Search

Opioid use in the United States and abroad is an endemic part of culture with yearly increases in overdose rates and deaths. As rates of overdose incidence increases, the use of the safe and effective reversal agent, naloxone, in the form of a nasal rescue spray is being fielded and used by emergency medical technicians (EMTs) at a greater and greater rate. Despite advances in deployment of these rescue products, deaths are continuing to increase. There is evidence that repeated dosing of a naloxone nasal spray (such as Narcan) is becoming more common due to the amount and type of opiate being abused. Despite the benefits of naloxone related to opioid reversals, we lack repeated dosing guidelines as a function of opiate and amount the patient has taken. Goal directed dosing is promising, where respiratory markers are being used as an indication of the patient recovery but require time and understanding by the EMT. We construct a whole-body model of the pharmacokinetics and dynamics of an opiate, fentanyl on respiratory depression. We then construct a model of nasal deposition and administration of naloxone to investigate repeat dosing requirements for large overdoses. We demonstrate that naloxone is highly effective at reversing respiratory symptoms of the patient and recommend dosing requirements as a function of opiate amount administered. By designing the model to include circulation and respiration we investigate physiological markers that may be used in goal directed therapy rescue treatments.

Xylella fastidiosa is a xylem-limited plant pathogen infecting many crops globally and is the cause of the recent olive disease epidemic in Italy. One strategy proposed to mitigate losses is to replant susceptible crops with resistant varieties. Several genetic, biochemical and biophysical traits are associated to X. fastidiosa disease resistance. However, mechanisms underpinning resistance are poorly understood. We hypothesize that the susceptibility of olive cultivars to infection will correlate to xylem vessel diameters, with narrower vessels being resistant to air embolisms and having slower flow rates limiting pathogen spread. To test this, we scanned stems from four olive cultivars of varying susceptibility to X. fastidiosa using X-ray computed tomography. Scans were processed by a bespoke methodology that segmented vessels, facilitating diameter measurements. Though significant differences were not found comparing stem-average vessel section diameters among cultivars, they were found when comparing diameter distributions. Moreover, the measurements indicated that although vessel diameter distributions may play a role regarding the resistance of Leccino, it is unlikely they do for FS17. Considering Young–Laplace and Hagen–Poiseuille equations, we inferred differences in embolism susceptibility and hydraulic conductivity of the vasculature. Our results suggest susceptible cultivars, having a greater proportion of larger vessels, are more vulnerable to air embolisms. In addition, results suggest that under certain pressure conditions, functional vasculature in susceptible cultivars could be subject to greater stresses than in resistant cultivars. These results support investigation into xylem morphological screening to help inform olive replanting. Furthermore, our framework could test the relevance of xylem geometry to disease resistance in other crops.

We provide strong evidence of the spin-nematic state in a paradigmatic ferro-antiferromagnetic $J_1$--$J_2$ model using analytical and density-matrix renormalization group methods. In zero field, the attraction of spin-flip pairs leads to a first-order transition and no nematic state, while pair-repulsion at larger $J_2$ stabilizes the nematic phase in a narrow region near the pair-condensation field. A devil's staircase of multi-pair condensates is conjectured for weak pair-attraction. A suppression of the spin-flip gap by many-body effects leads to an order-of-magnitude contraction of the nematic phase compared to na\"ive expectations. The proposed phase diagram should be broadly valid., Comment: 7 pages, 5 figures; 11 pages of supplemental materials; almost the same as the published version

Background Several treatment strategies for early stage hepatocellular cancers (HCC) have been evaluated in randomised controlled trials (RCTs). This network meta-analysis (NMA) aimed to explore the relative effectiveness of these different approaches on their impact on overall (OS) and recurrence-free survival (RFS). Methods A systematic review was conducted to identify RCT’s reported up to 23rd January 2020. Indirect comparisons of all regimens were simultaneously compared using random-effects NMA. Results Twenty-eight RCT's, involving 3,618 patients, reporting 13 different treatment strategies for early stage HCC were identified. Median follow-up, reported in 22 studies, ranged from 12–93 months. In this NMA, RFA in combination with iodine-125 was ranked first for both RFS (HR: 0.50, 95% CI: 0.19–1.31) and OS (HR: 0.41, 95% CI: 0.19–0.94). In subgroup with solitary HCC, lack of studies reporting RFS precluded reliable analysis. However, RFA in combination with iodine-125 was associated with markedly better OS (HR: 0.21, 95% CI: 0.05–0.93). Conclusion This NMA identified RFA in combination with iodine-125 as a treatment delivering better RFS and OS, in patients with early stage HCC, especially for those with solitary HCC. This technique warrants further evaluation in both Asia and Western regions.

