CRISPR-based genome editing of a diurnal rodent, Nile grass rat (Arvicanthis niloticus).

BACKGROUND: Diurnal and nocturnal mammals have evolved distinct pathways to optimize survival for their chronotype-specific lifestyles. Conventional rodent models, being nocturnal, may not sufficiently recapitulate the biology of diurnal humans in health and disease. Although diurnal rodents are potentially advantageous for translational research, until recently, they have not been genetically tractable. The present study aims to address this major limitation by developing experimental procedures necessary for genome editing in a well-established diurnal rodent model, the Nile grass rat (Arvicanthis niloticus). RESULTS: A superovulation protocol was established, which yielded nearly 30 eggs per female grass rat. Fertilized eggs were cultured in a modified rat 1-cell embryo culture medium (mR1ECM), in which grass rat embryos developed from the 1-cell stage into blastocysts. A CRISPR-based approach was then used for gene editing in vivo and in vitro, targeting Retinoic acid-induced 1 (Rai1), the causal gene for Smith-Magenis Syndrome, a neurodevelopmental disorder. The CRISPR reagents were delivered in vivo by electroporation using an improved Genome-editing via Oviductal Nucleic Acids Delivery (i-GONAD) method. The in vivo approach produced several edited founder grass rats with Rai1 null mutations, which showed stable transmission of the targeted allele to the next generation. CRISPR reagents were also microinjected into 2-cell embryos in vitro. Large deletion of the Rai1 gene was confirmed in 70% of the embryos injected, demonstrating high-efficiency genome editing in vitro. CONCLUSION: We have established a set of methods that enabled the first successful CRISPR-based genome editing in Nile grass rats. The methods developed will guide future genome editing of this and other diurnal rodent species, which will promote greater utility of these models in basic and translational research.

Daytime Light Deficiency Leads to Sex- and Brain Region-Specific Neuroinflammatory Responses in a Diurnal Rodent.

Seasonal changes in peripheral inflammation are well documented in both humans and animal models, but seasonal changes in neuroinflammation, especially the impact of seasonal lighting environment on neuroinflammation remain unclear. To address this question, the present study examined the effects of environmental lighting conditions on neuroinflammation in a diurnal rodent model, Nile grass rats (Arvicanthis niloticus). Male and female grass rats were housed in either bright (brLD) or dim (dimLD) light during the day to simulate a summer or winter light condition, respectively. After 4 weeks, microglia markers Iba-1 and CD11b, as well as pro-inflammatory cytokines TNF-α and IL-6, were examined in the anterior cingulate cortex (ACC), basolateral amygdala (BLA), and dorsal hippocampus (dHipp). The results revealed that winter-like dim light during the day leads to indicators of increased neuroinflammation in a brain site- and sex-specific manner. Specifically, relatively few changes in the neuroinflammatory markers were observed in the ACC, while numerous changes were found in the BLA and dHipp. In the BLA, winter-like dimLD resulted in hyper-ramified microglia morphology and increased expression of the pro-inflammatory cytokine IL-6, but only in males. In the dHipp, dimLD led to a higher number and hyper-ramified morphology of microglia as well as increased expression of CD11b and TNF-α, but only in females. Neuroinflammatory state is thus influenced by environmental light, differently in males and females, and could play a role in sex differences in the prevalence and symptoms of psychiatric or neurological disorders that are influenced by season or other environmental light conditions. Diurnal Nile grass rats were housed under bright or dim light during the day for 4 weeks, simulating seasonal fluctuations in daytime lighting environment. Dim light housing resulted in hyper-ramified morphology of microglia (scale bar, 15 µm) and altered expression of pro-inflammatory cytokines (TNF-α) in a sex- and brain region-specific manner.

A haplotype-resolved genome assembly of the Nile rat facilitates exploration of the genetic basis of diabetes.

