Myeloid cell expression of CD200R is modulated in active TB disease and regulates Mycobacterium tuberculosis infection in a biomimetic model.

A robust immune response is required for resistance to pulmonary tuberculosis (TB), the primary disease caused by Mycobacterium tuberculosis (Mtb). However, pharmaceutical inhibition of T cell immune checkpoint molecules can result in the rapid development of active disease in latently infected individuals, indicating the importance of T cell immune regulation. In this study, we investigated the potential role of CD200R during Mtb infection, a key immune checkpoint for myeloid cells. Expression of CD200R was consistently downregulated on CD14+ monocytes in the blood of subjects with active TB compared to healthy controls, suggesting potential modulation of this important anti-inflammatory pathway. In homogenized TB-diseased lung tissue, CD200R expression was highly variable on monocytes and CD11b+HLA-DR+ macrophages but tended to be lowest in the most diseased lung tissue sections. This observation was confirmed by fluorescent microscopy, which showed the expression of CD200R on CD68+ macrophages surrounding TB lung granuloma and found expression levels tended to be lower in macrophages closest to the granuloma core and inversely correlated with lesion size. Antibody blockade of CD200R in a biomimetic 3D granuloma-like tissue culture system led to significantly increased Mtb growth. In addition, Mtb infection in this system reduced gene expression of CD200R. These findings indicate that regulation of myeloid cells via CD200R is likely to play an important part in the immune response to TB and may represent a potential target for novel therapeutic intervention.

Acupuncture for Chronic Radiation-Induced Xerostomia in Head and Neck Cancer: A Multicenter Randomized Clinical Trial.

Importance: Patients with head and neck cancer who undergo radiotherapy can develop chronic radiation-induced xerostomia. Prior acupuncture studies were single center and rated as having high risk of bias, making it difficult to know the benefits of acupuncture for treating radiation-induced xerostomia. Objective: To compare true acupuncture (TA), sham acupuncture (SA), and standard oral hygiene (SOH) for treating radiation-induced xerostomia. Design, Setting, and Participants: A randomized, blinded, 3-arm, placebo-controlled trial was conducted between July 29, 2013, and June 9, 2021. Data analysis was performed from March 9, 2022, through May 17, 2023. Patients reporting grade 2 or 3 radiation-induced xerostomia 12 months or more postradiotherapy for head and neck cancer were recruited from community-based cancer centers across the US that were part of the Wake Forest National Cancer Institute Community Oncology Research Program Research Base. Participants had received bilateral radiotherapy with no history of xerostomia. Interventions: Participants received SOH and were randomized to TA, SA, or SOH only. Participants in the TA and SA cohorts were treated 2 times per week for 4 weeks. Those experiencing a minor response received another 4 weeks of treatment. Main Outcomes and Measures: Patient-reported outcomes for xerostomia (Xerostomia Questionnaire, primary outcome) and quality of life (Functional Assessment of Cancer Therapy-General) were collected at baseline, 4 (primary time point), 8, 12, and 26 weeks. All analyses were intention to treat. Results: A total of 258 patients (201 men [77.9%]; mean [SD] age, 65.0 [9.16] years), participated from 33 sites across 13 states. Overall, 86 patients were assigned to each study arm. Mean (SD) years from diagnosis was 4.21 (3.74) years, 67.1% (n = 173) had stage IV disease. At week 4, Xerostomia Questionnaire scores revealed significant between-group differences, with lower Xerostomia Questionnaire scores with TA vs SOH (TA: 50.6; SOH: 57.3; difference, -6.67; 95% CI, -11.08 to -2.27; P = .003), and differences between TA and SA (TA: 50.6; SA: 55.0; difference, -4.41; 95% CI, -8.62 to -0.19; P = .04) yet did not reach statistical significance after adjustment for multiple comparisons. There was no significant difference between SA and SOH. Group differences in Functional Assessment of Cancer Therapy-General scores revealed statistically significant group differences at week 4, with higher scores with TA vs SOH (TA: 101.6; SOH: 97.7; difference, 3.91; 95% CI, 1.43-6.38; P = .002) and at week 12, with higher scores with TA vs SA (TA: 102.1; SA: 98.4; difference, 3.64; 95% CI, 1.10-6.18; P = .005) and TA vs SOH (TA: 102.1; SOH: 97.4; difference, 4.61; 95% CI, 1.99-7.23; P = .001). Conclusions and Relevance: The findings of this trial suggest that TA was more effective in treating chronic radiation-induced xerostomia 1 or more years after the end of radiotherapy than SA or SOH. Trial Registration: ClinicalTrials.gov Identifier: NCT02589938.

