Search

Osimertinib is a third-generation, irreversible oral EGFR-tyrosine kinase inhibitor), that potently inhibits EGFR-tyrosine kinase inhibitor-sensitizing mutations and T790M resistance mutations together with efficacy in CNS metastases in patients with non-small-cell lung cancer (NSCLC). Here we describe the rationale and design for the Phase III NeoADAURA study (NCT04351555), which will evaluate neoadjuvant osimertinib with or without chemotherapy versus chemotherapy alone prior to surgery, in patients with resectable stage II–IIIB N2 EGFR mutation-positive NSCLC. The primary end point is centrally assessed major pathological response at the time of resection. Secondary end points include event-free survival, pathological complete response, nodal downstaging at the time of surgery, disease-free survival, overall survival and health-related quality of life. Safety and tolerability will also be assessed. Trial Registration number: NCT04351555 (ClinicalTrials.gov), Lay abstract A plain language version of this article is available and is published alongside the paper online: www.futuremedicine.com/doi/suppl/10.2217/fon-2021-0549

Common treatment for venous leg wounds includes topical wound dressings with compression. At each dressing change, wounds are debrided and washed; however, the effect of the washing procedure on the wound microbiome has not been studied. We hypothesized that wound washing may alter the wound microbiome. To characterize microbiome changes with respect to wound washing, swabs from 11 patients with chronic wounds were sampled before and after washing, and patient microbiomes were characterized using 16S rRNA sequencing and culturing. Microbiomes across patient samples prior to washing were typically polymicrobial but varied in the number and type of bacterial genera present. Proteus and Pseudomonas were the dominant genera in the study. We found that washing does not consistently change microbiome diversity but does cause consistent changes in microbiome composition. Specifically, washing caused a decrease in the relative abundance of the most highly represented genera in each patient cluster. The finding that venous leg ulcer wound washing, a standard of care therapy, can induce changes in the wound microbiome is novel and could be potentially informative for future guided therapy strategies.

Background The Hospital Readmissions Reduction Program (HRRP) was introduced to reduce readmission rates among Medicare beneficiaries, however little is known about readmissions and costs for HRRP-targeted conditions in younger populations. The primary objective of this study was to examine readmission trends and costs for targeted conditions during policy implementation among younger and older adults in the U.S. Methods We analyzed the Nationwide Readmission Database from January 2010 to September 2015 in younger (18–64 years) and older (≥65 years) patients with acute myocardial infarction (AMI), heart failure (HF), pneumonia, and acute exacerbations of chronic obstructive pulmonary disease (AECOPD). Pre- and post-HRRP periods were defined based on implementation of the policy for each condition. Readmission rates were evaluated using an interrupted time series with difference-in-difference analyses and hospital cost differences between early and late readmissions (≤30 vs. > 30 days) were evaluated using generalized linear models. Results Overall, this study included 16,884,612 hospitalizations with 3,337,266 readmissions among all age groups and 5,977,177 hospitalizations with 1,104,940 readmissions in those aged 18–64 years. Readmission rates decreased in all conditions. In the HRRP announcement period, readmissions declined significantly for those aged 40–64 years for AMI (p p = 0.003). Readmissions decreased significantly in the post-HRRP period for those aged 40–64 years at a slower rate for AMI (p = 0.003) and HF (p = 0.05). Readmission rates among younger patients (18–64 years) varied within all four targeted conditions in HRRP announcement and post-HRRP periods. Adjusted models showed a significantly higher readmission cost in those readmitted within 30 days among younger and older populations for AMI (p p p p Conclusion Readmissions for targeted conditions decreased in the U.S. during the enactment of the HRRP policy and younger age groups (

Purpose of review Eye pain is one of the most common presenting symptoms in ophthalmology. It can range from bothersome to debilitating for patients, and it can be vexing for clinicians, especially in the white and quiet eye. The purpose of this review is to provide updates of recent literature regarding eye pain and to communicate our current understanding regarding the evaluation and management of conditions that cause eye pain with a relatively normal examination. Recent findings This review concerns recent literature regarding eye pain in the white and quiet eye. It is arranged by cause of pain and discusses dry eye syndrome, recurrent corneal erosion, postrefractive surgical pain, eye strain, intermittent angle closure, benign essential blepharospasm, trochleodynia, trochleitis and trochlear headache, and posterior scleritis. Summary Eye pain in the white and quiet eye remains a difficult-to-navigate topic for practitioners. However, a careful history and focused physical examination can elucidate the diagnosis in many cases. Recent updates to the literature have advanced our knowledge of how to identify and treat the underlying causes of eye pain.

BACKGROUND/OBJECTIVES: To examine the prevalence of potentially inappropriate medication (PIM) prescribing and its association with healthcare utilization and related expenditures utilizing nationally representative data from the United States. DESIGN: Retrospective cohort study. SETTING: The 2011–2015 Medical Expenditure Panel Survey (MEPS). PARTICIPANTS: Community-dwelling sample of U.S. adults aged 65 and older during the first round of each MEPS cycle. MEASUREMENTS: A qualified definition operationalized from the 2019 American Geriatrics Society Beers Criteria(®) was used to estimate the prevalence of PIM prescribing over the study period. Negative binomial models were assembled to examine associations between PIM exposure and healthcare utilization including hospitalizations, emergency department (ED) visits, and outpatient provider visits. Generalized linear models with the log link function and gamma distribution were used to analyze associations between PIM exposure and healthcare expenditures. Sensitivity analyses were conducted utilizing inverse probability treatment weighting using propensity scores for being prescribed a PIM. RESULTS: The period prevalence of PIM prescribing over the 5-year sample was 34.4%. PIM prescribing was positively associated with hospitalizations (adjusted incidence rate ratio [aIRR] = 1.17; 95 confidence interval [CI] = 1.08–1.26; P < .001), ED visits (aIRR = 1.26; 95% CI = 1.17–1.35; P < .001), and outpatient provider visits (aIRR = 1.18; 95% CI = 1.14–1.21; P < .001). PIM exposure was associated with higher marginal costs within outpatient visits ($116; 95% CI = $105–$243; P < .001), prescription medications ($128; 95% CI = $72–$199; P < .001), and total healthcare expenditures ($458; 95% CI = $295–$664; P < .001). Similar results were found in our propensity score analyses. CONCLUSION: PIMs continue to be prescribed at a high rate among older adults in the United States. Our results suggest that receipt of PIMs is associated with higher rates of healthcare utilization and increased costs across the healthcare continuum. Further work is needed to implement evidence-based deprescribing interventions that may in turn reduce unnecessary healthcare utilization.

Purpose of review Ocular myasthenia gravis (OMG) is a complex condition with heterogenous phenotypes and ill-defined diagnostic criteria. Understanding concomitant risk factors and autoimmune serology can help inform prognosis for generalization and guide treatment. Recent findings Although antibodies to acetylcholine receptors or muscle-specific kinase likely increase risk of generalization, they are less frequent in OMG. Patients without either antibody tend to have a milder disease process and often have variable antibodies to other end-plate proteins such as LRP4, agrin, or cortactin. The treatment of OMG begins with pyridostigmine and is supplemented by oral prednisone if treatment-resistant or high risk for generalization. Variable oral prednisone regimens have been used with success and further immunosuppression may be best achieved with mycophenolate mofetil and azathioprine. Checkpoint inhibitor-induced myasthenia gravis is increasingly recognized and likely has high rates of mortality associated with myocarditis. Summary Our understanding of OMG and its variable phenotypes continues to evolve. Autoantibody testing increasingly provides valuable diagnostic and prognostic information. Despite these improvements, a lack of quality treatment trials creates significant challenges for evidence-based management guidelines.

