Comprehensive stability analysis of 13 ß-lactams and ß-lactamase inhibitors in in vitro media, and novel supplement dosing strategy to mitigate thermal drug degradation.

Non-clinical antibiotic development relies on in vitro susceptibility and infection model studies. Validating the achievement of the targeted drug concentrations is essential to avoid under-estimation of drug effects and over-estimation of resistance emergence. While certain ß-lactams (e.g., imipenem) and ß-lactamase inhibitors (BLIs; clavulanic acid) are believed to be relatively unstable, limited tangible data on their stability in commonly used in vitro media are known. We aimed to determine the thermal stability of 10 ß-lactams and 3 BLIs via LC-MS/MS in cation-adjusted Mueller Hinton broth at 25 and 36°C as well as agar at 4 and 37°C, and in water at -20, 4, and 25°C. Supplement dosing algorithms were developed to achieve broth concentrations close to their target over 24 h. During incubation in broth (pH 7.25)/agar, degradation half-lives were 16.9/21.8 h for imipenem, 20.7/31.6 h for biapenem, 29.0 h for clavulanic acid (studied in broth only), 23.1/71.6 h for cefsulodin, 40.6/57.9 h for doripenem, 46.5/64.6 h for meropenem, 50.8/97.7 h for cefepime, 61.5/99.5 h for piperacillin, and >120 h for all other compounds. Broth stability decreased at higher pH. All drugs were ≥90% stable for 72 h in agar at 4°C. Degradation half-lives in water at 25°C were >200 h for all drugs except imipenem (14.7 h, at 1,000 mg/L) and doripenem (59.5 h). One imipenem supplement dose allowed concentrations to stay within ±31% of their target concentration. This study provides comprehensive stability data on ß-lactams and BLIs in relevant in vitro media using LC-MS/MS. Future studies are warranted applying these data to antimicrobial susceptibility testing and assessing the impact of ß-lactamase-related degradation.

Small Bowel Crohn's Disease Recurrence is Common After Total Proctocolectomy for Crohn's Colitis.

