Constitutively active CaMKII Drives B lineage acute lymphoblastic leukemia/lymphoma in tp53 mutant zebrafish.

Acute lymphoblastic leukemia/lymphoma (ALL) is the most common pediatric cancer and is a malignancy of T or B lineage lymphoblasts. Dysregulation of intracellular Ca2+ levels has been observed in patients with ALL, leading to improper activation of downstream signaling. Here we describe a new zebrafish model of B ALL, generated by expressing human constitutively active CaMKII (CA-CaMKII) in tp53 mutant lymphocytes. In this model, B cell hyperplasia in the kidney marrow and spleen progresses to overt leukemia/lymphoma, with only 29% of zebrafish surviving the first year of life. Leukemic fish have reduced productive genomic VDJ recombination in addition to reduced expression and improper splicing of ikaros1, a gene often deleted or mutated in patients with B ALL. Inhibiting CaMKII in human pre-B ALL cells induced cell death, further supporting a role for CaMKII in leukemogenesis. This research provides novel insight into the role of Ca2+-directed signaling in lymphoid malignancy and will be useful in understanding disease development and progression.

Cyanocyclopentadiene-Annulated Polycyclic Aromatic Radical Anions: Predicted Negative Ion Photoelectron Spectra and Singlet-Triplet Energies of Cyanoindene and Cyanofluorene Radical Anions.

Isomer-specific negative ion photoelectron spectra (NIPES) of cyanoindene (C9H7CN) and cyanofluorene (C14H9N), acquired through the computation of Franck-Condon (FC) factors that utilize harmonic vibrational frequencies and normal mode vectors derived from density functional theory (DFT) at the B3LYP/aug-cc-pVQZ and 6-311++G(2d,2p) basis sets, are reported. The adiabatic electron affinity (EA) values of the ground singlet (S0) and the lowest lying triplet (T1) states are used to predict site-specific S0-T1 energies (ΔEST). The vibrational spectra of the S0 and T1 states are typified by ring distortion and ring C-C stretching vibrational progressions. Among all the S0 isomers in C9H7CN, the 2-cyanoindene (2-C9H7CN) is found to be the most stable at an EA of 0.716 eV, with the least stable isomer being the 1-C9H7CN at an EA of 0.208 eV. In C14H9N, the most stable S0 isomer, 2-cyanofluorene (2-C14H9N), has an EA of 0.781 eV. The least stable S0 isomer in C14H9N is the 9-C14H9N, with an EA of 0.364 eV. The FC calculations are designed to mimic simulations that would be performed to aid in the analysis of experimental spectra obtained in NIPE spectroscopic techniques. The vibrational spectra, adiabatic EAs, and ΔEST values reported in this study are intended to act as a guide for future gas-phase ion spectroscopic experiments and astronomical searches, especially with regard to the hitherto largely unexplored C14H9N isomers.

Cyanonaphthalene and cyanonaphthyl radicals: Vibrational structures via computed negative ion photoelectron spectra and thermochemistry of 1- and 2-cyanonaphthalene.

A double harmonic oscillator model is applied to compute the negative ion photoelectron spectra (NIPES) of the 1- and 2-cyanonaphthalene (CNN) radical anions. The computed Franck-Condon factors utilize optimized structures and harmonic vibrational frequencies obtained using density functional theory with the B3LYP 6-311++G (2d,2p) basis set while considering the mode-mixing Duschinsky effects. To test the accuracy of our model, the NIPES of α and ß naphthyl radical anions were computed, and a strong agreement between the slow electron velocity-map ion imaging spectra and the predicted spectra was found. The adiabatic electron affinities (EAs) of the ground singlet states (S0) in 1-CNN and 2-CNN are 0.856 and 0.798 eV, respectively. The origin of the lowest-lying triplet (T1) states in 1-CNN and 2-CNN is found to be 3.226 and 3.266 eV, resulting in singlet-triplet energy splittings (ΔEST) of 2.370 and 2.468 eV, respectively. Both the NIPES for electron detachment to the S0 and T1 states exhibit well-resolved vibrational features, allowing for the assignment of several vibrational fundamental frequencies. Following deprotonation, several isomers are formed, with the most stable deprotonated radical anions in 1-CNN and 2-CNN, corresponding to the removal of the most acidic proton, with EAs of 2.062 and 2.16 eV. The rich spectroscopic and thermochemical data obtained in the current study make the CNN radical anions and their deprotonated species interesting systems for investigation in gas-phase, negative-ion experiments.

