Molecular mechanism of choline and ethanolamine transport in humans.

Human feline leukaemia virus subgroup C receptor-related proteins 1 and 2 (FLVCR1 and FLVCR2) are members of the major facilitator superfamily1. Their dysfunction is linked to several clinical disorders, including PCARP, HSAN and Fowler syndrome2-7. Earlier studies concluded that FLVCR1 may function as a haem exporter8-12, whereas FLVCR2 was suggested to act as a haem importer13, yet conclusive biochemical and detailed molecular evidence remained elusive for the function of both transporters14-16. Here, we show that FLVCR1 and FLVCR2 facilitate the transport of choline and ethanolamine across the plasma membrane, using a concentration-driven substrate translocation process. Through structural and computational analyses, we have identified distinct conformational states of FLVCRs and unravelled the coordination chemistry underlying their substrate interactions. Fully conserved tryptophan and tyrosine residues form the binding pocket of both transporters and confer selectivity for choline and ethanolamine through cation-π interactions. Our findings clarify the mechanisms of choline and ethanolamine transport by FLVCR1 and FLVCR2, enhance our comprehension of disease-associated mutations that interfere with these vital processes and shed light on the conformational dynamics of these major facilitator superfamily proteins during the transport cycle.

Seek and ye shall find: The utility of perioperative VTE screening in high-risk oncologic patients undergoing abdominopelvic surgery.

BACKGROUND AND OBJECTIVE: The aim of this study was to evaluate the prevalence and risk factors associated with perioperative venous thromboembolism (VTE) in patients undergoing major oncologic surgery using an epidural catheter (EC) for postoperative analgesia with mechanical prophylaxis and without chemoprophylaxis. METHODS: Six hundred and twenty-six patients undergoing major oncologic surgery from 2009 to 2023 were evaluated. VTE was defined as deep vein thrombosis above the level of the knee. Lower extremity venous duplexes (LEVDs) were done preoperatively and postoperatively after the EC was removed. All patients received mechanical thromboprophylaxis, but not chemical prophylaxis, while the EC was in place. A generalized linear multivariable model was constructed to identify risk factors that predict pre and postoperative VTE. RESULTS: 29/626 patients (4.6%) were found to have preoperative VTE. 16/626 (2.6%) were found to have a postoperative VTE when their preoperative LEVD was negative. In comparison to patients without preoperative VTE, those with VTE were more likely to be male, anticoagulated, and have a history of coronary artery disease. Patients in the postoperative VTE group were older, male, anticoagulated, and had a history of VTE. On multivariable analysis, previous history of VTE was the risk factor most strongly associated with both pre and postoperative VTE. CONCLUSION: Oncologic patients undergoing elective abdominopelvic surgery with epidural analgesia should be screened in the perioperative setting with LEVD to identify VTE and possibly prevent PE.

The Association of Alcohol Outlet Density with Alcohol Intake: The Multiethnic Cohort.

OBJECTIVE: Neighborhood characteristics have been shown to influence lifestyle behaviors. Here we characterized alcohol outlet density in Los Angeles County, California, and Hawaii and assessed the association of alcohol outlet density with self-reported alcohol intake in the Multiethnic Cohort. METHOD: Participants (n=178,977) had their addresses geocoded, at cohort entry (1993-1996), and appended to block group-level alcohol outlet densities (on- and off-premises). Multinomial logistic regression was performed to assess the association between self-reported alcohol intake and on- and off-premise alcohol outlet densities by each state. Stratified analysis was conducted by sex, race, and ethnicity. RESULTS: Overall, we did not find associations between alcohol outlet density and self-reported alcohol intake in Los Angeles County, but we found that on-premise alcohol outlets were associated with 59% (OR=1.59, 95% CI:1.29,1.96) increased odds of consuming >2 drinks per day in Hawaii. Women living in neighborhoods with high density of on-premise alcohol outlets (Los Angeles County OR=1.15, 95% CI: 0.95,1.40) and (Hawaii OR=2.07, 95% CI: 1.43,3.01) had an increased odds of >2 drinks per day. CONCLUSION: This study suggests that neighborhood factors are associated with individual level behaviors and that there may be a need for multilevel interventions.

Increasing risk of hepatocellular carcinoma with successive generations in the United States among Mexican American adults: The Multiethnic Cohort.

