Microcystin-LR activates serine/threonine kinases and alters the phosphoproteome in human HepaRG cells.

Microcystin-LR (MCLR) exposure has been associated with development of hepatocellular carcinoma (HCC). Many of the carcinogenic mechanisms for MCLR have been attributed to the induction of cell survival and proliferation through altered protein phosphorylation pathways by inhibition of protein phosphatases 1 (PP1) and PP2A. The current study determined MCLR effects on the phosphoproteome in human HepaRG cells. Differentiated HepaRG cells were treated with either vehicle or MCLR followed by phosphoproteomic analysis and Western blotting of MAPK-activated proteins. MCLR decreased cell viability at 24 h at doses as low as 0.03 µM. MCLR also caused a dose-dependent increase in phosphorylation of signaling and stress kinases. The number of decreased phosphosites by 0.1 µM MCLR was similar between the 2 h (212) and 24 h (154) timepoints. In contrast, a greater number of phosphosites were increased at 24 h (567) versus the 2 h timepoint (136), indicating the hyperphosphorylation state caused by MCLR-mediated inhibition of PPs is time-dependent. A kinase perturbation analysis predicted that MCLR exposure at both 2 h and 24 h increased the function of aurora kinase B (AURKB), checkpoint kinase 1 (CHEK1), and serum and glucocorticoid-regulated kinase 1 (SGK1). STRING database analysis of the phosphosites altered by MCLR exposure revealed pathways associated with cell proliferation and survival, including ribosomal protein S6 kinase (RSK), and vascular endothelial growth factor receptor (VEGFR2)-mediated vascular permeability. In addition, several cancer-related KEGG pathways were enriched at both 2 h and 24 h timepoints, and multiple cancer-related disease-gene associations were identified at the 24 h timepoint. Many of the kinases and pathways described above play crucial roles in the development of HCC by affecting processes such as invasion and metastasis. Overall, our data indicate that MCLR-mediated changes in protein phosphorylation involve biological pathways related to carcinogenesis that may contribute to the development of HCC.

The impact of exchanging the light and heavy chains on the structures of bovine ultralong antibodies.

The third complementary-determining regions of the heavy-chain (CDR3H) variable regions (VH) of some cattle antibodies are highly extended, consisting of 48 or more residues. These `ultralong' CDR3Hs form ß-ribbon stalks that protrude from the surface of the antibody with a disulfide cross-linked knob region at their apex that dominates antigen interactions over the other CDR loops. The structure of the Fab fragment of a naturally paired bovine ultralong antibody (D08), identified by single B-cell sequencing, has been determined to 1.6 Šresolution. By swapping the D08 native light chain with that of an unrelated antigen-unknown ultralong antibody, it is shown that interactions between the CDR3s of the variable domains potentially affect the fine positioning of the ultralong CDR3H; however, comparison with other crystallographic structures shows that crystalline packing is also a major contributor. It is concluded that, on balance, the exact positioning of ultralong CDR3H loops is most likely to be due to the constraints of crystal packing.

Knowledge of Patients' Activation Level Changes Expert US Physicians' Communication in GERD Management.

BACKGROUND: Gastroesophageal reflux disease (GERD) is common. Treatment is to manage symptoms, but medication nonadherence is common. To date, little emphasis has been on understanding patient behaviors and reasons for medication nonadherence. METHODS: We performed a cross-sectional survey study among expert gastroenterologists specializing in esophageal disease. Survey studies consisted of a 6-item questionnaire measuring physician knowledge of patient activation, the Clinician Support for Patient Activation Measure (CS-PAM), and an adapted 20-item Patient Assessment of Chronic Illness Care (PACIC). All question stems were specified to GERD management. RESULTS: Thirty-six experts participated. Most indicated hearing the term patient engagement before this survey (88.9%), but fewer were aware of the term patient activation (33.3%). Respondents were then made aware of the clinical significance of patient activation and asked, based on this knowledge, the likelihood that patients' activation level before the clinic would impact their communication. Responses varied between "to a great extent" and "not at all." Overall, CS-PAM activation scores were high, indicating a high level of support for patient activation. Lastly, respondents indicated their frequency of participating in partnership-building behaviors with patients. More than half (52.8%) of expert physicians "almost always" asked how GERD affected their lives, while less often asked patients about their health habits (22.2%), help set specific goals to improve their eating or exercise lifestyle (19.4%), or refer patients to a dietician, health educator, or counselor for their GERD (11.1%). CONCLUSION: Patient activation is an important strategy and may provide a behavioral approach to address medication adherence in GERD.