Descriptive study of COVID-19 vaccinations and infections within an NHS workforce.

BACKGROUND: Healthcare workers were a priority group for coronavirus disease 2019 (COVID-19) vaccination during the pandemic. Occupational exposure may account for some of the increased risk faced. AIMS: Describe COVID-19 vaccine uptake and infection rates in staff across a large NHS board in Scotland to better understand occupational risk during the pandemic. METHODS: Descriptive cross-sectional study. Demographic data were extracted on 5 August 2021 from 26 058 members of staff. COVID-19 vaccination status and positive polymerase chain reaction (PCR) results were extracted on two separate dates to describe the timeline of staff infections between March 2020 and January 2022. RESULTS: There was high uptake of all three vaccine doses across all demographic groups in hospital staff. PCR positivity decreased with increasing age and Scottish Index of Multiple Deprivation score. Staff and nosocomial COVID-19 infections followed peaks in community infection rates. CONCLUSIONS: NHS Lothian is a typical NHS workforce with good vaccine uptake. Beyond very early cases, there seems to be minimal evidence of occupational acquisition of COVID-19. The large number of nosocomial infections at the start of the pandemic may, in fact, reflect lack of community testing at this time. Despite protection from high vaccine coverage, job type and good Infection Prevention and Control practices, it seems that staff remain at high risk of catching the highly transmissible omicron variant from the community rather than work.

MEASUREMENT OF PERSISTENT ORGANIC POLLUTANTS, PERFLUORINATED COMPOUNDS, AND TOXIC METALS IN THE BLOOD OF HUMBOLDT PENGUINS (SPHENISCUS HUMBOLDTI) AT PUNTA SAN JUAN, PERU USING DRIED BLOOD SPOTS.

The Humboldt penguin (Spheniscus humboldti) population at the Punta San Juan Marine Protected Area in Peru is considered critical to the long-term sustainability of this endangered species in Peru. Exposure of the rookery to environmental toxicants is a mounting concern because of regional growth of industries and human populations. Whole blood samples were collected from 30 free-ranging penguins in 2011 as part of a broader population health monitoring program. Dried blood spots (DBS) containing 50 µl of blood were prepared and analyzed to assess exposure to five groups of environmental contaminants. Concentrations of elements arsenic, cadmium, iron, lead, mercury, selenium, and thallium were analyzed using inductively coupled plasma mass spectrometry. Persistent organic pollutant concentrations were measured using gas chromatography-tandem mass spectrometry to analyze organochlorine pesticides (OCP; p,p'-DDT, p,p'-DDE, ß-hexachlorocyclohexane, t-nonachlor, and oxychlordane), polychlorinated biphenyls (congeners 138 and 153), and polybrominated flame retardants (polybrominated biphenyl-153 and polybrominated diphenyl ether congeners 47 and 99). Per- and polyfluoroalkyl substances, including perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid were measured using liquid chromatography-tandem mass spectrometry. Results revealed low levels of exposure to these selected contaminants, at levels not considered to be of concern for wildlife health. DBS methodology was considered effective in a field-based setting for quantification of whole blood concentrations of environmental contaminants in penguins.

Functional disorders as a common motor manifestation of COVID-19 infection or vaccination.

