Pentosan polysulfate sodium for Ross River virus-induced arthralgia: a phase 2a, randomized, double-blind, placebo-controlled study.

BACKGROUND: Alphaviruses, such as Ross River (RRV) and chikungunya virus (CHIKV), cause significant global morbidity, with outbreaks of crippling joint inflammation and pain, leaving patients incapacitated for months to years. With no available vaccine or specific therapeutic for any alphaviral disease, and a growing economic and public health burden, there is a serious need for the development of specific therapies. METHODS: This study evaluated the safety and efficacy of pentosan polysulfate sodium (PPS) in subjects with RRV-induced arthralgia in a double-blind, placebo-controlled trial. Twenty subjects were randomized 2:1 to subcutaneous PPS (2 mg/kg) or placebo (sodium chloride 0.9%) twice weekly for 6 weeks. Safety evaluation included physical examination, concomitant medications, and laboratory findings. Efficacy assessments included change from baseline in joint function (hand grip strength and RAPID3) and quality of life (SF-36) at Days 15, 29, 39 and 81 after treatment initiation. Inflammatory and cartilage degradation biomarkers were exploratory endpoints. RESULTS: PPS was well tolerated, with a similar proportion of subjects reporting at least one treatment-emergent adverse event (TEAE) in the treatment and placebo groups. Injection site reactions were the most common TEAE and occurred more frequently in the PPS group. Dominant hand grip strength and SF-36 scores improved with PPS at all time points assessed, with hand grip strength improvement of 6.99 kg (p = 0.0189) higher than placebo at Day 15. PPS showed significant improvements versus placebo in adjusted mean relative change from baseline for RAPID3 Pain (p = 0.0197) and Total (p = 0.0101) scores at Day 15. At the conclusion of the study overall joint symptoms, assessed by RAPID3, showed near remission in 61.5% of PPS subjects versus 14.3% of placebo subjects. Additionally, PPS treatment improved COMP, CTX-II, CCL1, CXCL12, CXCL16 and CCL17 biomarker levels versus placebo. CONCLUSIONS: Overall, the improvements in strength and joint symptoms warrant further evaluation of PPS as a specific treatment for RRV-induced and other forms of arthritis. TRIAL REGISTRATION: This trial is registered at the Australian New Zealand Clinical Trials Registry # ACTRN12617000893303 .

Planning and clinical role of acute medical home care services for COVID-19: consensus position statement by the Hospital-in-the-Home Society Australasia.

During a pandemic when hospitals are stretched and patients need isolation, the role of hospital-in-the-home (HITH) providing acute medical care at home has never been more relevant. We aimed to define and address the challenges to acute home care services posed by the COVID-19 pandemic. Planning for service operation involves staffing, equipment availability and cleaning, upskilling in telehealth and communication. Planning for clinical care involves maximising cohorts of patients without COVID-19 and new clinical pathways for patients with COVID-19. The risk of SARS-CoV-2 transmission, specific COVID-19 clinical pathways and the well-being of patients and staff should be addressed in advance.

Early initiation of antiretroviral therapy for people newly diagnosed with HIV infection in Australia: trends and predictors, 2004-2015.

OBJECTIVES: To determine trends in and predictors of early treatment for people newly diagnosed with human immunodeficiency virus (HIV) infection in Australia. DESIGN, SETTING: Retrospective cohort analysis of routinely collected longitudinal data from 44 sexual health clinics participating in the Australian Collaboration for Coordinated Enhanced Sentinel Surveillance (ACCESS) program. PARTICIPANTS: Patients diagnosed with HIV infections, January 2004 - June 2015. MAIN OUTCOME MEASURES: Commencement of antiretroviral therapy within 6 months of HIV diagnosis (early treatment); demographic, clinical, and risk group characteristics of patients associated with early treatment; trends in early treatment, by CD4+ cell count at diagnosis. RESULTS: 917 people were diagnosed with HIV infections, their median age was 34 years (interquartile range [IQR]: 27-43 years), and 841 (92%) were men; the median CD4+ cell count at diagnosis was 510 cells/µL (IQR, 350-674 cells/µL). The proportion of patients who received early treatment increased from 17% (15 patients) in 2004-06 to 20% (34 patients) in 2007-09, 34% (95 patients) in 2010-12, and 53% (197 patients) in 2013-15 (trend, P < 0.001). The probability of early treatment, which increased with time, was higher for patients with lower CD4+ cell counts and higher viral loads at diagnosis. CONCLUSIONS: The proportion of people newly diagnosed with HIV in sexual health clinics in Australia who received treatment within 6 months of diagnosis increased from 17% to 53% during 2004-2015, reflecting changes in the CD4+ cell count threshold in treatment guidelines. Nevertheless, further strategies are needed to maximise the benefits of treatment to prevent viral transmission and morbidity.

