Public health case for microbiome-sparing antibiotics and new opportunities for drug development.

Although antibiotics remain a cornerstone of modern medicine, the issues of widespread antibiotic resistance and collateral damage to the microbiome from antibiotic use are driving a need for drug developers to consider more tailored, patient-directed products to avoid antibiotic-induced perturbations of the structure and function of the indigenous microbiota. This perspective summarizes a cascade of microbiome health effects that is initiated by antibiotic-mediated microbiome disruption at an individual level and ultimately leads to infection and transmission of multidrug-resistant pathogens across patient populations. The scientific evidence behind each of the key steps of this cascade is presented. The interruption of this cascade through the use of highly targeted, microbiome-sparing antibiotics aiming to improve health outcomes is discussed. Further, this perspective reflects on some key clinical trial design and reimbursement considerations to be addressed as part of the drug development path.

Survival Analysis of Patients with Severe Acute Malnutrition Admitted at the In-patient Therapeutic Care of the Bicol Regional Training and Teaching Hospital.

Background: Severe acute malnutrition (SAM) in children under five years remains a major global health concern. It carries a burden to the overall health of a child, contributes to mortality, and adds financial strain to the family and the hospital. The Philippine Integrated Management of Acute Malnutrition was established to address acute malnutrition in Filipino children. Objective: This study aimed to determine the factors affecting survival of patients admitted at Bicol Regional Training and Teaching Hospital (BRTTH) In-patient Therapeutic Care (ITC). Methods: This is a retrospective cohort study design utilizing survival analysis. Accrual period was from January 1, 2018 to December 31, 2018. Follow-up ended on March 31, 2019. There were 154 admissions and excluded 17 missing charts. Survival analysis was done utilizing STATA 14. Results: The prevalence of SAM requiring ITC admission was 3.0 percent. Majority belonged to 6-59 months of age (63%), with equal predilection for both sexes (1:1) and 71% came from the home province, Albay. Most of patients' caretakers had middle educational attainment. Sixty-eight percent (68%) were new patients, 16% readmitted, 15% transferred from the Out-patient Therapeutic Care (OTC) and <1% relapsed. The top three most common complications and co-morbidities include: pneumonia, low electrolytes, and fever. Sixty-three percent (63%) of patients at the ITC had a desirable treatment outcome, of which, 8% were cured and 55% transferred to OTC. Undesirable outcomes accounted for 37% of the cases which included non-cured, defaulter, and died at 12%, 8%, and 17%, respectively. The risk of dying was higher in SAM patients with parents having middle and low educational attainment as compared to those with high educational attainment (2-5 folds to 100-200 folds). SAM patients presenting with hypovolemic shock were likely to die by 1.5-19 times (1.5-19x) as compared to those without. SAM patients with malignancy were more likely to die 4-44 folds as compared to patients without malignancy. Conclusion and Recommendations: Educational attainment of parents, malignancy, and hypovolemic shock were significant predictors of mortality. We recommend prompt intervention by educating families, strengthen policies targeting socio-economic determinants, capacitate medical staff, refine current clinical practice guidelines and treatment pathways to reduce the number of children who die from severe acute malnutrition.

Nutritional support in pancreatic cancer patients and its effect on nutritional status: an observational regional HPB network study investigating current practice.

PURPOSE: Preoperative malnutrition is associated with poor postoperative outcomes in patients with pancreatic cancer. This study evaluated the effectiveness of current practice in nutritional support for patients with pancreatic cancer. METHODS: Observational multicenter HPB network study conducted at the Isala Clinics Zwolle, Medical Spectrum Twente, Medical Center Leeuwarden, and University Medical Center Groningen between October 2021 and May 2023. Patients with a suspected pancreatic malignancy scheduled for surgery were screened for malnutrition using the Patient-Generated Subjective Global Assessment (PG-SGA) questionnaire and referred to a dedicated dietician for nutritional support comprising pancreatic enzyme replacement therapy, dietary advice, and nutritional supplements to achieve adequate caloric and protein intake. At baseline, 1 day preoperatively, and 3 months postoperatively, the nutritional status and muscle thickness were evaluated. RESULTS: The study included 30 patients, of whom 12 (40%) classified as malnourished (PG-SGA ≥ 4) at baseline. Compared to well-nourished patients, malnourished patients were younger, were predominantly female, and had a higher body mass index, despite having lost more body weight in the past 6 months. All malnourished patients and 78% of the well-nourished patients received nutritional support. Consequently, a preoperative increase in caloric and protein intake and body weight were observed. Postoperatively, despite a further increase in caloric intake, a considerable decrease in protein intake, body weight, and muscle thickness was observed. CONCLUSION: Malnutrition is prevalent in patients undergoing pancreatic surgery. Nutritional support by a dedicated dietician is effective in enhancing patients' preoperative nutritional status. However, postoperative monitoring of adequate nutritional intake in patients could be improved.