96-week retention in treatment with extended-release subcutaneous buprenorphine depot injections among people with opioid dependence: Extended follow-up after a single-arm trial.

BACKGROUND: The most recent formulation of buprenorphine treatment is extended-release depot injections (BUP-XR) that are administered subcutaneously by health care professionals. This study aimed to observe treatment outcomes of BUP-XR delivered in standard practice during a 96-week follow-up period in a community setting. METHODS: This study is an extension of the CoLAB study, a prospective single-arm, multicentre, open label trial (N=100, 7 sites in Australia) among people with opioid dependence who received monthly injections of BUP-XR to evaluate the retention in treatment. Participants were followed for 96 weeks, comprising 48 weeks of the CoLAB study followed by a 48-week extension. RESULTS: Of 100 participants at baseline, 47 were retained on BUP-XR at 96 weeks. The median time retained on monthly depot was 90 weeks. Heroin use (adjusted OR=0.19, P=0.012) in the month prior to baseline was associated with lower odds of retention on BUP-XR. Older age at first opioid use (adjusted OR= 1.08, P=0.009) and longer duration in OAT at baseline (adjusted OR= 1.12, P=0.001) were associated with increased retention. Prevalence of past four-weeks opioid use was estimated at 4% at 96 weeks of treatment (prevalence 0.04, 95%CI: 0.00-0.11) compared to 15% at baseline. Quality of life and medication treatment satisfaction improved over time for those retained in treatment. CONCLUSION: This is one of the few studies to describe long term (96 week) retention in treatment with BUP-XR in a community setting. It displayed retention rates with 47% of participants completing 96 weeks of treatment with BUP-XR. Patient reported outcomes suggest improvements in client wellbeing. FUNDING: Indivior.

Oral Toxicities Associated with Immune Checkpoint Inhibitors: Meta-Analyses of Clinical Trials.

Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment; however, their oral toxicity profile is not well elucidated. This review aimed to investigate the prevalence of oral toxicities including xerostomia, mucositis/stomatitis, dysgeusia, dysphagia, oral/oropharyngeal pain, oral infections, angular cheilitis, osteonecrosis, osteomyelitis, and oral mucosal reactions with ICIs. A review protocol was registered with PROSPERO (ID: CRD42023391674). A systematic search of ClinicalTrials.gov was conducted as of April 10, 2022. Studies were selected, assessed, and data extracted using PRISMA guidelines. Oral toxicity data were extracted from study arms using a single immunotherapy drug. Meta-analyses were conducted to summarize prevalence of oral toxicities using random-effects models. Of 750 screened records, 95 trials were included in the meta-analysis with published results. Time between study completion and first publication on ClinicalTrials.gov was 1 to 146 months (mean = 20.3, SD = 18.4). Weighted pooled prevalence was 5% (95% CI: 4-6%) for xerostomia, 3% (95% CI: 3-4%) for mucositis/stomatitis, 3% (95% CI: 2-3%) for dysgeusia, 2% (95% CI: 1-2%) for dysphagia, 3% (95% CI: 2-4%) for oropharyngeal/oral pain, 2% (95% CI: 1-3%) for oral candidiasis, and 2% (95% CI: 0-4%) for angular cheilitis. Subgroup differences based on ICI drugs were minimal. No trials reported lichenoid or pemphigoid mucosal reactions. Meta-analysis results revealed low prevalence of oral toxicities with ICIs; however, data reporting was limited and inconsistent. Limitations of study dataset reveal a significant need for systematic collection of oral morbidity data as well as improved consistency and compliance of reporting results on ClinicalTrials.gov.

Health utility among people who regularly use opioids in Australia.

