Macrophage heterogeneity in atherosclerosis: A matter of context.

During atherogenesis, plaque macrophages take up and process deposited lipids, trigger inflammation, and form necrotic cores. The traditional inflammatory/anti-inflammatory paradigm has proven insufficient in explaining their complex disease-driving mechanisms. Instead, we now appreciate that macrophages exhibit remarkable heterogeneity and functional specialization in various pathological contexts, including atherosclerosis. Technical advances for studying individual cells, especially single-cell RNA sequencing, indeed allowed to identify novel macrophage subsets in both murine and human atherosclerosis, highlighting the existence of diverse macrophage activation states throughout pathogenesis. In addition, recent studies highlighted the role of the local microenvironment in shaping the macrophages' phenotype and function. However, this remains largely undescribed in the context of atherosclerosis. In this review we explore the origins of macrophages and their functional specialization, shedding light on the diverse sources of macrophage accumulation in the atherosclerotic plaque. Next, we discuss the phenotypic diversity observed in both murine and human atherosclerosis, elucidating their distinct functions and spatial distribution within plaques. Finally, we highlight the importance of the local microenvironment in both phenotypic and functional specialization of macrophages in atherosclerosis and elaborate on the need for spatial multiomics approaches to provide a better understanding of the different macrophage subsets' roles in the pathogenesis of atherosclerosis.

Spatial Metabolomics Identifies LPC(18:0) and LPA(18:1) in Advanced Atheroma With Translation to Plasma for Cardiovascular Risk Estimation.

BACKGROUND: The metabolic alterations occurring within the arterial architecture during atherosclerosis development remain poorly understood, let alone those particular to each arterial tunica. We aimed first to identify, in a spatially resolved manner, the specific metabolic changes in plaque, media, adventitia, and cardiac tissue between control and atherosclerotic murine aortas. Second, we assessed their translatability to human tissue and plasma for cardiovascular risk estimation. METHODS: In this observational study, mass spectrometry imaging (MSI) was applied to identify region-specific metabolic differences between atherosclerotic (n=11) and control (n=11) aortas from low-density lipoprotein receptor-deficient mice, via histology-guided virtual microdissection. Early and advanced plaques were compared within the same atherosclerotic animals. Progression metabolites were further analyzed by MSI in 9 human atherosclerotic carotids and by targeted mass spectrometry in human plasma from subjects with elective coronary artery bypass grafting (cardiovascular risk group, n=27) and a control group (n=27). RESULTS: MSI identified 362 local metabolic alterations in atherosclerotic mice (log2 fold-change ≥1.5; P≤0.05). The lipid composition of cardiac tissue is altered during atherosclerosis development and presents a generalized accumulation of glycerophospholipids, except for lysolipids. Lysolipids (among other glycerophospholipids) were found at elevated levels in all 3 arterial layers of atherosclerotic aortas. LPC(18:0) (lysophosphatidylcholine; P=0.024) and LPA(18:1) (lysophosphatidic acid; P=0.025) were found to be significantly elevated in advanced plaques as compared with mouse-matched early plaques. Higher levels of both lipid species were also observed in fibrosis-rich areas of advanced- versus early-stage human samples. They were found to be significantly reduced in human plasma from subjects with elective coronary artery bypass grafting (P<0.001 and P=0.031, respectively), with LPC(18:0) showing significant association with cardiovascular risk (odds ratio, 0.479 [95% CI, 0.225-0.883]; P=0.032) and diagnostic potential (area under the curve, 0.778 [95% CI, 0.638-0.917]). CONCLUSIONS: An altered phospholipid metabolism occurs in atherosclerosis, affecting both the aorta and the adjacent heart tissue. Plaque-progression lipids LPC(18:0) and LPA(18:1), as identified by MSI on tissue, reflect cardiovascular risk in human plasma.

PML and PML-like exonucleases restrict retrotransposons in jawed vertebrates.

