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An efficient and scalable synthesis of persistent abscisic acid analog (+)-tetralone ABA. (+)-Me ABA was converted to (+)-tetralone Me ABA through a one-pot regioselective Knoevenagel condensation, cyclization, and oxidation.

We report here the synthesis and biological testing of 3′-(phenyl alkynyl) abscisic ABA analogs, a new class of potent ABA antagonists. These ABA analogs incorporate a rigid framework of eight carbon atoms attached at the 3′-carbon atom of ABA that prevents folding of the ABA analog-bound receptor required for ABA signalling. The two-step synthesis is based upon the optimized conversion of natural (S)-ABA to 3′-iodo ABA which can be coupled to phenyl acetylenes using Sonogashira conditions, or to styryl compounds through Suzuki chemistry. The parent 3′-(phenyl alkynyl) ABA analog 7 was obtained in 29% yield, 74% yield based on recovered starting material. In a lentil seed germination assay, compound 7 was found to have more potent activity than other known 3′-substituted ABA antagonists to date. In a structure activity study parasubstituted phenyl alkynyl analogs had comparable activity to the analog 7 while the 3′-styryl ABA 18 was only slightly less active. Analog 7 overcame ABA inhibition of germination and seedling growth in a wide range of mono and dicot plant species, including canola, lentil, soybean, rice, wheat, barley, cannabis and canary seed. 3′-(Phenyl alkynyl) ABA analogs have numerous potential practical agricultural applications including promoting ripening of crops, dormancy breaking of seeds and woody perennials, as well as promoting seed germination, and growth under stress conditions as demonstrated in this report.

Background: Receiving early treatment for aneurysmal subarachnoid hemorrhage (aSAH) is associated with better outcomes for the patient. However, delays in treatment of aSAH are common but the causes are not well understood. We explored predictors of early treatment within 12.5 hours or 24 hours after aSAH. Methods: Consecutive cases of confirmed first-ever aSAH were identified from two Australian tertiary referral centers between 2010 and 2016. We used medical and ambulance records to extract details of participants, including time from onset to definitive treatment of either endovascular coiling or neurosurgical clipping, demographics, severity of aSAH (modified Fisher grade; World Federation of Neurosurgeons Scale [WFNS]), risk factors, pre-hospital care, and presenting symptoms. Factors associated with treatment to secure the aneurysm within 12.5 hours or 24 hours on univariable logistic regression were entered into a multivariable model to identify factors independently associated with (odds ratio [OR], 95% CI) earlier treatment. Results: Among 482 patients (mean [SD] age 54.1 [14.5]; 69.9% female) with aSAH, median (IQR) time to treatment was 19.4 (10.6, 31.0) hours, 30% were treated Conclusions: A substantial proportion of people after aSAH were not treated within timeframes associated with better outcomes. Recognition of the urgency and severity aSAH cases were associated with more timely treatment of aSAH.

Delays in treatment of aSAH appear to be common but the causes are not well understood. We explored facilitators and barriers to timely treatment of aSAH.We used a multiple case study with cases of aSAH surviving 1 day identified prospectively. We conducted semi-structured interviews with the patient, their next-of-kin and health professionals involved in the case. Within-case analysis identified barriers and facilitators in 4 phases (pre-hospital, presentation, transfer, in-hospital) followed by thematic analysis across cases using a case-study matrix.Twenty-seven cases with 90 interviewees yielded five themes related to facilitators or barriers of timely treatment. "Early recognition" led to urgent response. "Accessibility to health care" depended on patient's location, transport, and environmental conditions. Good "Coordination" between and within health services was a key facilitator. "Complexity" of patient's condition affected time to treatment in multiple time periods. "Availability of resources" was identified most frequently during the diagnostic and treatment phases as both barrier and facilitator.The identified themes may be modifiable at the patient/health professional level and health system level and may improve timely treatment of aSAH through targeted interventions, subsequently contributing to improve morbidity and mortality of patients with aSAH.

ABA antagonists have potential application as growth regulators to improve germination and seedling growth at low temperatures for oilseeds and pulses grown in regions with short seasons such as those in western Canada. Towards development of practical ABA antagonists, a series of 3′-substituted ABA analogs were synthesized and screened in seed germination assays in canola (Brassica napus), lentil (Lens culinaris), and soybean (Glycine max) at low temperature and in overcoming exogenous ABA. The most promising analog, ABA 1009, was selected for further germination testing of dose responses in canola, lentil, and soybean. Analog ABA 1009 at 100 µM was effective in overcoming ABA (10 µM)-induced inhibition for canola, lentil, and soybean germination at ambient temperature, and also promoted germination at low temperature for canola (5 °C).