INTRODUCTION: Studies of health utilities among people who use opioids have mostly been based on in-treatment populations. We aim to report utility-based quality of life by participants' socio-demographic, drug and treatment characteristics, and to examine the determinants of health utility among people who use opioids regularly. METHODS: Cross-sectional study of participants who used opioids regularly, recruited across New South Wales, Victoria and Tasmania in 2018-2019. Differences in European Quality of Life (EQ-5D-5L) heath utility scores between socio-demographic and clinical subgroups were assessed using non-parametric Kruskal-Wallis test by rank. To address the unique distribution of EQ-5D-5L health utility scores in the current sample, a two-part model was applied to assess factors associated with health utility. RESULTS: Among 402 participants enrolled in the study, 385 (96%) completed the EQ-5D-5L questionnaire. The mean health utility of the total sample was 0.63 (SD 0.29). Participants who previously received opioid agonist treatment [OAT] (adj marginal effect (ME) -0.11; 95% confidence interval [CI] -0.20 to -0.02) and those currently in OAT (adj ME -0.13; 95% CI -0.22 to -0.06) reported lower health utility than those who had never received OAT. Participants who used both pharmaceutical opioids and benzodiazepines had lower health utility compared to no pharmaceutical opioids and no benzodiazepines use (adj ME -0.17; 95% CI -0.28 to -0.07). DISCUSSION AND CONCLUSIONS: Findings provide important health utility data for economic evaluations, useful for guiding allocation of resources for treatment strategies among people who use opioids. Lower health utilities among those using benzodiazepines and pharmaceutical opioids suggests interventions targeting these subgroups may be beneficial.

Effect of in vivo aging on the surface and electrochemical properties of magnetic attachments used in facial prostheses: A retrieval analysis study.

STATEMENT OF PROBLEM: Reasons associated with the failure of facial prosthesis are of major concern and may be associated with deterioration of both elastomeric materials and magnetic attachments. However, the extent of deterioration of these components is unclear. PURPOSE: The purpose of this in vitro study was to evaluate selected retrieved facial prostheses and provide information regarding the electrochemical characterization of the recovered magnetic attachments. MATERIAL AND METHODS: Five facial prostheses (RP1, RP2, RP3, RP4, RP5) fabricated at the University of Texas, M.D. Anderson Cancer Center were retrieved following clinical use. The intaglio and external surfaces of the prostheses along with the incorporated magnetic attachments were photographed. The areas with the detected failures on the retrieved prostheses, as well as the recovered magnetic attachments, were evaluated under a reflected light stereomicroscope at ×16 nominal magnification and photographed with a digital camera. Five magnetic attachments recovered from the prostheses (retrieved group RT) were evaluated for degradation of their corrosion resistance after electrochemical testing in artificial sweat solution and were compared with 5 unused magnetic attachments (control group, CT). To identify the elemental composition of the intact magnet surface, 1 specimen from the control group was investigated by X-ray energy dispersive spectroscopy (EDS). Means and standard deviations of the open circuit potential (EOCP), the zero-circuit potential (Ecorr), and Icorr were calculated and statistically analyzed by a t test (α=.05 for all tests). RESULTS: The main reasons of failure were discoloration, degradation and rupture of the silicone elastomer, marginal misfit, and delamination of the polyurethane sheet. Additional findings were tarnish and discoloration of the magnetic attachments accompanied by considerable smear build-up. EDS results verified the Ni plating of tested magnets. Electrochemical testing revealed that retrieved magnets showed significantly lower OCP (P<.001) and Ecorr (P<.001) but similar Icorr (P=0.083) while the pseudopassivity region of unused magnets vanished in the retrieved group, denoting a degradation of electrochemical properties after clinical use. CONCLUSIONS: In vivo aging exerts extended degradation on the elastomer part of facial prostheses as well as deterioration of their surface integrity and electrochemical properties.

Investigation of nasal epithelial cells as a surrogate for bronchial epithelial cells in the research of equine asthma.

