Testing and Validation of a Custom Retrained Large Language Model for the Supportive Care of HN Patients with External Knowledge Base.

PURPOSE: This study aimed to develop a retrained large language model (LLM) tailored to the needs of HN cancer patients treated with radiotherapy, with emphasis on symptom management and survivorship care. METHODS: A comprehensive external database was curated for training ChatGPT-4, integrating expert-identified consensus guidelines on supportive care for HN patients and correspondences from physicians and nurses within our institution's electronic medical records for 90 HN patients. The performance of our model was evaluated using 20 patient post-treatment inquiries that were then assessed by three Board certified radiation oncologists (RadOncs). The rating of the model was assessed on a scale of 1 (strongly disagree) to 5 (strongly agree) based on accuracy, clarity of response, completeness s, and relevance. RESULTS: The average scores for the 20 tested questions were 4.25 for accuracy, 4.35 for clarity, 4.22 for completeness, and 4.32 for relevance, on a 5-point scale. Overall, 91.67% (220 out of 240) of assessments received scores of 3 or higher, and 83.33% (200 out of 240) received scores of 4 or higher. CONCLUSION: The custom-trained model demonstrates high accuracy in providing support to HN patients offering evidence-based information and guidance on their symptom management and survivorship care.

Rescue of synaptosomal glutamate release defects in tau transgenic mice by the tau aggregation inhibitor hydromethylthionine.

Glutamatergic neurotransmission, important for learning and memory, is disrupted in different ways in patients with Alzheimer's disease (AD) and frontotemporal dementia (FTD) tauopathies. We have previously reported that two tau transgenic mouse models, L1 and L66, produce different phenotypes resembling AD and FTD, respectively. The AD-like L1 model expresses the truncated core aggregation domain of the AD paired helical filament (PHF) form of tau (tau296-390) whereas the FTD-like L66 model expresses full-length tau carrying two mutations at P301S/G335D. We have used synaptosomes isolated from these mice to investigate K+-evoked glutamate release and, if abnormal, to determine responsiveness to hydromethylthionine, a tau aggregation inhibitor previously shown to reduce tau pathology in these models. We report that the transgenes in these two mouse lines cause opposite abnormalities in glutamate release. Over-expression of the core tau unit in L1 produces a significant reduction in glutamate release and a loss of Ca2+-dependency compared with wild-type control mice. Full-length mutant tau produces an increase in glutamate release that retains normal Ca2+-dependency. Chronic pre-treatment with hydromethylthionine normalises both reduced (L1) and excessive glutamate (L66) and restores normal Ca2+-dependency in L1 mice. This implies that both patterns of impairment are the result of tau aggregation, but that the direction and Ca2+-dependency of the abnormality is determined by expression of the disease-specific transgene. Our results lead to the conclusion that the tauopathies need not be considered a single entity in terms of the downstream effects of pathological aggregation of tau protein. In this case, directionally opposite abnormalities in glutamate release resulting from different types of tau aggregation in the two mouse models can be corrected by hydromethylthionine. This may help to explain the activity of hydromethylthionine on cognitive decline and brain atrophy in both AD and behavioural-variant FTD.

Evaluation of the effects of blue-enriched white light on cognitive performance, arousal, and overall appreciation of lighting.

