Biomarkers of aging for the identification and evaluation of longevity interventions.

With the rapid expansion of aging biology research, the identification and evaluation of longevity interventions in humans have become key goals of this field. Biomarkers of aging are critically important tools in achieving these objectives over realistic time frames. However, the current lack of standards and consensus on the properties of a reliable aging biomarker hinders their further development and validation for clinical applications. Here, we advance a framework for the terminology and characterization of biomarkers of aging, including classification and potential clinical use cases. We discuss validation steps and highlight ongoing challenges as potential areas in need of future research. This framework sets the stage for the development of valid biomarkers of aging and their ultimate utilization in clinical trials and practice.

Evidence for protein leverage on total energy intake, but not body mass index, in a large cohort of older adults.

BACKGROUND: Protein leverage (PL) is the phenomenon of consuming food until absolute intake of protein approaches a 'target value', such that total energy intake (TEI) varies passively with the ratio of protein: non-protein energy (fat + carbohydrate) in the diet. The PL hypothesis (PLH) suggests that the dilution of protein in energy-dense foods, particularly those rich in carbohydrates and fats, combines with protein leverage to contribute to the global obesity epidemic. Evidence for PL has been reported in younger adults, children and adolescents. This study aimed to test for PL and the protein leverage hypothesis (PLH) in a cohort of older adults. METHODS: We conducted a retrospective analysis of dietary intake in a cohort of 1699 community-dwelling older adults aged 67-84 years from the NuAge cohort. We computed TEI and the energy contribution (EC) from each macronutrient. The strength of leverage of macronutrients was assessed through power functions ( TEI = µ * EC L ). Body mass index (BMI) was calculated, and mixture models were fitted to predict TEI and BMI from macronutrients' ECs. RESULTS: In this cohort of older adults, 53% of individuals had obesity and 1.5% had severe cases. The mean TEI was 7673 kJ and macronutrients' ECs were 50.4%, 33.2% and 16.4%, respectively for carbohydrates, fat, and protein. There was a strong negative association (L = -0.37; p < 0.001) between the protein EC and TEI. Each percent of energy intake from protein reduced TEI by 77 kJ on average, ceteris paribus. However, BMI was unassociated with TEI in this cohort. CONCLUSIONS: Findings indicate clear evidence for PL on TEI, but not on BMI, likely because of aging, body composition, sarcopenia, or protein wasting.

Effect of Extra Virgin Olive Oil on Anthropometric Indices, Inflammatory and Cardiometabolic Markers: a Systematic Review and Meta-Analysis of Randomized Clinical Trials.

BACKGROUND: A large body of literature associated extra virgin olive oil (EVOO) consumption with low risk of cardiovascular disease and mortality. However, findings from clinical trials related to EVOO consumption on blood pressure, lipid profile, and anthropometric and inflammation parameters are not univocal. OBJECTIVES: The aim of this systematic review and meta-analysis was to evaluate the effect of EVOO consumption on cardiometabolic risk factors and inflammatory mediators. METHODS: We searched PubMed/MEDLINE, Scopus, and Cochrane up through 31 March, 2023, without any particular language limitations, in order to identify randomized controlled trials (RCTs) that examined the effects of EVOO consumption on cardiometabolic risk factors, inflammatory mediators, and anthropometric indices. Outcomes were summarized as standardized mean difference (SMD) with 95% confidence intervals (CIs) estimated from Hedge's g and random-effects modeling. Heterogeneity was assessed by Cochran Q-statistic and quantified (I2). RESULTS: Thirty-three trials involving 2020 participants were included. EVOO consumption was associated with a significant decrease in insulin (n = 10; SMD: -0.28; 95% CI: -0.51, -0.05; I2 = 48.57%) and homeostasis model assessment of insulin resistance levels (HOMA-IR) (n = 9; SMD: -0.19; 95% CI: -0.35, -0.03; I2 = 00.00%). This meta-analysis indicated no significant effect of consuming EVOO on fasting blood glucose, triglycerides, total cholesterol, low density lipoproteins, very low density lipoproteins, high density lipoproteins, Apolipoprotein (Apo) A-I and B, lipoprotein a, blood pressure, body mass index, waist circumference, waist to hip ratio, C-reactive protein, interleukin-6, interleukin-10, and tumor necrosis factor α levels (P > 0.05). CONCLUSIONS: The present evidence supports a beneficial effect of EVOO consumption on serum insulin levels and HOMA-IR. However, larger well-designed RCTs are still required to evaluate the effect of EVOO on cardiometabolic risk biomarkers. This study was registered in PROSPERO as CRD42023409125.

