved to 20/20. Discussion Chorioretinitis sclopetaria is defined as a full-thickness chorioretinal disruption resulting from a high-velocity projectile passing adjacent to or into the orbit without penetrating the globe. Chorioretinal deformation and ocular comorbidities are influenced by the velocity of the missile and its spatial relationship to the orbit. While this pattern of injury is typically associated with indirect trauma to the globe by a BB or a bullet, this is the first report of chorioretinitis sclopetaria precipitated by a high-velocity liquid missile.

Purpose To investigate the efficacy and safety of bevacizumab plus carboplatin and paclitaxel in patients with advanced or recurrent non-small-cell lung cancer. Patients and Methods In a phase II trial, 99 patients were randomly assigned to bevacizumab 7.5 (n = 32) or 15 mg/kg (n = 35) plus carboplatin (area under the curve = 6) and paclitaxel (200 mg/m2) every 3 weeks or carboplatin and paclitaxel alone (n = 32). Primary efficacy end points were time to disease progression and best confirmed response rate. On disease progression, patients in the control arm had the option to receive single-agent bevacizumab 15 mg/kg every 3 weeks. Results Compared with the control arm, treatment with carboplatin and paclitaxel plus bevacizumab (15 mg/kg) resulted in a higher response rate (31.5% v 18.8%), longer median time to progression (7.4 v 4.2 months) and a modest increase in survival (17.7 v 14.9 months). Of the 19 control patients that crossed over to single-agent bevacizumab, five experienced stable disease, and 1-year survival was 47%. Bleeding was the most prominent adverse event and was manifested in two distinct clinical patterns; minor mucocutaneous hemorrhage and major hemoptysis. Major hemoptysis was associated with squamous cell histology, tumor necrosis and cavitation, and disease location close to major blood vessels. Conclusion Bevacizumab in combination with carboplatin and paclitaxel improved overall response and time to progression in patients with advanced or recurrent non-small-cell lung cancer. Patients with nonsquamous cell histology appear to be a subpopulation with improved outcome and acceptable safety risks.

The world’s first offshore methane hydrate extraction was conducted in 2013 at the Daini-Atsumi Knoll located in the eastern Nankai Trough. The results indicated that the gas production rate of a single vertical well cannot meet the requirement for commercialisation of methane hydrate production. Therefore, a trial multi-well system has been considered for future hydrate production. Understanding the ‘influence distance’ of extraction wells within methane hydrate turbidite reservoir formations, such as that of the Nankai Trough, is significant to the design of the proposed multi-well system. In this study, the boundary effects are examined for cases involving different values of permeability and initial hydrate saturation for the modelled turbidite formations. A relationship is proposed to predict the longest simulation time for a given set of lengths and parameters. The two concepts of critical production time (CPT) and turbidity/homogeneity coefficient ratio (THCR) are introduced to analyse the interaction between the effects of model size and heterogeneities. It is found that the CPT can be normalised by the radius of the model; the THCR is affected by the relative thickness of the sand and clay layers.

There are many photovoltaic (PV) applications where lighter weight and/or bendable PV power would be beneficial. This includes the curved surfaces of buildings, buildings with weight limitations, boats, automobiles, or other portable applications. In many of these cases, the bending will be only a single occurrence at installation or the amount of bending, even if repeated, is not dramatic. This allows for crystalline silicon modules to be used. For flexible applications, the dominant material for the frontsheet is polyethylene tetrafluoroethylene (PETFE). As a fluoropolymer it resists soiling, is UV stable, and PETFE is a more mechanically durable fluoropolymer. However, in the interests of keeping costs down, less expensive alternative polymers are desirable. In this study, highly accelerated ultraviolet light and heat stresses are applied to candidate materials and the degradation kinetics are determined to provide information to evaluate their suitability for use in a PV application.

Kidney disease is frequent in HIV-patients. We present a case of a 44-year-old woman, with known uncontrolled HIV infection and chronic kidney disease due to HIV-associated nephropathy. After starting dolutegravir, the patient developed eosinophilia and worsening kidney function. A kidney biopsy confirmed the diagnosis of acute interstitial nephritis. Given the time relation with dolutegravir introduction, it was deemed the culprit medication. Dolutegravir was stopped, and corticosteroids were initiated, with moderate improvement in renal function. To our knowledge, this is the first reported case of acute interstitial nephritis to dolutegravir, which should raise awareness of previously undocumented renal effects of antiretroviral therapy.