Introduction: Light's non-visual effects on the biological clock, cognitive performance, alertness, and mental health are getting more recognized. These are primarily driven by blue light, which triggers specific retinal cells containing melanopsin. Traditionally, research on light has relied on correlated color temperature (CCT) as a metric of its biological influence, given that bluer light corresponds to higher Kelvin values. However, CCT proves to be an inadequate proxy of light's biological effects. A more precise metric is melanopic Equivalent Daylight Illuminance (mel-EDI), which aligns with melanopsin spectrum. Studies have reported positive cognitive impacts of blue-enriched white light. It's unclear if the mixed results are due to different mel-EDI levels since this factor wasn't assessed. Method: Given recent recommendations from experts to aim for at least 250 mel-EDI exposure daily for cognitive benefits, our aim was to assess if a 50-minute exposure to LED light with 250 mel-EDI could enhance concentration and alertness, without affecting visual performance or comfort compared to conventional lighting producing around 150 mel-EDI. To ensure mel-EDI's impact, photopic lux levels were kept constant across conditions. Conditions were counterbalanced, parameters included subjective sleepiness (KSS; Karolinska Sleepiness Scale), concentration (d2-R test), visual performance (FrACT; Freiburg Visual Acuity and Contrast Test), general appreciation (VAS; Visual Analogous Scale), preferences and comfort (modified OLS; Office Lighting Survey). Results: The experimental light significantly reduced sleepiness (p = 0.03, Cohen's d = 0.42) and also decreased contrast sensitivity (p = 0.01, Cohen's d = 0.50). The conventional light was found to be more comfortable (p = 0.002, Cohen's d = 0.62), cheerful (p = 0.02, Cohen's d = 0.46) and pleasant (p = 0.005, Cohen's d = 0.55) while the experimental light was perceived as brighter (p = 0.004, Cohen's d = 0.58) and tended to be more stimulating (p = 0.10). Notably, there was a preference for conventional lighting (p = 0.004, Cohen's d=0.56) and concentration was equally improved in both conditions. Discussion: Despite the lack of further improvement in concentration from exposure to blue-enriched light, given the observed benefits in terms of vigilance, further research over an extended period would be justified. These findings could subsequently motivate cognitive optimization through lighting for workers that would benefit from artificial lighting such as in northern regions.

Considerations for biomarker strategies in clinical trials investigating tau-targeting therapeutics for Alzheimer's disease.

The use of biomarker-led clinical trial designs has been transformative for investigating amyloid-targeting therapies for Alzheimer's disease (AD). The designs have ensured the correct selection of patients on these trials, supported target engagement and have been used to support claims of disease modification and clinical efficacy. Ultimately, this has recently led to approval of disease-modifying, amyloid-targeting therapies for AD; something that should be noted for clinical trials investigating tau-targeting therapies for AD. There is a clear overlap of the purpose of biomarker use at each stage of clinical development between amyloid-targeting and tau-targeting clinical trials. However, there are differences within the potential context of use and interpretation for some biomarkers in particular measurements of amyloid and utility of soluble, phosphorylated tau biomarkers. Given the complexities of tau in health and disease, it is paramount that therapies target disease-relevant tau and, in parallel, appropriate assays of target engagement are developed. Tau positron emission tomography, fluid biomarkers reflecting tau pathology and downstream measures of neurodegeneration will be important both for participant recruitment and for monitoring disease-modification in tau-targeting clinical trials. Bespoke design of biomarker strategies and interpretations for different modalities and tau-based targets should also be considered.

Neuroprotection of Cholinergic Neurons with a Tau Aggregation Inhibitor and Rivastigmine in an Alzheimer's-like Tauopathy Mouse Model.

Basal forebrain cholinergic dysfunction, most likely linked with tau protein aggregation, is a characteristic feature of Alzheimer's disease (AD). Recent evidence suggests that tau protein is a putative target for the treatment of dementia, and the tau aggregation inhibitor, hydromethylthionine mesylate (HMTM), has emerged as a potential disease-modifying treatment. However, its efficacy was diminished in patients already receiving approved acetylcholinesterase inhibitors. In this study, we ask whether this negative interaction can also be mimicked in experimental tau models of AD and whether the underlying mechanism can be understood. From a previous age profiling study, 6-month-old line 1 (L1) tau transgenic mice were characterized by a severe reduction in several cholinergic markers. We therefore assessed whether long-term pre-exposure with the acetylcholinesterase inhibitor rivastigmine alone and in conjunction with the tau aggregation inhibitor HMTM can reverse cholinergic deficits in L1. Rivastigmine and HMTM, and combinations of the two compounds were administered orally for 11 weeks to both L1 and wild-type mice. The brains were sectioned with a focus on the basal forebrain, motor cortex and hippocampus. Immunohistochemical staining and quantification of choline acetyltransferase (ChAT), tyrosine kinase A (TrkA)-positive neurons and relative optical intensity (ROI) for vesicular acetylcholine transporter (VAChT), and acetylcholinesterase (AChE) reactivity confirmed reversal of the diminished cholinergic phenotype of interneurons (nucleus accumbens, striatum) and projection neurons (medial septum, nucleus basalis magnocellularis) by HMTM, to a greater extent than by rivastigmine alone in L1 mice. Combined administration did not yield additivity but, in most proxies, led to antagonistic effects in which rivastigmine decreased the benefits shown with HMTM alone. Local markers (VAChT and AChE) in target structures of the basal forebrain, motor cortex and hippocampal CA3 seemed to be normalized by HMTM, but not by rivastigmine or the combination of both drugs. HMTM, which was developed as a tau aggregation inhibitor, strongly decreased the tau load in L1 mice, however, not in combination with rivastigmine. Taken together, these data confirm a cholinergic phenotype in L1 tau transgenic mice that resembles the deficits observed in AD patients. This phenotype is reversible by HMTM, but at the same time appears to be subject to a homeostatic regulation induced by chronic pre-treatment with an acetylcholinesterase inhibitor, which interferes with the efficacy of HMTM. The strongest phenotypic reversal coincided with a normalization of the tau load in the cortex and hippocampus of L1, suggesting that tau accumulation underpins the loss of cholinergic markers in the basal forebrain and its projection targets.