BACKGROUND: US-born Latinos have a higher incidence of hepatocellular carcinoma (HCC) than foreign-born Latinos. Acculturation to unhealthy lifestyle behaviors and an immigrant self-selection effect may play a role. In this study, the authors examined the influence of generational status on HCC risk among Mexican American adults. METHODS: The analytic cohort included 31,377 self-reported Mexican Americans from the Multiethnic Cohort Study (MEC). Generational status was categorized as: first-generation (Mexico-born; n = 13,382), second-generation (US-born with one or two parents born in Mexico; n = 13,081), or third-generation (US-born with both parents born in the United States; n = 4914). Multivariable Cox proportional hazards regression was performed to examine the association between generational status and HCC incidence. RESULTS: In total, 213 incident HCC cases were identified during an average follow-up of 19.5 years. After adjusting for lifestyle and neighborhood-level risk factors, second-generation and third-generation Mexican Americans had a 37% (hazard ratio [HR], 1.37; 95% confidence interval [CI], 0.98-1.92) and 66% (HR, 1.66; 95% CI, 1.11-2.49) increased risk of HCC, respectively, compared with first-generation Mexican Americans (p for trend = 0.012). The increased risk associated with generational status was mainly observed in males (second-generation vs. first-generation: HR, 1.60 [95% CI, 1.05-2.44]; third-generation vs. first-generation: HR, 2.08 [95% CI, 1.29-3.37]). CONCLUSIONS: Increasing generational status of Mexican Americans is associated with a higher risk of HCC. Further studies are needed to identify factors that contribute to this increased risk.

Hypertensive disorders of pregnancy and occurrence of ADHD, ASD, and epilepsy in the child: A meta-analysis.

AIM: To synthesize epidemiologic literature pertaining to the association between preeclampsia (PE), attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and epilepsy. METHOD: A systematic search of PubMed and Embase was performed supplemented by hand-searching of reference lists of eligible studies. Two independent reviewers screened abstracts following a prepared protocol. Data extraction and quality appraisal using the Newcastle Ottawa Scale were performed by an independent reviewer. PRISMA guidelines were followed throughout. Random-effects meta-analyses were performed. Adjusted pooled Odds Ratios and their 95% confidence intervals were reported. RESULTS: Fifteen out of 121 identified studies were eligible for inclusion. Six reported adjusted estimates for ADHD, resulting in a pooled odds ratio of 1.29 (95% CI: 1.20, 1.38). Eight reported adjusted estimates for ASD, resulting in a pooled odds ratio of 1.27 (95% CI:1.22, 1.32). Three reported adjusted estimates for epilepsy, resulting in a pooled odds ratio of 1.35 (95% CI: 1.12, 1.63). INTERPRETATION: Intrauterine exposure to PE increased the risk of ADHD, ASD, and epilepsy, though it is unclear whether the true association is with pre-term birth. To our knowledge, this is the first meta-analysis to quantify the association between PE and epilepsy. The results of this meta-analysis can inform screening strategies among children born to preeclamptic mothers for early identification and treatment.

Population-attributable risk of modifiable lifestyle factors to hepatocellular carcinoma: The multi-ethnic cohort.

BACKGROUND AND AIMS: Lifestyle factors are well associated with risk of hepatocellular carcinoma (HCC). However, the impact of reducing adverse lifestyle behaviours on population-level burden of HCC is uncertain. METHODS: We conducted prospective analysis of the population-based multi-ethnic cohort (MEC) with linkage to cancer registries. The association of lifestyle factors (smoking, alcohol, diet quality assessed by alternate Mediterranean diet score, coffee drinking, physical activity and body mass index) with HCC incidence was examined using Cox regression. Population-attributable risk (PAR, %) for the overall, lean and overweight/obese populations was determined. RESULTS: A total of 753 incident cases of HCC were identified in 181,346 participants over median follow-up of 23.1 years. Lifestyle factors associated with elevated HCC risk included former/current smoking, heavy alcohol use, poor diet quality, lower coffee intake and obesity, but not physical activity. The lifestyle factor with highest PAR was lower coffee intake (21.3%; 95% CI: 8.9%-33.0%), followed by current smoking (15.1%; 11.1%-19.0%), obesity (14.5%; 9.2%-19.8%), heavy alcohol use (7.1%; 3.5%-10.6%) and lower diet quality (4.1%; 0.1%-8.1%). The combined PAR of all high-risk lifestyle factors was 51.9% (95% CI: 30.1%-68.6%). A higher combined PAR was observed among lean (65.2%, 26.8%-85.7%) compared to overweight/obese (37.4%, 11.7%-58.3%) participants. Adjusting for viral hepatitis status in a linked MEC-Medicare dataset resulted in similar PAR results. CONCLUSIONS: Modifying lifestyle factors, particularly coffee intake, may have a substantial impact on HCC burden in diverse populations, with greater impact among lean adults. Diet and lifestyle counselling should be incorporated into HCC prevention strategies.