Is ChatGPT an Accurate and Readable Patient Aid for Third Molar Extractions?

BACKGROUND: Artificial intelligence (AI) platforms such as Chat Generative Pre-Trained Transformer (ChatGPT) (Open AI, San Francisco, California, USA) have the capacity to answer health-related questions. It remains unknown whether AI can be a patient-friendly and accurate resource regarding third molar extraction. PURPOSE: The purpose was to determine the accuracy and readability of AI responses to common patient questions regarding third molar extraction. STUDY DESIGN, SETTING, SAMPLE: This is a cross sectional in-silico assessment of readability and soundness of a computer-generated report. INDEPENDENT VARIABLE: Not applicable. MAIN OUTCOME VARIABLES: Accuracy, or the ability to provide clinically correct and relevant information, was determined subjectively by 2 reviewers using a 5-point Likert scale, and objectively by comparing responses to American Association of Oral and Maxillofacial Surgeons (AAOMS) clinical consensus papers. Readability, or how easy a piece of text is to read, was assessed using the Flesch Kincaid Reading Ease (FKRE) and Flesch Kincaid Grade Level (FKGL). Both assess readability based on mean number of syllables per word, and words per sentence. To be deemed readable, FKRE should be >60 and FKGL should be <8. COVARIATES: Not applicable. ANALYSES: Descriptive statistics were used to analyze the findings of this study. RESULTS: AI-generated responses above the recommended level for the average patient (FKRE: 52; FKGL: 10). The average Likert score was 4.36, suggesting that most responses were accurate with minor inaccuracies or missing information. AI correctly deferred to the provider in instances where no definitive answer exists. Of the responses that addressed content in AAOMS consensus papers, 18/19 responses closely aligned with them. All prompts did not provide citations or references. CONCLUSION AND RELEVANCE: AI was able to provide mostly accurate responses, and content was closely aligned with AAOMS guidelines. However, responses were too complex for the average third molar extraction patient, and were deficient in citations and references. It is important for providers to educate patients on the utility of AI, and to decide whether to recommend using it for information. Ultimately, the best resource for answers is from the practitioners themselves because the AI platform lacks clinical experience.

Comparing 5-Fluorouracil Versus Modified Carnoy's Solution for the Treatment of Odontogenic Keratocysts: A Systematic Review and Meta-Analysis.

PURPOSE: The primary aim of this study was to compare time to odontogenic keratocyst (OKC) recurrence with 5-fluorouracil (5-FU) versus modified Carnoy's solution (MCS) following enucleation and curettage and peripheral ostectomy. The secondary aim was to compare the frequency (%) of permanent peripheral nerve injury characterized by hypoesthesia and neuropathic pain present at 12 months or more after surgery with 5-FU versus MCS. METHODS: The Cox hazard ratio was calculated to compare time to recurrence between the 2 groups. To compare the frequencies of permanent nerve damage, we fitted a fixed-effects model to the data and calculated the risk ratio. Other variables collected were sex, age, follow-up time, and cyst size. RESULTS: No significant differences in sex, age, follow-up time, and cyst size were found. The median follow-up time for all patients was 60 months (range: 12-180 months, Q1 = 32 months, Q3 = 86 months, interquartile range = 54 months). Of the 114 patients treated with MCS, 27 recurrences with a median recurrence time of 42 months (range = 12-108 months, Q1 = 26.3 months, Q3 = 54 months, interquartile range = 27.7 months) were recorded; no recurrences were observed among the 99 patients treated with 5-FU (hazard ratio = 0.02, 95% CI = 0.00018-0.16, P = 2.27e-07). Of the 112 patients treated with MCS, there were 20 (17.86%) instances of permanent peripheral nerve injury; of the 98 patients treated with 5-FU, there were 7 (7.14%) instances of permanent peripheral nerve injury (risk ratio = 0.44, 95% CI = 0.20-0.97, P = .04). CONCLUSION: The results of this meta-analysis significantly favored 5-FU over MCS for lower OKC recurrence and peripheral nerve injury, supporting the use of 5-FU as the superior adjuvant following enucleation and curettage and peripheral ostectomy for the treatment of OKCs.