Real-time single-molecule electronic DNA sequencing by synthesis using polymer-tagged nucleotides on a nanopore array.

DNA sequencing by synthesis (SBS) offers a robust platform to decipher nucleic acid sequences. Recently, we reported a single-molecule nanopore-based SBS strategy that accurately distinguishes four bases by electronically detecting and differentiating four different polymer tags attached to the 5'-phosphate of the nucleotides during their incorporation into a growing DNA strand catalyzed by DNA polymerase. Further developing this approach, we report here the use of nucleotides tagged at the terminal phosphate with oligonucleotide-based polymers to perform nanopore SBS on an α-hemolysin nanopore array platform. We designed and synthesized several polymer-tagged nucleotides using tags that produce different electrical current blockade levels and verified they are active substrates for DNA polymerase. A highly processive DNA polymerase was conjugated to the nanopore, and the conjugates were complexed with primer/template DNA and inserted into lipid bilayers over individually addressable electrodes of the nanopore chip. When an incoming complementary-tagged nucleotide forms a tight ternary complex with the primer/template and polymerase, the tag enters the pore, and the current blockade level is measured. The levels displayed by the four nucleotides tagged with four different polymers captured in the nanopore in such ternary complexes were clearly distinguishable and sequence-specific, enabling continuous sequence determination during the polymerase reaction. Thus, real-time single-molecule electronic DNA sequencing data with single-base resolution were obtained. The use of these polymer-tagged nucleotides, combined with polymerase tethering to nanopores and multiplexed nanopore sensors, should lead to new high-throughput sequencing methods.

Design and characterization of a nanopore-coupled polymerase for single-molecule DNA sequencing by synthesis on an electrode array.

Scalable, high-throughput DNA sequencing is a prerequisite for precision medicine and biomedical research. Recently, we presented a nanopore-based sequencing-by-synthesis (Nanopore-SBS) approach, which used a set of nucleotides with polymer tags that allow discrimination of the nucleotides in a biological nanopore. Here, we designed and covalently coupled a DNA polymerase to an α-hemolysin (αHL) heptamer using the SpyCatcher/SpyTag conjugation approach. These porin-polymerase conjugates were inserted into lipid bilayers on a complementary metal oxide semiconductor (CMOS)-based electrode array for high-throughput electrical recording of DNA synthesis. The designed nanopore construct successfully detected the capture of tagged nucleotides complementary to a DNA base on a provided template. We measured over 200 tagged-nucleotide signals for each of the four bases and developed a classification method to uniquely distinguish them from each other and background signals. The probability of falsely identifying a background event as a true capture event was less than 1.2%. In the presence of all four tagged nucleotides, we observed sequential additions in real time during polymerase-catalyzed DNA synthesis. Single-polymerase coupling to a nanopore, in combination with the Nanopore-SBS approach, can provide the foundation for a low-cost, single-molecule, electronic DNA-sequencing platform.

Lightning Rods, Earthquakes, and Regional Identities: Towards a Multi-Scale Framework of Assessing Fracking Risk Perception.