BACKGROUND: The Nile rat (Avicanthis niloticus) is an important animal model because of its robust diurnal rhythm, a cone-rich retina, and a propensity to develop diet-induced diabetes without chemical or genetic modifications. A closer similarity to humans in these aspects, compared to the widely used Mus musculus and Rattus norvegicus models, holds the promise of better translation of research findings to the clinic. RESULTS: We report a 2.5 Gb, chromosome-level reference genome assembly with fully resolved parental haplotypes, generated with the Vertebrate Genomes Project (VGP). The assembly is highly contiguous, with contig N50 of 11.1 Mb, scaffold N50 of 83 Mb, and 95.2% of the sequence assigned to chromosomes. We used a novel workflow to identify 3613 segmental duplications and quantify duplicated genes. Comparative analyses revealed unique genomic features of the Nile rat, including some that affect genes associated with type 2 diabetes and metabolic dysfunctions. We discuss 14 genes that are heterozygous in the Nile rat or highly diverged from the house mouse. CONCLUSIONS: Our findings reflect the exceptional level of genomic resolution present in this assembly, which will greatly expand the potential of the Nile rat as a model organism.

Isolation driven changes in Iba1-positive microglial morphology are associated with social recognition memory in adults and adolescents.

Microglia are critical for regulation of neuronal circuits that mature from adolescence to adulthood. The morphological complexity and process length of microglia can indicate different activation states. These states are sensitive to a variety of environmental and stress conditions. Microglia are sensitive to many factors that also regulate social behavior, and in turn, microglial manipulations can impact social function. Brief social isolation is one factor that can lead to robust social changes. Here, we explored the role of microglia in the effects of brief social isolation on social recognition memory. Using morphological measures of Iba1 to index microglial intensity, complexity, and process length, we identified different effects of brief isolation on microglial complexity in the basal region of the amygdala between adults and adolescents alongside overall increases in intensity of Iba1 in several cortical brain regions. Short-term social recognition memory is sensitive to the amount of social engagement, and provides an opportunity to test if social engagement produced by brief isolation enhances social learning in a manner that relies on microglia. We found that brief isolation facilitated social interaction across ages but had opposing effects on short-term social recognition. Isolation increased novel partner investigation in adolescents, which is consistent with better social recognition, but increased familiar partner investigation in adults. Depletion of microglia with PLX3397 prevented these effects of brief isolation in adolescents, and reduced them in adults. These results suggest that distinct changes in microglial function driven by the social environment may differentially contribute to subsequent social recognition memory during development.

Comparing six cardiovascular risk prediction models in Haiti: implications for identifying high-risk individuals for primary prevention.

BACKGROUND: Cardiovascular diseases (CVD) are rapidly increasing in low-middle income countries (LMICs). Accurate risk assessment is essential to reduce premature CVD by targeting primary prevention and risk factor treatment among high-risk groups. Available CVD risk prediction models are built on predominantly Caucasian risk profiles from high-income country populations, and have not been evaluated in LMIC populations. We aimed to compare six existing models for predicted 10-year risk of CVD and identify high-risk groups for targeted prevention and treatment in Haiti. METHODS: We used cross-sectional data within the Haiti CVD Cohort Study, including 1345 adults ≥ 40 years without known history of CVD and with complete data. Six CVD risk prediction models were compared: pooled cohort equations (PCE), adjusted PCE with updated cohorts, Framingham CVD Lipids, Framingham CVD Body Mass Index (BMI), WHO Lipids, and WHO BMI. Risk factors were measured during clinical exams. Primary outcome was continuous and categorical predicted 10-year CVD risk. Secondary outcome was statin eligibility. RESULTS: Sixty percent were female, 66.8% lived on a daily income of ≤ 1 USD, 52.9% had hypertension, 14.9% had hypercholesterolemia, 7.8% had diabetes mellitus, 4.0% were current smokers, and 2.5% had HIV. Predicted 10-year CVD risk ranged from 3.6% in adjusted PCE (IQR 1.7-8.2) to 9.6% in Framingham-BMI (IQR 4.9-18.0), and Spearman rank correlation coefficients ranged from 0.86 to 0.98. The percent of the cohort categorized as high risk using model specific thresholds ranged from 1.8% using the WHO-BMI model to 41.4% in the PCE model (χ2 = 1416, p value < 0.001). Statin eligibility also varied widely. CONCLUSIONS: In the Haiti CVD Cohort, there was substantial variation in the proportion identified as high-risk and statin eligible using existing models, leading to very different treatment recommendations and public health implications depending on which prediction model is chosen. There is a need to design and validate CVD risk prediction tools for low-middle income countries that include locally relevant risk factors. TRIAL REGISTRATION: clinicaltrials.gov NCT03892265 .

