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Antimicrobial peptides (AMPs) are a promising tool with which to fight rising antibiotic resistance. However, pathogenic bacteria are equipped with several AMP defense mechanisms, whose contributions to AMP resistance are often poorly defined. Here, we evaluate the genetic determinants of resistance to an insect AMP, cecropin B, in the opportunistic pathogen Enterobacter cloacae. Single-cell analysis of E. cloacae's response to cecropin revealed marked heterogeneity in cell survival, phenotypically reminiscent of heteroresistance (the ability of a subpopulation to grow in the presence of supra-MIC concentration of antimicrobial). The magnitude of this response was highly dependent on initial E. cloacae inoculum. We identified 3 genetic factors which collectively contribute to E. cloacae resistance in response to the AMP cecropin: The PhoPQ-two-component system, OmpT-mediated proteolytic cleavage of cecropin, and Rcs-mediated membrane stress response. Altogether, our data suggest that multiple, independent mechanisms contribute to AMP resistance in E. cloacae. Author summary: Antibiotics are losing their efficacy at an alarming rate, necessitating the development of novel strategies to combat bacterial infections. Antimicrobial peptides, which are essentially antibiotics produced by most animals, including humans, have been proposed as an alternative pathway to develop new clinical antimicrobials. However, similar to antibiotics, resistance against AMPs is widespread and varied, yet poorly-understood. Here, we have found that three major factors (the PhoPQ and Rcs cell envelope stress systems, and the protease OmpT) contribute to AMP resistance in the bacterium Enterobacter cloacae. We find that resistance is not equally distributed among a population, i.e. some cells are intrinsically more resistant than others. The number of resistant individuals in a population is determined by the three resistance factors we define here. Overall, our work provides new potential targets for the development of antibiotic compounds that may make AMPs work better against dangerous pathogens. [ABSTRACT FROM AUTHOR]

Background: Telemedicine use increased during the COVID-19 pandemic due to concerns for patient and provider safety. Given the lack of testing resources initially and the large geographical range served by Augusta University (AU), a telemedicine platform with up-to-date screening guidelines was implemented for COVID-19 testing in March 2020. Our objective was to understand the level of adherence to telemedicine screening guidelines for COVID-19. Methods: The study population included health care providers and population who participated in an encounter in the AU Health Express Care virtual care program from March 22 to May 21, 2020. All encounters were intended to be for COVID-19 screening, free, and available 24 h per day, 7 days per week. Screening guidelines were developed by AU based on information from the Centers for Disease Control and Prevention and the Georgia Department of Public Health. Results: Among 17,801 total encounters, 13,600 were included in the final analysis. Overall adherence to screening guidelines was 71% in the adult population and 57% in the pediatric population. When providers did not follow guidelines, 72% determined that the patient should have a positive screen. Guidelines themselves determined that only 52% of encounters should have a positive screen. Providers' specialty significantly correlated with guideline adherence (p = 0.002). Departments with the highest adherence were psychiatry, neurology, and ophthalmology. No significant correlation was found between guideline adherence and provider degree/position. Conclusions: This study provides proof of concept of a free telehealth screening platform during an ongoing pandemic. Our screening experience was effective and different specialties participated. Our patient population lived in lower than average income zip codes, suggesting that our free telemedicine screening program successfully reached populations with higher financial barriers to health care. Early training and a posteriori knowledge of telemedicine was likely key to screening guideline adherence. [ABSTRACT FROM AUTHOR]

The article presents the discussion on heritage regularly encompassing and crossing the perceived dichotomies such as natural/cultural and tangible fostering reciprocity between researchers and various stakeholders sharing experiences and knowledge.

