Memorial Medical Center

This article reviews current evidence for autism spectrum disorder (ASD) interventions for children aged <3 years, based on peer-reviewed articles published up to December 2013. Several groups have adapted treatments initially designed for older, preschool-aged children with ASD, integrating best practice in behavioral teaching methods into a developmental framework based on current scientific understanding of how infants and toddlers learn. The central role of parents has been emphasized, and interventions are designed to incorporate learning opportunities into everyday activities, capitalize on "teachable moments," and facilitate the generalization of skills beyond the familiar home setting. Our review identified several comprehensive and targeted treatment models with evidence of clear benefits. Although some trials were limited to 8- to 12-week outcome data, enhanced outcomes associated with some interventions were evaluated over periods as long as 2 years. Based on this review, recommendations are proposed for clinical practice and future research.

BACKGROUND AND METHODS: The development of a multifactorial coagulopathy after massive transfusion is a well-recognized clinical problem that is almost always accompanied by hypothermia. The purpose of this study was to investigate the isolated effect of alterations of temperature on the integrity of the coagulation cascade. Prothrombin times and partial thromboplastin times were each performed 15 times on samples of pooled normal plasma at the temperatures of 37 degrees C, 34 degrees C, 31 degrees C, and 28 degrees C, as well as 39 degrees C and 41 degrees C. RESULTS: Mean prothrombin time results increased from 11.8 +/- 0.3 (SD) secs at 37 degrees C to 12.9 +/- 0.5, 14.2 +/- 0.5, and 16.6 +/- 0.2 secs at 34 degrees C, 31 degrees C, and 28 degrees C, respectively (p < or = .001 for each). Partial thromboplastin time determinations increased from 36.0 +/- 0.7 (SD) secs at 37 degrees C to 39.4 +/- 1.0, 46.1 +/- 1.1, and 57.2 +/- 0.6 secs at 34 degrees C, 31 degrees C, and 28 degrees C, respectively (p < or = .001 for each). Both prothrombin time and partial thromboplastin time determinations were only minimally shortened at hyperthermic temperatures. CONCLUSIONS: The series of enzymatic reactions of the coagulation cascade are strongly inhibited by hypothermia, as demonstrated by the dramatic prolongation of prothrombin time and partial thromboplastin time tests at hypothermic deviations from normal temperature in a situation where factor levels were all known to be normal. Clinicians who deal with critically ill massively transfused hypothermic patients all recognize the inevitable appearance of a coagulopathy that has a multifactorial origin. Unless specifically considered, the contribution of hypothermia to the hemorrhagic diathesis may be overlooked since coagulation testing is performed at 37 degrees C, rather than at the patient's actual in vivo temperature.

In this article we study post-model selection estimators that apply ordinary least squares (OLS) to the model selected by first-step penalized estimators, typically Lasso. It is well known that Lasso can estimate the nonparametric regression function at nearly the oracle rate, and is thus hard to improve upon. We show that the OLS post-Lasso estimator performs at least as well as Lasso in terms of the rate of convergence, and has the advantage of a smaller bias. Remarkably, this performance occurs even if the Lasso-based model selection “fails” in the sense of missing some components of the “true” regression model. By the “true” model, we mean the best $s$-dimensional approximation to the nonparametric regression function chosen by the oracle. Furthermore, OLS post-Lasso estimator can perform strictly better than Lasso, in the sense of a strictly faster rate of convergence, if the Lasso-based model selection correctly includes all components of the “true” model as a subset and also achieves sufficient sparsity. In the extreme case, when Lasso perfectly selects the “true” model, the OLS post-Lasso estimator becomes the oracle estimator. An important ingredient in our analysis is a new sparsity bound on the dimension of the model selected by Lasso, which guarantees that this dimension is at most of the same order as the dimension of the “true” model. Our rate results are nonasymptotic and hold in both parametric and nonparametric models. Moreover, our analysis is not limited to the Lasso estimator acting as a selector in the first step, but also applies to any other estimator, for example, various forms of thresholded Lasso, with good rates and good sparsity properties. Our analysis covers both traditional thresholding and a new practical, data-driven thresholding scheme that induces additional sparsity subject to maintaining a certain goodness of fit. The latter scheme has theoretical guarantees similar to those of Lasso or OLS post-Lasso, but it dominates those procedures as well as traditional thresholding in a wide variety of experiments.