The Anterior Interhemispheric Transcallosal Approach to the Ventricles: How We Do It.

Intraventricular tumors of the lateral and third ventricles are relatively rare, accounting for 1-2% of all primary brain tumors in most large series [1-4]. They can be uniquely challenging to approach due to their deep location, propensity to become large before they are discovered, and association with hydrocephalus [5, 6]. The surgeon's goal is to develop a route to these deep lesions that will cause the least morbidity, provide adequate working space, and achieve a complete resection. This must be performed with minimal manipulation of the neural structures encircling the ventricles, avoiding functional cortical areas, and acquiring early control of feeding vessels [7, 8].

Prophylactic removal of a migratory missile from the cerebral ventricles: case report.

BACKGROUND AND IMPORTANCE: Nonpowder firearm injuries to the head pose major health risks, with retained fragments potentially causing harmful sequelae that require neurosurgical intervention. CLINICAL PRESENTATION: We report the case of 2-year-old girl who sustained an accidental gunshot wound to the head. She sustained a penetrating ballistic intracranial injury caused by a BB shot from a rifle. At presentation, she was neurologically intact with a punctate laceration on her left forehead. Head CT demonstrated a small depressed left frontal skull fracture, a small intracerebral hematoma, and a 5-mm metallic bullet fragment in the deep left frontal lobe near the frontal horn of the left lateral ventricle. She was admitted to the hospital and managed nonoperatively with levetiracetam and intravenous antibiotics, and discharged home in good condition. Follow-up CT in 1 week showed slight migration of the metallic bullet fragment to the left, placing it at the anterior horn of the lateral ventricle. Six weeks later, follow-up CT showed migration of the bullet to the temporal horn of the left lateral ventricle. Intraventricular migration of the bullet raised concern that it could move further to obstruct the foramen of Monro or cerebral aqueduct. Therefore, we removed the bullet through a small left temporal craniotomy with image guidance using a microsurgical approach through a translucent tube. CONCLUSION: The authors discuss the rationale and technique for removing a nonpowder firearm bullet that has migrated within the cerebral ventricles.

An unusual finding of an anaplastic meningioma in NF2-related schwannomatosis.

NF2-related schwannomatosis (NF2) is a rare autosomal-dominant genetic disorder characterized by bilateral vestibular schwannomas and multiple meningiomas. This case report presents the extremely rare occurrence of an anaplastic meningioma in a 12-year-old male with previously undiagnosed NF2. The patient presented with a history of abdominal pain and episodic emesis, gait unsteadiness, right upper and lower extremity weakness, and facial weakness. He had sensorineural hearing loss and wore bilateral hearing aids. MR imaging revealed a sizable left frontoparietal, dural-based meningioma with heterogeneous enhancement with mass effect on the brain and midline shift. Multiple additional CNS lesions were noted including a homogenous lesion at the level of T5 indicative of compression of the spinal cord. The patient underwent a frontotemporoparietal craniotomy for the removal of his large dural-based meningioma, utilizing neuronavigation and transdural ultrasonography for precise en bloc resection of the mass. Histopathology revealed an anaplastic meningioma, WHO grade 3, characterized by brisk mitotic activity, small-cell changes, high Ki-67 proliferation rate, and significant loss of P16. We report an anaplastic meningioma associated with an underlying diagnosis of NF2 for which we describe clinical and histopathological features.