A multimedia paediatric cardiology assessment tool for medical students and general paediatric trainees: development and validation.

BACKGROUND: Understanding how cardiovascular structure and physiology guide management is critically important in paediatric cardiology. However, few validated educational tools are available to assess trainee knowledge. To address this deficit, paediatric cardiologists and fellows from four institutions collaborated to develop a multimedia assessment tool for use with medical students and paediatric residents. This tool was developed in support of a novel 3-dimensional virtual reality curriculum created by our group. METHODS: Educational domains were identified, and questions were iteratively developed by a group of clinicians from multiple centres to assess understanding of key concepts. To evaluate content validity, content experts completed the assessment and reviewed items, rating item relevance to educational domains using a 4-point Likert scale. An item-level content validity index was calculated for each question, and a scale-level content validity index was calculated for the assessment tool, with scores of ≥0.78 and ≥0.90, respectively, representing excellent content validity. RESULTS: The mean content expert assessment score was 92% (range 88-97%). Two questions yielded ≤50% correct content expert answers. The item-level content validity index for 29 out of 32 questions was ≥0.78, and the scale-level content validity index was 0.92. Qualitative feedback included suggestions for future improvement. Questions with ≤50% content expert agreement and item-level content validity index scores <0.78 were removed, yielding a 27-question assessment tool. CONCLUSIONS: We describe a multi-centre effort to create and validate a multimedia assessment tool which may be implemented within paediatric trainee cardiology curricula. Future efforts may focus on content refinement and expansion to include additional educational domains.

Virtual reality curriculum increases paediatric residents' knowledge of CHDs.

OBJECTIVES: Virtual reality has emerged as a unique educational modality for medical trainees. However, incorporation of virtual reality curricula into formal training programmes has been limited. We describe a multi-centre effort to develop, implement, and evaluate the efficacy of a virtual reality curriculum for residents participating in paediatric cardiology rotations. METHODS: A virtual reality software program ("The Stanford Virtual Heart") was utilised. Users are placed "inside the heart" and explore non-traditional views of cardiac anatomy. Modules for six common congenital heart lesions were developed, including narrative scripts. A prospective case-control study was performed involving three large paediatric residency programmes. From July 2018 to June 2019, trainees participating in an outpatient cardiology rotation completed a 27-question, validated assessment tool. From July 2019 to February 2020, trainees completed the virtual reality curriculum and assessment tool during their cardiology rotation. Qualitative feedback on the virtual reality experience was also gathered. Intervention and control group performances were compared using univariate analyses. RESULTS: There were 80 trainees in the control group and 52 in the intervention group. Trainees in the intervention group achieved higher scores on the assessment (20.4 ± 2.9 versus 18.8 ± 3.8 out of 27 questions answered correctly, p = 0.01). Further analysis showed significant improvement in the intervention group for questions specifically testing visuospatial concepts. In total, 100% of users recommended integration of the programme into the residency curriculum. CONCLUSIONS: Virtual reality is an effective and well-received adjunct to clinical curricula for residents participating in paediatric cardiology rotations. Our results support continued virtual reality use and expansion to include other trainees.

Diet Quality and Pancreatic Cancer Incidence in the Multiethnic Cohort.