The diagnosis of BV extravasation injury was made and the patient was treated with local emollients. Primary cutaneous lymphomas are non-Hodgkin lymphomas without extracutaneous disease at the time of diagnosis and are typically indolent.1,2 CD30 positivity may suggest the potential for large cell transformation and progression.3 Brentuximab vedotin (BV) is an anti-CD30 antibody-drug conjugate newly approved to treat CD30+ cutaneous lymphomas.1 An 87-year-old man was diagnosed with patch-stage mycosis fungoides. [Extracted from the article]

Background: Despite a growing cohort of intensive care unit (ICU) survivors, little is known about the early ICU aftercare period. Objective: To identify gaps in early ICU aftercare and factors associated with poor hospital outcomes. Methods: A multisite, retrospective study (January 1 to December 31, 2017) was conducted among randomly selected patients admitted to the medical ICU and subsequently transferred to acute medical care units. Records were reviewed for patient characteristics, ICU course, and early ICU aftercare practices and syndromes. Associations between practices and hospital outcomes were calculated with χ2 and Wilcoxon rank sum tests, followed by logistic regression. Results: One hundred fifty-one patients met inclusion criteria (mean [SD] age, 64.2 [19.1] years; 51.7% male; 44.4% White). The most frequent diagnoses were sepsis (35.8%) and respiratory failure (33.8%). During early ICU aftercare, 46.4% had dietary restrictions, 25.8% had bed rest orders, 25.0% had a bladder catheter, 26.5% had advance directive documentation, 33.8% had dysphagia, 34.3% had functional decline, and 23.2% had delirium. Higher Charlson Comorbidity Index (odds ratio, 1.6) and midodrine use on medical units (odds ratio, 7.5) were associated with in-hospital mortality; mechanical ventilation in the ICU was associated with rapid response on medical unit (odds ratio, 12.9); and bladder catheters were associated with ICU readmission (odds ratio, 5.2). Conclusions: Delirium, debility, and dysphagia are frequently encountered in early ICU aftercare, yet bed rest, dietary restriction, and lack of advance directive documentation are common. Future studies are urgently needed to characterize and address early ICU aftercare. [ABSTRACT FROM AUTHOR]

Objective: The prevalence of type 2 diabetes is increasing among adults under age 45. Onset of type 2 diabetes at a younger age increases an individual's risk for diabetes-related complications. Given the lasting benefits conferred by early glycemic control, we compared glycemic control and initial care between adults with younger onset (21-44 years) and mid-age onset (45-64 years) of type 2 diabetes.Research Design and Methods: Using data from a large, integrated health care system, we identified 32,137 adults (aged 21-64 years) with incident diabetes (first HbA1c ≥6.5% [≥48 mmol/mol]). We excluded anyone with evidence of prior type 2 diabetes, gestational diabetes mellitus, or type 1 diabetes. We used generalized linear mixed models, adjusting for demographic and clinical variables, to examine differences in glycemic control and care at 1 year.Results: Of identified individuals, 26.4% had younger-onset and 73.6% had mid-age-onset type 2 diabetes. Adults with younger onset had higher initial mean HbA1c values (8.9% [74 mmol/mol]) than adults with onset in mid-age (8.4% [68 mmol/mol]) (P < 0.0001) and lower odds of achieving an HbA1c <7% (<53 mmol/mol) 1 year after the diagnosis (adjusted odds ratio [aOR] 0.70 [95% CI 0.66-0.74]), even after accounting for HbA1c at diagnosis. Adults with younger onset had lower odds of in-person primary care contact (aOR 0.82 [95% CI 0.76-0.89]) than those with onset during mid-age, but they did not differ in telephone contact (1.05 [0.99-1.10]). Adults with younger onset had higher odds of starting metformin (aOR 1.20 [95% CI 1.12-1.29]) but lower odds of adhering to that medication (0.74 [0.69-0.80]).Conclusions: Adults with onset of type 2 diabetes at a younger age were less likely to achieve glycemic control at 1 year following diagnosis, suggesting the need for tailored care approaches to improve outcomes for this high-risk patient population. [ABSTRACT FROM AUTHOR]

