A large-scale neural network training framework for generalized estimation of single-trial population dynamics.

Achieving state-of-the-art performance with deep neural population dynamics models requires extensive hyperparameter tuning for each dataset. AutoLFADS is a model-tuning framework that automatically produces high-performing autoencoding models on data from a variety of brain areas and tasks, without behavioral or task information. We demonstrate its broad applicability on several rhesus macaque datasets: from motor cortex during free-paced reaching, somatosensory cortex during reaching with perturbations, and dorsomedial frontal cortex during a cognitive timing task.

Supramolecular Control of the Temperature Responsiveness of Fluorescent Macrocyclic Molecular Rotamers.

To fully harness the potential of molecular machines, it is crucial to develop methods by which to exert control over their speed of motion through the application of external stimuli. A conformationally strained macrocyclic fluorescent rotamer, CarROT, displays a reproducible and linear fluorescence decrease towards temperature over the physiological temperature range. Through the external addition of anions, cations or through deprotonation, the compound can access four discreet rotational speeds via supramolecular interactions (very slow, slow, fast and very fast) which in turn stop, reduce or enhance the thermoluminescent properties due to increasing or decreasing non-radiative decay processes, thereby providing a means to externally control the temperature sensitivity of the system. Through comparison with analogues with a higher degree of conformational freedom, the high thermosensitivity of CarROT over the physiological temperature range was determined to be due to conformational strain, which causes a high energy barrier to rotation over this range. Analogues with a higher degree of conformational freedom display lower sensitivities towards temperature over the same temperature range. This study provides an example of an information rich small molecule, in which programable rotational speed states can be observed with facile read-out.

Association between number of Adverse Childhood Experiences and depression among older adults is moderated by race.

OBJECTIVE: This study aimed to assess the association between number of Adverse Childhood Experiences (ACE) and history of depression among older adults and to explore the interaction by race. METHODS: This study was a cross-sectional analysis of the 2020 Behavioral Risk Factor Surveillance System (BRFSS) data among 60,122 older respondents (≥ 60 years old). The ACE score (zero, one, two-three, ≥four) included questions assessing exposure to eight types of ACEs before age 18. The outcome was the respondent's self-report depression diagnosed (yes/no). Multivariable logistic regression models examined the association between ACEs and depression stratified by race. Each model adjusted for age, smoking status, income, education, marital status, and body mass index. RESULTS: In this sample of older adults, 47%, 23%, 19% and 10% reported having experienced zero, one, two-three, and four or more types of ACEs, respectively. Depression was reported by 16% of survey respondents. There was a significant interaction between ACE score and race and depression (p = 0.038). Respondents who experienced ≥4 ACEs had higher likelihood of reporting depression for all race/ethnicity groups: non-Hispanic Whites (aOR = 3.83; 95% CI: 3.07, 4.79), non-Hispanic Blacks (aOR = 3.39, 95% CI: 1.71, 6.71), or Hispanics (aOR = 12.61; 95% CI: 4.75, 33.43). This translated to a large effect size for non-Hispanic Whites and Hispanics although the magnitude was bigger for Hispanics. CONCLUSION: The association between number of ACEs and depression was strongest for older adults who identify as Hispanic, but weaker and less consistent for adults who identify as White and Black.

Factors Associated with Venous Thromboembolism Development in Patients with Traumatic Brain Injury.