BACKGROUND: Data on diet quality and pancreatic cancer are limited. We examined the relationship between diet quality, assessed by the Healthy Eating Index-2015 (HEI-2015), the Alternative Healthy Eating Index-2010 (AHEI-2010), the alternate Mediterranean Diet (aMED) score, the Dietary Approaches to Stop Hypertension (DASH) score and the energy-adjusted Dietary Inflammatory Index (E-DII), and pancreatic cancer incidence in the Multiethnic Cohort Study. METHODS: Diet quality scores were calculated from a validated food frequency questionnaire administered at baseline. Cox models were used to calculate HR and 95% confidence intervals (CI) adjusted for age, sex, race/ethnicity, education, diabetes, family history of pancreatic cancer, physical activity, smoking variables, total energy intake, body mass index (BMI), and alcohol consumption. Stratified analyses by sex, race/ethnicity, smoking status, and BMI were conducted. RESULTS: Over an average follow-up of 19.3 years, 1,779 incident pancreatic cancer cases were identified among 177,313 participants (average age of 60.2 years at baseline, 1993-1996). Overall, we did not observe associations between the dietary pattern scores and pancreatic cancer (aMED: 0.98; 95% CI, 0.83-1.16; HEI-2015: 1.03; 95% CI, 0.88-1.21; AHEI-2010: 1.03; 95% CI, 0.88-1.20; DASH: 0.92; 95% CI, 0.79-1.08; E-DII: 1.05; 95% CI, 0.89-1.23). An inverse association was observed with DASH for ever smokers (HR, 0.75; 0.61-0.93), but not for nonsmokers (HR, 1.05; 0.83-1.32). CONCLUSIONS: The DASH diet showed an inverse association with pancreatic cancer among ever smokers, but does not show a protective association overall. IMPACT: Modifiable measures are needed to reduce pancreatic cancer burden in these high-risk populations; our study adds to the discussion of the benefit of dietary changes.

Relationships Between Preoperative Mental Health and Improvements in Patient-Reported Outcomes After Total Hip and Knee Arthroplasty.

BACKGROUND: Poor preoperative mental health has been associated with worse outcomes after total hip (THA) and total knee arthroplasty (TKA). To fully understand these relationships, we assessed post-THA and post-TKA improvements in patient-reported mental and joint health by preoperative mental health groups. METHODS: Elective cases (367 THA, 462 TKA) were subgrouped by low (<25th percentile), middle (25th-74th), and high (≥75th) preoperative mental health, using Veterans RAND 12-Item Health Survey Mental Component Summary (MCS) scores. In each subgroup, we assessed the relationship between preoperative MCS and 1-year postoperative change in mental and joint health. Pairwise comparisons and multivariable regression models were applied for THA and TKA separately. RESULTS: Median postoperative mental health change was +14.0 points for the low-MCS THA group, +11.1 low-TKA, +2.0 middle-THA and TKA, -4.0 high-THA, and -4.9 high-TKA (between-group differences P < .001). All MCS groups had improved median joint health scores, without significant between-group differences. Preoperative mental health was negatively associated with mental health improvements in all groups (B = -0.94 - -0.68, P < .001-P = .01) but with improvements in joint health only in the low-THA group (B = -0.74, P = .02). Improvements in mental and joint health were positively associated for low and middle (B = 0.61-0.87, P < .001), but not for high-MCS groups, with this relationship differing for the low versus high group. CONCLUSION: Patients who have low preoperative mental health experienced greater postoperative mental health improvement and similar joint health improvement compared to patients who have high preoperative mental health. Findings can guide subgroup-targeted surgical decision-making and preoperative counseling.

Exposure to perfluoroalkyl substances and risk of hepatocellular carcinoma in a multiethnic cohort.