Outcomes of the EMDataResource cryo-EM Ligand Modeling Challenge.

The EMDataResource Ligand Model Challenge aimed to assess the reliability and reproducibility of modeling ligands bound to protein and protein-nucleic acid complexes in cryogenic electron microscopy (cryo-EM) maps determined at near-atomic (1.9-2.5 Å) resolution. Three published maps were selected as targets: Escherichia coli beta-galactosidase with inhibitor, SARS-CoV-2 virus RNA-dependent RNA polymerase with covalently bound nucleotide analog and SARS-CoV-2 virus ion channel ORF3a with bound lipid. Sixty-one models were submitted from 17 independent research groups, each with supporting workflow details. The quality of submitted ligand models and surrounding atoms were analyzed by visual inspection and quantification of local map quality, model-to-map fit, geometry, energetics and contact scores. A composite rather than a single score was needed to assess macromolecule+ligand model quality. These observations lead us to recommend best practices for assessing cryo-EM structures of liganded macromolecules reported at near-atomic resolution.

Polyglutamine-mediated ribotoxicity disrupts proteostasis and stress responses in Huntington's disease.

Huntington's disease (HD) is a neurodegenerative disorder caused by expansion of a CAG trinucleotide repeat in the Huntingtin (HTT) gene, encoding a homopolymeric polyglutamine (polyQ) tract. Although mutant HTT (mHTT) protein is known to aggregate, the links between aggregation and neurotoxicity remain unclear. Here we show that both translation and aggregation of wild-type HTT and mHTT are regulated by a stress-responsive upstream open reading frame and that polyQ expansions cause abortive translation termination and release of truncated, aggregation-prone mHTT fragments. Notably, we find that mHTT depletes translation elongation factor eIF5A in brains of symptomatic HD mice and cultured HD cells, leading to pervasive ribosome pausing and collisions. Loss of eIF5A disrupts homeostatic controls and impairs recovery from acute stress. Importantly, drugs that inhibit translation initiation reduce premature termination and mitigate this escalating cascade of ribotoxic stress and dysfunction in HD.

Lessons learned from revision procedures: a case series pleading for reinforcement of the anterior hiatus in recurrent hiatal hernia.

BACKGROUND: Hiatal Hernia (HH) is a common structural defect of the diaphragm. Laparoscopic repair with suturing of the hiatal pillars followed by fundoplication has become standard practice. In an attempt to lower HH recurrence rates, mesh reinforcement, commonly located at the posterior site of the esophageal hiatus, has been used. However, effectiveness of posterior mesh augmentation is still up to debate. There is a lack of understanding of the mechanism of recurrence requiring further investigation. We investigated the anatomic location of HH recurrences in an attempt to assess why HH recurrence rates remain high despite various attempts with mesh reinforcement. METHODS: A retrospective case series of prospectively collected data from patients with hiatal hernia repair between 2012 and 2020 was performed. In total, 54 patients with a recurrent hiatal hernia operation were included in the study. Video clips from the revision procedure were analyzed by a surgical registrar and senior surgeon to assess the anatomic location of recurrent HH. For the assessment, the esophageal hiatus was divided into four equal quadrants. Additionally, patient demographics, hiatal hernia characteristics, and operation details were collected and analyzed. RESULTS: 54 patients were included. The median time between primary repair and revision procedure was 25 months (IQR 13-95, range 0-250). The left-anterior quadrant was involved in 43 patients (80%), the right-anterior quadrant in 21 patients (39%), the left-posterior quadrant in 21 patients (39%), and the right-posterior quadrant in 10 patients (19%). CONCLUSION: In this study, hiatal hernia recurrences occured most commonly at the left-anterior quadrant of the hiatus, however, posterior recurrences were not uncommon. Based on our results, we hypothesize that both posterior and anterior hiatal reinforcement might be a suitable solution to lower the recurrence rate of hiatal hernia. A randomized controlled trial using a circular, bio-absorbable mesh has been initiated to test our hypothesis.