Introduction: To assess clinician response to real-time patient-reported data about diabetic peripheral neuropathy (DPN) symptoms, we analyzed DPN diagnosis and treatment patterns after administration of a 4-question symptom questionnaire in a large vertically integrated health care system. Methods: Retrospective cohort study to analyze data from 160,852 patients screened for DPN symptoms from April 2012 to March 2014. Electronic medical record data were used to study changes in DPN diagnosis, treatment initiation, and treatment intensification. We used logistic regression to study the association of patient characteristics with the odds of clinical response. Results: Of patients queried, 50,684 (31.5%) reported symptoms. Patients reporting DPN symptoms experienced a greater increase in new DPN diagnoses (16 percentage points; p < 0.0001) and medication use (4 percentage points; p < 0.0001) compared with those denying symptoms. Among patients reporting symptoms, women and nonwhite patients were less likely to receive a DPN diagnosis, whereas older patients were more likely to receive a DPN diagnosis. Overall, patients who were older, were Asian (hazard ratio = 0.67, 95% confidence interval = 0.63-0.77), and had lower socioeconomic status (hazard ratio = 0.89, 95% confidence interval = 0.80-0.99) were less likely to be treated. However, these racial and socioeconomic differences were not statistically significant for patients with preexisting DPN diagnoses. Conclusion: Patients' real-time reports of DPN symptoms were associated with increased clinical activity. Patient- and clinician-level factors associated with the likelihood of receiving a DPN diagnosis need further study because a formal diagnosis may be associated with more equitable treatment. [ABSTRACT FROM AUTHOR]

Like in many tumor types, immunotherapy is currently under investigation to assess its potential efficacy in glioblastoma patients. Trials are under way to assess the efficacy of new immune checkpoint inhibitors including anti‐PD‐1 or CTLA4. We here investigate the expression and efficacy of a novel immune‐checkpoint inhibitor, called LAG‐3. We show that LAG‐3 is expressed in human glioblastoma samples and in a mouse glioblastoma model we show that knock out or LAG‐3 inhibition with a blocking antibody is efficacious against glioblastoma and can be used in combination with other immune checkpoint inhibitors toward complete eradication of the model glioblastoma tumors. From a mechanistic standpoint we show that LAG‐3 expression is an early marker of T cell exhaustion and therefore early treatment with LAG‐3 blocking antibody is more efficacious than later treatment. These data provide insight and support the design of trials that incorporate LAG‐3 in the treatment of glioblastoma. What's new? Glioblastoma derives some of its lethality from its ability to escape destruction by the immune system. Researchers have begun investigating immune checkpoint inhibitors as a tool to combat glioblastoma. Here, the authors report on a novel immune‐checkpoint inhibitor, LAG‐3. In a mouse model of glioblastoma, they successfully improved survival by eliminating LAG‐3, either by genetic knockout or using antibodies against it. They show that TILs from human glioblastoma samples express LAG‐3, and that high LAG‐3 expression correlates with reduced interferon release. The authors propose that anti‐LAG‐3, alone or in combination with other anti‐PD‐1 treatment, could improve glioblastoma treatment. [ABSTRACT FROM AUTHOR]

Multiple populations of wake-promoting neurons have been characterized in mammals, but few sleep-promoting neurons have been identified. Wake-promoting cell types include hypocretin and GABA (γ-aminobutyric-acid)-releasing neurons of the lateral hypothalamus, which promote the transition to wakefulness from non-rapid eye movement (NREM) and rapid eye movement (REM) sleep. Here we show that a subset of GABAergic neurons in the mouse ventral zona incerta, which express the LIM homeodomain factor Lhx6 and are activated by sleep pressure, both directly inhibit wake-active hypocretin and GABAergic cells in the lateral hypothalamus and receive inputs from multiple sleep-wake-regulating neurons. Conditional deletion of Lhx6 from the developing diencephalon leads to decreases in both NREM and REM sleep. Furthermore, selective activation and inhibition of Lhx6-positive neurons in the ventral zona incerta bidirectionally regulate sleep time in adult mice, in part through hypocretin-dependent mechanisms. These studies identify a GABAergic subpopulation of neurons in the ventral zona incerta that promote sleep. [ABSTRACT FROM AUTHOR]

