Data-driven customer acceptance for attended home delivery.

Home delivery services require the attendance of the customer during delivery. Hence, retailers and customers mutually agree on a delivery time window in the booking process. However, when a customer requests a time window, it is not clear how much accepting the ongoing request significantly reduces the availability of time windows for future customers. In this paper, we explore using historical order data to manage scarce delivery capacities efficiently. We propose a sampling-based customer acceptance approach that is fed with different combinations of these data to assess the impact of the current request on route efficiency and the ability to accept future requests. We propose a data-science process to investigate the best use of historical order data in terms of recency and amount of sampling data. We identify features that help to improve the acceptance decision as well as the retailer's revenue. We demonstrate our approach with large amounts of real historical order data from two cities served by an online grocery in Germany.

Discovery of novel biaryl sulfonamide based Mcl-1 inhibitors.

Mcl-1 is an anti-apoptotic protein overexpressed in hematological malignancies and several human solid tumors. Small molecule inhibition of Mcl-1 would offer an effective therapy to Mcl-1 mediated resistance. Subsequently, it has been the target of extensive research in the pharmaceutical industry. The discovery of a novel class of Mcl-1 small molecule inhibitors is described beginning with a simple biaryl sulfonamide hit derived from a high through put screen. A medicinal chemistry effort aided by SBDD generated compounds capable of disrupting the Mcl-1/Bid protein-protein interaction in vitro. The crystal structure of the Mcl-1 bound ligand represents a unique binding mode to the BH3 binding pocket where binding affinity is achieved, in part, through a sulfonamide oxygen/Arg263 interaction. The work highlights the some of the key challenges in designing effective protein-protein inhibitors for the Bcl-2 class of proteins.

Squalamine as a broad-spectrum systemic antiviral agent with therapeutic potential.

Antiviral compounds that increase the resistance of host tissues represent an attractive class of therapeutic. Here, we show that squalamine, a compound previously isolated from the tissues of the dogfish shark (Squalus acanthias) and the sea lamprey (Petromyzon marinus), exhibits broad-spectrum antiviral activity against human pathogens, which were studied in vitro as well as in vivo. Both RNA- and DNA-enveloped viruses are shown to be susceptible. The proposed mechanism involves the capacity of squalamine, a cationic amphipathic sterol, to neutralize the negative electrostatic surface charge of intracellular membranes in a way that renders the cell less effective in supporting viral replication. Because squalamine can be readily synthesized and has a known safety profile in man, we believe its potential as a broad-spectrum human antiviral agent should be explored.

Clinical value of CT-guided biopsy of small (≤1.5 cm) suspicious lung nodules: Diagnostic accuracy, molecular characterization and long-term clinical outcomes.

Small pulmonary nodules (≤1.5 cm) are frequently detected on routine chest imaging and lung cancer screening studies. Our goal was to determine the clinical value of CT-guided core needle biopsy (CNB) in the evaluation of such nodules. In this single-center study, we retrospectively analyzed patient data (n = 44) for CNBs on lung nodules (≤1.5 cm) performed at our biopsy center between May 2017 and March 2020. We analyzed for the rate of pathology diagnosis, molecular/biomarker analysis, complications, and change in clinical management and outcome over a period ranging up to 60 months after biopsy. A pathology diagnosis of malignancy or benign lesion was obtained in 97.9% of biopsies in this cohort. The rate of complications was low with only 6.8% of patients requiring the insertion of a temporary small profile interventional radiology (IR) pigtail chest tube for pneumothorax. Out of the subset of biopsy specimens that were sent for tissue molecular analysis, 90% had enough tissue preserved after initial pathological analysis to obtain at least one molecular marker. Our data show that CT-guided CNB is safe and reliable, and should be considered for the evaluation of small, suspicious lung nodules found on routine screenings for the early detection and evaluation of malignant lesions.

Murine cytomegalovirus US22 protein pM140 protects its binding partner, pM141, from proteasome-dependent but ubiquitin-independent degradation.