We have uncovered a role for the promyelocytic leukemia (PML) gene and novel PML-like DEDDh exonucleases in the maintenance of genome stability through the restriction of LINE-1 (L1) retrotransposition in jawed vertebrates. Although the mammalian PML protein forms nuclear bodies, we found that the spotted gar PML ortholog and related proteins in fish function as cytoplasmic DEDDh exonucleases. In contrast, PML proteins from amniote species localized both to the cytoplasm and formed nuclear bodies. We also identified the PML-like exon 9 (Plex9) genes in teleost fishes that encode exonucleases. Plex9 proteins resemble TREX1 but are unique from the TREX family and share homology to gar PML. We also characterized the molecular evolution of TREX1 and the first non-mammalian TREX1 homologs in axolotl. In an example of convergent evolution and akin to TREX1, gar PML and zebrafish Plex9 proteins suppressed L1 retrotransposition and could complement TREX1 knockout in mammalian cells. Following export to the cytoplasm, the human PML-I isoform also restricted L1 through its conserved C-terminus by enhancing ORF1p degradation through the ubiquitin-proteasome system. Thus, PML first emerged as a cytoplasmic suppressor of retroelements, and this function is retained in amniotes despite its new role in the assembly of nuclear bodies.

Patients with autoimmune liver disease have glucose disturbances that mechanistically differ from steatotic liver disease.

Autoimmune liver diseases are associated with an increased risk of diabetes, yet the underlying mechanisms remain unknown. In this cross-sectional study, we investigated the glucose-regulatory disturbances in patients with autoimmune hepatitis (AIH, n = 19), primary biliary cholangitis (PBC, n = 15), and primary sclerosing cholangitis (PSC, n = 6). Healthy individuals (n = 24) and patients with metabolic dysfunction-associated steatotic liver disease (MASLD, n = 18) were included as controls. Blood samples were collected during a 120-min oral glucose tolerance test. We measured the concentrations of glucose, C-peptide, insulin, glucagon, and the two incretin hormones, glucose insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1). We calculated the homeostasis model assessment of insulin resistance (HOMA-IR), whole body insulin resistance (Matsuda index), insulin clearance, and insulinogenic index. All patient groups had increased fasting plasma glucose and impaired glucose responses compared with healthy controls. Beta-cell secretion was increased in AIH, PBC, and MASLD but not in PSC. Patients with AIH and MASLD had hyperglucagonemia and hepatic, as well as peripheral, insulin resistance and decreased insulin clearance, resulting in hyperinsulinemia. Patients with autoimmune liver disease had an increased GIP response, and those with AIH or PBC had an increased GLP-1 response. Our data demonstrate that the mechanism underlying glucose disturbances in patients with autoimmune liver disease differs from that underlying MASLD, including compensatory incretin responses in patients with autoimmune liver disease. Our results suggest that glucose disturbances are present at an early stage of the disease.NEW & NOTEWORTHY Patients with autoimmune liver disease but without overt diabetes display glucose disturbances early on in their disease course. We identified pathophysiological traits specific to these patients including altered incretin responses.

Live Biotherapeutic Products for the Prevention of Recurrent Clostridioides difficile Infection.

OBJECTIVE: To review the efficacy, safety, and role of live biotherapeutic products (LBPs) in the prevention of recurrent Clostridioides difficile infection (rCDI). DATA SOURCES: A literature search was performed using PubMed and Google Scholar (through February 2024) with search terms RBX2660, SER-109, and fecal microbiota. Other resources included abstracts presented at recent conferences, national clinical practice guidelines, and manufacturers' websites. STUDY SELECTION AND DATA EXTRACTION: All relevant studies, trial updates, conference abstracts, and guidelines in the English language were included. DATA SYNTHESIS: Two LBPs were recently approved by the Food and Drug Administration for the prevention of recurrence in adults following antibiotic treatment for rCDI. Fecal microbiota, live-jslm is administered rectally as a retention enema, whereas fecal microbiota spores, live-brpk is given orally after bowel preparation. Several phase 2 and phase 3 clinical trials have established the safety and efficacy of these LBPs in reducing rates of rCDI compared with placebo. Patients with severe immunosuppression and those with inflammatory bowel disease were largely excluded from these trials. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE IN COMPARISON WITH EXISTING DRUGS: Live biotherapeutic products offer a similar mechanism to conventional fecal microbiota transplant (FMT) in preventing rCDI through microbiota restoration. The primary advantages of LBPs over FMT are their standardized composition and donor stool screening processes for transmissible pathogens. Bezlotoxumab is also available for the prevention of Clostridioides difficile infection; however, there are no clinical data available to compare the efficacy of LBPs with bezlotoxumab, and the benefit of simultaneous use of these preventative therapies is unclear. CONCLUSIONS: Live biotherapeutic products provide a safe and effective option for the prevention of rCDI and represent an improvement over conventional FMT. Additional studies are needed to further determine their place in therapy relative to bezlotoxumab and in the setting of immunosuppression and inflammatory bowel disease.