Relative anemia and perioperative stroke in children with moyamoya.

OBJECTIVES: Surgical revascularization for moyamoya arteriopathy decreases long-term stroke risk but carries a risk of perioperative ischemic complications. We aimed to evaluate modifiable stroke risk factors in children undergoing surgical revascularization for moyamoya. MATERIALS AND METHODS: In this exploratory, single-center, retrospective cohort study, medical records of pediatric patients undergoing surgical revascularization for moyamoya arteriopathy at our center between 2003 and 2021 were reviewed. Candidate modifiable risk factors were analyzed for association with perioperative stroke, defined as ischemic stroke ≤7 days after surgery. RESULTS: We analyzed 53 surgeries, consisting of 39 individual patients undergoing indirect surgical revascularization of 74 hemispheres. Perioperative ischemic stroke occurred following five surgeries (9.4%). There were no instances of hemorrhagic stroke. Larger pre-to-postoperative decreases in hemoglobin (OR 3.90, p=0.017), hematocrit (OR 1.69, p=0.012) and blood urea nitrogen (OR 1.83, p=0.010) were associated with increased risk of perioperative ischemic stroke. Weight-adjusted intraoperative blood loss was not associated with risk of perioperative ischemic stroke (OR 0.94, p=0.796). Among children with sickle cell disease, all of whom underwent exchange transfusion within one week prior to surgery, none experienced perioperative stroke. CONCLUSIONS: Decreases in hemoglobin, hematocrit, and blood urea nitrogen between the preoperative and postoperative periods are associated with increased risk of perioperative stroke. These novel findings suggest that dilutional anemia, possibly due to standardly administered hyperhydration, may increase the risk of perioperative stroke in some children with moyamoya. Further work optimizing both mean arterial pressure and oxygen-carrying capacity in these patients, including consideration of alternative blood transfusion thresholds, is necessary.

William Macewen and the first documented successful resection of a brain tumor.

William Macewen was a visionary fearless Scottish surgeon who performed the first documented successful resection of a brain tumor on July 27, 1879. The pioneering operation received little attention at the time, and even today Macewen is under-recognized for his historic accomplishment. In this vignette, the author discusses details of Macewen's landmark procedure and describes two other groundbreaking brain tumor operations, one performed by Rickman Godlee 5 years later and another performed by Zanobi Pecchioli almost half a century earlier.

Intracranial arachnoid cysts.

PURPOSE: The purpose of this review article is to outline the natural history, pathogenesis, anatomic considerations and surgical decision-making in caring for patients with intracranial arachnoid cysts. METHODS: A review of the literature for intracranial arachnoid cysts was performed using Embase, PubMed, and Web of Science databases, including review of the bibliographies of eligible articles and the author's own experience. RESULTS: Among those reviewed, 59 relevant original articles were included as well as illustrative cases from the authors own experience. CONCLUSIONS: Arachnoid cysts are congenital lesions characterized by split arachnoid membrane, thick collagen in the cyst wall, absent traversing trabecular processes within the cyst, and hyperplastic arachnoid cells in the cyst wall. The underlying etiology is not entirely known, and they occur in greater proportion in males and in greater incidence with various genetic conditions including Down syndrome, mucopolysaccharidosis, schizencephaly, neurofibromatosis, autosomal dominant polycystic kidney disease (ADPKD), acrocallosal syndrome, and Aicardi syndrome. Most intracranial arachnoid cysts are incidentally found and occur in the middle cranial fossa, with the remaining occurring in the cerebellopontine angle, suprasellar cistern, quadrigeminal cistern, convexity, and posterior fossa/cisterna magna. The current article outlines the natural history, prevalence, demographic factors, and treatment decisions in managing patients with intracranial arachnoid cysts.

The Gordian knot of hydrocephalus: constrictive entanglement of distal ventriculoperitoneal shunt catheter.

