Evidence to support health system prioritization of health behaviors in the COVID-19 era.

BACKGROUND: Since the COVID-19 pandemic health systems have shifted necessarily from chronic to infectious disease treatment, but chronic disease remains critical. One large health system uniquely tracks member health behaviors. This analysis compares data from select months of an ongoing monthly cross-sectional survey before and during the pandemic. METHODS: Responses in April 2019 (pre-pandemic), April 2020 (early pandemic) or April 2021 (later pandemic) were included in the primary analysis (N = 252). Differences in meeting health behavior guidelines were analyzed via logistic regression. RESULTS: A significant decline was seen for physical activity (19% not meeting guidelines pre-pandemic vs. 41% later pandemic) but not fruit/vegetable, alcohol, or sleep from early to later pandemic. Prevalence of women not meeting tobacco guidelines increased from early (5%) to later pandemic (10%) while prevalence in men decreased (10% vs 4% respectively). The percent of people not thinking about the good things that happen to them fluctuated closely with reports of new COVID-19 cases. CONCLUSIONS: Findings show the nuance of changing health behaviors throughout the pandemic. Results should be used by health systems to tailor support based on insights from the pandemic experience.

Orexin Receptor Antagonism: Normalizing Sleep Architecture in Old Age and Disease.

Sleep is essential for human well-being, yet the quality and quantity of sleep reduce as age advances. Older persons (>65 years old) are more at risk of disorders accompanied and/or exacerbated by poor sleep. Furthermore, evidence supports a bidirectional relationship between disrupted sleep and Alzheimer's disease (AD) or related dementias. Orexin/hypocretin neuropeptides stabilize wakefulness, and several orexin receptor antagonists (ORAs) are approved for the treatment of insomnia in adults. Dysregulation of the orexin system occurs in aging and AD, positioning ORAs as advantageous for these populations. Indeed, several clinical studies indicate that ORAs are efficacious hypnotics in older persons and dementia patients and, as in adults, are generally well tolerated. ORAs are likely to be more effective when administered early in sleep/wake dysregulation to reestablish good sleep/wake-related behaviors and reduce the accumulation of dementia-associated proteinopathic substrates. Improving sleep in aging and dementia represents a tremendous opportunity to benefit patients, caregivers, and health systems.

Client-reported quality of facility-managed medication abortion compared with pharmacy-sourced self-managed abortion in Bangladesh.

OBJECTIVE: We used the newly developed Abortion Care Quality Tool (ACQTool) to compare client-reported quality of medication abortion care by source (facility-managed vs pharmacy-sourced self-managed abortion (SMA)) in Bangladesh. METHODS: We leveraged exit and 30-day follow-up surveys collected to develop and validate the ACQTool collected at nongovernmental organisation (NGO)-supported or -operated facilities in the public and private sector and pharmacies from three districts in Bangladesh. We used bivariate statistics to compare 18 client-reported quality indicators grouped in six domains and eight abortion outcomes, by source (facility vs pharmacy). We used multivariable logistic regression to identify factors associated with selected quality indicators and outcomes (abortion affordability, information provision, and knowing what to do for an adverse event), controlling for client sociodemographic characteristics. RESULTS: Of 550 abortion clients, 146 (26.5%) received a facility-managed medication abortion and 404 (73.5%) had a pharmacy-sourced SMA. Clients reported higher quality in facilities for five indicators, and higher in pharmacies for two indicators; the remaining 11 indicators were not different by source. Compared with facility-based clients, pharmacy clients had higher odds of reporting that the cost of abortion was affordable (adjusted odds ratio (aOR) 3.55; 95% CI 2.27 to 5.58) but lower odds of reporting high information provision (aOR 0.14; 95% CI 0.09 to 0.23). Seven of eight abortion outcomes showed no differences; pharmacy clients had lower odds of knowing what to do if an adverse event occurred (aOR 0.45; 95% CI 0.23 to 0.82). CONCLUSIONS: In Bangladesh, there is no difference in client-reported quality of medication abortion care between health facilities and pharmacies for the majority of quality and outcome indicators. However, information provision and preparedness were higher quality at facilities, while pharmacies were more affordable.

Orexin 2 receptor antagonism sex-dependently improves sleep/wakefulness and cognitive performance in tau transgenic mice.