Lenacapavir: A Novel Long-Acting Capsid Inhibitor for HIV.

OBJECTIVE: To review the efficacy, safety, and role of lenacapavir (LEN) in the treatment of HIV-1 infection. DATA SOURCES: A literature search was performed using PubMed and Google Scholar (through March 2023) with the search term LEN and GS-6207. Other resources included abstracts presented at recent conferences, the manufacturer's Web site, and prescribing information. STUDY SELECTION AND DATA EXTRACTION: All relevant articles, trial updates, and conference abstracts in the English language were included. DATA SYNTHESIS: Lenacapavir represents a new class of antiretrovirals (ARVs) with a novel mechanism of action as a capsid inhibitor and a unique twice-a-year subcutaneous administration schedule. Lenacapavir when combined with other ARVs has proven to benefit heavily treatment-experienced (HTE) patients with HIV-1 infection in achieving viral suppression and immune restoration. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE IN COMPARISON WITH EXISTING DRUGS: Lenacapavir is a new treatment option that patients who are HTE can consider adding as part of an ARV regimen. CONCLUSIONS: Lenacapavir is an effective and well-tolerated option for HTE patients which is a valuable addition to the arsenal of ARVs.

Early Celecoxib Use in Spontaneous Intracerebral Hemorrhage is Associated with Reduced Mortality.

BACKGROUND: Hemorrhagic strokes constitute 10-15% of all strokes and have the worst mortality and morbidity of all subtypes. Mortality and morbidity of spontaneous intracerebral hemorrhage (sICH) are often secondary to the effects of inflammation, brain edema, and swelling. Studies have shown that celecoxib, a selective cyclooxygenase 2 (COX-2) inhibitor, reduces perihematomal edema formation and inflammation. This study aimed to examine the impact of celecoxib on sICH outcomes. METHODS: TriNetX, a multi-institutional research database, was retrospectively queried to identify patients with sICH. Outcomes in patients who received celecoxib within 5 days (cohort 1) were analyzed and compared to those in patients who did not receive celecoxib (cohort 2). The primary end point was mortality within 1 year of sICH. Secondary end points included ventilator dependence, tracheostomy, percutaneous endoscopic gastrostomy tube placement, craniotomy, deep venous thrombosis, pulmonary embolism, ischemic stroke, transient ischemia attack, myocardial infarction, and seizures. Further analysis was performed to assess these outcomes for patients treated with ibuprofen, a nonselective COX inhibitor. RESULTS: After propensity score matching, 833 patients were identified in each cohort based on celecoxib use. Mortality at 1 year was significantly reduced in patients with sICH receiving celecoxib compared to those who did not (13.33% vs. 17.77%; p = 0.0124). Risks of ventilator dependence, tracheostomy, percutaneous endoscopic gastrostomy tube placement, craniotomy, deep venous thrombosis, pulmonary embolism, ischemic stroke, transient ischemia attack, myocardial infarction, and seizures were not significantly increased in patients who received celecoxib within 5 days of sICH compared to those who did not receive celecoxib. There was no significant difference in mortality between patients based on ibuprofen administration. CONCLUSIONS: There exists a growing interest in using COX-2 as a potential target strategy for neuroprotection in patients with sICH, with some evidence of a mortality benefit in small cohort studies. This study shows that early celecoxib use is associated with decreased mortality in patients with sICH.

Cabotegravir: The First Long-Acting Injectable for HIV Preexposure Prophylaxis.