Online team-based electrocardiogram training in Haiti: evidence from the field.

BACKGROUND: The electrocardiogram (ECG) is the most relied upon tool for cardiovascular diagnosis, especially in low-resource settings because of its low cost and straightforward usability. It is imperative that internal medicine (IM) and emergency medicine (EM) specialists are competent in ECG interpretation. Our study was designed to improve proficiency in ECG interpretation through a competition among IM and EM residents at a teaching hospital in rural central Haiti in which over 40% of all admissions are due to CVD. METHODOLOGY: The 33 participants included 17 EM residents and 16 IM residents from each residency year at the Hôpital Universitaire de Mirebalais (HUM). Residents were divided into 11 groups of 3 participants with a representative from each residency year and were given team-based online ECG quizzes to complete weekly. The format included 56 ECG cases distributed over 11 weeks, and each case had a pre-specified number of points based on abnormal findings and complexity. All ECG cases represented cardiovascular pathology in Haiti adapted from the Association of Program Directors in Internal Medicine evaluation list. The main intervention was sharing group performance and ECG solutions to all participants each week to promote competition and self-study without specific feedback or discussion by experts. To assess impact, pre- and post-intervention assessments measuring content knowledge and comfort for each participant were performed. RESULTS: Overall group participation was heterogeneous with groups participating a median of 54.5% of the weeks (range 0-100%). 22 residents completed the pre- and post-test assessments. The mean pre- and post-intervention assessment knowledge scores improved from 27.3% to 41.7% (p = 0.004). 70% of participants improved their test scores. The proportion of participants who reported comfort with ECG interpretation increased from 57.6% to 66.7% (p = 0.015). CONCLUSION: This study demonstrates improvement in ECG interpretation through a team-based, asynchronous ECG competition approach. This method is easily scalable and could help to fill gaps in ECG learning. This approach can be delivered to other hospitals both in and outside Haiti. Further adaptations are needed to improve weekly group participation.

Orexin (hypocretin) mediates light-dependent fluctuation of hippocampal function in a diurnal rodent.

Environmental lighting conditions play a central role in cognitive function, but the underlying mechanisms remain unclear. Utilizing a diurnal rodent model, the Nile grass rat (Arvicanthis niloticus), we previously found that daytime light intensity affects hippocampal function in this species in a manner similar to its effects in humans. Compared to animals housed in a 12:12 h bright light-dark (brLD) cycle, grass rats kept in a 12:12 h dim light-dark (dimLD) cycle showed impaired spatial memory in the Morris water maze (MWM) and reduced CA1 apical dendritic spine density. The present study explored the neural substrates mediating the effects of daylight intensity on hippocampal function focusing on the hypothalamic orexin (hypocretin) system. First, animals housed in dimLD were treated with daily intranasal administration of orexin A peptide over five training days of the MWM task. Compared to vehicle controls, this treatment led to superior spatial memory accompanied by increased phosphorylation of Ca2+ /calmodulin-dependent protein kinase II α and glutamate receptor 1 within the CA1. To assess the role of hippocampal orexinergic signaling, an adeno-associated viral vector (AAV) expressing an orexin receptor 1 (OX1R) shRNA was injected into the dorsal hippocampus targeting the CA1 of animals housed in brLD. AAV-mediated knockdown of OX1R within the hippocampus resulted in deficits in MWM performance and reduced CA1 apical dendritic spine density. These results are consistent with the view that the hypothalamic orexinergic system underlies the modulatory role of daytime illumination on hippocampal function in diurnal mammals.

Impact of daytime light intensity on the central orexin (hypocretin) system of a diurnal rodent (Arvicanthis niloticus).

