Local Anesthesia for Endovascular Repair of Abdominal Aortic Aneurysm Allows for Accurate Graft Deployment with Durable Results.

BACKGROUND: Local anesthesia (LA) is sparsely used in endovascular aneurysm repair (EVAR) despite short-term benefit, likely secondary to concerns over patient movement preventing accurate endograft deployment. The objective of this study is to examine the association between anesthesia type and endoleak, sac regression, reintervention, and mortality. METHODS: The Vascular Quality Initiative database was queried for all EVAR cases from 2014 to 2022. Patients were included if they underwent percutaneous elective EVAR with anatomical criteria within instructions for use of commercially approved endografts. Multivariable logistic regression with propensity score weighting was used to determine the association between anesthesia type on the risk of any endoleak noted by intraoperative completion angiogram and sac regression. Multivariable survival analysis with propensity score weighting was used to determine the association between anesthesia type and endoleak at 1 year, long-term reintervention, and mortality. RESULTS: Thirteen thousand nine hundred thirty two EVARs met inclusion criteria: 1,075 (8%) LA and 12,857 (92%) general anesthesia (GA). On completion angiogram, LA was associated with fewer rates of any endoleaks overall (16% vs. 24%, P < 0.001). On multivariable analysis with propensity score weighting, LA was associated with similar adjusted odds of any endoleak on intraoperative completion angiogram (odds ratio [OR] 0.56, 95% confidence interval [CI] 0.47-0.68) as well as combined type 1a and type 1b endoleaks (OR 0.72, 95% CI 0.47-1.09). Follow-up computed tomography imaging at 1 year was available for 4,892 patients, 377 (8%) LA and 4,515 (92%) GA. At 1 year, LA was associated with similar rate of freedom from any endoleaks compared to GA (0.66 [95% CI 0.63-0.69] vs. 0.71 [95% CI 0.70-0.72], P = 0.663) and increased rates of sac regression (50% vs. 45%, P = 0.040). On multivariable analysis with propensity score weighting, LA and GA were associated with similar adjusted odds of sac regression (OR 1.22, 95% CI 0.97-1.55). LA and GA had similar rates of endoleak at 1 year (hazard ratio [HR] 0.14, 95% CI 0.63-1.07); however, LA was associated with decreased hazards of combined type 1a and 1b endoleaks at 1 year (HR 0.87, 95% CI 0.80-0.96). LA and GA had similar adjusted long-term reintervention rate (HR 0.77, 95% CI 0.44-1.38) and long-term mortality (HR 1.100, 95% CI 079-1.25). CONCLUSIONS: LA is not associated with increased adjusted rates of any endoleak on completion angiogram or at 1-year follow-up compared to GA. LA is associated with decreased adjusted rates of type 1a and type 1b endoleak at 1 year, but similar rates of sac regression, long-term reintervention, and mortality. Concerns for accurate graft deployment should not preclude use of LA and LA should be increasingly considered when deciding on anesthetic type for standard elective EVAR.

The current landscape of nutrition care in oesophageal and gastric cancer - insights from the national oesophagogastric nutrition audit (NONA) survey.