Objective To develop and pilot-test a model in which a community-based clinical pharmacist was incorporated as part of a Medicare Annual Wellness Visit (AWV) to make deprescribing recommendations targeted at potentially inappropriate medications (PIMs) in seniors. Setting A family medicine patient-centered medical home (PCMH) clinic in Buffalo, NY. Practice description Implementation and evaluation of a pilot program incorporating a pharmacist-provided medication review targeting PIMs in seniors as part of a Medicare AWV. Practice innovation A community pharmacy–based clinical pharmacist provided face-to-face medication reviews for patients older than 65 years as part of their AWV with a focus on deprescribing PIMs. No clinical pharmacy service existed at the practice when this program was implemented. Evaluation Identified PIMs, pharmacist recommendations, recommendation acceptance rate, time spent on intervention, health care utilization at 6 months postvisit, and barriers to implementation. Results Of the 21 patients enrolled, 13 unique patients received a total of 20 deprescribing recommendations from the pharmacist. The overall acceptance rate for pharmacist recommendations was 20%. The pharmacist spent a mean (± SD) of 34 (± 6) minutes per patient encounter. One patient in the intervention group was hospitalized, and 1 was seen in the emergency department (ED) during the 6-month follow-up period compared with 1 patient in the control group who had an ED visit. We identified multiple logistical and organizational barriers to the implementation of the intervention. Conclusion In this prospective pilot study, a workflow to include a pharmacist medication review to facilitate deprescribing in the primary care setting was tested. We encountered several barriers to integrating the pharmacist into the AWV workflow to deliver the intervention. Future pragmatic clinical trials are warranted to improve provider awareness and comfort with deprescribing PIMs in seniors.

The ability to identify patients who are likely to have an adverse outcome is an essential component of good clinical care. Therefore, predictive risk stratification models play an important role in clinical decision making. Determining whether a given predictive model is suitable for clinical use usually involves evaluating the model’s performance on large patient datasets using standard statistical measures of success (e.g., accuracy, discriminatory ability). However, as these metrics correspond to averages over patients who have a range of different characteristics, it is difficult to discern whether an individual prediction on a given patient should be trusted using these measures alone. In this paper, we introduce a new method for identifying patient subgroups where a predictive model is expected to be poor, thereby highlighting when a given prediction is misleading and should not be trusted. The resulting “unreliability score” can be computed for any clinical risk model and is suitable in the setting of large class imbalance, a situation often encountered in healthcare settings. Using data from more than 40,000 patients in the Global Registry of Acute Coronary Events (GRACE), we demonstrate that patients with high unreliability scores form a subgroup in which the predictive model has both decreased accuracy and decreased discriminatory ability.

What is known and objective Use of potentially inappropriate medications (PIMs) remains common in older adults, despite the easy availability of screening tools such as the Beers and Screening Tool of Older Person's Prescriptions (STOPP) criteria. Multiple published studies have implemented these screening tools to encourage deprescribing of PIMs, with mixed results. Little is known about the reasons behind the success or failure of these interventions, or what could be done to improve their impact. Implementation science (IS) provides a set of theories, models and frameworks to address these questions. The goal of this study was to conduct a focused narrative review of the deprescribing literature through an IS lens-to determine the extent to which implementation factors were identified and the intermediate steps in the intervention were measured. A better understanding of the existing literature, including its gaps, may provide a roadmap for future research. Methods PubMed search from 2000-2019 using appropriate MeSH headings. Inclusion criteria controlled trials or prospective cohort studies intended to reduce PIMs in the elderly that used hospitalizations and/or emergency department visits as outcome measures. Studies were reviewed to identify potential implementation factors (known as determinants), using the Consolidated Framework for Implementation Research (CFIR) as a guide. In addition, intermediate outcomes were extracted. Results and discussion Of the 548 reviewed abstracts, 14 studies met the inclusion criteria and underwent detailed analysis. Of the 14 studies, 10 acknowledged potential implementation determinants that could be mapped onto CFIR. The most commonly identified determinant was the degree of pharmacist integration into the medical team (seven of 14 studies), which mapped onto the CFIR construct of 'networks and communication'. Several important CFIR constructs were absent in the reviewed literature. Intermediate measures were captured by 12 of the 14 reviewed papers, but the choice of measures was inconsistent across studies. What is new and conclusion In recent high-quality studies of deprescribing interventions, we found limited acknowledgement of factors known to be important to successful implementation and inconsistent reporting of intermediate outcomes. These findings indicate missed opportunities to understand the factors underlying study outcomes. As a result, we run the risk of rejecting worthwhile interventions due to negative results, when the correct interpretation might be that they failed in implementation. In other words, they were 'lost in translation'. Studies that rigorously examine and report on the implementation process are needed to tease apart this important distinction.

Plasmablastic lymphoma (PBL) is a rare subtype of large B-cell lymphoma most commonly seen in immunocompromised patients, particularly in those with HIV infection. In these patients, PBL often affects the oral mucosa.1 Other immunocompromised states, including immunosuppression for organ transplant and immunosenescence, have been linked to PBL.1 Epstein-Barr virus (EBV) reactivation is thought to be a major driver of PBL.1 PBL is characterized histologically by an absence of B- and T-cell markers and expression of plasma cell markers CD38 and CD138. The median overall survival of HIV-positive and HIV-negative patients with PBL is 15 months and 9 months, respectively.1 Some patients with PBL present with primary cutaneous disease (pcPBL), defined as no systemic involvement. These patients have a unique clinical presentation and an indolent course. We report the first case of iatrogenic pcPBL secondary to romidepsin therapy for primary cutaneous peripheral T-cell lymphoma not otherwise specified (pcPTCL-NOS).

Background: Triple antithrombotic therapy including an anticoagulant, P2Y12 inhibitor, and aspirin increases bleed risk up to 27%. The components of this regimen can vary, which may impact bleed risk. Objective: To compare the safety of various triple antithrombotic regimens. Methods: An Institutional Review Board approved retrospective cohort study was conducted from 2014 to 2017. Patients admitted to a large urban health system on triple therapy were evaluated for inclusion. The primary outcome compared rates of International Society of Thrombosis and Hemostasis major and clinically relevant nonmajor bleeding during index admission or within 90 days in patients receiving warfarin, rivaroxaban, or apixaban; aspirin; and a P2Y12 inhibitor. A multivariable logistic regression assessed the association between bleeding, antithrombotic use, and relevant confounding variables. Results: Three hundred and seventy-two patients were included: 238 patients received warfarin, 63 received rivaroxaban, and 71 received apixaban. Forty-five patients (12.1%) experienced a bleed, 25 of which (55.6%) were major. The rate of bleeding was 12.2% (n = 29) with warfarin, 14.3% (n = 9) with rivaroxaban, and 9.9% (n = 7) with apixaban ( P = .7335). The use of prasugrel versus clopidogrel (OR 4.35, 95% CI 1.20-15.72; P = .025) and admission hemoglobin less than 12 mg/dL (OR 2.54, 95% CI 1.28-5.04; P = .008) were identified as risk factors associated with bleeding in the model. Conclusion: In patients on triple antithrombotic therapy, choice of oral anticoagulant did not impact bleeding rates, but use of prasugrel and a low baseline hemoglobin were associated with increased bleed rates which warrants further investigation.

