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Background Internationally, clinical and economic advantages of low-risk penicillin delabeling have been explored, supporting changes to healthcare delivery systems where penicillin delabeling is embedded into inpatient usual care. Aim To determine if economic advantages of low-risk inpatient penicillin delabeling, described in the international literature, are realised in the Australian context. Methods This explorative economic evaluation had prospective patient data collection between January and August 2019, across two Australian health services. Part-1: Determine the cost per effectively delabeled patient for Penicillin Allergy Delabeling Program inpatients (PADP cohort) compared to Outpatient Antibiotic Allergy Testing Service outpatients (OAATS cohort). Part-2: A cost analysis to compare hospital costs for inpatients with low-risk penicillin allergy who did (PADP cohort) and did not (usual care cohort) undergo PADP delabeling. Results Part-1: The PADP (n=350) and OAATS (n=27 patients, n=36 individual visits) cohorts were comparable. In PADP, costs/proportion delabeled was $20.10/0.98, equating to $20.51 per effectively delabeled patient; in OAATS, it was $181.24/0.50, equating to $362. Compared to OAATS, PADP was associated with savings of $341.97 per effectively delabeled patient; indicating the outpatient testing was the dominated strategy, being more costly and less effective. Part-2: The PADP (n=218) and usual care (n=32) cohorts were comparable. Significantly favouring the delabeled PADP cohort, mean difference per patient was -4.41 days (95%CI -7.64, -1.18) and -$9,467.72 (95%CI -$15,419.98, -$3,515.46). Conclusions Consistent with international literature, delabeling low-risk penicillin allergies in the inpatient setting had economic advantages in the Australian context. Fully powered economic evaluations are urgently required to consolidate these findings. This article is protected by copyright. All rights reserved.

Background Early identification and treatment of serious infections improves clinical outcomes. Previous studies have found that septic patients without fever are more likely to die than those with fever, due to delay in antibiotic administration. Aim To determine whether antibiotic treatment and mortality differed in afebrile adult patients presenting to the Emergency Department with bacteraemia, compared with those with a history of fever. Methods Retrospective six-month audit of all adult patients with positive blood cultures taken in the Emergency Department (ED) of a single tertiary hospital. Outcomes included receipt of antibiotics within 4 and 24 h of ED arrival, in-hospital mortality and 30-day mortality. Results 227 patients with clinically significant bacteraemia were identified, of which 38 (16.7%) were afebrile in ED. There was no statistically significant difference in the proportion of afebrile or febrile patients receiving antibiotics within 4-h (44.7% vs 55.6%, p = 0.222) or 24-h (89.5% vs 95.2%, p = 0.163) of arrival at ED. Inpatient mortality was not statistically different in the afebrile and febrile groups 15.8% vs 6.9%, p = 0.070), but 30-day mortality was higher among afebrile patients (27.6% vs 10.1%, p = 0.010). Conclusions There was no significant difference in receipt of antibiotics within 4 h or 24 h ED arrival between the febrile and afebrile groups. However, afebrile patients experienced higher 30-day mortality. While most bacteraemic patients received antibiotics within 24 h, only half received antibiotics within 4 h, representing a key area for improvement. This article is protected by copyright. All rights reserved.

ObjectivesTo investigate the COVID-19 infections among staff at our institution and determine the interventions required to prevent subsequent staff infections.DesignRetrospective cohort studyParticipants and settingStaff working at a single tertiary referral hospital who returned a positive test result for SARS-CoV-2 between 25 January 2020 and 25 November 2020.Main outcome measuresSource of COVID-19 infection.ResultsOf 45 staff who returned a positive test result for SARS-CoV-2, 19 were determined to be acquired at Austin Health. Fifteen (15/19; 79% [95% CI: 54–94%]) of these were identified through contact tracing and testing following exposures to other infected staff and were presumed to be staff-staff transmission, including 10 healthcare workers (HCWs) linked to a single ward that cared for COVID-19 patients. Investigation of the outbreak identified the staff tearoom as the likely location for transmission, with subsequent reduction in HCW infections and resolution of the outbreak following implementation of enhanced control measures in tearoom facilities. No HCW contacts (0/204; 0% [95% CI: 0–2%]) developed COVID-19 infection following exposure to unrecognised patients with COVID-19.ConclusionsUnrecognised infections among staff may be a significant driver of HCW infections in healthcare settings. Control measures should be implemented to prevent acquisition from other staff as well as patient-staff transmission.