Hydromethylthionine rescues synaptic SNARE proteins in a mouse model of tauopathies: Interference by cholinesterase inhibitors.

In clinical trials for Alzheimer's disease (AD), hydromethylthionine mesylate (HMTM) showed reduced efficacy when administered as an add-on to symptomatic treatments, while it produced a significant improvement of cognitive function when taken as monotherapy. Interference of cholinesterase inhibition with HMTM was observed also in a tau transgenic mouse model, where rivastigmine reduced the pharmacological activity of HMTM at multiple brain levels including hippocampal acetylcholine release, synaptosomal glutamate release and mitochondrial activity. Here, we examined the effect of HMTM, given alone or in combination with the acetylcholinesterase inhibitor, rivastigmine, at the level of expression of selected pre-synaptic proteins (syntaxin-1; SNAP-25, VAMP-2, synaptophysin-1, synapsin-1, α-synuclein) in brain tissue harvested from tau-transgenic Line 1 (L1) and wild-type mice using immunohistochemistry. L1 mice overexpress the tau-core unit that induces tau aggregation and results in an AD-like phenotype. Synaptic proteins were lower in hippocampus and cortex but greater in basal forebrain regions in L1 compared to wild-type mice. HMTM partially normalised the expression pattern of several of these proteins in basal forebrain. This effect was diminished when HMTM was administered in combination with rivastigmine, where mean protein expression seemed supressed. This was further confirmed by group-based correlation network analyses where important levels of co-expression correlations in basal forebrain regions were lost in L1 mice and partially re-established when HMTM was given alone but not in combination with rivastigmine. These data indicate a reduction in pharmacological activity of HMTM when given as an add-on therapy, a result that is consistent with the responses observed in the clinic. Attenuation of the therapeutic effects of HMTM by cholinergic treatments may have important implications for other potential AD therapies.

Progress towards elimination of onchocerciasis in the Region du Sud-Ouest of Burkina Faso which was previously subject to a recrudescence event after vector control.

BACKGROUND: The Sud-Ouest region of Burkina Faso (especially the Bougouriba valley) has been historically problematic with respect to onchocerciasis control, with a recrudescence of infections after vector control carried out the WHO Onchocerciasis Control Programme was halted in 1989. After 1996, mass drug administration of ivermectin was instigated to control the recrudescence so that it would no longer constitute a public health problem. However, in 2010 WHO changed its recommended policy from control to elimination, and in 2013 biannual Community-Directed Treatment with Ivermectin (CDTI) was instigated. Epidemiological surveys were carried-out in 2011 and 2018 to determine whether CDTI was producing a decline in infection levels and progress towards elimination. METHODOLOGY/PRINCIPAL FINDINGS: A cross-sectional study was conducted across 20 villages in four health districts in 2011 and 29 villages in 2018. Individuals aged five years and above were examined by skin-snip, and the prevalence and microfilarial load was determined for each village. In 2011, 75% of villages had some infections and 20% had prevalences >5%, with a mean prevalence across all villages of 2.63% (range 0.0-9.7%), and community microfilarial load ranging from 0 to 0.25 microfilariae per biopsy. In 2018, nine villages (= 31% of total) had some infections, with prevalences ranging from 0.41% to 3.54%, and a mean prevalence across all villages of 0.37%. Community microfilarial load ranged from 0 to 0.1. Amongst those people found to be microfilarial positive, 87% had a history of migration. CONCLUSIONS/SIGNIFICANCE: The endemicity of onchocerciasis infection in the Sud-Ouest region has declined to low levels and seems to be progressing towards elimination. Our findings indicated that biannual CDTI is having good effect, but it should continue for a number of years to ensure elimination of transmission. However, progress towards elimination has a troublesome history in this region, and it would be advisable to select more sentinel villages to have confidence in any future epidemiological and entomological surveys, especially Stop-MDA surveys. With positive individuals migrating between countries, cross-border collaboration needs more attention to ensure effective treatment for onchocerciasis elimination.