BACKGROUND AND PURPOSE: Tau pathology contributes to a bidirectional relationship between sleep disruption and neurodegenerative disease. Tau transgenic rTg4510 mice model tauopathy symptoms, including sleep/wake disturbances, which manifest as marked hyperarousal. This phenotype can be prevented by early transgene suppression; however, whether hyperarousal can be rescued after onset is unknown. EXPERIMENTAL APPROACH: Three 8-week experiments were conducted with wild-type and rTg4510 mice after age of onset of hyperarousal (4.5 months): (1) Tau transgene suppression with doxycycline (200 ppm); (2) inactive phase rapid eye movement (REM) sleep enhancement with the dual orexin receptor antagonist suvorexant (50 mg·kg-1 ·day-1 ); or (3) Active phase non-NREM (NREM) and REM sleep enhancement using the selective orexin 2 (OX2 ) receptor antagonist MK-1064 (40 mg·kg-1 ·day-1 ). Sleep was assessed using polysomnography, cognition using the Barnes maze, and tau pathology using immunoblotting and/or immunohistochemistry. KEY RESULTS: Tau transgene suppression improved tauopathy and hippocampal-dependent spatial memory, but did not modify hyperarousal. Pharmacological rescue of REM sleep deficits did not improve spatial memory or tau pathology. In contrast, normalising hyperarousal by increasing both NREM and REM sleep via OX2 receptor antagonism restored spatial memory, independently of tauopathy, but only in male rTg4510 mice. OX2 receptor antagonism induced only short-lived hypnotic responses in female rTg4510 mice and did not improve spatial memory, indicating a tau- and sex-dependent disruption of OX2 receptor signalling. CONCLUSIONS AND IMPLICATIONS: Pharmacologically reducing hyperarousal corrects tau-induced sleep/wake and cognitive deficits. Tauopathy causes sex-dependent disruptions of OX2 receptor signalling/function, which may have implications for choice of hypnotic therapeutics in tauopathies.

Quality of care from the perspective of people obtaining abortion: a qualitative study in four countries.

OBJECTIVE: This qualitative study aimed to identify person-centred domains that would contribute to the definition and measurement of abortion quality of care based on the perceptions, experiences and priorities of people seeking abortion. METHODS: We conducted interviews with people seeking abortion aged 15-41 who obtained care in Argentina, Bangladesh, Ethiopia or Nigeria. Participants were recruited from hospitals, clinics, pharmacies, call centres and accompaniment models. We conducted thematic analysis and quantified key domains of quality identified by the participants. RESULTS: We identified six themes that contributed to high-quality abortion care from the clients' perspective, with particular focus on interpersonal dynamics. These themes emerged as participants described their abortion experience, reflected on their interactions with providers and defined good and bad care. The six themes included (1) kindness and respect, (2) information exchange, (3) emotional support, (4) attentive care throughout the process, (5) privacy and confidentiality and (6) prepared for and able to cope with pain. CONCLUSIONS: People seeking abortion across multiple country contexts and among various care models have confirmed the importance of interpersonal care in quality. These findings provide guidance on six priority areas which could be used to sharpen the definition of abortion quality, improve measurement, and design interventions to improve quality.

Association of maternal age 35 years and over and prenatal care utilization, preterm birth, and low birth weight, Mexico 2008-2019.

OBJECTIVE: To evaluate prenatal care utilization, low birth weight, and preterm birth among women aged 35 years and older in Mexico from 2008 to 2019. METHODS: We conducted a historical cohort study of all singleton live births in Mexico from 2008 to 2019. Outcomes were inadequate prenatal care, preterm birth, and low birth weight. We compared outcomes among women aged 35-39, 40-44, and 45-49 years with births to women aged 20-34 years. We used logistic regression to account for individual, health system, and contextual confounders. RESULTS: We included a total of 19 526 922 births; 2 325 725 (11.9%) were to women aged 35 years and older. Women aged 45-49 years had the lowest levels of education, were more likely to be uninsured, and came from highly marginalized municipalities while those aged 35-39 years had the highest levels of education and insurance and came from the least marginalized municipalities. The odds of inadequate prenatal care (adjusted odds ratio [aOR] 1.12; 95% confidence interval [CI] 1.09-1.15), preterm birth (aOR 2.05; 95% CI 1.97-2.13), and low birth weight (aOR 2.03; 95% CI 1.95-2.12) were highest for women aged 45-49 years, compared with women aged 20-34 years. The odds of adverse perinatal outcomes increased progressively with age, but the odds of inadequate prenatal care (aOR 0.77; 95% CI 0.76-0.77) were lowest for women aged 35-39 years, when compared with women aged 20-34 years. CONCLUSION: Women who deliver at 35 years and over are a heterogeneous group in Mexico. Being 35 years old and older is associated with increases in preterm birth and low birth weight neonates. Women who give birth between 45 and 49 years may be especially vulnerable.