BACKGROUND: Surgical intervention for Crohn's disease involving the colon is often a total proctocolectomy with end ileostomy. There are limited data regarding postoperative small bowel recurrence rates in the recent era. OBJECTIVE: The purpose of this study was to determine the rate of small bowel Crohn's disease recurrence following total proctocolectomy and secondarily define risk factors for disease recurrence. DESIGN: This was a retrospective cohort study. SETTINGS: The study was conducted at four hospitals within a single healthcare system. PATIENTS: Patients were those with Crohn's disease undergoing total proctocolectomy with end ileostomy between 2009-2019. MAIN OUTCOME MEASURES: Main outcome measures were clinical, endoscopic, radiographic, and/or surgical Crohn's disease recurrence. RESULTS: In total, 193 patients were included with a median follow-up of 1.8 years (IQR 0.4-4.6). Overall, 74.6% (n = 144) of patients had been previously exposed to biologic therapy, and 51.3% (n = 99) had a history of small bowel Crohn's disease. Postoperatively, 14.5% (n = 28) of patients received biologic therapy. Crohn's disease recurrence occurred in 23.3% (n = 45) of patients with an estimated median 5-year recurrence rate of 40.8% (95% CI' 30.2-51.4). Surgical recurrence occurred in 8.8% (n = 17) of patients with an estimated median 5-year recurrence rate of 16.9% (95% CI' 8.5-25.3). On multivariable analysis, prior small bowel surgery for Crohn's disease (HR 2.61; 95% CI' 1.42-4.81) and Crohn's diagnosis at age <18 years (HR 2.56; 95% CI' 1.40-4.71) were associated with Crohn's recurrence. In patients without prior small bowel Crohn's disease, 14.9% (n = 14) had Crohn's recurrence with an estimated 5-year overall recurrence rate of 31.1% (95% CI' 13.3-45.3) and 5-year surgical recurrence rate of 5.7% (95% CI' 0.0-12.0). LIMITATIONS: The study was limited by its retrospective design and lack of consistent follow-up on all patients. CONCLUSIONS: Greater than one third of patients who underwent total proctocolectomy for Crohn's disease were estimated to have small bowel Crohn's recurrence at 5 years after surgery. Patients with a history of small bowel surgery for Crohn's and diagnosis at any early age may benefit from more intensive postoperative surveillance and consideration for early medical prophylaxis. See Video Abstract at http://links.lww.com/DCR/B762. RECURRENCIA FRECUENTE DE LA ENFERMEDAD DE CROHN DEL INTESTINO DELGADO DESPUS DE LA PROCTOCOLECTOMA TOTAL POR COLITIS DE CROHN: ANTECEDENTES:La cirugia para la enfermedad de Crohn que involucra el colon es a menudo una proctocolectomía total con ileostomía terminal. Hay datos limitados con respecto a las tasas de recurrencia posoperatoria de la enfermedad de Crohn del intestino delgado en la actualidad.OBJETIVO:Buscamos determinar la tasa de recurrencia de la enfermedad de Crohn del intestino delgado después de la proctocolectomía total y, en segundo lugar, definir los factores de riesgo de recurrencia de la enfermedad.DISEÑO:Estudio de cohorte retrospectivo.ENTORNO CLINICO:Cuatro hospitales de un mismo sistema sanitario.PACIENTES:Pacientes con enfermedad de Crohn sometidos a proctocolectomía total con ileostomía terminal entre 2009-2019.PRINCIPALES MEDIDAS DE VALORACIÓN:Recurrencia clínica, endoscópica, radiográfica y / o quirúrgica de la enfermedad de Crohn.RESULTADOS:Se incluyeron 193 pacientes con un seguimiento promedio de 1,8 años (IQR 0,4-4,6). El 74,6% (n = 144) de los pacientes habían recibido previamente terapia biológica y el 51,3% (n = 99) tenían antecedentes de enfermedad de Crohn del intestino delgado. Después de la operación, el 14,5% (n = 28) de los pacientes recibieron terapia biológica. La recurrencia de la enfermedad de Crohn ocurrió en el 23,3% (n = 45) de los pacientes con una tasa de recurrencia media estimada a los 5 años del 40,8% (IC del 95%: 30,2-51,4). La recidiva quirúrgica se produjo en el 8,8% (n = 17) de los pacientes con una tasa de recidiva media estimada a los 5 años del 16,9% (IC del 95%: 8,5-25,3). En el análisis multivariable, la cirugía previa del intestino delgado para la enfermedad de Crohn (HR 2,61, IC del 95%: 1,42-4,81) y el diagnóstico de Crohn a la edad <18 (HR 2,56, IC del 95%: 1,40-4,71) se asociaron con la recurrencia de Crohn. En pacientes sin enfermedad previa de Crohn del intestino delgado, el 14,9% (n = 14) tuvo recurrencia de Crohn con una tasa de recurrencia general estimada a 5 años del 31,1% (IC del 95%: 13,3-45,3) y una tasa de recurrencia quirúrgica a 5 años del 5,7% (IC del 95%: 0,0-12,0).LIMITACIONES:Diseño retrospectivo, falta de seguimiento constante de todos los pacientes.CONCLUSIONES:Se estimó que más de un tercio de los pacientes que se sometieron a proctocolectomía total tenían recurrencia de Crohn del intestino delgado a los 5 años después de la cirugía. Los pacientes con antecedentes de cirugía por enfermedad de Crohn del intestino delgado y diagnóstico a una edad temprana pueden beneficiarse de una vigilancia posoperatoria más intensiva y la consideración de una profilaxis médica temprana. Consulte Video Resumen en http://links.lww.com/DCR/B762. (Traducción- Dr. Ingrid Melo).

Global variation in the fraction of leaf nitrogen allocated to photosynthesis.

Plants invest a considerable amount of leaf nitrogen in the photosynthetic enzyme ribulose-1,5-bisphosphate carboxylase-oxygenase (RuBisCO), forming a strong coupling of nitrogen and photosynthetic capacity. Variability in the nitrogen-photosynthesis relationship indicates different nitrogen use strategies of plants (i.e., the fraction nitrogen allocated to RuBisCO; fLNR), however, the reason for this remains unclear as widely different nitrogen use strategies are adopted in photosynthesis models. Here, we use a comprehensive database of in situ observations, a remote sensing product of leaf chlorophyll and ancillary climate and soil data, to examine the global distribution in fLNR using a random forest model. We find global fLNR is 18.2 ± 6.2%, with its variation largely driven by negative dependence on leaf mass per area and positive dependence on leaf phosphorus. Some climate and soil factors (i.e., light, atmospheric dryness, soil pH, and sand) have considerable positive influences on fLNR regionally. This study provides insight into the nitrogen-photosynthesis relationship of plants globally and an improved understanding of the global distribution of photosynthetic potential.