Functional lumen imaging probe use in a high-volume practice: Practical and technical implications.

BACKGROUND: The functional lumen imaging probe (FLIP) is a Food and Drug Administration approved tool to aid the diagnosis and management of esophageal disorders. However, widespread adoption of FLIP remains limited and its utility in high-volume practices remains unclear. AIM: To analyze large sample data on clinical use of FLIP and provide insight on several technical aspects when performing FLIP. METHODS: We conducted a retrospective comparative and descriptive analysis of FLIP procedures performed by a single provider at an academic medical center. There was a total of 398 FLIP procedures identified. Patient medical records were reviewed and data regarding demographics and procedural details were collected. Statistical tests, including chi-squared, t-test, and multivariable logistic and linear regression, were performed. RESULTS: There was an increase in FLIP cases with each successive time period of 13 months (n = 68, 146, 184, respectively) with notable rises specifically for indications of dysphagia and gastroesophageal reflux disease. There was a shift toward use of the longer FLIP balloon catheter for diagnostic purposes (overall 70.4% vs 29.6%, P < 0.01). Many cases (42.8%) were performed in conjunction with other diagnostics/interventions, such as dilation and wireless pH probe placement. Procedures were nearly equally performed with anesthesia vs moderate sedation (51.4% anesthesia), with no major complications. Patients who had anesthesia were less likely to have recurrent antegrade contractions [odds ratio (OR) = 0.4, 95%CI: 0.3-0.8] and were also more likely to have absent contractility (OR = 2.4, 95%CI: 1.3-4.4). CONCLUSION: FLIP cases have increased in our practice with expanding indications for its use. Given limited normative data, providers should be aware of several potential technical issues, including the possible impact of sedation choice when assessing esophageal motility patterns.

Martian atmospheric hydrogen and deuterium: Seasonal changes and paradigm for escape to space.

Mars' water history is fundamental to understanding Earth-like planet evolution. Water escapes to space as atoms, and hydrogen atoms escape faster than deuterium giving an increase in the residual D/H ratio. The present ratio reflects the total water Mars has lost. Observations with the Mars Atmosphere and Volatile Evolution (MAVEN) and Hubble Space Telescope (HST) spacecraft provide atomic densities and escape rates for H and D. Large increases near perihelion observed each martian year are consistent with a strong upwelling of water vapor. Short-term changes require processes in addition to thermal escape, likely from atmospheric dynamics and superthermal atoms. Including escape from hot atoms, both H and D escape rapidly, and the escape fluxes are limited by resupply from the lower atmosphere. In this paradigm for the escape of water, the D/H ratio of the escaping atoms and the enhancement in water are determined by upwelling water vapor and atmospheric dynamics rather than by the specific details of atomic escape.

Mechanisms of intestinal pharmacokinetic natural product-drug interactions.

The growing co-consumption of botanical natural products with conventional medications has intensified the need to understand potential effects on drug safety and efficacy. This review delves into the intricacies of intestinal pharmacokinetic interactions between botanical natural products and drugs, such as alterations in drug solubility, permeability, transporter activity, and enzyme-mediated metabolism. It emphasizes the importance of understanding how drug solubility, dissolution, and osmolality interplay with botanical constituents in the gastrointestinal tract, potentially altering drug absorption and systemic exposure. Unlike reviews that focus primarily on enzyme and transporter mechanisms, this article highlights the lesser known but equally important mechanisms of interaction. Applying the Biopharmaceutics Drug Disposition Classification System (BDDCS) can serve as a framework for predicting and understanding these interactions. Through a comprehensive examination of specific botanical natural products such as byakkokaninjinto, green tea catechins, goldenseal, spinach extract, and quercetin, we illustrate the diversity of these interactions and their dependence on the physicochemical properties of the drug and the botanical constituents involved. This understanding is vital for healthcare professionals to effectively anticipate and manage potential natural product-drug interactions, ensuring optimal patient therapeutic outcomes. By exploring these emerging mechanisms, we aim to broaden the scope of natural product-drug interaction research and encourage comprehensive studies to better elucidate complex mechanisms.

