Evidence-Based Approach to Chronic Antibiotic Refractory Pouchitis: A Review.

BACKGROUND: Chronic antibiotic refractory pouchitis after restorative proctocolectomy with IPAA, characterized by at least 4 weeks of pouchitis symptoms that have not responded to standard antibiotic therapy, presents a therapeutic challenge for patients and health care providers. OBJECTIVE: The aim of this narrative review was to summarize the current evidence regarding the management of chronic antibiotic refractory pouchitis. DATA SOURCES: Studies were identified through a search of the PubMed database from the National Library of Medicine. STUDY SELECTION: We included case series, cohort studies, randomized controlled trials, and systematic reviews with meta-analyses that addressed chronic antibiotic refractory pouchitis management, with prioritization of data published within the past 3 to 5 years. INTERVENTION: Studies examining pharmacologic and select nonpharmacologic interventions were included. MAIN OUTCOME MEASURE: Outcomes measures included clinical, endoscopic, and histologic end points. RESULTS: Mesalamine has demonstrated efficacy in symptom improvement but no improvement in quality of life. Budesonide has demonstrated high rates of clinical remission that have mostly been sustained in a small number of patients. Anti-tumor necrosis factor therapies have demonstrated efficacy in reaching clinical and even endoscopic end points, although rates of treatment discontinuation were not insignificant. Limited evidence is encouraging for the use of ustekinumab in achieving clinical response. Data for vedolizumab are favorable across clinical, endoscopic, and histologic end points, including one of the only randomized, placebo-controlled trials. Nonmedication therapies, including hyperbaric oxygen therapy and fecal microbiota transplant, have undergone limited evaluation, and concerns about the ultimate accessibility of these therapies remain. LIMITATIONS: Overall, studies assessing therapeutic options for chronic antibiotic refractory pouchitis are mostly limited to case series and retrospective studies with small sample sizes. CONCLUSIONS: Biologic therapies have demonstrated efficacy in the management of chronic antibiotic refractory pouchitis and offer a steroid-sparing option for refractory disease. Nonpharmacologic therapies, including hyperbaric oxygen and fecal microbiota transplant, require further exploration. See video from symposium .

Development and Evaluation of Dissolving Microarray Patches for Co-administered and Repeated Intradermal Delivery of Long-acting Rilpivirine and Cabotegravir Nanosuspensions for Paediatric HIV Antiretroviral Therapy.

PURPOSE: Whilst significant progress has been made to defeat HIV infection, the efficacy of antiretroviral (ARV) therapy in the paediatric population is often hindered by poor adherence. Currently, two long-acting (LA) intramuscular injectable nanosuspensions of rilpivirine (RPV) and cabotegravir (CAB) are in clinical development for paediatric populations. However, administration requires access to healthcare resources, is painful, and can result in needle-stick injuries to the end user. To overcome these barriers, this proof-of-concept study was developed to evaluate the intradermal delivery of RPV LA and CAB LA via self-disabling dissolving microarray patches (MAPs). METHODS: Dissolving MAPs of two conformations, a conventional pyramidal and a bilayer design, were formulated, with various nanosuspensions of RPV and CAB incorporated within the respective MAP matrix. MAPs were mechanically robust and were capable of penetrating ex vivo skin with intradermal ARV deposition. RESULTS: In a single-dose in vivo study in rats, all ARV MAPs demonstrated sustained release profiles, with therapeutically relevant plasma concentrations of RPV and CAB detected to at least 63 and 28 d, respectively. In a multi-dose in vivo study, repeated MAP applications at 14-d intervals maintained therapeutically relevant plasma concentrations throughout the duration of the study. CONCLUSIONS: These results illustrate the potential of the platform to repeatedly maintain plasma concentrations for RPV and CAB. As such, these MAPs could represent a viable option to improve adherence in the paediatric population, one that is capable of being painlessly administered in the comfort of the patient's own home on a biweekly or less frequent basis.

Avoidant Restrictive Food Intake Disorder Prevalent Among Patients With Inflammatory Bowel Disease.

