Immunogenicity, Efficacy, and Safety of Biosimilar Insulin Glargine (Gan & Lee Glargine) Compared with Originator Insulin Glargine (Lantus®) in Patients with Type 1 Diabetes after 26 Weeks Treatment.

OBJECTIVES: To compare the immunogenicity, safety, and efficacy of GL Glargine with that of the reference product (Lantus®) in patients with type 1 diabetes mellitus (T1DM). METHODS: This was a Phase 3, multicenter, randomized, open-label, equivalence study. 576 subjects with T1DM were randomized 1:1 to receive either GL Glargine or Lantus® treatment for 26 weeks. The primary endpoint was the percentage of subjects in each treatment group who developed treatment-induced anti-insulin antibody (AIA) after baseline and up to visit Week 26, which was evaluated using a country-adjusted logistic regression model. The study also compared the changes in glycated hemoglobin (HbA1c), and adverse events (AEs) including hypoglycemia. RESULTS: The percentage of subjects positive for treatment-induced AIA by Week 26 was 25.8% in the GL Glargine treatment group and 25.3% in the Lantus® treatment group, with a 90% confidence interval [CI] (-5.4, 6.5) of the difference in proportions that fell completely between the similarity margins (-11.3, 11.3). The least squares (LS) mean difference between treatment groups for changes in HbA1c was -0.08 (90% CI: -0.23, 0.06), and the other immunogenicity and safety profiles were comparable. CONCLUSION: GL Glargine demonstrated similar immunogenicity, efficacy, and safety compared to Lantus® over 26 weeks in patients with T1DM.

Immune Mechanisms in Hypertension.

It is now apparent that immune mediators including complement, cytokines, and cells of the innate and adaptive immune system contribute not only to blood pressure elevation but also to the target organ damage that occurs in response to stimuli like high salt, aldosterone, angiotensin II, and sympathetic outflow. Alterations of vascular hemodynamic factors, including microvascular pulsatility and shear forces, lead to vascular release of mediators that affect myeloid cells to become potent antigen-presenting cells and promote T-cell activation. Research in the past 2 decades has defined specific biochemical and molecular pathways that are engaged by these stimuli and an emerging paradigm is these not only lead to immune activation, but that products of immune cells, including cytokines, reactive oxygen species, and metalloproteinases act on target cells to further raise blood pressure in a feed-forward fashion. In this review, we will discuss these molecular and pathophysiological events and discuss clinical interventions that might prove effective in quelling this inflammatory process in hypertension and related cardiovascular diseases.

Barriers to the introduction of novel advanced targeted treatments for Australian dermatology patients: Are skin diseases symptomatic of a systemic healthcare problem?

The aim of this article is to provide education to clinicians about certain barriers restricting the use of advanced targeted treatments in Australian health care. For illustrative purposes, the article focuses on dermatological conditions, but the content is relevant to all specialties that treat inflammatory and chronic diseases. Barriers to care discussed result in a lower than necessary standard of care for patients in Australia despite important advancements in medicine.

Immunogenicity, efficacy, and safety of biosimilar insulin glargine (Gan & Lee glargine) compared with originator insulin glargine (Lantus®) in patients with type 2 diabetes after 26 weeks' treatment: A randomized open label study.

AIM: To evaluate the equivalence of immunogenicity, safety and efficacy of Gan & Lee (GL) Glargine (Basalin®; Gan & Lee Pharmaceutical) with that of the reference product (Lantus®) in adult participants with type 2 diabetes mellitus. METHODS: This was a phase 3, multicenter, open-label, equivalence trial conducted across 57 sites. In total, 567 participants with type 2 diabetes mellitus were randomized in a 1:1 ratio to undergo treatment with either GL Glargine or Lantus® for 26 weeks. The primary endpoint was the proportion of participants in each treatment arm who manifested treatment-induced anti-insulin antibodies (AIA). Secondary endpoints included efficacy and safety metrics, changes in glycated haemoglobin levels, and a comparative assessment of adverse events. Results were analysed using an equivalence test comparing the limits of the 90% confidence interval (CI) for treatment-induced AIA development to the prespecified margins. RESULTS: The percentages of participants positive for treatment-induced glycated haemoglobin by week 26 were similar between the GL Glargine (19.2%) and Lantus® (21.3%) treatment groups, with a treatment difference of -2.1 percentage points and a 90% CI (-7.6%, 3.5%) (predefined similarity margins: -10.7%, 10.7%). The difference in glycated haemoglobin was -0.08% (90% CI, -0.23, 0.06). The overall percentage of participants with any treatment-emergent adverse events was similar between the GL Glargine (80.1%) and Lantus® (81.6%) treatment groups. CONCLUSIONS: GL Glargine was similar to Lantus® in terms of immunogenicity, efficacy, and safety, based on the current study.