OBJECTIVE: Review the pharmacology, pharmacokinetics, efficacy, safety, and role of long-acting injectable cabotegravir (CAB-LA) in HIV preexposure prophylaxis (PrEP). DATA SOURCES: A literature search was performed using PubMed and Google Scholar (2012 to April 2022) with the search terms cabotegravir, preexposure prophylaxis, and PrEP. Other resources included abstracts presented at recent conferences, the manufacturer's Web site, prescribing information, and review articles. STUDY SELECTION AND DATA EXTRACTION: All English-language articles of studies assessing the efficacy and safety of CAB-LA for PrEP were included. DATA SYNTHESIS: CAB-LA is the first long-acting injectable therapy approved for HIV-1 PrEP in both men and women. It is a suspension given intramuscularly every other month. CAB-LA has been shown to be more effective than daily oral tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) in preventing HIV-1 infection among high-risk individuals. Two phase 3 trials were stopped early on the basis of superior efficacy of CAB-LA. The most common adverse effects were injection site reactions (ISRs), although they tended to decrease over time, and few participants in clinical trials discontinued use due to ISRs. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: CAB-LA may be particularly useful for individuals with known adherence problems to oral therapy, those with renal impairment, and those with decreased bone mineral density. However, CAB-LA is more expensive than generic TDF/FTC and may be associated with weight gain. CONCLUSIONS: CAB-LA is the first long-acting injectable agent for HIV PrEP. It is more effective than oral TDF/FTC, is well-tolerated aside from ISRs, and has few clinically significant drug-drug interactions.

PreHevbrio: A New 3-Antigen Hepatitis B Vaccine for Adults.

OBJECTIVE: The main objective of this article is to review the immunogenicity and safety of the 3-antigen recombinant hepatitis B vaccine (3A-HepB) in adults. DATA SOURCES: A literature search was performed using PubMed and Google Scholar (2000 to June 2022) with the search terms hepatitis B vaccine and 3-antigen. Other resources included the Centers for Disease Control and Prevention, conference abstracts of liver meetings, the prescribing information, and the manufacturer's website. STUDY SELECTION AND DATA EXTRACTION: All English-language articles of studies assessing the immunogenicity and safety of 3A-HepB in humans were included. DATA SYNTHESIS: The 3A-HepB is licensed to prevent infection caused by all known subtypes of the hepatitis B virus in adults. It contains 3 hepatitis B surface antigens. The 3A-HepB has been shown to be noninferior to a single-antigen hepatitis B vaccine (1A-HepB). It is administered intramuscularly as a 3-dose series at 0, 1, and 6 months. The most commonly reported local reactions were injection site pain and tenderness, and the most commonly reported systemic reactions were headache, fatigue, and myalgia. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: The introduction of 3A-HepB represents another step toward reducing the rates of new hepatitis B infections. However, clinical trials are needed to assess the immunogenicity of 3A-HepB in individuals at high-risk of nonresponse or low response to 1A-HepB, such as those with renal or hepatic impairment and those with altered immunocompetence. CONCLUSIONS: The 3A-HepB represents another vaccine to prevent hepatitis B in adults. It is safe and immunogenic but is associated with more adverse reactions than 1A-HepB.

Intravascular fasciitis of the scalp as a complication of ICP monitor placement: a case report and review of the literature.

BACKGROUND/IMPORTANCE: There are only 56 documented cases of intravascular fasciitis, a rare variant of nodular fasciitis. Of these cases, only 2 involved the scalp. This lesion is amenable to surgical resection, making it important to differentiate it from soft tissue malignancies of the scalp. CLINICAL PRESENTATION: We report an unusual case of intravascular fasciitis involving the scalp at the site of an intracranial pressure (ICP) monitor of a 13-year-old male patient. The lesion was surgically excised with no recurrence upon 1-month follow-up. CONCLUSION: Intravascular fasciitis is a benign, reactive proliferation of soft tissue that may arise at sites of prior trauma. It appears as a soft, painless, mobile lesion, and immunohistochemical studies are required to differentiate it from malignant lesions. The standard of care is surgical resection of the lesion.

Fatty filum terminale and low-lying conus medullaris in Gollop-Wolfgang complex: a case report and review of literature.

BACKGROUND/IMPORTANCE: Gollop-Wolfgang complex is a rare skeletal dysplasia with only 200 cases reported in the literature. This disorder is usually associated with several extraosseous anomalies. This report describes the first case of a fatty filum terminale and a low-lying conus medullaris in a patient with this complex. A review of the current literature of the Gollop-Wolfgang complex accompanies this case, highlighting the documented extraosseous anomalies seen in this complex. CLINICAL PRESENTATION: We report a case of an 18-month-old patient with Gollop-Wolfgang complex who underwent cord untethering with release of the filum terminale after extensive workup showed the presence of a dyssynergic bladder and radiological evaluation revealed a fatty filum terminale and low-lying conus medullaris. CONCLUSION: Gollop-Wolfgang complex is a skeletal dysplasia usually associated with several extra skeletal anomalies. Our report describes the first case of a fatty filum terminale and low-lying conus medullaris in this complex, as well as provides an overview of the documented anomalies seen in this disorder. A multidisciplinary approach is recommended when treating these infants in order to ensure that occult manifestations of the complex are not missed.