The integral role of microbial communities in plant growth and health is now widely recognized, and, increasingly, the constituents of the microbiome are being defined. While phylogenetic surveys have revealed the taxa present in a microbiome and show that this composition can depend on, and respond to, environmental perturbations, the challenge shifts to determining why particular microbes are selected and how they collectively function in concert with their host. In this study, we targeted the isolation of representative bacterial strains from environmental samples of Populus roots using a direct plating approach and compared them to amplicon-based sequencing analysis of root samples. The resulting culture collection contains 3,211 unique isolates representing 10 classes, 18 orders, 45 families, and 120 genera from 6 phyla, based on 16S rRNA gene sequence analysis. The collection accounts for ∼50% of the natural community of plant-associated bacteria as determined by phylogenetic analysis. Additionally, a representative set of 553 had their genomes sequenced to facilitate functional analyses. The top sequence variants in the amplicon data, identified as Pseudomonas, had multiple representatives within the culture collection. We then explore a simplified microbiome, comprised of 10 strains representing abundant taxa from environmental samples, and tested for their ability to reproducibly colonize Populus root tissue. The 10-member simplified community was able to reproducibly colonize on Populus roots after 21 days, with some taxa found in surface-sterilized aboveground tissue. This study presents a comprehensive collection of bacteria isolated from Populus for use in exploring microbial function and community inoculation experiments to understand basic concepts of plant and environmental selection. IMPORTANCE Microbial communities play an integral role in the health and survival of their plant hosts. Many studies have identified key members in these communities and led to the use of synthetic communities for elucidating their function; however, these studies are limited by the available cultured bacterial representatives. Here, we present a bacterial culture collection comprising 3,211 isolates that is representative of the root community of Populus. We then demonstrate the ability to examine underlying microbe-microbe interactions using a synthetic community approach. This culture collection will allow for the greater exploration of the microbial community function through targeted experimentation and manipulation.

We report a case of a 13-year-old boy with extensive lymphomatoid papulosis (LyP) involving his elbows, forearms, proximal thighs, and right hip, with treatment-resistant nodules on his right forearm. He was treated with full-body narrowband ultraviolet B and targeted photodynamic therapy (PDT) with 20% aminolevulinic acid (ALA). After two months, there was complete resolution of the right forearm nodules. Due to its minimal toxicity, PDT offers unique advantages and may be considered for pediatric LyP patients with symptomatic, localized disease resistant to conventional treatments.

Background Outpatient prescriptions comprise 60% of antibiotic use. This study prospectively identified inappropriate antibiotic use enabling a focused approach to outpatient antimicrobial stewardship. Methods Outpatients at the Veterans Affairs Western New York Healthcare System were identified via an electronic antibiotic alert from June 2017 to September 2017. Descriptive statistics and multivariable logistic regression identified stewardship targets. Results Of the 1,063 patients, 40% of antibiotic prescriptions were not indicated. Urinary tract infections (21%), bronchitis (20%), skin structure infections (17%), and sinusitis (10%) were common causes of inappropriate antibiotic use. Azithromycin (37%) was prescribed unnecessarily most often, followed by ciprofloxacin (16%), amoxicillin/clavulanate (13%), and cephalexin (12%). The correct drug was chosen in 52%, dose in 81%, and duration in 75% of patients. When the antibiotic was indicated, the correct drug was 2.9 times more likely to be prescribed and 2 times more likely to have the correct duration and receive care in the emergency room. Discussion Focusing on 4 drugs; amoxicillin/clavulanate, azithromycin, ciprofloxacin, and cephalexin accounted for 80% of unnecessary drug use. This study provides a guide to concentrate efforts during implementation of an outpatient stewardship program. Conclusions Poor antibiotic prescribing was found in the outpatient setting. This study identifies areas for improvement via stewardship.

Cycline antibiotics (CAs) are commonly used to treat acne, blepharitis, and dry eye syndrome. Prescribers or patients may hesitate to use Cas because they may increase the risk of pseudotumor cerebri syndrome (PTCS).We sought to assess whether CA use is associated with an increased risk of PTCS or papilledema and whether the risk depends upon dosage or duration of CA intake.We studied patients 12 to 65 years of age who were diagnosed with acne, blepharitis, or dry eye syndrome, who were enrolled in a nationwide managed care network between January 1, 2001 and December 31, 2015, and who had no preexisting diagnosis of papilledema or PTCS. Multivariable Cox regression modeling was used to assess the risk of developing papilledema or PTCS from exposure to CAs.Among the 728,811 eligible enrollees (mean age, 34.7 years; 72% female), 42.0% filled ≥1 CA prescription. Of the 305,823 CA users, 170 (0.06%) were diagnosed with papilledema or PTCS. By comparison, of the 57.0% with no record of CA use, 121 (0.03%) were diagnosed with papilledema or PTCS (P .0001). In the unadjusted model, every additional year of CA use was associated with a 70% (doxycycline: hazard ratio, 1.70 [95% confidence interval 0.98-2.97]; P = .06) or 91% (minocycline: hazard ratio, 1.91 [95% confidence interval 1.11-3.29]; P = .02) increased hazard of papilledema/PTCS relative to nonusers of CAs. After adjustment for confounders, the increased hazard of PTCS/papilledema with CA use was no longer statistically significant (P = .06, doxycycline; P = .08, minocycline).This study relies on claims data, which lack clinical data.This study offers some evidence that CAs may increase the risk of PTCS/papilledema. However, after accounting for confounding factors in our multivariable models, we found no statistically significant association between CA use and the development of PTCS. Moreover, there was no dose-response effect whereby greater CA use was associated with a higher PTCS risk.

Although the molecular effects of many anaesthetics have been well characterized, a network-level explanation for how these changes lead to loss of consciousness remains unclear. Studies using electroencephalography have characterized changes in neural oscillations in the cortex at specific frequency bands during propofol-induced anaesthesia and modelling work suggests these changes result from changes in thalamocortical functional connectivity. However, it is unclear if the neurophysiological changes seen at the cortex are due to enhanced or disrupted thalamocortical communication. Direct recordings from these sites during anaesthesia that could be used to confirm such models are rare. We recorded local field potentials from the ventral intermediate nucleus of the thalamus and electrocorticography signals from the ipsilateral sensorimotor cortex in 10 patients undergoing deep brain stimulation surgery. Signals were acquired during induction of propofol anaesthesia while subjects were resting. After confirming direct structural connectivity between the thalamus and the cortical recording site, we investigated propofol-associated changes in thalamic and cortical local power as well as thalamocortical functional connectivity, as measured with coherence, debiased weighted phase lag index, and phase amplitude coupling. Propofol anaesthesia resulted in local power increases at α frequencies (8-12 Hz) across both thalamic and cortical areas. At sensorimotor cortices, there was a broadband power increase (12-100 Hz), while the power of this same broad frequency band was suppressed within the thalamus. Despite the increase in local α power both within the thalamus and cortex, thalamocortical coherence and debiased weighted phase lag index in the α/low β frequencies (8-16 Hz, which was present in the awake state) significantly decreased with propofol administration (P < 0.05, two group test of coherence). Likewise, propofol administration resulted in decreased phase amplitude coupling between the phase of α/low β in the thalamus and the amplitude of broadband gamma (50-200 Hz) in the cortex (P = 0.031, Wilcoxon signed-rank test). We also report phase amplitude coupling between the phase of slow wave oscillations (0.1-1 Hz) and amplitude of broadband frequencies (8-200 Hz) within the cortex and across thalamocortical connections, during anaesthesia, both following a peak-max pattern. While confirming α-power increases with propofol administration both in thalamus and cortex, we observed decreased thalamocortical connectivity, contradicting models that suggest increasing cortical low frequency power is necessarily related to increased thalamocortical coherence but in support of the theory that propofol-induced loss of consciousness is associated with disrupted thalamocortical communication.