BACKGROUND: Venous thromboembolic (VTE) events are a major concern in trauma and intensive care, with the prothrombotic state caused by traumatic brain injury (TBI) increasing the risk in affected patients. We sought to identify critical demographic and clinical variables and determine their influence on subsequent VTE development in patients with TBI. METHODS: This was a cross-sectional study with data retrospectively collected from 818 patients with TBI admitted to a level I trauma center in 2015-2020 and placed on VTE prophylaxis. RESULTS: The overall VTE incidence was 9.1% (7.6% deep vein thrombosis, 3.2% pulmonary embolism, 1.7% both). The median time to diagnosis was 7 days (interquartile range 4-11) for deep vein thrombosis and 5 days (interquartile range 3-12) for pulmonary embolism. Compared with those who did not develop VTE, patients who developed VTE were younger (44 vs. 54 years, p = 0.02), had more severe injury (Glasgow Coma Scale 7.5 vs. 14, p = 0.002, Injury Severity Score 27 vs. 21, p < 0.001), were more likely to have experienced polytrauma (55.4% vs. 34.0%, p < 0.001), more often required neurosurgical intervention (45.9% vs. 30.5%, p = 0.007), more frequently missed ≥ 1 dose of VTE prophylaxis (39.2% vs. 28.4%, p = 0.04), and were more likely to have had a history of VTE (14.9% vs. 6.5%, p = 0.008). Univariate analysis demonstrated that 4-6 total missed doses predicted the highest VTE risk (odds ratio 4.08, 95% confidence interval 1.53-10.86, p = 0.005). CONCLUSIONS: Our study highlights patient-specific factors that are associated with VTE development in a cohort of patients with TBI. Although many of these are unmodifiable patient characteristics, a threshold of four missed doses of chemoprophylaxis may be particularly important in this critical patient population because it can be controlled by the care team. Development of intrainstitutional protocols and tools within the electronic medical record to avoid missed doses, particularly among patients who require operative interventions, may result in decreasing the likelihood of future VTE formation.

Analysis of narrative assessments of internal medicine resident performance: are there differences associated with gender or race and ethnicity?

BACKGROUND: Equitable assessment is critical in competency-based medical education. This study explores differences in key characteristics of qualitative assessments (i.e., narrative comments or assessment feedback) of internal medicine postgraduate resident performance associated with gender and race and ethnicity. METHODS: Analysis of narrative comments included in faculty assessments of resident performance from six internal medicine residency programs was conducted. Content analysis was used to assess two key characteristics of comments- valence (overall positive or negative orientation) and specificity (detailed nature and actionability of comment) - via a blinded, multi-analyst approach. Differences in comment valence and specificity with gender and race and ethnicity were assessed using multilevel regression, controlling for multiple covariates including quantitative competency ratings. RESULTS: Data included 3,383 evaluations with narrative comments by 597 faculty of 698 residents, including 45% of comments about women residents and 13.2% about residents who identified with race and ethnicities underrepresented in medicine. Most comments were moderately specific and positive. Comments about women residents were more positive (estimate 0.06, p 0.045) but less specific (estimate - 0.07, p 0.002) compared to men. Women residents were more likely to receive non-specific, weakly specific or no comments (adjusted OR 1.29, p 0.012) and less likely to receive highly specific comments (adjusted OR 0.71, p 0.003) or comments with specific examples of things done well or areas for growth (adjusted OR 0.74, p 0.003) than men. Gendered differences in comment specificity and valence were most notable early in training. Comment specificity and valence did not differ with resident race and ethnicity (specificity: estimate 0.03, p 0.32; valence: estimate - 0.05, p 0.26) or faculty gender (specificity: estimate 0.06, p 0.15; valence: estimate 0.02 p 0.54). CONCLUSION: There were significant differences in the specificity and valence of qualitative assessments associated with resident gender with women receiving more praising but less specific and actionable comments. This suggests a lost opportunity for well-rounded assessment feedback to the disadvantage of women.

'Who you gonna call?' A qualitative study of psychiatrists accessing mental health services.

OBJECTIVE: To identify motivation, capabilities and opportunities that enable psychiatrists and registrars to seek help for mental health problems and to inform design of interventions. METHOD: Data collected in qualitative semi-structured interviews were analysed using a framework approach with the COM-B model of behaviour as a theoretical frame. RESULTS: Accounts of the eight participants show help-seeking to be a complex process requiring cognitive and emotional capability to recognise a problem or goal, acceptance of vulnerability, and facilitated by access to professional networks. Help-seeking was enabled by openness about mental health problems in workplace culture. CONCLUSIONS: Interventions to enable help-seeking should focus on normalising the experience of mental health problems among doctors and challenge the notion that difficulties represent characterological flaws. Greater understanding of the mandatory reporting requirements is also required.