Stable assembly of murine cytomegalovirus (MCMV) virions in differentiated macrophages is dependent upon the expression of US22 family gene M140. The M140 protein (pM140) exists in complex with products of neighboring US22 genes. Here we report that pM140 protects its binding partner, pM141, from ubiquitin-independent proteasomal degradation. Protection is conferred by a stabilization domain mapping to amino acids 306 to 380 within pM140, and this domain is functionally independent from the region that confers binding of pM140 to pM141. The M140 protein thus contains multiple domains that collectively confer a structure necessary to function in virion assembly in macrophages.

Assessment of transportation system disruption and accessibility to critical amenities during flooding: Iowa case study.

Natural disasters, such as flooding, can cause severe social, environmental, and economic damage to a community. Transportation infrastructure plays an essential role in flood response and recovery efforts. However, flooding may disturb road functionality and generate direct and indirect adverse impacts, including the loss of access to essential services. This paper presents a comprehensive analysis of flood impacts on road network topology and accessibility to amenities for major communities in the State of Iowa using graph-theoretic methods, including single-source shortest path analyses. We assessed the disruption of transportation networks on the accessibility to critical amenities (e.g., hospitals) under 100 and 500-year flood scenarios. Our analysis methodology leads toward the development of an integrated real-time decision support system that will allow decision-makers to explore "what if" flood scenarios to identify vulnerable areas and population in their authority. These analyses could promote possible improvements (e.g., temporary relocation of critical services) to mitigate the consequences of road system failure during flooding. Due to varying environmental conditions at specific locations and effects on road topology under flood events, the results show differential impacts in edge and node losses as well as access to critical services. Results indicate that floods can lead to edge losses of up to 18%, and not only large cities but also some small cities can experience significant vulnerability to flooding. Some new or reconstructed bridges have failed to operate during analyzed flood events. During the 100 and 500-year flood return periods, the total number of inaccessible bridges within the selected cities is 184 and 294, respectively. Our work found that the shortest path length to the closest critical amenity under baseline condition can flip to the second or higher-orders during flooding. Many critical amenities have been found at risk of flooding in the studied cities.

DRUL for school: Opening Pre-K with safe, simple, sensitive saliva testing for SARS-CoV-2.

To address the need for simple, safe, sensitive, and scalable SARS-CoV-2 tests, we validated and implemented a PCR test that uses a saliva collection kit use at home. Individuals self-collected 300 µl saliva in vials containing Darnell Rockefeller University Laboratory (DRUL) buffer and extracted RNA was assayed by RT-PCR (the DRUL saliva assay). The limit of detection was confirmed to be 1 viral copy/µl in 20 of 20 replicate extractions. Viral RNA was stable in DRUL buffer at room temperature up to seven days after sample collection, and safety studies demonstrated that DRUL buffer immediately inactivated virus at concentrations up to 2.75x106 PFU/ml. Results from SARS-CoV-2 positive nasopharyngeal (NP) swab samples collected in viral transport media and assayed with a standard FDA Emergency Use Authorization (EUA) test were highly correlated with samples placed in DRUL buffer. Direct comparison of results from 162 individuals tested by FDA EUA oropharyngeal (OP) or NP swabs with co-collected saliva samples identified four otherwise unidentified positive cases in DRUL buffer. Over six months, we collected 3,724 samples from individuals ranging from 3 months to 92 years of age. This included collecting weekly samples over 10 weeks from teachers, children, and parents from a pre-school program, which allowed its safe reopening while at-risk pods were quarantined. In sum, we validated a simple, sensitive, stable, and safe PCR-based test using a self-collected saliva sample as a valuable tool for clinical diagnosis and screening at workplaces and schools.

Regulation of PURA gene transcription by three promoters generating distinctly spliced 5-prime leaders: a novel means of fine control over tissue specificity and viral signals.