A comparative study of body size evolution in moths: evidence of correlated evolution with feeding and phenology-related traits.

Interspecific variation in body size is one of the most popular topics in comparative studies. Despite recent advances, little is known about the patterns and processes behind the evolution of body size in insects. Here, we used a robust data set comprising all geometrid moth species occurring in Northern Europe to examine the evolutionary associations involving body size and several life-history traits under an explicitly phylogenetic framework. We provided new insights into the interactive effects of life-history traits on body size and evidence of correlated evolution. We further established the sequence of trait evolution linking body size with the life-history traits correlated with it. We found that most (but not all) of the studied life-history traits, to some extent, influenced interspecific variation in body size, but interactive effects were uncommon. Both bi- and multivariate phylogenetic analyses indicated that larger species tend to be nocturnal flyers, overwinter in the larval stage, feed on the foliage of trees rather than herbs, and have a generalist feeding behaviour. We found evidence of correlated evolution involving body size with overwintering stage, host-plant growth form, and dietary specialization. The examination of evolutionary transitions within the correlated evolution models signalled that overwintering as larvae commonly preceded the evolution of large sizes, as did feeding on tree foliage and the generalist feeding behaviour. By showing that both body size and all life-history traits correlated with it evolve at very slow rates, we caution against uncritical attempts to propose causal explanations for respective associations based on contemporary ecological settings.

Structural and functional characterization of nanobodies that neutralize Omicron variants of SARS-CoV-2.

The Omicron strains of SARS-CoV-2 pose a significant challenge to the development of effective antibody-based treatments as immune evasion has compromised most available immune therapeutics. Therefore, in the 'arms race' with the virus, there is a continuing need to identify new biologics for the prevention or treatment of SARS-CoV-2 infections. Here, we report the isolation of nanobodies that bind to the Omicron BA.1 spike protein by screening nanobody phage display libraries previously generated from llamas immunized with either the Wuhan or Beta spike proteins. The structure and binding properties of three of these nanobodies (A8, H6 and B5-5) have been characterized in detail providing insight into their binding epitopes on the Omicron spike protein. Trimeric versions of H6 and B5-5 neutralized the SARS-CoV-2 variant of concern BA.5 both in vitro and in the hamster model of COVID-19 following nasal administration. Thus, either alone or in combination could serve as starting points for the development of new anti-viral immunotherapeutics.

Absorbable Biosynthetic Scaffolds in Place of Silicone for Breast Reconstruction: A 9-Year Experience with 53 Patients.

Background: Few series report on using fat grafting as the primary form of breast reconstruction. A 9-year experience with absorbable biosynthetic scaffolds, used in place of silicone implants, for breast reconstruction is reviewed. Methods: A clinical quality improvement approach was used to evaluate real-world data on a single plastic surgeon's experience treating breast reconstruction patients over a 7-year period. Results: Fifty-three patients had 74 breasts reconstructed, (following 51 therapeutic mastectomies and 23 prophylactic). Five of the 51 breasts (9.80 %) developed a local recurrence (mean follow-up of 4.5-5.5 years). This compared favorably with the practice's previous 6 years of silicone reconstructions. The most common complications were benign fat necrosis and oil cysts. More than 100 radiologic examinations were performed without interference by the absorbable implants. By 12-18 months post implantation, very little immune response was seen on histologic examinations of the biosynthetic scaffold constructs. Mature collagen and robust vascularity characterized the "mesh zone," whereas regenerated adipose tissue was seen in between and on top of the folded sheets of the implants. The average number of fat graft sessions in immediate reconstructions was 2.3, with a mean total fat graft volume of 551 mL, to restore an average mastectomy defect volume of 307 mL. Aesthetic outcomes were much better in the immediate reconstruction of nipple-sparing mastectomy group, which saw 68% achieve an A/B grade; 19%, C grade; and 13%, D/F on subjective grading. Conclusion: This composite strategy, using biosynthetic scaffold and autologous fat grafting, yielded outcomes equivalent to flap reconstructions with the ease of implants.