We recently cared for a patient with a distal ventriculoperitoneal shunt malfunction. The peritoneal catheter was coiled in a scarred pseudocyst, and we encountered strong resistance while attempting to remove the distal shunt catheter. The catheter was successfully removed under laparoscopic guidance and was found to be tightly coiled in a constrictive knot. We describe a technique for managing this unusual presentation to minimize the risk of complications.

Nephrogenic rest vs immature teratoma associated with lumbosacral lipomyelomeningocele: a case report and review of the literature.

BACKGROUND: Lipomyelomeningoceles (LMMs) are subcutaneous lipomas with dural penetration that often present with spinal cord tethering and may lead to neurological deterioration if untreated. This report describes a rare case of an LMM associated with immature nephroblastic tissue, representing a nephrogenic rest (NR) or, less likely, an immature teratoma. CLINICAL PRESENTATION: An 8-day-old infant girl presented to the clinic with a sacral dimple. Imaging demonstrated a tethered spinal cord with low-lying conus medullaris and an LMM. A firm mass was noted in the subcutaneous lipoma. Detethering surgery and removal of the lipoma and mass were performed at the age of 6 months. Pathological examination identified the mass as cartilage, fat, and immature nephroblastic tissue consistent with NR tissue or, less likely, a teratoma with renal differentiation. CONCLUSION: This presentation of an LMM associated with an immature teratoma or NR poses a risk of malignant transformation in patients. As a result, careful surgical dissection, resection, and close clinical follow-up are recommended for these patients.

H3 K27-altered diffuse midline glioma presenting as massive cerebellopontine hemorrhage.

We report the case of a 14-year-old boy who presented with extensive cerebellar and brainstem hemorrhage. Our presumptive diagnosis was a ruptured arteriovenous malformation (AVM), but two cerebral angiograms showed no significant vascular abnormalities. The patient underwent posterior fossa craniotomy and microsurgical evacuation of the hematoma. Pathological analysis of the hemorrhagic tissue made the diagnosis of diffuse midline glioma, H3 K27-altered (WHO grade 4), based on immunohistochemistry. He subsequently developed diffuse craniospinal leptomeningeal disease and progressed rapidly, with respiratory failure followed by severe neurologic decline without further hemorrhage. He was compassionately extubated at the request of the family and died before initiation of adjuvant therapy. This unusual case of a diffuse midline glioma presenting with massive hemorrhage underscores the importance of searching for an underlying etiology of hemorrhage in a child when a vascular lesion cannot be identified.

Same-day versus staged revascularization of bilateral moyamoya arteriopathy in pediatric patients.

PURPOSE: To compare the outcomes of conducting left and right hemisphere surgical revascularization on the same day versus different days for bilateral pediatric moyamoya arteriopathy patients. METHODS: We retrospectively analyzed mortality, stroke, and transient neurologic event (TNE) rates in North American bilateral pediatric moyamoya arteriopathy patients who underwent bilateral cerebral revascularization. RESULTS: A total of 38 pediatric (≤ 18 years old) patients at our institution underwent bilateral cerebral revascularization for moyamoya arteriopathy. Of these patients, 24 (63.2%) had both operations on the same day and 14 (36.8%) had the two operations on different days. The average length of stay for patients who underwent same-day bilateral revascularization was 6.9 ± 2.0 days and the average length of stay for each operation for patients who underwent staged bilateral revascularization was 4.5 ± 1.4 days, p = 0.001. While there were 7 (14.6%) postoperative strokes in patients who had both hemispheres revascularized on the same day, 0 (0%) strokes occurred in hemispheres after they had been operated on in the staged cohort, p = 0.042. Additionally, the postoperative stroke-free survival time in the ipsilateral hemisphere and TNE-free survival time were significantly longer in patients in the staged revascularization cohort. CONCLUSION: Same-day bilateral revascularization was associated with longer length of stay per operation, higher rate of ipsilateral stroke, and shorter postoperative TNE-free and stroke-free survival time in the revascularized hemisphere.