BACKGROUND: Purα is an evolutionarily conserved cellular protein participating in processes of DNA replication, transcription, and RNA transport; all involving binding to nucleic acids and altering conformation and physical positioning. The distinct but related roles of Purα suggest a need for expression regulated differently depending on intracellular and external signals. RESULTS: Here we report that human PURA (hPURA) transcription is regulated from three distinct and widely-separated transcription start sites (TSS). Each of these TSS is strongly homologous to a similar site in mouse chromosomal DNA. Transcripts from TSS I and II are characterized by the presence of large and overlapping 5'-UTR introns terminated at the same splice receptor site. Transfection of lung carcinoma cells with wild-type or mutated hPURA 5' upstream sequences identifies different regulatory elements. TSS III, located within 80 bp of the translational start codon, is upregulated by E2F1, CAAT and NF-Y binding elements. Transcription at TSS II is downregulated through the presence of adjacent consensus binding elements for interferon regulatory factors (IRFs). Chromatin immunoprecipitation reveals that IRF-3 protein binds hPURA promoter sequences at TSS II in vivo. By co-transfecting hPURA reporter plasmids with expression plasmids for IRF proteins we demonstrate that several IRFs, including IRF-3, down-regulate PURA transcription. Infection of NIH 3T3 cells with mouse cytomegalovirus results in a rapid decrease in levels of mPURA mRNA and Purα protein. The viral infection alters the degree of splicing of the 5'-UTR introns of TSS II transcripts. CONCLUSIONS: Results provide evidence for a novel mechanism of transcriptional control by multiple promoters used differently in various tissues and cells. Viral infection alters not only the use of PURA promoters but also the generation of different non-coding RNAs from 5'-UTRs of the resulting transcripts.

Murine cytomegalovirus capsid assembly is dependent on US22 family gene M140 in infected macrophages.

Macrophages are an important target cell for infection with cytomegalovirus (CMV). A number of viral genes that either are expressed specifically in this cell type or function to optimize CMV replication in this host cell have now been identified. Among these is the murine CMV (MCMV) US22 gene family member M140, a nonessential early gene whose deletion (RVDelta140) leads to significant impairment in virus replication in differentiated macrophages. We have now determined that the defect in replication is at the stage of viral DNA encapsidation. Although the rate of RVDelta140 genome replication and extent of DNA cleavage were comparable to those for revertant virus, deletion of M140 resulted in a significant reduction in the number of viral capsids in the nucleus, and the viral DNA remained sensitive to DNase treatment. These data are indicative of incomplete virion assembly. Steady-state levels of both the major capsid protein (M86) and tegument protein M25 were reduced in the absence of the M140 protein (pM140). This effect may be related to the localization of pM140 to an aggresome-like, microtubule organizing center-associated structure that is known to target misfolded and overexpressed proteins for degradation. It appears, therefore, that pM140 indirectly influences MCMV capsid formation in differentiated macrophages by regulating the stability of viral structural proteins.

Gender differences in psychiatric symptomatology in adolescents attending a community drug and alcohol treatment program.

This study examines mental health symptoms in a cohort of adolescents with substance use disorder (SUD), and attempts to determine if mental health symptoms differed by gender. We retrospectively looked at the Beck's Youth Inventory Second Edition (BYI-II) scores of 88 clients attending a community drug and alcohol treatment service in Dublin, Ireland that were completed at intake as part of their assessment. The raw and T-scores of the male patients were compared against their female counterparts and both against their age- and gender-matched normative population. Participants were 65 boys and 23 girls with a mean age of 16.2 years. Polysubstance use was the norm. As a group, the girls had higher T scores than the boys in all the domains of the BYI-II, and these were statistically significant. Sixty (68%) of the participants had a psychological problem which was moderate or severe in at least one of the five domains. This study found that SUD girls differ from their male counterparts in having both more internalizing and externalizing psychiatric problems. We also note that comorbid psychological problems are not universal. Thus we should avoid a "one size fits all" approach to treatment such as delivering universal self-esteem enhancement interventions to all adolescents with SUD.

Structure-Based Design and Identification of FT-2102 (Olutasidenib), a Potent Mutant-Selective IDH1 Inhibitor.

