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Myelin is required for the function of neuronal axons in the central nervous system, but the mechanisms that support myelin health are unclear. Although macrophages in the central nervous system have been implicated in myelin health1, it is unknown which macrophage populations are involved and which aspects they influence. Here we show that resident microglia are crucial for the maintenance of myelin health in adulthood in both mice and humans. We demonstrate that microglia are dispensable for developmental myelin ensheathment. However, they are required for subsequent regulation of myelin growth and associated cognitive function, and for preservation of myelin integrity by preventing its degeneration. We show that loss of myelin health due to the absence of microglia is associated with the appearance of a myelinating oligodendrocyte state with altered lipid metabolism. Moreover, this mechanism is regulated through disruption of the TGFβ1–TGFβR1 axis. Our findings highlight microglia as promising therapeutic targets for conditions in which myelin growth and integrity are dysregulated, such as in ageing and neurodegenerative disease2,3.

Spinal muscular atrophy (SMA) is a rare, progressive neuromuscular disease that affects individuals with a broad age range. SMA is typically characterised by symmetrical muscle weakness but is also associated with cardiac defects, life-limiting impairments in respiratory function and bulbar function defects that affect swallowing and speech. Despite the advent of three innovative disease-modifying therapies (DMTs) for SMA, the cost of DMTs in addition to the costs of standard of care can be a barrier to treatment access for patients. Health Technology Assessment (HTA) decision makers evaluate the cost effectiveness of a new treatment before making a reimbursement decision. The primary objective was to conduct a systematic literature review (SLR) to identify the modelling approaches used in economic evaluations that assess current approved treatments in SMA, with a secondary objective to widen the scope and identify economic evaluations assessing other (non-SMA) neuromuscular disorders. An SLR was performed to identify available economic evaluations associated with any type of SMA (Type 1, 2, 3 and/or 4). Economic evaluations associated with other (non-SMA) neuromuscular disorders were identified but not further analysed. Electronic searches were conducted in Embase, MEDLINE, Evidence-Based Medicine Reviews and EconLit via the Ovid platform in August 2019, and were supplemented by searches of the grey literature (reference lists, conference proceedings, global HTA body websites and other relevant sources). Eligibility criteria were based on the population, interventions, comparators and outcomes (PICO) framework. Quality assessment of full publications was conducted with reference to a published checklist. Nine publications covering eight unique studies met all eligibility criteria for inclusion in the SLR, including four conference abstracts, two peer-reviewed original research articles and three HTA submissions (conducted in Canada, the US and the UK). Evaluations considered patients with early infantile-onset (most likely to develop Type 1 or Type 2 SMA), later-onset SMA and both infantile- and later-onset SMA. Data for the identified economic models were collected from literature reviews and relatively short-term clinical trials. Several intent-to-treat clinical trial populations were used in the studies, which resulted in variation in cycle length and different outcome measures to determine clinical efficacy. The results of the quality assessment on the five full-text, peer-reviewed publications found that they generally provided clear descriptions of objectives, modelling methods and results. However, key decisions, such as choice of economic evaluation, model type and choice of variables for sensitivity analysis, were often not adequately justified. This SLR highlights the need for economic evaluations in SMA to better align in modelling approaches with respect to (i) consistency in model structure and use of motor function milestones as health states; (ii) consensus on measuring quality of life to estimate utilities; (iii) consistency in data collection by registries; and (iv) consensus on SMA-type classification and endpoints that determine intervention efficacy. Future economic evaluations should also incorporate the review group critiques of previous HTA submissions relating to data inputs and approaches to modelling and should include patient data reflective of the SMA population being modelled. Economic evaluations would also be improved with inclusion of long-term efficacy and safety data from clinical trials and valid patient and caregiver utility data.

