Reporting on patients living with HIV "disengaging from care". Who is actually "lost to follow-up"?

Retention in care remains an important concern for health care providers. However, accurately identifying who is or is not retained in care can be problematic. Not all patients believed to be engaged in care are actually in care, and not all patients believed to be disengaged are truly disengaged. Identifying the status of individuals within populations is important for clinical, administrative and surveillance concerns. As part of the Linkage and Retention in Care Project at St Michael's Hospital in Toronto, Canada, we investigated the status of patients diagnosed with HIV. Detailed investigation determined who was actually Lost-to-Follow-Up (i.e., disengaged from care >12 months) and who had disengaged for known reasons. This approach determined more precisely who was currently followed in care and who was not, and to target efforts to contact and reengage patients more effectively. This study illustrates the importance of accurately monitoring populations enhancing disease management.

Characterization of pathogenic human monoclonal autoantibodies against GM-CSF.

The origin of pathogenic autoantibodies remains unknown. Idiopathic pulmonary alveolar proteinosis is caused by autoantibodies against granulocyte-macrophage colony-stimulating factor (GM-CSF). We generated 19 monoclonal autoantibodies against GM-CSF from six patients with idiopathic pulmonary alveolar proteinosis. The autoantibodies used multiple V genes, excluding preferred V-gene use as an etiology, and targeted at least four nonoverlapping epitopes on GM-CSF, suggesting that GM-CSF is driving the autoantibodies and not a B-cell epitope on a pathogen cross-reacting with GM-CSF. The number of somatic mutations in the autoantibodies suggests that the memory B cells have been helped by T cells and re-entered germinal centers. All autoantibodies neutralized GM-CSF bioactivity, with general correlations to affinity and off-rate. The binding of certain autoantibodies was changed by point mutations in GM-CSF that reduced binding to the GM-CSF receptor. Those monoclonal autoantibodies that potently neutralize GM-CSF may be useful in treating inflammatory disease, such as rheumatoid arthritis and multiple sclerosis, cancer, and pain.

Genetic Identification of Homozygous Familial Hypercholesterolemia by Long-Read Sequencing Among Patients With Clinically Diagnosed Heterozygous Familial Hypercholesterolemia.

BACKGROUND: Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disorder characterized by extremely elevated plasma low-density lipoprotein cholesterol and accelerated atherosclerosis. Accurate identification of patients with HoFH is essential as they may be eligible for specialized treatments. We hypothesized that a subset of patients with clinically diagnosed heterozygous FH (HeFH) may in fact have HoFH, and this could be identified by genetic diagnosis. METHODS: We recruited patients with a clinical diagnosis of HeFH based on a Dutch Lipid Clinic Network score ≥6 and no secondary cause of hypercholesterolemia. We performed targeted next-generation sequencing of the low-density lipoprotein receptor (LDLR), apolipoprotein B (APOB), proprotein convertase subtilisin/kexin type 9 (PCSK9), and low-density lipoprotein receptor adapter protein 1 (LDLRAP1) genes, followed by long-read sequencing of the LDLR gene in patients with >1 pathogenic LDLR variant. We examined lipid levels and cardiovascular events. RESULTS: Among 705 patients with clinically diagnosed HeFH, we identified a single pathogenic variant in 300 (42.6%) and >1 pathogenic variant in the LDLR gene in 11 patients (1.6%). We established a genetic diagnosis of HoFH in 6 (0.9%) patients (3 true homozygotes and 3 compound heterozygotes). The mean baseline low-density lipoprotein cholesterol and prevalence of premature cardiovascular disease of patients with genetically identified HoFH was significantly higher than patients with HeFH. CONCLUSIONS: In a cohort of patients with clinically diagnosed HeFH, genetic testing including long-read sequencing revealed that 0.9% had HoFH. These patients tended to have a more severe clinical phenotype. Genetic testing of patients with clinical FH may identify patients with HoFH that had eluded clinical diagnosis.

Optimization and structure-activity relationships of a series of potent inhibitors of methicillin-resistant Staphylococcus aureus (MRSA) pyruvate kinase as novel antimicrobial agents.

