Targeted Protein Degradation through Recruitment of the CUL4 Complex Adaptor Protein DDB1.

Targeted protein degradation has arisen as a powerful therapeutic modality for eliminating proteins. Thus far, most heterobifunctional proteolysis targeting chimeras (PROTACs) have utilized recruiters against substrate receptors of Cullin RING E3 ubiquitin ligases, such as cereblon and VHL. However, previous studies have surprisingly uncovered molecular glue degraders that exploit a CUL4 adaptor protein DDB1 to degrade neosubstrate proteins. Here, we sought to investigate whether DDB1 recruiters can be discovered that can be exploited for PROTAC applications. We utilized activity-based protein profiling and cysteine chemoproteomic screening to identify a covalent recruiter that targets C173 on DDB1 and exploited this recruiter to develop PROTACs against BRD4 and androgen receptor (AR). We demonstrated that the BRD4 PROTAC results in selective degradation of the short BRD4 isoform over the long isoform in a proteasome, NEDDylation, and DDB1-dependent manner. We also demonstrated degradation of AR with the AR PROTAC in prostate cancer cells. Our study demonstrated that covalent chemoproteomic approaches can be used to discover recruiters against Cullin RING adapter proteins and that these recruiters can be used for PROTAC applications to degrade neo-substrates.

Shedding light on eye disease in obesity: A review.

Obesity is known to be associated with numerous ocular manifestations, including but not limited to, diabetic retinopathy (DR), age-related macular degeneration (AMD), cataracts, glaucoma, and dry eye disease. This review aims to provide an overview of the ophthalmological findings in obesity. A literature search was conducted using PubMed and Cochrane databases for studies describing randomized clinical trials, meta-analyses, systematic reviews, and observational studies published from 1 January 2017 to 1 April 2023. The search terms used included relevant keywords such as 'obesity', 'body mass index', 'waist-to-hip ratio', 'bariatric', 'ophthalmology', 'eye disease', 'myopia', 'retinopathy', 'glaucoma', and 'cataract'. This literature search was performed on 1 April 2023. Obesity is associated with increased risk of developing DR, a sight-threatening complication of diabetes mellitus. Similarly, obesity has been shown to increase risk of AMD, cataracts, glaucoma, and ocular surface disease. Multiple mechanisms linking obesity to ophthalmic disease have been proposed. Adipose tissue produces various inflammatory cytokines that can affect ocular tissues, leading to disease progression. Additionally, obesity is associated with systemic metabolic changes that can influence ocular health. Bariatric surgery has been shown to be protective against development of ophthalmic disease. Obesity is a significant risk factor for several ophthalmological diseases. Healthcare providers should encourage weight loss in patients with overweight or obesity to prevent or delay the onset of ocular complications. Further research is needed to better understand the underlying mechanisms of this association, and to identify effective strategies for preventing or managing ophthalmic disease in patients with obesity.

Structural and biophysical comparisons of the pomalidomide- and CC-220-induced interactions of SALL4 with cereblon.

The design of cereblon-binding molecular glues (MGs) that selectively recruit a desired protein while excluding teratogenic SALL4 is an area of significant interest when designing therapeutic agents. Previous studies show that SALL4 is degraded in the presence of IKZF1 degraders pomalidomide, and to a lesser extent by CC-220. To expand our understanding of the molecular basis for the interaction of SALL4 with cereblon, we performed biophysical and structural studies demonstrating that SALL4 zinc finger domains one and two (ZF1-2) interact with cereblon (CRBN) in a unique manner. ZF1 interacts with the N-terminal domain of cereblon and ZF2 binds as expected in the C-terminal IMiD-binding domain. Both ZF1 and ZF2 contribute to the potency of the interaction of ZF1-2 with CRBN:MG complexes and the affinities of SALL4 ZF1-2 for the cereblon:CC-220 complex are less potent than for the corresponding pomalidomide complex. Structural analysis provides a rationale for understanding the reduced affinity of SALL4 for cereblon in the presence of CC-220, which engages both ZF1 and ZF2. These studies further our understanding of the molecular glue-mediated interactions of zinc finger-based proteins with cereblon and may provide structural tools for the prospective design of compounds with reduced binding and degradation of SALL4.