The neuropeptide orexin/hypocretin is implicated in sleep and arousal, energy expenditure, reward, affective state and cognition. Our previous work using diurnal Nile grass rats (Arvicanthis niloticus) found that orexin mediates the effects of environmental light, particularly daytime light intensity, on affective and cognitive behaviours. The present study further investigated how daytime light intensity affects the central orexin system in male and female grass rats. Subjects were housed for 4 weeks in 12:12 hr dim light:dark (50 lux, dimLD) or in 12:12 hr bright light:dark cycle (1000 lux, brightLD). Day/night fluctuations in some orexin measures were also assessed. Despite similar hypothalamic prepro-orexin mRNA expression across all conditions, there were significantly more orexin-immunoreactive neurons, larger somata, greater optical density or higher orexin A content at night (ZT14) than during the day (ZT2), and/or in animals housed in brightLD compared to dimLD. Grass rats in brightLD also had higher cisternal CSF levels of orexin A. Furthermore, orexin receptor OX1R and OX2R proteins in the medial prefrontal cortex were higher in brightLD than dimLD males, but lower in brightLD than dimLD females. In the CA1 and dorsal raphe nucleus, females had higher OX1R than males without any significant effects of light condition, and OX2R levels were unaffected by sex or light. These results reveal that daytime light intensity alters the central orexin system of both male and female diurnal grass rats, sometimes sex-specifically, and provides insight into the mechanisms underlying how daytime light intensity impacts orexin-regulated functions.

Education vs Clinician Feedback on Antibiotic Prescriptions for Acute Respiratory Infections in Telemedicine: a Randomized Controlled Trial.

BACKGROUND: Antibiotics prescribed for acute respiratory tract infections in the telemedicine setting are often unwarranted. OBJECTIVE: We hypothesized that education plus individualized feedback, compared with education alone, would significantly reduce antibiotic prescription rates for upper respiratory infections, bronchitis, sinusitis, and pharyngitis in a telemedicine setting. DESIGN: Two-arm, parallel-group randomized controlled trial conducted at a telemedicine practice from January 1, 2018, to November 30, 2018. PARTICIPANTS: Clinicians employed at the practice on or after January 1, 2017 (n = 45). INTERVENTIONS: The control group received education (treatment guideline presentation and online course) in April 2018. The intervention group received education plus individualized feedback via an online dashboard with monthly rates of personal and practice-wide antibiotic prescription rates starting May 2018. MAIN MEASURES: Antibiotic prescription for any visit with at least one target condition: upper respiratory tract infection, bronchitis, sinusitis, and pharyngitis. KEY RESULTS: Baseline antibiotic prescription rates in control and intervention groups across conditions were as follows: upper respiratory infection (URI): 626/3410 (18.4%), 413/2752 (15.0%), bronchitis: 689/1471 (46.8%), 742/1162 (64.0%), sinusitis: 5154/6131 (84.1%), 4250/4876 (87.2%), pharyngitis: 2308/2838 (81.3%), 1593/2126 (74.9%). Antibiotic prescriptions for all conditions decreased in the post-intervention period compared with those in the pre-intervention period, for both control and intervention groups. Reduction of antibiotic prescriptions for URI and bronchitis was greater for the group receiving education plus individualized feedback compared with that for the group receiving education alone (interaction term ratio 0.60, 95% CI 0.47 to 0.77 for URI; and interaction term ratio 0.42, 95% CI 0.32 to 0.55 for bronchitis), but not sinusitis and pharyngitis. CONCLUSION: Education plus individualized feedback in a telemedicine practice significantly decreased antibiotic prescription rates for upper respiratory tract infections and bronchitis, compared with education alone. Future studies should focus on tailoring antibiotic stewardship programs based on underlying conditions, and the maintenance of early reductions in antibiotic prescription.

Circadian and photic modulation of daily rhythms in diurnal mammals.

The temporal niche that an animal occupies includes a coordinated suite of behavioral and physiological processes that set diurnal and nocturnal animals apart. The daily rhythms of the two chronotypes are regulated by both the circadian system and direct responses to light, a process called masking. Here we review the literature on circadian regulations and masking responses in diurnal mammals, focusing on our work using the diurnal Nile grass rat (Arvicanthis niloticus) and comparing our findings with those derived from other diurnal and nocturnal models. There are certainly similarities between the circadian systems of diurnal and nocturnal mammals, especially in the phase and functioning of the principal circadian oscillator within the hypothalamic suprachiasmatic nucleus (SCN). However, the downstream pathways, direct or indirect from the SCN, lead to drastic differences in the phase of extra-SCN oscillators, with most showing a complete reversal from the phase seen in nocturnal species. This reversal, however, is not universal and in some cases the phases of extra-SCN oscillators are only a few hours apart between diurnal and nocturnal species. The behavioral masking responses in general are opposite between diurnal and nocturnal species, and are matched by differential responses to light and dark in several retinorecipient sites in their brain. The available anatomical and functional data suggest that diurnal brains are not simply a phase-reversed version of nocturnal ones, and work with diurnal models contribute significantly to a better understanding of the circadian and photic modulation of daily rhythms in our own diurnal species.