A novel series of hydrazones were synthesized and evaluated as inhibitors of methicillin-resistant Staphylococcus aureus (MRSA) pyruvate kinase (PK). PK has been identified as one of the most highly connected 'hub proteins' in MRSA. PK has been shown to be critical for bacterial survival which makes it a potential target for development of novel antibiotics and the high degree of connectivity implies it should be very sensitive to mutations and thus less able to develop resistance. PK is not unique to bacteria and thus a critical requirement for such a PK inhibitor would be that it does not inhibit the homologous human enzyme(s) at therapeutic concentrations. Several MRSA PK inhibitors (including 8d) were identified using in silico screening combined with enzyme assays and were found to be selective for bacterial enzyme compared to four human PK isoforms (M1, M2, R and L). However these lead compounds did not show significant inhibitory activity for MRSA growth presumably due to poor bacterial cell penetration. Structure-activity relationship (SAR) studies were carried out on 8d and led us to discover more potent compounds with enzyme inhibiting activities in the low nanomolar range and some were found to effectively inhibit bacteria growth in culture with minimum inhibitory concentrations (MIC) as low as 1 µg/mL. These inhibitors bind in two elongated flat clefts found at the minor interfaces in the homo-tetrameric enzyme complex and the observed SAR is in keeping with the size and electronic constraints of these binding sites. Access to the corresponding sites in the human enzyme is blocked.

Mapping the protein interaction network in methicillin-resistant Staphylococcus aureus.

Mortality attributable to infection with methicillin-resistant Staphylococcus aureus (MRSA) has now overtaken the death rate for AIDS in the United States, and advances in research are urgently needed to address this challenge. We report the results of the systematic identification of protein-protein interactions for the hospital-acquired strain MRSA-252. Using a high-throughput pull-down strategy combined with quantitative proteomics to distinguish specific from nonspecific interactors, we identified 13,219 interactions involving 608 MRSA proteins. Consecutive analyses revealed that this protein interaction network (PIN) exhibits scale-free organization with the characteristic presence of highly connected hub proteins. When clinical and experimental antimicrobial targets were queried in the network, they were generally found to occupy peripheral positions in the PIN with relatively few interacting partners. In contrast, the hub proteins identified in this MRSA PIN that are essential for network integrity and stability have largely been overlooked as drug targets. Thus, this empirical MRSA-252 PIN provides a rich source for identifying critical proteins essential for network stability, many of which can be considered as prospective antimicrobial drug targets.

Identification of pyruvate kinase in methicillin-resistant Staphylococcus aureus as a novel antimicrobial drug target.

Novel classes of antimicrobials are needed to address the challenge of multidrug-resistant bacteria such as methicillin-resistant Staphylococcus aureus (MRSA). Using the architecture of the MRSA interactome, we identified pyruvate kinase (PK) as a potential novel drug target based upon it being a highly connected, essential hub in the MRSA interactome. Structural modeling, including X-ray crystallography, revealed discrete features of PK in MRSA, which appeared suitable for the selective targeting of the bacterial enzyme. In silico library screening combined with functional enzymatic assays identified an acyl hydrazone-based compound (IS-130) as a potent MRSA PK inhibitor (50% inhibitory concentration [IC50] of 0.1 µM) with >1,000-fold selectivity over human PK isoforms. Medicinal chemistry around the IS-130 scaffold identified analogs that more potently and selectively inhibited MRSA PK enzymatic activity and S. aureus growth in vitro (MIC of 1 to 5 µg/ml). These novel anti-PK compounds were found to possess antistaphylococcal activity, including both MRSA and multidrug-resistant S. aureus (MDRSA) strains. These compounds also exhibited exceptional antibacterial activities against other Gram-positive genera, including enterococci and streptococci. PK lead compounds were found to be noncompetitive inhibitors and were bactericidal. In addition, mutants with significant increases in MICs were not isolated after 25 bacterial passages in culture, indicating that resistance may be slow to emerge. These findings validate the principles of network science as a powerful approach to identify novel antibacterial drug targets. They also provide a proof of principle, based upon PK in MRSA, for a research platform aimed at discovering and optimizing selective inhibitors of novel bacterial targets where human orthologs exist, as leads for anti-infective drug development.

Continuous Glucose Monitoring Versus Self-Monitoring of Blood Glucose to Assess Glycemia in Gestational Diabetes.