BACKGROUND AND PURPOSE: There have been over 500 million confirmed cases of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), also known as coronavirus disease 2019 (COVID-19), across the globe. To date, a broad spectrum of neurological manifestations following acute infections as well as COVID-19 vaccines have been reported. The aim of this study was to describe the spectrum of neurological manifestations seen in the 'COVID-19 clinic' established in a tertiary Movement Disorders clinic. METHODS: In this consecutive case-series study over the period March 2020-January 2022, clinical information regarding demographic data, clinical history and examination findings, investigation results and video recordings of outpatients with motor manifestations associated with COVID-19 infection or vaccination were reviewed. RESULTS: Twenty-one adult patients were reviewed in this ad hoc clinic at Toronto Western Hospital. The majority of the patients were female (76%) and the mean (range) age was 50.7 ± 17.2 (21-80) years. Nine patients (43%) presented with motor manifestations following COVID-19 infection. Twelve patients (57%) developed neurological symptoms following at least one dose of the mRNA or viral vector-based COVID-19 vaccine. The most common manifestation observed was a functional movement disorder (43%). The vaccine group demonstrated a higher number of functional disorders compared to the infection group (58% vs. 22%; p = 0.08). CONCLUSION: Functional motor manifestations can be associated with COVID-19 and are likely to be under-reported. In view of the co-existence of functional symptoms, movement disorders and mental health conditions observed in this study, we would advocate the use of dedicated COVID-19 Neurology clinics with full access to an experienced multidisciplinary team.

From Benzonitrile to Dicyanobenzenes: The Effect of an Additional CN Group on the Thermochemistry and Negative Ion Photoelectron Spectra of Dicyanobenzene Radical Anions.

The negative ion photoelectron spectra of 1,2-dicyanobenzene (o-DCNB), 1,3-dicyanobenzene (m-DCNB), and 1,4-dicyanobenzene (p-DCNB) radical anions (DCNB·-), acquired through the computation of Frack-Condon (FC) factors, are presented. The FC calculations utilize harmonic frequencies and normal mode vectors derived from density functional theory at the B3LYP/aug-cc-pVQZ basis set. All the totally symmetric vibrational modes are treated with Duschinsky rotations to yield neutral DCNBs in their singlet (So) and lowest triplet (T1) states, following an electron removal from the doublet anionic ground state. For the So state, the adiabatic electron affinities (EAs) for o-, m-, and p-DCNB are 1.179, 1.103, and 1.348 eV. The EAs for the lowest T1 state in o-, m-, and p-DCNB are 4.151, 4.185, and 4.208 eV, resulting in an So-T1 energy difference (ΔEST) of 2.973, 3.082, and 2.860 eV. A vibrational analysis reveals evidence of FC activity involving ring distortion, C-N bending, and ring C═C stretching vibrational progressions in both the So and T1 states. With the detection of cyanonaphthalene (C10H7CN) and cyanoindene (C9H7CN) in the interstellar medium (ISM), our results highlight the extent to which replacing a single hydrogen on an aromatic molecule with a cyano group, C≡N, can alter the vibrational structure of the molecule/radical anion. As such, dicyano-polyaromatic hydrocarbons may be reasonably robust in the ISM, making it appealing to search for them in future interstellar detection missions.

Predicted Negative Ion Photoelectron Spectra of 1-, 2-, and 9-Cyanoanthracene Radical Anions and Computed Thermochemical Values of the Three Cyanoanthracene Isomers.

In this work, the negative ion photoelectron spectra of 1-, 2-, and 9-cyanoanthracene (anthracenecarbonitrile, ACN) radical anions, obtained via the calculation of Franck-Condon (FC) factors based on a harmonic oscillator model, are reported. The FC calculations utilize harmonic vibrational frequencies and normal mode vectors derived from density functional theory using the B3LYP/6-311++G (2d,2p) basis set. The removal of an electron from the doublet anion allows for the computation of the negative ion photoelectron spectra that represents the neutral ground singlet state (So) and the lowest triplet state (T1) in each of the three ACN molecules. The respective adiabatic electron affinity (EA) values for the So state in 1-, 2-, and 9-ACN isomers are calculated to be 1.353, 1.360, and 1.423 eV. The calculated EA of the 9-cyanoanthracene singlet isomer is in close agreement with the previously reported experimental value of 1.27 ± 0.1 eV. Calculations show that the T1 states in 1-, 2-, and 9-ACN are located 1.656, 1.663, and 1.599 eV above the So state. The calculated T1 negative ion spectra exhibit intense vibrational origins and weak FC activity beyond the origins, indicating little change in geometry following electron detachment from the doublet anionic state. Upon deprotonation, the EA values of the radical isomers increase by ∼400-700 meV, resulting in neutral deprotonated radicals with EAs between 1.740 and 2.220 eV. The calculated site-specific gas-phase acidity values of ACN isomers indicate that ACN molecules are more acidic than benzonitrile.