P-wave alternans rebound following pulmonary vein isolation predicts atrial arrhythmia recurrence.

INTRODUCTION: Numerous P-wave indices have been explored as biomarkers to assess atrial fibrillation (AF) risk and the impact of therapy with variable success. OBJECTIVE: We investigated the utility of P-wave alternans (PWA) to track the effects of pulmonary vein isolation (PVI) and to predict atrial arrhythmia recurrence. METHODS: This medical records study included patients who underwent PVI for AF ablation at our institution, along with 20 control subjects without AF or overt cardiovascular disease. PWA was assessed using novel artificial intelligence-enabled modified moving average (AI-MMA) algorithms. PWA was monitored from the 12-lead ECG at ~1 h before and ~16 h after PVI (n = 45) and at the 4- to 17-week clinically indicated follow-up visit (n = 30). The arrhythmia follow-up period was 955 ± 112 days. RESULTS: PVI acutely reduced PWA by 48%-63% (p < .05) to control ranges in leads II, III, aVF, the leads with the greatest sensitivity in monitoring PWA. Pre-ablation PWA was ~6 µV and decreased to ~3 µV following ablation. Patients who exhibited a rebound in PWA to pre-ablation levels at 4- to 17-week follow-up (p < .01) experienced recurrent atrial arrhythmias, whereas patients whose PWA remained reduced (p = .85) did not, resulting in a significant difference (p < .001) at follow-up. The AUC for PWA's prediction of first recurrence of atrial arrhythmia was 0.81 (p < .01) with 88% sensitivity and 82% specificity. Kaplan-Meier analysis estimated atrial arrhythmia-free survival (p < .01) with an adjusted hazard ratio of 3.4 (95% CI: 1.47-5.24, p < .02). CONCLUSION: A rebound in PWA to pre-ablation levels detected by AI-MMA in the 12-lead ECG at standard clinical follow-up predicts atrial arrhythmia recurrence.

Diagnostic accuracy of the Enferplex Bovine TB antibody test using individual milk samples from cattle.

Bovine tuberculosis is usually diagnosed using tuberculin skin tests or at post-mortem. Recently, we have developed a serological test for bovine tuberculosis in cattle which shows a high degree of accuracy using serum samples. Here, we have assessed the performance of the test using individual bovine milk samples. The diagnostic specificity estimate using the high sensitivity setting of the test was 99.7% (95% CI: 99.2-99.9). This estimate was not altered significantly by tuberculin boosting. The relative sensitivity estimates of the test using the high sensitivity setting in milk samples from comparative skin test positive animals was 90.8% (95% CI: 87.1-93.6) with boosting. In animals with lesions, the relative sensitivity was 96.0% (95% CI: 89.6-98.7). Analysis of paired serum and milk samples from skin test positive animals showed correlation coefficients ranging from 0.756-0.955 for individual antigens used in the test. Kappa analysis indicated almost perfect agreement between serum and milk results, while McNemar marginal homogeneity analysis showed no statistically significant differences between the two media. The positive and negative likelihood ratio were 347.8 (95% CI: 112.3-1077.5) and 0.092 (95% CI: 0.07-0.13) respectively for boosted samples from skin test positive animals. The results show that the test has high sensitivity and specificity in individual milk samples and thus milk samples could be used for the diagnosis of bovine tuberculosis.

Rifampin- and Silymarin-Mediated Pharmacokinetic Interactions of Exogenous and Endogenous Substrates in a Transgenic OATP1B Mouse Model.