MiR-202-5p is identified as the maker microRNA (miRNA) of germplasm in fish. However, the role of miR-202-5p in gonadal development is still unclear. Here we investigated the expression patterns of miR-202-5p in Japanese flounder (Paralichthys olivaceus). Real-time PCR displayed that miR-202-5p was specifically expressed in bisexual gonads, and its transcription in the testis was relatively abundant than that in the ovary. Moreover, it was gradually increased in testis from stage II to stage IV. Fluorescent in situ hybridization (FISH) illustrated that miR-202-5p was co-localized with vasa (a marker gene of germ cells) in testis, and it was predominately expressed in spermatogonia and spermatocytes, implying that miR-202-5p might participate in spermatogenesis. Considering the important role of retinoic acid (RA) on regulating meiosis during spermatogenesis, we treated Japanese flounders by injecting all-trans retinoic acid (ATRA). MiR-202-5p in testis was shown to be up-regulated, and ccnd1, a key cell cycle regulator, was found to be down-regulated after ATRA treatment. Furthermore, ccnd1 was demonstrated to be a direct regulatory target of miR-202-5p using Dual-luciferase assay. In the primary testis cell from Japanese flounder, we further confirmed that ccnd1 was down-regulated by miR-202-5p. The results suggest that miR-202-5p exerts a crucial role in gonadal development by inhibiting ccnd1 in Japanese flounder.

Statement of problem The crystallization process of lithium disilicate crowns has been reported to cause dimensional change, but whether the fit of chairside computer-aided design and computer-aided manufactured (CAD-CAM) zirconia-reinforced lithium silicate crowns is affected is unclear. Purpose The purpose of this in vitro study was to evaluate with a 3-dimensional superimposition analysis technique the marginal and internal adaptation of fully crystallized versus partially crystallized zirconia-reinforced lithium silicate ceramic CAD-CAM fabricated crowns. Additionally, the silicone replica technique and direct viewing of marginal gap values were compared with the 3-dimensional superimposition analysis technique. Material and methods The marginal and internal adaptation of a fully crystallized zirconia-reinforced lithium silicate (CELTRA DUO) were compared with those of a partially crystallized zirconia-reinforced lithium silicate (VITA SUPRINITY) after crystallization. Sixteen crowns (n=8) were fabricated with a chairside CAD-CAM system. The crowns and die and crown assembly were scanned with an optical scanner for the 3-dimensional superimposition analysis. Four hundred sixty-eight measurements were made for each crown, 78 in each 2-dimensional section. Marginal discrepancy was measured by using the direct viewing technique. The internal adaptation of the shoulder area, axial space, and occlusal space was measured by using the silicone replica technique. Both gap values were compared with the 3-dimensional superimposition analysis results by using the independent t test. The 2-way ANOVA was used to detect the effect of each variable (group and site) (α=.05). Results The VITA SUPRINITY crowns showed statistically higher marginal discrepancy values than the CELTRA DUO crowns in both 3-dimensional superimposition analysis and the direct viewing method, and the lingual aspect recorded the highest marginal discrepancy mean value when compared with other aspects. The 3-dimensional superimposition analysis and the direct viewing method were statistically similar (P=.076). The VITA SUPRINTY crowns showed higher internal gap mean values than the CELTRA DUO crowns in both 3-dimensional superimposition analysis and silicone replica techniques. The occlusal space recorded the highest mean value in both groups. Assessment by 3-dimensional superimposition analysis and silicone replica techniques showed statistical difference in internal gap values (P=.04). Conclusions CELTRA DUO showed better precision fit values than VITA SUPRINITY. Three-dimensional superimposition analysis is a reliable method of evaluating marginal and internal adaptation.

Summary Objectives The understanding of vocal fold hydration state, including dehydrated, euhydrated, rehydrated tissue, and how hydration affects vocal fold biomechanical properties is still evolving. Although clinical observations support the benefits of increasing vocal fold hydration after dehydrating events, more mechanistic information on the effects of vocal fold dehydration and the beneficial effects of rehydration are needed. Alterations to hyaluronic acid (HA), an important component of the vocal fold extracellular matrix, are likely to influence the biomechanical properties of vocal folds. In this study, we investigated the influence of hydration state and HA on vocal fold tissue stiffness via biomechanical testing. Study design Prospective, ex vivo study design. Methods Fresh porcine vocal folds (N = 18) were examined following sequential immersion in hypertonic (dehydration) and isotonic solutions (rehydration). In a separate experiment, vocal folds were incubated in hyaluronidase (Hyal) to remove HA. Control tissues were not exposed to any challenges. A custom micromechanical system with a microforce sensing probe was used to measure the force-displacement response. Optical strain was calculated, and ultrasound imaging was used to measure tissue cross-sectional area to obtain stress-strain curves. Results Significant increases (P ≤ 0.05) were found in tangent moduli between dehydrated and rehydrated vocal folds at strains of e = 0.15. The tangent moduli of Hyal-digested tissues significantly increased at both e = 0.15 and 0.3 (P ≤ 0.05). Conclusion Vocal fold dehydration increased tissue stiffness and rehydration reduced the stiffness. Loss of HA increased vocal fold stiffness, suggesting a potential mechanical role for HA in euhydrated vocal folds.