Background There has been increasing uptake of minimally invasive pancreatoduodenectomy during the past decade, but it remains a highly specialized procedure as benefits over open pancreatoduodenectomy remain contentious. This study aimed to evaluate current evidence on minimally invasive pancreatoduodenectomy versus open pancreatoduodenectomy in terms of impact of center volume on outcomes. Methods A systematic review of articles on comparative cohort and registry studies on minimally invasive pancreatoduodenectomy versus open pancreatoduodenectomy published until 31st December 2019 were identified, and meta-analyses were performed. Primary endpoints were International Study Group on Pancreatic Fistula grade B/C postoperative pancreatic fistula and 30-day mortality. Results After screening 7,390 studies, 43 comparative cohort studies (8,755 patients) with moderate methodological quality and 3 original registry studies (43,735 patients) were included. For the cohort studies, the median annual hospital minimally invasive pancreatoduodenectomy volume was 10. No significant differences were found in grade B/C postoperative pancreatic fistula (odds ratio: 0.98, 95% confidence interval: 0.78–1.23) or 30-day mortality (odds ratio: 1.14, 95% confidence interval: 0.65–2.01) between minimally invasive pancreatoduodenectomy when compared with open. No publication biases were present and meta-regression identified no confounding for grade B/C postoperative pancreatic fistula, center volume or 30-day mortality. Minimally invasive pancreatoduodenectomy was only strongly associated with significantly lower rates of postoperative pulmonary complications and surgical site infection, shorter length of stay, and significantly higher rates of R0 margin resections. Conclusion Minimally invasive pancreatoduodenectomy remains noninferior to open pancreatoduodenectomy for grade B/C postoperative pancreatic fistula but is strongly associated with significantly lower rates of postoperative pulmonary complications and surgical site infection. Minimally invasive pancreatoduodenectomy can be adopted safely with good outcomes irrespective of annual center resection volume.

Background Data supporting the routine use of adjuvant chemotherapy (AC) compared with no AC (noAC) following neoadjuvant chemotherapy (NAC) and resection for pancreatic ductal adenocarcinoma (PDAC) are lacking. This study aimed to determine whether AC improves long-term survival in patients receiving NAC and resection. Methods Patients receiving resection for PDAC following NAC from 2004 to 2016 were identified from the National Cancer Data Base (NCDB). Patients with a survival rate of Results Of 4449 (68%) noAC patients and 2111 (32%) AC patients, 2016 noAC patients and 2016 AC patients remained after PSM. After matching, AC was associated with improved survival (median 29.4 vs. 24.9 months; p p p p p p = 0.007), no neoadjuvant radiotherapy (NART; HR 0.84, 95% CI 0.74–0.96; p = 0.009), and use of NART (HR 0.80, 95% CI 0.73–0.88; p Conclusion AC following NAC and resection is associated with improved survival, even in margin-negative and node-negative disease. These findings suggest completing planned systemic treatment should be considered in all resected PDACs previously treated with NAC.

Background Dextran 40 (D40) is a synthetic colloid with anticoagulant properties that is used instead of heparin after pancreas transplantation; however, there is a lack of evidence on which is more effective. Graft thrombosis and pancreatitis, which may be mediated through microthrombosis or macrothrombosis within the graft, remain significant complications after pancreas transplantation. We hypothesized that D40 reduces inflammation through its antithrombotic promicrocirculatory effects. We evaluated D40 compared to a heparin-based protocol by comparing postoperative complications and post-transplant levels of inflammation. Materials and Methods Data were collected retrospectively for pancreas transplant patients between December 2009 and August 2018. A total of 26 patients had been treated with the pre-dextran protocol and 37 had received D40. Postoperative complications and inflammatory markers (white cell count [WCC], C-reactive protein [CRP], and amylase) on postoperative days 1, 2, 3, and 7 were compared between groups. Potential confounders were also recorded. Results Patients in the D40 group had similar thrombosis rates but were less likely to have had graft loss as a result of thrombosis or substantial postoperative bleeding compared to the heparin-based protocol. The group who received D40 had significantly lower CRP and WCC on days 2, 3, and 7. The differences on days 3 and 7 remained when the results were adjusted for the significant confounders of cold ischemic time and donor age. Conclusions D40 appears to be as effective as intravenous heparin at preventing graft thrombosis after pancreas transplant and to confer a reduced risk for bleeding. It may also reduce postoperative inflammatory processes, leading to reduced graft pancreatitis.

