Exploring the interactions of glyphosate in soil: the sorption scenario upon soil depletion and effect on waterleaf (Talinum triangulare) growth.

The pesticide glyphosate has contributed immensely to the ease of farming and high yields. However, the ever-increasing environmental input of pesticides is of particular interest due to several unintended effects on non-target organisms. In soil, the sorption, transport, possible uptake, and effect on plant growth are still not well understood, and much so for the sub-Sahara. Sorption processes are contingent on the soil composition, characteristics, and ambient conditions, and these are becoming increasingly affected by climate change in a way that may alter pesticide fate. Hence, representative sub-Saharan whole soil (WS) treated to eliminate organic matter (OMR) and iron oxides (IOR) was employed to ascertain the contributions of these major constituents to glyphosate sorption processes, as well as ascertain the effect of glyphosate in soil on the growth of Talinum triangulare-waterleaf. Glyphosate sorption for all treatments was rapid with equilibrium at around 720 min. The sorption decreased as pH increased, and was concentration-dependent, gradually increasing with glyphosate concentration. The process was endothermic, and sorption data were better described by the fractal pseudo-second-order and Freundlich adsorption isotherm models, suggesting a complex interplay of interactive sorption forces. The IOR sample (with iron oxide depleted but organic matter intact) exhibited higher sorption than the OMR and WS, highlighting the contribution of organic matter in glyphosate sorption. Hysteresis was high for all samples and increased with temperature. Considering the unregulated usage of glyphosate in the sub-Sahara, the poor sorption, especially in treated soils, observed in this study suggests a high possibility of glyphosate leaching into the aquifer and poisoning of this water source, while the high hysteresis implied the bio-availability of glyphosate in surface soil for plant absorption, hence affecting growth; as confirmed in the waterleaf growth study where growth in the organic-matter/iron-oxide-depleted soils was substantially stunted. Hence, glyphosate affects waterleaf growth, especially in organic-matter/iron-oxide-depleted soils.

Clinicians' priorities for exercise programming for people receiving peritoneal dialysis: Qualitative content analysis from an international survey.

Exercise and physical activity have been shown to improve health outcomes among people receiving peritoneal dialysis (PD), however, little is known about PD clinicians' perceptions and practices regarding exercise counselling. To inform exercise program design and implementation, we distributed a cross-sectional online questionnaire to PD clinicians between July and December 2021 through professional nephrology societies and networks. As part of this survey, participants were asked, "What are the most important aspects you would like to see incorporated in an exercise program for PD patients?" Six hundred and nine respondents provided 1249 unique perspectives. Responses were coded using summative content analysis and grouped into themes. The overarching theme identified was the need for individualized and accessible programming. Under this umbrella, the four main sub-themes identified were: promotion of specific exercises, overcoming common barriers to exercise, perceived cornerstones of exercise prescriptions, and program design to address patient-relevant outcomes. Overall, PD clinicians believed that PD does not preclude exercise participation and recognized the potential for exercise to improve physical, mental, and social well-being. The involvement of exercise professionals was valued in PD clinical programs. However, additional education for practitioners and patients regarding safety and the benefits of exercise is required to assist in widespread implementation and acceptance of exercise programming in the PD population.

Causal relationships between diseases mined from the literature improve the use of polygenic risk scores.

MOTIVATION: Identifying causal relations between diseases allows for the study of shared pathways, biological mechanisms, and inter-disease risks. Such causal relations can facilitate the identification of potential disease precursors and candidates for drug re-purposing. However, computational methods often lack access to these causal relations. Few approaches have been developed to automatically extract causal relationships between diseases from unstructured text, but they are often only focused on a small number of diseases, lack validation of the extracted causal relations, or do not make their data available. RESULTS: We automatically mined statements asserting a causal relation between diseases from the scientific literature by leveraging lexical patterns. Following automated mining of causal relations, we mapped the diseases to the International Classification of Diseases (ICD) identifiers to allow the direct application to clinical data. We provide quantitative and qualitative measures to evaluate the mined causal relations and compare to UK Biobank (UKB) diagnosis data as a completely independent data source. The validated causal associations were used to create a directed acyclic graph that can be used by causal inference frameworks. We demonstrate the utility of our causal network by performing causal inference using the do-calculus, using relations within the graph to construct and improve polygenic risk scores, and disentangle the pleiotropic effects of variants. AVAILABILITY AND IMPLEMENTATION: The data is available through https://github.com/bio-ontology-research-group/causal-relations-between-diseases. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

The Evaluation of a Web-Based Intervention (Deprexis) to Decrease Depression and Restore Functioning in Veterans: Protocol for a Randomized Controlled Trial.