BACKGROUND AND AIMS: Specialist nutritional support is important during treatment for oesophagogastric (OG) cancer yet current practice remains unstandardised across the UK. The National Oesophagogastric Nutrition Audit (NONA) aimed to describe the current landscape of OG dietetic services in the UK and Ireland, with a specific focus on resource allocation, barriers to dietetic support, and the provision of support throughout the cancer pathway. METHODS: Tertiary cancer units, secondary care, and community services across the UK and Ireland were invited to complete a 28-point electronic questionnaire. Team leaders and senior specialist OG dietitians were the target respondents. All data points were peer-reviewed, piloted, and revised by the NONA steering committee before distribution. Data points covered a range of areas related to resources, skill mix, provision of support throughout the cancer pathway, and involvement with national audit and research. RESULTS: Complete responses were received from 50 individual units (tertiary surgical units, n = 35 and tertiary oncology units, n = 10). Secondary care and community services were underrepresented (n = 5). Of the units proving tertiary cancer care, the majority (77%) agreed or strongly agreed they were able to provide adequate nutritional care in the post-operative period. However, confidence dropped significantly in the early diagnostic phase and in the neoadjuvant period, with 52% and 67% of tertiary units disagreeing that they could provide adequate dietetic support during these parts of the cancer pathway, respectively. Inadequate funding, understaffing, and the prioritisation of inpatients were commonly reported barriers. There was significant variation in practice regarding nutritional assessment, service structure, and staffing resource allocation across specialist units. CONCLUSION: The NONA survey provides a 'real-world' landscape of nutritional care for patients with OG cancer. Lack of funding, resource, and evidence-base may explain the variation seen in services provided across the UK. Further research and consensus is required to help standardise nutritional care, guide service specification, and improve nutritional outcomes for patients with OG cancer.

Cost-benefit analysis of home visiting to reduce infant mortality among preterm infants.

PURPOSE: The Following Baby Back Home (FBBH) visiting program, which is provided by nurse and social worker teams, supports families of low-birthweight preterm infants after discharge from a neonatal intensive care unit. Enrollment in the FBBH program has been documented to reduce the likelihood of infant death. In this study, we conducted a cost-benefit analysis of the FBBH program. DESIGN AND METHODS: Infants enrolled in the FBBH program (N = 416) were identified through administrative records. Infants in the FBBH program were propensity score matched with comparison infants to estimate the difference in healthcare costs in the first year of life. RESULTS: Infants enrolled in the FBBH program incurred similar medical care costs compared to a comparison group. Avoided deaths, program costs, healthcare costs resulted in net economic benefits of the FBBH program to avoid infant death estimate at $83,020, cost per life saved at $3080, and benefit-to-cost ratio at 27.95. CONCLUSIONS: The FBBH program's net economic benefits from avoided deaths suggest a substantial return on investment of resources, yielding benefits in excess of program and healthcare costs. PRACTICE IMPLICATIONS: It is economically beneficial to provide home visiting services to families of low-birthweight babies by a team comprised of a registered nurse and social worker.

Effect of socioeconomic status on patients undergoing elective abdominal aortic aneurysm repair in a publicly funded health care system.

BACKGROUND: The association between socioeconomic status (SES) and outcomes after abdominal aortic aneurysm (AAA) repair in publicly funded health care systems is poorly described. The purpose of this study was to determine the effect of SES on postoperative outcomes in patients who underwent AAA repair in Nova Scotia, Canada. METHODS: We performed a retrospective analysis of all elective AAA repairs in Nova Scotia between November 2005 and March 2015 using administrative data sources. We compared postoperative 30-day outcomes and long-term survival across socio-economic quintiles, defined as the Pampalon Material Deprivation Index (MDI) and Social Deprivation Index (SDI). We also compared the relation between baseline characteristics, MDI quintile, SDI quintile and 30-day mortality. We used multivariable logistic regression and survival analysis to calculate adjusted 30-day mortality and long-term survival, respectively. RESULTS: A total of 1913 patients underwent AAA repair during the study period. The overall 30-day mortality rate was 2.6% (50 patients). Thirty-day outcomes including death (p = 0.8), stroke (p = 0.7), myocardial infarction (p = 0.06), length of stay (p = 0.3) and discharge disposition other than home (p = 0.8) were similar across MDI quintiles. Similarly, there was no statistically significant association between SDI quintile and postoperative outcomes. Multivariable analysis showed that age greater than 70 years (odds ratio [OR] 3.06, 95% confidence interval [CI] 1.55-6.06) and open repair (OR 3.22, 95% CI 1.59-6.52) but not MDI quintile (p = NS) or SDI quintile (p = NS) were associated with increased 30-day mortality. There was no effect of MDI or SDI quintile on long-term survival on univariable or multivariable analysis. CONCLUSION: Socioeconomic status does not appear to affect short- or long-term mortality after AAA repair in a publicly funded health care system. Further research is needed to address any existing gaps in screening and referral before repair.