Formación de promotores en salud menstrual como estrategia pedagógica / Training Menstrual Health Promoters as a pedagogical strategy

El profesional del área de la salud tiene un rol fundamental acompañando el desarrollo y crecimiento de niñas, niños y adolescentes, lo cual incluye educación en salud menstrual. Considerando lo anterior, se gestó el proyecto de Vinculación con el Medio de la Universidad San Sebastián “Juntos Crecemos Contigo”, el cual contempló la formación de estudiantes de Enfermería como promotores en salud menstrual por la Fundación Malva Miranda. Al año de haber llevado a cabo la actividad se encuestó al alumnado sobre esta experiencia, donde un 80% manifestó que fue un incentivo para la adquisición de conocimientos sobre salud menstrual; un 85,7% señaló que este tipo de metodología participativa les permitió adquirir y transferir nuevos conocimientos como parte de su formación profesional. Los resultados demuestran que es una metodología innovadora, altamente efectiva y que fortalece la promoción de la salud integral en niños y niñas. (AU)

Healthcare professionals play an essential role accompanying the development and growth of children and adolescents, which includes menstrual health education. Considering this, the project for Link with the Environment called “Juntos Crecemos Contigo” (“Together we grow with you”) was created by the University of San Sebastián, which provides for the training of Nursing students as Menstrual Health Promoters by the Malva Miranda Foundation. One year after conducting this activity, the students answered a survey about their experience, and 80% stated that it was an incentive for acquiring knowledge on menstrual health; while 85.7% pointed out that this type of participative methodology allowed them to acquire and transfer new knowledge as part of their professional training. Results show that this is an innovative methodology, highly effective, and which strengthens the promotion of integrated health in boys and girls. (AU)

Targeted Protein Degradation through Recruitment of the CUL4A Complex Adaptor Protein DDB1.

Targeted protein degradation has arisen as a powerful therapeutic modality for eliminating proteins. Thus far, most heterobifunctional Proteolysis Targeting Chimeras (PROTACs) have utilized recruiters against substrate receptors of Cullin RING E3 ubiquitin ligases, such as cereblon and VHL. However, previous studies have surprisingly uncovered molecular glue degraders that exploit a CUL4A adaptor protein DDB1 to degrade neosubstrate proteins. Here, we sought to investigate whether DDB1 recruiters can be discovered that can be exploited for PROTAC applications. We utilized activity-based protein profiling and cysteine chemoproteomic screening to identify a covalent recruiter that targets C173 on DDB1 and exploited this recruiter to develop PROTACs against BRD4 and androgen receptor (AR). We demonstrated that the BRD4 PROTAC results in selective degradation of the short BRD4 isoform over the long isoform in a proteasome, NEDDylation, and DDB1-dependent manner. We also demonstrated degradation of AR with the AR PROTAC in prostate cancer cells. Our study demonstrated that covalent chemoproteomic approaches can be used to discover recruiters against Cullin RING adapter proteins and that these recruiters can be used for PROTAC applications to degrade neo-substrates.

The forgotten material: Highly dispersible and swellable gelatin-based microspheres for pulmonary drug delivery of cromolyn sodium and ipratropium bromide.

Controlled-release formulations for pulmonary delivery are highly desirable for treating chronic diseases such as COPD. However, a limited number of polymers are currently approved for inhalation. The study presents a promising strategy using gelatin as a matrix for inhalable dry powders, allowing the controlled release of ionic drugs. Ionized cromoglicate sodium (CS) and ipratropium bromide (IBr) interacted in solution with charged gelatin before spray drying (SD). Calcium carbonate was used as a crosslinker. The microspheres showed remarkable aerosol performance after optimizing the SD parameters and did not cause cytotoxicity in A549 cells. The microspheres were highly dispersible with âˆ¼ 50-60% of respirable fraction and fine particle fraction 55-70%. Uncrosslinked microspheres increased their size from four to ten times by swelling after 5 min showing potential as a strategy to avoid macrophage clearance and prolong the therapeutic effect of the drug. Crosslinkers prevented particle swelling. Ionic interaction generated a moderate reduction of the drug release. Overall, this study provides a novel approach for developing DPI formulations for treating chronic respiratory diseases using a biopolymer approved by the FDA, potentially enhancing drug activity through controlled release and avoiding macrophage clearance.

Discovery and characterization of a selective IKZF2 glue degrader for cancer immunotherapy.