Does distance from a clinic and poverty impact visit adherence for noncommunicable diseases? A retrospective cohort study using electronic medical records in rural Haiti.

BACKGROUND: Adherence to regular outpatient visits is vital to managing noncommunicable diseases (NCDs), a growing burden in low and middle-income countries. We characterized visit adherence among patients with NCDs in rural Haiti, hypothesizing higher poverty and distance from the clinic were associated with lower adherence. METHODS: We analyzed electronic medical records from a cohort of adults in an NCD clinic in Mirebalais, Haiti (April 2013 to June 2016). Visit adherence was: 1) visit constancy (≥1 visit every 3 months), 2) no gaps in care (> 60 days between visits), 3) ≥1 visit in the last quarter, and 4) ≥6 visits per year. We incorporated an adapted measure of intensity of multidimensional poverty. We calculated distance from clinic as Euclidean distance or self-reported transit time. We used multivariable logistic regressions to assess the association between poverty, distance, and visit adherence. RESULTS: We included 463 adult patients, mean age 57.8 years (SE 2.2), and 72.4% women. Over half of patients had at least one visit per quarter (58.1%), but a minority (19.6%) had no gaps between visits. Seventy percent of patients had a visit in the last quarter, and 73.9% made at least 6 visits per year. Only 9.9% of patients met all adherence criteria. In regression models, poverty was not associated with any adherence measures, and distance was only associated with visit in the last quarter (OR 0.87, 95% CI [0.78 to 0.98], p = 0.03) after adjusting for age, sex, and hardship financing. CONCLUSIONS: Visit adherence was low in this sample of adult patients presenting to a NCD Clinic in Haiti. Multidimensional poverty and distance from clinic were not associated with visit adherence measures among patients seen in the clinic, except for visit in the last quarter. Future research should focus on identifying and addressing barriers to visit adherence.

Light as a modulator of emotion and cognition: Lessons learned from studying a diurnal rodent.

Light profoundly affects the behavior and physiology of almost all animals, including humans. One such effect in humans is that the level of illumination during the day positively contributes to affective well-being and cognitive function. However, the neural mechanisms underlying the effects of daytime light intensity on affect and cognition are poorly understood. One barrier for progress in this area is that almost all laboratory animal models studied are nocturnal. There are substantial differences in how light affects nocturnal and diurnal species, e.g., light induces sleep in nocturnal mammals but wakefulness in diurnal ones, like humans. Therefore, the mechanisms through which light modulates affect and cognition must differ between the chronotypes. To further understand the neural pathways mediating how ambient light modulates affect and cognition, our recent work has developed a diurnal rodent model, the Nile grass rat (Arvicanthis niloticus), in which daytime light intensity is chronically manipulated in grass rats housed under the same 12:12 hour light/dark cycle. This simulates lighting conditions during summer-like bright sunny days vs. winter-like dim cloudy days. Our work has revealed that chronic dim daylight intensity results in higher depression- and anxiety-like behaviors, as well as impaired spatial learning and memory. Furthermore, we have found that hypothalamic orexin is a mediator of these effects. A better understanding of how changes in daytime light intensity impinge upon the neural substrates involved in affect and cognition will lead to novel preventive and therapeutic strategies for seasonal affective disorder, as well as for non-seasonal emotional or cognitive impairments associated with light deficiency.

Orexinergic modulation of serotonin neurons in the dorsal raphe of a diurnal rodent, Arvicanthis niloticus.