Positionality and Its Problems: Questioning the Value of Reflexivity Statements in Research.

There has been a remarkable push for the use of positionality statements-also known as reflexivity statements-in scientific-journal articles and other research literatures. Grounded in reputable philosophical traditions, positionality statements are meant to address genuine concerns about the limits of knowledge production. However, there are at least three reasons why they should be avoided in scholarship. First, it is impossible to construct credible positionality statements because they are constrained by the very positionality they seek to address. Second, positionality statements are unnecessary because reducing bias-positional or otherwise-in scientific literatures does not hinge on the biographical details of individual scholars but on the integrity of the collective process of truth-seeking. Third, by asking scholars to disclose information about themselves, positionality statements undermine the very norms and practices that safeguard the impartiality of research. Instead of asking individual scholars to issue subjective declarations about their positionalities, scholarly communities should focus on improving the rules of intersubjective competition at the heart of scientific progress. In our view, the most productive path to increasing representation and reducing positional bias in research is to protect the freedom of scholarly inputs while insisting on methodological transparency and rigor.

Trends in Incidence of Abdominal Aortic Aneurysm Rupture, Repair, and Mortality in Nova Scotia.

BACKGROUND: The purpose of this study was to examine sex-based trends in incidence of elective abdominal aortic aneurysm (AAA), ruptured AAA, ruptured AAA repair, and AAA-related mortality. METHODS: A retrospective analysis of patients presenting with AAA from 2005 to 2015 was conducted. Rates of elective AAA repair, ruptured AAA, ruptured AAA repair, and mortality were obtained from linking provincial administrative data using medical services insurance billing number. The age-adjusted incidence of elective AAA repair, overall rate of ruptured AAA, ruptured AAA repair, and AAA-related mortality was calculated for each sex based on Canadian census estimates, adjusted to the Canadian standard population. Weighted linear regression was performed to analyze trends in incidence over time. RESULTS: One thousand nine hundred eighty-six elective AAA repairs were identified, of which 1,098 were repaired open and 898 underwent endovascular abdominal aneurysm repair (EVAR). Five hundred and seventy ruptured AAAs were identified, of which 295 (52%) were repaired: 259 open and 36 EVAR. The proportion of ruptured AAA that was repaired did not change over time (P = 0.54). The proportion repairs performed using EVAR increased significantly in both elective (P < 0.001) and rupture repairs (P < 0.001). During the study period, 662 patients died of AAA-associated mortality. The average incidence of elective AAA repair in men was 29.3 (95% confidence interval (CI): 27.8 to 30.8) per 100,000 and decreased over time (P = 0.04), whereas the average incidence in women was 9.2 [8.3 to 10.0] and stable (P = 0.07). The incidence of open elective AAA repair was 10.5 [9.9-11.1] with a decreasing trend over time (P < 0.001) and EVAR was 9.0 (8.5-9.6) with an increasing trend over time (P < 0.001). A decreasing trend of overall ruptured AAA (5.4 [5.0-5.9], P < 0.001), ruptured AAA repair (2.9 [2.5-3.2], P = 0.02), and of AAA-related mortality (6.2 [5.8-6.8], P < 0.001) was found, with consistent trends in both sexes. The incidence of open ruptured AAA repair decreased over time (P = 0.001) whereas the incidence of ruptured EVAR remained stable (P = 0.23). CONCLUSIONS: The incidence of elective AAA repair is decreasing in males but not females, whereas the incidence of rupture has decreased in both sexes. This has translated into reduced incidence of AAA-related mortality. Increased adoption of EVAR for ruptured AAA should continue these trends.

Effect of after-hours presentation in ruptured abdominal aortic aneurysm.