BACKGROUND: Depressive symptoms are common in veterans, and the presence of these symptoms increases disability as well as suicidal thoughts and behaviors. However, there is evidence that these symptoms often go untreated. Intervening before symptoms become severe and entrenched is related to better long-term outcomes, including improved functioning and less disease chronicity. Computer-delivered interventions may be especially appropriate for those veterans with mild to moderate depressive symptoms, because these interventions can require fewer resources and have lower barriers to access and thus have potential for wider reach. Despite this potential, there is a dearth of research examining computerized interventions for depressive symptoms in veteran samples. OBJECTIVE: The aim of this study is to evaluate the efficacy of Deprexis (GAIA AG), a computerized intervention for depressive symptoms and related functional impairment. METHODS: Veterans will be recruited through the US Department of Veterans Affairs electronic medical record and through primary care and specialty clinics. First, qualitative interviews will be completed with a small subset of veterans (n=16-20) to assess the acceptability of treatment procedures. Next, veterans (n=132) with mild to moderate depressive symptoms will be randomly assigned to the fully automated Deprexis intervention or a treatment-as-usual control group. The primary outcomes will be self-reported depressive symptoms and various dimensions of psychosocial functioning. RESULTS: This project was funded in May 2024, and data collection will be conducted between October 2024 and April 2029. Overall, 4 participants have been recruited as of the submission of the manuscript, and data analysis is expected in June 2029, with initial results expected in November 2029. CONCLUSIONS: This study will provide initial evidence for the efficacy of self-guided, computerized interventions for depressive symptoms and functional impairment in veterans. If effective, these types of interventions could improve veteran access to low-resource psychosocial treatments. TRIAL REGISTRATION: ClinicalTrials.gov NCT06217198; https://www.clinicaltrials.gov/study/NCT06217198. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/59119.

Electronic Structures and Spectra of Donor-Acceptor Conjugated Oligomers.

Narrow band gap donor-acceptor conjugated polymers present excellent paradigms in photonics and optoelectronics due to their chemical tunability, correlated electronic structures, and tunable open-shell electronic configurations. However, rational design for enhancing the properties of these molecular systems remains challenging. In this study, we employed density functional theory (DFT) calculations to investigate prototypical narrow band gap donor-acceptor conjugated oligomers, consisting of alternating cyclopentadithiophene (CPDT) donors paired with benzothiadiazole (BT), benzoselenadiazole (BSe), benzobisthiadiazole (BBT), and thiadiazoloquinoxaline (TQ) acceptors. Analyses of structures, singlet-triplet gaps, and absorption spectra of oligomers with up to ten repeat units have shown that when incorporating the BT, BSe, and TQ acceptors, the backbone curvature resulted in spiral structures that were energetically favored over their linear counterparts, causing differences in the calculated circular dichroism spectra. Oligomers with BBT-based acceptors preferred, however, a linear geometry, consistent with an open-shell electronic structure. Calculated singlet-triplet splittings demonstrated the importance of long chains and specific structures for consistency with the experiment, while effects of the solvent were also quantified. Based on the predicted low-energy conformations, one-photon absorption spectra for the considered oligomers have shown that using the Tamm-Dancoff approximation within time-dependent DFT for the large systems offers good agreement with the first absorption maxima in measured experimental spectra, thus validating the method for large donor-acceptor oligomers. Natural transition orbital analyses provided insights into the excited-state characteristics. Two-photon absorption maxima were accurately predicted, but the cross-sections were overestimated or underestimated, as dependent on the level of theory employed, to be addressed in future work.

In-field carbon dioxide removal via weathering of crushed basalt applied to acidic tropical agricultural soil.