BACKGROUND & AIMS: Patients with inflammatory bowel disease (IBD) alter their dietary behaviors to reduce disease-related symptoms, avoid feared food triggers, and control inflammation. This study aimed to estimate the prevalence of avoidant/restrictive food intake disorder (ARFID), evaluate risk factors, and examine the association with risk of malnutrition in patients with IBD. METHODS: This cross-sectional study recruited adult patients with IBD from an ambulatory clinic. ARFID risk was measured using the Nine-Item ARFID Screen. Nutritional risk was measured with the Patient Generated-Subjective Global Assessment. Logistic regression models were used to evaluate the association between clinical characteristics and a positive ARFID risk screen. Patient demographics, disease characteristics, and medical history were abstracted from medical records. RESULTS: Of the 161 participants (Crohn's disease, 45.3%; ulcerative colitis, 51.6%; IBD-unclassified, 3.1%), 28 (17%) had a positive ARFID risk score (≥24). Most participants (92%) reported avoiding 1 or more foods while having active symptoms, and 74% continued to avoid 1 or more foods even in the absence of symptoms. Active symptoms (odds ratio, 5.35; 95% confidence interval, 1.91-15.01) and inflammation (odds ratio, 3.31; 95% confidence interval, 1.06-10.29) were significantly associated with positive ARFID risk. Patients with a positive ARFID risk screen were significantly more likely to be at risk for malnutrition (60.7% vs 15.8%; P < .01). CONCLUSIONS: Avoidant eating behaviors are common in IBD patients, even when in clinical remission. Patients who exhibit active symptoms and/or inflammation should be screened for ARFID risk, with referrals to registered dietitians to help monitor and address disordered eating behaviors and malnutrition risk.

AL Lambda Amyloidosis Activates Acute Liver Failure in the Absence of Plasma Cell Dyscrasia.

A patient with systemic amyloidosis developed portal hypertension, acute liver failure and multiorgan dysfunction. Extensive testing was unrevealing for paraproteinemia, plasma cell dyscrasia, infectious, or inflammatory conditions. He was transferred to our institution for orthotopic liver transplant evaluation but was ultimately declined given clinical instability and dysautonomia. Post-mortem evaluation revealed extensive amyloid deposition in multiple organs determined to be AL-lambda amyloidosis.

Predicting Volume of Distribution in Humans: Performance of In Silico Methods for a Large Set of Structurally Diverse Clinical Compounds.

Volume of distribution at steady state (VD,ss) is one of the key pharmacokinetic parameters estimated during the drug discovery process. Despite considerable efforts to predict VD,ss, accuracy and choice of prediction methods remain a challenge, with evaluations constrained to a small set (<150) of compounds. To address these issues, a series of in silico methods for predicting human VD,ss directly from structure were evaluated using a large set of clinical compounds. Machine learning (ML) models were built to predict VD,ss directly and to predict input parameters required for mechanistic and empirical VD,ss predictions. In addition, log D, fraction unbound in plasma (fup), and blood-to-plasma partition ratio (BPR) were measured on 254 compounds to estimate the impact of measured data on predictive performance of mechanistic models. Furthermore, the impact of novel methodologies such as measuring partition (Kp) in adipocytes and myocytes (n = 189) on VD,ss predictions was also investigated. In predicting VD,ss directly from chemical structures, both mechanistic and empirical scaling using a combination of predicted rat and dog VD,ss demonstrated comparable performance (62%-71% within 3-fold). The direct ML model outperformed other in silico methods (75% within 3-fold, r 2 = 0.5, AAFE = 2.2) when built from a larger data set. Scaling to human from predicted VD,ss of either rat or dog yielded poor results (<47% within 3-fold). Measured fup and BPR improved performance of mechanistic VD,ss predictions significantly (81% within 3-fold, r 2 = 0.6, AAFE = 2.0). Adipocyte intracellular Kp showed good correlation to the VD,ss but was limited in estimating the compounds with low VD,ss SIGNIFICANCE STATEMENT: This work advances the in silico prediction of VD,ss directly from structure and with the aid of in vitro data. Rigorous and comprehensive evaluation of various methods using a large set of clinical compounds (n = 956) is presented. The scale of techniques evaluated is far beyond any previously presented. The novel data set (n = 254) generated using a single protocol for each in vitro assay reported in this study could further aid in advancing VD,ss prediction methodologies.