BACKGROUND The development of procedural skills is necessary for medical students. Computer-based video instruction (CBVI) increases knowledge and procedural skills. OBJECTIVE This pilot study's aim was to investigate the usefulness of CBVI in dermatologic procedure training for medical students and secondarily assess students' overall perception of the field of dermatology. METHODS Twenty-nine first- and second-year medical students were randomly assigned to the CVBI group or control group, in addition to in-person instructor demonstration of shave and punch biopsies using fresh cadaver tissue. Blinded evaluators graded student performances using a five-point Likert scale immediately after demonstration, and 1 week later to assess knowledge retention. RESULTS In overall performance, the CBVI group demonstrated higher scores both in shave (3.54 vs 2.59, p = .01) and punch biopsies (3.63 vs 2.88, p = .01) at immediate recall and knowledge retention (3.68 vs 2.67, p = .01; 4.00 vs 2.99, p < .001, respectively). Approximately 33.3% of the students stated that the experience increased their interest in the field of dermatology. CONCLUSION Incorporation of CBVI into the dermatology curriculum augments medical students' procedural skills. The CBVI group performed significantly better in all 7 grading categories for shave biopsy and in 5 of 7 categories for punch biopsy. Integration of procedural laboratory tests raises students' interest in dermatology.

Introduction: Antineutrophil cytoplasm antibody-associated vasculitides encompass a diverse spectrum of autoimmune diseases characterized by necrotizing small vessel vasculitis. Ocular manifestations may be the presenting findings of antineutrophil cytoplasm antibody-associated vasculitides. Methods: Single, retrospective case study. Results: We report the rare case of a 55-year-old woman with a cilioretinal artery occlusion as the presenting feature of perinuclear antineutrophil cytoplasm antibody-associated microscopic polyangiitis. Conclusions: Although rare, antineutrophil cytoplasm antibody-related vasculitis should be considered in any retinal vascular occlusion, particularly in the setting of patients with new vague headaches and a paucity of vasculopathic risk factors.

BACKGROUND Little research has been done in teledermatology to examine the effects of standardized templates and subject-specific learning modules. METHODS We performed a prospective study examining the effects of standardized templates and standardized cutaneous oncology learning modules on teledermatology referrals at Mayo Clinic. This data was then compared to previous teledermatology referrals before standardized templates were adopted. RESULTS A total of 42 teledermatology consultations were performed during the 4-month study period. The use of standardized templates resulted in an absolute reduction in face-to-face referrals. Teledermatology consultation increased the absolute diagnostic and management concordance by 26.2% (P = 0.02) and 33.3% (P < 0.01), respectively, and decreased the absolute diagnostic and management discordance by 19.1% (P = 0.03) and 31.0% (P < 0.01), respectively. The largest knowledge gaps were identified in cutaneous oncology. Educational intervention improved theoretical referral rates and confidence in diagnosis and management overall. CONCLUSION The implementation of standardized intake templates reduces the rate of face-to-face referrals. Teledermatology improves primary care-based dermatological care and reduces theoretical referral rates.

The authors report the case of a 75-year-old man with preexisting glaucoma and recurrent retinal detachment who underwent intraocular silicone oil placement OD resulting in subsequent retrolaminar silicone oil migration to the optic chiasm and vision loss OS. MRI showed silicone oil tracking posteriorly along the right optic nerve to the chiasm. He was placed on high-dose corticosteroids and underwent a successful optic nerve sheath fenestration with improvement of vision in the contralateral eye. Clinicians should be cognizant of the potential for translaminar posterior migration of intraocular silicone oil, as well as the utility of optic nerve sheath fenestration to decompress the anterior visual pathways and restore vision.

The aim of this study was to compare fecal microbiome, plasma, fecal and urine metabolomes, and serum biochemistry of adult companion dogs according to body condition scores. Blood, serum/plasma, urine, and fecal samples were collected from 66 clinically healthy, adult companion dogs of either normal weight (NW), overweight (OW), or obese dogs (OB). analyses included fecal microbiome analyses via 16S ribosomal RNA gene amplicon; sequencing, nontargeted plasma, fecal, and urine metabolomics using liquid chromatography/gas chromatography-mass; spectrometry, and serum biochemistry for each dog. Few significant differences in serum biochemistry and fecal microbiome Operational Taxonomic Unit (OTU) were found between weight groups and there was high OTU variation between individual dogs. NW dogs had higher relative abundance of the genus Eubacterium (log-fold change 4.3, adjusted P value = .003) and lower relative abundance of the family Bifidobacteriaceae (log-fold change −3.6, adjusted P value = .02) compared to OB dogs. The microbiome of NW dogs had higher OTU richness compared with OB dogs. Metabolome analysis showed 185 plasma, 37 fecal, and 45 urine metabolites that significantly differed between NW and OW or OB dogs. There were notable significant differences in relative abundance of several plasma phospholipid moieties and fecal volatile fatty acids between weight phenotypes. The combinations of host and gut microbiota and metabolic shifts suggest a pattern that could help detection of early metabolic changes in overweight dogs before the development of obesity related disease. The results of this study support the need for continued investigation into sensitive measures of metabolic aberrancies in overweight dogs.

Background: We present a rare case of a ruptured neoplastic aneurysms (NCA) caused by metastatic spread of triple-negative breast cancer (TNBC) in a female patient in her 60s. The patient had a medical history of TNBC and presented to the emergency department after experiencing 3 days of persistent headache. Case Description: Head computed tomography (CT) revealed a small volume subarachnoid hemorrhage and digital subtraction angiography revealed a 3.9 x 3.5 x 4.2 mm aneurysm or pseudoaneurysm involving the left middle cerebral artery. The aneurysm was successfully clipped and resected, and histopathological examination confirmed triple-negative invasive ductal breast carcinoma within the aneurysm. Six weeks after surgery, she underwent stereotactic radiosurgery and began treatment with chemotherapy. Four months later, the patient presented once again with acute severe headache, and magnetic resonance imaging revealed multiple small lesions within the brain parenchyma, compatible with new metastatic deposits. The patient was subsequently treated with whole-brain radiation therapy and chemotherapy. Over the ensuing 4 months, CT revealed progression of malignancy in the chest, abdomen, and pelvis. Chemotherapy and radiation therapy were terminated, and the patient unfortunately succumbed to her disease 6 months later. Conclusion: In patients with NCA with poor prognosis due to aggressive brain metastases, treatments that improve quality of life and survival time should be favored.

Klippel-Feil syndrome (KFS) is characterized by failed segmentation of the cervical spine leading to inappropriately fused vertebral bodies. A 64-year-old male with a previous L5-S1 decompression presented with significant neck pain with radiation into the entire right upper extremity and hand. Imaging demonstrated fusion of the vertebral bodies at C2-3, C4-6, and C7-T1 with associated disc bulges at C3-4 and C6-7. Common presentation of KFS includes significant spondylosis and cervical myeloradiculopathy in addition to the classic triad of short neck, low posterior hairline, and restricted neck motion. We present exemplary images of this rare condition to aid clinicians in future diagnoses.

The visualization of intracranial epidermoid tumors is often limited by difficulties associated with distinguishing the tumor from the surrounding cerebrospinal fluid using traditional computed tomography (CT) or magnetic resonance imaging (MRI) modalities. This report describes our experience using CT cisternography to visualize intracranial epidermoid tumors in three illustrative cases. CT cisternography of the epidermoid tumor provides more clarity and precision compared to traditional neuroimaging modalities. We demonstrate the feasibility of using CT cisternography to produce high-resolution images with well-defined tumor margins that can be used effectively for precise SRS treatment planning.