Enhanced weathering (EW) of silicate rocks such as basalt provides a potential carbon dioxide removal (CDR) technology for combatting climate change. Modelling and mesocosm studies suggest significant CDR via EW but there are few field studies. This study aimed to directly measure in-field CDR via EW of basalt applied to sugarcane on acidic (pH 5.8, 0-0.25 m) Ultisol in tropical northeastern Australia, where weathering potential is high. Coarsely crushed basalt produced as a byproduct of gravel manufacture (<5 mm) was applied annually from 2018 to 2022 at 0 or 50 t ha-1 a-1, incorporated into the soil in 2018 but not in subsequent years. Measurements in 2022 show increased soil pH and extractable Mg and Si at 0-0.25 m depth, indicating significant weathering of the basalt, but showed no increase in crop yield. Soil inorganic carbon content and bicarbonate (HCO3-) flux to deep drainage (1.25 m depth) were measured to quantify CDR in the 2022-2023 wet season (i.e. one year). Soil inorganic carbon was below detection limits. Mean HCO3- flux was 3.15 kmol ha-1 a-1 (±0.40) in the basalt-treated plots and 2.56 kmol ha-1 a-1 (±0.18) in the untreated plots but the difference (0.59 kmol ha-1 a-1 or 0.026 t CO2 ha-1 a-1) was not significant (p = 0.082). Most weathering of the basalt was attributed to acids stronger than carbonic acid. These were, in decreasing order of contribution, surface-bound protons (inherent soil acidity), nitric acid (from nitrification), organic acids, and acids associated with cation uptake by plants. These results indicate in-field CDR via EW of basalt is low where soil and regolith pH is well below the pKa1 of 6.4 for H2CO3. However, increased soil pH, and the consumption of strong acids by weathering will eventually lead to reduced CO2 emission from soil or evasion from rivers, with continued basalt addition.

Exploring the dynamic adult hard ticks-camel-pathogens interaction.

The ability of ticks to interact and adapt to different ecologies and hosts determines their vectorial competence for various pathogens; however, ticks-livestock-pathogens interaction studies are limited. With our ticks-hosts-pathogens interface studies, we found 14 species of hard ticks feeding on various livestock. Ticks showed a strong preference for one-humped camels (Camelus dromedarius). The camel nostril was the most preferred predilection site. The most prevalent tick species on camels was Hyalomma rufipes. We found two novel Amblyomma gemma variants which are distinct both morphologically and genetically from previously described Amblyomma gemma. The signature odors from camel breath and body were attractive to adult H. rufipes, demonstrating ticks utilize camel-derived metabolites to find their host. Our research shows that H. rufipes and camel hosts have unique and shared pathogens showing H. rufipes' vector and dromedary camel's reservoir host qualities. Our study unravels the dynamic interactions between hard ticks, pathogens, and host camels that all influence the likelihood of pathogen adaptation and transmission dynamics. IMPORTANCE: Ticks are obligatory hematophagous arachnids, serving as vectors for a wide array of pathogens that can be transmitted to animals and humans. The ability of ticks to acquire and transmit various pathogens depends on their attraction to quality reservoir hosts and the survival of the pathogens in ticks' gut and other tissues. However, the complex dynamics of tick-pathogen interaction and host-seeking behavior remain understudied. This investigation revealed notable variation in tick preference for domestic animals, with camel being the most preferred host. Moreover, our spatial analysis of tick attachment sites showed nostrils are the most preferred sites by various tick species. Our epidemiology data showed variation in the pathogens harbored by camel (host) and vector (Hyalomma rufipes), demonstrating the camel's efficiency as reservoir host and ticks' vector competence for various pathogens. With our behavioral experiment using H. rufipes and its preferred host's (camel) breath and body signature odors, we identified novel attractants for H. rufipes, thus offering new avenues for combating tick-borne diseases. Overall, our study presents novel insights into how multiple factors shape tick-host-pathogen interaction.

Inhibition of OXPHOS induces metabolic rewiring and reduces hypoxia in murine tumor models.