Orbitofrontal high-gamma reflects spike-dissociable value and decision mechanisms.

The orbitofrontal cortex (OFC) plays a crucial role in value-based decision-making. While previous research has focused on spiking activity in OFC neurons, the role of OFC local field potentials (LFPs) in decision-making remains unclear. LFPs are important because they can reflect synaptic and subthreshold activity not directly coupled to spiking, and because they are potential targets for less invasive forms of brain-machine interface (BMI). We recorded LFPs and spiking activity using multi-channel vertical probes while monkeys performed a two-option value-based decision-making task. We compared the value- and decision-coding properties of high-gamma range LFPs (HG, 50-150 Hz) to the coding properties of spiking multi-unit activity (MUA) recorded concurrently on the same electrodes. Results show that HG and MUA both represent the values of decision targets, and that their representations have similar temporal profiles in a trial. However, we also identified value-coding properties of HG that were dissociable from the concurrently-measured MUA. On average across channels, HG amplitude increased monotonically with value, whereas the average value encoding in MUA was net neutral. HG also encoded a signal consistent with a comparison between the values of the two targets, a signal which was much weaker in MUA. In individual channels, HG was better able to predict choice outcomes than MUA; however, when simultaneously recorded channels were combined in population-based decoder, MUA provided more accurate predictions than HG. Interestingly, HG value representations were accentuated in channels in or near shallow cortical layers, suggesting a dissociation between neuronal sources of HG and MUA. In summary, we find that HG signals are dissociable from MUA with respect to cognitive variables encoded in prefrontal cortex, evident in the monotonic encoding of value, stronger encoding of value comparisons, and more accurate predictions about behavior. High-frequency LFPs may therefore be a viable - or even preferable - target for BMIs to assist cognitive function, opening the possibility for less invasive access to mental contents that would otherwise be observable only with spike-based measures.

The Difficulty of Detecting Occult Metastases in Patients with Potentially Resectable Pancreatic Cancer: Development and External Validation of a Preoperative Prediction Model.

Occult metastases are detected in 10-15% of patients during exploratory laparotomy for pancreatic cancer. This study developed and externally validated a model to predict occult metastases in patients with potentially resectable pancreatic cancer. Model development was performed within the Dutch Pancreatic Cancer Audit, including all patients operated for pancreatic cancer (January 2013-December 2017). Multivariable logistic regression analysis based on the Akaike Information Criteria was performed with intraoperative pathologically proven metastases as the outcome. The model was externally validated with a cohort from the University Hospital of Verona (January 2013-December 2017). For model development, 2262 patients were included of whom 235 (10%) had occult metastases, located in the liver (n = 143, 61%), peritoneum (n = 73, 31%), or both (n = 19, 8%). The model included age (OR 1.02, 95% CI 1.00-1.03), BMI (OR 0.96, 95% CI 0.93-0.99), preoperative nutritional support (OR 1.73, 95% CI 1.01-2.74), tumor diameter (OR 1.60, 95% CI 1.04-2.45), tumor composition (solid vs. cystic) (OR 2.33, 95% CI 1.20-4.35), and indeterminate lesions on preoperative imaging (OR 4.01, 95% CI 2.16-7.43). External validation showed poor discrimination with a C-statistic of 0.56. Although some predictor variables were significantly associated with occult metastases, the model performed insufficiently at external validation.

Point-of-Need Additive Manufacturing in Austere Arctic Environments: An Evaluation of Medical Logistics Requirements and Capabilities Demonstration.

Medical response to military conflicts, natural disasters, and humanitarian crises are challenged by operational logistics with unreliable supply chains, delayed medical evacuation, and compatibility of the disparate medical equipment and consumables. In these environments, stocks of supplies will become more quickly depleted and the need for equipment parts increases secondary to their higher likelihood for failure from overuse. Additive Manufacturing (AM), or 3D printing, at or closer to the point-of-need provides potential solutions to mitigate these logistics challenges. AM's ability to tailor the resultant product through computer design enables real-time modification of a product to meet a specific situation. In this study, we deployed two different 3D printers to an arctic locale to demonstrate the utility of 3D printing and bioprinting in austere environments. Deployment of AM solutions in austere environments will likely impact medical care following natural disasters and conflicts with contested logistics. The work presented here furthers the readiness status of AM for use in austere environments to manufacture medical equipment parts and demonstrates its potential use for tissue engineering and advanced medical treatments in remote environments.

