Pharmacological and Toxicological Properties of the Potent Oral γ-Secretase Modulator BPN-15606.

Alzheimer's disease (AD) is characterized neuropathologically by an abundance of 1) neuritic plaques, which are primarily composed of a fibrillar 42-amino-acid amyloid-β peptide (Aβ), as well as 2) neurofibrillary tangles composed of aggregates of hyperphosporylated tau. Elevations in the concentrations of the Aβ42 peptide in the brain, as a result of either increased production or decreased clearance, are postulated to initiate and drive the AD pathologic process. We initially introduced a novel class of bridged aromatics referred tγ-secretase modulatoro as γ-secretase modulators that inhibited the production of the Aβ42 peptide and to a lesser degree the Aβ40 peptide while concomitantly increasing the production of the carboxyl-truncated Aβ38 and Aβ37 peptides. These modulators potently lower Aβ42 levels without inhibiting the γ-secretase-mediated proteolysis of Notch or causing accumulation of carboxyl-terminal fragments of APP. In this study, we report a large number of pharmacological studies and early assessment of toxicology characterizing a highly potent γ-secretase modulator (GSM), (S)-N-(1-(4-fluorophenyl)ethyl)-6-(6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl)-4-methylpyridazin-3-amine (BPN-15606). BPN-15606 displayed the ability to significantly lower Aβ42 levels in the central nervous system of rats and mice at doses as low as 5-10 mg/kg, significantly reduce Aβ neuritic plaque load in an AD transgenic mouse model, and significantly reduce levels of insoluble Aβ42 and pThr181 tau in a three-dimensional human neural cell culture model. Results from repeat-dose toxicity studies in rats and dose escalation/repeat-dose toxicity studies in nonhuman primates have designated this GSM for 28-day Investigational New Drug-enabling good laboratory practice studies and positioned it as a candidate for human clinical trials

Advancement of photospheric radius expansion and clocked type-I x-ray burst models with the new 22Mg(α,p)25 Al reaction rate determined at Gamow energy

We report the first (in)elastic scattering measurement of $^{25}\mathrm{Al}+p$ with the capability to select and measure in a broad energy range the proton resonances in $^{26}$Si contributing to the $^{22}$Mg$(\alpha,p)$ reaction at type I x-ray burst energies. We measured spin-parities of four resonances above the $\alpha$ threshold of $^{26}$Si that are found to strongly impact the $^{22}$Mg$(\alpha,p)$ rate. The new rate advances a state-of-the-art model to remarkably reproduce light curves of the GS 1826$-$24 clocked burster with mean deviation $<9$ % and permits us to discover a strong correlation between the He abundance in the accreting envelope of photospheric radius expansion burster and the dominance of $^{22}$Mg$(\alpha,p)$ branch.Comment: accepted by Physical Review Letters on 5 August 2021, published 19 October 202

Adapting HIV prevention evidence-based interventions in practice settings: an interview study

<p>Abstract</p> <p>Background</p> <p>Evidence-based interventions that are being delivered in real-world settings are adapted to enhance the external validity of these interventions. The purpose of this study was to examine multiple intervention adaptations made during pre-implementation, implementation, maintenance, and evolution phases of human immunodeficiency virus HIV prevention technology transfer. We examined two important categories of adaptations -- modifications to key characteristics, such as activities or delivery methods of interventions and reinvention of the interventions including addition and deletion of core elements.</p> <p>Methods</p> <p>Study participants were thirty-four community-based organization staff who were implementing evidence-based interventions in Los Angeles, California. Participants were interviewed twice and interviews were professionally transcribed. Transcriptions were coded by two coders with good inter-rater reliability (kappa coefficient = 0.73). Sixty-two open-ended codes for adaptation activities, which were linked to 229 transcript segments, were categorized as modifications of key characteristics or reinvention.</p> <p>Results</p> <p>Participants described activities considered modifications to key characteristics and reinvention of evidence-based interventions during pre-implementation, implementation, and maintenance phases. None of the participants reported accessing technical assistance or guidance when reinventing their interventions. Staff executed many of the recommended steps for sound adaptation of these interventions for new populations and settings.</p> <p>Conclusion</p> <p>Staff reported modifying and reinventing interventions when translating HIV prevention programs into practice. Targeted technical assistance for formative evaluation should be focused on the pre-implementation phase during which frequent modifications occur. Continuous or repeated measurements of fidelity are recommended. Increased technical assistance and guidance are needed to ensure that reinventions are evaluated and consistent with the aims of the original interventions. Providing strategic technical assistance and written guidance can facilitate effective HIV prevention technology transfer of evidence-based interventions.</p

Effects of sample handling and storage on quantitative lipid analysis in human serum

There is sparse information about specific storage and handling protocols that minimize analytical error and variability in samples evaluated by targeted metabolomics. Variance components that affect quantitative lipid analysis in a set of human serum samples were determined. The effects of freeze-thaw, extraction state, storage temperature, and freeze-thaw prior to density-based lipoprotein fractionation were quantified. The quantification of high abundance metabolites, representing the biologically relevant lipid species in humans, was highly repeatable (with coefficients of variation as low as 0.01 and 0.02) and largely unaffected by 1–3 freeze-thaw cycles (with 0–8% of metabolites affected in each lipid class). Extraction state had effects on total lipid class amounts, including decreased diacylglycerol and increased phosphatidylethanolamine in thawed compared with frozen samples. The effects of storage temperature over 1 week were minimal, with 0–4% of metabolites affected by storage at 4°C, −20°C, or −80°C in most lipid classes, and 19% of metabolites in diacylglycerol affected by storage at −20°C. Freezing prior to lipoprotein fractionation by density ultracentrifugation decreased HDL free cholesterol by 37% and VLDL free fatty acid by 36%, and increased LDL cholesterol ester by 35% compared with fresh samples. These findings suggest that density-based fractionation should preferably be undertaken in fresh serum samples because up to 37% variability in HDL and LDL cholesterol could result from a single freeze-thaw cycle. Conversely, quantitative lipid analysis within unfractionated serum is minimally affected even with repeated freeze-thaw cycles