This article presents a study that compared the effects of systemic chemotherapy (SC) and local chemotherapy (LC) on anti-programmed cell death protein 1 (anti-PD-1) efficacy in glioblastoma (GBM). It discusses the characteristics of GBM, the prevalence of severe lymphodepletion caused by the addition of SC to anti-PD-1 treatment, and the enrichment of tumor-infiltrating dendritic cells by LC.

Direct examination of the biliary tree with endoscopes has been a challenge since endoscopists began performing endoscopic retrograde cholangiopancreatography (ERCP) in the late 1960s. Previously, surgeons had used rigid instruments intraoperatively, which made examination difficult. The first direct cholangioscopy performed by an endoscopist was likely unintentionally done in a patient with postsurgical anatomy. Indirect imaging, ERCP, and percutaneous transhepatic cholangiography are helpful modalities for examining the biliary tree, but they are limited procedures, particularly with regard to the evaluation and treatment of strictures and bile duct stones. This article reviews the history and evolution of direct cholangioscopy since the advent of flexible endoscopes. Additionally, the article describes a new single-operator cholangioscopy technique for direct visualization of the biliary tree for diagnosis and intervention. There remains opportunity for innovation as endoscopists strive for safe and less-invasive methods for the identification and treatment of biliary pathology. [ABSTRACT FROM AUTHOR]

Background: Challenges to effective pharmacologic management of symptomatic diabetic peripheral neuropathy include the limited effectiveness of available medicines, frequent side effects, and the need for ongoing symptom assessment and treatment titration for maximal effectiveness. We present here the rationale and implementation challenges of the Diabetes Telephone Study, a randomized trial designed to improve medication treatment, titration, and quality of life among patients with symptomatic diabetic peripheral neuropathy. Methods: We implemented a pragmatic cluster randomized controlled trial to test the effectiveness of an automated interactive voice response tool designed to provide physicians with real-time patient-reported data about responses to newly prescribed diabetic peripheral neuropathy medicines. A total of 1834 primary care physicians treating patients in the diabetes registry at Kaiser Permanente Northern California were randomized into the intervention or control arm. In September 2014, we began identification and recruitment of patients assigned to physicians in the intervention group who receive three brief interactive calls every 2 months after a medication is prescribed to alleviate diabetic peripheral neuropathy symptoms. These calls provide patients with the opportunity to report on symptoms, side effects, self-titration of medication dose and overall satisfaction with treatment. We plan to compare changes in self-reported quality of life between the intervention group and patients in the control group who receive three non-interactive automated educational phone calls. Results: Successful implementation of this clinical trial required robust stakeholder engagement to help tailor the intervention and to address pragmatic concerns such as provider time constraints. As of 27 October 2015, we had screened 2078 patients, 1447 of whom were eligible for participation. We consented and enrolled 1206 or 83% of those eligible. Among those enrolled, 53% are women and the mean age is 67 (standard deviation = 12) years. The racial ethnic make-up is 56% White, 8% Asian, 13% Black or African American, and 19% Hispanic or Latino. Conclusion: Innovative strategies are needed to guide improvements in healthcare delivery for patients with symptomatic diabetic peripheral neuropathy. This trial aims to assess whether real-time collection and clinical feedback of patient treatment experiences can reduce patient symptom burden. Implementation of a clinical trial closely involving clinical care required researchers to partner with clinicians. If successful, this intervention provides a critical information feedback loop that would optimize diabetic peripheral neuropathy medication titration through widely available interactive voice response technology. [ABSTRACT FROM AUTHOR]