Malignant tumors can evade destruction by the immune system by attracting immune-suppressive regulatory T cells (Treg) cells. The IKZF2 (Helios) transcription factor plays a crucial role in maintaining function and stability of Treg cells, and IKZF2 deficiency reduces tumor growth in mice. Here we report the discovery of NVP-DKY709, a selective molecular glue degrader of IKZF2 that spares IKZF1/3. We describe the recruitment-guided medicinal chemistry campaign leading to NVP-DKY709 that redirected the degradation selectivity of cereblon (CRBN) binders from IKZF1 toward IKZF2. Selectivity of NVP-DKY709 for IKZF2 was rationalized by analyzing the DDB1:CRBN:NVP-DKY709:IKZF2(ZF2 or ZF2-3) ternary complex X-ray structures. Exposure to NVP-DKY709 reduced the suppressive activity of human Treg cells and rescued cytokine production in exhausted T-effector cells. In vivo, treatment with NVP-DKY709 delayed tumor growth in mice with a humanized immune system and enhanced immunization responses in cynomolgus monkeys. NVP-DKY709 is being investigated in the clinic as an immune-enhancing agent for cancer immunotherapy.

Design and Biochemical Characterization of Peptidic Inhibitors of the Myb/p300 Interaction.

The Myb transcription factor is involved in the proliferation of hematopoietic cells, and deregulation of its expression can lead to cancers such as leukemia. Myb interacts with various proteins, including the histone acetyltransferases p300 and CBP. Myb binds to a small domain of p300, the KIX domain (p300KIX), and inhibiting this interaction is a potential new drug discovery strategy in oncology. The available structures show that Myb binds to a very shallow pocket of the KIX domain, indicating that it might be challenging to identify inhibitors of this interaction. Here, we report the design of Myb-derived peptides which interact with p300KIX. We show that by mutating only two Myb residues that bind in or near a hotspot at the surface of p300KIX, it is possible to obtain single-digit nanomolar peptidic inhibitors of the Myb/p300KIX interaction that bind 400-fold tighter to p300KIX than wildtype Myb. These findings suggest that it might also be possible to design potent low molecular-weight compounds to disrupt the Myb/p300KIX interaction.

Leveling Up the Access to Radiation Therapy in Latin America: Economic Analysis of Investment, Equity, and Inclusion Opportunities Up to 2030.

PURPOSE: Latin America faces a shortage in radiation therapy (RT) units and qualified personnel for timely and high-quality treatment of patients with cancer. Investing in equitable and inclusive access to RT over the next decade would prevent thousands of deaths. Measuring the investment gap and payoff is necessary for stakeholder discussions and capacity planning efforts. METHODS AND MATERIALS: Data were collected from the International Atomic Energy Agency's Directory of Radiotherapy Centers, industry stakeholders, and individual surveys sent to national scientific societies. Nationwide data on available devices and personnel were compiled. The 10 most common cancers in 2020 with RT indication and their respective incidence rates were considered for gap calculations. The gross 2-year financial return on investment was calculated based on an average monthly salary across Latin America. A 10-year cost projection was calculated according to the estimated population dynamics for the period until 2030. RESULTS: Eleven countries were included in the study, accounting for 557,213,447 people in 2020 and 561 RT facilities. Approximately 1,065,684 new cancer cases were diagnosed, and a mean density of 768,469 (standard deviation ±392,778) people per available unit was found. By projecting the currently available treatment fractions to determine those required in 2030, it was found that 62.3% and 130.8% increases in external beam RT and brachytherapy units are needed from the baseline, respectively. An overall regional investment of approximately United States (US) $349,650,480 in 2020 would have covered the existing demand. An investment of US $872,889,949 will be necessary by 2030, with the expectation of a 2-year posttreatment gross return on investment of more than US $2.1 billion from patients treated in 2030 only. CONCLUSIONS: Investment in RT services is lagging in Latin America in terms of the population's needs. An accelerated outlay could save additional lives during the next decade, create a self-sustaining system, and reduce region-wide inequities in cancer care access. Cash flow analyses are warranted to tailor precise national-level intervention strategies.

Genome-wide association analyses of common infections in a large practice-based biobank.