Organic anion-transporting polypeptides (OATP) 1B1 and OATP1B3, encoded by the SLCO gene family of the solute carrier superfamily, are involved in the disposition of many exogenous and endogenous compounds. Preclinical rodent models help assess risks of pharmacokinetic interactions, but interspecies differences in transporter orthologs and expression limit direct clinical translation. An OATP1B transgenic mouse model comprising a rodent Slco1a/1b gene cluster knockout and human SLCO1B1 and SLCO1B3 gene insertions provides a potential physiologically relevant preclinical tool to predict pharmacokinetic interactions. Pharmacokinetics of exogenous probe substrates, pitavastatin and pravastatin, and endogenous OATP1B biomarkers, coproporphyrin-I and coproporphyrin-III, were determined in the presence and absence of known OATP/Oatp inhibitors, rifampin or silymarin (an extract of milk thistle [Silybum marianum]), in wild-type FVB mice and humanized OATP1B mice. Rifampin increased exposure of pitavastatin (4.6- and 2.8-fold), pravastatin (3.6- and 2.2-fold), and coproporphyrin-III (1.6- and 2.1-fold) in FVB and OATP1B mice, respectively, but increased coproporphyrin-I AUC0-24h only (1.8-fold) in the OATP1B mice. Silymarin did not significantly affect substrate AUC, likely because the silymarin flavonolignan concentrations were at or below their reported IC50 values for the relevant OATPs/Oatps. Silymarin increased the Cmax of pitavastatin 2.7-fold and pravastatin 1.9-fold in the OATP1B mice. The data of the OATP1B mice were similar to those of the pitavastatin and pravastatin clinical data; however, the FVB mice data more closely recapitulated pitavastatin clinical data than the data of the OATP1B mice, suggesting that the OATP1B mice are a reasonable, though costly, preclinical strain for predicting pharmacokinetic interactions when doses are optimized to achieve clinically relevant plasma concentrations.

Pharmacokinetic Effects of Different Models of Nonalcoholic Fatty Liver Disease in Transgenic Humanized OATP1B Mice.

Organic anion transporting polypeptide (OATP) 1B1 and OATP1B3 (collectively, OATP1B) transporters encoded by the solute carrier organic anion transporter (SLCO) genes mediate uptake of multiple pharmaceutical compounds. Nonalcoholic steatohepatitis (NASH), a severe form of nonalcoholic fatty liver disease (NAFLD), decreases OATP1B abundance. This research characterized the pathologic and pharmacokinetics effects of three diet- and one chemical-induced NAFLD model in male and female humanized OATP1B mice, which comprises knock-out of rodent Oatp orthologs and insertion of human SLCO1B1 and SLCO1B3. Histopathology scoring demonstrated elevated steatosis and inflammation scores for all NAFLD-treatment groups. Female mice had minor changes in SLCO1B1 expression in two of the four NAFLD treatment groups, and pitavastatin (PIT) area under the concentration-time curve (AUC) increased in female mice in only one of the diet-induced models. OATP1B3 expression decreased in male and female mice in the chemical-induced NAFLD model, with a coinciding increase in PIT AUC, indicating the chemical-induced model may better replicate changes in OATP1B3 expression and OATP substrate disposition observed in NASH patients. This research also tested a reported multifactorial pharmacokinetic interaction between NAFLD and silymarin, an extract from milk thistle seeds with notable OATP-inhibitory effects. Males showed no change in PIT AUC, whereas female PIT AUC increased 1.55-fold from the diet alone and the 1.88-fold from the combination of diet with silymarin, suggesting that female mice are more sensitive to pharmacokinetic changes than male mice. Overall, the humanized OATP1B model should be used with caution for modeling NAFLD and multifactorial pharmacokinetic interactions. SIGNIFICANCE STATEMENT: Advanced stages of NAFLD cause decreased hepatic OATP1B abundance and increase systemic exposure to OATP substrates in human patients. The humanized OATP1B mouse strain may provide a clinically relevant model to recapitulate these observations and predict pharmacokinetic interactions in NAFLD. This research characterized three diet-induced and one drug-induced NAFLD model in a humanized OATP1B mouse model. Additionally, a multifactorial pharmacokinetic interaction was observed between silymarin and NAFLD.

Green Tea Catechins Decrease Solubility of Raloxifene In Vitro and Its Systemic Exposure in Mice.