NETosis Drives Blood Pressure Elevation and Vascular Dysfunction in Hypertension.

BACKGROUND: Neutrophil extracellular traps (NETs) are composed of DNA, enzymes, and citrullinated histones that are expelled by neutrophils in the process of NETosis. NETs accumulate in the aorta and kidneys in hypertension. PAD4 (protein-arginine deiminase-4) is a calcium-dependent enzyme that is essential for NETosis. TRPV4 (transient receptor potential cation channel subfamily V member 4) is a mechanosensitive calcium channel expressed in neutrophils. Thus, we hypothesize that NETosis contributes to hypertension via NET-mediated endothelial cell (EC) dysfunction. METHODS: NETosis-deficient Padi4-/- mice were treated with Ang II (angiotensin II). Blood pressure was measured by radiotelemetry, and vascular reactivity was measured with wire myography. Neutrophils were cultured with or without ECs and exposed to normotensive or hypertensive uniaxial stretch. NETosis was measured by flow cytometry. ECs were treated with citrullinated histone H3, and gene expression was measured by quantitative reverse transcription PCR. Aortic rings were incubated with citrullinated histone H3, and wire myography was performed to evaluate EC function. Neutrophils were treated with the TRPV4 agonist GSK1016790A. Calcium influx was measured using Fluo-4 dye, and NETosis was measured by immunofluorescence. RESULTS: Padi4-/- mice exhibited attenuated hypertension, reduced aortic inflammation, and improved EC-dependent vascular relaxation in response to Ang II. Coculture of neutrophils with ECs and exposure to hypertensive uniaxial stretch increased NETosis and accumulation of neutrophil citrullinated histone H3. Histone H3 and citrullinated histone H3 exposure attenuates EC-dependent vascular relaxation. Treatment of neutrophils with the TRPV4 agonist GSK1016790A increases intracellular calcium and NETosis. CONCLUSIONS: These observations identify a role of NETosis in the pathogenesis of hypertension. Moreover, they define an important role of EC stretch and TRPV4 as initiators of NETosis. Finally, they define a role of citrullinated histones as drivers of EC dysfunction in hypertension.

Immunoproteasomal Processing of IsoLG-Adducted Proteins Is Essential for Hypertension.

BACKGROUND: Hypertension is characterized by CD8+ (cluster differentiation 8) T cell activation and infiltration into peripheral tissues. CD8+ T cell activation requires proteasomal processing of antigenic proteins. It has become clear that isoLG (isolevuglandin)-adduced peptides are antigenic in hypertension; however, IsoLGs inhibit the constitutive proteasome. We hypothesized that immunoproteasomal processing of isoLG-adducts is essential for CD8+ T cell activation and inflammation in hypertension. METHODS: IsoLG adduct processing was studied in murine dendritic cells (DCs), endothelial cells (ECs), and B8 fibroblasts. The role of the proteasome and the immunoproteasome in Ang II (angiotensin II)-induced hypertension was studied in C57BL/6 mice treated with bortezomib or the immunoproteasome inhibitor PR-957 and by studying mice lacking 3 critical immunoproteasome subunits (triple knockout mouse). We also examined hypertension in mice lacking the critical immunoproteasome subunit LMP7 (large multifunctional peptidase 7) specifically in either DCs or ECs. RESULTS: We found that oxidant stress increases the presence of isoLG adducts within MHC-I (class I major histocompatibility complex), and immunoproteasome overexpression augments this. Pharmacological or genetic inhibition of the immunoproteasome attenuated hypertension and tissue inflammation. Conditional deletion of LMP7 in either DCs or ECs attenuated hypertension and vascular inflammation. Finally, we defined the role of the innate immune receptors STING (stimulator of interferon genes) and TLR7/8 (toll-like receptor 7/8) as drivers of LMP7 expression in ECs. CONCLUSIONS: These studies define a previously unknown role of the immunoproteasome in DCs and ECs in CD8+ T cell activation. The immunoproteasome in DCs and ECs is critical for isoLG-adduct presentation to CD8+ T cells, and in the endothelium, this guides homing and infiltration of T cells to specific tissues.