Venoarterial extracorporeal membrane oxygenation (VA-ECMO)-also referred to as extracorporeal life support-is a form of temporary mechanical circulatory support and simultaneous extracorporeal gas exchange. The initiation of VA-ECMO has emerged as a salvage intervention in patients with cardiogenic shock, even cardiac arrest refractory to standard therapies. Analogous to veno-venous ECMO for acute respiratory failure, VA-ECMO provides circulatory support and allows time for other treatments to promote recovery or may be a bridge to a more durable mechanical solution in the setting of acute or acute on chronic cardiopulmonary failure. In this review, we provide a brief overview of VA-ECMO, the attendant physiological considerations of peripheral VA-ECMO, and its complications, namely that of left ventricular distention, bleeding, heightened systemic inflammatory response syndrome, thrombosis and thromboembolism, and extremity ischemia or necrosis.

BACKGROUND: Sodium phenylbutyrate and taurursodiol have been found to reduce neuronal death in experimental models. The efficacy and safety of a combination of the two compounds in persons with amyotrophic lateral sclerosis (ALS) are not known. METHODS: In this multicenter, randomized, double-blind trial, we enrolled participants with definite ALS who had had an onset of symptoms within the previous 18 months. Participants were randomly assigned in a 2:1 ratio to receive sodium phenylbutyrate-taurursodiol (3 g of sodium phenylbutyrate and 1 g of taurursodiol, administered once a day for 3 weeks and then twice a day) or placebo. The primary outcome was the rate of decline in the total score on the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R; range, 0 to 48, with higher scores indicating better function) through 24 weeks. Secondary outcomes were the rates of decline in isometric muscle strength, plasma phosphorylated axonal neurofilament H subunit levels, and the slow vital capacity; the time to death, tracheostomy, or permanent ventilation; and the time to death, tracheostomy, permanent ventilation, or hospitalization. RESULTS: A total of 177 persons with ALS were screened for eligibility, and 137 were randomly assigned to receive sodium phenylbutyrate-taurursodiol (89 participants) or placebo (48 participants). In a modified intention-to-treat analysis, the mean rate of change in the ALSFRS-R score was -1.24 points per month with the active drug and -1.66 points per month with placebo (difference, 0.42 points per month; 95% confidence interval, 0.03 to 0.81; P = 0.03). Secondary outcomes did not differ significantly between the two groups. Adverse events with the active drug were mainly gastrointestinal. CONCLUSIONS: Sodium phenylbutyrate-taurursodiol resulted in slower functional decline than placebo as measured by the ALSFRS-R score over a period of 24 weeks. Secondary outcomes were not significantly different between the two groups. Longer and larger trials are necessary to evaluate the efficacy and safety of sodium phenylbutyrate-taurursodiol in persons with ALS. (Funded by Amylyx Pharmaceuticals and others; CENTAUR ClinicalTrials.gov number, NCT03127514.).

Division of Vascular Surgery, University of Massachusetts Medical School, and Division of Hematology, The Medical Center of Central Massachusetts-Memorial, Worcester, Massachusetts

Early identification of autism spectrum disorder (ASD) is essential to ensure that children can access specialized evidence-based interventions that can help to optimize long-term outcomes. Early identification also helps shorten the stressful "diagnostic odyssey" that many families experience before diagnosis. There have been important advances in research into the early development of ASDs, incorporating prospective designs and new technologies aimed at more precisely delineating the early emergence of ASD. Thus, an updated review of the state of the science of early identification of ASD was needed to inform best practice. These issues were the focus of a multidisciplinary panel of clinical practitioners and researchers who completed a literature review and reached consensus on current evidence addressing the question "What are the earliest signs and symptoms of ASD in children aged ≤24 months that can be used for early identification?" Summary statements address current knowledge on early signs of ASD, potential contributions and limitations of prospective research with high-risk infants, and priorities for promoting the incorporation of this knowledge into clinical practice and future research.