The hypothalamic neuropeptide, orexin (or hypocretin), is implicated in numerous physiology and behavioral functions, including affective states such as depression and anxiety. The underlying mechanisms and neural circuits through which orexin modulates affective responses remain unclear. The objective of the present study was to test the hypothesis that the serotonin (5-HT) system of the dorsal raphe nucleus (DRN) is a downstream target through which orexin potentially manifests its role in affective states. Using a diurnal rodent, the Nile grass rat (Arvicanthis niloticus), we first characterized the expression of the orexin receptors OX1R and OX2R in the DRN using in situ hybridization. The results revealed distinct distributions of OX1R and OX2R mRNAs, with OX1R predominantly expressed in the dorsal and lateral wings of the DRN that are involved in affective processes, while OX2R was mostly found in the ventral DRN that is more involved in sensory-motor function. We next examined how the orexin-OX1R pathway regulates 5-HT in the DRN and some of its projection sites using a selective OX1R antagonist SB-334867 (10 mg/kg, i.p.). A single injection of SB-334867 decreased 5-HT-ir fibers within the anterior cingulate cortex (aCgC); five once-daily administrations of SB-334867 decreased 5-HT-ir not only in the aCgC but also in the DRN, oval bed nucleus of the stria terminalis (ovBNST), nucleus accumbens shell (NAcSh), and periaqueductal gray (PAG). HPLC analysis revealed that five once-daily administrations of SB-334867 did not affect 5-HT turnover to any of the five sites, although it increased the levels of both 5-HT and 5-HIAA in the NAcSh. These results together suggest that orexinergic modulation of DRN 5-HT neurons via OX1Rs may be one pathway through which orexin regulates mood and anxiety, as well as perhaps other neurobiological processes.

Light modulates hippocampal function and spatial learning in a diurnal rodent species: A study using male nile grass rat (Arvicanthis niloticus).

The effects of light on cognitive function have been well-documented in human studies, with brighter illumination improving cognitive performance in school children, healthy adults, and patients in early stages of dementia. However, the underlying neural mechanisms are not well understood. The present study examined how ambient light affects hippocampal function using the diurnal Nile grass rats (Arvicanthis niloticus) as the animal model. Grass rats were housed in either a 12:12 h bright light-dark (brLD, 1,000 lux) or dim light-dark (dimLD, 50 lux) cycle. After 4 weeks, the dimLD group showed impaired spatial memory in the Morris Water Maze (MWM) task. The impairment in their MWM performance were reversed when the dimLD group were transferred to the brLD condition for another 4 weeks. The results suggest that lighting conditions influence cognitive function of grass rats in a way similar to that observed in humans, such that bright light is beneficial over dim light for cognitive performance. In addition to the behavioral changes, grass rats in the dimLD condition exhibited reduced expression of brain-derived neurotrophic factor (BDNF) in the hippocampus, most notably in the CA1 subregion. There was also a reduction in dendritic spine density in CA1 apical dendrites in dimLD as compared to the brLD group, and the reduction was mostly in the number of mushroom and stubby spines. When dimLD animals were transferred to the brLD condition for 4 weeks, the hippocampal BDNF and dendritic spine density significantly increased. The results illustrate that not only does light intensity affect cognitive performance, but that it also impacts hippocampal structural plasticity. These studies serve as a starting point to further understand how ambient light modulates neuronal and cognitive functions in diurnal species. A mechanistic understanding of the effects of light on cognition can help to identify risk factors for cognitive decline and contribute to the development of more effective prevention and treatment of cognitive impairment in clinical populations.

Equity dimensions of the availability and quality of reproductive, maternal and neonatal health services in Zambia.

OBJECTIVE: To assess how quality and availability of reproductive, maternal, neonatal (RMNH) services vary by district wealth and urban/rural status in Zambia. METHODS: We conducted a retrospective analysis of data from the Millennium Development Goal Acceleration Initiative baseline assessment of 117 health facilities in 9 districts. Quality was assessed through a composite score of 23 individual RMNH indicators, ranging from 0 to 1. Availability was evaluated by density of providers and facilities. Districts were divided into wealth groups based on the multidimensional poverty index (MPI). Relative inequity was calculated using the concentration index for quality indicators (positive favours rich, negative favours poor). Multivariable linear regression was performed for the dependent variable composite quality indicator using MPI, urban/rural, and facility level of care as independent variables. RESULTS: 13 hospitals, 85 health centres and 19 health posts were included. The RMNH composite quality indicator was 0.64. Availability of facilities and providers was universally low. The concentration index for the composite quality indicator was -0.015 [-0.043, 0.013], suggesting no clustering to favour either rich or poor districts. Rich districts had the highest absolute numbers of health facilities and providers, but lowest numbers per facility per 1 000 000 population. Urban districts had slightly better service quality, but not availability. Using regression analysis, only facility level of care was significantly associated with quality outcome. CONCLUSIONS: Composite quality of RMNH services did not vary by district wealth, but was slightly higher in urban districts. The availability data suggest that the higher population in richer districts outpaces health infrastructure.