PURPOSE:Cyberattacks targeting health care organizations are becoming more frequent and affect all aspects of care delivery. Cancer care is particularly susceptible to major disruptions because of the potential of immediate and long-term consequences for patients who often rely on timely diagnostic testing and regular administration of systemic therapy in addition to other local treatment modalities to cure or control their diseases. On October 28, 2020, a cyberattack was launched on the University of Vermont Health Network with wide-ranging consequences for oncology, including loss of access to all network intranet servers, e-mail communications, and the electronic medical record (EMR).METHODS:This review details the immediate challenges faced by hematology and oncology during the cyberattack. The impact and response on inpatient, outpatient, and special patient populations are described. Steps that other academic- and community-based oncology practices can take to lessen the brunt of such an assault are suggested.RESULTS:The two areas of immediate impact after the cyberattack were communications and lack of EMR access. The oncology-specific impact included loss of the individualized EMR chemotherapy plan templates and electronic safeguards built into multistep treatment preparation and delivery. With loss of access to schedules, basic patient information, encrypted communications platforms and radiology, and laboratory and pharmacy services, clinical outpatient care delivery was reduced by 40%. The infusion visit volume dropped by 52% in the first week and new patients could not access necessary services for timely diagnostic evaluation, requiring the creation of command centers to oversee ethical and transparent triage and allocation of systemic therapies and address new patient referrals. This included appropriate transfer of patients to alternate sites to minimize delays. Inpatient care including transitions of care was particularly challenging and addressing patient populations whose survival might be affected by delays in care.CONCLUSION:Oncology health care leaders and providers should be aware of the potential impact of a cyberattack on cancer care delivery and preventively develop processes to mitigate the impact.

BACKGROUND This study aimed to investigate the influence of body weight, exercise modality, and pace on physiological and perceptual responses to determine the relation between perceptual and physiological responses. METHODS Aerobically untrained, normal weight, and overweight males and females participated. Participants were randomly assigned to one exercise condition for a 1-mile walk. RESULTS Prescribed pace resulted in a greater physiological stress than self-selected pace (all p

The cumulative incidence of symptomatic venous thromboembolism (VTE) among patients with malignant gliomas (MG) is estimated to be as high as 36% during the course of therapy. Development of VTE is associated with an increased risk of hospitalization, delays in cancer treatment, and an increased risk of complications including intracranial hemorrhage as well as VTE specific symptoms. Despite the high risk of VTE and associated morbidity, there is no standard recommendations regarding long term outpatient VTE prophylaxis in patients with MG due to the lack of clinical trial evidence in this patient population. In this study, we treated ten patients with newly diagnosed MG with apixaban, 2.5 mg twice daily beginning 2–21 days after craniotomy and continuing for up to 6 months. Unacceptable toxicity was defined by ≥ grade 2 CNS or non-CNS hemorrhage, a thromboembolic event (i.e. stroke) or cardiovascular event requiring anticoagulation or anti-platelet therapy. There were no unacceptable toxicities to report and no treatment-related adverse events. None of the patients on the study were diagnosed with a VTE while receiving apixaban. We conclude that apixaban can be given safely to patients with primary MG shortly after craniotomy and should be considered for VTE prevention in these high-risk patients.

Background: There is no gold standard approach for delirium diagnosis, making the assessment of its epidemiology difficult. Delirium can only be inferred though observation of behavioural disturbance and described with relevant nouns or adjectives. Objective: We aimed to use natural language processing (NLP) and its identification of words descriptive of behavioural disturbance to study the epidemiology of delirium in critically ill patients. Study design: Retrospective study using data collected from the electronic health records of a university-affiliated intensive care unit (ICU) in Melbourne, Australia. Participants: 12 375 patients Intervention: Analysis of electronic progress notes. Identification using NLP of at least one of a list of words describing behavioural disturbance within such notes. Results: We analysed 199 648 progress notes in 12 375 patients. Of these, 5108 patients (41.3%) had NLP-diagnosed behavioural disturbance (NLP-Dx-BD). Compared with those who did not have NLP-Dx-DB, these patients were older, more severely ill, and likely to have medical or unplanned admissions, neurological diagnosis, chronic kidney or liver disease and to receive mechanical ventilation and renal replacement therapy (P < 0.001). The unadjusted hospital mortality for NLP-Dx-BD patients was 14.1% versus 9.6% for patients without NLP-Dx-BD. After adjustment for baseline characteristics and illness severity, NLP-Dx-BD was not associated with increased risk of death (odds ratio [OR], 0.94; 95% CI, 0.80–1.10); a finding robust to multiple sensitivity, subgroups and time of observation subcohort analyses. In mechanically ventilated patients, NLP-Dx-BD was associated with decreased hospital mortality (OR, 0.80; 95% CI, 0.65–0.99) after adjustment for baseline severity of illness and year of admission. Conclusions: NLP enabled rapid assessment of large amounts of data identifying a population of ICU patients with typical high risk characteristics for delirium. Moreover, this technique enabled identification of previously poorly understood associations. Further investigations of this technique appear justified.

Malakoplakia is a chronic granulomatous disease associated with incomplete clearance of bacterial pathogens. A multimodal approach to therapy includes antimicrobials with intracellular activity, reduction in immunosuppression, and debulking of lesions. Azithromycin has an intracellular mechanism of action and enhanced Gram-negative activity compared to other macrolides. Despite some in vitro data to support its use, there are no clinical breakpoints or epidemiological cut-off values for most Enterobacterales from the European Committee on Antimicrobial Susceptibility Testing (EUCAST) or the Clinical and Laboratory Standards Institute (CLSI). We present two cases, previously unreported, of Escherichia coli associated renal allograft malakoplakia successfully treated with azithromycin.

Rationale: Staphylococcus aureus is the most common respiratory pathogen isolated from patients with cystic fibrosis (CF) in the United States. Although modes of acquisition and genetic adaptation ...

