Van der Waals interaction affects wrinkle formation in two-dimensional materials.

Nonlinear mechanics of solids is an exciting field that encompasses both beautiful mathematics, such as the emergence of instabilities and the formation of complex patterns, as well as multiple applications. Two-dimensional crystals and van der Waals (vdW) heterostructures allow revisiting this field on the atomic level, allowing much finer control over the parameters and offering atomistic interpretation of experimental observations. In this work, we consider the formation of instabilities consisting of radially oriented wrinkles around mono- and few-layer "bubbles" in two-dimensional vdW heterostructures. Interestingly, the shape and wavelength of the wrinkles depend not only on the thickness of the two-dimensional crystal forming the bubble, but also on the atomistic structure of the interface between the bubble and the substrate, which can be controlled by their relative orientation. We argue that the periodic nature of these patterns emanates from an energetic balance between the resistance of the top membrane to bending, which favors large wavelength of wrinkles, and the membrane-substrate vdW attraction, which favors small wrinkle amplitude. Employing the classical "Winkler foundation" model of elasticity theory, we show that the number of radial wrinkles conveys a valuable relationship between the bending rigidity of the top membrane and the strength of the vdW interaction. Armed with this relationship, we use our data to demonstrate a nontrivial dependence of the bending rigidity on the number of layers in the top membrane, which shows two different regimes driven by slippage between the layers, and a high sensitivity of the vdW force to the alignment between the substrate and the membrane.

PLTP is a p53 target gene with roles in cancer growth suppression and ferroptosis.

The tumor suppressor protein p53 suppresses cancer by regulating processes such as apoptosis, cell cycle arrest, senescence, and ferroptosis, which is an iron-mediated and lipid peroxide-induced cell death pathway. Whereas numerous p53 target genes have been identified, only a few appear to be critical for the suppression of tumor growth. Additionally, while ferroptosis is clearly implicated in tumor suppression by p53, few p53 target genes with roles in ferroptosis have been identified. We have previously studied germline missense p53 variants that are hypomorphic or display reduced activity. These hypomorphic variants are associated with increased risk for cancer, but they retain the majority of p53 transcriptional function; as such, study of the transcriptional targets of these hypomorphs has the potential to reveal the identity of other genes important for p53-mediated tumor suppression. Here, using RNA-seq in lymphoblastoid cell lines, we identify PLTP (phospholipid transfer protein) as a p53 target gene that shows impaired transactivation by three different cancer-associated p53 hypomorphs: P47S (Pro47Ser, rs1800371), Y107H (Tyr107His, rs368771578), and G334R (Gly334Arg, rs78378222). We show that enforced expression of PLTP potently suppresses colony formation in human tumor cell lines. We also demonstrate that PLTP regulates the sensitivity of cells to ferroptosis. Taken together, our findings reveal PLTP to be a p53 target gene that is extremely sensitive to p53 transcriptional function and which has roles in growth suppression and ferroptosis.

Assessing predictors of futility in patients receiving massive transfusions.

BACKGROUND: Massive transfusions are associated with a high mortality rate, but there is little evidence indicating when such efforts are futile. The purpose of this study was to identify clinical variables that could be used as futility indicators in massively transfused patients. METHODS: We retrospectively analyzed 138 adult surgical patients at our institution receiving a massive transfusion (2016-2019). Peak lactate and nadir pH within 24 h of massive transfusion initiation, along with other clinical variables, were assessed as predictors of the primary outcome, in-hospital mortality. RESULTS: The overall rate of in-hospital mortality among our patient population was 52.9% (n = 73). Increasing lactate and decreasing pH were associated with greater mortality among massively transfused patients. Mortality rates were ~2-fold higher for patients in the highest lactate category (≥10.0 mmol/L: 25 of 37; 67.6%) compared to the lowest category (0.0-4.9 mmol/L: 17 of 48; 35.4%) (p = .005), and ~2.5-fold higher for patients in the lowest pH category (<7.00: 8 of 9; 88.9%) compared to the highest category (≥7.40: 8 of 23; 34.7%) (p = .016). Increasing age was also associated with higher mortality (≥65 years: 24 of 33; 72.7%) when compared to younger patients (18-64 years: 49 of 105; 46.7%) (p = .010). CONCLUSIONS: Peak lactate ≥10.0 mmol/L, nadir pH <7.00, and age ≥65 years were significantly associated with higher rates of in-hospital mortality among massively transfused patients. Incorporating these clinical parameters into a futility index for massive transfusions will be useful in situations where blood products are scarce and/or mortality may be unavoidable.