Inhibition of mutant IDH1 is being evaluated clinically as a treatment option for oncology. Here we describe the structure-based design and optimization of quinoline lead compounds to identify FT-2102, a potent, orally bioavailable, brain penetrant, and selective mIDH1 inhibitor. FT-2102 has excellent ADME/PK properties and reduces 2-hydroxyglutarate levels in an mIDH1 xenograft tumor model. This compound has been selected as a candidate for clinical development in hematologic malignancies, solid tumors, and gliomas with mIDH1.

Discovery and Optimization of Quinolinone Derivatives as Potent, Selective, and Orally Bioavailable Mutant Isocitrate Dehydrogenase 1 (mIDH1) Inhibitors.

Mutations at the arginine residue (R132) in isocitrate dehydrogenase 1 (IDH1) are frequently identified in various human cancers. Inhibition of mutant IDH1 (mIDH1) with small molecules has been clinically validated as a promising therapeutic treatment for acute myeloid leukemia and multiple solid tumors. Herein, we report the discovery and optimization of a series of quinolinones to provide potent and orally bioavailable mIDH1 inhibitors with selectivity over wild-type IDH1. The X-ray structure of an early lead 24 in complex with mIDH1-R132H shows that the inhibitor unexpectedly binds to an allosteric site. Efforts to improve the in vitro and in vivo absorption, distribution, metabolism, and excretion (ADME) properties of 24 yielded a preclinical candidate 63. The detailed preclinical ADME and pharmacology studies of 63 support further development of quinolinone-based mIDH1 inhibitors as therapeutic agents in human trials.

Night duty as an opportunity for learning.

AIM: This paper is a report of a study to examine what opportunities night nurses have to learn in terms of being able to distinguish variations in the patients' conditions. BACKGROUND: Night nurses often lack access to the formalized in-service training offered to day nurses. As every clinical experience can be seen as an opportunity for learning, learning takes place even at night. However, the learning of night nurses has not been studied previously. METHOD: This study is based on interviews with a convenience sample of 10 night nurses at a medium-sized Swedish hospital in 2001. These interviews were reanalysed in 2006 concerning learning situations. The interviews were tape-recorded, transcribed verbatim, coded and examined using latent content analysis. FINDINGS: There are certain opportunities for learning during the night shift, and three learning situations come to the fore: (1) the report situation, (2) the personal assessment round, where the nurses form their own picture of the patient, (3) in assessment prior to contact with the doctor on duty. Nurses learn from variations in patients' conditions and when they have to report their experience verbally. Learning does take place at night and gestalt psychology is a helpful tool for understanding how former knowledge and experience affect night nurses' learning. CONCLUSION: Knowledge developed during the night shift is a neglected field. There is a need for further investigations of what night nurses learn, and this knowledge ought to be integrated in the body of nursing knowledge.

Night nursing - staff's working experiences.

BACKGROUND: Although the duties and working conditions of registered, and enrolled nurses have previously been described from different perspectives, they have not been examined from the night nursing aspect. The aim of the study was to describe the night nursing staff's working experiences. METHODS: The design of the study is qualitative and descriptive. Interviews were conducted with 10 registered and 10 enrolled nurses working as night staff at a Swedish University Hospital. The interview guide was thematic and concerned the content of their tasks, as well as the working conditions that constitute night nursing. In addition, the interviews were transcribed verbatim and analyzed using content analysis. RESULTS: The night duties have to be performed under difficult conditions that include working silently in dimmed lighting, and making decisions when fatigue threatens. According to the night staff, its main goals are to provide the patients with rest and simultaneously ensure qualified care. Furthermore, the night nursing staff must prepare the ward for the daytime activities. CONCLUSION: The most important point is the team work, which developed between the registered and enrolled nurses and how necessary this team work is when working at night. In order for nurses working at night to be fully appreciated, the communication between day and night staff in health care organizations needs to be developed. Furthermore, it is important to give the night staff opportunities to use its whole field of competence.

Violence and abuse against people with disabilities: A comparison of the approaches of the European Court of Human Rights and the United Nations Committee on the Rights of Persons with Disabilities.