LETC inhibits α-Syn aggregation and ameliorates motor deficiencies in the L62 mouse model of synucleinopathy.

Alpha-Synuclein (α-Syn) aggregation is a pathological feature of synucleinopathies, neurodegenerative disorders that include Parkinson's disease (PD). Here, we explored the efficacy of N,N,N',N'-tetraethyl-10H-phenothiazine-3,7-diamine dihydrochloride (LETC), a protein aggregation inhibitor, on α-Syn aggregation. In both cellular models and transgenic mice, α-Syn aggregation was achieved by the overexpression of full-length human α-Syn fused with a signal sequence peptide. α-Syn accumulated in transfected DH60.21 neuroblastoma cells and α-Syn aggregation was inhibited by LETC with an EC50 of 0.066 ± 0.047 µM. Full-length human α-Syn overexpressing Line 62 (L62) mice accumulated neuronal α-Syn that was associated with a decreased motor performance in the open field and automated home cage. LETC, administered orally for 6 weeks at 10 mg/kg significantly decreased α-Syn-positive neurons in multiple brain regions and this resulted in a rescue of movement deficits in the open field in these mice. LETC however, did not improve activity deficits of L62 mice in the home cage environment. The results suggest that LETC may provide a potential disease modification therapy in synucleinopathies through the inhibition of α-Syn aggregation.

Solubility of α-synuclein species in the L62 mouse model of synucleinopathy.

The accumulation of α-synuclein (α-Syn) into Lewy bodies is a hallmark of synucleinopathies, a group of neurological disorders that include Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Small oligomers as well as larger fibrils of α-Syn have been suggested to induce cell toxicity leading to a degenerative loss of neurones. A richer understanding of α-Syn aggregation in disease, however, requires the identification of the different α-Syn species and the characterisation of their biochemical properties. We here aimed at a more in-depth characterisation of the α-Syn transgenic mice, Line 62 (L62), and examined the deposition pattern and solubility of human and murine α-Syn in these mice using immunohistochemical and biochemical methods. Application of multiple antibodies confirmed mAb syn204 as the most discriminatory antibody for human α-Syn in L62. Syn204 revealed an intense and widespread immunohistochemical α-Syn labelling in parietal cortex and hippocampus, and to a lower level in basal forebrain and hindbrain regions. The labelled α-Syn represented somatic inclusions as well as processes and synaptic endings. Biochemical analysis revealed a Triton-resistant human α-Syn pool of large oligomers, a second pool of small oligomers that was not resistant to solubilization with urea/Triton. A third SDS-soluble pool of intermediate sized aggregates containing a mixture of both, human and mouse α-Syn was also present. These data suggest that several pools of α-Syn can exist in neurones, most likely in different cellular compartments. Information about these different pools is important for the development of novel disease modifying therapies aimed at α-Syn.

Assays for the Screening and Characterization of Tau Aggregation Inhibitors.

Aggregation of tau protein is a pathological hallmark of Alzheimer's disease and other neurodegenerative tauopathies. Inhibition of tau aggregation may provide a method for treatment of these disorders. Methods to identify tau aggregation inhibitors (TAIs) in vitro are useful and here we describe assays for TAIs using purified recombinant tau protein fragments in a cell-free immunoassay format and in a stably transfected cell model to create a more physiological environment.

Measuring susceptibility to use tobacco in an increasingly complex consumer marketplace: How many questions do we really need?