Nasopharyngeal angiotensin converting enzyme 2 (ACE2) expression as a risk-factor for SARS-CoV-2 transmission in concurrent hospital associated outbreaks.

BACKGROUND: Widespread human-to-human transmission of the severe acute respiratory syndrome coronavirus two (SARS-CoV-2) stems from a strong affinity for the cellular receptor angiotensin converting enzyme two (ACE2). We investigate the relationship between a patient's nasopharyngeal ACE2 transcription and secondary transmission within a series of concurrent hospital associated SARS-CoV-2 outbreaks in British Columbia, Canada. METHODS: Epidemiological case data from the outbreak investigations was merged with public health laboratory records and viral lineage calls, from whole genome sequencing, to reconstruct the concurrent outbreaks using infection tracing transmission network analysis. ACE2 transcription and RNA viral load were measured by quantitative real-time polymerase chain reaction. The transmission network was resolved to calculate the number of potential secondary cases. Bivariate and multivariable analyses using Poisson and Negative Binomial regression models was performed to estimate the association between ACE2 transcription the number of SARS-CoV-2 secondary cases. RESULTS: The infection tracing transmission network provided n = 76 potential transmission events across n = 103 cases. Bivariate comparisons found that on average ACE2 transcription did not differ between patients and healthcare workers (P = 0.86). High ACE2 transcription was observed in 98.6% of transmission events, either the primary or secondary case had above average ACE2. Multivariable analysis found that the association between ACE2 transcription (log2 fold-change) and the number of secondary transmission events differs between patients and healthcare workers. In health care workers Negative Binomial regression estimated that a one-unit change in ACE2 transcription decreases the number of secondary cases (ß = -0.132 (95%CI: -0.255 to -0.0181) adjusting for RNA viral load. Conversely, in patients a one-unit change in ACE2 transcription increases the number of secondary cases (ß = 0.187 (95% CI: 0.0101 to 0.370) adjusting for RNA viral load. Sensitivity analysis found no significant relationship between ACE2 and secondary transmission in health care workers and confirmed the positive association among patients. CONCLUSION: Our study suggests that ACE2 transcription has a positive association with SARS-CoV-2 secondary transmission in admitted inpatients, but not health care workers in concurrent hospital associated outbreaks, and it should be further investigated as a risk-factor for viral transmission.

Using a targeted metabolomics approach to explore differences in ARDS associated with COVID-19 compared to ARDS caused by H1N1 influenza and bacterial pneumonia.

RATIONALE: Acute respiratory distress syndrome (ARDS) is a life-threatening critical care syndrome commonly associated with infections such as COVID-19, influenza, and bacterial pneumonia. Ongoing research aims to improve our understanding of ARDS, including its molecular mechanisms, individualized treatment options, and potential interventions to reduce inflammation and promote lung repair. OBJECTIVE: To map and compare metabolic phenotypes of different infectious causes of ARDS to better understand the metabolic pathways involved in the underlying pathogenesis. METHODS: We analyzed metabolic phenotypes of 3 ARDS cohorts caused by COVID-19, H1N1 influenza, and bacterial pneumonia compared to non-ARDS COVID-19-infected patients and ICU-ventilated controls. Targeted metabolomics was performed on plasma samples from a total of 150 patients using quantitative LC-MS/MS and DI-MS/MS analytical platforms. RESULTS: Distinct metabolic phenotypes were detected between different infectious causes of ARDS. There were metabolomics differences between ARDSs associated with COVID-19 and H1N1, which include metabolic pathways involving taurine and hypotaurine, pyruvate, TCA cycle metabolites, lysine, and glycerophospholipids. ARDSs associated with bacterial pneumonia and COVID-19 differed in the metabolism of D-glutamine and D-glutamate, arginine, proline, histidine, and pyruvate. The metabolic profile of COVID-19 ARDS (C19/A) patients admitted to the ICU differed from COVID-19 pneumonia (C19/P) patients who were not admitted to the ICU in metabolisms of phenylalanine, tryptophan, lysine, and tyrosine. Metabolomics analysis revealed significant differences between C19/A, H1N1/A, and PNA/A vs ICU-ventilated controls, reflecting potentially different disease mechanisms. CONCLUSION: Different metabolic phenotypes characterize ARDS associated with different viral and bacterial infections.

