Transitions Between Mild Cognitive Impairment, Dementia, and Mortality: The Importance of Olfaction.

BACKGROUND: The existing literature suggests that impaired olfaction may be an early marker for cognitive decline. Tracking the earliest stages of the progression to dementia is paramount, and yet the importance of olfactory ability throughout cognitive states and death remains unclear. METHODS: Drawing data from the Rush Memory and Aging Project (N = 1 501; 74% female), olfactory ability was assessed using the Brief Smell Identification Test (range = 0-16), while cognitive states (unimpaired, mild cognitive impairment [MCI], and dementia) were determined using a 3-step neuropsychological diagnostic protocol at up to 15 annual occasions. Multistate survival models simultaneously estimated the association of olfactory ability on transitions through cognitive states and death, while multinomial regression models estimated cognitively unimpaired and total life expectancies. RESULTS: Higher olfactory scores were associated with a reduced risk of transitioning from unimpaired cognition to MCI (hazard ratio [HR] = 0.86, 95% confidence interval [CI] = 0.82-0.88) and from MCI to dementia (HR = 0.89, 95% CI = 0.86-0.93), indicating that 1-unit increase in olfactory scores was associated with an approximate 14% and 11% reduction in risk, respectively. Additionally, higher olfactory scores were associated with a greater likelihood of transitioning backward from MCI to unimpaired cognition (HR = 1.07, 95% CI = 1.02-1.12). Furthermore, higher baseline olfactory scores were associated with more years of longevity without cognitive impairment. However, olfaction was not associated with the transition to death when accounting for transitions through cognitive states. CONCLUSIONS: Findings suggest that higher olfactory identification scores are associated with a decreased risk of transitioning to impaired cognitive states and that associations between olfaction and mortality may occur primarily through the pathway of neurodegeneration.

Discovery of GDC-0077 (Inavolisib), a Highly Selective Inhibitor and Degrader of Mutant PI3Kα.

Small molecule inhibitors that target the phosphatidylinositol 3-kinase (PI3K) signaling pathway have received significant interest for the treatment of cancers. The class I isoform PI3Kα is most commonly associated with solid tumors via gene amplification or activating mutations. However, inhibitors demonstrating both PI3K isoform and mutant specificity have remained elusive. Herein, we describe the optimization and characterization of a series of benzoxazepin-oxazolidinone ATP-competitive inhibitors of PI3Kα which also induce the selective degradation of the mutant p110α protein, the catalytic subunit of PI3Kα. Structure-based design informed isoform-specific interactions within the binding site, leading to potent inhibitors with greater than 300-fold selectivity over the other Class I PI3K isoforms. Further optimization of pharmacokinetic properties led to excellent in vivo exposure and efficacy and the identification of clinical candidate GDC-0077 (inavolisib, 32), which is now under evaluation in a Phase III clinical trial as a treatment for patients with PIK3CA-mutant breast cancer.

Direct Spectroscopic Quantification of the Absorption and Scattering Properties for Single Aerosol Particles.

Understanding the optical properties of micrometer-scale light-absorbing aerosol particles is of paramount importance in addressing key challenges in atmospheric and physical chemistry. For example, the absorption of solar radiation by atmospheric aerosols represents one of the largest uncertainties in climate models. Moreover, reaction acceleration within the unique environments of aerosol droplets cannot be replicated in bulk solutions. The causes of these reaction rate enhancements remain controversial, but ultrasensitive spectroscopic measurements of evolving aerosol optical properties should provide new insights. We demonstrate a new approach using cavity ring-down spectroscopy that allows the first direct spectroscopic quantification of the continuously evolving absorption and scattering cross sections for single, levitated, micrometer-scale particles as their size and chromophore concentration change. For two-component droplets composed of nigrosin and 1,2,6-hexanetriol, the unprecedented sensitivity of our measurements reveals the evolving real and imaginary components of the refractive index caused by changes in concentration as 1,2,6-hexanetriol slowly evaporates.

Longitudinal associations between C-reactive protein and cognitive performance in normative cognitive ageing and dementia.

BACKGROUND: systemic inflammation appears to play an important role in the pathogenesis and expression of Alzheimer's disease and other dementias. Previous research has found that elevated levels of serum C-reactive protein (CRP) is associated with poorer cognitive functioning and increased risk for dementia. However, most studies are limited by single CRP measurements, which fail to capture long-term inflammatory exposures or dynamic changes in inflammation and cognition which may occur across repeated measurements. METHODS: using data from 3,563 older adults aged 65-101 from the Health and Retirement Study, we examined bivariate changes in CRP and cognition measured repeatedly over a 10-year follow-up. Bivariate multilevel models estimated the effect of time-varying CRP on cognition among cognitively healthy older adults and in a subset of 427 participants who reported incident dementia onset during the follow-up period. RESULTS: in cognitively healthy participants, CRP was associated with lower level of cognitive functioning, but not rate of change over time. This effect was significant in participants under 80 years of age (b = -0.09, standard error (SE) = 0.05, P = 0.04), but not in older participants. In participants with incident dementia, those with higher CRP experienced smaller rates of cognitive decline, leading up to dementia diagnosis. CONCLUSIONS: elevated levels of CRP predict poorer cognition and increased dementia risk in cognitively healthy adults under the age of 80. Conversely, increased CRP may confer protective effects on cognition in the prodromal stage of dementia.