BACKGROUND: Historically, Australian cases of invasive meningococcal disease (IMD) have been most frequently caused by Neisseria meningitidis serogroup B, but recently an increase in cases due to serogroup W (MenW) and serogroup Y (MenY) has occurred. AIM: To determine whether clinical manifestations of IMD have changed due to increased incidence of MenW and MenY. METHODS: We performed a retrospective review of IMD cases notified to the Department of Health and Human Services in Victoria, Australia. We compared the period between January 2013 and June 2015 (defined as P1) immediately before the increase in MenW and MenY was noted, with the equal time period of July 2015 to December 2017 (P2), when this increase was observed. RESULTS: IMD was notified more frequently in P2 than P1 (1.24 vs 0.53 per 100 000 person-years, P

Parvovirus B19 (B19V) infection is well known for its mild, self-limiting clinical presentations in children, such as erythema infectiosum. Approximately 40% of women of childbearing age are susceptible to B19V infection. While maternal B19V infection usually has a good prognosis, B19V can cause severe fetal anaemia and pregnancy loss due to its ability to suppress erythroid progenitor cells. Non-invasive ultrasound monitoring for fetal anaemia is usually performed if maternal seroconversion occurs in the first 20 weeks of gestation, with amniocentesis for fetal infection reserved for those who first present with fetal anaemia or hydrops of unknown cause. Intrauterine transfusion is the standard treatment for severe fetal anaemia and is associated with a significant improvement in survival. However, survivors of hydrops fetalis may have a higher rate of long-term neurodevelopmental complications compared with non-hydropic survivors. This review aims to synthesise published data on the diagnosis, surveillance and outcomes of congenital parvovirus infection to assist clinicians in diagnosing and managing this important condition.

PURPOSE: Guidelines recommend venous thromboembolism (VTE) risk assessment in outpatients with cancer and pharmacologic thromboprophylaxis in selected patients at high risk for VTE. Although validated risk stratification tools are available, < 10% of oncologists use a risk assessment tool, and rates of VTE prophylaxis in high-risk patients are low in practice. We hypothesized that implementation of a systems-based program that uses the electronic health record (EHR) and offers personalized VTE prophylaxis recommendations would increase VTE risk assessment rates in patients initiating outpatient chemotherapy. PATIENTS AND METHODS: Venous Thromboembolism Prevention in the Ambulatory Cancer Clinic (VTEPACC) was a multidisciplinary program implemented by nurses, oncologists, pharmacists, hematologists, advanced practice providers, and quality partners. We prospectively identified high-risk patients using the Khorana and Protecht scores (≥ 3 points) via an EHR-based risk assessment tool. Patients with a predicted high risk of VTE during treatment were offered a hematology consultation to consider VTE prophylaxis. Results of the consultation were communicated to the treating oncologist, and clinical outcomes were tracked. RESULTS: A total of 918 outpatients with cancer initiating cancer-directed therapy were evaluated. VTE monthly education rates increased from < 5% before VTEPACC to 81.6% (standard deviation [SD], 11.9; range, 63.6%-97.7%) during the implementation phase and 94.7% (SD, 4.9; range, 82.1%-100%) for the full 2-year postimplementation phase. In the postimplementation phase, 213 patients (23.2%) were identified as being at high risk for developing a VTE. Referrals to hematology were offered to 151 patients (71%), with 141 patients (93%) being assessed and 93.8% receiving VTE prophylaxis. CONCLUSION: VTEPACC is a successful model for guideline implementation to provide VTE risk assessment and prophylaxis to prevent cancer-associated thrombosis in outpatients. Methods applied can readily translate into practice and overcome the current implementation gaps between guidelines and clinical practice.

PURPOSE OF REVIEW: Glycopeptide antibiotics such as vancomycin are frequently utilized to treat resistant Gram-positive infections such as methicillin-resistant Staphylococcus aureus. The current literature on glycopeptide and lipoglycopeptide structure, hypersensitivity and potential cross-reactivity was reviewed, highlighting implications for safe prescribing. RECENT FINDINGS: Structurally similar, glycopeptides could theoretically cross-react. Immediate reactions to vancomycin include non-IgE-mediated reactions (e.g. red man syndrome) and IgE-mediated hypersensitivity (e.g. anaphylaxis), sharing clinical features. Vancomycin can activate mast cells via MAS-related G-protein-coupled receptor X2, an IgE-independent receptor implicated in non-IgE reactions. In-vivo and in-vitro testing for suspected IgE-mediated reactions to glycopeptides remain ill-defined. Vancomycin is increasingly recognized to cause severe cutaneous adverse reactions (SCAR), with drug reaction with eosinophilia and systemic symptoms (DRESS) predominantly reported. Vancomycin DRESS has been associated with HLA-A32:-01, with a number needed to prevent of 1 in 74. Data demonstrating cross-reactivity amongst glycopeptides and lipoglycopeptides is limited to case reports/series. SUMMARY: Further studies and in-vivo/in-vitro diagnostics are required for better differentiation between IgE and non-IgE glycopeptide reactions. Despite its association with vanomycin DRESS, utility of pharmacogenomic screening for HLA-A32: 01 is ill-defined. Although HLA-A32:01 has been associated with vancomycin DRESS, its utility for pharmacogenomic screening is ill defined. Further clinical and immunological cross-reactivity data for glycopeptide/lipoglycopeptide antibiotics is required.

