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Cerebrospinal fluid (CSF) flows through the central nervous system (CNS) via the glymphatic pathway to clear the interstitium of metabolic waste. In preclinical studies, glymphatic fluid flow rate increases with low central noradrenergic tone and slow-wave activity during natural sleep and general anesthesia. By contrast, sleep deprivation reduces glymphatic clearance and leads to intracerebral accumulation of metabolic waste, suggesting an underlying mechanism linking sleep disturbances with neurodegenerative diseases. The selective α2-adrenergic agonist dexmedetomidine is a sedative drug that induces slow waves in the electroencephalogram, suppresses central noradrenergic tone, and preserves glymphatic outflow. As recently developed dexmedetomidine formulations enable self-administration, we suggest that dexmedetomidine could serve as a sedative-hypnotic drug to enhance clearance of harmful waste from the brain of those vulnerable to neurodegeneration.

Nanoparticles are ultrafine particulate matter having considerable potential for treatment of central nervous system (CNS) disorders. Despite their tiny size, the blood-brain barrier (BBB) restricts their access to the CNS. Their direct cerebrospinal fluid (CSF) administration bypasses the BBB endothelium, but still fails to give adequate brain uptake. We present a novel approach for efficient CNS delivery of 111In-radiolabelled gold nanoparticles (AuNPs; 10–15 nm) via intra-cisterna magna administration, with tracking by SPECT imaging. To accelerate CSF brain influx, we administered AuNPs intracisternally in conjunction with systemic hypertonic saline, which dramatically increased the parenchymal AuNP uptake, especially in deep brain regions. AuNPs entered the CNS along periarterial spaces as visualized by MRI of gadolinium-labelled AuNPs and were cleared from brain within 24 h and excreted through the kidneys. Thus, the glymphatic-assisted perivascular network augment by systemic hypertonic saline is a pathway for highly efficient brain-wide distribution of small AuNPs.

Background Several opioids are metabolized by the inducible cytochrome P450 (CYP) 3A isozymes. Coadministration with strong inducers of drug metabolism, such as rifampin, can dramatically reduce systemic exposure to these opioids. As the CYP metabolism of hydromorphone is of minor importance, we studied in healthy volunteers whether hydromorphone would be an effective analgesic for patients who concomitantly receive the prototypical enzyme inducer rifampin. Methods In this paired, randomized, crossover study, 12 participants received oral placebo or rifampin for 8 days. Oral hydromorphone (2.6 mg) was administered on day 6 followed by intravenous hydromorphone (0.02 mg/kg) on day 8. Hydromorphone and hydromorphone-3-glucuronide (HM3G) plasma concentrations were measured for 24 hours and psychomotor responses, including perceived drug effect, change in pupil diameter, and cold pressor threshold were evaluated for 6 hours. Our primary outcome was the change in the area under the concentration-time curve (AUC0-last) of oral and intravenous hydromorphone after pretreatment with rifampin or placebo. Pharmacodynamic parameters and other pharmacokinetic parameters were analyzed as secondary outcomes. Results Rifampin reduced the AUC0-last of oral and intravenous hydromorphone by 43% (ratio to control: 0.57, 90% confidence interval [CI], 0.50-0.65) and 26% (ratio to control: 0.74, 90% CI, 0.69-0.79), respectively. The maximum concentration of oral hydromorphone was reduced by 37% (ratio to control: 0.63, 90% CI, 0.55-0.72), and oral bioavailability decreased from 33% to 26% (ratio to control: 0.78, 90% CI, 0.67-0.91) in the rifampin phase compared with placebo. The HM3G-to-hydromorphone ratio increased by 50% (90% CI, 25-79) and 42% (90% CI, 29-55) after oral and intravenous hydromorphone, respectively. Rifampin did not significantly affect the pharmacodynamic parameters. Conclusions Rifampin significantly reduces the concentrations of oral and intravenous hydromorphone. This interaction is due to an increase in the first-pass and systemic metabolism of hydromorphone, likely involving induction of uridine 5'-diphospho- glucuronosyltransferase enzymes by rifampin. The enhancement of hydromorphone elimination should be considered when managing pain of patients who are treated with strong enzyme inducers.

Summary Background Maternal and perinatal mortality are still unacceptably high in many countries despite steep increases in facility birth. The evidence that childbirth in facilities reduces mortality is weak, mainly because of the scarcity of robust study designs and data. We aimed to assess this link by quantifying the influence of major determinants of facility birth (cluster-level facility birth, wealth, education, and distance to childbirth care) on several mortality outcomes, while also considering quality of care. Methods Our study is a secondary analysis of surveillance data on 119 244 pregnancies from two large population-based cluster-randomised controlled trials in Brong Ahafo, Ghana. In addition, we specifically collected data to assess quality of care at all 64 childbirth facilities in the study area. Outcomes were direct maternal mortality, perinatal mortality, first-day and early neonatal mortality, and antepartum and intrapartum stillbirth. We calculated cluster-level facility birth as the percentage of facility births in a woman's village over the preceding 2 years, and we computed distances from women's regular residence to health facilities in a geospatial database. Associations between determinants of facility birth and mortality outcomes were assessed in crude and multivariable multilevel logistic regression models. We stratified perinatal mortality effects by three policy periods, using April 1, 2005, and July 1, 2008, as cutoff points, when delivery-fee exemption and free health insurance were introduced in Ghana. These policies increased facility birth and potentially reduced quality of care. Findings Higher proportions of facility births in a cluster were not linked to reductions in any of the mortality outcomes. In women who were wealthier, facility births were much more common than in those who were poorer, but mortality was not lower among them or their babies. Women with higher education had lower mortality risks than less-educated women, except first-day and early neonatal mortality. A substantially higher proportion of women living in areas closer to childbirth facilities had facility births and caesarean sections than women living further from childbirth facilities, but mortality risks were not lower despite this increased service use. Among women who lived in areas closer to facilities offering comprehensive emergency obstetric care (CEmOC), emergency newborn care, or high-quality routine care, or to facilities that had providers with satisfactory competence, we found a lower risk of intrapartum stillbirth (14·2 per 1000 deliveries at >20 km from a CEmOC facility vs 10·4 per 1000 deliveries at ≤1 km; odds ratio [OR] 1·13, 95% CI 1·06–1·21) and of composite mortality outcomes than among women living in areas where these services were further away. Protective effects of facility birth were restricted to the two earlier policy periods (from June 1, 2003, to June 30, 2008), whereas there was evidence for higher perinatal mortality with increasing wealth (OR 1·09, 1·03–1·14) and lower perinatal mortality with increasing distance from childbirth facilities (OR 0·93, 0·89–0·98) after free health insurance was introduced in July 1, 2008. Interpretation Facility birth does not necessarily convey a survival benefit for women or babies and should only be recommended in facilities capable of providing emergency obstetric and newborn care and capable of safe-guarding uncomplicated births. Funding The Baden-Wurttemberg Foundation, the Daimler and Benz Foundation, the European Social Fund and Ministry of Science, Research, and the Arts Baden-Wurttemberg, WHO, US Agency for International Development, Save the Children, the Bill & Melinda Gates Foundation, and the UK Department for International Development.