Autoimmune pancreatitis (AIP), a clinical entity originally described in East Asia and more recently recognized in the United States and Europe, poses a diagnostic conundrum for clinicians in the West due to immunoglobulin G4 seronegativity. Although expert panels classify this disease into 2 types, it remains difficult to stratify the disease given that both types share most clinical, biochemical, and imaging characteristics. The classic presentation of AIP can mimic that of pancreatic carcinoma, which increases the urgency of evaluation, diagnosis, and treatment. In this article, we elucidate the differences between the 2 types of AIP, highlight the shortcomings of the current classification system, and propose a more inclusive view of the disorder. [ABSTRACT FROM AUTHOR]

The article discusses the court case Nelson versus State Board of Veterinary Medicine wherein the Commonwealth Court of Pennsylvania addressed the issue of what behaviors constitute veterinary medicine malpractice. It provides information on the law of veterinary malpractice in Pennsylvania and in the U.S. It presents an assessment of the Commonwealth Court's decision from the perspective of administrative law.

Immune checkpoint blockade targeting programmed cell death protein 1 (PD-1) is emerging as an important treatment strategy in a growing list of cancers, yet its clinical benefits are limited to a subset of patients. Further investigation of tumor-intrinsic predictors of response and how extrinsic factors, such as iatrogenic immunosuppression caused by conventional therapies, impact the efficacy of anti-PD-1 therapy are paramount. Given the widespread use of corticosteroids in cancer management and their immunosuppressive nature, this study sought to determine how corticosteroids influence anti-PD-1 responses and whether their effects were dependent on tumor location within the periphery versus central nervous system (CNS), which may have a more limiting immune environment. In well-established anti-PD-1-responsive murine tumor models, corticosteroid therapy resulted in systemic immune effects, including severe and persistent reductions in peripheral CD4+ and CD8 + T cells. Corticosteroid treatment was found to diminish the efficacy of anti-PD-1 therapy in mice bearing peripheral tumors with responses correlating with peripheral CD8/Treg ratio changes. In contrast, in mice bearing intracranial tumors, corticosteroids did not abrogate the benefits conferred by anti-PD-1 therapy. Despite systemic immune changes, anti-PD-1-mediated antitumor immune responses remained intact during corticosteroid treatment in mice bearing intracranial tumors. These findings suggest that anti-PD-1 responses may be differentially impacted by concomitant corticosteroid use depending on tumor location within or outside the CNS. As an immune-specialized site, the CNS may potentially play a protective role against the immunosuppressive effects of corticosteroids, thus sustaining antitumor immune responses mediated by PD-1 blockade. [ABSTRACT FROM AUTHOR]

The use of inhibitory checkpoint blockade in the management of glioblastoma has been studied in both preclinical and clinical settings. TIGIT is a novel checkpoint inhibitor recently discovered to play a role in cancer immunity. In this study, we sought to determine the effect of anti-PD-1 and anti-TIGIT combination therapy on survival in a murine glioblastoma (GBM) model, and to elucidate the underlying immune mechanisms. Using mice with intracranial GL261-luc+ tumors, we found that TIGIT expression was upregulated on CD8+ and regulatory T cells (Tregs) in the brain compared to draining cervical lymph nodes (CLN) and spleen. We then demonstrated that treatment using anti-PD-1 and anti-TIGIT dual therapy significantly improved survival compared to control and monotherapy groups. The therapeutic effect was correlated with both increased effector T cell function and downregulation of suppressive Tregs and tumor-infiltrating dendritic cells (TIDCs). Clinically, TIGIT expression on tumor-infiltrating lymphocytes was shown to be elevated in patient GBM samples, suggesting that the TIGIT pathway may be a valuable therapeutic target. Expression of the TIGIT ligand, PVR, further portended a poor survival outcome in patients with low-grade glioma. We conclude that anti-TIGIT is an effective treatment strategy against murine GBM when used in combination with anti-PD-1, improving overall survival via modifications of both the T cell and myeloid compartments. Given evidence of PVR expression on human GBM cells, TIGIT presents as a promising immune therapeutic target in the management of these patients. [ABSTRACT FROM AUTHOR]

