Allosteric inhibition of SHP2 phosphatase inhibits cancers driven by receptor tyrosine kinases.

The non-receptor protein tyrosine phosphatase SHP2, encoded by PTPN11, has an important role in signal transduction downstream of growth factor receptor signalling and was the first reported oncogenic tyrosine phosphatase. Activating mutations of SHP2 have been associated with developmental pathologies such as Noonan syndrome and are found in multiple cancer types, including leukaemia, lung and breast cancer and neuroblastoma. SHP2 is ubiquitously expressed and regulates cell survival and proliferation primarily through activation of the RAS­ERK signalling pathway. It is also a key mediator of the programmed cell death 1 (PD-1) and B- and T-lymphocyte attenuator (BTLA) immune checkpoint pathways. Reduction of SHP2 activity suppresses tumour cell growth and is a potential target of cancer therapy. Here we report the discovery of a highly potent (IC50 = 0.071 µM), selective and orally bioavailable small-molecule SHP2 inhibitor, SHP099, that stabilizes SHP2 in an auto-inhibited conformation. SHP099 concurrently binds to the interface of the N-terminal SH2, C-terminal SH2, and protein tyrosine phosphatase domains, thus inhibiting SHP2 activity through an allosteric mechanism. SHP099 suppresses RAS­ERK signalling to inhibit the proliferation of receptor-tyrosine-kinase-driven human cancer cells in vitro and is efficacious in mouse tumour xenograft models. Together, these data demonstrate that pharmacological inhibition of SHP2 is a valid therapeutic approach for the treatment of cancers.

Self-perception and self-representation preference between 2-dimensional and 3-dimensional facial reconstructions among dentists, dental students, and laypersons.

STATEMENT OF PROBLEM: Computer-aided design (CAD) software can merge the intraoral digital scan with patient photographs or 3-dimensional (3D) facial reconstructions for treatment planning purposes. However, whether an individual perceives a 3D facial reconstruction as a better self-representation compared with a 2-dimensional (2D) photograph is unclear. PURPOSE: The purpose of this observational study was to compare self-perception ratings and self-representation preference of the 2D and 3D facial reconstructions among laypersons, dental students, and dentists. MATERIAL AND METHODS: Three populations participated in the study: laypersons, dental students, and dentists (n=20, N=60). Facial and intraoral features were digitized by using facial and intraoral scanners, and a complete-face smile photograph was obtained. Two simulations were performed for each participant: 2D (2D group) and 3D (3D group) reconstructions. In the 2D group, a maxillary digital veneer waxing from the left to the right second premolars was produced without altering the shape, position, or length of the involved teeth. A software program (Dental Systems; 3Shape A/S) was used to merge the maxillary digital waxing with the full-face smile photograph. One image was obtained for each participant. In the 3D group, a dental software program (Matera 2.4; exocad GmbH) was used to merge the intraoral and facial scans. Subsequently, 1 video of a 180-degree rotation of each 3D superimposition was obtained. Participants evaluated both superimpositions on a scale from 1 (least esthetically pleasing) to 6 (most esthetically pleasing). Finally, participants were asked which superimposition they preferred for a potential treatment outcome representation. RESULTS: All the ratings were esthetically pleasing (median group rating 5 or 6). When analyzed solely for differences across occupation groups, ratings for the 2D representation varied significantly across populations (Kruskal-Wallis chi-squared=13.241, df=2, P=.001), but the ratings for the 3D representation did not exhibit statistically significant differences (Kruskal-Wallis chi-squared=4.3756, df=2, P=.112). Ordinal logistic regression revealed no significant main effects but a significant effect of the population×image-type interaction on the esthetic rating. All participants felt well-represented in both the 2D and 3D representations. Also, 40% of dentists, 55% of dental students, and 50% of laypersons preferred the 3D reconstructions. Sex and occupation in general had no effect on the ratings. However, students tended to give higher ratings to the 3D representations of themselves. CONCLUSIONS: There is no evidence based on the current study that 2D and 3D representations were perceived differently, but representation preferences may depend on a person's occupation. When individuals rated 3D visualization higher than 2D visualization, they strongly preferred the 3D visualization for representing the treatment outcome.

Variation in Patient-Reported Advance Care Preferences in the Preoperative Setting.