BACKGROUND: Previous studies have demonstrated increasing mortality due to falls among older adults. The objective of this study was to determine whether there was an increase in fall risk increasing drug prescribing and if this is concurrent with an increase in fall-related mortality in persons 65 years and older in the United States. METHODS: The study is a serial cross-sectional analysis utilizing data from both the National Vital Statistics System (NVSS) and the medical expenditure panel survey (MEPS) for years 1999–2017. Adults aged 65 years and older were evaluated for death due to falls from the NVSS and for prescription fills of fall risk increasing drugs per the Stopping Elderly Accidents, Deaths, and Injuries-Rx (STEADI-Rx) fall checklist from the MEPS. RESULTS: The analysis included 374 972 fall-related mortalities and 7 858 177 122 fills of fall risk increasing drugs. 563 037 964 persons age 65 and older received at least one fall risk increasing drug. Age-adjusted mortality due to falls increased from 29.40 per 100 000 in 1999 to 63.27 per 100 000 in 2017. The percent of persons who received at least one prescription for a fall risk increasing drug increased from 57% in 1999 to 94% in 2017 (p for trend

Objectives Prone positioning has been shown to be a beneficial adjunctive supportive measure for patients who develop acute respiratory distress syndrome. Studies have excluded patients with reduced intracranial compliance, whereby patients with concomitant neurologic diagnoses and acute respiratory distress syndrome have no defined treatment algorithm or recommendations for management. In this study, we aim to determine the safety and feasibility of prone positioning in the neurologically ill patients. Design and setting A systematic review of the literature, performed in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analyses 2009 guidelines, yielded 10 articles for analysis. Using consensus from these articles, in combination with review of multi-institutional proning protocols for patients with nonneurologic conditions, a proning protocol for patients with intracranial pathology and concomitant acute respiratory distress syndrome was developed. Measurements and main results Among 10 studies included in the final analysis, we found that prone positioning is safe and feasible in the neurologically ill patients with acute respiratory distress syndrome. Increased intracranial pressure and compromised cerebral perfusion pressure may occur with prone positioning. We propose a prone positioning protocol for the neurologically ill patients who require frequent neurologic examinations and intracranial monitoring. Conclusions Although elevations in intracranial pressure and reductions in cerebral perfusion pressure do occur during proning, they may not occur to a degree that would warrant exclusion of prone ventilation as a treatment modality for patients with acute respiratory distress syndrome and concomitant neurologic diagnoses. In cases where intracranial pressure, cerebral perfusion pressure, and brain tissue oxygenation can be monitored, prone position ventilation should be considered a safe and viable therapy.

STUDY DESIGN Retrospective review at a single institution of all adult patients who underwent elective lumbar fusion surgery for degenerative spinal disease from 2013 to 2018. Reoperation rates and change in clinical management due to routine imaging findings were the primary outcomes. OBJECTIVE To investigate what effects immediate routine postoperative imaging has on the clinical management of patients following lumbar fusion surgery. SUMMARY OF BACKGROUND DATA The clinical utility of routine postoperative imaging following lumbar fusion surgery remains uncertain. Existing studies on the clinical utility of postoperative imaging in lumbar fusion patients have largely focused on imaging obtained post-discharge. We present a retrospective analysis that to our knowledge is the first study reporting on the clinical utility of routine imaging in lumbar fusion patients during the immediate postoperative period. METHODS The medical records of patients who had undergone elective lumbar instrumented fusion for degenerative disease from 2013 to 2018 by neurosurgeons across one regional healthcare system were retrospectively analyzed. Inpatient records and imaging orders for patients were reviewed. Routine immediate postoperative imaging was defined by any lumbar spine imaging prior to discharge in the absence of specific indications. RESULTS Analysis identified 115 patients who underwent elective lumbar instrumented fusion for degenerative disease. One-hundred-twelve patients received routine postoperative imaging. Routine imaging was abnormal in four patients (4%). There was one instance (

Mitochondrial dysfunction is a hallmark of Parkinson’s disease (PD). Astrocytes are the most abundant glial cell type in the brain and are thought to play a pivotal role in the progression of PD. Emerging evidence suggests that many astrocytic functions, including glutamate metabolism, Ca2+ signaling, fatty acid metabolism, antioxidant production, and inflammation are dependent on healthy mitochondria. Here, we review how mitochondrial dysfunction impacts astrocytes, highlighting translational gaps and opening new questions for therapeutic development.

Infection with Influenza A virus can lead to the development of encephalitis and subsequent neurological deficits ranging from headaches to neurodegeneration. Post-encephalitic parkinsonism has been reported in surviving patients of H1N1 infections, but not all cases of encephalitic H1N1 infection present with these neurological symptoms, suggesting that interactions with an environmental neurotoxin could promote more severe neurological damage. The heavy metal, manganese (Mn), is a potential interacting factor with H1N1 because excessive exposure early in life can induce long-lasting effects on neurological function through inflammatory activation of glial cells. In the current study, we used a two-hit model of neurotoxin-pathogen exposure to examine whether exposure to Mn during juvenile development would induce a more severe neuropathological response following infection with H1N1 in adulthood. To test this hypothesis, C57BL/6 mice were exposed to MnCl2 in drinking water (50 mg/kg/day) for 30 days from days 21–51 postnatal, then infected intranasally with H1N1 three weeks later. Analyses of dopaminergic neurons, microglia and astrocytes in basal ganglia indicated that although there was no significant loss of dopaminergic neurons within the substantia nigra pars compacta, there was more pronounced activation of microglia and astrocytes in animals sequentially exposed to Mn and H1N1, as well as altered patterns of histone acetylation. Whole transcriptome Next Generation Sequencing (RNASeq) analysis was performed on the substantia nigra and revealed unique patterns of gene expression in the dual-exposed group, including genes involved in antioxidant activation, mitophagy and neurodegeneration. Taken together, these results suggest that exposure to elevated levels of Mn during juvenile development could sensitize glial cells to more severe neuro-immune responses to influenza infection later in life through persistent epigenetic changes.

Significance Parkinson’s disease (PD) is the second most prevalent neurodegenerative disease of aging, affecting approximately 10 million patients worldwide with no approved therapies to modify progression of disease. Further understanding of the cellular mechanisms contributing to the development of PD is necessary to discover therapies. Here, we characterize the role of a recently identified GWAS hit for sporadic PD, ITPKB, in the aggregation of α-synuclein, the primary pathological feature of disease. These results identify inhibition of inositol-1,4,5,-triphosphate (IP3)-mediated ER-to-mitochondria calcium release as a potential therapeutic approach for reducing neuropathology in PD., Inositol-1,4,5-triphosphate (IP3) kinase B (ITPKB) is a ubiquitously expressed lipid kinase that inactivates IP3, a secondary messenger that stimulates calcium release from the endoplasmic reticulum (ER). Genome-wide association studies have identified common variants in the ITPKB gene locus associated with reduced risk of sporadic Parkinson’s disease (PD). Here, we investigate whether ITPKB activity or expression level impacts PD phenotypes in cellular and animal models. In primary neurons, knockdown or pharmacological inhibition of ITPKB increased levels of phosphorylated, insoluble α-synuclein pathology following treatment with α-synuclein preformed fibrils (PFFs). Conversely, ITPKB overexpression reduced PFF-induced α-synuclein aggregation. We also demonstrate that ITPKB inhibition or knockdown increases intracellular calcium levels in neurons, leading to an accumulation of calcium in mitochondria that increases respiration and inhibits the initiation of autophagy, suggesting that ITPKB regulates α-synuclein pathology by inhibiting ER-to-mitochondria calcium transport. Furthermore, the effects of ITPKB on mitochondrial calcium and respiration were prevented by pretreatment with pharmacological inhibitors of the mitochondrial calcium uniporter complex, which was also sufficient to reduce α-synuclein pathology in PFF-treated neurons. Taken together, these results identify ITPKB as a negative regulator of α-synuclein aggregation and highlight modulation of ER-to-mitochondria calcium flux as a therapeutic strategy for the treatment of sporadic PD.