A comprehensive review of treatments for hydrogen sulfide poisoning: past, present, and future.

Hydrogen sulfide (H2S) poisoning remains a significant source of occupational fatalities and is the second most common cause of toxic gas-induced deaths. It is a rapidly metabolized systemic toxicant targeting the mitochondria, among other organelles. Intoxication is mostly acute, but chronic or in-between exposure scenarios also occur. Some genetic defects in H2S metabolism lead to lethal chronic H2S poisoning. In acute exposures, the neural, respiratory, and cardiovascular systems are the primary target organs resulting in respiratory distress, convulsions, hypotension, and cardiac irregularities. Some survivors of acute poisoning develop long-term sequelae, particularly in the central nervous system. Currently, treatment for H2S poisoning is primarily supportive care as there are no FDA-approved drugs. Besides hyperbaric oxygen treatment, drugs in current use for the management of H2S poisoning are controversial. Novel potential drugs are under pre-clinical research development, most of which target binding the H2S. However, there is an acute need to discover new drugs to prevent and treat H2S poisoning, including reducing mortality and morbidity, preventing sequalae from acute exposures, and for treating cumulative pathology from chronic exposures. In this paper, we perform a comprehensive review of H2S poisoning including perspectives on past, present, and future.

Long-term outcome of patients receiving haematopoietic allogeneic stem cell transplantation as first transplant for high-risk Hodgkin lymphoma: a retrospective analysis from the Lymphoma Working Party-EBMT.

We analysed long-term outcome of patients receiving haematopoietic allogeneic stem cell transplantation (allo-HSCT) as a first transplant for high-risk Hodgkin lymphoma (HL). One hundred and ninety patients were included in this study, 63% of them had previously received brentuximab vedotin and/or checkpoint inhibitors. Seventy patients (37%) received an unrelated donor allo-HSCT, 99 (51%) had myeloablative conditioning (MAC) and 60% had in vivo T-cell/depleted grafts (TCD). The 100-day cumulative incidence (CI) of grade II-IV acute graft-versus-host disease (GVHD) was 25% and the 3-year CI of chronic GVHD was 38%. The 3-year CI of non-relapse mortality (NRM) and relapse rate were 21% and 38% respectively. After a median follow-up of 58 months, 3-year overall survival (OS) and progression-free survival (PFS) were 58% and 41% respectively. Multivariate analysis showed that, in comparison to reduced-intensity conditioning regimens with or without TCD, MAC using TCD had similar NRM and a lower risk of relapse leading to significantly better OS and PFS. MAC without TCD was associated with higher NRM and worse survival outcomes. These results suggest that in patients with high-risk HL and candidates of allo-HSCT, a MAC strategy with TCD might be the best option.

Short-chain fatty acid concentrations in the incidence and risk-stratification of colorectal cancer: a systematic review and meta-analysis.

BACKGROUND: The beneficial role of gut microbiota and bacterial metabolites, including short-chain fatty acids (SCFAs), is well recognized, although the available literature around their role in colorectal cancer (CRC) has been inconsistent. METHODS: We performed a systematic review and meta-analysis to examine the associations of fecal SCFA concentrations to the incidence and risk of CRC. Data extraction through Medline, Embase, and Web of Science was carried out from database conception to June 29, 2022. Predefined inclusion/exclusion criteria led to the selection of 17 case-control and six cross-sectional studies for quality assessment and analyses. Studies were categorized for CRC risk or incidence, and RevMan 5.4 was used to perform the meta-analyses. Standardized mean differences (SMD) with 95% confidence intervals (CI) were calculated using a random-effects model. Studies lacking quantitation were included in qualitative analyses. RESULTS: Combined analysis of acetic, propionic, and butyric acid revealed significantly lower concentrations of these SCFAs in individuals with a high-risk of CRC (SMD = 2.02, 95% CI 0.31 to 3.74, P = 0.02). Additionally, CRC incidence was higher in individuals with lower levels of SCFAs (SMD = 0.45, 95% CI 0.19 to 0.72, P = 0.0009), compared to healthy individuals. Qualitative analyses identified 70.4% of studies reporting significantly lower concentrations of fecal acetic, propionic, butyric acid, or total SCFAs in those at higher risk of CRC, while 66.7% reported significantly lower concentrations of fecal acetic and butyric acid in CRC patients compared to healthy controls. CONCLUSIONS: Overall, lower fecal concentrations of the three major SCFAs are associated with higher risk of CRC and incidence of CRC.