Mismatch: a comparative study of vitamin D status in British-Bangladeshi migrants.

BACKGROUND AND OBJECTIVES: Low levels of vitamin D among dark-skinned migrants to northern latitudes and increased risks for associated pathologies illustrate an evolutionary mismatch between an environment of high ultraviolet (UV) radiation to which such migrants are adapted and the low UV environment to which they migrate. Recently, low levels of vitamin D have also been associated with higher risks for contracting COVID-19. South Asians in the UK have higher risk for low vitamin D levels. In this study, we assessed vitamin D status of British-Bangladeshi migrants compared with white British residents and Bangladeshis still living in Bangladesh ('sedentees'). METHODOLOGY: The cross-sectional study compared serum vitamin D levels among 149 women aged 35-59, comprising British-Bangladeshi migrants (n = 50), white British neighbors (n = 54) and Bangladeshi sedentees (n = 45). Analyses comprised multivariate models to assess serum levels of 25-hydroxyvitamin D (25(OH)D), and associations with anthropometric, lifestyle, health and migration factors. RESULTS: Vitamin D levels in Bangladeshi migrants were very low: mean 25(OH)D = 32.2 nmol/L ± 13.0, with 29% of migrants classified as deficient (<25 nmol/L) and 94% deficient or insufficient (≤50 nmol/L). Mean levels of vitamin D were significantly lower among British-Bangladeshis compared with Bangladeshi sedentees (50.9 nmol/L ± 13.3, P < 0.001) and were also lower than in white British women (55.3 nmol/L ± 20.9). Lower levels of vitamin D were associated with increased body mass index and low iron status. CONCLUSIONS AND IMPLICATIONS: We conclude that lower exposure to sunlight in the UK reduces vitamin D levels in Bangladeshi migrants. Recommending supplements could prevent potentially adverse health outcomes associated with vitamin D deficiency. LAY SUMMARY: Vitamin D deficiency is one example of mismatch between an evolved trait and novel environments. Here we compare vitamin D status of dark-skinned British-Bangladeshi migrants in the UK to Bangladeshis in Bangladesh and white British individuals. Migrants had lower levels of vitamin D and are at risk for associated pathologies.

High-speed microjets issue from bursting oil gland reservoirs of citrus fruit.

The rupture of oil gland reservoirs housed near the outer surface of the citrus exocarp is a common experience to the discerning citrus consumer and bartenders the world over. These reservoirs often rupture outwardly in response to bending the peel, which compresses the soft material surrounding the reservoirs, the albedo, increasing fluid pressure in the reservoir. Ultimately, fluid pressure exceeds the failure strength of the outermost membrane, the flavedo. The ensuing high-velocity discharge of oil and exhaustive emptying of oil gland reservoirs creates a method for jetting small quantities of the aromatic oil. We compare this jetting behavior across five citrus hybrids through high-speed videography. The jetting oil undergoes an extreme acceleration to reach velocities in excess of 10 m/s. Through material characterization and finite element simulations, we rationalize the combination of tuned material properties and geometries enabling the internal reservoir pressures that produce explosive dispersal, finding the composite structure of the citrus peel is critical for microjet production.

Dataset of the livability performance of the city of Birmingham, UK, as measured by its citizen wellbeing, resource security, resource efficiency and carbon emissions.

This data article presents the UK City LIFE1 data set for the city of Birmingham, UK. UK City LIFE1 is a new, comprehensive and holistic method for measuring the livable sustainability performance of UK cities. The Birmingham data set comprises 346 indicators structured simultaneously (1) within a four-tier, outcome-based framework in order to aid in their interpretation (e.g., promote healthy living and healthy long lives, minimize energy use, uncouple economic vitality from CO2 emissions) and (2) thematically in order to complement government and disciplinary siloes (e.g., health, energy, economy, climate change). Birmingham data for the indicators are presented within an Excel spreadsheet with their type, units, geographic area, year, source, link to secondary data files, data collection method, data availability and any relevant calculations and notes. This paper provides a detailed description of UK city LIFE1 in order to enable comparable data sets to be produced for other UK cities. The Birmingham data set is made publically available at http://epapers.bham.ac.uk/3040/ to facilitate this and to enable further analyses. The UK City LIFE1 Birmingham data set has been used to understand what is known and what is not known about the livable sustainability performance of the city and to inform how Birmingham City Council can take action now to improve its understanding and its performance into the future (see "Improving city-scale measures of livable sustainability: A study of urban measurement and assessment through application to the city of Birmingham, UK" Leach et al. [2]).