BACKGROUND: High-quality shared decision-making for patients undergoing elective surgical procedures includes eliciting patient goals and treatment preferences. This is particularly important, should complications occur and life-sustaining therapies be considered. Our objective was to determine the preoperative care preferences of older higher-risk patients undergoing elective procedures and to determine any factors associated with a preference for limitations to life-sustaining treatments. METHODS: Cross-sectional survey conducted between May and December 2018. Patients ≥55 years of age presenting for a preprocedural evaluation in a high-risk anesthesia clinic were queried on their desire for life-sustaining treatments (cardiopulmonary resuscitation, mechanical ventilation, dialysis, and artificial nutrition) as well as tolerance for declines in health states (physical disability, cognitive disability, and daily severe pain). RESULTS: One hundred patients completed the survey. The median patient age was 68. Most patients were Caucasian (87%) and had an American Society of Anesthesiologists (ASA) score of III (88%). The majority of patients (89%) desired cardiopulmonary resuscitation. However, most patients would not accept mechanical ventilation, dialysis, or artificial nutrition for an indefinite period of time. Similarly, most patients (67%-81%) indicated they would not desire treatments to sustain life in the event of permanent physical disability, cognitive disability, or daily severe pain. CONCLUSIONS: Among older, higher-risk patients presenting for elective procedures, most patients chose limitations to life-sustaining treatments. This work highlights the need for an in-depth goals of care discussion and establishment of advance care preferences before a procedure or operative intervention.

Confronting complexity and supporting transformation through health systems mapping: a case study.

INTRODUCTION: Health systems are a complex web of interacting and interconnected parts; introducing an intervention, or the allocation of resources, in one sector can have effects across other sectors and impact the entire system. A prerequisite for effective health system reorganisation or transformation is a broad and common understanding of the current system amongst stakeholders and innovators. Chronic obstructive pulmonary disease (COPD) and heart failure (HF) are common chronic diseases with high health care costs that require an integrated health system to effectively treat. STUDY DESCRIPTION: This case study documents the first phase of system transformation at a regional level in Ontario, Canada. In this first phase, visual representations of the health system in its current state were developed using a collaborative co-creation approach, and a focus on COPD and HF. Multiple methods were used including focus groups, open-ended questionnaires, and document review, to develop a series of graphical and visual representations; a health care ecosystem map. RESULTS: The ecosystem map identified key sectoral components, inter-component interactions, and care requirements for patients with COPD and HF and inventoried current programs and services available to deliver this care. Main findings identified that independent system-wide navigation for this vulnerable patient group is limited, primary care is central to the accessibility of nearly half of the identified care elements, and resources are not equitably distributed. The health care ecosystem mapping helped to identify care gaps and illustrates the need to resource the primary care provider and the patient with system navigation resources and interdisciplinary team care. CONCLUSION: The co-created health care ecosystem map brought a collective understanding of the health care system as it applies to COPD and HF. The map provides a blueprint that can be adapted to other disease states and health systems. Future transformation will build on this foundational work, continuing the robust interdisciplinary co-creation strategies, exploring predictive health system modelling and identifying areas for integration.

Accuracy (trueness and precision) of a dual-structured light facial scanner and interexaminer reliability.

STATEMENT OF PROBLEM: Digital waxing procedures should be guided by facial references to improve the esthetic outcome of a restoration. The development of facial scanners has allowed the digitalization of the extraoral soft tissues of the patient's face. However, the reliability of facial digitizers is questionable. PURPOSE: The purpose of this study was to evaluate the accuracy (trueness and precision) of extraoral 3D facial reconstructions performed by using a dual-structured light facial scanner and to measure the interexaminer variability. MATERIAL AND METHODS: Ten participants were included. Six soft-tissue landmarks were determined on each participant, specifically reference (Ref), glabella (Gb), subnasal (Sn), menton (Me), chelion right (ChR), and chelion left (ChL). Interlandmark distances Ref-Sn, Sn-Gb, Ref-Gb, Sn-Me, and ChR-ChL (intercommissural) were measured by 2 different operators by using 2 different methods: directly on the participant' face (manual group) and digitally (digital group) on the 3D facial reconstruction of the participant (n=20). For the manual group, interlandmark measurements were made by using digital calipers. For the digital group, 10 three-dimensional facial reconstructions were acquired for each participant by using a dual-structured light facial scanner (Face Camera Pro Bellus; Bellus3D). Interlandmark measurements were made by using an open-source software program (Meshlab; Meshlab). Both operators were used to note 10 measurements for each manual and digital interlandmark distance per participant. The intraclass correlation coefficient between the 2 operators was calculated. The Shapiro-Wilk test revealed that the data were not normally distributed. The data were analyzed by using the Mann-Whitney U test. RESULTS: Significant differences were found between manual and digital interlandmark measurements in all participants. The mean value of the manual and digital group discrepancy was 0.91 ±0.32 mm. The dual-structured light facial scanner tested obtained a trueness mean value of 0.91 mm and a precision mean value of 0.32 mm. Trueness values were always higher than precision mean values, indicating that precision was relatively high. The intraclass correlation coefficient between the 2 operators was 0.99. CONCLUSIONS: The facial digitizing procedure evaluated produced clinically acceptable outcomes for virtual treatment planning. The interexaminer reliability between the 2 operators was rated as excellent, suggesting that the type of facial landmark used in this study provides reproducible results among different examiners.