Impact of premorbid oral anticoagulant use on survival in patients with traumatic intracranial hemorrhage.

OBJECTIVE: Although oral anticoagulant use has been implicated in worse outcomes for patients with a traumatic brain injury (TBI), prior studies have mostly examined the use of vitamin K antagonists (VKAs). In an era of increasing use of direct oral anticoagulants (DOACs) in lieu of VKAs, the authors compared the survival outcomes of TBI patients on different types of premorbid anticoagulation medications with those of patients not on anticoagulation. METHODS: The authors retrospectively reviewed the records of 1186 adult patients who presented at a level I trauma center with an intracranial hemorrhage after blunt trauma between 2016 and 2022. Patient demographics; comorbidities; and pre-, peri-, and postinjury characteristics were compared based on premorbid anticoagulation use. Multivariable Cox proportional hazards regression modeling of mortality was performed to adjust for risk factors that met a significance threshold of p < 0.1 on bivariate analysis. RESULTS: Of 1186 patients with a traumatic intracranial hemorrhage, 49 (4.1%) were taking DOACs and 53 (4.5%) used VKAs at the time of injury. Patients using oral anticoagulants were more likely to be older (p < 0.001), to have a higher Charlson Comorbidity Index (p < 0.001), and to present with a higher Glasgow Coma Scale (GCS) score (p < 0.001) and lower Injury Severity Score (ISS; p < 0.001) than those on no anticoagulation. Patients using VKAs were more likely to undergo reversal than patients using DOACs (53% vs 31%, p < 0.001). Cox proportional hazards regression demonstrated significantly increased hazard ratios (HRs) for VKA use (HR 2.204, p = 0.003) and DOAC use (HR 1.973, p = 0.007). Increasing age (HR 1.040, p < 0.001), ISS (HR 1.017, p = 0.01), and Marshall score (HR 1.186, p < 0.001) were associated with an increased risk of death. A higher GCS score on admission was associated with a decreased risk of death (HR 0.912, p < 0.001). CONCLUSIONS: Patients with a traumatic intracranial injury who were on oral anticoagulant therapy before injury demonstrated higher mortality rates than patients who were not on oral anticoagulation after adjusting for age, comorbid conditions, and injury presentation.

Academic Leadership Academy Summer Program: Clerkship Transition Preparation for Underrepresented in Medicine Medical Students.

PROBLEM: Enhancing workforce diversity by increasing the recruitment of students who have been historically excluded/underrepresented in medicine (UIM) is critical to addressing healthcare inequities. However, these efforts are inadequate when undertaken without also supporting students' success. The transition to clerkships is an important and often difficult to navigate inflection point in medical training where attention to the specific needs of UIM students is critical. INTERVENTION: We describe the design, delivery, and three-year evaluation outcomes of a strengths-based program for UIM second year medical students. The program emphasizes three content areas: clinical presentations/clinical reasoning, community building, and surfacing the hidden curriculum. Students are taught and mentored by faculty, residents, and senior students from UIM backgrounds, creating a supportive space for learning. CONTEXT: The program is offered to all UIM medical students; the centerpiece of the program is an intensive four-day curriculum just before the start of students' second year. Program evaluation with participant focus groups utilized an anti-deficit approach by looking to students as experts in their own learning. During focus groups mid-way through clerkships, students reflected on the program and identified which elements were most helpful to their clerkship transition as well as areas for programmatic improvement. IMPACT: Students valued key clinical skills learning prior to clerkships, anticipatory guidance on the professional landscape, solidarity and learning with other UIM students and faculty, and the creation of a community of peers. Students noted increased confidence, self-efficacy and comfort when starting clerkships. LESSONS LEARNED: There is power in learning in a community connected by shared identities and grounded in the strengths of UIM learners, particularly when discussing aspects of the hidden curriculum in clerkships and sharing specific challenges and strategies for success relevant to UIM learners. We learned that while students found unique benefits to preparing for clerkships in a community of UIM students, near peers, and faculty, future programs could be enhanced by pairing this formal intensive curriculum with more longitudinal opportunities for community building, mentoring, and career guidance.