Background It remains unclear whether minimally invasive pancreaticoduodenectomy (MIPD) and open pancreaticoduodenectomy (OPD) influences long-term survival in periampullary cancers. This review aims evaluate long-term survival between MIPD and OPD for periampullary cancers. Methods A systematic review was performed to identify studies comparing long-term survival after MIPD and OPD. The I2 test was used to test for statistical heterogeneity and publication bias using Egger test. Random-effects meta-analysis was performed for all-cause 5-year (main outcome) and 3-year survival, and disease-specific 5-year and 3-year survival. Meta-regression was performed for the 5-year and 3-year survival outcomes with adjustment for study (region, design, case matching), hospital (centre volume), patient (ASA grade, gender, age), and tumor (stage, neoadjuvant therapy, subtype (i.e. ampullary, distal bile duct, duodenal, pancreatic)). Sensitivity analyses performed on studies including pancreatic ductal adenocarcinoma (PDAC) only. Results The review identified 31 relevant studies. Among all 58,622 patients, 8716 (14.9%) underwent MIPD and 49,875 (85.1%) underwent OPD. Pooled analysis revealed similar 5-year overall survival after MIPD compared with OPD (HR: 0.78, 95% CI 0.50–1.22, p = 0.2). Meta-regression indicated case matching, and ASA Grade II and III as confounding covariates. The statistical heterogeneity was limited (I2 = 12, χ2 = 0.26) and the funnel plot was symmetrical both according to visual and statistical testing (Egger test = 0.32). Sensitivity subset analyses for PDAC demonstrated similar 5-year overall survival after MIPD compared with OPD (HR 0.69, 95% CI: 0.32–1.50, p = 0.3). Conclusion Long-term survival after MIPD is non-inferior to OPD. Thus, MIPD can be recommended as a standard surgical approach for periampullary cancers.

Maternal asthma (MA) is among the most consistent risk factors for asthma in children. Possible mechanisms for this observation are epigenetic modifications in utero that have lasting effects on developmental programs in children of mothers with asthma. To test this hypothesis, we performed differential DNA methylation analyses of 398,186 individual CpG sites in primary bronchial epithelial cells (BECs) from 42 nonasthma controls and 88 asthma cases, including 56 without MA (NMA) and 32 with MA. We used weighted gene coexpression network analysis (WGCNA) of 69 and 554 differentially methylated CpGs (DMCs) that were specific to NMA and MA cases, respectively, compared with controls. WGCNA grouped 66 NMA-DMCs and 203 MA-DMCs into two and five comethylation modules, respectively. The eigenvector of one MA-associated module (turquoise) was uniquely correlated with 85 genes expressed in BECs and enriched for 36 pathways, 16 of which discriminated between NMA and MA using machine learning. Genes in all 16 pathways were decreased in MA compared with NMA cases (P = 7.1 × 10−3), a finding that replicated in nasal epithelial cells from an independent cohort (P = 0.02). Functional interpretation of these pathways suggested impaired T cell signaling and responses to viral and bacterial pathogens. The MA-associated turquoise module eigenvector was additionally correlated with clinical features of severe asthma and reflective of type 2 (T2)-low asthma (i.e., low total serum immunoglobulin E, fractional exhaled nitric oxide, and eosinophilia). Overall, these data suggest that MA alters diverse epigenetically mediated pathways that lead to distinct subtypes of severe asthma in adults, including hard-to-treat T2-low asthma.

The insect-vectored, bacterial plant pathogenXylella fastidiosais currently absent from Scotland and the wider UK, but if introduced could be a serious threat to trees and other plants. However, there is a lack of knowledge about the ecology and distributions ofXylellavectors in Scotland and the potential effects of this on any outbreak of the disease, which this project aimed to address. Sampling of xylem-feeding potential vector insects (order Hemiptera, Aphrophoridae and Cicadellidae families) was conducted in 2021, including weekly sampling of different habitats at Loch Leven, Fife, and a wider survey across 16 sites in central Scotland. Overall, this project has produced better understanding of vector phenology, species composition and habitat preferences in Scotland, as well as guidance for sampling vectors and controlling future outbreaks. It highlights a previously unappreciated risk to Scottish heathland, though this should be set in the overall context of a less suitable climate forXylellaoutbreak growth and impact at present. Better understanding of vector dispersal ranges and ofXylellatransmission and disease progression in heathland plants under Scottish climatic conditions would further inform on the potential risk of introducingXylellato Scotland.