Introduction: Tumor hypoxia is a feature of many solid malignancies and is known to cause radio resistance. In recent years it has become clear that hypoxic tumor regions also foster an immunosuppressive phenotype and are involved in immunotherapy resistance. It has been proposed that reducing the tumors' oxygen consumption will result in an increased oxygen concentration in the tissue and improve radio- and immunotherapy efficacy. The aim of this study is to investigate the metabolic rewiring of cancer cells by pharmacological attenuation of oxidative phosphorylation (OXPHOS) and subsequently reduce tumor hypoxia. Material and methods: The metabolic effects of three OXPHOS inhibitors IACS-010759, atovaquone and metformin were explored by measuring oxygen consumption rate, extra cellular acidification rate, and [18F]FDG uptake in 2D and 3D cell culture. Tumor cell growth in 2D cell culture and hypoxia in 3D cell culture were analyzed by live cell imaging. Tumor hypoxia and [18F]FDG uptake in vivo following treatment with IACS-010759 was determined by immunohistochemistry and ex vivo biodistribution respectively. Results: In vitro experiments show that tumor cell metabolism is heterogeneous between different models. Upon OXPHOS inhibition, metabolism shifts from oxygen consumption through OXPHOS towards glycolysis, indicated by increased acidification and glucose uptake. Inhibition of OXPHOS by IACS-010759 treatment reduced diffusion limited tumor hypoxia in both 3D cell culture and in vivo. Although immune cell presence was lower in hypoxic areas compared with normoxic areas, it is not altered following short term OXPHOS inhibition. Discussion: These results show that inhibition of OXPHOS causes a metabolic shift from OXPHOS towards increased glycolysis in 2D and 3D cell culture. Moreover, inhibition of OXPHOS reduces diffusion limited hypoxia in 3D cell culture and murine tumor models. Reduced hypoxia by OXPHOS inhibition might enhance therapy efficacy in future studies. However, caution is warranted as systemic metabolic rewiring can cause adverse effects.

Understanding hospital antimicrobial prescribing decisions and determinants of uptake of new local antimicrobial prescribing guidelines in Laos.

Background: Antimicrobial use in Laos is among the highest in Southeast Asia. The first Lao comprehensive antimicrobial prescribing guidelines have been available since 2021. This study explored the determinants of antibiotic prescribing decisions and how the new prescribing guidelines were being used. Methods: In August 2022, in-depth interviews were conducted with 16 Lao prescribers from two hospitals. Participants were questioned about their prescribing behaviours, attitudes to guidelines, how they learned about the guidelines and factors influencing their uptake. The interviews were audio-recorded, transcribed, and translated into English. Thematic analysis of the transcripts was conducted. Results: Lao prescribers considered multiple factors before deciding to prescribe antibiotics to their patients. The most common factor was based on the clinical judgement of the prescribers. Lack of certain antibiotics and turnaround times of laboratory results were the main challenges to prescribing antibiotics appropriately. The majority of participants were satisfied with the guidelines, regarding them as comprehensive, simple and convenient. However, most participants admitted that they did not access the guidelines very often. The main reason was that they could remember the treatment recommendations because they treat similar diseases on a daily basis. Improving antibiotic knowledge was the most common recommendation in order to improve the appropriate use of antibiotics. Raising awareness of the guidelines and promoting their use should also be considered. In addition, heads of the wards, and policy and implementation leaders, should support, monitor and feedback their use to encourage all prescribers to follow the guidelines. Conclusions: Several factors contribute to enhancing appropriate antibiotic prescription. Key factors for improving antibiotic prescription include enhancing prescribers' clinical knowledge, ensuring access to essential antibiotics, and updating guidelines regularly. Health leaders must get involved to promote their use.

In Laos, antibiotic use is high compared to other Southeast Asian countries. In 2021, the first guidelines for prescribing antibiotics were introduced in Laos. This study aims to explore what influences doctors' decisions in prescribing antibiotics and how they used the new guidelines. In August 2022, we conducted in-depth interviews with 16 doctors in two Lao hospitals. We asked them how they decided which antibiotics to give, what they thought about the guidelines, how they found the guidelines and what could make them use the guidelines more. We recorded, transcribed, and translated the conversations. Then, we identified common themes and patterns. Before giving antibiotics, doctors in Laos considered many things. The most important thing was their own judgment based on their medical knowledge. Not having some antibiotics and waiting long time for the laboratory results were the main issues that made it challenging for doctors to prescribe antibiotics. Most interviewees liked the guidelines. They found the guidelines easy to understand and useful. Many of them said that they did not use the guidelines a lot. The main reason was that they remembered the treatment recommendations because they treat similar diseases every day. The most common suggestion to use antibiotics better was to learn and understand more about them. Also, leaders of hospital departments and those in charge of making rules should help, keep an eye on the use, and give feedback to make sure everyone who prescribes antibiotics uses the guidelines. To make sure doctors prescribe antibiotics better, they need to know and understand more about infectious diseases, have easy access to essential antibiotics, and regularly update the guidelines with support from the leaders.