Exploring gender and thematic differences in qualitative assessments of internal medicine resident performance.

INTRODUCTION: Evidence suggests gender disparities in medical education assessment, including differences in ratings of competency and narrative comments provided in resident performance assessments. This study explores how gender manifests within the content of qualitative assessments (i.e., narrative comments or performance feedback) of resident performance. METHODS: Qualitative content analysis was used to explore gender-based differences in narrative comments included in faculty assessments of resident performance during inpatient medicine rotations at six Internal Medicine residency programs, 2016-2017. A blinded, multi-analyst approach was employed to identify themes across comments. Patterns in themes with resident gender and post-graduate year (PGY) were explored, focusing on PGY2 and PGY3 when residents are serving in the team leader role. RESULTS: Data included 3,383 evaluations with narrative comments of 385 men (55.2%) and 313 women residents (44.8%). There were thematic differences in narrative comments received by men and women residents and how these themes manifested within comments changed with training time. Compared to men, comments about women had a persistent relationship-orientation and emphasized confidence over training including as interns and in PGY2 and PGY3, when serving as team leader. The relationship-orientation was characterized not only by the residents' communal attributes but also their interpersonal and communication skills, including efforts supporting others and establishing the tone for the team. Comments about women residents often highlighted confidence, including recommendations around behaviors that convey confidence in decision-making and team leadership. DISCUSSION: There were gender-based thematic differences in qualitative assessments. Comments about women resident team leaders highlight relationship building skills and urge confidence and actions that convey confidence as team leader. Persistent attention to communal skills suggests gendered expectations for women resident team leaders and a lost opportunity for well-rounded feedback to the disadvantage of women residents. These findings may inform interventions to promote equitable assessment, such as providing feedback across the competencies.

A Mediterranean-Style Diet Improves the Parameters for the Management and Prevention of Type 2 Diabetes Mellitus.

Background and Objectives: Type 2 diabetes mellitus (T2DM) is a chronic condition recognized as the inability to maintain glucose homeostasis, typically presenting with insulin resistance and systemic inflammation. With the prevalence of T2DM and major risk factors, such as prediabetes and obesity, increasing each year, the need to address risk factor reduction strategies is crucial. Materials and Methods: Twenty-two men and women, overweight-to-obese adults (BMI mean: 26.1-31.6) (age range mean: 44.6-51.8) with T2DM, indicators of prediabetes, or who were metabolically healthy, participated in Cal Poly's Nutrition and Exercise in Type 2 Diabetes (CPNET) study. There were no significant differences in terms of age, BMI, or sex distribution among the groups at the baseline. This study's protocol included following a Mediterranean-style diet, the daily consumption of a high-quality whey protein supplement, and physical activity recommendations for 16 weeks. Body composition data, via dual-energy X-ray absorptiometry (DXA), and fasting blood samples were collected at the baseline and following the intervention. Due to restrictions associated with the outbreak of the COVID-19 pandemic, only 13 of the 22 participants who started this study were able to return for the second data collection to complete this study following the 16-week intervention. Results: The prediabetic and T2DM groups exhibited reductions in their fasting plasma glucose (12.0 mg/dL reduction in the prediabetic group; 19.6 mg/dL reduction in the T2DM group) to that of normal and prediabetic levels, respectively, while the T2DM group also demonstrated improvement in their hemoglobin A1c (reduced from 6.8% to 6.0%) to prediabetic levels. Additionally, the metabolically healthy, overweight group exhibited significant improvements in adiposity, while the obese prediabetic and T2DM groups showed non-significant improvements in all the measured metrics of body composition. No significant changes were observed in the inflammatory biomarkers (p-values ranged from 0.395 to 0.877). Conclusions: Collectively, our results suggest that adherence to a well-balanced, nutritious diet and activity may improve the parameters of glycemic control and provide benefits to body composition that help to manage and prevent the development of T2DM. Our study was able to yield significant findings signifying that the effects of a Mediterranean-style diet are observed even for a more conservative sample size.