Multidimensional associations between nutrient intake and healthy ageing in humans.

BACKGROUND: Little is known about how normal variation in dietary patterns in humans affects the ageing process. To date, most analyses of the problem have used a unidimensional paradigm, being concerned with the effects of a single nutrient on a single outcome. Perhaps then, our ability to understand the problem has been complicated by the fact that both nutrition and the physiology of ageing are highly complex and multidimensional, involving a high number of functional interactions. Here we apply the multidimensional geometric framework for nutrition to data on biological ageing from 1560 older adults followed over four years to assess on a large-scale how nutrient intake associates with the ageing process. RESULTS: Ageing and age-related loss of homeostasis (physiological dysregulation) were quantified via the integration of blood biomarkers. The effects of diet were modelled using the geometric framework for nutrition, applied to macronutrients and 19 micronutrients/nutrient subclasses. We observed four broad patterns: (1) The optimal level of nutrient intake was dependent on the ageing metric used. Elevated protein intake improved/depressed some ageing parameters, whereas elevated carbohydrate levels improved/depressed others; (2) There were non-linearities where intermediate levels of nutrients performed well for many outcomes (i.e. arguing against a simple more/less is better perspective); (3) There is broad tolerance for nutrient intake patterns that don't deviate too much from norms ('homeostatic plateaus'). (4) Optimal levels of one nutrient often depend on levels of another (e.g. vitamin E and vitamin C). Simpler linear/univariate analytical approaches are insufficient to capture such associations. We present an interactive tool to explore the results in the high-dimensional nutritional space. CONCLUSION: Using multidimensional modelling techniques to test the effects of nutrient intake on physiological dysregulation in an aged population, we identified key patterns of specific nutrients associated with minimal biological ageing. Our approach presents a roadmap for future studies to explore the full complexity of the nutrition-ageing landscape.

Which interventions with youths counter ageism toward older adults? Results from a realist review.

Age-related social biases - ageism - are developed at an early age. Interventions to counter ageism have been identified but little is known about their mechanisms, particularly in children. This study aimed to provide a comprehensive understanding of which interventions in youths are most effective, under which circumstances, how, and with what outcomes. Using 46 keywords in 6 databases, a realist review identified 24 studies published between 2000 and 2022 targeting youths under 18. A content analysis of these studies led to the construction of a Context-Mechanisms-Outcomes explanatory model. Contextual facilitators triggering mechanisms for changing stereotypes, prejudices and discrimination were: 1) enhancing knowledge about aging and older adults by providing nuanced information, 2) improving the quality of intergenerational contacts, 3) increasing opportunities to apply previously acquired knowledge in intergenerational interactions, and 4) promoting reflective thinking about experiences with older adults. However, stereotypes and prejudices appeared to be resistant and changes difficult to generalize. Insufficiently advanced cognitive development in children or viewing healthy and socially engaged older adults as unrepresentative of their age group were obstacles that reduced intervention effectiveness. Future studies should explore how advancing age influences interventions as well as the characteristics of older adults involved.

An update on the US adult thalassaemia population: a report from the CDC thalassaemia treatment centres.

Thalassaemia is caused by genetic globin defects leading to anaemia, transfusion-dependence and comorbidities. Reduced survival and systemic organ disease affect transfusion-dependent thalassaemia major and thalassaemia intermedia. Recent improvements in clinical management have reduced thalassaemia mortality. The therapeutic landscape of thalassaemia may soon include gene therapies as functional cures. An analysis of the adult US thalassaemia population has not been performed since the Thalassemia Clinical Research Network cohort study from 2000 to 2006. The Centers for Disease Control and Prevention supported US thalassaemia treatment centres (TTCs) to compile longitudinal information on individuals with thalassaemia. This dataset provided an opportunity to evaluate iron balance, chelation, comorbidities and demographics of adults with thalassaemia receiving care at TTCs. Two adult cohorts were compared: those over 40 years old (n = 75) and younger adults ages 18-39 (n = 201). The older adult cohort was characterized by higher numbers of iron-related comorbidities and transfusion-related complications. By contrast, younger adults had excess hepatic and cardiac iron and were receiving combination chelation therapy. The ethnic composition of the younger cohort was predominantly of Asian origin, reflecting the demographics of immigration. These findings demonstrate that comprehensive care and periodic surveys are needed to ensure optimal health and access to emerging therapies.