Immune checkpoints have come to the forefront of cancer therapies as a powerful and promising strategy to stimulate antitumor T cell activity. Results from recent preclinical and clinical studies demonstrate how checkpoint inhibition can be utilized to prevent tumor immune evasion and both local and systemic immune suppression. This review encompasses the key immune checkpoints that have been found to play a role in tumorigenesis and, more specifically, gliomagenesis. The review will provide an overview of the existing preclinical and clinical data, antitumor efficacy, and clinical applications for each checkpoint with respect to GBM, as well as a summary of combination therapies with chemotherapy and radiation. [ABSTRACT FROM AUTHOR]

Enrollment in high-deductible health plans is increasing out-of-pocket spending. But innovative plans that pair deductibles with value-based insurance designs can help preserve low-cost access to high-value treatments for patients by aligning coverage with clinical value. Among adults in high-deductible health plans who were prescribed medications for chronic conditions, we examined what impact a value-based pharmacy benefit that offered free chronic disease medications had on medication adherence. Overall, we found that the value-based plan offset reductions in medication adherence associated with switching to a deductible plan. The value-based plan appeared particularly beneficial for patients who started with low levels of medication adherence. Patients with additional clinical complexity or vulnerable populations living in neighborhoods with lower socioeconomic status, however, did not show adherence improvements and might not be taking advantage of value-based insurance design provisions. Additional efforts may be needed to educate patients about their nuanced benefit plans to help overcome initial confusion about these complex plans. [ABSTRACT FROM AUTHOR]

The cone-beam computed tomography (CBCT)–guided small animal radiation research platform (SARRP) has provided unique opportunities to test radiobiologic hypotheses. However, CBCT is less adept to localize soft tissue targets growing in a low imaging contrast environment. Three-dimensional bioluminescence tomography (BLT) provides strong image contrast and thus offers an attractive solution. We introduced a novel and efficient BLT-guided conformal radiation therapy and demonstrated it in an orthotopic glioblastoma (GBM) model. A multispectral BLT system was integrated with SARRP for radiation therapy (RT) guidance. GBM growth curve was first established by contrast CBCT/magnetic resonance imaging (MRI) to derive equivalent sphere as approximated gross target volume (aGTV). For BLT, mice were subject to multispectral bioluminescence imaging, followed by SARRP CBCT imaging and optical reconstruction. The CBCT image was acquired to generate anatomic mesh for the reconstruction and RT planning. To ensure high accuracy of the BLT-reconstructed center of mass (CoM) for target localization, we optimized the optical absorption coefficients μ a by minimizing the distance between the CoMs of BLT reconstruction and contrast CBCT/MRI-delineated GBM volume. The aGTV combined with the uncertainties of BLT CoM localization and target volume determination was used to generate estimated target volume (ETV). For conformal irradiation procedure, the GBM was first localized by the predetermined ETV centered at BLT-reconstructed CoM, followed by SARRP radiation. The irradiation accuracy was qualitatively confirmed by pathologic staining. Deviation between CoMs of BLT reconstruction and contrast CBCT/MRI-imaged GBM is approximately 1 mm. Our derived ETV centered at BLT-reconstructed CoM covers >95% of the tumor volume. Using the second-week GBM as an example, the ETV-based BLT-guided irradiation can cover 95.4% ± 4.7% tumor volume at prescribed dose. The pathologic staining demonstrated the BLT-guided irradiated area overlapped well with the GBM location. The BLT-guided RT enables 3-dimensional conformal radiation for important orthotopic tumor models, which provides investigators a new preclinical research capability. [ABSTRACT FROM AUTHOR]