PURPOSE: Green tea is a widely consumed beverage. A recent clinical study reported green tea decreased systemic exposure of raloxifene and its glucuronide metabolites by 34-43%. However, the underlying mechanism(s) remains unknown. This study investigated a change in raloxifene's solubility as the responsible mechanism. METHODS: The effects of green tea extract, (-)-epigallocatechin gallate (EGCG), and (-)-epigallocatechin (EGC) on raloxifene's solubility were assessed in fasted state simulated intestinal fluids (FaSSIF) and fed state simulated intestinal fluids (FeSSIF). EGCG and EGC represent green tea's main bioactive constituents, flavan-3-gallate and flavan-3-ol catechins respectively, and the tested concentrations (mM) match the µg/mg of each compound in the extract. Our mouse study (n = 5/time point) evaluated the effect of green tea extract and EGCG on the systemic exposure of raloxifene. RESULTS: EGCG (1 mM) and EGC (1.27 mM) decreased raloxifene's solubility in FaSSIF by 78% and 13%, respectively. Micelle size in FaSSIF increased with increasing EGCG concentrations (> 1000% at 1 mM), whereas EGC (1.27 mM) did not change micelle size. We observed 3.4-fold higher raloxifene solubility in FeSSIF compared to FaSSIF, and neither green tea extract nor EGCG significantly affected raloxifene solubility or micelle size in FeSSIF. The mice study showed that green tea extract significantly decreased raloxifene Cmax by 44%, whereas EGCG had no effect. Green tea extract and EGCG did not affect the AUC0-24 h of raloxifene or the metabolite-to-parent AUC ratio. CONCLUSIONS: This study demonstrated flavan-3-gallate catechins may decrease solubility of poorly water-soluble drugs such as raloxifene, particularly in the fasted state.

Quality Indicator Development for the Approach to Ineffective Esophageal Motility: A Modified Delphi Study.

GOALS: Develop quality indicators for ineffective esophageal motility (IEM). BACKGROUND: IEM is identified in up to 20% of patients undergoing esophageal high-resolution manometry (HRM) based on the Chicago Classification. The clinical significance of this pattern is not established and management remains challenging. STUDY: Using RAND/University of California, Los Angeles Appropriateness Methods, we employed a modified-Delphi approach for quality indicator statement development. Quality indicators were proposed based on prior literature. Experts independently and blindly scored proposed quality statements on importance, scientific acceptability, usability, and feasibility in a 3-round iterative process. RESULTS: All 10 of the invited esophageal experts in the management of esophageal diseases invited to participate rated 12 proposed quality indicator statements. In round 1, 7 quality indicators were rated with mixed agreement, on the majority of categories. Statements were modified based on panel suggestion, modified further following round 2's virtual discussion, and in round 3 voting identified 2 quality indicators with comprehensive agreement, 4 with partial agreement, and 1 without any agreement. The panel agreed on the concept of determining if IEM is clinically relevant to the patient's presentation and managing gastroesophageal reflux disease rather than the IEM pattern; they disagreed in all 4 domains on the use of promotility agents in IEM; and had mixed agreement on the value of a finding of IEM during anti-reflux surgical planning. CONCLUSION: Using a robust methodology, 2 IEM quality indicators were identified. These quality indicators can track performance when physicians identify this manometric pattern on HRM. This study further highlights the challenges met with IEM and the need for additional research to better understand the clinical importance of this manometric pattern.

Temporal dynamics of the early immune response following Mycobacterium bovis infection of cattle.

Bovine tuberculosis is an infectious disease of global significance that remains endemic in many countries. Mycobacterium bovis infection in cattle is characterized by a cell-mediated immune response (CMI) that precedes humoral responses, however the timing and trajectories of CMI and antibody responses determined by newer generation assays remain undefined. Here we used defined-antigen interferon-gamma release assays (IGRA) and an eleven-antigen multiplex ELISA (Enferplex TB test) alongside traditional tuberculin-based IGRA and IDEXX M. bovis antibody tests to assess immune trajectories following experimental M. bovis infection of cattle. The results show CMI responses developed as early as two-weeks post-infection, with all infected cattle testing positive three weeks post-infection. Interestingly, 6 of 8 infected animals were serologically positive with the Enferplex TB assay as early as 4 weeks post-infection. As expected, application of the tuberculin skin test enhanced subsequent serological reactivity. Infrequent M. bovis faecal shedding was observed but was uncorrelated with observed immune trajectories. Together, the results show that early antibody responses to M. bovis infection are detectable in some individuals and highlight an urgent need to identify biomarkers that better predict infection outcomes, particularly for application in low-and-middle income countries where test-and-slaughter based control methods are largely unfeasible.

Enferplex bovine TB antibody test and bovine TB diagnosis: letter to the editor.