BACKGROUND: Although a role for resection of solitary metastases from renal cell carcinoma (RCC) has been described, the utility of surgery in patients with multiple sites of disease has been less well defined. The authors report the survival of patients who underwent complete metastasectomy for multiple RCC metastases. METHODS: The authors identified 887 patients who underwent nephrectomy for RCC between 1976 and 2006 who developed multiple metastatic lesions. The impact of complete metastasectomy on survival was evaluated controlling for the timing, location, and number of metastases and for patient performance status. RESULTS: Of 887 patients, 125 (14%) underwent complete surgical resection of all metastases. Complete metastasectomy was associated with a significant prolongation of median cancer-specific survival (CSS) (4.8 years vs 1.3 years; P < .001). Patients who had lung-only metastases had a 5-year CSS rate of 73.6% with complete resection versus 19% without complete resection (P < .001). A survival advantage from complete metastasectomy also was observed among patients with multiple, nonlung-only metastases, who had a 5-year CSS rate of 32.5% with complete resection versus 12.4% without complete resection (P < .001). Complete resection remained predictive of improved CSS for patients who had ≥ 3 metastatic lesions (P < .001) and for patients who had synchronous (P < .001) and asynchronous (P = .002) multiple metastases. Moreover, on multivariate analysis, the absence of complete metastasectomy was associated significantly with an increased risk of death from RCC (hazard ratio, 2.91; 95% confidence interval, 2.17-3.90; P < .001). CONCLUSIONS: The current results indicated that complete resection of multiple RCC metastases may be associated with long-term survival and should be considered when technically feasible in appropriate surgical candidates.

Background: Endovascular treatment with mechanical thrombectomy (MT) is beneficial for patients with acute stroke suffering a large-vessel occlusion, although treatment efficacy is highly time-dependent. We hypothesized that interhospital transfer to endovascular-capable centers would result in treatment delays and worse clinical outcomes compared with direct presentation. Methods: STRATIS (Systematic Evaluation of Patients Treated With Neurothrombectomy Devices for Acute Ischemic Stroke) was a prospective, multicenter, observational, single-arm study of real-world MT for acute stroke because of anterior-circulation large-vessel occlusion performed at 55 sites over 2 years, including 1000 patients with severe stroke and treated within 8 hours. Patients underwent MT with or without intravenous tissue plasminogen activator and were admitted to endovascular-capable centers via either interhospital transfer or direct presentation. The primary clinical outcome was functional independence (modified Rankin Score 0–2) at 90 days. We assessed (1) real-world time metrics of stroke care delivery, (2) outcome differences between direct and transfer patients undergoing MT, and (3) the potential impact of local hospital bypass. Results: A total of 984 patients were analyzed. Median onset-to-revascularization time was 202.0 minutes for direct versus 311.5 minutes for transfer patients ( P <0.001). Clinical outcomes were better in the direct group, with 60.0% (299/498) achieving functional independence compared with 52.2% (213/408) in the transfer group (odds ratio, 1.38; 95% confidence interval, 1.06–1.79; P =0.02). Likewise, excellent outcome (modified Rankin Score 0–1) was achieved in 47.4% (236/498) of direct patients versus 38.0% (155/408) of transfer patients (odds ratio, 1.47; 95% confidence interval, 1.13–1.92; P =0.005). Mortality did not differ between the 2 groups (15.1% for direct, 13.7% for transfer; P =0.55). Intravenous tissue plasminogen activator did not impact outcomes. Hypothetical bypass modeling for all transferred patients suggested that intravenous tissue plasminogen activator would be delayed by 12 minutes, but MT would be performed 91 minutes sooner if patients were routed directly to endovascular-capable centers. If bypass is limited to a 20-mile radius from onset, then intravenous tissue plasminogen activator would be delayed by 7 minutes and MT performed 94 minutes earlier. Conclusions: In this large, real-world study, interhospital transfer was associated with significant treatment delays and lower chance of good outcome. Strategies to facilitate more rapid identification of large-vessel occlusion and direct routing to endovascular-capable centers for patients with severe stroke may improve outcomes. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02239640.