Small trials have demonstrated promising results utilising intravenous milrinone for the treatment of delayed cerebral ischaemia (DCI) after subarachnoid haemorrhage (SAH). Here we summarise and contextualise the literature and discuss the future directions of intravenous milrinone for DCI. A systematic, pooled analysis of literature was performed in accordance with the PRISMA statement. Methodological rigour was analysed using the MINORS criteria. Extracted data included patient population; treatment protocol; and clinical, radiological, and functional outcome. The primary outcome was clinical resolution of DCI. Eight hundred eighteen patients from 10 single-centre, observational studies were identified. Half (n = 5) of the studies were prospective and all were at high risk of bias. Mean age was 52 years, and females (69%) outnumbered males. There was a similar proportion of low-grade (WFNS 1-2) (49.7%) and high-grade (WFNS 3-5) (50.3%) SAH. Intravenous milrinone was administered to 523/818 (63.9%) participants. Clinical resolution of DCI was achieved in 375/424 (88%), with similar rates demonstrated with intravenous (291/330, 88%) and combined intra-arterial-intravenous (84/94, 89%) therapy. Angiographic response was seen in 165/234 (71%) receiving intravenous milrinone. Hypotension (70/303, 23%) and hypokalaemia (31/287, 11%) were common drug effects. Four cases (0.5%) of drug intolerance occurred. Good functional outcome was achieved in 271/364 (74%) patients. Cerebral infarction attributable to DCI occurred in 47/250 (19%), with lower rates in asymptomatic spasm. Intravenous milrinone is a safe and feasible therapy for DCI. A signal for efficacy is demonstrated in small, low-quality trials. Future research should endeavour to establish the optimal protocol and dose, prior to a phase-3 study.

Women are over-represented in aSAH cohorts, but whether their outcomes differ to men remains unclear. We examined if sex differences in neurological complications and aneurysm characteristics contributed to aSAH outcomes.In a retrospective cohort (2010-2016) of all aSAH cases across two hospital networks in Australia, information on severity, aneurysm characteristics and neurological complications (rebleed before/after treatment, postoperative stroke 48 h, neurological infections, hydrocephalus, seizures, delayed cerebral ischemia [DCI], cerebral infarction) were extracted. We estimated sex differences in (1) complications and aneurysm characteristics using chi square/t-tests and (2) outcome at discharge (home, rehabilitation or death) using multinomial regression with and without propensity score matching on prestroke confounders.Among 577 cases (69% women, 84% treated) aneurysm size was greater in men than women and DCI more common in women than men. In unadjusted log multinomial regression, women had marginally greater discharge to rehabilitation (RRR 1.15 95% CI 0.90-1.48) and similar likelihood of in-hospital death (RRR 1.02 95% CI 0.76-1.36) versus discharge home. Prestroke confounders (age, hypertension, smoking status) explained greater risk of death in women (rehabilitation RRR 1.13 95% CI 0.87-1.48; death RRR 0.75 95% CI 0.51-1.10). Neurological complications (DCI and hydrocephalus) were covariates explaining some of the greater risk for poor outcomes in women (rehabilitation RRR 0.87 95% CI 0.69-1.11; death RRR 0.80 95% CI 0.52-1.23). Results were consistent in propensity score matched models.The marginally poorer outcome in women at discharge was partially attributable to prestroke confounders and complications. Improvements in managing complications could improve outcomes.

Background/Aims: Microalbuminuria is a marker for early kidney disease and cardiovascular risk. The purposes of this study were to determine the prevalence of microalbuminuria in an HIV-infected clinic population, to test the predictive value of a single urine albumin/creatinine ratio (ACR) to identify persistent microalbuminuria and to examine covariates of microalbuminuria. Methods: We conducted a prospective cohort study of HIV-infected subjects (n = 182) without proteinuria (urine protein/creatinine ratio ≥0.5 g/g), elevated serum creatinine, diabetes, or chronic inflammatory conditions. Subjects completed three research visits within 9 months. Microalbuminuria was defined as the geometric mean ACR of 25-355 mg/g for females and 17-250 mg/g for males. Results: The prevalence of microalbuminuria was 14%. The negative predictive value of a single urine ACR determination was 98%, whereas the positive predictive value was only 74%. Microalbuminuria was similar among Black (15%) and non-Black (14%) subjects (p = 0.8). Subjects with microalbuminuria were more likely to have hypertension (p = 0.02) and metabolic syndrome (p = 0.03). While duration of HIV infection and the level of HIV viremia were similar between groups, those with microalbuminuria were more likely to have a CD4 count Conclusion: The prevalence of microalbuminuria in an HIV-infected clinic population was similar to earlier reports, and was associated with hypertension and impaired immune function. A single normal ACR determination effectively excludes microalbuminuria, whereas an elevated ACR requires confirmation.