Facility delivery is an important aspect of the strategy to reduce maternal and newborn mortality. Geographic access to care is a strong determinant of facility delivery, but few studies have simultaneously considered the influence of facility quality, with inconsistent findings. In rural Brong Ahafo region in Ghana, we combined surveillance data on 11,274 deliveries with quality of care data from all 64 delivery facilities in the study area. We used multivariable multilevel logistic regression to assess the influence of distance and several quality dimensions on place of delivery. Women lived a median of 3.3 km from the closest delivery facility, and 58% delivered in a facility. The probability of facility delivery ranged from 68% among women living 1 km from their closest facility to 22% among those living 25 km away, adjusted for confounders. Measured quality of care at the closest facility was not associated with use, except that facility delivery was lower when the closest facility provided substandard care on the EmOC dimension. These results do not imply, however, that we should increase geographic accessibility of care without improving facility quality. While this may be successful in increasing facility deliveries, such care cannot be expected to reduce maternal and neonatal mortality.

Objective To evaluate quality of routine and emergency intrapartum and postnatal care using a health facility assessment, and to estimate “effective coverage” of skilled attendance in Brong Ahafo, Ghana. Methods We conducted an assessment of all 86 health facilities in seven districts in Brong Ahafo. Using performance of key signal functions and the availability of relevant drugs, equipment and trained health professionals, we created composite quality categories in four dimensions: routine delivery care, emergency obstetric care (EmOC), emergency newborn care (EmNC) and non-medical quality. Linking the health facility assessment to surveillance data we estimated “effective coverage” of skilled attendance as the proportion of births in facilities of high quality. Findings Delivery care was offered in 64/86 facilities; only 3-13% fulfilled our requirements for the highest quality category in any dimension. Quality was lowest in the emergency care dimensions, with 63% and 58% of facilities categorized as “low” or “substandard” for EmOC and EmNC, respectively. This implies performing less than four EmOC or three EmNC signal functions, and/or employing less than two skilled health professionals, and/or that no health professionals were present during our visit. Routine delivery care was “low” or “substandard” in 39% of facilities, meaning 25/64 facilities performed less than six routine signal functions and/or had less than two skilled health professionals and/or less than one midwife. While 68% of births were in health facilities, only 18% were in facilities with “high” or “highest” quality in all dimensions. Conclusion Our comprehensive facility assessment showed that quality of routine and emergency intrapartum and postnatal care was generally low in the study region. While coverage with facility delivery was 68%, we estimated “effective coverage” of skilled attendance at 18%, thus revealing a large “quality gap.” Effective coverage could be a meaningful indicator of progress towards reducing maternal and newborn mortality.

OBJECTIVE: To assess the structural capacity for, and quality of, immediate and essential newborn care (ENC) in health facilities in rural Ghana, and to link this with demand for facility deliveries and admissions. DESIGN: Health facility assessment survey and population-based surveillance data. SETTING: Seven districts in Brong Ahafo Region, Ghana. PARTICIPANTS: Heads of maternal/neonatal wards in all 64 facilities performing deliveries. MAIN OUTCOME MEASURES: Indicators include: the availability of essential infrastructure, newborn equipment and drugs, and personnel; vignette scores and adequacy of reasons given for delayed discharge of newborn babies; and prevalence of key immediate ENC practices that facilities should promote. These are matched to the percentage of babies delivered in and admitted to each type of facility. RESULTS: 70% of babies were delivered in health facilities; 56% of these and 87% of neonatal admissions were in four referral level hospitals. These had adequate infrastructure, but all lacked staff trained in ENC and some essential equipment (including incubators and bag and masks) and/or drugs. Vignette scores for care of very low-birth-weight babies were generally moderate-to-high, but only three hospitals achieved high overall scores for quality of ENC. We estimate that only 33% of babies were born in facilities capable of providing high quality, basic resuscitation as assessed by a vignette plus the presence of a bag and mask. Promotion of immediate ENC practices in facilities was also inadequate, with coverage of early initiation of breastfeeding and delayed bathing both below 50% for babies born in facilities; this represents a lost opportunity. CONCLUSIONS: Unless major gaps in ENC equipment, drugs, staff, practices and skills are addressed, strategies to increase facility utilisation will not achieve their potential to save newborn lives. TRIAL REGISTRATION: http://clinicaltrials.gov NCT00623337.