Implications of the 2022 lung function update and GLI global reference equations among patients with interstitial lung disease.

BACKGROUND: Lung function testing remains a cornerstone in the assessment and management of interstitial lung disease (ILD) patients. The clinical implications of the Global Lung function Initiative (GLI) reference equations and the updated interpretation strategies remain uncertain. METHODS: Adult patients with ILD with baseline forced vital capacity (FVC) were included from the Australasian ILD registry and the National Healthcare Group ILD registry, Singapore.The European Coal and Steel Community and Miller reference equations were compared with the GLI reference equations to assess (a) differences in lung function percent predicted values; (b) ILD risk prediction models and (c) eligibility for ILD clinical trial enrolment. RESULTS: Among 2219 patients with ILD, 1712 (77.2%) were white individuals. Idiopathic pulmonary fibrosis (IPF), connective tissue disease-associated ILD and unclassifiable ILD predominated.Median FVC was 2.60 (2.01-3.36) L, forced expiratory volume in 1 s was 2.09 (1.67-2.66) L and diffusing capacity of the lungs for carbon monoxide (DLCO) was 13.60 (10.16-17.60) mL/min/mm Hg. When applying the GLI reference equations, the mean FVC percentage predicted was 8.8% lower (87.7% vs 78.9%, p<0.01) while the mean DLCO percentage predicted was 4.9% higher (58.5% vs 63.4%, p<0.01). There was a decrease in 19 IPF and 119 non-IPF patients who qualified for the nintedanib clinical trials when the GLI reference equations were applied. Risk prediction models performed similarly in predicting mortality using both reference equations. CONCLUSION: Applying the GLI reference equations in patients with ILD leads to higher DLCO percentage predicted values and smaller lung volume percentage predicted values. While applying the GLI reference equations did not impact on prognostication, fewer patients met the clinical trial criteria for antifibrotic agents.

Talking about diseases; developing a model of patient and public-prioritised disease phenotypes.

Deep phenotyping describes the use of standardised terminologies to create comprehensive phenotypic descriptions of biomedical phenomena. These characterisations facilitate secondary analysis, evidence synthesis, and practitioner awareness, thereby guiding patient care. The vast majority of this knowledge is derived from sources that describe an academic understanding of disease, including academic literature and experimental databases. Previous work indicates a gulf between the priorities, perspectives, and perceptions held by different healthcare stakeholders. Using social media data, we develop a phenotype model that represents a public perspective on disease and compare this with a model derived from a combination of existing academic phenotype databases. We identified 52,198 positive disease-phenotype associations from social media across 311 diseases. We further identified 24,618 novel phenotype associations not shared by the biomedical and literature-derived phenotype model across 304 diseases, of which we considered 14,531 significant. Manifestations of disease affecting quality of life, and concerning endocrine, digestive, and reproductive diseases were over-represented in the social media phenotype model. An expert clinical review found that social media-derived associations were considered similarly well-established to those derived from literature, and were seen significantly more in patient clinical encounters. The phenotype model recovered from social media presents a significantly different perspective than existing resources derived from biomedical databases and literature, providing a large number of associations novel to the latter dataset. We propose that the integration and interrogation of these public perspectives on the disease can inform clinical awareness, improve secondary analysis, and bridge understanding and priorities across healthcare stakeholders.

Ethnic Diversity and Distinctive Features of Familial Versus Multifactorial Chylomicronemia Syndrome: Insights From the UK FCS National Registry.