Association of hypertension and treatment outcomes in advanced stage non-small cell lung cancer patients treated with bevacizumab or non-bevacizumab containing regimens.

Background Studies suggest that bevacizumab-induced hypertension is prognostic of better outcomes in bevacizumab-treated patients with metastatic colorectal, HER2-negative breast, kidney, and pancreatic cancer. Few have examined this correlation in metastatic non-small cell lung cancer and evaluated whether hypertension independent of bevacizumab can improve the treatment outcomes. Objectives The primary objective was to determine the effect of hypertension on the overall response of advanced non-small cell lung cancer patients from start of the first-line chemotherapy to maintenance therapy. Secondary objectives include the effect of hypertension on the overall survival in all patients and on the overall response in bevacizumab-treated patients. Methods A retrospective chart review for a single institution was conducted from 2008 to 2013 on all patients with advanced non-squamous non-small cell lung cancer who received ≥ 1 cycle of combination chemotherapy. Patients were divided into hypertension versus no hypertension and into bevacizumab versus non-bevacizumab groups. Results Of the 188 advanced non-small cell lung cancer patients evaluated, 62 were treated with bevacizumab-containing regimens. The mean age at diagnosis was 58 years in both the groups. Hypertension independent of bevacizumab did not lead to improved treatment outcomes. However, in the bevacizumab subgroup, hypertensive patients had significantly higher response rates versus non-hypertensive patients (36.7% vs. 12.5%; p = 0.02). There was no significant difference in the overall survival between hypertensive versus non-hypertensive patients. Conclusion While hypertension alone did not significantly improve the treatment outcomes, hypertension in bevacizumab-treated patients with metastatic non-small cell lung cancer led to significantly improved responses. Further prospective studies are needed to confirm the association of hypertension with improved treatment outcomes in metastatic NSCLC.

Entraining to the polar day: circadian rhythms in arctic ground squirrels.

Circadian systems are principally entrained to 24 h light-dark cycles, but this cue is seasonally absent in polar environments. Although some resident polar vertebrates have weak circadian clocks and are seasonally arrhythmic, the arctic ground squirrel (AGS) maintains daily rhythms of physiology and behavior throughout the summer, which includes 6 weeks of constant daylight. Here, we show that persistent daily rhythms in AGS are maintained through a circadian system that readily entrains to the polar day yet remains insensitive to entrainment by rapid light-dark transitions, which AGS generate naturally as a consequence of their semi-fossorial behavior. Additionally, AGS do not show 'jet lag', the slow realignment of circadian rhythms induced by the inertia of an intrinsically stable master circadian clock in the suprachiasmatic nucleus (SCN). We suggest this is due to the low expression of arginine vasopressin in the SCN of AGS, as vasopressin is associated with inter-neuronal coupling and robust rhythmicity.

Hypertension management in rural primary care facilities in Zambia: a mixed methods study.