The Importance of Engaging in Physical Activity in Older Adulthood for Transitions Between Cognitive Status Categories and Death: A Coordinated Analysis of 14 Longitudinal Studies.

BACKGROUND: Given increasing incidence of cognitive impairment and dementia, further understanding of modifiable factors contributing to increased healthspan is crucial. Extensive literature provides evidence that physical activity (PA) delays the onset of cognitive impairment; however, it is unclear whether engaging in PA in older adulthood is sufficient to influence progression through cognitive status categories. METHOD: Applying a coordinated analysis approach, this project independently analyzed 14 longitudinal studies (NTotal = 52 039; mean baseline age across studies = 69.9-81.73) from North America and Europe using multistate survival models to estimate the impact of engaging in PA on cognitive status transitions (nonimpaired, mildly impaired, severely impaired) and death. Multinomial regression models were fit to estimate life expectancy (LE) based on American PA recommendations. Meta-analyses provided the pooled effect sizes for the role of PA on each transition and estimated LEs. RESULTS: Controlling for baseline age, sex, education, and chronic conditions, analyses revealed that more PA is significantly associated with decreased risk of transitioning from nonimpaired to mildly impaired cognitive functioning and death, as well as substantially longer LE. Results also provided evidence for a protective effect of PA after onset of cognitive impairment (eg, decreased risk of transitioning from mild-to-severe cognitive impairment; increased likelihood of transitioning backward from severe-to-mild cognitive impairment), though between-study heterogeneity suggests a less robust association. CONCLUSIONS: These results yield evidence for the importance of engaging in PA in older adulthood for cognitive health, and a rationale for motivating older adults to engage consistently in PA.

Variability and Coupling of Olfactory Identification and Episodic Memory in Older Adults.

OBJECTIVES: To determine whether assessment-to-assessment fluctuations in episodic memory (EM) reflect fluctuations in olfaction over time. METHODS: Within-person coupled variation in EM and the Brief Smell Identification Test (BSIT) was examined in 565 participants aged 58-106 with autopsy data from the Rush Memory and Aging Project. A growth model for up to 15 years of EM data, with BSIT as time-varying covariate, was estimated accounting for main effects of sex, education, ε4 allele, and Alzheimer's disease (AD) pathology, BSIT and time-varying BSIT, as well as the interaction between AD pathology and time-varying BSIT. RESULTS: Individuals with higher BSIT scores (b = .01, standard error [SE] = .004, p = .009) had slower declines in EM. High AD pathology (b = -.06, SE = .02, p = .001) was associated with more rapid declines in EM. The association between time-specific fluctuations in EM and BSIT differed by level of AD pathology (b = .08, SE = .034, p = .028), with a higher EM-BSIT association at higher levels of pathology. DISCUSSION: BSIT and EM fluctuate together over measurement occasions, particularly for individuals with AD pathology. Repeated intraindividual measurements provide information that could lead to early detection and inexpensive monitoring of accumulating AD pathology.

Discovery of a Noncovalent, Mutant-Selective Epidermal Growth Factor Receptor Inhibitor.

Inhibitors targeting the activating mutants of the epidermal growth factor receptor (EGFR) have found success in the treatment of EGFR mutant positive non-small-cell lung cancer. A secondary point mutation (T790M) in the inhibitor binding site has been linked to the acquired resistance against those first generation therapeutics. Herein, we describe the lead optimization of a series of reversible, pan-mutant (L858R, del746-750, T790M/L858R, and T790M/del746-750) EGFR inhibitors. By use of a noncovalent double mutant (T790M/L858R and T790M/del746-750) selective EGFR inhibitor (2) as a starting point, activities against the single mutants (L858R and del746-750) were introduced through a series of structure-guided modifications. The in vitro ADME-PK properties of the lead molecules were further optimized through a number of rational structural changes. The resulting inhibitor (21) exhibited excellent cellular activity against both the single and double mutants of EGFR, demonstrating target engagement in vivo and ADME-PK properties that are suitable for further evaluation. The reversible, noncovalent inhibitors described complement the covalent pan-mutant EGFR inhibitors that have shown encouraging results in recent clinical trials.

Noncovalent Mutant Selective Epidermal Growth Factor Receptor Inhibitors: A Lead Optimization Case Study.