Proteomic Evolution from Acute to Post-COVID-19 Conditions.

Many COVID-19 survivors have post-COVID-19 conditions, and females are at a higher risk. We sought to determine (1) how protein levels change from acute to post-COVID-19 conditions, (2) whether females have a plasma protein signature different from that of males, and (3) which biological pathways are associated with COVID-19 when compared to restrictive lung disease. We measured protein levels in 74 patients on the day of admission and at 3 and 6 months after diagnosis. We determined protein concentrations by multiple reaction monitoring (MRM) using a panel of 269 heavy-labeled peptides. The predicted forced vital capacity (FVC) and diffusing capacity of the lungs for carbon monoxide (DLCO) were measured by routine pulmonary function testing. Proteins associated with six key lipid-related pathways increased from admission to 3 and 6 months; conversely, proteins related to innate immune responses and vasoconstriction-related proteins decreased. Multiple biological functions were regulated differentially between females and males. Concentrations of eight proteins were associated with FVC, %, and they together had c-statistics of 0.751 (CI:0.732-0.779); similarly, concentrations of five proteins had c-statistics of 0.707 (CI:0.676-0.737) for DLCO, %. Lipid biology may drive evolution from acute to post-COVID-19 conditions, while activation of innate immunity and vascular regulation pathways decreased over that period. (ProteomeXchange identifiers: PXD041762, PXD029437).

Quality of antibiotic prescribing for pediatric community-acquired Pneumonia in outpatient care.

BACKGROUND: Antibiotics remain the primary treatment for community acquired pneumonia (CAP), however rising rates of antimicrobial resistance may jeopardize their future efficacy. With higher rates of disease reported in the youngest populations, effective treatment courses for pediatric pneumonia are of paramount importance. This study is the first to examine the quality of pediatric antibiotic use by agent, dose and duration. METHODS: A retrospective cohort study included all outpatient/primary care physician visits for pediatric CAP (aged < 19 years) between January 1 2014 to December 31 2018. Relevant practice guidelines were identified, and treatment recommendations extracted. Amoxicillin was the primary first-line agent for pediatric CAP. Categories of prescribing included: guideline adherent, effective but unnecessary (excess dose and/or duration), under treatment (insufficient dose and/or duration), and not recommended. Proportions of attributable-antibiotic use were examined by prescribing category, and then stratified by age and sex. RESULT(S): A total of 42,452 episodes of pediatric CAP were identified. Of those, 31,347 (76%) resulted in an antibiotic prescription. Amoxicillin accounted for 51% of all prescriptions. Overall, 27% of prescribing was fully guideline adherent, 19% effective but unnecessary, 10% under treatment, and 44% not recommended by agent. Excessive duration was the hallmark of effective but unnecessary prescribing (97%) Macrolides accounted for the majority on non-first line agent use, with only 32% of not recommended prescribing preceded by a previous course of antibiotics. CONCLUSION(S): This study is the first in Canada to examine prescribing quality for pediatric CAP by agent, dose and duration. Utilizing first-line agents, and shorter-course treatments are targets for stewardship.

Retrospective cohort analysis of outpatient antibiotic prescribing for community-acquired pneumonia in Canadian older adults.