Semaglutide has demonstrated safe and effective weight loss for overweight and obesity, including participants with concomitant type 2 diabetes mellitus (T2DM), in randomized placebo-controlled trials (RCTs). We conducted a systematic literature review (SLR) and network meta-analyses (NMA) to compare weekly semaglutide 2.4 mg with pharmacological comparators for weight management in overweight or obesity.The SLR was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) checklist. NMAs were performed to compare weight change for semaglutide 2.4 mg with comparators using data identified in the SLR. The populations of interest were total population, normal glucose tolerance, non-T2DM, pre-diabetes, and T2DM. Included outcomes were weight change from baseline (CFB, %) at 52 weeks and proportion of participants losing ≥5% baseline fasting body weight at 12 weeks (at full therapeutic dose).The SLR identified 108 RCTs examining non-surgical interventions, of which 41 were considered for inclusion in the NMAs. In all populations, semaglutide 2.4 mg was associated with a greater percentage weight CFB with 52 weeks of treatment versus all available comparators. In all populations, semaglutide was associated with a higher likelihood of participants losing ≥5% of baseline fasting body weight at 12 weeks versus all available comparators.In NMA, semaglutide 2.4 mg demonstrated effective weight loss (≥5%) in the total population and all subpopulations of glucose tolerance versus active comparators. Semaglutide is an effective treatment that may address unmet need in the management of overweight and obesity.

Objectives The current systematic review (SR) was undertaken to identify and summarise the published literature reporting on the clinical and economic value of automated in-hospital pharmacy services with a primary focus on systems supporting the dispensing of medicines. Methods Literature searches were conducted in MEDLINE, Embase and the Cochrane Library on 17 December 2017 to identify English-language publications investigating any automated dispensing systems (ADSs) in the inpatient setting to include central pharmacy and ward-based systems. Results 4320 publications were screened by title and abstract and 45 of 175 full publications screened were included. Grey literature searching identified an additional three publications. Therefore, 48 publications relating to ADSs were eligible for inclusion. Although a relatively large evidence base was identified as part of the current SR, the eligible studies were inconsistent in terms of their design and the format of reporting of outcomes. The studies demonstrate that both pharmacy and ward-based ADSs offer benefits over traditional manual dispensing methods in terms of clinical and economic outcomes. The primary benefits following implementation of an ADS include reductions in medication errors, medication administration time and costs. Studies examining optimisation/inventory management strategies/refill programmes for these systems suggest that optimal implementation of the ADS is required to ensure that clinical success and economic benefits are maximised. Conclusions The published evidence suggests positive impacts of ADS and should encourage hospitals to invest in automation, with a global strategy to improve the reliability and the efficiency of the medication process. However, one of the key findings of the current SR is the need for further data from adequately powered studies reporting clinically relevant outcomes which would allow for robust, evidence-based recommendations on the return on investment of the technologies. These studies would probably contribute to a larger adoption of these technologies by European hospitals.

The Döşeme Boğazı (‘Pass with the Pavement’) is one of the ancient routes through the Taurus Mountains that connected the Anatolian interior with the southern coastal regions (fig. 1). From an early date it was an important component of the Roman road-system in Asia Minor (fig. 2). The pass lay near the S end of the Republican route from the Dardanelles to Side which was created by Manius Aquillius, first proconsul of Asia between 129 and 126 B.C. The S part of this road was incorporated into the via Sebaste, built in 6/5 B.C., which linked several of the Roman colonies founded by Augustus in south-central Anatolia to the Mediterranean coast. By good fortune, the ancient settlements and the Roman and post-Roman road in this defile have survived largely untouched by modern development. The course of the road between the Roman colony of Comama (Pisidia) and Perge (Pamphylia), as well as branch roads leading to other settlements, can be traced precisely. Well-preserved remains of two settlements, both occupied between the 2nd and 6th c., are identifiable at the upper and lower ends of the defile: in them are houses having from 2 to 10 rooms, the larger ones arranged around courtyards and some having cisterns and towers (Turmgehöfte), a bath-house and public cisterns, roadside shops, sarcophagi and small heroa in prominent positions by the road, and numerous churches. The lower site includes a large walled structure probably of the 6th c., that was almost certainly designed as an animal enclosure to control transhumant flocks. Most remarkable of all the surviving structures in the pass, however, are the remains of a mansio or way-station, which survives up to roof level and is the best-preserved building of this type in the entire empire.