Simple budget-neutral tool to improve intraoperative communication.

BACKGROUND: Communication failure is a common cause of medical errors and adverse events. Within the operating room (OR), there are many barriers to good communication, which can adversely affect patient outcome. OBJECTIVE: Implementing a simple, cost-neutral tool aimed at improving intraoperative communication and engagement. METHODS: Three anaesthesiology residents collected data using a data sheet and tailored surveys distributed to OR staff. Data were collected over a 2-week period in 2019, with 1 week each of preintervention and postintervention data collection. The intervention consisted of wearing OR caps displaying the first name and role of the anaesthesia resident clearly on the front. RESULTS: A total of 20 data sheets and 48 preintervention and postintervention surveys were collected for a response rate of 57%. There was a statistically significant increase in OR staff knowledge of the anaesthesia resident's name (66% vs 100%, p=<0.001), an increase in the mean number of times the surgical providers addressed the anaesthesia residents (3.6 vs 7.8, p=0.0074) and an increase in the mean number of times the surgical providers addressed them by their first name (0.7 vs 4, p=0.0067). Comments received during the intervention were positive with overwhelming support. CONCLUSIONS: This study demonstrated that a simple, cost-effective intervention can result in dramatic improvement in intraoperative communication and engagement between teams.

A revised model of energy transactions and body composition in sheep.

A mechanistic, dynamic model was developed to calculate body composition in growing lambs by calculating heat production (HP) internally from energy transactions within the body. The model has a fat pool (f) and three protein pools: visceral (v), nonvisceral (m), and wool (w). Heat production is calculated as the sum of fasting heat production, heat of product formation (HrE), and heat associated with feeding (HAF). Fasting heat production is represented as a function of visceral and nonvisceral protein mass. Heat associated with feeding (HAF) is calculated as ((1 - km) x MEI), where km is partial efficiency of ME use for maintenance, and MEI = metabolizable energy intake) applies at all levels above and below maintenance. The value of km derived from data where lambs were fed above maintenance was 0.7. Protein change (dp/dt) is the sum of change in the m, v, and w pools, and change in fat is equal to net energy available for gain minus dp/dt. Heat associated with a change in body composition (HrE) is calculated from the change in protein and fat with estimated partial efficiencies of energy use of 0.4 and 0.7 for protein and fat, respectively. The model allows for individuals to gain protein while losing fat or vice versa. When evaluated with independent data, the model performed better than the current Australian feeding standards (Freer et al., 2007) for predicting protein gain in the empty body but did not perform as well as for gain of fat and fleece-free empty body weight. Models performed similarly for predicting clean wool growth. By explicit representation of the major energy using processes in the body, and through simplification of the way body composition is computed in growing animals, the model is more transparent than current feeding systems while achieving similar performance. An advantage of this approach is that the model has the potential for wider applicability across different growth trajectories and can explicitly account for the effects of systematic changes on energy transactions, such as the effects of selective breeding, growth manipulation, or environmental changes.

Based on prior work by Oltjen et al. (2006), a revised dynamic, mechanistic model was developed to improve the prediction of the composition of protein and fat in the body of growing ruminants. The revised model calculates heat production (HP) internally as a function of fasting HP, heat associated with feeding, and HP from changes in fat and protein within the body. Heat associated with product formation is calculated from changes in body protein and fat, with separate efficiencies for each, while heat associated with feeding is a constant proportion of metabolizable energy intake and applies at all levels of feeding above and below maintenance. When evaluated against novel data, the revised model performed similarly to current Australian feeding standards (Freer et al., 2007) Unlike the Freer model, the revised model captures variation in HP arising from feed as well as gain of protein and fat. The revised model explicitly represents protein in the body as two pools with markedly different rates of energy expenditure, improving representation of the underlying biology compared to current feeding systems. This provides a more flexible way to predict energy requirements and body composition in growing animals while achieving similar performance to current feeding systems.