Objective The aim of this article is to describe the incidence and characteristics of pregnancy-related death in low- and middle-resource settings, in relation to the availability of key obstetric resources. Design This is a secondary analysis of a stepped-wedge cluster randomised controlled trial. Setting This trial was undertaken at ten sites across eight low- and middle-income countries in sub-Saharan Africa, India and Haiti. Population Institutional-level consent was obtained and all women presenting for maternity care were eligible for inclusion. Methods Pregnancy-related deaths were collected prospectively from routine data sources and active case searching. Main outcome measures Pregnancy-related death, place, timing and age of maternal death, and neonatal outcomes in women with this outcome. Results Over 20 months, in 536 233 deliveries there were 998 maternal deaths (18.6/10 000, range 28/10 000-630/10 000). The leading causes of death were obstetric haemorrhage (36.0%, n = 359), hypertensive disorders of pregnancy (20.6%, n = 206), sepsis (14.1%, n = 141) and other (26.5%, n = 264). Approximately a quarter of deaths occurred prior to delivery (28.4%, n = 283), 35.7% (n = 356) occurred on the day of delivery and 35.9% (n = 359) occurred after delivery. Half of maternal deaths (50.6%; n = 505) occurred in women aged 20-29 years, 10.3% (n = 103) occurred in women aged under 20 years, 34.5% (n = 344) occurred in women aged 30-39 years and 4.6% (n = 46) occurred in women aged ≥40 years. There was no measured association between the availability of key obstetric resources and the rate of pregnancy-related death. Conclusions The large variation in the rate of pregnancy-related death, irrespective of resource availability, emphasises that inequality and inequity in health care persists. Tweetable abstract Inequality and inequity in pregnancy-related death persists globally, irrespective of resource availability.

A role for glial cells in brain circuits controlling feeding has begun to be identified with hypothalamic astrocyte signaling implicated in regulating energy homeostasis. The nucleus of the solitary tract (NTS), within the brainstem dorsal vagal complex (DVC), integrates vagal afferent information from the viscera and plays a role in regulating food intake. We hypothesized that astrocytes in this nucleus respond to, and influence, food intake. Mice fed high‐fat chow for 12 hr during the dark phase showed NTS astrocyte activation, reflected in an increase in the number (65%) and morphological complexity of glial‐fibrillary acidic protein (GFAP)‐immunoreactive cells adjacent to the area postrema (AP), compared to control chow fed mice. To measure the impact of astrocyte activation on food intake, we delivered designer receptors exclusively activated by designer drugs (DREADDs) to DVC astrocytes (encompassing NTS, AP, and dorsal motor nucleus of the vagus) using an adeno‐associated viral (AAV) vector (AAV‐GFAP‐hM3Dq_mCherry). Chemogenetic activation with clozapine‐N‐oxide (0.3 mg/kg) produced in greater morphological complexity in astrocytes and reduced dark‐phase feeding by 84% at 4 hr postinjection compared with vehicle treatment. hM3Dq‐activation of DVC astrocytes also reduced refeeding after an overnight fast (71% lower, 4 hr postinjection) when compared to AAV‐GFAP‐mCherry expressing control mice. DREADD‐mediated astrocyte activation did not impact locomotion. hM3Dq activation of DVC astrocytes induced c‐FOS in neighboring neuronal feeding circuits (including in the parabrachial nucleus). This indicates that NTS astrocytes respond to acute nutritional excess, are involved in the integration of peripheral satiety signals, and can reduce food intake when activated., MAIN POINTS High‐fat feeding in mice induces morphological changes in brainstem astrocytes.Chemogenetic activation of astrocytes in the dorsal vagal complex reduces feeding.Glial activation recruits local neural circuits known to be involved in food intake. Chemogenetic activation of astrocytes in the mouse dorsal vagal complex reduces food intake and activates local neuronal circuits

International humanitarian programs are one way for individuals within low-income countries to access hearing health care. Faculty and students from the Idaho State University (ISU) Audiology Program have traveled to several locations within less developed countries over the past 15 years. Most recently, the ISU Audiology Program has partnered with Idaho Condor Humanitarian to provide hearing health care services to Peruvian indigenous people. The humanitarian expedition provides medical, dental, and audiology services to rural villages surrounding Cusco, Peru. Each year the ISU Audiology team gathers data on the hearing health care needs of the Peruvian people and fits donated hearing aids. The ISU Audiology team navigates a variety of barriers associated with limited resources to provide quality hearing health care focused on best practice guidelines for the people of Peru. This article highlights the specific needs of the people served, which the team identified and prioritized, as well as initiated a plan for continuing to develop follow-up care and sustainability.