BACKGROUND: Familial chylomicronemia syndrome (FCS) is a rare autosomal recessive disorder. This study aimed to study the genotype distribution of FCS-causing genes in the United Kingdom, genotype-phenotype correlation, and clinical differences between FCS and multifactorial chylomicronemia syndrome (MCS). METHODS: The study included 154 patients (FCS, 74; MCS, 80) from the UK FCS national registry and the UK arm of the FCS International Quality Improvement and Service Evaluation Project. RESULTS: FCS was relatively common in non-Europeans and those with parental consanguinity (P<0.001 for both). LPL variants were more common in European patients with FCS (European, 64%; non-European, 46%), while the genotype was more diverse in non-European patients with FCS. Patients with FCS had a higher incidence compared with patients with MCS of acute pancreatitis (84% versus 60%; P=0.001), recurrent pancreatitis (92% versus 63%; P<0.001), unexplained abdominal pain (84% versus 52%; P<0.001), earlier age of onset (median [interquartile range]) of symptoms (15.0 [5.5-26.5] versus 34.0 [25.2-41.7] years; P<0.001), and of acute pancreatitis (24.0 [10.7-31.0] versus 33.5 [26.0-42.5] years; P<0.001). Adverse cardiometabolic features and their co-occurrence was more common in individuals with MCS compared with those with FCS (P<0.001 for each). Atherosclerotic cardiovascular disease was more prevalent in individuals with MCS than those with FCS (P=0.04). However, this association became nonsignificant after adjusting for age, sex, and body mass index. The prevalence of pancreatic complications and cardiometabolic profile of variant-positive MCS was intermediate between FCS and variant-negative MCS. CONCLUSIONS: The frequency of gene variant distribution varies based on the ethnic origin of patients with FCS. Patients with FCS are at a higher risk of pancreatic complications while the prevalence of atherosclerotic cardiovascular disease is lower in FCS compared with MCS. Carriers of heterozygous pathogenic variants have an intermediate phenotype between FCS and variant-negative MCS.

Siglec-7 and Siglec-9 expression in primary triple negative and oestrogen receptor positive breast cancer and in vitro signalling.

Objectives: PD-1/PD-L1 immune checkpoint blockade can be an effective treatment for advanced breast cancer patients. However, patients with oestrogen receptor positive (ER+) tumors often display only low lymphocyte infiltration, while a large part of triple negative (TN) breast tumors does not generate an effective immunotherapy response. Therefore, new treatment strategies have to be developed. Here, we investigate Siglec-7 and Siglec-9 as novel ITIM-bearing inhibitory immune checkpoint receptors similar to PD-1, but expressed on a broader range of immune cells. Methods: We assessed Siglec-7 and Siglec-9 (ligand) expression in TN and ER+ breast cancer tumors and their breast cancer cell line-induced signalling. Results: We report that Siglec-7 and Siglec-9 are highly expressed in TN tumors, and to a low extent in ER+ tumors. Siglec-7 was observed on myeloid cells, T cells, and NK cells and Siglec-9 preferentially on myeloid cells. Expression of sialoglycans, including Siglec-7 and Siglec-9 ligands, was observed in both TN and ER+ breast cancer tissue sections. Expression levels of Siglec-7 and Siglec-9 ligands were higher on in vitro cultured TN cell lines than ER+ cell lines. Importantly, by applying chimeric Siglec-7 reporter cells, we showed the induction of Siglec-7 signalling by multiple TN cell lines, but only by one ER+ cell line. Moreover, Siglec-7 signalling is directly related to Siglec-7 ligand expression levels of breast cancer cell lines. Conclusion: These data imply that immunotherapy targeting Siglec receptors may be particularly interesting for TN breast cancer patients not responding to current treatment strategies with tumors displaying high immune cell infiltration.

Determinants of Prognosis in Head and Neck Cutaneous Squamous Cell Carcinoma With Nodal Metastases.