Hydraulic fracturing has provided a persistent, polarizing, and highly politicized source of controversy internationally and in numerous national contexts for just under a decade. This research uses hydraulic fracturing (i.e., fracking) operations in New Zealand as a vignette through which to understand the underlying causes of controversy and the appropriateness of attempts to address them. A multi-method approach using interviews (n = 25), diagrammatic analysis, and newsprint media was applied to evidence two major findings. First, previous attempts to explain fracking controversy based on social constructivist theory lack a multi-scalar approach to the assessment of factors that influence risk perceptions. It is found that risk perception surrounding fracking in New Zealand reflects intra-scalar interactions between factors originating at the international, national, regional, and local scale. Second, there is a concerning absence of critique pertaining to the concept of "social license to operate" (SLO), which has been advocated both internationally and nationally as an appropriate form of stakeholder engagement. This article contributes to the SLO outcomes literature by establishing a need to consider multi-scalar influences on risk perception when explaining diverse SLO outcomes in communities where fracking operations are prospective or already taking place.

Bilateral osteomyelitis and liver abscess caused by hypervirulent Klebsiella pneumoniae- a rare clinical manifestation (case report).

BACKGROUND: Hypervirulent strains of Klebsiella pneumoniae are a recognized cause of a distinct invasive syndrome that results in pyogenic liver abscesses and metastatic complications, particularly in the Asia Pacific region. Reports of hypervirulent K.pneumoniae in Europe, the Americas and Australia indicate worldwide spread. We present a case of multi-focal osteomyelitis, a rarely described complication of hypervirulent K.pneumoniae in the medical literature. The prevalence of this condition in countries outside Asia may be expected to rise with increasing travel. CASE PRESENTATION: A 20-year-old Chinese man residing in Australia for 2 years presented with a 2-week history of gradually worsening leg pain preceded by 2 weeks of constitutional symptoms. Imaging with computerized axial tomography (CT) and other modalities revealed bilateral tibial lesions described as lattice-like linear lucencies involving the cortices with scalloping of the outer involved cortex. Cultures of tissue from a left tibial bone biopsy were positive cultures for K.pneumoniae. Whole-genome sequencing identified the isolate as K1 serotype ST23, a well-recognized hyper virulent strain capable of causing invasive disease. An abdominal CT revealed a 27x22mm liver abscess. The patient had no other metastatic manifestations of the disease, and responded to 6 weeks of intravenous ceftriaxone followed by 3 months of oral Ciprofloxacin. CONCLUSIONS: Increased awareness of the manifestations and subsequent management of hyper virulent strains of K.pneumoniae by clinicians is important to assist early recognition and help minimize serious sequelae. Cases with overseas links, such as previous residence in the Asia Pacific area, are at higher risk for infection with the hyper virulent strain. This case highlights the need for clinicians to be able to recognize this important disease, especially in patients with the right epidemiological links, and to investigate and treat appropriately to prevent severe metastatic complications.

Outpatient parenteral antibiotic therapy (OPAT) in Asia: missing an opportunity.

Objectives: Healthcare facilities internationally have grown outpatient parenteral antibiotic administration services for the last few decades. The literature contains publications from dozens of countries describing systematized processes with specialist oversight and their levels of service provision and outcomes. Such descriptions are absent in the majority of Asian countries. We sought to elucidate the extent and nature of outpatient parenteral antibiotic therapy (OPAT) in Asia and to consider the ramifications and opportunities for improvement. Methods: Utilizing colleagues and their personal networks, we surveyed healthcare facilities across 17 countries in Asia to ascertain the current means (if any) of providing OPAT. In that survey we also sought to explore the capacity and interest of these facilities in developing systematized OPAT services. Results: Responses were received from 171 different healthcare facilities from 17 countries. Most (97/171, 57%) stated that they administer outpatient parenteral antibiotics, but only 5 of 162 facilities (3%) outside of Singapore described comprehensive services with specialist oversight. Conclusions: There is very likely a large unrecognized problem of unchecked outpatient parenteral antibiotic administration in Asia. Developing comprehensive and systematized OPAT in Asia is needed as a priority in an environment in which the infectious diseases community is demanding broad stewardship approaches. There are nonetheless challenges in establishing and sustaining OPAT programmes. Local champions and leverage off identified local incentives and needs are key to regional advancement.