Background: Majority of ALS cases are sporadic (sALS), as they lack defined genetic causes. Metabolic alterations shared between the nervous system and skin fibroblasts have emerged in ALS. Recently, we found that a subgroup of sALS fibroblasts (sALS1) is characterized by metabolic profiles (metabotype) distinct from other sALS cases (sALS2) and controls, suggesting that metabolic therapies could be effective in sALS. The metabolic modulators nicotinamide riboside and pterostilbene (EH301) are under clinical development for the treatment of ALS. Here, we studied the metabolome and transcriptome of sALS cells to understand the molecular bases of sALS metabotypes and the impact of EH301.Methods: Six fibroblast cell lines (3 male and 3 female subjects of similar ages) were used for each group (sALS1, sALS2, and controls). Metabolomics and transcriptomics were investigated at baseline and after EH301 treatment. Differential gene expression (DEGs) and metabolite abundance were assessed by a Wald Test and ANOVA, respectively, with FDR correction, and pathway analyses were performed. EH301 protection against metabolic stress was tested by thiol depletion. Weighted gene co-expression network analysis (WGCNA) was used to investigate the association of metabolic and clinical features and was also performed on the Answer ALS dataset from induced motor neurons (iMN). A machine learning model based on DEGs was tested as a sALS disease progression predictor. Results: We found that the sALS1 transcriptome is distinct from sALS2 and that EH301 modifies gene expression differently in sALS1, sALS2, and controls. Furthermore, EH301 had strong protective effects against metabolic stress, which is linked to anti-inflammatory and antioxidant pathways. WGCNA revealed that ALS functional rating scale and metabotypes are associated with gene modules enriched for cell cycle, immunity, autophagy, and metabolism terms, which are modified by EH301. Meta-analysis of publicly available transcriptomics data from iMNs confirmed functional associations of genes correlated with disease traits. A small subset of genes differentially expressed in sALS fibroblasts could be used in a machine learning model to predict disease progression.Conclusions: Multi-omics analyses of patient-derived fibroblasts highlighted differential metabolic and transcriptomic profiles in sALS metabotypes, which translate into differential responses to the investigational drug EH301.

Background: Metabolic syndrome (MetS) increases the risk of premature morbidity and mortality. Physical activity (PA) beneficially affects MetS; however, it is unclear if PA types differ among adolescents 12–15 years old, according to their MetS status. This study compared self-reported PA types by MetS status. Methods: Using the 2015–2016 National Health and Nutritional Examination Survey (NHANES) data, 664 adolescents self-reported PA in the past seven days. MetS status was assessed using Ford’s pediatric adaptation of the ATP-III adult criteria. Pearson chi-square and t-tests were conducted to determine self-reported PA differences. Results: The adolescents’ mean age was 13.47 years (95% CIs; 13.04, 14.38) and 52.69% were male (352). Twenty-seven (4.07%) adolescents were MetS positive. The prevalence of PA engagement in the past seven days was similar for MetS-positive and -negative adolescents (77.67% and 70.51%, respectively; p > 0.05). No significant differences were observed for PA type by MetS status. MetS-positive adolescents reported higher sedentary time (565.77 [438.99, 692.56] vs. 490.59 [377.86, 603.33] minutes per day, respectively; p = 0239). Conclusions: Engagement in specific PA types does not appear to differ by MetS status, but MetS-positive adolescents have significantly higher sedentary time. PA promotion should target a variety of activities to maximize the effectiveness of public health programs and interventions should target reducing sedentary time.

Although pregnancy poses a greater risk for severe COVID-19, the underlying immunological changes associated with SARS-CoV-2 infection during pregnancy are poorly understood. We defined immune responses to SARS-CoV-2 in pregnant and non-pregnant women during acute and convalescent COVID-19 up to 258 days post symptom onset, quantifying 217 immunological parameters. Additionally, matched maternal and cord blood were collected from COVID-19 convalescent pregnancies. Although serological responses to SARS-CoV-2 were similar in pregnant and non-pregnant women, cellular immune analyses revealed marked differences in key NK cell and unconventional T cell responses during COVID-19 in pregnant women. While NK, γδ T cells and MAIT cells displayed pre-activated phenotypes in healthy pregnant women when compared to non-pregnant age-matched women, activation profiles of these pre-activated NK and unconventional T cells remained unchanged at acute and convalescent COVID-19 in pregnancy. Conversely, activation dynamics of NK and unconventional T cells were prototypical in non-pregnant women in COVID-19. In contrast, activation of αβ CD4+ and CD8+ T cells, T follicular helper cells and antibody-secreting cells was similar in pregnant and non-pregnant women with COVID-19. Elevated levels of IL-1β, IFN-γ, IL-8, IL-18 and IL-33 were also found in pregnant women in their healthy state, and these cytokine levels remained elevated during acute and convalescent COVID-19. Collectively, our study provides the first comprehensive map of longitudinal immunological responses to SARS-CoV-2 infection in pregnant women, providing insights into patient management and education during COVID-19 pregnancy.

The medicinal use of Cannabis sativa L. can be traced back thousands of years to ancient China and Egypt. While marijuana has recently shown promise in managing chronic pain and nausea, scientific investigation of cannabis has been restricted due its classification as a schedule 1 controlled substance. A major breakthrough in understanding the pharmacology of cannabis came with the isolation and characterization of the phytocannabinoids trans-Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD). This was followed by the cloning of the cannabinoid CB1 and CB2 receptors in the 1990s and the subsequent discovery of the endocannabinoid system. In addition to the major phytocannabinoids, Δ9-THC and CBD, cannabis produces over 120 other cannabinoids that are referred to as minor and/or rare cannabinoids. These cannabinoids are produced in smaller amounts in the plant and are derived along with Δ9-THC and CBD from the parent cannabinoid cannabigerolic acid (CBGA). While our current knowledge of minor cannabinoid pharmacology is incomplete, studies demonstrate that they act as agonists and antagonists at multiple targets including CB1 and CB2 receptors, transient receptor potential (TRP) channels, peroxisome proliferator-activated receptors (PPARs), serotonin 5-HT1a receptors and others. The resulting activation of multiple cell signaling pathways, combined with their putative synergistic activity, provides a mechanistic basis for their therapeutic actions. Initial clinical reports suggest that these cannabinoids may have potential benefits in the treatment of neuropathic pain, neurodegenerative diseases, epilepsy, cancer and skin disorders. This review focuses on the molecular pharmacology of the minor cannabinoids and highlights some important therapeutic uses of the compounds.