Vitamin B-12 Intake from Dairy but Not Meat Is Associated with Decreased Risk of Low Vitamin B-12 Status and Deficiency in Older Adults from Quebec, Canada.

BACKGROUND: Vitamin B-12 deficiency can result in irreversible neurologic damages. It is most prevalent among older adults (∼5%-15%), mainly due to impaired absorption. Vitamin B-12 bioavailability varies between food sources, so their importance in preventing deficiency may also vary. OBJECTIVES: Using the NuAge Database and Biobank, we examined the associations between vitamin B-12 intake (total and by specific food groups) and low vitamin B-12 status and deficiency in older adults. METHODS: NuAge-the Quebec Longitudinal Study on Nutrition and Successful Aging-included 1753 adults aged 67-84 y who were followed 4 y. Analytic samples comprised 1230-1463 individuals. Dietary vitamin B-12 intake was assessed annually using three 24-h dietary recalls. Vitamin B-12 status was assessed annually as low serum vitamin B-12 (<221 pmol/L), elevated urinary methylmalonic acid (MMA)/creatinine ratio (>2 µmol/mmol), and a combination of both (deficiency). Vitamin B-12 supplement users were excluded. Multilevel logistic regressions, adjusted for relevant confounders, were used. RESULTS: Across all study years, 21.8%-32.5% of participants had low serum vitamin B-12, 12.5%-17.0% had elevated urine MMA/creatinine, and 10.1%-12.7% had deficiency. Median (IQR) total vitamin B-12 intake was 3.19 µg/d (2.31-4.37). Main sources were "dairy" and "meat, poultry, and organ meats." The ORs (95% CIs) in the fifth quintile compared with the first of total vitamin B-12 intake were as follows: for low serum vitamin B-12, 0.52 (0.37, 0.75; P-trend < 0.0001); for elevated urine MMA/creatinine, 0.63 (0.37, 1.08; P-trend = 0.091); and for vitamin B-12 deficiency, 0.38 (0.18, 0.79; P-trend = 0.006). Similarly, ORs (95% CIs) in the fourth quartile compared with the first of dairy-derived vitamin B-12 intake were 0.46 (0.32, 0.66; P-trend < 0.0001), 0.51 (0.30, 0.87; P-trend = 0.006), and 0.35 (0.17, 0.73; P-trend = 0.003), respectively. No associations were observed with vitamin B-12 from "meat, poultry, and organ meats." CONCLUSIONS: Higher dietary vitamin B-12 intake, especially from dairy, was associated with decreased risk of low vitamin B-12 status and deficiency in older adults. Food groups might contribute differently at reducing risk of deficiency in older populations.

An objective metric of individual health and aging for population surveys.