Glutaraldehyde crosslinking of native or reconstituted collagen fibrils and tissues rich in collagen significantly reduces biodegradation. Other aldehydes are less efficient than glutaraldehyde in generating chemically, biologically, and thermally stable crosslinks. Tissues crosslinked with glutaraldehyde retain many of the viscoelastic properties of the native collagen fibrillar network which render them suitable for bioprostheses. Implants of collagenous materials crosslinked with glutaraldehyde are subject long-term to calcification, biodegradation, and low-grade immune reactions. We have attempted to overcome these problems by enhancing crosslinking through bridging of activated carboxyl groups with diamines and using glutaraldehyde to crosslink the epsilon-NH2 groups in collagen and the unreacted amines introduced by aliphatic diamines. This crosslinking reduces tissue degradation and nearly eliminates humoral antibody induction. Covalent binding of diphosphonates, specifically 3-amino-1-hydroxypropane-1, 1-diphosphonic acid (3-APD), and chondroitin sulfate to collagen or to the crosslink-enhanced collagen network reduces its potential for calcification. Platelet aggregation is also reduced by glutaraldehyde crosslinking and nearly eliminated by the covalent binding of chondroitin sulfate to collagen. The cytotoxicity of residual glutaraldehyde--leaching through the interstices of the collagen fibrils or the tissue matrix--and of reactive aldehydes associated with the bound polymeric glutaraldehyde can be minimized by neutralization and thorough rinsing after crosslinking and storage in a nontoxic bacteriostatic solution.

BACKGROUND: A report from a high-volume single center indicated a survival benefit of receiving a kidney transplant from an HLA-incompatible live donor as compared with remaining on the waiting list, whether or not a kidney from a deceased donor was received. The generalizability of that finding is unclear. METHODS: In a 22-center study, we estimated the survival benefit for 1025 recipients of kidney transplants from HLA-incompatible live donors who were matched with controls who remained on the waiting list or received a transplant from a deceased donor (waiting-list-or-transplant control group) and controls who remained on the waiting list but did not receive a transplant (waiting-list-only control group). We analyzed the data with and without patients from the highest-volume center in the study. RESULTS: Recipients of kidney transplants from incompatible live donors had a higher survival rate than either control group at 1 year (95.0%, vs. 94.0% for the waiting-list-or-transplant control group and 89.6% for the waiting-list-only control group), 3 years (91.7% vs. 83.6% and 72.7%, respectively), 5 years (86.0% vs. 74.4% and 59.2%), and 8 years (76.5% vs. 62.9% and 43.9%) (P<0.001 for all comparisons with the two control groups). The survival benefit was significant at 8 years across all levels of donor-specific antibody: 89.2% for recipients of kidney transplants from incompatible live donors who had a positive Luminex assay for anti-HLA antibody but a negative flow-cytometric cross-match versus 65.0% for the waiting-list-or-transplant control group and 47.1% for the waiting-list-only control group; 76.3% for recipients with a positive flow-cytometric cross-match but a negative cytotoxic cross-match versus 63.3% and 43.0% in the two control groups, respectively; and 71.0% for recipients with a positive cytotoxic cross-match versus 61.5% and 43.7%, respectively. The findings did not change when patients from the highest-volume center were excluded. CONCLUSIONS: This multicenter study validated single-center evidence that patients who received kidney transplants from HLA-incompatible live donors had a substantial survival benefit as compared with patients who did not undergo transplantation and those who waited for transplants from deceased donors. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases.).