OBJECTIVE: Predicting which young people are likely to use tobacco in the future is critical for prevention and intervention. Although measures for assessing susceptibility to using tobacco have fulfilled this goal for decades, there is almost no standard for the number of items that should be administered, or which items should be administered for which products. This study explored whether brief but psychometrically sound versions of commonly used susceptibility measures can adequately capture the construct relative to longer measures. METHOD: A sample of young people (N = 451; Mage = 16.5 years; 64% females; 65% White) completed 33 susceptibility items, which are designed to assess susceptibility to use different types of tobacco products (cigarette, smokeless tobacco, vaping products, and little cigars/cigarillos) of various flavors (tobacco, menthol, and sweet). RESULTS: Analysis of these 33 items indicated that asking about the likelihood of using each tobacco product class when a best friend offers it (four items in all) captures 98.5% of information that is captured using the longer set of items; asking the best friend question for each product by each flavor category (11 items in all) captures 99.7% of the information. CONCLUSIONS: Depending on research needs, tobacco use susceptibility can be measured with little loss of information by administering a limited set of items assessing the likelihood that a young person will use a tobacco product if a friend offers it for any product-flavor combination. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Towards consistency in dietary pattern scoring: standardising scoring workflows for healthy dietary patterns using 24-h recall and two variations of a food frequency questionnair.

Healthy dietary patterns such as the Mediterranean diet (MeDi), Dietary Approaches to Stop Hypertension (DASH) and the Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) have been evaluated for their potential association with health outcomes. However, the lack of standardisation in scoring methodologies can hinder reproducibility and meaningful cross-study comparisons. Here we provide a reproducible workflow for generating the MeDi, DASH and MIND dietary pattern scores from frequently used dietary assessment tools including the 24-h recall tool and two variations of FFQ. Subjective aspects of the scoring process are highlighted and have led to a recommended reporting checklist. This checklist enables standardised reporting with sufficient detail to enhance the reproducibility and comparability of their outcomes. In addition to these aims, valuable insights in the strengths and limitations of each assessment tool for scoring the MeDi, DASH and MIND diet can be utilised by researchers and clinicians to determine which dietary assessment tool best meets their needs.

Does Reducing the Size of the Tobacco Power Wall Affect Young People's Risk of Future Use of Tobacco Products? An Experimental Investigation.

OBJECTIVE: A ban on tobacco power walls (in-store package displays) is unlikely in the United States because of concerns that such bans violate commercial free speech rights. This experiment evaluated the effectiveness of a more measured strategy for mitigating the influence of the power wall on young people's susceptibility to tobacco use: limiting its size. METHOD: The experiment took place in the RAND StoreLab, a life-sized replica of a convenience store. Participants (N = 275) ages 11-20 years were randomly assigned to shop in a variant of the StoreLab that had either a large (status quo), medium, or small power wall situated behind the checkout counter. Before and after shopping, participants completed measures of risk of future use of unflavored and flavored cigarettes and vaping products. RESULTS: Study condition was unrelated to future risk of smoking unflavored cigarettes, using menthol vaping products, and using sweet-flavored vaping products. Study condition was related to future risk of smoking menthol cigarettes and using unflavored vaping products; compared with exposure to a large power wall, exposure to a small power wall increased the odds of a participant's being at risk for future smoking of menthol cigarettes (odds ratio [OR] = 3.29, 95% CI [1.10, 9.83]) and the odds of a participant's being at risk for using unflavored vaping products (OR = 4.09, 95% CI [1.41, 11.85]). CONCLUSIONS: These findings call into question the viability of reducing the size of the power wall as a singular strategy for dampening its effect on young people's susceptibility to tobacco use.

Mean Oral Cavity Organ-at-Risk Dose Predicts Opioid Use and Hospitalization during Radiotherapy for Patients with Head and Neck Tumors.