INTRODUCTION: Infectious diseases are common causes of morbidity and mortality worldwide. Susceptibility to infection is highly heritable; however, little has been done to identify the genetic determinants underlying common infectious diseases. One GWAS was performed using 23andMe information about self-reported infections; we set out to confirm previous loci and identify new ones using medically diagnosed infections. METHODS: We used the electronic health record (EHR)-based biobank at Vanderbilt and diagnosis codes to identify cases of 12 infectious diseases in white patients: urinary tract infection, pneumonia, chronic sinus infections, otitis media, candidiasis, streptococcal pharyngitis, herpes zoster, herpes labialis, hepatitis B, infectious mononucleosis, tuberculosis (TB) or a positive TB test, and hepatitis C. We selected controls from patients with no diagnosis code for the candidate disease and matched by year of birth, sex, and calendar year at first and last EHR visits. We conducted GWAS using SAIGE and transcriptome-wide analysis (TWAS) using S-PrediXcan. We also conducted phenome-wide association study to understand associations between identified genetic variants and clinical phenotypes. RESULTS: We replicated three 23andMe loci (p ≤ 0.05): herpes zoster and rs7047299-A (p = 2.6 × 10-3) and rs2808290-C (p = 9.6 × 10-3;); otitis media and rs114947103-C (p = 0.04). We also identified 2 novel regions (p ≤ 5 × 10-8): rs113235453-G for otitis media (p = 3.04 × 10-8), and rs10422015-T for candidiasis (p = 3.11 × 10-8). In TWAS, four gene-disease associations were significant: SLC30A9 for otitis media (p = 8.06 × 10-7); LRP3 and WDR88 for candidiasis (p = 3.91 × 10-7 and p = 1.95 × 10-6); and AAMDC for hepatitis B (p = 1.51 × 10-6). CONCLUSION: We conducted GWAS and TWAS for 12 infectious diseases and identified novel genetic contributors to the susceptibility of infectious diseases.

Adipose Tissue Inflammation Is Not Related to Adipose Insulin Resistance in Humans.

The role of adipose tissue (AT) inflammation in AT function in humans is unclear. We tested whether AT macrophage (ATM) content, cytokine gene expression, and senescent cell burden (markers of AT inflammation) predict AT insulin resistance measured as the insulin concentration that suppresses lipolysis by 50% (IC50). We studied 86 volunteers with normal weight or obesity at baseline and a subgroup of 25 volunteers with obesity before and after weight loss. There was a strong positive relationship between IC50 and abdominal subcutaneous and femoral fat cell size (FCS). The positive, univariate relationships between IC50 and abdominal AT inflammatory markers CD68, CD14, CD206 ATM/100 adipocytes, senescent cells, IL-6, and TNF-α mRNA were not significant after adjustment for FCS. A 10% weight loss significantly reduced IC50; however, there was no reduction in adipose ATM content, senescent cells, or cytokine gene expression. Our study suggests that commonly used markers of AT inflammation are not causally linked to AT insulin resistance, whereas FCS is a strong predictor of AT insulin resistance with respect to lipolysis.

Senescent cells in human adipose tissue: A cross-sectional study.

OBJECTIVE: Adipose tissue (AT) senescence is associated with AT dysfunction in rodents, but little is known about human AT senescence. The study goal was to define the distribution of senescent cells in two subcutaneous depots and understand relationships with adiposity and inflammation. METHODS: Sixty-three volunteers (48 females) underwent abdominal and femoral subcutaneous fat biopsies. Fat cell size, senescent cells using senescence-associated ß-galactosidase staining per 100 nucleated cells (percentage), and mRNA expression of four cytokines were measured. RESULTS: There was a larger proportion of senescent cells in femoral than abdominal subcutaneous AT (mean difference 1.6% [95% CI: 0.98%-2.3%], p < 0.001), and the percentage of femoral AT senescent cells was greater in women than men (median 3.9% vs. 2.1%, p < 0.01). There was a positive correlation between senescence and fat cell size in abdominal (rs  = 0.44, p < 0.001) and femoral (rs  = 0.35, p = 0.007) AT depots. Abdominal AT tumor necrosis factor alpha (rs  = 0.49, p < 0.01) and interleukin-1ß (rs  = 0.44, p = 0.01) expression was positively correlated with abdominal, but not femoral, AT senescence. CONCLUSIONS: In human subcutaneous AT, there are more senescent cells in femoral than abdominal depots; abdominal AT senescent cells are more associated with inflammatory signals than femoral AT senescent cells.

Multisystem Progeroid Syndrome With Lipodystrophy, Cardiomyopathy, and Nephropathy Due to an LMNA p.R349W Variant.