The Role of Medical Interpretation on Breast and Cervical Cancer Screening Among Asian American and Pacific Islander Women

We examined whether the impact of medical interpretation services was associated with the receipt of a mammogram, clinical breast exam, and Pap smear. We conducted a large cross-sectional study involving four Asian American and Pacific Islander (AAPI) communities with high proportions of individuals with limited English proficiency (LEP). Participants were recruited from community clinics, churches and temples, supermarkets, and other community gathering sites in Northern and Southern California. Among those that responded, 98% completed the survey rendering a total of 1,708 AAPI women. In a series of multivariate logistic regression models, it was found that women who typically used a medical interpreter had a greater odds of having received a mammogram (odds ratio [OR] = 1.85; 95% confidence interval [CI] = 1.21, 2.83), clinical breast exam (OR = 3.03; 95% CI = 1.82, 5.03), and a Pap smear (OR = 2.34; 95% CI = 1.38, 3.97) than those who did not usually use an interpreter. The study provides support for increasing language access in healthcare settings. In particular, medical interpreters may help increase the utilization of breast and cervical cancer screening among LEP AAPI women

Antibiotic use and prescription and its effects on Enterobacteriaceae in the gut in children with mild respiratory infections in Ho Chi Minh City, Vietnam. A prospective observational outpatient study.

BACKGROUND AND OBJECTIVES: Treatment guidelines do not recommend antibiotic use for acute respiratory infections (ARI), except for streptococcal pharyngitis/tonsillitis and pneumonia. However, antibiotics are prescribed frequently for children with ARI, often in absence of evidence for bacterial infection. The objectives of this study were 1) to assess the appropriateness of antibiotic prescriptions for mild ARI in paediatric outpatients in relation to available guidelines and detected pathogens, 2) to assess antibiotic use on presentation using questionnaires and detection in urine 3) to assess the carriage rates and proportions of resistant intestinal Enterobacteriaceae before, during and after consultation. MATERIALS AND METHODS: Patients were prospectively enrolled in Children's Hospital 1, Ho Chi Minh City, Vietnam and diagnoses, prescribed therapy and outcome were recorded on first visit and on follow-up after 7 days. Respiratory bacterial and viral pathogens were detected using molecular assays. Antibiotic use before presentation was assessed using questionnaires and urine HPLC. The impact of antibiotic usage on intestinal Enterobacteriaceae was assessed with semi-quantitative culture on agar with and without antibiotics on presentation and after 7 and 28 days. RESULTS: A total of 563 patients were enrolled between February 2009 and February 2010. Antibiotics were prescribed for all except 2 of 563 patients. The majority were 2nd and 3rd generation oral cephalosporins and amoxicillin with or without clavulanic acid. Respiratory viruses were detected in respiratory specimens of 72.5% of patients. Antibiotic use was considered inappropriate in 90.1% and 67.5%, based on guidelines and detected pathogens, respectively. On presentation parents reported antibiotic use for 22% of patients, 41% of parents did not know and 37% denied antibiotic use. Among these three groups, six commonly used antibiotics were detected with HPLC in patients' urine in 49%, 40% and 14%, respectively. Temporary selection of 3rd generation cephalosporin resistant intestinal Enterobacteriaceae during antibiotic use was observed, with co-selection of resistance to aminoglycosides and fluoroquinolones. CONCLUSIONS: We report overuse and overprescription of antibiotics for uncomplicated ARI with selection of resistant intestinal Enterobacteriaceae, posing a risk for community transmission and persistence in a setting of a highly granular healthcare system and unrestricted access to antibiotics through private pharmacies. REGISTRATION: This study was registered at the International Standard Randomised Controlled Trials Number registry under number ISRCTN32862422: http://www.isrctn.com/ISRCTN32862422

Early Pandemic Influenza (2009 H1N1) in Ho Chi Minh City, Vietnam: A Clinical Virological and Epidemiological Analysis

Rogier van Doorn and colleagues analyze the initial outbreak, attempts at containment, and establishment of community transmission of pandemic H1N1 influenza in Ho Chi Minh City, Vietnam

Thermal modeling of lesion growth with radiofrequency ablation devices

BACKGROUND: Temperature is a frequently used parameter to describe the predicted size of lesions computed by computational models. In many cases, however, temperature correlates poorly with lesion size. Although many studies have been conducted to characterize the relationship between time-temperature exposure of tissue heating to cell damage, to date these relationships have not been employed in a finite element model. METHODS: We present an axisymmetric two-dimensional finite element model that calculates cell damage in tissues and compare lesion sizes using common tissue damage and iso-temperature contour definitions. The model accounts for both temperature-dependent changes in the electrical conductivity of tissue as well as tissue damage-dependent changes in local tissue perfusion. The data is validated using excised porcine liver tissues. RESULTS: The data demonstrate the size of thermal lesions is grossly overestimated when calculated using traditional temperature isocontours of 42°C and 47°C. The computational model results predicted lesion dimensions that were within 5% of the experimental measurements. CONCLUSION: When modeling radiofrequency ablation problems, temperature isotherms may not be representative of actual tissue damage patterns