Background: Gestational diabetes mellitus (GDM) management using self-monitoring blood glucose (SMBG) does not normalize pregnancy outcomes. Objective: We aimed to conduct an observational study to explore if continuous glucose monitoring (CGM) could identify elevated glucose levels not apparent in women with GDM managed using SMBG. Study Design: A 7-day masked-CGM (iPro; Medtronic) was performed within 2 weeks of GDM diagnosis, immediately post-GDM education, but before insulin commencement as determined by SMBG. CGM data regarding hyperglycemia (sensor glucose >126 mg/dL [06:00-00:00 h] and >99 mg/dL [00:00-06:00 h] for >10% of time), time with health care professionals, treatment, and pregnancy outcome were collected. Comparisons (Mann-Whitney test) were performed between subjects subsequently commenced on insulin versus those continued with diet and lifestyle measures alone. Results: Ninety women of mean (standard deviation) gestational age weeks 27(1) were studied. Those prescribed insulin (n = 34) compared with those managed with diet and lifestyle alone (n = 56) had a greater time in hyperglycemia (P = 0.0001). Of those not prescribed insulin, 35/56 (61%) breached CGM cutoffs between 00:00 and 06:00 h; 11/56 (20%) breached 6.00-00.00 h CGM cutoffs for >10% of the time; and 21/45 (47%) with optimal CGM glucose levels during the daytime spent >10% time in hyperglycemia between 00.00 and 06:00 h. In contrast, SMBG measurements exceeded the clinical targets of <120 mg/dL postdinner in 5.4% and <100 mg/dL fasting in 0% of the subjects. Conclusions: CGM provides a more comprehensive assessment of nocturnal hyperglycemia than SMBG and could improve targeting of interventions in GDM. Larger studies to better define CGM targets are required, which once established will inform studies aimed at targeting nocturnal glucose levels.

Ascertainment Bias in the Association Between Elevated Lipoprotein(a) and Familial Hypercholesterolemia.

BACKGROUND: Lipoprotein(a) is an atherogenic low-density lipoprotein-like particle and circulating levels are largely determined by genetics. Patients with familial hypercholesterolemia (FH) have elevated lipoprotein(a); however, it remains unclear why. OBJECTIVES: This study compared the levels of lipoprotein(a) and associated genetic factors between individuals that were ascertained for FH clinically versus genetically. METHODS: We investigated causes of elevated lipoprotein(a) in individuals with clinically diagnosed FH (FH cohort, n = 391) and in individuals with genetically diagnosed FH from the general population (UK Biobank; n = 37,486). RESULTS: Patients in the FH cohort had significantly greater lipoprotein(a) levels than either the general population or non-FH dyslipidemic patients. This was accounted for by increased frequency of the rs10455872-G LPA risk allele (15.1% vs. 8.8%; p < 0.05). However, within the FH cohort, lipoprotein(a) levels did not differ based on the presence or absence of an FH-causing variant (means = 1.43 log mg/dl vs. 1.42 log mg/dl; p = 0.97). Lipoprotein(a) levels were also not statistically different between individuals with and without an FH-causing variant in the UK Biobank cohort, which represents a population sample not biased to cardiovascular ascertainment (n = 221 vs. 37,486). We performed a phenome-wide association study between LPA genotypes and 19,202 phenotypes to demonstrate that elevated lipoprotein(a) is associated with increased low-density lipoprotein cholesterol, a family history of cardiovascular disease, premature coronary artery disease, and a diagnosis of FH. CONCLUSIONS: These results suggest that FH does not cause elevated lipoprotein(a), but that elevated lipoprotein(a) increases the likelihood that an individual with genetic FH will be clinically recognized.

Chromosome 1q21.2 and additional loci influence risk of spontaneous coronary artery dissection and myocardial infarction.

Spontaneous coronary artery dissection (SCAD) is a non-atherosclerotic cause of myocardial infarction (MI), typically in young women. We undertook a genome-wide association study of SCAD (Ncases = 270/Ncontrols = 5,263) and identified and replicated an association of rs12740679 at chromosome 1q21.2 (Pdiscovery+replication = 2.19 × 10-12, OR = 1.8) influencing ADAMTSL4 expression. Meta-analysis of discovery and replication samples identified associations with P < 5 × 10-8 at chromosome 6p24.1 in PHACTR1, chromosome 12q13.3 in LRP1, and in females-only, at chromosome 21q22.11 near LINC00310. A polygenic risk score for SCAD was associated with (1) higher risk of SCAD in individuals with fibromuscular dysplasia (P = 0.021, OR = 1.82 [95% CI: 1.09-3.02]) and (2) lower risk of atherosclerotic coronary artery disease and MI in the UK Biobank (P = 1.28 × 10-17, HR = 0.91 [95% CI :0.89-0.93], for MI) and Million Veteran Program (P = 9.33 × 10-36, OR = 0.95 [95% CI: 0.94-0.96], for CAD; P = 3.35 × 10-6, OR = 0.96 [95% CI: 0.95-0.98] for MI). Here we report that SCAD-related MI and atherosclerotic MI exist at opposite ends of a genetic risk spectrum, inciting MI with disparate underlying vascular biology.