BACKGROUND: Pathogenic variants in lamin A/C (LMNA) cause a variety of progeroid disorders including Hutchinson-Gilford progeria syndrome, mandibuloacral dysplasia, and atypical progeroid syndrome. Six families with 11 patients harboring a pathogenic heterozygous LMNA c.1045C>T; p.R349W variant have been previously reported to have partial lipodystrophy, cardiomyopathy, and focal segmental glomerulosclerosis (FSGS), suggesting a distinct progeroid syndrome. METHODS: We report 6 new patients with a heterozygous LMNA p.R349W variant and review the phenotype of previously reported patients to define their unique characteristics. We also performed functional studies on the skin fibroblasts of a patient to seek the underlying mechanisms of various clinical manifestations. RESULTS: Of the total 17 patients, all 14 adults with the heterozygous LMNA p.R349W variant had peculiar lipodystrophy affecting the face, extremities, palms, and soles with variable gain of subcutaneous truncal fat. All of them had proteinuric nephropathy with FSGS documented in 7 of them. Ten developed cardiomyopathy, and 2 of them died early at ages 33 and 45 years. Other common features included premature graying, alopecia, high-pitched voice, micrognathia, hearing loss, and scoliosis. Metabolic complications, including diabetes mellitus, hypertriglyceridemia, and hepatomegaly, were highly prevalent. This variant did not show any abnormal splicing, and no abnormal nuclear morphology was noted in the affected fibroblasts. CONCLUSIONS: The heterozygous LMNA p.R349W variant in affected individuals has several distinct phenotypic features, and these patients should be classified as having multisystem progeroid syndrome (MSPS). MSPS patients should undergo careful assessment at symptom onset and yearly metabolic, renal, and cardiac evaluation because hyperglycemia, hypertriglyceridemia, FSGS, and cardiomyopathy cause major morbidity and mortality.

Two Distinct Mechanisms of Inhibition of LpxA Acyltransferase Essential for Lipopolysaccharide Biosynthesis.

The lipopolysaccharide biosynthesis pathway is considered an attractive drug target against the rising threat of multi-drug-resistant Gram-negative bacteria. Here, we report two novel small-molecule inhibitors (compounds 1 and 2) of the acyltransferase LpxA, the first enzyme in the lipopolysaccharide biosynthesis pathway. We show genetically that the antibacterial activities of the compounds against efflux-deficient Escherichia coli are mediated by LpxA inhibition. Consistently, the compounds inhibited the LpxA enzymatic reaction in vitro. Intriguingly, using biochemical, biophysical, and structural characterization, we reveal two distinct mechanisms of LpxA inhibition; compound 1 is a substrate-competitive inhibitor targeting apo LpxA, and compound 2 is an uncompetitive inhibitor targeting the LpxA/product complex. Compound 2 exhibited more favorable biological and physicochemical properties than compound 1 and was optimized using structural information to achieve improved antibacterial activity against wild-type E. coli. These results show that LpxA is a promising antibacterial target and imply the advantages of targeting enzyme/product complexes in drug discovery.

Structural and Biological Basis of Small Molecule Inhibition of Escherichia coli LpxD Acyltransferase Essential for Lipopolysaccharide Biosynthesis.

LpxD, acyl-ACP-dependent N-acyltransferase, is the third enzyme of lipid A biosynthesis in Gram-negative bacteria. A recent probe-based screen identified several compounds, including 6359-0284 (compound 1), that inhibit the enzymatic activity of Escherichia coli (E. coli) LpxD. Here, we use these inhibitors to chemically validate LpxD as an attractive antibacterial target. We first found that compound 1 was oxidized in solution to the more stable aromatized tetrahydro-pyrazolo-quinolinone compound 1o. From the Escherichia coli strain deficient in efflux, we isolated a mutant that was less susceptible to compound 1o and had an lpxD missense mutation (Gly268Cys), supporting the cellular on-target activity. Using surface plasma resonance, we showed direct binding to E. coli LpxD for compound 1o and other reported LpxD inhibitors in vitro. Furthermore, we determined eight cocrystal structures of E. coli LpxD/inhibitor complexes. These costructures pinpointed the 4'-phosphopantetheine binding site as the common ligand binding hotspot, where hydrogen bonds to Gly269 and/or Gly287 were important for inhibitor binding. In addition, the LpxD/compound 1o costructure rationalized the reduced activity of compound 1o in the LpxDGly268Cys mutant. Moreover, we obtained the LpxD structure in complex with a previously reported LpxA/LpxD dual targeting peptide inhibitor, RJPXD33, providing structural rationale for the unique dual targeting properties of this peptide. Given that the active site residues of LpxD are conserved in multidrug resistant Enterobacteriaceae, this work paves the way for future LpxD drug discovery efforts combating these Gram-negative pathogens.