BACKGROUND: Improved primary health care is needed in developing countries to effectively manage the growing burden of hypertension. Our objective was to evaluate hypertension management in Zambian rural primary care clinics using process and outcome indicators to assess the screening, monitoring, treatment and control of high blood pressure. METHODS: Better Health Outcomes through Mentoring and Assessment (BHOMA) is a 5-year, randomized stepped-wedge trial of improved clinical service delivery underway in 46 rural Zambian clinics. Clinical data were collected as part of routine patient care from an electronic medical record system, and reviewed for site performance over time according to hypertension related indicators: screening (blood pressure measurement), management (recorded diagnosis, physical exam or urinalysis), treatment (on medication), and control. Quantitative data was used to develop guides for qualitative in-depth interviews, conducted with health care providers at a proportional sample of half (20) of clinics. Qualitative data was iteratively analyzed for thematic content. RESULTS: From January 2011 to December 2014, 318,380 visits to 46 primary care clinics by adults aged ≥ 25 years with blood pressure measurements were included. Blood pressure measurement at vital sign screening was initially high at 89.1% overall (range: 70.1-100%), but decreased to 62.1% (range: 0-100%) by 48 months after intervention start. The majority of hypertensive patients made only one visit to the clinics (57.8%). Out of 9022 patients with at least two visits with an elevated blood pressure, only 49.3% had a chart recorded hypertension diagnosis. Process indicators for monitoring hypertension were <10% and did not improve with time. In in-depth interviews, antihypertensive medication shortages were common, with 15/20 clinics reporting hydrochlorothiazide-amiloride stockouts. Principal challenges in hypertension management included 1) equipment and personnel shortages, 2) provider belief that multiple visits were needed before official management, 3) medication stock-outs, leading to improper prescriptions and 4) poor patient visit attendance. CONCLUSIONS: Our findings suggest that numerous barriers stand in the way of hypertension diagnosis and management in Zambian primary health facilities. Future work should focus on performance indicator development and validation in low resource contexts, to facilitate regular and systematic data review to improve patient outcomes. TRIAL REGISTRATION: ClinicalTrials.gov, Identifier NCT01942278 . Date of Registration: September 2013.

Voluntary running depreciates the requirement of Ca2+-stimulated cAMP signaling in synaptic potentiation and memory formation.

Mental health and cognitive functions are influenced by both genetic and environmental factors. Although having active lifestyle with physical exercise improves learning and memory, how it interacts with the specific key molecular regulators of synaptic plasticity is largely unknown. Here, we examined the effects of voluntary running on long-term potentiation (LTP) and memory formation in mice lacking type 1 adenylyl cyclase (AC1), a neurospecific synaptic enzyme that contributes to Ca(2+)-stimulated cAMP production. Following 1 mo of voluntary running-wheel exercise, the impaired LTP and object recognition memory in AC1 knockout (KO) mice were significantly attenuated. Running up-regulated exon II mRNA level of BDNF (brain-derived neurotrophic factor), though it failed to increase exon I and IV mRNAs in the hippocampus of AC1 KO mice. Intrahippocampal infusion of recombinant BDNF was sufficient to rescue LTP and object recognition memory defects in AC1 KO mice. Therefore, voluntary running and exogenous BDNF application overcome the defective Ca(2+)-stimulated cAMP signaling. Our results also demonstrate that alteration in Ca(2+)-stimulated cAMP can affect the molecular outcome of physical exercise.

Outcomes of hospitalized neutropenic oncology patients with Pseudomonas aeruginosa bloodstream infections: focus on oral fluoroquinolone conversion.

BACKGROUND: Pseudomonas aeruginosa bacteremia is a major cause of morbidity and mortality, especially in neutropenic oncology patients. Few studies have been published in the last decade on treatment outcomes of neutropenic oncology patients with Pseudomonas aeruginosa bacteremia. In addition, there is a lack of data addressing the role of oral fluoroquinolones in this patient setting. METHODS: A retrospective chart review from 1999 to 2013 was conducted at a large academic medical center in neutropenic oncology patients with documented Pseudomonas aeruginosa bacteremia, who were initially treated with intravenous anti-pseudomonal antibiotics and then converted to an oral anti-pseudomonal fluoroquinolone. Patients were evaluated for the rate of cure and for the time from onset of intravenous antibiotic therapy to conversion to oral fluoroquinolones. RESULTS: Twenty-nine patients with Pseudomonas aeruginosa bacteremia were evaluated. The median absolute neutrophil count at the time of the first positive blood culture was 50 cells/mm(3), and the median duration of time below an absolute neutrophil count of 1000 cells/mm(3) was five days. The change to oral fluoroquinolones occurred at a median (range) of six (2-18) days after initiation of intravenous antibiotics and at a median absolute neutrophil count of 2610 (110-24790) cells/mm(3). The initial cure was 93.1%, while ultimate cure was 91.7%. CONCLUSION: Converting to oral fluoroquinolones after initial intravenous antibiotic therapy for Pseudomonas aeruginosa bacteremia in clinically stable neutropenic oncology patients appears to achieve successful outcomes. However, prospective trials are needed to validate these results in neutropenic oncology patients with Pseudomonas aeruginosa bacteremia who are converted to oral fluoroquinolones.