Immunotoxicological and neurotoxicological profile of health effects following subacute exposure to geogenic dust from sand dunes at the Nellis Dunes Recreation Area, Las Vegas, NV.

Exposure to geogenic particulate matter (PM) comprised of mineral particles has been linked to human health effects. However, very little data exist on health effects associated with geogenic dust exposure in natural settings. Therefore, we characterized particulate matter size, metal chemistry, and health effects of dust collected from the Nellis Dunes Recreation Area (NDRA), a popular off-road vehicle area located near Las Vegas, NV. Adult female B6C3F1 mice were exposed to several concentrations of mineral dust collected from active and vegetated sand dunes in NDRA. Dust samples (median diameter: 4.4 µm) were suspended in phosphate-buffered saline and delivered at concentrations ranging from 0.01 to 100 mg dust/kg body weight by oropharyngeal aspiration. ICP-MS analyses of total dissolution of the dust resulted in aluminum (55,090 µg/g), vanadium (70 µg/g), chromium (33 µg/g), manganese (511 µg/g), iron (21,600 µg/g), cobalt (9.4 µg/g), copper (69 µg/g), zinc (79 µg/g), arsenic (62 µg/g), strontium (620 µg/g), cesium (13 µg/g), lead 25 µg/g) and uranium (4.7 µg/g). Arsenic was present only as As(V). Mice received four exposures, once/week over 28-days to mimic a month of weekend exposures. Descriptive and functional assays to assess immunotoxicity and neurotoxicity were performed 24 h after the final exposure. The primary observation was that 0.1 to 100 mg/kg of this sand dune derived dust dose-responsively reduced antigen-specific IgM antibody responses, suggesting that dust from this area of NDRA may present a potential health risk.

Health effects following subacute exposure to geogenic dusts from arsenic-rich sediment at the Nellis Dunes Recreation Area, Las Vegas, NV.

Geogenic dust from arid environments is a possible inhalation hazard for humans, especially when using off-road vehicles that generate significant dust. This study focused on immunotoxicological and neurotoxicological effects following subacute exposure to geogenic dust generated from sediments in the Nellis Dunes Recreation Area near Las Vegas, Nevada that are particularly high in arsenic; the naturally-occurring arsenic concentrations in these surficial sediments ranged from 4.8 to 346µg/g. Dust samples from sediments used in this study had a median diameter of 4.5µm and also were a complex mixture of naturally-occurring metals, including aluminum, vanadium, chromium, manganese, iron, cobalt, copper, zinc, strontium, cesium, lead, uranium, and arsenic. Adult female B6C3F1 mice exposed via oropharyngeal aspiration to 0.01 to 100mg dust/kg body weight, four times, a week apart, for 28days, were evaluated 24h after the last exposure. Peripheral eosinophils were increased at all concentrations, serum creatinine was dose responsively increased beginning at 1.0mg/kg/day, and blood urea nitrogen was decreased at 10 and 100mg/kg/day. Antigen-specific IgM responses and natural killer cell activity were dose-responsively suppressed at 0.1mg/kg/day and above. Splenic CD4+CD25+ T cells were decreased at 0.01, 0.1, 10, and 100mg/kg/day. Antibodies against MBP, NF-68, and GFAP were selectively reduced. A no observed adverse effect level of 0.01mg/kg/day and a lowest observed adverse effect level of 0.1mg/kg/day were determined from IgM responses and natural killer cell activity, indicating that exposure to this dust, under conditions similar to our design, could affect these responses.

Oral versus intravenous antibiotics in the treatment of uncomplicated colonic diverticulitis: results of a randomized non-inferiority control trial.