Nebulized in-line endotracheal dornase alfa and albuterol administered to mechanically ventilated COVID-19 patients: a case series.

BACKGROUND: Mechanically ventilated patients with COVID-19 have a mortality of 24-53%, in part due to distal mucopurulent secretions interfering with ventilation. DNA from neutrophil extracellular traps (NETs) contribute to the viscosity of mucopurulent secretions and NETs are found in the serum of COVID-19 patients. Dornase alfa is recombinant human DNase 1 and is used to digest DNA in mucoid sputum. Here, we report a single-center case series where dornase alfa was co-administered with albuterol through an in-line nebulizer system. METHODS: Demographic and clinical data were collected from the electronic medical records of five mechanically ventilated patients with COVID-19-including three requiring veno-venous extracorporeal membrane oxygenation-treated with nebulized in-line endotracheal dornase alfa and albuterol, between March 31 and April 24, 2020. Data on tolerability and response were analyzed. RESULTS: The fraction of inspired oxygen requirements was reduced for all five patients after initiating dornase alfa administration. All patients were successfully extubated, discharged from hospital and remain alive. No drug-associated toxicities were identified. CONCLUSIONS: Results suggest that dornase alfa will be well-tolerated by patients with severe COVID-19. Clinical trials are required to formally test the dosing, safety, and efficacy of dornase alfa in COVID-19, and several have been recently registered.

AMPL: A Data-Driven Modeling Pipeline for Drug Discovery.

One of the key requirements for incorporating machine learning (ML) into the drug discovery process is complete traceability and reproducibility of the model building and evaluation process. With this in mind, we have developed an end-to-end modular and extensible software pipeline for building and sharing ML models that predict key pharma-relevant parameters. The ATOM Modeling PipeLine, or AMPL, extends the functionality of the open source library DeepChem and supports an array of ML and molecular featurization tools. We have benchmarked AMPL on a large collection of pharmaceutical data sets covering a wide range of parameters. Our key findings indicate that traditional molecular fingerprints underperform other feature representation methods. We also find that data set size correlates directly with prediction performance, which points to the need to expand public data sets. Uncertainty quantification can help predict model error, but correlation with error varies considerably between data sets and model types. Our findings point to the need for an extensible pipeline that can be shared to make model building more widely accessible and reproducible. This software is open source and available at: https://github.com/ATOMconsortium/AMPL.

Computer-assembled cross-species/cross-modalities two-pore physiologically based pharmacokinetic model for biologics in mice and rats.

Two-pore physiologically-based pharmacokinetic (PBPK) models can be expected to describe the tissue distribution and elimination kinetics of soluble proteins, endogenous or dosed, as function of their size. In this work, we amalgamated our previous two-pore PBPK model for an inert domain antibody (dAb) in mice with the cross-species platform PBPK model for monoclonal antibodies described in literature into a unified two-pore platform that describes protein modalities of different sizes and includes neonatal Fc receptor (FcRn) mediated recycling. This unified PBPK model was parametrized for organ-specific lymph flow rates and the endosomal recycling rate constant using an extended tissue distribution time-course dataset that included an inert dAb, albumin and IgG in rats and mice. The model was evaluated by comparing the ab initio predictions for the tissue distribution and elimination properties of albumin-binding dAbs (AlbudAbsTM) in mice and rats with the experimental observations. Due to the large number of molecular species and reactions involved in large-scale PBPK models, we have also developed and deployed a MatlabTM script for automating the assembly of SimBiologyTM-based two-pore biologics PBPK models which drastically cuts the time and effort required for model building.

Spin-Resolved Electronic Response to the Phase Transition in MoTe_{2}.