BACKGROUND: Approximately 75% of all head and neck cancer patients are treated with radiotherapy (RT). RT to the oral cavity results in acute and late adverse events which can be severe and detrimental to a patient's quality of life and function. The purpose of this study was to explore associations between RT dose to a defined oral cavity organ-at-risk (OAR) avoidance structure, provider- and patient-reported outcomes (PROs), opioid use, and hospitalization. METHODS: This was a retrospective analysis of prospectively obtained outcomes using multivariable modeling. The study included 196 patients treated with RT involving the oral cavity for a head and neck tumor. A defined oral cavity OAR avoidance structure was used in all patients for RT treatment planning. Validated PROs were collected prospectively. Opioid use and hospitalization were abstracted electronically from medical records. RESULTS: Multivariable modeling revealed the mean dose to the oral cavity OAR was significantly associated with opioid use (p = 0.0082) and hospitalization (p = 0.0356) during and within 30 days of completing RT. CONCLUSIONS: The findings of this study may be valuable in RT treatment planning for patients with tumors of the head and neck region to reduce the need for opioid use and hospitalization during treatment.

Doing more with less: A proposal to advance cigarette packaging regulations in the United States.

Cigarette packages are potent marketing tools. Following guidance from the WHO Framework Convention on Tobacco Control, many countries have sought to diminish this marketing power by mandating that (1) large graphic health warnings be affixed to the packages (i.e., text warnings combined with graphic images of the health consequences of smoking) and (2) all packages be fully "plain" in their design (i.e., all packages use the same drab/bland color and font type; no brand logos, other colors, or designs are permitted). Yet, the United States lags other countries in implementing regulations designed to blunt the marketing power of cigarette packages. This is not because of a lack of effort on the part of the Food and Drug Administration, the main governmental body charged with regulating tobacco products in the United States. Rather, it is because the regulatory options that that have been advanced in the country (e.g., graphic health warnings) have not been found - yet - to be legally feasible by its courts. This commentary works through some of the conceptual, practical, and legal issues regarding packaging regulations in the United States. It considers the political and bureaucratic risks involved with issuing new regulations. The overall intent is to prompt our field to think creatively about what is realistic in this regulatory space and to offer a novel perspective that may help move the United States tobacco control community forward in its efforts to reduce the promotional power of cigarette packages.

A Meta-Analysis on Presynaptic Changes in Alzheimer's Disease.

BACKGROUND: A key aspect of synaptic dysfunction in Alzheimer's disease (AD) is loss of synaptic proteins. Previous publications showed that the presynaptic machinery is more strongly affected than postsynaptic proteins. However, it has also been reported that presynaptic protein loss is highly variable and shows region- and protein-specificity. OBJECTIVE: The objective of this meta-analysis was to provide an update on the available literature and to further characterize patterns of presynaptic protein loss in AD. METHODS: Systematic literature search was conducted for studies published between 2015-2022 which quantified presynaptic proteins in postmortem tissue from AD patients and healthy controls. Three-level random effects meta-analyses of twenty-two identified studies was performed to characterize overall presynaptic protein loss and changes in specific regions, proteins, protein families, and functional categories. RESULTS: Meta-analysis confirmed overall loss of presynaptic proteins in AD patients. Subgroup analysis revealed region specificity of protein loss, with largest effects in temporal and frontal cortex. Results concerning different groups of proteins were also highly variable. Strongest and most consistently affected was the family of synaptosome associated proteins, especially SNAP25. Among the most severely affected were proteins regulating dense core vesicle exocytosis and the synaptic vesicle cycle. CONCLUSIONS: Results confirm previous literature related to presynaptic protein loss in AD patients and provide further in-depth characterization of most affected proteins and presynaptic functions.

Epizootic of enterocolitis and clostridial overgrowth in NSG and NSG-related mouse strains.

While the immunodeficient status of NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) and NSG-related mice provides utility for numerous research models, it also results in increased susceptibility to opportunistic pathogens. Over a 9-week period, a high rate of mortality was reported in a housing room of NSG and NSG-related mice. Diagnostics were performed to determine the underlying etiopathogenesis. Mice submitted for evaluation included those found deceased (n = 2), cage mates of deceased mice with or without diarrhea (n = 17), and moribund mice (n = 8). Grossly, mice exhibited small intestinal and cecal dilation with abundant gas and/or digesta (n = 18), serosal hemorrhage and congestion (n = 6), or were grossly normal (n = 3). Histologically, there was erosive to ulcerative enterocolitis (n = 7) of the distal small and large intestine or widespread individual epithelial cell death with luminal sloughing (n = 13) and varying degrees of submucosal edema and mucosal hyperplasia. Cecal dysbiosis, a reduction in typical filamentous bacteria coupled with overgrowth of bacterial rods, was identified in 18 of 24 (75%) mice. Clostridium spp. and Paeniclostridium sordellii were identified in 13 of 23 (57%) and 7 of 23 (30%) mice, respectively. Clostridium perfringens (7 of 23, 30%) was isolated most frequently. Toxinotyping of C. perfringens positive mice (n = 2) identified C. perfringens type A. Luminal immunoreactivity to several clostridial species was identified within lesioned small intestine by immunohistochemistry. Clinicopathologic findings were thus associated with overgrowth of various clostridial species, though direct causality could not be ascribed. A diet shift preceding the mortality event may have contributed to loss of intestinal homeostasis.