BACKGROUND: This retrospective cohort study is the first in North America to examine population-level appropriate antibiotic use for community-acquired pneumonia (CAP) in older adults, by agent, dose and duration. With the highest rates of CAP reported in the elderly populations, appropriate antibiotic use is essential to improve clinical outcomes. Given the ongoing crisis of antimicrobial resistance, understanding inappropriate antibiotic prescribing is integral to direct community stewardship efforts. METHODS: All outpatient primary care visits for CAP (aged ≥65 years) were identified using physician billing codes between January 1 2014 to December 31 2018 in British Columbia (BC) and Ontario (ON). Categories of prescribing were derived from existing literature, and constructed for clinical relevance using Canadian and international guidelines available during the study period. Categories were mutually exclusive and included: guideline adherent (first-line agent, adherent dose/duration), clinically appropriate (non-first line agent, presence of comorbidities), effective but unnecessary (first-line agent, excess dose/duration), undertreatment (first-line agent, subtherapeutic dose/duration), and not recommended (non-first line agent, absence of comorbidities). Proportions of prescribing were examined by category. Temporal trends in prescribing were examined using Poisson regression. RESULTS: A total of 436,441 episodes of CAP were identified, with 46% prescribed an antibiotic in BC, and 52% in Ontario. Guideline adherent prescribing was minimal for both provinces (BC: 2%; ON: 1%) however the largest magnitude of increase was reported in this category by the final study year (BC-Rate Ratio [RR]: 3.4, 95% Confidence Interval [CI]: 2.7-4.3; ON-RR: 4.62, 95% CI: 3.4-6.5). Clinically appropriate prescribing accounted for the most antibiotics issued, across all study years (BC: 61%; ON: 74%) (BC-RR: 0.8, 95% CI: 0.8-0.8; ON-RR: 0.9, 95% CI: 0.8-0.9). Excess duration of therapy was the hallmark characteristic for effective but unnecessary prescribing (BC: 92%; ON: 99%). The most common duration prescribed was 7 days, followed by 10. Not recommended prescribing was minimal in both provinces (BC: 4%; ON: 7%) and remained stable by the final study year (BC-RR: 1.1, 95% CI: 0.9-1.2; ON-RR: 0.9, 95% CI: 0.9-1.1). CONCLUSION: Three quarters of antibiotic prescribing for CAP was appropriate in Ontario, but only two thirds in BC. Shortening durations-in line with evidence for 3 to 5-day treatment presents a focused target for stewardship efforts.

Cohort profile: investigating SARS-CoV-2 infection and the health and psychosocial impact of the COVID-19 pandemic in the Canadian CHILD Cohort.

The coronavirus disease 2019 (COVID-19) pandemic has affected all Canadian families, with some impacted differently than others. Our study aims to: (1) determine the prevalence and transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection among Canadian families, (2) identify predictors of infection susceptibility and severity of SARS-CoV-2, and (3) identify health and psychosocial impacts of the COVID-19 pandemic. This study builds upon the CHILD Cohort Study, an ongoing multi-ethnic general population prospective cohort consisting of 3,454 Canadian families with children born in Vancouver, Edmonton, Manitoba, and Toronto between 2009 and 2012. During the pandemic, CHILD households were invited to participate in the CHILD COVID-19 Add-On Study involving: (1) brief biweekly surveys about COVID-19 symptoms and testing; (2) quarterly questionnaires assessing COVID-19 exposure and testing, vaccination status, physical and mental health, and pandemic-driven life changes; and (3) in-home biological sampling kits to collect blood and stool. In total, 1,462 households (5,378 participants) consented to the CHILD COVID-19 Add-On Study: 2,803 children (mean±standard deviation [SD], 9.0±2.7 years; range, 0-17 years) and 2,576 adults (mean±SD, 43.0±6.5 years; range, 18-85 years). We will leverage the wealth of pre-pandemic CHILD data to identify risk and resilience factors for susceptibility and severity to the direct and indirect pandemic effects. Our short-term findings will inform key stakeholders and knowledge users to shape current and future pandemic responses. Additionally, this study provides a unique resource to study the long-term impacts of the pandemic as the CHILD Cohort Study continues.

Outcomes and characteristics of patients hospitalized for COVID-19 in British Columbia, Ontario and Quebec during the Omicron wave.