Equine asthma, previously known as Recurrent Airway Obstruction (RAO) or Inflammatory Airway Disease (IAD), is an often-debilitating condition that may severely affect both performance and quality of life. Research is hindered by the low sample numbers of subjects recruited to studies, a consequence in part of the invasive nature of the sampling methods of bronchial brushing and biopsy. We present an alternative method of sampling equine airway epithelial cells, the 'nasal brush method' (NBM). Obtained by light brushing of the ventral meatus whilst the horse is under standing sedation, these cells express the same markers of differentiation as their deeper counterparts. Grown as 3-D spheroids or as air-liquid interface cultures, nasal epithelial cells are responsive to the inflammatory cytokine interleukin-13. This may be attenuated by modulation of the Notch signalling pathway using the gamma-secretase inhibitor Semagecestat; a previously unreported finding that cements the link between equine and human asthma research and strengthens the case for a One Health approach in researching asthma pathophysiology and therapeutic intervention.

Identification and Optimization of RNA-Splicing Modulators as Huntingtin Protein-Lowering Agents for the Treatment of Huntington's Disease.

Huntington's disease (HD) is caused by an expanded CAG trinucleotide repeat in exon 1 of the huntingtin (HTT) gene. We report the design of a series of HTT pre-mRNA splicing modulators that lower huntingtin (HTT) protein, including the toxic mutant huntingtin (mHTT), by promoting insertion of a pseudoexon containing a premature termination codon at the exon 49-50 junction. The resulting transcript undergoes nonsense-mediated decay, leading to a reduction of HTT mRNA transcripts and protein levels. The starting benzamide core was modified to pyrazine amide and further optimized to give a potent, CNS-penetrant, and orally bioavailable HTT-splicing modulator 27. This compound reduced canonical splicing of the HTT RNA exon 49-50 and demonstrated significant HTT-lowering in both human HD stem cells and mouse BACHD models. Compound 27 is a structurally diverse HTT-splicing modulator that may help understand the mechanism of adverse effects such as peripheral neuropathy associated with branaplam.

A nondepleting anti-CD19 antibody impairs B cell function and inhibits autoimmune diseases.

B cells contribute to multiple aspects of autoimmune disorders, and B cell-targeting therapies, including B cell depletion, have been proven to be efficacious in treatment of multiple autoimmune diseases. However, the development of novel therapies targeting B cells with higher efficacy and a nondepleting mechanism of action is highly desirable. Here we describe a nondepleting, high-affinity anti-human CD19 antibody LY3541860 that exhibits potent B cell inhibitory activities. LY3541860 inhibits B cell activation, proliferation, and differentiation of primary human B cells with high potency. LY3541860 also inhibits human B cell activities in vivo in humanized mice. Similarly, our potent anti-mCD19 antibody also demonstrates improved efficacy over CD20 B cell depletion therapy in multiple B cell-dependent autoimmune disease models. Our data indicate that anti-CD19 antibody is a highly potent B cell inhibitor that may have potential to demonstrate improved efficacy over currently available B cell-targeting therapies in treatment of autoimmune conditions without causing B cell depletion.

Many leveled ordinal models for frequency of alcohol and drug use.

Background: The numbers of days people consume alcohol and other drugs over a fixed interval, such as 28 days, are often collected in surveys of substance use. The presence of an upper bound on these variables can result in response distributions with "ceiling effects." Also, if some peoples' substance use behaviors are characterized by weekly patterns of use, summaries of substance days-of-use over longer periods can exhibit multiple modes.Objective: To highlight advantages of ordinal models with a separate level for each distinct survey response, for bounded, and potentially multimodal, count data.Methods: We fitted a Bayesian proportional odds ordinal model to longitudinal cannabis days-of-use reported by 443 individuals who used illicit drugs (206 female, 214 male, 23 non-binary). We specified an ordinal level for each unique response to allow the exact numeric distribution implied by the predicted ordinal response to be inferred. We then compared the fit of the proportional odds model with binomial, negative binomial, hurdle negative binomial and beta-binomial models.Results: Posterior predictive checks and the leave one out information criterion both suggested that the proportional odds model gave a better fit to the cannabis days-of-use data than the other models. Cannabis use among the target population declined during the COVID-19 pandemic in Australia, with the odds of a member of the population exceeding any specified frequency of cannabis use in Wave 4 estimated to be 73% lower than in Wave 1 (median odds ratio 0.27, 90% credible interval 0.19, 0.38).Conclusion: Ordinal models can be suitable for complex count data.