Patterns and distribution of regional nodal involvement and recurrence in a surgically treated oropharyngeal squamous cell carcinoma cohort at a tertiary center.

OBJECTIVES: To investigate and describe the patterns of regional metastases and recurrences after surgical treatment of oropharyngeal squamous cell cancer (OPSCC). MATERIALS AND METHODS: Retrospective study of patients diagnosed with OPSCC from 2006 to 2021 at a tertiary referral center. Only patients treated with surgery including a neck dissection were included. Patients with unknown human papillomavirus (HPV) status, prior head and neck cancer, distant metastases, or synchronous head and neck cancer were excluded. RESULTS: A total of 928 patients were included. 89% were males, the average age was 58.6 years (range: 25.2-87.5), 874 (94%) were HPV(+), and 513 (55.3%) had a tonsil cancer. Among cN + patients, the most commonly involved levels at presentation were level II (85.2%), level III (33.3%), and level IV (9.4%). In cN0 patients, metastases were only observed in level II (16.2%) and level III (9.2%). Nodal recurrence occurred in 48 (5.2%) patients after a median time of 1.0 years (interquartile range: 0.6-2.0). Nodal recurrence incidence was similar in HPV(+) and HPV(-) patients (5.0% vs. 7.4%, p = 0.44). The most common levels for regional recurrence were ipsilateral level II (45.8%), contralateral level II (43.8%), and ipsilateral level V (25.0%). Multivariable analysis revealed that pN was a significant predictor for regional recurrence (p = 0.02). CONCLUSION: There is no difference in the distribution of regional metastases and recurrences in HPV(+) and HPV(-) OPSCC patients. Our findings align with the established understanding that regional metastases predominantly manifest in the ipsilateral level II-IV at presentation. Moreover, the data support the clinical recommendation to restrict elective neck dissection in cN0 patients to ipsilateral levels IIa and III, excluding level IIb. Regional recurrence is significantly associated with pN status.

Exploring the Anti-Hypoxaemia Effect of Hydromethylthionine: A Prospective Study of Phase 3 Clinical Trial Participants.

Methylthioninium chloride (MTC) is a standard treatment for methaemoglobinaemia. A preparation of reduced MTC has been reported to increase blood oxygen saturation (SpO2) and lower respiratory rates in patients with severe COVID-19. We have developed a stable form of reduced methylthionine (hydromethylthionine-mesylate, HMTM) having a benign safety profile in two Phase 3 trials in Alzheimer's disease. The aim of this prospective study was to determine the effects of oral HMTM on SpO2 and methaemoglobin (metHb) levels in a cohort of patients with mild hypoxaemia not due to COVID-19. Eighteen participants randomised to a single dose of 4, 75, 100 or 125 mg doses of HMTM had SpO2 levels below 94% at baseline. Patients were routinely monitored by pulse oximetry after 4 h, and after 2 and 6 weeks of twice daily dosing. Significant ~3% increases in SpO2 occurred within 4 h and were sustained over 2 and 6 weeks with no dose differences. There were small dose-dependent increases (0.060-0.162%) in metHb levels over 2 to 6 weeks. Minimum-energy computational chemistry revealed that HMT can bind within 2.10 Å of heme iron by donating a pair of electrons from the central nitrogen of HMT to d orbitals of heme iron, but with lower affinity than oxygen. In conclusion, HMTM can increase SpO2 without reducing metHb by acting as a strong displaceable field ligand for heme iron. We hypothesise that this facilitates a transition from the low oxygen affinity T-state of heme to the higher affinity R-state. HMTM has potential as an adjunctive treatment for hypoxaemia.