Introduction This survey of Canadian pathology residents was designed to quantify the number of autopsies Canadian residents aim to complete during residency training, to better understand the perception of residents about access and quality of autopsy skills education. In addition, the interest of current pathology residents in autopsy and forensic pathology as a future career was also assessed. Methods A web-based survey was sent to all Canadian pathology residents. This survey consisted of 19 questions on institution, level of training, intention to complete the American Board of Pathology examination, number of autopsies completed, perception of quality/access to autopsy skills education, interest, and factors contributing to autopsy and forensic pathology. Results Eighty two (26%) of a possible 310 residents (12/47 general pathology, 70/263 anatomical pathology) across all Canadian institutions offering anatomical or general pathology programs (16/16 institutions) participated in the survey. Eighty-three percent of the respondents rated autopsy education as either very important or important. Fifty-five percent of the respondents intended to either challenge the American Board of Pathology examination or wanted the option to do so in the future, whereas only 47% of the participants agreed that all residents who wish to challenge the examination will easily be able to complete 50 autopsies during residency. Only 18% of the respondents were interested in performing autopsies as a major part of their career, and a combined 52% were only interested in performing autopsies to secure a desired position or felt that having to do autopsies would be a job deterrent. The quality of autopsy teaching received and the number of autopsies performed was identified as the most significant factors affecting interest in performing autopsies as part of a future career. A combined 68% of the respondents felt that the job market in forensic pathology in Canada was either good (better than most subspecialties) or very good (more jobs than graduating fellows). Seventy-one percent (12/17) of postgraduate year 5 respondents reported having completed 50 or more autopsies at the time of survey completion. Eleven percent of the respondents did not agree that all residents who document having completed an autopsy at their institution will have participated in all 8 essential autopsy tasks. Twenty four (29%) of the 82 respondents provided detailed narrative comments. Discussion Most Canadian pathology residents believe that autopsy education is an important component of residency training. Limited access to quality autopsy teaching seems to be an important factor in resident interest in forensic pathology as a future career, despite a perceived good job market in comparison with most other subspecialties.

Background Minimally invasive surgery is the standard technique for many operations. Laparoscopic training has a long learning curve. Robotic solutions may shorten the training pathway. The aim of this study was to compare laparoscopic with robotic training in surgical trainees and medical students. Methods Surgical trainees (ST group) were randomized to receive 6 h of robotic or laparoscopic simulation training. They then performed three surgical tasks in cadaveric specimens. Medical students (MS group) had 2 h of robotic or laparoscopic simulation training followed by one surgical task. The Global Rating Scale (GRS) score (maximum 30), number of suture errors, and time to complete each procedure were recorded. Results The median GRS score for the ST group was better for each procedure after robotic training compared with laparoscopic training (total GRS score: 27·00 (i.q.r. 22·25–28·33) versus 18·00 (16·50–19·04) respectively, P, Medical students and surgical trainees were randomized to robotic or laparoscopic simulator training followed by cadaveric surgical tasks. The robotic groups had a shorter learning curve with better task performance. Another advantage for robotic surgery

Background: Theoretical advantages of robotic surgery compared to conventional laparoscopic surgery include improved instrument dexterity, 3D visualization, and better ergonomics. This systematic review and meta-analysis aimed to determine advantages of robotic surgery over laparoscopic surgery in patients undergoing liver resections. Method: A systematic literature search was conducted for studies comparing robotic assisted or totally laparoscopic liver resection. Meta-analysis of intraoperative (operative time, blood loss, transfusion rate, conversion rate), oncological (R0 resection rates), and postoperative (bile leak, surgical site infection, pulmonary complications, 30-day and 90-day mortality, length of stay, 90-day readmission and reoperation rates) outcomes was performed using a random effects model. Result: Twenty-six non-randomized studies including 2630 patients (950 robotic and 1680 laparoscopic) were included, of which 20% had major robotic liver resection and 14% had major laparoscopic liver resection. Intraoperatively, robotic liver resection was associated with significantly less blood loss (mean: 286 vs 301 mL, p Conclusions: Robotic liver resection appears to offer some advantages compared to conventional laparoscopic surgery, although both techniques appear equivalent. Importantly, the quality of evidence is generally limited to cohort studies and a high-quality randomized trial comparing both techniques is needed.