Effect of spatial arrangement and clinical service lifetime simulation on the retention of magnetic units used in implant-anchored orbital prostheses.

STATEMENT OF PROBLEM: Evidence for the optimal spatial arrangement of magnetic attachments in implant-supported orbital prostheses is lacking. PURPOSE: The purpose of this in vitro study was to assess the effect of 6 different spatial arrangements on the retentive force of magnetic attachments following the in vitro simulation of clinical service by insertion-removal test cycles and the contribution of artificial aging to the morphological alterations induced on the magnetic surfaces. MATERIAL AND METHODS: Ni-Cu-Ni plated disk-shaped neodymium (Nd) magnetic units (d=5 mm, h=1.6 mm) were secured on leveled (50×50×5 mm, n=3) and angled (40×45×40 mm, interior angle=90 degrees, n=3) pairs of test panels in 6 different spatial arrangements: triangular_leveled (TL), triangular_angled (TA), square_leveled (SL), square_angled (SA), circular_leveled (CL), and circular_angled (CA) generating corresponding test assemblies (N=6). TL and TA arrangements included 3 magnetic units (3-magnet groups) and SL, SA, CL, and CA 4 (4-magnet groups). The retentive force (N) was measured at a mean crosshead speed of 10 mm/min (n=10). Each test assembly was subjected to insertion-removal test cycles with a 9-mm amplitude, ν=0.1 Hz, and n=10 consequent retentive force measurements at a crosshead speed of 10 mm/min at 540, 1080, 1620, and 2160 test cycles. Surface roughness alterations following the 2160 test cycles were measured by calculating the Sa, Sz, Sq, Sdr, Sc, and Sv parameters with an optical interferometric profiler with 5 new magnetic units used as a control group. Data were analyzed with 1-way ANOVA and Tukey HSD post hoc tests (α=.05). RESULTS: The 4-magnet groups had statistically significantly higher retentive force than the 3-magnet ones at baseline and following the 2160 test cycles (P<.05). In the 4-magnet group, the ranking at baseline was SA.05). CONCLUSIONS: Four magnetic attachments placed on an SL spatial arrangement resulted in the highest retention force but presented with the highest force reduction following the in vitro simulation of clinical service by insertion-removal test cycles.

Mapping the evidence of the effects of environmental factors on the prevalence of antibiotic resistance in the non-built environment: Protocol for a systematic evidence map.

BACKGROUND: Human, animal, and environmental health are increasingly threatened by the emergence and spread of antibiotic resistance. Inappropriate use of antibiotic treatments commonly contributes to this threat, but it is also becoming apparent that multiple, interconnected environmental factors can play a significant role. Thus, a One Health approach is required for a comprehensive understanding of the environmental dimensions of antibiotic resistance and inform science-based decisions and actions. The broad and multidisciplinary nature of the problem poses several open questions drawing upon a wide heterogeneous range of studies. OBJECTIVE: This study seeks to collect and catalogue the evidence of the potential effects of environmental factors on the abundance or detection of antibiotic resistance determinants in the outdoor environment, i.e., antibiotic resistant bacteria and mobile genetic elements carrying antibiotic resistance genes, and the effect on those caused by local environmental conditions of either natural or anthropogenic origin. METHODS: Here, we describe the protocol for a systematic evidence map to address this, which will be performed in adherence to best practice guidelines. We will search the literature from 1990 to present, using the following electronic databases: MEDLINE, Embase, and the Web of Science Core Collection as well as the grey literature. We shall include full-text, scientific articles published in English. Reviewers will work in pairs to screen title, abstract and keywords first and then full-text documents. Data extraction will adhere to a code book purposely designed. Risk of bias assessment will not be conducted as part of this SEM. We will combine tables, graphs, and other suitable visualisation techniques to compile a database i) of studies investigating the factors associated with the prevalence of antibiotic resistance in the environment and ii) map the distribution, network, cross-disciplinarity, impact and trends in the literature.

The Etiology of Abnormal TSH in Veterans Cared by a VA Medical Center - One High Serum Thyrotropin is Associated with Higher 5-Years Mortality.