Patient-reported outcome (PRO) results from the AGITG DOCTOR trial: a randomised phase 2 trial of tailored neoadjuvant therapy for resectable oesophageal adenocarcinoma.

BACKGROUND: AGITG DOCTOR was a randomised phase 2 trial of pre-operative cisplatin, 5 fluorouracil (CF) followed by docetaxel (D) with or without radiotherapy (RT) based on poor early response to CF, detected via PET, for resectable oesophageal adenocarcinoma. This study describes PROs over 2 years. METHODS: Participants (N = 116) completed the EORTC QLQ-C30 and oesophageal module (QLQ-OES18) before chemotherapy (baseline), before surgery, six and 12 weeks post-surgery and three-monthly until 2 years. We plotted PROs over time and calculated the percentage of participants per treatment group whose post-surgery score was within 10 points (threshold for clinically relevant change) of their baseline score, for each PRO scale. We examined the relationship between Grade 3+ adverse events (AEs) and PROs. This analysis included four groups: CF responders, non-responders randomised to DCF, non-responders randomised to DCF + RT, and "others" who were not randomised. RESULTS: Global QOL was clinically similar between groups from 6 weeks post-surgery. All groups had poorer functional and higher symptom scores during active treatment and shortly after surgery, particularly the DCF and DCF + RT groups. DCF + RT reported a clinically significant difference (-13points) in mean overall health/QOL between baseline and pre-surgery. Similar proportions of patients across groups scored +/- 10 points of baseline scores within 2 years for most PRO domains. Instance of grade 3+ AEs were not related to PROs at baseline or 2 years. CONCLUSIONS: By 2 years, similar proportions of patients scored within 10 points of baseline for most PRO domains, with the exception of pain and insomnia for the DCF + RT group. Non-responders randomised to DCF or DCF + RT experienced additional short-term burden compared to CF responders, reflecting the longer duration of neoadjuvant treatment and additional toxicity. This should be weighed against clinical benefits reported in AGITG DOCTOR. This data will inform communication of the trajectory of treatment options for early CF non-responders. TRIAL REGISTRATION: Australia New Zealand Clinical Trials Registry (ANZCTR), ACTRN12609000665235 . Registered 31 July 2009.

Negative Ion Photoelectron Spectra of Deprotonated Benzonitrile Isomers via Computation of Franck-Condon Factors.

Negative ion photoelectron spectra of ortho (o-), meta (m-), and para (p-) deprotonated benzonitrile (o-, m-, p-C6H4(CN)-) isomers as well as the associated thermochemical values corresponding to deprotonation at o-, m-, and p-positions in C6H5(CN) are presented. Quantum mechanical results based on the density functional theory (DFT) utilizing the aug-cc-pVQZ basis set indicate that the o-, m-, p-C6H4(CN)● radicals have electron affinity values (EAs) of 1.901, 1.778, and 1.789 eV, respectively. The computed Franck-Condon (FC) factors give rise to o-, m-, and p-C6H4(CN)- negative ion spectra with FC active ring distortion vibrational modes with harmonic vibrational frequencies of ∼450, 760, and 1000 cm-1 as the dominant vibrational progressions. Deprotonation at the o-, m-, and p-positions in C6H5(CN) results in calculated gas-phase acidity values (ΔacidH298Ko) of 383.9, 385.7, and 385.3 kcal mol-1, respectively. The calculated ΔacidH298Ko is in close agreement with the previously reported high-pressure mass spectrometry experimental value of 383.4.0 ± 4.4 kcal mol-1. The computed ΔacidH298Ko and EAs are utilized to estimate the bond dissociation energy (DH298(H-C6H4CN)) associated with the formation o-, m-, and p-C6H4(CN)● using the negative ion thermochemical cycle: DH298(C6H5CN) = ΔacidH298Ko (H-C6H4(CN) + EA (C6H5CN)● - IP(H). The respective values of DH298(H-C6H4CN) corresponding to the formation of ortho, meta, and para C6H4(CN) radicals are 114.15, 113.11, and 113.51 kcal mol-1.

