Climate change drives migratory range shift via individual plasticity in shearwaters.

How individual animals respond to climate change is key to whether populations will persist or go extinct. Yet, few studies investigate how changes in individual behavior underpin these population-level phenomena. Shifts in the distributions of migratory animals can occur through adaptation in migratory behaviors, but there is little understanding of how selection and plasticity contribute to population range shift. Here, we use long-term geolocator tracking of Balearic shearwaters (Puffinus mauretanicus) to investigate how year-to-year changes in individual birds' migrations underpin a range shift in the post-breeding migration. We demonstrate a northward shift in the post-breeding range and show that this is brought about by individual plasticity in migratory destination, with individuals migrating further north in response to changes in sea-surface temperature. Furthermore, we find that when individuals migrate further, they return faster, perhaps minimizing delays in return to the breeding area. Birds apparently judge the increased distance that they will need to migrate via memory of the migration route, suggesting that spatial cognitive mechanisms may contribute to this plasticity and the resulting range shift. Our study exemplifies the role that individual behavior plays in populations' responses to environmental change and highlights some of the behavioral mechanisms that might be key to understanding and predicting species persistence in response to climate change.

Discovery of Chemicals to Either Clear or Indicate Amyloid Aggregates by Targeting Memory-Impairing Anti-Parallel Aß Dimers.

Amyloid-ß (Aß) oligomers are implicated in Alzheimer disease (AD). However, their unstable nature and heterogeneous state disrupts elucidation of their explicit role in AD progression, impeding the development of tools targeting soluble Aß oligomers. Herein parallel and anti-parallel variants of Aß(1-40) dimers were designed and synthesized, and their pathogenic properties in AD models characterized. Anti-parallel dimers induced cognitive impairments with increased amyloidogenesis and cytotoxicity, and this dimer was then used in a screening platform. Through screening, two FDA-approved drugs, Oxytetracycline and Sunitinib, were identified to dissociate Aß oligomers and plaques to monomers in 5XFAD transgenic mice. In addition, fluorescent Astrophloxine was shown to detect aggregated Aß in brain tissue and cerebrospinal fluid samples of AD mice. This screening platform provides a stable and homogeneous environment for observing Aß interactions with dimer-specific molecules.

Evaluation of Hypoglycemia and Potential Risk Factors in a Veterans Affairs Community Living Center.

OBJECTIVES: To describe hypoglycemic events in a Veterans Affairs (VA) community living center (CLC) population and to determine predictive risk factors associated with hypoglycemia. DESIGN: Retrospective, exploratory, observational chart review. SETTING: Tertiary-care VA Healthcare System CLC. PATIENTS: Residents residing in a VA CLC with at least one active order for insulin between June 1, 2009, and June 30, 2013, were evaluated over a 90-day study period. MAIN OUTCOME MEASURES: The primary outcome was the number of days to the first hypoglycemic event as described by the survival curve analysis. The secondary outcomes included the overall incidence of hypoglycemia, the association of potential risk factors on the proportion of hypoglycemic events, and the association of potential risk factors on the development of an additional hypoglycemic event. RESULTS: There was a 49% incidence of a hypoglycemic event in the 90-day study period with a 24% incidence within the first 7 days of resident admission, representing approximately half of all events that occurred. The only statistically significant risk factor for having a hypoglycemic event was the number of units of insulin/kg/day (hazard ratio = 1.008, 95% confidence interval 1.001, 1.015; P = 0.0317) that a resident was prescribed. CONCLUSIONS: Residents are at increased risk for hypoglycemia within the first seven days of admission to a CLC. It is imperative that providers closely monitor and reevaluate antidiabetic regimens at this time of transition.

Application of the Layered Learning Practice Model in an Academic Medical Center.