To compare the outcomes of sodium glucose linked cotransporter 2 inhibitors (SGLT2i) and dipeptidyl peptidase 4 inhibitors (DPP4i) in hospitalized patients.Electronic medical records-based cohort study. Identification of patients with type 2 diabetes and treatment with SGLT2i (n = 466) or DPP4i (n = 1541). Outcomes compared between those who received SGLT2i and those who received DPP4i. The primary outcome: adjusted percentage of blood glycemia within 4-10 mmol/L.After adjustment, SGLT2i use had a statistically equivalent percentage of glycemia within range (coefficient: 4.55, 95% CI -3.23 to 12.32, p = 0.25) or4 mmol/L (coefficient -0.17, 95% CI -0.71 to 3.72, p = 0.54). There were no significant differences in hospital length of stay (p = 0.22), complications, (p = 0.11) or mortality (p = 0.57). When measured, ketone levels were higher in the SGLT2i group on admission, but lower on days 3, 4 and 5 (p 0.001 for interaction). Bicarbonate levels were not statistically different between groups. Finally, 54% of patients whose SGLT2i was ceased during admission, were discharged home without it.Among inpatients with type 2 diabetes, SGLT2i use was associated with equivalent within-target glycaemia and no significant increase in hypoglycemia, ketonemia, or lower bicarbonate levels. These hypothesis-generating findings support further investigation of SGLT2i therapy in inpatients.

We describe severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)–specific immune responses in a patient with lymphoma and recent programmed death 1 (PD-1) inhibitor therapy with late onset of severe coronavirus disease 2019 disease and prolonged SARS-CoV-2 replication, in comparison to age-matched and immunocompromised controls. High levels of HLA-DR+/CD38+ activation, interleukin 6, and interleukin 18 in the absence of B cells and PD-1 expression was observed. SARS-CoV-2–specific antibody responses were absent and SARS-CoV-2–specific T cells were minimally detected. This case highlights challenges in managing immunocompromised hosts who may fail to mount effective virus-specific immune responses., We describe defects in severe acute respiratory syndrome coronavirus 2–specific immune responses and persistent viral replication in a patient with lymphoma. This case highlights challenges in managing immunocompromised hosts who may fail to mount effective virus-specific immune responses.

All fifteen patients with HLA-A*32:01 restricted vancomycin-induced DRESS, showed negative ex vivo responses to dalbavancin however two showed cross-reactivity to teicoplanin and telavancin. Adjunctive diagnostic testing should be considered to detect potential cross-reactivity amongst glycopeptides.

Syntrophic interspecies electron exchange is essential for the stable functioning of diverse anaerobic microbial communities. Hydrogen/formate interspecies electron transfer (HFIT), in which H2 and/or formate function as diffusible electron carriers, has been considered to be the primary mechanism for electron transfer because most common syntrophs were thought to lack biochemical components, such as electrically conductive pili (e-pili), necessary for direct interspecies electron transfer (DIET). Here we report that Syntrophus aciditrophicus, one of the most intensively studied microbial models for HFIT, produces e-pili and can grow via DIET. Heterologous expression of the putative S. aciditrophicus type IV pilin gene in Geobacter sulfurreducens yielded conductive pili of the same diameter (4 nm) and conductance of the native S. aciditrophicus pili and enabled long-range electron transport in G. sulfurreducens. S. aciditrophicus lacked abundant c-type cytochromes often associated with DIET. Pilin genes likely to yield e-pili were found in other genera of hydrogen/formate-producing syntrophs. The finding that DIET is a likely option for diverse syntrophs that are abundant in many anaerobic environments necessitates a reexamination of the paradigm that HFIT is the predominant mechanism for syntrophic electron exchange within anaerobic microbial communities of biogeochemical and practical significance.Access opt

BACKGROUND Mohs surgery was developed for the treatment of advanced skin cancers. Advanced centrofacial tumors are among the most challenging lesions. OBJECTIVE The objective of the study was to review the most complex midface cases from our practice and to delineate how to plan the approach to these lesions, how to remove them in a step-by-step fashion, and how the patients were managed in a multidisciplinary manner when indicated. METHODS We reviewed 15 years of the most complex tumors to present to our practice for which Mohs micrographic surgery was performed. Follow-up for patients ranged from 3 to 13 years and is ongoing. RESULTS Twenty cases were identified in which tumors of the central face extended to bone and created extensive operative wounds. Eleven lesions were recurrent at presentation, and 9 had perineural disease. These cases are reviewed sequentially and demonstrate the challenges, successes, and pitfalls of Mohs micrographic surgery in the treatment of the most difficult tumors. Two patients died from disease. CONCLUSION Mohs surgery is an excellent technique for the removal of extensive midfacial lesions and allows for the surgical removal of lesions that might otherwise be considered inoperable. Approach to these lesions requires careful planning, meticulous surgical technique, excellence in histology, and an experienced reconstructive surgeon. Such tumors often require a multidisciplinary approach, imaging, and adjuvant therapy. All such cases require diligent follow-up. Although many such lesions will be cured, regional recurrence and metastasis may result, even when clear margins are achieved.