OBJECTIVE: Ruptured abdominal aortic aneurysms (RAAAs) are surgical emergencies that require immediate and expert treatment. It has been unclear whether presentation during evenings and weekends, when "on call" teams are primarily responsible for patient care, is associated with worse outcomes. Our objective was to evaluate the outcomes of patients presenting with RAAAs after-hours vs during the workday. METHODS: A retrospective cohort study of all RAAAs in Nova Scotia between 2005 and 2015 was performed through linkage of administrative databases. Patients who had presented to the hospital with RAAAs during the workday (Monday through Friday, 6 am to 6 pm) were compared with those who had presented after-hours (6 pm to 6 am during the week and on weekends). The baseline and operative characteristics were identified for all patients through the available databases and a review of the medical records. Mortality before surgery, 30-day mortality, and operative mortality were compared between groups using multivariable logistic regression, adjusting for factors clinically significant on univariable analysis. RESULTS: A total of 390 patients with RAAAs were identified from 2005 to 2015, of whom 205 (53%) had presented during the workday and 185 (47%) after-hours. The overall chance of survival (OCS) was 45% overall, 49% if admitted to hospital, and 64% if surgery had been performed. During the workday, the OCS was 43% overall, 48% if admitted to hospital, and 67% if surgery had been performed. After-hours, the OCS was 46% overall, 49% if admitted to hospital, and 61% if surgery had been performed. Mortality before surgery was increased for patients who had presented to the hospital during the workday compared with after-hours (36% vs 26%; P = .04). The 30-day mortality (57% vs 54%; P = .62), rates of operative management (63% vs 72%; P = .06), and operative mortality (33% vs 39%; P = .33) were similar between the workday and after-hours groups (57% vs 54%; P = .06). After adjusting for significant clinical variables, the patients who had presented with RAAAs after-hours had had a similar odds of dying before surgery (odds ratio [OR], 0.64; 95% confidence interval [CI], 0.41-1.03), operative management (OR, 1.47; 95% CI, 0.93-2.31), 30-day mortality (OR, 0.98; 95% CI, 0.63-1.51), and operative mortality (OR, 1.33; 95% CI, 0.78-2.26). In the subgroup of patients presenting to a hospital with endovascular capabilities, patients presenting after-hours had had similar odds of 30-day mortality (OR, 1.07; 95% CI, 0.57-2.02), and operative mortality (OR, 1.14; 95% CI, 0.58-2.23). CONCLUSIONS: We found that patients presenting to the hospital with RAAAs after-hours did not have increased adjusted odds of mortality before surgery, operative management, 30-day mortality, or operative mortality.

Dying to Get There: Patients Who Reside at Increased Distance from Tertiary Center Experience Increased Mortality Following Abdominal Aortic Aneurysm Rupture.

BACKGROUND: Centralization of vascular surgery care for Ruptured Abdominal Aortic Aneurysms (RAAAs) to high-volume tertiary centers may hinder access to timely surgical intervention for patients in remote areas. The objective of this study was to determine the association between distance from vascular care and mortality from RAAAs in the province of Nova Scotia, Canada. METHODS: A retrospective cohort study of all RAAAs in Nova Scotia between 2005 and 2015 was performed through linkage of administrative databases. Patients were divided into groups by estimated travel time from their place of residence to the tertiary center (<1 hr and ≥1 hr) using geographic information software. Baseline and operative characteristics were identified for all patients through available databases and completed through chart review. Mortality at home, during transfer to the vascular center, and overall 30-day mortality were compared between groups using t-test and chi-squared test, as appropriate. Multivariable logistic regression analysis was used to calculate the independent effect of travel time on survival outcomes. RESULTS: A total of 567 patients with RAAA were identified from 2005-2015, of which 250 (44%) resided <1 hr travel time to the tertiary center and 317 (56%) resided ≥1 hr. On multivariable analysis, travel time ≥1 hr from vascular care was an independent predictor of mortality at home (odds ratio [OR] 1.68, 95% confidence interval [CI] 1.07-2.63, P = 0.02), mortality prior to operation (OR 2.64, 95% CI 1.81-3.83, P < 0.001), and overall 30-day mortality (OR 1.61, 95% CI 1.10-2.37, P = 0.02). In patients who received an operation (n = 294), there was no association between increased travel time and mortality (OR 1.02, 95% CI 0.60-1.73, P = 0.94). CONCLUSIONS: Travel time ≥1 hr to the tertiary center is associated with significantly higher mortality from ruptured abdominal aortic aneurysm (AAA). However, there was no difference in overall chance of survival between groups for patients that underwent AAA repair. Therefore, strategies to facilitate early detection, and timely transfer to a vascular surgery center may improve outcomes for patients with RAAA.