Comparison of Daily versus Admission and Discharge Surveillance Cultures for Multidrug-Resistant Organism Detection in an Intensive Care Unit.

BACKGROUND: Admission and discharge screening of patients for asymptomatic gut colonization with multidrug-resistant organisms (MDROs) is a traditional approach to active surveillance, but its sensitivity for detecting colonization is uncertain. METHODS: Daily rectal or fecal swab samples and clinical data were collected over 12 months from patients in one 25-bed intensive care unit (ICU) in Chicago, IL USA and tested for the following multidrug-resistant organisms (MDROs): vancomycin-resistant enterococci (VRE); third-generation cephalosporin-resistant Enterobacterales, including extended-spectrum ß-lactamase-producing Enterobacterales (ESBL); and carbapenem-resistant Enterobacterales (CRE). MDRO detection by (1) admission/discharge surveillance cultures or (2) clinical cultures were compared to daily surveillance cultures. Samples underwent 16S rRNA gene sequencing to measure the relative abundance of operational taxonomic units (OTUs) corresponding to each MDRO. RESULTS: Compared with daily surveillance cultures, admission/discharge cultures detected 91% of prevalent MDRO colonization and 63% of incident MDRO colonization among medical ICU patients. Only a minority (7%) of MDRO carriers were identified by clinical cultures. Higher relative abundance of MDRO-associated OTUs and specific antibiotic exposures were independently associated with higher probability of MDRO detection by culture. CONCLUSION: Admission and discharge surveillance cultures underestimated MDRO acquisitions in an ICU. These limitations should be considered when designing sampling strategies for epidemiologic studies that use culture-based surveillance.

Outcomes of the EMDataResource Cryo-EM Ligand Modeling Challenge.

The EMDataResource Ligand Model Challenge aimed to assess the reliability and reproducibility of modeling ligands bound to protein and protein/nucleic-acid complexes in cryogenic electron microscopy (cryo-EM) maps determined at near-atomic (1.9-2.5 Å) resolution. Three published maps were selected as targets: E. coli beta-galactosidase with inhibitor, SARS-CoV-2 RNA-dependent RNA polymerase with covalently bound nucleotide analog, and SARS-CoV-2 ion channel ORF3a with bound lipid. Sixty-one models were submitted from 17 independent research groups, each with supporting workflow details. We found that (1) the quality of submitted ligand models and surrounding atoms varied, as judged by visual inspection and quantification of local map quality, model-to-map fit, geometry, energetics, and contact scores, and (2) a composite rather than a single score was needed to assess macromolecule+ligand model quality. These observations lead us to recommend best practices for assessing cryo-EM structures of liganded macromolecules reported at near-atomic resolution.

Maturational trend of daytime sleep propensity in adolescents.

STUDY OBJECTIVES: The teenage increase in sleepiness is not simply a response to decreasing nighttime sleep duration. Daytime sleepiness increases across adolescence even when prior sleep duration is held constant. Here we determine the maturational trend in daytime sleep propensity assessed with the multiple sleep latency test (MSLT) and assess the trend's relation to pubertal maturation and changes in the sleep electroencephalogram. We also evaluate whether the relation of daytime sleep propensity to prior sleep duration changes between ages 10 and 23 years. METHODS: Participants (n = 159) entered the study between ages 9.8 and 22.8 years and were studied annually for up to 3 years. Annually, participants kept each of three sleep schedules in their homes: 7, 8.5, and 10 hours in bed for 4 consecutive nights with polysomnography on nights 2 and 4. MSLT-measured daytime sleep propensity was assessed in the laboratory on the day following the fourth night. RESULTS: A two-part linear spline model described the maturation of daytime sleep propensity. MSLT sleep likelihood increased steeply until age 14.3 years, after which it did not change significantly. The maturational trend was strongly associated with the adolescent decline in slow-wave (delta, 1-4 Hz) EEG power during NREM sleep and with pubertal maturation assessed with Tanner stage measurement of breast/genital development. The effect of prior sleep duration on sleep likelihood decreased with age. CONCLUSIONS: Adolescent brain changes related to pubertal maturation and those reflected in the delta decline contribute to the adolescent increase in daytime sleep propensity.