Objective: By analyzing the etiology of abnormal TSH in randomly selected veteran patients, we set our heart on improving future clinical care/management of the clinical/subclinical hyper- and hypothyroidism in the aging veteran population. Methods: A total of 1100 patients' charts in alphabetical order were selected. Excluded cases of insufficient information, 897 patients' charts were reviewed and analyzed for causes of abnormal TSH. Among them, 602 for the cause of low TSH (below 0.55 uU/mL) and 295 for high TSH (above 4.78 uU/mL) were reviewed retrospectively. Findings: Among the 1100 patients selected, 680 (61.8%) were 60 y or older (female=44, 6.8%); 420 were under 60 y (female=80, 19.0%); significantly more female patients were found in the younger age group (P<0.001). After excluding patients with insufficient data, the most common cause of suppressed TSH is iodine-induced, CT iodinated contrast and betadine use caused 35.0% in the older group (n=126) compared to 23.6% in the younger group(n=57) (P = 0.027). The significant difference is that older veterans received more contrast CTs (P < 0.05 compared to the younger group). In both age groups with concurrent FT4 study, we found four high FT4 among 90 studies, 4.4% overt hyperthyroidism. The second most common cause of suppressed TSH is due to thyroid hormone (TH) replacement in the older group (119 patients, 33.1%) with age > 60y, significantly more frequent compared to the younger group, P<0.001. There is significantly more overt hyperthyroidism, 27.8/%, than the iodine-load induced suppression of TSH, P<0.001, due to 17 patients on TSH suppression therapy after total thyroidectomy for thyroid cancer. Among the 295 patients with elevated TSH, the most common cause of high TSH was due to hypothyroidism on T4 replacement: a total of 128 (59.3%) in the older group (N=216) is, similar to 47 (59.5%) in the younger group (N=79). In both age groups, there were 139 patients with concomitant FT4 measurement; 17 overt hypothyroidism were found, 12.2%. No significant difference is seen in the two age groups. The next most common causes of elevated TSH are CT contrast infusion, 23 (10.6%) in the older group and 7 (8.9%) in the younger group. We find high TSH is associated with a higher death rate of 101/238 (42.4%) in a 5-year follow-up (from 2016 to 2021), as compared to low TSH of 68/238 (28.6%), in the older age group, p<0.03； both were significantly higher than the age- and sex-matched general US population, 19.7%, P<0.01. Conclusion: Even though most, ~ 90%, were subclinical, the suppressed and elevated TSH are associated with severe consequences in CV/CNS and immune-suppression complications in aging veterans. Therefore, cautious use (and more frequent check of TSH) of TH replacement and CT contrast in aging veterans is recommended. The alarming increase in 5 years death rate in older patients with elevated TSH deserves further study.

Colocation of Lipids, Drugs, and Metal Biomarkers Using Spatially Resolved Lipidomics with Elemental Mapping.

Elemental imaging is widely used for imaging cells and tissues but rarely in combination with organic mass spectrometry, which can be used to profile lipids and measure drug concentrations. Here, we demonstrate how elemental imaging and a new method for spatially resolved lipidomics (DAPNe-LC-MS, based on capillary microsampling and liquid chromatography mass spectrometry) can be used in combination to probe the relationship between metals, drugs, and lipids in discrete areas of tissues. This new method for spatial lipidomics, reported here for the first time, has been applied to rabbit lung tissues containing a lesion (caseous granuloma) caused by tuberculosis infection. We demonstrate how elemental imaging with spatially resolved lipidomics can be used to probe the association between ion accumulation and lipid profiles and verify local drug distribution.

Uptake of baits by wild badgers: Influences of deployment method, badger age and activity patterns on potential delivery of an oral vaccine.