Esthetic dental perception comparisons between 2D- and 3D-simulated dental discrepancies.

STATEMENT OF PROBLEM: Intraoral scanners (IOSs), facial scanners (FSs), and computer-aided design (CAD) software programs have become powerful tools for treatment planning. However, discrepancies in perception regarding 2-dimensional (2D) or 3-dimensional (3D) simulations by dentists, dental students, and laypeople have not been analyzed. PURPOSE: The purpose of this observational study was to analyze the perceptions of laypersons, dental students, and dentists regarding disparities of the maxillary dental midline and the occlusal plane when analyzing the dental discrepancies on 2D- and 3D-clinical simulations. MATERIAL AND METHODS: A female model was digitized by using an FS, IOS, and a full-face smile photograph. Dental discrepancies were simulated by using a 2D photograph (2D group) and 3D scan (3D group) of the model. In both simulation groups, 2 subgroups were produced. The occlusal plane of the first subgroup was modified in 1-degree increments without changing the dental midline or the position of the maxillary dental incisors. In the second subgroup, the occlusal plane was modified by using the same increments, but the maxillary central incisors and dental midline were altered to match the inclination of the occlusal plane. A total of 300 participants (N=300) were asked to rate the 2D images (N=12) and 3D videos (N=12) on a 1-to-6 scale and answer a questionnaire. Ordinal logistic regression was used to analyze the ratings. RESULTS: The ratings decreased with the increased tilt of the occlusal plane, and the layperson group gave consistently higher ratings than the other 2 groups. For dentists, the odds of giving a higher versus lower rating decreased by almost a half for each degree of tilt. However, for students, that effect was diminished by a positive interaction term, and for laypersons, the effect was even less. Students gave similar ratings to dentists, but laypersons gave higher ratings. As the age of the participants increased, however, the ratings also increased. The use of 3D versus 2D images had a positive effect on the ratings, but the effect decreased for the student observers and decreased even further for laypersons. Furthermore, midline alteration led to higher ratings but also resulted in worsening of the odds ratio for the tilt. Seventy percent of the dentists, 57% of the dental students, and 52% of the laypersons preferred 2D simulations to 3D simulations. CONCLUSIONS: Dentists, dental students, and laypersons decreased their ratings with increased inclination of the occlusal plane; however, laypersons still graded all the 2D and 3D images as esthetically pleasant, giving consistently higher ratings than the dentists and dental students. Overall, 3D simulations obtained higher ratings than 2D images, but the positive effect decreased for the student observers and decreased even further for laypersons.

Additive manufacturing technologies for processing zirconia in dental applications.