RAB4A GTPase regulates epithelial-to-mesenchymal transition by modulating RAC1 activation.

Epithelial-to-mesenchymal transition (EMT) is a critical underpinning process for cancer progression, recurrence and resistance to drug treatment. Identification of new regulators of EMT could lead to the development of effective therapies to improve the outcome of advanced cancers. In the current study we discovered, using a variety of in vitro and in vivo approaches, that RAB4A function is essential for EMT and related manifestation of stemness and invasive properties. Consistently, RAB4A suppression abolished the cancer cells' self-renewal and tumor forming ability. In terms of downstream signaling, we found that RAB4A regulation of EMT is achieved through its control of activation of the RAC1 GTPase. Introducing activated RAC1 efficiently rescued EMT gene expression, invasion and tumor formation suppressed by RAB4A knockdown in both the in vitro and in vivo cancer models. In summary, this study identifies a RAB4A-RAC1 signaling axis as a key regulatory mechanism for the process of EMT and cancer progression and suggests a potential therapeutic approach to controlling these processes.

The current use of ultrasound to measure skeletal muscle and its ability to predict clinical outcomes: a systematic review.

Quantification and monitoring of lean body mass is an important component of nutrition assessment to determine nutrition status and muscle loss. The negative impact of reduced muscle mass and muscle function is increasingly evident across acute and chronic disease states but is particularly pronounced in patients with cancer. Ultrasound is emerging as a promising tool to directly measure skeletal muscle mass and quality. Unlike other ionizing imaging techniques, ultrasound can be used repeatedly at the bedside and may compliment nutritional risk assessment. This review aims to describe the current use of skeletal muscle ultrasound (SMUS) to measure muscle mass and quality in patients with acute and chronic clinical conditions and its ability to predict functional capacity, severity of malnutrition, hospital admission, and survival. Databases were searched from their inception to August 2021 for full-text articles in English. Relevant articles were included if SMUS was investigated in acute or chronic clinical contexts and correlated with a defined clinical outcome measure. Data were synthesized for narrative review due to heterogeneity between studies. This review analysed 37 studies (3100 patients), which met the inclusion criteria. Most studies (n = 22) were conducted in critical care. The clinical outcomes investigated included functional status at discharge (intensive care unit-acquired weakness), nutritional status, and length of stay. SMUS was also utilized in chronic conditions such as chronic obstructive pulmonary disease, chronic heart failure, and chronic renal failure to predict hospital readmission and disease severity. Only two studies investigated the use of SMUS in patients with cancer. Of the 37 studies, 28 (76%) found that SMUS (cross-sectional area, muscle thickness, and echointensity) showed significant associations with functional capacity, length of stay, readmission, and survival. There was significant heterogeneity in terms of ultrasound technique and outcome measurement across the included studies. This review highlights that SMUS continues to gain momentum as a potential tool for skeletal muscle assessment and predicting clinically important outcomes. Further work is required to standardize the technique in nutritionally vulnerable patients, such as those with cancer, before SMUS can be widely adopted as a bedside prognostic tool.

Twelve-month clinical outcomes after implantation of a new, modular, anterior shape-changing fluid optic intraocular lens.