Background Despite increasing reports of pregnancy in liver transplant recipients, questions remain about the impact of transplantation in pregnancy. Methods This systematic review was performed according to PRISMA guidelines and eligible studies were identified through a search of PubMed, Scopus and Cochrane CENTRAL databases up to 26th December 2019 for studies reporting pregnancy with liver transplant. A meta-analysis was conducted with the use of random-effects modelling and prospectively registered with the PROSPERO database. Results Of 1239 unique studies, 28 met inclusion criteria, representing 1496 pregnancies in 1073 liver transplant recipients. The live-birth rate was 85.6% (CI95%: 80.5%–90.7%). The rate of other pregnancy outcomes was as follows: induced abortions (5.7%), miscarriages (7.8%) and stillbirths (3.3%). Pooled rates of obstetric complications were hypertension (18.2%), pre-eclampsia (12.8%) and gestational diabetes (7.0%). Pooled rates of delivery outcomes for caesarean section (C-section) and pre-term birth were 42.2% and 27.8%, respectively. Conclusion In conclusion, live birth outcomes are good among liver transplant recipients and this favourable trend is consistent at an international level. However, special attention should be given to obstetric complications such as hypertension, pre-eclampsia, and preterm delivery. The high incidence of these complications supports the high-risk classification of post-liver transplant pregnancies and it is necessary for a multidisciplinary team to be involved in the monitoring and counselling of liver transplant recipients both before and during pregnancy. Whilst majority data originate from institutions from high-income countries, data from low-middle income countries (LMIC) are needed owing to rising rates of liver transplantation in LMIC.

Repurposing commonly prescribed noncancer medications for use in oncology has substantial advantages over de-novo development of anticancer drugs. Calcium signalling has been implicated in many of the hallmarks of cancer. Previous in-vitro and in-vivo studies have shown that calcium channel blockers (CCBs) are able to promote apoptosis, inhibit proliferation and prevent invasion and metastasis in a variety of cancer types. This retrospective cohort study aimed to translate this into the clinic by investigating the effect of CCBs on survival in pancreatic cancer. One hundred sixty-four patients with unresectable pancreatic ductal adenocarcinoma were included. Data were collected on CCB prescription, and for a range of other potentially important prognostic factors: ECOG performance status, AJCC cancer stage, chemotherapy regimen, radiotherapy, age, hypertension and sex. Participants prescribed CCB (n = 30) were more likely to be older (P = 0.004) and have hypertension (P < 0.0005); baseline demographics were otherwise similar between groups. On adjusted cox regression patients prescribed CCBs demonstrated significantly improved overall survival; hazard ratio -0.496 (0.297-0.827; P = 0.007). Performance status (P < 0.0005), tumour stage (P < 0.0005), chemotherapy regimen (P < 0.0005), radiotherapy (0.002) and age (P = 0.012) were also independent predictors of survival. The Kaplan-Meier estimated median survival was 15.3 months for patients prescribed CCBs versus 10.1 months for patients not prescribed CCBs (P = 0.131). This study supports previous work suggesting CCBs may be beneficial in pancreatic cancer. Further work on larger datasets will allow for subgroup analysis delineating the effects of specific CCBs in combination with different forms of chemotherapy, paving the way for future prospective studies.

Background: African ancestry is associated with a higher prevalence and greater severity of asthma than European ancestries, yet genetic studies of the most common locus associated with childhood-onset asthma, 17q12–21, in African Americans have been inconclusive. The aim of this study was to leverage both the phenotyping of the Children's Respiratory and Environmental Workgroup (CREW) birth cohort consortium, and the reduced linkage disequilibrium in African Americans, to fine map the 17q12–21 locus. Methods: We first did a genetic association study and meta-analysis using 17q12–21 tag single-nucleotide polymorphisms (SNPs) for childhood-onset asthma in 1613 European American and 870 African American children from the CREW consortium. Nine tag SNPs were selected based on linkage disequilibrium patterns at 17q12–21 and their association with asthma, considering the effect allele under an additive model (0, 1, or 2 effect alleles). Results were meta-analysed with publicly available summary data from the EVE consortium (on 4303 European American and 3034 African American individuals) for seven of the nine SNPs of interest. Subsequently, we tested for expression quantitative trait loci (eQTLs) among the SNPs associated with childhood-onset asthma and the expression of 17q12–21 genes in resting peripheral blood mononuclear cells (PBMCs) from 85 African American CREW children and in upper airway epithelial cells from 246 African American CREW children; and in lower airway epithelial cells from 44 European American and 72 African American adults from a case-control study of asthma genetic risk in Chicago (IL, USA). Findings: 17q12–21 SNPs were broadly associated with asthma in European Americans. Only two SNPs (rs2305480 in gasdermin-B [GSDMB] and rs8076131 in ORMDL sphingolipid biosynthesis regulator 3 [ORMDL3]) were associated with asthma in African Americans, at a Bonferroni-corrected threshold of p