Default Mode Network Modulation by Psychedelics: A Systematic Review.

Psychedelics are a unique class of drug that commonly produce vivid hallucinations as well as profound psychological and mystical experiences. A grouping of interconnected brain regions characterized by increased temporal coherence at rest have been termed the Default Mode Network (DMN). The DMN has been the focus of numerous studies assessing its role in self-referencing, mind wandering, and autobiographical memories. Altered connectivity in the DMN has been associated with a range of neuropsychiatric conditions such as depression, anxiety, post-traumatic stress disorder, attention deficit hyperactive disorder, schizophrenia, and obsessive-compulsive disorder. To date, several studies have investigated how psychedelics modulate this network, but no comprehensive review, to our knowledge, has critically evaluated how major classical psychedelic agents-lysergic acid diethylamide, psilocybin, and ayahuasca-modulate the DMN. Here we present a systematic review of the knowledge base. Across psychedelics there is consistent acute disruption in resting state connectivity within the DMN and increased functional connectivity between canonical resting-state networks. Various models have been proposed to explain the cognitive mechanisms of psychedelics, and in one model DMN modulation is a central axiom. Although the DMN is consistently implicated in psychedelic studies, it is unclear how central the DMN is to the therapeutic potential of classical psychedelic agents. This article aims to provide the field with a comprehensive overview that can propel future research in such a way as to elucidate the neurocognitive mechanisms of psychedelics.

Altered EEG power spectrum, but not sleep-wake architecture, in HCN1 knockout mice.

Sleep is a complex biological state characterized by large populations of neurons firing in a rhythmic or synchronized manner. HCN channels play a critical role in generating and sustaining synchronized neuronal firing and are involved in the actions of anaesthetics. However, the role of these channels in sleep-wakefulness per se has yet to be studied. We conducted polysomnographic recordings of Hcn1 constitutive knockout (Hcn1 KO) and wild-type (WT) mice in order to investigate the potential role of HCN1 channels in sleep/wake regulation. EEG and EMG data were analysed using the Somnivore™ machine learning algorithm. Time spent in each vigilance state, bout number and duration, and EEG power spectral activity were compared between genotypes. There were no significant differences in the time spent in wake, rapid eye movement (REM) or non-REM (NREM) sleep between Hcn1 KO and WT mice. Wake bout duration during the inactive phase was significantly shorter in Hcn1 KO mice whilst no other bout parameters were affected by genotype. Hcn1 KO mice showed a reduction in overall EEG power which was particularly prominent in the theta (5-9 Hz) and alpha (9-15 Hz) frequency bands and most evident during NREM sleep. Together these data suggest that HCN1 channels do not play a major role in sleep architecture or modulation of vigilance states. However, loss of these channels significantly alters underlying neuronal activity within these states which may have functional consequences.

An Updated Model Does Not Reveal Sex Differences in Patellofemoral Joint Stress during Running.