Multisensory object perception in infancy: 4-month-olds perceive a mistuned harmonic as a separate auditory and visual object.

Infants learn to use auditory and visual information to organize the sensory world into identifiable objects with particular locations. Here we use a behavioural method to examine infants' use of harmonicity cues to auditory object perception in a multisensory context. Sounds emitted by different objects sum in the air and the auditory system must figure out which parts of the complex waveform belong to different sources (auditory objects). One important cue to this source separation is that complex tones with pitch typically contain a fundamental frequency and harmonics at integer multiples of the fundamental. Consequently, adults hear a mistuned harmonic in a complex sound as a distinct auditory object (Alain, Theunissen, Chevalier, Batty, & Taylor, 2003). Previous work by our group demonstrated that 4-month-old infants are also sensitive to this cue. They behaviourally discriminate a complex tone with a mistuned harmonic from the same complex with in-tune harmonics, and show an object-related event-related potential (ERP) electrophysiological (EEG) response to the stimulus with mistuned harmonics. In the present study we use an audiovisual procedure to investigate whether infants perceive a complex tone with an 8% mistuned harmonic as emanating from two objects, rather than merely detecting the mistuned cue. We paired in-tune and mistuned complex tones with visual displays that contained either one or two bouncing balls. Four-month-old infants showed surprise at the incongruous pairings, looking longer at the display of two balls when paired with the in-tune complex and at the display of one ball when paired with the mistuned harmonic complex. We conclude that infants use harmonicity as a cue for source separation when integrating auditory and visual information in object perception.

In vitro inhibitory activities of selected Australian medicinal plant extracts against protein glycation, angiotensin converting enzyme (ACE) and digestive enzymes linked to type II diabetes.

BACKGROUND: There is a need to develop potential new therapies for the management of diabetes and hypertension. Australian medicinal plants collected from the Kuuku I'yu (Northern Kaanju) homelands, Cape York Peninsula, Queensland, Australia were investigated to determine their therapeutic potential. Extracts were tested for inhibition of protein glycation and key enzymes relevant to the management of hyperglycaemia and hypertension. The inhibitory activities were further correlated with the antioxidant activities. METHODS: Extracts of five selected plant species were investigated: Petalostigma pubescens, Petalostigma banksii, Memecylon pauciflorum, Millettia pinnata and Grewia mesomischa. Enzyme inhibitory activity of the plant extracts was assessed against α-amylase, α-glucosidase and angiotensin converting enzyme (ACE). Antiglycation activity was determined using glucose-induced protein glycation models and formation of protein-bound fluorescent advanced glycation endproducts (AGEs). Antioxidant activity was determined by measuring the scavenging effect of plant extracts against 1, 1-diphenyl-2-picryl hydrazyl (DPPH) and using the ferric reducing anti-oxidant potential assay (FRAP). Total phenolic and flavonoid contents were also determined. RESULTS: Extracts of the leaves of Petalostigma banksii and P. pubescens showed the strongest inhibition of α-amylase with IC50 values of 166.50 ± 5.50 µg/mL and 160.20 ± 27.92 µg/mL, respectively. The P. pubescens leaf extract was also the strongest inhibitor of α-glucosidase with an IC50 of 167.83 ± 23.82 µg/mL. Testing for the antiglycation potential of the extracts, measured as inhibition of formation of protein-bound fluorescent AGEs, showed that P. banksii root and fruit extracts had IC50 values of 34.49 ± 4.31 µg/mL and 47.72 ± 1.65 µg/mL, respectively, which were significantly lower (p < 0.05) than other extracts. The inhibitory effect on α-amylase, α-glucosidase and the antiglycation potential of the extracts did not correlate with the total phenolic, total flavonoid, FRAP or DPPH. For ACE inhibition, IC50 values ranged between 266.27 ± 6.91 to 695.17 ± 15.38 µg/mL. CONCLUSIONS: The tested Australian medicinal plant extracts inhibit glucose-induced fluorescent AGEs, α-amylase, α-glucosidase and ACE with extracts of Petalostigma species showing the most promising activity. These medicinal plants could potentially be further developed as therapeutic agents in the treatment of hyperglycaemia and hypertension.