Background Major liver resection can lead to significant morbidity and mortality. Blood loss is one of the most important factors predicting a good outcome. Although various transection methods have been reported, there is no consensus on the best technique. This systematic review and network meta-analysis aims to characterise and identify the best reported technique for elective parenchymal liver transection based on published randomised controlled trials (RCT's). Methods A systematic review was conducted using MEDLINE, EMBASE, and Cochrane Central to identify RCT's up to 5th June 2019 that examined parenchymal transection for liver resection. Data including study characteristics and outcomes including intraoperative (blood loss, operating time) and postoperative measures (overall and major complications, bile leaks) were extracted. Indirect comparisons of all regimens were simultaneously compared using random-effects network meta-analyses (NMA) which maintains randomisation within trials. Results This study identified 22 RCT's involving 2360 patients reporting ten parenchymal transection techniques. Bipolar cautery has lower blood loss and shorter operating time than stapler (mean difference: 85 mL; 22min) and Tissue Link (mean difference: 66 mL; 29min). Bipolar cautery was ranked first for blood loss and operating time followed by stapler and TissueLink. Harmonic scalpel is associated with lower overall complications than Hydrojet (Odds ratio (OR): 0.48), BiClamp forceps (OR: 0.46) and clamp crushing (OR: 0.41). Conclusion Bipolar cautery techniques appear to best at reducing blood loss and associated with shortest operating time. In contrast, Harmonic scalpel appears best for overall and major complications. Given the paucity of data and selective outcome reporting, it is still hard to identify what is the best technique for liver resection. Therefore, further high-quality large-scale RCT's are still needed.

Background: Cardiomyopathies are a group of diseases of the heart that can lead to heart failure, cardiac arrhythmia, and sudden death. They typically manifest as an enlarged heart or a normal heart with microscopic anomalies [fibrosis, inflammation, etc.]. The aim of the study is to investigate the prevalence of deaths due to cardiomyopathies of unknown etiology in young subjects in a forensic pathology setting. Materials and Methods: Deaths due to cardiomyopathy in decedents less than 40 years old evaluated at the Cook County Medical Examiner’s Office in Chicago from January 2013 to June 2018 were studied. Results and Conclusions: In total, 140 cases of cardiomyopathies were identified in the study period: among these, in 20 cases [14%] no underlying etiology could be found through medical history and autopsy investigation. The demographics and the macroscopic and microscopic findings of these cases are described, highlighting the importance of medical history review and adequate histological sampling of hearts in cases of sudden, unexpected death in children and young adults.

It was brought to our attention that the transformation matrix from the cubic to crystallographic reference frame, Scryst = ^ R c S cubic , Eq. (43) of our work, used an unconventional orientation of the cubic axes triad, corresponding to x?-x and y?-y of the conventional choice for the cubic reference frame. While presumably leading to the same physical results, our transformation should have resulted in a model that is different from the extended Kitaev-Heisenberg model listed in Eq. (44) by more complicated sign conventions for the G and G' terms on different bonds. To adhere to the conventional and symmetric choice, the transformation matrix ^Rc in Eq. (43) should read as (Formula Presented) (Figure Presented).

Asthma is a heterogeneous disease, with multiple underlying inflammatory pathways and structural airway abnormalities that impact disease persistence and severity. Recent progress has been made in developing targeted asthma therapeutics, especially for subjects with eosinophilic asthma. However, there is an unmet need for new approaches to treat patients with severe and exacerbation-prone asthma, who contribute disproportionately to disease burden. Extensive deep phenotyping has revealed the heterogeneous nature of severe asthma and identified distinct disease subtypes. Acurrent challenge in the field is to translate new and emerging knowledge about different pathobiologic mechanisms in asthma into patient-specific therapies, with the ultimate goal of modifying the natural history of disease. Here, we describe the Precision Interventions for Severe and/or Exacerbation-Prone Asthma (PrecISE) Network, a groundbreaking collaborative effort of asthma researchers and biostatisticians from around the United States. The PrecISE Network was designed to conduct phase II/proof-of-concept clinical trials of precision interventions in the population with severe asthma, and is supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health. Using an innovative adaptive platform trial design, the PrecISE Network will evaluate up to 6 interventions simultaneously in biomarker-defined subgroups of subjects. We review the development and organizational structure of the PrecISE Network, and choice of interventions being studied. We hope that the PrecISE Network will enhance our understanding of asthma subtypes and accelerate the development of therapeutics for severe asthma.