Background & Aims: Exposure to poly- and perfluoroalkyl substances (PFAS), a class of persistent organic pollutants, is ubiquitous. Animal studies suggest that PFAS may increase risk of fatty liver and hepatocellular carcinoma (HCC) via impacts on hepatic lipid, amino acid, and glucose metabolism, but human data is lacking. We examined associations between PFAS exposure, altered metabolic pathways, and risk of non-viral HCC. Methods: In this nested case-control study, pre-diagnostic plasma PFAS and metabolomics were measured in 50 incident HCC cases and 50 individually matched controls from the Multiethnic Cohort (MEC) study. Cases/controls were matched by age, sex, race, and study area. PFAS exposure and risk of HCC were examined using conditional logistic regression. A metabolome-wide association study and pathway enrichment analysis was performed for PFAS exposure and HCC risk, and key metabolites/metabolic pathways were identified using a meet in the middle approach. Results: High perfluorooctane sulfonic acid (PFOS) levels (90th percentile from NHANES; >55 µg/L) were associated with 4.5-fold increased risk of HCC (odds ratio 4.5, 95% CI 1.2-16.0). Pathway enrichment analysis showed that PFOS exposure was associated with alterations in amino acid and glycan biosynthesis pathways, which were also associated with HCC risk. We identified 4 metabolites linking PFOS exposure with HCC, including glucose, butyric acid (a short-chain fatty acid), α-ketoisovaleric acid (a branched-chain α-keto acid), and 7α-hydroxy-3-oxo-4-cholestenoate (a bile acid), each of which was positively associated with PFOS exposure and risk of HCC. Conclusion: This proof-of-concept analysis shows that exposure to high PFOS levels was associated with increased risk of non-viral HCC, likely via alterations in glucose, amino acid, and bile acid metabolism. Larger studies are needed to confirm these findings. Lay summary: Per- and polyfluoroalkyl substances (PFAS), often referred to as "forever chemicals" because they are difficult to break down and stay in the human body for years, are extremely common and can cause liver damage. In a first of its kind study, we found that exposure to high levels of perfluorooctanesulfonic acid, one of the most common PFAS chemicals, was linked to increased risk of hepatocellular carcinoma in humans. Hepatocellular carcinoma is difficult to treat and is one of the most common forms of liver cancer, and these findings may provide new avenues for helping to prevent this disease.

Genipin-crosslinked fibrin seeded with oxidized alginate microbeads as a novel composite biomaterial strategy for intervertebral disc cell therapy.

Discectomy procedures alleviate disability caused by intervertebral disc (IVD) herniation, but do not repair herniation-induced annulus fibrosus (AF) defects. Cell therapy shows promise for IVD repair, yet cell delivery biomaterials capable of sealing AF defects and restoring biomechanical function have poor biological performance. To balance the biomechanical and biological demands of IVD cell delivery biomaterials, we engineered an injectable composite biomaterial using cell-laden, degradable oxidized alginate (OxAlg) microbeads (MBs) to deliver AF cells within high-modulus genipin-crosslinked fibrin (FibGen) hydrogels (FibGen + MB composites). Conceptually, the high-modulus FibGen would immediately stabilize injured IVDs, while OxAlg MBs would protect and release cells required for long-term healing. We first showed that AF cells microencapsulated in OxAlg MBs maintained high viability and, upon release, displayed phenotypic AF cell morphology and gene expression. Next, we created cell-laden FibGen + MB composites and demonstrated that OxAlg MBs functionalized with RGD peptides (MB-RGD) minimized AF cell apoptosis and retained phenotypic gene expression. Further, we showed that cell-laden FibGen + MB composites are biomechanically stable and promote extracellular matrix (ECM) synthesis in long-term in vitro culture. Lastly, we evaluated cell-laden FibGen + MB-RGD composites in a long-term bovine caudal IVD organ culture bioreactor and found that composites had low herniation risk, provided superior biomechanical and biological repair to discectomy controls, and retained anabolic cells within the IVD injury space. This novel injectable composite hydrogel strategy shows promise as an IVD cell delivery sealant with potentially broad applications for its capacity to balance biomechanical and biological performance.

Risk factors for early morbidity and mortality following pancreatoduodenectomy with concomitant vascular reconstruction.

BACKGROUND: Locally advanced pancreatic tumors may require vascular reconstruction for complete resection. However, pancreatoduodenectomy with vascular resection (PDVR) remains a subject of debate due to increased complications. METHODS: Patients were identified using the ACS NSQIP Participant User Data Files from 2014 to 2019. RESULTS: The 30-day mortality rate was 2.7%; major complications occurred in 32.2%. There is an increasing trend of PDVR in patients requiring pancreatectomy. There were no significant differences in mortality between PDVR with vein, artery, or venous and arterial resections. High BMI and postoperative biliary stent were risk factors for early complications. High BMI and COPD increased risk of early mortality. Chemotherapy and chemoradiotherapy were negative predictors for early morbidities and mortality, respectively. CONCLUSION: This study identifies the predictors of early morbidity and mortality in PDVR. The results of this study may assist decision making in perioperative management to optimize overall survival and guide additional research.