A Randomized Controlled Trial of Tai Chi Chih or Health Education for Geriatric Depression.

OBJECTIVES: Geriatric depression is difficult to treat and frequently accompanied by treatment resistance, suicidal ideations and polypharmacy. New adjunctive mind-body treatment strategies can improve clinical outcomes in geriatric depression and reduce risk for side-effects of pharmacological treatments. METHODS: We conducted a 3-month randomized controlled trial to assess the efficacy and tolerability of combining Tai Chi Chih (TCC) or Health Education and Wellness training (HEW) with the stable standard antidepressant treatment on mood and cognitive functioning in depressed older adults (NCT02460666). Primary outcome was change in depression as assessed by the Hamilton Rating Scale for Depression (HAM-D) post-treatment. Remission was defined as HAM-D ≤ 6; naturalistic follow-up continued for 6 months. We also assessed psychological resilience, health-related quality of life and cognition. RESULTS: Of the 178 randomized participants, 125 completed the 3-month assessment and 117 completed the 6-month assessment. Dropout and tolerability did not differ between groups. Remission rate within TCC was 35.5% and 33.3%, compared to 27.0% and 45.8% in HEW, at 3 and 6 months respectively (χ2(1) = 1.0, p = 0.3; χ2(1) = 1.9, p =0.2). Both groups improved significantly on the HAM-D at 3 and 6 months. TCC demonstrated a greater improvement in general health compared to HEW. CONCLUSIONS: Both TCC and HEW combined with a standard antidepressant treatment improved symptoms of depression in older adults. While TCC was superior to HEW in improving general health, we did not find group differences in improvement in mood and cognition.

The Effect of Cumulative Lifetime Estrogen Exposure on Cognition in Depressed Versus Non-Depressed Older Women.

OBJECTIVES: Two-thirds of individuals living with Alzheimer's disease are women. Declining estrogen levels influence mood and cognition. Cumulative lifetime estrogen exposure (CLEE) correlates with cognition later in life. We examined the relationship of CLEE to depression and cognition in older women with major depression compared to non-depressed women. DESIGN: Older women (age ≥60 years) with depression were compared to non-depressed women using a lifetime estrogen exposure questionnaire. CLEE was defined as combined durations of reproductive span (age of menopause minus age of menarche) and any post-menopausal hormone replacement therapy use. Higher vs lower CLEE groups were based on a median of 474 months of estrogen exposure. SETTING: University hospital outpatient research program. PARTICIPANTS: 135 women ≥60 years; 64 depressed and 71 non-depressed. MEASURMENTS: Participants completed a comprehensive cognitive test battery. General linear models were used to examine the association between cognitive domain scores and CLEE in depressed and non-depressed women, controlling for age, education, and ethnicity. RESULTS: Depressed and non-depressed groups had significantly different levels of CLEE, measured in months: mean 495.7 (SD 108.6) vs 456.4 (SD 66.0) months, F(1,130) = 5.01, p = .03. Within the non-depressed participants, higher CLEE was associated with improved delayed recall (F(1,59) = 5.94, p = .02, effect size = .61), while no such relationship was observed in the depressed group. CONCLUSION: Higher CLEE was associated with improvement in delayed recall among non-depressed, but not among depressed participants. This suggests a protective role of estrogen on memory in non-depressed older postmenopausal women. Further research should examine the role of the CLEE in antidepressant response and cognitive decline.

Complementary and Integrative Medicine for Neurocognitive Disorders and Caregiver Health.