Background: Structure-specific loading may have implications in understanding the mechanisms of running related injury. As females demonstrate a prevalence of patellofemoral pain twice that of males, this may indicate differences in patellofemoral loads between males and females. Previous works investigating differences in patellofemoral joint stress have shown conflicting results, but the models employed have not used estimates of muscle forces or sex specific contact areas. Hypothesis/Purpose: The aim of this study was to examine sex differences in patellofemoral joint stress using an updated model to include estimates of quadriceps muscle force and sex-specific patellofemoral contact area. Study Design: Descriptive Laboratory Study. Methods: Forty-five healthy recreational runners ran at a controlled speed down a 20-meter runway. Kinetic and kinematic data were utilized to estimate muscle forces using static optimization. Quadriceps muscle force was utilized with sex-specific patellofemoral joint contact area in a two-dimensional patellofemoral joint model to estimate patellofemoral joint stress. Multivariate tests were utilized to detect sex differences in patellofemoral loading and hip and knee kinematics. Results: No differences were found between sexes in measures of patellofemoral loading or quadriceps force. Females displayed a reduced knee extension moment and greater hip adduction and internal rotation than males. Conclusion: The inclusion of static optimization to estimate quadriceps muscle force and sex-specific contact area of the patellofemoral joint did not reveal sex differences in patellofemoral joint stress, but differences in non-sagittal plane hip motion were detected. Therefore, two-dimensional patellofemoral models may not fully characterize differences in patellofemoral joint stress between males and females. Three-dimensional patellofemoral models may be necessary to determine if sex differences in patellofemoral joint stress exist. Level of Evidence: 3b.

"I was afraid they will be judging me and even deny me the service": Experiences of denial and dissuasion during abortion care in Ethiopia.

Introduction: Disrespect and abuse are components of poor quality abortion care. This analysis aimed to understand negative experiences of care from perspectives of abortion clients in public and private facilities in Ethiopia. Study Design: We conducted 23 in-depth interviews with people who obtained abortion care in Addis Ababa, Ethiopia as well as Aksum and Mekele in Tigray State, Ethiopia. The interviews were coded using a priori and emergent codes and we conducted thematic analysis to understand negative interactions with providers from participant's perspectives. Results: Participants experienced denial of abortion services along their pathway to care and attempts by providers to dissuade them prior to providing an abortion. Underlying both the denial and the dissuasion were reports of disrespect and condemnation from providers. Participants described how providers doubted or forced them to justify their reasons for having an abortion, stigmatized them for seeking multiple abortions or later abortions, and ascribed misinformation about abortion safety. Despite reports of denial, dissuasion, and disrespect, abortion clients generally felt that providers had their best interest at heart and were grateful for having access to an abortion. Conclusions: Participants in Ethiopia experienced providers as gatekeepers to legal abortion services, facing disrespect and judgment at facilities where they sought care. Interventions aimed at increasing awareness of abortion laws such that clients understand their rights and values clarification interventions for providers could help reduce barriers to accessing care and improve the quality of abortion services.

Adolescent Reproductive Health Outcomes Among Mexican-Origin Women on Both Sides of the U.S.-Mexico Border.

PURPOSE: Much reproductive health research on the Latina population overlooks heterogeneity by national origin, nativity, and age and also ignores how U.S.-based populations differ from those in "sending" nations. The purpose of this study is to describe a history of adolescent birth, age at first sex, and contraceptive use at first sex in the Mexican-origin population in both the United States and Mexico. METHODS: We developed a binational dataset merging two comparable nationally representative cross-sectional surveys in the United States and Mexico and used covariate balancing propensity scores to balance the age structure of our four samples: U.S.-born Latinas of Mexican origin, foreign-born Latinas of Mexican origin, U.S.-born non-Latina Whites, and Mexican women residing in Mexico. We used a negative binomial regression and calculated the predicted probability of experiencing at least one adolescent birth for each ethnicity/nativity group, stratified by 5-year age group. We also described age and contraceptive use at first sex. RESULTS: Foreign-born Latinas of Mexican origin and Mexicans in Mexico had similar adjusted probabilities of reporting an adolescent birth (30.1% and 29.9%, respectively), which were higher than those of Mexican-Americans (26.2%) and U.S.-born non-Latina Whites (11.6%). History of an adolescent birth is declining across all four groups among younger ages. Differences do not appear to be driven by the timing of first sex but by contraceptive use, which is increasing among younger age groups. DISCUSSION: Access to and use of effective contraception rather than timing of initiation of sexual activity is a key determinant of U.S. Latina and Mexican adolescent births.

Orexin Signaling: A Complex, Multifaceted Process.