It is important to recognize the signs and symptoms of human African trypanosomiasis (HAT) in order to facilitate early diagnosis and treatment. A 36-year-old man developed encephalitis caused by HAT. This encephalitis can appear many years after well-tolerated systemic infection. The neurologic manifestations developed 7 years after he had emigrated from Cameroon to the United States. We demonstrate the magnetic resonance imaging before, during, and after his treatment with intravenous eflornithine. Clinical signs and symptoms of HAT can be nonspecific and precede abnormalities on magnetic resonance imaging. Human African trypanosomiasis should be considered in the differential diagnosis of patients who have lived in sub-Saharan Africa and have a clinical presentation of subacute encephalitis.

Introduction: Prior studies (predominantly from Europe) have demonstrated blood culture-negative endocarditis due to Bartonella. Our objective was to describe three cases of Bartonella quintana endocarditis identified within one year at a large hospital in Washington, DC, USA. Case presentation: We constructed a descriptive case series from a retrospective review of medical records from April to December 2013 at an 800-bed urban hospital. All three patients (ages: 52, 55 and 57 years) were undomiciled/homeless men with a history of alcoholism. Although they had negative blood cultures, echocardiography demonstrated aortic/mitral valve perforation and regurgitation in one patient, aortic/mitral valve vegetation with mitral regurgitation in the second patient, and aortic valve vegetation with regurgitation in the third patient. The patients had positive Bartonella quintana serum immunoglobulin G (IgG) with negative immunoglobulin M (IgM). PCR on DNA extracted from cardiac valves was positive for Bartonella, and DNA sequencing of PCR amplicons identified Bartonella quintana. Patients received treatment with doxycycline/rifampin or doxycycline/gentamicin. Conclusion: Clinicians should consider Bartonella endocarditis as a differential diagnosis in patients who fit elements of the Duke Criteria, as well as having a history of homelessness and alcoholism.

Temperature effects significantly reduce load ratings of reinforced concrete openspandrel arch bridges, particularly when temperature drop is included in the analyses. Because of the non-linear axial force-moment (P-M) capacity interaction behavior, lower dead load factor results in a lower rating factor. For a symmetrical structure, the eccentricity (moment to axial force ratio) at every location in an arch rib due to uniform temperature changes is geometry dependent and it is an important factor affecting load ratings. The uniform temperature effect is more significant for bridges with lower rise to span ratios (flatter geometry) because the eccentricity is higher. Based on limited field measurements uniform temperature is observed only in the early morning after the heat has dispatched overnight and before the structure is subjected to solar heat. Vertical temperature gradient in the arch rib significantly depends on the exposure to the sun. The vertical temperature gradient in each rib does not appear to follow any pattern. Additional data will be needed to develop an applicable procedure to include vertical temperature gradient for open-spandrel arch bridge rating analyses.

The interactions of vanadate and its complexes of uridine, 5,6-dihydrouridine, and methyl β-D-ribofuranoside with bovine pancreatic ribonuclease A (RNase A) (EC 3.1.27.5) were studied by51V NMR spectroscopy and enzyme kinetics. From kinetic studies, it was found that neither inorganic vanadate nor the methyl β-D-ribofuranoside–vanadate complex significantly inhibited the RNase A catalyzed hydrolysis of uridine 2′,3′-cyclic monophosphate. The NMR binding studies were in full agreement with the kinetics studies and showed that neither inorganic vanadate nor the methyl β-D-ribofuranoside–vanadate complex was bound tightly by the enzyme. Approximate binding constants were (5.0 ± 1.0) × 10−7 M and (3.0 ± 0.6) × 10−6 M for the uridine–and 5,6-dihydrouridine–vanadate complexes, respectively. An induced-fit mechanism is suggested, in which the pyrimidine subsite of the active site of RNase A must be fully occupied for the enzyme to be able to tightly bind the transition state or transition state analog. Calculation of the binding energies of vanadate complexes in ribonuclease, phosphoglycerate mutase, and phosphoglucomutase revealed an excess of binding energy over the analogous phosphate derivative of about 25 kJ/mol for all enzymes, even though the binding constants themselves varied by about six orders of magnitude. This energy represents about 40% of that expected to be available for a trigonal-bipyramidal transition state and requires a reassessment of the role of vanadate as a transition state analogue for phosphate transfer. Key words: vanadate, ribonuclease, transition state, binding constants, phosphate analogues, kinetics.