The layered learning practice model (LLPM) is a teaching strategy designed to train residents to precept students and other residents with the oversight of a seasoned clinical pharmacist. This model serves as a tool for residency programs to implement quality precepting opportunities and learning experiences as they look for new ways to integrate multiple learners into the practice setting. The levels of the LLPM include a senior preceptor, resident, and student. It is best implemented through utilization of 4 steps: orientation to the LLPM, preexperience planning, implementation, and postexperience evaluation. Orientation introduces preceptors and residents to the LLPM and outlines expectations for each precepting level. Preexperience planning allows the resident to take a leadership role in developing calendars, rotation activities, rubrics, and activities that match goals and objectives. For implementation, the senior preceptor maintains an active role with all learners; the resident serves as the student's primary preceptor and is responsible for incorporating the student into clinical activities, evaluating student work, and providing feedback. Postexperience evaluation is designed to solicit and provide feedback to the resident and student and to identify recommendations for improvement of the LLPM. Overall, the LLPM is a multilayered model incorporating the expertise and unique learning positions of the senior preceptor, resident, and student. Redistributing components of the senior preceptor's responsibility amongst learners may result in expansion of patient care and clinical services and help satisfy the increasing demands placed on pharmacists.

Inhaler misuse in an older adult population.

OBJECTIVE: To determine the prevalence of inhaler misuse in an older adult population. DESIGN: Prospective observational study. SETTING: Two primary care outpatient clinics in a Veterans Affairs Medical Center in North Carolina. PARTICIPANTS: Male veterans 65 years of age and older (N = 24) prescribed a pressurized metered dose inhaler (pMDI) or a dry powder inhaler (DPI). MEASUREMENTS: Inhaler technique was evaluated using placebo inhaler devices and a standardized technique assessment form that included critical steps. Potential risk factors for misuse were obtained from the medical record, and the time for technique evaluation was collected. MAIN RESULTS: Study participants yielded 44 unique device observations. Patients were male with an average age of 82 years. All patients made at least one error, with a mean error rate of 2.5 errors/patient/inhaler, while 20 of 24 (83%) patients made at least one critical error with a mean error rate of 1.2 critical errors/patient/inhaler. Assessment of inhaler technique required 2.3 minutes/inhaler. Critical errors were made during 15 of 19 (79%) pMDI observations and 22 of 25 (88%) DPI observations. Patients with multiple inhalers or a history of stroke committed errors more often, although no risk factors demonstrated meaningful differences in error rates. CONCLUSIONS: Inhaler misuse in older adults is common, including committing critical errors that have been shown to reduce drug delivery. The time necessary for technique evaluation is relatively small. The high rate of misuse observed should serve as motivation for increased vigilance, individualized technique education, and routine re-assessment in the highly heterogeneous older adult population.

Galantamine-associated nightmares and anxiety.

BACKGROUND: This case report describes recurrent nightmares and anxiety possibly caused by the administration and rapid dose titration of galantamine. CASE SUMMARY: A 90-year-old male with Alzheimer's disease was initiated on galantamine 4 mg twice daily for 10 days, followed by 8 mg twice daily thereafter. On followup to the geriatric clinic, the patient reported complaints of nightmares and associated anxiety. The occurrences of nightmares developed after initiating galantamine and temporally increased with galantamine titration. After discontinuation of galantamine, the patient reported no further occurrences of nightmares or anxiety and memory function remained stable. CONCLUSION: Galantamine-associated nightmares are an uncommon adverse event and may have been exacerbated by rapid titration. Although such adverse events are unlikely to cause harm in the patient, such sleep abnormalities have the potential to decrease a patient's quality of life and may require the need for alternative therapy.

Catalytic antibody degradation of ghrelin increases whole-body metabolic rate and reduces refeeding in fasting mice.

Obesity is a chronic, costly, and globally prevalent condition, with excess caloric intake a suspected etiologic factor. Nonsurgical treatments are modestly efficacious, and weight loss maintenance is hampered by anti-famine homeostatic mechanisms. Ghrelin, a gastric hormone linked to meal initiation, energy expenditure, and fuel partitioning, is hypothesized to facilitate weight gain and impede weight loss. Unique among known animal peptides, the serine-3 residue of ghrelin is posttranslationally acylated with an n-octanoic acid, a modification important for the peptide's active blood-brain transport and growth hormone secretagogue receptor-1 agonist activity. Pharmacological degradation of ghrelin would be hypothesized to reduce ghrelin's biological effects. To study endogenous ghrelin's role in appetite and energy expenditure, we generated antibodies that hydrolyze the octanoyl moiety of ghrelin to form des-acyl ghrelin. The most proficient antibody catalyst, GHR-11E11, was found to display a second-order rate constant of 18 M(-1) x s(-1) for the hydrolysis of ghrelin to des-acyl ghrelin. I.v. administration of GHR-11E11 (50 mg/kg) maintained a greater metabolic rate in fasting C57BL/6J mice as compared with mice receiving a control antibody and suppressed 6-h refeeding after 24 h of food deprivation. Indirect respiratory measures of metabolism after refeeding and relative fuel substrate utilization were unaffected. The results support the hypothesis that acylated ghrelin stimulates appetite and curbs energy expenditure during deficient energy intake, whereas des-acyl ghrelin does not potently share these functions. Catalytic anti-ghrelin antibodies might thereby adjunctively aid consolidation of caloric restriction-induced weight loss and might also be therapeutically relevant to Prader-Willi syndrome, characterized after infancy by hyperghrelinemia, hyperphagia, and obesity.