The semimetal MoTe_{2} is studied by spin- and angle-resolved photoemission spectroscopy across the centrosymmetry-breaking structural transition temperature of the bulk. A three-dimensional spin-texture is observed in the bulk Fermi surface in the low temperature, noncentrosymmetric phase that is consistent with first-principles calculations. The spin texture and two types of surface Fermi arc are not completely suppressed above the bulk transition temperature. The lifetimes of quasiparticles forming the Fermi arcs depend on thermal history and lengthen considerably upon cooling toward the bulk structural transition. The results indicate that a new form of polar instability exists near the surface when the bulk is largely in a centrosymmetric phase.

Solid Contact Ion-Selective Electrodes for in Situ Measurements at High Pressure.

Solid contact polymeric ion-selective electrodes (SC-ISEs) have been fabricated using microporous carbon (µPC) as the ion-to-electron transducer, loaded with a liquid membrane cocktail containing both ionophore and additive dissolved in plasticizer. These SC-ISEs were characterized and shown to be suitable for analysis in aqueous environments at pressures of 100 bar. Potassium ISEs, prepared in this manner, showed excellent performance at both atmospheric and elevated pressures, as evaluated by their response slopes and potential stability. These novel SC-ISEs were shown to be capable of measuring K+ at pressures under which traditional liquid-filled ISEs fail. Furthermore, the effect of pressure on the response of these sensors had little or no effect on potential, sensitivity, or limit of detection. High pressure sensor calibrations were performed in standard solutions as well as simulated seawater samples to demonstrate their usefulness as sensors in a deep-sea environment. These novel SC-ISE sensors show promise of providing the ability to make in situ real-time measurements of ion-fluxes near deep-ocean geothermal vents.

Electrochemistry of aqueous colloidal graphene oxide on Pt electrodes.

The electrochemical behavior of colloidal solutions of graphene oxide (GO) is described here in detail. The GO reduction is shown to exhibit near-reversible electron transfer on Pt electrodes, based on E1/2 and ΔEp values. The observed peak current is found to depend linearly on the concentration of the GO and the square root of the scan rate, suggesting that the response is diffusion-limited. The difference between the experimental and diffusion-only limited theoretical current values suggests that migration may be hindering mass transport to the electrode surface. Varying the type and concentration of the supporting electrolyte showed that mass transport is weakly influenced by the presence of negative charges on the graphene particles. The effect of pH on GO was also investigated, and it was found that the reduction peak heights were directly related to proton concentration in acidic solutions. On the basis of the results presented here, we propose that the observed response of GO on Pt electrodes is a result of the reduction of protons from the colloidal double layer. This difference is observed only because the Pt electrode surface can efficiently catalyze proton reduction.

Preoperative Exclusive Enteral Nutrition Is Associated With Reduced Skin and Soft Tissue and Intra-abdominal Infections in Patients With Crohn's Disease Undergoing Intestinal Surgery: Results from a Meta-Analysis.

BACKGROUND: Malnutrition is an independent risk factor for adverse postoperative outcomes and is common among patients with Crohn's disease (CD). The objective of this meta-analysis was to precisely quantify the association of preoperative exclusive enteral nutrition (EEN) and total parenteral nutrition (TPN) with surgical outcomes in patients undergoing intestinal surgery for CD. METHODS: PubMed, Embase, and Scopus were queried for comparative studies evaluating the impact of preoperative nutritional support on postoperative outcomes in patients undergoing surgery for CD. Random effects modeling was used to compute pooled estimates of risk difference. Heterogeneity was assessed using I2. RESULTS: Fourteen studies, all nonrandomized cohort studies, met inclusion criteria for studying EEN. After pooling data from 14 studies (874 EEN treated and 1044 control patients), the relative risk of intra-abdominal septic complications was decreased 2.1-fold in patients receiving preoperative EEN (relative risk 0.47, 95% confidence interval [CI], 0.35-0.63, I2 = 0.0%). After pooling data from 9 studies (638 EEN treated and 819 control patients), the risk of skin and soft tissue infection was decreased 1.6-fold (relative risk 0.63; 95% CI, 0.42-0.94, I2 = 42.7%). No significant differences were identified in duration of surgery, length of bowel resected, or operative blood loss. Among the 9 studies investigating TPN, no significant differences were identified in infectious outcomes. CONCLUSIONS: Preoperative nutritional optimization with EEN was associated with reduced risk of infectious complications in CD patients undergoing intestinal surgery. Preoperative nutritional support with EEN should be considered for optimizing outcomes in CD patients requiring bowel resection surgery.