The orexin system comprises two G protein-coupled receptors, OX1 and OX2 receptors (OX1R and OX2R, respectively), along with two endogenous agonists cleaved from a common precursor (prepro-orexin), orexin-A (OX-A) and orexin-B (OX-B). For the receptors, a complex array of signaling behaviors has been reported. In particular, it becomes obvious that orexin receptor coupling is very diverse and can be tissue-, cell- and context-dependent. Here, the early signal transduction interactions of the orexin receptors will be discussed in depth, with particular emphasis on the direct G protein interactions of each receptor. In doing so, it is evident that ligands, additional receptor-protein interactions and cellular environment all play important roles in the G protein coupling profiles of the orexin receptors. This has potential implications for our understanding of the orexin system's function in vivo in both central and peripheral environments, as well as the development of novel agonists, antagonists and possibly allosteric modulators targeting the orexin system.

Characterizing persistent urinary incontinence after successful fistula closure: the Uganda experience.

BACKGROUND: Obstetric fistula is a devastating childbirth injury. Despite successful closure of the fistula, 16% to 55% of women suffer from persistent urinary incontinence after surgery. OBJECTIVE: This study assessed the type and severity of persistent incontinence after successful fistula closure and its impact on the quality of life of Ugandan women post-fistula treatment. STUDY DESIGN: This cross-sectional study enrolled women with a history of obstetric fistula repair who continued to have persistent urinary incontinence (cases, N=36) and women without incontinence (controls, N=52) after successful fistula closure. Data were collected in central and eastern Uganda between 2017 and 2019. All the participants completed a semistructured questionnaire. Cases underwent a clinical evaluation and a 2-hour pad test and completed a series of incontinence questionnaires, including two novel tools designed to assess the severity of incontinence in low-literacy populations. RESULTS: Cases were more likely to have acquired a fistula during their first delivery (63% vs 37%, P=.02), were younger when they developed a fistula (20.3±5.8 vs 24.8±7.5 years old, P=.003), and were more likely to have had >2 fistula surgeries (67% vs 2%, P≤.001). Cases reported a much higher rate of planned home birth for their index pregnancy compared to controls (44% vs 11%), though only 14% of cases and 12% of controls actually delivered at home. Cases reported higher rates of pain with intercourse (36% vs 18%, P=.05), but recent sexual activity status (intercourse within the previous six months) was not significantly different between the groups (47% vs 62%, P=.18). Among cases, 67% reported stress incontinence, 47% reported urgency incontinence, and 47% reported mixed incontinence. The cough stress test was successfully done with 92% of the cases, and of these, almost all (97%) had a positive cough stress test. More than half (53%) rated their incontinence as "very severe," which was consistent with objective findings. The 24-hour voiding diary indicated both high urinary frequency (average 14) and very frequent leakage episodes (average 20). Two-hour pad-tests indicated that 86% of cases had >4 g change in pad weight within 2 hours. Women with more severe incontinence reported a more negative impact on their quality of life. The mean score of the International Consultation on Incontinence Questionnaire-Quality of Life was 62.77±12.76 (range, 28-76, median=67), with a higher score indicating a greater impact on the quality of life. There was also a high mental health burden, with both cases and controls reporting high rates of suicidal ideation at any point since developing fistula (36% vs 31%, P=.67). CONCLUSION: Women with obstetric fistulas continue to suffer from severe persistent urinary incontinence even after successful fistula closure. Both stress and urgency incontinence are highly prevalent in this population. Worsening severity of incontinence is associated with a greater negative impact on the quality of life.

Losing sleep with age.

Hypocretin neuron hyperexcitability underlies disrupted sleep quality associated with age.

Differential sleep/wake response and sex differences following acute suvorexant, MK-1064 and zolpidem administration in the rTg4510 mouse model of tauopathy.