Re-admission is an important source of patient dissatisfaction and increased hospital costs. A simple calculator to determine the probability of re-admission may help guide patient dismissal planning.Using the national readmissions database (NRD), we identified admissions for isolated primary coronary artery bypass (CABG) and stratified them according to 30-day readmission. Including pre, intra and postoperative variables, we prepared a logistic regression model to determine the probability for re-admission. The model was tested for reliability with boot-strapping and 10-fold cross-validation.From 135,699 procedures, 19,355 were readmitted at least once within 30days of dismissal. Patients who were readmitted were older (67±10 vs 65 ± 10 years, p0.01), females (32% vs 24%; p0.01) and had a higher Elixhauser comorbidity score (1.5±1.4 vs 1.1±1.2; p0.01). Our final model (c- statistic=0.65) consisted of 16 pre and three postoperative factors. End-stage renal disease (OR 1.79 [1.57-2.04]) and length of stay9days (OR 1.60 [1.52-1.68]) were most prominent indicators for readmission. Compared to Medicaid beneficiaries, those with private insurance (OR 0.62 [0.57-0.68]) and Medicare (OR 0.85 [0.79-0.92]) coverage were less likely to be readmitted.Our simple 30-days CABG readmission calculator can be used as a strategic tool to help reduce readmissions after coronary artery bypass surgery.

Vagus nerve stimulation (VNS) Therapy® is an adjunctive neurostimulation treatment for people with drug-resistant epilepsy (DRE) who are unwilling to undergo resective surgery, have had unsuccessful surgery or are unsuitable for surgery. A systematic review and meta-analysis were conducted to determine the treatment effects of VNS Therapy as an adjunct to anti-seizure medications (ASMs) for the management of adults with DRE. A literature search was performed in August 2020 of the Medline®, Medline® Epub Ahead of Print, Embase, and the Cochrane library databases. Outcomes examined included reduction in seizure frequency, seizure freedom, ASM load, discontinuations, and serious adverse events (SAEs). Comparators included best medical practice, ASMs, low-stimulation or sham VNS Therapy. Four RCTs and six comparative observational studies were identified for inclusion. Against comparators, individuals treated with VNS had a significantly better odds of experiencing a ≥ 50% reduction in seizure frequency (OR: 2.27 [95% CI 1.47, 3.51]; p = 0.0002), a ≥ 75% reduction in seizure frequency (OR: 3.56 [95% CI 1.59, 7.98]; p = 0.002) and a reduced risk for increased ASM load (risk ratio: 0.36 [95% CI 0.21, 0.62]; p = 0.0002). There was no difference in the odds of discontinuation or the rate of SAEs between VNS versus comparators. This meta-analysis demonstrated the benefits of VNS Therapy in people with DRE, which included improvement in seizure frequency without an increase in the rate of SAEs or discontinuations, thereby supporting the consideration of VNS Therapy for people who are not responding to ASMs and those unsuitable or unwilling to undergo surgery.

In a recent study, identifying and supporting patients' care goals was named the highest priority in hospital medicine. Although sepsis is one of the leading causes of death and postdischarge morbidity among hospitalized patients, little is known about how frequently care goals are assessed prior to discharge and adhered to in the 90 days after sepsis hospitalization. Evaluating a cohort of 679 high-risk sepsis survivors enrolled in a clinical trial, we found that care goals were documented explicitly in a standardized tool in 130 patients; an additional 139 patients were identified using all available clinical documentation, resulting in only 269 (40%) patients with goals that could be ascertained from the electronic health record (EHR). Among those categorized, goals were classified as prioritizing longevity (35%), function (52%), and comfort (12%). Based on expert review of the care provided during the 90 days subsequent to discharge, goal-concordant care was identified in 184 (68%) cases for which goals were specified. Documentation of goals in a standardized EHR tool was associated with increased likelihood of receiving goal-concordant care (odds ratio, 3.6; 95% CI, 2.4-5.5). Hospitalization and peridischarge time points represent important opportunities to address deficits in the documentation of goals and provision of goal-concordant care for sepsis survivors.