BACKGROUND: Colonic diverticular disease is common and its incidence increases with age, with uncomplicated diverticulitis being the most common acute presentation (1). This typically results in inpatient admission, placing a significant burden on healthcare services (2). We aimed to determine the safety and effectiveness of using intravenous or oral antibiotics in the treatment of uncomplicated diverticulitis on 30-day unplanned admissions, c-reactive protein (CRP), White Cell Count (WCC), pain resolution, cessation of pain medication, return to normal nutrition, and return to normal bowel function. METHODS: This single centre, 2-arm, parallel, 1:1, unblinded non-inferiority randomized controlled trial compared the safety and efficacy of oral antibiotics versus intravenous antibiotics in the outpatient treatment of uncomplicated colonic diverticulitis. Inclusion criteria were patients older than 18 years of age with CT proven acute uncomplicated colonic diverticulitis (Modified Hinchey Classification Stage 0-1a). Patients were randomly allocated receive either intravenous or oral antibiotics, both groups being treated in the outpatient setting with a Hospital in the Home (HITH) service. The primary outcome was the 30-day unplanned admission rate, secondary outcomes were biochemical markers, time to pain resolution, time to cessation of pain medication, time to return to normal function and time to return to normal bowel function. RESULTS: In total 118 patients who presented with uncomplicated colonic diverticulitis were recruited into the trial. Fifty-eight participants were treated with IV antibiotics, and 60 were given oral antibiotics. We found there was no significant difference between groups with regards to 30-day unplanned admissions or inflammatory markers. There was also no significant difference with regards to time to pain resolution, cessation of pain medication use, return to normal nutrition, or return to normal bowel function. CONCLUSION: Outpatient management of uncomplicated diverticulitis with oral antibiotics proved equally as safe and efficacious as intravenous antibiotic treatment in this randomized non-inferiority control trial.

Safety and efficacy of outpatient parenteral antimicrobial therapy: A systematic review and meta-analysis of randomized clinical trials.

BACKGROUND: Outpatient parenteral antimicrobial therapy (OPAT) offers an alternative to inpatient (hospital bed-based) treatment of infections that require intravenous administration of antimicrobials. This meta-analysis aimed to summarise the evidence available from randomised controlled trials (RCTs) regarding the efficacy and safety of OPAT compared to inpatient parenteral antimicrobial therapy. METHODS: We searched the Cochrane Library, MEDLINE, Embase, PubMed, and Web of Sciences databases for RCTs comparing outpatient versus inpatient parenteral antimicrobial therapy. We included studies without restrictions on language or publication year. Eligibility was reviewed independently by two assessors, and data extraction was cross validated. We evaluated bias risk via the Cochrane tool and determined the evidence certainty using GRADE. Meta-analysis was conducted using a random effects model. The protocol of this review was registered on PROSPERO (CRD42023460389). RESULT: Thirteen RCTs, involving 1,310 participants were included. We found no difference in mortality (Risk Ratio [RR] 0.54, 95% Confidence Interval [CI] 0.23 to 1.26; P = 0.93), treatment failure (RR 1.0, CI 0.59 to 1.72; P = 0.99), adverse reaction related to antimicrobials (RR 0.89, CI 0.69 to 1.15; P = 0.38), and administration device (RR 0.58, CI 0.17 to 1.98; P = 0.87) between outpatient and inpatient parenteral antimicrobial therapy. The overall body of evidence had a low level of certainty. CONCLUSION: Existing evidence suggests OPAT is a safe and effective alternative to inpatient treatment. Further RCTs are warranted for a thorough comparison of inpatient and outpatient parenteral antimicrobial therapy with a high level of certainty.

Prevalence of Clostridium difficile colonization among healthcare workers.

BACKGROUND: Clostridium difficile infection (CDI) has increased to epidemic proportions in recent years. The carriage of C. difficile among healthy adults and hospital inpatients has been established. We sought to determine whether C. difficile colonization exists among healthcare workers (HCWs) in our setting. METHODS: A point prevalence study of stool colonization with C. difficile among doctors, nurses and allied health staff at a large regional teaching hospital in Geelong, Victoria. All participants completed a short questionnaire and all stool specimens were tested by Techlab® C.diff Quik Check enzyme immunoassay followed by enrichment culture. RESULTS: Among 128 healthcare workers, 77% were female, of mean age 43 years, and the majority were nursing staff (73%). Nineteen HCWs (15%) reported diarrhoea, and 12 (9%) had taken antibiotics in the previous six weeks. Over 40% of participants reported having contact with a patient with known or suspected CDI in the 6 weeks before the stool was collected. C. difficile was not isolated from the stool of any participants. CONCLUSION: Although HCWs are at risk of asymptomatic carriage and could act as a reservoir for transmission in the hospital environment, with the use of a screening test and culture we were unable to identify C. difficile in the stool of our participants in a non-outbreak setting. This may reflect potential colonization resistance of the gut microbiota, or the success of infection prevention strategies at our institution.