In-Service Education: Evolving Internationally to Meet Nurses' Lifelong Learning Needs.

In-service education (ISE) in nursing is teaching that occurs in the workplace. Internationally, ISE activities have been evident in nursing for many years because it has been seen as a convenient and cost-effective way to deliver education to nurses with minimal disruption to staffing levels and the delivery of patient care. ISE-related literature was sought to address the aim of tracing development and focus of nursing ISE in New Zealand. A key finding of this literature review is that ISE has been adapted in New Zealand and internationally to meet the demands of evolving nursing practice, and for this reason it remains relevant and essential to nurses. The embeddedness of ISE within clinical environments also supports its relevance. Future research is called for to establish which aspects of ISE are critical to ensuring its ongoing success. [J Contin Educ Nurs. 2019;50(7):313-318.].

Dental Students' Intent to Practice in Rural Communities Before and After Community-Based Rotations in a Rural Area.

Community-based dental education (CBDE) has the potential to positively impact the educational process in a manner that both contributes to educational outcomes and shapes the learner's behavior. The aim of this study was to determine the correlation between dental students' intended practice location and the size of their hometown and to assess any impact their CBDE rotation in a rural location had on practice location intention. From March 7, 2016, to August 12, 2018, fourth-year students at one U.S. dental school were invited to complete a ten-item questionnaire prior to and after their four-week clinical rotations at a rural clinic. Of the 123 dental students on rotation at the clinic during this time, 106 completed the pre-rotation survey and 112 the post-rotation survey, for response rates of 86% and 91%, respectively. Prior to the rotation, 58.6% selected one of the rural locations as an ideal practice location, and that percentage increased slightly to 61.4% after the rotation; the difference was not statistically significant (p=0.984). The results did show a significant increase from pre to post rotation for women intending to practice in rural communities (p=0.0413). This study found that students' intent to practice in a rural location was not significantly affected by a clinical rotation in a rural clinic; however, there was strong evidence that students from rural communities intended to practice in rural communities after graduation.

Risk of Premature Atherosclerotic Disease in Patients With Monogenic Versus Polygenic Familial Hypercholesterolemia.

BACKGROUND: A pathogenic variant in LDLR, APOB, or PCSK9 can be identified in 30% to 80% of patients with clinically-diagnosed familial hypercholesterolemia (FH). Alternatively, ∼20% of clinical FH is thought to have a polygenic cause. The cardiovascular disease (CVD) risk associated with polygenic versus monogenic FH is unclear. OBJECTIVES: This study evaluated the effect of monogenic and polygenic causes of FH on premature (age <55 years) CVD events in patients with clinically diagnosed FH. METHODS: Targeted sequencing of genes known to cause FH as well as common genetic variants was performed to calculate polygenic scores in patients with "possible," "probable," or "definite" FH, according to Dutch Lipid Clinic Network Criteria (n = 626). Patients with a polygenic score ≥80th percentile were considered to have polygenic FH. We examined the risk of unstable angina, myocardial infarction, coronary revascularization, or stoke. RESULTS: A monogenic cause of FH was associated with significantly greater risk of CVD (adjusted hazard ratio: 1.96; 95% confidence interval: 1.24 to 3.12; p = 0.004), whereas the risk of CVD in patients with polygenic FH was not significantly different compared with patients in whom no genetic cause of FH was identified. However, the presence of an elevated low-density lipoprotein cholesterol (LDL-C) polygenic risk score further increased CVD risk in patients with monogenic FH (adjusted hazard ratio: 3.06; 95% confidence interval: 1.56 to 5.99; p = 0.001). CONCLUSIONS: Patients with monogenic FH and superimposed elevated LDL-C polygenic risk scores have the greatest risk of premature CVD. Genetic testing for FH provides important prognostic information that is independent of LDL-C levels.

What children do on the Internet: domains visited and their relationship to socio-demographic characteristics and academic performance.

HomeNetToo is a longitudinal field study designed to examine the antecedents and consequences of home Internet use in low-income families. Participants included 140 children, mostly 13-year-old African American (83%) boys (58%), living in single-parent households (75%) where the median annual income was $15,000 (USD). This report focuses on children's Internet activities, socio-demographic characteristics related to their Internet activities, and the relationship between academic performance and Internet activities. Overall, findings indicate that low-income children initially use the Internet primarily for entertainment. As home Internet use loses its novelty children become more focused in their Internet activities, reducing the number of websites they visit and visiting more websites targeted to their specific interests. Pornography websites are popular initially, especially among boys, but their popularity decreases dramatically after 3 months. Age, race, and sex have little influence on which websites are most popular. Academic performance predicts subsequent Internet activities, and Internet activities predict subsequent academic performance. Directions for future research to identify mechanisms that mediate the relationship between Internet activities and academic performance and implications for the digital divide are discussed.