Development and Evaluation of a Topical Anti-Inflammatory Preparation Containing Dodonaea polyandra Extract.

PURPOSE: We have previously reported that the Australian Northern Kaanju (Kuuku I'yu) medicinal plant Dodonaea polyandra has anti-inflammatory activity. This is attributed largely to the presence of clerodane diterpenoids contained within the leaf resin. We envisaged developing a topical preparation to treat indications relating to skin inflammation. However, it was unknown whether the resin could be incorporated into a suitable dosage form while retaining the therapeutic value demonstrated in previous work. Therefore, the following study was undertaken to assess parameters of safety and efficacy for a prototype formulation containing the leaf resin extracted from D. polyandra. METHODS: Using the assessment criteria of optimum appearance, tactile feeling, spreadability and odour, 78 different formulations were developed. Formulation stability was assessed using a centrifugal test with preparations displaying phase separation further modified or re-formulated. A prototype formulation containing 5% w/w plant resin was selected and subjected to in vitro release studies. This was quantified through HPLC analysis using two major bioactive diterpenoids as reference. The prototype formulation was tested for efficacy in a TPA-induced acute murine skin inflammation model as well as a 3D human skin model for irritancy/toxicity (Epiderm™). RESULTS: The prototype resin cream was a chartreuse-coloured homogenous semisolid preparation that was readily spreadable upon contact with skin with no sensation of tackiness, residual greasiness, or irritation. The optimized cream showed no phase separation after 30 min centrifugation at 825 g. In the TPA-induced inflammation model, the resin formulation significantly reduced ear thickness and interleukin-1 beta levels in mouse ear tissue. The 5% w/w resin cream formulation showed no irritancy in a 3D human skin model. CONCLUSIONS: Our results demonstrate that bioactive resin from D. polyandra can be formulated into a stable and non-irritant semi-solid dosage form and reduce parameters of acute skin inflammation in vivo. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

The effect of calcium plus vitamin D supplementation on the risk of venous thromboembolism. From the Women's Health Initiative Randomized Controlled Trial.

Experimental and epidemiological studies suggest that vitamin D may be implicated in haemostatic regulations and influence the risk of venous thromboembolism (VTE). The aim of this study was to investigate whether oral supplementation of vitamin D3 combined with calcium reduces the risk of VTE. In the randomised, double-blind, placebo-controlled Women's Health Initiative Calcium Plus Vitamin D trial, 36,282 postmenopausal women aged 50-79 years were randomised to receive 1,000 mg of calcium carbonate and 400 IU of vitamin D3 per day (n=18,176) or a matching placebo (n=18,106) during an average of seven years. This secondary analysis of the trial compared the incidence of VTE by treatment group using an intention-to-treat Cox regression analysis. The incidence of VTE did not differ between women randomised to calcium plus vitamin D and women randomised to placebo (320 vs 348 VTE events, respectively; hazard ratio (HR) 0.92, 95 % confidence interval (CI) 0.79-1.07). Results were not modified in an analysis using inverse-probability weights to take non-adherence into account (HR 0.94, 95 %CI 0.73-1.22) or in multiple subgroups. Whereas the risk of a non-idiopathic VTE was similar between groups, the risk of idiopathic VTE was lower in women randomised to calcium plus vitamin D (40 vs 65 events; HR 0.62, 95 %CI 0.42-0.92). In conclusion, daily supplementation with 1,000 mg of calcium and 400 IU of vitamin D did not reduce the overall incidence of VTE in generally healthy postmenopausal women. However, the observed reduced risk of idiopathic VTE in women randomised to calcium and vitamin D warrants further investigations.

Neural correlates of auditory stream segregation: an analysis of onset- and change-related responses.

The temporal order discrimination of target tone pairs is hindered by the presence of flanker tones but is improved when the flanker tones are captured by a separate stream of tones that match the flankers in frequency [Bregman and Rudnicky (1975). J. Exp. Psychol. 1, 263-267]. In an event-related potential (ERP) study with these stimuli, listeners' mismatch negativity (MMN) responses were temporally linked to the position of the changing target tones, irrespective of streaming. In contrast, N1 response latency varied as a function of the perceived grouping of flanker tones established by previous behavioral studies, providing a neurophysiological index of auditory stream segregation.