Introduction: Laparoscopic distal pancreatectomy (LDP) has potential advantages over its open equivalent open distal pancreatectomy (ODP) for pancreatic disease in the neck, body and tail. Within the United Kingdom (UK), there has been no previous experience describing the role of robotic distal pancreatectomy (RDP). This study evaluated differences between ODP, LDP and RDP. Methods: Patients undergoing distal pancreatectomy performed in the Department of Hepatobiliary and Pancreatic Surgery at the Freeman Hospital between September 2007 and December 2018 were included from a prospectively maintained database. The primary outcome measure was length of hospital stay, and the secondary outcome measures were complication rates graded according to the Clavien–Dindo classification. Results: Of the 125 patients, the median age was 61 years and 46% were male. Patients undergoing RDP (n = 40) had higher American Society of Anesthesiologists grading III compared to ODP (n = 38) and LDP (n = 47) (57% vs. 37% vs. 38%, P = 0.02). RDP had a slightly lower but not significant conversion rate (10% vs. 13%, P = 0.084), less blood loss (median: 0 vs. 250 ml, P < 0.001) and a higher rate of splenic preservation (30% vs. 2%, P < 0.001) and shorter operative time, once docking time excluded (284 vs. 300 min, P < 0.001) compared to LDP. RDP had a higher R0 resection rate than ODP and LDP (79% vs. 47% vs. 71%, P = 0.078) for neoplasms. RDP was associated with significantly shorter hospital stay than LDP and ODP (8 vs. 9 vs. 10 days, P = 0.001). While there was no significant different in overall complications across the groups, RDP was associated with lower rates of Grade C pancreatic fistula than ODP and LDP (2% vs. 5% vs. 6%, P = 0.194). Conclusion: Minimally invasive pancreatic resection offers potential advantages over ODP, with a trend showing RDP to be marginally superior when compared to conventional LDP, but it is accepted that that this is likely to be at greater expense compared to the other current techniques.

We present conditional probability (CP) density functional theory (DFT) as a formally exact theory. In essence, CP-DFT determines the ground-state energy of a system by finding the CP density from a series of independent Kohn-Sham (KS) DFT calculations. By directly calculating CP densities, we bypass the need for an approximate XC energy functional. In this work we discuss and derive several key properties of the CP density and corresponding CP-KS potential. Illustrative examples are used throughout to help guide the reader through the various concepts and theory presented. We explore a suitable CP-DFT approximation and discuss exact conditions, limitations, and results for selected examples.

BACKGROUND Pharmacogenetic studies in asthma cohorts, primarily made up of White people of European descent, have identified loci associated with response to inhaled beta agonists and corticosteroids (ICSs). Differences exist in how individuals from different ancestral backgrounds respond to long-acting beta agonist (LABA) and ICSs. Therefore, we sought to understand the pharmacogenetic mechanisms regulating therapeutic responsiveness in individuals of African descent. METHODS We did ancestry-based pharmacogenetic studies of children (aged 5-11 years) and adolescents and adults (aged 12-69 years) from the Best African Response to Drug (BARD) trials, in which participants with asthma uncontrolled with low-dose ICS (fluticasone propionate 50 μg in children, 100 μg in adolescents and adults) received different step-up combination therapies. The hierarchal composite outcome of pairwise superior responsiveness in BARD was based on asthma exacerbations, a 31-day difference in annualised asthma-control days, or a 5% difference in percentage predicted FEV1. We did whole-genome admixture mapping of 15 159 ancestral segments within 312 independent regions, stratified by the two age groups. The two co-primary outcome comparisons were the step up from low-dose ICS to the quintuple dose of ICS (5 × ICS: 250 μg twice daily in children and 500 μg twice daily in adolescents and adults) versus double dose (2-2·5 × ICS: 100 μg twice daily in children, 250 μg twice daily in adolescents and adults), and 5 × ICS versus 100 μg fluticasone plus a LABA (salmeterol 50 μg twice daily). We used a genome-wide significance threshold of p