In parts of the United Kingdom and Ireland, the European badger is a wildlife host for Mycobacterium bovis (the causative agent of bovine tuberculosis). Badger vaccination is one management option for reducing disease spread. Vaccination is currently achieved by parenteral vaccination of captured badgers, but an oral vaccine delivered in a bait may provide an additional approach in the future. We conducted two field experiments in wild badger populations to identify factors that influence uptake (% of individuals with evidence of bait consumption) of candidate oral vaccine baits. In both instances, baits containing the biomarker iophenoxic acid (as a proxy for the vaccine) were fed at burrows (setts) associated with badger social groups (study A = 48 groups, study B = 40 groups). Badgers were captured following a period of bait deployment to quantify uptake in relation to age, sex and social group. In addition, groups were allocated different treatments and the bait deployment protocol was varied to identify effects on uptake. Study A tested the effects of season, bait type, bait placement and packaging, while study B investigated the effects of bait quantity and badger activity levels. Overall bait uptake was low (Study A = 24 %, Study B = 37 %) but this varied among treatment groups (range 0-58 %). In both studies, bait uptake was significantly higher in cubs than in adults. Uptake was substantially higher where baits were placed directly into sett entrances (rather than under tiles near setts), and by badgers caught at main setts rather than at outlier setts. Season, bait type and packaging did not influence uptake, while increasing the quantity of bait available increased uptake by cubs but not by adults. Levels of badger activity at setts varied over time (suggesting potential disturbance), but were positively associated with levels of bait uptake.

Potential to Use Fingerprints for Monitoring Therapeutic Levels of Isoniazid and Treatment Adherence.

A fingerprint offers a convenient, noninvasive sampling matrix for monitoring therapeutic drug use. However, a barrier to widespread adoption of fingerprint sampling is the fact that the sample volume is uncontrolled. Fingerprint samples (n = 140) were collected from patients receiving the antibiotic isoniazid as part of their treatment, as well as from a drug-naive control group (n = 50). The fingerprint samples were analyzed for isoniazid (INH) and acetylisoniazid (AcINH), using liquid chromatography high-resolution mass spectrometry. The data set was analyzed retrospectively for metabolites known to be present in eccrine sweat. INH or AcINH was detected in 89% of the fingerprints collected from patients and in 0% of the fingerprints collected from the control group. Metabolites lysine, ornithine, pyroglutamic acid, and taurine were concurrently detected alongside INH/AcINH and were used to determine whether the fingerprint sample was sufficient for testing. Given a sufficient sample volume, the fingerprint test for INH use has sensitivity, specificity, and accuracy of 100%. Normalization to taurine was found to reduce intradonor variability. Fingerprints are a novel and noninvasive approach to monitor INH therapy. Metabolites can be used as internal markers to demonstrate a sufficient sample volume for testing and reduce intradonor variability.

Simulating partial vaccine protection: BCG in badgers.

In wildlife disease management there are few diseases for which vaccination is a viable option. The human vaccine BCG has been used for the control of bovine tuberculosis in badgers since 2010 and is expected to increase. Understanding the long-term effects of repeated vaccination campaigns on disease prevalence is vital, but modelling thus far has generally assumed that a vaccine provides perfect protection to a proportion of the population, and that animals exposed to a repeated vaccination have a second independent chance of becoming protected. We held a workshop with experts in the field to obtain consensus over the main pathways for partial protection in the badger, and then simulated these using an established model. The available data supported the possibility that some individuals receive no benefit from the BCG vaccine, others may result in a delayed disease progression and in the remaining animals, vaccine protected the individual from any onward transmission. Simulating these pathways using different levels of overall efficacy demonstrated that partial protection leads to a reduced effect of vaccination, but in all of the identified scenarios it was still possible to eradicate disease in an isolated population with no disease introduction. We also identify those potential vaccination failures that require further investigation to determine which of our proposed pathways is the more likely.

Genetic susceptibility to patient-reported xerostomia among long-term oropharyngeal cancer survivors.