The metabotropic glutamate receptor 5 (mGluR5) is a promising treatment target for psychiatric disorders due to its modulatory effects on glutamate transmission. Using [11C]ABP688, we previously showed that the rapidly acting antidepressant ketamine decreases mGluR5 availability. The mGluR5 radioligand [18F]FPEB offers key advantages over [11C]ABP688; however, its suitability for drug challenge studies is unknown. We evaluated whether [18F]FPEB can be used to capture ketamine-induced effects on mGluR5. Seven healthy subjects participated in three [18F]FPEB scans: a baseline, a same-day post-ketamine, and a 24-h post-ketamine scan. The outcome measure was VT/ fP, obtained using a two-tissue compartment model and a metabolite-corrected arterial input function. Dissociative symptoms, heart rate and blood pressure increased following ketamine infusion. [18F]FPEB VT/ fP decreased by 9% across the cortex after ketamine infusion, with minimal difference between baseline and 24-h scans. Compared to our previous work using [11C]ABP688, the magnitude of the ketamine-induced change in mGluR5 was smaller using [18F]FPEB; however, effect sizes were similar for the same-day post-ketamine vs. baseline scan (Cohen’s d = 0.75 for [18F]FPEB and 0.88 for [11C]ABP688). [18F]FPEB is therefore able to capture some of the effects of ketamine on mGluR5, but [11C]ABP688 appears to be more suitable in drug challenge paradigms designed to probe glutamate transmission.

Essentials Uncontrolled clot breakdown with active bleeding can be seen in advanced cirrhosis. A literature review found little information on optimal management. We report a case of successful treatment with tranexamic acid for persistent subdural hematoma in this setting. A 50‐year‐old woman with advanced cirrhosis presented with spontaneous subdural hematoma. She had a worsening clinical course following craniotomy despite administration of multiple blood products. With elevation in D‐dimer, persistently low fibrinogen and poor response to factor/fibrinogen replacement therapies, we had a suspicion for uncontrolled fibrinolysis. A literature review was conducted on treatment of hyperfibrinolysis in cirrhosis, finding 4 reports in which antifibrinolytics were used to control bleeding with different outcomes. The dose of tranexamic acid used in our patient was employed from previous experience in trauma patients. We transitioned from intravenous to oral administration based on expected pharmacokinetics. Our patient had a successful outcome with resolution of bleeding.

Recent evidence implicates dysregulation of metabotropic glutamatergic receptor 5 (mGluR5) in pathophysiology of PTSD and suicidality. Using positron emission tomography and [18F]FPEB, we quantified mGluR5 availability in vivo in individuals with PTSD (n = 29) and MDD (n = 29) as a function of suicidal ideation (SI) to compare with that of healthy comparison controls (HC; n = 29). Volume of distribution was computed using a venous input function in the five key frontal and limbic brain regions. We observed significantly higher mGluR5 availability in PTSD compared with HC individuals in all regions of interest (P's = 0.001-0.01) and compared with MDD individuals in three regions (P's = 0.007). mGluR5 availability was not significantly different between MDD and HC individuals (P = 0.17). Importantly, we observed an up-regulation in mGluR5 availability in the PTSD-SI group (P's = 0.001-0.007) compared with PTSD individuals without SI. Findings point to the potential role for mGluR5 as a target for intervention and, potentially, suicide risk management in PTSD.

Disinfection byproducts are formed during most drinking water treatment and presently number >800, some of which are implicated in human health outcomes including bladder cancer and infertility, with unknown mechanisms of action. In particular, it is not yet understood whether these compounds can disrupt the estrogen-signaling pathway through binding to the human estrogen receptor (ER). In the present study, 21 disinfection byproducts, selected for their predicted involvement in endocrine-related diseases and their structural diversity, were individually evaluated for their binding affinity to the human ER and in silico, and then a subset of these chemicals was studied in binary mixtures with the known weak estrogen, 4-n-nonylphenol. Individually, 9 of the 21 disinfection byproducts were able to weakly bind to the ER, with affinities ranging from log median inhibitory concentration values of -3.83 to -2.19 M. In binary mixtures, the chemicals followed concentration addition, with their weak binding affinities having little contribution to the overall mixture affinity. These results demonstrate the variety of small-molecule disinfection byproduct structures that are capable of binding to the ER, and that their weak binding can still be of importance when overall human exposure to mixtures of disinfection byproducts in disinfected drinking water is considered. Environ Toxicol Chem 2019;9999:1-9. © 2019 SETAC.

Allergic reaction to liposomal amphotericin B is rare. We report a case of cardiac arrest in a 64-year-old woman following liposomal amphotericin B infusion, requiring resuscitation. We also present the results of subsequent skin prick and intradermal testing to liposomal amphotericin on the patient and three healthy controls, highlighting the need for further research into the immunopathogenesis of this reaction.