Clinical Pharmacy Practice Patterns Among North Carolina Rural Hospitals.

INTRODUCTION: Rural hospitals are isolated without adequate funding needed to provide for clinical services offered at larger health systems. The purpose of this study is to determine the clinical pharmacy services available and desired by rural hospitals in North Carolina. METHODS: This prospective, cross-sectional, survey was distributed to a cohort of rural pharmacy directors and managers at rural hospitals across North Carolina. Data collected pertained to characteristics of the hospital and pharmacy, pharmacy director, clinical services, and responder impressions on their ability to maintain or enhance clinical services. Responses were summarized utilizing descriptive statistics and free-responses were coded for similar themes. RESULTS: Seventeen respondents (32.6%) completed the survey. Clinical activities varied, as did characteristics of the hospitals and staff. Improved patient care is the primary reason why hospital pharmacies expand their clinical participation (46.7%). Pharmacy directors believed growth of clinical activities was a long-term goal while reporting regulations, staff, and finances as barriers to growth. CONCLUSION: Clinical pharmacy services vary in NC rural hospitals. Directors exhibit a willingness to expand clinical responsibilities. Rural hospital pharmacy directors desire pharmacists to be active clinically in patient care, but face barriers in reaching that goal.

Antibiotic susceptibility patterns of ocular bacterial flora in patients undergoing intravitreal injections.

PURPOSE: To determine the antibiotic susceptibility patterns of conjunctival flora in patients undergoing intravitreal (IVT) injection. DESIGN: Prospective, observational study. PARTICIPANTS: Patients (n = 85) scheduled to undergo 136 IVT injections at California Vitreoretinal Center at Stanford University. METHODS: Conjunctival cultures were obtained on the day of the IVT injection from the injection site bulbar conjunctiva before the application of povidone-iodine or antibiotics. MAIN OUTCOME MEASURES: Bacterial isolates were identified and tested for antibiotic susceptibility using either the Kirby-Bauer disc-diffusion technique or MicroScan-WalkAway system. RESULTS: Our analysis included 136 samples collected from 90 eyes of 85 patients. Of those with positive cultures (n = 65), the most common bacterial isolates were coagulase-negative staphylococci (CNS), comprising 59 (83%) of the 71 bacterial strains. Among the CNS, all were susceptible to vancomycin and >80% were susceptible to gentamicin, chloramphenicol, tetracycline, and imipenem. Between 60% and 80% of the CNS were susceptible to the cephalosporins and newer generation fluoroquinolones. Fewer than 60% were susceptible to the penicillin analogs, erythromycin, and the earlier generation fluoroquinolones. Nearly half of the CNS (47%) were resistant to oxacillin/methicillin. CONCLUSIONS: Bacteria isolated from the injection site of patients undergoing IVT injections were mostly CNS. Most are sensitive to vancomycin, gentamicin, and chloramphenicol. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Design and synthesis of Hsp90 inhibitors: exploring the SAR of Sansalvamide A derivatives.

Utilizing the structure-activity relationship we have developed during the synthesis of the first two generations and mechanism of action studies that point to the interaction of these molecules with the key oncogenic protein Hsp90, we report here the design of 32 new Sansalvamide A derivatives and their synthesis. Our new structures, designed from previously reported potent compounds, were tested for cytotoxicity on the HCT116 colon cancer cell line, and their binding to the biological target was analyzed using computational studies involving blind docking of derivatives using Autodock. Further, we show new evidence that our molecules bind directly to Hsp90 and modulate Hsp90's binding with client proteins. Finally, we demonstrate that we have integrated good ADME properties into a new derivative.