A Genetic Approach to the Association Between PCSK9 and Sepsis.

Importance: Whether the PCSK9 gene is associated with the progress from infection to sepsis is unknown to date. Objective: To test the associations between PCSK9 genetic variants, a PCSK9 genetic risk score (GRS), or genetically estimated PCSK9 expression levels and the risk of sepsis among patients admitted to a hospital with infection. Design, Setting, and Participants: This retrospective cohort study used deidentified electronic health records to identify patients admitted to Vanderbilt University Medical Center, Nashville, Tennessee, with infection. Patients were white adults, had a code indicating infection from the International Classification of Diseases, Ninth Revision, Clinical Modification, or the International Statistical Classification of Diseases, Tenth Revision, Clinical Modification, and received an antibiotic within 1 day of hospital admission (N = 61 502). Data were collected from January 1, 1993, through December 31, 2017, and analyzed from April 1, 2018, to March 16, 2019. Exposures: Four known PCSK9 functional variants, a GRS for PCSK9, and genetically estimated PCSK9 expression. Main Outcomes and Measures: The primary outcome was sepsis; secondary outcomes included cardiovascular failure and in-hospital death. Results: Of patients with infection, genotype information was available in 10 922 white patients for PCSK9 functional variants (5628 men [51.5%]; mean [SD] age, 60.1 [15.7] years), including 7624 patients with PCSK9 GRS and 6033 patients with estimated PCSK9 expression. Of these, 3391 developed sepsis, 835 developed cardiovascular failure, and 366 died during hospitalization. None of the 4 functional PCSK9 variants were significantly associated with sepsis, cardiovascular failure, or in-hospital death, with or without adjustment for (1) age and sex or (2) age, sex, and Charlson-Deyo comorbidities (in model adjusted for age, sex, and comorbidities, odds ratios for any loss-of function variant were 0.96 [95% CI, 0.88-1.04] for sepsis, 1.05 [95% CI, 0.90-1.22] for cardiovascular failure, and 0.89 [95% CI, 0.72-1.11] for death). Similarly, neither the PCSK9 GRS nor genetically estimated PCSK9 expression were significantly associated with sepsis, cardiovascular failure, or in-hospital death in any of the analysis models. For GRS, in the full model adjusted for age, sex, and comorbidities, the odds ratios were 1.01 for sepsis (95% CI, 0.96-1.06; P = .70), 1.03 for cardiovascular failure (95% CI, 0.95-1.12; P = .48), and 1.05 for in-hospital death (95% CI, 0.92-1.19; P = .50). For genetically estimated PCSK9 expression, in the full model adjusted for age, sex, and comorbidities, the odds ratios were 1.01 for sepsis (95% CI, 0.95-1.06; P = .86), 0.96 for cardiovascular failure (95% CI, 0.88-1.05; P = .41), and 0.99 for in-hospital death (95% CI, 0.87-1.14; P = .94). Conclusions and Relevance: In this study, PCSK9 genetic variants were not significantly associated with risk of sepsis or the outcomes of sepsis in patients hospitalized with infection.

Integrated specialty pharmacy yields high PCSK9 inhibitor access and initiation rates.

BACKGROUND: Access to proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors that lower low-density lipoprotein cholesterol in patients at high risk of atherosclerotic cardiovascular disease events has proven challenging. Methods to overcome access barriers are needed to fully realize the benefits of these novel agents. OBJECTIVE: This study evaluated medication access rates in patients prescribed a PCSK9 inhibitor at a health care system with integrated specialty pharmacy services. METHODS: We performed a single-center, ambispective cohort study of patients prescribed a PCSK9 inhibitor between September 2015 and December 2016 at Vanderbilt University Medical Center outpatient clinics. The primary end point was the percentage of PCSK9 inhibitor prescriptions resulting in access of the total prescriptions triaged to Vanderbilt Specialty Pharmacy. Secondary end points assessed among patients approved for therapy included time between benefits investigation and insurance approval, financial assistance use, and treatment initiation rates. RESULTS: Two hundred ninety-nine patients met inclusion criteria (average age = 63 years). Forty-six percent were female, 57% held commercial insurance, and 70% had an atherosclerotic cardiovascular disease indication. Overall, 96% of prescriptions resulted in access to a PCSK9 inhibitor. Most patients were approved with an initial prior authorization (58%) or after one appeal (29%). The median time to approval was 8 days. Among patients approved for therapy, 53% received financial assistance and 94% initiated therapy. CONCLUSION: An integrated specialty pharmacy service model in outpatient clinics produced high rates of PCSK9 inhibitor therapy access and initiation. This high level of access supports this model as a best practice for prescribing PCSK9 inhibitor therapy.