The association of spiritual care providers' activities with family members' satisfaction with care after a death in the ICU*.

OBJECTIVES: Spiritual distress is common in the ICU, and spiritual care providers are often called upon to provide care for patients and their families. Our goal was to evaluate the activities spiritual care providers' conduct to support patients and families and whether those activities are associated with family satisfaction with ICU care. DESIGN: Prospective cohort study. SETTING: Three hundred fifty-bed tertiary care teaching hospital with 65 ICU beds. SUBJECTS: Spiritual care providers and family members of patients who died in the ICU or within 30 hours of transfer from the ICU. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Spiritual care providers completed surveys reporting their activities. Family members completed validated measures of satisfaction with care and satisfaction with spiritual care. Clustered regression was used to assess the association between activities completed by spiritual care providers and family ratings of care. Of 494 eligible patients, 275 family members completed surveys (response rate, 56%). Fifty-seven spiritual care providers received surveys relating to 268 patients, completing 285 surveys for 244 patients (response rate, 91%). Spiritual care providers commonly reported activities related to supporting religious and spiritual needs (≥ 90%) and providing support for family feelings (90%). Discussions about the patient's wishes for end-of-life care and a greater number of spiritual care activities performed were both associated with increased overall family satisfaction with ICU care (p < 0.05). Discussions about a patient's end-of-life wishes, preparation for a family conference, and total number of activities performed were associated with improved family satisfaction with decision-making in the ICU (p < 0.05). CONCLUSIONS: Spiritual care providers engage in a variety of activities with families of ICU patients; several are associated with increased family satisfaction with ICU care in general and decision-making in the ICU specifically. These findings provide insight into spiritual care provider activities and provide guidance for interventions to improve spiritual care delivered to families of critically ill patients.

Learning from both sides: Experiences and opportunities in the investigation of Australian aboriginal medicinal plants.

With one of the oldest surviving cultures in the world, Australian Aboriginal people have developed immense knowledge about the diverse Australian flora. Western scientific investigation of some Australian Aboriginal medicinal plants has demonstrated interesting pharmacological activities and chemistry, however the majority of these species have not yet been extensively examined. We argue that research that is locally initiated and driven by Indigenous traditional owners in collaboration with Western scientists has significant potential to develop new plant-based products. Locally driven medicinal plants research in which traditional owners work as researchers in collaboration with University-based colleagues in the investigation of medicines rather than "stakeholders" or "informants" is one model that may be used in characterising plants with the potential to be developed into sustainable plant-based medicinal products with commercial value. Our team has taken this approach in research located both on traditional homelands and in the laboratory. Research being conducted by the University of South Australia and Chuulangun Aboriginal Corporation has led to patent filing for protection of intellectual property associated with novel compounds and extracts with the potential for development through cosmetic, complementary medicine and pharmaceutical routes. Ongoing research is examining the commercial developmental pathways and requirements for product development in these spaces. This review will address the opportunities that might exist for working in partnership with Australian Indigenous communities, some of the scientific knowledge which has been generated so far from our work together and the lessons learnt since the inception of the collaboration between the Chuulangun Aboriginal Corporation and scientists from the University of South Australia.

Association of body mass index, diabetes, hypertension, and blood pressure levels with risk of permanent atrial fibrillation.