Because of their increased activity against activating mutants, first-generation epidermal growth factor receptor (EGFR) kinase inhibitors have had remarkable success in treating non-small-cell lung cancer (NSCLC) patients, but acquired resistance, through a secondary mutation of the gatekeeper residue, means that clinical responses only last for 8-14 months. Addressing this unmet medical need requires agents that can target both of the most common double mutants: T790M/L858R (TMLR) and T790M/del(746-750) (TMdel). Herein we describe how a noncovalent double mutant selective lead compound was optimized using a strategy focused on the structure-guided increase in potency without added lipophilicity or reduction of three-dimensional character. Following successive rounds of design and synthesis it was discovered that cis-fluoro substitution on 4-hydroxy- and 4-methoxypiperidinyl groups provided synergistic, substantial, and specific potency gain through direct interaction with the enzyme and/or effects on the proximal ligand oxygen atom. Further development of the fluorohydroxypiperidine series resulted in the identification of a pair of diastereomers that showed 50-fold enzyme and cell based selectivity for T790M mutants over wild-type EGFR (wtEGFR) in vitro and pathway knock-down in an in vivo xenograft model.

A 6-month, office-based, low-carbohydrate diet intervention in obese teens.

BACKGROUND: Previous studies have shown the success of a low-carbohydrate diet (LCD) in adults. In one study, the LCD has also been shown as safe and effective in teens, the study period was only 12 weeks. Furthermore, there is no information on whether the LCD is a practical intervention in a pediatric office setting. OBJECTIVE: The object of this study was to demonstrate the effectiveness of a LCD in obese children in a primary care pediatric setting. DESIGN/METHODS: The study was done in 11 community pediatric practices. Children ages 12 to 18 years with a body mass index (BMI) greater than 95th percentile were put on a LCD of less than 50 grams of carbohydrate daily. RESULTS: A total of 38 of the 63 teens finished the 6-month study and 32 (84%) lost weight (range from a gain of 5.5 kg to a loss of 23.9 kg). There was also a significant decrease in mean BMI (34.9 to 32.5). CONCLUSIONS: The LCD appears to an effective and practical office-based intervention in obese teenagers.

A safety-net antibiotic prescription for otitis media: the effects of a PBRN study on patients and practitioners.

Pediatricians can decrease antibiotic use by treating acute otitis media (AOM) with a safety-net antibiotic prescription (SNAP). This study assessed whether the practitioners of the Practice-Based Research Network who participated in the study continued to use the SNAP and report a 60-day follow-up of the study patients. Charts were reviewed of study patients for 60 days following study enrollment. A survey on antibiotic use for AOM was mailed to the 17 study practitioners (SP) and 30 randomly selected community pediatricians (CP). Eight of the SP used the SNAP more than 20 times over the year following the study vs 1 of the CP. Sixty-two percent of patients never received antibiotics. The recurrence/relapse rate was greater in children younger than 2 years old compared to those older, 34% vs 10%. Practitioners who participate in a Practice-Based Research Network study are more likely to use a study intervention than others.

A detailed observation of variations of the facial artery, with emphasis on the superior labial artery.

The reconstruction of lip defects through the use of the Abbe flap and other lip flap procedures involves surgical manipulation of one of the major branches of the facial artery, specifically the superior labial artery (SLA). We examined 284 hemifaces derived from 142 formalin fixed cadavers. Observations regarding the distribution patterns of the facial artery were recognized and categorized into five Types, labeled "A" through "E". Type A (135, 47.5%): facial artery bifurcates into SLA and lateral nasal (the latter gives off inferior and superior alar and ends as angular); Type B (110, 38.7%): similar to Type A, except lateral nasal terminates as superior alar (angular artery is absent); Type C (24, 8.4%): facial artery terminates as SLA; Type D (11, 3.8%): angular artery arises directly from facial arterial trunk rather than as the termination of lateral nasal, with the facial artery ending as superior alar; Type E (4, 1.4%): facial artery terminates as a rudimentary twig without providing any significant branches. Furthermore, we were able to categorize variations within each Type. Sub-Type variations were examined in Types A through C (A: 1-7; B: 1-4; C: 1-3). Our aim was to equip both the anatomist and surgeon with a more thorough understanding of the vasculature of the face, as well as to enable plastic surgeons to have a more confident approach to reconstructive procedures in this region.

Oxaziridine-mediated amination of primary amines: scope and application to a one-pot pyrazole synthesis.

Electrophilic amination of primary aliphatic and aromatic amines is reported using a diethylketomalonate-derived oxaziridine to afford the corresponding N-Boc hydrazines in good to excellent yields. The method allows a one-pot synthesis of pyrazoles from primary amines. [Reaction: see text]

Synthesis and structural analysis of dehydrophenylalanine cyclophanes.

The syntheses and structures of three cyclophanes containing two (Z)-dehydrophenylalanine residues are reported; the length of the tethers between the two amino acid residues is easily altered and changing this parameter has a significant effect on the solid state structures of the cyclophanes.