Impact of COVID-19 on emergency oral health care in New Jersey.

BACKGROUND: The COVID-19 pandemic led to reduced services of private dental practices. The public emergency clinic of Rutgers School of Dental Medicine (RSDM) (Newark, NJ) faced changing demands during various periods of the pandemic. METHODS: Records of patients visiting the emergency clinic at RSDM during 3 distinct periods (prelockdown, lockdown, teledentistry) from January 10, 2020, through June 30, 2020, were retrospectively reviewed. Qualitative and quantitative attributes pertaining to patient encounters were reviewed and analyzed. RESULTS: A total of 1,799 records were included in this study. Patient visits increased during the early lockdown but were reduced after the implementation of teledentistry. Trends were noted in patient volume, reasons for visits, treatment needs, symptoms, diagnostic methodology, prescription use, and final disposition of patients. CONCLUSIONS: The lockdown affected emergency dental clinic services at RSDM. Teledentistry visits played a key role in screening patients and in facilitating the delivery of oral health care and timely follow-ups to patients who needed urgent in-person emergency visits. PRACTICAL IMPLICATIONS: Data gathered will lead to a better understanding of patients seen in the emergency clinic and can help with long-term planning for both institutional and smaller outpatient clinics during public health emergencies.

Long-Term Outcome of Immediate Versus Postponed Intervention in Patients With Infected Necrotizing Pancreatitis (POINTER): Multicenter Randomized Trial.

OBJECTIVE: To compare the long-term outcomes of immediate drainage versus the postponed-drainage approach in patients with infected necrotizing pancreatitis. BACKGROUND: In the randomized POINTER trial, patients assigned to the postponed-drainage approach using antibiotic treatment required fewer interventions, as compared with immediate drainage, and over a third were treated without any intervention. METHODS: Clinical data of those patients alive after the initial 6-month follow-up were re-evaluated. The primary outcome was a composite of death and major complications. RESULTS: Out of 104 patients, 88 were re-evaluated with a median follow-up of 51 months. After the initial 6-month follow-up, the primary outcome occurred in 7 of 47 patients (15%) in the immediate-drainage group and 7 of 41 patients (17%) in the postponed-drainage group (RR 0.87, 95% CI 0.33-2.28; P =0.78). Additional drainage procedures were performed in 7 patients (15%) versus 3 patients (7%) (RR 2.03; 95% CI 0.56-7.37; P =0.34). The median number of additional interventions was 0 (IQR 0-0) in both groups ( P =0.028). In the total follow-up, the median number of interventions was higher in the immediate-drainage group than in the postponed-drainage group (4 vs. 1, P =0.001). Eventually, 14 of 15 patients (93%) in the postponed-drainage group who were successfully treated in the initial 6-month follow-up with antibiotics and without any intervention remained without intervention. At the end of follow-up, pancreatic function and quality of life were similar. CONCLUSIONS: Also, during long-term follow-up, a postponed-drainage approach using antibiotics in patients with infected necrotizing pancreatitis results in fewer interventions as compared with immediate drainage and should therefore be the preferred approach. TRIAL REGISTRATION: ISRCTN33682933.

Predicting Long-term Disease-free Survival After Resection of Pancreatic Ductal Adenocarcinoma: A Nationwide Cohort Study.