Pooled data from this meta-analysis demonstrated significantly decreased rates of skin/soft tissue and intra-abdominal infections following intestinal surgery for Crohn's disease after preoperative treatment with exclusive enteral nutrition.

Ultraconfined Plasmons in Atomically Thin Crystalline Silver Nanostructures.

The ability to confine light down to atomic scales is critical for the development of applications in optoelectronics and optical sensing as well as for the exploration of nanoscale quantum phenomena. Plasmons in metallic nanostructures with just a few atomic layers in thickness can achieve this type of confinement, although fabrication imperfections down to the subnanometer scale hinder actual developments. Here, narrow plasmons are demonstrated in atomically thin crystalline silver nanostructures fabricated by prepatterning silicon substrates and epitaxially depositing silver films of just a few atomic layers in thickness. Specifically, a silicon wafer is lithographically patterned to introduce on-demand lateral shapes, chemically process the sample to obtain an atomically flat silicon surface, and epitaxially deposit silver to obtain ultrathin crystalline metal films with the designated morphologies. Structures fabricated by following this procedure allow for an unprecedented control over optical field confinement in the near-infrared spectral region, which is here illustrated by the observation of fundamental and higher-order plasmons featuring extreme spatial confinement and high-quality factors that reflect the crystallinity of the metal. The present study constitutes a substantial improvement in the degree of spatial confinement and quality factor that should facilitate the design and exploitation of atomic-scale nanoplasmonic devices for optoelectronics, sensing, and quantum-physics applications.

Ferromagnetic Order in 2D Layers of Transition Metal Dichlorides.

Magnetism in two dimensions is traditionally considered an exotic phase mediated by spin fluctuations, but far from collinearly ordered in the ground state. Recently, 2D magnetic states have been discovered in layered van der Waals compounds. Their robust and tunable magnetic state by material composition, combined with reduced dimensionality, foresee a strong potential as a key element in magnetic devices. Here, a class of 2D magnets based on metallic chlorides is presented. The magnetic order survives on top of a metallic substrate, even down to the monolayer limit, and can be switched from perpendicular to in-plane by substituting the metal ion from iron to nickel. Using functionalized STM tips as magnetic sensors, local exchange fields are identified, even in the absence of an external magnetic field. Since the compounds are processable by molecular beam epitaxy techniques, they provide a platform with large potential for incorporation into current device technologies.

Risk factors in idiopathic adhesive capsulitis: a case control study.

BACKGROUND: The etiology of idiopathic adhesive capsulitis (IAC) of the shoulder is poorly understood. In this case control study, we examine potential risk factors for the development of IAC. METHODS: Consecutive patients who presented to the senior author with IAC between 2000 and 2009 were included retrospectively in this case control study. Complete data were available for 87 patients. An age- and sex-matched group of 176 patients who presented to the same practice during the same time period with non-shoulder related orthopedic complaints were recruited as the control group. Health records and patient-completed questionnaires were utilized to identify comorbidities and other risk factors. RESULTS: Bivariate analyses demonstrated that diabetes, hypothyroidism, a lower body weight, a lower body mass index (BMI), and a positive family history of IAC were all risk factors for IAC. Diabetes, BMI, and positive family history of IAC remained independent variables with multivariate logistic regression analyses. There was a trend towards increased incidence of Dupuytren's disease in those with IAC, but this was not statistically significant. With regard to racial predilection, being born in the British Isles or having parents/grandparents born in the British Isles were risk factors for IAC. CONCLUSION: We confirm diabetes as an independent predictor of IAC. In addition, we identify a possible racial predilection for the development of IAC. Future research is needed to confirm whether a specific genetic component or environmental factors is responsible.

A 65-Year-Old Man With Concerns of Hemoptysis After Recent Motor Vehicle Accident and Blunt Trauma to Chest.