Pregnancy in spina bifida patients: a comparative analysis of peripartum procedures and complications.

PURPOSE: Spina bifida (SB) is caused by a failure in neural tube closure that can present with lower extremity sensory deficits, paralysis, and hydrocephalus. Medical advances have allowed increased pregnancies among SB patients, but management and pregnancy-associated complications have not been thoroughly investigated. The objective is to delineate peripartum procedures and complications in patients with SB. METHODS: A national de-identified database, TriNetX, was retrospectively queried to evaluate pregnant SB patients and the general population. Procedures and complications were investigated using corresponding ICD-10 and CPT codes within 1 year of pregnancy diagnosis. RESULTS: 11,405 SB patients were identified and compared to 9,269,084 non-SB patients. SB patients were significantly more likely to undergo cesarean delivery (1.200; 95% CI [1.133-1.271]) and less likely to receive neuraxial analgesia (0.406; 95% CI [0.383-0.431]). Additionally, patients with SB had an increased risk of seizures (3.922; 95% CI [3.529-4.360]) and venous thromboembolism (VTE) (3.490; 95% CI [3.070-3.969]). Risks of preeclampsia and hemorrhage were comparable. SB patients with hydrocephalus and Chiari malformation type 1 (CM-1) or type 2 (CM-2) were compared to patients without these comorbid conditions. This sub-group analysis showed a significantly increased risk of having cesarean deliveries (SB with hydrocephalus: 12.55%, S.B. with CM-1 or CM-2: 12.81% vs. SB without hydrocephalus or CM, 6.16%) and VTE (3.74%, 2.43% vs. 0.81%). There were also increased risks of hemorrhage and seizures and decreased use of neuraxial analgesia, but the sample size was insufficient. CONCLUSION: SB patients were more likely to undergo cesarean section and exhibit peripartum complications compared to those without SB.

Direct ventriculoatrial shunt in a pediatric patient: case report and technical note.

BACKGROUND /IMPORTANCE: The safety of direct cardiac shunts has been historically described in the pediatric population before the introduction of silastic catheters but are rarely utilized in modern practice. Herein, we describe several technical nuances regarding the placement of a direct ventriculoatrial catheter in a pediatric patient, including the creation of a sternal divot to accommodate for the movement of the catheter during growth. CLINICAL PRESENTATION: We report a complex case of a 2-year-old former premature infant with multiple systemic congenital abnormalities, including tracheal atresia (type 2), complete atrioventricular septal defect status post repair, and shunted hydrocephalus. She developed multiple shunt malfunctions secondary to abdominal malabsorption and shunt infections. CONCLUSION: Multiple options for distal shunt placement, including the atrium via open and endovascular techniques, the abdomen, gallbladder, and pleura, were considered, but the direct cardiac placement was felt to be the safest option given the patient's coexisting conditions. Placement requires a multidisciplinary team. Special consideration should be made for linear growth in children.

ASSOCIATIONS BETWEEN SCREENING FOR FUNCTIONAL JAW DISTURBANCES AND PATIENT REPORTED OUTCOMES ON JAW LIMITATIONS AND ORAL BEHAVIORS.

OBJECTIVES: Temporomandibular disorders (TMDs) is a collective term for pain and functional disturbances related to the jaw muscles and the temporomandibular joint. In contrast to screening for orofacial pain, knowledge is limited on the association between patient-reported outcomes and screening for joint-related functional jaw disturbances. Therefore, our aim was to evaluate the association between a screening question for functional jaw disturbances, and disease-specific outcome measures for functional jaw limitations and oral behaviors. METHODS: This study included 299 individuals (201 women; 20-69 years, median 37.0) in a general population sample from Västerbotten, Northern Sweden in 2014. A single screening question for functional jaw disturbances "Does your jaw lock or become stuck once a week or more?" was used to categorize individuals as cases or controls. Patient-reported outcomes on functional jaw disturbances were assessed with the 20-item jaw functional limitation scale (JFLS-20) and oral behaviors with the 21-item Oral Behaviors Checklist (OBC-21). RESULTS: The strongest predictive probability to have a positive screening outcome was functional jaw limitations related to mobility (AUCboot=0.78, 95 CI:0.71-0.86, P < .001), followed by limitations related to communication (AUCboot = 0.74, 95 CI:0.63-0.80, P < .001) and mastication (AUCboot = 0.73, 95 CI:0.66-0.81, P < .001). The frequency of oral behaviors was not significantly associated with a positive screening outcome (AUCboot = 0.65, 95 CI:0.55-0.72, P = .223). CONCLUSIONS: Self-reported functional limitations, but not oral behaviors, are strongly associated with a single screening question for frequent functional jaw disturbances. This finding provides support for incorporating a question on jaw catching/locking once a week or more in screening instruments for TMDs.