PURPOSE OF REVIEW: Integrative medicine is the practice of combining conventional medical treatments with "alternative" or "complementary" therapies. Integrative psychiatry is a holistic, person-centered approach to neuropsychiatric disorders that emphasizes a person's physical, emotional, interpersonal, behavioral, nutritional, environmental, and spiritual dimensions to achieve well-being. Older adults are more prone to physical injury, interpersonal loss, chronic illnesses, and physical and cognitive decline that can manifest as anxiety, depression, with functional decline and inability to care for self. Additionally, stress of caring for older adults with dementia can adversely affect caregivers' health. Although integrative approaches are perceived as safer and less stigmatizing, it is important to understand the risks and benefits of such therapies for older adults with neurocognitive disorders and their caregivers. RECENT FINDINGS: Here, we summarize the results of the recent clinical trials and meta-analyses that provide evidence for integrative approaches to treating older adults with cognitive disorders and their caregivers which include the use of diet and supplements, and mind-body therapies. Dietary and mind-body therapies have become increasingly popular and show the strongest evidence of effectiveness for cognitive disorders and caregiver stress. Vitamins and supplements are the most popular integrative intervention, but there is mixed evidence supporting their use and the concern for herb (supplement)-drug interactions. While there is increasing popularity of integrative treatments, information to guide clinicians providing care for older adults remains limited, with variable scientific rigor of the available RCTs for a large number of commonly used integrative interventions particularly for cognitive disorders and caregiver stress and well-being.

Development of a residents-as-teachers curriculum for neurosurgical training programs.

Neurosurgery residents spend a significant amount of their time teaching patients, families, students, residents, and other health professionals. To help ensure competence in their residents' teaching abilities, many specialties have established formal residents-as-teachers (RAT) curricula; however, such formalized curricula are often lacking in neurosurgery programs. The authors' goal was to develop and implement a formal RAT curriculum, designed with neurosurgery residents' other responsibilities in mind, to improve residents' formal and informal teaching abilities. Here, the authors report on the design of a formalized teaching curriculum tailored for the needs of neurosurgical residents, with a focus on deliberate practice and minimal time needed for preparation. The curriculum, designed using Kern's 6 steps of curriculum design as a framework, comprises 5 lecture series spread over 3 years, repeated twice through a resident's training, with each lecture series outlined with its respective topics and objectives. Opportunities for observed teaching as well as informal and formal evaluation will be provided to residents. The program will be evaluated on a yearly basis using direct and anonymized resident feedback on the RAT curriculum. Measures of program success will also include pre- and postprogram medical student and peer evaluation of residents. These data will be used for continual improvement of the curriculum as it is implemented. Successes and shortcomings of this program will be disseminated by publication, presentations, and placement on the authors' department website and social media. This paper may serve as a foundation for other neurosurgical programs to develop RAT curricula for greater enhancement of resident teaching abilities.

Evaluating the utility and quality of large administrative databases in pediatric spinal neurosurgery research.

PURPOSE: The purpose of this study was to assess the quality of articles utilizing large administrative databases to answer questions related to pediatric spinal neurosurgery by quantifying their adherence to standard reporting guidelines. METHODS: A systematic literature search was conducted with search terms including "pediatric" and "neurosurgery," associated neurosurgical diagnoses, and the names of known databases. Study abstracts were reviewed to identify clinical studies involving pediatric populations, spine-related pathology or procedures, and large administrative databases. Included studies were graded using the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) criteria. RESULTS: A total of 28 papers of the initial 1496 identified met inclusion criteria. These papers involved 10 databases and had a mean study period of 11.46 ± 12.27 years. The subjects of these research papers were undergoing treatment of scoliosis (n = 5), spinal cord injury (n = 5), spinal cord tumors (n = 9), and spine surgery in general (n = 9). The mean STROBE score was 19.41 ± 2.02 (out of 22). CONCLUSION: Large administrative databases are commonly used within pediatric spine-related neurosurgical research to cover a broad spectrum of research questions and study topics. The heterogeneity of research to this point encourages the continued use of large databases to better understand treatment and diagnostic trends, perioperative and long-term outcomes, and rare pathologies within pediatric spinal neurosurgery.

Engaging Church Leaders in the Reduction of Teen Birth Rate in High-Risk Areas.