QTc Prolongation and Risk of Torsades de Pointes in Hospitalized Pediatric Oncology Patients.

OBJECTIVE: To evaluate the prevalence of torsades de pointes and to identify risk factors associated with QTc prolongation of ≥500 milliseconds in hospitalized pediatric oncology patients. A QTc prolongation of ≥500 milliseconds is associated with higher mortality in hospitalized adults but has not been demonstrated in pediatrics. STUDY DESIGN: A single-center, retrospective review of all hospitalized oncology patients ≤21 years of age was performed from 2014 to 2016. Patients with long/short QT syndrome or a QRS interval of ≥120 ms were excluded. Rapid response events were reviewed to determine the prevalence of torsades. In patients with ECGs for review, data were compared between patients with a QTc of <500 and ≥500 ms via logistic regression. RESULTS: There were 1934 hospitalized patients included. Rapid response events occurred in 90 patients (4.7%) with 2 torsades events (0.1%). There were 1412 electrocardiograms performed in 287 unique patients (10.6 ± 6.3 years of age; 43% female). The mean QTc was 448 ± 31 ms; 25 patients (8.7%) had ≥1 ECG with a QTc of ≥500 ms. The prevalence of torsades was greater in patients with a QTc of ≥500 ms (8% vs 0%; P<.01). In multivariate analysis, factors associated with a QTc of ≥500 ms included female sex, (OR 2.95) and ≥2 QT-prolonging medications (OR, 2.95). CONCLUSIONS: The prevalence of torsades in hospitalized pediatric oncology patients was low (0.1%), although the risk was significantly greater in patients with a QTc of ≥500 ms. Routine monitoring of electrocardiograms and electrolytes is essential in patients with risk factors predisposing to QTc prolongation.

Endothelial Regeneration of Large Vessels Is a Biphasic Process Driven by Local Cells with Distinct Proliferative Capacities.

The cellular and mechanistic bases underlying endothelial regeneration of adult large vessels have proven challenging to study. Using a reproducible in vivo aortic endothelial injury model, we characterized cellular dynamics underlying the regenerative process through a combination of multi-color lineage tracing, parabiosis, and single-cell transcriptomics. We found that regeneration is a biphasic process driven by distinct populations arising from differentiated endothelial cells. The majority of cells immediately adjacent to the injury site re-enter the cell cycle during the initial damage response, with a second phase driven by a highly proliferative subpopulation. Endothelial regeneration requires activation of stress response genes including Atf3, and aged aortas compromised in their reparative capacity express less Atf3. Deletion of Atf3 reduced endothelial proliferation and compromised the regeneration. These findings provide important insights into cellular dynamics and mechanisms that drive responses to large vessel injury.

Association of dead space ventilation and prolonged ventilation after repair of tetralogy of Fallot with pulmonary atresia.

BACKGROUND: We set out to determine whether patients with tetralogy of Fallot with pulmonary atresia and major aortopulmonary collateral arteries (TOF/PA/MAPCA) are at risk for elevated dead space ventilation fraction (VD/VT), and whether this is associated with prolonged mechanical ventilation. We hypothesized that elevated VD/VT (>20%) in the first 24 hours after unifocalization surgery is associated with increased risk for prolonged mechanical ventilation (>7 days). METHODS: All patients with TOF/PA/MAPCA undergoing unifocalization surgery between January 2003 and December 2015 were included in this study. Average VD/VT was calculated over the first 24 hours after surgery. Demographic and surgical data were collected. Outcome data included duration of mechanical ventilation. Patients were separated into 2 groups: elevated VD/VT and normal DVSF. Groups were compared using the Student t test, Wilcoxon rank-sum test, and χ2 test. Univariable and multivariable regression analyses were performed with VD/VT as a continuous variable to test for association. RESULTS: Of the 265 included patients, 127 (48%) had an elevated VD/VT. The 2 groups did not differ significantly in any demographic characteristic. Patients with an elevated VD/VT had longer cardiopulmonary bypass times (P = .03), were more likely to have delayed sternal closure, and more likely to have prolonged respiratory failure (odds ratio, 2.2; 95% confidence interval, 1.2-4.0; P = .007). The percent VD/VT was associated with duration of mechanical ventilation in univariable (P < .001) and multivariable (P < .001) regression analyses when controlled for age, weight and bypass time. CONCLUSIONS: Elevated postoperative VD/VT is associated with prolonged mechanical ventilation in patients with TOF/PA/MAPCA following unifocalization. Elevated postoperative VD/VT may be an early indicator of patients who will require prolonged duration of mechanical ventilation, allowing optimization of medical management to promote better outcomes.