OBJECTIVE: The objective of this narrative review was to summarize the current status and future perspectives of additive manufacturing (AM) technologies with a particular emphasis on manufacturing zirconia-based materials. AM technologies include vat photopolymerization, material jetting, material extrusion, selective laser sintering (SLS), and selective laser melting (SLM) technologies based on either powder bed fusion (PBF) technologies or direct energy deposition, or sheet lamination based on binder jetting technologies. MATERIALS AND METHODS: A comprehensive literature review was performed, specifically evaluating AM technologies assigned for processing zirconia. An electronic database search was performed using keywords and MeSH terms. The search was confined to full-text articles written in English and published in peer-reviewed journals between 1999 and 2018. RESULTS: A total of 62 articles were included in this review, of which 56 described the AM processes and 6 reported on AM applications in the field of dentistry. A broad diversity of literature exists regarding AM technologies for ceramic materials, which complicates the establishment of a classification system for the current AM technologies for zirconia. The variations in the composition of zirconia slurries or mixtures across different technologies often made it difficult to identify the proper nature of such information. Mechanical properties of printed zirconia materials utilizing different technologies were investigated through a wide range of tests. Overall, the review indicates that manufacturing zirconia using AM technologies could be achieved without issues, but mechanical properties appear to be poor compared with conventional manufacturing procedures. CONCLUSIONS: The results of this review indicate the necessity for further potential improvement in AM technologies for manufacturing zirconia reconstructions along with advances in material composition before zirconia could be considered as a material for standard care.

Layperson and Dental Professional Perception When Evaluating Their Own Virtually 2D or 3D Simulated Esthetic Discrepancies.

PURPOSE: To analyze the perceptions of laypersons, dental students, and dentists regarding disparities of the maxillary dental midline and the occlusal plane (OP) when analyzing their own 2D or 3D clinical simulation. MATERIAL AND METHODS: 20 participants per group volunteered (N = 60). Intraoral and facial scans, and a photograph were obtained from each participant. Two simulation groups were created: 2D and 3D groups, which were subdivided into two subgroups. In the first subgroup, the OP was modified by 1-degree increments without changing the maxillary midline. In the second subgroup, the OP was modified by the same increments, but the maxillary midline was altered to match the OP inclination. Participants were asked to rate the simulations on a 1-to-6 scale and a question survey. Ordinal logistic regression (OR) was used to analyze the ratings. RESULTS: Tilt of the OP had the strongest negative effect on the ratings which was further amplified by the dental midline inclination (OR = 0.122). Midline modification alone did not affect the ratings (OR = 0.744). 3D simulations had a stronger positive effect on the ratings compared to 2D simulations. For dental students, the positive rating effect of 3D simulations was similar to dentists. For laypersons, the positive rating effect of 3D simulations compared to the 2D simulations decreased relative to dentists. The survey revealed that 45% of the dentists, 80% of the students, and 50% of the laypersons preferred the 3D simulation. CONCLUSIONS: The type of dimensional representation affected the esthetic perception of all participants. 3D simulations obtained higher esthetic ratings for the same esthetic discrepancy than 2D simulations. However, all participants' ratings decreased with increased tilt of the OP and were further decreased with the inclination of the dental midline.

Operational Definitions and Estimates of Return to Work Poststroke: A Systematic Review and Meta-Analysis.

OBJECTIVE: To examine operational definitions of return to work (RTW) poststroke and provide more precise estimates of RTW through meta-analysis. DATA SOURCES: A systematic search was conducted using MEDLINE, CINAHL, PsycINFO, and SCOPUS (2005 to March 26, 2018). The search strategy involved expansion of medical subjective headings using terms related to stroke and work. The reference lists of review articles and included studies were checked for additional relevant studies. STUDY SELECTION: Studies were included if they (1) quantitatively analyzed RTW outcomes or factors associated with RTW; (2) reported RTW outcomes for participants employed prior to stroke; and (3) were written in English or French. Two reviewers independently screened titles and abstracts. Of 7265 articles initially identified, 55 studies were included. DATA EXTRACTION: Data were extracted and study quality was assessed by 1 reviewer and verified by a second reviewer. DATA SYNTHESIS: Explicit and implicit operational definitions of RTW were determined and categorized. Ranges of RTW estimates were presented for study and participant characteristics. Pooled summary estimates were calculated for comparable studies by follow-up time poststroke: 55.7% at 1 year (95% confidence interval [95% CI], 51.3%-60.0%) and 67.4% at 2 years (95% CI, 60.4%-74.4%). Similar summary estimates were noted when only population-based studies were considered: 56.7% at 1 year (95% CI, 48.3%-65.1%) and 66.7% at 2 years (95% CI, 60.2%-73.2%). CONCLUSIONS: Operational definitions varied across studies and were often not explicitly reported. To promote comparability of RTW outcomes in future studies, we recommend working toward a universal operational definition and consistent follow-up times. The more precise estimates calculated in this review could be used as benchmarks for health care and social service providers.

Perception of occlusal plane that is nonparallel to interpupillary and commissural lines but with the maxillary dental midline ideally positioned.