PURPOSE: To report the initial safety and effectiveness profile for an anterior shape-changing, modular IOL, Juvene IOL (JIOL), for the treatment of aphakia and presbyopia after removal of the natural crystalline lens due to cataract. SETTING: 2 private practices in Monterrey and Tijuana, Mexico. DESIGN: Exploratory prospective multicenter open-label noncomparative clinical trial. METHODS: A convenience sample of patients aged 50 to 80 years with planned cataract surgery was recruited to undergo unilateral or bilateral implantation with the JIOL. Patients were required to complete an informed consent and be able to dilate to at least 6.0 mm pharmacologically, be in good overall health, and have no significant eye health history to qualify. Visual acuities, defocus curves, and contrast sensitivity were measured for all patients 12 months postoperatively. RESULTS: 51 of 58 eyes completed the 12-month visit. Intraoperative complication rates were extremely low (n = 1; missed base lens tab). The most frequent adverse events (AEs) were prolonged inflammation (N = 6) and cystoid macular edema (N = 4); all AEs were resolved without sequelae by the 12-month visit. The mean monocular logMAR corrected distance visual acuity, distance-corrected intermediate visual acuity, and distance-corrected near visual acuity were 0.01, 0.08, and 0.24, respectively. Defocus testing showed visual acuity > 20/40 from approximately +1.00 through -2.00 diopters. Binocular implantation (n = 16) provided superior performance over monocular implantation. CONCLUSIONS: The JIOL offers a new solution to treat presbyopia, providing clear functional vision performance across a range of distances with an acceptable initial safety profile.

Biophysical fitness landscape of the SARS-CoV-2 Delta variant receptor binding domain

Among the five known SARS-CoV-2 variants of concern, Delta is the most virulent leading to severe symptoms and increased number of deaths. Our study seeks to examine how the biophysical parameters of the Delta variant correlate to the clinical observations. Receptor binding domain (RBD) is the first point of contact with the human host cells and is the immunodominant form of the spike protein. Delta variant RBD contains two novel mutations L452R and T478K. We examined the effect of single mutations as well as the double mutation on RBD expression in human Expi293 cells, RBD stability using urea and thermal denaturation, and RBD binding to angiotensin converting enzyme 2 (ACE2) receptor and to neutralizing antibodies using isothermal titration calorimetry. Delta variant RBD showed significantly higher expression compared to the wild-type RBD, and the increased expression is due to L452R mutation. Despite their non-conservative nature, none of the mutations significantly affected RBD structure and stability. All mutants showed similar binding affinity to ACE2 and to Class 1 antibodies (CC12.1 and LY-CoV016) as that of the wild-type. Delta double mutant L452R/T478K showed no binding to Class 2 antibodies (P2B-2F6 and LY-CoV555) and a hundred-fold weaker binding to a Class 3 antibody (REGN10987), and the decreased antibody binding is determined by the L452R mutation. These results indicate that the immune escape from neutralizing antibodies, rather than receptor binding, is the main biophysical parameter determining the fitness landscape of the Delta variant RBD and is determined by the L452R mutation.

The emerging roles of Gα12/13 proteins on the hallmarks of cancer in solid tumors.

G12 proteins comprise a subfamily of G-alpha subunits of heterotrimeric GTP-binding proteins (G proteins) that link specific cell surface G protein-coupled receptors (GPCRs) to downstream signaling molecules and play important roles in human physiology. The G12 subfamily contains two family members: Gα12 and Gα13 (encoded by the GNA12 and GNA13 genes, respectively) and, as with all G proteins, their activity is regulated by their ability to bind to guanine nucleotides. Increased expression of both Gα12 and Gα13, and their enhanced signaling, has been associated with tumorigenesis and tumor progression of multiple cancer types over the past decade. Despite these strong associations, Gα12/13 proteins are underappreciated in the field of cancer. As our understanding of G protein involvement in oncogenic signaling has evolved, it has become clear that Gα12/13 signaling is pleotropic and activates specific downstream effectors in different tumor types. Further, the expression of Gα12/13 proteins is regulated through a series of transcriptional and post-transcriptional mechanisms, several of which are frequently deregulated in cancer. With the ever-increasing understanding of tumorigenic processes driven by Gα12/13 proteins, it is becoming clear that targeting Gα12/13 signaling in a context-specific manner could provide a new strategy to improve therapeutic outcomes in a number of solid tumors. In this review, we detail how Gα12/13 proteins, which were first discovered as proto-oncogenes, are now known to drive several "classical" hallmarks, and also play important roles in the "emerging" hallmarks, of cancer.