Development of Biodegradable Osteopromotive Citrate-Based Bone Putty.

The burden of bone fractures demands development of effective biomaterial solutions, while additional acute events such as noncompressible bleeding further motivate the search for multi-functional implants to avoid complications including osseous hemorrhage, infection, and nonunion. Bone wax has been widely used in orthopedic bleeding control due to its simplicity of use and conformation to irregular defects; however, its nondegradability results in impaired bone healing, risk of infection, and significant inflammatory responses. Herein, a class of intrinsically fluorescent, osteopromotive citrate-based polymer/hydroxyapatite (HA) composites (BPLP-Ser/HA) as a highly malleable press-fit putty is designed. BPLP-Ser/HA putty displays mechanics replicating early nonmineralized bone (initial moduli from ≈2-500 kPa), hydration induced mechanical strengthening in physiological conditions, tunable degradation rates (over 2 months), low swelling ratios (<10%), clotting and hemostatic sealing potential (resistant to blood pressure for >24 h) and significant adhesion to bone (≈350-550 kPa). Simultaneously, citrate's bioactive properties result in antimicrobial (≈100% and 55% inhibition of S. aureus and E. coli) and osteopromotive effects. Finally, BPLP-Ser/HA putty demonstrates in vivo regeneration in a critical-sized rat calvaria model equivalent to gold standard autograft. BPLP-Ser/HA putty represents a simple, off-the-shelf solution to the combined challenges of acute wound management and subsequent bone regeneration.

SPOT: a web-tool enabling swift profiling of transcriptomes.

The increasing number of single cell and bulk RNAseq datasets describing complex gene expression profiles in different organisms, organs or cell types calls for an intuitive tool allowing rapid comparative analysis. Here, we present Swift Profiling Of Transcriptomes (SPOT) as a web tool that allows not only differential expression analysis but also fast ranking of genes fitting transcription profiles of interest. Based on a heuristic approach the spot algorithm ranks the genes according to their proximity to the user-defined gene expression profile of interest. The best hits are visualized as a table, bar chart or dot plot and can be exported as an Excel file. While the tool is generally applicable, we tested it on RNAseq data from malaria parasites that undergo multiple stage transformations during their complex life cycle as well as on data from multiple human organs during development and cell lines infected by SARS-CoV-2. SPOT should enable non-bioinformaticians to easily analyse their own and any available dataset. AVAILABILITY AND IMPLEMENTATION: SPOT is freely available for (academic) use at: https://frischknechtlab.shinyapps.io/SPOT/ and https://github.com/EliasFarr/SPOT. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Heavy lone coronary artery thrombosis treated by stent retriever, in the setting of COVID-19 infection.

We present a case of heavy lone coronary thrombosis in the setting of COVID-19 infection. We highlight the special angiographic, ultrasonographic, and histological features of this thrombus, and we describe the application of carotid stent retriever for its removal.

Acute effects on glucose tolerance by neprilysin inhibition in patients with type 2 diabetes.