BACKGROUND: Omicron is the current predominant variant of concern of SARS-CoV-2. We hypothesized that vaccination alters outcomes of patients hospitalized with COVID-19 during the Omicron wave and that these patients have different characteristics and outcomes than in previous waves. METHODS: This is a substudy of the Host Response Mediators in Coronavirus (COVID-19) Infection (ARBs CORONA I) trial, which included adults admitted to hospital with acute COVID-19 up to July 2022 from 9 hospitals in British Columbia, Ontario and Quebec. We excluded emergency department visits without hospital admission, readmissions and admissions for another reason. Using adjusted regression analysis, we compared mortality and organ dysfunction between vaccinated (≥ 2 doses) and unvaccinated patients during the Omicron wave, as well as between all patients in the Omicron and first 3 waves of the COVID-19 pandemic. RESULTS: During the Omicron wave, 28-day mortality was significantly lower in vaccinated (n = 19/237) than unvaccinated hospitalized patients (n = 12/127) (adjusted odds ratio [OR] 0.36, 95% confidence interval [CI] 0.15-0.89); vaccinated patients had lower risk of admission to the intensive care unit, invasive ventilation and acute respiratory distress syndrome and shorter hospital length of stay. Patients hospitalized during the Omicron wave had more comorbidities than in previous waves, and lower 28-day mortality than in waves 1 and 2 (adjusted OR 0.38, 95% CI 0.24-0.59; and 0.42, 95% CI 0.26-0.65) but not wave 3 (adjusted OR 0.81, 95% CI 0.43-1.51) and had less organ dysfunction than in the first 2 waves. INTERPRETATION: Patients who were at least double vaccinated had lower mortality than unvaccinated patients hospitalized during the Omicron wave. Patients hospitalized during the Omicron wave had more chronic disease and lower mortality than in the first 2 waves, but not wave 3. Changes in vaccination, treatments and predominant SARS-CoV-2 variant may have decreased mortality in patients hospitalized during the Omicron wave.

Minutes matter: Time it takes to perform point-of-care ultrasound.

Background: While point-of-care ultrasound (PoCUS) is a safe, versatile tool that can improve patient care, the perceived time investment needed to incorporate PoCUS into clinical care is cited as a barrier to performance. We sought to determine the time it takes to perform a PoCUS examination and whether this time was influenced by training level and prior ultrasound experience. Methods: This was a retrospective study looking at time stamps of all emergency medicine (EM) provider-performed PoCUS examinations during clinical shifts from August 10, 2019, to June 7, 2022, at a suburban academic emergency department that is the site for a 3-year EM residency. Our workflow is order-based; when PoCUS is ordered, that patient's information populates the ultrasound machine worklist. Selecting the patient's name from the worklist generates a time-stamped patient information page (PIP). We defined the PIP time stamp as the start of the PoCUS examination. The duration of one PoCUS examination was defined as the time of the last image acquired minus the time of the PIP. General estimating equations were used to estimate differences between training level and between prior scan status using an exchangeable correlation and Tukey adjusted pairwise comparisons. A two-tailed chi-square analysis was used for comparing accuracy according to training level. Results: Of 4187 PoCUS examinations abstracted, 2144 met study criteria. The median (IQR) time spent per examination was 6.0 (3-9) min. First-year residents took the longest to perform PoCUS among all providers (p < 0.0001). Residents with fewer than 250 prior scans took longer than residents with 501-800 (p = 0.0002) and >800 (p = 0.0013). Resident accuracy was not significantly different according to training level. Conclusions: Overall median time to perform PoCUS was 6.0 min. EM residents became more efficient in performing PoCUS as they advanced from first- to third-year, without compromising accuracy.

A cluster randomized trial assessing the impact of personalized prescribing feedback on antibiotic prescribing for uncomplicated acute cystitis to family physicians.