For more than 20 years, physiologists have observed a morning-to-evening increase in human muscle strength. Recent data suggest that time-of-day differences are the result of intrinsic, nonneural, muscle factors. We evaluate circadian clock data sets from human and mouse circadian studies and highlight possible mechanisms through which the muscle circadian clock may contribute to time-of-day muscle strength outcomes.

Graphical abstract, Microbial communities colonize plant tissues and contribute to host function. How these communities form and how individual members contribute to shaping the microbial community are not well understood. Synthetic microbial communities, where defined individual isolates are combined, can serve as valuable model systems for uncovering the organizational principles of communities. Using genome-defined organisms, systematic analysis by computationally-based network reconstruction can lead to mechanistic insights and the metabolic interactions between species. In this study, 10 bacterial strains isolated from the Populus deltoides rhizosphere were combined and passaged in two different media environments to form stable microbial communities. The membership and relative abundances of the strains stabilized after around 5 growth cycles and resulted in just a few dominant strains that depended on the medium. To unravel the underlying metabolic interactions, flux balance analysis was used to model microbial growth and identify potential metabolic exchanges involved in shaping the microbial communities. These analyses were complemented by growth curves of the individual isolates, pairwise interaction screens, and metaproteomics of the community. A fast growth rate is identified as one factor that can provide an advantage for maintaining presence in the community. Final community selection can also depend on selective antagonistic relationships and metabolic exchanges. Revealing the mechanisms of interaction among plant-associated microorganisms provides insights into strategies for engineering microbial communities that can potentially increase plant growth and disease resistance. Further, deciphering the membership and metabolic potentials of a bacterial community will enable the design of synthetic communities with desired biological functions.

Burning scrotum syndrome (male genital dysesthesia or red scrotum syndrome) is a cutaneous dysesthesia characterized by persistent erythema of the anterior half of the scrotum.1 It is accompanied by a burning sensation, heat, irritation, and hyperalgesia of the scrotum.1 Previous reports have shown oral gabapentin, pregabalin, doxycycline, and beta-blockers as possible treatment modalities.2, 3, 4 Here, we report a case of burning scrotum syndrome treated with indomethacin.

Pharmacists play a key role in deprescribing medications. Incorporation of this concept into pharmacy school curricula is important in ensuring that graduates can address the complex needs of an aging population. The aims of this study were to assess if and how student pharmacists were exposed to deprescribing within their curriculum, to assess students&rsquo, perceptions regarding their attitudes, ability and confidence in deprescribing, and to assess if reported curricular exposure to this topic resulted in improved perceptions or objective knowledge assessment scores. An electronic survey was distributed to third- and fourth-year pharmacy students at 132 schools of pharmacy. The survey included three sections including: (i) demographics and questions on their exposure to deprescribing and other experiences within their curriculum, (ii) questions regarding their attitudes, ability, and confidence regarding deprescribing on a 5-point Likert-scale, (iii) a knowledge assessment on polypharmacy and deprescribing in the form of 12 multiple-choice questions. Likert-scale questions were analyzed as scales utilizing the mean score for items measuring student perceptions regarding deprescribing attitudes, ability, and confidence. Comparisons were made on each variable between students with and without curricular exposure to deprescribing using t-tests. Ninety-one responses were included in the analysis. Only 59.3% of respondents reported exposure to deprescribing in their didactic coursework. The mean scores on the polypharmacy and deprescribing knowledge assessments were 61.0% and 64.5%, respectively. Those with exposure to deprescribing concepts within their curriculum were more likely to agree that their school&rsquo, s curriculum prepared them to deprescribe in clinical practice (t(89) = &minus, 2.26, p = 0.03). Pharmacy schools should evaluate their curricula and consider the addition of specific deprescribing objectives and outcome measures for didactic and experiential training.

Background Cranial surgical site infections (cSSIs) are associated with significant morbidity. Measures to reduce cSSI are necessary to reduce patient morbidity as well as hospital costs and resource utilization. Objective To identify and characterize interventions or bundled interventions aimed at reduction of the incidence of cranial surgical site infections. Methods A systematic review of the literature was conducted according to the PRISMA guidelines. The search strategy included randomized trials, quasi-experimental studies, cohort studies, and case series published between 2000 and 2020 that evaluated interventions implemented to reduce cSSI. Bias assessments and data extraction were performed on included studies. Results The initial search generated 1249 studies. Application of inclusion and exclusion criteria and review of references yielded 15 single-intervention and 6 bundled-intervention studies. The single interventions included handwashing protocols, use of vancomycin powder, hair washing and clipping practices, and incision closure techniques. Bundled interventions addressed a variety of preoperative, intraoperative, and postoperative changes. Despite a lack of strong evidence to support the adoption of statistically significant interventions, the use of vancomycin powder may be effective in reducing cSSI. In addition, bundled interventions that involved cultural changes, such as increased teaching/education, personal accountability, direct observation, and feedback, showed some success in decreasing SSI rates. Conclusions The strength of the conclusions is limited by small sample sizes, study heterogeneity, relatively low cSSI incidence, and high case variability. Some evidence supports the use of intraoperative vancomycin powder in adult noncranioplasty cases and the application of accountability, teaching, and surveillance of faculty, particularly those early in training.

Background The Penumbra SMART coil is a novel device that becomes progressively softer from its distal to proximal end to maximize coil packing and prevent microcatheter prolapse or coil migration. Here, we report a large series of patients detailing the long-term experience of a single institution using the SMART coil among patients with intracranial aneurysms (IAs). Methods Prospective data of 105 consecutive patients with 106 IAs treated using SMART coils was collected between March 2015 and July 2018. Clinical and angiographic data were analyzed. Results Forty-nine patients (46.7%) presented with subarachnoid hemorrhage and 16 (14.2%) had recurrent aneurysms. Two patients had minor intraprocedural ruptures and remained neurologically stable. One patient had a thromboembolic complication with progressive neurologic decline. There was only one case microcatheter prolapse related to placement of a stent before coiling. An initial post-treatment modified Raymond-Roy Occlusion Classification (mRROC) I or II closure was achieved in 56 (52.8%) aneurysms. The average time to last follow-up was 8.4 months at which 70 (81.4%) aneurysms had mRROC I or II occlusion and a major recurrence was seen in 5 (5.8%) patients. Thirteen (12.3%) aneurysms required re-treatment of which one aneurysm was clipped. Conclusions The Penumbra SMART coil is safe and effective for the endovascular treatment of appropriately selected IAs. Additional studies at multiple centers comparing safety and efficacy profile over long-term periods to other mainstream coils are necessary.

• PURPOSE: To characterize the clinical features of idiopathic intracranial hypertension (IIH) in patients > 50 years of age compared to the typical IIH population and existing data for this older cohort. • DESIGN: Retrospective, clinical cohort study. • METHODS: Medical records of 65 patients > 50 years of age at first diagnosis of IIH were reviewed based on the Modified Dandy Criteria from 4 academic centers. Each center provided randomly selected controls from IIH patients < 50 years of age for each study patient at their location. Data recorded included patient demographics, presenting symptoms, medications, coexisting medical conditions, cerebrospinal fluid (CSF) opening pressure, treatments, and neuro-ophthalmic data from initial and final visits. • RESULTS: Compared to controls, the older cohort showed the following characteristics: fewer females (n = 51 [78.5%] vs. controls: n = 60 [92.3%]; P = .045), fewer headaches (n = 33 [50.8%] vs. controls: 52 [80.0%]; P = .001), more frequent incidental discoveries of papilledema (n = 19 [29.2%] vs. controls: 7 [10.8%]; P = .015), and lower CSF opening pressure [median: 33 cm H(2)O [range: 21-58 cm H(2)O] vs. the median for controls: 34 cm H(2)O [range: 24-67 cm H(2)O; P = .029). • CONCLUSIONS: Patients with IIH diagnosed at > 50 years of age were less often female and had lower CSF opening pressure, fewer headaches, a higher chance of incidentally identified papilledema, and body mass index similar to that of younger IIH patients. Older IIH onset was not associated with worse visual outcome.