OBJECTIVE: To develop a prediction model for long-term (≥5 years) disease-free survival (DFS) after the resection of pancreatic ductal adenocarcinoma (PDAC). BACKGROUND: Despite high recurrence rates, ~10% of patients have long-term DFS after PDAC resection. A model to predict long-term DFS may aid individualized prognostication and shared decision-making. METHODS: This nationwide cohort study included all consecutive patients who underwent PDAC resection in the Netherlands (2014-2016). The best-performing prognostic model was selected by Cox-proportional hazard analysis and Akaike's Information Criterion, presented by hazard ratios (HRs) with 95% confidence intervals (CIs). Internal validation was performed, and discrimination and calibration indices were assessed. RESULTS: In all, 836 patients with a median follow-up of 67 months (interquartile range 51-79) were analyzed. Long-term DFS was seen in 118 patients (14%). Factors predictive of long-term DFS were low preoperative carbohydrate antigen 19-9 (logarithmic; HR 1.21; 95% CI 1.10-1.32), no vascular resection (HR 1.33; 95% CI 1.12-1.58), T1 or T2 tumor stage (HR 1.52; 95% CI 1.14-2.04, and HR 1.17; 95% CI 0.98-1.39, respectively), well/moderate tumor differentiation (HR 1.44; 95% CI 1.22-1.68), absence of perineural and lymphovascular invasion (HR 1.42; 95% CI 1.11-1.81 and HR 1.14; 95% CI 0.96-1.36, respectively), N0 or N1 nodal status (HR 1.92; 95% CI 1.54-2.40, and HR 1.33; 95% CI 1.11-1.60, respectively), R0 resection margin status (HR 1.25; 95% CI 1.07-1.46), no major complications (HR 1.14; 95% CI 0.97-1.35) and adjuvant chemotherapy (HR 1.74; 95% CI 1.47-2.06). Moderate performance (concordance index 0.68) with adequate calibration (slope 0.99) was achieved. CONCLUSIONS: The developed prediction model, readily available at www.pancreascalculator.com, can be used to estimate the probability of long-term DFS after resection of pancreatic ductal adenocarcinoma.

Development of Highly Potent, G-Protein Pathway Biased, Selective, and Orally Bioavailable GPR84 Agonists.

Orphan G-protein-coupled receptor 84 (GPR84) is a receptor that has been linked to cancer, inflammatory, and fibrotic diseases. We have reported DL-175 as a biased agonist at GPR84 which showed differential signaling via Gαi/cAMP and ß-arrestin, but which is rapidly metabolized. Herein, we describe an optimization of DL-175 through a systematic structure-activity relationship (SAR) analysis. This reveals that the replacement of the naphthalene group improved metabolic stability and the addition of a 5-hydroxy substituent to the pyridine N-oxide group, yielding compounds 68 (OX04528) and 69 (OX04529), enhanced the potency for cAMP signaling by 3 orders of magnitude to low picomolar values. Neither compound showed detectable effects on ß-arrestin recruitment up to 80 µM. Thus, the new GPR84 agonists 68 and 69 displayed excellent potency, high G-protein signaling bias, and an appropriate in vivo pharmacokinetic profile that will allow investigation of GPR84 biased agonist activity in vivo.

Biased agonists of GPR84 and insights into biological control.

GPR84 was first identified as an open reading frame encoding an orphan Class A G protein coupled receptor in 2001. Gpr84 mRNA is expressed in a limited number of cell types with the highest levels of expression being in innate immune cells, M1 polarised macrophages and neutrophils. The first reported ligands for this receptor were medium chain fatty acids with chain lengths between 9 and 12 carbons. Subsequently, a series of synthetic agonists that signal via the GPR84 receptor were identified. Radioligand binding assays and molecular modelling with site-directed mutagenesis suggest the presence of three ligand binding sites on the receptor, but the physiological agonist(s) of the receptor remain unidentified. Here, we review the effects of GPR84 agonists on innate immune cells following a series of chemical discoveries since 2001. The development of highly biased agonists has helped to probe receptor function in vitro, and the remaining challenge is to follow the effects of biased signalling to the physiological functions of innate immune cell types. LINKED ARTICLES: This article is part of a themed issue GPR84 Pharmacology. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v181.10/issuetoc.

The Relationship Between the Microbiome and Antimicrobial Resistance.

Antibiotics have benefitted human health since their introduction nearly a century ago. However, the rise of antibiotic resistance may portend the dawn of the "post-antibiotic age." With the narrow pipeline for novel antimicrobials, we need new approaches to deal with the rise of multidrug resistant organisms. In the last 2 decades, the role of the intestinal microbiota in human health has been acknowledged and studied widely. Of the various activities carried out by the gut microbiota, colonization resistance is a key function that helps maintain homeostasis. Therefore, re-establishing a healthy microbiota is a novel strategy for treating drug resistance organisms. Preliminary studies suggest that this is a viable approach. However, the extent of their success still needs to be examined. Herein, we will review work in this area and suggest where future studies can further investigate this method for dealing with the threat of antibiotic resistance.