OBJECTIVE: To evaluate the impact of personalized prescribing portraits on antibiotic prescribing for treating uncomplicated acute cystitis (UAC) by Family Physicians (FPs). DESIGN: Cluster randomized control trial. SETTING: The intervention was conducted in the primary care setting in the province of BC between December 2010 and February 2012. PARTICIPANTS: We randomized 4 833 FPs by geographic location into an Early intervention arm (n = 2 417) and a Delayed control arm (n = 2 416). INTERVENTION: The Education for Quality Improvement in Patient Care (EQIP) program mailed to each FP in BC, a 'portrait' of their individual prescribing of antibiotics to women with UAC, plus therapeutic recommendations and a chart of trends in antibiotic resistance. MAIN OUTCOME MEASURES: Antibiotic prescribing preference to treat UAC. RESULTS: Implementing exclusion criteria before and after a data system change in the Ministry of Health caused the arms to be unequal in size-intervention arm (1 026 FPs, 17 637 UAC cases); control arm (1 352 FPs, 25 566 UAC cases)-but they were well balanced by age, sex and prior rates of prescribing antibiotics for UAC. In the early intervention group probability of prescribing nitrofurantoin increased from 28% in 2010 to 38% in 2011, a difference of 9.9% (95% confidence interval [CI], 9.1% to 10.7. Ciprofloxacin decreased by 6.2% (95% CI: 5.6% to 6.9%) and TMP-SMX by 3.7% (95% CI: 3.1% to 4.2%). Among 295 FPs who completed reflective surveys, 52% said they were surprized by the E. coli resistance statistics and 57% said they planned to change their treatment of UAC. CONCLUSION: The EQIP intervention demonstrated that feedback of personal data to FPs on their prescribing, plus population data on antibiotic resistance, with a simple therapeutic recommendation, can significantly improve prescribing of antibiotics. Trial registration: ISRCTN 16938907.

Immunoproteasomal Processing of Isolevuglandin Adducts in Hypertension.

Isolevuglandins (isoLGs) are lipid aldehydes that form in the presence of reactive oxygen species (ROS) and drive immune activation. We found that isoLG-adducts are presented within the context of major histocompatibility complexes (MHC-I) by an immunoproteasome dependent mechanism. Pharmacologic inhibition of LMP7, the chymotrypsin subunit of the immunoproteasome, attenuates hypertension and tissue inflammation in the angiotensin II (Ang II) model of hypertension. Genetic loss of function of all immunoproteasome subunits or conditional deletion of LMP7 in dendritic cell (DCs) or endothelial cells (ECs) attenuated hypertension, reduced aortic T cell infiltration, and reduced isoLG-adduct MHC-I interaction. Furthermore, isoLG adducts structurally resemble double-stranded DNA and contribute to the activation of STING in ECs. These studies define a critical role of the immunoproteasome in the processing and presentation of isoLG-adducts. Moreover they define a role of LMP7 as a regulator of T cell activation and tissue infiltration in hypertension.

Do Patients' Psychosocial Characteristics Impact Antibiotic Prescription Rates?

Previous research suggests that the characteristics of both patients and physicians can contribute to the overuse of antibiotics. Until now, patients' psychosocial characteristics have not been widely explored as a potential contributor to the overuse of antibiotics. In this study, the relationship between a patient's psychosocial characteristics (self-reported in postal surveys in 2003) and the number of antibiotics they were prescribed (recorded in Finnish national registry data between 2004-2006) were analyzed for 19,300 working-aged Finns. Psychosocial characteristics included life satisfaction, a sense of coherence, perceived stress, hostility, and optimism. In a structural equation model, patients' adverse psychosocial characteristics were not related to increased antibiotic prescriptions in the subsequent three years. However, these characteristics were strongly associated with poor general health status, which in turn was associated with an increased number of subsequent antibiotic prescriptions. Furthermore, mediation analysis showed that individuals who used healthcare services more frequently also received more antibiotic prescriptions. The current study does not support the view that patients' adverse psychosocial characteristics are related to an increased number of antibiotic prescriptions. This could encourage physicians to actively discuss treatment options with their patients.

Randomized trial to evaluate the safety, tolerability, and immunogenicity of a booster (third dose) of BNT162b2 COVID-19 vaccine coadministered with 20-valent pneumococcal conjugate vaccine in adults ≥65 years old.