STATEMENT OF PROBLEM: How disparities in parallelism between the occlusal plane and the interpupillary (IP) or commissural facial front lines are perceived is unclear. PURPOSE: The purpose of this observational study was to examine the perceptions of laypersons, dental students, and dentists regarding disparities of the anterior occlusal plane (AOP) and posterior occlusal plane (POP) with respect to the IP and commissural line (CL) with the maxillary dental midline ideally positioned. MATERIAL AND METHODS: A model of a symmetric female face was digitally created with the IP and CL parallel and the facial midline coincident with the maxillary dental midline. Two groups of images were created, one with the POP modified in 1-degree increments, in which both the maxillary dental midline and the position of the maxillary central incisors were not manipulated, and the other with the POP modified in the same increments but with the position of both maxillary central incisors lengthened to follow the inclination of the occlusal plane. Participants (N=312) were asked to rate the images on a 1-to-6 scale. The Kruskal-Wallis medians test and ordinal logistic regression were used to analyze the ratings. RESULTS: Group median ratings for different occupations gradually decreased with increased inclination of the occlusal plane. Significant differences were found for inclinations from 2 to 5 degrees. Significant odd ratios were found for age and sex. CONCLUSIONS: Dental professionals detected smaller POP disparities. The dentist and dental student groups gave lower ratings in proportion to the amount of POP inclination. Laypersons gave lower ratings only after 3 degrees of POP inclination but still graded all the images as esthetically pleasant. Older people and men tended to give higher ratings to the same image.

Metal additive manufacturing technologies: literature review of current status and prosthodontic applications.

OBJECTIVES: To review the current metal-based additive manufacturing (AM) technologies, namely powder bed fusion (PBF) technologies, and their current prosthodontic applications. The PBF technologies reviewed are selective laser sintering (SLS), selective laser melting (SLM), and electron beam melting (EBM). MATERIALS AND METHODS: The literature on metal AM technologies was considered, and the AM procedures and their current applications in prosthodontics were collated and described. Published articles about AM metal in dental care were searched (MEDLINE, EMBASE, EBSCO, and Web of Science). All studies related to the description, analysis, and evaluation of prosthodontic applications using metal AM technologies. RESULTS AND CONCLUSIONS: AM technologies are reliable for many applications in dentistry, including metal frameworks for removable partial dentures (RPDs), overdentures, tooth- and implant-supported fixed dental prostheses (FDPs), and metal frameworks for splinting implant impression abutments. However, further studies are needed in future to evaluate the accuracy, reproducibility, and clinical outcome throughout function of AM technologies.

Reduction in Operating Room Plasma Waste After Evidence-Based Quality Improvement Initiative.

Anesthesiologists request units of plasma in anticipation of transfusion. The amount of plasma transfused intraoperatively is less than that issued (requested, thawed, and sent). We presented institutional-specific data on plasma usage including anesthesiologist-specific ratios of plasma issued-to-transfused. In month-to-month comparisons from the year before the presentation (June-December 2015) to 7 months after (June-December 2016), plasma issued to the operating room was reduced from 434.9 ± 81 to 327.3 ± 65 units, a change of 107.6 units per month (95% confidence interval [CI], 22-193); plasma discarded by the blood bank was reduced from 109.7 ± 48 units to 69.1 ± 9 units, a change of 40.6 units per month (95% CI, 0.2-81); and plasma transfused went from 188.4 ± 42 units to 160.7 ± 52 units, a nonsignificant change of 27.7 units per month (95% CI, -27 to 83).

Early, goal-directed mobilisation in the surgical intensive care unit: a randomised controlled trial.