Bovine tuberculosis is usually diagnosed using tuberculin skin and interferon gamma tests. However, it is clear these tests miss infected animals due to poor sensitivity. The Enferplex Bovine TB antibody test has been validated by the World Organisation for Animal Health as fit for purpose in diagnosing bovine TB. A recent paper by Madden and colleagues (Veterinary Research Communications published online 17 August 2023) presented data on the future risk of Enferplex test antibody positive animals developing bovine TB. We argue in this communication that this does not make sense. Also, the study design did not include measuring antibodies at the point of censure of the animals and hence the survival analysis performed was meaningless. Most significantly, the study misses the point that skin and interferon gamma tests fail to detect a significant proportion of infected animals identified by the Enferplex test.

A decade of Campylobacter and Campylobacter bacteraemias in a district general hospital and the surrounding London and South East region, England.

BACKGROUND: Campylobacter bacteraemia is a rare complication of the most common bacterial gastrointestinal infection but is associated with significant morbidity and mortality. There is limited data describing current trends in surveillance and antimicrobial resistance for the Campylobacter strains involved. At the Epsom and St Helier's University Hospital (ESTH), we noted a marked increase in Campylobacter bacteraemia infections in 2021. METHODS: We extracted Campylobacter reports using the UK Health Security Agency's (UKHSA) Second Generation Surveillance System (laboratory reporting system) between 1st January 2012 and 31st December 2021. We reviewed patient records of patients with Campylobacter bacteraemia for details including presentation, past medical history, duration of hospital stay, and antibiotic use. RESULTS: Between 2012 and 2021, ESTH reported a total of 34 cases of Campylobacter bacteraemia. In 2021, the estimated incidence was 6.8 cases per 100,000 population and in the surrounding area, the incidence was 0.4 per 100,000 population. The incidence rate of Campylobacter bacteraemia in London and the South East region was significantly lower than ESTH (RR = 0.17, p < 0.0001). Campylobacter bacteraemia cases at ESTH reported a high number of co-morbidities (average number of comorbidities = 2.3) and had a duration of stay in hospital of a median of 7 days (IQR = 4-10 days). Campylobacter jejuni was the most commonly reported species for stool and blood Campylobacter in ESTH, London, and South East England. CONCLUSION: Campylobacter bacteraemia reports at ESTH were significantly (p < 0.001) higher than the surrounding London and South East region. While no common cause for the exceedance of Campylobacter bacteraemia has been identified, common risk factors for Campylobacter bacteraemia infection include underlying health conditions, being older, and male.

The Dubai Definition and Diagnostic Criteria of Laryngopharyngeal Reflux: The IFOS Consensus.

OBJECTIVE: The objective of this work was to gather an international consensus group to propose a global definition and diagnostic approach of laryngopharyngeal reflux (LPR) to guide primary care and specialist physicians in the management of LPR. METHODS: Forty-eight international experts (otolaryngologists, gastroenterologists, surgeons, and physiologists) were included in a modified Delphi process to revise 48 statements about definition, clinical presentation, and diagnostic approaches to LPR. Three voting rounds determined a consensus statement to be acceptable when 80% of experts agreed with a rating of at least 8/10. Votes were anonymous and the analyses of voting rounds were performed by an independent statistician. RESULTS: After the third round, 79.2% of statements (N = 38/48) were approved. LPR was defined as a disease of the upper aerodigestive tract resulting from the direct and/or indirect effects of gastroduodenal content reflux, inducing morphological and/or neurological changes in the upper aerodigestive tract. LPR is associated with recognized non-specific laryngeal and extra-laryngeal symptoms and signs that can be evaluated with validated patient-reported outcome questionnaires and clinical instruments. The hypopharyngeal-esophageal multichannel intraluminal impedance-pH testing can suggest the diagnosis of LPR when there is >1 acid, weakly acid or nonacid hypopharyngeal reflux event in 24 h. CONCLUSION: A global consensus definition for LPR is presented to improve detection and diagnosis of the disease for otolaryngologists, pulmonologists, gastroenterologists, surgeons, and primary care practitioners. The approved statements are offered to improve collaborative research by adopting common and validated diagnostic approaches to LPR. LEVEL OF EVIDENCE: 5 Laryngoscope, 134:1614-1624, 2024.