BACKGROUND: After an initial episode of atrial fibrillation (AF), AF may recur and become permanent. AF progression is associated with higher morbidity and mortality. Understanding the risk factors for permanent AF could help identify people who would benefit most from interventions. OBJECTIVE: To determine whether body mass index (BMI), diabetes, hypertension, and blood pressure levels are associated with permanent AF among people whose initial AF episode terminated. DESIGN: Population-based inception cohort study. PARTICIPANTS: Enrollees in Group Health, an integrated health care system, aged 30-84 with newly diagnosed AF in 2001-2004, whose initial AF terminated within 6 months and who had at least 6 months of subsequent follow-up (N = 1,385). MAIN MEASURES: Clinical characteristics were determined from medical records. Permanent AF was determined from medical records and ECG and administrative databases. Permanent AF was defined as AF present on two separate occasions 6-36 months apart, without any documented sinus rhythm between the two occasions. Cox proportional hazards models were used to estimate adjusted hazard ratios (HRs). KEY RESULTS: Five-year cumulative incidence of permanent AF was 24 %. Compared with normal BMI (18.5-24.9 kg/m(2)), BMI levels of 25.0-29.9 (overweight), 30.0-34.9 (obese 1), 35.0-39.9 (obese 2), and ≥ 40.0 kg/m(2) (obese 3) were associated with HRs of permanent AF of 1.26 (95 % CI: 0.92, 1.72); 1.35 (0.96, 1.91); 1.50 (0.97, 2.33); and 1.79 (1.13, 2.84), adjusted for age, sex, diabetes, hypertension, blood pressure, coronary heart disease, valvular heart disease, heart failure, and prior stroke. Diabetes, hypertension, and blood pressure were not associated with permanent AF. CONCLUSIONS: For people whose initial AF episode terminates, benefits of having lower BMI may include a lower risk of permanent AF. Risk of permanent AF was similar for people with and without diabetes or hypertension and across blood pressure levels.

The rise of global warming skepticism: exploring affective image associations in the United States over time.

This article explores how affective image associations to global warming have changed over time. Four nationally representative surveys of the American public were conducted between 2002 and 2010 to assess public global warming risk perceptions, policy preferences, and behavior. Affective images (positive or negative feelings and cognitive representations) were collected and content analyzed. The results demonstrate a large increase in "naysayer" associations, indicating extreme skepticism about the issue of climate change. Multiple regression analyses found that holistic affect and "naysayer" associations were more significant predictors of global warming risk perceptions than cultural worldviews or sociodemographic variables, including political party and ideology. The results demonstrate the important role affective imagery plays in judgment and decision-making processes, how these variables change over time, and how global warming is currently perceived by the American public.

Discovery of a highly potent series of TLR7 agonists.

The discovery of a series of highly potent and novel TLR7 agonist interferon inducers is described. Structure-activity relationships are presented, along with pharmacokinetic studies of a lead molecule from this series of N9-pyridylmethyl-8-oxo-3-deazapurine analogues. A rationale for the very high potency observed is offered. An investigation of the clearance mechanism of this class of compounds in rat was carried out, resulting in aldehyde oxidase mediated oxidation being identified as a key component of the high clearance observed. A possible solution to this problem is discussed.

Diabetes mellitus, glycemic control, and risk of atrial fibrillation.

BACKGROUND: Diabetes may be an independent risk factor for atrial fibrillation. However, results from prior studies are in conflict, and no study has examined diabetes duration or glycemic control. OBJECTIVE: To examine the association of diabetes with risk of atrial fibrillation and to describe risk according to diabetes duration and glycemic control. DESIGN: A population-based case-control study. PARTICIPANTS: Within a large, integrated healthcare delivery system, we identified 1,410 people with newly-recognized atrial fibrillation from ICD-9 codes and validated cases by review of medical records. 2,203 controls without atrial fibrillation were selected from enrollment lists, stratified on age, sex, hypertension, and calendar year. MAIN MEASURES: Information on atrial fibrillation, diabetes and other characteristics came from medical records. Diabetes was defined based on physician diagnoses recorded in the medical record, and pharmacologically treated diabetes was defined as receiving antihyperglycemic medications. Information about hemoglobin A1c levels came from computerized laboratory data. KEY RESULTS: Among people with atrial fibrillation, 252/1410 (17.9%) had pharmacologically treated diabetes compared to 311/2203 (14.1%) of controls. The adjusted OR for atrial fibrillation was 1.40 (95% CI 1.15-1.71) for people with treated diabetes compared to those without diabetes. Among those with treated diabetes, the risk of developing atrial fibrillation was 3% higher for each additional year of diabetes duration (95% CI 1-6%). Compared to people without diabetes, the adjusted OR for people with treated diabetes with average hemoglobin A1c 7 but 8 but 9, 1.96 (1.22-3.14). CONCLUSIONS: Diabetes was associated with higher risk of developing atrial fibrillation, and risk was higher with longer duration of treated diabetes and worse glycemic control. Future research should identify and test approaches to reduce the risk of atrial fibrillation in people with diabetes.

Antihypertensive treatment with ACE inhibitors or beta-blockers and risk of incident atrial fibrillation in a general hypertensive population.