Importance: The eighth edition tumor, node, metastasis (TNM) staging for head and neck cutaneous squamous cell carcinoma (HNcSCC) is a poor predictor of survival in patients with lymph node metastases, possibly due to the inclusion of extranodal extension (ENE). Objective: To identify the key determinants of prognosis in patients with nodal metastatic HNcSCC and analyze the association of ENE with TNM stage and investigate for prognostic heterogeneity in ENE-positive disease. Design, Setting, and Participants: This retrospective, multicenter cohort study was conducted at 4 Australian tertiary referral centers using prospectively collected data in patients treated between 1980 and 2017 with a median (IQR) follow-up of 3.2 (3.9) years. The study population included 1309 consecutive patients with HNcSCC that was metastatic to parotid and/or cervical nodes. After excluding cases with perioperative mortality, missing data, or follow-up, the final study population included 1151 patients. Exposure: Curative intent surgery ± adjuvant radiotherapy. Main Outcomes and Measures: Differences in locoregional control (LRC), disease-specific survival (DSS), and overall survival were determined using Cox regression analysis. Results: Among 1151 patients, 976 (84.8%) were male and 175 (15.2%) female, with a median age of 73.3 years (range, 18-100 years). On multivariable analysis, immunosuppression (hazard ratio [HR], 2.48; 95% CI, 1.64-3.74), perineural invasion (HR, 1.69; 95% CI, 1.25-2.30), ENE (HR, 1.53; 95% CI, 0.95-2.44), size (>3-6 cm vs ≤3 cm [HR, 1.41; 95% CI, 1.03-1.93]; >6 cm vs ≤3 cm [HR, 5.01; 95% CI, 2.98-8.42]), and number of nodal metastases (3-4 vs 1-2 [HR, 1.54; 95% CI, 1.01-2.34]; ≥5 vs 1-2 [HR, 2.86; 95% CI, 1.99-4.11]) were associated with DSS. Similar results were found for LRC and overall survival. More than 90% of the population was categorized as TNM stage IV, with 32% attributable to ENE. In the ENE-positive subset (n = 860), DSS ranged from 8% to 88% based on stratification using other clinicopathological factors. Conclusions and Relevance: The study results suggest that immunosuppression, perineural invasion, ENE, and size and number of nodal metastases are associated with reduced survival and LRC in HNcSCC with nodal metastases. The inclusion of ENE in HNcSCC staging needs to be reassessed, as it ascribes excessive importance to ENE and upstages most patients to TNM stage IV, despite many having a high chance of cure.

Bridged Treatment Comparisons: an Illustrative Application in HIV Treatment.

Comparisons of treatments, interventions, or exposures are of central interest in epidemiology, but direct comparisons are not always possible due to practical or ethical reasons. Here, we detail a fusion approach to compare treatments across studies. The motivating example entails comparing the risk of the composite outcome of death, AIDS, or greater than a 50% CD4 cell count decline in people with HIV when assigned triple versus mono antiretroviral therapy, using data from the AIDS Clinical Trial Group (ACTG) 175 (mono versus dual therapy) and ACTG 320 (dual versus triple therapy). We review a set of identification assumptions and estimate the risk difference using an inverse probability weighting estimator that leverages the shared trial arms (dual therapy). A fusion diagnostic based on comparing the shared arms is proposed that may indicate violation of the identification assumptions. Application of the data fusion estimator and diagnostic to the ACTG trials indicates triple therapy results in a reduction in risk compared to monotherapy in individuals with baseline CD4 counts between 50 and 300 cells/mm3. Bridged treatment comparisons address questions that none of the constituent data sources could address alone, but valid fusion-based inference requires careful consideration of the underlying assumptions.

[Vertebroplasty for chronic back pain due to osteoporotic vertebral compression fractures]. / Chronische rugpijn na osteoporotische wervelinzakking.