This paper explores how, and how effectively, two systems of international law have addressed exploitation, violence and abuse of people with mental disabilities. The two international systems reviewed were the Council of Europe's European Court of Human Rights and the United Nations Committee on the Rights of Persons with Disabilities. The two issues dealt with are (a) forced institutionalisation and denial of community-based services and (b) medically-sanctioned treatment as abuse or violence. The paper offers a comparative analysis of the way in which the two bodies have dealt with exploitation, violence and abuse of people with disabilities, and offers recommendations as to how the two bodies could adjust their approaches to come into closer alignment.

Safety and feasibility of autologous myoblast transplantation in patients with ischemic cardiomyopathy: four-year follow-up.

BACKGROUND: Successful autologous skeletal myoblast transplantation into infarcted myocardium in a variety of animal models has demonstrated improvement in cardiac function. We evaluated the safety and feasibility of transplanting autologous myoblasts into infarcted myocardium of patients undergoing concurrent coronary artery bypass grafting (CABG) or left ventricular assist device (LVAD) implantation. In addition, we sought to gain preliminary information on graft survival and any associated changes in cardiac function. METHODS AND RESULTS: Thirty patients with a history of ischemic cardiomyopathy participated in a phase I, nonrandomized, multicenter pilot study of autologous skeletal myoblast transplantation concurrent with CABG or LVAD implantation. Twenty-four patients with a history of previous myocardial infarction and a left ventricular ejection fraction <40% were enrolled in the CABG arm. In a second arm, 6 patients underwent LVAD implantation as a bridge to heart transplantation, and patients donated their explanted native hearts for testing at the time of heart transplantation. Myoblasts were successfully transplanted in all patients without any acute injection-related complications or significant long-term, unexpected adverse events. Follow-up positron emission tomography scans showed new areas of glucose uptake within the infarct scar in CABG patients. Echocardiography measured an average change in left ventricular ejection fraction from 28% to 35% at 1 year and of 36% at 2 years. Histological evaluation in 4 of 6 patients who underwent heart transplantation documented survival and engraftment of the skeletal myoblasts within the infarcted myocardium. CONCLUSIONS: These results demonstrate the survival, feasibility, and safety of autologous myoblast transplantation and suggest that this modality offers a potential therapeutic treatment for end-stage heart disease.

A percutaneous swine model of myocardial infarction.

INTRODUCTION: The aim of this study was to develop a percutaneous, low risk, and reproducible technique of MI that simulates human disease. METHODS: MI was induced in 44 swine (32.8+/-7.2 kg) by percutaneous embolization coil deployment in the left anterior descending coronary artery. Hemodynamic measurements, left heart catheterization, and echocardiography were performed pre, post, and 30 days after MI. 3D NOGA viability mapping was performed at baseline and 30 days. Excised hearts were examined histologically. RESULTS: Pre-MI mortality was 6.8% and 24 h mortality was 13.6%. All pigs that survived 24 h after MI remained alive at 30 days. The mean left ventricular ejection fraction decreased from 58.4% to 42.1% (p<0.001) at 30 days. The average thrombolysis in myocardial infarction score was 3, 0, and 1.5 at baseline, post-MI, and 30 days, respectively. At 30 days, the end diastolic diameter, end diastolic volume, end systolic volume, and wall motion index increased from 3.76 to 3.89 cm, 32.5 to 50.0 ml, 14.9 to 27.0 ml, and 1.01 to 1.38, respectively (all p<0.05), while the ejection fraction decreased from 56.5% to 49.4% (p<0.01). Additionally, at 30 days, statistically significant reductions in both unipolar and bipolar voltage in the mid and apical regions of the left ventricle were observed. Postmortem pathology showed a transmural scar in the apical anteroseptal regions with fibrosis in the MI region, which accounted for 14.8% and 14.2% of the total left and right ventricular myocardial area and volume, respectively. DISCUSSION: This model of MI is reliable, reproducible, has a pathophysiology similar to humans, and a lower mortality and ventricular fibrillation rates compared to other models. This model may be used to evaluate the effects of pharmacologics, gene therapy, and stem cell transplantation for the treatment of cardiovascular disease as well as studying mechanisms of cardiac remodeling.