Involving faith-based organizations in community health promotion has gained widespread interest and has been a successful approach in addressing various health disparities in vulnerable communities. However, there is comparatively little evidence regarding sexual health promotion among faith-based organizations. Some agencies have responded to the challenge of reducing teen pregnancy with broad-based initiatives involving many different sectors of the community including faith-based organizations. Focus groups with key church leaders (n = 25) from zip codes with identified birth rates of 95 or higher were conducted to explore their perception of teen pregnancy among their communities. Purposive and snowball sampling were utilized. Recruitment was conducted through calls, email, and flyers. This study identified the barriers that church leaders encounter in their efforts to address teen pregnancy in their communities. Common themes that emerged include church education, parent support and communication, cultural barriers, availability of resources, awareness of services, and the need for comprehensive sexual education. Findings and recommendations to help those working in the faith community overcome identified barriers are addressed. Recent decreases in teen birth rates should not lead to complacency; rather they should inspire public health practitioners to do more, especially when some communities have not experienced the same success. Collaborating with faith-based organizations is one method to consider when considering community prevention efforts.

A Pharmacokinetic and Pharmacodynamic Study of Oral Dexmedetomidine.

BACKGROUND: Dexmedetomidine is only approved for use in humans as an intravenous medication. An oral formulation may broaden the use and benefits of dexmedetomidine to numerous care settings. The authors hypothesized that oral dexmedetomidine (300 mcg to 700 mcg) would result in plasma concentrations consistent with sedation while maintaining hemodynamic stability. METHODS: The authors performed a single-site, open-label, phase I dose-escalation study of a solid oral dosage formulation of dexmedetomidine in healthy volunteers (n = 5, 300 mcg; followed by n = 5, 500 mcg; followed by n = 5, 700 mcg). The primary study outcome was hemodynamic stability defined as lack of hypertension, hypotension, or bradycardia. The authors assessed this outcome by analyzing raw hemodynamic data. Plasma dexmedetomidine concentrations were determined by liquid chromatograph-tandem mass spectrometry. Nonlinear mixed effect models were used for pharmacokinetic and pharmacodynamic analyses. RESULTS: Oral dexmedetomidine was associated with plasma concentration-dependent decreases in heart rate and mean arterial pressure. All but one subject in the 500-mcg group met our criteria for hemodynamic stability. The plasma concentration profile was adequately described by a 2-compartment, weight allometric, first-order absorption, first-order elimination pharmacokinetic model. The standardized estimated parameters for an individual of 70 kg was V1 = 35.6 [95% CI, 23.8 to 52.8] l; V2 = 54.7 [34.2 to 81.7] l; CL = 0.56 [0.49 to 0.64] l/min; and F = 7.2 [4.7 to 14.4]%. Linear models with effect sites adequately described the decreases in mean arterial pressure and heart rate associated with oral dexmedetomidine administration. However, only the 700-mcg group reached plasma concentrations that have previously been associated with sedation (>0.2 ng/ml). CONCLUSIONS: Oral administration of dexmedetomidine in doses between 300 and 700 mcg was associated with decreases in heart rate and mean arterial pressure. Despite low oral absorption, the 700-mcg dose scheme reached clinically relevant concentrations for possible use as a sleep-enhancing medication.

Oral Dexmedetomidine Promotes Non-rapid Eye Movement Stage 2 Sleep in Humans.