Extracellular pH (pHe) is an important chemical factor in many cellular processes and disease pathologies. The routine sampling of pHe in vitro could lead to innovative advances in therapeutics. To this end, we have fabricated a novel gold-coated polymer mesh, which facilitates the real-time measurement of pHe via surface-enhanced Raman scattering (SERS). In this proof of concept study, we apply our SERS sensor to measure metabolically induced changes in the pHe of carcinoma-derived cell line HepG2/C3A. We demonstrate that gold-coated polyurethane electrospun nanofibers (AuNF) have strong and reproducible SERS spectra of surface-adsorbed analytes. By functionalizing AuNF with pH-responsive reporter 4-mercaptobenzoic acid (MBA), we have developed an accurate pH SERS sensor for the extracellular microenvironment. We cultured HepG2/C3A on the surface of MBA-AuNF and measured an acidic shift in pHe at the cell-fiber interface. Following exposure to staurosporine, an apoptosis-inducing drug, we observed changes in the HepG2/C3A cellular morphology indicative of controlled cell death, and detected an increase in the pHe of HepG2/C3A. These results demonstrate how subtle changes in pHe, induced by the metabolic activity of cells, can be measured with our novel SERS sensor MBA-AuNF. The excellent pH measurement performance of MBA-AuNF provides a unique platform to study extracellular pH on the microscale and will help to deepen our understanding of pHe in disease pathology.

Objectives Comparative economic assessments of renal replacement therapies (RRT) are common and often used to inform national policy in the management of end-stage renal disease (ESRD). This study aimed to assess existing cost-effectiveness analyses of dialysis modalities and consider whether the methods applied and results obtained reflect the complexities of the real-world treatment pathway experienced by ESRD patients. Methods A systematic literature review (SLR) was conducted to identify cost-effectiveness studies of dialysis modalities from 2005 onward by searching Embase, MEDLINE, EBM reviews, and EconLit. Economic evaluations were included if they compared distinct dialysis modalities (e.g. in-centre haemodialysis [ICHD], home haemodialysis [HHD] and peritoneal dialysis [PD]). Results In total, 19 cost-effectiveness studies were identified. There was considerable heterogeneity in perspectives, time horizon, discounting, utility values, sources of clinical and economic data, and extent of clinical and economic elements included. The vast majority of studies included an incident dialysis patient population. All studies concluded that home dialysis treatment options were cost-effective interventions. Conclusions Despite similar findings across studies, there are a number of uncertainties about which dialysis modalities represent the most cost-effective options for patients at different points in the care pathway. Most studies included an incident patient cohort; however, in clinical practice, patients may switch between different treatment modalities over time according to their clinical need and personal circumstances. Promoting health policies through financial incentives in renal care should reflect the cost-effectiveness of a comprehensive approach that considers different RRTs along the patient pathway; however, no such evidence is currently available.

The utility of electrodiagnostic tests (EDx) for patients with a high pretest probability of idiopathic median neuropathy at the carpal tunnel (IMNCT) based on characteristic symptoms and signs is debated. Decision-making and care strategies could be informed by a better understanding of factors associated with surgeon recommendations for electrodiagnostic testing.Ninety-one upper-extremity surgeons participated in an online, survey-based experiment. Participants viewed 7 vignettes of patients with carpal tunnel syndrome, with the following factors randomized in each vignette: patient age, gender, magnitude of incapability, symptom intensity and the presence of nocturnal symptoms, palmar abduction weakness, and positive provocative tests results. We sought patient and surgeon factors associated with ordering EDx and surgeon-rated comfort with performing carpal tunnel release (CTR) without EDx.Surgeons recommended EDx for over half of the patient vignettes, with notable variation (median, 57%; interquartile range, 14-100), and felt relatively neutral, on average, offering CTR without EDx. Twenty-six (29%) out of 91 surgeons ordered EDx for all patient scenarios, and 18 surgeons (20%) did not order testing for any scenario. A lower likelihood of EDx was associated with older age and positive provocative tests results. Greater surgeon comfort offering CTR without EDx was associated with older patients, the presence of nocturnal symptoms, palmar abduction weakness, and positive provocative tests results.Upper-extremity surgeons are neutral regarding diagnosing IMNCT based on electrodiagnostic evidence of pathology and are relatively more comfortable offering surgery without EDx in older patients that present with key aspects of carpal tunnel syndrome. There is notable variation in care, with half of all surgeons always or never ordering EDx.Future studies can investigate whether a treatment strategy offering surgery to patients with a high pretest probability of IMNCT and only using EDx in intermediate probability scenarios can limit use of testing without affecting patient health.