Spinal cord tumors (SCTs) may rarely cause increased intracranial pressure without hydrocephalus (IICPWH). A review of the English literature published after 1970 revealed 29 cases of IICPWH secondary to SCT. The following data were acquired: demographics, tumor characteristics, ophthalmic and neurological manifestations, and cerebral spinal fluid (CSF) features. We summarize the existing literature regarding various theories of pathophysiology, spinal imaging recommendations, and treatment modalities used in managing such patients. Patients with papilledema who also have neurological signs or symptoms of myelopathy or elevated CSF protein particularly in the setting of an atypical demographic for pseudotumor cerebri should raise a suspicion for a spinal tumor and prompt further investigation with a spinal MRI.

Background Despite making great strides in improving the treatment of diseases, the minimization of unintended harm by medication therapy continues to be a major hurdle facing the health care system. Medication error and prescription of potentially inappropriate medications (PIMs) represent a prevalent source of harm to patients and are associated with increased rates of adverse events, hospitalizations, and increased health care costs. Attempts to improve medication management systems in primary care have had mixed results. Implementation of new interventions is difficult because of complex contextual factors within the health care system. Abstraction hierarchy (AH), the first step in cognitive work analysis (CWA), is used by human factors practitioners to describe complex sociotechnical systems. Although initially intended for the nuclear power domain and interface design, AH has been used successfully to aid the redesign of numerous health care systems such as the design of decision support tools, mobile patient monitoring apps, and a telephone triage system. Objective This paper aims to refine our understanding of the primary care office in relation to a patient’s medication through the development of an AH. Emphasis was placed on the elements related to medication safety to provide guidance for the design of a safer medication management system in primary care. Methods The AH development was guided by the methodology used by seminal CWA literature. It was initially developed by 2 authors and later fine-tuned by an expert panel of clinicians, social scientists, and a human factors engineer. It was subsequently refined until an agreement was reached. A means-ends analysis was performed and described for the nodes of interest. The model represents the primary care office space through functional purposes, values and priorities, function-related purposes, object-related processes, and physical objects. Results This model depicts the medication management system at various levels of abstraction. The resulting components must be balanced and coordinated to provide medical treatment with limited health care resources. Understanding the physical and informational constraints on activities that occur in a primary care office depicted in the AH defines areas in which medication safety can be improved. Conclusions Numerous means-ends relationships were identified and analyzed. These can be further evaluated depending on the specific needs of the user. Recommendations for optimizing a medication management system in a primary care facility were made. Individual practices can use AH for clinical redesign to improve prescribing and deprescribing practices.

Purpose of review Although deep learning represents an exciting platform for the development of risk stratification models, it is challenging to evaluate these models beyond simple statistical measures of success, which do not always provide insight into a model’s clinical utility. Here we propose a framework for evaluating deep learning models and discuss a number of interesting applications in light of these rubrics. Recent findings Data scientists and clinicians alike have applied a variety of deep learning techniques to both medical images and structured electronic medical record data. In many cases, these methods have resulted in risk stratification models that have improved discriminatory ability relative to more straightforward methods. Nevertheless, in many instances, it remains unclear how useful the resulting models are to practicing clinicians. Summary To be useful, deep learning models for cardiovascular risk stratification must not only be accurate but they must also provide insight into when they are likely to yield inaccurate results and be explainable in the sense that health care providers can understand why the model arrives at a particular result. These additional criteria help to ensure that the model can be faithfully applied to the demographic for which it is most accurate.

Volatile organic compounds (VOCs), such as vinyl chloride (VC), can be directly toxic at high concentrations. However, we have shown that ‘nontoxic’ exposures to VC and its metabolite chloroethanol (CE) enhances experimental non-alcoholic fatty liver disease (NAFLD), suggesting an unpredicted interaction. Importantly, VOC exposure has been identified as a potential risk factor for the development of obesity and its sequelae in humans. As there is a known axis between adipose and hepatic tissue in NAFLD, the impact of CE on white adipose tissue (WAT) inflammation and lipolysis was investigated. Mice were administered CE (or vehicle) once, after 10 weeks of being fed high-fat or low-fat diet (LFD). CE significantly enhanced hepatic steatosis and inflammation caused by HFD. HFD significantly increased the size of epididymal fat pads, which was enhanced by CE. The relative size of adipocyte lipid droplets increased by HFD + CE, which was also correlated with increased expression of lipid-associated proteins (e.g., PLINs). CE also enhanced HFD-induced indices of WAT inflammation, and ER stress. Hepatic-derived circulating FGF21, a major modulator of WAT lipolysis, which is hypothesized to thereby regulate hepatic steatosis, was significantly increased by CE in animals fed HFD. Taken together these data support the hypothesis that environmental toxicant exposure can exacerbate the severity of NAFLD/NASH, involving the liver-adipose axis in this process. Specifically, CE enhances local inflammation and alters lipid metabolism and WAT-mediated hepatic steatosis due to changes in WAT lipolysis.

Purpose As a general rule, homonymous hemianopic defects localize to the retrochiasmal visual pathway and a monocular defect localizes at or anterior to the chiasm. We report three patients with a monocular hemianopia on automated static perimetry following cerebral stroke. Observations In this retrospective, consecutive case series, the charts of individuals presenting with stroke and monocular hemianopia were reviewed. Three individuals suffered cerebral stroke. Automated, static perimetry revealed a normal visual field in one eye and a monocular hemianopia in the other eye. No other neurologic, orbital or ocular causes were found. Conclusions and Importance To our knowledge, this is the first report of this pattern of visual field loss following stroke, and we hypothesize that this phenomenon may be a unique feature of automated perimetry. Magnetic resonance imaging of the brain could be considered in patients with a monocular hemianopia on static perimetry.

Comprehensive characterization of the genomic landscape of epidermal growth factor receptor (EGFR)-mutated lung cancers have identified patterns of secondary mutations beyond the primary oncogenic EGFR mutation. These include concurrent pathogenic alterations affecting p53 (60-65%), RTKs (5-10%), PIK3CA/KRAS (3-23%), Wnt (5-10%), and cell cycle (7-25%) pathways as well as transcription factors such as MYC and NKX2-1 (10-15%). The majority of these co-occurring alterations were detected or enriched in samples collected from patients at resistance to tyrosine kinase inhibitor (TKI) treatment, indicating a potential functional role in driving resistance to therapy. Of note, these co-occurring tumor genomic alterations are not necessarily mutually exclusive, and evidence suggests that multiple clonal and sub-clonal cancer cell populations can co-exist and contribute to EGFR TKI resistance. Computational tools aimed to classify, track and predict the evolution of cancer clonal populations during therapy are being investigated in pre-clinical models to guide the selection of combination therapy switching strategies that may delay the development of treatment resistance. Here we review the most frequently identified tumor genomic alterations that co-occur with mutated EGFR and the evidence that these alterations effect responsiveness to EGFR TKI treatment.