PURPOSE Limitations of the paclitaxel-doxorubicin-cisplatin (TAP) regimen in the treatment of endometrial cancer include tolerability and cumbersome scheduling. The Gynecologic Oncology Group studied carboplatin plus paclitaxel (TC) as a noninferior alternative to TAP. METHODS GOG0209 was a phase III, randomized, noninferiority, open-label trial. Inclusion criteria were stage III, stage IV, and recurrent endometrial cancers; performance status 0-2; and adequate renal, hepatic, and marrow function. Prior radiotherapy and/or hormonal therapy were permitted, but chemotherapy, including radiosensitization, was not. Patients were treated with doxorubicin 45 mg/m 2 and cisplatin 50 mg/m 2 (day 1), followed by paclitaxel 160 mg/m 2 (day 2) with granulocyte colony-stimulating factor or paclitaxel 175 mg/m 2 and carboplatin area under the curve 6 (day 1) every 21 days for seven cycles. The primary endpoint was overall survival (OS; modified intention to treat). Progression-free survival (PFS), health-related quality of life (HRQoL), and toxicity were secondary endpoints. RESULTS From 2003 to 2009, 1,381 women were enrolled. Noninferiority of TC to TAP was concluded for OS (median, 37 v 41 months, respectively; hazard ratio [HR], 1.002; 90% CI, 0.9 to 1.12), and PFS (median, 13 v 14 months; HR, 1.032; 90% CI, 0.93 to 1.15). Neutropenic fever was reported in 7% of patients receiving TAP and 6% of those receiving TC. Grade > 2 sensory neuropathy was recorded in 26% of patients receiving TAP and 20% receiving TC ( P = .40). More grade ≥ 3 thrombocytopenia (23% v 12%), vomiting (7% v 4%), diarrhea (6% v 2%), and metabolic (14% v 8%) toxicities were reported with TAP. Neutropenia (52% v 80%) was more common with TC. Small HRQoL differences favored TC. CONCLUSION With demonstrated noninferiority to TAP, TC is the global first-line standard for advanced endometrial cancer.

This article reviews current evidence for autism spectrum disorder (ASD) screening based on peer-reviewed articles published to December 2013. Screening provides a standardized process to ensure that children are systematically monitored for early signs of ASD to promote earlier diagnosis. The current review indicates that screening in children aged 18 to 24 months can assist in early detection, consistent with current American Academy of Pediatrics' recommendations. We identify ASD-specific and broadband screening tools that have been evaluated in large community samples which show particular promise in terms of accurate classification and clinical utility. We also suggest strategies to help overcome challenges to implementing ASD screening in community practice, as well as priorities for future research.

Fournier gangrene is a rapidly progressing necrotizing fasciitis involving the perineal, perianal, or genital regions and constitutes a true surgical emergency with a potentially high mortality rate. Although the diagnosis of Fournier gangrene is often made clinically, emergency computed tomography (CT) can lead to early diagnosis with accurate assessment of disease extent. CT not only helps evaluate the perineal structures that can become involved by Fournier gangrene, but also helps assess the retroperitoneum, to which the disease can spread. Findings at CT include asymmetric fascial thickening, subcutaneous emphysema, fluid collections, and abscess formation. Subcutaneous emphysema is the hallmark of Fournier gangrene but is not seen in all cases. Compared with radiography and ultrasonography, CT provides a higher specificity for the diagnosis of Fournier gangrene and superior evaluation of disease extent; however, diagnosis and evaluation can also be performed with these other modalities. The administration of broad-spectrum antibiotics and aggressive surgical débridement of the nonviable tissue are both essential for successful treatment. An awareness of the CT features of Fournier gangrene is imperative for prompt diagnosis and effective treatment planning.