An African-Specific Variant of TP53 Reveals PADI4 as a Regulator of p53-Mediated Tumor Suppression.

TP53 is the most frequently mutated gene in cancer, yet key target genes for p53-mediated tumor suppression remain unidentified. Here, we characterize a rare, African-specific germline variant of TP53 in the DNA-binding domain Tyr107His (Y107H). Nuclear magnetic resonance and crystal structures reveal that Y107H is structurally similar to wild-type p53. Consistent with this, we find that Y107H can suppress tumor colony formation and is impaired for the transactivation of only a small subset of p53 target genes; this includes the epigenetic modifier PADI4, which deiminates arginine to the nonnatural amino acid citrulline. Surprisingly, we show that Y107H mice develop spontaneous cancers and metastases and that Y107H shows impaired tumor suppression in two other models. We show that PADI4 is itself tumor suppressive and that it requires an intact immune system for tumor suppression. We identify a p53-PADI4 gene signature that is predictive of survival and the efficacy of immune-checkpoint inhibitors. SIGNIFICANCE: We analyze the African-centric Y107H hypomorphic variant and show that it confers increased cancer risk; we use Y107H in order to identify PADI4 as a key tumor-suppressive p53 target gene that contributes to an immune modulation signature and that is predictive of cancer survival and the success of immunotherapy. See related commentary by Bhatta and Cooks, p. 1518. This article is highlighted in the In This Issue feature, p. 1501.

Ultrasound-assisted catheter-directed thrombolytic therapy for management of acute pulmonary embolism.

Acute pulmonary embolism (PE) is a common and potentially lethal condition. Anticoagulation is considered the mainstay therapy while systemic thrombolytic therapy is reserved only for patients who are hemodynamically unstable. However, therapy for PE with evidence of right ventricular strain is not well-defined. We report a case of PE treated successfully with an ultrasound-assisted catheter-directed thrombolytic therapy.

Association Between Time-in-Therapeutic Tacrolimus Range and Early Rejection After Heart Transplant.

BACKGROUND: Historically, there is perceived pressure to achieve therapeutic levels of tacrolimus quickly after heart transplant (HT). We evaluated the association between time within therapeutic tacrolimus range and time to therapeutic trough and rejection in the 30 days following HT. METHODS: This is a single-center retrospective cohort study of consecutive adult HT patients receiving immunosuppression. Goal trough tacrolimus levels were 10-15 ng/ml. Surveillance endomyocardial biopsies were performed weekly for 4 weeks. Outcomes included the effect of time to and time-in-therapeutic tacrolimus range (Rosendaal method) on 30-day clinical rejection, 1R/1B, and 2R or higher histologic occurrences. RESULTS: We reviewed 67 HT patients (median age 58.8 yrs). For clinical rejection versus no-rejection groups, the median (25th, 75th percentile) time to therapeutic tacrolimus levels was 9.5 (8, 12.3) days versus 9.0 (7, 13) days (p=0.623). The median time-in-therapeutic tacrolimus range was 34.1% (23.2, 42.2) versus 36.2% (19.9, 51.2), respectively (p=0.512). Similarly, we observed no significant differences in time to and time-in-therapeutic tacrolimus range in patients who developed grade 1R/1B (p=0.650 and p=0.725) or grade 2R or higher histology (p=0.632 and p=0.933). CONCLUSIONS: Our small single-center analysis suggests that neither time to nor time in therapeutic tacrolimus range predicted acute rejection within 30 days of HT.

Postpartum dissection of the left main coronary artery.

Peripartum coronary artery dissection is rare, but it is an increasingly recognized risk to women of childbearing age. Literature reviews reveal that about 80% of the population with spontaneous coronary artery dissections (SCAD) are female, and approximately 25-33% of cases occurred while the woman was pregnant or in the peripartum phase. Most cases have presented within 2 weeks of delivery. The left anterior descending is the most commonly affected vessel. The etiology is poorly understood, but many reports suggest that SCAD occurs as a result of protease release secondary to an eosinophilic vasculitis resulting in vessel lysis. Many investigators have examined the correlation between peripartum SCAD and estrogen levels; however, case studies have shown conflicting results regarding estrogen levels as the putative causative factor. Optimal treatment remains controversial. Presently, stenting appears to be best employed in the patients who have single-vessel dissection not involving the left main coronary artery (LMCA). Surgical revascularization via coronary artery bypass graft remains the optimal therapy in patients whose dissection involves the LMCA, in patients with concurrent multivessel dissection, and in patients with disease refractory to medical management. It is important to consider coronary artery dissection in the differential of any young woman who presents with signs or symptoms consistent with acute coronary syndrome, particularly if she is peripartum. Furthermore, once suspected, it is imperative that a definitive diagnostic study, that is, coronary angiography, be completed prior to the initiation of treatment whenever possible.