Genetic susceptibility for xerostomia, a common sequela of radiotherapy and chemoradiotherapy for head and neck cancer, is unknown. Therefore, to identify genetic variants associated with moderate to severe xerostomia, we conducted a GWAS of 359 long-term oropharyngeal cancer (OPC) survivors using 579,956 autosomal SNPs. Patient-reported cancer treatment-related xerostomia was assessed using the MD Anderson Symptom Inventory. Patient response was dichotomized as moderate to severe or none to mild symptoms. In our study, 39.2% of OPC survivors reported moderate to severe xerostomia. Our GWAS identified eight SNPs suggestively associated with higher risk of moderate to severe xerostomia in six genomic regions (2p13.3, rs6546481, Minor Allele (MA) = A, ANTXR1, P = 4.3 × 10-7; 5p13.2-p13.1, rs16903936, MA = G, EGFLAM, P = 5.1 × 10-6; 4q21.1, rs10518156, MA = G, SHROOM3, P = 7.1 × 10-6; 19q13.42, rs11882068, MA = G, NLRP9, P = 1.7 × 10-5; 12q24.33, rs4760542, MA = G, GLT1D1, P = 1.8 × 10-5; and 3q27.3, rs11714564, MA = G, RTP1, P = 2.9 × 10-5. Seven SNPs were associated with lower risk of moderate to severe xerostomia, of which only one mapped to specific genomic region (15q21.3, rs4776140, MA = G, LOC105370826, a ncRNA class RNA gene, P = 1.5 × 10-5). Although our small exploratory study did not reach genome-wide statistical significance, our study provides, for the first time, preliminary evidence of genetic susceptibility to xerostomia. Further studies are needed to elucidate the role of genetic susceptibility to xerostomia.

Effect of vaping on past-year smoking cessation success of Australians in 2019-evidence from a national survey.

BACKGROUND AND AIMS: Previous analyses of the effect of e-cigarettes on real world smoking cessation success have mainly been based on surveys undertaken in the United States and United Kingdom, where nicotine e-cigarettes can be readily obtained. In Australia, regulations have made obtaining e-cigarettes containing nicotine difficult. The effectiveness of e-cigarette use as a smoking cessation aid in Australia might therefore be lower than survey-based estimates published to date. This study aimed to estimate the effect of using e-cigarettes for a smoking cessation attempt on past-year smoking cessation success in Australia. DESIGN: Multivariable logistic regression models for past-year smoking cessation success. SETTING AND PARTICIPANTS: Respondents to the 2019 wave of Australia's National Drug Strategy Household Survey who made a smoking cessation attempt in the 12 months leading up to the survey. MEASUREMENTS: Past-year smoking cessation success was assumed if a smoking cessation attempt resulted in abstinence of more than a month at the time of the survey. FINDINGS: In 2019, Australians who attempted to quit smoking using e-cigarettes achieved greater success than smokers attempting to quit without e-cigarettes [adjusted odds ratio (aOR) = 1.68; 95% confidence interval (CI) = 1.09-2.60]. If people who only tried e-cigarettes once or twice are considered not to have used e-cigarettes, the estimated effect was slightly stronger (aOR = 1.98; 95% CI = 1.27-3.10). Also, the estimated odds ratio was higher among vapers who acquired their e-cigarettes from overseas websites (aOR = 2.24; 95% CI = 1.02-4.93). CONCLUSIONS: Use of e-cigarettes for a smoking cessation attempt appears to be associated with greater success among Australians who attempted to quit tobacco in 2019 compared with Australians attempting to quit without e-cigarettes, after adjusting for confounding effects.

The Use of Comparative Genomic Analysis for the Development of Subspecies-Specific PCR Assays for Mycobacterium abscessus.

Mycobacterium abscessus complex (MABC) is an important pathogen of immunocompromised patients. Accurate and rapid determination of MABC at the subspecies level is vital for optimal antibiotic therapy. Here we have used comparative genomics to design MABC subspecies-specific PCR assays. Analysis of single nucleotide polymorphisms and core genome multilocus sequence typing showed clustering of genomes into three distinct clusters representing the MABC subspecies M. abscessus, M. bolletii and M. massiliense. Pangenome analysis of 318 MABC genomes from the three subspecies allowed for the identification of 15 MABC subspecies-specific genes. In silico testing of primer sets against 1,663 publicly available MABC genomes and 66 other closely related Mycobacterium genomes showed that all assays had >97% sensitivity and >98% specificity. Subsequent experimental validation of two subspecies-specific genes each showed the PCR assays worked well in individual and multiplex format with no false-positivity with 5 other mycobacteria of clinical importance. In conclusion, we have developed a rapid, accurate, multiplex PCR-assay for discriminating MABC subspecies that could improve their detection, diagnosis and inform correct treatment choice.