Description of Pharmacist Recommendations in the Caring for Older Adults and Caregivers at Home (COACH) Program.

OBJECTIVE: To describe recommendations made by geriatric clinical pharmacists within an innovative care model focusing on patients with dementia living at home. DESIGN: Retrospective chart review. SETTING: Outpatients in a tertiary care Veterans Affairs health care system. PARTICIPANTS: Veterans who underwent a Caring for Older Adults and Caregivers at Home (COACH) Program assessment and had at least one medicationrelated recommendation made by a geriatric clinical pharmacist. MAIN OUTCOME MEASURES: The primary endpoint was the number and category of medication-related recommendations made by a geriatric clinical pharmacist at the initial COACH program assessment. Secondary endpoints were recommendation acceptance rates and change in potentially inappropriate medications (PIMs) at six months. RESULTS: There were 104 patients included. The mean age was 81 years and the majority of patients were male and Caucasian. At baseline, patients were receiving a mean of 12 medications/person, and 59% of patients were receiving at least one PIM. There were 248 total medication recommendations made, with a mean of 2.4 recommendations/person (range 1-5). The three most common recommendation categories were to discontinue a drug, decrease the dose, and switch to a potentially safer alternative. Providers accepted 110 (44%) recommendations within six months. Patients were receiving a mean of one PIM/person at baseline, and no change was observed at six months.CONCLUSION: This study describes recommendations made through medication reviews by geriatric clinical pharmacists within an innovative care model for patients with dementia living at home. These data may provide information to other clinical pharmacists implementing consult services in similar settings.

A prospective randomized evaluation of topical gatifloxacin on conjunctival flora in patients undergoing intravitreal injections.

PURPOSE: We sought to assess the efficacy of 3-day topical gatifloxacin use in combination with povidone-iodine (PVI) versus PVI alone in eliminating conjunctival bacterial flora in patients scheduled to undergo intravitreal (IVT) injection. DESIGN: Prospective, randomized single-blind clinical trial. PARTICIPANTS: We included 129 patients scheduled to undergo 273 IVT injections at California Vitreoretinal Center at Stanford University. METHODS: Study patients were randomized to self-administration of gatifloxacin drops for 3 days before injection, or no pretreatment antibiotics. Cultures were collected from the bulbar conjunctiva at the injection site and at the corresponding location in the fellow eye before PVI preparation. After topical PVI treatment and immediately before injection, a third culture was obtained at the injection site. Additionally, the injection needle was also cultured after the procedure. MAIN OUTCOME MEASURES: Incidence of positive bacterial samples collected from injection site conjunctiva and injection needles. RESULTS: Three-day gatifloxacin use resulted in a significantly lower rate of SeptiChek (Becton Dickinson, Franklin Lakes, NJ) positive cultures compared with untreated controls (21% vs 48% respectively, P = 0.005). After topical PVI, the rate of positive bacterial cultures in gatifloxacin-treated and control eyes were similar (8% and 4%, respectively; P = 0.324). CONCLUSIONS: Although 3-day topical gatifloxacin use is effective in reducing the frequency of conjunctival bacterial growth relative to untreated eyes, antibiotic use confers no additional benefit in combination with PVI than eyes receiving PVI alone. This supports that topical PVI is an effective preinjection monotherapy for infection prophylaxis in the setting of IVT injections.

An Interdisciplinary Academic Detailing Approach to Decrease Inappropriate Medication Prescribing by Physician Residents for Older Veterans Treated in the Emergency Department.