Obesity is a serious medical condition that often co-occurs with stress-related psychiatric disorders. It is recognized that the brain plays a key role in the (patho)physiology of obesity and that there is a bidirectional relationship between obesity and psychopathology, yet molecular mechanisms altered in obesity have not been fully elucidated. Thus, we investigated relationships between obesity and synaptic density in vivo using the radioligand [(11)C]UCB-J (which binds to synaptic glycoprotein SV2A) and positron emission tomography in individuals with obesity, and with or without stress-related psychiatric disorders. Regions of interest were the dorsolateral prefrontal cortex, orbitofrontal cortex, ventromedial, amygdala, hippocampus, and cerebellum. Forty individuals with a body mass index (BMI) ≥ 25 kg/m(2) (overweight/obese), with (n = 28) or without (n = 12) psychiatric diagnosis, were compared to 30 age- and sex-matched normal weight individuals (BMI

Objective: To investigate differences between a controlled and non-controlled exercise modality when walking and running at self-selected pace. Methods: Male and female participants (N=30, 21.07±0.88 years of age) engaged in four sessions testing V̇O2max, one-mile walk and run on an indoor track, and one-mile walk and run on a laboratory treadmill. With a significance level set at p

BackgroundThe association of pro-inflammatory markers such as interleukin-6 (IL-6) and other biomarkers with severe coronavirus disease 2019 (COVID-19) is of increasing interest, however their kinetics, response to current COVID-related treatments, association with disease severity and comparison with other disease states associated with potential cytokine storm (CS) such as Staphylococcus aureus bacteraemia (SAB) are ill-defined.MethodsA cohort of 55 hospitalized SARS-CoV-2 positive patients was prospectively recruited – blood sampling was performed at baseline, post-treatment and hospital discharge. Serum IL-6, C-reactive protein (CRP) and other laboratory investigations were compared between treatment groups and across timepoints. Acute serum IL-6 and CRP levels were then compared to those with suspected COVID-19 (SCOVID) and age and sex matched patients with SAB and patients hospitalized for any non-infectious condition (NIC).ResultsIL-6 was elevated at admission in the SARS-CoV-2 cohort but at lower levels compared to matched SAB patients. Median (IQR) IL-6 at admission was 73.89 pg/mL (30.9, 126.39) in SARS-CoV-2 compared to 92.76 pg/mL (21.75, 246.55) in SAB (p=0.017); 12.50 pg/mL (3.06, 35.77) in patients with NIC; and 95.51 pg/mL (52.17, 756.67) in SCOVID. Median IL-6 and CRP levels decreased between admission and discharge timepoints. This reduction was amplified in patients treated with remdesivir and/or dexamethasone. CRP and bedside vital signs were the strongest predictors of COVID-19 severity.ConclusionsKnowledge of the kinetics of IL-6 did not offer enhanced predictive value for disease severity in COVID-19 over common investigations such as CRP and vital signs.

In our study, procalcitonin was associated with both antibiotic use and duration in patients with COVID-19, as well as established biochemical markers of COVID-19 disease severity and oxygen requirement, suggesting a potential role for procalcitonin in COVID-19 antimicrobial stewardship.

We present a kidney-pancreas transplant recipient who achieved complete recovery from COVID-19. A 45-year-old patient with T3 paraplegia underwent kidney-pancreas transplantation 18 years ago, followed by a subsequent kidney transplant 9 years ago, and presented with fever, hypoxia and hypotension after exposure to two confirmed cases of COVID-19. History of solid organ transplant, pre-existing renal impairment, asthma and an elevated D-dimer were identified as established risk factors for severe COVID-19. Supportive management was provided, baseline immunosuppression with everolimus was continued, and oral prednisolone was increased. A complete recovery was observed. Given the favourable outcome despite risk factors for severe COVID-19, we identify and review the potential mitigating roles of immunosuppression and mammalian target of rapamycin (mTOR) inhibitors in this disease. Further investigation is required to establish whether mTOR inhibitors could be used as therapeutic agents to treat COVID-19, or as alternative immunosuppression implemented early in the COVID-19 disease course.

Introduction: The COVID-19 pandemic and restrictions placed on movement to prevent its transmission has led to a surge in demand for remote medical care. We investigated whether COVID-Care, a patient-reported telehealth symptom monitoring system, was successful at delivering safe monitoring and care for these patients leading to decreased hospital presentations. Methods: We performed a single centre, prospective, interventional cohort study with symptomatic outpatients who presented for COVID-19 screening at Austin Health, Australia. Participants were invited to take part in the COVID-Care program, entering common COVID-19 symptoms on a purpose-built, online survey monitored by infectious diseases physicians, and matched with clinical data including date of symptom onset, hospital admission, and screening clinic presentations. Results: 42,158 COVID-19 swabs were performed in 31,626 patients from March to October 2020, with 414 positive cases. 20,768 people used the COVID-Care survey at least once. COVID-Care users were significantly younger than non-users. Of the 414 positive cases, 254 used COVID-Care, with 160 non-users. Excluding presentations on the same day or prior to the COVID-19 swab, there were 56 hospital presentations. 4.3% of COVID-Care users and 28.1% non-users were admitted to hospital or the Emergency Department (p