RationaleChronic obstructive pulmonary disease (COPD) predominantly affects older adults. However, the co-morbid occurrence of geriatric conditions has been understudied.ObjectiveCharacterize the prevalence of geriatric conditions among community-dwelling U.S. older adults with self-reported COPD.MethodsWe conducted a nationally representative, cross-sectional study of 3,005 U.S. community-dwelling older adults (ages 57–85 years) from the National Social Life, Health, and Aging Project (NSHAP). We evaluated the prevalence of select geriatric conditions (multimorbidity, functional disability, impaired physical function, low physical activity, modified frailty assessment, falls, polypharmacy, and urinary incontinence) and psychosocial measures (frequency of socializing, sexual activity in the last year, loneliness, cognitive impairment, and depressive symptoms) among individuals with self-reported COPD as compared to those without. Using multivariate logistic and linear regressions, we investigated the relationships between COPD and these geriatric physical and psychosocial conditions.Main ResultsSelf-reported COPD prevalence was 10.7%, similar to previous epidemiological studies. Individuals with COPD had more multimorbidity [modified Charlson score 2.6 (SD 1.9) vs. 1.6 (SD 1.6)], more functional disability (58.1 vs. 29.6%; adjusted OR 3.1, 95% CI 2.3, 4.3), falls in the last year (28.4 vs. 20.8%; adjusted OR 1.4, 95% CI 1.01, 2.0), impaired physical function (75.8 vs. 56.6%; adjusted OR 2.1, 95% CI 1.1, 3.7), more frequently reported extreme low physical activity (18.7 vs. 8.1%; adjusted OR 2.3, 95% CI 1.5, 3.5) and higher frailty prevalence (16.0 vs. 2.7%; adjusted OR 6.3, 95% CI 3.0,13.0) than those without COPD. They experienced more severe polypharmacy (≥10 medications, 37.5 vs. 16.1%; adjusted OR 2.9, 95% CI 2.0, 4.2). They more frequently reported extreme social disengagement and were lonelier, but the association with social measures was eliminated when relationship status was accounted for, as those with COPD were less frequently partnered. They more frequently endorsed depressive symptoms (32.0 vs. 18.9%, adjusted OR 1.9, 95% CI 1.4, 2.7). There was no noted difference in cognitive impairment between the two populations.ConclusionsGeriatric conditions are common among community-dwelling older adults with self-reported COPD. A “beyond the lung” approach to COPD care should center on active management of geriatric conditions, potentially leading to improved COPD management, and quality of life.

A whole-body physiology model of inflammatory burn injury was used to train an algorithm to correctly detect patients’ states. The physiology model of a thermal injury takes the surface area of patient skin burned as an input to the model and responds to common treatments. This model is leveraged to build a database of patient physiology as a function of total body surface area burn, without treatment, over a 48-h window. Using this database, we train a model to determine patient injury status as a function of the available physiology data. The algorithm can group virtual patients into three distinct categories, corresponding to long term patient health. The results show that, given an initial virtual patient and injury, the algorithm can correctly determine the placement of that patient into the corresponding category, effectively classifying long term patient outcomes.

Significance Theoretical efforts to understand the superconducting cuprates have focused on a few simplified but challenging models: notably the Hubbard and the t - t ′ - J models. Using density matrix renormalization group (DMRG) simulations on width-8 cylinders, we study the ground-state phase diagram of the t - t ′- J model. The next nearest-neighbor hopping t ′ allows one to distinguish between hole ( t ′ < 0 ) and electron doping ( t ′ > 0 ). We find for the magnetic, charge, and single-particle properties that this model roughly captures the differences between the electron- and hole-doped cuprates. However, the superconducting properties differ. For hole doping ( t ′ < 0 ), there is an absence of superconductivity, while for electron doping ( t ′ > 0), we find d -wave superconductivity coexisting with antiferromagnetism and a secondary triplet p -wave pairing component.

Data supporting routine use of adjuvant chemotherapy (AC) compared to no AC (noAC) for perihilar cholangiocarcinoma (hCCA) is unclear. This study aimed to determine whether AC improves long-term survival following resection for hCCA.Patients receiving resection for hCCA followed by AC or no AC from 2010 to 2016 were identified from the National Cancer Database (NCDB). Propensity score matching (PSM) and Cox regression was performed to account for selection bias and analyze impact of AC on overall survival.Of 924 (56%) noAC and 719 (44%) AC, 320 noAC and 320 AC patients remained after PSM. After matching, AC was associated with improved survival (median: 28.2 vs 19.9 months, p 0.001), which remained after multivariable adjustment (HR: 0.61, CIAC following resection for hCCA was associated with improved survival in this study, even in margin-negative and node-negative disease. These findings suggest incorporation of AC into multimodality therapy for hCCA in all cases, where appropriate.