Modified Weaver-Dunn Technique Using Transosseous Bone Tunnels and Coracoid Suture Augmentation.

INTRODUCTION: A modified Weaver-Dunn procedure for the management of acromioclavicular joint injuries that uses transosseous bone tunnels and coracoid suture augmentation is described with associated clinical results. METHODS: A retrospective review of 39 consecutive patients who underwent a primary mWD procedure by a single surgeon from January 2013 to July 2019 was conducted. Patient charts and radiographs were reviewed for clinical course, complications and management, and radiographic evaluation. Satisfaction, American Shoulder and Elbow Surgeons (ASES), Single Assessment Numeric Evaluation, and Simple Shoulder Test scores were obtained. RESULTS: A total of 28 patients (72%) with a mean follow-up of 37.5 (12 to 84 months) and a mean age of 44.3 ± 15.1 years were included. Postoperative ASES, Simple Shoulder Test, Single Assessment Numeric Evaluation, and satisfaction scores were 90.6 ± 14.2, 11.1 ± 1.5, 87.3 ± 10.2, and 4.4 ± 1.2 (out of 5), respectively, with a significant improvement in ASES of 42.2 ± 21.8 points (P < 0.001). All patients had significant decrease in coracoclavicular distance (P < 0.001). Three patients (10.7%) had complications, with two (7.1%) requiring additional surgery. CONCLUSION: Excellent functional and radiographic outcomes can be achieved with this modified Weaver-Dunn technique. Complication and revision rates are comparable with those that are found in the literature. LEVEL OF EVIDENCE: Level IV, Retrospective cohort study.

SARS-CoV-2 comes up with a perfect recipe for disaster: Each mutation plays a specific role in the evolution of variants of concern

Multiple mutations have been seen to undergo convergent evolution in SARS-CoV-2 variants of concern. One such evolution occurs in Beta, Gamma, and Omicron variants at three amino acid positions K417, E484, and N501 in the receptor binding domain of the spike protein. We examined the physical mechanisms underlying the convergent evolution of three mutations K417T/E484K/N501Y by delineating the individual and collective effects of mutations on binding to angiotensin converting enzyme 2 receptor, immune escape from neutralizing antibodies, protein stability and expression. Our results show that each mutation serves a distinct function that improves virus fitness supporting its positive selection, even though individual mutations have deleterious effects that make them prone to negative selection. Compared to the wild-type, K417T escapes Class 1 antibodies, has increased stability and expression; however, it has decreased receptor binding. E484K escapes Class 2 antibodies; however, it has decreased receptor binding, stability and expression. N501Y increases receptor binding; however, has decreased stability and expression. When these mutations come together, the deleterious effects are mitigated due to the presence of compensatory effects. Triple mutant K417T/E484K/N501Y has increased receptor binding, escapes both Class 1 and Class 2 antibodies, and has similar stability and expression as that of the wild-type. These results show the implications of presence of multiple mutations on virus evolution that enhance viral fitness on different fronts by balancing both positive and negative selection and improves the chances of selection of mutations together.

Suppression of isoprenylcysteine carboxylmethyltransferase compromises DNA damage repair.