BACKGROUND AND PURPOSE: Transgenic mouse models of tauopathy display prominent sleep/wake disturbances which manifest primarily as a hyperarousal phenotype during the active phase, suggesting that tau pathology contributes to sleep/wake changes. However, no study has yet investigated the effect of sleep-promoting compounds in these models. Such information has implications for the use of hypnotics as potential therapeutic tools in tauopathy-related disorders. EXPERIMENTAL APPROACH: This study examined polysomnographic recordings in 6-6.5-month-old male and female rTg4510 mice following acute administration of suvorexant (50 mg·kg-1 ), MK-1064 (30 mg·kg-1 ) or zolpidem (10 mg·kg-1 ), administered at the commencement of the active phase. KEY RESULTS: Suvorexant, a dual OX receptor antagonist, promoted REM sleep in rTg4510 mice, without affecting wake or NREM sleep. MK-1064, a selective OX2 receptor antagonist, reduced wake and increased NREM and total sleep time. MK-1064 normalised the hyperarousal phenotype of male rTg4510 mice, whereas female rTg4510 mice exhibited a more transient response. Zolpidem, a GABAA receptor positive allosteric modulator, decreased wake and increased NREM sleep in both male and female rTg4510 mice. Of the three compounds, the OX2 receptor antagonist MK-1064 promoted and normalised physiologically normal sleep, especially in male rTg4510 mice. CONCLUSIONS AND IMPLICATIONS: Our findings indicate that hyperphosphorylated tau accumulation and associated hyperarousal does not significantly alter the responses of tauopathy mouse models to hypnotics. However, the sex differences observed in the sleep/wake response of rTg4510 mice to MK-1064, but not suvorexant or zolpidem, raise questions about therapeutic implications for the use of OX2 receptor antagonists in human neurodegenerative disorders.

Hypocretins (orexins): The ultimate translational neuropeptides.

The hypocretins (Hcrts), also known as orexins, are two neuropeptides produced exclusively in the lateral hypothalamus. They act on two specific receptors that are widely distributed across the brain and involved in a myriad of neurophysiological functions that include sleep, arousal, feeding, reward, fear, anxiety and cognition. Hcrt cell loss in humans leads to narcolepsy with cataplexy (narcolepsy type 1), a disorder characterized by intrusions of sleep into wakefulness, demonstrating that the Hcrt system is nonredundant and essential for sleep/wake stability. The causal link between Hcrts and arousal/wakefulness stabilisation has led to the development of a new class of drugs, Hcrt receptor antagonists to treat insomnia, based on the assumption that blocking orexin-induced arousal will facilitate sleep. This has been clinically validated: currently, two Hcrt receptor antagonists are approved to treat insomnia (suvorexant and lemborexant), with a New Drug Application recently submitted to the US Food and Drug Administration for a third drug (daridorexant). Other therapeutic applications under investigation include reduction of cravings in substance-use disorders and prevention of neurodegenerative disorders such as Alzheimer's disease, given the apparent bidirectional relationship between poor sleep and worsening of the disease. Circuit neuroscience findings suggest that the Hcrt system is a hub that integrates diverse inputs modulating arousal (e.g., circadian rhythms, metabolic status, positive and negative emotions) and conveys this information to multiple output regions. This neuronal architecture explains the wealth of physiological functions associated with Hcrts and highlights the potential of the Hcrt system as a therapeutic target for a number of disorders. We discuss present and future possible applications of drugs targeting the Hcrt system for the treatment of circuit-related neuropsychiatric and neurodegenerative conditions.

Travelling for abortion services in Mexico 2016-2019: community-level contexts of Mexico City public abortion clients.

OBJECTIVE: To describe the community context of women who travel to access Mexico City's public sector abortion programme and identify factors associated with travelling from highly marginalised settings. METHODS: We used data from the Interrupción Legal de Embarazo (ILE) programme (2016-2019) and identified all abortion clients who travelled from outside Mexico City. We merged in contextual information at the municipality level and used descriptive statistics to describe ILE clients' individual characteristics and municipalities on several measures of vulnerability. We also compared municipalities that ILE clients travelled from with those where no one travelled from. We used logistic regression to identify factors associated with travelling to access ILE services from highly marginalised versus less marginalised municipalities. RESULTS: Our sample included 21 629 ILE clients who travelled to Mexico City from 491 municipalities within all 31 states outside Mexico City. The majority of clients travelled from the least marginalised (81.9%) and most populated (over 100 000 inhabitants; 91.3%) municipalities. Most (91.2%) ILE clients came from municipalities with adolescent fertility rates in the bottom three quintiles. Clients with a primary or secondary education (vs high school or more) and those from a municipality with a high adolescent fertility rate (top two quintiles) had higher odds of travelling from a highly marginalised (vs less) municipality (adjusted odds ratio (aOR) 1.46, 95% CI 1.35 to 1.58 and aOR 1.89, 95% CI 1.68 to 2.12, respectively). CONCLUSION: ILE clients travel from geographically and socioeconomically diverse communities. There is an unmet need for legal abortion across Mexico.