Background A scarcity of data has been reported on tandem thoracic lumbar stenosis, which might be related to either the rarity or underdiagnosis of the condition. We have presented a systematic review of the clinical presentation, diagnosis, and treatment patterns for patients with symptomatic tandem thoracic and lumbar stenosis. Methods A PubMed/MEDLINE search was performed to find reports of patients with symptomatic tandem thoracic and lumbar stenosis. Results The review identified 10 studies with a total of 48 patients with tandem thoracic and lumbar stenosis. Most patients (n = 41; 85%) had had tandem stenosis diagnosed at the initial investigation, with 71% of the reports citing ossification of the ligamentum flavum as a contributing etiology. A few patients (n = 7; 15%) had had thoracic lesions diagnosed after neurologic deterioration that had occurred after lumbar surgery for previously suspected isolated lumbar stenosis. Surgical management varied from isolated thoracic decompression, staged decompression, and simultaneous decompression. Most patients (n = 41; 87%) showed improved neurologic status after surgery. Conclusion Ossification of the ligamentum flavum might play a key role in the pathogenesis of the condition. Most patients with tandem thoracic and lumbar stenosis will show improvement after surgical decompression. Although the limited evidence available has raised concerns regarding neurologic deterioration after initial lumbar decompression in patients with coexisting thoracic stenosis, the data are insufficient to definitively determine an optimal surgical strategy. Further research is needed to identify the optimal diagnostic and management criteria for patients with symptomatic tandem thoracic and lumbar stenosis.

PURPOSE. Nintedanib enhances the activity of chemotherapy in metastatic NSCLC. In this phase I/II study, we assessed safety and efficacy of nintedanib plus neoadjuvant chemotherapy, using major pathologic response (MPR) as primary endpoint. EXPERIMENTAL DESIGN: Eligible patients had stage IB (≥4 cm)-IIIA resectable NSCLC. A safety run-in phase was followed by an expansion phase with nintedanib 200 mg PO bid (28 days), followed by 3 cycles of cisplatin (75 mg/m(2)), docetaxel (75 mg/m(2)) q21 days plus nintedanib, followed by surgery. With 33 planned patients, the study had 90% power to detect an MPR increase from 15% to 35%. RESULTS: 21 patients (stages I/II/III, N=1/8/12) were treated. One of 15 patients treated with nintedanib 200 mg achieved MPR (7%, 95% CI 0.2%−32%). Best ORR in 20 evaluable patients was 30% (6/20, 95% CI 12%−54%). 12-month RFS and OS were 66% (95% CI 47%−93%) and 91% (95% CI, 79%−100%), respectively. Most frequent treatment-related G3–4 toxicities were transaminitis and electrolyte abnormalities. Based on an interim analysis the study was discontinued for futility. Higher levels of CD3+ and cytotoxic CD3+CD8+ T cells were found in treated tumors of patients who were alive than in those who died (652.8 vs. 213.4 cells/mm(2), P=0.048; 142.3 vs. 35.6 cells/mm(2), P=0.018). CONCLUSIONS: Although tolerated, neoadjuvant nintedanib plus chemotherapy did not increase MPR rate compared to chemotherapy historical controls. Additional studies of the combination in this setting are not recommended. Post-treatment levels of tumor infiltrating T cells were associated with patient survival. Use of MPR facilitates the rapid evaluation of neoadjuvant therapies.

Background Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy, but to the authors' knowledge, limited data exist regarding the safety and efficacy of these agents in transplant recipients. Herein, the authors have reported their experience with 17 patients who were treated with ICIs for metastatic malignancies after undergoing solid organ transplantation. Methods Data were abstracted for solid organ transplant recipients who received ICIs for the treatment of malignancy between January 1, 2016, and September 30, 2019. The authors identified 7 kidney, 8 liver, and 2 heart transplant recipients. Outcomes of interest were adverse drug reactions, cancer progression, and patient survival. Results The most common malignancies treated with ICIs were metastatic squamous cell carcinoma (5 patients; 29%) and hepatocellular carcinoma (5 patients; 29%), which were noted exclusively among liver transplant recipients. The median duration on ICIs was 1.7 months (interquartile range, 0.4-7.6 months). Five patients (29%) developed adverse reactions, including 4 patients (24%) with immune-related adverse events(irAEs), 3 patients (18%) with acute allograft rejections, 1 patient (6%) with autoimmune colitis, and 1 patient (6%) with ICI-induced cardiotoxicity (the patient was a heart transplant recipient). The cumulative incidence of cancer progression was 50% and 69%, respectively, at 6 months and 12 months. Eleven patients (65%) died over the median follow-up period of 4.6 months (interquartile range, 1.5-13.2 months) from the time of ICI initiation, with cancer progression being the most common cause of death. Conclusions ICIs can be used as individualized therapy in selected patients who have undergone solid organ transplantation but more studies are needed to determine how best to use these agents to improve outcomes further.

Many antibiotics carry caution stickers that warn against alcohol consumption. Data regarding concurrent use are sparse. An awareness of data that address this common clinical scenario is important so health care professionals can make informed clinical decisions and address questions in an evidence-based manner. The purpose of this systematic review was to determine the evidence behind alcohol warnings issued for many common antimicrobials. The search was conducted from inception of each database to 2018 using PubMed, Medline via Ovid, and Embase. It included studies that involved interactions, effects on efficacy, and toxicity/adverse drug reactions (ADR) due to concomitant alcohol consumption and antimicrobials. All interactions were considered in terms of three components: (i) alteration in pharmacokinetics/pharmacodynamics (PK/PD) of antimicrobials and/or alcohol, (ii) change in antimicrobial efficacy, and (iii) development of toxicity/ADR. Available data support that oral penicillins, cefdinir, cefpodoxime, fluoroquinolones, azithromycin, tetracycline, nitrofurantoin, secnidazole, tinidazole, and fluconazole can be safely used with concomitant alcohol consumption. Data are equivocal for trimethoprim-sulfamethoxazole. Erythromycin may have reduced efficacy with alcohol consumption, and doxycycline may have reduced efficacy in chronic alcoholism. Alcohol low in tyramine may be consumed with oxazolidinones. The disulfiram-like reaction, though classically associated with metronidazole, occurs with uncertain frequency and with varied severity. Cephalosporins with a methylthiotetrazole (MTT) side chain or a methylthiodioxotriazine (MTDT) ring, ketoconazole, and griseofulvin have an increased risk of a disulfiram-like reaction. Alcohol and antimicrobial interactions are often lacking evidence. This review questions common beliefs due to poor, often conflicting data and identifies important knowledge gaps.

This study sought to compare the appropriateness of antibiotic prescribing by drug, dose, duration, and indication between the emergency department (ED) and primary care (PC) within the Veterans Affairs Western New York Healthcare System (VAWNYHCS) to aid in focusing antimicrobial stewardship efforts.In this prospective observational cohort study, patients were identified using electronic alerts at the time of antibiotic prescribing. Prescriptions were retrospectively analyzed for appropriateness of antibiotic indication, drug choice, dose, and duration on the basis of current guideline recommendations. Data were compared between the ED and PC to determine the impact of visit location on prescribing habits. Baseline characteristics were compared using descriptive statistics, and a multivariable analysis was performed to identify statistically significant risk factors for inappropriate prescribing.Patients prescribed outpatient antibiotics at the VAWNYHCS ED and PC settings between June 2017 and February 2018.Appropriateness of antibiotic prescribing by drug, dose, duration, and indication between the ED and PC settings.The cohort included 1566 antibiotic prescriptions (ED = 488, PC = 1078). The appropriate drug, dose, and duration for antibiotics prescribed in the ED versus PC were 63.1% versus 43.4% (P0.001), 88.1% versus 88.2% (P = 0.953), and 86.1% versus 71.1% (P0.001), respectively. Azithromycin was the most inappropriately prescribed antibiotic in both the ED (37.8%) and PC (49.0%). Two factors predicted whether patients received the correct antibiotic empirically: location of the visit and antibiotic allergy. Overall, 56.6% of ED prescriptions and 82% of PC prescriptions were inappropriate with respect to at least 1 component.Stewardship is needed in both the ED and PC settings. However, initial efforts should be focused on PC because this setting had a statistically significant amount of inappropriate antibiotic prescribing. Pharmacist-led education and interventions should focus on the determination of drug, duration, and indication for the use of antibiotics.