BACKGROUND: We have previously developed and validated a biomarker-based metric of overall health status using Mahalanobis distance (DM) to measure how far from the norm of a reference population (RP) an individual's biomarker profile is. DM is not particularly sensitive to the choice of biomarkers; however, this makes comparison across studies difficult. Here we aimed to identify and validate a standard, optimized version of DM that would be highly stable across populations, while using fewer and more commonly measured biomarkers. METHODS: Using three datasets (the Baltimore Longitudinal Study of Aging, Invecchiare in Chianti and the National Health and Nutrition Examination Survey), we selected the most stable sets of biomarkers in all three populations, notably when interchanging RPs across populations. We performed regression models, using a fourth dataset (the Women's Health and Aging Study), to compare the new DM sets to other well-known metrics [allostatic load (AL) and self-assessed health (SAH)] in their association with diverse health outcomes: mortality, frailty, cardiovascular disease (CVD), diabetes, and comorbidity number. RESULTS: A nine- (DM9) and a seventeen-biomarker set (DM17) were identified as highly stable regardless of the chosen RP (e.g.: mean correlation among versions generated by interchanging RPs across dataset of r = 0.94 for both DM9 and DM17). In general, DM17 and DM9 were both competitive compared with AL and SAH in predicting aging correlates, with some exceptions for DM9. For example, DM9, DM17, AL, and SAH all predicted mortality to a similar extent (ranges of hazard ratios of 1.15-1.30, 1.21-1.36, 1.17-1.38, and 1.17-1.49, respectively). On the other hand, DM9 predicted CVD less well than DM17 (ranges of odds ratios of 0.97-1.08, 1.07-1.85, respectively). CONCLUSIONS: The metrics we propose here are easy to measure with data that are already available in a wide array of panel, cohort, and clinical studies. The standardized versions here lose a small amount of predictive power compared to more complete versions, but are nonetheless competitive with existing metrics of overall health. DM17 performs slightly better than DM9 and should be preferred in most cases, but DM9 may still be used when a more limited number of biomarkers is available.

Age and Ageing journal 50th anniversary commentary seriesWhy illness is more important than disease in old age.

Clinical reasoning and research in modern geriatrics often prioritises the disease concept. This is understandable as it has brought impressive advances in medicine (e.g. antibiotics, vaccines, successful cancer treatment and many effective surgeries). However, so far the disease framework has not succeeded in getting us to root causes of many age-related chronic diseases (e.g. Alzheimer's disease, diabetes, osteoarthritis). Moreover, in aging and disease constructs alone fail to explain the variability in illness presentations. Therefore, we propose to apply the underused illness concept in a new way by reconsidering the importance of common symptoms in the form of a dynamic network of symptoms as a complementary framework. We show that concepts and methods of complex system thinking now enable to fruitfully monitor and analyse the multiple interactions between symptoms in such in networks, offering new routes for prognosis and treatment. Moreover, close attention to the symptoms that bother older persons may also improve weighing the therapeutic objectives of well-being and survival and aligning treatment targets with the patients' priorities.

The evolution of mean arterial pressure in critically ill patients on vasopressors before and during a trial comparing a specific mean arterial pressure target to usual care.

BACKGROUND: In randomized clinical controlled trials, the choice of usual care as the comparator may be associated with better clinician uptake of the study protocol and lead to more generalizable results. However, if care processes evolve to resemble the intervention during the course of a trial, differences between the intervention group and usual care control group may narrow. We evaluated the effect on mean arterial pressure of an unblinded trial comparing a lower mean arterial pressure target to reduce vasopressor exposure, vs. a clinician-selected mean arterial pressure target, in critically ill patients at least 65 years old. METHODS: For this multicenter observational study using data collected both prospectively and retrospectively, patients were recruited from five of the seven trial sites. We compared the mean arterial pressure of patients receiving vasopressors, who met or would have met trial eligibility criteria, from two periods: [1] at least 1 month before the trial started, and [2] during the trial period and randomized to usual care, or not enrolled in the trial. RESULTS: We included 200 patients treated before and 229 after trial initiation. There were no differences in age (mean 74.5 vs. 75.2 years; p = 0.28), baseline Acute Physiology and Chronic Health Evaluation II score (median 26 vs. 26; p = 0.47) or history of chronic hypertension (n = 126 [63.0%] vs. n = 153 [66.8%]; p = 0.41). Mean of the mean arterial pressure was similar between the two periods (72.5 vs. 72.4 mmHg; p = 0.76). CONCLUSIONS: The initiation of a trial of a prescribed lower mean arterial pressure target, compared to a usual clinician-selected target, was not associated with a change in mean arterial pressure, reflecting stability in the net effect of usual clinician practices over time. Comparing prior and concurrent control groups may alleviate concerns regarding drift in usual practices over the course of a trial or permit quantification of any change.