OBJECTIVE: Evidence regarding percutaneous vertebroplasty (PV) for chronic painful osteoporotic vertebral compression fractures (OVCFs) remains limited. To compare pain relief, quality of life, and disability between PV and active control (anesthetic infiltration) interventions for chronic OVCF. DESIGN: Randomized controlled trial. METHODS: This prospective randomized clinical trial was conducted between May 2013 and June 2019 in participants with pain due to OVCF lasting longer than 3 months with bone marrow edema present at MRI. Study participants were randomly assigned to undergo PV (n = 40) or active control intervention (n = 40). The primary outcome was pain severity, assessed with the visual analog scale (VAS) (range, 0-10) during 12 months after treatment. Secondary outcomes included Quality of Life Questionnaire of the European Foundation for Osteoporosis (QUALEFFO) score (range, 0-100) and Roland Morris Disability Questionnaire (RMDQ) score (range, 0-100). Outcomes were analyzed according to a longitudinal multilevel model used to test the difference between groups in change from baseline across follow-up. RESULTS: The mean age of the 80 participants (54 women) was 69 years ± 10 (SD) in the PV group and 71 years ± 10 in the active control group. VAS score was 7.6 (95% CI: 7.0, 8.2) in the PV group and 7.3 (95% CI: 6.9, 7.8) in the active control group at baseline (P = .47) and 3.9 (95% CI: 3.1, 4.8) and 5.1 (95% CI: 4.3, 6.0), respectively, at month 12 (P = .045). At month 12, the group difference from baseline was 1.3 (95% CI: 0.1, 2.6; P = .02) for VAS, 5.2 (95% CI: 0.9, 9.4; P = .02) for QUALEFFO, and 7.1 (95% CI: -3.3, 17.5; P = .18) for RMDQ, favoring the PV group. CONCLUSION: In the treatment of pain caused by chronic OVCFs, PV is more effective for pain relief and quality of life improvement than anesthetic injection alone, with similar improvement for disability between the groups.

Decoding drivers of carbon flux attenuation in the oceanic biological pump.

The biological pump supplies carbon to the oceans' interior, driving long-term carbon sequestration and providing energy for deep-sea ecosystems1,2. Its efficiency is set by transformations of newly formed particles in the euphotic zone, followed by vertical flux attenuation via mesopelagic processes3. Depth attenuation of the particulate organic carbon (POC) flux is modulated by multiple processes involving zooplankton and/or microbes4,5. Nevertheless, it continues to be mainly parameterized using an empirically derived relationship, the 'Martin curve'6. The derived power-law exponent is the standard metric used to compare flux attenuation patterns across oceanic provinces7,8. Here we present in situ experimental findings from C-RESPIRE9, a dual particle interceptor and incubator deployed at multiple mesopelagic depths, measuring microbially mediated POC flux attenuation. We find that across six contrasting oceanic regimes, representing a 30-fold range in POC flux, degradation by particle-attached microbes comprised 7-29 per cent of flux attenuation, implying a more influential role for zooplankton in flux attenuation. Microbial remineralization, normalized to POC flux, ranged by 20-fold across sites and depths, with the lowest rates at high POC fluxes. Vertical trends, of up to threefold changes, were linked to strong temperature gradients at low-latitude sites. In contrast, temperature played a lesser role at mid- and high-latitude sites, where vertical trends may be set jointly by particle biochemistry, fragmentation and microbial ecophysiology. This deconstruction of the Martin curve reveals the underpinning mechanisms that drive microbially mediated POC flux attenuation across oceanic provinces.

Auto-expansion of in vivo HDAd-transduced hematopoietic stem cells by constitutive expression of tHMGA2.

We developed an in vivo hematopoietic stem cell (HSC) gene therapy approach that does not require cell transplantation. To achieve therapeutically relevant numbers of corrected cells, we constructed HSC-tropic HDAd5/35++ vectors expressing a 3' UTR truncated HMGA2 gene and a GFP reporter gene. A SB100x transposase vector mediated random integration of the tHMGA2/GFP transgene cassette. HSCs in mice were mobilized by subcutaneous injections of G-CSF and AMD3100/Plerixafor and intravenously injected with the integrating tHMGA2/GFP vector. This resulted in a slow but progressive, competitive expansion of GFP+ PBMCs, reaching about 50% by week 44 with further expansion in secondary recipients. Expansion occurred at the level of HSCs as well as at the levels of myeloid, lymphoid, and erythroid progenitors within the bone marrow and spleen. Importantly, based on genome-wide integration site analyses, expansion was polyclonal, without any signs of clonal dominance. Whole-exome sequencing did not show significant differences in the genomic instability indices between tHGMGA2/GFP mice and untreated control mice. Auto-expansion by tHMGA2 was validated in humanized mice. This is the first demonstration that simple injections of mobilization drugs and HDAd vectors can trigger auto-expansion of in vivo transduced HSCs resulting in transgene-marking rates that, theoretically, are curative for hemoglobinopathies.