Exposures of Sus scrofa to a TASER(®) conducted electrical weapon: no effects on 2-dimensional gel electrophoresis patterns of plasma proteins.

In an earlier study, we found significant changes in red-blood-cell, leukocyte, and platelet counts, and in red-blood-cell membrane proteins, following exposures of anesthetized pigs to a conducted electrical weapon. In the current study, we examined potential changes in plasma proteins [analyzed via two-dimensional gel electrophoresis (2-DGE)] following two 30 s exposures of anesthetized pigs (Sus scrofa) to a TASER (®) C2 conducted electrical weapon. Patterns of proteins, separated by 2-DGE, were consistent and reproducible between animals and between times of sampling. We determined that the blood plasma collection, handling, storage, and processing techniques we used are suitable for swine blood. There were no statistically significant changes in plasma proteins following the conducted-electrical-weapon exposures. Overall gel patterns of fibrinogen were similar to results of other studies of both pigs and humans (in control settings, not exposed to conducted electrical weapons). The lack of significant changes in plasma proteins may be added to the body of evidence regarding relative safety of TASER C2 device exposures.

Effects of a TASER® conducted energy weapon on the circulating red-blood-cell population and other factors in Sus scrofa.

In previous studies hematocrit has been consistently increased in an anesthetized animal model after exposures to TASER(®) conducted energy weapons (CEWs). In the present study we analyzed changes in blood cell counts and red blood cell membrane proteins following two 30-s applications of a TASER C2 device (which is designed for civilian use). Hematocrit increased significantly from 33.2 ± 2.4 (mean ± SD) to 42.8 ± 4.6 % immediately after CEW exposure of eleven pigs (Sus scrofa). Red blood cell count increased significantly from 6.10 ± 0.55 × 10(12)/L to 7.45 ± 0.94 × 10(12)/L, and mean corpuscular volume increased significantly from 54.5 ± 2.4 fl to 57.8 ± 2.6 fl. Mean corpuscular hemoglobin concentration decreased significantly from 20.5 ± 0.7 to 18.5 ± 0.6 mM. Thirty protein spots (from two-dimensional sodium dodecyl sulfate polyacrylamide gel electrophoresis, selected for detailed comparison) exhibited greater densities 30-min post-exposure compared with pre-exposure values. A greater number of echinocytes were observed following CEW exposure. On the basis of these results it appears that, during the strong muscle contractions produced by TASER CEWs, a specific population of red blood cells (RBCs) may be released from the spleen or other reservoirs within the body. The total time of CEW exposure in the present study was relatively long compared with exposures in common law-enforcement scenarios. Despite statistically significant changes in red blood cell counts (and other measures directly related to RBCs), the alterations were short-lived. The transient nature of the changes would be likely to counteract any potentially detrimental effects.

A novel cell cycle inhibitor stalls replication forks and activates S phase checkpoint.

DNA replication checkpoint is activated in response to replication stresses. It maintains the integrity of stalled replication forks and prevents premature segregation of largely unreplicated chromosomes. In budding yeast, Mec1 and Rad53 kinases (homologous to mammalian ATM/ATR and Chk2 kinases, respectively) are the main effectors of this checkpoint control. Using a yeast based screen, we have identified a compound (named here ENA) which inhibits DNA replication and activates Mec1/Rad53 checkpoint. A brief exposure to this compound stops fork progression at or near replication origin and renders the forks incompetent to resume replication despite the presence of a functional checkpoint. ENA also inhibits DNA synthesis in mammalian cells leading to the activation of ATM/ATR pathway and the induction of apoptosis in a p53 independent manner. Interestingly, ENA acts as an effective anti-proliferative agent against a subset of cancer cell lines and as an anti-tumor agent against human xenografts in mice. Thus, ENA is a potent cell cycle inhibitor with conceivable therapeutic potential.