Aspergillus endocarditis 2003-2009.

A retrospective study of 35 case reports of Aspergillus endocarditis published between 2003 and 2009 was carried out. Fifteen percent of cases presented with a new cardiac murmur, 38% with an embolus. Eighty percent of cases involved the aortic or mitral valves. Seventy-four percent of cases involved patients with a history of prior surgery, 48% of these involved a heart valve, 20% had other cardiac surgery and 32% had non-cardiac surgery. Galactomannan testing was helpful diagnostically in four out of nine cases, but PCR testing was positive in six out of six cases. Overall mortality was 68%, all eight survivors had heart valve surgery apart from one - an 8-month-old child. Seven out of eight survivors received liposomal amphotericin B, three of these in combination with other antifungals. We need to think more about the possibility of Aspergillus endocarditis, particularly in immunocompromised patients with recent surgery. Galactomannan and PCR testing may be used more vigorously. Valve replacement, or at least vegetectomy, should be carried out in all patients. Liposomal amphotericin B, 3-5mg/kg/day, for at least 4 weeks is the treatment of choice. Oral voriconazole should be used for at least 2 years. Posaconazole may be an alternative, however there have been no prior cases reported to suggest its efficacy. The value of combination antifungal therapy is uncertain, but consideration should be given to the use of a second agent in addition to liposomal amphotericin. While further case reports on this condition will be helpful, more definitive management guidelines will depend on a prospective study.

Electrocardiogram machine learning for detection of cardiovascular disease in African Americans: the Jackson Heart Study.

AIMS: Almost half of African American (AA) men and women have cardiovascular disease (CVD). Detection of prevalent CVD in community settings would facilitate secondary prevention of CVD. We sought to develop a tool for automated CVD detection. METHODS AND RESULTS: Participants from the Jackson Heart Study (JHS) with analysable electrocardiograms (ECGs) (n=3679; age, 6212 years; 36% men) were included. Vectorcardiographic (VCG) metrics QRS, T, and spatial ventricular gradient vectors magnitude and direction, and traditional ECG metrics were measured on 12-lead ECG. Random forests, convolutional neural network (CNN), lasso, adaptive lasso, plugin lasso, elastic net, ridge, and logistic regression models were developed in 80% and validated in 20% samples. We compared models with demographic, clinical, and VCG input (43 predictors) and those after the addition of ECG metrics (695 predictors). Prevalent CVD was diagnosed in 411 out of 3679 participants (11.2%). Machine learning models detected CVD with the area under the receiver operator curve (ROC AUC) 0.690.74. There was no difference in CVD detection accuracy between models with VCG and VCG + ECG input. Models with VCG input were better calibrated than models with ECG input. Plugin-based lasso model consisting of only two predictors (age and peak QRS-T angle) detected CVD with AUC 0.687 [95% confidence interval (CI) 0.6250.749], which was similar (P=0.394) to the CNN (0.660; 95% CI 0.5970.722) and better (P<0.0001) than random forests (0.512; 95% CI 0.4930.530). CONCLUSIONS: Simple model (age and QRS-T angle) can be used for prevalent CVD detection in limited-resources community settings, which opens an avenue for secondary prevention of CVD in underserved communities.

Sex differences in vectorcardiogram of African-Americans with and without cardiovascular disease: a cross-sectional study in the Jackson Heart Study cohort.