Defining complexity in anaesthesia: description and validation of the Oxford Anaesthetic Complexity (OxAnCo) score.

Increasing demand for surgery and anaesthesia has created an imperative to manage anaesthetic workforce and caseload. This may include changes to distribution of cases amongst anaesthetists of different grades, including non-physician anaesthetists. To achieve this safely, an assessment of case complexity is essential. We present a novel system for scoring complexity of cases in anaesthesia, the Oxford Anaesthetic Complexity score. This integrates patient, anaesthetic, surgical and systems factors, and is different from assessments of risk. We adopted an end-user development approach to the design of the score, and validated it using a dataset of anaesthetic cases. Across 688 cases, the median (IQR [range]) complexity score was 19 (17-22 [15-33]). Cases requiring a consultant anaesthetist had a significantly higher median (IQR [range]) score than those requiring a senior trainee at 22 (20-25 [15-33]) vs. 19(17-21 [15-28]), p < 0.001. Cases undertaken in a tertiary acute hospital had a significantly higher score than those in a district general hospital, the median (IQR [range]) scores being 20 (17-22 [15-33]) vs. 17 (16-19 [17-28]), p < 0.001. Receiver-operating characteristic analysis showed good prediction of complexity sufficient to require a consultant anaesthetist, with area under the curve of 0.84. Any rise in complexity above baseline (score > 15) was strongly predictive of a case too complex for a junior trainee (positive predictive value 0.93). The Oxford Anaesthetic Complexity score can be used to match cases to different grades of anaesthetist, and can help in defining cases appropriate for the expanding non-physician anaesthetist workforce.

Postpartum circulating microRNA enhances prediction of future type 2 diabetes in women with previous gestational diabetes.

AIMS/HYPOTHESIS: Type 2 diabetes mellitus is a major cause of morbidity and death worldwide. Women with gestational diabetes mellitus (GDM) have greater than a sevenfold higher risk of developing type 2 diabetes in later life. Accurate methods for postpartum type 2 diabetes risk stratification are lacking. Circulating microRNAs (miRNAs) are well recognised as biomarkers/mediators of metabolic disease. We aimed to determine whether postpartum circulating miRNAs can predict the development of type 2 diabetes in women with previous GDM. METHODS: In an observational study, plasma samples were collected at 12 weeks postpartum from 103 women following GDM pregnancy. Utilising a discovery approach, we measured 754 miRNAs in plasma from type 2 diabetes non-progressors (n = 11) and type 2 diabetes progressors (n = 10) using TaqMan-based real-time PCR on an OpenArray platform. Machine learning algorithms involving penalised logistic regression followed by bootstrapping were implemented. RESULTS: Fifteen miRNAs were selected based on their importance in discriminating type 2 diabetes progressors from non-progressors in our discovery cohort. The levels of miRNA miR-369-3p remained significantly different (p < 0.05) between progressors and non-progressors in the validation sample set (n = 82; 71 non-progressors, 11 progressors) after adjusting for age and correcting for multiple comparisons. In a clinical model of prediction of type 2 diabetes that included six traditional risk factors (age, BMI, pregnancy fasting glucose, postpartum fasting glucose, cholesterol and triacylglycerols), the addition of the circulating miR-369-3p measured at 12 weeks postpartum improved the prediction of future type 2 diabetes from traditional AUC 0.83 (95% CI 0.68, 0.97) to an AUC 0.92 (95% CI 0.84, 1.00). CONCLUSIONS: This is the first demonstration of miRNA-based type 2 diabetes prediction in women with previous GDM. Improved prediction will facilitate early lifestyle/drug intervention for type 2 diabetes prevention.

Pre-exposure to hydrogen sulfide modulates the innate inflammatory response to organic dust.