OBJECTIVE: To evaluate the impact of an academic detailing intervention delivered as part of a quality improvement project by a physician-pharmacist pair on (1) self-reported confidence in prescribing for older adults and (2) rates of potentially inappropriate medications (PIMs) prescribed to older adults by physician residents in a Veteran Affairs emergency department (ED). METHODS: This quality improvement project at a single site utilized a questionnaire that assessed knowledge of Beers Criteria, self-perceived barriers to appropriate prescribing in older adults, and self-rated confidence in ability to prescribe in older adults which was administered to physician residents before and after academic detailing delivered during their emergency medicine rotation. PIM rates in the resident cohort who received the academic detailing were compared to residents who did not receive the intervention. RESULTS: Sixty-three residents received the intervention between February 2013 and December 2014. At baseline, approximately 50% of the residents surveyed reported never hearing about nor using the Beers Criteria. A significantly greater proportion of residents agreed or strongly agreed in their abilities to identify drug-disease interactions and to prescribe the appropriate medication for the older adult after receiving the intervention. The resident cohort who received the educational intervention was less likely to prescribe a PIM when compared to the untrained resident cohort with a rate ratio of 0.73 ( P < .0001). CONCLUSION: Academic detailing led by a physician-pharmacist pair resulted in improved confidence in physician residents' ability to prescribe safely in an older adult ED population and was associated with a statistically significant decrease in PIM rates.

Optimized sample preparation for MALDI mass spectrometry analysis of protected synthetic peptides.

The recent development and commercialization of Fuzeon (enfuvirtide) demonstrated that a convergent strategy comprised of both solid- and solution-phase synthetic methodologies presents a viable route for peptide manufacturing on a multi-ton scale. In this strategy, the target sequence is prepared by stepwise solid-phase synthesis of protected peptide fragments, which are then coupled together in the solution-phase to give the full-length sequence. These synthetic methodologies pose a unique challenge for mass spectrometry (MS), as protected peptide intermediates are often marked by poor solubility, structural lability, and low ionization potential. Matrix-assisted laser desorption/ionization (MALDI) MS is uniquely suited to such analytes; however, generalized protocols for MALDI analysis of protected peptides have yet to be demonstrated. Herein, we report an operationally simple sample preparation method for MALDI analysis of protected peptides, which greatly facilitates the collection and interpretation of MS data. In this method, the difficulty in MS analysis of protected peptides has been greatly diminished by use of dithranol as a matrix and CsCl as an additive, giving rise to intentionally-formed Cs(+) adducts. With greatly reduced fragmentation, better crystalline morphology, and easier data interpretation, we anticipate that these findings will find utility in peptide process development and manufacturing settings for reaction monitoring, troubleshooting, and quality control.

Comparison of one-day versus one-hour application of topical gatifloxacin in eliminating conjunctival bacterial flora.

PURPOSE: To compare efficacies of 1-day, 1-hour, and combined 1-day/1-hour preoperative topical gatifloxacin in eliminating conjunctival bacterial flora. DESIGN: Prospective, comparative case series. PARTICIPANTS: Sixty patients (120 eyes) scheduled to undergo anterior segment intraocular surgery at Stanford University Medical Center. METHODS: Cultures were collected from the palpebral conjunctival sac at baseline and after 1 day (4 doses), 1 hour (3 doses), and 1 day/1 hour (7 doses) of gatifloxacin use. MAIN OUTCOME MEASURES: Incidence of positive bacterial samples collected pre- and post-antibiotic treatment and number of colony forming units (CFUs). RESULTS: SeptiChek (Becton Dickinson, Franklin Lakes, NJ) positive cultures significantly decreased from 67% growth at baseline to 28% (P<0.0001) after 1 day and from 60% at baseline to 37% (P = 0.018) after 1 hour of gatifloxacin use. Reductions of 44% growth at baseline to 12% (P = 0.0001) after 1 day and 32% at baseline to 13% (P = 0.029) after 1 hour of gatifloxacin use were observed on blood agar. Surgical eyes that received both 1-day and 1-hour preoperative gatifloxacin had reductions from 67% growth at baseline to 18% posttreatment (P<0.0001) and 45% at baseline to 7% posttreatment (P<0.0001) on SeptiChek and blood agar media, respectively. In addition to a lower frequency of positive cultures, a significantly lower CFU count was found after 1-day (P = 0.004) and 1-hour (P = 0.049) gatifloxacin use compared with pretreatment levels. Combined 1-day/1-hour doses of gatifloxacin were associated with a greater reduction in CFUs (P = 0.001) when compared with 1-hour treatment alone. CONCLUSIONS: Both 1-hour and 1-day topical gatifloxacin use are effective in reducing the frequency of conjunctival bacterial growth and the overall bacterial load as measured by CFUs, relative to baseline. Although a 1-hour pretreatment is associated with a reduction in bacterial growth, the combination of 1-day and 1-hour preoperative gatifloxacin dosing results in an even lower overall bacterial load, suggesting that the latter might be the preferred preoperative regimen for eyes undergoing anterior segment surgery.