OBJECTIVES: We hypothesised that (1) the prevalent cardiovascular disease (CVD) is associated with global electrical heterogeneity (GEH) after adjustment for demographic, anthropometric, socioeconomic and traditional cardiovascular risk factors, (2) there are sex differences in GEH and (3) sex modifies an association of prevalent CVD with GEH. DESIGN: Cross-sectional, cohort study. SETTING: Prospective African-American The Jackson Heart Study (JHS) with a nested family cohort in 2000-2004 enrolled residents of the Jackson, Mississippi metropolitan area. PARTICIPANTS: Participants from the JHS with analysable ECGs recorded in 2009-2013 (n=3679; 62±12 y; 36% men; 863 family units). QRS, T and spatial ventricular gradient (SVG) vectors' magnitude and direction, spatial QRS-T angle and sum absolute QRST integral (SAI QRST) were measured. OUTCOME: Prevalent CVD was defined as the history of (1) coronary heart disease defined as diagnosed/silent myocardial infarction, or (2) revascularisation procedure defined as prior coronary/peripheral arterial revascularisation, or (3) carotid angioplasty/carotid endarterectomy, or (4) stroke. RESULTS: In adjusted mixed linear models, women had a smaller spatial QRS-T angle (-12.2 (95% CI -19.4 to -5.1)°; p=0.001) and SAI QRST (-29.8 (-39.3 to -20.3) mV*ms; p<0.0001) than men, but larger SVG azimuth (+16.2(10.5-21.9)°; p<0.0001), with a significant random effect between families (+20.8 (8.2-33.5)°; p=0.001). SAI QRST was larger in women with CVD as compared with CVD-free women or men (+15.1 (3.8-26.4) mV*ms; p=0.009). Men with CVD had a smaller T area (by 5.1 (95% CI 1.2 to 9.0) mV*ms) and T peak magnitude (by 44 (95%CI 16 to 71) µV) than CVD-free men. T vectors pointed more posteriorly in women as compared with men (peak T azimuth + 17.2(8.9-25.6)°; p<0.0001), with larger sex differences in T azimuth in some families by +26.3(7.4-45.3)°; p=0.006. CONCLUSIONS: There are sex differences in the electrical signature of CVD in African-American men and women. There is a significant effect of unmeasured genetic and environmental factors on cardiac repolarisation.

Kidney Function and Aortic Stiffness, Pulsatility, and Endothelial Function in African Americans: The Jackson Heart Study.

RATIONALE & OBJECTIVE: The relation of vascular stiffness, endothelial function, and kidney function is incompletely elucidated in African Americans. Our hypothesis was that increased vascular stiffness and endothelial dysfunction are associated with low estimated glomerular filtration rate (eGFR) and albuminuria in African Americans. STUDY DESIGN: Cross-sectional cohort analysis of data from the Jackson Heart Study. SETTINGS & PATIENTS: 2,244 Jackson Heart Study participants (2012-2017 after Exam 3) who had undergone noninvasive hemodynamic assessment using arterial tonometry. PREDICTORS: Baseline carotid-femoral pulse wave velocity, pulsatile hemodynamics forward wave amplitude, and hyperemic brachial artery flow were measured. Reduced eGFR was defined as eGFR between 15 and 60 mL/min/1.73 m2. OUTCOMES: Prevalent albuminuria, urinary albumin-creatinine ratio. ANALYTICAL APPROACH: 2-sample t test for continuous variables and χ2 test for categorical variables in addition to logistic and linear regression models to assess the risk for chronic kidney disease with each proposed hemodynamic variable. RESULTS: Among 2,244 participants, mean age was 66 ± 11 years and 64% were women. Reduced eGFR was present in 233 (10.4%), and elevated urinary albumin-creatinine ratio, in 232 (10.4%). In multivariable-adjusted analyses, higher carotid-femoral pulse wave velocity was associated with the presence of reduced eGFR (OR, 1.37 [95% CI, 1.08-1.75] per SD; P = 0.01) and with prevalent albuminuria (OR, 1.66 [95% CI, 1.32-2.11]; P < 0.001). Higher forward wave amplitude was significantly associated with prevalent albuminuria (OR, 1.37 [95% CI, 1.14-1.65]; P = 0.001). LIMITATIONS: Cross-sectional analyses cannot inform causality. CONCLUSIONS: Higher arterial stiffness and pulsatility are associated with higher odds of reduced eGFR in African Americans. Future studies should focus on whether improving arterial stiffness contributes to kidney protection in African Americans.