Animal production units produce and store many contaminants on-site, including organic dust (OD) and hydrogen sulfide (H2S). Workers in these settings report various respiratory disease symptoms. Both OD and H2S have shown to induce lung inflammation. However, impact of co-exposure to both H2S and OD has not been investigated. Therefore, we tested a hypothesis that pre-exposure to H2S modulates the innate inflammatory response of the lungs to organic dust. In a mouse model of H2S and organic dust extract (ODE) exposure, we assessed lung inflammation quantitatively. We exposed human airway epithelial and monocytic cells to medium or H2S alone or H2S followed by ODE and measured cell viability, oxidative stress, and other markers of inflammation. Exposure to 10 ppm H2S followed by ODE increased the lavage fluid leukocytes. However, exposure to 10 ppm H2S alone resulted in changes in tight junction proteins, an increase in mRNA levels of tlr2 and tlr4 as well as ncf1, ncf4, hif1α, and nrf2. H2S alone or H2S and ODE exposure decreased cell viability and increased reactive nitrogen species production. ODE exposure increased the transcripts of tlr2 and tlr4 in both in vitro and in vivo models, whereas increased nfkbp65 transcripts following exposure to ODE and H2S was seen only in in vitro model. H2S alone and H2S followed by ODE exposure increased the levels of IL-1ß. We conclude that pre-exposure to H2S modulates lung innate inflammatory response to ODE.

Immune Checkpoint Blockade in Lower Gastrointestinal Cancers: A Systematic Review.

BACKGROUND: Limited therapy options exist for patients with treatment-refractory metastatic colorectal or anal cancers, prompting investigation into alternative therapies. Immunotherapy in the form of immune checkpoint blockade is one such emerging treatment that has demonstrated promising results in other tumour streams.x This review aims to assess the current use of immune checkpoint blockade in patients with lower gastrointestinal tumours. PATIENTS AND METHODS: Embase, Medline and Cochrane databases were searched for included studies. Clinical trials published in English and utilising immune checkpoint blockade for primary tumours situated in the lower gastrointestinal tract were included. Databases were searched for studies reporting on at least one of overall survival, progression-free survival or response to therapy. RESULTS: In total, 972 abstracts were screened, with 10 studies included in the final review. Eight trials (833 patients) assessed immune checkpoint blockade in the setting of colorectal cancers. These included pembrolizumab, nivolumab, durvalumab, atezolizumab, tremelimumab and ipilimumab. A total of 20 patients across all studies achieved a complete response, and 111 patients achieved a partial response to treatment. Two trials (62 patients) assessed immune checkpoint blockade in anal cancer, utilising nivolumab and pembrolizumab. Two patients across both studies achieved a complete response, and 11 patients achieved a partial response. CONCLUSIONS: A number of patients with advanced lower gastrointestinal tumours achieved a complete response to treatment for what would otherwise be considered palliative disease. Presented data have highlighted that particular patients may benefit from first-line or combination immunotherapy, and thus, further investigation is warranted to individualise treatment.

Evaluating institutional fit for the conservation of threatened species.

Recovery and conservation of threatened species require adequate institutional responses. We tested an approach to systematically identify and measure how an institutional framework acknowledges threats and required responses for the recovery of endangered species. We measured institutional functional fit with a drivers-pressure-state-impacts-response (DPSIR) model integrated with a quantitative text mining method and qualitative analysis of statutory instruments to examine regulatory responses that support the recovery of 2 endangered species native to Australia, the bridled nailtail wallaby (Onychogalea fraenata) and the Eastern Bristlebird (Dasyornis brachypterus). The key components of the DPSIR model were present in the institutional framework at statutory and operational levels, but some institutional gaps remained in the protection and recovery of the Eastern Bristlebird, including feral predator control, weed control, and grazing management in some locations. However, regulatory frameworks varied in their geographic scope and the application and implementation of many instruments remained optional. Quantitative text mining can be used to quickly navigate a large volume of regulatory documents, but challenges remain in selection of terms, queries of co-occurrence, and interpretation of word frequency counts. To inform policy, we recommend that quantitative assessments of institutional fit be complemented with qualitative analysis and interpreted in light of the sociopolitical and institutional context.