Infection control by antibody disruption of bacterial quorum sensing signaling.

Quorum sensing (QS) is the process through which bacteria communicate utilizing small diffusible molecules termed autoinducers. It has been demonstrated that QS controls a plethora of microbial processes including the expression of virulence factors. Here we report an immunopharmacotherapeutic approach for the attenuation of QS in the Gram-positive human pathogen Staphylococcus aureus. An anti-autoinducer monoclonal antibody, AP4-24H11, was elicited against a rationally designed hapten, and efficiently inhibited QS in vitro through the sequestration of the autoinducing peptide (AIP)-4 produced by S. aureus RN4850. Importantly, AP4-24H11 suppressed S. aureus pathogenicity in an abscess formation mouse model in vivo and provided complete protection against a lethal S. aureus challenge. These findings provide a strong foundation for further investigations of immunopharmacotherapy for the treatment of bacterial infections in which QS controls the expression of virulence factors.

Diagnosing and treating postpartum uterine artery pseudoaneurysm.

Uterine artery pseudoaneurysm (UAP) is an uncommon cause of postpartum hemorrhage. We present a case of a 19-year-old woman 6 weeks postpartum after low transverse cesarean delivery with recurrent heavy vaginal bleeding requiring a blood transfusion. Transvaginal sonogram revealed a UAP. Embolization of the uterine artery was performed, with resolution of her symptoms.

Magnetic resonance imaging of the collateral ligaments and the anatomic quadrants of the knee.

Injuries to the lateral and medial supporting structures of the knee can be significantly disabling and somewhat difficult to detect and evaluate clinically. An accurate imaging evaluation of these structures requires the use of the appropriate MR imaging sequences and the detailed knowledge of the anatomic structures that are present in these locations. Normal function is dependent on the integrity of the complex functional structures and effective clinical treatment, including surgical repair, of these structures is predicated on an optimal diagnostic evaluation. A successful diagnostic evaluation can expedite treatment and provide the best opportunity for a favorable long-term outcome.

Apolipoprotein E modifies the CNS response to injury via a histamine-mediated pathway.

Recent evidence demonstrates that apolipoprotein E (apoE) influences the central nervous system (CNS) response to both acute and chronic injury. To address the mechanisms by which apoE influences neurological disease, we examined differential gene expression in the brains of apoE transgenic mice after closed head injury. Apart from confirming the knockout of apoE, the largest differential gene expression occurred for the interleukin-9 receptor (IL-9R), which was > 100-fold up-regulated in apoE-deficient versus wild-type mice. We observed a similar pattern of posttraumatic IL-9R up-regulation in APOE4 targeted replacement mice as compared with their APOE3 counterparts. This difference in gene expression was associated with increased neuronal protein expression of IL-9R in E4 animals compared with E3 as demonstrated by immunohistochemistry. The consequence of IL-9R binding in mast cells is the induction of proliferation and differentiation. This indirectly favors degranulation and release of histamine and inflammatory mediators, which have previously been demonstrated to exacerbate secondary neuronal injury. We found that apoE-deficient animals had increased levels of systemic histamine after injury and that pre-treatment with antihistamines improved functional outcomes in apoE-deficient but not wild-type animals after head injury. These results suggest that apoE modifies secondary neuronal injury caused by histamine release and are consistent with previous observations that apoE affects the CNS inflammatory response in an isoform-specific manner.

Real-time correction of heart interbeat intervals.

Heart rate variability (HRV) is traditionally analyzed while a subject is in a controlled environment, such as at rest in a clinic, where it can be used as a medical indicator. This paper concerns analyzing HRV outside of controlled environments, such as on an actively moving person. We describe automated methods for inter-heartbeat interval (IBI) error detection and correction. We collected 124,998 IBIs from 18 subjects, undergoing a variety of active motions, for use in evaluating our methods. Two human graders manually labeled each IBI, evaluating 10% of the IBIs as having an error, which is a far greater error percentage than has been examined in any previous study. Our automated method had a 96% agreement rate with the two human graders when they themselves agreed, with a 49% rate of matching specific error corrections and a 0.01% false alarm rate.