Safety and feasibility of percutaneous autologous skeletal myoblast transplantation in the coil-infarcted swine myocardium.

INTRODUCTION: Autologous skeletal myoblast transplantation (ASMT) for myocardial regeneration is a promising new treatment for patients with congestive heart failure secondary to myocardial infarction (MI). However, non-surgical delivery could broaden the utility of this approach. The present study was designed to evaluate the safety and feasibility of transplanting autologous skeletal myoblast (ASM) via endovascular delivery into the infarcted swine myocardium. METHODS: Seven female Yorkshire swine successfully underwent induced left ventricular MI. ASM biopsies were obtained from the hind limb of each animal and myoblasts were expanded in vitro. In a pilot experiment, ASM were labeled with iridium and short-term retention and biodistribution was determined 2 h after ASM delivery via the MyoStar needle-injection catheter inserted through the femoral artery. At 30 days post-infarction, the remaining animals were divided into three groups containing 2 animals each for percutaneous catheter delivery into the infarcted zone: group 1 control animals were injected with media only, group 2 and 3 animals were injected with approximately 300 x 10(6) and 600 x 10(6) ASM, respectively. Sixty days post-transplantation, the swine hearts were harvested. RESULTS: During the 60-day period between transplantation and harvest, no adverse events were recorded, and continuous rhythm monitoring revealed no arrhythmias. In the small sampling size, myocardial function assessments revealed a trend toward improvement in the treatment groups with respect to ejection fraction, viability, and cardiac index. However, histology of treated swine hearts identified no skeletal muscle cells. DISCUSSION: Percutaneous ASMT into an infarcted swine myocardium is feasible and safe, and may contribute to overall improved heart function.

The impact of physician training and experience on the survival of patients with active tuberculosis.

BACKGROUND: Physician training and experience may be important factors influencing treatment outcomes of patients with tuberculosis. We conducted an analysis to evaluate physician and patient characteristics and their association with the rate of death among tuberculosis patients. METHODS: We retrospectively reviewed all reported cases of active tuberculosis in Toronto between July 1, 1999, and June 30, 2002. We obtained extensive clinical data on cases as well as information on the training and clinical experience of treating physicians. We subsequently identified factors associated with patient mortality in a survival analysis. RESULTS: In a multivariable Cox regression analysis involving 1154 patients, factors associated with all-cause mortality included patient age (in years) (hazard ratio [HR] 1.05, 95% confidence interval [CI] 1.04-1.07, p < 0.001), use of directly observed therapy (HR 0.22, CI 0.13-0.39, p < 0.001), receipt of care from a physician experienced with tuberculosis (per case managed per year) (HR 0.98, CI 0.97-0.99; p = 0.01) and admission to hospital during the course of treatment (HR 15.44, CI 7.06-33.76, p < 0.001). Factors that were not associated with patient survival included whether the physician graduated from a foreign medical school, the physician's medical specialty and the number of years in clinical practice. INTERPRETATION: Physician experience with tuberculosis and use of directly observed therapy positively influenced the survival of patients with active tuberculosis in our setting.

Priorities and challenges of health system chief nursing executives: insights for nursing educators.

The health system chief nursing executive (CNE) is responsible for providing high-quality, service-oriented nursing care; delivering such care with disciplined cost management; leading and developing a group of nursing executives and managers at the facility level to establish nursing professional development programs and to build and maintain an effective supply of nurses; and advocating nurses and patients. This article provides insight into the strategies and priorities of large health system CNEs in balancing their obligations to their health systems, to patients and their families, and to the nurses they lead. It is hoped that these insights will provide perspectives that will support the ability of nursing educators to meet their own obligations to their schools of nursing, the faculty and students they represent, and to the profession. These insights will also set a context for further dialogue between two very important groups of nursing leaders-nursing executives and nursing educators.