Prospective exploratory analysis of the association between tumor response, quality of life, and expenditures among patients receiving paclitaxel monotherapy for refractory metastatic breast cancer.

PURPOSE: To prospectively evaluate the association between tumor response, change in quality of life (QoL), and hospital expenditures in patients with metastatic breast cancer (MBC) receiving single-agent paclitaxel. PATIENTS AND METHODS: Eligible patients had bidimensionally measurable MBC and any number of previous therapies, excluding taxane chemotherapy. Paclitaxel was administered by various different infusion schedules. QoL measures were evaluated for each patient at baseline and serially using the Memorial Symptom Assessment Scale (MSAS)-Global Distress Index (GDI) and Functional Assessment of Cancer Therapy-Breast (FACT-B) instruments. Patients were assessed for early (first 6 weeks) and ever changes in QoL parameters. Charges were monitored through the hospital's centralized computer billing system and converted to cost ratios for the analysis. Correlations between response and improvement in QoL were assessed by Fisher's exact test statistic. Associations between improvements in QoL with cost ratios were assessed by logistic regression and likewise between response and cost ratios. RESULTS: Of the 59 patients treated, 50 had sufficient data for comparative analyses. The overall response rate was 24% (all partial responses). Minor responses were observed in 17% of patients, 25% had stable disease, and 29% had progression. Responding patients had significant improvement in QoL as assessed by MSAS-GDI (P =.004) and FACT-B (P =.028). The mean total cost/month ratios for patients experiencing improved GDI QoL scores was 1.31 versus 1.56 for those without QoL benefit (P =.52) and 1.05 versus 1.76 for responders versus nonresponders, respectively (P =.07). CONCLUSION: Patients with evidence of tumor response on paclitaxel had a QoL benefit not observed in nonresponders, and this response was associated with a trend for lower overall costs.

The influence of hospital and surgeon volume on in-hospital mortality for colectomy, gastrectomy, and lung lobectomy in patients with cancer.

BACKGROUND: This study explores the volume-mortality relationship for 3 groups of cancer procedures to determine whether higher-volume hospitals, higher-volume surgeons, or both are associated with lower in-hospital mortality. METHODS: New York's Statewide Planning and Research Cooperative System was used to identify more than 32,000 hospital inpatients with a cancer diagnosis who underwent colectomy, lobectomy of the lung, or gastrectomy between January 1, 1994, and December 31, 1997. The association of in-hospital mortality rates with provider (hospital and surgeon) volume was examined after adjusting for differences in age, demographics, organ metastasis, socioeconomic status, and comorbidities. RESULTS: For hospital volume for gastrectomy, the highest-volume quartile had an absolute risk-adjusted mortality rate that was 7.1% lower (P <.0001) than the lowest-volume quartile, although the overall mortality rate for the procedure was only 6.2%. For surgeon volume for colectomy, the highest- and lowest- volume quartiles differed by 1.9% (P <.0001), although the procedure mortality rate was only 3.5%. For hospital volume for lung lobectomy, the absolute difference in mortality was 1.7%. Patients undergoing operations performed by high-volume surgeons in high-volume hospitals usually had significantly lower risk-adjusted mortality rates than did patients who had low-volume surgeons or who were in low-volume hospitals, or both. CONCLUSIONS: For all 3 procedure groups, the risk-adjusted in-hospital mortality is significantly lower when the procedures are performed by high-volume providers.

Initial experience with a transcatheter septal closure system for secondary stroke prevention in patients with interatrial septal defects.