BACKGROUND: Immobilisation predicts adverse outcomes in patients in the surgical intensive care unit (SICU). Attempts to mobilise critically ill patients early after surgery are frequently restricted, but we tested whether early mobilisation leads to improved mobility, decreased SICU length of stay, and increased functional independence of patients at hospital discharge. METHODS: We did a multicentre, international, parallel-group, assessor-blinded, randomised controlled trial in SICUs of five university hospitals in Austria (n=1), Germany (n=1), and the USA (n=3). Eligible patients (aged 18 years or older, who had been mechanically ventilated for <48 h, and were expected to require mechanical ventilation for ≥24 h) were randomly assigned (1:1) by use of a stratified block randomisation via restricted web platform to standard of care (control) or early, goal-directed mobilisation using an inter-professional approach of closed-loop communication and the SICU optimal mobilisation score (SOMS) algorithm (intervention), which describes patients' mobilisation capacity on a numerical rating scale ranging from 0 (no mobilisation) to 4 (ambulation). We had three main outcomes hierarchically tested in a prespecified order: the mean SOMS level patients achieved during their SICU stay (primary outcome), and patient's length of stay on SICU and the mini-modified functional independence measure score (mmFIM) at hospital discharge (both secondary outcomes). This trial is registered with ClinicalTrials.gov (NCT01363102). FINDINGS: Between July 1, 2011, and Nov 4, 2015, we randomly assigned 200 patients to receive standard treatment (control; n=96) or intervention (n=104). Intention-to-treat analysis showed that the intervention improved the mobilisation level (mean achieved SOMS 2·2 [SD 1·0] in intervention group vs 1·5 [0·8] in control group, p<0·0001), decreased SICU length of stay (mean 7 days [SD 5-12] in intervention group vs 10 days [6-15] in control group, p=0·0054), and improved functional mobility at hospital discharge (mmFIM score 8 [4-8] in intervention group vs 5 [2-8] in control group, p=0·0002). More adverse events were reported in the intervention group (25 cases [2·8%]) than in the control group (ten cases [0·8%]); no serious adverse events were observed. Before hospital discharge 25 patients died (17 [16%] in the intervention group, eight [8%] in the control group). 3 months after hospital discharge 36 patients died (21 [22%] in the intervention group, 15 [17%] in the control group). INTERPRETATION: Early, goal-directed mobilisation improved patient mobilisation throughout SICU admission, shortened patient length of stay in the SICU, and improved patients' functional mobility at hospital discharge. FUNDING: Jeffrey and Judy Buzen.

Fresh-Frozen Plasma: Ordering Patterns and Utilization in the Operating Rooms of a Tertiary Referral Hospital.

BACKGROUND: Blood product transfusion is the most commonly performed hospital procedure. Intraoperative blood product utilization varies between institutions and anesthesiologists. In the United States in 2011, nearly 4 million plasma units were transfused. METHODS: A retrospective analysis of intraoperative plasma ordering patterns and utilization (thawing and transfusing) was performed at a tertiary, academic hospital between January 2015 and March 2016. RESULTS: Over 15 months, 46,002 operative procedures were performed. In 1540 of them, plasma was thawed or transfused: 8297 plasma units were thawed and 3306 of those units were transfused. These 3306 plasma units were transfused in 749 cases with a median of 2 plasma units (interquartile range, 2-4) transfused. The percentage of average monthly procedures with plasma thawed and none transfused was 51.3% (confidence interval, 49.0%-53.6%). The cardiac surgery service requested the greatest number of plasma units to be thawed (2143) but only transfused 712 (33.2%) of them. Of all plasma units not transfused, 45% were generated by procedures with 1 to 4 units of plasma thawed; 95.7% of these units were thawed as even integers (ie, 2, 4). CONCLUSIONS: For operative procedures, far more plasma was thawed than was transfused and this practice occurred across surgical specialties and anesthesiologists. Considering the plasma that was not transfused, 45% occurred in procedures with 4 or fewer units of plasma requested suggesting these low-volume requests were a primary source of potential waste. Further studies are needed to examine associations between plasma utilization and clinical outcomes.

Functional epigenetics approach identifies BRM/SMARCA2 as a critical synthetic lethal target in BRG1-deficient cancers.

Defects in epigenetic regulation play a fundamental role in the development of cancer, and epigenetic regulators have recently emerged as promising therapeutic candidates. We therefore set out to systematically interrogate epigenetic cancer dependencies by screening an epigenome-focused deep-coverage design shRNA (DECODER) library across 58 cancer cell lines. This screen identified BRM/SMARCA2, a DNA-dependent ATPase of the mammalian SWI/SNF (mSWI/SNF) chromatin remodeling complex, as being essential for the growth of tumor cells that harbor loss of function mutations in BRG1/SMARCA4. Depletion of BRM in BRG1-deficient cancer cells leads to a cell cycle arrest, induction of senescence, and increased levels of global H3K9me3. We further demonstrate the selective dependency of BRG1-mutant tumors on BRM in vivo. Genetic alterations of the mSWI/SNF chromatin remodeling complexes are the most frequent among chromatin regulators in cancers, with BRG1/SMARCA4 mutations occurring in ∼10-15% of lung adenocarcinomas. Our findings position BRM as an attractive therapeutic target for BRG1 mutated cancers. Because BRG1 and BRM function as mutually exclusive catalytic subunits of the mSWI/SNF complex, we propose that such synthetic lethality may be explained by paralog insufficiency, in which loss of one family member unveils critical dependence on paralogous subunits. This concept of "cancer-selective paralog dependency" may provide a more general strategy for targeting other tumor suppressor lesions/complexes with paralogous subunits.