Generation of Native Chromatin Immunoprecipitation Sequencing Libraries for Nucleosome Density Analysis.

We present a modified native chromatin immunoprecipitation sequencing (ChIP-seq) experimental protocol compatible with a Gaussian mixture distribution based analysis methodology (nucleosome density ChIP-seq; ndChIP-seq) that enables the generation of combined measurements of micrococcal nuclease (MNase) accessibility with histone modification genome-wide. Nucleosome position and local density, and the posttranslational modification of their histone subunits, act in concert to regulate local transcription states. Combinatorial measurements of nucleosome accessibility with histone modification generated by ndChIP-seq allows for the simultaneous interrogation of these features. The ndChIP-seq methodology is applicable to small numbers of primary cells inaccessible to cross-linking based ChIP-seq protocols. Taken together, ndChIP-seq enables the measurement of histone modification in combination with local nucleosome density to obtain new insights into shared mechanisms that regulate RNA transcription within rare primary cell populations.

Lactation Skills Workshop: A Collaboration of the City of Dallas WIC and Local Hospitals.

The Baby-Friendly Hospital Initiative, a global endeavor of the World Health Organization and the United Nations Children's Fund, is an evidence-based program identifying 10 interventions that when hospitals implement them, breastfeeding (BF) rates improve. It recognizes the powerful role that health care workers have in successful BF and the need for competent hands-on skills to support lactation. The City of Dallas, TX, Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) program collaborated with 3 urban hospitals and developed a training of practical techniques and information for staff to use while working with BF patients. Since implementation, 1,600 workers were trained, 1 hospital achieved Baby-Friendly designation, and all have increased BF rates by 10%.

Does home internet use influence the academic performance of low-income children?

HomeNetToo is a longitudinal field study designed to examine the antecedents and consequences of home Internet use in low-income families (http://www.HomeNetToo.org). The study was done between December 2000 and June 2002. Among the consequences considered was children's academic performance. Participants were 140 children, mostly African American (83%), mostly boys (58%), and most living in single-parent households (75%) in which the median annual income was 15,000 (U.S. dollars) or less. Average age was 13.8 years. Ages ranged between 10 and 18 years, Internet use was continuously recorded, and multiple measures of academic performance were obtained during the 16-month trial. Findings indicated that children who used the Internet more had higher scores on standardized tests of reading achievement and higher grade point averages 6 months, 1 year, and 16 months later than did children who used it less. Older children used the Internet more than did younger children, but age had no effect on the nature or the academic performance benefits of Internet use. Implications for the digital "use" divide are discussed.

Instructional set and internet use by low-income adults.

This research examined the effects of instructional set on Internet use by low-income adults during a 16-month longitudinal study. Participants (n = 117) received instructions that focused on either the Internet's communication tools or its information tools. Internet use was continuously and automatically recorded. Survey measures of computer and Internet experiences, affect and attitudes were obtained to examine their mediational role in the relationship between instructional set and Internet use. Results indicated that instructions focused on the Internet's information tools led to greater Internet use than instructions focused on its communication tools or only basic instructions about how to use the Internet. Implications for reducing the digital divide are discussed.

An evaluation of the timing between key insulin administration-related processes: the reasons why these processes happen when they do, and how to improve their timing.

We investigated the incidence of timing problems with insulin-related processes in a subacute inpatient unit in Melbourne and found that nursing staff often conduct blood glucose level (BGL) testing longer than 30 minutes before insulin administration (between 22% and 41%). Nurses are better at administering rapid-acting insulin doses within the recommended time before food intake (94%) than conventional insulin analogue doses (43%). BGL testing is carried out too early due to established ward practices and busy mornings, as well as poor guidance from an outdated policy. The timing of conventional insulin analogue administration is by nature more complex than that of rapid-acting analogues. Current timing places inpatients at risk of harm from hypoglycaemia. The high level of care demand in our subacute unit contributed to timing problems, and this is likely to be a problem in other units. Process redesign, policy revision and staff education could be used to reduce the risk of hypoglycaemia in this subacute inpatient unit.