CASE PRESENTATION: A 65-year-old man with a medical history of anxiety and depression came to the ED with concerns of coughing blood-tinged phlegm for the past 3 days. Four days before the presentation, the patient had a motor vehicle accident as a restrained driver with airbag deployment. The patient struck his chest against the steering wheel. He was evaluated at a level 1 trauma center and underwent a whole-body scan, including a CT scan of the chest, which showed no acute abnormalities. Apart from mild-to-moderate bruising and tenderness on the right side of his face, nose, and anterior chest, the patient was stable and was discharged the next day. After returning home, the patient started coughing blood-tinged phlegm, which became progressively bloodier for the next 3 days, achieving individual posttussive volumes of 1 T of frank blood. In the ED, the patient denied any similar symptoms in the past. He denied any recent or distant known history of malignancy, infections, or travel outside the United States. He lives by himself and previously worked various jobs. He endorsed active tobacco use and smoking 3 to 6 cigarettes per day for the past 20 years with 5 pack-year history. Patient reported consuming one to two alcohol drinks per month.

Septic Shock From Pan-Spinal Epidural Abscess Attributed to Recent Acupuncture and Trigger Point Injections for Acute Lower Back Pain in a Previously Undiagnosed Diabetic Patient: A Case Report.

Epidural abscesses can lead to devastating neurological consequences if not diagnosed and managed in a timely manner, especially in immunocompromised patients. We report the case of a 60-year-old woman with undiagnosed diabetes mellitus who presented to the hospital with a complaint of progressive altered mental status for the past two days. Eight days prior to presentation, the patient tripped over a pillow at home and developed mildly nagging, acute lower back pain. Upon the recommendation of her friends, she underwent two sessions of acupuncture around the lumbar area on days six and five prior to being brought to the hospital. She also saw her primary care physician on day three prior to presentation, who performed a history and physical examination and, after feeling that she did not have any red flags, empirically administered lidocaine-based trigger point injections near the same lumbar areas with the patient's consent. On the day of presentation, the patient fell at home and was unable to walk, after which she was immediately brought to the hospital, where she demonstrated toxic metabolic encephalopathy due to diabetic ketoacidosis (DKA) and lower extremity paraplegia. Emergent imaging revealed a pan-spinal epidural abscess (PSEA) after an attempted lumbar puncture led to immediate pus in the syringe. Diagnosing an epidural abscess can be difficult as signs and symptoms can mimic other conditions such as meningitis, encephalitis, and stroke. High suspicion on the physician's end is needed when a patient presents with acute back pain, fevers, and neurological deterioration if the condition is otherwise unexplained, and especially in the presence of risk factors for PSEA that may be recognized only upon presentation.

Rare malignant glomus tumor of the esophagus with pulmonary metastasis: a case report.

Background: Glomus tumors are typically benign soft tissue neoplasms that arise in peripheral cutaneous structures. Visceral organ involvement is exceedingly rare. Case Description: Here we present a case of malignant glomus tumor of the esophagus with pulmonary metastases in a 57-year-old woman presenting with three weeks of progressive dysphagia, epigastric pain, and 35-pound weight loss. Upper endoscopy revealed a 5×3.5×2.5 cm vascular esophageal mass. Contrast-enhanced CT showed multiple, scattered sub-centimeter pulmonary nodules bilaterally. Diagnosis of metastatic glomus tumor was confirmed immunohistochemically on primary tumor and lung biopsies. Localized resection was not feasible due to the patient's poor condition. A trial of gemcitabine and docetaxel was planned, but the patient experienced rapid clinical deterioration after a single dose of gemcitabine before electing for hospice care. Conclusions: We have reviewed the 11 other published cases of esophageal glomus tumors, only one of which was similarly metastatic at time of presentation. Of those patients with localized disease treated with surgical excision, all were alive and had no evidence of recurrence (NER) at their times of publication. In contrast, disease ultimately progressed despite surgery and chemoradiotherapy in the sole other case of metastatic glomus tumor of the esophagus. Although glomus tumors are largely benign entities, this case highlights their rare and aggressive malignant potential.