Serial changes in left ventricular (LV) size and function during the adaptation to chronic pressure overload and the transition to pump failure were studied in 16 conscious dogs (aortic bands placed at 8 weeks of age). Echocardiographic data at baseline and at 3, 6, 9, and 12 months after banding revealed a progressive increase in LV mass in all dogs. In six dogs with LV pump failure, there was a progressive decline in circumferential fiber shortening (29 +/- 4% at 12 months); this was significantly less than that seen in five littermate controls (38 +/- 3%, p less than 0.05). The average LV to body weight ratio in this group was 9.8 +/- 2.7 g/kg. In 10 dogs without pump failure (compensated LVH group), shortening exceeded that seen in the controls (43 +/- 4%, p less than 0.05); the LV to body weight ratio was 7.7 +/- 1.0 g/kg. At 12 months (cardiac catheterization), the LV end-diastolic pressure was higher in the failure (25 +/- 15 mm Hg) than in the compensated group (8 +/- 5 mm Hg, p less than 0.05); mean systolic stress was also higher in the failure group (313 +/- 67 g/cm2) than in the compensated group (202 +/- 53 g/cm2, p less than 0.05). The transmural distribution of myocardial blood flow was measured (at 12 months) with the radioactive microsphere technique; flow data were then related to an index of demand (a stress-time index). There was preferential blood flow to the subendocardial layers in the control (endo/epi = 1.28) and compensated hearts (endo/epi = 1.10), but in the failure group there was a relative decrease in subendocardial flow (endo/epi = 0.92). However, the absolute values for subendocardial flow in the normal, compensated, and failure groups were 77 +/- 54, 125 +/- 48, and 113 +/- 64 ml/min/100 g; the stress-time indexes in the subendocardial shell were 38 +/- 11, 74 +/- 19, and 93 +/- 34 g sec.10(2)/cm2/min. Despite what appears to be a marginal balance between blood flow and the stress time index in the failure group, the myocardial high energy phosphates were not depleted and the inoptropic state was not depressed. In this model of LV hypertrophy, the observed differences in fiber shortening can be explained on the basis of the inverse afterload-shortening relation; pump failure was due to an inadequate LV hypertrophy with afterload excess.(ABSTRACT TRUNCATED AT 400 WORDS)

Patients who have undergone total hip or knee replacement (THR and TKR, respectively) are at high risk of venous thromboembolism. We aimed to determine the time courses of both the incidence of venous thromboembolism and effective prophylaxis. Patients with elective primary THR and TKR were enrolled in the multi-national Global Orthopaedic Registry. Data on the incidence of venous thromboembolism and prophylaxis were collected from 6639 THR and 8326 TKR patients. The cumulative incidence of venous thromboembolism within three months of surgery was 1.7% in the THR and 2.3% in the TKR patients. The mean times to venous thromboembolism were 21.5 days (sd 22.5) for THR, and 9.7 days (sd 14.1) for TKR. It occurred after the median time to discharge in 75% of the THR and 57% of the TKA patients who developed venous thromboembolism. Of those who received recommended forms of prophylaxis, approximately one-quarter (26% of THR and 27% of TKR patients) were not receiving it seven days after surgery, the minimum duration recommended at the time of the study. The risk of venous thromboembolism extends beyond the usual period of hospitalisation, while the duration of prophylaxis is often shorter than this. Practices should be re-assessed to ensure that patients receive appropriate durations of prophylaxis.

This study investigated the role of spontaneous and induced spreading depression (SD) on the evolution of focal ischemia in vivo. We induced focal ischemia in 12 rats using the middle cerebral artery suture occlusion (MCAO) method. Chemical stimulation of nonischemic ipsilateral cortex by potassium chloride application (KCl group; n = 7) and saline (NaCl group; n = 5) was performed at 15, 30, 45, and 60 minutes following MCAO, and SD was detected electrophysiologically. Ischemic lesion volumes assessed over 15-minute intervals, evaluated by continuous apparent diffusion coefficient (ADC) of water mapping, demonstrated that the ischemic region increased significantly during 15-minute time epochs with a single SD episode (36.5 +/- 12.9 mm3, mean +/- SD) or multiple SD episodes (39.8 +/- 22.3) compared with those without SD (13.9 +/- 11.5) (p = 0.0009). Infarct volume at postmortem 24 hours after MCAO was significantly larger in the KCl group, with more total SDs (237.8 +/- 13.8) than the NaCl group (190.5 +/- 12.6) (p = 0.0001). This study demonstrates that ischemia-related and induced SDs increase significantly ischemic lesion volume in vivo, supporting the hypothesis for a causative role of SD in extending focal ischemic injury.