La recuperación y la conservación de las especies amenazadas requieren de respuestas institucionales adecuadas. Evaluamos una estrategia para identificar y medir sistemáticamente cómo un marco de trabajo reconoce las amenazas y las respuestas requeridas para la recuperación de las especies en peligro. Medimos la aptitud funcional institucional mediante un modelo de fuerzas motrices-presión-estado-impacto-respuesta (DPSIR) integrado con un método cuantitativo de extracción de textos y un análisis cualitativo de los instrumentos legales para examinar las respuestas regulatorias que apoyan a la recuperación de dos especies en peligro nativas de Australia: Onychogalea fraenata y Dasyornis brachypterus. Los componentes clave del modelo DPSIR estuvieron presentes en el marco de trabajo institucional a niveles legales y operativos, pero algunos vacíos institucionales permanecieron en la protección y recuperación de D. brachypterus, incluyendo el control de depredadores ferales, el control de malezas y el manejo del pastoreo en algunas localidades. Sin embargo, los marcos de trabajo regulatorios variaron en cuanto a su enfoque geográfico y la aplicación e implementación de muchos de los instrumentos siguieron siendo opcionales. La extracción cuantitativa de textos puede usarse para navegar rápidamente un gran volumen de documentación regulatoria, pero todavía existen obstáculos en la selección de términos, consultas sobre la coocurrencia e interpretación de los conteos de frecuencia de palabras. Para orientar a las políticas recomendamos que las evaluaciones cuantitativas de la aptitud institucional estén complementadas con análisis cuantitativos e interpretadas a la luz del contexto institucional y sociopolítico.

COVID-19 stressors, wellbeing and health behaviours: a cross-sectional study.

BACKGROUND: Following the implementation of pandemic response measures, concerns arose regarding the impact for population health and wellbeing. METHODS: This study reports findings from a survey (N = 2510) conducted in Warwickshire (UK) during August and September 2020, and for the first time investigates behaviours which may worsen or mitigate the association between COVID-19-related stressors and wellbeing. RESULTS: Increased stressors were associated with lower mental wellbeing and higher loneliness. Participants with a mental health condition reported lower wellbeing, as did younger groups, women and participants not in employment. To cope with restrictions, more participants engaged in healthier behaviours over unhealthy behaviours, and relaxing reduced the association between stressors and poor wellbeing. Some participants reported increasing alcohol and unhealthy dietary behaviours to cope with restrictions, however, these behaviours did not mitigate the impact of COVID-19 stressors and were instead negatively associated with wellbeing. Around half of participants helped neighbours during the pandemic, a behaviour positively associated with wellbeing particularly among older adults. CONCLUSION: These findings contribute understanding about how various positive and negative health behaviours may mitigate or worsen the impact of COVID-19 on wellbeing, and how public health interventions may effectively target behaviours and groups in similar populations.

Behavioral and Neuronal Effects of Inhaled Bromine Gas: Oxidative Brain Stem Damage.

The risk of accidental bromine (Br2) exposure to the public has increased due to its enhanced industrial use. Inhaled Br2 damages the lungs and the heart; however, adverse effects on the brain are unknown. In this study, we examined the neurological effects of inhaled Br2 in Sprague Dawley rats. Rats were exposed to Br2 (600 ppm for 45 min) and transferred to room air and cage behavior, and levels of glial fibrillary acidic protein (GFAP) in plasma were examined at various time intervals. Bromine exposure resulted in abnormal cage behavior such as head hitting, biting and aggression, hypervigilance, and hyperactivity. An increase in plasma GFAP and brain 4-hydroxynonenal (4-HNE) content also was observed in the exposed animals. Acute and delayed sympathetic nervous system activation was also evaluated by assessing the expression of catecholamine biosynthesizing enzymes, tryptophan hydroxylase (TrpH1 and TrpH2), and tyrosine hydroxylase (TyrH), along with an assessment of catecholamines and their metabolites. TyrH was found to be increased in a time-dependent manner. TrpH1 and TrpH2 were significantly decreased upon Br2 exposure in the brainstem. The neurotransmitter content evaluation indicated an increase in 5-HT and dopamine at early timepoints after exposure; however, other metabolites were not significantly altered. Taken together, our results predict brain damage and autonomic dysfunction upon Br2 exposure.