BACKGROUND: Older adults are at increased risk of adverse outcomes from pneumococcal disease and COVID-19. Vaccination is an established strategy for preventing both illnesses. This study evaluated the safety and immunogenicity of coadministration of the 20-valent pneumococcal conjugate vaccine (PCV20) and a booster (third dose) of BNT162b2 COVID-19 vaccine. METHODS: This phase 3, randomized, double-blind, multicentre study included 570 participants aged ≥65 years randomized 1:1:1 to PCV20 and BNT162b2 coadministered, or PCV20 or BNT162b2 only (administered with saline for blinding). Primary safety endpoints included local reactions, systemic events, adverse events (AEs) and serious AEs (SAEs). Secondary objectives were immunogenicity of PCV20 and BNT162b2 when administered together or separately. RESULTS: Coadministration of PCV20 and BNT162b2 was well tolerated. Local reactions and systemic events were generally mild-moderate; injection-site pain and fatigue were the most frequent local and systemic events, respectively. AE and SAE rates were low and similar across groups. No AEs led to discontinuation; no SAEs were considered vaccination-related. Robust immune responses were observed, with opsonophagocytic activity geometric mean fold rises (GMFRs; from baseline to 1 month) of 2.5-24.5 and 2.3-30.6 across PCV20 serotypes in Coadministration and PCV20-only groups, respectively. GMFRs for full-length S-binding IgG of 35.5 and 39.0, and for neutralizing titres against SARS-CoV-2-wild type virus of 58.8 and 65.4, were observed in the Coadministration and BNT162b2-only groups, respectively. CONCLUSIONS: Safety and immunogenicity of coadministered PCV20 and BNT162b2 were similar to those of PCV20 or BNT162b2 administered alone, suggesting that the 2 vaccines may be coadministered. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04887948.

Cardiac and vascular complications in lupus: Is there a role for sex?

Systemic lupus erythematosus (SLE) is a common systemic autoimmune disorder and is characterized by autoantibody formation and subsequent immune complex deposition into target organs. SLE affects nearly nine women to every one man worldwide. Patients with SLE are at an enhanced risk for cardiovascular disease (CVD) morbidity and mortality. CVD is the leading cause of death worldwide and includes heart and blood vessel disorders, cerebrovascular disease, and rheumatic heart disease. Specific mechanisms by which cardiac and vascular pathophysiology develops in patients with SLE are still not fully known. Not only do we not understand this correlation between SLE and CVD, but there is also a critical gap in scientific knowledge on the contribution of sex. In this review, we will discuss the cardiac and vascular pathological disease states that are present in some patients with SLE. More importantly, we will discuss the potential mechanisms for the role of sex and sex hormones in the development of CVD with SLE.

Antimicrobial susceptibility surveillance and antimicrobial resistance in Neisseria gonorrhoeae in Africa from 2001 to 2020: A mini-review.

Antimicrobial resistance (AMR) in Neisseria gonorrhoeae (NG), compromising gonorrhea treatment, is a global public health concern. Improved, quality-assured NG AMR monitoring at the global level is essential. This mini-review examined NG AMR susceptibility surveillance and AMR data from the African continent from 2001 to 2020. Eligible peer-reviewed publications (n = 30) containing NG AMR data for antimicrobials currently recommended for gonorrhea treatment were included. Overall, very limited NG surveillance and AMR data was available. Furthermore, the NG AMR surveillance studies varied greatly regarding surveillance protocols (e.g., populations and samples tested, sample size, antimicrobials examined), methodologies (e.g., antimicrobial susceptibility testing method [agar dilution, minimum inhibitory concentration (MIC) gradient strip test, disc diffusion test] and interpretative criteria), and quality assurance (internal quality controls, external quality assessments [EQA], and verification of AMR detected). Moreover, most studies examined a suboptimal number of NG isolates, i.e., less than the WHO Global Gonococcal Antimicrobial Surveillance Program (GASP) and WHO Enhanced GASP (EGASP) recommendations of ≥100 isolates per setting and year. The notable inter-study variability and frequently small sample sizes make appropriate inter-study and inter-country comparisons of AMR data difficult. In conclusion, it is imperative to establish an enhanced, standardized and quality-assured NG AMR surveillance, ideally including patient metadata and genome sequencing as in WHO EGASP, in Africa, the region with the highest gonorrhea incidence globally. This will enable the monitoring of AMR trends, detection of emerging AMR, and timely refinements of national and international gonorrhea treatment guidelines. To achieve this aim, national and international leadership, political and financial commitments are imperative.