BACKGROUND: The administration of dexmedetomidine is limited to highly monitored care settings because it is only available for use in humans as intravenous medication. An oral formulation of dexmedetomidine may broaden its use to all care settings. The authors investigated the effect of a capsule-based solid oral dosage formulation of dexmedetomidine on sleep polysomnography. METHODS: The authors performed a single-site, placebo-controlled, randomized, crossover, double-blind phase II study of a solid oral dosage formulation of dexmedetomidine (700 mcg; n = 15). The primary outcome was polysomnography sleep quality. Secondary outcomes included performance on the motor sequence task and psychomotor vigilance task administered to each subject at night and in the morning to assess motor memory consolidation and psychomotor function, respectively. Sleep questionnaires were also administered. RESULTS: Oral dexmedetomidine increased the duration of non-rapid eye movement (non-REM) stage 2 sleep by 63 (95% CI, 19 to 107) min (P = 0.010) and decreased the duration of rapid eye movement (REM) sleep by 42 (5 to 78) min (P = 0.031). Overnight motor sequence task performance improved after placebo sleep (7.9%; P = 0.003) but not after oral dexmedetomidine-induced sleep (-0.8%; P = 0.900). In exploratory analyses, we found a positive correlation between spindle density during non-REM stage 2 sleep and improvement in the overnight test performance (Spearman rho = 0.57; P = 0.028; n = 15) for placebo but not oral dexmedetomidine (Spearman rho = 0.04; P = 0.899; n = 15). Group differences in overnight motor sequence task performance, psychomotor vigilance task metrics, and sleep questionnaires did not meet the threshold for statistical significance. CONCLUSIONS: These results demonstrate that the nighttime administration of a solid oral dosage formulation of dexmedetomidine is associated with increased non-REM 2 sleep and decreased REM sleep. Spindle density during dexmedetomidine sleep was not associated with overnight improvement in the motor sequence task.

Pharmacist impact on health outcomes in a homeless population.

OBJECTIVE: The aim of this study was to analyze the effect of clinical pharmacy services on health outcomes and medication adherence concerning hypertension and diabetes in the homeless population. METHODS: This was a retrospective quasi-experimental study conducted between January 1, 2015, and December 31, 2016. The primary outcomes included median blood pressure and median glycosylated hemoglobin (A1C) change from baseline. The secondary end points included adherence to hypertension and diabetes medication, in addition to the differences in the number of admissions to urgent care clinics, emergency departments, or hospitals pre- and postpharmacist clinic visit. RESULTS: One-hundred ninety-eight homeless patients were seen by a pharmacist over the study time frame, and 116 of these patients were included. There was a decrease in systolic and diastolic blood pressure in the 6-months postpharmacist visit (139 mm Hg vs. 135 mm Hg, P = 0.413, and 85 mm Hg vs. 82 mm Hg, P = 0.197, respectively). The percentage of patients who met the blood pressure goals increased from 55% to 66% (P = 0.093). A statistically significant decrease in A1C was found (7.7% vs 7.2%, P = 0.038). The number of patients who met the A1C goal increased from 20% to 41% (P = 0.267) after pharmacist intervention. No medication class was associated with a median proportion of days covered of 80% or greater. However, differences were seen with biguanides (34% vs. 43%, P = 0.004), calcium channel blockers (44% vs. 59%, P < 0.001), and thiazides (28% vs. 39%, P = 0.039) pre- and postintervention. There was no difference in the number of visits to emergency departments or urgent care clinics, or hospitalizations. CONCLUSION: Homeless patients with hypertension and type 2 diabetes who had at least 1 visit with a pharmacist showed some improved health outcomes. Statistically significant benefits were seen in diabetes management, but not for blood pressure control.

Second Generation G-Quadruplex Stabilizing Trimethine Cyanines.

G-Quadruplex DNA has been recognized as a highly appealing target for the development of new selective chemotherapeutics, which could result in markedly reduced toxicity toward normal cells. In particular, the cyanine dyes that bind selectively to G-quadruplex structures without targeting duplex DNA have attracted attention due to their high amenability to structural modifications that allows fine-tuning of their biomolecular interactions. We have previously reported pentamethine and symmetric trimethine cyanines designed to effectively bind G-quadruplexes through end stacking interactions. Herein, we are reporting a second generation of drug candidates, the asymmetric trimethine cyanines. These have been synthesized and evaluated for their quadruplex binding properties. Incorporating a benz[c,d]indolenine heterocyclic unit increased overall quadruplex binding, and elongating the alkyl length increases the quadruplex-to-duplex binding specificity.