BACKGROUND: Percutaneous transcatheter closure of a patent foramen ovale (PFO) has been utilized over the last several years to prevent thromboembolic events in selected patients with a prior cryptogenic stroke. We describe our initial experience at Hartford Hospital with a transcatheter PFO closure system and our multidisciplinary approach. METHODS: From March to November 2002, we performed percutaneous transcatheter closure of a PFO in 16 patients with a prior history of cryptogenic stroke(s) and/or transient ischemic attack using the CardioSEAL Septal Occluder system. All 16 patients had a PFO visualized on their transesophageal echocardiogram (TEE) study, and 15 patients also had an atrial septal aneurysm. PFO closure was performed with a CardioSEAL Septal Occluder in the cardiac catheterization laboratory under general anesthesia with TEE guidance. Following device placement, all patients were discharged on a regimen of aspirin and clopidigrel, with follow-up in the Stroke Clinic. RESULTS: Successful deployment of the septal occluder and effective PFO closure was achieved in all 16 patients with no major procedural or in-hospital complications. Short-term clinical follow-up has demonstrated no recurrent neurologic thromboembolic events, but one patient was rehospitalized for de novo atrial fibrillation. Follow-up transthoracic echocardiographic assessment at three to six months postprocedure, obtained in eight patients thus far, has demonstrated no residual interatrial shunting. CONCLUSION: Our early results suggest that percutaneous PFO closure with the CardioSEAL Septal Occluder system is a safe option for secondary stroke prevention in carefully selected patients with interatrial septal defects and a history of cryptogenic stroke or TIA. Patient selection and the long-term effectiveness and safety of this approach require further assessment.

Creating a CD-ROM program for cancer-related patient education.

PURPOSE/OBJECTIVES: To describe the process of developing a cancer-related patient and family education CD-ROM program and initial evaluation results. DATA SOURCES: Published research, theory, practice, and personal experience. DATA SYNTHESIS: CD-ROM programs can be far more comprehensive than the booklets and videotapes used more commonly in patient education. Developing CD-ROM programs requires funding, organizational skills, access to content experts, and a team composed of people who have the varied skills required for a finished multimedia product. The time frame for CD-ROM production is often longer than that of other patient-education formats. Published reports and this institution's experience confirm that patients accept this medium. Evaluation to date suggests that CD-ROMs may be more useful to patients and their families than any other single information source. CONCLUSIONS: CD-ROM technology is more expensive than videotapes and booklets, but it allows for greater depth of content and may satisfy a broader range of educational needs than other media. Funding often can be obtained through foundations and with unrestricted educational grants from pharmaceutical companies. IMPLICATIONS FOR NURSING: Nurses can lead multidisciplinary teams to produce CD-ROMs for their patient populations. These programs can be used before a patient has a first consultation to introduce a cancer or treatment and anytime during cancer diagnosis and treatment. They can reinforce one-on-one teaching or provide greater depth of content than ever could be provided in individualized teaching sessions. They can facilitate patients' self-directed learning and may allow nurses and doctors to teach on a different level. These programs also can complement patients' Internet searches either by creating a solid foundation for further investigation or by confirming the reliability of information gained through a variety of Internet sources.

Online cancer patient education: evaluating usability and content.

PURPOSE: Two patient education CD-ROMs were converted to a web-based environment. This article reports on users' evaluations of the programs' usability and content. DESCRIPTION OF EVALUATION: Subscribers to a center's web newsletter were asked to view one of two web programs and to complete a survey. The first 150 respondents were offered a free patient education CD-ROM of their choice, but users continued to respond to the survey even after a notice stated that 150 responses were received. A total of 301 surveys were completed (Colorectal Cancer Program 168; Chemotherapy Program 133). RESULTS: Sixty-eight percent of Colorectal Cancer Program respondents and 50% of Chemotherapy Program respondents considered the program to be more useful or much more useful than any other source of information on the topic. A majority of users for both programs preferred to view the information on the Internet rather than on CD-ROM. Many users reported trouble accessing certain segments of the media. Common complaints included the inability to open video or audio clips and the length of time needed for each page to load, despite a high-speed Internet connection. CLINICAL IMPLICATIONS: Internet use is high, with 60% of US households reporting having used the Internet to search for health information. However, little is known about user satisfaction with specific sites and what about them users like or do not like. It is hoped that these and other user evaluations will help web site authors and developers improve their sites.