Normal, Regular, and Standard: Scaling the Body through Fecal Microbial Transplants.

In 2013, the National Institutes of Health (NIH) and the Food and Drug Administration (FDA) held a workshop to determine the risks and benefits associated with the experimental use of fecal microbial transplants to treat Clostridium difficile and other gastroenterological disorders. By focusing on the proceedings of the NIH-FDA workshop on the treatment of the human microbiome, the question of how medicine colonizes human bodies through microbial transplants raises questions about what an individual body is, how determinative of human health the microbiome is, and what the limits of molecular biomedicine are when the microbiome is taken into consideration. In the workshop presentations and discussion of this emerging treatment, experts used ideas about the normal, regular, and standard to move between scales of bodily analysis, from the microbial to the body politic, demonstrating how the individual and society are deeply influenced by the unruly community of microbial symbiotes that humans host.

Effects of Depth of Propofol and Sevoflurane Anesthesia on Upper Airway Collapsibility, Respiratory Genioglossus Activation, and Breathing in Healthy Volunteers.

BACKGROUND: Volatile anesthetics and propofol impair upper airway stability and possibly respiratory upper airway dilator muscle activity. The magnitudes of these effects have not been compared at equivalent anesthetic doses. We hypothesized that upper airway closing pressure is less negative and genioglossus activity is lower during deep compared with shallow anesthesia. METHODS: In a randomized controlled crossover study of 12 volunteers, anesthesia with propofol or sevoflurane was titrated using a pain stimulus to identify the threshold for suppression of motor response to electrical stimulation. Measurements included bispectral index, genioglossus electromyography, ventilation, hypopharyngeal pressure, upper airway closing pressure, and change in end-expiratory lung volume during mask pressure drops. RESULTS: A total of 393 attempted breaths during occlusion maneuvers were analyzed. Upper airway closing pressure was significantly less negative at deep versus shallow anesthesia (-10.8 ± 4.5 vs. -11.3 ± 4.4 cm H2O, respectively [mean ± SD]) and correlated with the bispectral index (P < 0.001), indicating a more collapsible airway at deep anesthesia. Respiratory genioglossus activity during airway occlusion was significantly lower at deep compared with light anesthesia (26 ± 21 vs. 35 ± 24% of maximal genioglossus activation, respectively; P < 0.001) and correlated with bispectral index (P < 0.001). Upper airway closing pressure and genioglossus activity during airway occlusion did not differ between sevoflurane and propofol anesthesia. CONCLUSIONS: Propofol and sevoflurane anesthesia increased upper airway collapsibility in a dose-dependent fashion with no difference at equivalent anesthetic concentrations. These effects can in part be explained by a dose-dependent inhibiting effect of anesthetics on respiratory genioglossus activity.

A Synthesis of Peer-Reviewed Literature on Team-Coordinated and Delivered Early Supported Discharge After Stroke.

This review aimed to summarize data from peer-reviewed studies of team-coordinated and delivered early supported discharge (ESD) for postacute, poststroke rehabilitation. A systematic review was performed in Medline, Embase, and CINAHL for appropriate studies. Information on program details and patient cohorts was synthesized. All programs sought patients with mild-to-moderate functional impairment and minimal cognitive impairment (often based on Barthel Index and Mini-Mental State Examination scores, respectively). All also included at least one subjective admission criterion related to rehabilitation suitability or the suitability of the home environment. Based on the identified studies, ESD programs can assume that 15% of patients screened for ESD will be eligible and care should be provided for 4 to 5 weeks postdischarge. Although the benefits of team-coordinated and delivered ESD poststroke have been well-documented, this review may be helpful for clinicians, administrators, and policy makers looking to establish or refine an ESD program for stroke.