DNA damage is a double-edged sword for cancer cells. On the one hand, DNA damage-induced genomic instability contributes to cancer development; on the other hand, accumulating damage compromises proliferation and survival of cancer cells. Understanding the key regulators of DNA damage repair machinery would benefit the development of cancer therapies that induce DNA damage and apoptosis. In this study, we found that isoprenylcysteine carboxylmethyltransferase (ICMT), a posttranslational modification enzyme, plays an important role in DNA damage repair. We found that ICMT suppression consistently reduces the activity of MAPK signaling, which compromises the expression of key proteins in the DNA damage repair machinery. The ensuing accumulation of DNA damage leads to cell cycle arrest and apoptosis in multiple breast cancer cells. Interestingly, these observations are more pronounced in cells grown under anchorage-independent conditions or grown in vivo. Consistent with the negative impact on DNA repair, ICMT inhibition transforms the cancer cells into a "BRCA-like" state, hence sensitizing cancer cells to the treatment of PARP inhibitor and other DNA damage-inducing agents.

Home Visiting for NICU Graduates: Impacts of Following Baby Back Home.

BACKGROUND AND OBJECTIVES: The Following Baby Back Home (FBBH) home visiting program supports families of high-risk low birth weight preterm infants after discharge from a hospital NICU. This study compares the health care use, immunization, and infant mortality rate of low birth weight preterm infants enrolled in FBBH with similar infants not in the program. METHODS: From January 2013 to December 2017, 498 children enrolled in FBBH were identified in Arkansas vital statistics records and the Arkansas All-Payer Claims Database. Infants in FBBH were matched with children in a control group on the basis of demographics and medical conditions of the infant. Generalized linear mixed models with double propensity-score adjustment were used to estimate program effects. RESULTS: In the first year after discharge and compared with a propensity-score matched cohort of control infants, those enrolled in FBBH were significantly more likely to have higher numbers of medical appointments and more compliant immunization history. The odds of dying in the first year of life for control infants was 4.4 times (95% confidence interval: 1.2-20.7) higher than those managed in the program. CONCLUSIONS: A goal of the FBBH home visiting program is to work with parents to educate and support them as they care for their medically fragile infants. We conclude that education and support was instrumental in the infant health care use and outcome differences we observed during the first year of life.

Spontaneous regression of oesophageal squamous cell carcinoma.

Partial or complete spontaneous regression (SR) of cancer is unusual, particularly in patients with oesophageal cancer. This case report describes a patient with biopsy-proven squamous cell carcinoma of the oesophagus which spontaneously regressed without any treatment. Regression of the primary tumour was confirmed on histological examination of the resected specimen. The process of SR remains an enigma, but potential mechanisms are considered.

Evaluating the Epithelial-Mesenchymal Program in Human Breast Epithelial Cells Cultured in Soft Agar Using a Novel Macromolecule Extraction Protocol.

The ability to grow in anchorage-independent conditions is an important feature of malignant cells, and it is well-established that cellular phenotypes in adherent cultures can differ widely from phenotypes observed in xenografts and anchorage-independent conditions. The anchorage-independent soft-agar colony formation assay has been widely used as a bridge between adherent cell cultures and animal tumor studies, providing a reliable in vitro tool to predict the tumorigenicity of cancer cells. However, this functional assay is limited in its utility for molecular mechanistic studies, as currently there is no reliable method that allows the extraction of biological macromolecules from cells embedded in soft-agar matrices, especially in experimental conditions where no visible colonies form. We developed a set of new methods that enable the extraction of DNA, RNA and proteins directly from cells embedded in soft agar, allowing for a wide range of molecular signaling analysis. Using the new methods and human mammary epithelial cells (HMECs), we studied the role of epithelial-mesenchymal transition (EMT) in the ability of HMECs to form colonies in soft agar. We found that, when cultured in soft agar instead of in adherent cultures, immortalized non-malignant HME-hTERT cells upregulated the epithelial program, which was noted to be necessary for their survival in this anchorage-independent condition. Overexpression of SV40 small T antigen (ST) or the EMT master-regulator SNAI1 negates this requirement and significantly enhances colony formation in soft agar driven by mutant-RAS. Interestingly, we found that, similar to SNAI1, ST also promotes EMT changes in HMECs, providing further support for EMT as a prerequisite for the efficient anchorage-independent colony formation driven by mutant-RAS in our HMEC model.