INTRODUCTION: While propofol is associated with an infusion syndrome (PRIS) that may cause death, the incidence of PRIS is unknown. Determining the incidence of PRIS and the frequency of PRIS-related clinical manifestations are key steps prior to the completion of any controlled studies investigating PRIS. This prospective, multicenter study sought to determine the incidence of PRIS and PRIS-related clinical manifestations in a large cohort of critically ill adults prescribed propofol. METHODS: Critically ill adults from 11 academic medical centers administered an infusion of propofol for [>or=] 24 hours were monitored at baseline and then on a daily basis until propofol was discontinued for the presence of 11 different PRIS-associated clinical manifestations and risk factors derived from 83 published case reports of PRIS. RESULTS: Among 1017 patients [medical (35%), neurosurgical (25%)], PRIS (defined as metabolic acidosis plus cardiac dysfunction and [>or=] 1 of: rhabdomyolysis, hypertriglyceridemia or renal failure occurring after the start of propofol therapy) developed in 11 (1.1%) patients an average of 3 (1-6) [median (range)] days after the start of propofol. While most (91%) of the patients who developed PRIS were receiving a vasopressor (80% initiated after the start of propofol therapy), few received a propofol dose >83 mcg/kg/min (18%) or died (18%). Compared to the 1006 patients who did not develop PRIS, the APACHE II score (25 +/- 6 vs 20 +/- 7, P = 0.01) was greater in patients with PRIS but both the duration of propofol use (P = 0.43) and ICU length of stay (P = 0.82) were similar. CONCLUSIONS: Despite using a conservative definition for PRIS, and only considering new-onset PRIS clinical manifestations, the incidence of PRIS slightly exceeds 1%. Future controlled studies focusing on evaluating whether propofol manifests the derangements of critical illness more frequently than other sedatives will need to be large. These studies should also investigate the mechanism(s) and risk factors for PRIS.

BACKGROUND: The development of effective therapies for acute ischemic stroke presumes the existence of potentially salvageable ischemic tissue when therapy is initiated because it is widely assumed that the effectiveness of most acute stroke therapies under development is related to reducing ultimate infarct size to promote functional improvement. Such salvageable ischemic tissue was previously labeled the ischemic penumbra and must be distinguished from irreversible injury. SUMMARY OF REVIEW: Pathological identification of irreversibility (infarction) appears to lag behind the actual development of this condition, and reversible injury after focal ischemia should be differentiated from infarction. Imaging and biochemical markers apparently can provide clues for distinguishing potentially salvageable from irreversibly injured ischemic tissue in experimental and clinical stroke. Recent positron emission tomography and MRI studies suggest that these clinically available imaging technologies will be useful for determining the presence of ischemic penumbra in individual stroke patients. The progression from potentially reversible to irreversible injury after focal brain ischemia has many potential mechanisms that may be synergistic and vary among individuals. CONCLUSIONS: Delineating and prioritizing these mechanisms provides the opportunity to develop multiple potential acute stroke therapies that ultimately will be used in combination, perhaps directed by imaging technology.

Abstract Metastatic castration-resistant prostate cancer is typically lethal, exhibiting intrinsic or acquired resistance to second-generation androgen-targeting therapies and minimal response to immune checkpoint inhibitors 1 . Cellular programs driving resistance in both cancer and immune cells remain poorly understood. We present single-cell transcriptomes from 14 patients with advanced prostate cancer, spanning all common metastatic sites. Irrespective of treatment exposure, adenocarcinoma cells pervasively coexpressed multiple androgen receptor isoforms, including truncated isoforms hypothesized to mediate resistance to androgen-targeting therapies 2,3 . Resistance to enzalutamide was associated with cancer cell–intrinsic epithelial–mesenchymal transition and transforming growth factor-β signaling. Small cell carcinoma cells exhibited divergent expression programs driven by transcriptional regulators promoting lineage plasticity and HOXB5, HOXB6 and NR1D2 (refs. 4–6 ). Additionally, a subset of patients had high expression of dysfunction markers on cytotoxic CD8 + T cells undergoing clonal expansion following enzalutamide treatment. Collectively, the transcriptional characterization of cancer and immune cells from human metastatic castration-resistant prostate cancer provides a basis for the development of therapeutic approaches complementing androgen signaling inhibition.