Evaluation of Shared Experiences Among Patients and Providers Following Behavioral Health Integration in Primary Care.

Behavioral health integration (BHI) changes the paradigm of primary care delivery by integrating behavioral healthcare into primary care. Thus, BHI likely alters the shared experiences of both patients and providers in an interrelated manner; however, their experiences are usually evaluated separately. The purpose of this study was to analyze these shared experiences together within patient-provider pairs in integrated clinics. First, patient interviews were conducted using semi-structured interview guides and transcripts were analyzed for major themes of patient experience. Next, providers named in patient interviews were interviewed around these same themes. Thematic analysis was performed on 18 transcripts (11 patients, 7 providers). Common themes included BHI experience, pain management, feeling heard by providers, and health care experiences. Areas of alignment included positive perception of BHI, an absence of long-term care, and a desire to share decision-making. Pain management was a persistent area of conflict, and the differing experiences were consistent with a change in the psychodynamic patient-provider model. This conflict highlights a gap in BHI and a need for provider education about psychodynamic relationship models.

Discovery of Umibecestat (CNP520): A Potent, Selective, and Efficacious ß-Secretase (BACE1) Inhibitor for the Prevention of Alzheimer's Disease.

After identification of lead compound 6, 5-amino-1,4-oxazine BACE1 inhibitors were optimized in order to improve potency, brain penetration, and metabolic stability. Insertion of a methyl and a trifluoromethyl group at the 6-position of the 5-amino-1,4-oxazine led to 8 (NB-360), an inhibitor with a pKa of 7.1, a very low P-glycoprotein efflux ratio, and excellent pharmacological profile, enabling high central nervous system penetration and exposure. Fur color changes observed with NB-360 in efficacy studies in preclinical animal models triggered further optimization of the series. Herein, we describe the steps leading to the discovery of 3-chloro-5-trifluoromethyl-pyridine-2-carboxylic acid [6-((3R,6R)-5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-fluoro-pyridin-2-yl]amide 15 (CNP520, umibecestat), an inhibitor with superior BACE1/BACE2 selectivity and pharmacokinetics. CNP520 reduced significantly Aß levels in mice and rats in acute and chronic treatment regimens without any side effects and thus qualified for Alzheimer's disease prevention studies in the clinic.

Effects of simvastatin on white matter integrity in healthy middle-aged adults.

BACKGROUND: The brain is the most cholesterol-rich organ and myelin contains 70% of total brain cholesterol. Statins are potent cholesterol-lowing medications used by millions of adults for prevention of vascular disease, yet the effect of statins on cholesterol-rich brain white matter (WM) is largely unknown. METHODS: We used longitudinal neuroimaging data acquired from 73 healthy, cognitively unimpaired, statin-naïve, middle-aged adults during an 18-month randomized controlled trial of simvastatin 40 mg daily (n = 35) or matching placebo (n = 38). ANCOVA models (covariates: age, sex, APOE-ɛ4) tested the effect of treatment group on percent change in WM, gray matter (GM), and WM hyperintensity (WMH) neuroimaging measures at each study visit. Mediation analysis tested the indirect effects of simvastatin on WM microstructure through change in serum total cholesterol levels. RESULTS: At 18 months, the simvastatin group showed a significant preservation in global WM fractional anisotropy (ß = 0.88%, 95% CI 0.27 to 1.50, P = 0.005), radial diffusivity (ß = -1.10%, 95% CI -2.13 to -0.06, P = 0.039), and WM volume (ß = 0.72%, 95% CI 0.13 to 1.32, P = 0.018) relative to the placebo group. There was no significant effect of simvastatin on GM or WMH volume. Change in serum total cholesterol mediated approximately 30% of the effect of simvastatin on WM microstructure. CONCLUSIONS: Simvastatin treatment in healthy, middle-aged adults resulted in preserved WM microstructure and volume at 18 months. The partial mediation by serum cholesterol reduction suggests both peripheral and central mechanisms. Future studies are needed to determine whether these effects persist and translate to cognitive outcomes. TRIAL REGISTRATION: NCT00939822 (ClinicalTrials.gov).