BACKGROUND: Secondary analyses of clinical trial data suggest that, compared with other agents, angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) are associated with lower risk of incident atrial fibrillation (AF) in patients with heart failure, but data from the hypertension trials have been inconsistent. Information is scant about the association of beta-blocker use with AF risk in hypertensive patients without heart failure. METHODS: We conducted a population-based case-control study to determine whether antihypertensive treatment with ACE inhibitors/ARBs or beta-blockers, compared with diuretics, was associated with the risk of incident AF in a community practice setting. All patients (810 AF cases, 1,512 control subjects) were members of Group Health (GH), an integrated health-care delivery system, were pharmacologically treated for hypertension, and did not have heart failure. Medical records were reviewed to confirm the diagnosis of incident AF and to collect information on medical conditions and health behaviors. Information on antihypertensive medications was obtained from a pharmacy database. RESULTS: Single-drug users of an ACE inhibitor/ARB had a lower risk of incident AF compared with single-drug users of a diuretic (adjusted odds ratio 0.63, 95% confidence interval 0.44-0.91). Single-drug use of beta-blockers was not significantly associated with lower AF risk (odds ratio 1.05, 95% confidence interval 0.73-1.52), and also none of the most commonly used two-drug regimens was significantly associated with AF risk, in comparison with single-drug use of diuretic. CONCLUSIONS: In a general hypertensive population without heart failure, single-drug use of ACE inhibitors/ARBs was associated with lower AF risk.

Use of alendronate and risk of incident atrial fibrillation in women.

BACKGROUND: A recent publication from the HORIZON (Health Outcomes and Reduced Incidence With Zoledronic Acid Once Yearly) trial in women with postmenopausal osteoporosis reported a higher risk of serious atrial fibrillation (AF) in zoledronic acid recipients than in placebo recipients. This adverse effect was unexpected and had not been recognized previously. METHODS: We studied alendronate sodium ever use in relation to the risk of incident AF in women in a clinical practice setting. This population-based case-control study was conducted at Group Health, an integrated health care delivery system in Washington State. We identified 719 women with confirmed incident AF between October 1, 2001, and December 31, 2004, and 966 female control subjects without AF, selected at random from the Group Health enrollment and frequency matched on age, presence or absence of treated hypertension, and calendar year. RESULTS: More AF case patients than controls had ever used alendronate (6.5% [n = 47] vs 4.1% [n = 40]; P = .03). Compared with never use of any bisphosphonate, ever use of alendronate was associated with a higher risk of incident AF (odds ratio, 1.86; 95% confidence interval, 1.09-3.15) after adjustment for the matching variables, a diagnosis of osteoporosis, and a history of cardiovascular disease. Based on the population-attributable fraction, we estimated that 3% of incident AF in this population might be explained by alendronate use. CONCLUSION: Ever use of alendronate was associated with an increased risk of incident AF in clinical practice.

Matrix metalloproteinase-3 (MMP3) and MMP9 genes and risk of myocardial infarction, ischemic stroke, and hemorrhagic stroke.

OBJECTIVE: We assessed the association of genetic variation in MMP3 and MMP9 with risk of myocardial infarction and stroke. METHODS: A case-control study was conducted among members of Group Health (GH), a large-integrated health care delivery system. Case subjects with incident non-fatal myocardial infarction (n=854), ischemic stroke (n=367), and hemorrhagic stroke (n=66) were identified and validated. A matched control group was selected from among GH members without myocardial infarction or stroke (n=2696). Haplotype-tagging sets of single-nucleotide polymorphisms (SNPs) in MMP3 and MMP9 were genotyped. RESULTS: MMP3 haplotype 2 was associated with reduced risk of myocardial infarction (adjusted odds ratio (OR) per copy=0.80, 95% confidence interval 0.66, 0.98) and increased risk of hemorrhagic stroke (OR=1.69, 95% confidence interval 1.05, 2.75). Results for MMP3 haplotype 2 and ischemic stroke resembled those for myocardial infarction but did not achieve statistical significance (OR=0.85, 95% confidence interval 0.64, 1.12). No individual SNP identified MMP3 haplotype 2, and none of the individual MMP3 SNPs were associated with myocardial infarction or stroke. MMP9 haplotypes or SNPs were not associated with myocardial infarction or stroke. CONCLUSIONS: MMP3 haplotype may predict both cardiac events and stroke.