Association Between Low-Density Lipoprotein Cholesterol Levels and Risk for Sepsis Among Patients Admitted to the Hospital With Infection.

Importance: Whether low levels of low-density lipoprotein cholesterol (LDL-C) are associated with increased risk of sepsis and poorer outcomes is unknown. Objective: To examine the association between LDL-C levels and risk of sepsis among patients admitted to the hospital with infection. Design, Setting, and Participants: Cohort study in which deidentified electronic health records were used to define a cohort of patients admitted to Vanderbilt University Medical Center, Nashville, Tennessee, with infection. Patients were white adults, had a code indicating infection from the International Classification of Diseases, Ninth Revision, Clinical Modification, and received an antibiotic within 1 day of hospital admission (N = 61 502). Data were collected from January 1, 1993, through December 31, 2017, and analyzed from January 24 through October 31, 2018. Interventions: Clinically measured LDL-C levels (excluding measurements <1 year before hospital admission and those associated with acute illness) and a genetic risk score (GRS). Main Outcomes and Measures: The primary outcome was sepsis; secondary outcomes included admission to an intensive care unit (ICU) and in-hospital death. Results: Among the 3961 patients with clinically measured LDL-C levels (57.8% women; mean [SD] age, 64.1 [15.9] years) and the 7804 with a GRS for LDL-C (54.0% men; mean [SD] age, 59.8 [15.2] years), lower measured LDL-C levels were significantly associated with increased risk of sepsis (odds ratio [OR], 0.86; 95% CI, 0.79-0.94; P = .001) and ICU admission (OR, 0.85; 95% CI, 0.76-0.96; P = .008), but not in-hospital mortality (OR, 0.80; 95% CI, 0.63-1.00; P = .06); however, none of these associations were statistically significant after adjustment for age, sex, and comorbidity variables (OR for risk of sepsis, 0.96 [95% CI, 0.88-1.06]; OR for ICU admission, 0.94 [95% CI, 0.83-1.06]; OR for in-hospital death, 0.97 [95% CI, 0.76-1.22]; P > .05 for all). The LDL-C GRS correlated with measured LDL-C levels (r = 0.24; P < 2.2 × 10-16) but was not significantly associated with any of the outcomes. Conclusions and Relevance: Results of this study suggest that lower measured LDL-C levels were significantly associated with increased risk of sepsis and admission to ICU in patients admitted to the hospital with infection; however, this association was due to comorbidities because both clinical models adjusted for confounders, and the genetic model showed no increased risk. Levels of LDL-C do not appear to directly alter the risk of sepsis or poor outcomes in patients hospitalized with infection.

Managing Endocrine Disorders in Adults After Hematopoietic Stem Cell Transplantation.

Hematopoietic stem cell transplantation (HSCT) has become a potentially curative therapy for an increasing number of malignant and non-malignant conditions. As survival rates continue to improve, the focus of patient care has shifted from managing not only immediate but also long-term complications. Endocrine disorders are among the most prevalent late effects following HSCT. Detecting and treating such conditions offer new challenges, as well as opportunities to reduce preventable morbidity and mortality associated with HSCT. Our objective is to summarize recent literature and describe practical approaches to screening for and managing endocrine-related late effects. We focus on dyslipidemia, diabetes, thyroid disorders, osteoporosis, and hypogonadism. Mechanisms, monitoring, and management recommendations for each disorder are outlined. Growing data on these disorders in the post-transplant setting highlight the need for future study and evidence-based guidelines.

Author Correction: Acylated-acyl carrier protein stabilizes the Pseudomonas aeruginosa WaaP lipopolysaccharide heptose kinase.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.