Multiplex Single-Molecule Kinetics of Nanopore-Coupled Polymerases.

DNA polymerases have revolutionized the biotechnology field due to their ability to precisely replicate stored genetic information. Screening variants of these enzymes for specific properties gives the opportunity to identify polymerases with different features. We have previously developed a single-molecule DNA sequencing platform by coupling a DNA polymerase to an α-hemolysin pore on a nanopore array. Here, we use this approach to demonstrate a single-molecule method that enables rapid screening of polymerase variants in a multiplex manner. In this approach, barcoded DNA strands are complexed with polymerase variants and serve as templates for nanopore sequencing. Nanopore sequencing of the barcoded DNA reveals both the barcode identity and kinetic properties of the polymerase variant associated with the cognate barcode, allowing for multiplexed investigation of many polymerase variants in parallel on a single nanopore array. Further, we develop a robust classification algorithm that discriminates kinetic characteristics of the different polymerase mutants. As a proof of concept, we demonstrate the utility of our approach by screening a library of ∼100 polymerases to identify variants for potential applications of biotechnological interest. We anticipate our screening method to be broadly useful for applications that require polymerases with altered physical properties.

Measuring antimicrobial prescribing quality in outpatient parenteral antimicrobial therapy (OPAT) services: development and evaluation of a dedicated national antimicrobial prescribing survey.

BACKGROUND: Antimicrobial stewardship programmes are important in driving safety and quality of antimicrobial prescribing. The National Antimicrobial Prescribing Survey (NAPS) is a point-prevalence audit of inpatient antimicrobial prescribing in Australian hospitals. OBJECTIVES: To design and adapt the NAPS tool for use in the outpatient parenteral antimicrobial therapy (OPAT) and hospital-in-the-home (HITH) setting. METHODS: An inter-disciplinary working group with expertise in OPAT and HITH services was established to adapt the NAPS template for use in the OPAT setting-called HITH-NAPS. This was initially trialled in 5 HITH services, subsequently adapted following participant feedback, then offered nationally to 50 services in 2017. RESULTS: There were 1154 prescriptions for 715 patients audited via the HITH-NAPS. The most common antimicrobials prescribed were cefazolin (22%), flucloxacillin (12%), piperacillin/tazobactam (10%) and ceftriaxone (10%). The most common infections treated were cellulitis (30%) and respiratory tract infections (14%). Eighty-seven percent of prescriptions were assessed as appropriate, 11% inappropriate and 2% not assessable. Prolonged durations of antimicrobials and unnecessarily broad-spectrum antibiotics were used in 9% of prescriptions. CONCLUSIONS: The HITH-NAPS pilot project revealed that auditing of this type is feasible in HITH. It showed that antibiotic use in these HITH services was generally appropriate, but there are some areas for improvement. A national OPAT/HITH-NAPS can facilitate benchmarking between services, identify potentially inappropriate prescribing and help guide quality improvement.

Harmonising topographic & remotely sensed datasets, a reference dataset for shoreline and beach change analysis.

This paper presents a novel reference dataset for North Norfolk, UK, that demonstrates the value of harmonising coastal field-based topographic and remotely sensed datasets at local scales. It is hoped that this reference dataset and the associated methodologies will facilitate the use of topographic and remotely sensed coastal datasets, as demonstrated here using open-access UK Environment Agency datasets. Two core methodologies, used to generate the novel reference dataset, are presented. Firstly, we establish a robust approach to extracting shorelines from vertical aerial photography, validated against LiDAR (Light Detection and Ranging) and coastal topography surveys. Secondly, we present a standard methodology for quantifying sediment volume change from spatially continuous LiDAR elevation datasets. As coastal systems are monitored at greater spatial resolution and temporal frequency there is an unprecedented opportunity to determine how and why coastal systems have changed in the past with a view to informing future forecasting. With revelation of trends that suggest increasing coastal risk, coastal change research is needed to inform the management and protection of coasts.