AIMS: Sacubitril/valsartan is a neprilysin-inhibitor/angiotensin II receptor blocker used for the treatment of heart failure. Recently, a post-hoc analysis of a 3-year randomized controlled trial showed improved glycaemic control with sacubitril/valsartan in patients with heart failure and type 2 diabetes. We previously reported that sacubitril/valsartan combined with a dipeptidyl peptidase-4 inhibitor increases active glucagon-like peptide-1 (GLP-1) in healthy individuals. We now hypothesized that administration of sacubitril/valsartan with or without a dipeptidyl peptidase-4 inhibitor would lower postprandial glucose concentrations (primary outcome) in patients with type 2 diabetes via increased active GLP-1. METHODS: We performed a crossover trial in 12 patients with obesity and type 2 diabetes. A mixed meal was ingested following five respective interventions: (a) a single dose of sacubitril/valsartan; (b) sitagliptin; (c) sacubitril/valsartan + sitagliptin; (d) control (no treatment); and (e) valsartan alone. Glucose, gut and pancreatic hormone responses were measured. RESULTS: Postprandial plasma glucose increased by 57% (incremental area under the curve 0-240 min) (p = .0003) and increased peak plasma glucose by 1.7 mM (95% CI: 0.6-2.9) (p = .003) after sacubitril/valsartan compared with control, whereas postprandial glucose levels did not change significantly after sacubitril/valsartan + sitagliptin. Glucagon, GLP-1 and C-peptide concentrations increased after sacubitril/valsartan, but insulin and glucose-dependent insulinotropic polypeptide did not change. CONCLUSIONS: The glucose-lowering effects of long-term sacubitril/valsartan treatment reported in patients with heart failure and type 2 diabetes may not depend on changes in entero-pancreatic hormones. Neprilysin inhibition results in hyperglucagonaemia and this may explain the worsen glucose tolerance observed in this study. CLINICALTRIALS: gov (NCT03893526).

Antibiotic Approvals in the Last Decade: Are We Keeping Up With Resistance?

OBJECTIVE: To review the spectrum of activity, efficacy, safety, and role in therapy of all antibiotics and related biologics approved by the Food and Drug Administration (FDA) in the last decade. DATA SOURCES: A literature search was performed using PubMed and Google Scholar (2010 to end May 2021) with the search terms' name of the antibiotic or the biologic. Data were also obtained from the prescribing information, FDA, and ClinicalTrials.gov websites. STUDY SELECTION: All relevant English-language, late phase clinical trials assessing the safety and efficacy of the identified drugs were included. Review articles and references of retrieved articles were evaluated for relevant data. DATA SYNTHESIS: Antibiotic resistance is a public health crisis, and antibiotic development is imperative to outpace the ability of bacteria to develop resistance. Only 17 new systemic antibiotics and 1 related biologic have been approved by the FDA since 2010. Among these drugs, 14 were approved for common bacterial infections, 1 was approved for Clostridioides difficile infection (CDI), 1 was licensed to prevent CDI recurrence, and 2 were approved for drug-resistant tuberculosis. Very few antibiotics are in clinical development. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: The arrival of these new antibiotics was welcomed with great enthusiasm, particularly when they met previously unmet medical needs. Unfortunately, the majority of them represent modifications to existing chemical structures rather than new drug classes. Despite the availability of these antibiotics, managing patients with deep-seated infections and those with extensively resistant gram-negative organisms remains challenging. CONCLUSIONS: The number of new antibiotics and their indications are not keeping up with resistance and the needs of the patients.

A Continuing Education Activity Durably Addressed Knowledge Gaps Related to Penicillin Allergies Among Pharmacists and Pharmacy Technicians.

Background: Penicillin allergy is one of the most frequent self-reported allergies; however, only about 10% of reported allergies are accurate. Objectives: Through the creation of a continuing pharmacy education (CPE) activity, we sought to assess knowledge gaps and comfort levels in the management of penicillin allergies. Methods: A 1-hour enduring-content CPE activity was offered as an interactive course from September 20, 2019, to September 20, 2020. Participants completed 3 surveys (pre-survey, post-survey, and follow-up survey). Participants were pharmacists and pharmacy technicians who completed, at a minimum, the activity and both pre- and post-surveys. The primary outcome was the percentage of participants scoring >80% on knowledge-based questions on the post-survey compared with the pre-survey. Secondary outcomes included pre-post comparisons on knowledge-based questions, participants' self-report of an allergy, and comfort levels dispensing cephalosporins in a patient with a self-reported penicillin allergy. Results: A total of 389 participants completed the CPE activity, with 176 included for analysis. Significantly more participants scored >80% on knowledge-based questions on the post-survey compared with the pre-survey (71.6% vs 22.7%, P < .001). There was no significant difference between the percentage of participants scoring >80% on the post-survey and the follow-up survey (71.6% vs 65%, P = .119). The majority of participants (74%) felt comfortable dispensing a cephalosporin in a patient with a penicillin allergy on the pre-survey, with similar percentages on the post- and follow-up surveys (77% and 90%, respectively). Conclusion: A targeted continuing education program improved overall knowledge, which was sustained for up to 2 months.