PURPOSE To present a new technique to treat refractory retinal detachment secondary to optic disc pit. METHODS An interventional case report. RESULTS A 25-year-old man with congenital optic disc pit had two failed vitrectomies involving laser around the optic disc, internal limiting membrane peel and flap to plug the disc pit, and gas tamponade to reattach the retina. With all options running out, a further vitrectomy with autologous retinal transplant and silicone oil tamponade was carried out to treat the refractory serous retinal detachment; the silicone oil was removed at 6 weeks after the last procedure. The retina remained successfully attached at 6 months post-surgery with the patient maintaining his baseline visual acuity. CONCLUSION The use of autologous retinal transplant is a new approach to treat refractory retinal detachment secondary to congenital optic disc anomalies, and adds to our options of dealing with this complex condition when first-line approaches have failed.

The hydrate morphology in sandy methane hydrate (MH)-bearing sediment (MHBS) is commonly classified as pore-filling, cementation, grain-coating and load-bearing. This paper presents a numerical investigation into the mechanical behaviour of coexistence-type MHBS using the discrete-element method (DEM). The coexistence type is represented as a combination of pore-filling and cementation types. For MHBS with a given MH saturation (S MH), the relative content of pore-filling and cementation is characterised by the cement ratio λ (λ = 0 means pure pore-filling and λ = 1 means pure cementation). A series of drained triaxial compression tests is simulated, and micromechanical variables such as bond breakage are examined. The results show that (a) the strength and dilatancy of the coexistence-type MHBS are higher when the cement ratio is larger. The normalised strength and secant modulus increase linearly with the cement ratio. (b) When the cement ratio increases, the critical-state line on the mineral void ratio e cr–ln p′ projection shifts towards a higher position and the bond breakage ratio is larger. (c) The shear stress of the coexistence-type MHBS with cementation is affected by the MH generation process due to the MH bond breakages.

Background Hepatic lipid disorder impaired mitochondrial homeostasis and intracellular redox balance, triggering development of non-alcohol fatty liver disease (NAFLD), while effective therapeutic approach remains inadequate. Ginsenosides Rc has been reported to maintain glucose balance in adipose tissue, while its role in regulating lipid metabolism remain vacant. Thus, we investigated the function and mechanism of ginsenosides Rc in defending high fat diet (HFD)-induced NAFLD. Methods Mice primary hepatocytes (MPHs) challenged with oleic acid & palmitic acid were used to test the effects of ginsenosides Rc on intracellular lipid metabolism. RNAseq and molecular docking study were performed to explore potential targets of ginsenosides Rc in defending lipid deposition. Wild type and liver specific sirtuin 6 (SIRT6, 50721) deficient mice on HFD for 12 weeks were subjected to different dose of ginsenosides Rc to determine the function and detailed mechanism in vivo. Results We identified ginsenosides Rc as a novel SIRT6 activator via increasing its expression and deacetylase activity. Ginsenosides Rc defends OA&PA-induced lipid deposition in MPHs and protects mice against HFD-induced metabolic disorder in dosage dependent manner. Ginsenosides Rc (20mg/kg) injection improved glucose intolerance, insulin resistance, oxidative stress and inflammation response in HFD mice. Ginsenosides Rc treatment accelerates peroxisome proliferator activated receptor alpha (PPAR-α, 19013)-mediated fatty acid oxidation in vivo and in vitro. Hepatic specific SIRT6 deletion abolished ginsenoside Rc-derived protective effects against HFD-induced NAFLD. Conclusion Ginsenosides Rc protects mice against HFD-induced hepatosteatosis by improving PPAR-α-mediated fatty acid oxidation and antioxidant capacity in a SIRT6 dependent manner, and providing a promising strategy for NAFLD.

BACKGROUND Environmental and genetic factors are suggested to exhibit factor-based association with HDL-cholesterol (HDL-C) levels. However, the population-based effects of environmental and genetic factors have not been compared clearly. We conducted a cross-sectional study using data from the Japan Multi-Institutional Collaborative Cohort (J-MICC) Study to evaluate the population-based impact of smoking, drinking, and genetic factors on low HDL-C. METHODS Data from 11,498 men and women aged 35-69 years were collected for a genome-wide association study (GWAS). Sixty-five HDL-C-related SNPs with genome-wide significance (P < 5 × 10-8) were selected from the GWAS catalog, and seven representative SNPs were defined, and the population-based impact was estimated using population attributable fraction (PAF). RESULTS We found that smoking, drinking, daily activity, habitual exercise, egg intake, BMI, age, sex and the SNPs CETP rs3764261, APOA5 rs662799, LIPC rs1800588, LPL rs328, ABCA1 rs2575876, LIPG rs3786247, and APOE rs429358 were associated with HDL-C levels. The gene-environmental interactions on smoking and drinking were not statistically significant. The PAF for low HDL-C was the highest in men (63.2%) and in rs3764261 (31.5%) of the genetic factors, and the PAFs of smoking and drinking were 23.1% and 41.8%, respectively. CONCLUSIONS The present study showed that the population-based impact of genomic factor CETP rs3764261 for low HDL-C was higher than that of smoking and lower than that of drinking.